USP Veterinary Pharmaceutical Information Monographs

Home , Aminoacyltransferase, Clostridium cadaveris, Corynebacterium renale, Pirlimycin, Tylosin

volume 26 supplement 2 october 2003

USP Veterinary Pharmaceutical Information Monographs – Antibiotics

USP VETERINARY PHARMACEUTICAL INFORMATION MONOGRAPHS – ANTIBIOTICS

CONTENTS

v Introduction 1 Aminoglycosides (Veterinary—Systemic) 33 Aminopenicillins (Veterinary—Intramammary-Local) 36 Aminopenicillins (Veterinary—Systemic) 46 Amoxicillin and Clavulanate (Veterinary—Systemic) 51 Cephalosporins (Veterinary—Systemic) 71 Cephapirin (Veterinary—Intramammary-Local) 74 Chloramphenicol (Veterinary—Systemic) 79 Erythromycin (Veterinary—Intramammary-Local) 81 Florfenicol (Veterinary—Systemic) 87 Fluoroquinolones (Veterinary—Systemic) 109 Lincosamides (Veterinary—Systemic) 119 Macrolides (Veterinary—Systemic) 144 Metronidazole (Veterinary—Systemic) 149 Penicillin G (Veterinary—Intramammary-Local) 151 Penicillin G (Veterinary—Systemic) 161 Pirlimycin (Veterinary—Intramammary-Local) 164 Potentiated Sulfonamides (Veterinary—Systemic) 185 Pyrimethamine (Veterinary—Systemic) 191 Rifampin (Veterinary—Systemic) 202 Spectinomycin (Veterinary—Systemic) 207 Sulfonamides (Veterinary—Systemic) 225 Tetracyclines (Veterinary—Systemic) 253 Indications Index 257 Dosing Index 262 Veterinary Brand and Generic Name Index 269 Human Brand and Generic Name Index

Introduction v

Introduction

WHAT’S DIFFERENT ABOUT A USP DRUG INFORMATION included where it may be helpful. Each draft chapter or monograph is MONOGRAPH then put through a review process that includes USP Veterinary The Veterinary Medicine Expert Committee on Drug Information Medicine Committee members, regulatory representatives, pharma- gratefully acknowledges the financial support of its parent organiza- ceutical manufacturers, ad hoc specialists, and public review. At tion, the United States Pharmacopeia, to publish these monographs. It present, USP monographs are the only drug information source in also is appreciative to the Food Animal Residue Avoidance Databank veterinary medicine undergoing such extensive expert review, (FARAD) for supplying slaughter and milk withdrawal information a process through which the credibility of the information is where extra-label drug use in food animals is noted. This information is maintained. provided in cooperation with MICROMEDEX, a Thomson Healthcare USP drug information is a work-in-progress. The information is in Company. constant revision and is a continuous collection of the current judgments of experts in the use of medications. The following chapters have been developed over 7 years, with information added and revised, USP history, organizational structure, and publications as necessary. In pursuit of its mission to promote public health, the United States Pharmacopeia (USP) develops authoritative information about the appropriate use of medicines, including those used in animals. This Unique features non-government, not-for-profit organization draws on a long-standing This special issue of the Journal of Veterinary Pharmacology and dedication to public involvement in the establishment of scientific Therapeutics contains a series of drug information monographs on standards. USP achieves its goals through the contributions of antimicrobials used in veterinary medicine. What makes this volunteers representing health care professions, as well as science, information different from other sources of veterinary drug informa- academia, the U.S. government, the pharmaceutical industry, and tion? A succinct listing would include: consumer organizations. • The incorporation of extra-label and label indications and dosages USP was established in 1820 with the primary goal of setting standards for all domestic species. See the section below, ‘‘Finding the specific for the identity, strength, and quality of medicinal compounds and this drug information you need; Label and extra-label uses,’’ for details remains at the core of the organization. Currently, USP provides on how this information is differentiated. standards for more than 3,800 prescription and non-prescription • The inclusion of slaughter and milk withdrawals when extra-label drugs, nutritional and dietary supplements, veterinary drugs, and drug use in food animals is considered an acceptable option for health care products. These standards are published in the United therapy. Withdrawal times have been provided by FARAD for the States Pharmacopeia (USP) and the National Formulary (NF), which are specified conditions noted. officially recognized in the Federal Food, Drug, and Cosmetic Act (21 • The inclusion of information about both U.S. and Canadian U.S.C. § 321 et seq.). USP also produces Reference Standards, which veterinary drug products. are an integral part of USP’s standards program. • The grouping of indications into three categories. The ‘‘Accepted’’ The development of USP information on the best use of medications was category indicates that clear evidence exists to support use of the begun in 1970, growing out of the public process of developing quality drug for a particular purpose. ‘‘Acceptance not established’’ standards. USP information advisory panels were created to assure (potentially useful) indicates that use of the drug for an indication that the information under development is evidence-based, consensus- may be worthy of consideration if superior therapies do not exist, established, practical, and clinically relevant. This work was expanded but the evidence is either scant or subject to concern based on into a separate public health program and in 1980, the first USP DI experimental design. If a use is viewed as ineffective or has been was published. Today, in association with MICROMEDEX, USP replaced by clearly superior therapies, the indication is deemed continues to provide oversight and approval of drug information ‘‘Unaccepted.’’ These categorizations are applied to label and extra- content in the USP DI database, which covers nearly all medicines in label uses. the U.S. and Canada. • The use of tables of scientific evidence to address controversial issues during the review process, particularly relative to extra-label drug use. The veterinary drug information monograph creation process • Review of the information by a Food and Drug Administration (FDA) Very soon after the USP DI was first published, an advisory panel on liaison to the committee. Although comments made by the FDA are veterinary medicine was created. Since 1982, veterinary pharmacol- taken quite seriously, those opinions are nonbinding on the USP. ogists, veterinary pharmacists, and other specialists have contributed The information contained in these monographs should not be their time and expertise in creating and revising drug information considered an endorsement or ‘‘acceptance’’ by the FDA as to a through USP’s unique process. This drug information is developed by given use or dosage. exhaustive compilation of approved product label information and also • The review of each monograph by the USP Veterinary Medicine collection and analysis of publicly available data on each drug from Committee. This committee consists of 10 to 15 volunteers research studies and clinical reports. Careful attention is paid to recognized as experts in pharmacology, internal medicine, or species differentiating species-specific information. With the agreement of discipline(s). MICROMEDEX, information from the human USP DI database is

Finding the specific drug information you need ACKNOWLEDGEMENTS The following individuals are recognized for their contributions and Label and extra-label uses support towards the production of this body of work: The Indications section of each drug monograph is designed to provide information about indications in drug product labeling in the U.S. and USP Staff Canada. Extra-label indications for which clinical and research data Roger Williams, MD (CEO and Executive Vice President, USP) have been evaluated are also included. Indications found in product Ian DeVeau, PhD (Senior Scientist, Veterinary Drugs, Information and labeling are listed first. Brackets around an indication signify that it is Standards Development, USP) not found in any product labeling in the U.S. at the time of last major Amy S. Neal, DVM (USP consultant, writer and editor) revision. Some indications are followed by a superscript 1, meaning Jerome A. Halperin, BS, MPH, MS (former CEO and Executive Vice they are not included in Canadian product labeling. President, USP) Keith Johnson (former Director, Drug Information Division, USP) Examples of bracket and superscript 1 placement in the monographs: David Nash, DVM (former Director, Veterinary Medicine, Information [Pneumonia, bacterial (treatment)] An extra-label use in the U.S. and Standards Development, USP) An indication is included in E. Kathryn Meyer, VMD (former Drug Information Specialist and Canadian product labeling. Coordinator, Veterinary Practitioners’ Reporting Program, Pneumonia, bacterial (treatment)1 An indication found in U.S. USP) product labeling but not in Canadian product labeling. 2000 to 2005 Veterinary Medicine Committee [Pneumonia, bacterial (treatment)]1 An extra-label use in both the Cory Langston, DVM, PhD, DACVCP, Chair U.S. and Canada. Michael D. Apley, DVM, PhD, BS, DACVCP Dawn M. Boothe, BS, MS, DVM, PhD, DACVCP, DACVIM Species and dosage forms Terrence P. Clark, DVM, PhD, DACVCP Within each category of the Indications section the information is arranged Gigi F. Davidson, BS, RPh, DICVP in a hierarchy as follows: indication, followed by the species to which Patricia Dowling, DVM, MS, DACVIM, DACVCP that indication applies, and finally the dosage forms used in that species Douglas T. Kemp, PharmD, DICVP for that indication. You will see that some species and dosage forms are Mark G. Papich, DVM, MS, BS, DACVCP also given bracket and superscript 1 designations; these have the same M. Gatz Riddell, DVM, MS meaning for species and dosage forms as described above for indications. Jim E. Riviere, DVM, PhD, MS, BS To decrease clutter and confusion, only the highest level of the hierarchy Roderick C. Tubbs, DVM, PhD is given a bracket or superscript 1 (indication > species > dosage form). Jeff R. Wilcke, DVM, MS, DACVCP That is, if the indication is not found on any label in the U.S. (a bracketed, extralabel use) then the species under it will not be bracketed 1995 to 2000 Veterinary Medicine Advisory Panel because it is obvious that no species are on the label of any product in the Cory Langston, DVM, PhD, DACVCP, Chair United States for this indication. Michael D. Apley, DVM, PhD, BS, DACVCP Gordon Brumbaugh, DVM, PhD, DACVCP Dosing Thomas Burkgren, DVM, MBA In the USP veterinary drug information monographs, dosage forms are Cynthia T. Culmo, RPh always listed separately to provide an opportunity to list specific Lloyd E. Davis, PhD, DVM information for each type of product. In the Dosage Forms section, Patricia Dowling, DVM, MS, DACVIM, DACVCP indications and species are bracketed or given a superscript 1 following Stuart Forney, RPh, MS the same rules applied in the Indications section, except that they reflect Antoinette D. Jernigan, DVM, PhD, DACVCP the labeling of the specific dosage form. Dosages listed are not always Mark G. Papich, DVM, MS, DACVCP label dosages even if the species is in the product labeling. Thomas E. Powers, DVM, PhD Jim E. Riviere, DVM, PhD Label and extra-label withdrawal times Charles R. Short, DVM, PhD, DACVCP Established withdrawal times from product labeling are listed in the Withdrawal Hector Sumano Lopez, DVM, PhD times tables for each dosage form labeled for use in food-producing animals. Jeff R. Wilcke, DVM, MS, DACVCP But be sure to consult the approved labeling on the product you are using for the specific government established dose and withdrawal time. 1990 to 1995 Veterinary Medicine Advisory Panel Extra-label withdrawal times are listed in the Withdrawal times section for Lloyd E. Davis, DVM, PhD, Chair each extra-label use and/or dose recommended for food-producing animals. Arthur L. Aronson, DVM, PhD As always, veterinarians will use their own clinical judgment, following the Gordon Brumbaugh, DVM, PhD, DACVCP guidelines of the Animal Medicinal Drug Use Clarification Act, to determine Gordon L Coppoc, DVM, PhD a safe extra-label withdrawal time. Sidney A. Ewing, DVM, PhD Cory Langston, DVM, PhD, DACVCP Stuart D. Forney, RPh, MS Chair, USP Veterinary Medicine Expert Committee on Drug William G. Huber, DVM, PhD Information William L. Jenkins, DVM, PhD, DACVCP

Cory Langston, DVM, PhD, DACVCP Arthur L. Aronson, DVM, PhD Mark G. Papich, DVM, MS, DACVCP Nicholas H. Booth, DVM, PhD John W. Paul, DVM, PhD Gordon L Coppoc, DVM, PhD Thomas E. Powers, DVM, PhD, DACVCP George T. Edds, DVM, PhD Charles R. Short, DVM, PhD, DACVCP Sidney A. Ewing, DVM, PhD Richard H. Teske, DVM, PhD Peter A. Eyre, BVMS, PhD Jeff R. Wilcke, DVM, MS, DACVCP Stuart D. Forney, RPh, MS William G. Huber, DVM, PhD 1985 to 1990 Panel on Veterinary Medicine Robert W. Phillips, DVM, PhD Lloyd E. Davis, PhD, DVM, Chair Thomas E. Powers, DVM, PhD Arthur L. Aronson, DVM, PhD I.A. Schipper, DVM, PhD Nicholas H. Booth, DVM, PhD Richard H. Teske, DVM, PhD Gordon L Coppoc, DVM, PhD Sidney A. Ewing, DVM, PhD For more information about USP Veterinary Pharmaceutical Stuart D. Forney, RPh, MS Information monographs you may contact: Diane K. Gerken, DVM, PhD Ian F. DeVeau, PhD William G. Huber, DVM, PhD United States Pharmacopeia William L. Jenkins, DVM, PhD 12601 Twinbrook Parkway Robert W. Phillips, DVM, PhD Rockville, Maryland 20852 Thomas E. Powers, DVM, PhD United States Charles R. Short, DVM, PhD Telephone number: 1-301-881-0666 Richard H. Teske, DVM, PhD E-mail: [email protected] Jeff R. Wilcke, DVM, MS www.usp.org

1983 to 1985 Panel on Veterinary Medicine Lloyd E. Davis, PhD, DVM, Chair H. Richard Adams, DVM, PhD

AMINOGLYCOSIDES Veterinary—Systemic 1

AMINOGLYCOSIDES Veterinary—Systemic

This monograph includes information on the following aminoglycoside synergistic effect. However, the use of aminoglycosides in the aminocyclitols: Amikacin; Dihydrostreptomycin*; Gentamicin; Kana- treatment of infection in animals has been tempered by toxicity mycin; Neomycin; Streptomycin. It also contains information on the considerations in the animal treated{R-116}. Often, systemic use is following aminocyclitol: Apramycin. limited to the treatment of serious gram-negative infections resistant to less toxic medications. Also, local environment at the therapeutic site Some commonly used brand names are: can affect the efficacy of these drugs, acidic or purulent conditions can Amifuse E [Amikacin] Gen-Gard [Gentamicin] hamper their effect{R-5; 7; 20; 116; 160}, and the presence of cations Amiglyde-V [Amikacin] Genta-fuse [Gentamicin] Amiglyde-V Injection [Amikacin] GentaMax 100 [Gentamicin] (calcium or magnesium ions, for example) can decrease antibacterial Amiglyde-V Intrauterine Solution GentaVed 50 [Gentamicin] effect{R-266}. [Amikacin] Streptomycin was the earliest aminoglycoside introduced{R-116}.Itis Amiject D [Amikacin] GentaVed 100 [Gentamicin] {R-243; 244} Amikacin C Injection [Amikacin] Gentocin [Gentamicin] active against mycobacteria, Leptospira , Francisella tularen- Amikacin E Solution [Amikacin] Gentocin Solution [Gentamicin] sis, and Yersinia pestis, but only some mycoplasma, gram-negative AmTech AmiMax C Injection [Amikacin] Gentocin Solution Injectable organisms, and Staphylococcus species{R-116}. Dihydrostreptomycin is [Gentamicin] chemically very similar to streptomycin{R-116}. The introduction of AmTech AmiMax E Solution [Amikacin] Gentozen [Gentamicin] AmTech GentaMax 100 [Gentamicin] Kantrim [Kanamycin] newer aminoglycosides has eclipsed the significance of dihydrostrep- AmTech Gentamicin Sulfate Pig Legacy [Gentamicin] tomycin and streptomycin in the face of increasing bacterial resis- Pump Oral Solution [Gentamicin] tance{R-122; 235; 239}, although some dosage forms of these medications AmTech Gentapoult [Gentamicin] Neo-325 [Neomycin] are still available. AmTech Neomycin Oral Solution Neomed 325 [Neomycin] [Neomycin] Neomycin became available for use a few years after streptomycin. Apralan [Apramycin] Neomix 325 [Neomycin] Neomycin has been effective against many gram-negative organisms Apralan Soluble [Apramycin] Neomix AG 325 [Neomycin] and Staphylococcus aureus{R-116}. However, the use of neomycin is Biosol Liquid [Neomycin] Neomix AG 325 Medicated {R-116} Premix [Neomycin] limited by a relatively high risk of toxicity with systemic use ;itis CaniGlide [Amikacin] Neomix Soluble Powder [Neomycin] not available for parenteral administration. Equi-Phar EquiGlide [Amikacin] Neomycin 200 [Neomycin] Kanamycin was introduced as a less toxic alternative to older amino- Ethamycin [Dihydrostreptomycin] Neomycin 325 [Neomycin] glycosides and was soon followed by gentamicin and later by Garacin Pig Pump [Gentamicin] Neo-Sol 50 [Neomycin] {R-116} Garacin Piglet Injection [Gentamicin] Neosol-Oral [Neomycin] amikacin . The spectrum of activity of kanamycin primarily Garacin Soluble Powder [Gentamicin] Neosol Soluble Powder [Neomycin] focuses on gram-negative organisms and a few gram-positive organ- Garasol Injection [Gentamicin] Neoved 200 [Neomycin] isms{R-93}. The prevalence of resistance of some pathogens, including Garasol Pig Pump Oral Solution Neovet 325/100 [Neomycin] [Gentamicin] Escherichia coli and Salmonella species, to kanamycin is higher than to {R-108; 109–113; 144} Garasol Solution Injectable [Gentamicin] Neovet Neomycin Oral Solution gentamicin , and this has limited the use of [Neomycin] kanamycin. The use of kanamycin has also been eclipsed by the derivation of amikacin, a drug with a very similar pharmacokinetic Note: For a listing of dosage forms and brand names by country profile{R-178} but superior activity against pathogens such as Pseudo- availability, see the Dosage Forms section(s). monas species and kanamycin-resistant Enterobacteriaceae{R-178}. CATEGORY: Gentamicin has been widely used in the treatment of gram-negative organisms and some gram-positive organisms{R-5}. As with other Antibacterial (systemic). aminoglycosides, use is limited by risk of toxicity. In vitro tests have shown gentamicin to be active against Salmonella arizonae (Arizona INDICATIONS hinshawii){R-7}, Enterobacter aerogenes{R-7; 125}, E. coli{R-1; 5; 7; 125}, Note: Bracketed information in the Indications section refers to uses that Klebsiella species{R-1; 5; 7; 125}, Neisseria{R-1; 5; 7; 125}, most indole- either are not included in U.S. product labeling or are for products not positive and some indole-negative Proteus species{R-1; 5; 7; 125}, some commercially available in the U.S. Pasteurella multocida{R-122; 127}, Pseudomonas aeruginosa{R-1; 5; 7; 125}, Salmonella{R-1; 5; 7; 125}, Serratia marcescens{R-1; 5; 7; 125}, Shigella{R-1; 5; 7; 125} {R-1; 5; 7; 109–111; 123; 125} GENERAL CONSIDERATIONS , Staphylococcus species , including Staphylococcus intermedius{R-109–111},andsomeStreptococcus species{R-1; Aminoglycosides are utilized primarily in the treatment of infections 5; 7; 125}. caused by aerobic gram-negative organisms{R-107; 108; 116}. They are Amikacin was developed from kanamycin and has the broadest spectrum not active against anaerobic organisms. In addition to their strength in of activity of the aminoglycosides{R-37}. It is considered effective the treatment of gram-negative pathogens, aminoglycosides can be against strains not susceptible to other aminoglycosides because it effective against some gram-positive organisms, such as Staphylococcus resists some aminoglycoside inactivating enzymes{R-91; 137; 178}.In aureus{R-107; 108}, some mycobacteria{R-116; 124}, some mycoplasma addition to those organisms listed above for gentamicin, in vitro tests strains{R-116}, and some spirochetes{R-263}. They are sometimes have shown amikacin to be effective against E. coli, Klebsiella and administered concurrently with other antibacterials for a possible Pseudomonas species resistant to gentamicin{R-143; 266}, Citrobacter freundii, Listeria monocytogenes, and Providencia species{R-91; 92}. There *Not commercially available in the U.S. as a single entity. are reports in the U.S. and abroad of some in vitro resistance to Not commercially available in Canada as a single entity.

gentamicin and other aminoglycosides by Salmonella species{R-113; antimicrobials should rely on a specific diagnosis and knowledge of 117–119}, but the strains tested are still susceptible to amikacin{R-118; pathogen susceptibility. 199; 250}. Calves1: Neomycin sulfate for medicated feed is indicated in the Apramycin is an aminocyclitol antibiotic with a chemical structure very control and treatment of enteritis caused by susceptible Escherichia similar to that of the aminoglycosides but different enough to leave it coli{R-94}. Streptomycin oral solution{R-181; 182} is indicated in the unaffected by many aminoglycoside inactivating enzymes{R-245}.At treatment of bacterial enteritis caused by susceptible organisms. low concentrations, apramycin is more effective in inhibiting bacterial Cattle and sheep: Neomycin sulfate for medicated feed1, neomycin protein synthesis than kanamycin A, streptomycin, amikacin, or sulfate powder for oral solution{R-97; 104} and neomycin sulfate oral gentamicin{R-96}. Apramycin is active against Staphylococcus aureus, solution{R-98; 103} are indicated in the control and treatment of many gram-negative organisms, and some mycoplasma strains{R-163}. bacterial enteritis caused by susceptible Escherichia coli. If systemic Apramycin has been reported to be effective in vitro against E. coli and signs develop, medications that are well absorbed systemically should Salmonella species{R-96; 164} that are resistant to streptomycin and be considered for addition to or substitution for therapy with this neomycin{R-167; 173}. medication{R-98}. Resistance to aminoglycosides is produced primarily by enzymes encoded Chickens: [Neomycin oral powder]{R-104}, [neomycin oral solution]{R-103}, by genes located on bacterial plasmids{R-116; 168}. The enzymes act and streptomycin1 {R-181; 182} are indicated in the control and inside the bacterium to modify the aminoglycoside, thereby preventing treatment of bacterial enteritis in chickens. it from binding to ribosomes{R-116; 168}. This type of plasmid- Goats1: Neomycin sulfate for medicated feed, neomycin sulfate powder associated resistance is transferable between bacteria. A single type for oral solution{R-97; 104} and neomycin sulfate oral solution{R-98; of plasmid may confer cross-resistance to multiple aminoglyco- 103} are indicated in the control and treatment of bacterial enteritis sides{R-116; 117; 120; 145} and also resistance to other unrelated caused by susceptible Escherichia coli. If systemic signs develop, antimicrobials{R-7; 114; 115; 120; 145; 168}. In some cases, a single medications that are well absorbed systemically should be considered plasmid gene encoding for one enzyme, an acetyltransferase, may for addition to or substitution for therapy with this medication{R-98}. confer resistance to several aminoglycosides{R-171}. For example, the Kids1 and lambs1: Neomycin sulfate for medicated feed{R-94} is enzyme aminoglycoside 3-N-acetyltransferase IV allows the bacterium indicated in the control and treatment of bacterial enteritis caused to be resistant to apramycin, gentamicin, netilmicin, and tobramy- by susceptible Escherichia coli. cin{R-171}. A single bacterial isolate may have any one of a variety of Piglets: Apramycin sulfate powder for oral solution1{R-95}, gentamicin combinations of resistance to different antibiotics conferred by the injection{R-7; 9; 125}, gentamicin powder for oral solution1 {R-15}, particular plasmid it carries{R-168}. As an example, an E. coli strain gentamicin oral solution{R-11; 14}, neomycin sulfate for medicated may be resistant to ampicillin, apramycin, chloramphenicol, gentami- feed1{R-94}, neomycin sulfate oral solution{R-98; 103}, neomycin sulfate cin, kanamycin, sulfonamide, streptomycin, tetracycline, and trimeth- powder for oral solution{R-97; 104}, [dihydrostreptomycin]{R-106}, and oprim{R-168}. Other E. coli isolates cultured from the same geographic streptomycin{R-181; 182} are indicated in the control and treatment of region may carry resistance to a few or many of the same antibiotics in enteritis (weanling pig scours) in piglets caused by susceptible E. coli. different combinations{R-168}. The nature of resistance in organisms If systemic signs develop, medications that are well absorbed such as E. coli and Salmonella species has been a focus of international systemically should be considered{R-98}. research because of concerns about potential transferance of antimi- Pigs1: Neomycin sulfate for medicated feed is indicated in the control crobial resistance from animal to human pathogens{R-168–172}. and treatment of enteritis (weanling pig scours) in piglets caused by Bacteria may also utilize other methods of reducing the efficacy of susceptible E. coli{R-94}. aminoglycosides. Some strains of bacteria are less permeable to [Horses]: Neomycin sulfate powder for oral solution{R-97; 104} and aminoglycosides, requiring much higher concentrations of aminogly- neomycin sulfate oral solution{R-103} are indicated in the control and cosides to kill them and, therefore, can be selected during treatment{R-116}. treatment of bacterial enteritis caused by susceptible Escherichia coli. Resistance developed by chromosomal resistance is minimal and If systemic signs develop, medications that are well absorbed develops slowly for most of the aminoglycosides, with the exception of systemically should be considered for addition to or substitution for streptomycin or dihydrostreptomycin; resistance to streptomycin can therapy with this medication. occur from a single-step mutation{R-116}. [Turkeys]: Neomycin sulfate powder for oral solution{R-104} and neomycin oral solution{R-103} are indicated in the control and treatment of bacterial enteritis in turkeys. ACCEPTED E. coli infection (treatment)— Bacteremia (treatment); or Chicks, 1-day-old: Gentamicin injection{R-7; 8} is indicated in the pre- Septicemia (treatment)—Cats and dogs: Kanamycin sulfate injec- vention of early mortality in chicks caused by susceptible E. coli. tion1{R-93}, [amikacin injection]1{R-264}, and [gentamicin injection]1{R-7} Turkeys, growing1: Neomycin sulfate powder for oral solution is are indicated in the treatment of bacteremia or septicemia caused indicated in the control of mortality associated with susceptible E. coli by susceptible organisms. in growing turkeys{R-2}. Bone and joint infections (treatment)1—Cats and dogs: Kanamycin Paracolon (treatment)—Turkey poults, 1- to 3-day-old: Gentamicin sulfate injection{R-93}, [amikacin injection]1{R-264}, and [gentamicin injection{R-7; 8} is indicated in the treatment of infections in turkeys injection]{R-264} are indicated in the treatment of bone and joint caused by susceptible Salmonella arizonae. infections caused by susceptible organisms{R-93}. Pseudomonas aeruginosa infection (treatment); or Enteritis (treatment)—The primary treatment for enteritis in many Salmonella typhimurium infection (treatment)—Chicks, 1-day-old: Genta- cases is aggressive fluid replacement. Treatment of enteritis with micin injection{R-7; 8} is indicated in the prevention of early mortality

in chicks caused by suceptible Pseudomonas aeruginosa, and Salmonella Infections, bacterial (treatment)— typhimurium. [Calves]1 and [cattle]1: The extralabel use of aminoglycosides in cattle Respiratory tract infections, bacterial (treatment)—Cats and dogs: Gen- has been strongly discouraged because of the long duration of drug tamicin injection{R-4; 7}, kanamycin injection1{R-93}, and [amikacin residues in some tissues (see the Regulatory Considerations section). injection]1{R-264} are indicated in the treatment of susceptible respi- However, in the case of bacterial infections susceptible to gentamicin ratory tract infections, including pneumonia and upper respiratory in cattle that will not be used for food production, there are tract infections. pharmacokinetic data available to estimate dosing for amikacin in Skin and soft tissue infections, bacterial (treatment)— calves{R-141; 144} and gentamicin in calves and cattle{R-21; 22; 25}. Cats: Gentamicin injection{R-4; 7; 123}, kanamycin injection1{R-93}, and Use of aminoglycosides should be restricted to susceptible bacterial [amikacin injection{R-139; 140; 264}]1 are indicated in the treatment infections caused by pathogens resistant to antimicrobials that are of susceptible skin and soft tissue infections. less likely to produce prolonged residues. Dogs: Amikacin injection1{R-91}, gentamicin injection{R-4; 7}, and [Donkeys]1,[foals]1,[horses]1, and [ponies]1: Although the safety and kanamycin injection1{R-93} are indicated in the treatment of suscep- efficacy have not been established, amikacin has been recommended tible skin and soft tissue infections. In the case of staphyloccocal in the treatment of susceptible bacterial infections in donkeys, foals, dermatitis, although the in vitro susceptibility of canine Staphylococ- horses (systemic administration), and ponies, based on pharmaco- cus intermedius to gentamicin is persistently high{R-109–111}, practical kinetic studies{R-130–132; 136; 137} and in vitro antimicrobial suscep- administration and toxicity considerations with long-term therapy tibility of common pathogens{R-159; 253}. have limited the usefulness of aminoglycosides{R-109}. Although the safety and efficacy have not been established, Swine dysentery (treatment)1—Pigs: Gentamicin powder for oral solu- gentamicin has been recommended in the treatment of susceptible tion{R-15} and gentamicin oral solution{R-11} are indicated in the bacterial infections in foals and horses, based on pharmacokinetic treatment of swine dysentery caused by susceptible Treponema hyody- studies{R-46–52; 53; 55} and in vitro antimicrobial susceptibility of senteriae. common pathogens{R-159; 253}. Urinary tract infections, bacterial (treatment)— [Minor species]1: Although the safety and efficacy have not been Cats: Gentamicin injection{R-4; 7}, kanamycin injection1 {R-93}, and established, amikacin has been suggested for the treatment of [amikacin injection{R-139; 140; 264}]1 are indicated in the treatment susceptible bacterial infections in African gray parrots{R-150}, ball of urinary tract infections, such as cystitis, caused by susceptible pythons{R-155}, goats that will not be used for food production{R-151}, organisms. gopher snakes{R-154}, gopher tortoises{R-156}, guinea pigs{R-152}, and Dogs: Amikacin injection1{R-4; 7}, gentamicin injection{R-4; 7}, and red-tailed hawks{R-147}, based on pharmacokinetic studies. kanamycin injection1{R-93} are indicated in the treatment of urinary Although the safety and efficacy have not been established, tract infections caused by susceptible organisms. gentamicin has been suggested for the treatment of susceptible Uterine infections, bacterial (treatment)— bacterial infections in the following species, if not used for food Cats: Kanamycin injection1{R-93}, [amikacin injection{R-139; 140; 264}]1, production: baboons{R-76}, budgerigars{R-86}, buffalo calves{R-78}, and [gentamicin injection{R-264}]1 are indicated in the treatment of eagles{R-88}, goats{R-40}, hawks{R-88}, llamas{R-82}, owls{R-88}, and endometritis in cats{R-93}. pythons{R-89}, based on pharmacokinetic studies. Dogs: Kanamycin injection1{R-93}, [gentamicin injection{R-7}], and Panleukopenia (treatment)1;or [amikacin injection{R-264}]1 are indicated in the treatment of uterine Pneumonitis (treatment)1—Cats: U.S. product labeling includes the use of infections (metritis) in dogs caused by susceptible organisms. gentamicin in the treatment of secondary bacterial infections associ- Horses: Amikacin uterine solution{R-92}, gentamicin uterine infusion{R-1}, ated with panleukopenia in cats{R-4} and the use of kanamycin in the and gentamicin injection{R-4; 7} are indicated in the control of treatment of bacterial complications of feline pneumonitis{R-93}. These bacterial infections of the uterus caused by susceptible organisms. uses may be appropriate for bacterial infections that are susceptible to these medications; however, they are not considered more appropriate ACCEPTANCE NOT ESTABLISHED or more generally accepted than other antimicrobials in the treatment of bacterial infections associated with viral infections. Distemper, canine (treatment)1—Dogs: U.S. product labeling includes [Leptospirosis (treatment)]—Cattle, dogs, and pigs: Canadian product the use of kanamycin in the treatment of bacterial complications of labeling includes the use of dihydrostreptomycin in the treatment of canine distemper{R-93}. This use may be appropriate for bacterial leptospirosis in cattle, dogs, and pigs{R-106}. Studies have shown that, infections that are susceptible to kanamycin; however, it is not while shedding of leptospires in the urine of cattle can be halted for at considered more appropriate or more generally accepted than other least 2 months by the administration of a single dose of dihydrostrep- antimicrobials in the treatment of bacterial infections associated tomycin, carriers are not necessarily eliminated{R-243; 244}. Equally with viral infections. effective alternative medicines exist. Gastrointestinal infections (treatment)1; Mastitis (treatment)1; Otitis media (treatment)1;or UNACCEPTED Pancreatitis (treatment)1—Cats and dogs: U.S. product labeling for [Mastitis (treatment)]—Cattle and pigs: Although some Canadian kanamycin includes use in the treatment of gastrointestinal infections, product labeling has listed the use of dihydrostreptomycin in the mastitis, otitis media, and pancreatitis in cats and dogs{R-93}; however, treatment of mastitis in cows and sows, there is no published based on current knowledge about tissue penetration and pathogen evidence that this treatment is effective. Dihydrostreptomycin is susceptibility, there are more appropriate antibiotics for use in the irregularly distributed into milk when administered at the labeled treatment of these infections. dose{R-247}. Another member of this drug family, gentamicin, has

been shown in some studies to be ineffective in the treatment of gentamicin injection in chickens, cows, piglets, and turkey poults; coliform mastitis{R-259–260}. and neomycin sulfate oral solution and neomycin sulfate powder [Pneumonia (treatment)]—Calves and cattle: Although Canadian product for oral solution in cattle, chickens, pigs, sheep, and turkeys. See labeling includes the use of dihydrostreptomycin in the treatment of the Dosage Forms section. bacterial pneumonia in calves{R-106}, there is no published evidence available pertaining to efficacy of this therapy. Such use is not CHEMISTRY recommended by the USP Veterinary Medicine Advisory Panel{R-258} Source: due to the lack of efficacy data and the potential for extended tissue Amikacin—Semi-synthetic; derived from kanamycin{R-91}. withdrawal times. Apramycin—Produced by fermentation of Streptomyces tenebrarius{R-18; [Uterine infections (treatment)]— 96}. Cattle: Although Canadian product labeling has included the use of Gentamicin—Created from fermentation of Micromonospora purpurea{R-1; gentamicin uterine solution or gentamicin injection administered by 5; 18}. the intrauterine route in the treatment of uterine infections in Kanamycin—Produced through fermentation by Streptomyces kanamy- cattle{R-7}, this use is not recommended. Intrauterine gentamicin ceticus{R-93}. dosage regimens necessary to produce therapeutic concentrations in Neomycin—The sulfate of an antibacterial substance produced by uterine tissue other than the endometrium can lead to significant Streptomyces fradiae{R-256}. systemic drug distribution and a risk of long-term tissue residues of Streptomycin—Prepared from fermentation of Streptomyces griseus, an gentamicin{R-28–30}. actinomycete organism isolated from soil{R-256}. Dogs: Although Canadian product labeling includes the use of Chemical group: gentamicin injection administered by the intrauterine route in the Amikacin, dihydrostreptomycin, gentamicin, kanamycin, neomycin, and treatment of uterine infections in dogs, such use is not recom- streptomycin—Aminoglycoside antibiotics. mended{R-258}. Apramycin—Aminocyclitol. 1Not included in Canadian product labeling or product not commercially Note: The aminoglycosides are defined by their mechanism of action, {R-251} available in Canada. binding with the 30S ribosomal subunit . The term aminocyclitol describes the structure of both the aminoglycosides and apramycin; however, the structure of apramycin differs just enough from other REGULATORY CONSIDERATIONS aminoglycosides that it may be listed as an aminocyclitol rather than U.S.— specifically an aminoglycoside. It is very similar physicochemically to Because drug residues can persist in some tissues for many months, the other aminoglycosides{R-164}. extralabel use of aminoglycosides in food-producing animals should Chemical name: be avoided when there are no established scientific data on residue Amikacin sulfate—d-Streptamine, O-3-amino-3-deoxy-alpha-d-glucopyr- depletion. A voluntary resolution against the administration of anosyl-(1 fi 6)-O-[6-amino-6-deoxy-alpha-d-glucopyranosyl-(1 fi 4)]- aminoglycosides to cattle has been instituted by the Academy of N1-(4-amino-2-hydroxy-1-oxobutyl)-2-deoxy, (S)-, sulfate (1:2) Veterinary Consultants, the American Association of Bovine Prac- (salt){R-18}. titioners, the National Cattlemen’s Beef Association, and the Amer- Apramycin—d-Streptamine, 4-O-[(8R)-2-amino-8-O-(4-amino-4-deoxy- {R-257} ican Veterinary Medical Association (AVMA) . The AMVA alpha-d-glucopyranosyl)-2,3,7-trideoxy-7-(methylamino)-d-glycero- resolution states that, ‘‘Until further scientific information becomes alpha-d-allo-octodialdo-1,5:8,4-dipyranos-1-yl]-2-deoxy-{R-18}. available, aminoglycoside antibiotics should not be used in cattle, Dihydrostreptomycin sulfate—Dihydrostreptomycin sulfate (2:3) (salt){R- {R-257} except as specifically approved by the FDA .’’ At issue is the 18}. need for a clearer understanding of the complexity of aminoglycoside Gentamicin sulfate—A complex antibiotic substance formulated as sulfate {R-25; 32; 34; 36} residue depletion for food-producing animals . Drug salts, including aminosugars{R-24}; three major components, sulfates of {R-18} residues can persist in some tissues for many months. gentamicin C1, gentamicin C2, and gentamicin C1A and minor

Gentamicin is not labeled for use in horses intended for food components that are sometimes present, called A, B, B1, and X. production. Neomycin is not labeled for use in veal calves. Kanamycin sulfate—d-Streptamine, O-3-amino-3-deoxy-alpha-d-gluco- Withdrawal times have been established for the use of apramycin pyranosyl(1 fi 6)-O-[6-amino-6-deoxy-alpha-d-glucopyranosyl(1 fi 4)]- sulfate powder for oral solution, gentamicin sulfate oral solution, and 2-deoxy-, sulfate (1:1) (salt){R-18}. gentamicin sulfate powder for oral solution in pigs; gentamicin Neomycin sulfate—Neomycin sulfate{R-18}. injection in chicks, piglets, and turkey poults; neomycin sulfate for Streptomycin sulfate—d-Streptamine, O-2-deoxy-2-(methylamino)-alpha- medicated feed, neomycin sulfate oral solution or neomycin sulfate l-glucopyranosyl-(1 fi 2)-O-5-deoxy-3-C-formyl-alpha-l-lyxofurano- powder for oral solution in cattle, goats, pigs, and sheep; and syl-(1 fi 4)-N,N’-bis(aminoiminomethyl)-, sulfate (2:3) (salt){R-18}. streptomycin sulfate oral solution in calves, chickens, and pigs. See Molecular formula: {R-18} the Dosage Forms section. Amikacin sulfate—C22H43N5O13Æ2H2SO4 . {R-18} Canada— Apramycin—C21H41N5O11 . {R-18} Gentamicin is not labeled for use in horses intended for food Dihydrostreptomycin sulfate—(C21H41N7O12)2Æ3H2SO4 . production. Gentamicin— {R-17} Withdrawal times have been established for the use of apramycin Gentamicin C1:C21H43N5O7 . {R-17} sulfate powder for oral solution or gentamicin sulfate oral solution Gentamicin C2:C20H41N5O7 . {R-17} in pigs; dihydrostreptomycin injection in cattle and pigs; Gentamicin C1A:C19H39N5O7 .

{R-18} Kanamycin sulfate—C18H36N4O11ÆH2SO4 . synthesis by disruption of polysomes and may prevent the initiation of {R-18} {R-107} Streptomycin sulfate—(C21H39N7O12)2Æ3H2SO4 . DNA replication . Molecular weight: Aminocyclitols—Apramycin is bactericidal. It also acts against bacteria Amikacin sulfate—781.76{R-18}. by inhibiting protein synthesis at the ribosome level{R-96}. Like the Apramycin—539.58{R-19}. aminoglycosides, it inhibits the translocation step of protein synthesis Dihydrostreptomycin sulfate—1461.42{R-18}. and induces translation errors{R-96}. Gentamicin— {R-17} Gentamicin C1: 477.61 . Absorption: {R-17} Gentamicin C2: 463.59 . Intramammary administration—In cows with mastitis, gentamicin is {R-17} Gentamicin C1A: 449.56 . well absorbed systemically following intramammary administration. Kanamycin sulfate—582.58{R-18}. With a single dose (1.1 mg per kg of body weight), concentrations of Streptomycin sulfate—1457.39{R-18}. antibiotic in the serum (measured in one study up to 1.09 ± 0.15 mcg Description: per mL) could result in prolonged tissue residues{R-26}. Amikacin Sulfate USP—White, crystalline powder{R-19}. Intramuscular or subcutaneous administration—Amikacin, dihydro- Dihydrostreptomycin Sulfate USP—White or almost white, amorphous streptomycin, gentamicin, and kanamycin generally are rapidly and or crystalline powder. Amorphous form is hygroscopic{R-19}. well absorbed from intramuscular and subcutaneous routes of Gentamicin Sulfate USP—White to buff powder{R-19}. administration{R-177; 230; 247}. Kanamycin Sulfate USP—White, odorless, crystalline powder{R-19}. Intrauterine administration—Cows: In healthy cows, 39% of a total Neomycin Sulfate USP—White to slightly yellow powder, or cryodesic- intrauterine dose of 2500 mg, administered once a day for 3 days, was cated solid. Is odorless or practically so and is hygroscopic{R-19}. absorbed systemically and produced serum concentrations of up to 6.6 Streptomycin Sulfate USP—White or practically white powder. Is mcg/mL{R-28}. In cows with endometritis, absorption was similar, with odorless or has not more than a faint odor. Is hygroscopic, but is 36% of an intrauterine dose of 4 mg/kg of body weight administered stable in air and on exposure to light. Its solutions are acid to once a day for 3 days absorbed systemically, producing peak serum practically neutral to litmus{R-19}. concentrations of 6 to 11 mcg/mL{R-29}. A smaller total intrauterine pKa: dose of 225 to 275 mg produced plasma concentrations of 0 to 2.5 Amikacin—8.1{R-256}. mcg/mL{R-30}, while 70% of the dose administered remained in the Dihydrostreptomycin—8.8{R-254}. lumen of the uterus{R-17; 30}. Gentamicin sulfate—8.2{R-254}. Because of the demonstrated intrauterine absorption of aminoglyco- Kanamycin—7.2{R-256}. sides, some clinicians have warned that intrauterine administration is Neomycin sulfate—8.3{R-254}. likely to result in residues above regulatory limits in food-producing Solubility: animals{R-60}. Amikacin Sulfate USP—Freely soluble in water{R-19}. Oral administration—In general, aminoglycosides and apramycin are Apramycin sulfate—Highly soluble in water and slightly soluble in the very poorly absorbed from oral administration in adult animals, lower alcohols{R-96}. including cattle, chickens, and pigs{R-46; 96; 166; 230}. However, 11% of Dihydrostreptomycin Sulfate USP—Freely soluble in water; practically an oral neomycin dose of 30 mg per kg of body weight (mg/kg) was insoluble in acetone, in chloroform, and in methanol{R-19}. absorbed in 3-day-old calves and 1 to 2% of the dose was absorbed by Gentamicin Sulfate USP—Freely soluble in water; insoluble in alcohol, in 2-month-old calves, regardless of ruminant status{R-238}. In very acetone, in chloroform, and in ether{R-19}. young calves, this absorption can be significant. When neomycin was Kanamycin Sulfate USP—Freely soluble in water; insoluble in acetone administered orally to 2- to 4-day-old calves at a dose of 33 mg/kg for and in ethyl acetate{R-19}. 14 days, absorption was significant enough to produce relatively high Neomycin Sulfate USP—Its solutions are dextrorotatary. Freely soluble in concentrations of drug in the kidneys (approximately 300 mcg per water; very slightly soluble in alcohol; insoluble in acetone, in gram of tissue){R-240}. Some absorption of apramycin has also been chloroform, and in ether{R-19}. shown to occur in neonatal pigs{R-296}. Damage to the gastrointestinal Streptomycin Sulfate USP—Freely soluble in water, very slightly soluble mucosa can also lead to increased aminoglycoside absorption{R-166; in alcohol; practically insoluble in chloroform{R-19}. 230}. Moderate enteritis from induction of coccidial infection in chickens caused a significant increase in absorption of a 43 mg/kg PHARMACOLOGY/PHARMACOKINETICS dose of apramycin for 5 days{R-166}. Serum concentrations were Note: See also Tables I and II for this monograph. increased from 0.04 to 0.06 mcg/mL and tissue concentrations were also increased{R-166}. Mechanism of action/effect: Aminoglycosides—Bactericidal{R-107; 116}. Aminoglycosides enter sus- Distribution: Aminoglycosides are distributed primarily into the ceptible bacteria by oxygen-dependent active transport (making extracellular space{R-46} and over time accumulate in tissues{R-25}. anaerobes impervious to them){R-107} and by passive diffusion{R-37}. The amount of antibiotic in most tissues appears to be dependent on Once the antibiotic has gained access, it binds irreversibly to a receptor the total dose administered over time rather than the size of each protein on the 30S ribosomal subunit{R-5; 107} and blocks the individual dose{R-25; 34}. Aminoglycosides do not distribute well across formation of a complex that includes mRNA, formylmethionine, and membrane barriers and, therefore, are not found at high concentra- tRNA{R-107}. As a result, the tRNA is translated incorrectly, producing tions in brain tissue, cerebrospinal fluid, ocular fluid, or respiratory a nonfunctional protein{R-107}. Aminoglycosides also disrupt protein secretions{R-20; 153; 230}.

Systemic administration— Gentamicin—Intrauterine administration of 2.5 grams of gentamicin Otic tissue: Aminoglycosides concentrate in the perilymph of the inner once daily for 5 days resulted in endometrial tissue concentrations of ear. The damage to the ciliated cells can result in deafness; vestibular 41.65 ± 17 mcg/gram 24 hours after the last dose{R-60}. The addition nerve injury may result as well{R-263}. of progesterone, administered concurrently, increased the sample to Renal tissue: When aminoglycosides are administered systemically, the 100.33 ± 19.27 and the administration of estradiol concurrently with predominant site of drug accumulation is the renal cortex in most gentamicin increased the sample to 74.09 ± 8.6 mcg/gram{R-60}. species tested, including cats, cattle, pigs, and sheep{R-20; 25; 34; 42; At the same time, measured serum concentrations of gentamicin 67; 230}. Therapeutic concentrations are also reached in other tissues peaked at 0.64 ± 0.06 for gentamicin administered alone; the and slow depletion from some tissues may prolong the presence of concurrent administration of progesterone or estradiol increased residues{R-25; 230}. For cats, cattle, pigs, and sheep, the following gentamicin serum concentrations to a peak of 8.34 ± 1.34{R-60}. general relative gentamicin concentrations are reached over time Regional limb perfusion—Horses: Amikacin—Regional intravenous with repeated doses, from highest to lowest concentrations: renal perfusion of amikacin (125 mg diluted in 60 mL of electrolyte cortex; renal medulla; liver/lung/spleen; skeletal muscle{R-25; 34; 42; solution) into the distal limb of horses produced sufficiently high 67; 230}. Renal proximal tissues actively take up and accumulate concentrations of antibiotic in local joint fluid, bone, and serum in aminoglycosides by pinocytosis{R-265}. Once within the tubular cells, the limb to be effective in the treatment of most susceptible the drug may cause dysfunction in lysosomes, mitochondria, organisms{R-267}. proximal tubule cell plasma membrane phospholipids and enzymes, and glomerular filtration{R-37}. Protein binding: Other tissues: Amikacin—Calves: 6% at a concentration of 5 to 150 mcg per mL of {R-141} Cats: Amikacin is distributed into uterine tissue so that tissue serum (mcg/mL) . concentrations are about 25% of the current serum concentra- Dihydrostreptomycin— {R-129} tion{R-140}. Cows: 8%, at a concentration of 2.5 to 5 mcg/mL . {R-129} Horses: Ewes: 12%, at a concentration of 2.5 to 5 mcg/mL . {R-1; 47} Amikacin—Amikacin is distributed into peritoneal fluid and Gentamicin—Horses and foals: < 30% . {R- synovial fluid in the horse with a peak of 13.7 ± 3.2 mcg/mL and Kanamycin—Ewes: 0 to 4%, at a concentration of 2.5 to 5 mcg/mL 129} 16.8 ± 8.8 mcg/mL, respectively, at the first sample, 1 hour after . an intravenous dose of 6.6 mg per kg of body weight{R-137}. Neomycin— {R-129} Gentamicin—Gentamicin is distributed into endometrial tissue Cows: 45%, at a concentration of 5 to 10 mcg/mL . {R-129} so that tissue concentration is higher than plasma concentrations Ewes: 50%, at a concentration of 5 to 10 mcg/mL . {R- reached after 7 days of intramuscular therapy with a dose of 5 mg/ Spectinomycin—Cows: 6%, at a concentration of 12.5 to 25 mcg/mL 129} kg every 8 hours{R-53}. . Gentamicin is distributed into synovial fluid in normal horses to Biotransformation: In many species, aminoglycosides are eliminated produce a peak of 6.4 mcg/mL at 2 hours with a single 4.4 mg/kg in the form of the administered drug{R-96; 143; 150; 177; 180; 238}; that {R-58} intravenous dose . However, local inflammation may increase is, they are not biotransformed. drug concentrations in the joint and concentrations may increase with repeated doses. Elimination: Parenterally administered aminoglycosides are predomi- Gentamicin is distributed into jejunal and colonic tissue with a nantly excreted unchanged in the urine{R-96; 164; 177; 180}. Only a maximum gentamicin concentration of 4.13 ± 1.8 mcg/mL small amount is excreted in the bile in some species, such as cattle{R-1}. measured in the large colon at 0.5 hour after administration and For amikacin in dogs and gray parrots, gentamicin in calves, cows, 2.26 ± 1.35 mcg/mL measured in jejunum at 0.33 hour{R-59}. horses, and sheep, and kanamycin in dogs, 75 to 100% of the dose is Intra-articular administration—Horses: Intra-articular administration of eliminated unchanged in the urine in the first 8 to 24 hours{R-1; 7; 20; 150 mg of gentamicin resulted in a peak synovial concentration of 22; 32; 143; 150; 178; 204}. 1828 ± 240 mcg/mL 15 minutes after administration{R-61}. Because the kidney is the site of predominant accumulation and The intra-articular administration of buffered gentamicin produced elimination of drug, the analysis of elimination seems straightforward. more synovitis and higher gentamicin concentrations (2680 ± However, researchers have described a dose-dependent slow elimina- 1069 mcg/mL) than unbuffered gentamicin{R-61}; however, tion phase (gamma phase) many times longer than the initial synovial concentrations 12 hours later were very similar for buffered elimination phase{R-32}. It is postulated that gentamicin is bound to and unbuffered gentamicin. Synovial concentrations remained tissues by one of at least two different processes so that some >10 mcg/mL for at least 24 hours{R-61}. A peak plasma concentra- gentamicin is released quickly and gentamicin bound by another tion of 0.69 mcg/mL at 15 minutes after intra-articular administra- process is released more slowly{R-25; 32; 34; 36}. It is not known if these tion was measured{R-61}; gentamicin was no longer detectable in processes are tissue-specific. plasma at 6 hours. Intrauterine administration—Horses: Amikacin—Intrauterine administration of a total dose of 2 grams produces a peak of greater than 40 mcg per gram of endometrial PRECAUTIONS TO CONSIDER {R-92} tissue within 1 hour after infusion . Twenty-four hours after PREGNANCY/REPRODUCTION infusion, 2 to 4 mcg of amikacin per gram of endometrial tissue is Amikacin— still present{R-92}. Dogs: Reproductive studies have not been performed in dogs{R-91}.

Horses: No evidence was found of impaired fertility in mares given an adults. Higher doses may be necessary in animals less than 6 weeks old intrauterine dose of 2 grams of amikacin 8 hours before natural compared with adults{R-266}. breeding{R-92}.Inin vitro studies, equine sperm exposed to 0.1 mg of Very young animals may absorb significant amounts of orally admin- benzethonium chloride per mL of solution, present in some amikacin istered apramycin or neomycin. See Absorption, above in this mono- products, showed impaired viability{R-92}. Product labeling recom- graph. mends that mares not be bred for 8 hours after intrauterine treatment with amikacin{R-92}. Apramycin—No adverse effects have been observed in laboratory GERIATRICS animals pertaining to mutagenicity, teratology, or reproduction{R-96}. In a case report study of dogs, advanced age of more than 8 years Dihydrostreptomycin—Bulls: No effect was noted on spermatogenesis, appeared to be a risk factor in susceptibility to gentamicin {R-215} seminal pH, ejaculate volume, percentage of motile spermatozoa, rate nephrotoxicity . However, it is not known if these dogs had of spermatozoal motility, or concentration of spermatozoa from nine subclinical renal compromise, which is known to increase the {R-217} beef bulls on the third or seventh days after the second dose of 22 mg nephrotoxicity of gentamicin , or some other dysfunction of dihydrostreptomycin per kg of body weight every 12 hours for two associated with aging. doses{R-242}. Gentamicin— DRUG INTERACTIONS AND/OR RELATED PROBLEMS Cats and dogs: Reproductive studies have not been performed with The following drug interactions and/or related problems have been gentamicin in cats and dogs{R-4}. selected on the basis of their potential clinical significance (possible Horses: Intrauterine treatment of mares with gentamicin is not mechanism in parentheses where appropriate)—not necessarily inclu- recommended the day of breeding{R-4}. sive (» = major clinical significance): Rats: Ototoxicity has been shown to be a risk even before the auditory Note: Combinations containing any of the following medications, organs have begun to function in developing rats{R-188}. depending on the amount present, may also interact with this medication. {R-4; 91} LACTATION Aminoglycosides, two or more concurrently (concurrent administration may increase the risk of ototoxicity, Because of poor lipid solubility, aminoglycosides have relatively poor nephrotoxicity, or neuromuscular blockade{R-4}) penetration from plasma into milk{R-22; 26}. In general, parenteral Calcium administration of gentamicin has not been shown to produce (intravenous calcium supplementation may decrease nephrotoxicity therapeutic milk concentrations (greater than 3 to 5 mcg/mL) for associated with aminoglycosides; in horses, 20 mg of intravenous the treatment of most gram-negative mammary pathogens{R-22; 23; calcium gluconate per kg of body weight administered every 12 hours 25}. At any one time, approximately 10 to 15% of plasma gentamicin decreased nephrotoxicity of high dose gentamicin [20 mg/kg every levels may appear in milk{R-22; 26}. Intramammary administration of 8 hours for 14 days] administered to adult ponies{R-223}) gentamicin to cows with experimental mastitis results in significant Calcium channel blocker{R-232} systemic absorption (88%), leading to long persistence of drug residues (an increased risk of neuromuscular blockade may occur with in some tissues, such as renal tissue{R-23; 26}. concomitant administration with an aminoglycoside{R-232}) Apramycin—Cows, goats, and sheep: Apramycin has limited distribution Halothane anesthesia from parenteral administration into milk in healthy glands{R-163}.Itis (horses administered gentamicin, 4 mg/kg, while under halothane distributed into bovine milk at higher concentrations during acute anesthesia have significant changes in the pharmacokinetics of genta- clinical mastitis, but it is not known if concentrations would be high micin; total body clearance and volume of distribution decrease while enough to have clinical effect without significant residue and toxicity half-life of elimination increases; a longer gentamicin dosing interval considerations{R-163}. after anesthesia may help correct for the changes, but serious consid- Dihydrostreptomycin—Cows: When administered at an intramusuclar eration should be given to choice of another antimicrobial{R-204}) dose of 11 mg/kg, dihydrostreptomycin is irregularly distributed into Iron, supplemental the milk for at least 18 hours{R-247}. (the risk of auditory and renal toxicity might be increased when Gentamicin—Cows: With an intramuscular dose of 5 mg/kg, a peak aminoglycosides are administered with iron supplements; guinea pigs concentration of 1.5 to 1.8 mcg/mL is measured 2 to 6 hours after administered gentamicin at 100 mg/kg a day for 30 days showed a administration{R-22; 26}. more rapid and profound hearing loss within the treatment period with concurrent administration of supplemental iron at a dose of 2 to 6 mg/ PEDIATRICS kg a day; the effect was iron dose–dependent{R-198}; a study in rats The susceptibility of young animals to toxicity from aminoglycosides may showed increased renal tubular damage when gentamicin was be species-specific and drug-specific. Young dogs, rabbits, and rats administered at a dose of 100 mg/kg a day to rats given iron have shown resistance to gentamicin nephrotoxicity in some studies{R- supplementation{R-202}) 219; 268}, while 2- to 3-month-old foals may be more susceptible than Ketorolac{R-224}, adults to toxicity{R-208; 219}. The renal function of young rats, 21-days Phenylbutazone{R-203},or old, was more strongly affected by the administraton of amikacin than Nonsteroidal anti-inflammatory drugs (NSAIDs), other was the renal function of adults given the same dose{R-192}. (in the horse, concurrent administration of phenylbutazone with Young animals typically have a higher percentage of extracellular water gentamicin affects the pharmacokinetics of gentamicin by decreasing and, therefore, have a higher volume of distribution compared with the half-life of elimination by 23% and decreasing the volume of

distribution [area] by 26%; the pharmacokinetics of phenylbutazone measurement of plasma concentrations and/or evidence of toxicity do not appear to be affected{R-203}; also, the nephrotoxic potential of may also be required) NSAIDs can increase the risk of renal toxicity, as ketorolac does Methoxyflurane or when administered to rats concurrently with gentamicin{R-224}; Polymyxins, parenteral however, flunixin was shown to have no effect on the pharmaco- (concurrent and/or sequential use of these medications with amino- kinetics of gentamicin when administered concurrently to adult glycosides should be avoided since the potential for nephrotoxicity horses{R-265}) and/or neuromuscular blockade may be increased; neuromuscular Loop diuretics, including{R-143} blockade may result in skeletal muscle weakness and respiratory Ethacrynic acid{R-143; 197; 229} or depression or paralysis [apnea]; caution is also recommended when Furosemide{R-4; 91; 185; 207} methoxyflurane or polymyxins are used concurrently with amino- (because these medications can cause ototoxicity in patients with renal glycosides during surgery or in the postoperative period) compromise, the risk of potentiating toxicity during concurrent use with aminoglycosides should be considered{R-143}; also, there is LABORATORY VALUE ALTERATIONS evidence that the combination of kanamycin and ethacrynic acid The following have been selected on the basis of their potential clinical can cause permanent auditory ototoxicity in healthy cats without significance (possible effect in parentheses where appropriate)—not subsequent signs of renal compromise{R-197}; concurrently adminis- necessarily inclusive (» = major clinical significance): tered systemic gentamicin and ethacrynic acid also causes more With physiology/laboratory test values profound ototoxicity in guinea pigs than either drug administered Aspartamine aminotransferase (AST [SGOT]), serum and alone{R-229}) Lactate dehydrogenase (LDH), serum Nephrotoxic medications, other{R-4} or (in galahs [cockatoos] and macaws, values are reported to increase Ototoxic medications, other{R-4} with therapeutic gentamicin administration of 5 mg/kg every 12 (concurrent use may increase the risk of ototoxicity or nephrotoxicity) hours{R-205}) Neuromuscular blocking agents or drugs with neuromuscular blocking activity{R-4; 186; 187; 199–201}, other {R-255} (concurrent use with aminoglycosides can increase the risk of HUMAN LABORATORY VALUE ALTERATIONS neuromuscular blockade, particularly during anesthesia{R-186} but In addition to the above laboratory value alterations, the following there may be little clinical significance; administration of gentamicin alterations have been reported in humans, and are included in the [2 to 6 mg/kg dose] does potentiate the neuromuscular blocking human monograph Aminoglycosides (Systemic) in the USP DI Volume I; effect of atracurium in inhalant-anesthetized cats, dogs, and horses; these laboratory value alterations are intended for informational however, minimal to no effect on recovery from anesthesia was purposes only and may or may not be applicable to the use of noted{R-199–201}; edrophonium reversed any remaining neuromus- aminoglycosides in animals: cular block during recovery{R-199–201}; calcium supplementation can With physiology/laboratory test values also help reverse neuromuscular blockade [see Treatment of overdose]) Alanine aminotransferase (ALT [SGPT]), serum and Alkaline phosphatase, serum and HUMAN DRUG INTERACTIONS{R-255} Aspartate aminotransferase (AST [SGOT]), serum and Bilirubin, serum and In addition to the above drug interactions reported in animals, the Lactate dehydrogenase (LDH), serum following drug interactions have been reported in humans, and are (values may be increased) included in the human monograph, Aminoglycosides (Systemic) in USP Blood urea nitrogen (BUN) and DI Volume I; these drug interactions are intended for informational Creatinine, serum purposes only and may or may not be applicable to the use of (concentrations may be increased) aminoglycosides in the treatment of animals: Calcium, serum and Antimyasthenics Magnesium, serum and (concurrent use of medications with neuromuscular blocking action Potassium, serum and may antagonize the effect of antimyasthenics on skeletal muscle; Sodium, serum temporary dosage adjustments of antimyasthenics may be necessary (concentrations may be decreased) to control symptoms of myasthenia gravis during and following use of medications with neuromuscular blocking action) Beta-lactam antibiotics MEDICAL CONSIDERATIONS/CONTRAINDICATIONS (aminoglycosides can be inactivated by many beta-lactam antibiotics The medical considerations/contraindications included have been [cephalosporins, penicillins] in vitro and in vivo in patients with selected on the basis of their potential clinical significance (reasons significant renal failure; degradation depends on the concentration of given in parentheses where appropriate)—not necessarily inclusive the beta-lactam agent, storage time, and temperature) (» = major clinical significance). Indomethacin, intravenous Except under special circumstances, this medication should not be (when aminoglycosides are administered concurrently with intrave- used when the following medical problems exist: nous indomethacin in the premature neonate, renal clearance of » Dehydration, hypovolemic{R-4; 5; 91} aminoglycosides may be decreased, leading to increased plasma (hypovolemic animals can have increased susceptibility to renal concentrations, increased elimination half-lives, and risk of amino- toxicity and should be rehydrated prior to treatment with aminoglycoside toxicity; dosage adjustment of aminoglycosides based on glycosides{R-91}; however, clinicians may administer the first dose of

aminoglycoside to treat life-threatening infections while rehydration Aminoglycoside, serum concentration is in progress{R-262}) (because of the risk of nephrotoxicity and the wide variability in drug » Hypersensitivity to aminoglycosides{R-7; 92; 93} disposition, it is recommended that, whenever possible, serum amino- (a previous reaction to one aminoglycoside may contraindicate use of glycoside concentration should be monitored in animals receiving the same or other aminoglycosides due to cross-sensitivity) repeated doses, and dosage adjustments made{R-55; 56}; when multiple » Renal dysfunction{R-4; 91} dosing is done in a 24-hour period, peak and trough concentrations have (alternative antimicrobials should be considered in animals with been considered the most helpful with the least number of tests{R-57}. severe renal compromise and/or renal azotemia{R-4; 5}; because they With once-daily dosing, serum concentrations are more typically lack the ability to compensate, even dogs with subclinical renal measured at 1 and 2 hours or 2 and 4 hours after the daily dose{R-266}. dysfunction can develop nonreversible acute renal failure from a dose Many sources recommend serum concentrations be allowed to drop that produces only mild polyuria in dogs with healthy kidneys{R-213; below 1 mcg/mL for gentamicin and below 2.5 to 5 mcg/mL for amikacin 214}; if an aminoglycoside must be given, increasing the dosing interval or kanamycin for an extended period within a dosing interval to reduce is more effective in preventing toxicity than decreasing the dose{R-217}) the risk of toxicity{R-47; 51; 63; 148; 185; 209; 230}.) Risk-benefit should be considered when the following medical Renal function tests{R-4; 91} problems exist: (serial urinalyses may be the most sensitive tests for renal toxicosis in Cardiac dysfunction{R-5} spite of the fact that no early urinary test has been developed that can (gentamicin may exacerbate a decreasing heart rate or depression of consistently warn clinicians when serious renal toxicity occurs; serial blood pressure{R-5}) urinalyses may be monitored for decreased specific gravity in the Endotoxemia absence of fluid therapy or appearance of casts, protein, albumin, (even a low serum concentration of endotoxin may increase the glucose, or blood in the absence of leukocytes and bacteria{R-4; 208}; toxicity of the aminoglycosides by increasing their concentration in proteinuria may be seen within 24 hours with extremely high toxic the kidneys{R-184}; the administration of an aminoglycoside to treat doses{R-206}; early indication of nephrotoxicity may be possible with gram-negative bacterial infections may also increase the amount of the ratio of urinary gamma glutamyltranspeptidase to urinary {R-184} endotoxin released ; see the Veterinary Dosing Information creatinine excretion [UGGT/UCr] ]; this enzyme concentraton ratio is section) increased to three times the baseline within 2 to 3 days of a Hypocalcemia nephrotoxic gentamicin dose of 30 mg/kg{R-206; 209; 210; 211}; (although the clinical impact is not clear, aminoglycosides, including however, because even a single dose of gentamicin can cause some

dihydrostreptomycin and neomycin, have been shown to decrease renal tubule changes, elevations in the UGGT/UCr ratio may occur the total blood calcium concentration in cattle through decreasing without subsequent severe kidney damage; therefore, some clinicians the protein-bound calcium{R-187}; this effect caused signs of hypo- believe that other tests may be needed to decide if gentamicin therapy calcemia in 77% of lactating cows treated with 4.5 mg of must be discontinued{R-210; 220; 221}; serum creatinine, creatinine intravenous neomycin per kg of body weight{R-187}) clearance tests, specific gravity, blood urea nitrogen and/or clinical Potential risk factors for acute renal failure{R-185; 215}, other, including signs of nephrotoxicity may not be diagnostic of severe kidney damage Acidosis for at least 7 days{R-4; 206; 210; 216}) Advanced age Diabetes mellitus SIDE/ADVERSE EFFECTS Dirofilarial infection{R-91} The following side/adverse effects have been selected on the basis of their Electrolyte imbalances potential clinical significance (possible signs and, for humans, symp- Fever toms in parentheses where appropriate)—not necessarily inclusive: Sepsis Hepatic dysfunction THOSE INDICATING NEED FOR MEDICAL ATTENTION Hyperviscosity syndromes Incidence more frequent Hypoalbuminemia All species Hypotension Nephrotoxicity{R-7; 212}; ototoxicity, auditory; ototoxicity, Septicemia vestibular Trauma, severe Note: Evidence of physiological effects on the kidneys has been demon- (level of risk of nephrotoxicity with administration of aminogly- strated with a single dose of gentamicin at 15 mg per kg of body cosides can be difficult to assess, but caution is indicated in weight (mg/kg) in 5-month-old beagles, although clinical disease is not animals with one or several factors associated with increased risk, necessarily produced{R-209; 212}. It is assumed that renal damage such as those affecting renal perfusion) associated with aminoglycoside administration runs a range from Pyelonephritis{R-226} mild, subclinical changes to more severe nephrotoxicity, to acute renal (rats with infected kidneys are more susceptible to gentamicin failure{R-4; 209; 212}. The animal’s ability to recover most likely toxicity than healthy rats{R-226}) depends on the type of medication exposure and the amount of healthy renal tissue remaining to compensate{R-213}. Neomycin is considered PATIENT MONITORING the most nephrotoxic aminoglycoside, dihydrostreptomycin and The following may be especially important in patient monitoring (other streptomycin the least nephrotoxic, and the other common aminogly- tests may be warranted in some patients, depending on condition; » = cosides included in this monograph are considered somewhere major clinical significance): between those three drugs in their toxicity{R-254}. Aminoglycoside

administration is, as a rule, immediately withdrawn when evidence of nonhuman primates{R-186}. However, respiratory depression and renal damage is found; however, many signs of toxicity may be delayed apnea occurred only at the highest antibiotic dosages{R-186}. for some time after significant damage has occurred. Neuromuscular blockade and respiratory paralysis have been Although renal toxicity is dependent on the concentration of amino- reported in response to high doses of gentamicin (40 mg/kg) in the glycoside in the renal cortex, many variables can affect how much of cat{R-7}. The postsynaptic blocking component of this effect can be the medication reaches the cortex and how serious the effects will be, reversed by a cholinesterase inhibitor, such as neostigmine, and the making it difficult to consistently predict which animal is likely to apparent presynapic effect can be antagonized by the administration develop clinical toxicity with a particular therapeutic dosage regimen. of calcium{R-186}. Aminoglycosides cause nephrotoxicity by accumulating in the proximal tubular cells and, once there, interfering with cellular metabolism and transport processes{R-218; 225}. The tubular changes can progress THOSE INDICATING NEED FOR MEDICAL ATTENTION to proximal tubular necrosis with increasing exposure to the drug. ONLY IF THEY CONTINUE OR ARE BOTHERSOME Fairly late in the process, glomerular filtration rate is affected and Incidence more frequent azotemia appears{R-225}. These changes may simultaneously occur at Birds different rates in different parts of the renal cortex, making it possible Local tissue trauma, mild—at site of injection{R-86} to have both reabsorption defects and glomerular filtration rate Incidence rare reduction at the same time{R-225}. Dogs The toxic renal changes caused by gentamicin and other aminogly- Diarrhea{R-91}—with amikacin; vomiting{R-91}—with amikacin cosides will decrease elimination of the antibiotic and increase serum Incidence unknown antibiotic concentrations, thereby increasing the potential toxic- Calves and pigs ity{R-57; 209}. Elimination half-lives of 24 to 45 hours have been Diarrhea—seen in animals given oral doses of apramycin or reported in the horse with renal toxicity, prolonging the toxic neomycin that are higher than the label dose{R-96; 241}. exposure to the drug{R-57}. While peritoneal dialysis is useful in Cats lowering creatinine and blood urea nitrates, it may not be effective in Local tissue trauma, mild—at site of intramuscular injection with significantly speeding the elimination of the accumulating aminogly- amikacin{R-93; 139} coside{R-57}. If there is enough healthy tissue remaining in the Dogs kidneys, acute renal failure may be reversible by regeneration and Local tissue trauma, mild—at site of injection, with amikacin or hypertrophy of remaining tissue{R-193; 213}. Dogs with subclinical gentamicin{R-5; 91; 93} renal dysfunction are more sensitive to the toxicity of gentamicin; they develop oliguria and acute renal failure that may not be HUMAN SIDE/ADVERSE EFFECTS{R-255} reversible from a high gentamicin dose that produces only mild In addition to the above side/adverse effects reported in animals, the polyuria in dogs with healthy kidneys{R-213; 214}. Therefore, merely following side/adverse effects have been reported in humans, and are adjusting dosage regimens to compensate for renal dysfunction may included in the human monograph Aminoglycosides (Systemic) in USP not be sufficient to avoid toxicity. Careful selection of candidates for DI Volume I; these side/adverse effects are intended for informational aminoglycoside therapy and a dosage regimen designed to minimize purposes only and may or may not be applicable to the use of risk of nephrotoxicity is recommended. aminoglycosides in the treatment of animals: Some aminoglycosides are more likely to cause auditory ototoxicity Incidence more frequent and others are more likely to cause vestibular ototoxicity{R-4; 7}. This Nephrotoxicity; neurotoxicity; ototoxicity, auditory; ototoxic- may be due to the distribution characteristics of each drug and its ity, vestibular; peripheral neuritis—only with streptomycin ability to concentrate in each sensory organ{R-183}. As demonstrated Incidence less frequent in studies on guinea pigs,{R-183; 190} amikacin, kanamycin, and Hypersensitivity; optic neuritis—only with streptomycin dihydrostreptomycin are more toxic to the cochlea than to vestibular Incidence rare organs{R-183; 190; 191; 233}. Neomycin causes severe cochlear Endotoxin-like reaction—gentamicin only; neuromuscular toxicity{R-233}. Studies in guinea pigs have shown that auditory blockade toxicity is often delayed{R-189}, requiring at least 4 days after admini- Note: Neuromuscular blockade, respiratory paralysis, ototoxicity, and stration of a toxic dose for hearing loss to be measurable{R-189}. nephrotoxicity may occur following local irrigation or topical This period of delay may shorten with higher doses{R-189}. Vesti- application of aminoglycosides during surgery. bular toxicity is more often seen than auditory toxicity with Because of its potential toxicity, use of parenteral neomycin is not streptomycin{R-233}. recommended. Incidence less frequent or rare All species Neuromuscular blockade{R-7} OVERDOSE Note: Neuromuscular paralysis{R-7} is considered rare compared with the For more information on the management of overdose or uninten- nephrotoxic and ototoxic effects of aminoglycosides{R-232}. The tional ingestion, contact the American Society for the Pre- neuromuscular blocking effects of dihydrostreptomycin, gentamicin, vention of Cruelty to Animals (ASPCA) National Animal kanamycin, neomycin, and streptomycin at a dose of 14 to 43 mg per Poison Control Center (888–426–4435 or 900–443–0000; a fee kg of body weight have been demonstrated during pentobarbital may be required for consultation) and/or the drug manufac- anesthesia (28 to 32 mg per kg of body weight [mg/kg]) in turer.

GENERAL CONSIDERATIONS Dogs: Toxic effect—A parenteral dose of 30 mg/kg a day for 10 days When systemically absorbed, the aminoglycosides have the potential to (or 10 mg/kg every 8 hours for 8 days) produced evidence of renal cause nephrotoxicity, neurotoxicity, or ototoxicity{R-91}. This includes toxicity, including elevated serum urea nitrogen concentration, absorption through irrigation of tissues in surgery and sometimes elevated serum creatinine, proteinuria, decreased urine specific from topical application{R-91}. Because of the narrow therapeutic gravity, decreased exogenous creatinine clearance, decreased index, the margin between therapeutic concentrations and toxic glomerular filtration rate, and histological evidence of renal {R-269; 270} concentrations, for aminoglycosides used in animals, toxicity is a toxicity . potential risk in the best of circumstances. The minimum gentamicin Foals: Toxic effect—Nephrotoxicity occurred in one of twelve foals dose required to produce nephrotoxicity is variable between species given 17.6 mg/kg every 12 hours and one of twelve given 8.8 mg/ {R-218} and between animals{R-212} and the data listed in this section cannot kg every 12 hours for 15 days . clearly define the dose that will produce serious toxicity in a particular Hawks, red tailed: Toxic effect—An intravenous dose of 10 mg/kg animal. every 12 hours for 4 days caused significantly increased serum {R-87} Toxic dose—Information about toxicity of the aminoglycosides has been uric acid concentrations . drawn primarily from human therapeutic literature. It has been Lambs: Toxic effect—An intravenous dose of 80 mg/kg a day for up {R-206} reported that minimum serum concentrations within a dosing interval to 20 days produced renal tubular necrosis and dilation . of greater than 2 mcg/mL for gentamicin and greater than 2.5 to Serum creatinine concentrations of up to 132 micromoles per liter 5 mcg/mL for amikacin or kanamycin significantly increase the risk of were measured beginning 14 days, on average, after initiation of {R-206} toxicity{R-148; 185; 209}. Persistant peak serum concentrations of therapy . gentamicin greater than 10 to 12 mcg/mL and of amikacin or Kanamycin: Dogs—Toxic effect: A single dose of 100 mg/kg kanamycin greater than 30 to 40 mcg/mL are also considered to administered to three dogs caused a transient decrease in auditory increase the risk of toxicity{R-230}. perception in one dog as measured by auditory brain stem {R-196} Amikacin: response . Administration of 100 mg/kg daily for 9 weeks Dogs—Renal toxicity: Minimal to mild renal changes are seen with a caused a complete loss of hearing for high-frequency tone, dose of 45 mg per kg of body weight (mg/kg) a day for 2 although changes did not begin until about 2 weeks after the {R-196} weeks{R-91} or 30 mg/kg a day for 90 days{R-91}. beginning of therapy . Guinea pigs: Auditory and vestibular ototoxicity— Streptomycin: Cats— Marked hearing loss—150 to 225 mg/kg a day in divided doses No effect: A dose of 25 mg/kg a day, administered for 9 to 28 days, {R-246} every 8 hours for 1 week{R-190; 191}. did not cause signs of toxicity . Hearing loss, less pronounced—When the 150 mg/kg dose was Toxic effect: An intramuscular dose of 50 mg/kg a day, divided into administered every 24 hours for 7 to 21 days, there was a doses administered every 8 hours for 9 to 28 days, produced {R-246} significant decrease in vestibular and auditory damage{R-190; nonreversible hearing loss in most cats . A dose of 200 mg/kg 191}. produced both permanent hearing loss and vestibular impair- {R-246} Apramycin: ment . Chickens— Lethal dose— No effect: With a dose of 50 mg per kg of feed, fed as the only Note: These doses have been reported as lethal but are not necessarily the ration, no toxic signs are noted{R-195}. minimum lethal dose in a particular animal. No effect is listed if the With a dose of 150 to 250 mg per kg of feed, a reduction in serum research was intended to define a lethal dose. {R- hemoglobin and erythrocytes may be noted, as well as Amikacin: LD50—Dogs: Intramuscular or intravenous, >250 mg/kg 91} dystrophic changes in the internal organs{R-195}. . Dogs—No effect: Chronic administration yielded no toxicity with 50 Apramycin: parts per million (ppm) fed to dogs for 1 year{R-96}. Chickens and dogs—No effect: No mortality was observed with 520 {R-96} Pigs— mg/kg as a single dose in chickens and dogs . No effect: With a dose of up to 300 mg per liter of drinking water Mice—In mice, greater than 5200 mg/kg as a single dose produced {R-96} for 15 days, no signs of toxicity were noted. no mortality . With a dose of 500 to 1000 mg per liter of drinking water (5 to 10 Gentamicin: times the label dose) for more than 15 days, some animals Cats—40 to 70 mg/kg a day administered subcutaneously caused {R-227} developed a drop in the percentage of neutrophils and an renal necrosis and death within 10 days . increase in lymphocyte percentage in the complete blood Hawks, red-tailed—An intravenous dose of 20 mg/kg every 12 hours count{R-194}. was lethal for all five birds in 2 to 6 days; predominant signs were {R-87} Rats—No effect: Chronic administration yielded no toxicity with indicative of neuromuscular blockade . 10,000 ppm fed to rats for 2 years{R-96}. Gentamicin: Renal— CLINICAL EFFECTS OF OVERDOSE Cats: The following effects have been selected on the basis of their potential No significant effect—A dose of 4.4 mg/kg every 12 hours for 12 clinical significance (possible signs in parentheses where appropri- days produced no significant effects{R-228}. ate)—not necessarily inclusive: Toxic effect—Only mild nephritis was produced by 20 mg/kg a day Note: The following overdose effects mirror the side/adverse effects administered subcutaneously for 70 days{R-227}. listed in this monograph because of the small therapeutic index for

aminoglycosides. These effects may occur in some animals with which pathogen growth is inhibited after the serum concentration therapeutic doses so that most animals treated should be monitored for falls below minimum inhibitory concentrations{R-80}. The PAE has adverse effects. These are also dose-related effects, however, with risk been shown to occur when amikacin or gentamicin is administered increasing as the dose rises above recommended levels{R-7}. to treat gram-negative infections{R-174}. Postantibiotic effect may be All species evidence that exposure to a high concentration of antimicrobial Nephrotoxicity{R-7; 212}; neuromuscular blockade; ototoxicity, causes cellular changes in the pathogen that will inevitably cause auditory; ototoxicity, vestibular death after drug concentrations have dropped below the MIC{R-158}. The PAE may be shortened in neutropenic animals but prolonged in animals with renal impairment{R-174}. TREATMENT OF OVERDOSE 3) An extended period of serum drug concentrations below a minimum Recommended treatment consists of the following: amount is expected to decrease the risk of aminoglycoside toxicity. Note: Some experts suggest that administration of a beta-lactam Dosing is usually designed to produce peaks above the MIC and troughs antibiotic that binds an aminoglycoside (ticarcillin, for example) will below a minimum concentration to prevent adverse effects, regardless decrease the toxicity after accidental overdose of aminoglycosides{R- of the frequency of dosing within a 24-hour period. Many sources 266}. recommend serum concentrations be allowed to drop below 2 mcg/mL For neuromuscular blockade for gentamicin and to less than 2.5 to 5 mcg/mL for amikacin or • Administration of edrophonium, 0.5 mg/kg, will reverse neuromus- kanamycin for an extended period within a dosing interval to reduce cular blocking effects{R-200; 201}. Administration of calcium chloride the risk of toxicity{R-47; 51; 63; 148; 185; 209; 230}. A plasma or serum at 10 to 20 mg/kg, calcium gluconate at 30 to 60 mg/kg, or concentration of at least 8 to 10 times the MIC of the organism has been neostigmine at a dose of 100 to 200 mcg per kg of body weight can recommended for the aminoglycoside antibiotics to be effective{R-155}. also reverse muscle response depression and associated dysp- Individualized dosing/Patient monitoring: Even within the same species, nea{R-186}. individual animals can differ widely in the serum concentrations For renal toxicity produced from the same dosage regimen{R-83; 89; 213; 230}. When this • Aminoglycoside administration should be immediately discontin- relative unpredictability is combined with the often small difference ued{R-208}. between therapeutic and toxic serum concentrations of aminoglyco- • Polyionic electrolyte fluid therapy should be initiated to stimulate sides, the determination of serum concentrations in a particular diuresis{R-208}. animal becomes very valuable. When it is economically possible to Note: Three or more weeks of therapy may be required for recovery in measure plasma or serum concentrations during aminoglycoside animals with sufficient remaining renal tissue to compensate{R-215}. therapy, the information can be used to maximize efficacy and Oliguria may be a poor prognostic sign{R-215}. minimize toxicity{R-130–132}. Note: There can be up to a fourfold difference between avian species in CLIENT CONSULTATION the elimination of gentamicin{R-85}. It is recommended that species- There are reports that aminoglycosides, such as neomycin or strepto- specific pharmacokinetic data be used to develop dosing for birds, if at mycin, can cause contact dermatitis in human beings{R-236}. Direct all possible{R-148}. contact with skin should be avoided by people handling these Once daily dosing: The continuing effort to maximize therapeutic effect products{R-236}. and minimize toxic effect of aminoglycosides has led to ongoing research on the efficacy of a 24-hour dosing interval{R-160; 232; 252}. VETERINARY DOSING INFORMATION Dosing once a day is considered by some clinicians to be a rational use Resistance: Reports of antimicrobial resistance support recommendations of aminoglycosides in specific situations{R-232}. The supporting argu- to culture pathogens to be sure the use of an aminoglycoside is ments include that use of the highest safe single dose has been linked warranted. There is also some evidence that limiting the use of to increased efficacy in human studies, greater bacterial killing and a aminglycosides and, in particular, limiting administration at subther- longer postantibiotic effect are expected with a higher peak concen- apeutic concentrations to a population of animals may limit the tration, and once-a-day dosing allows for the longest period of low increase in E. coli resistance that is seen with more intense antimi- serum concentration to minimize toxicity{R-160; 232; 252}. {R-234} crobial use . Concern has been expressed that dosing once every 24 hours may be less effective than repeated daily dosing in some situations, such as in FOR PARENTERAL DOSAGE FORMS ONLY immunocompromised patients{R-158}. Studies with guinea pigs have Systemic aminoglycosides are generally dosed to achieve a high peak demonstrated no significant difference in bacterial killing between serum concentration followed by a period of subtherapeutic serum gentamicin administered subcutaneously at 6 mg/kg every 24 hours concentration. This strategy is built on several factors: versus 2 mg/kg every 8 hours{R-80}. However, once-a-day dosing has 1) Aminoglycosides kill bacteria by a concentration-dependent mech- been less effective in treating some infections in neutropenic ani- anism{R-80} rather than dependence on the length of time the mals{R-158; 232}. Some researchers have demonstrated a potential for organism is exposed to the antibiotic{R-160}. A spike in concentra- development of resistance with dosing once a day{R-232}; but others tion{R-80; 232} or, in some situations, a plateau{R-155; 157} above the have described an adaptive resistance to aminoglycosides in Pseudo- minimum inhibitory concentration is neccessary for effective bacte- monas species that occurs with doses repeated within 16 hours in rial killing. animal models but that is reduced by longer dosing intervals in the first 2) A high peak of antibiotic will cause the most killing of bacteria and 3 days{R-160}. Some clinicians have expressed reservations about once- will also cause the most prolonged postantibiotic effect (PAE), in daily dosing when intestinal damage allows continued exposure to

bacteria that may replicate during the prolonged periods of subther- from gentamicin overdose compared with horses not receiving apeutic aminoglycoside concentration{R-263}. calcium{R-223}. Desired benefits include reduction of toxicity. If the total daily dose of Sheep: Sheep fed a low protein diet (straw and barley) have a significantly aminoglycoside is kept constant, less frequent dosing per day is lower total clearance and volume of distribution at steady state than associated with decreasing renal toxicity{R-232}. The same is true for sheep fed a high protein diet (alfalfa and barley). This results in an gentamicin ototoxicity in guinea pigs but, while the single daily dose increased serum concentration of gentamicin in the group fed a low has not been shown to be more toxic for amikacin or kanamycin, the protein diet{R-38}. benefit in reducing ototoxicity is less clear for amikacin or kanamycin in guinea pigs{R-190; 191; 232}. Renal dysfunction: Treatment with gentamicin every 8 hours is not AMIKACIN {R-72} recommended in patients with subclinical renal disease . Because SUMMARY OF DIFFERENCES drug clearance may be slowed with gentamicin treatment, the risk of Category: Aminoglycoside nephrotoxicity may be increased. Trough serum concentrations can be Indications: General considerations—Has the broadest spectrum of {R- reduced by increasing the dosing interval and decreasing the dose activity of the aminoglycosides and is considered effective against 185} . Some clinicians have developed methods to calculate an strains not susceptible to other aminoglycosides. increased dosing interval based on the creatinine clearance concen- Side/adverse effects: Intermediate renal toxicity. More toxic to the tration; however, the most prudent course may be to avoid use of cochlea than to vestibular organs. Diarrhea and vomiting in dogs. Mild aminoglycosides if it is necessary to significantly reduce the amino- local tissue trauma in cats and dogs. glycoside dose because of poor renal function{R-72}. Endotoxemia: Producing high serum and tissue concentrations of aminoglycoside as early as possible in animals with gram-negative MUCOSAL DOSAGE FORMS sepsis is important{R-72}. The release of endotoxin by gram-negative organisms may be enhanced by administration of the antibiotic{R-184}. AMIKACIN SULFATE UTERINE SOLUTION The systemic effects of endotoxemia will also increase the risk of Usual dose: Uterine infections—Horses: Intrauterine, 2 grams, admin- {R-92; 105; 138} concentrating aminoglycosides in the renal tissue and causing acute istered every twenty-four hours for three days . The renal failure{R-185}. medication should be mixed with 200 mL of 0.9% sodium chloride {R-92} Diabetes mellitus: It appears that diabetic dogs may have increased injection before administration . Note: Product labeling recommends that mares not be bred for eight clearance of gentamicin and reduced volume of distribution (VolDss)of {R-92} gentamicin, which make them less susceptible to nephrotoxicity at hours after intrauterine treatment with amikacin . therapeutic doses of the medication{R-71}; however, the possibility of {R-231} subclinical renal disease should also be considered. Strength(s) usually available : Concurrent fluid administration: In horses, the administration of thera- U.S.— peutic fluids, similar to those that are used in the treatment of colic, Veterinary-labeled product(s): does not significantly change the pharmacokinetics of concurrently 250 mg per mL (Rx) [Amifuse E; Amiglyde-V Intrauterine Solu- {R-92} administered gentamicin{R-45}. tion ; Amikacin E Solution; AmTech AmiMax E Solution; Equi- generic Gastointestinal microflora: Parenterally administered amikacin appears to Phar EquiGlide; ]. have minimal effect on gastrointestinal microflora in horses{R-136}. Note: These products contain 0.1 mg benzethonium chloride per mL as {R-92} Gastrointestinal surgery: When gentamicin administration (4 to 6.6 mg/ kg a preservative . every 24 hours) is begun immediately after abdominal surgery for Canada— naturally occurring colic, the pharmacokinetics of the gentamicin has Veterinary-labeled product(s): been measured to be within the reference range for normal healthy 250 mg per mL (Rx) [Amiglyde-V]. horses{R-265}. Withdrawal times: U.S. and Canada—Product is not labeled for use in horses to be used for food production{R-92}. FOR ORAL DOSAGE FORMS ONLY Chickens: Because poultry litter may contain bacteria with multiple Stability: A change from a colorless solution to pale yellow in color does antibiotic resistance, treatment of litter to prevent contamination not indicate a decrease in potency of the antimicrobial{R-92}. before reutilization in soil or bedding is recommended{R-121}. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specified by DIET/NUTRITION manufacturer. Dogs: Dogs with normal renal function consuming a higher protein diet (26%) for 3 weeks before treatment have a faster gentamicin clearance USP requirements: Not in USP{R-19}. and a larger volume of distribution than dogs fed a medium (13%) or low (9%) protein diet{R-73}. Horses: Horses fed an alfalfa diet rather than oats alone have a smaller PARENTERAL DOSAGE FORMS degree of nephrotoxicosis from administration of gentamicin{R-222}. Note: Bracketed information in the Dosage Forms section refers to uses Likewise, horses administered supplemental calcium gluconate, that either are not included in U.S. product labeling or are for products 20 mg/kg every 12 hours, have a decreased risk of acute renal failure not commercially available in the U.S.

AMIKACIN SULFATE INJECTION USP weight every twelve hours has been suggested for the treatment of {R-152} Note: Intravenous administration—When amikacin is administered by susceptible bacterial infections in guinea pigs . 1 the intramuscular or subcutaneous route, it is rapidly and completely [Hawks, red-tailed] —Although the safety and efficacy of amikacin absorbed. Although not always listed on product labeling, this have not been established, a dose of 15 to 20 mg per kg of body weight medication is also commonly administered intravenously. An indwell- every twenty-four hours or 7 to 10 mg per kg of body weight every ing catheter is used for convenience and to minimize the discomfort of twelve hours, administered intramuscularly, has been suggested for repeated dosing{R-263}. To further decrease the risk of neuromuscular the treatment of susceptible bacterial infections in red-tailed {R-147} blockade, it is recommended that the drug be diluted in saline or hawks . This recommendation is based on pharmacokinetic administered slowly{R-263}. data. In this study, it was also noted that larger birds tended to develop lower peak serum drug concentrations than smaller birds in response Usual dose: to the same dose{R-147}. 1 [Bacteremia] ; [Horses]1 and [foals, more than 30 days of age]1—Although the safety 1 [Bone and joint infections] ; and efficacy have not been established, an intramuscular or intrave- 1 [Respiratory tract infections] ; nous dose of 10 mg per kg of body weight every twenty-four hours has 1 [Septicemia] ; been recommended in the treatment of susceptible bacterial infections, 1 Skin and soft tissue infections ; based on pharmacokinetic data{R-6}. For some infections in horses, 1 Urinary tract infections ;or dosing more than once a day may still be necessary and, in those cases, 1 [Uterine infections] —Dogs: an intravenous dose of 6 mg per kg of body weight every eight hours Intramuscular or subcutaneous, 10 mg per kg of body weight every has been recommended{R-136}. {R-91; 143} eight to twelve hours . [Parrots, African gray]1—Although the safety and efficacy of amikacin Once-daily dosing—Intramuscular or subcutaneous, 15 to 30 mg per have not been established, an intravenous or intramuscular dose of 10 {R-266} kg of body weight every twenty-four hours . to 20 mg per kg of body weight every eight to twelve hours has been 1 [Bacteremia] ; recommended in the treatment of susceptible bacterial infections, based 1 [Bone and joint infections] ; on pharmacokinetic data{R-150}. 1 [Respiratory tract infections] ; [Pythons, ball]1—Although the safety and efficacy of amikacin have 1 [Septicemia] ; not been established, an intramuscular dose of 3.48 mg per kg of body 1 [Skin and soft tissue infections] ; weight as a single dose has been recommended in the treatment of 1 [Urinary tract infections] ;or susceptible bacterial infections in ball pythons{R-155}. 1 [Uterine infections] —Cats: [Snakes, gopher]1—Although the safety and efficacy of amikacin have Intramuscular or subcutaneous, 10 mg per kg of body weight every not been established, an intramuscular loading dose of 5 mg per kg {R-139; 140; 264} eight hours . of body weight, followed by 2.5 mg per kg of body weight every Once-daily dosing—Intramuscular or subcutaneous, 10 to 15 mg seventy-two hours has been suggested in the treatment of susceptible {R-266} per kg of body weight every twenty-four hours . bacterial infections in gopher snakes{R-154}. It has also been recom- 1 Note: [Calves] —Animal Medicinal Drug Use Clarification Act (AMDUCA) mended that snakes be kept at the high end of their preferred regulations should be considered before the extra-label use of temperature range (37 C) to maximize distribution of drug in the aminoglycosides in food-producing animals: Although the safety and body{R-154}. efficacy of amikacin have not been established, a dose of 12 mg per kg [Tortoises, gopher]1—Although the safety and efficacy of amikacin of body weight every twelve hours has been suggested for use in the have not been established, an intramuscular dose of 5 mg per kg of {R-141; 144} treatment of susceptible bacterial infections . body weight (including shell), administered every forty-eight hours, 1 1 [Donkeys] and [ponies] —Although the safety and efficacy of has been suggested for the treatment of susceptible bacterial infections amikacin have not been established, a dose of 6 mg per kg of body in gopher tortoises{R-156}. weight every six hours, administered intravenously, has been recommended in the treatment of bacterial infections in donkeys and {R-136} ponies . Strength(s) usually available{R-231}: [Foals, less than 30 days of age]1—Although the safety and efficacy of U.S.— amikacin have not been established, a dose of 20 to 25 mg per kg of Veterinary-labeled product(s): body weight every twenty-four hours, administered by the intramus- 50 mg per mL (Rx) [Amiglyde-V Injection{R-91}; Amiject D; Amikacin C cular or intravenous route, has been recommended in the treatment of Injection; AmTech AmiMax C Injection; CaniGlide; GENERIC]. susceptible bacterial infections in foals{R-6; 130–132; 134; 266; 271}. Note: These products contain 0.1 mg benzethonium chloride per mL{R- [Goats]1—AMDUCA regulations should be considered before the extra 92}. label use of aminoglycosides in food-producing animals—Although the Canada— safety and efficacy of amikacin have not been established, a subcu- Veterinary-labeled product(s): taneous dose of 8 mg per kg of body weight every twelve hours has Not commercially available. been suggested in the treatment of susceptible bacterial infections in goats{R-151}. In one study, this was predicted to provide peak serum Withdrawal times: concentrations of 32.3 mcg/mL{R-151}. U.S.—This product is not labeled for use in food-producing animals and [Guinea pigs]1—Although the safety and efficacy of amikacin have not should not be administered to such animals because of the risk of long- been established, an intramuscular dose of 15 mg per kg of body term antibiotic residues{R-258}.

Packaging and storage: Store below 40 C (104 F), preferably Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by manufacturer. manufacturer. Protect from moisture and excessive heat{R-96}.

USP requirements: Preserve in single-dose or in multiple-dose con- Preparation of dosage form: Prepare fresh solution daily according to tainers, preferably of Type I or Type III glass. A sterile solution of manufacturer’s labeling{R-96}. Amikacin Sulfate in Water for Injection, or of Amikacin in Water for Injection prepared with the aid of Sulfuric Acid. Contains an amount of Incompatibilities: Activity of the medication may be reduced if water amikacin sulfate equivalent to the labeled amount of amikacin, within delivery system contains rust{R-96}. –10% to +20%. Meets the requirements for Identiﬁcation, Bacterial endotoxins, pH (3.5–5.5), and Particulate matter, and for Injections{R-19}. USP requirements: Not in USP{R-19}.

1Not included in Canadian product labeling or product not commercially available in Canada DIHYDROSTREPTOMYCIN

APRAMYCIN SUMMARY OF DIFFERENCES Category: Aminoglycoside. SUMMARY OF DIFFERENCES Indications: General considerations—Active against mycobacteria, Category: Aminocyclitol. Leptospira{R-243; 244}, Francisella tularensis, and Yersinia pestis, but Indications: General considerations—Apramycin is active against Staph- only some mycoplasma, gram-negative organisms, and Staphylococcus ylococcus aureus, many gram-negative organisms, and some myco- species{R-116}. The introduction of newer aminoglycosides has eclipsed plasma. It has been reported to be effective in vitro against Escherichia the signiﬁcance of dihydrostreptomycin in the face of increasing {R-96; 164} coli and Salmonella species that are resistant to streptomycin bacterial resistance. {R-167; 173} and neomycin . Lactation: Irregularly distributed into the milk of cows for 18 hours or Side/adverse effects: This medication produces minimal side/adverse more. effects and toxicity when administered by the oral route. Side/adverse effects: Less nephrotoxic than other aminoglycosides. Unlike streptomycin, dihydrostreptomycin is associated with more auditory {R-233} ORAL DOSAGE FORMS than vestibular toxicity .

APRAMYCIN SULFATE POWDER FOR ORAL SOLUTION Usual dose: Enteritis, E. coli—Piglets: Oral, 12.5 mg per kg of body ORAL DOSAGE FORMS weight a day for seven days (375 mg per gallon or 100 mg per liter), Note: Bracketed information in the Dosage Forms section refers to uses administered in the only source of water{R-95; 96}. that either are not included in U.S. product labeling or are for products Note: Water consumption should be monitored closely and adjusted to not commercially available in the U.S. avoid overdose.

Strength(s) usually available{R-231}: DIHYDROSTREPTOMYCIN INJECTION USP U.S.— Usual dose: Veterinary-labeled product(s): Note: [Cattle], [dogs], and [pigs]—Although Canadian product labeling 48 grams per packet (OTC) [Apralan Soluble]. includes a dose of 25 mg per kg of body weight for three to five days Canada— in the treatment of leptospirosis in cattle, dogs, and pigs, studies have Veterinary-labeled product(s): shown that while shedding of leptospires will be halted for at least 2 48 grams per packet (OTC) [Apralan]. months, carriers are not necessarily eliminated{R-243; 244}. Although Canadian product labeling includes the use of dihydro- Withdrawal times: streptomycin in the treatment of bacterial pneumonia in calves, there is U.S.{R-95}— no published evidence available pertaining to efficacy of this therapy. Withdrawal time Such use is not recommended by the USP Veterinary Medicine Advisory Panel{R-258} due to the lack of efficacy data and the Species Meat (days) potential for extended tissue withdrawal times. Pigs 28 Strength(s) usually available{R-231}: {R-96} Canada — U.S.— Veterinary-labeled product(s): Withdrawal time Not commercially available. Species Meat (days) Canada— Veterinary-labeled product(s): Pigs 28 500 mg per mL (OTC) [Ethamycin{R-106}].

Withdrawal times: USP requirements: Preserve in single-dose or in multiple-dose con- Canada— tainers, preferably of Type I glass. A sterile solution of Gentamicin

Withdrawal time Sulfate in Water for Injection. Label Uterine Infusion to indicate that it is for veterinary use only. The label states that it must be diluted with Species Meat(days) Milk (hours) 0.9% Sodium Chloride Irrigation before aseptic uterine infusion. May

Calves, pigs 30 contain suitable buffers, preservatives, and sequestering agents. Con- Cattle 30 96 tains the labeled amount, within –10 to +25%. Meets the requirements for Identiﬁcation, Sterility, and pH (3.0–5.5).{R-19}

Packaging and storage: Store below 40 C (104 F), preferably ORAL DOSAGE FORMS between 15 and 30 C (59 and 86 F), unless otherwise specified by manufacturer. GENTAMICIN ORAL SOLUTION Usual dose: USP requirements: Preserve in single-dose or in multiple-dose con- Enteritis, E. coli— tainers. Label it to indicate that it is intended for veterinary use Piglets, 1 to 3 days of age: Oral, 5 mg as a total dose, administered only. Contains an amount of Dihydrostreptomycin Sulfate equivalent once at the onset of signs{R-13; 14}. to the labeled amount of dihydrostreptomycin, within –10% to Note: The above dose is for ‘‘pig pump’’ solutions, administered +20%. Contains one or more suitable preservatives. Meets the at the strength provided in metered dose packaging{R-13; 14}; see requirements for Identification, Bacterial endotoxins, Sterility, and manufacturer’s product labeling. pH (5.0–8.0){R-19}. Piglets, weanling1: Oral, 25 mg per gallon of water (approximately 1.1 mg per kg of body weight), administered as the sole source of drinking water for three consecutive days{R-11}. GENTAMICIN Swine dysentery1—Pigs: Oral, 50 mg per gallon of water SUMMARY OF DIFFERENCES (approximately 2.2 mg per kg of body weight), administered as the sole source of drinking water for three consecutive days{R-11}. Category: Aminoglycoside. Indications: General considerations—Gentamicin has been widely used in the treatment of gram-negative organisms and some gram-positive Strength(s) usually available{R-231}: organisms. As with other aminoglycosides, use is limited by risk of U.S.— toxicity. Veterinary-labeled product(s): Side/adverse effects: Intermediate nephrotoxicity. It is considered to be 4.35 mg per mL (OTC) [Garacin Pig Pump{R-13}]. equally toxic to the cochlea and to vestibular organs. 5 mg per mL (OTC) [AmTech Gentamicin Sulfate Pig Pump Oral Solution]. Canada— MUCOSAL DOSAGE FORMS Veterinary-labeled product(s): 4.35 mg per mL (OTC) [Garasol Pig Pump Oral Solution{R-14}]. GENTAMICIN UTERINE INFUSION USP Usual dose: Withdrawal times: {R-13} Uterine infections, bacterial—Horses: Intrauterine, 2 to 2.5 grams as a U.S. — {R-1} total dose a day for three to five days during estrus . Before Withdrawal time administration, the dose should be diluted with 200 to 500 mL of Species Meat (days) sterile physiological saline{R-1}. Piglets 14 Strength(s) usually available{R-231}: U.S.— Canada{R-14}— Veterinary-labeled product(s): 50 mg per mL (Rx) [Gentocin Solution{R-1}]. Withdrawal time 100 mg per mL (Rx) [AmTech GentaMax 100; GentaMax 100; {R-3} Species Meat (days) GentaVed 100; Gentocin Solution; Gentozen; Legacy; GENERIC ]. Canada— Piglets 11 Veterinary-labeled product(s): Not commercially available. Packaging and storage: Store below 40 C (104 F), preferably Withdrawal times: between 15 and 30 C (59 and 86 F), unless otherwise specified by {R-13} U.S.—This product is not labeled for use in food-producing animals in the manufacturer. Protect from freezing . U.S., including horses intended for food production{R-1}. Preparation of dosage form: This medication is dispensed in a ‘‘pig Packaging and storage: Store between 2 and 30 C (36 and 86 F){R-1}, pump.’’ Medication is administered by one plunger depression to unless otherwise specified by manufacturer. deliver 5 mg into each pig’s mouth{R-12}.

Stability: absorbed. Although not always listed on product labeling, this Contents of ‘‘pig pump’’ medication bottle should be destroyed 90 days medication is also commonly administered intravenously. An indwell- after opening, if unused{R-12}. ing catheter is used for convenience and to minimize the discomfort of Medicated drinking water should be prepared daily{R-11}. repeated dosing{R-263}. To further decrease the risk of neuromuscular blockade, it is recommended that the drug be diluted in saline or Incompatibilities: To prevent inactivation of the drug, medicated administered slowly{R-263}. drinking water should not be stored in rusty containers{R-11}. Usual dose: USP requirements: Not in USP{R-19}. [Bacteremia]; [Bone and joint infections]1; GENTAMICIN POWDER FOR ORAL SOLUTION Respiratory tract infections; Usual dose: [Septicemia]; Enteritis, E. coli1—Piglets: Oral, 25 mg per gallon of water (approx- Skin and soft tissue infections; imately 1.1 mg per kg of body weight), administered as the sole Urinary tract infections; or source of drinking water for three consecutive days{R-15}. [Uterine infections]1— Swine dysentery1—Pigs: Oral, 50 mg per gallon of water (approxi- Cats: mately 2.2 mg per kg of body weight), administered as the sole Intramuscular, intravenous, or subcutaneous, 3 mg per kg of body source of drinking water for three consecutive days{R-15}. weight every eight hours{R-63; 64}. Note: Under extreme hot or cold weather conditions, product labeling Once-daily dosing—Intramuscular, intravenous, or subcutaneous, recommends that the concentration of medication be adjusted, based 5 to 8 mg per kg of body weight every twenty-four hours{R-266}. on expected changes in water consumption{R-15}. Dogs: Strength(s) usually available{R-231}: Intramuscular or subcutaneous, 4.4 mg per kg of body weight {R-4; 7} U.S.— every eight hours . Veterinary-labeled product(s): Once-daily dosing—Intramuscular or subcutaneous, 10 to 15 mg {R-266} 66.7 mg of gentamicin per gram of powder (OTC) [Garacin Soluble per kg of body weight every twenty-four hours . Powder]. Note: Authors of a study of obese cats considered to be approximately 333.3 mg of gentamicin per gram of powder (OTC) [Gen-Gard]. 45% overweight (4.6 to 6.6 kg body weight) recommended an Canada— intramuscular, intravenous, or subcutaneous dose of 2.5 mg per kg Not commercially available. of body weight every eight hours to compensate for pharmacokinetic differences from normal-weight cats{R-68}. Withdrawal times: Treatment of urinary tract infections with aminoglycosides should be {R-15} U.S. — reserved for those cases in which resistance exists to safer alternative Withdrawal time antimicrobials. Despite label directions to limit treatment duration to 7 days{R-4}, most urinary tract infections will require extended Species Meat (days) therapy. This is possible with the aminoglycosides, provided careful Pigs, piglets 10 monitoring is performed (see Patient monitoring). According to product labeling, treatment with gentamicin injection should not exceed 7 days{R-4}. Packaging and storage: Store below 40 C (104 F), preferably Enteritis, Escherichia coli—Piglets, 1- to 3-day-old: Intramuscular, 5 mg between 15 and 30 C (59 and 86 F), unless otherwise specified by as a single total dose{R-7; 9}. manufacturer. To avoid degradation of medication, this product should E. coli infection; not be stored in rusty containers{R-15}. Pseudomonas aeruginosa infection; or Salmonella typhimurium infection—Chicks, 1-day-old: Subcutaneous, Preparation of dosage form: Prepare daily according to manufac- 0.2 mg as a total single dose{R-7; 8}. turer’s recommendation{R-15}. Paracolon—Turkey poults, 1- to 3-day-old: Subcutaneous, 1 mg as a {R-7; 8} USP requirements: Not in USP{R-19}. total single dose . Uterine infections, bacterial—Horses: Intrauterine, 2 to 2.5 grams a day for three to five days during estrus{R-4; 7}. Before administration, 1Not included on Canadian product labeling or product not commercially the dose should be diluted with 200 to 500 mL of sterile available in Canada. physiological saline{R-4; 7}. PARENTERAL DOSAGE FORMS Note: The following recommendations have been suggested based on pharmacokinetic studies: Note: Bracketed information in the Dosage Forms section refers to uses [Baboons]1—Although the safety and efficacy of gentamicin have not that either are not included in U.S. product labeling or are not been established, an intramuscular dose of 3 mg per kg of body commercially available in the U.S. weight every six to eight hours has been suggested in the treatment GENTAMICIN INJECTION USP of Pseudomonas aeruginosa infections in baboons{R-76}. Note: Intravenous administration—When gentamicin is administered by [Buffalo calves]1—Animal Medicinal Drug Use Clarification Act the intramuscular or subcutaneous route, it is rapidly and completely (AMDUCA) regulations should be considered before the extra label

use of aminoglycosides in food-producing animals: Although the weight as an initial dose, followed by 1.5 mg per kg of body weight at safety and efficacy of gentamicin have not been established, an ninety-six–hour intervals has been suggested in the treatment of intramuscular dose of 3.25 mg per kg of body weight as an initial susceptible bacterial infections in pythons{R-89}. dose, followed by 2 to 3 mg per kg of body weight every twelve hours {R-231} has been recommended in the treatment of susceptible bacterial Strength(s) usually available : infections in buffalo calves{R-77; 78}. U.S.— [Budgerigars]1—Although the safety and efficacy of gentamicin have Veterinary-labeled products: {R-9} not been established, an intramuscular dose of 5 mg per kg of body 5 mg per mL (Rx) [Garacin Piglet Injection ]. {R-4} weight every eight hours for three days has been suggested in the 50 mg per mL (Rx) [GentaVed 50; Gentocin ]. {R-8} treatment of susceptible bacterial infections in budgerigars{R-86}. 100 mg per mL (OTC) [AmTech Gentapoult; Garasol Injection ; generic]. [Calves, less than 2 weeks of age]1—AMDUCA regulations should be Genta-fuse; considered before the extra label use of aminoglycosides in food- Canada— producing animals: Although the safety and efficacy have not been Veterinary-labeled products: {R-10} established, an intravenous dose of 12 to 15 mg per kg of body 5 mg per mL (Rx) [Garasol Solution Injectable ]. {R-7} weight every twenty-four hours has been recommended in the 50 mg per mL (Rx) [Gentocin Solution Injectable ]. treatment of susceptible bacterial infections, based on pharmacokinetic 100 mg per mL (Rx [Gentocin Solution Injectable]. data{R-21; 266}. Withdrawal times: [Cattle]1—AMDUCA regulations should be considered before the extra U.S.—This product is not labeled for use in horses to be used in food label use of aminoglycosides in food-producing animals: Although the production{R-4}. safety and efficacy have not been established, an intramuscular dose of 5 to 6 mg per kg of body weight every twenty-four hours has been Withdrawal time recommended in the treatment of susceptible bacterial infections, based Species Meat (days) on pharmacokinetic data{R-22; 25; 261; 266}. [Eagles]1,[hawks]1,or[owls]1—Although the safety and efficacy of Chicks 35 Piglets 40 gentamicin have not been established, an intramuscular or intrave- Turkey poults 63 nous dose of 2.5 mg per kg of body weight every eight hours has been recommended in the treatment of susceptible bacterial infections Canada—This product is not labeled for use in horses to be used in food {R-88} in eagles, hawks, and owls . Caution is advised in extrapolating production{R-7}. dosage recommendations from one avian species to another, as Withdrawal time pharmacokinetics can vary widely. [Goats]1—AMDUCA regulations should be considered before the Species Meat (days) extra label use of aminoglycosides in food-producing animals: Chicks 35 Although the safety and efficacy of gentamicin have not been Piglets 42 established, an intravenous dose of 4 mg per kg of body weight every Turkey poults 63 eight hours has been recommended for use in the treatment of susceptible bacterial infections in goats{R-40}. Note: The administration of gentamicin to cattle in the treatment of [Horse foals]1 and [pony foals]1, less than 30 days of uterine infections is included in Canadian product labeling. However, age—Although the safety and efficacy have not been established, gentamicin is not labeled for use in food-producing animals in the U.S. some researchers suggest that dosing of gentamicin for horse and and the USP Veterinary Medicine Advisory Panel does not recommend pony foals less than 30 days of age should be an intramuscular or use in the treatment of uterine infections in cattle. Therefore, the intravenous dose of 10 to 14 mg per kg of body weight every labeled intrauterine dose and withdrawal time for cattle are not listed twenty-four hours{R-6; 266}. in this monograph. [Horses]1 and [foals, more than 30 days of age]1—Although the Packaging and storage: Store between 15 and 30 C(59and86F){R-4}, safety and efficacy of gentamicin have not been established, an unless otherwise specified by manufacturer. Keep from freezing{R-4}. intramuscular or intravenous dose of 4 to 6.8 mg per kg of body weight every twenty-four hours has been suggested for the treatment USP requirements: Preserve in single-dose or in multiple-dose con- of susceptible bacterial infections in horses and foals more than 30 tainers, preferably of Type I glass. May contain suitable buffers, pre- {R-6; 46; 50; 52; 53; 55; 252; 265; 266} days of age . servatives, and sequestering agents, unless it is intended for intrathecal 1 [Llamas] —AMDUCA regulations should be considered before the use, in which case it contains only suitable tonicity agents. Contains extra label use of aminoglycosides in food-producing animals: an amount of gentamicin sulfate equivalent to the labeled amount of Although the safety and efficacy of gentamicin have not been gentamicin, within –10% to +25%. Meets the requirements for Iden- established, a dose of 2.5 mg per kg of body weight every eight hours tification, Bacterial endotoxins, pH (3.0–5.5), and Particulate matter, for six days has been suggested in the treatment of bacterial infections and for Injections{R-19}. in llamas{R-82}. [Pythons]1—Although the safety and efficacy of gentamicin have not 1Not included on Canadian product labeling or product not commercially been established, an intramuscular dose of 2.5 mg per kg of body available in Canada.

KANAMYCIN Side/adverse effects: High risk of nephrotoxicity and severe cochlear toxicity when parenterally administered. SUMMARY OF DIFFERENCES Category: Aminoglycoside. Indications: General considerations—Spectrum of activity focuses primar- ORAL DOSAGE FORMS ily on gram-negative organisms and a few gram-positive organisms. Note: Bracketed information in the Dosage Forms section refers to uses Side/adverse effects: Intermediate nephrotoxicity. More toxic to the that either are not included in U.S. product labeling or are not cochlea than to vestibular organs. commercially available in the U.S. NEOMYCIN SULFATE FOR MEDICATED FEED PARENTERAL DOSAGE FORMS Usual dose: Enteritis, Escherichia coli (treatment)1—Cattle, goats, pigs, and sheep: Oral, 22 mg per kg of body weight a day for up to a maxi- KANAMYCIN INJECTION USP mum of fourteen days{R-16; 94}. Usual dose: Note: This product is labeled for use in the preparation of Type B or 1 Bacteremia or septicemia ; Type C medicated feeds; Type C medicated feeds may be either 1 Bone and joint infections ; medicated solid feeds or milk replacers. To administer the recom- 1 Otitis media ; mended dosage, adjustments must be made in the concentration of 1 Pancreatitis ; neomycin in feed or milk replacer, based on factors altering 1 Respiratory tract infections ; consumption, such as age and weight of the animal, disease signs, 1 Skin and soft tissue infections ; and environmental factors{R-94}. Urinary tract infections1;or 1 Uterine infections —Cats and dogs: Subcutaneous, 5.5 mg per kg of Strength(s) usually available{R-231}: {R-93} body weight every twelve hours . According to product labeling, U.S.— this medication may also be given by intramuscular injection, if Veterinary-labeled product(s): {R-93} necessary . 715 grams per kg (OTC) [Neomix AG 325 Medicated Premix]. Note: Another source recommends a dose of 10 mg per kg of Canada— body weight every six hours in the dog, based on pharmacokinetic Veterinary-labeled product(s): {R-177} data . Not commerically available.

Strength(s) usually available{R-231}: Withdrawal times: U.S.— U.S.— Veterinary-labeled product(s): Withdrawal time 200 mg per mL (Rx) [Kantrim]. Species Meat (days) Canada— Veterinary-labeled product(s): Cattle and ruminating calves 1 Not commercially available. Goats and kids, pigs and piglets 3 Sheep and lambs 2

Packaging and storage: Store below 40 C (104 F), preferably Note: Products are not labeled for use in preruminating calves to be between 15 and 30 C (59 and 86 F), unless otherwise specified by processed for veal or for lactating dairy cattle or goats producing milk manufacturer. for human consumption. Stability: Unopened vials may darken in color during storage, but Packaging and storage: Store below 40 C (104 F), preferably be- potency is unaffected{R-93}. tween 15 and 30 C (59 and 86 F), in a tightly closed container, unless otherwise specified by manufacturer. USP requirements: Preserve in single-dose or in multiple-dose con- Store in a dry place, securely closing packaging to prevent caking of tainers, preferably of Type I or Type III glass. Contains suitable buffers contents{R-231}. and preservatives. Contains an amount of Kanamycin Sulfate equivalent to the labeled amount of kanamycin, within –10% to +15%. Preparation of dosage form: Prepare solutions daily according to Meets the requirements for Identification, Bacterial endotoxins, Ste- manufacturer’s instructions. rility, pH (3.5–5.0), and Particulate matter and for Injections{R-19}. USP requirements: Not in USP{R-19}. 1Not included on Canadian product labeling or product not commercially available in Canada. NEOMYCIN SULFATE ORAL SOLUTION USP Usual dose: Enteritis, E. coli—Cattle, goats1,[horses], pigs, and sheep: NEOMYCIN Oral, 22 mg per kg of body weight a day, administered in the only source of drinking water for fourteen days{R-98–100}. SUMMARY OF DIFFERENCES Note: For many of these products, individual animal treatment is also Category: Aminoglycoside. possible by dividing the daily dose and administering as a drench with Indications: General considerations—Effective against many gram- milk or water or by mixing in an individual animal’s only water negative organisms and Staphylococcus aureus. supply{R-98–100}. Consult the manufacturer’s product labeling.

Canadian product labeling lists the dose of neomycin in terms of mL USP requirements: Preserve in tight, light-resistant containers, pref- per liter of drinking water and an incrementally increasing dose from erably at controlled room temperature. Contains an amount of neo- 2 weeks to adult, or 2 weeks to 26 weeks of age, for chickens and mycin sulfate equivalent to the labeled amount of neomycin, within – turkeys, respectively{R-103}. See product labeling for speciﬁc dosing 10 to +25%. Meets the requirements for Identiﬁcation and pH directions. (5.0–7.5){R-19}.

Strength(s) usually available{R-231}: NEOMYCIN SULFATE POWDER FOR ORAL SOLUTION U.S.— Usual dose: 1 Veterinary-labeled product(s): E. coli infection —Turkeys, growing: Oral, 22 mg per kg of body weight 200 mg per mL (OTC) [AmTech Neomycin Oral Solution; Biosol a day, administered in the only source of drinking water for ﬁve {R-2; 97} Liquid{R-98}; Neomycin 200{R-100}; Neosol-Oral; Neoved 200; Neovet days . 1 Neomycin Oral Solution; generic{R-99}]. Enteritis, E. coli—Cattle, goats , [horses], pigs, and sheep: Oral, 22 mg Canada— per kg of body weight a day for fourteen days, administered in the {R-97; 104} Veterinary-labeled product(s): only source of drinking water . 200 mg per mL (OTC) [Biosol Liquid{R-103}]. Note: For many of these products, individual animal treatment is also possible by dividing the daily dose and administering as a drench with Withdrawal times: milk or water or by mixing in an individual animal’s only water U.S.— supply{R-97}. Consult manufacturer’s product labeling for speciﬁc dosing directions. Withdrawal time Canadian product labeling lists the dose of neomycin in terms of mL Species Meat (days) per liter of drinking water and an incrementally increasing dose from 2

Cattle 1 weeks to adult, or 2 weeks to 26 weeks of age, for chickens and turkeys, {R-104} Goats, pigs 3 respectively . Consult manufacturer’s product labeling for spe- Sheep 2 ciﬁc dosing directions.

Note: Products are not labeled for use in preruminating calves to be {R-231} processed for veal or for lactating dairy cattle or goats producing milk Strength(s) usually available : for human consumption. U.S.— Veterinary-labeled product(s): Withdrawal time 715 mg per gram of powder (OTC) [Neo-325; Neomix 325{R-97}; Neomix AG 325; Neomycin 325{R-101}; Neo-Sol 50; Neosol Soluble Species Meat (days) Powder; Neovet 325/100]. Cattle, goats 30 Canada— Pigs, sheep 20 Veterinary-labeled product(s): 715 mg per gram of powder (OTC) [Neomix Soluble Powder{R-104}]. Note: Products are not labeled for use in preruminating calves to be 813 mg per gram of powder (OTC) [Neomed 325; Neomycin 325]. processed for veal or for lactating dairy cattle or goats producing milk for human consumption. Withdrawal times: U.S.— Canada— Withdrawal time Withdrawal time Species Meat (days) Species Meat (days) Cattle 1 Cattle 30 Goats, pigs 3 Chickens, broiler 7 Sheep 2 Chickens, laying, pigs, sheep, turkeys 14 Turkeys, growing 0 Note: This product is not labeled for use in lactating dairy cattle or horses to be slaughtered for human consumption. Note: Products are not labeled for use in preruminating calves to be processed for veal or for lactating dairy cattle or goats producing milk for human consumption.{R-97; 101} Packaging and storage: Store below 40 C (104 F), preferably

between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by Withdrawal time manufacturer. Species Meat (days)

Cattle, goats 30 Preparation of dosage form: Prepare solutions daily according to Pigs, sheep 20 manufacturer’s instructions. When administered in the drinking water, adjustments must be made in concentration, based on factors Note: Products are not labeled for use in preruminating calves to be altering water consumption, such as age, disease signs, and environ- processed for veal or for lactating dairy cattle or goats producing milk mental factors{R-98}. for human consumption{R-97}.

Canada— Note: Strength of administered solution may be adjusted to compensate for variations in age or weight, the severity of disease Withdrawal time signs, and environmental factors that may affect water consump- {R-182} Species Meat (days) tion .

Cattle 30 Chickens, broiler 7 Chickens, laying, pigs, sheep, turkeys 14 Strength(s) usually available{R-231}: U.S.— Veterinary-labeled product(s): Packaging and storage: Store below 40 C (104 F), preferably 250 mg per mL (OTC) [GENERIC]. between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by Canada— manufacturer. Veterinary-labeled product(s): Not commercially available. Preparation of dosage form: Prepare solutions daily according to manufacturer’s instructions. When administered in the drinking wa- Withdrawal times: ter, adjustments must be made in concentration, based on factors U.S.— altering water consumption, such as age, disease signs, and environmental factors{R-98}. Withdrawal time

Species Meat (days) USP requirements: Not in USP{R-19}. Calves 2 Chickens 4 1 Not included in Canadian product labeling or product not commercially Pigs 0 available in Canada. Note: Product labeling listing the above withdrawal times states that they STREPTOMYCIN are not labeled for use in chickens producing eggs for human consumption. SUMMARY OF DIFFERENCES Category: Aminoglycoside. Packaging and storage: Store below 40 C (104 F), preferably be- Indications: General considerations—First aminoglycoside introduced. tween 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by {R-243; 244} Active against mycobacteria, Leptospira , Francisella tularen- manufacturer. sis, and Yersinia pestis, but only some mycoplasma, gram-negative organisms, and Staphylococcus species{R-116}. The introduction of Preparation of dosage form: Prepare according to manufacturer’s newer aminoglycosides has eclipsed the signiﬁcance of streptomycin instruction. in the face of increasing bacterial resistance. Side/adverse effects: Less nephrotoxic than other aminoglycosides. Vestibular toxicity is more often seen than auditory toxicity. USP requirements: Not in USP{R-19}.

ORAL DOSAGE FORMS 1Not included in Canadian product labeling or product not commercially available in Canada. STREPTOMYCIN SULFATE ORAL SOLUTION Usual dose: Enteritis, bacterial1—Calves, chickens, and pigs: Oral, 22 to Developed: 05/1/00 33 mg per kg of body weight, administered in the only source of Revised: 09/30/02 drinking water{R-181; 182}. Interim revision: 04/04/03

Table 1. Pharmacology/pharmacokinetics—intravenous administration.

VolD VolD Elimination Elimination Dose Number area steady state Clearance half-life, initial half-life, gamma Species (mg/kg) of doses (L/kg) (L/kg) (mL/min/kg) phase (hour) phase* (hour)

AMIKACIN Birds Chickens{R-146} 10 Single 0.229 ± 0.08 0.193 ± 0.06 1.82 ± 0.28 Emus{R-149} 7.2 Single 0.18 ± 0.03 0.17 ± 0.07 0.5 ± 0.16 0.87 6.06 Parrots, African grey{R-150} 5 Single 0.289 0.233 3.1 1.06 10 Single 0.184 0.122 2.4 0.9 20 Single 0.444 0.308 3.8 1.34 Calves{R-142} 7.5 Single 0.35 ± 0.01 1.5 ± 0.2 2.51 ± 0.58 {R-141} 10 Single 0.4 ± 0.03 0.27 ± 0.02 1.5 ± 0.03 3.09 ± 0.27

Cats{R-139} 5 Single 0.17 ± 0.02 1.46 ±0.26 1.31 ± 0.32 {R-140} 5 Single 0.134 ± 0.008 1.83 ± 0.26 0.8 to 1.3 10 Single 0.141 ± 0.08 2.02 ± 0.38 0.8 to 1.3 20 Single 0.184 ± 0.22 2.3 ± 0.04 0.8 to 1.3 Dogs{R-143} 5 Single 0.258 2.82 1.07 10 Single 0.227 2.66 0.98 20 Single 0.361 3.57 1.03 Donkeys{R-136} 6 Single 0.157 0.15 0.97 1.9 Foals, 3 days of age{R-130} 7 Single 0.473 ± 0.067 0.422 ± 0.051 1.92 ± 0.37 2.69 5 days of age{R-130} 7 Single 2.22 ± 0.35 Premature, hypoxic{R-131} 7 Every 8 hours 0.60 ± 0.09 1.9 ± 1.13 5.39 ± 3.46 for 2 days Neonatal, critically ill{R-131; 132} 7 Every 8 hours 0.56 ± 0.11 2.44 ± 0.73 2.86 ± 0.89 for 2 d/6 days Neonatal, critically ill, azotemic, 7 Every 8 hours 0.43 ± 0.05 1.3 ± 0.3 4 ± 1.11 and hypoxemic{R-132} for 6 days Horses{R-137} 4.4 Single 0.198 ± 0.052 1.49 ± 0.39 1.44 {R-136} 6 Single 0.215 0.207 0.75 2.8 {R-137} 6.6 Single 0.174 ± 0.028 1.28 ± 0.19 1.57 {R-137} 11 Single 0.138 ± 0.018 1.41 ± 0.22 1.14 Ponies{R-136} 6 Single 0.173 0.15 1.5 1.3 Pythons, ball{R-155} 25 C 3.48; IC Single 0.46 ± 0.17 0.04 ± 0.01 126 37 C 3.48; IC Single 0.41 ± 0.11 0.04 ± 0.01 110 Sheep{R-142} 7.5 Single 0.2 ± 0.03 0.7 ± 0.06 1.93 ± 0.27 APRAMYCIN Birds Chicks, 18-day-old{R-62} 10 Single 0.245 ± 0.01 3.63 ± 0.23 0.8 ± 0.01 Chickens{R-162} 10 Single 0.182 ± 0.021 1.3 ± 0.17 1.68 ± 0.07 Chickens{R-165} 75 Single 5.62 ± 0.14 4.82 ± 0.08 31.3 ± 0.83 2.1 ± 0.01 Pigeons{R-162} 10 Single 0.077 ± 0.001 3.5 ± 0.03 0.25 ± 0 Quail, Japanese{R-167} 10 Single 0.133 ± 0.007 3.1 ± 0.01 0.5 ± 0.02

Calves, 3- to 5-week old{R-164} 20 Single 0.708 ± 0.012 3.22 ± 0.44 4.4 ± 1.21 Cows, lactating{R-163} 20 Single 1.26 ± 0.18 12.16 ± 1.69 2.10 ± 0.24 Goats, lactating{R-163} 20 Single 1.36 ± 0.11 11.69 ± 2.31 0.47 ± 0.16 Rabbits{R-162} 10 Single 0.284 ± 0.035 4.3 ± 0.68 0.80 ± 0.14 Sheep{R-162} 10 Single 0.167 ± 0.08 1.3 ± 0.07 1.51 ± 0.14 Ewes, lactating{R-163} 20 Single 1.45 ± 0.10 14.14 ± 1.75 1.84 ± 0.19 GENTAMICIN Birds Eagles{R-88} 10 Single 0.21 ± 0.01 1.01 ± 0.09 2.46 ± 0.32 Hawks, red-tailed{R-88} 10 Single 0.24 ± 0.03 2.09 ± 0.16 1.35 ± 0.18 Owls{R-88} 10 Single 0.23 ± 0.02 1.41 ± 0.1 1.93 ± 0.24 Roosters{R-84} 5 Single 0.23 ± 0.02 0.21 ± 0.01 0.78 ± 0.13 3.38 ± 0.62 Buffalo calves, 3 to 4 months 5 Single 0.43 ± 0.03 0.91 ± 0.12 5.69 ± 0.54 of age (Murrah){R-77} Camels{R-79} 2 Single 0.32 ± 0.02 1.35 ± 0.11 2.93 ± 0.24 Cats,{R-65} with induced endotoxemia 3 Single 0.19 ± 0.02 2.6 ± 0.7 1.1 ± 0.2 without endotoxemia 3 Single 0.2 ± 0.03 2 ± 0. 2 1.28 ± 0.21

Table 1. (Contd.)

VolD VolD Elimination Elimination Dose Number area steady state Clearance half-life, initial half-life, gamma Species (mg/kg) of doses (L/kg) (L/kg) (mL/min/kg) phase (hour) phase* (hour)

Cats, obese{R-68} 3 Single 0.12 ± 0.02 1.07 ± 0.25 1.37 ± 0.24 Cats{R-64} 3 Every 8 hours 1.79 ± 0.21 for 5 days {R-63} 5 Single 0.14 ± 0.02 1.38 ± 0.35 1.25 ± 0.3 Calves,{R-21} 1 day of age 4 Single 0.4 ± 0.04 0.37 ± 0.04 1.92 ± 0.43 2.5 ± 0.6 5 days of age 4 Single 0.4 ± 0.05 0.38 ± 0.04 2.44 ± 0.34 2 ± 0.3 10 days of age 4 Single 0.34 ± 0.02 0.32 ± 0.02 2.02 ± 0.27 2 ± 0.2 15 days of age 4 Single 0.33 ± 0.04 0.31 ± 0.03 2.10 ± 0.32 1.9 ± 0.1 Calves,{R-20} 4 to 5 weeks of age 3 Single 1.95 ± 1.24 0.75 ± 0.2 4.9 ± 1.9 3.9 ± 1.7 Calves,{R-180} 6 weeks of age 5 Single 0.3 ± 0.08 1.68 ± 0.4 2.16 ± 0.25 Cows, adult{R-21} 4 Single 0.14 ± 0.02 0.13 ± 0.02 1.29 ± 0.26 1.3 ± 0.2 {R-26} 4.4 Single 0.25 1.12 1.9 Cows, lactating{R-22} 5 Single 0.19 ± 0.04 0.16 ± 0.03 1.32 ± 0.17 1.83 ± 0.18 Puppies, 5 months of age 10 Single 0.35 ± 0.04 4.08 ± 0.62 (beagles){R-70} Dogs (mixed breed){R-69} 3 Single 0.17 ± 0.03 2.29 ± 0.48 0.91 ± 0.26 Dogs,{R-71} with diabetes mellitus 4.4 Single 0.32 ± 0.13 0.2 ± 0.05 2.84 ± 0.95 1.1 without diabetes 4.4 Single 0.23 ± 0.08 0.18 ± 0.03 2.27 ± 0.41 1.08 Donkeys{R-43} 2.2 Single 0.2 ± 0.06 1.67 ± 0.48 1.87 Goats{R-39} 5 Single 0.26 ± 0.04 3.10 ± 0.27 0.96 ± 0.09 {R-40} 5 Single 0.24 0.2 1.7 1.73 Horse foals,{R-47} 1 day of age 4 Single 0.32 ± 0.03 0.3 ± 0.03 1.75 ± 0.47 2.12 ± 0.39 5 days of age 4 Single 0.38 ± 0.08 0.35 ± 0.06 2.98 ± 1.48 1.51 ± 0.53 10 days of age 4 Single 0.4 ± 0.13 0.34 ± 0.1 2.60 ± 0.96 1.69 ± 0.55 15 days of age 4 Single 0.36 ± 0.05 0.33 ± 0.05 2.4 ± 0.87 1.77 ± 0.55 30 days of age 4 Single 0.32 ± 0.05 0.28 ± 0.03 3.66 ± 1.93 1.01 ± 0.52 Horses{R-47} 4 Single 0.17 ± 0.03 0.16 ± 0.22 1.69 ± 0.65 1.09 ± 0.92 {R-61} 2.2 Single 0.3 ± 0.05 2.18 ± 0.5 1.52 ± 0.32 {R-45} 2.2 Single 0.18 ± 0.02 0.15 ± 0.01 1.04 ± 0.13 1.96 {R-50} 2.2 Every 8 hours 0.46 ± 0.05 0.83 for 24 hours 2.2 Every 8 hours 0.18 ± 0.02 1.06 for 10 days Horses,{R-54} with induced endotoxemia 3 Single 0.15 ± 0.04 0.14 ± 0.04 1.17 ± 0.35 1.54 ± 0.15 without endotoxemia 3 Single 0.2 ± 0.03 0.17 ± 0.01 1.41 ± 0.19 1.66 ± 0.06 Horses{R-46} 3.3 Single 0.12 ± 0.02 1.4 ± 0.2 1.2 ± 0.3 3.3 Every 12 hours 0.18 ± 0.01 1.4 ± 0.2 1.2 ± 0.2 for 2.5 days Horses,{R-204} without halothane 4 Single 0.26 ± 0.02 1.54 ± 0.27 2.01 ± 0.35 with halothane anesthesia 4 Single 0.26 ± 0.03 0.81 ± 0.32 4.03 ± 1.69 Horses{R-44} 5 Single 0.25 ± 0.03 0.24 ± 0.03 1.15 ± 0.12 2.54 ± 0.33 {R-252} 6.6 Single 0.14 ± 0.06 3.44 ± 0.44 3 ± 2.8 {R-50} 6.6 Every 8 hours for 0.12 ± 0.04 0.78 24 hours 6.6 Every 8 hours for 0.21 ± 0.01 1.08 10 days Llamas{R-82} 2.5 Single 0.22 ± 0.06 0.97 ± 0.13 2.75 ± 0.67 5 Single 0.25 ± 0.03 1.1 ± 0.14 2.77 ± 0.34 {R-81} 4 Single 0.12 0.51 3.03 Piglets,{R-41} newborn 5 Single 0.59 ± 0.11 0.79 ± 0.04 2 ± 0.17 5.19 ± 0.3 42 days of age 5 Single 0.43 ± 0.06 0.47 ± 0.03 2.8 ± 0.17 3.5 ± 0.23 Pigs{R-42} 2 Every 8 hours 0.32 ± 0.32 0.24 ± 0.03 1.66 ± 0.12 1. 9 20.2 for 7 days Rabbits{R-75} 3 Single 0.14 ± 0.01 1.69 ± 0.07 0.94 ± 0.04 Rabbits,{R-76} with induced endotoxemia 3 Single 0.77 ± 0.08 without endotoxemia 3 Single 1.5 ± 0.029 Rabbits{R-74} 3.5 Single 0.11 ± 0.02 2.82 ± 0.97 0.74 ± 0.25

Table 1. (Contd.)

VolD VolD Elimination Elimination Dose Number area steady state Clearance half-life, initial half-life, gamma Species (mg/kg) of doses (L/kg) (L/kg) (mL/min/kg) phase (hour) phase* (hour)

Sheep{R-31} 2.2 Single 0.19 ± 0.06 1.56 ± 0.40 1.4 ± 0.08 {R-35} 3 Single 0.16 ± 0.01 0.15 ± 0.01 1.15 ± 0.08 1.68 ± 0.28 {R-36; 37} 3 Single 0.41 ± 0.2 0.66 ±0.26 41.9 ± 18.5 {R-36} 3 Every 8 hours 57.5 ± 26.2 for 7 days {R-33} 4 Single 0.16 1.03 1.75 {R-32} 10 Single 0.24 ± 0.03 1.03 ± 0.15 2.4 ± 0.5 30.4 ± 18.9 {R-36; 37} 10 Single 0.38 ± 0.2 0.81 ± 0.32 88.9 ± 19.8 {R-36; 37} 20 Single 0.71 ± 0.75 0.88 ± 0.34 167.2 ± 42.7 KANAMYCIN Birds Chicks, 18-day-old{R-162} 10 Single 0.671 ± 0.045 4.78 ± 0.26 1.6 Chickens{R-162} 10 Single 0.294 ± 0.004 1.4 ± 0.1 2.4 Pigeons{R-162} 10 Single 0.292 ± 0.034 3.55 ± 0.08 0.9 Dogs{R-177} 10 Single 0.255 ± 0.030 3.21 ± .72 0.97 ± 0.31 10 Every 8 hours 0.252 ± 0.018 3.04 ± 0.55 0.98 ± 0.18 for 7 doses Goats{R-162} 10 Single 0.263 ± 0.022 1.5 ± 0.18 1.9 Horses{R-176} 10 Single 0.228 ± 0.025 1.48 ± 0.19 1.8 ± 0.17 Rabbits{R-162} 10 Single 0.254 ± 0.017 2.95 ± 0.20 1 Sheep{R-162} 10 Single 0.262 ± 0.027 1.67 ± 0.15 1.8

NEOMYCIN Calves,{R-180} 2 days of age 10 Single 0.356 ± 0.042 2.26 ± 0.61 2.12 ± 0.39 1 week of age 10 Single 0.472 ± 0.085 3.62 ± 0.58 1.5 ± 0.03 2 weeks of age 10 Single 0.322 ± 0.056 2.31 ± 0.31 1.59 ± 0.08 4 weeks of age 10 Single 0.462 ± 0.065 2.63 ± 0.24 1.9 ± 0.01 >8 months of age 10 Single 0.355 ± 0.075 2.03 ± 0.54 2.04 ± 0.19 Calves, 3 months of age{R-237} 12 Single 1.17 ± 0.23 4.16 ± 0.67 1.4 ± 0.47 7.48 ± 2.02 Horses{R-176} 10 Single 0.232 ± 0.06 1.38 ± 0.39 2.1 ± 0.97 Sheep{R-248} 10 Single 0.304 ± 0.08 1.52 ± 0.33 1.98 ± 0.5

STREPTOMYCIN Horses{R-176} 10 Single 0.231 ± 0.04 0.79 ± 0.13 3.40 ± 0.42

*Researchers have described a dose-dependent slow elimination phase (gamma) many times longer than the initial elimination phase{R-32}. It is postulated that gentamicin is bound to tissues by one of at least two different processes so that some gentamicin is released quickly and gentamicin bound to tissue by another process is more gradually eliminated{R-25; 32; 34; 36}. Clearance was the only pharmacokinetic value that differed with statistical signiﬁcance for amikacin between 3 and 5 days of age{R-130}. Another study showed no pharmacokinetic differences for amikacin between foals of 1 and 7 days of age{R-133}. IC = Intracardiac

Table 2. Pharmacology/pharmacokinetics—other systemic data.

Terminal Dose Absorption Peak serum Time to peak half-life, Terminal half-life, (mg/kg); Number of half-life concentration concentration Bioavailability initial phase gamma phase* Species Route doses (hour) (mcg/mL) (hour) (%) (hours) (hours)

AMIKACIN Birds Chickens{R-157} 10; IM Single 19.9 0.25 2.3 20; IM Single 30.8 0.25 2.9 {R-146} 20; IM Single 0.48 ± 0.158 50.79 ± 4.05 0.5 ± 0.258 91 1.43 ± 0.34 20; IM Every 8 hours 38.58 ± 6.96 0.79 ± 0.37 1.86 ± 0.42 for 10 doses Cockatiels {R-148} 15; IM Every 12 hours 27.3 ± 6.89 1 1.29 for 3 days Hawks, red tailed{R-147} 20; IM Single 0.16 ± 0.05 56 ± 8.8 0.64 ± 0.16 2.02 ± 0.63 Parrots, African gray{R-150} 5; IM Single 10.8 ± 0.63 1 98 1.08 10; IM Single 21.1 ± 1.77 0.75 61 1.04 20; IM Single 32.7 ± 1.23 0.75 106 0.97

Table 2. (Contd.)

Calves{R-142} 7.5; IM Single 23.5 ± 2.4 0.83 ± 0.14 99 1.94 ± 0.34 {R-144} 10; IM Single 30 ± 3.7 0.05 2.2 25; IM Single 57.7 ± 3.6 0.05 Cats{R-139} 5; IM Single 16.41 ± 1.98 0.75 ± 0.2 95 5; SC Single 22.61 ± 4.29 0.67 ± 0.12 123 {R-140} 5; IM Single 18.45 0.5 94 5; SC Single 23.17 0.75 100 10; IM Single 38.51 0.5 94 10; SC Single 39.55 0.75 100 20; IM Single 65.57 0.5 94 20; SC Single 67.88 0.75 100 Dogs{R-143} 10; IM Single 1 1 10; SC Single 14 (from graph) 1 1.5 Goats{R-151} 10; IM Single 0.24 27.63 ± 1.61 0.75 102 10; SC Single 0.21 38.93 ± 3.06 0.5 107 Guinea pigs{R-152} 3.75; IM Single 0.03 ± 0 12.2 ± 0.4 0.14 ±0.03 0.98 ± 0.07 7.5; IM Single 0.11 ± 0.06 20.5 ± 1.1 0.3 ± 0.09 1.25 ± 0.07 15; IM Single 0.14 ± 0.05 41.6 ± 1.5 0.4 ± 0.07 1.17 ± 0.75 Horse foals, 3- to 5-day 7; IO Single 34.17 ± 3.54 0.05 98 old{R-130} Horses{R-137} 4.4; IM Single 13.3 ± 1.6 1 6.6; IM Single 23 ± 0.6 1 11; IM Single 29.8 ± 3.2 1 Pony foals, 2- to 11-day 7; IM Single 14.7 ± 1.14 0.5 3 ± 0.29 old{R-135} Pythons, ball{R-155} 25 C 3.48; IM Single 1.31 11.94 ± 1.67 1.47 ± 0.72 109 37 C 3.48; IM Single 2.27 13.87 ± 2.61 1.27 ± 0.6 109 Sheep{R-139} 7.5; IM Single 34.4 ± 6.5 1.26 ± 0.34 87 1.96 ± 0.38 Snakes, gopher{R-154} 25 C 5; IM Single 5.58 ± 2.77 71.9 ± 10 37 C 5; IM Single 5.69 ± 1.11 75.4 ± 30.1 Tortoises, gopher{R-156} 5; IM Single 25 (from graph) 0.5

APRAMYCIN Calves, 3- to 5-week 10; IM Single 18.6 0.5 old{R-164} 20; IM Single 40.8 1 30; IM Single 1.49 1 40; IM Single 1.84 1 Cows, lactating{R-163} 20; IM Single 42.52 ± 4.79 0.5 ± 0 60 4.42 ± 0.63 Birds Chickens{R-165} 75; IM Single 0.19 ± 0 11.06 ± 0.31 0.76 ± 0.03 58 2.31 ± 0.02 75; PO Single 0.1 ± 0 0.79 ± 0.02 0.2 ± 0.01 2 1.22 ± 0.01 Quail, Japanese{R-167} 50; PO Single 0.84 ± 0.24 0.53 ± 0.09 56 2.31 ± 0.38 Ewes, lactating{R-163} 10; IM Single 31.04 ± 3.67 0.5 ± 0 70 2.42 ± 0.29

DIHYDROSTREPTOMYCIN Cattle{R-247} 11; IM Single 44.7 ± 25.6 1 16.5; IM Single 65 {R-249} 25; IM Single 78 1.5 Pigs{R-249} 25; IM Single 87 2.5

GENTAMICIN Baboons{R-76} 3; IM Single 1.58 Birds Budgerigars{R-86} 5; IM Single 17.3 0.25 0.53 10; IM Single 37 0.25 0.53 Cockatiels{R-148} 5; IM Every 12 hours 4.66 ± 1.45 1 1.29 for 3 days Cranes{R-85} 5 to 20; Single 2.75 ± 0.62 IM Galahs{R-205} (cockatoos) 5; IM Single 20.55 ± 1.3 0.5 1.23

Table 2. (Contd.)

Eagles{R-88} 10; IM Single 70 Hawks{R-88} 10; IM Single 95 Macaws{R-205} 5; IM Single 20.62 ± 2.45 0.5 1.17 5; IM Every 12 hours 14.15 ± 1.75 0.5 for 7 days Owls{R-88} 10; IM Single 95 Quail{R-85} 5 to 20; Single 0.7 ± 0.2 IM Pheasants{R-85} 5 to 20; Single 1.25 ± 0.25 IM Buffalo calves, 3 to 4 months 10; IM Single 0.43 ± 0.08 39.4 ± 9.6 0.75 3.79 ± 0.23 of age{R-78} Camels,{R-79} normal hydration 2; IM Single 5.4 ± 0.4 1.09 ± 0.21 135 dehydrated 2; IM Single 3 ± 0.36 1.83 ± 0.48 54 Cats{R-62} 2.5; IM Single 9.1 ± 0.8 0.5 5; IM Single 23.1 ± 2.1 0.5 Cats,{R-65} with endotoxemia 3; IM Single 12.53 ± 3.57 0.54 ± 0.16 1.0 ± 0.23 3; SC Single 12.43 ± 2.05 0.42 ± 0.12 1.08 ± 0.23 without endotoxemia 3; IM Single 13.79 ± 3.15 0.43 ± 0.11 1.0 ± 0.17 3; SC Single 15.25 ± 1.49 0.54 ± 0.17 1.24 ± 0.1 Cats{R-68} 3; SC Single 0.11 ± 0.16 17 ± 2 0.58 ± 0.13 84 1.24 ± 0.22 {R-63} 5; IM Single 21.6 ± 1.96 0.67 ± 0.12 68 1.27 ± 0.27 5; SC Single 23.5 ± 3.57 0.25 76 1.14 ± 0.11 Cows{R-29} 5; IM Single 0.28 ± 0.02 40.46 ± 1.05 0.98 ± 0.05 2.52 ± 0.1 {R-29} 5; IM Every 8 hours 0.23 ± 0.01 32.56 ± 2.39 0.98 ± 0.09 70 2.65 ± 0.27 for 3 days Cows, lactating{R-22} 5; IM Single 0.63 ± 0.28 15.39 ± 6.19 0.75 92 Cows, lactating{R-22} 5; IM Every 8 hours 44.91 ± 9.38 For 10 days Cows, with endometritis{R-29} 5; IM Single 0.21 ± 0.02 19.36 ± 1.56 0.84 ± 0.06 2.71 ± 0.35 Dogs, (mixed-breed){R-69} 3; IM Single 0.16 10.7 0.52 96 3; SC Single 0.26 10.2 0.69 94 Goats{R-39} 5; IM Single 33.9 ± 4.37 0.67 ± 0 96 2.37 ± 0.47 {R-39} 5; SC Single 28 ± 3.84 0.66 ± 0 77 3.56 ± 0.39 Horse foals{R-48} 1 month of age 2; IM Single 0.19 ± 0.08 18.2 ± 5.3 0.5 4.28 ± 2.23 1 month of age 4; IM Single 0.22 ± 0.09 52 0.5 3.07 ± 0.68 3 months of age 2; IM Single 0.21 ± 0.11 18.2 ± 5.3 0.5 3.68 ± 0.71 3 months of age 4; IM Single 0.15 ± 0.03 66 0.5 2.87 ± 0.82 Horses{R-46} 3.3; IM Single 11.7 ± 1.7 0.8 ± 0.3 2.5 ± 0.9 3.3; IM Every 12 hours 12.2 ± 2.8 0.8 ± 0.1 3.5 ± 0.6 for 2.5 days {R-57} 4.4; IM Single 16.8 0.5 {R-252} 6.6; IM Single 22 ± 4.9 1.3 ± 0.5 100 Pony foals{R-49} 2; IM Single 6.85 0.25 2.81 ± 0.28 Ponies{R-53} 5; IM Every 8 hours 0.25 ± 0.06 12.74 ± 1.94 1 2.13 ± 0.48 for 7 days Pythons, blood{R-89} 2.5; IM Single 5.76 50.9 Rabbits{R-74} 3.5; IM Single 14.5 ± 1.7 0.48 ± 0.25 132 0.83 ± 0.14 3.5; SC Single 11.5 0.57 ± 0.16 113 0.78 ± 0.15 Sheep{R-32} 4; IM Single 99 1.82 {R-33} 3; IM Every 8 hours 13.7 82.1 ± 17.8 for 7 days KANAMYCIN Calves{R-144; 179} 10; IM Single 31 ± 3.1 0.5 2.2 25; IM Single 57.3 ± 4.9 0.5 2.2 Cattle{R-179} 10; IM Single 30.7 ± 6.54 1 Chickens{R-179} 10; IM Single 19.28 ± 3.7 0.5 25; IM Single 58.98 ± 4.58 0.5 Dogs{R-178} 7.5; IM Single 0.4 25.8 0.49 1.03 {R-177} 10; IM Single 0.15 ± 0.02 27.6 ± 7.5 0.53 ± 0.37 89 0.77 ± 0.094

Table 2. (Contd.)

Dogs{R-179} 15; IM Single 37.75 ± 1.32 0.5 {R-178} 25; IM Single 0.5 55.6 0.68 0.93 {R-179} 39; IM Single 84.56 ± 24.81 0.5 Horses{R-175} 5; IM Single 12.55 ± 1.89 1 {R-176} 10; IM Single 0.32 ± 0.04 35.8 ± 5.7 1 100 2.66 ± 0.51 10; IM Every 12 hours 0.38 ± 0.13 36.8 ± 12.5 1 96 2.34 ± 0.45 for 7 doses Pigs{R-179} 10; IM Single 32.2 ± 9.01 0.5 20; IM Single 55.62 ± 8.12 1 Sheep{R-179} 15; IM Single 36.9 ± 8.97 1 20; IM Single 54.74 ± 18.53 0.5 30; IM Single 58.5 ± 27.11 0.5

NEOMYCIN Calves, 3 months of age{R-237} 24; IM Single 31.7 ± 11.8 1.38 ± 0.95 127 11.5 ± 3.8 96; PO Every 12 hours 0.26 ± 0.37 2.6 ± 2.9 0.45 for 15.5 days Horses{R-176} 10; IM Single 0.16 ± 0.05 2.43 ± 9.9 74 2.58 ± 0.69 10; IM Every 12 hours 0.21 ± 0.08 25.6 ± 8.8 66 2.67 ± 0.69 for 7 doses Sheep{R-248} 10; IM Single 0.31 ± 0.13 17.63 ± 2.27 1.33 ± 0.41 75 2.68 ± 0.29 10; SC Single 0.35 ± 0.14 18.66 ± 3.05 1 ± 0.32 85 2.82 ± 0.51

STREPTOMYCIN Horses{R-176} 10; IM Single 0.34 ± 0.15 43.4 ± 21.4 1 83 3.83 ± 0.3 10; IM Every 12 hours 0.32 ± 0.14 44.5 ± 2.7 1 98 3.84 ± 1.18 for 7 doses

*Researchers have described a slow elimination phase (gamma) many times longer than the initial elimination phase{R-32}. It is postulated that gentamicin is bound to tissues by one of at least two different processes so that some gentamicin is released quickly and gentamicin bound to tissue by another process is more gradually eliminated{R-25; 32; 34; 36}. The major pharmacokinetic values for intraosseus administration of amikacin did not signiﬁcantly differ from those measured for intravenous administration{R-130}. Although the half-lives of absorption and elimination were similar at different temperatures, the estimated volume of distribution and clearance were signiﬁcantly higher at the warmer temperature{R-154}. IM = intramuscular, IO = intraosseous, SC = subcutaneous

REFERENCES 15. Gentamicin product information (Garacin Soluble Powder, Schering- 1. Gentamicin package insert (Gentocin, Schering-Plough—US), Rev 3/90, Rec Plough—US). Downloaded 3/3/03 from www.spah.com. 11/12/97. 16. Neomix AG 325 Medicated Premix Freedom of Information Summary. 2. Neomix 325 Soluble Powder/Neomix AG 325 Soluble Powder Supplemental NADA 140–976. Sponsor: Pharmacia & Upjohn Company. Approval Date: New Animal Drug Application Freedom of Information Summary. NADA November 3, 1999. 011–315. Sponsor: Pharmacia & Upjohn Company. Approval date: July 9, 17. Gentamicin package insert (Gentocin, Schering-Plough—US), Rec 12/10/97. 1999. Downloaded from www.fda.gov/cvm on 1/30/03. 18. USP dictionary of USAN and international drug names, 2002 ed. Rockville, 3. Gentamicin package insert (Generic, Aspen/Sanoﬁ—US), Rev 6/94, Rec 11/ MD: The United States Pharmacopeial Convention Inc. 2002. 12/97. 19. The United States Pharmacopeia. The national formulary. USP 26th revision 4. Gentamicin package insert (Gentocin, Schering-Plough—US), Rev 3/93, Rec (January 1, 2003). NF 21st ed. (January 1, 2003). Rockville, MD: The United 11/12/97. States Pharmacopeial Convention Inc; 2002. p. 113, 619, 620, 852, 1044, 5. Gentamicin package insert (Generic, Boehringer Ingelheim—US), Rec 11/97. 1045, 1280, 2547, 2558, 2562, 2566, 2571. 6. Committee comment, Rec 7/29/02. 20. Ziv G, Nouws JFM, Van Ginneken CA. The pharmacokinetics and tissue levels 7. Gentamicin package insert (Gentocin, Schering-Plough—Canada), Rec 12/ of polymyxin B, colistin and gentamicin in calves. J Vet Pharmacol Ther 10/97. 1982; 5: 45–58. 8. Gentamicin product information (Garasol Injection, Schering-Plough—US). 21. Clarke CR, Short CR, Ruei-Ching H, et al. Pharmacokinetics of gentamicin in Downloaded 3/3/03 from www.spah.com. the calf: developmental changes. Am J Vet Res 1985 Dec; 46: 12. 9. Gentamicin product information (Garacin Piglet Injection, Schering- 22. Haddad NS, Ravis WR, Pedersoli WM, et al. Pharmacokinetics of single doses Plough—US). Downloaded 3/3/03 from www.spah.com. of gentamicin given by intravenous and intramuscular routes to lactating 10. Gentamicin package insert (Garasol, Schering-Plough—Canada), Rec 12/10/ cows. Am J Vet Res 1986 Apr; 47(4): 808–13. 97. 23. Pedersoli WM, Jackson J, Frobish RA. Depletion of gentamicin in the milk of 11. Gentamicin package insert (Garacin Oral Solution, Schering-Plough—US), Holstein cows after single and repeated intramammary and parenteral Rev 9/92, Rec 3/1/96. treatments. J Vet Pharmacol Ther 1995; 18: 457–63. 12. Gentamicin package insert (Generic, Phoenix—US), Rev 4/97, Rec 10/30/97. 24. Evaluation of certain veterinary drug residues in food. Forty-third report of 13. Gentamicin product information (Garacin Pig Pump, Schering-Plough—US). the Joint FAO/WHO Expert Committee on Food Additives. World Health Downloaded 3/3/03 from www.spah.com. Organ Tech Rep Ser 1995; 855: 1–59. 14. Gentamicin product information (Garasol Pig Pump, Schering-Plough—Can- 25. Haddad NS, Ravis WR, Pedersoli WM, et al. Pharmacokinetics and tissue ada). Downloaded from Schering-Plough Animal Health Product Label residues of gentamicin in lactating cows after multiple intramuscular doses Retrieval Service on 2/21/03. are administered. Am J Vet Res 1987 Jan; 48(1): 21–7.

26. Sweeney RW, Fennell MA, Smith CM, et al. Systemic absorption of 52. Gilman JM, Davis LE, Neff-Davis CA, et al. Plasma concentration of gentamicin following intramammary administration to cows with mastitis. gentamicin after intramuscular or subcutaneous administration to horses. J Vet Pharmacol Ther 1996; 19: 155–7. J Vet Pharmacol Ther 1987; 10: 101–3. 27. Moretain JP, Boisseau J. Elimination of aminoglycoside antibiotics in milk 53. Haddad NS, Pedersoli WM, Ravis WR, et al. Pharmacokinetics of gentamicin following intramammary administration. Vet Q 1993 Sep; 15(3): 112–7. at steady-state in ponies: serum, urine, and endometrial concentrations. Am 28. Haddad NS, Pedersoli WM, Carson RL, et al. Concentrations of gentamicin J Vet Res 1985 Jun; 46(6): 1268–71. in serum, milk, urine, endometrium, and skeletal muscle of cows after 54. Wilson RC, Moore JN, Eakle N. Gentamicin pharmacokinetics in horses given repeated intrauterine injections. Am J Vet Res 1986 Jul; 47(7): 1597– small doses of Escherichia coli endotoxin. Am J Vet Res 1983; 44(9): 1748–9. 601. 55. Sweeney RW, Divers TJ, Rossier Y. Disposition of gentamicin administered 29. El-Sayed MGA, Hatem ME, El-Komy AAA. Disposition kinetics of gentamicin intravenously to horses with sepsis. J Am Vet Med Assoc 1992 Feb 15; in normal and endometritic cows using a microbiological assay. DTW Dtsch 200(4): 503–6. Tierarztl Wochenschr 1989 Sep; 96(8): 412–5. 56. Sojka JE, Brown SA. Pharmacokinetic adjustment of gentamicin dosing in 30. Al-Guedawy SA, Neff-Davis CA, Davis LE, et al. Disposition of gentamicin in horses with sepsis. J Am Vet Med Assoc 1986 Oct 1; 189(7): 784–9. the genital tract of cows. J Vet Pharmacol Ther 1983; 6: 85–92. 57. Sweeney RW, MacDonald M, Hall J, et al. Kinetics of gentamicin elimination 31. Wilson RC, Whelan SC, Coulter DB, et al. Kinetics of gentamicin after in two horses with acute renal failure. Equine Vet J 1988; 20(3): 182–4. intravenous, intramuscular, and intratracheal administration in sheep. Am J 58. Beech J, Kohn C, Leitch M, et al. Therapeutic use of gentamicin in horses: Vet Res 1981; 42: 1901–32. concentrations in serum, urine, and synovial fluid and evaluation of renal 32. Brown SA, Riviere JE, Coppoc GL, et al. Single intravenous and multiple function. Am J Vet Res 1977 Jul; 38(7): 1085–7. intramuscular dose pharmacokinetics and tissue residue profile of gentamicin 59. Snyder JR, Pascoe JR, Hietala SK, et al. Gentamicin tissue concentrations in in sheep. Am J Vet Res 1985 Jan; 46(1): 69–74. equine small intestine and large colon. Am J Vet Res 1986 May; 47(5): 33. Toke SK, Gatne MM, Nemade PK, et al. Studies of serum gentamicin 1092–5. disposition after parenteral administration in ewes. Hindustan Antibiot Bull 60. Pedersoli WM, Fazeli MH, Haddad NS, et al. Endometrial and serum 1993 Aug-Nov; 35(3–4): 212–5. gentamicin concentrations in pony mares given repeated intrauterine 34. Brown SA, Coppoc GL, Riviere JE. Effects of dose and duration of therapy on infusions. Am J Vet Res 1985 May; 46(5): 1025–8. gentamicin tissue residues in sheep. Am J Vet Res 1986 Nov; 47(11): 2373– 61. Lloyd KC, Stover SM, Pascoe JR, et al. Plasma and synovial fluid 9. concentrations of gentamicin in horses after intra-articular administration 35. Wilson RC, Goetsch DD, Huber TL. Influence of endotoxin-induced fever on of buffered and unbuffered gentamicin. Am J Vet Res 1988 May; 49(5): the pharmacokinetics of gentamicin in ewes. Am J Vet Res 1984 Dec; 644–9. 45(12): 2495–7. 62. Jacobson ER, Groff JM, Gronwall RR, et al. Serum concentrations of 36. Brown SA, Coppoc GL, Riviere JE, et al. Dose-independent pharmacokinetics gentamicin in cats. Am J Vet Res 1985 Jun; 46(6): 1356–8. of gentamicin in sheep. Am J Vet Res 1986 Apr; 47(4): 789–94. 63. Jernigan AD, Wilson RC, Hatch RC, et al. Pharmacokinetics of gentamicin 37. Riviere JE, Spoo JW. Aminoglycoside antibiotics. In: Adams HR, editor. after intravenous, intramuscular, and subcutaneous administration in cats. Veterinary pharmacology and therapeutics. 7th ed. Ames, IA: Iowa State Am J Vet Res 1988 Jan; 49(1): 32–5. University Press; 1995. p. 797–819. 64. Jernigan AD, Hatch RC, Brown J, et al. Pharmacokinetic and pathological 38. Oukessou M, Toutain PL. Effect of dietary nitrogen intake on gentamicin evaluation of gentamicin in cats given a small intravenous dose repeatedly disposition in sheep. J Vet Pharmacol Ther 1992; 15(4): 416–20. for five days. Can J Vet Res 1988; 52(2): 177–80. 39. Garg SK, Verma SP, Uppal RP. Pharmacokinetics of gentamicin following 65. Jernigan AD, Hatch RC, Wilson RC, et al. Pharmacokinetics of gentamicin in single-dose parenteral administration to goats. Br Vet J 1995 Jul-Aug; cats given Escherichia coli endotoxin. Am J Vet Res 1988 May; 49(5): 151(4): 453–8. 603–7. 40. Ahmad AH, Gahga HS, Sharma LD. Pharmacokinetics of gentamicin 66. Anderson BH, Firth EC, Whittem T. The disposition of gentamicin in equine following single dose intravenous administration in normal and febrile plasma, synovial fluid and lymph. J Vet Pharmacol Ther 1995; 18: 124–31. goats. J Vet Pharmacol Ther 1994; 17: 369–73. 67. Jernigan AD, Hatch RC, Wilson RC, et al. Pathologic changes and tissue 41. Giroux D, Sirois G, Martineau GP. Gentamicin pharmacokinetics in newborn gentamicin concentrations after intravenous gentamicin administration in and 42-day-old male piglets. J Vet Pharmacol Ther 1995; 18: 407–12. clinically normal and endotoxemic cats. Am J Vet Res 1988 May; 49(5): 42. Riond JL, Riviere JE. Multiple intravenous dose pharmacokinetics and residue 613–7. depletion profile of gentamicin in pigs. J Vet Pharmacol Ther 1988; 11: 68. Wright LC, Horton CR, Jernigan AD, et al. Pharmacokinetics of gentamicin 210–4. after intravenous and subcutaneous injection in obese cats. J Vet Pharmacol 43. Welfare RE, Mealey KL, Matthews NS, et al. Pharmacokinetics of gentamicin Ther 1991; 14: 96–100. in donkeys. J Vet Pharmacol Ther 1996; 19: 167–9. 69. Wilson RE, Duran SH, Horton CR, et al. Bioavailability of gentamicin in dogs 44. Pedersoli WM, Belmonte AA, Purohit RC, et al. Pharmacokinetics of after intramuscular or subcutaneous injections. Am J Vet Res 1989 Oct; gentamicin in the horse. Am J Vet Res 1980; 41: 351–4. 50(10): 1748–50. 45. Jones SL, Wilson WD, Milhalyi JE. Pharmacokinetics of gentamicin in 70. Riviere JE, Coppoc GL. Pharmacokinetics of gentamicin in the juvenile dog. healthy horses during intravenous fluid administration. J Vet Pharmacol Am J Vet Res 1981 Sep; 42(9): 1621–3. Ther 1998; 21: 247–9. 71. Brown SA, Nelson RW, Scott-Moncreiff C. Gentamicin pharmacokinetics in 46. Swan GE, Guthrie AJ, Mulders MSG, et al. Single and multiple dose diabetic dogs. J Vet Pharmacol Ther 1991; 14: 90–5. pharmacokinetics of gentamicin administered intravenously and intramus- 72. Frazier DL, Riviere JE. Gentamicin dosing strategies for dogs with subclinical cularly in adult conditioned thoroughbred mares. J S Afr Vet Assoc 1995 renal dysfunction. Antimicrob Agents Chemother 1987; 31(12): 1929–34. Sep; 66(3): 151–6. 73. Behrend EN, Grauer GF, Greco DS, et al. Effects of dietary protein 47. Cummings LE, Guthrie AJ, Harkins JD, et al. Pharmacokinetics of gentamicin conditioning on gentamicin pharmacokinetics in dogs. J Vet Pharmacol in newborn to 30-day-old foals. Am J Vet Res 1990 Dec; 51(12): 1988–92. Ther 1994; 17: 259–64. 48. Baggot JD. Gentamicin dosage in foals aged one month and three months. 74. Ogden L, Wilson RC, Clark CH, et al. Pharmacokinetics of gentamicin in Equine Vet J 1986; 18(2): 113–6. rabbits. J Vet Pharmacol Ther 1995; 18: 156–9. 49. Gronwall R, Brown MP, Hobbs S. Serum gentamicin concentrations and 75. Curl JL, Curl JS. Pharmacokinetics of gentamicin in laboratory rabbits. Am J pharmacokinetics in 2-week-old pony foals after intramuscular administra- Vet Res 1988 Dec; 49(12): 2065–7. tion. J Equine Vet Sci 1988 May/Jun; 8(3): 205–7. 76. Watson JR, Stoskopf MK, Rozmiarek H, et al. Kinetic study of serum 50. Godber LM, Walker RD, Stein GE, et al. Pharmacokinetics, nephrotoxicosis, gentamicin concentrations in baboons after single-dose administration. Am J and in vitro antibacterial activity associated with single versus multiple Vet Res 1991 Aug; 52(8): 1285–7. (three times) daily gentamicin treatments in horses. Am J Vet Res 1995 May; 77. Garg SK, Verma SP, Garg BD. Disposition kinetics of gentamicin in buffalo 56(5): 613–8. calves (Bubalus bubalis) following single intravenous administration. J Vet 51. Geor RJ, Brashier MK. Rational approach to gentamicin dosage in neonatal Pharmacol Ther 1991; 14: 335–40. foals. Proceedings of the Annual Convention of the American Association of 78. Garg SK, Verma SP, Garg BD. Pharmacokinetics and urinary excretion of Equine Practitioners. Lexington, Kentucky: The Association; 1992. (37) p. gentamicin in Bubalus bubalis calves following intramuscular administra- 603–9. tion. Res Vet Sci 1991; 50(1): 102–5.

79. Ziv G, Ben-Zvi Z, Yagil R, et al. Disposition kinetics of gentamicin in the 111. Medleau L, Long RE, Brown J, et al. Frequency and antimicrobial suscep- normal and dehydrated camel. Acta Vet Scand Suppl 1991; 87: tibility of Staphylococcus species isolated from canine pyodermas. Am J Vet 110–3. Res 1986 Feb; 47(2): 229–31. 80. Campbell BG, Bartholow S, Rosin E. Bacterial killing by use of once daily 112. Rohrich PJ, Ling GV, Ruby AL, et al. In vitro susceptibilities of canine urinary gentamicin dosage in guinea pigs with Escherichia coli infection. Am J Vet bacteria to selected antimicrobial agents. J Am Vet Med Assoc 1983 Oct 15; Res 1996 Nov; 57(11): 1627–30. 183(8): 863–7. 81. Dowling PM, Ferguson JG, Gibney RF. Pharmacokinetics of gentamicin in 113. Bottner A, Schmid P, Humke R. In vitro efficacy of cefquinome (INN) and llamas. J Vet Pharmacol Ther 1996; 19: 161–3. other anti-infective drugs against bovine bacterial isolates from Belgium, 82. Lackey MN, Belknap EB, Greco DS, et al. Single intravenous and multiple France, Germany, The Netherlands, and the United Kingdom. Zentralbl dose pharmacokinetics of gentamicin in healthy llamas. Am J Vet Res 1996 Veterinarmed [B] 1995; 42: 377–83. Aug; 57(8): 1193–9. 114. Johnson AP, Burns L, Woodford N, et al. Gentamicin resistance in clinical 83. Zaske DE, Cipolle RJ, Rotschafer JC, et al. Gentamicin pharmacokinetics in isolates of Escherichia coli encoded by genes of veterinary origin. J Med 1,620 patients: method for control of serum concentrations. Antimicrob Microbiol 1994 Mar; 40(3): 221–6. Agents Chemother 1982 Mar; 21(3): 407–11. 115. Thal LA, Chow JW, Mahayni R, et al. Characterization of antimicrobial 84. Pedersoli WM, Ravis WR, Askins DR, et al. Pharmacokinetics of single-dose resistance in enterococci of animal origen. Antimicrob Agents Chemother intravenous or intramuscular administration of gentamicin in roosters. Am J 1995 Sep; 39(9): 2112–5. Vet Res 1990 Feb; 51(2): 286–9. 116. Aminoglycosides and aminocyclitols. In: Prescott JF, Baggot JD, editors. 85. Custer RS, Bush M, Carpenter JW. Pharmacokinetics of gentamicin in Antimicrobial therapy in veterinary medicine. 2nd ed. Ames, Iowa: Iowa blood plasma of quail, pheasants, and cranes. Am J Vet Res 1979; 40(6): State University Press; 1993. p. 144–78. 892–5. 117. Blackburn BO, Swanson MR, Schlater LK. Antibiotic resistance of members of 86. Itoh N, Okada H. Pharmacokinetics and potential use of gentamicin in the genus Salmonella isolated from chickens, turkeys, cattle, and swine in budgerigars (Melopsittacus undulatus). Zentralbl Veterinarmed [A] 1993 the United States during October 1981 through September 1982. Am J Vet Apr; 40(3): 194–9. Res 1984 Jun; 45(6): 1245–9. 87. Bird JE, Walser MM, Duke GE. Toxicity of gentamicin in red-tailed hawks. 118. Benson CE, Palmer JE, Bannister MF. Antibiotic susceptibilities of Salmonella 1983 Jul; 44(7): 1289–93. species isolated at a large animal veterinary medical center: a three year 88. Bird JE, Miller KW, Larson AA, et al. Pharmacokinetics of gentamicin in birds study. Can J Comp Med 1985; 49: 125–8. of prey. Am J Vet Res 1983 Jul; 44(7): 1245–7. 119. Poppe C, Kolar JJ, Demczuk WHB, et al. Drug resistance and biochemical 89. Hilf M, Swanson D, Wagner R. A new dosing schedule for gentamicin in characteristics of salmonella from turkeys. Can J Vet Res 1995; 59: 241–8. blood pythons (Python curtus): a pharmacokinetic study. Res Vet Sci 1991; 120. Chaslus-Dancla E, Martel J, Carlier C, et al. Emergence of aminoglycoside 50: 127–30. 3-N-acetyltransferase IV in Escherichia coli and Salmonella typhimurium 90. Angus JC, Jang SS, Hirsh DC. Microbiological study of transtracheal aspirates isolated from animals in France. Antimicrob Agents Chemother 1986 Feb; from dogs with suspected lower respiratory tract disease: 264 cases (1989– 29(2): 239–43. 1995). J Am Vet Med Assoc 1997 Jan 1; 210(1): 55–8. 121. Kelley TR, Pancorbo OC, Merka WC, et al. Antibiotic resistance of bacterial 91. Amikacin package insert (Amiglyde-V [50mg/mL], Fort Dodge—US), Rev 5/ litter isolates. Poult Sci 1998 Feb; 77(2): 243–7. 90, Rec 2/15/96. 122. Morishita TY, Brooks DL, Lowenstine LJ. Pasteurella multocida in psittacines: 92. Amikacin package insert (Amiglyde-V [250 mg/mL], Fort Dodge—US), Rev prevalence, pathology, and characterization of isolates. Avian Dis 1996 Oct- 3/93, Rec 2/15/96. Dec; 40(4): 900–7. 93. Kanamycin package insert (Kantrim, Fort Dodge—US), Rev 9/96, Rec 10/ 123. Medleau L, Blue JL. Frequency and antimicrobial susceptibility of Staphylo- 24/97. coccus species isolated from feline skin lesions. J Am Vet Med Assoc 1988 94. Neomycin package insert (Neomix AG 325 Medicated Premix, Pharmacia Nov 1; 193(9): 1080–1. Animal Health—US). Downloaded 6/4/02 from www.pharmaciaah.com. 124. Malik R, Hunt GB, Goldsmid SE, et al. Diagnosis and treatment of 95. Apramycin sulfate product labeling (Apralan Soluble Powder, Elanco—US), pyogranulomatous panniculitis due to Mycobacterium smegmatis in cats. Rev 9/92. Downloaded 3/3/03 from www.elanco.com. J Small Anim Pract 1994; 35(10): 524–30. 96. Apramycin sulfate product insert (Apralan, Provel—Canada), Rec 2/13/96. 125. Ensley LE, Hennessey PW, Houdeshell JW. Gentamicin for the treatment of 97. Neomycin product labeling (Neomix 325, Pharmacia—US). Downloaded colibacillosis in piglets. Vet Med Small Anim Clin 1979 Jan; 73(1): 89–92. 3/3/03 from www.pharmaciaah.com. 126. Raemdonck DL, Tanner AC, Tolling ST, et al. Antimicrobial susceptibility of 98. Neomycin product labeling (Biosol Liquid, Pharmacia—US). Downloaded Actinobacillus pleuropneumoniae, Pasteurella multocida and Salmonella 3/3/03 from www.pharmaciaah.com. choleraesuis isolates from pigs. Vet Rec 1994 Jan 1; 134(1): 5–7. 99. Neomycin product labeling (Generic, Phoenix—US), Rec 11/3/97. 127. Diker KS, Akan M, Haziroglu R. Antimicrobial susceptibility of Pasteurella 100. Neomycin product labeling (Neomycin 200, Aspen—US), Rev 11/95, Rec haemolytica and Pasteurella multocida isolated from pneumonic ovine 11/12/97. lungs. Vet Rec 1994 Jun 4; 134(23): 597–8. 101. Neomycin product labeling (Neomycin 325, Durvet—US), Rec 10/24/97. 128. Turgeon PL, Higgins R, Gottschalk M, et al. Antimicrobial susceptibility of 102. Neomycin product labeling (Neomycin 325, Rhone Merieux—US), Rec 12/ Streptococcus suis isolates. Br Vet J 1994; 150: 263. 4/97. 129. Ziv G, Sulman FG. Binding of antibiotics to bovine and ovine serum. 103. Neomycin package insert (Biosol, Upjohn—Canada), Rev 7/92, Rec 10/23/97. Antimicrob Agents Chemother 1972 Sep; 2(3): 206–13. 104. Neomycin package insert (Neomix, Upjohn—Canada), Rev 7/95, Rec 10/23/ 130. Golenz MR, Wilson WD, Carlson GP, et al. Effect of route of administration 97. and age on the pharmacokinetics of amikacin administered by the 105. Amiglyde-V. In: Arrioja-Dechert A, editor. Compendium of veterinary intravenous and intraosseous routes to 3- and 5-day-old foals. Equine Vet products. 5th edition. Hensall, Ontario: North American Compendiums J 1994; 26(5): 367–73. Ltd; 1997. p. 115–6. 131. Green SL, Conlon PD. Clinical pharmacokinetics of amikacin in hypoxic 106. Dihydrostreptomycin package insert (Ethamycin, rogar/STB—Canada), Rec premature foals. Equine Vet J 1993; 25(4): 276–80. 10/30/97. 132. Green SL, Conlon PD, Mama K, et al. Effects of hypoxia and azotaemia on the 107. Brown SA. Treatment of gram-negative infections. Vet Clin North Am Small pharmacokinetics of amikacin in neonatal foals. Equine Vet J 1992; 24(6): Anim Pract 1988 Nov; 18(6): 1141–65. 475–9. 108. Calvert CA, Greene CE, Hardie EM. Cardiovascular infections in dogs: 133. Wichtel MG, Breuhaus BA, Aucoin D. Relation between pharmacokinetics of epizootiology, clinical manifestations, and prognosis. J Am Vet Med Assoc amikacin sulfate and sepsis score in clinically normal and hospitalized 1985 Sep 15; 187(6): 612–6. neonatal foals. J Am Vet Med Assoc 1992 May 1; 200(9): 1339–43. 109. Piriz S, Valle J, Mateos EM, et al. In vitro activity of fifteen antimicrobial 134. Adland-Davenport P, Brown MP, Robinson JD, et al. Pharmacokinetics of agents against methicillin-resistant and methicillin-susceptible Staphylococ- amikacin in critically ill neonatal foals treated for presumed or confirmed cus intermedius. J Vet Pharmacol Ther 1996; 19: 118–23. sepsis. Equine Vet J 1990; 22(1): 18–22. 110. Phillips WE, Williams BJ. Antimicrobial susceptibility patterns of canine 135. Brown MP, Gronwall RR, Martinez DS, et al. Pharmacokinetics of amikacin Staphylococcus intermedius isolates from veterinary clinical specimens. Am J in pony foals after a single intramuscular injection. Am J Vet Res 1986 Feb; Vet Res 1984 Nov; 45(11): 2376–9. 47(2): 453–4.

136. Horspool LJI, Taylor DJ, McKellar QA. Plasma disposition of amikacin 162. Lashev LD, Pashov DA, Marinkov TN. Interspecies differences in the and interactions with gastrointestinal microflora in Equidae following pharmacokinetics of kanamycin and apramycin. Vet Res Commun 1992; intravenous and oral administration. J Vet Pharmacol Ther 1994; 17: 16(4): 293–300. 291–8. 163. Ziv G, Kurtz B, Risenberg R, et al. Serum and milk concentrations of 137. Orsini JA, Park M, Rourke JE, et al. Pharmacokinetics of amikacin in the apramycin in lactating cows, ewes, and goats. J Vet Pharmacol Ther 1995; horse following intravenous and intramuscular administration. J Vet 18: 346–51. Pharmacol Ther 1985 Jun; 8(2): 194–201. 164. Ziv G, Bor A, Soback S, et al. Clinical pharmacology of apramycin in calves. 138. Orsini JA, Spencer PA, Park MI. Tissue and serum concentrations of J Vet Pharmacol Ther 1985; 8: 95–104. amikacin after intramuscular and intrauterine administration to mares in 165. Afifi NA, Ramadan A. Kinetic disposition, systemic bioavailability and tissue estrus. Can Vet J 1996 Mar; 37(3): 157–60. distribution of apramycin in broiler chickens. Res Vet Sci 1997 May-Jun; 139. Jernigan AD, Wilson RC, Hatch RC. Pharmacokinetics of amikacin in cats. 62(3): 249–52. Am J Vet Res 1988 Mar; 49(3): 355–8. 166. Thomson TD, Watkins KL, Novilla MN, et al. Effects of intestinal pathology 140. Shille VM, Brown MP, Gronwall R, et al. Amikacin sulfate in the cat: serum, due to coccidial infection on the oral absorption of apramycin in 4-week-old urine and uterine tissue concentrations. Theriogenology 1985 May; 23(5): broiler chickens. Acta Vet Scand Suppl 1991; 87: 275–7. 829–37. 167. Lashev LD, Mihailov R. Pharmacokinetics of apramycin in Japanese quail. 141. Saini SPS, Srivastava AK. The disposition kinetics, urinary excretion and J Vet Pharmacol Ther 1994 Oct; 17(5): 394–5. dosage regimen of amikacin in cross-bred bovine calves. Vet Res Commun 168. Pohl P, Glupczynski Y, Marin M, et al. Replicon typing characterization of 1998 Jan; 22(1): 59–65. plasmids encoding resistance to gentamicin and apramycin in Escherichia 142. Carli S, Montesissa C, Sonzogni O, et al. Comparative pharmacokinetics of coli and Salmonella typhimurium isolated from human and animal sources amikacin sulphate in calves and sheep. Res Vet Sci 1990; 48: 231–4. in Belgium. Epidemiol Infect 1993 Oct; 111(2): 229–38. 143. Baggot JD, Ling GV, Chatfield RC. Clinical pharmacokinetics of amikacin in 169. Low JC, Angus M, Hopkins G, et al. Antimicrobial resistance of Salmonella dogs. Am J Vet Res 1985 Aug; 46(8): 1793–6. enterica Typhimurium DT104 isolates and investigation of strains with 144. Ziv G. Comparative clinical pharmacology of amikacin and kanamycin in transferable apramycin resistance. Epidemiol Infect 1997; 118(2): 97–103. dairy calves. Am J Vet Res 1977; 38: 337–40. 170. Hunter JEB, Bennett M, Hart CA, et al. Apramycin resistant Escherichia coli 145. Platt DJ, Smith I. Gentamicin-resistant Salmonella typhimurium phage type isolated from pigs and a stockman. Epidemiol Infect 1994 Jun; 112(3): 473– 204c: molecular studies and strain diversity in a putative bovine outbreak. 80. Epidemiol Infect 1991; 107: 213–23. 171. Hunter JEB, Shelley JC, Walton JR, et al. Apramycin resistant plasmids in 146. El-Gammal AA, Ravis WR, Krista LM, et al. Pharmacokinetics and Escherichia coli: possible transfer to Salmonella typhimurium in calves. intramuscular bioavailability of amikacin in chickens following single and Epidemiol Infect 1992 Apr; 108(2): 271–8. multiple dosing. J Vet Pharmacol Ther 1992; 15: 133–42. 172. Chaslus-Dancla E, Pohl P, Meurisse M, et al. High genetic homology between 147. Bloomfield RB, Brooks D, Vulliet R. The pharmacokinetics of a single plasmids of human and animal origins conferring resistance to the intramuscular dose of amikacin in red-tailed hawks (Buteo Jamaicensis). J aminoglycosides gentamicin and apramycin. Antimicrob Agents Chemother Zoo Wildl Med 1997 Mar; 28(1): 55–61. 1991 Mar; 35(3): 590–3. 148. Ramsay EC, Vulliet R. Pharmacokinetic properties of gentamicin and 173. Ryden R, Moore BJ. The in vitro activity of apramycin, a new aminocyclitol amikacin in the cockatiel. Avian Dis 1993 Apr-Jun; 37(2): 628–34. antibiotic. J Antimicrob Chemother 1977; 3: 609–13. 149. Helmick KE, Boothe DM, Jensen JM. Disposition of single-dose intravenously 174. Fantin B, Ebert S, Leggett J, et al. Factors affecting duration of in vivo administered amikacin in emus (Dromaius novaehollandiae). J Zoo Wildl postantibiotic effect for aminoglycosides against gram-negative bacilli. Med 1997 Mar; 28(1): 49–54. J Antimicrob Chemother 1991 Jun; 27(6): 829–36. 150. Gronwall R, Brown MP, Clubb S. Pharmacokinetics of amikacin in African 175. Brown MP, Stover SM, Kelly RH, et al. Kanamycin sulfate in the horse: gray parrots. Am J Vet Res 1989 Feb; 50(2): 250–2. serum, synovial fluid, peritoneal fluid, and urine concentrations after 151. Uppal RP, Verma SP, Verma V, et al. Comparative pharmacokinetics of single-dose intramuscular administration. Am J Vet Res 1981 Oct; 42(10): amikacin following a single intramuscular or subcutaneous administration 1823–5. in goats (Capra hircus). Vet Res 1997 Nov-Dec; 28(6): 565–70. 176. Baggot JD, Love DN, Rose RJ, et al. The pharmacokinetics of some 152. McClure JT, Rosin E. Comparison of amikacin dosing regimens in neutrope- aminoglycoside antibiotics in the horse. J Vet Pharmacol Ther 1981 Dec; nic guinea pigs with Escherichia coli infection. Am J Vet Res 1998 Jun; 4(4): 277–84. 59(6): 750–5. 177. Baggot JD. Pharmacokinetics of kanamycin in dogs. J Vet Pharmacol Ther 153. El-Massry A, Meredith TA, Aguilar HE, et al. Aminoglycoside levels in the 1978; 1: 163–70. rabbit vitreous cavity after intravenous administration. Am J Ophthalmol 178. Cabana BE, Taggart JG. Comparative pharmacokinetics of BB-K8 and 1996 Nov; 122(5): 684–9. kanamycin in dogs and humans. Antimicrob Agents Chemother 1973 154. Mader DR, Conzelman GM, Baggot JD. Effects of ambient temperature on the Apr; 3(4): 478–83. half-life and dosage regimen of amikacin in the gopher snake. J Am Vet Med 179. Andreini G, Pignattelli P. Kanamycin blood levels and residues in domestic Assoc 1985 Dec 1; 187(11): 1134–6. animals. Veterinaria 1972; 21: 51–72. 155. Johnson JH, Jensen JM, Brumbaugh GW, et al. Amikacin pharmacokinetics 180. Burrows GE, Barto PB, Martin B. Comparative pharmacokinetics of genta- and the effects of ambient temperature on the dosage regimen in ball pythons micin, neomycin, and oxytetracycline in newborn calves. J Vet Pharmacol (Python regius). J Zoo Wildl Med 1997 Mar; 28(1): 80–8. Ther 1987; 10: 54–63. 156. Caligiuri R, Kollias GV, Jacobson E, et al. The effects of ambient temperature 181. Strep-Sol Freedom of Information Summary, NADA 065–252. Sponsor: on amikacin pharmacokinetics in gopher tortoises. J Vet Pharmacol Ther Veterinary Services, Inc. Supplemental September 5, 1993. 1990; 13: 287–91. 182. Streptomycin Oral Solution Freedom of Information Summary, ANADA: 157. Itoh N, Kikuchi N, Hiramune T. Antimicrobial effects of amikacin therapy on 200–197. Sponsor: Contemporary Products, Inc. experimentally induced Salmonella typhimurium infection in fowls. J Vet 183. Kitasato I, Yokota M, Inouye S, et al. Comparative ototoxicity of ribostamy- Med Sci 1996 May; 58(5): 425–9. cin, dactimicin, dibekacin, kanamycin, amikacin, tobramycin, gentamicin, 158. Staneva M, Markova B, Atanasova I, et al. Pharmacokinetic and pharma- sisomicin and netilmicin in the inner ear of guinea pigs. Chemotherapy codynamic approach for comparing two therapeutic regimens using amika- 1990; 36(2): 155–68. cin. Antimicrob Agents Chemother 1994 May; 38(5): 981–5. 184. Bergeron MG, Bergeron Y. Influence of endotoxin on the intrarenal 159. Moore RM, Schneider RK, Kowalski J, et al. Antimicrobial susceptibility of distribution of gentamicin, netilmicin, tobramycin, amikacin, and cephalo- bacterial isolates from 233 horses with musculoskeletal infection during thin. Antimicrob Agents Chemother 1986 Jan; 29(1): 7–12. 1979–1989. Equine Vet J 1992; 24(6): 450–6. 185. Grauer GF. Prevention of acute renal failure. Vet Clin North Am Small Anim 160. Xiong Y, Caillon J, Kergueris MF, et al. Adaptive resistance of Pseudo- Pract 1996 Nov; 26(6): 1447–59. monas aeruginosa induced by aminoglycosides and killing kinetics in a 186. Adams HR. Neuromuscular blocking effect of aminoglycoside antibiotics in rabbit endocarditis model. Antimicrob Agents Chemother 1997 Apr; nonhuman primates. J Am Vet Med Assoc 1973 Sep 15; 163(6): 613–6. 41(4): 823–6. 187. Crawford LM, Harvey T, Campbell DL. Hypocalcemic effect of aminoglycoside 161. Orsini JA, Benson CE, Spencer PA, et al. Resistance to gentamicin and antibiotics in the dairy cow. Can J Comp Med 1977 Jul; 41(3): 251–6. amikacin of gram-negative organisms isolated from horses. Am J Vet Res 188. O’Leary SJ, Moore DR. Development of cochlear sensitivity to aminoglycoside 1989 Jun; 50(6): 923–5. antibiotics. Ann Otol Rhinol Laryngol 1998 Mar; 107(3): 220–6.

189. Beaubien AR, Desjardins S, Ormsby E, et al. Delay in hearing loss following 215. Brown SA, Barsanti JA, Crowell WA. Gentamicin-associated acute renal drug administration. Acta Otolaryngol (Stockh) 1990; 109: 345–52. failure in the dog. J Am Vet Med Assoc 1985 Apr 1; 186(7): 686–90. 190. Bamonte F, Dionsotti S, Gamba M, et al. Relation of dosing regimen to 216. Greco DS, Turnwald GH, Adams R, et al. Urinary gamma-glutamyl aminoglycoside ototoxicity: evaluation of auditory damage in the guinea pig. transpeptidase activity in dogs with gentamicin-induced nephrotoxicity. Chemotherapy 1990; 36(1): 41–50. Am J Vet Res 1985 Nov; 46(11): 2332–5. 191. Pettorossi VE, Ferraresi A, Errico P, et al. The impact of different dosing 217. Riviere JE, Carver MP, Coppoc GL. Pharmacokinetics and comparative regimens of the aminoglycosides netilmicin and amikacin on vestibulo- nephrotoxicity of fixed-dose versus fixed-interval reduction of gentamicin toxicity in the guinea pig. Eur Arch Otorhinolaryngol 1990; 247: 277– dosage in subtotal nephrectomized dogs. Toxicol Appl Pharmacol 1984; 75: 82. 496–509. 192. Melendez E, Lopez M, Lopez C, et al. Age-related differences in the glomerular 218. Riviere JE, Hinsman EJ, Coppoc GL, et al. Morphological and functional and renal tubular effects of amikacin in the rat. Biol Neonate 1996; 70: aspects of experimental gentamicin nephrotoxicity in young beagles and 229–34. foals. Vet Res Commun 1983 Dec; 7(1/4): 211–3. 193. Scherberich JE, Mondorf WA. Nephrotoxic potential of antiinfective drugs as 219. Riviere JE, Coppoc GL, Hinsman EJ, et al. Species dependent gentamicin assessed by tissue-specific proteinuria of renal antigens. Int J Clin Pharmacol pharmacokinetics and nephrotoxicity in the young horse. Fundam Appl Ther 1998 Mar; 36(3): 152–8. Toxicol 1983; 3: 448–57. 194. Pashov D, Diakov L, Lashev L. Subchronic toxicity of apramycin in pigs. Vet 220. Garry F, Chew DJ, Hoffsis GF. Enzymuria as an index of renal damage in Med Nauki 1987; 24(7): 37–42. sheep with induced aminoglycoside nephrotoxicosis. Am J Vet Res 1990 195. Pashov D, Diakov L, Vangelov S. Chronic 90-day toxicity of apramycin in Mar; 51(3): 428–32. chickens. Vet Med Nauki 1987; 24(9): 41–6. 221. Rossier Y, Divers TJ, Sweeney RW. Variations in urinary gamma glutamyl 196. Uzuka Y, Furuta T, Yamaoka M, et al. Threshold changes in auditory transferase/urinary creatinine ratio in horses with or without pleuropneu- brainstem response (ABR) due to the administration of kanamycin in dogs. monia treated with gentamicin. Equine Vet J 1995; 27(3): 217–20. Exp Anim 1996 Oct; 45(4): 325–31. 222. Schumacher J, Wilson RC, Spano JS, et al. Effect of diet on gentamicin- 197. Xu S, Shepherd RK, Chen Y, et al. Profound hearing loss in the cat following induced nephrotoxicosis in horses. Am J Vet Res 1991 Aug; 52(8): the single co-administration of kanamycin and ethacrynic acid. Hear Res 1274–8. 1993 Nov; 70(2): 205–15. 223. Brasheir MK, Geor RJ, Ames TR, et al. Effect of intravenous administration on 198. Conlon BJ, Smith DW. Supplemental iron exacerbates aminoglycoside gentamicin-induced nephrotoxicosis in ponies. Am J Vet Res 1998 Aug; ototoxicity in vivo. Hear Res 1998 Jan; 115(1–2): 1–5. 59(8): 1055–62. 199. Hildebrand SV, Hill T. Interaction of gentamycin and atracurium in 224. Jaquenod M, Ronnhedth C, Cousins MJ, et al. Factors influencing ketorolac- anaesthetised horses. Equine Vet J 1994; 26(3): 209–11. associated perioperative renal dysfunction. Anesth Analg 1998 May; 86(5): 200. Forsyth SF, Ilkiw JE, Hildebrand SV. Effect of gentamicin administration on 1090–7. the neuromuscular blockade induced by atracurium in cats. Am J Vet Res 225. Brown SA, Rakich PM, Barsanti JA, et al. Fanconi syndrome and acute renal 1990 Oct; 51(10): 1675–8. failure associated with gentamicin therapy in a dog. J Am Anim Hosp Assoc 201. Martinez EA, Mealey KL, Wooldridge AA, et al. Pharmacokinetics, effects on 1986 Sep/Oct; 22(5): 635–40. renal function, and potentiation of atracurium-induced neuromuscular 226. Beauchamp K, Poirier A, Bergeron MG. Increased nephrotoxicity of blockade after administration of a high dose of gentamicin in isoflurane- gentamicin in pyelonephritic rats. Kidney Int 1985; 28: 106–13. anesthetized dogs. Am J Vet Res 1996 Nov; 57(11): 1623–6. 227. Waitz JA, Moss EL, Weinstein MJ. Aspects of the chronic toxicity of 202. Kays SE, Crowell WA, Johnson MA. Iron supplementation increases gentamicin sulfate in cats. J Infect Dis 1971 Dec; 124 (Suppl): S125-S129. gentamicin nephrotoxicity in rats. J Nutr 1991 Nov; 121(11): 1869–75. 228. Short CR, Hardy ML, Clarke CR, et al. The nephrotoxic potential of 203. Whittem T, Firth EC, Hodge H, et al. Pharmacokinetic interactions between gentamicin in the cat: a pharmacokinetic and histopathologic investigation. repeated dose phenylbutazone and gentamicin in the horse. J Vet Pharmacol J Vet Pharmacol Ther 1986; 9(3): 325–9. Ther 1996; 19: 454–9. 229. Conlon BJ, McSwain SD, Smith DW. Topical gentamicin and ethacrynic acid: 204. Smith CM, Steffey EP, Baggot JD, et al. Effects of halothane anesthesia on the effects on cochlear function. Laryngoscope 1998 Jul; 108(7): 1087–9. clearance of gentamicin sulfate in horses. Am J Vet Res 1988 Jan; 49(1): 19–22. 230. Brown SA, Riviere JE. Comparative pharmacokinetics of aminoglycoside 205. Flammer K, Fiorello-Barrett J, Wilson RC, et al. Adverse effects of gentamicin antibiotics. J Vet Pharmacol Ther 1991; 14: 1–35. in scarlet macaws and galahs. Am J Vet Res 1990 Mar; 51(3): 404–7. 231. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port 206. Fadel AA, Larkin HA. Gentamicin-induced nephrotoxicosis in lambs. Res Vet Huron, MI: North American Compendiums, Inc. 2002. Sci 1996; 61: 187–92. 232. Gilbert DN. Once-daily aminoglycoside therapy. Antimicrob Agents Chemo- 207. Raisbeck MF, McIntyre WB. Fatal nephrotoxicosis associated with furosemide ther 1991 Mar; 35(3): 399–405. and gentamicin therapy in a dog. J Am Vet Med Assoc 1983 Oct 15; 183(8): 233. Wersall J. Ototoxic antibiotics: a review. Acta Otolaryngol Suppl (Stockh) 892–3. 1995; 519: 26–9. 208. Riviere JE, Traver DS, Coppoc GL. Gentamicin toxic nephropathy in horses 234. Mathew AG, Upchurch WG, Chattin SE. Incidence of antibiotic resistance in with disseminated bacterial infection. J Am Vet Med Assoc 1982 Mar 15; fecal Escherichia coli isolated from commercial swine farms. J Anim Sci 1998 180(6): 648–51. Feb; 76(2): 429–34. 209. Brown SA, Garry FB. Comparison of serum and renal gentamicin concen- 235. Cote S, Harel J, Higgins, et al. Resistance to antimicrobial agents and trations with fractional urinary excretion tests as indicators of nephrotox- prevalence of R plasmids in Pasteurella multocida from swine. Am J Vet Res icity. J Vet Pharmacol Ther 1988 Dec; 11(4): 330–7. 1991 Oct; 52(10): 1653–7. 210. Rivers BJ, Walter PA, O’Brien TD, et al. Evaluation of urine gamma-glutamyl 236. Gauchia R, Rodriguez-Serna M, Silvestre JF, et al. Allergic contact dermatitis transpeptidase-to-creatinine ratio as a diagnostic tool in an experimental from streptomycin in a cattle breed. Contact Dermatitis 1996 Dec; 35(6): model of aminoglycoside-induced acute renal failure in the dog. J Am Anim 374–5. Hosp Assoc 1996 Jul-Aug; 32(4): 323–36. 237. Pedersoli WM, Ravis WR, Jackson J. Disposition and bioavailability 211. Grauer GF, Creco DS, Behrend EN, et al. Estimation of quantitative of neomycin in Holstein calves. J Vet Pharmacol Ther 1994; 17: enzymuria in dogs with gentamicin-induced nephrotoxicosis using urine 5–11. enzyme/creatinine rations from spot urine samples. J Vet Intern Med 1995 238. Aschbacher PW, Feil VJ. Neomycin metabolism in calves. J Anim Sci 1994 Sep/Oct; 9(5): 324–7. Mar; 22(3): 683–9. 212. Riviere JE, Hinsman EJ, Coppoc GL, et al. Single dose gentamicin nephro- 239. Cid D, Piriz S, Ruiz-Santa-Quiteria JA, et al. In vitro susceptibility of toxicity in the dog: early functional and ultrastructural changes. Res Escherichia coli strains isolated from diarrhoeic lambs and goat kids to 14 Commun Chem Pathol Pharmacol 1981 Sep; 33(3): 403–18. antimicrobial agents. J Vet Pharmacol Ther 1996; 19: 397–401. 213. Frazier DL, Aucoin DP, Riviere JE. Gentamicin pharmacokinetics and 240. Shaikh B, Jackson J, Thaker NH. Neomycin residues in kidneys of orally nephrotoxicity in naturally acquired and experimentally induced disease in dosed non-ruminating calves determined by high-performance liquid chro- dogs. J Am Vet Med Assoc 1988 Jan 1; 192(1): 57–63. matographic and microbiological assay methods. J Vet Pharmacol Ther 214. Frazier DL, Dix LP, Bowman KF, et al. Increased gentamicin nephrotoxicity in 1995; 18: 150–2. normal and diseased dogs administered identical serum drug concentration 241. Rollin RE, Mero KN, Kozisek PB, et al. Diarrhea and malabsorption in calves profiles: increased sensitivity in subclinical renal dysfunction. J Pharmacol associated with therapeutic doses of antibiotics: absorptive and clinical Exp Ther 1986; 239(3): 946–51. changes. Am J Vet Res 1986 May; 47(5): 987–91.

242. Abbitt B, Berndtson WE, Seidel GE. Effect of dihydrostreptomycin or 255. Klasco RK, editor. USP DI Drug information for the healthcare professional. oxytetracycline on reproductive capacity of bulls. Am J Vet Res 1984 Nov; Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 45(11): 2243–6. 256. Gennaro AR, editor. Remington: the science and practice of pharmacy. 19th 243. Gerritsen MJ, Koopmans MJ, Dekker TCEM, et al. Effective treatment with ed. Easton, PA: Mack Publishing Company; 1995. p. 1299–303. dihydrostreptomycin of naturally infected cows shedding Leptospira interr- 257. Resolutions submitted for HOD actions. J Am Vet Med Assoc 1998 Jun 15; igans serovar hardjo subtype hardjobovis. Am J Vet Res 1994 Mar; 55(3): 212(12): 1852–3. 339–43. 258. Panel comment, Rec 6/99. 244. Ellis WE, Montgomery J, Cassells JA. Dihydrostreptomycin treatment of 259. Erskine RJ, Davis BS, Spears HJ. Intramammary administration of gentamicin bovine carriers of Leptospira interrogans serovar hardjo. Res Vet Sci 1985; as treatment for experimentally induced Escherichia coli mastitis in cows. 39: 292–5. Am J Vet Res 1992 Mar; 53(3): 375–81. 245. Barragry TB. Veterinary Drug Therapy. Philadelphia: Lea & Febiger; 1994. p. 260. Jones GF, Ward GE. Evaluation of systemic administration of gentamicin for 248–9. treatment of coliform mastitis in cows. J Am Vet Med Assoc 1990 Sep 15; 246. Christiansen G. The toxicity of selected therapeutic agents used in cats. Vet 197(6): 731–5. Med Small Anim Clin 1980 Jul; 75(7): 1133–7. 261. Panel comment, Rec 6/1/99. 247. Hammond PB. Dihydrostreptomycin dose-serum level relationships in cattle. 262. Panel comment, Rec 6/1/99. J Am Vet Med Assoc 1953; 122: 203–6. 263. Panel comment, Rec 6/1/99. 248. Errecalde JO, Lanusse CE, Landoni MF. Pharmacokinetics of neomycin in 264. Panel consensus, 9/10/99. sheep after intravenous, intramuscular, subcutaneous, and intratracheal 265. Tudor RA, Papich MG, Redding WR. Drug disposition and dosage determi- administration. Zentralbl Veterinarmed [A] 1990 Apr; 37(3): 163–9. nation of once daily administration of gentamicin sulfate in horses after 249. Stalheim OHV. Absorption and excretion of tritiated dihydrostreptomycin in abdominal surgery. J Am Vet Med Assoc 1999 Aug 15; 215(4): 503–6. cattle and swine. Am J Vet Res 1970 Mar; 31(3): 497–500. 266. Panel comment, Rec 8/7/99. 250. National Antimicrobial susceptibility Monitoring Program-Veterinary 267. Murphey ED, Santschi EM, Papich MG. Regional intravenous perfusion of the Isolates. FDA/USDA/CDC. Center for Veterinary Medicine. April 1998. distal limb of horses with amikacin sulfate. J Vet Pharmacol Ther 1999; 22: p. 1–27. 68–71. 251. Dorland’s illustrated medical dictionary. 28th ed. Philadelphia: W.B. 268. Cowan RH, Jukkola AF, Avant BS. Pathophysiologic evidence of gentamicin Saunders Company; 1994. p. 58. nephrotoxicity in neonatal puppies. Pediatr Res 1980; 14: 1204–11. 252. Magdesian KG, Hogan PM, Cohen ND, et al. Pharmacokinetics of a high dose 269. Cronin RE, Bulger RE, Southern P, et al. Natural history of aminoglycoside of gentamicin administered intravenously or intramuscularly to horses. J Am nephrotoxicity in the dog. J Lab Clin Med 1980; 95(3): 463–74.

Vet Med Assoc 1998 Oct 1; 213(7): 1007–11. 270. Davies C, Forrester SD, Troy GC, et al. Effects of a prostaglandin E1 analogue, 253. Snyder JR, Pascoe JR, Hirsh DC. Antimicrobial susceptibility of microorgan- misoprostol, on renal function in dogs receiving nephrotoxic doses of isms isolated from equine orthopedic patients. Vet Surg 1987 May-Jun; gentamicin. Am J Vet Res 1998; 59(8): 1048–54. 16(3): 197–201. 271. McFarlane D, Papich M, Breuhaus B, et al. Pharmacokinetics of amikacin 254. Riviere JE, Craigmill AL, Sundlof SF. Handbook of comparative pharmaco- sulfate in sick and healthy foals. International Veterinary Emergency kinetics and residues of veterinary antimicrobials. Boca Raton, FL: CRC Press, and Critical Care Society. Proceedings of the 5th Conference. San Antonio, Inc; 1991. p. 263–75. Texas.

AMINOPENICILLINS Veterinary—Intramammary-Local

{R-9} This monograph includes information on the following: Amoxicillin; Hetacillin potassium—C19H22KN3O4S. Hetacillin. Molecular weight: Some commonly used brand names for veterinary-labeled products are: Amoxicillin—419.45.{R-9} Amoxi-Mast and Hetacin-K Intramammary Infusion. Hetacillin potassium—427.56.{R-9} Note: For a listing of dosage forms and brand names by country Description: availability, see the Dosage Forms section(s). Amoxicillin USP—White, practically odorless, crystalline powder.{R-10} Hetacillin potassium—White to light buff, crystalline powder. Not commercially available in Canada. Solubility: Amoxicillin USP—Slightly soluble in water and in methanol; insoluble in {R-10} CATEGORY: carbon tetrachloride and in chloroform. Antibacterial (intramammary-local). Hetacillin potassium—Freely soluble in water; soluble in alcohol.

PHARMACOLOGY/PHARMACOKINETICS INDICATIONS Mechanism of action/effect: Like other penicillins, the aminopenicil- GENERAL CONSIDERATIONS lins produce their bactericidal effect by inhibiting bacterial cell wall Aminopenicillins have activity against penicillin-sensitive gram-positive synthesis.{R-11} These antibiotics must penetrate the cell wall to attach bacteria as well as some gram-negative bacteria. Aminopenicillins are to speciﬁc proteins on the inner surface of the bacterial cell membrane. susceptible to destruction by beta-lactamases and therefore are not In actively growing cells, the binding of ampicillin or amoxicillin effective against bacteria that produce these enzymes.{R-1-3} Most within the cell wall leads to interference with production of cell wall strains of Klebsiella, Proteus, Pseudomonas, and Staphylococcus{R-17} peptidoglycans and subsequent lysis of the cell in an isoosmotic envi- are resistant.{R-1; 4} ronment.{R-11–13}

ACCEPTED Distribution: Medications infused into a teat are considered to be fairly Mastitis (treatment)1—Cows, lactating: Amoxicillin and hetacillin are evenly distributed in that quarter of the healthy mammary gland; indicated in the treatment of mastitis caused by susceptible organisms however, in an udder affected by moderate to severe mastitis, the such as Streptococcus agalactiae.{R-5; 6} Intramammary therapy alone is presence of edema, blockage of milk ducts, and reduced blood circu- indicated only in the treatment of subacute or subclinical mastitis lation causes uneven distribution.{R-14} manifested by mild changes in the milk or udder. Acute or peracute mastitis, in which gross inflammatory changes in the milk or udder or PRECAUTIONS TO CONSIDER systemic signs appear, requires administration of other medications also, which may include systemic antibiotics and/or supportive therapy.{R-7} PATIENT MONITORING The following may be especially important in patient monitoring (other 1Not included in Canadian product labeling or product not commercially tests may be warranted in some patients, depending on condition; » = available in Canada. major clinical significance): Bacteriologic pathogens in milk REGULATORY CONSIDERATIONS (milk samples should be tested 3 weeks after treatment is discontinued; U.S.— mastitis is not considered bacteriologically cured until samples show Withdrawal times have been established. See the Dosage Forms section. an absence of the mastitis-causing organisms) Clinical signs of mastitis CHEMISTRY (although a resolution of clinical signs of mastitis is not an indication {R-15} Source: that a bacteriologic cure has been achieved , monitoring of the Amoxicillin—Semisynthetic derivative of ampicillin.{R-8} clinical condition of the mammary gland, teat, and milk produced can Hetacillin—Derived from the penicillin nucleus, 6-aminopenicillanic acid aid in diagnosis of a recurrence of mastitis or initial diagnosis of and chemically related to ampicillin.{R-6} mastitis in another cow in the herd) Chemical group: Beta-lactam antibiotics. Somatic cell count Chemical name: (somatic cell counts performed on milk to monitor the dairy herd are Amoxicillin—4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6- used primarily to maintain milk quality, but they are also used to [[amino(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-, trihy- assess the approximate overall effectiveness of mastitis control {R-7} drate [2S-[2alpha,5alpha,6beta(S*)]]-.{R-9} programs, which may include antibiotic treatment of cows). Hetacillin potassium—4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6-(2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl)-3,3-dimethyl- SIDE/ADVERSE EFFECTS 7-oxo-, monopotassium salt, [2S-[2alpha,5alpha,6beta(S*)]]-.{R-9} The following side/adverse effects have been selected on the basis of their Molecular formula: potential clinical significance (possible signs in parentheses where {R-9} Amoxicillin—C16H19N3O5SÆ3H2O. appropriate)—not necessarily inclusive:

THOSE INDICATING NEED FOR MEDICAL ATTENTION Withdrawal times: {R-5} Incidence unknown U.S.— Cows Withdrawal time Allergic reactions{R-6}—local or systemic Species Meat (days) Milk (hours)

OVERDOSE Cows, lactating 12 60 For information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals {R-5} (ASPCA) National Animal Poison Control Center (888-426-4435 Packaging and storage: Store below 24 C (75 F) , unless or 900-443-0000; a fee may be required for consultation) and/or the otherwise specified by manufacturer. drug manufacturer. USP requirements: Preserve in well-closed disposable syringes. A suspension of Amoxicillin in a suitable vegetable oil vehicle. Label it to CLIENT CONSULTATION indicate that it is intended for veterinary use only. Contains the labeled Treatment of mastitis in dairy cattle is best achieved by a comprehen- amount, within )10% to +20%. Contains a suitable dispersing agent sive mastitis control program in which herd management is the and preservative. Meets the requirements for Identification and Water primary focus. The program should include good maintenance of (not more than 1.0%).{R-10} milking equipment and constant evaluation of milking procedures and teat health as well as strategic treatment of clinical cases of 1 mastitis. Not included in Canadian product labeling or product not commercially available. VETERINARY DOSING INFORMATION The choice of antibiotic for the treatment of mastitis should be based on HETACILLIN knowledge of culture and sensitivity of pathogens causing mastitis in the cow and the dairy herd. SUMMARY OF DIFFERENCES The available intramammary aminopenicillin products are formulated Pharmacology/pharmacokinetics: Hetacillin must undergo a rapid and {R-15; 16} for use in the lactating cow only. spontaneous local hydrolysis to ampicillin to be therapeutically active. Before administration of intramammary amoxicillin or hetacillin, the Hydrolysis is believed to occur in aqueous solution with high {R-5; 6} following steps should be performed: efficiency; however, hydrolysis is slower in strongly acidic environ- • The udder should be milked out completely and the teats and udder ments.{R-17–19} washed with warm water and a disinfectant. Care should be taken to avoid washing excess dirt down from the udder onto the teat ends. The area should be dried thoroughly and each teat wiped with a INTRAMAMMARY DOSAGE FORMS separate cotton ball soaked with an antiseptic such as 70% isopropyl alcohol. HETACILLIN POTASSIUM INTRAMAMMARY • Persons performing the treatment should wash and dry their hands INFUSION before each treatment. Note: The dosing and strength of the dosage form available are expressed {R-6} • The tip of the syringe should be inserted into the teat end as little as in terms of ampicillin activity. possible and the contents of the syringe should be injected into each 1 streak canal while the teat is held firmly. The medication should Usual dose: Mastitis —Cows, lactating: Intramammary, 62.5 mg then be gently massaged up the teat canal into the udder. (ampicillin activity) into each affected quarter of the udder every {R-6} A teat dip is recommended on all teats following treatment. twenty-four hours for a maximum of three doses.

AMOXICILLIN Strength(s) usually available: U.S.— INTRAMAMMARY DOSAGE FORMS Veterinary-labeled product(s): 62.5 mg (ampicillin activity) per 10 mL (Rx) [Hetacin-K Intramam- AMOXICILLIN INTRAMAMMARY INFUSION USP mary Infusion]. Usual dose: Mastitis1—Cows, lactating: Intramammary, 62.5 mg into Canada— each affected quarter of the udder every twelve hours for a maximum Veterinary-labeled product(s): of three doses.{R-5} Not commercially available.

Strength(s) usually available: Withdrawal times: U.S.—{R-5} U.S.—

Veterinary-labeled product(s): Withdrawal time 62.5 mg per 10 mL (Rx) [Amoxi-Mast]. Canada— Species Meat (days) Milk (hours)

Veterinary-labeled product(s): Cows, lactating 10 72 Not commercially available.

Packaging and storage: Store below 40 C (104 F), preferably be- 6. Hetacillin intramammary infusion package insert (Hetacin-K, Fort Dodge tween 15 and 30 C (59 and 86 F), unless otherwise specified by Laboratories, Inc.—US), Rec 10/24/94. 7. Heath SE. Bovine mastitis. In: Howard JL. Current veterinary therapy 3: food manufacturer. animal practice. Philadelphia: W. B. Saunders; 1993. p. 762–9. 8. Amoxicillin package insert (Amoxi-Tabs, SmithKline Beecham—US), Rev {R-10} USP requirements: Not in USP. 7/93, Rec 10/18/94. 9. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention, Inc. 2002. 1 Not included in Canadian product labeling or product not commercially 10. The United States pharmacopeia. The national formulary. USP 26th revision available in Canada. (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc. 2002. p. 141, 2548. Developed: 06/05/95 11. Donowitz GR, Mandell GL. Beta-lactam antibiotics. N Engl J Med 1988; 318: Interim revision: 04/24/96; 05/14/97; 5/26/98; 10/12/99; 09/30/02; 419–26. 12. Papich MG. The beta-lactam antibiotics: clinical pharmacology and recent 02/28/03 developments. Compend Contin Educ Pract Vet 1987; 9(1): 68–74. 13. Wright AJ, Wilkowski CJ. The penicillins. Mayo Clin Proc 1983; 58: 21–32. REFERENCES 14. Jarp J, Bugge JP, Larsen S. Clinical trial of three therapeutic regimens for 1. Ampicillin package insert (Amp-equine, SmithKline Beecham—US), Rev bovine mastitis. 1989; 124: 630–4. 5/1991, Rec 10/18/94. 15. Craven N. Efficacy and financial value of antibiotic treatment of bovine clinical 2. Amoxicillin package insert (Moxilean, M.T.C. Pharmaceuticals—Canada), Rec mastitis during lactation—a review. Br Vet J 1987; 143: 410–22. 9/27/94. 16. Hady PJ, Lloyd JW, Kaneene JB. Antibacterial use in lactating dairy cattle. J Am 3. Ampicillin package insert (Polyflex, Fort Dodge Laboratories, Inc.—US), Rev Vet Med Assoc 1993 Jul; 203(2): 210–20. 1/94, Rec 10/24/94. 17. Panel comment, 2/20/95. 4. Sarasola P, McKellar QA. Pharmacokinetics and applications of ampicillin 18. Manufacturer comment, 2/28/95. sodium as an intravenous infusion in the horse. J Vet Pharmacol Ther 1993; 19. Sutherland R, Robinson OP. Laboratory and pharmacological studies in man 16: 63–9. with hetacillin and ampicillin. Br Med J 1967 Jun 24; 2(555): 804–8. 5. Amoxicillin intramammary infusion package insert (Amoxi-Mast, Pfizer Animal Health—US), Rev 9/97. Downloaded from www.pfizer.com/ah on 8/26/02.

AMINOPENICILLINS Veterinary—Systemic

This monograph includes information on the following: Amoxicillin; Pneumonia, bacterial (treatment)— Ampicillin. Calves, nonruminating1: Parenteral ampicillin is indicated for the treatment of respiratory tract infections caused by susceptible Some commonly used brand names are: organisms, including some bacterial pneumonias associated with For veterinary-labeled products— shipping fever complex.{R-3} Amoxi-Drop [Amoxicillin] Biomox Tablets [Amoxicillin] Cats and dogs: Parenteral ampicillin and [amoxicillin] are indicated in the Amoxi-Inject [Amoxicillin] Moxilean-50 Suspension [Amoxicillin] {R-12} Amoxil Tablets [Amoxicillin] Polyﬂex [Ampicillin] treatment of pneumonia caused by susceptible organisms. Amoxi-Tabs [Amoxicillin] Robamox-V Oral Suspension [Amoxicillin] Cattle: Parenteral amoxicillin and parenteral ampicillin are indicated Biomox Oral Suspension Robamox-V Tablets for the treatment of respiratory tract infections caused by susceptible [Amoxicillin] [Amoxicillin] organisms, including some bacterial pneumonias associated with For human-labeled products— shipping fever complex.{R-3; 5; 11} Ampicin [Ampicillin] Penbritin [Ampicillin] 1 Apo-Ampi [Ampicillin] Polycillin-N [Ampicillin] [Horses] : Parenteral ampicillin is used for the treatment of pneumo- {R-1} Novo-Ampicillin [Ampicillin] Principen [Ampicillin] nia caused by susceptible organisms. Nu-Ampi [Ampicillin] Totacillin [Ampicillin] Pododermatitis, necrotic, acute (treatment)1—Cattle: Parenteral amoxi- Omnipen [Ampicillin] Totacillin-N [Ampicillin] cillin is indicated in the treatment of acute necrotic pododermatitis Omnipen-N [Ampicillin] caused by susceptible Fusobacterium necrophorum{R-11}; if administered CATEGORY: early in the course of the disease, amoxicillin may reduce the severity of lesions.{R-62} Antibacterial (systemic). Skin and soft tissue infections (treatment)— INDICATIONS Cats and dogs: Amoxicillin and parenteral ampicillin are indicated in the treatment of soft tissue infections and wounds caused by Note: Bracketed information in the Indications section refers to uses that susceptible organisms.{R-3; 5; 6; 13} either are not included in U.S. product labeling or are for products not [Horses]1: Parenteral ampicillin is used in the treatment of skin and soft commercially available in the U.S. tissue infections, including abscesses and wounds, caused by susceptible organisms.{R-1} GENERAL CONSIDERATIONS [Strangles (treatment)]1—Horses: Parenteral ampicillin may be used in the The aminopenicillins have activity against penicillin-sensitive gram- treatment of strangles caused by susceptible Streptococcus equi.{R-1} positive bacteria as well as some gram-negative bacteria. Ampicillin is Tonsillitis, bacterial (treatment); or effective against alpha- and beta-hemolytic streptococci, including Tracheobronchitis, bacterial (treatment); or Streptococcus equi{R-1}, non–penicillinase-producing Staphylococcus spe- Upper respiratory tract infections (treatment)—Cats and dogs: Amoxicil- cies, some Bacillus anthracis, and most strains of Clostridia.{R-3} lin and parenteral ampicillin are indicated in the treatment of Ampicillin is also effective against gram-negative bacteria, including tonsillitis, tracheobronchitis, and upper respiratory tract infections many strains of Escherichia coli (E. coli), Salmonella, and Pasteurella caused by susceptible organisms{R-3; 5; 6}. multocida.{R-3} Amoxicillin has the same spectrum of activity as ampicillin, but has slightly better activity against some gram-negative ACCEPTANCE NOT ESTABLISHED bacteria, including E. coli, and Salmonella species.{R-4} Most anaerobic [Bacterial infections (treatment)]1—Calves, nonruminating: Until re- bacteria, except beta-lactamase–producing strains of Bacteroides, are cently, amoxicillin tablets were labeled in the United States for use in sensitive to amoxicillin{R-78}. The aminopenicillins are subject to the treatment of infections in calves caused by susceptible E. coli{R-8}. destruction by beta-lactamases and therefore are not effective against Although the labeled product is no longer available, oral amoxicillin some bacteria that produce these enzymes.{R-1; 3} Most strains of may be used in the treatment of susceptible infections in calves. Klebsiella, Proteus, and Pseudomonas are resistant.{R-1; 23} [Leptospirosis (treatment)]1—Dogs: Although the efﬁcacy has not been established, amoxicillin is used in therapy of leptospirosis in dogs. ACCEPTED Penicillin and penicillin derivatives (including amoxicillin) are consid- Dermatitis, bacterial (treatment)—Dogs: Amoxicillin is indicated in the ered to be effective for eliminating leptospiremia, but it is not known if {R-30; 31; 91} treatment of bacterial dermatitis caused by susceptible organisms; they are effective in terminating the carrier state . however, amoxicillin is not the treatment of choice because bacteria that 1Not included in Canadian product labeling or product not commercially cause dermatitis are often resistant to this medication{R-7; 14; 68–70}. available in Canada. Gastroenteritis, bacterial (treatment)—Cats and dogs: Amoxicillin and parenteral ampicillin are indicated in the treatment of bacterial gas- REGULATORY CONSIDERATIONS trointestinal tract infections caused by susceptible organisms.{R-3; 6} U.S.— Genitourinary tract infections, bacterial (treatment)—Cats and dogs: Ampicillin is not labeled for use in horses to be used for food Amoxicillin and parenteral ampicillin are indicated and [oral] production.{R-1} ampicillin is used in the treatment of genitourinary tract infections, {R-3; Withdrawal times have been established for amoxicillin and ampicillin. including cystitis and urethritis, caused by susceptible organisms. {R-3; 8} 5; 6; 15; 24} See the Dosage Forms section.

Canada— The aminopenicillins penetrate gram-negative bacterial cell walls more Withdrawal times have been established for ampicillin. See the Dosage rapidly than do the natural penicillins such as penicillin G and therefore Forms section.{R-5} are more efficient in destroying those organisms. Amoxicillin enters the gram-negative cell more easily than does ampicillin; this is considered to be the basis for the greater activity of amoxicillin against some gram- CHEMISTRY negative bacteria.{R-19} Source: Amoxicillin—Semisynthetic derivative of ampicillin{R-14}. Absorption: Ampicillin—Semisynthetic penicillin{R-1}. The aminopenicillins are stable in gastric fluid.{R-8} One of the primary Chemical name: differences between ampicillin and amoxicillin is the difference in Amoxicillin—4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, absorption after oral administration. A higher percentage of amoxi- 6-[[amino(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-, trihy- cillin than of ampicillin is absorbed after oral administration to cats, drate[2S-[2 alpha,5 alpha,6 beta(S*)]]-{R-16}. dogs, pigs, and preruminant calves.{R-25–28; 46} In people, the more Ampicillin—4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, complete oral absorption of amoxicillin leaves less drug remaining in 6-[(aminophenylacetyl)amino]-3,3-dimethyl-7-oxo-, [2S-[2 alpha,5 the intestinal tract than does ampicillin; therefore amoxicillin is alpha,6 beta(S*)]]-{R-16}. associated with a lower incidence of diarrhea as a side effect; however, Ampicillin sodium—4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic amoxicillin is also less effective than ampicillin in the treatment of acid, 6-[(aminophenylacetyl)amino]-3,3-dimethyl-7-oxo-, mono- some intestinal bacterial infections in people.{R-20} sodium salt, [2S-[2 alpha,5 alpha,6 beta(S*)]]-{R-16}. In horses, ampicillin sodium is well absorbed following intramuscular or Molecular formula: subcutaneous administration; however, oral dosage forms are poorly {R-16} {R-84} Amoxicillin—C16H19N3O5SÆ3H2O . absorbed by adult horses . Oral absorption of amoxicillin has been {R-16} {R-42; 86} Ampicillin—C16H19N3O4S . reported to be between 5.3 and 10.4% . Ampicillin trihydrate {R-16} Ampicillin sodium—C16H18N3NaO4S . administered intramuscularly produces lower ampicillin blood con- Molecular weight: centrations that extend over a longer period of time than does Amoxicillin—419.45{R-16}. ampicillin sodium{R-27; 49}. Ampicillin—349.41{R-16}. Note: There is evidence that giving amoxicillin and clavulanate Ampicillin sodium—371.39{R-16}. concurrently has little effect on the pharmacokinetics of either Description: medication{R-82}; therefore, the following information based on Amoxicillin USP—White, practically odorless, crystalline powder{R-17}. dosing with amoxicillin and clavulanate combination may be useful Ampicillin USP—White, practically odorless, crystalline powder{R-17}. in predicting the absorption of amoxicillin alone. Ampicillin Sodium USP—White to off-white, odorless or practically Calves—{R-82} odorless, crystalline powder. Is hygroscopic.{R-17} Preruminant calves (2 weeks old): Absorption of amoxicillin pKa:{R-22} when administered orally in combination with clavulanate at Amoxicillin—2.8 and 7.2. doses of 10 to 20 mg per kg of body weight (mg/kg) is 34 to 36%. Ampicillin—2.7 and 7.3. Early ruminant calves (6 weeks old): Absorption of amoxicillin Solubility: and clavulanate combination is much poorer than in preruminant Amoxicillin USP—Slightly soluble in water and in methanol; insoluble in calves given the same oral dose; therapeutic serum amoxicillin carbon tetrachloride and in chloroform{R-17}. concentrations are not achieved in early ruminant calves. Ampicillin USP—Slightly soluble in water and in methanol; insoluble in carbon tetrachloride and in chloroform{R-17}. Distribution: The aminopenicillins are rapidly and widely distributed Ampicillin Sodium USP—Very soluble in water and in isotonic sodium into most body fluids{R-6; 8; 23; 39} with the exception of fluids of the chloride and dextrose solutions{R-17}. eye and the prostate gland{R-69}; also, distribution into cerebrospinal fluid is low unless the meninges are inflamed{R-8}. Penetration into synovial fluid is high{R-87; 89}. PHARMACOLOGY/PHARMACOKINETICS Volume of distribution— Note: Unless otherwise noted, pharmacokinetic data in this section are Amoxicillin: Horses— based on intravenous administration of ampicillin or amoxicillin. Adult: There is evidence that administering ampicillin concurrently with Area—325 mL per kg of body weight (mL/kg){R-42}. either gentamicin or kanamycin does not alter the pharmacokinetics of Steady state—192 mL/kg{R-86}. either of the medications in horses{R-84; 89}. Foal (6 to 7 days of age): Area—369 mL/kg{R-41}. Mechanism of action/effect: Like other penicillins, the aminopeni- Steady state—265 mL/kg{R-41}. cillins produce their bactericidal effect by inhibiting bacterial cell wall Ampicillin: synthesis.{R-18} These antibiotics must penetrate the cell wall to attach Cats—Area: 116 mL/kg{R-40}. to specific proteins within the bacterial cell membrane. In actively Horses—Steady state: 180 mL/kg{R-23; 86}; 263 mL/kg{R-85}. growing cells, the binding of ampicillin or amoxicillin within the cell wall leads to interference with production of cell wall peptidoglycans Protein binding: and subsequent lysis of the cell in an iso-osmotic environment{R-18–20}. Amoxicillin—Horses: Moderate (37 to 38%){R-45}.

Ampicillin— Guinea pigs, hamsters, and rabbits—Oral ampicillin often disturbs the Cattle: Low (18%).{R-43; 44} normal microflora; the severity of this side effect makes the use of Horses: Very low (6.8 to 8%).{R-48} aminopenicillins in these species contraindicated.{R-58; 73} Rabbits: Low (17.5%).{R-44} Horses—Large oral doses of the aminopenicillins can disturb the normal Sheep: Low (13.8%).{R-43; 44} cecal microflora and are generally contraindicated.{R-49; 58} Ruminants—Oral ampicillin administration disrupts the rumen flora.

Half-life: Distribution—Ampicillin: PREGNANCY/REPRODUCTION {R-40} Cats—13 minutes. The safety of amoxicillin and ampicillin in the treatment of infections {R-39} Pigs—5 to 7 minutes. during pregnancy has not been established.{R-33} Penicillins have been Elimination— shown to cross the placenta; however, laboratory animal reproduction Amoxicillin: studies have shown no evidence of adverse effects in the fetus.{R-28; 33; 36} Goats—67 minutes.{R-47} Horses— Adult: 39 minutes{R-42}; 85 minutes{R-45; 86}. LACTATION {R-33; 37} Foal (6 to 7 days of age): 44 minutes.{R-41} In humans, penicillins are distributed into milk . Ampicillin has {R-50} Sheep—46 minutes.{R-47} been shown to be distributed into the milk of cows and ewes. Ampicillin: {R-40} Cats—73 minutes. DRUG INTERACTIONS AND/OR RELATED PROBLEMS {R-44} Dogs—20 minutes. The following drug interactions and/or related problems have been {R-23} {R-85} {R-48} Horses—37 minutes ; 42 minutes ; 93 minutes ; 103 selected on the basis of their potential clinical significance (possible {R-86} minutes . mechanism in parentheses where appropriate)—not necessarily inclu- {R-39} Pigs—30 to 35 minutes. sive (» = major clinical significance): {R-44} Rabbits—24 minutes. Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this Peak serum concentration: Ampicillin—Horses: medication. 6.2 to 9.7 mcg/mL at 16 minutes (intramuscular dose of 10 mg of Antibacterials, bacteriostatic, such as: {R-84} ampicillin sodium per kg of body weight) . Tetracycline{R-46} 21.6 mcg/mL in nonpregnant mares (intramuscular dose of 22 mg of (because the aminopenicillins act only on cells that are actively {R-87} ampicillin sodium per kg of body weight) . reproducing, bacteriostatic antibiotics may decrease the efficacy of 8.9 mcg/mL in pregnant mares (intramuscular dose of 22 mg of amoxicillin and ampicillin by depressing the activity of target {R-87} ampicillin sodium per kg of body weight) . cells{R-53}; however, the clinical significance of this interference is not well documented) {R-6} {R-23} Elimination: Amoxicillin and ampicillin are primarily ex- Probenecid creted unchanged in the urine. Ten to twenty-five percent of the (probenecid is a competitive inhibitor of renal tubular secretion administered dose of amoxicillin is excreted in the form of penicilloic and slows the body clearance of aminopenicillins in horses, calves, acid. pigs, and possibly other species, resulting in increased serum Total clearance— concentrations and longer elimination half-life){R-51; 52; 55} Amoxicillin: Goats—11.4 mL per minute per kg of body weight (mL/min/kg).{R-47} {R-41; 42} Horses and foals, 6 to 7 days of age—5.7 mL/min/kg. LABORATORY VALUE ALTERATIONS {R-47} Sheep—10.1 mL/min/kg. The following have been selected on the basis of their potential clinical- {R-89} Ampicillin: Horses—3.5 mL/min/kg . significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance): Note: Laboratory value alterations relating specifically to use of amino- PRECAUTIONS TO CONSIDER penicillins in animals appear to be rarely described. Human laboratory value alterations have been reported and are included in this CROSS-SENSITIVITY AND/OR RELATED PROBLEMS section. Animals allergic to one penicillin may be allergic to other penicillins also.{R-49} HUMAN LABORATORY VALUE ALTERATIONS{R-2} SPECIES SENSITIVITY The following laboratory value alterations have been reported in Calves—In neonatal calves, ampicillin administered orally at 12 mg per kg humans, and are included in the human monograph Penicillins of body weight (mg/kg) every eight hours has been shown to cause (Systemic) in USP DI Volume I; these laboratory value alterations are diarrhea and malabsorption. Aminopenicillins are not recommended intended for informational purposes only and may or may not be for treatment of enteritis in calves unless secondary complications, such applicable to the use of amoxicillin or ampicillin in the treatment of as septicemia or bacterial arthritis, are present.{R-9; 10} animals:

With diagnostic test results THOSE INDICATING NEED FOR MEDICAL ATTENTION Glucose, urine Incidence more frequent (high urinary concentrations of a penicillin may produce false Calves positive or falsely elevated test results with copper sulfate tests Diarrhea and malabsorption{R-9} [Benedict’s, Clinitest, or Fehling’s]; glucose enzymatic tests [Clinis- Note: In healthy neonatal calves, oral administration of 12 mg of tix or Testape] are not affected) ampicillin per kg of body weight (mg/kg) every eight hours has been Direct antiglobulin (Coombs’) tests shown to cause diarrhea and malabsorption.{R-9} (false-positive result may occur during therapy with any penicillin) Incidence unknown With physiology/laboratory test values All species {R-1; 6; 8; 11; 49} Alanine aminotransferase (ALT [SGPT]) and Hypersensitivity reactions, speciﬁcally acute anaphylaxis; Alkaline phosphatase and hypersensitivity (urticaria, fever) Aspartate aminotransferase (AST [SGOT]) and Horses Lactate dehydrogenase (LDH) Diarrhea—primarily with oral dosage forms{R-49} (serum values may be increased) Estradiol or THOSE INDICATING NEED FOR MEDICAL ATTENTION Estriol, total conjugated, or Estriol-glucuronide or ONLY IF THEY CONTINUE OR ARE BOTHERSOME Estrone, conjugated Incidence more frequent (concentrations may be transiently decreased in pregnant women Horses following administration of ampicillin) Injection site reaction (mild to moderate heat, pain, or swell- {R-1; 57} White blood cell count ing)—with ampicillin trihydrate {R-63} (leukopenia or neutropenia is associated with the use of all Incidence less frequent penicillins; the effect is more likely to occur with prolonged Cats and dogs {R-28} {R-28} {R-28} therapy and severe hepatic function impairment) Anorexia ; diarrhea ; vomiting

{R-2} MEDICAL CONSIDERATIONS/CONTRAINDICATIONS HUMAN SIDE/ADVERSE EFFECTS The medical considerations/contraindications included have been In addition to the above side/adverse effects reported in animals, the selected on the basis of their potential clinical significance (reasons following side/adverse effects have been reported in humans, and are given in parentheses where appropriate)—not necessarily inclusive included in the human monograph Penicillins (Systemic) in USP DI (» = major clinical significance). Volume I; these side/adverse effects are intended for informational Risk-benefit should be considered when the following medical purposes only and may or may not be applicable to the use of amox- problems exist: icillin or ampicillin in the treatment of animals: Congestive heart failure or Incidence more frequent Renal function impairment or Gastrointestinal reactions; headache; oral candidiasis; vaginal Electrolyte imbalance due to other causes candidiasis (the sodium content of ampicillin sodium administered at high doses Incidence less frequent may contribute to electrolyte imbalances associated with congestive Allergic reactions, specifically anaphylaxis; exfoliative derma- heart failure, renal function impairment, or other causes; also, titis; serum sickness–like reactions; skin rash, hives, or itching because the aminopenicillins are excreted primarily by the kidneys, Incidence rare the dosage regimen should be adjusted to avoid unneccessary Clostridium difficile colitis; interstitial nephritis; leukopenia or accumulation of medication in the plasma and tissues of animals neutropenia; pain at site of injection; thrombocytopenia; seizures with renal function impairment{R-54}) Note: Clostridium difficile colitis may occur up to several weeks after discontinuation of these medications. Patient monitoring Interstitial nephritis is seen primarily with methicillin, and to a lesser The following may be especially important in patient monitoring degree with nafcillin and oxacillin, but may occur with any penicillin. (other tests may be warranted in some patients, depending on Seizures are more likely to occur in patients receiving high doses of a condition; » = major clinical significance): penicillin and/or patients with severe renal function impairment. Culture and pathogen susceptibility, in vitro, and Minimum inhibitory concentration (MIC) OVERDOSE (in vitro cultures and MIC tests should be done on samples collected For information in cases of overdose or unintentional ingestion, contact prior to aminopenicillin administration to determine pathogen the American Society for the Prevention of Cruelty to Animals susceptibility) (ASPCA) National Animal Poison Control Center (888-426-4435 or 900-443-0000; a fee may be required for consultation) and/or the SIDE/ADVERSE EFFECTS drug manufacturer. The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and, for humans, VETERINARY DOSING INFORMATION symptoms in parentheses where appropriate)—not necessarily inclu- All species: Beta-lactam antibiotics are believed to produce time- sive: dependent bacterial killing; that is, efficacy is related to the time the

serum concentrations are maintained above the minimum inhibitory recommended to improve efficacy. Once daily dosing should be used concentration (MIC) of the pathogen. As such, in critical cases frequent only when organisms with very low MICs are suspected.{R-80} dosings (short dosage intervals) may be preferred. Strength(s) usually available: When reconstituted according to manufacturer’s instructions— FOR ORAL DOSAGE FORMS ONLY U.S.:{R-6; 13; 21; 38} Calves—Both amoxicillin and ampicillin are more bioavailable in calves Veterinary-labeled product(s)— when administered in a glucose-glycine-electrolyte solution than when 50 mg per mL (Rx) [Amoxi-Drop; Biomox Oral Suspension; Robamox-V administered with water or milk; however, unlike ampicillin, the Oral Suspension]. bioavailability of amoxicillin is not significantly altered by adminis- Canada:{R-38} {R-60} tration with milk as compared with water. Veterinary-labeled product(s)— Dogs—There is some decrease in systemic availability when oral amox- 50 mg per mL (Rx) [Moxilean-50 Suspension]. icillin or ampicillin is administered after a standard meal instead of on {R-25} an empty stomach. However, because amoxicillin has twice the Packaging and storage: Store below 40 C (104 F), preferably oral bioavailability of ampicillin in dogs, the therapeutic efficacy of between 15 and 30 C (59 and 86 F). Store in a tight container. amoxicillin may be less affected than that of ampicillin by adminis- {R-25} tration with food. Preparation of dosage form: To reconstitute, add the amount of water Horses—Oral ampicillin is not recommended in adult horses because of recommended by the manufacturer and shake vigorously. Before each poor oral bioavailability (5%) and the risk of disturbing gastrointestinal use, shake well to resuspend.{R-6; 21} bacterial balance, thus causing diarrhea.{R-49} Amoxicillin trihydrate is also poorly absorbed following oral administration, with a fractional Stability: After reconstitution, the suspension retains potency for 14 absorption of 10%; oral amoxicillin trihydrate should be used to treat days. Some products require refrigeration.{R-6; 21} only highly susceptible pathogens.{R-42} Sheep—In adult sheep, oral administration of ampicillin does not USP requirements: Preserve in tight containers, at controlled room provide therapeutically significant ampicillin plasma concentra- temperature. Contains the labeled amount, within –10% to +20%. {R-61} tions. Contains one or more suitable buffers, colors, flavors, preservatives, stabilizers, sweeteners, and suspending agents. Meets the requirements FOR TREATMENT OF ADVERSE EFFECTS for Identification, Uniformity of dosage units (single-unit containers), Treatment includes the following: Deliverable volume (multiple-unit containers), pH (5.0–7.5 in the For anaphylaxis: suspension constituted as directed in the labeling), and Water (not {R-17} {R-6} • Administration of parenteral epinephrine. more than 3.0%). • Oxygen administration and respiratory support. • Parenteral fluid administration as needed. AMOXICILLIN TABLETS USP Usual dose: Antibacterial—Cats and dogs: See Amoxicillin For Oral AMOXICILLIN Suspension USP. 1 SUMMARY OF DIFFERENCES Note: [Calves, nonruminating] —An oral dose of 10 to 22 mg per kg of body weight every eight, twelve, or twenty-four hours has been used in Pharmacology/pharmacokinetics: Absorption—Cats, dogs, pigs, and pre- the treatment of suceptible bacterial infections.{R-69} ruminant calves: A higher percentage of amoxicillin than of ampicillin is As beta-lactams appear to have time-dependent bacterial killing absorbed after oral administration.{R-25–28; 46} In dogs, orally admin- properties, shorter dosing intervals, whenever possible, are recom- istered amoxicillin is about 70% absorbed.{R-46} mended to improve efficacy. Once daily dosing should be used only when organisms with very low MICs are suspected.{R-80} ORAL DOSAGE FORMS Note: Bracketed information in the Dosage Forms section refers to uses Strength(s) usually available: that either are not included in U.S. product labeling or are for products U.S.—{R-7; 8; 13; 14; 38} not commercially available in the U.S. Veterinary-labeled product(s): 50 mg (Rx) [Amoxi-Tabs; Biomox Tablets; Robamox-V Tablets]. AMOXICILLIN FOR ORAL SUSPENSION USP 100 mg (Rx) [Amoxi-Tabs; Biomox Tablets; Robamox-V Tablets]. Usual dose: Antibacterial—Cats and dogs: Oral, 10 to 22 mg per kg of 150 mg (Rx) [Amoxi-Tabs]. body weight every eight, twelve, or twenty-four hours.{R-14; 26; 69} 200 mg (Rx) [Amoxi-Tabs; Biomox Tablets; Robamox-V Tablets]. Note: Although the efficacy has not been established, amoxicillin is 400 mg (Rx) [Amoxi-Tabs; Biomox Tablets; Robamox-V Tablets]. used in the treatment of [leptospirosis]1 in dogs at an intravenous Canada—{R-29; 38} or oral dose of 22 mg per kg of body weight every six to eight Veterinary-labeled product(s): hours{R-91; 92}. It is not known if this therapy will eliminate the 50 mg (Rx) [Amoxil Tablets]. carrier state. 100 mg (Rx) [Amoxil Tablets; GENERIC]. Note: As beta-lactams appear to have time-dependent bacterial killing 200 mg (Rx) [Amoxil Tablets]. properties, shorter dosing intervals, whenever possible, are 400 mg (Rx) [Amoxil Tablets].

Withdrawal times: There are no established withdrawal times for food- Withdrawal times:{R-11} producing animals in the United States or Canada because products U.S.— labeled for this use are not available. Based on previously available U.S. product labeling, if oral amoxicillin is administered to nonruminating Withdrawal time

calves at a dose of 8.8 mg per kg of body weight every twelve hours for Species Meat (days) Milk (hours) ﬁve days or less, a meat withdrawal time of 20 days should be sufﬁ- cient to avoid residues{R-8}. Cattle 25 96

Packaging and storage: Store below 40 C (104 F), preferably Note: Product labeling listing the above withdrawal times states that between 15 and 30 C (59 and 86 F). Store in a tight container. the recommended withdrawal times are based on a dose of 6.6 mg per kg of body weight every twenty-four hours and a course of therapy not USP requirements: Preserve in tight containers, at controlled room exceeding five days.{R-11} temperature. Label chewable Tablets to indicate that they are to be chewed before swallowing. Tablets intended solely for veterinary use Packaging and storage: Store below 40 C (104 F), preferably are so labeled. Contain the labeled amount, within )10% to +20%. between 15 and 30 C (59 and 86 F), unless otherwise specified by Meet the requirements for Thin-layer chromatographic identification manufacturer. test and Dissolution (80% in 90 minutes in water in Apparatus 2 at 75 rpm; and for products labeled as Chewable Tablets: 70% in 90 minutes Preparation of dosage form: Dosage form is reconstituted by adding in water in Apparatus 2 at 75 rpm).{R-17} the amount of sterile water for injection recommended by the manufacturer.{R-11} 1Not included in Canadian product labeling or product not commercially available in Canada. Stability: After reconstitution, the suspension retains potency for twelve months when refrigerated or for three months when stored at room temperature (72 F).{R-11} PARENTERAL DOSAGE FORMS Note: Bracketed information in the Dosage Forms section refers to uses USP requirements: Preserve in Containers for Sterile Solids. A sterile that either are not included in U.S. product labeling or are for products mixture of Amoxicillin and one or more suitable buffers, preservatives, not commercially available in the U.S. stabilizers, and suspending agents. Label it to indicate that it is for veterinary use only. Contains the labeled amount, within )10% to AMOXICILLIN FOR INJECTABLE SUSPENSION USP +20%. Meets the requirements for Identification, Bacterial endotoxins, Sterility, pH (5.0–7.0, in the suspension constituted as directed in the Usual dose: Antibacterial1— labeling), and Water (11.0–14.0%).{R-17} Cats and dogs: Intramuscular or subcutaneous, 11 to 22 mg per kg of body weight every eight, twelve, or twenty-four hours.{R-64; 69} 1Not included in Canadian product labeling or product not commercially Note: Although the efficacy has not been established, amoxicillin is available in Canada. used in the treatment of [leptospirosis]1 in dogs at an intravenous or oral dose of 22 mg per kg of body weight every six to eight hours{R-91; 92}. It is not known if this therapy will eliminate the carrier state. AMPICILLIN Cattle: Intramuscular or subcutaneous, 6.6 to 22 mg per kg of body weight every eight, twelve, or twenty-four hours.{R-69} SUMMARY OF DIFFERENCES Note: Maximum volume per injection site should not exceed thirty Pharmacology/pharmacokinetics: Absorption—Calves, nonruminating, mL.{R-11} cats, dogs, and pigs: With oral administration, ampicillin is more poorly Note: As beta-lactams appear to have time-dependent bacterial killing absorbed than is amoxicillin; the dosage is adjusted to compen- properties, shorter dosing intervals, whenever possible, are recom- sate.{R-25; 26} In dogs, orally administered ampicillin trihydrate is only mended to improve efficacy. Once daily dosing should be used only about 35% absorbed{R-46}; in cats, oral anhydrous ampicillin is about when organisms with very low MICs are suspected.{R-80} 20 to 40% absorbed.{R-40}

Strength(s) usually available: When reconstituted according to manufacturer’s instructions— ADDITIONAL DOSING INFORMATION U.S.:{R-11; 38; 64} See also Veterinary Dosing Information. Veterinary-labeled product(s)— Pharmacology/pharmacokinetics: Horses—There is evidence that admin- 100 mg per mL (Rx) [Amoxi-Inject (3-gram vial labeled for cats and istering ampicillin concurrently with either gentamicin or kanamycin dogs)]. does not alter the pharmacokinetics of either of the medications{R-84; 250 mg per mL (Rx) [Amoxi-Inject (3-gram vial labeled for cats and 89}. dogs or 25-gram vial labeled for cattle)]. Parenteral dosage forms—Ampicillin sodium produces higher plasma Canada: concentrations than does ampicillin trihydrate; ampicillin trihydrate Veterinary-labeled product(s)— produces relatively low plasma concentrations but maintains measur- Not commercially available.{R-38} able concentrations for a longer period of time.{R-49}

ORAL DOSAGE FORMS Dogs: Intramuscular or subcutaneous, 10 to 50 mg per kg of body {R-32} Note: Bracketed information in the Dosage Forms section refers to uses weight every twelve hours. 1 1 that either are not included in U.S. product labeling or are for products Cattle and calves , including nonruminating calves : Intramuscular, 4.4 {R-3} not commercially available in the U.S. to 11 mg per kg of body weight every twenty-four hours. Note: As beta-lactams appear to have time-dependent bacterial killing AMPICILLIN CAPSULES USP properties, shorter dosing intervals, whenever possible, are Usual dose: [Antibacterial]1— recommended to improve efficacy. Once daily dosing should be used {R-80} Cats: Oral, 10 to 20 mg per kg of body weight every eight to twenty- only when organisms with very low MICs are suspected. four hours.{R-40; 69} Dogs: Oral, 20 to 40 mg per kg of body weight every eight to twelve Size(s) usually available: {R-32; 69} hours. U.S.—{R-3; 38} Note: As beta-lactams appear to have time-dependent bacterial killing Veterinary-labeled product(s): properties, shorter dosing intervals, whenever possible, are recom- 10 grams (Rx) [Polyflex]. mended to improve efficacy. Once daily dosing should be used only 25 grams (Rx) [Polyflex]. {R-80} when organisms with very low MICs are suspected. Canada—{R-5; 38} Veterinary-labeled product(s): Strength(s) usually available: 10 grams (Rx) [Polyflex]. {R-33; 34; 35} U.S.— 25 grams (Rx) [Polyflex]. Veterinary-labeled product(s): Not commercially available. {R-3} Human-labeled product(s): Withdrawal times: U.S.—{R-3} 250 mg (Rx) [Omnipen; Principen; Totacillin; GENERIC]. 500 mg (Rx) [Omnipen; Principen; Totacillin; GENERIC]. Withdrawal time Canada—{R-36; 37} Veterinary-labeled product(s): Species Meat (days) Milk (hours) Not commercially available. Cattle 648 Human-labeled product(s): 250 mg (Rx) [Apo-Ampi; Novo-Ampicillin; Nu-Ampi; Penbritin]. Note: Product labeling listing the above withdrawal times states that 500 mg (Rx) [Apo-Ampi; Novo-Ampicillin; Nu-Ampi; Penbritin]. treatment should not exceed seven days for withdrawal times to apply.{R-3} Packaging and storage: Store below 40 C (104 F), preferably be- Canada—{R-5} tween 15 and 30 C (59 and 86 F), unless otherwise specified by manufacturer. Store in a tight container. Withdrawal time

Species Meat (days) Milk (hours) USP requirements: Preserve in tight containers. Label Capsules to indicate whether the ampicillin therein is in the anhydrous form or is Cattle 648 the trihydrate. Contain an amount of ampicillin (anhydrous or as the Pigs 4 trihydrate) equivalent to the labeled amount of ampicillin, within ) 10% to +20%. Meet the requirements for Identiﬁcation, Dissolution Note: Product labeling listing the above withdrawal times states that the (75% in 45 minutes in water in Apparatus 1 at 100 rpm), Uniformity recommended withdrawal times are based on a dose of 6 mg per kg of of dosage units, and Loss on drying (not more than 4.0% for the body weight every twenty-four hours and a course of therapy not {R-17} anhydrous and 10.0–15.0% for the trihydrate). exceeding seven days.{R-5}

1Not included in Canadian product labeling or product not commercially Packaging and storage: Store below 40 C (104 F), preferably available in Canada. between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by manufacturer. PARENTERAL DOSAGE FORMS Note: Bracketed information in the Dosage Forms section refers to uses Preparation of dosage form: that either are not included in U.S. product labeling or are for products The sizes may be reconstituted according to manufacturer’s directions to not commercially available in the U.S. one of the following strengths: 100, 200, 250, 300, or 400 mg per mL. {R-5} The dosing and strengths of the dosage forms available are expressed Before each use, shake well to resuspend. in terms of ampicillin free acid (not the sodium salt). Stability: After reconstitution, the solution retains potency for twelve months when refrigerated and for three months when stored at AMPICILLIN FOR INJECTABLE SUSPENSION USP 25 C.{R-3} Usual dose: Antibacterial— Cats: Intramuscular or subcutaneous, 10 to 20 mg per kg of body USP requirements: Preserve in Containers for Sterile Solids. A dry weight every twelve to twenty-four hours.{R-40} mixture of ampicillin trihydrate and one or more suitable buffers,

preservatives, stabilizers, and suspending agents. Contains the equiv- Concentrated solutions (100 mg per mL) prepared from pharmacy bulk alent of the labeled amount of ampicillin, within -10% to +20%. Meets vials retain their potency for 2 hours at room temperature or 4 hours if the requirements for Identiﬁcation, Bacterial endotoxins, Sterility, pH refrigerated.{R-75} (5.0–7.0, in the suspension constituted as directed in the labeling), and Diluted solutions (20 mg per mL or less) in 5% dextrose injection retain Water (11.4–14.0%), and for Uniformity of dosage units, and Labeling their potency for 2 hours at room temperature or 3 hours if under Injections.{R-17} refrigerated.{R-75}

AMPICILLIN FOR INJECTION USP Incompatibilities: Extemporaneous admixtures of beta-lactam anti- Usual dose: [Antibacterial]1— bacterials (penicillins and cephalosporins) and aminoglycosides may Cats and dogs: Intramuscular or intravenous, 10 to 20 mg (free acid) result in substantial mutual inactivation. These types of antibacterial per kg of body weight every six to eight hours.{R-32; 40} agents should not be mixed in the same intravenous bag, bottle, or Horses: Intramuscular or intravenous, 10 to 20 mg (free acid) per kg of tubing. body weight every six to eight hours.{R-78; 79} Note: The dose of 10 to 20 mg per kg of body weight every six to Additional information: This product contains approximately 3 mil- eight hours is sufficient for most sensitive bacteria; however, for liequivalents (mEq; millimoles [mmol]) of sodium per gram of ampi- infections due to moderately resistant organisms or infections cillin and could result in electrolyte overload in some animals.{R-54} associated with natural tissue barriers, such as those of the central nervous system, doses of up to 25 to 40 mg per kg of body weight USP requirements: Preserve in Containers for Sterile Solids. Protect the every six to eight hours have been used.{R-83} constituted solution from freezing. Contains an amount of Ampicillin A possible increased risk of gastrointestinal side effects with Sodium equivalent to the labeled amount of ampicillin within )10% to increasing dose should be considered. +15%. Meets the requirements for Constituted solution, Bacterial endotoxins, Particulate matter, Uniformity of dosage units, and for Size(s) usually available: Identification tests, Crystallinity, pH, and Water under Ampicillin {R-1; 38; 76} U.S.— Sodium, and for Sterility tests, and Labeling under Injections{R-17}. Veterinary-labeled product(s): Not commercially available. 1Not included in Canadian product labeling or product not commercially Human-labeled product(s): available in Canada. 125 mg (free acid) (Rx) [Omnipen-N; Polycillin-N; GENERIC]. 250 mg (free acid) (Rx) [Omnipen-N; Polycillin-N; Totacillin-N; GENERIC]. Developed: 07/25/95 500 mg (free acid) (Rx) [Omnipen-N; Polycillin-N; Totacillin-N; GENERIC]. Revised: 06/30/02 1 gram (free acid) (Rx) [Omnipen-N; Polycillin-N; Totacillin-N; GENERIC]. Interim revision: 07/18/96; 06/02/97; 05/27/98; 10/12/99; 04/04/03 2 grams (free acid) (Rx) [Omnipen-N; Polycillin-N; Totacillin-N; GENERIC]. 10 grams (free acid) (Rx) [Omnipen-N; Polycillin-N; GENERIC]. REFERENCES {R-77} Canada— 1. Ampicillin package insert (Amp-equine, SmithKline Beecham—US), Rev 5/91, Veterinary-labeled product(s): Rec 10/18/94 [discontinued product]. Not commercially available. 2. Klasco RK, editor. USP DI Drug information for the healthcare professional. Volume I. Greenwood Village, CO: MICROMEDEX; 2003. Human-labeled product(s): 3. Ampicillin package insert (Polyflex, Fort Dodge Laboratories, Inc.—US). 125 mg (free acid) (Rx) [Ampicin; Penbritin]. Downloaded 2/11/03 from www.wyeth.com. 250 mg (free acid) (Rx) [Ampicin; Penbritin]. 4. Nathwani D, Wood MJ. Penicillins. A current review of their clinical 500 mg (free acid) (Rx) [Ampicin; Penbritin]. pharmacology and therapeutic use. Drugs 1993; 45(6): 866–94. 5. Polyflex. In: Bennett K, editor. Compendium of veterinary products. 3rd ed. 1 gram (free acid) (Rx) [Ampicin; Penbritin]. Hensall, ON: North American Compendiums Inc., 1993: 407. 2 grams (free acid) (Rx) [Ampicin; Penbritin]. 6. Amoxicillin package insert (Amoxi-Drop, SmithKline Beecham—US), Rev 9/90, Rec 10/18/94. Packaging and storage: Prior to reconstitution, store below 40 C 7. Amoxicillin package insert (Robamox-V, Fort Dodge Laboratories, Inc.—US), Rev 10/93, Rec 10/24/94. (104 F), preferably between 15 and 30 C (59 and 86 F), unless 8. Amoxicillin package insert (Amoxi-Bol, SmithKline Beecham—US), Rev 4/92, otherwise specified by manufacturer. Protect the reconstituted solution Rec 10/18/94 [discontinued product]. from freezing. 9. Rollins RE, et al. Diarrhea and malabsorption in calves associated with therapeutic doses of antibiotics: Absorptive and clinical changes. Am J Vet Res 1986 May; 47(5): 987–91. Preparation of dosage form: Dosage form should be reconstituted 10. Hunt EH. Diarrheal diseases of neonatal ruminants. In: Howard JL. Current according to manufacturer’s directions.{R-1} veterinary therapy 3. Food animal practice. Philadelphia: W.B. Saunders Company; 1993. p. 103–9. Stability: 11. Amoxicillin package insert (Amoxi-Inject [Cattle], SmithKline Beecham—US), Rev 3/91, Rec 10/18/94. After reconstitution, the solution retains potency for 1 hour at room 12. Roudebush P. Infectious pneumonia. In: Kirk RW, Bonagura JD, editors. {R-1} temperature (70 to 75 C). Current veterinary therapy XI. Small animal practice. Philadelphia: W.B. After reconstitution for intravenous infusion, solutions with concentra- Saunders Company; 1992. p. 228–36. 13. Amoxicillin package insert (Biomox, Biocraft Laboratories, Inc.—US), Rev 1/ tions of up to 30 mg per mL retain at least 90% of their potency for 2 to 93, Rec 9/27/94. 8 hours at room temperature or up to 72 hours if refrigerated in 14. Amoxicillin package insert (Amoxi-Tabs, SmithKline Beecham—US), Rev 7/ suitable diluents (see manufacturer’s package insert).{R-75} 93, Rec 10/18/94.

15. Ling GV, Gilmore CJ. Penicillin G or ampicillin for oral treatment of canine 48. Durr A. Comparison of the pharmacokinetics of penicillin G and ampicillin in urinary tract infections. J Am Vet Med Assoc 1977 Aug; 171(4): 358–61. the horse. Res Vet Sci 1976; 20: 24–9. 16. USP dictionary of USAN and international drug names, 2002 ed. Rockville, 49. Sarasola P, McKellar QA. Ampicillin and its congener prodrugs in the horse. Br MD: The United States Pharmacopeial Convention, Inc.; 2002. Vet J 1994; 150(2): 173–87. 17. The United States pharmacopeia. The national formulary. USP 26th 50. Ziv G, Shani J, Sulman FG. Pharmacokinetic evaluation of penicillin and revision (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: cephalosporin derivatives in serum and milk of lactating cows and ewes. Am J The United States Pharmacopeial Convention, Inc., 2002. p. 141–3, 148–50, Vet Res 1973 Dec; 34(12): 1561–5. 2548. 51. Ziv G, Horsey J. Elevation and prolongation of serum ampicillin and 18. Donowitz GR, Mandell GL. Beta-lactam antibiotics. N Engl J Med 1988; 318: amoxycillin concentrations in calves by the concomitant administration of 419–26. probenecid. J Vet Pharmacol Ther 1979; 2: 187–94. 19. Papich MG. The beta-lactam antibiotics: clinical pharmacology and recent 52. Sarasola P, McKellar QA. Effect of probenecid on disposition kinetics of developments. Compend Contin Educ Pract Vet 1987; 9(1): 68–74. ampicillin in horses. Vet Rec 1992; 131: 173–5. 20. Wright AJ, Wilkowski CJ. The penicillins. Mayo Clin Proc 1983: 58: 21–32. 53. Huber WG. Penicillins. In: Booth NH, McDonald LE. Veterinary pharmacol- 21. Amoxicillin package insert (Robamox-V, Fort Dodge Laboratories, Inc.—US), ogy and therapeutics, 5th ed. Ames, IA: Iowa State University Press; 1988. Rev 9/92, Rec 10/24/94. p. 796–812. 22. Riviere JE, Craigmill AL, Sundlof SF. Handbook of comparative pharmacoki- 54. Riviere JE, Coppoc GL. Dosage of antimicrobial drugs in patients with renal netics and residues of veterinary antimicrobials. Boca Raton, FL: CRC Press, insufficiency. J Am Vet Med Assoc 1981 Jan; 178(1): 70–2. Inc.; 1991. p. 52. 55. Galtier P, Alvinerie M. Enhancement of ampicillin bioavailability in pigs. J Vet 23. Sarasola P, McKellar QA. Pharmacokinetics and applications of ampicillin Pharmacol Ther 1979; 2: 181–6. sodium as an intravenous infusion in the horse. J Vet Pharmacol Ther 1993; 56. Mason MJ, Mason KV. A pemphigus foliaceus-like eruption associated with the 16: 63–9. use of ampicillin in a cat. Aust Vet J 1987 Jul; 64(7): 223–4. 24. Ling GV. Therapeutic strategies involving antimicrobial treatment of the 57. Traver DS, Riviere JE. Penicillin and ampicillin therapy in horses. J Am Vet canine urinary tract. J Am Vet Med Assoc 1984; 185(10): 1162–4. Med Assoc 1981 Jun; 178(11): 1186–9. 25. Watson ADJ, et al. Effect of ingesta on systemic availability of penicillins 58. Prescott JF, Baggot JD. Antimicrobial therapy in veterinary medicine, 2nd ed. administered orally in dogs. J Vet Pharmacol Ther 1986; 9: 140–9. Ames, IA: Iowa State University Press; 1993. p. 90–5. 26. Papich MG. Therapy of gram-positive bacterial infections. Vet Clin North Am 59. Leib MS. Acute vomiting: a diagnostic approach and symptomatic manage- Small Anim Pract 1988; 18(6): 1267–85. ment. In: Kirk RW, Bonagura JD, editors. Current veterinary therapy XI. Small 27. Spurlock SL, Wilcke JR. Penicillins and cephalosporins. In: Proceedings of the animal practice. Philadelphia: W.B. Saunders Company; 1992. p. 583–7. thirty-second annual convention of the American Association of Equine 60. Palmer GH, Bywater RJ, Stanton A. Absorption in calves of amoxicillin, Practitioners. 1987. p. 175–82. ampicillin, and oxytetracycline given in milk replacer, water or an oral 28. Plumb DC. Veterinary drug handbook. White Bear Lake, MN: PharmaVet rehydration formulation. Am J Vet Res 1983 Jan; 44(1): 68–71. Publishing, 1991: 467–9, 480–6. 61. Oukessou M, Toutain PL. Effect of water deprivation on absorption (oral, 29. Amoxil tablets. In: Bennett K, editor. Compendium of veterinary products. 3rd intramuscular) and disposition of ampicillin in sheep. J Vet Pharmacol Ther ed. Hensall, ON: North American Compendiums Inc.; 1993. p. 96. 1992; 15: 421–32. 30. Greene CE, editor. Infectious diseases of the dog and cat, 2nd ed. Philadelphia: 62. Braun RK, et al. Efficacy of amoxicillin trihydrate for the treatment of WB Saunders; 1998. p. 279–80. experimentally induced foot rot in cattle. Am J Vet Res 1987 Dec; 48(12): 31. Ross LA. Leptospirosis. In: Bonagura J, Kersey R, editors. Kirk’s current 1751–4. veterinary therapy XIII: small animal practice. Philadelphia: WB Saunders. 63. Francis ME, Marshall AB, Turner WT. Amoxycillin: clinical trials in dogs and 1999. p. 308–10. cats. Vet Rec 1978 Apr; 102: 377–80. 32. Kirk RW, Bonagura JD, editors. Current veterinary therapy XI. Small animal 64. Amoxicillin package insert (Amoxi-Inject [Cats and Dogs], SmithKline practice. Philadelphia: W.B. Saunders Company; 1992. p. 1234. Beecham—US), Rev 3/91, Rec 10/18/94. 33. Ampicillin package insert (Principen, Apothecon—US), Rev 4/90, Rec 7/93. 65. Hjerpe CA. The bovine respiratory disease complex. In: Howard JL. Current 34. Ampicillin package insert (Totacillin, Beecham—US), Rev 5/88, Rec 7/93. veterinary therapy 3. Food animal practice. Philadelphia: W.B. Saunders 35. Ampicillin (Omnipen, Wyeth Ayerst). In: PDR Physicians’ desk reference. 48th Company; 1993. p. 653–64. ed. 1994. Montvale, NJ: Medical Economics Data Production Company; 1994. 66. Robinson NE, editor. Current therapy in equine medicine 3. Philadelphia: W.B. p. 2569–71. Saunders Company; 1992. p. 815. 36. Ampicillin package insert (Nu-Ampi, Nu-Pharm—Canada), Rev 1/94, Rec 67. Brown MP, et al. Ampicillin trihydrate in foals: serum concentrations and 4/94. clearance after a single oral dose. Equine Vet J 1984; 16(4): 371–3. 37. Ampicillin (Apo-Ampi, Apotex). In: Krogh CME, editor. CPS Compendium of 68. Panel comment, Rec 2/23/95. pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical 69. Panel comment, Rec 3/9/95. Association; 1994. p. 83, 893, 995. 70. Panel comment, Rec 2/22/95. 38. Arrioja-Dechert A, editor. Compendium of veterinary products, CD edition. 71. Panel comment, Rec 3/6/95. Port Huron, MI: North American Compendiums, Inc., 2002. 72. Panel comment, Rec 3/29/95. 39. Galtier P, Charpenteau JL. Pharmacokinetics of ampicillin in pigs. J Vet 73. Panel comment, Rec 2/17/95. Pharmacol Ther 1979; 2: 173–80. 74. Panel comment, Rec 2/27/95. 40. Mercer HD, et al. Bioavailability and pharmacokinetics of several dosage forms 75. Ampicillin package insert (Principen, Apothecon—US), Rev 4/90, Rec 7/93. of ampicillin in the cat. Am J Vet Res 1977 Sep; 38(9): 1353–9. 76. PDR Physicians’ desk reference, 48th ed. 1994. Montvale, NJ: Medical 41. Baggot JD, et al. Bioavailability and disposition kinetics of amoxicillin in Economics Data Production Company; 1994. p. 2571. neonatal foals. Equine Vet J 1988; 20(2): 125–7. 77. Krogh, CME, editor. CPS Compendium of pharmaceuticals and specialities, 42. Wilson WD, et al. Pharmacokinetics and estimated bioavailability of amox- 29th ed. Ottawa: Canadian Pharmaceutical Association; 1994. p. 63–4, 995. icillin in mares after intravenous, intramuscular, and oral administration. Am 78. Panel comment, Rec 6/22/95. J Vet Res 1988 Oct; 49(10): 1688–94. 79. Panel comment, Rec 6/29/95. 43. Ziv G, Sulman FG. Binding of antibiotics to bovine and ovine serum. 80. Committee comment, Rec 1/15/02. Antimicrob Agents Chemother 1972 Sep; 2(3): 206–13. 81. Bywater RJ, Palmer GH, Buswell JF, Stanton A. Clavulanate and amoxycillin: 44. Powers TE, Garg RC. Pharmacotherapeutics of newer penicillins and cepha- activity in vitro and bioavailability in the dog. Vet Rec 1985; 116: 33–6. losporins. J Am Vet Med Assoc 1980 May; 10(2): 1054–60. 82. Soback S, Bor A, Kurtz B, et al. Clavulanate-potentiated amoxycillin: in vitro 45. Montesissa C, et al. Pharmacokinetics of sodium amoxicillin in horses. Res Vet antibacterial activity and oral bioavailability in calves. J Vet Pharmacol Ther Sci 1988; 44: 233–6. 1987; 10: 105–13. 46. Yeoman GH. Microbiology and bioavailability of amoxicillin. Vet Med Small 83. Panel comment, Rec 11/30/95. Anim Clin 1977; 4(suppl): 720–38. 84. Firth EC, Klein WR, Nouws JFM, et al. Effect of induced synovial inflammation 47. Craigmill AL, Pass MA, Wetzslich S. Comparative pharmacokinetics of on pharmacokinetics and synovial concentration of sodium ampicillin and amoxicillin administered intravenously to sheep and goats. J Vet Pharmacol kanamycin sulfate after systemic administration in ponies. J Vet Pharmacol Ther 1992; 15: 72–7. Ther 1988; 11: 56–62.

85. Sarasola P, McKellar QA. Pharmacokinetics of bacampicillin in equids. Am J sodium-gentamicin sulfate in serum and synovia of healthy horses. Am J Vet Vet Res 1995 Nov; 56(11): 1486–92. Res 1986; 47(7): 1590–6. 86. Ensink JM, Klein WR, Mevius DJ, et al. Bioavailability of oral penicillins in the 90. Beech J, Leitch M, Kohn CW, et al. Serum and synovial ﬂuid levels of sodium horse: a comparison of pivampicillin and amoxicillin. J Vet Pharmacol Ther ampicillin and ampicillin trihydrate in horses. J Equine Med Surg 1979; 3: 1992; 15: 221–30. 350–4. 87. Panel comment, Rec 11/28/95. 91. Adin CA, Cowgill LD. Treatment and outcome of dogs with leptospirosis: 36 88. Traver DS, Riviere JE. Ampicillin in mares: a comparison of intramuscular cases (1990-1998). J Am Vet Med Assoc 2000 Feb 1; 216(3): 371–5. sodium ampicillin or sodium ampicillin-ampicillin trihydrate injection. Am J 92. Committee comment, 1/22/02. Vet Res 1982 Mar; 43(3): 402–4. 89. Bowman KF, Dix LP, Riond JL, Riviere JE. Prediction of pharmacokinetic proﬁles of ampicillin sodium, gentamicin sulfate, and combination ampicillin

AMOXICILLIN AND CLAVULANATE Veterinary—Systemic

A commonly used brand name for a veterinary-labeled product is Urinary tract infections, bacterial (treatment)—Cats{R-7} and [dogs]:{R-9– Clavamox. 11} Amoxicillin and clavulanate combination is indicated in the Note: For a listing of dosage forms and brand names by country treatment of urinary tract infections, including those caused by availability, see the Dosage Forms sections(s). susceptible E. coli.

CATEGORY: ACCEPTANCE NOT ESTABLISHED Antibacterial (systemic). [Osteomyelitis (treatment)]1—Cats and dogs: There are insufﬁcient data to show that amoxicillin and clavulanate combination is effective in INDICATIONS the treatment of osteomyelitis in cats and dogs; however, in vitro Note: Bracketed information in the Indications section refers to uses that studies show that the bacteria causing this type of infection are often either are not included in U.S. product labeling or are for products not susceptible.{R-32–34; 37} commercially available in Canada. 1Not included in Canadian product labeling or product not commercially available in Canada. GENERAL CONSIDERATIONS Amoxicillin has activity against penicillin-sensitive gram-positive bacteria as well as some gram-negative bacteria. The gram-positive CHEMISTRY spectrum of activity includes alpha- and beta-hemolytic streptococci, Source: some Staphylococci species, Clostridia species, and some Bacillus Amoxicillin—Semisynthetic derivative of ampicillin.{R-12} anthracis{R-2}. Amoxicillin is also effective against gram-negative Clavulanate—A fermentation product of the actinomycete Streptomyces bacteria, including Escherichia coli (E. coli), many strains of Salmonella, clavuligerus.{R-7; 8} and Pasteurella multocida.{R-2} Amoxicillin is sensitive to destruction by Chemical name: beta-lactamases and therefore when administered by itself is not Amoxicillin—4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6- effective against bacteria, such as Klebsiella and Proteus, that produce [[amino(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-, trihy- these enzymes.{R-2} drate[2S-[2alpha,5alpha,6beta(S*)]]-.{R-13} Clavulanate is a naturally occurring noncompetitive inhibitor of beta- Clavulanate potassium—4-Oxa-1-azabicyclo[3.2.0]heptane-2-carboxylic lactamase produced by gram-positive, and also many gram-negative, acid, 3-(2-hydroxyethylidene)-7-oxo-, monopotassium salt, [2R- bacteria.{R-3; 4} Although it has a beta-lactam chemical structure, (2alpha,3Z,5alpha)]-.{R-13} clavulanic acid has little antibacterial activity of its own. However, Molecular formula: {R-13} when clavulanic acid is administered concurrently with amoxicillin, it Amoxicillin—C16H19N3O5SÆ3H2O. {R-13} extends the activity of amoxicillin by preventing its destruction by Clavulanate potassium—C8H8KNO5. bacterial enzymes. Beta-lactamase inhibitors will only assist in the Molecular weight: destruction of bacteria that produce beta-lactamase enzymes; other Amoxicillin—419.45.{R-13} forms of resistance, such as alteration of penicillin-binding protein, are Clavulanate potassium—237.25.{R-13} not affected. Also, the beta-lactam structure of amoxicillin and Description: clavulanate may stimulate some bacteria to produce more beta- Amoxicillin USP—White, practically odorless, crystalline powder.{R-14} lactamase; it is easier for clavulanate to protect amoxicillin against a Clavulanate Potassium USP—White to off-white powder. Is moisture- small amount of enzyme than against a large amount. sensitive.{R-14} Clavulanate extends the spectrum of activity of amoxicillin to include pKa: beta-lactamase producing E. coli, Klebsiella, Proteus, and Staphylo- Amoxicillin—2.8 and 7.2.{R-16} coccus species.{R-4; 6} Most anaerobes, including Bacterioides fragilis, Clavulanate—2.7.{R-17} are susceptible to the combination of clavulanic acid and Solubility: amoxicillin.{R-5} However, some beta-lactamase enzymes, including Amoxicillin USP—Slightly soluble in water and in methanol; insoluble in those produced by Enterobacter and Pseudomonas, are unaffected by carbon tetrachloride, and in chloroform.{R-14} clavulanate.{R-6} Clavulanate Potassium USP—Freely soluble in water, but stability in aqueous solution is not good; optimum stability at a pH of 6.0 to 6.3; soluble in methanol, with decomposition.{R-14} ACCEPTED Periodontal infections (treatment)—Dogs: Amoxicillin and clavulanate combination is indicated in the treatment of periodontal PHARMACOLOGY/PHARMACOKINETICS infections caused by susceptible strains of aerobic and anaerobic Note: There is evidence that giving amoxicillin with clavulanate has little {R-17; 24} bacteria{R-1; 31}. effect on the pharmacokinetics of either medication. Skin and soft tissue infections (treatment)—Cats and dogs:{R-7; 8} Amoxicillin and clavulanate combination is indicated in the treatment Mechanism of action/effect: of skin and soft tissue infections caused by susceptible Staphylococcus Amoxicillin—Bactericidal. Amoxicillin must reach and bind to the species, E. coli, Pasteurella species, and Streptococcus species. penicillin-binding proteins on the inner membrane of the bacterial

cell wall. In actively growing cells, the binding of amoxicillin within LACTATION the cell wall leads to interference with production of cell wall In humans, penicillins are distributed into milk, and the same is true for peptidoglycans and subsequent lysis of the cell in an iso-osmotic many animals.{R-27; 28} environment.{R-18–20} Clavulanate—Binds irreversibly to susceptible beta-lactamase enzymes, DRUG INTERACTIONS AND/OR RELATED PROBLEMS preventing hydrolysis of the amoxicillin beta-lactam ring. When The following drug interactions and/or related problems have been clavulanate binds with the enzyme, a chemical complex is formed, selected on the basis of their potential clinical significance (possible which destroys the clavulanate and inactivates the beta-lactama- mechanism in parentheses where appropriate)—not necessarily se.{R-3; 4; 6} inclusive (» = major clinical significance): Note: Combinations containing any of the following medications, Absorption: depending on the amount present, may also interact with this Cats and dogs—Both amoxicillin and clavulanate are stable in medication. gastric fluid and, therefore, are well absorbed after oral admini- Probenecid stration.{R-6; 7; 21–23} (probenecid decreases tubular secretion and slows the body clearance Calves— of amoxicillin, resulting in increased serum concentrations and Preruminant calves (2 weeks old): Absorption of amoxicillin when longer elimination half-lives in many species{R-24; 29}; however, administered in combination with clavulanate at doses of 10 to 20 clavulanic acid is unlikely to be affected because it is cleared mg per kg of body weight (mg/kg) is 34 to 36%. primarily by glomerular filtration{R-17}) Early ruminant calves (6 weeks old): Absorption of amoxicillin and clavulanate combination is much poorer than in preruminant calves given the same dose; early ruminant calves do not develop LABORATORY VALUE ALTERATIONS therapeutic serum amoxicillin concentrations.{R-26} The following have been selected on the basis of their potential clinical Horses—Orally administered amoxicillin is only 10% absorbed in adult significance (possible effect in parentheses where appropriate)—not horses.{R-36} necessarily inclusive (» = major clinical significance): Note: Laboratory value alterations relating specifically to use of Peak serum concentration: Amoxicillin— amoxicillin and clavulanate in animals appear to be rare. Human Calves, preruminant: laboratory value alterations have been reported and are included in Oral, 10 mg/kg dose—2 mcg per mL (mcg/mL) at 78 minutes.{R-26} this section. Oral, 20 mg/kg dose—3.3 mcg/mL at 64 minutes.{R-26} {R-38} Dogs: Oral, 12.5 mg/kg dose—5 to 6 mcg/mL at 60 minutes. HUMAN LABORATORY VALUE ALTERATIONS{R-15} The following laboratory value alterations have been reported in Distribution: Cats and dogs—Amoxicillin and clavulanate diffuse humans, and are included in the human monograph Penicillins and into most body tissues and fluids; however, distribution of amoxi- Beta-lactamase Inhibitors (Systemic) in USP DI Volume I; these cillin into cerebrospinal fluid is low unless the meninges are in- laboratory value alterations are intended for informational purposes flamed.{R-7; 8} only and may or may not be applicable to the use of amoxicillin and clavulanate combination in the treatment of animals: Elimination: Amoxicillin—Primarily excreted unchanged in the urine. With diagnostic test results 10 to 25% is excreted in the form of penicilloic acid.{R-25} Glucose, urine (high urinary concentrations of a penicillin may produce false- positive or falsely elevated test results with copper-reduction tests PRECAUTIONS TO CONSIDER [Benedict’s, Clinitest, or Fehling’s]; glucose enzymatic tests CROSS-SENSITIVITY AND/OR RELATED PROBLEMS [Clinistix or Testape] are not affected) Direct antiglobulin (Coombs’) tests Animals allergic to one penicillin or cephalosporin may also be allergic to (false-positive result may occur during therapy with any penicillin) amoxicillin or clavulanate.{R-9} With physiology/laboratory test values Alanine aminotransferase (ALT [SGPT]) and SPECIES SENSITIVITY Alkaline phosphatase and Horses and rabbits—This medication is generally contraindicated in these Aspartate aminotransferase (AST [SGOT]) and species because of the potential for disturbance of the normal Lactate dehydrogenase (LDH), serum gastrointestinal microflora.{R-6} (values may be increased) Bilirubin, serum (concentrations may be increased) PREGNANCY/REPRODUCTION Estradiol or The safety of administration of amoxicillin and clavulanate to Estriol-glucuronide or pregnant or breeding animals is unknown.{R-8; 9} Penicillins have Estriol, total conjugated, or been shown to cross the placenta; however, laboratory animal Estrone, conjugated reproduction studies have shown no evidence of adverse effects on (concentrations may be transiently decreased in pregnant women the fetus.{R-17} following administration of amoxicillin)

White blood count Seizures are more likely to occur in patients receiving high doses of a (leukopenia or neutropenia is associated with the use of all penicillin and/or patients with severe renal function impairment. penicillins; the effect is more likely to occur with prolonged therapy and severe hepatic function impairment) OVERDOSE For information in cases of overdose or unintentional ingestion, contact PATIENT MONITORING the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888-426-4435 The following may be especially important in patient monitoring (other or 900-443-000; a fee may be required for consultation) and/or the tests may be warranted in some patients, depending on condition; » = drug manufacturer. major clinical significance): Culture and susceptibility, in vitro, and Minimum inhibitory concentration (MIC) VETERINARY DOSING INFORMATION {R-21} (in vitro cultures and MIC test should be done on samples collected In cats and dogs, the therapeutic efficacy of amoxicillin and prior to amoxicillin and clavulanate administration to determine clavulanate is not significantly affected by administration with food. pathogen susceptibility{R-7; 8}) FOR TREATMENT OF ADVERSE EFFECTS SIDE/ADVERSE EFFECTS For anaphylaxis {R-25} The following side/adverse effects have been selected on the basis of their • Parenteral epinephrine. potential clinical significance (possible signs and, for humans, • Oxygen administration and breathing support. symptoms in parentheses where appropriate)—not necessarily inclusive: ORAL DOSAGE FORMS Note: The dosing and strengths of the dosage forms available are THOSE INDICATING NEED FOR MEDICAL ATTENTION expressed in terms of clavulanic acid (not the potassium salt). Incidence unknown All species{R-7; 8; 25} AMOXICILLIN AND CLAVULANATE POTASSIUM FOR Hypersensitivity reactions, specifically acute anaphylaxis, fever, ORAL SUSPENSION USP or urticaria Usual dose: Antibacterial—Cats and dogs: Oral, 11 to 20 mg of amoxicillin and 2.75 to 5 mg of clavulanic acid per kg of body weight every {R-32–34} THOSE INDICATING NEED FOR MEDICAL ATTENTION eight to twelve hours. ONLY IF THEY CONTINUE OR ARE BOTHERSOME Note: Urinary tract infections should be treated for fourteen days or longer. Deep pyoderma may require treatment for twenty-one Incidence less frequent days. Treatment for any indication should not exceed thirty Cats and dogs{R-6; 17} days.{R-8} Anorexia; diarrhea; vomiting

Strength(s) usually available{R-30}: When reconstituted according to HUMAN SIDE/ADVERSE EFFECTS{R-15} manufacturer’s instructions— In addition to the above side/adverse effects reported in animals, the U.S.: following side/adverse effects have been reported in humans, and are Veterinary-labeled product(s)— included in the human monograph Penicillins and Beta-lactamase 50 mg of amoxicillin and 12.5 mg clavulanic acid per mL (Rx) Inhibitors (Systemic) in USP DI Volume I; these side/adverse effects are [Clavamox]. intended for informational purposes only and may or may not be Canada: applicable to the use of amoxicillin and clavulanate in the treatment of Veterinary-labeled product(s)— animals: 50 mg of amoxicillin and 12.5 mg of clavulanic acid per mL (Rx) Incidence more frequent [Clavamox]. Gastrointestinal reactions; headache Incidence less frequent Packaging and storage: Store below 40 C (104 F), preferably Allergic reactions, specifically anaphylaxis; oral candidiasis; between 15 and 30 C (59 and 86 F). Store in a tight container. serum sickness–like reactions; skin rash, hives, or itching; vaginal candidiasis Stability: After reconstitution, suspensions retain their potency for ten Incidence rare days if refrigerated.{R-8} Chest pain; chills; Clostridium difficile colitis; dysuria or urinary retention; edema; epistaxis; erythema multiforma or Auxiliary labeling: Stevens-Johnson syndrome; fatigue; glossitis; hepatic dysfunc- • Refrigerate. tion, including cholestatic hepatitis; leukopenia or neutrope- • Shake well. nia; malaise; platelet dysfunction; proteinuria or pyuria; seizures; toxic epidermal necrolysis USP requirements: Preserve in tight containers, at controlled room Note: Clostridium difficile colitis may occur up to several weeks after temperature. Contains the labeled amount of amoxicillin, within –10% discontinuation of these medications. to +20%, and an amount of clavulanate potassium equivalent to the

labeled amount of clavulanic acid, within )10% to +25%. Contains REFERENCES one or more suitable buffers, colors, flavors, preservatives, stabilizers, 1. Clavamax Drops Freedom of Information Summary. NADA 055-101. 12/23/ sweeteners, and suspending agents. Meets the requirements for Iden- 97. Sponsor: Pfizer Inc. 2. Ampicillin package insert (Polyflex, Fort Dodge—US), Rec 9/27/94. tification, pH (3.8–6.6, in the suspension constituted as directed in the 3. Barragry TB. Veterinary drug therapy. Philadelphia: Lea & Febiger; 1994. labeling, the test being performed immediately after constitution), and p. 221–4. Water (not more than 7.5%, where the label indicates that after 4. Kilgore WR, Simmons RD, Jackson JW. Beta-lactamase inhibition: a new constitution as directed, the suspension contains 25 mg of amoxicillin approach in overcoming bacterial resistance. Compend Contin Educ Pract Vet 1986; 8: 325. per mL; not more than 8.5%, where the label indicates that after 5. Indiveri MC, Hirsh DC. Clavulanic acid-potentiated activity of amoxicillin constitution as directed, the suspension contains 50 mg of amoxicillin against Bacteroides fragilis. Am J Vet Res 1985; 46(10): 2207–9. per mL).{R-14} 6. Prescott JF, Baggot JD, editors. Antimicrobial therapy in veterinary medicine. 2nd ed. Ames, IA: Iowa State University Press 1993: 119–26. 7. Amoxicillin and clavulanic acid package insert (Clavamox Tablets, SmithKline AMOXICILLIN AND CLAVULANATE POTASSIUM Beecham—US), Rev 9/90, Rec 2/7/95. TABLETS USP 8. Amoxicillin and clavulanic acid package insert (Clavamox Drops, SmithKline Usual dose: See Amoxicillin and Clavulanate Potassium for Oral Suspension Beecham—US), Rev 9/90, Rec 2/7/95. 9. Clavamox drops. In: Bennett K, editor. Compendium of veterinary products. USP. 3rd ed. Hensall, ON: North American Compendiums Inc., 1993; 173–4. 10. Clavamox tablets. In: Bennett K, editor. Compendium of veterinary products. Strength(s) usually available{R-30}: 3rd ed. Hensall, ON: North American Compendiums Inc., 1993: 173. 11. Senior, et al. Amoxycillin and clavulanic acid combination in the treatment U.S.— of experimentally induced bacterial cystitis in cats. Res Vet Sci 1985; 39(1): Veterinary-labeled product(s): 41–6. 50 mg of amoxicillin and 12.5 mg of clavulanic acid (Rx) [Clavamox]. 12. Amoxicillin package insert (Amoxitabs, SmithKline Beecham—US), Rev 7/93, 100 mg of amoxicillin and 25 mg of clavulanic acid (Rx) [Clavamox]. Rec 10/18/94. 13. USP dictionary of USAN and international drug names, 2002. Rockville, MD: 200 mg of amoxicillin and 50 mg of clavulanic acid (Rx) [Clavamox]. The United States Pharmacopeial Convention, Inc.; 2002. 300 mg of amoxicillin and 75 mg of clavulanic acid (Rx) [Clavamox]. 14. The United States pharmacopeia. The national formulary. USP 26th revision Canada— (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United States Pharmacopeial Convention, Inc.; 2002. p. 143, 144, 2548, 2555. Veterinary-labeled product(s): 15. Klasco RK, editor. USP DI Drug information for the healthcare professional. 50 mg of amoxicillin and 12.5 mg of clavulanic acid (Rx) [Clavamox]. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 100 mg of amoxicillin and 25 mg of clavulanic acid (Rx) [Clavamox]. 16. Riviere JE, Craigmill AL, Sundlof SF. Handbook of comparative pharmacoki- 200 mg of amoxicillin and 50 mg of clavulanic acid (Rx) [Clavamox]. netics and residues of veterinary antimicrobials. Boca Raton, FL: CRC Press, Inc. 1991. 300 mg of amoxicillin and 75 mg of clavulanic acid (Rx) [Clavamox]. 17. Plumb DC. Veterinary drug handbook. White Bear Lake, MN: PharmaVet Publishing 1991: 467–9, 480–6. Packaging and storage: Store below 25 C (77 F), unless otherwise 18. Donowitz DR, Mandell GL. Beta-lactam antibiotic. N Engl J Med 1988; 318: specified by manufacturer. Store in a tight container. 419–26. 19. Wright AJ, Wilkowski CJ. The penicillins. Mayo Clin Proc 1983; 58: 21–32. 20. Papich MG. The beta-lactam antibiotics: Clinical pharmacology and recent Auxiliary labeling: developments. Compend Contin Educ Pract Vet 1987; 9(1): 68–74. • Do not remove from foil strip until ready to use. 21. Watson ADJ, et al. Effect of ingesta on systemic availability of penicillins administered orally in dogs. J Vet Pharmacol Ther 1986: 9: 140–9. 22. Papich MG. Therapy of gram-positive bacterial infections. Vet Clin North Am USP requirements: Preserve in tight containers. Label chewable Ta- Small Anim Pract 1988; 18(6): 1267–85. blets to include the word ‘‘chewable’’ in juxtaposition to the official 23. Spurlock SL, Wilcke JR. Penicillins and cephalosporins. In: Proceedings of the name. The labeling indicates that chewable Tablets may be chewed thirty-second annual convention of the American Association of Equine Practitioners; 1987. p. 175–82. before being swallowed or may be swallowed whole. Tablets intended 24. Soback S, et al. Clavulanate-potentiated amoxycillin: in vitro antibacterial for veterinary use only are so labeled. Contain the labeled amount of activity and oral bioavailability in calves. J Vet Pharmacol Ther 1987; 10: amoxicillin, within )10% to +20%, and an amount of clavulanate 105–13. 25. Amoxicillin package insert (Amoxi-drops, SmithKline Beecham—US), Rev potassium equivalent to the labeled amount of clavulanic acid, within 9/90, Rec 10/18/94. )10% to +20%. Meet the requirements for Identification, Disintegra- 26. Soback S, Bor A, Kurtz B, et al. Clavulanate-potentiated amoxycillin: in vitro tion (for Tablets labeled for veterinary use only, 30 minutes, in antibacterial activity and oral bioavailability in calves. J Vet Pharmacol Ther simulated gastric fluid TS), Dissolution (85% of amoxicillin and 80% of 1987; 10: 105–13. 27. Ampicillin package insert (Principen, Apothecon—US), Rev 4/90, Rec 7/93. clavulanic acid in 30 minutes [or 45 minutes where the Tablets are 28. Ampicillin (Apo-Ampi, Apotex). In: Krogh CME, editor. CPS Compendium of labeled as chewable] in water in Apparatus 2 at 75 rpm [Note: Tablets pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical labeled for veterinary use only are exempt from this requirement]), Association, 1994; 83: 995. Uniformity of dosage units, and Water (not more than 6.0% where the 29. Ziv G, Horsey J. Elevation and prolongation of serum ampicillin and amoxycillin concentrations in calves by the concomitant administration of Tablets are labeled as being chewable; not more than 7.5% where the probenecid. J Vet Pharmacol Ther 1979; 2: 187–94. labeled amount of amoxicillin in each Tablet is 250 mg or less; not 30. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port more than 10.5% where the labeled amount of amoxicillin in each Huron, MI: North American Compendiums, Inc. 2002. 31. Clavamox Tabs Freedom of Information Summary. NADA 055-099. 12/23/ Tablet is greater than 250 mg).{R-14} 97. Sponsor: Pfizer Inc. 32. Panel comment, 4/7/95. 33. Budsberg SC, Kemp DT. Antimicrobial distribution and therapeutics in bone. Developed: 06/30/95 Compend Contin Ed Small Animal Pract 1990; 12(12): 1758–62. Interim revision: 06/26/96; 05/14/97; 5/26/98; 10/12/99; 09/30/02; 34. Fossum TW, Hulse DA. Osteomyelitis. Semin Vet Med Surg (Small Anim) 1992 04/04/03 Feb; 7(1): 85–97.

35. Sarkiala E, Harvey C. Systemic antimicrobials in the treatment of periodontitis 37. Johnson KA. Osteomyelitis in dogs and cats. J Am Vet Med Assoc 1994 June; in dogs. Semin Vet Med Surg (Small Anim) 1993 Aug; 8(3): 197–203. 205(12): 1882–7. 36. Wilson WD, Spensley MS, Baggot JD, et al. Pharmacokinetics and estimated 38. Bywater RJ, Palmer GH, Buswell JF, et al. Clavulanate and amoxycillin: bioavailability of amoxicillin in mares after intravenous, intramuscular, and activity in vitro and bioavailability in the dog. Vet Rec 1985; 116: 33–6. oral administration. Am J Vet Res 1988 Oct; 49(10): 1688–94. 39. Todd PA, Benﬁeld P. Amoxicillin/Clavulanic acid. Drugs 1990; 39: 264–307.

CEPHALOSPORINS Veterinary—Systemic

This monograph includes information on the following: Cefaclor; the exception of beta-lactamase–producing Bacteroides{R-1; 4} and Cefadroxil; Cefazolin; Cefixime; Cefotaxime; Cefotetan; Cefoxitin; Cef- Clostridium difficile{R-98}. tiofur; Cephalexin; Cephalothin; Cephapirin; Cephradine. Second-generation cephalosporins include cefaclor, cefamandole, cef- metazole, cefonicid, cefotetan, cefoxitin, cefprozil, and cefuroxime. Some commonly used brand names are: Second-generation cephalosporins have the same efficacy as or perhaps For veterinary-labeled products— slightly less efficacy than first-generation cephalosporins against Cefa-Drops [Cefadroxil] Excenel RTU [Ceftiofur] gram-positive pathogens; however, this lack of efficacy is primarily Cefa-Tabs [Cefadroxil] Naxcel [Ceftiofur] Excenel [Ceftiofur] against S. aureus and S. intermedius. Second-generation are more effective than first-generation cephalosporins in the treatment of For selected human-labeled products— infections caused by gram-negative bacteria such as E. coli, Klebsiella, Ancef [Cefazolin] Keflin [Cephalothin] Enterobacter, and Proteus.{R-1; 4; 7} Many anaerobic bacteria are Apo-Cefaclor [Cefaclor] Keftab [Cephalexin] susceptible to second-generation cephalosporins; cefoxitin{R-7–9} and Apo-Cephalex [Cephalexin] Kefzol [Cefazolin] {R-80} Ceclor [Cefaclor] Mefoxin [Cefoxitin] cefotetan can also be effective against Bacteroides fragilis. Cefadyl [Cephapirin] Novo-Lexin [Cephalexin] However, Enterococcus and Pseudomonas species are resistant to Cefotan [Cefotetan] Nu-Cephalex [Cephalexin] second-generation cephalosporins{R-80}. Use of these antimicrobials is Ceporacin [Cephalothin] PMS-Cephalexin [Cephalexin] generally reserved for infections that are resistant to first-generation Claforan [Cefotaxime] Suprax [Cefixime] Keflex [Cephalexin] Velosef [Cephradine] cephalosporins. Third-generation cephalosporins include cefixime, cefoperazone, cefotax- Note: For a listing of dosage forms and brand names by country ime, cefpodoxime, ceftazidime, ceftizoxime, and ceftriaxone. availability, see the Dosage Forms section(s). Third-generation cephalosporins are the most effective of the cephalosporins against antibiotic-resistant gram-negative bacteria{R-1; 2; 7}. Not commercially available in Canada. Ceftazidime and cefoperazone are active against Pseudomonas, but the majority of the third-generation cephalosporins commonly used in {R-4; 80} CATEGORY: veterinary practice are not . Third-generation cephalosporins, Antibacterial (systemic). in general, are no more and perhaps are less effective than other cephaosporins against gram-positive bacteria{R-1; 4; 7}. Cefotaxime, ceftazidine, ceftizoxine, and ceftriaxone are the only cephalosporins INDICATIONS that consistently reach effective antibacterial concentrations in the Note: Bracketed information in the Indications section refers to uses that central nervous system in people with inflamed meninges. either are not included in U.S. product labeling or are for products not Ceftiofur is a cephalosporin that does not clearly fit into the third- commercially available in the U.S. generation category and has been called a ‘‘new-generation’’ cephalosporin{R-91}. It has broader gram-positive activity, including good activity against Streptococci, and less activity against Pseudomo- GENERAL CONSIDERATIONS nas than other third-generation cephalosporins{R-68}. It is active Cephalosporins are wide-spectrum antibiotics used to treat a variety of against beta-lactamase–producing strains as well as anaerobes, such infections in animals. They have been grouped into three ‘‘genera- as Fusobacterium necrophorum and Bacteroides melaninogenicus{R-81}. {R-1; 2} tions’’ based primarily on their spectrum of antibacterial activity . Ceftiofur is rapidly metabolized to desfuroylceftiofur in vivo and Some of the more recently developed cephalosporins may not easily fit S. aureus is four- to eightfold{R-100} less sensitive to desfuroylceftiofur into one of the generations, but are usually included in the generation than to the parent ceftiofur{R-63}. Proteus mirabilis has a widely their antibacterial properties most closely resemble. variable susceptibility to some metabolites of ceftiofur{R-72}. First-generation cephalosporins include cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, and cephradine. First-generation cephalosporins have the highest activity of the ceph- ACCEPTED alosporins against gram-positive bacteria, including most Corynebac- Escherichia coli infections (treatment)—Chicks1 and turkey poults, day-old: teria, Streptococci, and Staphylococci, particularly Staphylococcus Ceftiofur sodium for injection is indicated in the treatment of infections aureus{R-3} and Staphylococcus intermedius{R-32}. Cephalothin and (colibacillosis) caused by susceptible E. coli{R-11; 12}. cephapirin generally have the greatest activity against staphylo- Metritis (treatment)1—Cattle: Ceftiofur hydrochloride injection is indi- cocci{R-2}; Staphylococcus epidermidis is only variably susceptible to cated in the treatment of acute metritis (up to 14 days postpartum), cephalexin and cefadroxil.{R-1} Rhodococcus equi, methicillin-resistant caused by susceptible organisms{R-81}. S. aureus, and Enterococcus species are usually resistant.{R-1} The first- Pododermatitis, acute (treatment)—Cattle: Ceftiofur sodium for injection generation cephalosporins have activity against gram-negative bac- and ceftiofur hydrochloride injection are indicated in the treatment of teria, including some Escherichia coli{R-3}, Klebsiella pneumoniae, bovine interdigital necrobacillosis associated with F. necrophorum and Haemophilus influenzae, Proteus mirabilis{R-3}, Actinobacillus, Pasteurel- B. melaninogenicus{R-11; 12; 81; 99}. la, and Salmonella; however, Actinobacter, Citrobacter, Enterobacter, Respiratory tract infections (treatment)— indole-positive Proteus, and Pseudomonas are resistant.{R-1; 4; 53} Cattle: Ceftiofur sodium for injection and ceftiofur hydrochloride Many anaerobic bacteria are susceptible to these antibacterials, with injection are indicated in the treatment of respiratory tract infections,

including bovine respiratory disease complex (shipping fever), determination of minimum inhibitory concentrations against com- caused by susceptible organisms, including Mannheimia (Pasteurella) mon pathogens show that cefixime is likely to be effective in the haemolytica, Pasteurella multocida, and Haemophilus somnus{R-11; 12; treatment of bone, bladder, skin, and soft tissue infections{R-77}. There 81; 99}. are insufficient data to establish the clinical efficacy and safety of Goats1: Ceftiofur sodium for injection is indicated in the treatment of [cefotetan]1 and [cefoxitin]1 in the treatment of gram-negative or caprine respiratory disease caused by susceptible organisms, includ- polymicrobial infections (such as Enterobacteriaceae species and an ing M. haemolytica and P. multocida{R-11}. obligate anaerobe) in dogs; however, pharmacokinetics and a Horses: Ceftiofur sodium for injection is indicated in the treatment of determination of minimum inhibitory concentrations against com- respiratory tract infections caused by susceptible organisms, includ- mon pathogens show that cefotetan and cefoxitin are likely to be ing Streptococcus zooepidemicus{R-11; 12}. effective in the treatment of these types of infections{R-84}. Pigs: Ceftiofur hydrochloride injection and ceftiofur sodium for [Foals]1 : There are insufficient data to establish the efficacy and safety injection are indicated in the treatment of respiratory tract infections of ceftiofur{R-48} and cephradine{R-85} in foals for the treatment of caused by susceptible organisms, including Actinobacillus pleuropneu- bacterial infections; however, based on the pharmacokinetics known, moniae, P. multocida, Salmonella choleraesuis, and Streptococcus suis pathogen sensitivities, and the apparent wide margin of safety, these type 2.{R-11; 81; 96; 99} medications are used to treat a variety of susceptible infections, Sheep: Ceftiofur sodium for injection is indicated in the treatment of including certain bone, joint, respiratory, skin, soft tissue, and urinary respiratory tract infections caused by susceptible M. haemolytica and tract infections. There are also insufficient data to establish the P. multocida{R-11; 12; 97}. efficacy and safety of cefotaxime and other third-generation ceph- Skin and soft tissue infections (treatment)—Cats and dogs: Cefadroxil and alosporins in the treatment of neonatal sepsis and secondary bacterial [cephalexin]1{R-32} are indicated in the treatment of skin and soft tissue meningitis in foals; however, based on known human central nervous infections caused by susceptible organisms, including P. multocida, system distribution and clinical response in foals, cefotaxime is used S. aureus, some S. epidermidis, S. intermedius{R-32}, and Streptococcus to treat these infections when they are not responsive to other species.{R-3; 79} antimicrobials{R-62; 67}. Urinary tract infections (treatment)—Dogs: Cefadroxil and ceftiofur sodium Horses: There are insufficient data to establish the efficacy and safety of for injection are indicated in the treatment of urinary tract infections [cefoxitin]1{R-29} and [cephalothin]1 {R-9; 19} in horses for the caused by susceptible organisms, including E. coli, P. mirabilis, and treatment of bacterial infections; however, based on the pharmaco- S. aureus{R-3; 11; 12}. kinetics known, pathogen sensitivities, and the apparent wide [Perioperative infections (prophylaxis)]1—Dogs: Cefazolin is used in the margin of safety, these medications are used to treat a variety of prevention of infections associated with surgery, including bone susceptible infections, including certain bone, joint, respiratory, skin, surgery, and caused by susceptible organisms when the risk of soft tissue, and urinary tract infections.1 infection is high or potentially severely damaging.{R-1; 2; 6; 82; 83}

1 ACCEPTANCE NOT ESTABLISHED Not included in Canadian product labeling or product not commercially available in Canada. Infections, bacterial (treatment)— [Birds]1: There are insufficient data to establish the efficacy and safety of cephalexin and cephalothin in the treatment of bacterial infections REGULATORY CONSIDERATIONS in birds, such as cranes, ducks, emu, pigeons, and quail; however, U.S. and Canada—{R-11; 12} based on pharmacokinetic studies and the apparent wide margin of Withdrawal times have been established for ceftiofur (see the Dosage safety, they have been used in the treatment of susceptible bacterial Forms section). Ceftiofur is not for use in horses intended for human infections{R-34}. consumption. Cats: There are insufficient data to establish the efficacy and safety of [cefotaxime] 1{R-42} and [cephalexin]1{R-49; 50} in the treatment of CHEMISTRY bacterial infections in cats; however, based on pharmacokinetics, Source: Most cephalosporins are semisynthetic derivatives of the met- pathogen sensitivities, and the apparent wide margin of safety, these abolic products of the fungus Cephalosporium acremonium.{R-1–3} medications are used to treat a variety of susceptible infections, Chemical group: Beta-lactam antibiotics.{R-2; 7} including certain bone, respiratory, skin, soft tissue, and urinary tract Molecular formula:{R-13}

infections. Cefaclor—C15H14ClN3O4S Æ H2O.

Dogs: There are insufficient data to establish the efficacy and safety of Cefadroxil—C16H17N3O5S Æ H2O. 1 1 1 [cefaclor] , [cefazolin] , [cefotaxime] , ceftiofur (for non–urinary Cefazolin sodium—C14H13N8NaO4S3. 1 1 1 tract infections), [cephalexin] , [cephalothin] , [cephapirin] , and Cefixime—C16H15N5O7S2 Æ H2O. 1 [cephradrine] for the treatment of bacterial infections in dogs; Cefotaxime sodium—C16H16N5NaO7S2. {R-43; 49; 50; 72; 82; 83} however, based on pharmacokinetic data , Cefotetan disodium—C17H15N7Na2O8S4.

knowledge about in vitro efﬁcacy, and the apparent wide margin of Cefoxitin sodium—C16H16N3NaO7S2.

safety, these medications are used to treat a variety of susceptible Ceftiofur hydrochloride—C19H17N5O7S3 Æ HCl.

infections, including certain bone, respiratory, skin, soft tissue, and Ceftiofur sodium—C19H16N5NaO7S3.

urinary tract infections. Also, there are insufficient data to establish Cephalexin—C16H17N3O4S Æ H2O. 1 the clinical efficacy and safety of [cefixime] in the treatment Cephalexin hydrochloride—C16H17N3O4S Æ HCl Æ H2O.

of bacterial infections in dogs; however, pharmacokinetics and Cephalothin sodium—C16H15N2NaO6S2.

Cephapirin sodium—C17H16N3NaO6S2. Cefotaxime Sodium USP—Freely soluble in water; practically insoluble in

Cephradine—C16H19N3O4S. organic solvents. Molecular weight:{R-13} Cefotetan disodium—Very soluble in water. Cefaclor—385.82. Cefoxitin Sodium USP—Very soluble in water; soluble in methanol; Cefadroxil—381.40; 372.39 (hemihydrate); 363.4 (anhydrous){R-14}. sparingly soluble in dimethylformamide; slightly soluble in acetone; Cefazolin sodium—476.49. insoluble in ether and in chloroform. Cefixime—507.50. Ceftiofur sodium—Solubility is pH dependent (greater than 400 mg per Cefotaxime sodium—477.45. mL at pH > 5.5){R-68}. Cefotetan disodium—619.59. Cephalexin USP—Slightly soluble in water; practically insoluble in Cefoxitin sodium—449.44. alcohol, in chloroform, and in ether. Ceftiofur hydrochloride—560.03. Cephalexin Hydrochloride USP—Soluble to the extent of 10 mg per mL in Ceftiofur sodium—545.55. water, in acetone, in acetonitrile, in alcohol, in dimethylformamide, Cephalexin—365.41. and in methanol; practically insoluble in chloroform, in ether, in ethyl Cephalexin hydrochloride—401.87. acetate, and in isopropyl alcohol. Cephalothin sodium—418.42. Cephalothin Sodium USP—Freely soluble in water, in saline TS, and in Cephapirin sodium—445.45. dextrose solutions; insoluble in most organic solvents. Cephradine—349.41. Cephapirin Sodium USP—Very soluble in water; insoluble in most Description:{R-14} organic solvents. Cefaclor USP—White to off-white, crystalline powder. Cephradine USP—Sparingly soluble in water; very slightly soluble in Cefadroxil USP—White to off-white, crystalline powder. alcohol and in chloroform; practically insoluble in ether. Cefazolin Sodium USP—White to off-white, practically odorless, crystalline powder, or white to off-white solid. PHARMACOLOGY/PHARMACOKINETICS Cefixime USP—White to light yellow, crystalline powder. Note: See also Table 1. Pharmacology/Pharmacokinetics at the end of this Cefotaxime Sodium USP—Off-white to pale yellow crystalline powder. monograph. Cefotaxime sodium injection—Solutions of cefotaxime sodium range from very pale yellow to light amber depending on the concentration Mechanism of action/effect: Cephalosporins are beta-lactam antibi- and the diluent used. otics that produce their bactericidal effect by inhibition of cell wall Cefotetan disodium—White to pale yellow powder. synthesis. The site of action for beta-lactam antibiotics is the penicillin- Cefotetan disodium injection—Solution varies from colorless to yellow, binding proteins (PBPs) on the inner surface of the bacterial cell depending on the concentration. membrane that are involved in synthesis of the cell wall.{R-2} In ac- Cefoxitin Sodium USP—White to off-white, granules or powder, having a tively growing cells, the cephalosporins bind to the PBPs within the slight characteristic odor. Is somewhat hydroscopic. cell wall and lead to interference in production of cell wall peptido- Cephalexin USP—White to off-white, crystalline powder. glycans and subsequent lysis of the cell in an iso-osmotic environ- Cephalexin Hydrochloride USP—White to off-white crystalline powder. ment.{R-7; 9} Differences in affinity for the types of PBPs by different Cephalothin Sodium USP—White to off-white, practically odorless, beta-lactam antibiotics and the bacterial defense mechanisms explain crystalline powder. the variations in bactericidal activity among cephalosporins.{R-9} Cephapirin Sodium USP—White to off-white crystalline powder, odorless or having a slight odor. Distribution: Cephalosporins distribute into most body tissues and Cephradine USP—White to off-white, crystalline powder. fluids.{R-18} They penetrate into pleural fluid, synovial fluid, pericardial pKa: fluid, and urine. Cephalosporins can be found in bile fluid if no biliary Cefotaxime—3.35.{R-15} obstruction is present.{R-1} The cephalosporins penetrate aqueous Cefoxitin—2.2.{R-16; 17} humor and prostatic fluid less than other body fluids. Most of the Cephalexin—5.3 and 7.3.{R-16; 17} cephalosporins have poor penetration of the blood-brain barrier.{R-2} Cephalothin—5.0.{R-17} Cefuroxime is the only second-generation cephalosporin known to Cephapirin—2.15 and 5.44.{R-16} adequately penetrate into cerebrospinal fluid in people; also, the third- Cephradine—2.6 and 7.3.{R-17} generation antibiotics cefotaxime and cefoxitin{R-1} have been shown Solubility:{R-14} to penetrate inflamed meninges in people. Ceftriaxone has been shown Cefaclor USP—Slightly soluble in water; practically insoluble in meth- to penetrate normal meninges in horses{R-103}. anol and in chloroform. The high level of protein binding by ceftiofur in adult animals causes its Cefadroxil USP—Slightly soluble in water; practically insoluble in distribution to differ from that of other cephalosporins{R-91}. Also, the alcohol, in chloroform, and in ether. primary metabolite of ceftiofur, desfuroylceftiofur, has a reactive Cefazolin Sodium USP—Freely soluble in water, in saline TS, and in sulfhydryl group that forms reversible covalent bonds with plasma and dextrose solutions; very slightly soluble in alcohol; practically insoluble tissue proteins{R-63}. Free concentrations of ceftiofur and its active in chloroform; and in ether. metabolites tend to be lower than expected when dosages shown to be Cefixime USP—Freely soluble in methanol; soluble in propylene glycol; effective in the treatment of a disease are administered, possibly because slightly soluble in alcohol, in acetone, and in glycerin; very slightly of their unique protein binding abilities{R-63}. Concentrations of ceftiofur soluble in 70% sorbitol and in octanol; practically insoluble in ether, in and active metabolites in Pasteurella-infected tissue chambers implanted ethyl acetate, in hexane, and in water. into cattle tend to be higher than concentrations in uninfected

chambers{R-73}. Studies of distribution of ceftiofur into other tissues have Although cephalothin has been associated with an increased human also shown it to be unique, although the way in which this affects risk of nephrotoxicity when administered with an aminoglycoside, this efﬁcacy in the extra-label treatment of infections is not known. interaction may not apply to other cephalosporins{R-98}. In fact, there is some evidence that certain cephalosporins such as cefamandole, Biotransformation: Cefotaxime{R-20},cephalothin{R-19},andcephapirin cefazolin, and cephalothin provide a protective effect against amino- undergo biotransformation in the liver to desacetyl derivatives.{R-1; 2} glycoside-induced nephrotoxicity in rats{R-101} while others, such as Ceftiofur is rapidly converted in vivo to desfuroylceftiofur, which is cephalexin, have no effect{R-102}. structurally similar to and, in most instances, equally active micro- Probenecid biologically to, ceftiofur.{R-30} The signiﬁcant exceptions are that (probenecid administered concurrently with a cephalosporin will Staphylococcus aureus is four- to eightfold{R-100} less sensitive to des- inhibit renal tubular secretion and in some cases increase the serum furoylceftiofur than to ceftiofur{R-63}, and that Proteus mirabilis has a concentrations and prolong the serum half-life of the cephalosporin{R-2}, widely variable susceptibility to some ceftiofur metabolites{R-72}. The including cefadroxil{R-3}, cefoxitin{R-26}, cephalothin{R-30}, and ceph- metabolites of other cephalosporins may retain some antibacterial apirin{R-27}; probenecid has not been shown to alter the renal tubular activity. secretion of ceftiofur{R-70})

Elimination: For most cephalosporins, elimination is by renal tubular secretion and/or glomerular filtration. HUMAN DRUG INTERACTIONS{R-46} In addition to the above drug interactions reported in animals, the following drug interactions have been reported in humans, and are PRECAUTIONS TO CONSIDER included in the human monograph Cephalosporins (Systemic) in USP DI SPECIES SENSITIVITY Volume I; these drug interactions are intended for informational Rabbits and small rodents{R-80}—Cephalosporins may disturb the normal purposes only and may or may not be applicable to the use of intestinal microflora, particularly when administered orally at high cephalosporins in the treatment of animals: doses.{R-21} Antacids (the extent of absorption of cefaclor is decreased with concurrent use of aluminum hydroxide- or magnesium-containing antacids; cefaclor CROSS-SENSITIVITY should not be taken within 1 hour of taking these antacids) The incidence of cross-sensitivity in animals is unknown. Caution should Anticoagulants, coumarin- or indandione-derivative, or be used when cephalosporins are administered to patients with a Heparin or history of an anaphylactic reaction to other beta-lactam antibiotics Thrombolytic agents because cross-reaction may occur{R-1}; however, a history of a delayed (concurrent use of these medications with cefotetan may increase allergic reaction to penicillin does not contraindicate use of a the risk of bleeding because of the N-methylthiotetrazole [NMTT] {R-2} cephalosporin. side chain on these medications; however, critical illness, poor nutritional status, and the presence of liver disease may be more PREGNANCY/REPRODUCTION important risk factors for hypoprothrombinemia and bleeding; Pregnancy—Cephalosporins have been shown to cross the placenta in because all cephalosporins can inhibit vitamin K synthesis by animals. Studies in laboratory animals have not shown the cephalo- suppressing gut flora, prophylactic vitamin K therapy is recom- sporins to cause adverse effects in the fetus.{R-22–24} Studies with mended when any of these medications is used for prolonged cefoxitin have not shown that the medication is teratogenic or periods in malnourished or seriously ill patients; dosage adjust- fetotoxic in mice and rats, but a slight decrease in fetal weight{R-21} ments of anticoagulants may be necessary during and after has occurred. therapy with cefotetan; concurrent use with thrombolytic agents may increase the risk of severe hemorrhage and is not recommended) LACTATION (an increased anticoagulant effect has been reported with concur- Cephalosporins are distributed into milk{R-25}; however, when adminis- rent use of cefaclor and oral anticoagulants) tered systemically at accepted doses, therapeutic concentrations are not Nephrotoxic medications reached in milk.{R-67; 69} When ceftiofur is administered systemically at (cephalothin has been associated with an increased incidence of recommended dosages, distribution is too low to produce residues nephrotoxicity when used concurrently with aminoglycosides; this greater than established regulatory tolerances.{R-68; 69} effect has rarely been seen with other commercially available cephalosporins used at appropriate doses; the potential for increased DRUG INTERACTIONS AND/OR RELATED PROBLEMS nephrotoxicity exists when cephalosporins are used with other The following drug interactions and/or related problems have been nephrotoxic medications, such as loop diuretics, especially in patients selected on the basis of their potential clinical significance (possible with pre-existing renal function impairment; renal function should mechanism in parentheses where appropriate)—not necessarily inclu- be monitored carefully in patients receiving cephalosporins and sive (» = major clinical significance): aminoglycosides concurrently) Note: Combinations containing any of the following medications, Platelet aggregation inhibitors, other depending on the amount present, may also interact with this (hypoprothrombinemia induced by large doses of salicylates and/or medication. cephalosporins, and the gastrointestinal ulcerative or hemorrhagic

potential of nonsteroidal anti-inflammatory drugs [NSAIDs], salicy- Creatinine, serum lates, or sulfinpyrazone may increase the risk of hemorrhage) (concentrations may be increased) Complete blood count (CBC) or LABORATORY VALUE ALTERATIONS Platelet count (transient leukopenia, neutropenia, agranulocytosis, thrombocy- The following have been selected on the basis of their potential clinical topenia, eosinophilia, lymphocytosis, and thrombocytosis have significance (possible effect in parentheses where appropriate)—not been reported on rare occasions) necessarily inclusive (» = major clinical significance): With diagnostic test results Coombs’ test (positive reactions for the Coombs’ test may be seen in animals MEDICAL CONSIDERATIONS/CONTRAINDICATIONS receiving cephalosporins; this may be due to changes in the red blood The medical considerations/contraindications included have been cells, but hemolytic anemia usually is not occurring{R-2}) selected on the basis of their potential clinical significance (reasons With physiology/laboratory test values given in parentheses where appropriate)—not necessarily inclusive Ketones, urine (» = major clinical significance). (values may be increased){R-68} Risk-benefit should be considered when the following medical problems exist: HUMAN LABORATORY VALUE ALTERATIONS{R-46} Bleeding disorders, history of The following laboratory value alterations have been reported in (some of the second- and third-generation cephalosporins have been {R-65} humans, and are included in the human monograph Cephalosporins associated with an increased risk of bleeding in people due to a (Systemic) in USP DI Volume I; these laboratory value alterations are decrease in prothrombin activity, and bleeding is considered a intended for informational purposes only and may or may not be potential human risk with all the cephalosporins; there is evidence of applicable to the use of cephalosporins in the treatment of animals: a significant increase in bleeding time after cephalothin administra- {R-28} With diagnostic test results tion to beagles but not outside normal reference ranges; clinical Coombs’ (antiglobulin) tests problems have not been reported in animals and the clinical (a positive Coombs’ reaction frequently appears in patients who significance is unknown) receive large doses of a cephalosporin; hemolysis rarely occurs, but Hepatic dysfunction, severe has been reported; test may be positive in neonates whose mothers (because cefotaxime, cephalothin, and cephapirin are hepatically received cephalosporins before delivery) metabolized before renal elimination, severe liver dysfunction can {R-2} Creatinine, serum and urine inhibit metabolism ) (cefotetan, cefoxitin, or cephalothin may falsely elevate test values Renal insufficiency when the Jaffe´’s reaction method is used; serum samples should (nephrotoxicity may occur in patients with renal insufficiency who not be obtained within 2 hours after administration) are receiving the full dosage of cephalosporin; dosage should be {R-1} Glucose, urine adjusted) (some cephalosporins [cefaclor, cefazolin, cefixime, cefotetan, cefoxitin, cephalexin, cephalothin, cephapirin, cephradine] may produce false-positive or falsely elevated test results with copper SIDE/ADVERSE EFFECTS sulfate tests [Benedict’s, Fehling’s, or Clinitest]; glucose enzymatic The following side/adverse effects have been selected on the basis of tests, such as Clinistix and Tes-Tape, are not affected) their potential clinical significance (possible signs and, for humans, Protein, urine symptoms in parentheses where appropriate)—not necessarily inclu- (cefamandole may produce false-positive tests for proteinuria with sive: acid and denaturization-precipitation tests) Prothrombin time (PT) THOSE INDICATING NEED FOR MEDICAL ATTENTION (may be prolonged; cephalosporins may inhibit vitamin K synthe- Incidence unknown sis by suppressing gut flora; also, cephalosporins with the NMTT All species side chain [cefamandole, cefoperazone, cefotetan] have been Hypersensitivity reactions (acute anaphylaxis or angioedema, associated with an increased incidence of hypoprothrombinemia; allergic agranulocytosis{R-31}, fever{R-31}, serum sickness, urticaria{R- patients who are critically ill, malnourished, or have liver function 2}) impairment may be at the highest risk of bleeding) With physiology/laboratory test values Dogs {R-11} Alanine aminotransferase (ALT [SGPT]), serum, or Anemia; thrombocytopenia Alkaline phosphatase, serum, or Note: Anemia and thrombocytopenia have been seen in dogs given Aspartate aminotransferase (AST [SGOT]), serum, or ceftiofur at high doses (three to five times the labeled dose) or for long Lactate dehydrogenase (LDH), serum periods of time (5 to 6 weeks). These side effects appear to be (values may be increased) reversible when treatment is discontinued. Bilirubin, serum, or Horses Blood urea nitrogen (BUN) or Diarrhea{R-11}—with ceftiofur

THOSE INDICATING NEED FOR MEDICAL FOR ORAL DOSAGE FORMS ONLY ATTENTION ONLY IF THEY CONTINUE OR ARE Administration of oral cephalosporins, such as cefadroxil, with food BOTHERSOME appears to decrease nausea in those animals prone to the side All species effect{R-33}; however, administration of cefixime with food can Anorexia{R-10; 32}; diarrhea and vomiting{R-3}—possibly due to decrease by one half the bioavailability of the antibiotic{R-77}. local irritation from the oral dosage forms{R-1}; diarrhea caused by altered gut flora{R-2; 10}; local reactions{R-1; 11} (mild to moderate pain, heat, swelling)—with parenteral dosage forms, FOR PARENTERAL DOSAGE FORMS ONLY especially cephalothin and cephapirin; phlebitis{R-2}—with intrave- Many cephalosporins can be reconstituted with 1% lidocaine to decrease {R-80} nous administration injection pain. See the manufacturer’s package insert . Note: Diarrhea and vomiting can occur with any dosage but are more common with high doses.{R-33} Administration of the antibiotic FOR TREATMENT OF ADVERSE EFFECTS with food may decrease the incidence of gastrointestinal For anaphylaxis {R-33} effects. Recommended treatment consists of the following: • Parenteral epinephrine. • Oxygen administration and breathing support. HUMAN SIDE/ADVERSE EFFECTS{R-46} • Parenteral fluid administration as needed. In addition to the above side/adverse effects reported in animals, the following side/adverse effects have been reported in humans, and are CEFACLOR included in the human monograph Cephalosporins (Systemic) in USP DI Volume I; these side/adverse effects are intended for information SUMMARY OF DIFFERENCES purposes only and may or may not be applicable to the use of Indications: General considerations—Second-generation cephalosporin. cephalosporins in the treatment of animals: Incidence more frequent ORAL DOSAGE FORMS Gastrointestinal reactions; headache; oral candidiasis; vaginal Note: Bracketed information in the Dosage Forms section refers to uses candidiasis that either are not included in U.S. product labeling or are for products Incidence less frequent or rare not commercially available in the U.S. Hypoprothrombinemia—more frequent for cefotetan; pseudomembranous colitis CEFACLOR CAPSULES USP Incidence rare Usual dose: 1 Allergic reactions, specifically anaphylaxis, erythema multi- Note: [Dogs] —Although the efficacy and safety of cefaclor in dogs forme, or Stevens-Johnson syndrome (blistering, peeling, or have not been established, an oral dose of 4 to 20 mg per kg of body loosening of skin and mucous membranes, which may involve the weight every eight hours has been used in the treatment of {R-2} eyes or other organ systems); hearing loss—has occurred rarely in susceptible bacterial infections in dogs. There is very pediatric patients being treated for meningitis, but more frequently little canine-specific information about cefaclor; therefore, dose with cefuroxime; hemolytic anemia, immune, drug-induced— recommendations are based primarily on human pharmacokinetics has occurred with many cephalosporins, but reported more commonly with cefotetan; hypersensitivity reactions—has occurred Strength(s) usually available: {R-24} with many cephalosporins, but reported more commonly with U.S.— cefazolin; renal dysfunction; serum sickness–like reac- Veterinary-labeled product(s): tions—may be more frequent with cefaclor; seizures—especially Not commercially available. with high doses and in patients with renal function impairment; Human-labeled product(s): thrombophlebitis 250 mg (Rx) [Ceclor]. 500 mg (Rx) [Ceclor]. Canada—{R-36} OVERDOSE Veterinary-labeled product(s): For information in cases of overdose or unintentional ingestion, contact Not commercially available. the American Society for the Prevention of Cruelty to Animals Human-labeled product(s): (ASPCA) National Animal Poison Control Center (888-426-4435 250 mg (Rx) [Apo-Cefaclor; Ceclor]. or 900-443-0000; a fee may be required for consultation) and/or the 500 mg (Rx) [Apo-Cefaclor; Ceclor]. drug manufacturer. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specified by VETERINARY DOSING INFORMATION manufacturer. Store in a tight container. Except for specific veterinary labeled medications, most doses listed have been derived from phamacokinetic data, rather than from clinical USP requirements: Preserve in tight containers. Contain the equiva- studies.{R-74} lent of the labeled amount of anhydrous cefaclor, within )10% to

+20%. Meet the requirements for Identification, Dissolution (80% in Drug interactions and/or related problems: Concurrent administration of 30 minutes in water in Apparatus 2 at 50 rpm), Uniformity of dosage probenecid may prolong the serum half-life of cefadroxil.{R-3} units, and Water (not more than 8.0%).{R-14} ORAL DOSAGE FORMS CEFACLOR FOR ORAL SUSPENSION USP CEFADROXIL FOR ORAL SUSPENSION USP Usual dose: See Cefaclor Capsules USP. Usual dose: Skin and soft tissue infections— Strength(s) usually available: When reconstituted according to Cats: Oral, 22 mg per kg of body weight every twenty-four manufacturer’s instructions— hours{R-37; 38}. U.S.:{R-24} Dogs: Oral, 22 mg per kg of body weight every twelve hours{R-37; 38}. Veterinary-labeled product(s)— Urinary tract infections—Dogs: Oral, 22 mg per kg of body weight Not commercially available. every twelve hours{R-37; 38}. Human-labeled product(s)— 25 mg per mL (Rx) [Ceclor; GENERIC]. Strength(s) usually available: When reconstituted according to 37.4 mg per mL (Rx) [Ceclor; GENERIC]. manufacturer’s instructions— 50 mg per mL (Rx) [Ceclor; GENERIC]. U.S.: 75 mg per mL (Rx) [Ceclor; GENERIC]. Veterinary-labeled product(s)— Canada:{R-36} 50 mg per mL (Rx) [Cefa-Drops]. Veterinary-labeled product(s)— Canada: Not commercially available. Veterinary-labeled product(s)— Human-labeled product(s)— 50 mg per mL (Rx) [Cefa-Drops]. 25 mg per mL (Rx) [Apo-Cefaclor; Ceclor]. 50 mg per mL (Rx) [Apo-Cefaclor; Ceclor]. Packaging and storage: Store below 40 C (104 F), preferably be- 75 mg per mL (Rx) [Apo-Cefaclor; Ceclor]. tween 15 and 30 C (59 and 86 F), unless otherwise specified by manufacturer. Store in a tight container. Packaging and storage: Prior to reconstitution, store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless Stability: When reconstituted according to manufacturer’s directions otherwise specified by manufacturer. Store in a tight container. and refrigerated, suspensions retain their potency for 14 days.{R-37}

Stability: After reconstitution, suspensions retain their potency for 14 USP requirements: Preserve in tight containers. A dry mixture of days if refrigerated. Cefadroxil and one or more suitable buffers, colors, diluents, and flavors. Contains the equivalent of the labeled amount of anhydrous Auxiliary labeling: cefadroxil, within –10% to +20%. Meets the requirements for Identi- • Refrigerate. fication, Uniformity of dosage units (solid packaged in single-unit • Shake well. containers), Deliverable volume (solid packaged in multiple-unit containers), pH (4.5–6.0, in the suspension constituted as directed in the {R-14} USP requirements: Preserve in tight containers. A dry mixture of labeling), and Water (not more than 2.0%). Cefaclor and one or more suitable buffers, colors, diluents, and flavors. Contains the equivalent of the labeled amount of anhydrous cefaclor, CEFADROXIL TABLETS USP within –10% to +20%. Meets the requirements for Identification, Usual dose: See Cefadroxil for Oral Suspension USP. Uniformity of dosage units (solid packaged in single-unit containers), Deliverable volume (solid packaged in multiple-unit containers), pH Strength(s) usually available: (2.5–5.0, in the suspension constituted as directed in the labeling), and U.S.— Water (not more than 2.0%).{R-14} Veterinary-labeled product(s): 50 mg (Rx) [Cefa-Tabs]. 100 mg (Rx) [Cefa-Tabs]. 1Not included in Canadian product labeling or product not commercially 200 mg (Rx) [Cefa-Tabs]. available in Canada. 1 gram (Rx) [Cefa-Tabs]. Canada— Veterinary-labeled product(s): 50 mg (Rx) [Cefa-Tabs]. CEFADROXIL 100 mg (Rx) [Cefa-Tabs]. SUMMARY OF DIFFERENCES 200 mg (Rx) [Cefa-Tabs]. Indications: General considerations—First-generation cephalosporin. Packaging and storage: Store below 40 C (104 F), preferably Indicated for treatment of susceptible genitourinary tract infections in between 15 and 30 C (59 and 86 F), unless otherwise specified by dogs and skin and soft tissue infections in cats and dogs. manufacturer. Store in a tight container.

in a diluent containing one or more suitable tonicity-adjusting agents. USP requirements: Preserve in tight containers. The Tablets prepared It meets the requirements for Labeling under Injections. The label using the hemihydrate form of Cefadroxil are so labeled. Contain the states that it is to be thawed just prior to use, describes conditions for labeled amount of anhydrous cefadroxil, within –10% to +20%. Meet proper storage of the resultant solution, and directs that the solution is the requirements for Identiﬁcation, Dissolution (75% in 30 minutes in not to be refrozen. Contains the labeled amount, within –10% to water in Apparatus 2 at 50 rpm), Uniformity of dosage units, and +15%. Meets the requirements for Identiﬁcation, Bacterial endotoxins, Water (not more than 8.0%).{R-14} Sterility, pH (4.5–7.0), and Particulate matter.{R-14}

CEFAZOLIN FOR INJECTION USP CEFAZOLIN Usual dose: [Perioperative infections (prophylaxis)]1—Dogs: Intrave- SUMMARY OF DIFFERENCES nous, 22 mg (base) per kg of body weight every two hours, or 8 mg Indications: General considerations—First-generation cephalosporin. (base) per kg of body weight every hour, starting at the beginning of surgery and continuing until the end of surgery{R-82}. Note: The above dose is based on pharmacokinetic studies, including PARENTERAL DOSAGE FORMS studies performed during surgical procedures. Note: Bracketed information in the Dosage Forms section refers to uses Also for [dogs]1, based on pharmacokinetics studies, an intramuscu- that either are not included in U.S. product labeling or are for products lar or intravenous dose of 20 to 35 mg (base) per kg of body weight not commercially available in the U.S. every four to eight hours has been used for the treatment of The dosing and strengths of the dosage forms available are expressed susceptible bacterial infections{R-2; 38; 86}. in terms of cefazolin base (not the sodium salt).

Size(s) usually available: CEFAZOLIN INJECTION USP U.S.—{R-39} Usual dose: Although Cefazolin Injection USP is the same antimicrobial Veterinary-labeled product(s): as Cefazolin For Injection USP, it is only available frozen in premixed Not commercially available. dilute concentrations, making it less practical for veterinary use. For Human-labeled product(s): dosing information, see Cefazolin For Injection USP. 500 mg (base) (Rx) [Ancef; Kefzol; GENERIC]. 1 gram (base) (Rx) [Ancef; Kefzol; GENERIC]. Strength(s) usually available: 5 grams (base) (Rx) [Ancef]. U.S.— 10 grams (base) (Rx) [Ancef; Kefzol; GENERIC]. {R-40} Veterinary-labeled product(s): Canada— Not commercially available. Veterinary-labeled product(s): Human-labeled product(s): Not commercially available. 500 mg (base) in 50 mL (Rx) [Ancef]. Human-labeled product(s): 1 gram (base) in 50 mL (Rx) [Ancef]. 50 mg (base) (Rx) [Kefzol]. Canada— 500 mg (base) (Rx) [Ancef; Kefzol; GENERIC]. Not commercially available. 1 gram (base) (Rx) [Ancef; Kefzol; GENERIC]. 10 grams (base) (Rx) [Ancef; Kefzol; GENERIC].

Packaging and storage: Store at –10 C (14 F) or below, unless Packaging and storage: Prior to reconstitution, store below 40 C otherwise speciﬁed by the manufacturer. (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by manufacturer. Preparation of dosage form: Cefazolin sodium injection should be thawed at room temperature, and all ice crystals should have melted, Preparation of dosage form: To prepare the 100 mg of cefazolin (base) before administration. Thawing should not be forced by immersion in per mL dilution commonly used in veterinary practice for intramuscular water baths or by microwave irradiation. or intravenous administration, 9.6 mL of sterile water for injection should be added to each 1-gram vial{R-39; 95}. See manufacturer’s Stability: See manufacturer’s product labeling for stability information. package insert for other preparation instructions.

Incompatibilities: Stability: See manufacturer’s product labeling for stability information. The admixture of cefazolin sodium injection with other medications is not recommended. Incompatibilities: The admixture of beta-lactam antibacterials (peni- The admixture of beta-lactam antibacterials (penicillins and cephalospo- cillins and cephalosporins) and aminoglycosides may result in sub- rins) and aminoglycosides may result in substantial mutual inactiva- stantial mutual inactivation; they should not be mixed in the same tion; they should not be mixed in the same intravenous bag or bottle. intravenous bag or bottle.

USP requirements: Preserve in Containers for Injections. Maintain in USP requirements: Preserve in containers for Sterile Solids. Contains the frozen state. A sterile solution of Cefazolin and Sodium Bicarbonate an amount of Cefazolin Sodium equivalent to the labeled amount of

cefazolin, within –10% to +15%. Meets the requirements for Consti- therein is in the trihydrate form. Contains the labeled amount of tuted solution, Identification, Specific rotation (–10 to –24), Bacterial anhydrous cefixime, within –10% to +20%, per mL when constituted endotoxins, Sterility, pH (4.0–6.0, in a solution containing 100 mg of as directed in the labeling. Meets the requirements for Identification, cefazolin per mL), Uniformity of dosage units, Water (not more than Uniformity of dosage units (solid packaged in single-unit containers), 6.0%), and Particulate matter, and for Labeling under Injections {R-14}. Deliverable volume (solid packaged in multiple-unit containers), pH (2.5–4.5, in the suspension constituted as directed in the labeling), and 1Not included in Canadian product labeling or product not commercially Water (not more than 2.0%).{R-14} available in Canada. CEFIXIME TABLETS USP Usual dose: See Cefixime for Oral Suspension USP. CEFIXIME Strength(s) usually available: SUMMARY OF DIFFERENCES U.S.— Indications: General considerations—Third-generation cephalosporin. Veterinary-labeled product(s): Veterinary Dosing Information: Administration with food decreases the Not commercially available. bioavailability by one half. Human-labeled product(s): 200 mg (Rx) [Suprax]. ORAL DOSAGE FORMS 400 mg (Rx) [Suprax]. Note: Bracketed information in the Dosage Forms section refers to uses Canada— that either are not included in U.S. product labeling or are for products Veterinary-labeled product(s): not commercially available in the U.S. Not commercially available. Human-labeled product(s): 200 mg (Rx) [Suprax]. CEFIXIME FOR ORAL SUSPENSION USP 400 mg (Rx) [Suprax]. Usual dose: Note: [Dogs]1—Although the efficacy and safety of cefixime have not Packaging and storage: Store below 40 C (104 F), preferably been established, an oral dose of 5 mg per kg of body weight every between 15 and 30 C (59 and 86 F), unless otherwise specified by twelve to twenty-four hours has been used in the treatment of cystitis manufacturer. in dogs, based on pharmacokinetic data.{R-77} There are also some pharmacokinetic data to suggest that the same USP requirements: Preserve in tight containers. Label Tablets to dose, administered for two to four weeks, is likely to be effective for indicate that the cefixime contained therein is in the trihydrate form. {R-77} treatment of bone, skin, and soft tissue infections in dogs . Contain the labeled amount of anhydrous cefixime, within ±10%. Meet the requirements for Identification, Dissolution (75% in 45 Strength(s) usually available: When reconstituted according to minutes in 0.05 M potassium phosphate buffer [pH 7.2] in Apparatus manufacturer’s directions— 1 at 100 rpm), Uniformity of dosage units, and Water (not more than U.S.— 10.0%).{R-14} Veterinary-labeled product(s): Not commercially available. 1Not included in Canadian product labeling or product not commercially Human-labeled product(s): available in Canada. 20 mg per mL (Rx) [Suprax]. Canada— CEFOTAXIME Veterinary-labeled product(s): Not commercially available. SUMMARY OF DIFFERENCES Human-labeled product(s): Indications: General considerations—Third-generation cephalosporin. 20 mg per mL (Rx) [Suprax]. Pharmacology/pharmacokinetics: Biotransformation—Significant metabolism occurs with the major Packaging and storage: Prior to reconstitution, store below 40 C pathway yielding a desacetyl derivative. Desacetylcefotaxime is less (104 F), preferably between 15 and 30 C (59 and 86 F), unless active against staphylococci but acts synergistically with the parent {R-1} otherwise specified by manufacturer. compound against sensitive gram-negative bacteria. Distribution—In people, when administered at high doses, cefotaxime Stability: After reconstitution, suspension retains its potency for 14 enters the cerebrospinal fluid in therapeutic concentrations when {R-1} days at room temperature or if refrigerated. meninges are inflamed. Medical considerations/contraindications: Severe hepatic dysfunction {R-2} Auxiliary labeling: can inhibit metabolism. • Shake well. PARENTERAL DOSAGE FORMS USP requirements: Preserve in tight containers. A dry mixture of Note: Bracketed information in the Dosage Forms section refers to uses Cefixime and one or more suitable diluents, flavors, preservatives, and that either are not included in U.S. product labeling or are for products suspending agents. Label it to indicate that the cefixime contained not commercially available in the U.S.

The dosing and strengths of the dosage forms available are expressed Human-labeled product(s): in terms of cefotaxime free acid (not the sodium salt). 500 mg (free acid) (Rx) [Claforan]. 1 gram (free acid) (Rx) [Claforan]. CEFOTAXIME INJECTION USP 2 grams (free acid) (Rx) [Claforan]. Usual dose: 10 grams (free acid) (Rx) [Claforan]. 1 Note: [Cats] —Although the efficacy and safety have not been Canada— established, an intramuscular or intravenous dose of 20 to 80 mg Veterinary-labeled product(s): (free acid) per kg of body weight every six hours has been used in the Not commercially available. treatment of susceptible bacterial infections in cats, based on Human-labeled product(s): {R-42} pharmacokinetic data . 500 mg (free acid) (Rx) [Claforan]. 1 [Dogs] —Although the efficacy and safety have not been established, 1 gram (free acid) (Rx) [Claforan]. a subcutaneous dose of 50 mg (free acid) per kg of body weight every 2 grams (free acid) (Rx) [Claforan]. twelve hours has been used in the treatment of susceptible bacterial infections in dogs, based on pharmacokinetic data. When adminis- Packaging and storage: Prior to reconstitution, store below 30 C (86 tered intramuscularly, the dose should be repeated every eight F), preferably between 15 and 30 C (59 and 86 F), unless otherwise {R-43} hours . specified by manufacturer. [Foals]1—Although the efficacy and safety have not been established, an intravenous dose of 40 mg (free acid) per kg of body weight every Preparation of dosage form: Dilutions should be prepared according six hours has been used in the treatment of neonatal sepsis or to manufacturer’s instructions. susceptible bacterial meningitis in foals{R-62}. Stability: See manufacturer’s product labeling for stability information. Strength(s) usually available: U.S.—{R-44} Additional information: A solution containing 1 gram of cefotaxime Veterinary-labeled product(s): sodium in 14 mL of sterile water for injection is isotonic{R-44}. Not commercially available. Human-labeled product(s): USP requirements: Preserve in Containers for Sterile Solids. Contains 20 mg (free acid) per mL (Rx) [Claforan]. an amount of Cefotaxime Sodium equivalent to the labeled amount of 40 mg (free acid) per mL (Rx) [Claforan]. cefotaxime, within –10% to +15%. Meets the requirements for Con- Canada— stituted solution, Identification, Bacterial endotoxins, Sterility, Unifor- Not commercially available. mity of dosage units, Particulate matter, and Chromatographic purity, for pH and Loss on drying under Cefotaxime Sodium, and for Labeling Packaging and storage: Store at –20 C (–4 F) or below, unless under Injections.{R-14} otherwise specified by manufacturer.{R-44}

1 Preparation of dosage form: {R-44} Cefotaxime sodium injection should Not included in Canadian product labeling or product not commercially be thawed at room temperature, and all ice crystals should have available in Canada. melted, before administration.

Stability: See manufacturer’s product labeling for stability information. CEFOTETAN SUMMARY OF DIFFERENCES USP requirements: Preserve in single-dose containers. Maintain in the Indications: General considerations—Second-generation cephalosporin. frozen state. A sterile solution of Cefotaxime Sodium in Water for Injection. Contains one or more suitable buffers. It meets the requirements for Labeling under Injections. The label states that it is to PARENTERAL DOSAGE FORMS be thawed just prior to use, describes conditions for proper storage of Note: Bracketed information in the Dosage Forms section refers to uses the resultant solution, and directs that the solution is not to be that either are not included in U.S. product labeling or are for products refrozen. Contains an amount of cefotaxime sodium equivalent to the not commercially available in the U.S. labeled amount of cefotaxime, within ±10%. Meets the requirements The dosing and strengths of the dosage forms available are expressed for Identiﬁcation, Bacterial endotoxins, Sterility, pH (5.0–7.5), Partic- in terms of cefotetan base (not the disodium salt). ulate matter, and Chromatographic purity.{R-14} CEFOTETAN FOR INJECTION USP CEFOTAXIME FOR INJECTION USP Usual dose: Usual dose: See Cefotaxime Sodium Injection USP. Note: [Dogs]1—Although the efﬁcacy and safety have not been established, an intravenous dose of 30 mg (base) per kg of body Size(s) usually available: weight every eight hours or the same dose administered subcutane- U.S.—{R-44} ously every twelve hours has been used in the treatment of Veterinary-labeled product(s): susceptible bacterial infections in dogs, based on pharmacokinetic Not commercially available. data{R-80; 84}.

Size(s) usually available: CEFOXITIN INJECTION USP U.S.— Usual dose: Veterinary-labeled product(s): Note: [Dogs]1—Although the efficacy and safety have not been Not commercially available. established, an intravenous dose of 30 mg (base) per kg of body Human-labeled product(s): weight every six hours or the same dose administered subcutaneously 1 gram (base) (Rx) [Cefotan]. every eight hours has been used in the treatment of susceptible 2 grams (base) (Rx) [Cefotan]. bacterial infections in dogs, based on pharmacokinetic data{R-38; 84}. 10 grams (base) (Rx) [Cefotan]. [Horses]1—Although the efficacy and safety have not been Canada— established, an intravenous dose of 20 mg (base) per kg of body Veterinary-labeled product(s): weight every four to six hours has been used in the treatment of Not commercially available. susceptible bacterial infections in horses, based on pharmacokinetic Human-labeled product(s): data{R-29}. 1 gram (base) (Rx) [Cefotan]. Strength(s) usually available:{R-45} 2 grams (base) (Rx) [Cefotan]. U.S.— Veterinary-labeled product(s): Packaging and storage: Prior to reconstitution, do not store above Not commercially available. 22 C (72 F), unless otherwise specified by manufacturer. Protect Human-labeled product(s): from light. 20 mg (base) per mL (Rx) [Mefoxin]. 40 mg (base) per mL (Rx) [Mefoxin]. Preparation of dosage form: Dilutions should be prepared according Canada— to manufacturer’s instructions. Not commercially available. Stability: See manufacturer’s product labeling for stability information. Packaging and storage: {R-45} Store at –20 C (–4 F) or below, unless Incompatibilities: The admixture of beta-lactam antibacterials and otherwise specified by manufacturer. aminoglycosides may result in substantial mutual inactivation. They should not be mixed in the same intravenous bag or bottle. Preparation of dosage form: See manufacturer’s product labeling.

USP requirements: Preserve in containers for Sterile Solids. Contains USP requirements: Preserve in Containers for Injections. Maintain in an amount of Cefotetan Disodium equivalent to the labeled amount the frozen state. A sterile solution of Cefoxitin Sodium and one or more of cefotetan, within –10 to +20%. Meets the requirements for suitable buffer substances in Water for Injection. Contains Dextrose or Constituted solution, Bacterial endotoxins, Sterility, and Particulate Sodium Chloride as a tonicity-adjusting agent. It meets the require- matter, for Identiﬁcation, pH, and Water under Cefotetan Disodi- ments for Labeling under Injections. The label states that it is to be um, for Uniformity of dosage units, and for Labeling under Injec- thawed just prior to use, describes conditions for proper storage of the tions.{R-14} resultant solution, and directs that the solution is not to be refrozen. Contains an amount of cefoxitin sodium equivalent to the labeled 1Not included in Canadian product labeling or product not commercially amount of cefoxitin, within –10% to +20%. Meets the requirements for available in Canada. Identiﬁcation, Bacterial endotoxins, Sterility, pH (4.5–8.0), and Par- ticulate matter.{R-14}

CEFOXITIN CEFOXITIN FOR INJECTION USP SUMMARY OF DIFFERENCES Usual dose: See Cefoxitin Injection USP. Indications: General considerations—Second-generation cephalosporin; good activity against anaerobic organisms, but only active against Size(s) usually available: {R-21} some Bacteroides fragilis.{R-1} U.S.— Pharmacology/pharmacokinetics: Distribution—In people, when admin- Veterinary-labeled product(s): istered at high doses, cefoxitin enters the cerebrospinal ﬂuid in Not commercially available. therapeutic concentrations when meninges are inﬂamed.{R-1} Human-labeled product(s): Drug interactions and/or related problems: Concurrent administration 1 gram (base) (Rx) [Mefoxin]. with probenecid may prolong the serum half-life of cefoxitin.{R-26} 2 grams (base) (Rx) [Mefoxin]. 10 grams (base) (Rx) [Mefoxin]. Canada— PARENTERAL DOSAGE FORMS Veterinary-labeled product(s): Note: Bracketed information in the Dosage Forms section refers to uses Not commercially available. that either are not included in U.S. product labeling or are for products Human-labeled product(s): not commercially available in the U.S. 1 gram (base) (Rx) [Mefoxin; GENERIC]. The dosing and strengths of the dosage forms available are expressed 2 grams (base) (Rx) [Mefoxin; GENERIC]. in terms of cefoxitin base (not the sodium salt). 10 grams (base) (Rx) [Mefoxin].

Packaging and storage: Prior to reconstitution, store below 40 C Strength(s) usually available{R-81; 96; 99}: (104 F), preferably between 15 and 30 C (59 and 86 F), unless U.S.— otherwise speciﬁed by manufacturer. Veterinary-labeled product(s): 50 mg per mL (Rx) [Excenel RTU]. Preparation of dosage form: Dilutions should be prepared according Note: Be aware that this product differs from Excenel available in to manufacturer’s instructions. Canada. Stability: See manufacturer’s product labeling for stability information. Canada— Veterinary-labeled product(s): USP requirements: Preserve in Containers for Sterile Solids. Con- 50 mg per mL (Rx) [Excenel RTU]. tains Cefoxitin Sodium equivalent to the labeled amount of cefoxitin, within –10% to +20%. Meets the requirements for Constituted solu- Withdrawal times{R-81; 96; 99}: tion, Bacterial endotoxins, Sterility, and Particulate matter, for Iden- U.S.— tiﬁcation tests, pH, and Water under Cefoxitin Sodium, for Uniformity of dosage units, and for Labeling under Injections.{R-14} Withdrawal time Species Meat (days) Milk (hours) 1Not included in Canadian product labeling or product not commercially available in Canada. Cattle 2 None Pigs 0–

Note: At labeled doses, discarding of milk during treatment is not CEFTIOFUR required. SUMMARY OF DIFFERENCES Product labeling listing the above withdrawal times states that treatment should not exceed ﬁve days for cattle or three days for pigs Indications: for these withdrawal times to apply. General considerations—‘‘New-generation’’ cephalosporin{R-11}. This product is not labeled for use in preruminating calves. Trim-out of Indicated in the treatment of susceptible Escherichia coli infections in edible tissue at slaughter may occur within 11 days of injection because chicks and turkey poults; metritis and pododermatitis in cattle, of areas of discoloration associated with the injection site{R-81}. respiratory tract infections in cattle, goats, horses, pigs, and sheep, Canada— and urinary tract infections in dogs.

Pharmacology/pharmacokinetics: Biotransformation—Biotransforma- Withdrawal time tion to an active antibacterial metabolite, desfuroylceftiofur, occurs.{R-66} Species Meat (days) Milk (hours) Drug interactions and/or related problems: Probenecid has not been Cattle 3 None shown to alter the excretion of ceftiofur.{R-70} Pigs 2– Side/adverse effects: Often-reversible anemia and thrombocytopenia can occur in animals given three to ﬁve times the recommended dose of Note: Product labeling listing the above withdawal times states that it ceftiofur.{R-66} applies to a dose for pigs of 3 mg per kg of body weight every twenty- four hours for three days and a dose for cattle of 1 mg per kg of body PARENTERAL DOSAGE FORMS weight every twenty-four hours for up to ﬁve days{R-99}. Note: Bracketed information in the Dosage Forms section refers to uses In pigs, trim-out of edible tissue at slaughter may occur within 11 days that either are not included in U.S. product labeling or are for products of intramuscular injection. not commercially available in the U.S. In cattle, trim-out of edible tissue at slaughter may occur within 11 The dosing and strengths of the dosage forms available are expressed days of the last subcutaneous injection or within 28 days of the last in terms of ceftiofur free acid (not the sodium salt). intramuscular injection into the neck{R-99}.

CEFTIOFUR HYDROCHLORIDE INJECTION Packaging and storage: Store below 40 C (104 F), preferably Usual dose: between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by Metritis1—Cattle: Intramuscular or subcutaneous, 2.2 mg per kg of manufacturer. Protect from freezing. body weight every twenty-four hours for ﬁve days{R-81}. Pododermatitis—Cattle: Intramuscular or subcutaneous, 1.1 to 2.2 mg Auxiliary labeling: {R-35} per kg of body weight every twenty-four hours{R-81}. • Shake well before using . {R-81} Respiratory tract infections— • Keep out of reach of children . Cattle: Intramuscular or subcutaneous, 1.1 to 2.2 mg per kg of {R-14} body weight every twenty-four hours{R-81}. Alternatively, the USP requirements: Not in USP . clinician may choose, based on the severity of disease, pathogen susceptibility, and the clinical response, to administer CEFTIOFUR SODIUM FOR INJECTION intramuscularly or subcutaneously, 2.2 mg per kg of body weight Usual dose: every forty-eight hours for two doses{R-81}. Escherichia coli infections— Pigs: Intramuscular, 3 to 5 mg per kg of body weight every twenty- Chicks1, day-old: Subcutaneous, 0.08 to 0.2 mg (free acid) per chick four hours for three days{R-81; 96}. as a single dose{R-11}.

Turkey poults, day-old: Subcutaneous, 0.17 to 0.5 mg (free acid) per Product labeling listing the above withdrawal times states that poult as a single dose{R-11}. treatment should not exceed five days for cattle or three days for Pododermatitis—Cattle: Intramuscular, 1.1 to 2.2 mg (free acid) per kg lambs or pigs for these withdrawal times to apply. of body weight every twenty-four hours{R-11}. Respiratory tract infections— Packaging and storage: Cattle: Intramuscular, 1.1 to 2.2 mg (free acid) per kg of body weight Store unreconstituted product at controlled room temperature, 20 {R-11} every twenty-four hours{R-11}. to 25 C (68 to 77 F) , unless otherwise specified by manu- Goats1: Intramuscular, 1.1 to 2.2 mg (free acid) per kg of body facturer. weight every twenty-four hours{R-11}. Store reconstituted product either in a refrigerator at 2 to 8 C (36 to 46 F) Horses: Intramuscular, 2.2 to 4.4 mg (free acid) per kg of body for up to seven days or at controlled room temperature, 20 to 25 C (68 to {R-11} weight every twenty-four hours{R-11; 12}. 77 F), for up to twelve hours , unless otherwise specified by Note: For treatment of susceptible infections in foals, a dose of 2.2 to manufacturer. 6.6 mg (free acid) per kg of body weight every twelve to twenty- Protect from light. four hours has been used, based on pharmacokinetic data{R-48}. Pigs: Intramuscular, 3 to 5 mg (free acid) per kg of body weight every Preparation of dosage form: To prepare dilution for intramuscular twenty-four hours{R-11}. use, 20 or 80 mL of sterile water for injection should be added to the {R-11} Sheep: Intramuscular, 1.1 to 2.2 mg (free acid) per kg of body weight 1-gram or 4-gram vial, respectively . every twenty-four hours for three days{R-11; 97}. If a satisfactory response is not seen, the dose may be repeated on the fourth and Stability:{R-11} fifth days{R-11; 97}. After reconstitution, solutions retain their potency for 7 days when Urinary tract infections—Dogs: Subcutaneous, 2.2 mg (free acid) per refrigerated at 2 to 8 C (36 to 46 F) or 12 hours at room kg of body weight every twenty-four hours{R-11}. temperature, 15 to 30 C (59 to 86 F). Note: Also for dogs, for treatment of [bacterial infections other than After reconstitution, solutions may be frozen for up to eight weeks. urinary tract infections]1 a dose of 2.2 to 4.4 mg (free acid) per kg of Frozen ceftiofur sodium may be thawed at room temperature or under body weight every twenty-four hours has been used, based on warm to hot running water. Solutions should not be refrozen. pharmacokinetic data{R-74; 76}. Variations in color do not affect potency.

Strength(s) usually available: When reconstituted according to USP requirements: Not in USP{R-14}. manufacturer’s instructions— U.S.:{R-11} 1Not included in Canadian product labeling or product not commercially Veterinary-labeled product(s)— available in Canada. 50 mg per mL (Rx) [Naxcel]. Canada:{R-12} Veterinary-labeled product(s)— 50 mg per mL (Rx) [Excenel]. CEPHALEXIN Withdrawal times: SUMMARY OF DIFFERENCES {R-11} U.S.— Indications: General considerations—First-generation cephalosporin. Withdrawal time

Species Meat (days) Milk (hours) ORAL DOSAGE FORMS Note: Bracketed information in the Dosage Forms section refers to uses Cattle 0 None Goats, pigs, sheep 0–that either are not included in U.S. product labeling or are for products not commercially available in the U.S. Note: At labeled doses, discarding of milk during treatment is not required.{R-68} Product labeling listing the above withdrawal times states that CEPHALEXIN CAPSULES USP treatment should not exceed ﬁve days for cattle, goats, or sheep; or Usual dose: three days for pigs, for these withdrawal times to apply. Note: [Birds]1—Although the efﬁcacy and safety have not been established, an oral dose of 35 to 50 mg per kg of body weight Canada—{R-12} every two to six hours has been used in the treatment of susceptible Withdrawal time bacterial infections in birds, based on pharmacokinetic studies{R-34}.

Species Meat (days) Milk (hours) In general, larger birds maintain measurable serum concentrations of cephalexin longer than do smaller birds; adequate concentrations may Cattle 0 None be achieved in larger birds with a six-hour dosing interval{R-34}. Pigs, sheep 1— [Dogs]1—Although the efﬁcacy and safety have not been established, an oral dose of 10 to 30 mg per kg of body weight every six to twelve Note: At labeled doses, discarding of milk during treatment is not hours has been used in the treatment of susceptible bacterial infections required. in dogs, based on pharmacokinetic data{R-49; 50}.

For pyoderma in dogs, a dose of 25 mg per kg of body weight USP requirements: Preserve in tight containers. A dry mixture of every twelve hours for three weeks has been used, based on Cephalexin and one or more suitable buffers, colors, diluents, and clinical efficacy studies{R-32}. Recurrent pyodermas may require at flavors. Contains the equivalent of the labeled amount of anhydrous least five weeks of therapy and deep pyodermas, nine weeks{R-32}. cephalexin per mL when constituted as directed in the labeling, within –10% to +20%. Meets the requirements for Identification, Uniformity Strength(s) usually available: of dosage units (solid packaged in single-unit containers), Deliverable U.S.—{R-23} volume (solid packaged in multiple-unit containers), pH (3.0–6.0, in Veterinary-labeled product(s): the suspension constituted as directed in the labeling), and Water (not Not commercially available. more than 2.0%).{R-14} Human-labeled product(s): 250 mg (Rx) [Keflex; GENERIC]. CEPHALEXIN TABLETS USP 500 mg (Rx) [Keflex; GENERIC]. Usual dose: See Cephalexin Capsules USP. Canada— Veterinary-labeled product(s): Strength(s) usually available: Not commercially available. U.S.— Human-labeled product(s): Veterinary-labeled product(s): 250 mg (Rx) [Novo-Lexin]. Not commercially available. 500 mg (Rx) [Novo-Lexin]. Human-labeled product(s): 250 mg (Rx) [GENERIC]. Packaging and storage: Store below 40 C (104 F), preferably 500 mg (Rx) [GENERIC]. between 15 and 30 C (59 and 86 F), unless otherwise specified by Canada— manufacturer. Store in a tight container. Veterinary-labeled product(s): Not commercially available. USP requirements: Preserve in tight containers. Contain the equiva- Human-labeled product(s): lent of the labeled amount of anhydrous cephalexin, within –10% to 250 mg (Rx) [Apo-Cephalex; Keflex; Novo-Lexin; Nu-Cephalex; PMS- +20%. Meet the requirements for Identification, Dissolution (80% in Cephalexin]. 30 minutes in water in Apparatus 1 at 100 rpm), Uniformity of dosage 500 mg (Rx) [Apo-Cephalex; Keflex; Novo-Lexin; Nu-Cephalex; PMS- units, and Water (not more than 10.0%).{R-14} Cephalexin].

Packaging and storage: Store below 40 C (104 F), preferably CEPHALEXIN FOR ORAL SUSPENSION USP between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by Usual dose: See Cephalexin Capsules USP. manufacturer. Store in a tight container.

Strength(s) usually available: When reconstituted according to USP requirements: Preserve in tight containers. They are prepared manufacturer’s instructions— from Cephalexin or Cephalexin Hydrochloride. The label states whe- U.S.:{R-23} ther the Tablets contain Cephalexin or Cephalexin Hydrochloride. Veterinary-labeled product(s)— Contain the equivalent of the labeled amount of anhydrous cephalexin, Not commercially available. within –10% to +20%. Meet the requirements for Identification, Dis- Human-labeled product(s)— solution (80% in 30 minutes in water in Apparatus 1 [use 40-mesh 25 mg per mL (Rx) [Keflex; GENERIC]. cloth] at 100 rpm for cephalexin and 75% in 45 minutes in water in 50 mg per mL (Rx) [Keflex; GENERIC]. Apparatus 1 [use 10-mesh cloth] at 150 rpm for cephalexin hydro- Canada: chloride), Uniformity of dosage units, and Water (not more than 9.0% Veterinary-labeled product(s)— where Tablets contain cephalexin; not more than 8.0% where Tablets {R-14} Not commercially available. contain cephalexin hydrochloride). Human-labeled product(s)— CEPHALEXIN HYDROCHLORIDE TABLETS USP 25 mg per mL (Rx) [Keflex; Novo-Lexin; PMS-Cephalexin]. Usual dose: See Cephalexin Capsules USP. 50 mg per mL (Rx) [Keflex; Novo-Lexin; PMS-Cephalexin].

Strength(s) usually available: Packaging and storage: Prior to reconstitution, store below 40 C U.S.—{R-51} (104 F), preferably between 15 and 30 C (59 and 86 F), unless Veterinary-labeled product(s): otherwise speciﬁed by manufacturer. Store in a tight container. Not commercially available. Human-labeled product(s): {R-23} Stability: After reconstitution, suspensions retain their potency for 500 mg (Rx) [Keftab]. 14 days if refrigerated. Canada— Not commercially available. Auxiliary labeling: • Refrigerate. Packaging and storage: Store between 15 and 30 C (59 and 86 F), • Shake well. unless otherwise speciﬁed by manufacturer. Store in a tight container.

USP requirements: Preserve in tight containers. They are prepared Human-labeled product(s): from Cephalexin or Cephalexin Hydrochloride. The label states whe- Not commercially available. ther the Tablets contain Cephalexin or Cephalexin Hydrochloride. Canada—{R-54} Contain the equivalent of the labeled amount of anhydrous cephalexin, Veterinary-labeled product(s): within –10% to +20%. Meet the requirements for Identification, Dis- Not commercially available. solution (80% in 30 minutes in water in Apparatus 1 [use 40-mesh Human-labeled product(s): cloth] at 100 rpm for cephalexin and 75% in 45 minutes in water in 1 gram (base) (Rx) [Ceporacin; Keflin]. Apparatus 1 [use 10-mesh cloth] at 150 rpm for cephalexin hydrochloride), Uniformity of dosage units, and Water (not more than 9.0% Packaging and storage: Prior to reconstitution, store below 40 C where Tablets contain cephalexin; not more than 8.0% where Tablets (104 F), preferably between 15 and 30 C (59 and 86 F), unless {R-14} contain cephalexin hydrochloride). otherwise specified by manufacturer.

1 Not included in Canadian product labeling or product not commercially Preparation of dosage form: {R-22; 53} Dilutions should be prepared available in Canada. according to manufacturer’s instructions.

{R-22} CEPHALOTHIN Stability: After reconstitution, solutions retain their potency for 96 hours if SUMMARY OF DIFFERENCES refrigerated. Solutions for intramuscular use retain their potency for Indications: General considerations—First-generation cephalosporin. 12 hours at room temperature. Drug interactions and/or related problems: Concurrent administration A precipitate may form in the solution. Upon being warmed to room with probenecid may prolong the serum half-life of cephalothin.{R-30} temperature and shaken, the precipitate will dissolve. Medical considerations/contraindications: Severe hepatic dysfunction Concentrated solutions will darken in color, especially at room temper- may inhibit metabolism.{R-2} ature. However, slight discoloration does not affect potency. Side/adverse effects: Local irritation may occur.{R-1} If frozen immediately after reconstitution with sterile water for injection, 5% dextrose injection, or 0.9% sodium chloride injection, solutions PARENTERAL DOSAGE FORMS retain their potency in the original container up to 12 weeks at –20 C (–4 F). Once thawed, solutions should not be refrozen. Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. Incompatibilities: The dosing and strengths of the dosage forms available are expressed The admixture of other medications with cephalothin sodium injection is in terms of cephalothin base (not the sodium salt). not recommended. The admixture of beta-lactam antibiotics (penicillins and cephalosporins) CEPHALOTHIN FOR INJECTION USP and aminoglycosides may result in substantial mutual inactivation; they should not be mixed in the same intravenous bag or bottle. Usual dose: Note: [Birds]1—Although the efficacy and safety have not been established, an intramuscular dose of 100 mg (base) per kg of body USP requirements: Preserve in Containers for Sterile Solids. Contains weight every two to six hours has been used in the treatment of an amount of Cephalothin Sodium equivalent to the labeled amount of susceptible bacterial infections in birds, based on pharmacokinetic cephalothin, within –10% to +15%. May contain Sodium Bicarbonate. studies{R-34}. Meets the requirements for Constituted solution, Specific rotation In general, larger birds maintain measurable serum concentrations (+124 to +134, calculated on the dried and sodium bicarbonate-free of cephalothin longer than do smaller birds; adequate concentrations basis), Content of sodium bicarbonate (if present), Bacterial endotox- may be achieved in larger birds with a six-hour dosing interval{R-34}. ins, Sterility, pH (6.0–8.5, in the solution constituted as directed in the [Dogs]1—Although the efficacy and safety have not been established, labeling), Uniformity of dosage units, and Particulate matter, for an intramuscular or intravenous dose of 10 to 30 mg (base) per kg of Identification test A and Loss on drying under Cephalothin Sodium, {R-14} body weight every four to eight hours has been used in the treatment and for Labeling under Injections. of susceptible bacterial infections in dogs, based on pharmacokinetic 1Not included in Canadian product labeling or product not commercially data{R-38}. available in Canada. [Horses]1—Although the efficacy and safety have not been established, an intramuscular or intravenous dose of 10 to 25 mg (base) per kg of body weight every four hours has been used in the CEPHAPIRIN treatment of susceptible bacterial infections in horses, based on pharmacokinetic data{R-9; 19}. SUMMARY OF DIFFERENCES Indications: General considerations—First-generation cephalosporin. Size(s) usually available: Pharmacology/pharmacokinetics: Human biotransformation—Hepatic U.S.—{R-22; 53} metabolism to the desacetyl form occurs.{R-2} Veterinary-labeled product(s): Drug interactions and/or related problems: Concurrent administration Not commercially available. with probenicid may prolong the serum half-life of cephapirin.{R-30}

Medical considerations/contraindications: In people, severe hepatic Sodium, and for Uniformity of dosage units and Labeling under dysfunction can inhibit metabolism.{R-2} Injections.{R-14} Side/adverse effects: Local reactions may occur.{R-1} 1Not included in Canadian product labeling or product not commercially available in Canada. PARENTERAL DOSAGE FORMS Note: Bracketed information in the Dosage Forms section refers to uses CEPHRADINE that either are not included in U.S. product labeling or are for products not commercially available in the U.S. SUMMARY OF DIFFERENCES The dosing and strengths of the dosage forms available are expressed Indications: General considerations—First-generation cephalosporin. in terms of cephapirin base (not the sodium salt). ORAL DOSAGE FORMS Note: Bracketed information in the Dosage Forms section refers to uses CEPHAPIRIN FOR INJECTION USP that either are not included in U.S. product labeling or are for products Usual dose: not commercially available in the U.S. Note: [Dogs]1—Although the efficacy and safety have not been established, an intramuscular or intravenous dose of 10 to 30 mg CEPHRADINE CAPSULES USP (base) per kg of body weight every four to eight hours has been used Usual dose: in the treatment of susceptible bacterial infections in dogs, based on Note: [Dogs]1—Although the efficacy and safety have not been estab- pharmacokinetic data{R-2; 38; 86}. lished, an oral dose of 10 to 25 mg per kg of body weight every six to [Horses]1—Although the efficacy and safety have not been estab- twelve hours has been used in the treatment of susceptible bacterial lished, an intramuscular or intravenous dose of 20 to 30 mg per kg infections in dogs, based on pharmacokinetic data{R-2; 38}. of body weight every four to eight hours has been used in the [Foals]1—Although the efficacy and safety have not been established, treatment of susceptible bacterial infections in horses, based on an oral dose of 25 mg per kg of body weight every six to eight hours has pharmacokinetic data{R-18; 29; 35; 86}. been used in the treatment of susceptible bacterial infections in foals, based on pharmacokinetic data{R-85}. Size(s) usually available: U.S.—{R-55} Veterinary-labeled product(s): Strength(s) usually available: Not commercially available. U.S.— Human-labeled product(s): Veterinary-labeled product(s): 500 mg (base) (Rx) [Cefadyl]. Not commercially available. 1 gram (base) (Rx) [Cefadyl]. Human-labeled product(s): 2 grams (base) (Rx) [Cefadyl]. 250 mg (Rx) [Velosef; GENERIC]. 4 grams (base) (Rx) [Cefadyl]. 500 mg (Rx) [Velosef; GENERIC]. 20 grams (base) (Rx) [Cefadyl]. Canada— Canada— Not commercially available. Not commercially available. Packaging and storage: Store below 30 C (86 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specified by manu- Packaging and storage: Prior to reconstitution, store below 40 C facturer. Store in a tight container. (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specified by manufacturer. USP requirements: Preserve in tight containers. The quantity of cephradine stated in the labeling is in terms of anhydrous cephradine. Preparation of dosage form: Dilutions should be prepared according Contain the labeled amount of cephradine, within –10% to +20%, to manufacturer’s instructions. calculated as the sum of cephradine and cephalexin. Meet the requirements for Identification, Dissolution (75% in 45 minutes in Stability: See manufacturer’s product labeling for stability information. 0.12 N hydrochloric acid in Apparatus 1 at 100 rpm), Uniformity of dosage units, and Loss on drying (not more than 7.0%).{R-14} Incompatibilities: The admixture of beta-lactam antibiotics (penicillins and cephalosporins) and aminoglycosides may result in substantial mutual inactivation; they should not be mixed in the same intrave- CEPHRADINE FOR ORAL SUSPENSION USP nous bag or bottle. Usual dose: See Cephradine Capsules USP.

USP requirements: Preserve in Containers for Sterile Solids. Contains Strength(s) usually available: When reconstituted according to an amount of Cephapirin Sodium equivalent to the labeled amount of manufacturer’s instructions— cephapirin, within –10% to +15%. Meets the requirements for Con- U.S.: stituted solution, Bacterial endotoxins, Sterility, and Particulate mat- Veterinary-labeled product(s)— ter, for Identiﬁcation, Crystallinity, pH, and Water under Cephapirin Not commercially available.

Human-labeled product(s)— USP requirements: Preserve in tight containers. A dry mixture of 25 mg per mL (Rx) [Velosef; GENERIC]. Cephradine and one or more suitable buffers, colors, diluents, and 50 mg per mL (Rx) [Velosef; GENERIC]. flavors. Contains the labeled amount of cephradine, within –10% to Canada: +25%, calculated as the sum of cephradine and cephalexin. Meets the Not commercially available. requirements for Identification, Uniformity of dosage units (solid packaged in single-unit containers), Deliverable volume (solid pack- Packaging and storage: Prior to reconstitution, store below 40 C aged in multiple-unit containers), pH (3.5–6.0, in the suspension (104 F), preferably between 15 and 30 C (59 and 86 F), unless constituted as directed in the labeling), and Water (not more than otherwise specified by manufacturer. Store in a tight container. 1.5%).{R-14}

Stability: After reconstitution, suspensions retain their potency for 7 days at room 1Not included in Canadian product labeling or product not commercially temperature or for 14 days if refrigerated. available in Canada.

Auxiliary labeling: • Refrigerate. Developed: 08/02/95 • Shake well. Interim revision: 07/08/98; 11/5/99; 09/30/02; 04/04/03

Table 1. Pharmacology/Pharmacokinetics*.

Protein Half-life of VolD binding elimination Steady state Clearance Route; Dose Tmax Cmax Bioavailability Drug (%) (hr) (L/kg) (mL/min/kg) (mg/kg) (min) (mcg/mL) (%)

First-Generation Cefadroxil Cats {R-3} Low (20) Oral; 22 60–120 17.4 Dogs {R-3} Low (20) Oral; 22 60–120 18.6 Horses Adult{R-78} 0.8 0.46 7 IV; 25 Foal{R-56} 1.4 Oral; 100 90 23.4 37–100 Cefazolin Dogs{R-5} 0.8–1.2 IV; 15 Horses{R-57} Low (8) 0.6–0.8 0.19 5.51 IV; 11 Pigs{R-5} 0.27 IV; 15 Cephalexin Birds{R-34} Oral; 25–50 30–60 20 Cats{R-50} Oral; 15 120 11–29 Oral; 25 60–120 15 {R-49} SQ; 20 66 54 IM; 20 42 61.8 Dogs{R-2; 49} 1.3 Oral; 10–15 108 18.6 SQ; 10 72 24.9 IM; 10 54 31.9 Pigs{R-5} 1 IV; 15 Cephalothin Birds{R-34} IM; 100 30 18 Dogs{R-5} 0.7 IV; 15 Horses{R-19} Low (18) 0.25 0.15 13.6 IV; 11 IM; 11 47 11.3 65 Cephapirin Calves{R-58} (3–16 wks) IM; 10 20 6.3 Cows{R-25} IM; 10 10 13.3 Dogs{R-2} 0.4 Foals{R-59} IM; 20 10 21.2 (4–6 days) Horses{R-18} 0.9 0.17 10 IV; 20 IM; 20 25 14.8 95 Cephradine Dogs{R-2} 1.4 Foals{R-85} 1.6 0.4 6.7 IV; 25 Oral; 25 90 13.2 Second-Generation Cefaclor Dogs{R-5} 2 IV; 3.75

Table 1 (Contd.)

Protein Half-life of VolD Binding Elimination Steady state Clearance Route; Dose Tmax Cmax Bioavailability Drug (%) (hr) (L/kg) (mL/min/kg) (mg/kg) (min) (mcg/mL) (%)

Cefotetan Dogs{R-84} 1.1 IV; 30 SC; 30 30-60 84 Cefoxitin Calves{R-26} Moderate 1.1 0.32 4.9 IV; 20 (42–55) IM; 20 74 Dogs{2; 84) 0.7; 1.3 Horses{R-29} 0.8 0.12 4.32 IV; 20 IM; 20 77 Third-Generation Ceﬁxime Calves{R-78} High (90) 3.5–4 0.34 Oral; 5 240 3.4 Fed; 20–28 Dogs{R-77; 87–89} High 7 to 8 0.22 Oral; 5 360 2 55 (82–92) Oral; 5 (6 days) 144 4.8 Cefotaxime Cats{R-42} 1 0.18 2.8 IV; 10 IM; 10 42 36 93–98 IM; 50 24–36 47 86.5 SQ; 50 36–60 30 100 Dogs{R-2; 43} 0.8 0.4 10.5 IV; 50 IM; 50 30 47 85 SQ; 50 48 30 100 Goats{R-15} 0.4 IV Sheep{R-20; 60} 0.3–04 0.78 2.9 IV

New Generation Ceftioﬂur Calves{R-61} IM; 2.2 120 8.8 IM; 4.4 120 17.3 Cows{R-70} 7.1 0.2 0.5 IV; 2 Cows, lactating 3.6 0.39 1.27 IV; 2 IM; 2 60 4.6 100 Dogs{R-72} 5 to 7 SQ; 0.22 45 1.7 SQ; 2.2 60 8.9 SQ; 4.4 90 26.7 Foals{R-48} IM; 2.2 45 3.6 Horses{R-93} 3–5{R-75} IM; 2.2 60 4.4 Pigs{R-75} 12-13 IM; 3 35 19.2 Sheep{R-97} 5-6 IV; 1.1–2.2 IM; 1.1–2.2 30 4.1–6.2

* Abbrevations: IM = Intramuscular, IV = Intravenous, SQ = Subcutaneous, VolD = Volume of distribution, Tmax = Time to peak concentration, Cmax = Peak serum concentration. Assays for serum concentrations of ceftiofur listed include ceftiofur and its active desfuroylceftiofur metabolite.

REFERENCES 10. Plumb DC. Veterinary drug handbook. White Bear Lake, MN: PharmaVet 1. Caprile KA. The cephalosporin antimicrobial agents: a comprehensive review. Publishing; 1991. p. 452-67. J Vet Pharmacol Ther 1988; 11(1): 1–32. 11. Ceftiofur package insert (Naxcel, Upjohn—US), Rev 9/01. Downloaded8/1/02 2. Papich MG. Clinical pharmacology of cephalosporin antibiotics. J Am Vet Med from www.pharmaciaah.com. Assoc 1984; 184(3): 344–7. 12. Ceftiofur package insert (Excenel, Upjohn—Canada). In: Arrioja-Dechert A, 3. Cefadroxil package insert (Cefa-Tabs, Fort Dodge—US), Rev 9/93, Rec editor. Compendium of veterinary products, CD ed. Port Huron, MI: North 1/20/95. American Compendiums, Inc. 2002. 4. BarragryTB. Veterinary drug therapy. Baltimore: Lea & Febiger; 1994. p. 231–40. 13. USP dictionary of USAN and international drug names, 2002 ed. Rockville, 5. Thomson TD. Cephalosporin group of antimicrobial drugs. J Am Vet Med MD: The United States Pharmacopeial Convention, Inc.; 2002. Assoc 1984; 185(10): 1109–14. 14. The United States pharmacopeia. The national formulary. USP 26th revision 6. Rosin E, et al. Cefazolin antibacterial activity and concentrations in serum (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United and the surgical wound in dogs. Am J Vet Res 1993; 54(8): 1317–21. States Pharmacopeial Convention, Inc.; 2002. p. 351-4, 357, 361, 362, 370, 7. Donowitz GR, Mandell GL. Beta-lactam antibiotics. N Engl J Med 1988; 318: 371, 373, 376, 377, 395–9, 401, 402. 419–26. 15. Atef M, et al. Pharmacokinetic proﬁle of cefotaxime in goats. Res Vet Sci 8. Thompson RL, Wright AJ. Cephalosporin antibiotics. Mayo Clin Proc 1983; 1990; 49: 34–8. 58: 79–87. 16. Gennaro AR, editor. Remington’s pharmaceutical sciences. 18th ed. Easton, 9. Papich MG. The beta-lactam antibiotics: clinical pharmacology and recent PA: Mack Publishing Company; 1990. p. 1196, 1199. developments. Compend Contin Educ Pract Vet 1987; 9: 68–75.

17. Riviere JE, Cragmill AL, Sundlof SF. Handbook of comparative pharmacoki- 50. Crosse R, Burt DG. Antibiotic concentration in the serum of dogs and cats netics and residues of veterinary antimicrobials. Boca Raton, FL: CRC Press; following a single oral dose of cephalexin. Vet Rec 1984; 115: 106–7. 1991. p. 52–3. 51. Cephalexin package insert (Keftab, Lilly—US), Rev 9/92, Rec 5/8/92. 18. Brown MP, Gronwall RR, Houston AE. Pharmacokinetics and body fluid and 52. Riviere JE. Dosage of antimicrobial drugs in patients with renal insufficiency. endometrial concentrations of cephapirin in mares. Am J Vet Res 1986; J Am Vet Med Assoc 1981; 178(1); 70–2. 47(4): 784–8. 53. Cephalothin sodium package insert (Lyphomed—US), Rev 3/91, Rec 7/8/91. 19. Ruoff WW, Sams RA. Pharmacokinetics and bioavailability of cephalothin in 54. Cephalothin (Keflin, Lilly). In: Krogh CME, editor. CPS Compendium of horse mares. Am J Vet Res 1985; 46(10): 2085–90. pharmaceuticals and specialities. 29th ed. Ottawa: Canadian Pharmaceutical 20. Guerrini VH, et al. Effect of probenecid on the pharmacokinetics of cefotaxime Association; 1994. p. 653–4. in sheep. J Vet Pharmacol Ther 1985; 89: 38–46. 55. Cephapirin package insert (Cefadyl, Bristol—US), Rec 7/13/93. 21. Cefoxitin package insert (Mefoxin, Merck—US), Rev 10/92, Rec 9/94. 56. Duffee NE, Christensen JM, Craig AM. The pharmacokinetics of cefadroxil in 22. Cephalothin package insert (Keflin, Lilly—US), Rev 12/91, Rec 1/3/93. the foal. J Vet Pharmacol Ther 1989; 12: 322–6. 23. Cephalexin package insert (Keflex, Lilly—US), Rev 12/91, Rec 6/30/93. 57. Sams RA, Ruoff WW. Pharmacokinetics and bioavailability of cefazolin in 24. Cefaclor package insert (Ceclor, Lilly—US), Rev 7/93, Rec 10/20/93. horses. Am J Vet Res 1985; 46(2): 348–52. 25. Prades M, Brown MP, Gronwall R, et al. Pharmacokinetics of sodium 58. Brown MP, Gronwall RR, Pattio N, et al. Pharmacokinetics and synovial fluid cephapirin in lactating dairy cows. Am J Vet Res 1988; 49(11): 1888–90. concentrations of cephapirin in calves with suppurative arthritis. Am J Vet 26. Soback S. Pharmacokinetics of single doses of cefoxitin given by the Res 1991; 52(9): 1438–40. intravenous and intramuscular routes to unweaned calves. J Vet Pharmacol 59. Brown MP, Gronwall RR, Gossman TB, et al. Pharmacokinetics and serum Ther 1988; 11: 155–62. concentrations of cephapirin in neonatal foals. Am J Vet Res 1987; 49(5): 27. Juzwiak JS, Brown MP, Gronwall R, et al. Effect of probenecid administration 805–6. on cephapirin pharmacokinetics and concentrations in mares. Am J Vet Res 60. Guerrini VH, Filippich L, English PB, et al. Pharmacokinetics of cefotaxime in 1989; 50(10): 1742–7. sheep. Am J Vet Res 1983; 44: 1488–91. 28. Schermerhorn T, et al. Whole-blood platelet aggregation, buccal mucosa 61. Halstead SL, Walker RD, Baker JC, et al. Pharmacokinetic evaluation of bleeding time, and serum cephalothin concentration in dogs receiving a ceftiofur in serum, tissue chamber fluid, and bronchial secretions from presurgical antibiotic protocol. Am J Vet Res 1994; 55(1): 1602–7. healthy beef-bred calves. Can J Vet Res 1992; 56: 269–74. 29. Brown MP, Gronwall RR, Houston AE. Pharmacokinetics and body fluid and 62. Morris DD, Rutkowski J, Lloyd KCK. Therapy in two cases of neonatal foal endometrial concentrations of cefoxitin in mares. Am J Vet Res 1986; 47(8): septicaemia and meningitis with cefotaxime sodium. Equine Vet J 1987; 1734–8. 19(2): 151–4. 30. Jaglan PS, et al. Metabolism of ceftiofur. Nature of urinary and plasma 63. Jaglan PS, Roof RD, Yein FS, et al. Concentration of ceftiofur metabolites in metabolites in rats and cattle. J Agric Food Chem 1989; 37: 1112–8. the plasma and lungs of horses following intramuscular treatment. J Vet 31. Davis LE. Hypersensitivity reactions induced by antimicrobial drugs. J Am Vet Pharmacol Ther 1994; 17: 24–30. Med Assoc 1984; 185(10); 1131–5. 64. Kietzmann M, Nolte I, Strothmann A, et al. Tolerance and pharmacokinetics 32. Frank LA, Kunkle GA. Comparison of the efficacy of cefadroxil and generic of cephalexin in cats after oral administration. J Small Anim Pract 1992; 33: and proprietary cephalexin in the treatment of pyoderma in dogs. J Am Vet 521–5. Med Assoc 1993: 203(4): 530–2. 65. Cefotetan package insert (Cefotan, Zeneco, Inc.—US), Rev 7/93, Rec 10/8/ 33. Chatfield RC, Gingerich DA, Rourke JE, et al. Cefadroxil: a new orally effective 93. cephalosporin antibiotic. Vet Med 1984; 79(3); 339–45. 66. Freedom of Information Summary, Naxcel Sterile Powder for treatment of 34. Bush M, Locke D, Neal LA, et al. Pharmacokinetics of cephalothin and canine urinary tract infections. New Animal Drug Application 140–338 cephalexin in selected avian species. Am J Vet Res 1981; 42: 1014–7. (Upjohn—US), 9/94. 35. Robinson NE, editor. Current therapy in equine medicine 3. Philadelphia: 67. Panel comment, 4/26/95. W.B. Saunders; 1992. p. 816. 68. Manufacturer comment, 4/24/95. 36. Cefaclor (Ceclor, Lilly). In: Krogh CME, editor. CPS Compendium of pharma- 69. Erskine RJ, Wilson RC, Tyler JW, et al. Ceftiofur distribution in serum and ceuticals and specialities. 29th ed. Ottawa: Canadian Pharmaceutical milk from clinically normal cows and cows with experimental Escherichia Association; 1995. p. 221–2. coli-induced mastitis. Am J Vet Res 1995 Apr; 56(4): 481–5. 37. Cefadroxil package insert (Cefa-Drops, Fort Dodge—US), Rev 9/93, Rec 70. Whittem T, Freeman DA, Hanlon D, et al. The effects on pharmacokinetics of 1/20/95. intravenous ceftiofur sodium in dairy cattle of simultaneous intravenous 38. Kirk RW, Bonagura JD, editors. Current veterinary therapy XI small animal acetyl salicylate (aspirin) or probenecid. J Vet Pharmacol Ther 1995; 18: practice. Philadelphia: W.B. Saunders; 1992. p. 1235. 61–7. 39. Cefazolin (Ancef, SKF). In: PDR Physicians’ desk reference. 49th ed. 1995. 71. Soback S, Ziv G, Winkler M, et al. Pharmacokinetics of ceftiofur administered Montvale, NJ: Medical Economics Data Production Company; 1995. intravenously and intramuscularly to lactating cows. Isr J Vet Med 1989; 45: p. 2352–4. 118–23. 40. Cefazolin (Ancef, SmithKline Beecham). In: Krogh CME, editor. CPS 72. Brown SA, Arnold TS, Hamlow PJ, et al. Plasma and urine disposition and Compendium of pharmaceuticals and specialities. 29th ed. Ottawa: Canadian dose proportionality of ceftiofur and metabolites in dogs after a subcutaneous Pharmaceutical Association; 1994. p. 72–3. administration of ceftiofur sodium. J Vet Pharmacol Ther 1995 Oct; 18(5): 41. Cefazolin (Kefzol, Lilly). In: PDR Physicians’ desk reference. 49th ed. 1995. 363–9. Montvale, NJ: Medical Economics Data Production Company; 1995. p. 1346–8. 73. Clarke CR, Brown SA, Streeter RN, et al. Penetration of parenterally 42. McElroy D, Ravis WR, Clark CH. Pharmacokinetics of cefotaxime in the administered ceftiofur into sterile vs. Pasteurella haemolytica-infected tissue domestic cat. Am J Vet Res 1986; 47(1): 86–8. chambers in cattle. J Vet Pharmacol Ther 1996 Oct; 19(5): 376–81. 43. Guerrini VH, English PB, Filippich LJ, et al. Pharmacokinetics of cefotaxime in 74. Panel comment, 6/16/95. the dog. Vet Rec 1986; 119: 81–3. 75. Manufacturer comment, 9/25/95. 44. Cefotaxime package insert (Claforan, Hoechst—US), Rev 5/91, Rec 6/21/93. 76. Panel comment, 5/25/95. 45. Cefoxitin (Mefoxin, Merck). In PDR Physicians’ desk reference. 49th ed. 77. Lavy E, Ziv G, Aroch I, et al. Clinical pharmacologic aspects of cefixime in 1995. Montvale, NJ: Medical Economics Data Production Company; 1995. dogs. Am J Vet Res 1995 May; 56 (5): 633–8. p. 1580–2. 78. Wilson WD, Baggot JD, Adamson PJW, et al. Cefadroxil in the horse: 46. Klasco RK, editor. USP DI Drug information for the healthcare professional. pharmacokinetics and in vitro antibacterial activity. J Vet Pharmacol Ther Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 1985; 8: 246–53. 47. Cervantes CC, et al. Pharmacokinetics and concentrations of ceftiofur sodium 79. Angarano DW, MacDonald JM. Efficacy of cefadroxil in the treatment of in body fluids and endometrium after repeated intramuscular injections in bacterial dermatitis in dogs. J Am Vet Med Assoc 1989 Jan; 194 (1): 57–9. mares. Am J Vet Res 1993; 54(4): 573–5. 80. Panel comment, 6/16/95. 48. Meyer JC, et al. Pharmacokinetics of ceftiofur sodium in neonatal foals after 81. Ceftiofur package insert (Excenel RTU, Pharmacia Animal Health—US), Rev intramuscular injection. Equine Vet J 1992; 24(6): 485–6. 1/02. Downloaded 8/1/02 from www.pharmaciaah.com. 49. Silley P, Brown MP, Gronwall RR, et al. Pharmacokinetics of cephalexin in 82. Marcellin-Little D, Papich MG, DeYoung DJ, et al. A pharmacokinetic model dogs and cats after oral, subcutaneous, and intramuscular administration. for cefazolin distribution during total hip arthroplasty in dogs. Am J Vet Res Vet Rec 1988; 122: 15–7. 1996; 57(5): 720–3.

83. Richardson DC, Aucoin DP, DeYoung DJ, et al. Pharmacokinetic disposition of 93. Reviewer comment, 8/30/96. cefazolin in serum and tissue during canine total hip replacement. Vet Surg 94. Salmon SA, Watts JL, Yancey RJ. In vitro activity of ceftiofur and its primary 1992; 21 (1): 1–4. metabolite desfuroylceftiofur, against organisms of veterinary importance. J 84. Petersen SW, Rosin E. In vitro antibacterial activity of cefoxitin and cefotetan Vet Diagn Invest 1996 Jul; 8(3): 332–6. and pharmacokinetics in dogs. Am J Vet Res 1993 Sep; 54(9): 1496–9. 95. Panel comment, 8/29/96. 85. Henry MM, Morris DD, Lakritz J, et al. Pharmacokinetics of cephradine in 96. Freedom of Information Summary. Ceftiofur hydrochloride sterile suspension neonatal foals after single oral dosing. Equine Vet J 1992; 24(3): 242–3. for the control and treatment of swine respiratory disease. NADA 140-890. 86. Vaden SL, Riviere JE. Penicillins. In: Adams HR, editor. Veterinary pharma- The Upjohn Company. cology and therapeutics. 7th ed. Ames, Iowa: Iowa State University Press; 97. Freedom of Information Summary. Ceftiofur sodium sterile powder for the 1995. p. 778–83. treatment of sheep respiratory disease. Public Master File Number 5544. 87. Bialer M, Wu WH, Look ZM, et al. Pharmacokinetics of cefixime after oral and NRSP-7 Minor Use Animal Drug Program. intravenous doses in dogs: bioavailability assessment for a drug showing 98. Panel comment, 10/2/96. nonlinear serum protein binding. Res Commun Chem Pathol Pharmacol 99. Ceftiofur package insert (Excenel RTU, Pharmacia Animal Health—Canada). 1987; 56: 21–32. In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port 88. Bialer M, Tonelli AP, Kantrowitz JD, et al. Serum protein binding of a new oral Huron, MI: North American Compendiums, Inc. 2002. cephalosporin, CL 284,635, in various species. Drug Metab Dispos 1986; 14: 100. Manufacturer comment, Rec 2/24/97. 132–6. 101. Barza M, Pinn V, Tanguay P, et al. Nephrotoxicity of newer cephalosporins 89. Bialer M, Barta VK, Morrison JA, et al. Dose-dependent pharmacokinetics of a and aminoglycosides alone and in combination in a rat model. J Antimicrob new oral cephalosporin, cefixime, in the dog. Pharm Res 1987; 4: 32–6. Chemother 1978; 4(Suppl A): 59–68. 90. Ziv G, Lavy E, Glickman A, et al. Clinical pharmacology of cefixime in 102. Diaz JAO, Sumano LH, Ocampo CL. Evaluacion de la nefrotoxicidad de unweaned calves. J Vet Pharmacol Ther 1995; 18: 94–100. cejelexiuagentamicin eu perros. Vet Mex 1995; 26: 247–9. 91. Panel comment, 6/19/96. 103. Ringer NC, Pearson EG, Gronwall R, et al. Pharmacokinetics of ceftriaxone in 92. Panel comment, 6/18/96. healthy horses. Equine Vet J 1996; 28(6): 476–9.

CEPHAPIRIN Veterinary—Intramammary-Local

Some commonly used brand names for veterinary-labeled products are: pKa: Cephapirin sodium—2.15 and 7.3.{R-13} Cefa-Dri; Cefa-Lak; ToDay; and ToMorrow. Solubility: Note: For a listing of dosage forms and brand names by country Cephapirin Benzathine USP—Practically insoluble in water, in ether, and availability, see the Dosage Forms section(s). in toluene; freely soluble in alcohol; soluble in 0.1 N hydrochloric acid{R-21}. CATEGORY: Cephapirin Sodium USP—Very soluble in water; insoluble in most Antibacterial (intramammary-local). organic solvents{R-21}.

PHARMACOLOGY/PHARMACOKINETICS INDICATIONS Mechanism of action/effect: Cephapirin produces its bactericidal effect by inhibiting cell wall synthesis. Its action is only effective in GENERAL CONSIDERATIONS actively growing cells. Cephapirin is a first-generation cephalosporin that has a wide spectrum of activity against gram-positive and gram-negative organisms.{R-5} Distribution: Medications infused into a teat are considered to be fairly Cephapirin is more resistant to beta-lactamases than are the evenly distributed in the treated quarter of the healthy mammary penicillins{R-6} and so is effective against staphylococci, with the gland; however, in an udder affected by moderate to severe mastitis, exception of methicillin-resistant staphylococci.{R-5} the presence of edema, blockage of milk ducts, and reduced blood circulation can cause uneven distribution of medication.{R-14} ACCEPTED Mastitis (treatment)—Cattle: Cephapirin is indicated in the treatment of mastitis caused by susceptible bacteria, such as Staphylococcus PRECAUTIONS TO CONSIDER aureus{R-1-4; 7} and Streptococcus agalactiae.{R-1–4} Cephalosporins are PATIENT MONITORING the primary treatment of choice for acute staphylococcal mastitis{R-9}; The following may be especially important in patient monitoring (other however, cows with acute or peracute mastitis are often given other tests may be warranted in some patients, depending on condition; » = medications, such as systemic antibiotics and/or supportive therapy, major clinical significance): concurrently with intramammary therapy.{R-10} Bacterial pathogens in milk (milk samples should be tested 3 weeks after treatment is REGULATORY CONSIDERATIONS discontinued; mastitis is not considered bacteriologically cured until U.S. and Canada— samples show an absence of the mastitis-causing organisms) Withdrawal times have been established for cephapirin benzathine and Clinical signs cephapirin sodium intramammary infusion (see the Dosage Forms (although resolution of clinical signs of mastitis is not an indication section).{R-1–4; 17; 18} that a bacteriologic cure has been achieved{R-15}, monitoring of the clinical condition of the mammary gland, teat, and milk produced CHEMISTRY can aid in diagnosis of a recurrence of mastitis or initial diagnosis of Source: Cephalosporins are semi-synthetic derivatives of metabolic mastitis in another cow in the herd) products of the fungus Cephalosporium acremonium.{R-6; 11} Somatic cell count Chemical group: Beta-lactam antibiotics.{R-5} (somatic cell counts performed on milk to monitor the dairy herd are Chemical name: used primarily to maintain milk quality but are also used to assess Cephapirin benzathine—5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxy- the approximate overall effectiveness of mastitis control programs, lic acid, 3-[(acetyloxy)methyl]-8-oxo-7-[[(4-pyridinylthio)acetyl]amino]-, which may include antibiotic treatment of cows){R-10} (6R-trans)-, cmpd. with N,N¢-bis(phenylmethyl)-1,2-ethanediamine {R-12} (2:1) . SIDE/ADVERSE EFFECTS Cephapirin sodium—5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic The following side/adverse effects have been selected on the basis of their acid, 3-[(acetyloxy)methyl]-8-oxo-7-[[(4-pyridinylthio)acetyl]amino]-, potential clinical significance (possible signs in parentheses where monosodium salt, [6R-trans]-.{R-12} appropriate)—not necessarily inclusive: Molecular formula: {R-12} Cephapirin benzathine—(C17H17N3O6S2)2 Æ C16H20N2 . {R-12} Cephapirin sodium—C17H16N3NaO6S2. THOSE INDICATING NEED FOR MEDICAL ATTENTION Molecular weight: Incidence unknown Cephapirin benzathine—1087.27{R-12}. Cows Cephapirin sodium—445.45.{R-12} Allergic reactions{R-1; 2}—local or systemic; drug fever{R-19} Description: Cephapirin Benzathine USP—White, crystalline powder{R-21}. OVERDOSE Cephapirin Sodium USP—White to off-white crystalline powder, odorless For information in cases of overdose or unintentional ingestion, contact or having a slight odor{R-21}. the American Society for the Prevention of Cruelty to Animals

(ASPCA) National Animal Poison Control Center (888-426-4435 Note: Cephapirin benzathine intramammary infusion should not be used or 900-443-0000; a fee may be required for consultation) and/or the any later than thirty days prior to calving. drug manufacturer. Canada—{R-17; 22} CLIENT CONSULTATION Treatment of mastitis in dairy cattle is best achieved by a comprehensive Withdrawal time

mastitis control program in which herd management is the primary Species Meat (days) Milk (hours) focus. The program should include routine milk testing, good maintenance of milking equipment, and constant evaluation of Cows, nonlactating 42 84 milking procedures and teat health as well as strategic treatment of clinical cases of mastitis.{R-16} Note: Cephapirin benzathine intramammary infusion should not be used any later than thirty days prior to calving. VETERINARY DOSING INFORMATION Antibiotic therapy in the dry cow is more effective than treatment during Packaging and storage: Store between 15 and 30 C (59 and 86 F), lactation for mastitis caused by Staphylococcus aureus.{R-15; 16; 20} unless otherwise specified by manufacturer. Protect from freezing. Choice of antibiotic for treatment of mastitis should be based on knowledge of identity and sensitivity of pathogens causing mastitis in USP requirements: Preserve in well-closed unit-dose disposable syringes the cow and the dairy herd. at controlled room temperature. A suspension of Cephapirin Benzathine Before intramammary administration of cephapirin, the following actions in a suitable vegetable oil vehicle. Contains a suitable dispersing agent. should be taken:{R-1–4} Label Intramammary Infusion to indicate that it is for veterinary use • The udder should be milked out completely and the teats washed only. Contains an amount of cephapirin benzathine equivalent to the with warm water and a disinfectant. Care should be taken to avoid labeled amount of cephapirin, within -10% to +20%. Meets the washing excess dirt down from the udder onto the teat ends. The requirements for Identification and Water (not more than 1.0%){R-21}. area should be dried thoroughly. An effective germicidal teat dip should be applied for one minute and then each teat wiped with a CEPHAPIRIN SODIUM INTRAMAMMARY INFUSION separate cotton ball soaked with an antiseptic such as 70% alcohol. USP • Persons performing the treatment should wash and dry their hands before each treatment. Usual dose: Mastitis—Cows, lactating: Intramammary, 200 mg into • The tip of the syringe should be inserted into the teat end as little as each affected quarter of the udder every twelve hours for two treat- possible and the contents of the syringe should be injected into each ments.{R-3; 4} streak canal while the teat is held firmly. The medication should then be gently massaged up the teat canal into the udder. Strength(s) usually available: Following treatment, an effective teat dip is recommended on all teats. U.S.—{R-3; 4; 22} Veterinary-labeled product(s): INTRAMAMMARY DOSAGE FORMS 200 mg per 10 mL (OTC) [Cefa-Lak; ToDay]. Canada—{R-18; 22} Veterinary-labeled product(s): CEPHAPIRIN BENZATHINE INTRAMAMMARY 200 mg per 10 mL (Rx) [Cefa-Lak]. INFUSION USP Usual dose: Mastitis—Cows, nonlactating: Intramammary, 300 mg Withdrawal times: administered into each quarter of the udder at the time of drying- U.S. and Canada—{R-3; 4; 18; 22} off.{R-1; 2} Withdrawal time Strength(s) usually available: U.S.—{R-1; 2; 22} Species Meat (days) Milk (hours) Veterinary-labeled product(s): Cows, lactating 4 96 300 mg per 10 mL (OTC) [Cefa-Dri; ToMorrow]. Canada—{R-17; 22} Packaging and storage: Store between 15 and 30 C (59 and 86 F), Veterinary-labeled product(s): unless otherwise specified by manufacturer. Protect from freezing. 300 mg per 10 mL (Rx) [Cefa-Dri].

Withdrawal times: USP requirements: Preserve in well-closed unit-dose disposable syr- U.S.—{R-1; 2; 22} inges at controlled room temperature. A suspension of Cephapirin Sodium in a suitable vegetable oil vehicle. Contains a suitable disper- Withdrawal time sing agent. Label Intramammary Infusion to indicate that it is for veterinary use only. Contains an amount of cephapirin sodium Species Meat (days) Milk (hours) equivalent to the labeled amount of cephapirin, within )10% to +20%. Cows, nonlactating 42 72 Meets the requirements for Identiﬁcation and Water (not more than 1.0%){R-21}.

Developed: 06/30/95 11. Papich MG. Clinical pharmacology of cephalosporin antibiotics. J Am Vet Med Interim revision: 04/24/96; 05/19/97; 5/26/98; 10/15/99; 06/30/02; Assoc 1984; 184(3): 344–7. 12. USP dictionary of USAN and international drug names, 2002 ed. Rockville, 02/28/03 MD: The United States Pharmacopeial Convention, Inc., 2002. 13. Gennaro AR, editor. Remington’s pharmaceutical sciences. 18th ed. Easton, REFERENCES PA: Mack Publishing Company, 1990. p. 1199. 1. Cefa-Dri package insert (Fort Dodge—US). Downloaded 2/16/03 from 14. Jarp J, Bugge HP, Larsen S. Clinical trial of three therapeutic regimens for www.wyeth.com. bovine mastitis. 1989; 124: 630–4. 2. ToMorrow package insert (Fort Dodge—US). Downloaded 8/6/03 from 15. Craven N. Efficacy and financial value of antibiotic treatment of bovine clinical www.wyeth.com. mastitis during lactation—a review. Br Vet J 1987; 143: 410–22. 3. Cefa-Lak package insert (Fort Dodge—US), Rev 3/00. Downloaded 8/6/03 16. Hady PJ, Lloyd JW, Kaneene JB. Antibacterial use in lactating dairy cattle. J Am from www.wyeth.com. Vet Med Assoc 1993 Jul; 203(2): 210–20. 4. ToDay package insert (Fort Dodge—US). Downloaded 8/6/03 from www. 17. Cephapirin (Cefa-Dri, Wyeth Ayerst—Canada). In: Bennett K, editor. wyeth.com. Compendium of veterinary products. 3rd ed. Hensall, ON: North American 5. Donowitz GR, Mandell GL. Beta-lactam antibiotics. N Engl J Med 1988; 318: Compendiums Inc., 1993. p. 163. 419–26. 18. Cephapirin (Cefa-Lak, Wyeth Ayerst—Canada). In: Bennett K, editor. 6. Caprile KA. The cephalosporin antimicrobial agents: a comprehensive review. Compendium of veterinary products. 3rd ed. Hensall, ON: North American J Vet Pharmacol Ther 1988; 11(1): 1–32. Compendiums Inc., 1993. p. 164. 7. Owens WE, et al. Efficacy of a cephapirin dry cow product for treatment of 19. Panel comment, Rec 3/24/95. experimentally induced Staphylococcus aureus mastitis in heifers. J Dairy Sci 20. Manufacturer comment, Rec 4/20/95. 1991; 74(10): 3376–82. 21. The United States pharmacopeia. The national formulary. USP 26th revision 8. Watson ADJ. Penicillin G and the alternatives. Vet Annu 1985; 25: 277-83. (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United 9. Barragry TB. Veterinary drug therapy. Philadelphia: Lea & Febiger, 1994. States Pharmacopeial Convention, Inc., 2002. p. 398, 400, 2554. p. 665. 22. Arrioja-Dechert A, editor. Compendium of Veterinary Products, CD edition. 10. Heath SE. Bovine mastitis. In: Howard JL. Current veterinary therapy 3 food Port Huron, MI: North American Compendiums, Inc., 2002. animal practice. Philadelphia: W.B. Saunders, 1993. p. 762–9.

CHLORAMPHENICOL Veterinary—Systemic

Some commonly used brand names are: Molecular formula: {R-9} For veterinary-labeled products—Amphicol Film-Coated Tablets; Azra- Chloramphenicol—C11H12Cl2N2O5. {R-9} mycine S125; Azramycine S250; Chlor 100; Chlor 250; Chlor 500; Chloramphenicol palmitate—C27H42Cl2N2O6. {R-9} Chlor 1000; Chlor Palm 125; Chlor Palm 250; Duricol; Karomycin Chloramphenicol sodium succinate—C15H15Cl2N2NaO8. Palmitate 125; Karomycin Palmitate 250; and Viceton. Molecular weight: For human-labeled products—Chloromycetin and Novochlorocap. Chloramphenicol—323.13.{R-9} Note: For a listing of dosage forms and brand names by country Chloramphenicol palmitate—561.54.{R-9} availability, see the Dosage Forms section(s). Chloramphenicol sodium succinate—445.18.{R-9} Description:{R-10} CATEGORY: Chloramphenicol USP—Fine, white to grayish white or yellowish white, Antibacterial (systemic). needle-like crystals or elongated plates. Its solutions are practically neutral to litmus. Is reasonably stable in neutral or moderately acid INDICATIONS solutions. Its alcohol solution is dextrorotatory and its ethyl acetate Note: Bracketed information in the Indications section refers to uses that solution is levorotatory. either are not included in U.S. product labeling or are for products not Chloramphenicol Palmitate USP—Fine, white, unctuous, crystalline commercially available in the U.S. powder, having a faint odor. Chloramphenicol Sodium Succinate USP—Light yellow powder. Solubility:{R-10} ACCEPTED Chloramphenicol USP—Slightly soluble in water; freely soluble in Chloramphenicol is a broad-spectrum antibiotic shown to have speciﬁc alcohol, in propylene glycol, in acetone, and in ethyl acetate. activity against a wide variety of organisms that are the causative Chloramphenicol Palmitate USP—Insoluble in water; freely soluble in agents of several disease conditions in domestic animals. Such acetone and in chloroform; soluble in ether; sparingly soluble in organisms include Staphylococcus aureus, Streptococcus pyogenes, Bru- alcohol; very slightly soluble in solvent hexane. cella bronchoseptica, Escherichia coli, Proteus vulgaris, Aerobacter aerog- Chloramphenicol Sodium Succinate USP—Freely soluble in water and in enes, Corynebacterium renale, Salmonella species, Pseudomonas species, alcohol. Shigella species, Neisseria catarrhalis, anaerobic bacteria, and many rickettsiae. The species treated with chloramphenicol include dogs, [cats]1, and [horses]1. PHARMACOLOGY/PHARMACOKINETICS 1Not included in Canadian product labeling or product not commercially Note: See also Table 1. Pharmacokinetic Parameters at the end of this available in Canada. monograph.

Mechanism of action/effect: REGULATORY CONSIDERATIONS Chloramphenicol is bacteriostatic. However, it may be bactericidal in high U.S.— concentrations or when used against highly susceptible organisms. Food and Drug Administration regulations ban chlorampheni- Chloramphenicol, which is lipid soluble, diffuses through the bacterial cell col from use in animals that are used for food production. membrane and reversibly binds to the 50 S subunit of the bacterial There are no safe residue levels, and no withdrawal times have been ribosomes where transfer of amino acids to growing peptide chains is established. prevented (perhaps by suppression of peptidyl transferase activity), thus Chloramphenicol Tablets USP are labeled for veterinary use only. inhibiting peptide bond formation and subsequent protein synthesis. Canada— Chloramphenicol is prohibited from use in food-producing Absorption: animals by the Canadian Health Protection Branch. Chloramphenicol is rapidly absorbed from the gastrointestinal tract after Chloramphenicol Tablets USP are labeled for veterinary use only. oral administration in many simple-stomach animals. Cats—Chloramphenicol palmitate is not absorbed well after oral administration to fasted cats.{R-1; 2} CHEMISTRY Source: Distribution: Originally derived from Streptomyces venezuelae.{R-8} Chloramphenicol diffuses readily into all body tissues, but at different Chemical name: concentrations. Highest concentrations are found in the liver and Chloramphenicol—Acetamide, 2,2-dichloro-N-[2-hydroxy-1-(hydroxy- kidneys of dogs. methyl)-2-(4-nitrophenyl)ethyl]-, [R-(R*,R*)]-.{R-9} The lungs, spleen, heart, and skeletal muscles contain concentrations Chloramphenicol palmitate—Hexadecanoic acid, 2-[(2,2-dichloroacetyl)- similar to that in the blood. Chloramphenicol reaches significant amino]-3-hydroxy-3-(4-nitrophenyl) propyl ester, [R-(R*,R*)]-.{R-9} concentrations in the aqueous and vitreous humors of the eye. Within Chloramphenicol sodium succinate—Butanedioic acid, mono[2-[(2,2- 3 to 4 hours after administration, the concentration in the cerebrospinal dichloroacetyl)amino]-3-hydroxy-3-(4-nitrophenyl)propyl]ester,mono- fluid reaches, on the average, 50% of the concentration in the serum. sodium salt, [R-(R*,R*)]-{R-9}. The percentage increases if there is inflammation of the meninges.

Chloramphenicol diffuses readily into milk and pleural and ascitic fluids PATIENT MONITORING and crosses the placenta, attaining concentrations of about 75% of The following may be especially important in patient monitoring (other that in maternal blood. tests may be warranted in some patients, depending on condition; » = major clinical significance): Biotransformation: Chloramphenicol is rather rapidly metabolized, » Complete blood counts (CBCs) mainly in the liver, by conjugation with glucuronic acid. (CBCs may be required during therapy with chloramphenicol, particularly during prolonged administration, to detect aplastic anemia or bone marrow depression) Elimination: Approximately 55% of a single daily dose can be recov- Culture and susceptibility, in vitro, and ered from the urine of a treated dog. A small fraction of this is in the Minimum inhibitory concentration (MIC) form of unchanged chloramphenicol. The unchanged chloramphenicol (in vitro cultures and MIC tests should be done on samples collected is excreted by glomerular filtration (5 to 10%), whereas 80% is prior to chloramphenicol administration to determine pathogen excreted via tubular secretion as inactive metabolite. susceptibility)

SIDE/ADVERSE EFFECTS PRECAUTIONS TO CONSIDER Note: Although aplastic anemia has occurred in human patients as a SPECIES SENSITIVITY result of chloramphenicol administration, it has not been documented {R-6; 7} Cats—Chloramphenicol should not be used in the cat for more than 14 in animals. A dose-related reversible bone marrow suppression days{R-2} because it can cause dose-related blood dyscrasias. The may occur, sometimes manifesting as pancytopenia or agranulocyto- reported increased susceptibility of cats to development of blood sis. dyscrasias relative to dogs or horses may be attributable to chloram- The following side/adverse effects have been selected on the basis of phenicol’s signiﬁcantly longer elimination half-life in the cat.{R-6} their potential clinical signiﬁcance (possible signs and, for humans, symptoms in parentheses where appropriate)—not necessarily inclusive: PEDIATRICS All species THOSE INDICATING NEED FOR MEDICAL ATTENTION In the fetus and neonate, the immature liver cannot conjugate All species chloramphenicol, and toxic concentrations of active drug accumulate. Anorexia; bone marrow suppression{R-7}; depression; diarrhea Dogs and cats and vomiting{R-6} Sudden death has been reported in puppies and kittens receiving Note: Intermediate metabolites are thought to be responsible for the intravenous chloramphenicol. reversible bone marrow suppression seen in domestic animals. The effect is dose-dependent, often occurring with long-term therapy.

DRUG INTERACTIONS AND/OR RELATED PROBLEMS {R-12} The following drug interactions and/or related problems have been HUMAN SIDE/ADVERSE EFFECTS selected on the basis of their potential clinical significance (possible In addition to the above side/adverse effects reported in animals, the mechanism in parentheses where appropriate)—not necessarily inclu- following side/adverse effects have been reported in humans, and are sive (» = major clinical significance): included in the human monograph Chloramphenicol (Systemic) in USP Note: Combinations containing any of the following medications, depend- DI Volume I; these side/adverse effects are intended for informational ing on the amount present, may also interact with this medication. purposes only and may or may not be applicable to the use of Digitalis glycosides chloramphenicol in the treatment of animals: (chloramphenicol decreases the rate of elimination of digitalis Note: The hematologic toxicity of chloramphenicol can manifest glycosides, which may lead to their accumulation to toxic concen- itself in 1 of 2 ways—either as a reversible bone marrow trations{R-3}) depression or an idiosyncratic aplastic anemia. Bone marrow Erythromycin depression is dose-related and most commonly seen when serum (erythromycin and chloramphenicol compete for the same ribosome; concentrations of chloramphenicol exceed 25 mcg/mL. Bone therefore, the 2 medications may antagonize each other if used marrow changes are usually reversible when chloramphenicol is concurrently) discontinued. Aplastic anemia is an idiosyncratic reaction that Medications metabolized by mixed function oxidase system, especially: occurs in 1 of every 25,000 to 40,000 courses of treatment. It is Phenobarbital or not related to dose or duration of therapy. Most cases have been Primidone associated with oral chloramphenicol, and the onset of aplasia (chloramphenicol irreversibly inhibits the hepatic microsomal may not occur until weeks or months after treatment with enzymes of the cytochrome P450 complex, which may potentiate chloramphenicol has been discontinued. the effects of other medications that are metabolized by this Incidence less frequent complex) Blood dyscrasias; gastrointestinal reaction Pentobarbital Incidence rare (pentobarbital-induced anesthesia in dogs can be significantly Gray syndrome—in neonates only; hypersensitivity reactions; prolonged by concurrent administration of chloramphenicol{R-4}) neurotoxic reactions; optic neuritis; peripheral neuritis

Note: Gray syndrome (or ‘‘gray baby syndrome’’) almost always The dosing and strengths of the dosage forms available are expressed occurs in newborn infants treated with inappropriately high doses in terms of chloramphenicol base. of chloramphenicol. Typically, the infant has been started on chloramphenicol within the first 48 hours of life; symptoms first CHLORAMPHENICOL CAPSULES USP appear after 3 to 4 days of continued treatment with high doses of Usual dose: Antibacterial1— chloramphenicol; and serum concentrations are high, often Dogs: Oral, 45 to 60 mg per kg of body weight every eight hours. between 40 and 200 mcg/mL. If detected early and chloramphe- [Cats]: Oral, 13 to 20 mg per kg of body weight every twelve hours. nicol is discontinued, the infant may have a complete recovery. On Note: The oral dose for cats is based on the best information rare occasion, older patients, including adults with severe liver available, which may, however, underestimate the dose needed in disease, have also had a gray syndrome–type reaction. some cases. Doses of 25 to 50 mg per kg of body weight every Symptoms of possible fatal, irreversible bone marrow depression twelve hours have been recommended, and may be necessary for Pale skin; sore throat and fever; unusual bleeding or bruising; some infections, but could increase the risk of side effects. unusual tiredness or weakness [Horses]: Oral, 45 to 60 mg per kg of body weight every eight hours. Note: Pale skin, sore throat and fever, unusual bleeding or bruising, unusual tiredness or weakness may be symptoms of irreversible bone Strength(s) usually available: marrow depression leading to aplastic anemia, and the need for U.S.{R-11; 12}— immediate medical attention if they occur weeks or months after Veterinary-labeled product(s): medication is discontinued. 50 mg (Rx) [Duricol]. 100 mg (Rx) [Duricol]. OVERDOSE 250 mg (Rx) [Duricol]. For information in cases of overdose or unintentional ingestion, contact 500 mg (Rx) [Duricol]. the American Society for the Prevention of Cruelty to Animals Human-labeled product(s): (ASPCA) National Animal Poison Control Center (888-426-4435 250 mg (Rx) [GENERIC]. or 900-443-0000; a fee may be required for consultation) and/or the Canada— drug manufacturer. Veterinary-labeled product(s): Not commercially available. CLIENT CONSULTATION Human-labeled product(s): Because of the risk of idiosyncratic aplastic anemia that occurs in 250 mg (Rx) [Novochlorocap]. people after exposure to chloramphenicol, extreme care during administration to animals should be exercised. Animals do not Packaging and storage: Store below 40 °C (104 °F), preferably be- appear prone to develop the idiosyncratic aplastic anemia that can tween 15 and 30 °C (59 and 86 °F), unless otherwise specified by occur in people weeks or months after cessation of drug therapy.{R-5} manufacturer. Store in a tight container. In humans, the reported incidence of idiosyncratic aplastic anemia following chloramphenicol exposure ranges from 1/25,000 to 1/ USP requirements: Preserve in tight containers. Contain the labeled 40,000. Aplastic anemia in humans may occur following oral, amount, within –10 to +20%. Meet the requirements for Identifi- intramuscular, intravenous, ophthalmic, and/or topical administra- cation, Dissolution (85% in 30 minutes in 0.01 N hydrochloric acid tion. Due to these risks, chloramphenicol is banned in food- in Apparatus 1 at 100 rpm), and Uniformity of dosage units{R-10}. producing animals in the United States and people should avoid other types of exposure as well. CHLORAMPHENICOL PALMITATE ORAL SUSPENSION When administering chloramphenicol to animals, people should avoid USP direct contact with the medication (for example, avoid opening the Usual dose: [Antibacterial]— capsules). Dogs: Oral, 45 to 60 mg per kg of body weight every eight hours. 1 VETERINARY DOSING INFORMATION Cats : Oral, 13 to 20 mg per kg of body weight every twelve hours. Note: The oral dose for cats is based on the best information Most susceptible infectious disease organisms will respond to chloram- available, which may, however, underestimate the dose needed in phenicol therapy in 3 to 5 days when the recommended dosage some cases. Doses of 25 to 50 mg every twelve hours have been regimen is followed. recommended, and may be necessary for some infections, but If no response to chloramphenicol therapy is obtained in 3 to 5 days, use could increase the risk of side effects. should be discontinued and the diagnosis reviewed. Cats—Chloramphenicol should not be used in the cat for more than 14 Strength(s) usually available: days{R-2} because it can cause dose-related blood dyscrasias. U.S.— Chloramphenicol palmitate is not absorbed well after oral administration Veterinary-labeled product(s): to fasted cats.{R-1; 2} Not commercially available.

ORAL DOSAGE FORMS Canada{R-11}— Note: Bracketed information in the Dosage Forms section refers to uses Veterinary-labeled product(s): that either are not included in U.S. product labeling or are for products 25 mg (base) per mL (Rx) [Azramycine S125; Chlor Palm 125; not commercially available in the U.S. Karomycin Palmitate 125].

50 mg (base) per mL (Rx) [Azramycine S250; Chlor Palm 250; PARENTERAL DOSAGE FORMS Karomycin Palmitate 250]. Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products Packaging and storage: Store below 40 °C (104 °F), preferably not commercially available in the U.S. between 15 and 30 °C (59 and 86 °F), unless otherwise specified by The dosing and strengths of the dosage forms available are expressed manufacturer. Store in a tight, light-resistant container. Protect from in terms of chloramphenicol base. freezing. CHLORAMPHENICOL SODIUM SUCCINATE FOR INJECTION USP USP requirements: Preserve in tight, light-resistant containers. Con- Usual dose: [Antibacterial]1— tains an amount of chloramphenicol palmitate equivalent to the Cats: Intramuscular, intravenous, or subcutaneous, 12 to 30 mg ) labeled amount of chloramphenicol, within 10 to +20%. Contains (base) per kg of body weight every twelve hours. one or more suitable buffers, colors, flavors, preservatives, and sus- Dogs and horses: Intramuscular, intravenous, or subcutaneous, 45 to pending agents. Meets the requirements for Identification, Uniformity 60 mg (base) per kg of body weight every six to eight hours. of dosage units (suspension packaged in single-unit containers), Deliverable volume (suspension packaged in multiple-unit containers), Strength(s) usually available{R-8; 12}: {R-10} pH (4.5–7.0), and Limit of polymorph A . U.S.— Veterinary-labeled product(s): CHLORAMPHENICOL TABLETS USP Not commercially available. Human-labeled product(s): Usual dose: Antibacterial— 1 gram (base) per vial (Rx) [Chloromycetin; GENERIC]. Dogs: Oral, 45 to 60 mg per kg of body weight every eight hours. Canada— [Cats]1: Oral, 13 to 20 mg per kg of body weight every twelve hours. Veterinary-labeled product(s): Note: The oral dose for cats is based on the best information Not commercially available. available, which may, however, underestimate the dose needed in Human-labeled product(s): some cases. Doses of 25 to 50 mg per kg of body weight every 1 gram (base) (Rx) [Chloromycetin]. twelve hours have been recommended, and may be necessary for some infections, but could increase the risk of side effects. Packaging and storage: Prior to reconstitution, store below 40 °C [Horses]1: Oral, 45 to 60 mg per kg of body weight every eight (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless hours. otherwise specified by manufacturer.

Strength(s) usually available{R-11}: Preparation of dosage form: To prepare a 10% (100-mg-per-mL) U.S.— solution, add 10 mL of an aqueous diluent such as sterile water for Veterinary-labeled product(s): injection or 5% dextrose injection to each 1-gram vial{R-8}. 100 mg (Rx) [Viceton]. 250 mg (Rx) [Amphicol Film-Coated Tablets; Viceton]. USP requirements: Preserve in Containers for Sterile Solids. Contains 500 mg (Rx) [Amphicol Film-Coated Tablets; Viceton]. an amount of chloramphenicol sodium succinate equivalent to the 1000 mg (Rx) [Amphicol Film-Coated Tablets; Viceton]. labeled amount of chloramphenicol, within –10 to +15%. Meets the Canada— requirements for Bacterial endotoxins, Sterility, Particulate matter, Veterinary-labeled product(s): and Limit of free chloramphenicol (not more than 2.0%), and for 100 mg (Rx) [Chlor 100]. Identiﬁcation, Speciﬁc rotation, pH, and Water under Chloramphenicol 250 mg (Rx) [Chlor 250]. Sodium Succinate{R-10}. 500 mg (Rx) [Chlor 500]. 1 1000 mg (Rx) [Chlor 1000]. Not included in Canadian product labeling or product not commercially available in Canada.

Packaging and storage: Store below 40 °C (104 °F), preferably Revised: 07/28/94 between 15 and 30 °C (59 and 86 °F), unless otherwise speciﬁed by Interim revision: 03/30/95; 04/24/96; 05/07/97; 05/27/98; 10/15/99; manufacturer. Store in a tight container. 09/30/02; 04/04/03

USP requirements: Preserve in tight containers. Label Tablets to Table 1. Pharmacokinetic Parameters indicate that they are for veterinary use only and are not to be used in First order animals raised for food production. Contain the labeled amount, within elimination Total body –10 to +20%. Meet the requirements for Identiﬁcation, Disintegration Elimination rate constant clearance )1 (60 minutes), and Uniformity of dosage units. Species half-life (hours) (min ) VolD (L/kg) (mL/min/kg)

Cats 5.1 0.0023 2.36 5.55 1Not included in Canadian product labeling or product not commercially Dogs 1.20 ± 0.10 0.0098 ± 0.001 0.85 ± 0.06 8.57 ± 0.83 Horses 0.63 ± 0.04 0.0188 ± 0.001 1.41 ± 0.08 26.14 ± 1.28 available in Canada.

REFERENCES 8. Chloromycetin Sodium Succinate Product Information (King Pharmaceuti- 1. Watson ADJ. Effect of ingesta on systemic availability of chloramphenicol from cals—US), Rev 5/99. Downloaded 2/16/03 from www.kingpharm.com. 2 oral preparations in cats. J Vet Pharm Ther 1979; 2: 117–21. 9. USP dictionary of USAN and international drug names, 2002 ed. Rockville, 2. Panel comment, Rec 3/8/94. MD: The United States Pharmacopeial Convention, Inc., 2002. 3. Davis LE. Emergency drugs. In: Zaslow IM, editor. Veterinary trauma and 10. The United States pharmacopeia. The national formulary. USP 26th revision critical care. Philadelphia: Lea and Febiger 1984. p. 287–338. (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United 4. Teske RH, Carter GG. Effect of chloramphenicol on pentobarbital- States Pharmacopeial Convention, Inc., 2002. p. 407, 413, 414, 2554. induced anesthesia in dogs. J Am Vet Med Assoc 1971 Sep; 159(6): 11. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port 777–80. Huron, MI: North American Compendiums, Inc. 2002. 5. Booth NH, McDonald LE. Veterinary pharmacology and therapeutics, 6th ed. 12. Klasco RK, editor. USP DI Drug information for the healthcare professional. Ames: Iowa State University Press 1988. p. 837–8. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 6. Plumb DC. Veterinary drug handbook. St. Paul: PharmaVet Publishing 1991. p. 530–4. 7. Weiss DJ. Aplastic anemia. In: Kirk RW, Bonagura JD, editors. Current veterinary therapy XI small animal practice. Philadelphia: W.B. Saunders 1992. p. 479–84.

ERYTHROMYCIN Veterinary—Intramammary-Local

Some commonly used brand names for veterinary-labeled products are: synthesis.{R-11} Erythromycin is effective only against rapidly dividing Erythro-36; Erythro-Dry Cow; Gallimycin-36; and Gallimycin-Dry Cow. bacteria. Bacterial resistance occurs by alteration of the ribosome Note: For a listing of dosage forms and brand names by country receptor site and/or by not allowing erythromycin to enter the cell. availability, see the Dosage Forms section(s). Distribution: Medications infused into a teat are thought to be fairly CATEGORY: evenly distributed in that quarter of the healthy mammary gland; Antibacterial (intramammary-local). however, in an udder affected by moderate to severe mastitis, the presence of edema, blockage of milk ducts, and reduced blood circu- INDICATIONS lation can cause uneven distribution.{R-12}

GENERAL CONSIDERATIONS PRECAUTIONS TO CONSIDER Erythromycin is an antibiotic that is active primarily against gram- positive bacteria, such as Staphylococcus and Streptococcus species, PREGNANCY/REPRODUCTION including many that are, by means of beta-lactamase production, Pregnancy—Erythromycin crosses the placenta; however, there was no resistant to penicillins. Resistant strains of streptococci have been evidence of teratogenicity or other adverse effects when pregnant rats reported{R-1}, particularly in populations recently treated with eryth- were fed erythromycin base{R-13}. romycin.{R-2} Cross-resistance to the other macrolide antibiotics can {R-2} also occur. PATIENT MONITORING The following may be especially important in patient monitoring (other ACCEPTED tests may be warranted in some patients, depending on condition; » = Mastitis (treatment)—Cattle: Erythromycin is indicated in the treatment major clinical significance): of mastitis caused by susceptible Staphylococcus aureus{R-4}, Streptococ- Bacteriologic pathogens in milk cus agalactiae, Streptococcus dysgalactiae,andStreptococcus uberis{R-3; 14}. It (milk samples should be tested 3 weeks after treatment is discon- may be most effective against Streptococcus agalactiae{R-5; 17} and tinued; mastitis is not considered bacteriologically cured until Streptococcus dysgalactiae{R-4}. Intramammary therapy alone is indi- samples show an absence of the mastitis-causing organisms) cated only in the treatment of subacute or subclinical mastitis Clinical signs of mastitis manifested by mild changes in the milk or udder. Cows with acute (although a resolution of clinical signs of mastitis is not an or peracute mastitis, which has been defined as the presence of gross indication that a bacteriologic cure has been achieved, monitoring changes in the milk or udder or systemic signs, should be administered of the clinical condition of the mammary gland, teat, and milk other medications also, which may include systemic antibiotics and/or produced can aid in diagnosis of a recurrence of mastitis or initial supportive therapy.{R-6} diagnosis of mastitis in another cow in the herd) Somatic cell count REGULATORY CONSIDERATIONS (somatic cell counts performed on milk to monitor the dairy herd U.S. and Canada—{R-3} are used primarily to maintain milk quality, but they are also Withdrawal times have been established. See the Dosage Forms section. used to assess the approximate overall effectiveness of mastitis control programs, which may include antibiotic treatment of CHEMISTRY cows) Source: Produced from a strain of Streptomyces erythraeus. Chemical group: Macrolide group of antibiotics.{R-2} SIDE/ADVERSE EFFECTS Chemical name: Erythromycin.{R-7} The following side/adverse effects have been selected on the basis of their {R-7} Molecular formula: C37H67NO13. potential clinical significance (possible signs in parentheses where Molecular weight: 733.93.{R-7} appropriate)—not necessarily inclusive: Description: Erythromycin USP—White or slightly yellow, crystalline {R-8} powder. Is odorless or practically odorless. THOSE INDICATING NEED FOR MEDICAL ATTENTION pKa: Erythromycin base—8.8.{R-9; 10} Incidence unknown Solubility: Erythromycin USP—Slightly soluble in water; soluble in Cows alcohol, in chloroform, and in ether.{R-8} Allergic reaction—local or systemic

OVERDOSE PHARMACOLOGY/PHARMACOKINETICS For information in cases of overdose or unintentional ingestion, contact Mechanism of action/effect: Bacteriostatic; however, high concentra- the American Society for the Prevention of Cruelty to Animals tions may be bactericidal.{R-2; 11} Erythromycin is thought to enter the (ASPCA) National Animal Poison Control Center (888-426-4435 cell and reversibly bind to the 50S ribosomal subunit, inhibiting or 900-443-0000; a fee may be required for consultation) and/or the translocation of peptides and therefore inhibiting protein drug manufacturer.

CLIENT CONSULTATION Note: Also, for nonlactating cows, treated animals should not be Treatment of mastitis in dairy cattle is best achieved by a comprehensive slaughtered for food within 96 hours post-calving. Calves born to mastitis control program in which herd management is the primary treated cows should not be slaughtered for food until they are 10 days {R-3} focus. The program should include good maintenance of milking of age. {R-16; 17} equipment and constant evaluation of milking procedures and teat Canada— health as well as strategic treatment of clinical cases of mastitis.{R-15} Withdrawal time

VETERINARY DOSING INFORMATION Species Milk (hours) The choice of antibiotic for the treatment of mastitis should be based on Cows, lactating 36 knowledge of the identity and sensitivity of the pathogens causing mastitis in the cow and the dairy herd. Before administration of intramammary erythromycin, the following Packaging and storage: Store at 15 to 30 C (59 to 86 F). Protect actions should be taken: from freezing. • The udder should be milked out completely and the teats and udder washed with warm water and a disinfectant. Care should be taken to USP requirements: Preserve in single-dose disposable syringes that are avoid washing excess dirt down from the udder onto the teat ends. well-closed containers. A solution of Erythromycin in a suitable veg- The area should be dried thoroughly and each teat wiped with a etable oil vehicle. Contains one or more suitable preservatives. Label it separate cotton ball soaked with an antiseptic such as 70% isopropyl to state that it is for veterinary use only. Contains the labeled amount, alcohol. within )10% to +20%. Meets the requirements for Identification, {R-8} • Persons performing the treatment should wash and dry their hands Minimum fill, and Water (not more than 1.0%). before each treatment. • The tip of the syringe should be inserted into the teat end as little as possible and the contents of the syringe should be injected into each Developed: 07/25/95 streak canal while the teat is held firmly. The medication should Interim revision: 04/24/96; 05/07/97; 06/16/98; 10/15/99; 9/30/02; then be gently massaged up the teat canal into the udder. 03/28/03 A teat dip is recommended on all teats following treatment. REFERENCES 1. Mondel GL, Douglas RG, Bennett JE, editors. Principles and practice of INTRAMAMMARY DOSAGE FORMS infectious diseases. 3rd ed. New York: Churchill Livingstone, 1990. p. 308–12, 800, 1594, 1818, 1940. ERYTHROMYCIN INTRAMAMMARY INFUSION USP 2. Barragry TB. Veterinary drug therapy. Philadelphia: Lea & Febiger, 1994. p. 224–6, 256. Usual dose: Mastitis— 3. Gallimycin-Dry Cow package insert (Bimeda—US), Rec 2/17/03. Cows, lactating: Intramammary, 300 mg administered into each 4. Craven N. Efficacy and financial value of antibiotic treatment of bovine clinical affected quarter every twelve hours for three treatments.{R-14; 17} mastitis during lactation—a review. Br Vet J 1987; 143: 410–22. 5. Edmonson PW. An economic justification of ‘‘blitz’’ therapy to eradicate Cows, nonlactating: Intramammary, 600 mg administered into each Streptococcus agalactiae from a dairy herd. Vet Rec 1989; 125: 591–3. {R-3; 17} quarter at the time of drying-off. 6. Heath SE. Bovine mastitis. In: Howard JL. Current veterinary therapy 3 food animal practice. Philadelphia: W.B. Saunders, 1993. p. 762–9. Strength(s) usually available: 7. USP dictionary of USAN and international drug names, 2002 ed. Rockville, {R-3; 14; 16} MD: The United States Pharmacopeial Convention Inc. 2002. U.S.— 8. The United States pharmacopeia. The national formulary. USP 26th revision Veterinary-labeled product(s): (January 1, 2003). NF 21st ed. (January 1, 2003). Rockville, MD: The United 50 mg per mL (OTC) [Gallimycin-36 (lactating cows); Gallimycin-Dry States Pharmacopeial Convention Inc. 2002. p. 729, 2560. Cow (dry cows only)]. 9. Ewing PJ, Burrows G, MacAllister C, et al. Comparison of oral erythromycin formulations in the horse using pharmacokinetic profiles. J Vet Pharmacol {R-16; 17} Canada— Ther 1994; 17: 17–23. Veterinary-labeled product(s): 10. Clarke CR, Barron SJ, Ayalew S, et al. Response of Pasteurella haemolytica to 50 mg per mL (OTC) [Erythro-36 (dry or lactating cows); Erythro-Dry erythromycin and dexamethasone in calves with established infection. Am J Vet Res 1992; 53(5): 684–7. Cow (dry cows only); Gallimycin-36 (dry or lactating cows)]. 11. Prescott JF, Baggot JD, editors. Antimicrobial therapy in veterinary medicine. 2nd ed. Ames, Iowa: State University Press, 1993. p. 119–26. 12. Jarp J, Bugge JP, Larsen S. Clinical trial of three therapeutic regimens for bovine mastitis. 1989; 124: 630–4. Withdrawal times: 13. Erythromycin base (Novo-rythro Encap, Novopharm). In: Krogh CME. CPS U.S.—{R-3; 14; 16} Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association, 1993. Withdrawal time 14. Gallimycin-36 package insert (Bimeda—US), Rec 2/17/03. 15. Hady PJ, Lloyd JW, Kaneene JB. Antibacterial use in lactating dairy cattle. Species Meat (day) Milk (hours) J Am Vet Med Assoc 1993; 203(2): 19–20. 16. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Cows 14 36 Huron, MI: North American Compendiums, Inc. 2002. 17. Gallimycin-36 package insert (A.P.A. of Sanofi—Canada), Rec 2/13/95.

FLORFENICOL Veterinary—Systemic Some commonly used brand names for veterinary-labeled products are: REGULATORY CONSIDERATIONS Aquaflor and Nuflor. U.S.— Note: For a listing of dosage forms and brand names by country Withdrawal times have been established for florfenicol in cattle; availability, see the Dosage Forms section(s). however, it is not labeled for use in lactating dairy cattle or in veal calves{R-1} (see the Dosage Forms section). CATEGORY: Canada— Antibacterial (systemic). Withdrawal times have been established for florfenicol in cattle and salmon; however, it is not labeled for use in lactating dairy cattle{R-1} INDICATIONS (see the Dosage Forms section). Note: Bracketed information in the Indications section refers to uses that either are not included in U.S. product labeling or are for products not CHEMISTRY commercially available in the U.S. Source: A fluorinated derivative of thiamphenicol{R-12}. Chemical name: Acetamide, 2,2-dichloro-N-[1-(flouromethyl)-2-hy- GENERAL CONSIDERATIONS droxy-2-[4-(methylsulfonyl)phenyl]ethyl]-[R-(R*,S*)]-{R-4}. {R-14}. Florfenicol is a broad-spectrum, primarily bacteriostatic, antibiotic with a Molecular formula: C12H14Cl2FNO4S range of activity similar to that of chloramphenicol, including many Molecular weight: 358.21{R-4}. gram-negative and gram-positive organisms{R-1}; however, florfenicol Description: Melting point 153 to 154 C{R-12}. does not carry the risk of inducing human aplastic anemia that is Solubility: Soluble in water{R-12; 13}. Lipid soluble{R-13}. associated with chloramphenicol{R-13}. Florfenicol has been demonstrated to be active in vitro and in vivo against Mannheimia (Pasteurella) PHARMACOLOGY/PHARMACOKINETICS haemolytica, Pasteurella multocida, and Haemophilus somnus{R-1; 2}. In vitro studies have demonstrated florfenicol activity against Enterob- Mechanism of action/effect: Florfenicol is a bacteriostatic antibiotic acter cloacae, Escherichia coli, Klebsiella pneumoniae, Salmonella typhi, and that inhibits protein synthesis by binding to ribosomal subunits Shigella dysenteriae{R-2; 15; 16} but with at least a 2- to 10-fold higher of susceptible bacteria, leading to the inhibition of peptidyl trans- {R-1; 13; 26} minimum inhibitory concentration than that for the Mannheimia, ferase and thereby preventing the transfer of amino acids to Pasteurella and Haemophilus species listed above{R-15; 16}. It also has growing peptide chains and subsequent protein formation. The bac- activity against some chloramphenicol-resistant strains of bacte- terial receptor that is the site of action for florfenicol is considered to be {R-13; 26} ria{R-17}, possibly because it is less affected by the major enzyme the same as that for chloramphenicol and thiamphenicol .In produced in plasmid-mediated bacterial resistance against chloram- the treatment of bovine respiratory disease, florfenicol may be con- phenicol and thiamphenicol{R-2; 26}. Although the activity of florfeni- sidered bactericidal against some Mannheimia (Pasteurella) hemolytica col against obligate anaerobes is not addressed in the literature, it is and Pasteurella multocida when it is administered to achieve minimum {R-14} likely to be quite effective{R-28}. inhibitory concentrations (MICs) ; the minimum bactericidal concentrations (MBCs) are very close to the MICs. Florfenicol has a fluorine atom instead of the hydroxyl group located ACCEPTED {R-13} at C-3 in the structure of chloramphenicol and thiamphenicol . Pneumonia, bacterial (treatment and control1)—Cattle: Florfenicol This may allow florfenicol to be less susceptible to deactivation by injection is indicated in the treatment of bacterial pneumonia and bacteria with plasmid-transmissible resistance that involves acetyla- associated respiratory infections (bovine respiratory disease) in cattle tion of the C-3 hydroxyl group in chloramphenicol and thiamphe- caused by susceptible M. haemolytica, P. multocida, and H. somnus{R-1; 3}. nicol, and prevents their interaction with bacterial ribosomes{R-13; 26}. Florfenicol injection is also indicated in the control of bacterial pneumonia and associated respiratory disease in cattle at high risk of Other actions/effects: Florfenicol, like thiamphenicol, lacks the nitro developing bovine respiratory disease associated with susceptible group located on the chloramphenicol aromatic ring that has been M. haemolytica, P. multocida, and H. somnus{R-1; 3; 32}. associated with chloramphenicol-induced, non–dose-related, irrevers- Pododermatitis (treatment)—Cattle: Florfenicol injection is indicated in ible aplastic anemia in people{R-13; 24; 25}. However, chloramphenicol the treatment of infectious pododermatitis (interdigital phlegmon) and thiamphenicol also cause a dose-dependent, reversible bone associated with susceptible Fusobacterium necrophorum and Bacteroides marrow suppression in some animals and people{R-13} due to mito- melaninogenicus{R-1; 3; 30}. chondrial injury{R-24}. It is theoretically possible that florfenicol could [Furunculosis (treatment)]—Salmon: Florfenicol premix is indicated in cause some dose-dependent, reversible bone marrow suppression, but the treatment of furunculosis caused by susceptible strains of Aeromo- it has not been clinically reported{R-13}. nas salmonicida in salmon{R-11}. [Keratoconjunctivitis (treatment)]—Cattle: Florfenicol injection is indicated in Canadian product labeling in the treatment of infectious Absorption: Bioavailability— {R-3; 33; 34} bovine keratoconjunctivitis caused by Moraxella bovis . Intramuscular administration: Calves, 3 to 6 months of age—78.5% (range 59.3 to 106%), with a 1Not included in Canadian product labeling or product not commercially dose of 20 mg per kg of body weight (mg/kg){R-1; 2; 8}. available in Canada. Cattle, lactating—38 ± 14%, with a dose of 20 mg/kg{R-9}.

Horses—81%, with a dose of 22 mg/kg{R-19}. Low (17.5%), with serum concentration of 5 mcg/mL{R-5}. Oral administration: Low (18.6%), with serum concentration of 50 mcg/mL{R-5}. Calves, 2 to 5 weeks of age—89%, at a dose of either 11 or 22 mg/kg; however, the absorption was widely variable{R-6; 7}. Oral absorp- Biotransformation: tion may decrease when florfenicol is administered with milk Cattle—Approximately 64% of a 20 mg/kg dose of intramuscular replacers{R-6; 7}; one study reported bioavailability that ranged from florfenicol administered two times, 48 hours apart, is excreted as 44 to 86% among calves when florfenicol was administered 5 parent drug in the urine{R-13}. Urinary metabolites include florfenicol minutes after feeding{R-7}. amine, florfenicol alcohol, florfenicol oxamic acid, and mono- Horses—83.3%, with a dose of 22 mg/kg{R-19}. chloroflorfenicol{R-13}. Florfenicol and its metabolites, such as Salmon, Atlantic—96.5%, with a dose of 10 mg/kg when water monochloroflorfenicol and florfenicol oxamic acid, also are eliminated temperature is 10.8 ± 1.5 C{R-22}. in the feces{R-13}. Florfenicol amine is the longest-lived major Note: After intramammary administration of a 20 mg/kg dose to lactating metabolite in the liver, and, therefore, it was used as the marker dairy cows, the systemic bioavailability was found to be 54 ± 18%{R-9}. residue for withdrawal calculations{R-13}. Salmon, Atlantic—Florfenicol is rapidly metabolized at water temperatures Distribution: of 8.5 to 11.5 C and the major metabolite is florfenicol amine{R-23}. Cattle, 2 to 5 weeks of age—After multiple oral dosing (11 mg/kg every twelve hours for seven doses), florfenicol was well distributed into Half-life: many tissues, reaching concentrations of 4 to 8 mcg per gram (mcg/ Distribution—Intravenous administration: Calves, less than 8 weeks of gram) in lungs, heart, pancreas, skeletal muscle, spleen, and age—0.13 hour (range, 0.075 to 0.27 hour){R-6}; 0.098 hour (range, synovia{R-6}. These concentrations were at least as high as serum 0.081 to 0.17 hour){R-7}. concentrations{R-6}. Relatively high concentrations were found in Elimination— bile, kidney, small intestine, and urine{R-6}. Concentrations in the Intravenous administration: brain (1 to 2 mcg/gram), cerebrospinal fluid (2 to 3 mcg/mL), and Calves, less than 8 weeks of age—2.86 hours (range, 2.3 to 3.39 aqueous humor (2 to 3 mcg/mL) have been found to be one quarter hours){R-7}; 3.71 hours (range, 3.5 to 4.11 hours){R-6}. to one half the serum concentration in healthy calves{R-6}. Calves, 3 to 6 months of age—2.6 hours (range, 2.4 to 3 hours){R-2; 8}. Salmon, Atlantic—Florfenicol is distributed to all organs and tissues Cows— with a dose of 10 mg/kg when the water temperature is 8.5 to Lactating: 2.9 hours{R-9}. 11.5 C{R-23}. Concentrations in muscle and blood are similar to Nonlactating: 3.2 hours{R-5}. serum concentrations, while fat and the central nervous system Goats, lactating—2.3 ± 0.2 hours{R-18}. (CNS) have lower concentrations. Only 25% of serum drug and Horses—1.8 ± 0.9 hours{R-19}. metabolite concentrations are found in the brain{R-23}. Salmon, Atlantic—12.2 hours at a water temperature of 10.8 ± Volume of distribution (Vol ) —Intravenous administration: D 1.5 C{R-22}. Calves, 2 weeks to 6 months of age— Intramuscular administration (terminal half-life): Calves, 3to6 Area: 0.88 liter per kg (L/kg){R-2}; 0.91 L/kg{R-6}. months of age—18.3 hours (range, 8.3 to 44 hours){R-1; 2}. Steady state: 0.77 L/kg{R-1; 2; 8}; 0.87 L/kg{R-6}. Cattle— Lactating: Steady state—0.35 L/kg{R-9}. Concentrations: Nonlactating: Peak serum concentration— Area—0.67 L/kg (range, 0.62 to 0.76 L/kg){R-5}. Intramuscular administration: Steady state—0.62 L/kg (range, 0.57 to 0.68 L/kg){R-5}. Calves, 3 to 6 months of age—3 mcg per mL (range, 1.43 to 5.6 mcg/ Note: Although the data above imply that lactation causes a decrease mL), with a dose of 20 mg/kg{R-1; 2; 8}. in the volume of distribution of florfenicol, other data from these Cows, lactating—2.3 mcg/mL, with a dose of 20 mg/kg{R-9}. studies, including half-life of elimination and clearance, correlate Horses—4 ± 1.2 mcg/mL, with a dose of 22 mg/kg{R-19}. well between the two trials, one conducted in lactating and one in Oral administration: nonlacting cattle. The apparent difference here between lactating Calves, less than 8 weeks of age—11.32 ± 4.04 mcg/mL, with a dose and nonlactating cattle may be due to calculation methods or of 22 mg/kg{R-7}. dosing{R-27}. Horses—13.8 ± 4.8 mcg/mL, with a dose of 22 mg/kg{R-19}. Goats, lactating—Steady state: 0.98 ± 0.09 L/kg{R-18}. Salmon, Atlantic—4 mcg/mL, with a dose of 10 mg/kg when water Horses—Steady state: 0.72 ± 0.17 L/kg{R-19}. temperature is 10.8 ± 1.5 C{R-22}. Salmon, Atlantic—Steady state: 1.12 L/kg at a water temperature of Note: After intramammary administration of 20 mg/kg to lactating 10.8 ± 1.5 C{R-22}. dairy cows, the peak serum concentration was 6.9 mcg/mL at 6 hours{R-9}. Protein binding: Time to peak serum concentration— Calves, 3 to 6 months of age— Intramuscular administration: Low (12.7%), with serum concentration of 0.5 mcg/mL{R-2}. Calves, 3 to 6 months of age—3.33 hours (range, 0.75 to 8 hours), Low (13.2%), with serum concentration of 3 mcg/mL{R-1; 2}. with a dose of 20 mg/kg{R-1; 2; 8}. Low (18.3%), with serum concentration of 16 mcg/mL{R-1; 2}. Cows, lactating—3 hours, with a dose of 20 mg/kg{R-9}. Cattle—Considered independent of drug concentration: Horses—1.3 ± 0.5 hours, with a dose of 22 mg/kg{R-19}.

Oral administration: LACTATION Calves, less than 8 weeks of age—2.5 ± 0.72 hours, with a dose of 22 The effect of florfenicol on lactation has not been determined{R-1}. {R-7} mg/kg . Goats: Florfenicol concentrations in milk equal serum concentrations {R-19} Horses—1.1 ± 0.5 hours, with a dose of 22 mg/kg . when serum concentrations are nearly constant{R-18}. Salmon, Atlantic—10.3 hours, with a dose of 10 mg/kg when water temperature is 10.8 ± 1.5 C{R-22}. Other peak concentrations—In milk: MEDICAL CONSIDERATIONS/CONTRAINDICATIONS Intramuscular administration— The medical considerations/contraindications included have been {R-9} Cows, lactating: 1.6 mcg/mL at 10 hours, with a 20 mg/kg dose . selected on the basis of their potential clinical significance (reasons Intravenous administration: given in parentheses where appropriate)—not necessarily inclusive (» {R-9} Cows, lactating: 5.4 mcg/mL at 3 hours, with a 20 mg/kg dose . = major clinical significance). Goats, lactating: 13.2 ± 1.9 mcg/mL at 1 hour, with a 25 mg/kg Except under special circumstances, this medication should not be {R-18} dose . used when the following medical problem exists: » Previous allergy or toxic reaction to florfenicol Duration of action: Calves, 3 to 6 months of age—The serum concentration of florfenicol was maintained above 1 mcg per mL for 22.3 ± 5.9 hours after SIDE/ADVERSE EFFECTS intramuscular administration and 11.5 ± 1.1 hours after intravenous The following side/adverse effects have been selected on the basis of their administration of 20 mg/kg{R-2}. potential clinical significance (possible signs in parentheses where Salmon, Atlantic—Plasma concentrations were maintained above the appropriate)—not necessarily inclusive: minimum inhibitory concentration of 0.8 mcg/mL reported for Aeromonas salmonicida, Vibrio anguillarum, and V. salmonicida for 36 to 40 hours after a single oral florfenicol dose of 10 mg/kg in water THOSE INDICATING NEED FOR MEDICAL ATTENTION temperatures of 10.8 ± 1.5 C{R-22}. Note: There is no documentation of dose-dependent, reversible bone- marrow suppression caused by florfenicol use in animals; however, the Elimination: protection against human aplastic anemia, due to the difference in Calves, less than 8 weeks of age—Approximately 50% of a 22 mg/ structure of florfenicol from chloramphenicol, does not necessarily kg intravenous dose is eliminated unchanged in the urine within 30 protect against suppression of mitochondrial protein synthesis in bone {R-7} hours . marrow and subsequent reversible anemia{R-13}. This phenomenon is Cattle—Approximately 64% of a 20 mg/kg intramuscular dose not considered a side/adverse effect with normal clinical use, but an administered two times, 48 hours apart, is excreted as parent drug awareness of this possibility may be useful if long-term therapy with {R-13} in the urine . this medication is considered. Horses—Approximately 13% of a 22 mg/kg intravenous dose, 7% of Incidence unknown the same dose given intramuscularly, and 6% when given orally, is Horses, ponies {R-19} excreted unchanged in the urine in the first 30 hours . Diarrhea, mild—in one study, occurred in all three horses and three Rats—Approximately 60 to 70% of a 20 mg/kg oral dose administered ponies administered a single dose of 22 mg per kg of body weight by {R-13} once a day for 7 days is eliminated in the urine . Approximately either the oral or parenteral route{R-19}. 20 to 30% is eliminated in the feces in the first 24 hours after a 20 mg/kg oral dose{R-13}. Total clearance—Intravenous administration: THOSE INDICATING NEED FOR MEDICAL ATTENTION Calves— ONLY IF THEY CONTINUE OR ARE BOTHERSOME Less than 8 weeks of age: 2.9 mL per minute per kg (range, 2.44 to 4 Incidence unknown {R-6; 7} mL/min/kg) . Cattle 3 to 6 months of age: 3.75 mL/min/kg (range, 3.17 to 4.31 mL/ Decreased food consumption{R-1}—usually transient; decreased {R-1; 2; 8} min/kg) . water consumption{R-1}—usually transient; diarrhea{R-1}—usually Cows— transient; local tissue reactions—more severe if administered at {R-9} Lactating: 2.7 ± 0.6 mL/min/kg . injection sites other than the neck{R-10}. {R-5} Nonlactating: 2.45 mL/min/kg (range, 2.25 to 2.67 mL/min/kg) . Note: In a controlled study over 43 days, florfenicol administration had {R-18} Goats, lactating—8.1 ± 2.6 mL/min/kg . no long-term effect on body weight, rate of weight gain, or feed {R-19} Horses—6.7 ± 1.7 mL/min/kg . consumption, although a transient decrease in food and water Salmon, Atlantic—1.4 mL/min/kg when water temperature is 10.8 ± consumption occurred at the start of therapy{R-1; 10}. 1.5 C{R-22}.

PRECAUTIONS TO CONSIDER OVERDOSE For more information in cases of overdose or unintentional ingestion, PREGNANCY/REPRODUCTION contact the American Society for the Prevention of Cruelty to The effects of ﬂorfenicol on reproductive performance and pregnancy Animals (ASPCA) National Animal Poison Control Center (888- have not been determined{R-1}. Administration to breeding cattle is not 426-4435 or 900-443-0000; a fee may be required for consultation) recommended by product labeling{R-3}. and/or the drug manufacturer.

CLINICAL EFFECTS OF OVERDOSE ORAL DOSAGE FORMS The following effects have been selected on the basis of their potential Note: Bracketed information in the Dosage Forms section refers to uses clinical signiﬁcance (possible signs in parentheses where appropri- that either are not included in U.S. product labeling or are for products ate)—not necessarily inclusive: not commercially available in the U.S. Acute— Calves, with intramuscular administration of 200 mg per kg of body FLORFENICOL FOR MEDICATED FEED weight (mg/kg) repeated in forty-eight hours (10 times the label Usual dose: [Furunculosis]—Salmon: Oral, 10 mg per kg of body weight dose){R-1} a day, administered in the only ration, according to manufacturer Anorexia, marked{R-1}; decreased body weight{R-1}; decreased labeling{R-11}. rumen activity{R-10}; decreased water consumption{R-1; 10}; ketosis, slight{R-10}—secondary to anorexia; serum enzymes, including Strength(s) usually available{R-35}: alanine aminotransferase [SGPT], aminoacyltransferase [GGT], U.S.— aspartate aminotransferase [SGOT], and lactase dehydrogenase Veterinary-labeled product(s): [LDH], mildy increased{R-1; 10}; soft feces{R-10} Not commercially available. Chronic— Canada— Dogs, 4- to 6-months old, with oral administration of 12 mg/kg a day Veterinary-labeled product(s): for thirteen weeks{R-10} 500 grams per kg of premix (Rx) [Aquaﬂor{R-11}]. Hepatotoxicity Note: Oral dosing of 100 mg/kg for thirteen weeks resulted in CNS Withdrawal times: vacuolation, hematopoietic toxicity, renal tubule dilation, and Canada— testicular atrophy{R-10}. Withdrawal time

TREATMENT OF OVERDOSE Species Meat (days) There is no specific treatment for florfenicol overdose. Therapy should be Salmon 12 supportive. Note: Not labeled for use in fish maintained at water temperatures less VETERINARY DOSING INFORMATION than 5 C. Minimum inhibitory concentrations (MICs) of florfenicol were determined for pathogens involved in natural bovine respiratory complex in the Packaging and storage: Store between 2 and 30 C (36 and 86 F), U.S., Canada, and Europe between 1990 and 1993{R-1; 3}: unless otherwise specified by the manufacturer. Keep separate from other feeds{R-11}. Store in a dry place{R-29}. Number of Organism Isolates MIC (mcg/mL) MIC (mcg/mL) 50 90 Stability: Premix should be used within 12 months of opening {R-11} Mannheimia (Pasteurella) 398 0.5 1 pouch . Medicated feed should be used within 6 months of the haemolytica manufacture date{R-11}. Pasteurella multocida 350 0.5 0.5 Haemophilus somnus 66 0.25 0.5 Caution: Product labeling recommends that handlers avoid inhalation of dust and contact with skin and eyes{R-11}. Protective clothing Note: MIC can vary according to pathogen strain; therefore, cattle in should be worn when handling the medication and hands should be different geographic locations may harbor organisms with different washed after administration{R-11}. MICs{R-10}. USP requirements: Not in USP{R-31}. Safety considerations—Precautions for personnel administering florfenicol injection include the recommendation to avoid direct contact with eyes, skin, and clothing{R-1}. In case of accidental eye exposure, flush PARENTERAL DOSAGE FORMS with water for 15 minutes; for skin exposure, wash with soap and Note: Bracketed information in the Dosage Forms section refers to uses water{R-1}. Remove exposed clothing and consult a physician if that either are not included in U.S. product labeling or are for products irritation persists. Accidental injection may cause local irritation and a not commercially available in the U.S. physician should be consulted immediately{R-1}. FLORFENICOL INJECTION Usual dose: FOR TREATMENT OF ADVERSE EFFECTS Pneumonia (bovine respiratory disease) (treatment); or Recommended treatment consists of the following: Pododermatitis—Cattle: For anaphylaxis Intramuscular, 20 mg per kg of body weight to be repeated in forty- • Parenteral epinephrine and cardiovascular support. eight hours{R-1; 3}. • Oxygen administration and respiratory support. Subcutaneous, 40 mg per kg of body weight as a single dose{R-1}.

Note: Canadian product labeling lists the same dose as above, a single Developed: 07/08/98 subcutaneous dose of 40 mg per kg of body weight or two Revised: 6/30/02 intramuscular doses of 20 mg per kg of body weight, administered Interim revision: 10/15/99; 04/04/03 forty-eight hours apart, in the treatment of [keratoconjunctivitis] in cattle{R-3}. REFERENCES Pneumonia (bovine respiratory disease) (control)1—Cattle: Subcuta- 1. Nuflor product information (Schering-Plough—US). Downloaded 1/16/03 neous, 40 mg per kg of body weight as a single dose{R-1; 32} from www.spah.com. {R-1} 2. Lobell RD, Varma KJ, Johnson JC, et al. Pharmacokinetics of florfenicol Note: No more than 10 mL should be injected at each site . following intravenous and intramuscular doses to cattle. J Vet Pharmacol Ther Injections should be given in the neck to avoid local reaction and 1994; 17: 253–8. trim loss of edible tissues at slaughter{R-1}. According to the 3. Nuflor product information(Schering-Plough—Canada).Downloaded fromScher- ing-Plough Animal Health Product Label Retrieval Service on 2/21/03. product labeling, if clinical improvement is not noted within 4. USP dictionary of USAN and international drug names, 2002 ed. Rockville, {R-1} twenty-four hours, the diagnosis should be reevaluated . MD: The United States Pharmacopeial Convention, Inc.; 2002. 5. Bretzlaff KM, Neff-Davis CA, Ott RS, et al. Florfenicol in nonlactating dairy Strength(s) usually available{R-35}: cows: pharmacokinetics, binding to plasma proteins, and effects on phagocy- U.S.— tosis by blood neutrophils. J Vet Pharmacol Ther 1987; 10: 233–40. 6. Adams PE, Varma KJ, Powers TE, et al. Tissue concentrations and pharma- Veterinary-labeled product(s): cokinetics of florfenicol in male veal calves given repeated doses. Am J Vet Res {R-1} 300 mg per mL (Rx) [Nuflor ]. 1987 Dec; 48(12): 1725–32. Canada— 7. Varma KJ, Adams PE, Powers TE, et al. Pharmacokinetics of florfenicol in veal Veterinary-labeled product(s): calves. J Vet Pharmacol Ther 1986; 9: 412–25. {R-3} 8. Varma KJ, Sams RA, Lobell RD, et al. Pharmacokinetics and efficacy of a new 300 mg per mL (Rx) [Nuflor ]. broad spectrum antibiotic, florfenicol in cattle. Acta Vet Scand Suppl 1991; 87: 102–4. Withdrawal times: 9. Soback S, Paape MJ, Filep R, et al. Florfenicol pharmacokinetics in lactating cows after intravenous, intramuscular and intramammary administration. U.S.{R-1}— J Vet Pharmacol Ther 1995; 18: 413–7. 10. Freedom of Information Summary. Nuflor Injectable Solution for the treatment Withdrawal time of bovine respiratory disease. NADA 141-063. Sponsor: Schering-Plough. June Species Meat (days) 1996. 11. Aquaflor product labeling (Schering-Plough—Canada). Downloaded Cattle from Schering-Plough Animal Health Product Label Retrieval Service on Intramuscular injection 28 2/21/03. Subcutaneous injection 38 12. Budavari S, editor. The Merck Index. An encyclopedia of chemicals, drugs, and biologicals. 12th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1996. p. 4146. Note: This product is not labeled for use in dairy cattle 20 months of age 13. Sams RA. Florfenicol: chemistry and metabolism of a novel broad-spectrum or older, veal calves, calves under 1 month of age, or calves being fed antibiotic. In: Proceedings of the XVIII World Buiatrics Congress. Bologna, {R-1} Italy; 1994. p. 13–7. an all-milk diet as withdrawal times have not been studied. 14. Varma KJ. Microbiology, pharmacokinetic disposition and safety of florfenicol If florfenicol is injected at sites other than the neck, local reaction may in cattle. In: Proceedings of the XVIII World Buiatrics Congress. Bologna, Italy; result in trim loss of edible tissue at slaughter{R-1}. 1994. p. 18–24. 15. Syriopoulou VP, Harding AL, Goldmann DA, et al. In vitro antibacterial Canada{R-3}— activity of flourinated analogs of chloramphenicol and thiamphenicol. Anti- Withdrawal time microb Agents Chemother 1981 Feb; 19(2): 294–7. 16. Marshall SA, Jones RN, Wanger A, et al. Proposed MIC quality control Species Meat (days) guidelines for national committee for clinical laboratory standards susceptibility tests using seven veterinary antimicrobial agents: ceftiofur, enrofloxacin, Cattle florfenicol, penicillin G-novobiocin, pirlimycin, premafloxacin, and spectino- Intramuscular injection 36 mycin. J Clin Microbiol 1996 Aug; 34(8): 2027–9. Subcutaneous injection 55 17. Martel J. In vitro activity of florfenicol on the primary pathogenic bacteria of the respiratory tract in european cattle. In: Proceedings of the XVIII World Note: This product is not labeled for use in lactating dairy cattle{R-3}. Buiatrics Congress. Bologna, Italy; 1994. p. 25–30. 18. Lavy E, Ziv G, Soback S, et al. Clinical pharmacology of florfenicol in lactating goats. Acta Vet Scand 1991; 87 Suppl: 133–6. Packaging and storage: Store below 40 C (104 F), preferably 19. McKeller QA, Varma KJ. Pharmacokinetics and tolerance of florfenicol in between 15 and 30 C (59 and 86 F), unless otherwise specified by Equidae. Equine Vet J 1996; 28(3): 209–13. the manufacturer. Protect from freezing. 20. Wilson DJ, Sears PM, Gonzalez RN, et al. Efficacy of florfenicol for treatment of clinical and subclinical bovine mastitis. Am J Vet Res 1996 Apr; 57(4): 526–8. 21. Paape MJ, Miller RH. Effects of florfenicol, chloramphenicol, and thiamphenicol Caution: Florfenicol injection can be irritating to eyes and skin; there- on phagocytosis, chemiluminescence, and morphology of bovine polymorpho- {R-1} fore, avoid direct contact with skin, eyes, and clothes . Accidental nuclear neutrophil leukocytes. J Dairy Sci 1990; 73: 1734–44. injection may cause local irritation{R-1}. 22. Martinsen B, Horsberg TE, Varma KJ, et al. Single dose pharmacokinetic study of florfenicol in Atlantic salmon (Salmo salar) in seawater at 11 C. Additional information: The light yellow to straw color of the solution Aquaculture 1993; 112: 1–11. 14 {R-1} 23. Horsberg TE, Martinsen B, Varma KJ. The disposition of C-florfenicol in does not affect potency . Atlantic salmon (Salmo salar). Aquaculture 1994; 122: 97–106. 24. Yunis AA. Chloramphenicol: relation of structure to activity and toxicity. {R-31} USP requirements: Not in USP . Annu Rev Pharmacol Toxicol 1988; 28: 83–100. 25. Skolimowski IM, Knight RC, Edwards DI. Molecular basis of chloramphenicol 1 Not included in Canadian product labeling or product not commercially and thiamphenicol toxicity to DNA in vitro. J Antimicrob Chemother 1983; available in Canada. 12: 535–42.

26. Cannon M, Harford S, Davies J. A comparative study on the inhibitory 32. Freedom of Information Summary. Nuflor injectable solution for the control of actions of chloramphenicol, thiamphenicol and some fluorinated derivatives. respiratory disease in cattle at high risk. NADA 141-063. Sponsor: Schering- J Antimicrob Chemother 1990; 26: 307–17. Plough Animal Health. December 17, 1998. 27. Panel comment, Rec 8/25/97. 33. Dueger EL, Angelos JA, Cosgrove S, et al. Efficacy of florfenicol in the treatment 28. Panel comment, Rec 1/5/98. of experimentally induced infectious bovine keratoconjunctivitis. Am J of Vet 29. Manufacturer comment, Rec 12/2/97. Res 1999; 60(8), 960–964. 30. Freedom of information summary. Nuflor Injectable Solution for the treatment 34. Angelos JA, Dueger EL, George LW, et al. Efficacy of florfenicol for treatment of of bovine interdigital phlegmon. NADA 141-063 Sponsor: Schering-Plough naturally occurring infectious bovine keratoconjunctivitis. J Am Vet Med Animal Health. Rev 1/99, Rec 5/5/99. Assoc 2000 January 1; 216(1): 62–4. 31. The United States pharmacopeia. The national formulary. USP 26th revision 35. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United Huron, MI: North American Compendiums, Inc. 2003. States Pharmacopeial Convention, Inc., 2002.

FLUOROQUINOLONES Veterinary—Systemic

This monograph includes information on the following: Ciprofloxacin, positive bacteria, mutation occurs at the topoisomerase-IV target Difloxacin, Enrofloxacin, Marbofloxacin, and Orbifloxacin. (parC){R-9; 21; 86}. Other mechanisms of resistance occur when Some commonly used brand names for veterinary-labeled products are: bacteria decrease the ability of the drug to enter the cell or increase active transport out of the cell{R-9; 21}. Resistance is usually chromo- Baytril 3.23% Concentrate Baytril Taste Tabs somally developed and, therefore, remains after antimicrobial therapy Solution [Enrofloxacin] [Enrofloxacin] ends{R-90; 95}. While there is evidence for plasmid-mediated resistance, Baytril Injectable Solution Dicural Tablets [Difloxacin] [Enrofloxacin] its clinical significance in veterinary medicine has not been Baytril Injectable Solution Orbax Tablets [Orbifloxacin] shown{R-90}. Cross-resistance of enrofloxacin with other fluoroquinol- 2.27% [Enrofloxacin] ones can occur{R-9; 10; 50}. Changes in levels of resistance to Baytril 100 Injectable Solution Zeniquin Tablets [Enrofloxacin] [Marbofloxacin] fluoroquinolones over time by Campylobacter and Salmonella species Baytril Tablets [Enrofloxacin] are being monitored because of their possible impact on human {R-55; 56; 91} Some commonly used brand names for human-labeled products are: Cipro health . [Ciprofloxacin] and Cipro I.V. [Ciprofloxacin]. Note: For a listing of dosage forms and brand names by country and ACCEPTED availability, see the Dosage Forms section(s). Colibacillosis (treatment)1—Chickens and turkeys: Enrofloxacin oral solution is indicated in the control of mortality associated with CATEGORY: Escherichia coli infection in chickens and turkeys{R-3; 49}. Antibacterial (systemic). Fowl cholera (treatment)1—Turkeys: Enrofloxacin oral solution is indicated in the control of mortality associated with Pasteurella multocida infection in turkeys{R-3}. INDICATIONS Infections, bacterial (treatment), including Note: Bracketed information in the Indications section refers to uses that Cystitis, urinary, bacterial (treatment); either are not included in U.S. product labeling or are for products not Respiratory infections, bacterial (treatment); or commercially available in the U.S. Skin and soft tissue infections (treatment)— Cats: Enrofloxacin [injection]1 and tablets{R-1; 104}, marbofloxacin tablets1{R-97; 101}, and orbifloxacin tablets{R-98; 100} are indicated in GENERAL CONSIDERATIONS the treatment of susceptible bacterial infections in cats. Clinical The fluoroquinolone antimicrobials are rapidly bactericidal against a efficacy has been established specifically in the treatment of skin and variety of clinically important organisms, are well tolerated by soft tissue infections{R-1; 97; 98; 100; 102}. animals, and can be administered by a variety of routes{R-95}. The Dogs: Difloxacin tablets{R-96; 99}, enrofloxacin injection and tablets{R-1; members of this group that are currently labeled for use in animals 104}, marbofloxacin tablets{R-97; 101}, and orbifloxacin tablets{R-98; have the same quinolone structure, each with modifications that 100} are indicated in the treatment of susceptible bacterial infections account for pharmacokinetic variations in the medications but do not in dogs. Clinical efficacy has been established specifically in the significantly change the antibacterial spectrum of activity.{R-1; 95–98; treatment of skin and soft tissue infections and urinary tract 100; 102; 112}. infections, as noted on product labeling{R-96–101}. Clinical Fluoroquinolones exhibit good activity against most gram-negative efficacy has also been established for enrofloxacin injection and bacteria, including Escherichia coli, Enterobacter species, Klebsiella tablets in the treatment of respiratory tract infections in dogs{R-1}. species, Pasteurella species, Proteus species, and Salmonella species. [There is evidence to suggest that enrofloxacin is as effective as Pseudomonas aeruginosa is variably susceptible, usually having a higher chloramphenicol or tetracycline in the treatment of Rocky Moun- minimum inhibitory concentration (MIC) than other susceptible tain spotted fever in dogs{R-84}.]1 organisms.{R-1; 95–98; 100; 102; 112}. Pneumonia (treatment)1—Cattle: Enrofloxacin injection is indicated in Some gram-positive bacteria are susceptible to fluoroquinolones. the treatment of bovine respiratory disease caused by susceptible Staphylococcus aureus and Staphylococcus intermedius usually are organisms, including Mannheimia (Pasteurella) haemolytica, Pasteurella susceptible{R-1; 96–98; 112}. However, the MIC values for staphylococci multocida, and Haemophilus somnus{R-2; 57}. typically are higher than for gram-negative bacteria and staphylococcal resistance to fluoroquinolones has been a problem in human patients{R-95}. ACCEPTANCE NOT ESTABLISHED Chlamydia, mycobacteria, mycoplasma, and ureaplasma can also be Infections, bacterial (treatment)— moderately to very susceptible to fluoroquinolones{R-9}. [Bustards, camels, ducks, emus, llamas, oryx, red pacu, African grey Local factors that affect activity are cations at the site of infection and low parrots, and pythons]1: In the U.S., for use only in animals not to be pH; however, fluoroquinolones are active in abscesses in spite of often used for food production—Although the safety and efficacy of unfavorable environmental conditions {R-95}. enrofloxacin have not been established, dose recommendations for Bacterial resistance to fluoroquinolones most commonly occurs by use in the treatment of susceptible bacterial infections have been alteration of the target, DNA-gyrase (topoisomerase II), via mutation made, based on pharmacokinetic data, for bustards{R-41}, camels{R-45}, (gyr-A). Less commonly, but perhaps more importantly for gram- ducks{R-42}, emus{R-43}, llamas{R-46}, oryx{R-47}, red pacu{R-44},

African grey parrots{R-39; 40}, and pythons{R-48}. Further treatment of human brucellosis{R-137}. It is not known whether the clinical studies are necessary. See also the Regulatory Considerations fluoroquinolones have any efficacy in the treatment of canine section. brucellosis. [Horses]1: For use only in animals not to be used for food produc- [Chlamydial infections (treatment)]1—Cats: There are no studies to tion—Although the safety and efficacy of enrofloxacin and orbiflox- document the effectiveness of the veterinary fluoroquinolones, difloxacin in the treatment of susceptible bacterial infections in horses acin, enrofloxacin, marbofloxacin, and orbifloxacin, in the treatment of have not been established, pharmacokinetic evidence and case chlamydial infections in cats. Clinical trials of related human-labeled reports are available to suggest that they may be safe and effec- fluoroquinolones in the treatment of genital, respiratory, or ocular tive{R-25–27; 79–80; 136}. Due to reports of articular cartilage damage chlamydial infections in human patients have shown efficacy; how- in foals from administration of enrofloxacin, neither enrofloxacin nor ever, concern exists that the organisms are not eradicated and orbifloxacin should be administered to horses less than 3 years of recrudecense is common. age, except as a last resort for severe infections not treatable with [Endophthalmitis, bacterial (treatment)]1—Cats and dogs: There are no other medications{R-25; 26; 85}. Although there have been reports of specific studies to document the effectiveness of the veterinary unpublished studies showing articular damage from enrofloxacin fluoroquinolones, difloxacin, enrofloxacin, marbofloxacin and orbiflox- administration to adult horses, subsequent studies have shown no acin, in the treatment of bacterial endophthalmitis due to susceptible effect on cartilage in adults when used continuously for up to 21 organisms. However, these bactericidal drugs have been shown to days{R-86}. produce aqueous and vitreous humor concentrations within the [Pigs, potbellied and minature]1: In the U.S., for use only in animals therapeutic range for many pathogens{R-1; 102}. Also, related human- not to be used in food production—Although the safety and efficacy labeled fluoroquinolones, including ciprofloxacin (a metabolite of of enrofloxacin in the treatment of susceptible bacterial infections in enrofloxacin), have been reported as efficacious in several small pigs have not been established, there is some pharmacokinetic studies and case reports in human patients{R-120–125}. evidence to suggest that this therapy may be effective{R-29}. See also [Meningitis, bacterial (treatment)]1—Cats and dogs: There are no studies the Regulatory Considerations section. to document the effectiveness of the veterinary fluoroquinolones, [Sheep, pet and research]1: In the U.S., for use only in animals not to be difloxacin, enrofloxacin, marbofloxacin, and orbifloxacin, in the used in food production—Although the safety and efficacy of treatment of bacterial meningitis due to susceptible organisms. enrofloxacin in the treatment of susceptible bacterial infections in However, these bactericidal drugs have been shown to obtain central sheep have not been established, there is some pharmacokinetic nervous system concentrations within the therapeutic range for many evidence to suggest that this therapy may be effective{R-28}. See also pathogens{R-1; 102}. Also, related human-labeled fluoroquinolones, the Regulatory Considerations section. including ciprofloxacin (a metabolite of enrofloxacin), have been [Bartonella infections (treatment)]1;or reported as efficacious in several small studies and case reports in [Hemobartonella felis infections (treatment)]1—Cats: Although the safety human patients{R-126–132}. Although the potential for fluoroquinol- and efficacy have not been established, enrofloxacin has been used in ones to induce seizures has been suggested as a reason to avoid these an attempt to eradicate Bartonella bacteremia in cats{R-72; 73}. drugs in the treatment of meningitis, the above mentioned human Controlled therapeutic trials investigating the efficacy of enrofloxacin studies, as well as disease models in animals, have failed to indicate an in clearing Bartonella from cats show a positive response in some increased incidence of seizures in fluoroquinolone-treated subjects. animals, but tests used to document that an infection has been Careful monitoring for seizures is nevertheless advised if fluoroquinol- cleared remain unreliable, making the results difficult to interpret{R-72}. ones are used in such infections. It should not be assumed that a Bartonella infection is cleared by a [Mycobacterial infections (treatment)]1—Cats: Although the safety and course of enrofloxacin. Long-term monitoring is necessary{R-72; 73}. efficacy have not been established, enrofloxacin and ciprofloxacin have Although the safety has not been clearly established, a controlled, been used in the treatment of mycobacterial infections in cats, based randomized study demonstrated the efficacy of enrofloxacin in the on case reports of successful treatment of cutaneous lesions of treatment of Hemobartonella felis infection, by showing it more quickly opportunistic mycobacteria{R-75; 76; 142}. There is some evidence to resolved clinical signs, raised hematocrit, and decreased organism suggest that fluoroquinolones are effective in the treatment of counts than in control animals. In this study, some cats treated with a tubercular mycobacteriosis, an often serious but also often asymp- high dose of enrofloxacin or with doxycycline were apparently cleared tomatic or insidious disease in cats. Cats are also prone to infection of the organism{R-83; 148}. with Mycobacterium lepraemurium, which is a nontubercular form of [Brucellosis (treatment)]1—Dogs: Historically, the treatment of dogs mycobacteria. Safety and efficacy of fluoroquinolones have not yet infected with Brucella canis has been controversial. Due to the been proven in the treatment of M. lepraemurium, but successful zoonotic potential and the difficulty in clearing the infection, some treatment of the cutaneous form of mycobacterial infection with have advocated euthanasia of infected animals. Studies using a enrofloxacin indicates possible efficacy in the treatment of nontuber- combination of tetracycline and dihydrostreptomycin did demon- cular forms.{R-142} strate that infected animals, following neutering, could be cured of [Mycoplasmal infections (treatment)]1—Although the efficacy has not the infection{R-139}. However, dihydrostreptomycin is no longer been established, fluoroquinolones have been used to treat infections available in the US. The Centers for Disease Control recommend a caused by Mycoplasma species in animals. Activity of these antibiotics combination of doxycycline and rifampin for the treatment of against Mycoplasma can be variable but enrofloxacin and danofloxacin brucellosis in human patients{R-140}. In a clinical trial, rifampin plus have been shown to be consistently more active in vitro (minimum ciprofloxacin, a metabolite of enrofloxacin, was shown to be as inhibitory concentrations [MIC] of 0.05 to 1.0 mcg/mL) against effective as the standard rifampin and doxycyline regimen in the veterinary isolates than flumequine{R-143}.

[Pasteurellosis (treatment)]1—Rabbits, pet and research: In the U.S., for Orbifloxacin—1-Cyclopropyl-7-(cis-3,5-dimethyl-1-piperazinyl)-5,6,8-tri- use only in animals not to be used for food production—Although the fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid{R-7}. safety and efficacy have not been established, there are some research Molecular formula: {R-7} data suggesting that parenteral enrofloxacin can resolve clinical signs Ciprofloxacin—C17H28FN3O3 . {R-7} of pasteurellosis in many naturally infected rabbits, even though the Difloxacin hydrochloride—C21H19F2N3O3ÆHCl . {R-67–69} {R-7} organism is not consistently eradicated . See also the Regula- Enrofloxacin—C19H22FN3O3 . {R-7; 97} tory Considerations section. Marbofloxacin—C17H19FN4O4 . {R-7; 98} Orbifloxacin—C19H20F3N3O3 . Molecular weight: UNACCEPTED Ciprofloxacin—331.34{R-7}. [Ehrlichiosis (treatment)]1—Cats and dogs: The American College of Difloxacin hydrochloride—435.85{R-7}. Veterinary Internal Medicine Infectious Disease Study Group has Enrofloxacin—359.39{R-7}. stated that the treatment of choice for ehrlichiosis is doxycycline and Marbofloxacin—362.36{R-7; 97}. that enrofloxacin has not been found to be an effective treat- Orbifloxacin—395.38{R-7; 98}. ment{R-149}. A small, short-term (15-day) study without follow-up Description: showed that enrofloxacin can be as effective as doxycycline in the Ciprofloxacin Hydrochloride USP—Faintly yellowish to light yellow treatment of naturally aquired ehrlichiosis in dogs{R-77}; however, crystals{R-105}. another study of experimentally induced disease in which dogs were Difloxacin hydrochloride—White to light yellow powder. monitored after 21-day enrofloxacin therapy showed poor efficacy in Enrofloxacin—Pale yellow crystals with a melting point of 219 to clearing the infection{R-138}. 221 C. {R-82} 1Not included in Canadian product labeling or product not commercially Orbifloxacin—White to pale yellow crystalline powder . available in Canada. pKa: Ciprofloxacin—Carboxylic acid group, 6.1; tertiary amine, 7.8{R-95}. Difloxacin—Carboxylic acid group, 4.33; methyl substituted nitrogen {R-96} REGULATORY CONSIDERATIONS group, 9.05 . Enrofloxacin—Carboxylic acid group, 6.0; tertiary amine, 8.8{R-95}. U.S.— Orbifloxacin—5.95 and 9.01{R-98}. Federal law prohibits the extralabel use of fluoroquinolones in Solubility: food-producing animals (21 CFR 530.41). The prohibition is Ciprofloxacin hydrochloride—Sparingly soluble in water; slightly soluble based on a finding by the Food and Drug Administration that the in acetic acid and in methanol; very slightly soluble in dehydrated extralabel use of these antibiotics in food-producing animals presents alcohol; practically insoluble in acetone, in acetonitrile, in ethyl a risk to the public health because such use could increase the level acetate, in hexane, and in methylene chloride{R-105}. of drug-resistant zoonotic pathogens at the time of slaughter{R-106}. Difloxacin—Poorly water soluble at neutral pH, more soluble under Some researchers are concerned that such use can lead to the acidic conditions, and highly water soluble under basic condi- transfer of pathogens resistant to fluoroquinolones from animals to tions{R-96}. human beings. Enrofloxacin—Slightly soluble in water at pH 7. Difloxacin, enrofloxacin, marbofloxacin, and orbifloxacin are restricted Marbofloxacin—Soluble in water; less soluble under alkaline condi- to use by or on the order of a licensed veterinarian{R-1; 2; 94; 96–98}. tions{R-97}. Ciprofloxacin is not labeled for veterinary use. Orbifloxacin—Slightly soluble in water; more soluble in both acidic and Canada— alkaline conditions{R-98}. Difloxacin, enrofloxacin, marbofloxacin, and orbifloxacin are restricted to use by or on the order of a licensed veterinarian. They are not labeled for use in food-producing animals. Ciprofloxacin is not labeled for veterinary use. PHARMACOLOGY/PHARMACOKINETICS Note: See also Table 1 and Table 2 at the end of this monograph. CHEMISTRY Chemical group: Quinolone carboxylic acid derivatives{R-1}. Mechanism of action/effect: Bactericidal{R-2; 95–100}. The fluoroqui- Chemical name: nolones inhibit bacterial DNA gyrase or topoisomerase IV (a type II Ciprofloxacin—3-Quinolinecarboxylic acid, 1-cyclopropyl-6-fluoro-1, topoisomerase), thereby preventing DNA supercoiling and replica- 4-dihydro-4-oxo-7-(1-piperazinyl)-{R-7}. tion{R-1; 2; 86}. Cell respiration and division end, and other processes Difloxacin hydrochloride—3-Quinolinecarboxylic acid, 6-fluoro-1-(4-flu- are interrupted, including membrane integrity{R-1}. Mammalian cell orophenyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo, monohy- topoisomerase II is not affected by fluoroquinolones until drug con- drochloride{R-7}. centrations are at least 100 times higher than concentrations rec- Enrofloxacin—3-Quinolinecarboxylic acid, 1-cyclopropyl-7-(4-ethyl- ommended to inhibit the bacteria{R-95}. 1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-{R-7}. Fluoroquinolones enter cells via porins and accumulate rapidly in Marbofloxacin—9-Fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperaz- susceptible bacteria{R-9}. Some bacteria are able to pump the antibiotic inyl)-7-oxo-7H-pyrido[3,2,1-ij][4,1,2]benzoxadiazine-6-carboxylic agent back out of the cell by an energy-dependent efflux transport acid{R-7}. system{R-9}.

The efficacy of the fluoroquinolones is concentration dependent as horses, urine concentrations are higher than serum concentra- {R-27} measured by either the maximum concentration above MIC (Cmax: tions . MIC) or the area under the curve above MIC (AUC : MIC; AUIC){R-9}. Marbofloxacin—Dogs: Tissue concentrations of marbofloxacin were A post-antibiotic effect, in which growth of pathogens may remain determined in healthy male beagle dogs at 2, 18, and 24 hours after inhibited for varying periods after fluoroquinolone concentrations fall a single oral dose (2.75 or 5.5 mg/kg). Based on the terminal below inhibitory concentrations, has been demonstrated with enro- elimination half-life and the dosing interval, steady-state levels are floxacin and orbifloxacin in some bacteria{R-9; 82}. reached after the third dose and are expected to be approximately 25% greater than those achieved after a single dose. Absorption: Oral absorption of fluoroquinolones is high for most animals studied{R-1; 10; 97; 98}. It is not affected by administration with Protein binding: food, although absorption may be delayed{R-95}. Divalent and trivalent Ciprofloxacin—Dogs: 44 ± 3%{R-12}. cations can affect absoprtion (see the Drug interactions section in this Difloxacin—Dogs: 46 to 52%{R-97}. monograph){R-96}. In cats, dogs, and pigs, oral absorption of Enrofloxacin— fluoroquinolones approaches 100%, but in ruminants, it is generally Camels: Concentration dependent— less.{R-95} The horse may be unique regarding oral absorption patterns 1.7% at 1.8 mcg of enrofloxacin per mL of serum (mcg/mL){R-45}. in that while enrofloxacin is well absorbed, ciprofloxacin is poorly 5% at 0.6 mcg/mL{R-45}. absorbed.{R-144} Other fluoroquinolones have not been studied as to 24.2% at 0.33 mcg/mL{R-45}. oral bioavailability in horses. Cattle, lactating: 36 to 45%{R-11}. Absorption from parenteral administration of fluoroquinolones is rapid Chickens: 24 ± 2%{R-30}; 21 ± 0.1{R-12}. and often nearly complete{R-9; 11; 22; 28; 29; 32; 41; 45}. In some Dogs: 72% at 1 mcg/mL{R-86}. animals, there is delayed absorption from intramuscular or subcuta- Horses: 22 ± 2%{R-12}. neous administration, producing longer half-lives from these routes Pigs: 27 ± 3%{R-12}. compared to intravenous absorption.{R-95} Rabbits: Enrofloxacin— Up to 30 days of age—40 to 50%{R-34; 35}. Oral—Rapidly absorbed in monogastric species and preruminant Adult—53 ± 1%{R-12}. calves{R-1; 10}. Absorption in adult ruminants is variable and has Does, pregnant—35 ± 5%{R-63}. ranged from 10 to 50%{R-86}. Marbofloxacin{R-97}— Cats: 7.3% Distribution: Fluoroquinolones achieve concentrations that are at least Dogs: 9.1% as high as plasma in a wide range of tissues, with the exception of the Orbifloxacin—Dogs: 7.7 to 14.5%{R-82}. central nervous system and the eye{R-1; 26; 95–98}. This is true in many species, including cats, cattle, chickens, dogs, horses, and rabbits{R-1; 5; 15; 18; 26; 31; 32}. Biotransformation: Differences in volume of distribution among the fluoroquinolones Difloxacin—In the dog, difloxacin is metabolized to an ester glucuronide however, account for a range of maximum plasma concentrations and the desmethyl derivative{R-96}. among the drugs. Drugs with the lowest volume of distribution are Enrofloxacin—Enrofloxacin is de-ethylated to form ciprofloxacin, an diluted less in body fluid and produce higher plasma concentrations antimicrobically active metabolite in many species{R-11; 13; 18; 22; 24; than drugs with a higher volume. The consequence of this difference is 28; 29; 31; 39; 42; 46; 71; 72}. Therefore, microbiologic assays in reflected in the dose administered; to achieve the same peak serum pharmacokinetic studies are likely to measure the activity of both concentration, drugs with a high volume of distribution require a enrofloxacin and ciprofloxacin combined. Because minimum higher dose{R-95}. inhibitory concentrations for some pathogens are lower for ciproflox- Fluoroquinolones are rapidly accumulated in macrophages acin than for enrofloxacin{R-13}, therapeutic concentrations of cipro- and neutrophils. Unlike other antibiotics that concentrate in floxacin can be reached with dosing calculated to achieve effective subcellular sites within phagocytic cells, the quinolones are enrofloxacin concentrations{R-16; 25; 28}. Ciprofloxacin can be consid- distributed into the cytosol where they can reach intracellular ered an important contributor to the activity of enrofloxacin{R-16; 28}. pathogens{R-20}. This concentration in leukocytes may explain the Evaluations of enrofloxacin activity based on serum or tissue concen- higher fluoroquinolone concentrations in infected tissue compared trations should consider the contributions of both enrofloxacin and to healthy tissue{R-95}. ciprofloxacin. It is also possible that other as yet undiscovered Because of renal elimination, urine concentration of fluoroquinolones metabolites have antimicrobial activity{R-16}. occurs in many species. Enrofloxacin concentration in canine Cats: After oral administration, the half-time for conversion of prostate tissue matches that in the serum and concentration in enrofloxacin to ciprofloxacin is about 13 minutes{R-22}. Ciprofloxacin urine reaches about 100 times that in the serum{R-18; 19}. The serum concentration is about 20% of the enrofloxacin concentration orbifloxacin concentration in canine prostate tissue exceeds that in in the serum at any one time; about 10% at maximum serum serum and concentration in urine reaches about 50 times that in concentrations{R-22; 72; 86}. serum{R-82}. Even difloxacin, for which less than 5% of the dose is Cattle, lactating: The serum concentration of ciprofloxacin is 35% that excreted into the urine in the dog, concentrations in the urine of enrofloxacin during the elimination phase, after an intravenous are 10 times plasma concentration after a single dose of 10 mg dose of 5 mg/kg{R-11}. per kg of body weight (mg/kg){R-96}. After multiple oral doses in Chickens: Enrofloxacin is extensively metabolized to ciprofloxacin{R-31}.

Dogs: Overall, 40% of the oral or intravenous enrofloxacin dose feces while renal clearance accounts for less than 5% of difloxacin administered is metabolized to ciprofloxacin{R-23}. Ciprofloxacin elimination{R-96}. makes up about 20% of the total serum concentration of enro- Enrofloxacin—Renal. Primarily by glomerular filtration and tubular floxacin and ciprofloxacin after enrofloxacin administration; secretion{R-10}. ciprofloxacin makes up about 35% of the total body concentration Marbofloxacin— when calculated based on the area under the concentration-time Cats: Primarily renal. 70% of an oral dose is excreted into the urine as curve (AUC){R-16; 18; 86}. parent drug and metabolites{R-97}. Ducks: Less than 10% of the administered enrofloxacin dose is Dogs: 40% of an oral or subcutaneous dose is excreted as parent drug converted to ciprofloxacin after a 10 mg/kg dose{R-42}. into the urine. Elimination of parent drug into the feces is also a Horses: The concentration of ciprofloxacin in the serum reaches 20 to significant route of elimination{R-97; 115}. 35% of the enrofloxacin concentration in adult horses{R-24}. In foals, Orbifloxacin— the amount of ciprofloxacin measured is negligible{R-85}. Cats: Of the orbifloxacin eliminated in urine after subcutaneous Llamas: Approximately 36% of enrofloxacin administered is converted administration, 96% is unchanged parent drug and 4% is N-hydroxy to ciprofloxacin in llamas{R-46}. orbifloxacin, an active metabolite with somewhat higher MICs for Macaques, long-tailed: Ciprofloxacin makes up about 22% of the total pathogens sensitive to orbifloxacin{R-111}. amount of active drug measured in the serum after intramuscular Dogs: 40% of an oral dose is excreted as parent drug into the urine{R-97}. administration of 5 mg/kg of enrofloxacin{R-71}. Of the orbifloxacin eliminated in the urine after a subcutaneous dose, Parrots, African grey: Ciprofloxacin concentration in the serum 87% is parent compound and 13% is glucuronide metabolite{R-111}. reaches 3 to 78% of the enrofloxacin dose administered{R-39}. The ratio of ciprofloxacin to enrofloxacin in the serum increases with multiple dosing over 10 days{R-39}. Pigs: The concentration of ciprofloxacin in the plasma comprises less PRECAUTIONS TO CONSIDER than 10% of the amount of enrofloxacin present in the plasma{R-29}. Sheep: In one study, the concentration of ciprofloxacin in the plasma BACTERIAL RESISTANCE reached 35 and 55% of the serum enrofloxacin concentrations, with Concerns about the risk of increasing resistance of human pathogens to intravenous and intramuscular administration, respectively, of a 2.5 fluoroquinolones as well as the ability of infections in animals to resist mg/kg dose{R-28}. Another study found the concentration of cipro- treatment should be considered by health practitioners when prescrib- floxacin in the plasma to be 10 to 20% of the serum drug ing these medications. There have been warnings by infectious disease concentration{R-86}. experts that widespread use of fluoroquinolones may lead to increased Marbofloxacin—Dogs: 10 to 15% of the dose is metabolized in the resistance, and transfer of resistance to humans has been suggested for liver{R-97}. Campylobacter species and Salmonella typhimurium type DT-104. Increased resistance in Campylobacter jejuni infecting people was reported after 1995, the same period in which fluoroquinolones were Serum concentrations: first approved for use in poultry. There has also been discussion about Chickens— the appearance of resistant strains of Salmonella typhimurium during Mean plasma concentrations at 6, 12, and 24 to 168 hours after the time fluoroquinolones have been used in livestock. However, some beginning oral administration of enrofloxacin at a dose of 25 parts resistant strains have been traced to farms that were not administering per million (ppm) in the drinking water were 0.241, 0.317, and fluoroquinolones, leading to the suggestion that the resistance may 0.381 mcg/mL, respectively{R-3}. have arisen spontaneously{R-95}. Mean plasma concentrations at 6, 12, and 24 to 168 hours after As scientists continue to uncover evidence pertaining to the potential beginning oral administration of enrofloxacin at a dose of 50 ppm in for transfer of fluoroquinolone-resistant pathogens from animals to the drinking water were 0.464, 0.653, and 0.712 mcg/mL, man, fluoroquinolones have had limited approval for use in food- respectively{R-3}. producing animals and extra-label use in these animals is prohibited in Turkeys— the United States{R-95; 106}. Mean plasma concentrations at 6 hours and 24 to 168 hours after beginning oral administration of enrofloxacin at a dose of 25 ppm in the drinking water were 0.204 and 0.240 mcg/mL, respectively{R-3}. SPECIES SENSITIVITY Mean plasma concentrations at 6 hours and 24 to 168 hours Cats: Because of the risk of retinal degeneration that has been associated after beginning oral administration of enrofloxacin at a dose of with enrofloxacin administration at high doses (20 mg per kg of body {R-1} 50 ppm in the drinking water were 0.352 and 0.458 mcg/mL, weight [mg/kg] a day) , it has been recommended that adminis- respectively{R-3}. tration of high doses of all fluoroquinolones be avoided in cats whenever possible. However, it may be that not all fluoroquinolones have the same potential to cause retinal damage. Limited studies show Elimination: that marbofloxacin caused no retinal changes visible with fundiscopic Difloxacin—Dogs: Primarily through glucuronidation and subsequent or histologic examination when administered to 8-month-old cats at biliary secretion. The glucuronide metabolite may be hydrolyzed back 10 times the recommended dosage for 2 weeks{R-97}, whereas to the parent compound and reabsorbed in the gastrointestinal tract. enrofloxacin has been shown to cause ocular lesions at 4 times the After intravenous administration, 80% of the dose is eliminated in the recommended dosage{R-1}. A study with orbifloxacin showed that no

retinal changes were visible with fundoscopic or histologic examina- Cattle: Federal law prohibits the extra-label use of fluoroquinolones in tion when administered to cats at levels which exceeded the highest food-producing animals (see the Regulatory Considerations section). The recommended dose of 7.5 mg/kg{R-146}. following information is included in case of accidental dosing. Enrofloxacin appears rapidly in milk after parenteral administration, CARCINOGENICITY reaching a peak concentration at 30 to 60 minutes after intravenous injection, followed by a gradual decline in milk concentration similar Enrofloxacin—No evidence of carcinogenicity was found in studies of to that occurring in serum concentration{R-11; 14}. Approximately laboratory animal models{R-3}. 0.2% of a 5 mg per kg of body weight dose of enrofloxacin is measured in milk in the first 24 hours; therapeutic antimicrobial PREGNANCY/REPRODUCTION concentrations can be reached{R-11}. The attributes of fluoroquinolones make them likely to cross the placenta The ciprofloxacin metabolite of enrofloxacin also appears rapidly in in many species; however, adverse effects have not yet been reported milk, but this occurs 4 to 8 hours after parenteral administration. when fluoroquinolones have been administered to pregnant It concentrates to a higher peak than enrofloxacin animals{R-95}. itself{R-11; 14}. Adequate and well-controlled studies of the effects of fluoroquinolones in Horses: Following an oral dose of 5 mg/kg to lactating mares, pregnant human beings have not been done; however, administration concentration of ciprofloxacin and enrofloxacin in milk ranged from during human pregnancy is generally not recommended, based on 0.25 to 0.78 mcg per mL. At this concentration, a nursing foal would reports of arthropathy in immature animals{R-107}. ingest a dose of less than 0.1 mg per kg of body weight a day, Ciprofloxacin—Ciprofloxacin crosses the human placenta{R-107}. Intra- producing plasma concentrations in the foal below detection lim- venous doses of ciprofloxacin of up to 20 mg per kg of body weight its{R-86}. (mg/kg) in pregnant rats and mice have not shown evidence of Rabbits: Therapeutic concentrations of enrofloxacin are reached in milk maternal toxicity, embryotoxicity, or teratogenic effects{R-107}. following a dose of 7.5 mg per kg of body weight{R-34}. Difloxacin, marbofloxacin, and orbifloxacin—Safety in breeding or pregnant animals has not been determined{R-96–98}. Enrofloxacin— PEDIATRICS Cats, cattle, turkeys: Effect on reproduction or pregnancy has not been See also the Side/Adverse Effects section for information on risk of established{R-1–3}. arthropathies in immature animals. Chickens: No adverse effects were noted in measured reproductive Enrofloxacin— parameters when male and female chickens were given an enrofloxacin Calves: Until at least 1 week of age, the elimination of enrofloxacin is {R-13} dose of 150 parts per million in the drinking water for 7 days. This slower in calves than in adult cattle . Adjustment of dosage, {R-13} regimen was repeated at five different ages between 1 day and 206 days including increased dosing interval, may be necessary . of age with no reproductive effect noted{R-3}. The parameters measured Foals: Elimination of enrofloxacin in foals (half-life = 18 hrs) is slower included egg production, egg weight, hatchability, chick viability, and than in adult horses and oral absorption in foals is approximately {R-86; 88} reproductive histology of treated birds and their hatched chicks{R-4}. 42% . Administering enrofloxacin at a dose of 10 mg per kg Dogs: a day caused every one of five healthy foals to have lesions on {R-85} No adverse effects were noted in measured reproductive parameters, articular cartilage . including libido, successful pregnancy, and number of pups per Rabbits: Elimination of enrofloxacin is significantly less in neonates litter, when male dogs were administered 5 to 15 mg/kg a day for until at least 16 days of age compared with that in adult {R-34} 10 days beginning at 90, 45, or 14 days before breeding{R-1; 5}. rabbits . The ease of penetration of enrofloxacin into milk No adverse effects were noted in female dogs administered 15 mg/kg should be considered when treating lactating does that continue to {R-35} a day for 10 days in the last 30 days before breeding, between the nurse . Enrofloxacin pharmacokinetics in 30-day-old rabbits are {R-35} 10th and 30th days of gestation, between the 40th and 60th days similar to those in adult rabbits . of gestation, or during the first 28 days of lactation{R-1; 5; 6}. Rabbits: Enrofloxacin is transferred across the placenta in rabbits{R-63}; DRUG INTERACTIONS AND/OR RELATED PROBLEMS adverse effects on pups have not been reported. Ciprofloxacin also The following drug interactions and/or related problems have been crosses the placenta but at a much slower pace (6% of the rate of selected on the basis of their potential clinical significance (possible enrofloxacin){R-63}. mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance): LACTATION Note: Combinations containing any of the following medications, Because of the risk of producing arthropathies in immature animals, it depending on the amount present, may also interact with this has been recommended that significant levels of fluoroquinolones in medication. the milk of nursing animals be avoided{R-95; 107}. Fluoroquinolones Digoxin: A small study investigating specifically the effect of enroflox- can be distributed into milk, sometimes at a higher concentration than acin administration on digoxin clearance and serum concentrations in in plasma,{R-11–14; 34} but it is not known under what conditions dogs showed no effect with concomitant administration{R-59}. significant amounts might be absorbed by nursing animals{R-86}. Antacids, aluminum-, calcium-, or magnesium-containing or Mastitis—It has not been shown that fluoroquinolones are effective in Laxatives, magnesium-containing or treating mastitis{R-95}, perhaps because of factors in milk that inhibit Multivitamins or activity{R-11}. Sucralfate or

Zinc quinolone antibiotics may increase the risks of CNS stimulation and (compounds containing divalent or trivalent cations, such as convulsions) aluminum, calcium, iron, magnesium, or zinc, administered con- Cyclosporine currently with a fluoroquinolone, may reduce the absorption of the (concurrent use with ciprofloxacin has been reported to elevate fluoroquinolone{R-1; 96–98}) serum creatinine and serum cyclosporine concentrations; other Theophylline{R-61} or studies have not found ciprofloxacin to alter the pharmacokinetics of Hepatically metabolized drugs, other{R-1} cyclosporine; cyclosporine concentrations should be monitored when (in dogs, the clearance of theophylline was reduced by 43% with the used concurrently with fluoroquinolones, and dosage adjustments concurrent administration of enrofloxacin [5 mg per kg of body may be required) weight every 24 hours]; peak serum concentration of theophylline Probenecid was significantly increased; the pharmacokinetics of enrofloxacin (concurrent use of probenecid decreases the renal tubular secretion were unaffected{R-62}) of fluoroquinolones, resulting in decreased urinary excretion of the (the concurrent administration of a fluoroquinolone with other drugs fluoroquinolone, prolonged elimination half-life, and increased risk of metabolized by hepatic enzymes may affect the pharmacokinetics of toxicity; this interaction is more significant with fluoroquinolones one or both drugs{R-1}; enrofloxacin has been shown to inhibit liver excreted largely unchanged in the urine, and of less clinical microsomal mixed-function oxidases in broiler chicks, including significance with fluoroquinolones that have larger nonrenal elim- aniline hydroxylase and aminopyrine N-demethylase{R-60}; cyto- ination, such as ciprofloxacin) chrome P450 activity was not significantly affected in chickens{R-60}; Warfarin in mice, there is indirect evidence that cytochrome P450 enzymes (concurrent use of warfarin with ciprofloxacin has been reported to may be affected by enrofloxacin administration{R-62}; the effect of increase the anticoagulant effect of warfarin, increasing the chance these enzyme inhibitions on specific drugs has not yet been of bleeding; other studies have not found fluoroquinolones to alter demonstrated) the prothrombin time [PT] significantly; however, it is recommended that the PT of patients receiving warfarin and fluoroquinolones concurrently be monitored carefully) HUMAN DRUG INTERACTIONS AND/OR RELATED {R-107} PROBLEMS HUMAN LABORATORY VALUE ALTERATIONS{R-107} In addition to the above drug interactions reported in animals, the The following laboratory value alterations have been reported in following drug interactions have been reported in humans, and are humans, and are included in the human monograph Fluoroquinolones included in the human monograph Fluoroquinolones (Systemic) in USP (Systemic) in USP DI Volume I; these laboratory value alterations are DI Volume I; these drug interactions are intended for informational intended for informational purposes only and may or may not be purposes only and may or may not be applicable to the use of applicable to the use of fluoroquinolones in the treatment of animals: fluoroquinolones in animals: Note: There are no difloxacin, enrofloxacin, marbofloxacin, or orbiflox- Note: There are no difloxacin, enrofloxacin, marbofloxacin, or orbifloxacin products labeled for use in human beings. acin products labeled for use in human beings. With physiology/laboratory test values Anticonvulsants, hydantoin, especially: Alanine aminotransferase (ALT [SGPT]) and Phenytoin Alkaline phosphatase and (concurrent administration of ciprofloxacin with phenytoin has Amylase and resulted in a 34 to 80% decrease in the plasma concentration of Aspartate aminotransferase (AST [SGOT]) and phenytoin; caution should be used when administering quinolones, Lactate dehydrogenase (LDH) especially ciprofloxacin, to patients stabilized on phenytoin; careful (serum values may be increased) monitoring of phenytoin dosage after discontinuation of quinolones is highly recommended) Antidiabetic agents, sulfonylurea, especially: MEDICAL CONSIDERATIONS/CONTRAINDICATIONS Glyburide or The medical considerations/contraindications included have been Insulin selected on the basis of their potential clinical significance (reasons (concurrent use of ciprofloxacin with glyburide or other antidiabetic given in parentheses where appropriate)—not necessarily inclusive agents has, on rare occasions, resulted in hypoglycemia; also, (» = major clinical significance). hyperglycemia and hypoglycemia have been reported in patients Except under special circumstances, this medication should not be taking quinolone antibiotics and antidiabetic agents concurrently; used when the following medical problems exist: since the mechanism is not understood, similar effects with other Hypersensitivity to quinolones{R-1; 3} sulfonylurea antidiabetic agents may be expected when these (animals with a history of hypersensitivity to quinolones are at risk medications are used with fluoroquinolones; careful monitoring of for developing reactions to them{R-1; 97; 98}) blood glucose concentrations is recommended when these medica- Immature animals in some species{R-1} tions are used concurrently) (fluoroquinolone administration during rapid growth has been Anti-inflammatory drugs, nonsteroidal (NSAIDs) associated with arthropathies and cartilage erosions in weight- (fluoroquinolones are competitive inhibitors of gamma-aminobutyric bearing joints in immature cats, dogs, and horses{R-1; 4; 5; 25; 26; 85; acid receptor binding, and some NSAIDs have been shown to 96-98}; in dogs, enrofloxacin has been shown to cause abnormal enhance this effect; concurrent administration of NSAIDs with carriage of the carpal joint and hindlimb weakness, as well as

cartilage lesions; administration of enrofloxacin should be avoided in In unpublished manufacturer data, a dose of 5 mg/kg administered small and medium breed dogs during rapid growth, typically 2 to 8 to foals once a day was reported to cause cartilage lesions and signs months of age; large or giant breeds may rapidly grow until 18 of arthropathy after 6 days{R-25}; however, studies have shown no months of age{R-1}) effect on cartilage in adults when used continuously for up to 21 Risk-benefit should be considered when the following medical days{R-86; 136}. In 23-day-old calves, a dose of 25 mg/kg a day for 15 problems exist: days had no measurable effect on articular cartilage in the stifle joint Central nervous system (CNS) disorders{R-1} at 2 and 9 days after the end of treatment{R-2}. Seizures, history of Marbofloxacin—Lameness and articular cartilage lesions were (fluoroquinolones have been associated with CNS stimulation that reported in large breed, 3- to 4-month-old dogs administered 11 may lead to seizures in a few rare cases and should be used with mg/kg a day for 14 days{R-97}. caution{R-1; 2}; the clinical significance of a report of increased Orbifloxacin—Microscopic cartilage lesions typical of fluoroquino- seizure incidence with enrofloxacin administration to dogs with lone arthropathy have also been reported with orbifloxacin phenobarbital-controlled seizures is not known{R-10}) administration; in one of eight, 8- to 10-week-old puppies given Hepatic disease, severe 12.5 mg/kg a day and all 8 puppies given 25 mg/kg a day{R-98}. Cats Renal failure appear to be resistant to this effect, showing no cartilage lesions after (fluoroquinolones are primarily eliminated by a combination of renal one month of a 25 mg/kg-a-day dose{R-98}. clearance and hepatic metabolism, sometimes with significant biliary Cats secretion; the predominance of one route over another depends on Retinal degeneration (acute blindness, mydriasis)—reported with the quinolone and the animal species; there is little research enrofloxacin at doses higher than 5 mg per kg of body weight information on changes in elimination in various disease states in (mg/kg) a day animals; the induction of moderate renal impairment in dogs Note: Administering enrofloxacin to cats at a dose of 20 mg/kg can [glomerular filtration rate decreased 37% and serum creatinine cause retinal degeneration{R-1; 103}, often manifested as temporary or values increased 85% from normal controls] had only a minor effect permanent blindness with mydriasis{R-1; 103; 119}. Mild to severe on the clearance of marbofloxacin{R-108}) fundic lesions are observed on ophthalmologic exam of affected cats, including changes in the color of the fundus and central or generalized retinal degeneration. There are also abnormal electro- PATIENT MONITORING retinogram results and diffuse light microscopic changes in the The following may be especially important in patient monitoring (other retinas{R-1}. Retinal degeneration has not been reported in cats in tests may be warranted in some patients, depending on condition; association with other fluoroquinolones; however, caution is recom- » = major clinical significance): mended when considering high dose therapy of any fluoroquinolone Culture and sensitivity in vitro and in cats. Minimum inhibitory concentration (MIC) Cats and dogs (in vitro cultures and MIC tests should be done on samples collected Ataxia; seizures—with enrofloxacin prior to fluoroquinolone administration to determine pathogen Note: Although ataxia and seizures were not observed during preap- susceptibility) proval clinical field trials, they have been noted as part of voluntary postapproval adverse drug experience reporting{R-1}. SIDE/ADVERSE EFFECTS Parrots, African grey The following side/adverse effects have been selected on the basis of their Appetite, decreased{R-40}; polydipsia and polyuria{R-39; 40}—with potential clinical significance (possible signs in parentheses where a dose of 30 mg/kg every 12 hours for 10 days{R-39} or in drinking appropriate)—not necessarily inclusive: water with 1.5 to 3 mg/mL of water{R-40}; may resolve within 2 or 3 days of treatment cessation{R-39} THOSE INDICATING NEED FOR MEDICAL ATTENTION Incidence unknown THOSE INDICATING NEED FOR MEDICAL ATTENTION Multiple species ONLY IF THEY CONTINUE OR ARE BOTHERSOME Arthropathy—in immature animals, especially dogs and foals Incidence more frequent Note: The risk of arthropathy increases with increasing dose but has Cats been reported to occur at recommended dosages in young dogs. Vomiting—with enrofloxacin, occasional vomiting was observed in Difloxacin—Articular cartilage lesions were seen in 15- to 16-week- up to 75% of 7- to 10-month-old cats administered a 5 to 15 mg/kg old puppies administered difloxacin at 5, 25, or 35 mg per kg of body dose for 30 days; however, 25% of untreated cats also vomited weight (mg/kg) a day for 90 days{R-96}. Cartilage lesions and occasionally{R-1}. lameness were observed in puppies administered 50 and 125 mg/kg Incidence less frequent a day{R-96}. Cats Enrofloxacin—Cartilage damage has been observed in 10- to 28- Diarrhea—reported with marbofloxacin (2.1% of cats in one week-old puppies with an oral enrofloxacin dose of 5 to 25 mg/kg a report){R-97} day for 30 days and 5- to 7-month-old kittens with an oral dose of 25 Dogs mg/kg a day for 30 days{R-1; 5}; changes include splitting of the Decreased activity—reported with marbofloxacin (4.4% of dogs in articular cartilage surface and, in some cases, necrosis of the hyaline one report){R-97}; decreased appetite—reported with marbofloxacin cartilage{R-4}. Arthropathy has been reported in growing horses{R-25; 26}. (5.4%){R-97}; vomiting—reported with marbofloxacin (2.9%){R-97}

Incidence rare Some patients note a reduced incidence of nausea and taste perversion Cats if the dose is administered in the evening. Vomiting—with marbofloxacin (<1%){R-97} Photosensitivity reactions generally appear within a few days of the Dogs start of fluoroquinolone treatment but can occur up to 3 weeks after Vomiting—with enrofloxacin (0.7% of dogs){R-1} its discontinuation. The reactions usually subside within 1 month of Incidence unknown discontinuation. Cattle{R-2}, horses{R-24}, and rabbits{R-68; 69} Indicating possible phototoxicity, pseudomembranous colitis, or ten- Local tissue reaction, transient—in cattle, can cause trim loss of dinitis or tendon rupture and the need for medical attention if they edible tissue at slaughter{R-2} occur after medication is discontinued: Dogs Abdominal or stomach cramps and pain, severe; abdominal Anorexia; decreased appetite; diarrhea; vomiting—with difloxa- tenderness; blisters; diarrhea, watery and severe, which may cin also be bloody; fever; pain in calves, radiating to heels; Note: No adverse effects were reported in association with a clinical sensation of skin burning; skin rash, itching, or redness; study using recommended dosages of difloxacin in dogs. Anorexia, swelling of calves or lower legs decreased appetite, diarrhea, and vomiting have been reported in clinical cases{R-96} but the incidence is unknown. OVERDOSE For more information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to {R-107} HUMAN SIDE/ADVERSE EFFECTS Animals (ASPCA) National Animal Poison Control Center (888- In addition to the above side/adverse effects reported in animals, the 426-4435 or 900-443-0000; a fee may be required for consultation) following side/adverse effects have been reported in humans and are and/or the drug manufacturer. included in the human monograph Fluoroquinolones (Systemic) in USP Reported lethal doses of enrofloxacin— DI Volume I; these side/adverse effects are intended for informational Cats: 125 mg per kg of body weight (mg/kg) a day for 5 days{R-1}. purposes only and may or may not be applicable to the use of Dogs: Oral—125 mg/kg a day for up to 11 days{R-1; 5}. fluoroquinolones in the treatment of animals: Mice: Oral—LD50 for female mice is 4335 mg/kg and for male mice is Note: The following human side/adverse effects are those pertaining to 5000 mg/kg{R-4}. ciprofloxacin or fluoroquinolones in general. Difloxacin, enrofloxacin, Rabbits: Oral—LD50 for male and female rabbits is 500 to 800 mg/ marbofloxacin, and orbifloxacin are not available as products labeled kg{R-4}. for human use. {R-2; Rats: Oral—LD50 for male and female rats is more than 5000 mg/kg Note: The relative insolubility of ciprofloxacin at an alkaline pH has 3; 4}. A dose of 500 parts per million (40 mg/kg) has no observable resulted in crystalluria, usually when the urinary pH exceeds 7. effect{R-4}. Seizures have been reported very rarely with ciprofloxacin therapy; Turkey poults, 1-day-old: Oral—626 parts of enrofloxacin per million however, the patients who did have seizures either had a previous parts of drinking water administered for 21 days caused the death of seizure history, were alcoholic, or were taking ciprofloxacin concur- 11 out of 40 birds in the first 10 days{R-3; 4}. Surviving birds showed rently with theophylline. signs of listlessness and decreased body weight gain{R-3}. Incidence more frequent Central nervous system (CNS) toxicity; gastrointestinal reactions; vaginitis CLINICAL EFFECTS OF OVERDOSE Incidence less frequent or rare The following effects have been selected on the basis of their potential Arthralgia; back pain; cardiovascular reactions such as palpi- clinical significance—not necessarily inclusive: tation, vasodilation, or tachycardia; central nervous system For difloxacin (CNS) stimulation; change in sense of taste; dreams, abnormal; Dogs, with doses of 5, 15, or 25 mg/kg a day for 30 consecutive dysuria; headache; hematuria; hepatotoxicity; hypersensitivity days{R-96} reactions; interstitial nephritis; moniliasis, oral; moniliasis, Decreased appetite; diarrhea; erythema/edema on the facial vaginal; myalgia; phlebitis—for intravenous ciprofloxacin; area, transient; weight loss photosensitivity; phototoxicity; pseudomembranous colitis; For enrofloxacin Stevens-Johnson Syndrome (blistering, itching, loosening, peeling, Calves, feeder, with a dose of 15 or 25 mg/kg a day for 10 to 15 days or or redness of skin; diarrhea); tendinitis or tendon rupture; vision, a dose of 50 mg/kg a day for 3 days{R-2} abnormal Note: Federal law prohibits the extra-label use of fluoroquinolones in Note: Achilles tendinitis and tendon rupture have been reported in food-producing animals (see the Regulatory Considerations section). patients receiving fluoroquinolones. The ruptures occurred 2 to 42 The following information is included in case of accidental dosing. days after the start of therapy. Concommitant use of corticosteroids Depression; decreased appetite; incoordination; muscle fascicu- with fluoroquinolones may increase the risk of tendon disorders or lations ruptures. These injuries may require surgical repair or result in Cats, with a dose of 20 mg/kg a day for 21 days{R-1} prolonged disability. It is recommended that fluoroquinolone treat- Depression; retinal degenerative effects; salivation; vomiting ment be discontinued at the first sign of tendon pain or inflamma- Cats, with a dose ‡ 50 mg/kg a day for 6 days{R-1} tion, and that patients refrain from exercising until the diagnosis of Convulsions; depression; incoordination; loss of appetite; reti- tendinitis has been excluded. nal degenerative effects; vomiting

Chicks, 1-day-old, with a dose in drinking water of 625 ppm for 21 to create a ‘‘flexible’’ product label that includes a dosage range allowing 28 days{R-4} for doses at the low end to be used to treat pathogens susceptible at a Decreased water consumption; decreased weight lower MIC and higher doses for less susceptible organisms. The upper Dogs, with an oral dose of 50 to 125 mg/kg a day for 11 to 14 days{R-1; end of the dosage range is determined by safety factors. 5; 8} Product labeling for veterinary fluoroquinolone products include Convulsions; depression or excitation; incoordination; loss of MIC data for bacterial pathogens for specific indications in which appetite; muscle tremors; salivation; vomiting efficacy was confirmed, and a dosage range{R-1; 96–98}.Itis For marbofloxacin recommended that the dose be chosen based on clinical experience, Cats, with a dose of 5.5, 16.5, or 27.5 mg/kg a day for 42 days the type and severity of infection, and susceptibility of the Dermatitis, perivascular to diffuse (often reddened pinnae); pathogen{R-1}. excessive salivation; softened stools The effective treatment of canine infections caused by Pseudomonas Cats, with a dose of 55 mg/kg a day for 14 days aeruginosa {R-17} and Staphylococcus species{R-21} may require the high Decreased activity; decreased food consumption; dermatitis, end of the dosage range. perivascular to diffuse (often reddened pinnae); excessive salivation; vomiting, occasional Breakpoints determined for ciprofloxacin by the National Committee for Dogs, with a dose of 5.5, 16.5, or 27.5 mg/kg a day for 42 days Clinical Laboratory Standards{R-95} Decreased food consumption; reddened mucous membranes; reddened skin (usually involving the ears); vomiting; weight loss MIC (mcg/mL) Interpretation

Dogs, with a dose of 55 mg/kg a day for 12 days £ 1.0 Susceptible Decreased food consumption; dehydration; decreased activity; 2.0 Intermediacate excessive salivation; facial swelling; reddened skin (usually the ‡ 4 Resistant ears); tremors; vomiting; weight loss Note: Be aware that ciprofloxacin may not be appropriate for use as a For orbifloxacin representative of veterinary fluoroquinolones in susceptibility testing. {R-98} Cats, with a dose of 22.5 and 37.5 mg/kg a day Use of specific antibiotic MIC ranges has been recommended{R-110}. Softened stools Cats, with a dose of 75 mg/kg a day for 10 days{R-98} Breakpoints determined for difloxacin for veterinary pathogens by the Decreased food consumption; diarrhea, vomiting National Committee for Clinical Laboratory Standards{R-147}

Zone diameter TREATMENT OF OVERDOSE (millimeters) MIC (mcg/mL) Interpretation Although there is no speciﬁc information available on treatment of ‡ 21 £ 0.5 Susceptible ﬂuoroquinolone overdose in animals, treatment of human overdose 18–20 1–2 Intermediate £ 17 ‡ 4 Resistant includes induction of vomiting or use of gastric lavage, observation, and supportive care, including hydration and dialysis. Note: The disk content is 10 mcg.

Breakpoints determined for oral dosing of enroﬂoxacin for cats and CLIENT CONSULTATION dogs by the National Committee for Clinical Laboratory Standards{R-87; Care should be exercised to avoid contact of medication with the eyes or 88} skin while handling solutions{R-3}. Zone diameter (millimeters) MIC (mcg/mL) Interpretation

VETERINARY DOSING INFORMATION ‡ 23 £ 0.5 Susceptible 17–22 1–2 Flexible* Flouroquinolone antibiotics have concentration-dependent bactericidal £ 16 ‡ 4 Resistant activity or AUIC{R-21}. Serum and tissue concentrations must be high *Flexible indicates the availability of an FDA-approved Flexible Label; the enough for a long enough period of time to be effective against the pathogens originating from dermal, respiratory tract, and other tissues target pathogen. Fortunately, minimum inhibitory concentrations could be considered susceptible with an MIC £ 2 if appropriate dosing, (MIC) for fluoroquinolones are relatively low. Depending on many explained in the package insert, is used{R-86; 87}. variables, such as the organism treated and the presence of neutrophils, fluoroquinolones can also produce a post-antibiotic effect, suppressing bacterial growth after local drug concentrations have Breakpoints recommended for marbofloxacin by the manufacturer{R-145} fallen{R-21; 112}. Cats: Because of the risk of retinal damage associated with high dosages Zone diameter (millimeters) MIC (mcg/mL) Interpretation of enrofloxacin, it is recommended that caution be used when considering administering fluoroquinolone at dosages higher than ‡ 17 £ 1 Susceptible those recommended for cats. 14–16 2 Intermediate £ 13 ‡ 4 Resistant Flexible Labeling—Because there is a wide minimum inhibitory range among bacteria susceptible to fluoroquinolones, it was possible to Note: The disk content is 5 mcg.

Breakpoints recommended for orbiﬂoxacin by the National Committee for CIPROFLOXACIN TABLETS {R-147} Clinical Laboratory Standards Usual dose: See Ciproﬂoxacin for Oral Suspension.

Zone diameter Strength(s) usually available: (millimeters) MIC (mcg/mL) Interpretation U.S.— ‡ 23 £ 1 Susceptible Veterinary-labeled product(s): 18–22 2–4 Intermediate Not commercially available. £ 17 ‡ 8 Resistant Human-labeled product(s): Note: The disk content is 10 mcg. 100 mg (base) (Rx) [Cipro]. 250 mg (base) (Rx) [Cipro]. 500 mg (base) (Rx) [Cipro]. CIPROFLOXACIN 750 mg (base) (Rx) [Cipro]. SUMMARY OF DIFFERENCES Canada— Veterinary-labeled product(s): Regulatory considerations: Ciprofloxacin is not labeled for use in Not commercially available. animals. Human-labeled product(s): 100 mg (base) (Rx) [Cipro]. ORAL DOSAGE FORMS 250 mg (base) (Rx) [Cipro]. Note: Bracketed information in the Dosage Forms section refers to uses 500 mg (base) (Rx) [Cipro]. that either are not included in U.S. product labeling or are for products 750 mg (base) (Rx) [Cipro]. not commercially available in the U.S. Packaging and storage: Store below 30 C (86 F), in a well-closed container, unless otherwise specified by manufacturer. CIPROFLOXACIN FOR ORAL SUSPENSION Usual dose: Note: [Dogs]1—Although the safety and efficacy have not USP requirements: Preserve in well-closed containers. Contain an been established, an oral dose of 10 to 20 mg per kg of body weight every amount of ciprofloxacin hydrochloride equivalent to the labeled twenty-four hours has been recommended in the treatment of suscep- amount of ciprofloxacin, within ± 10%. Meet the requirements for tible bacterial infections, based on pharmacokinetic data{R-95; 118; 134}. Identification, Dissolution (80% in 30 minutes in 0.01 N hydro- For empiric treatment of infections in dogs caused by probable chloric acid in Apparatus 2 at 50 rpm), and Uniformity of dosage Pseudomonas aeruginosa or Staphylococcus infections, the higher end of units{R-105}. the dosage range may be preferable, pending susceptibility results. 1 [Horses]1—Due to poor bioavailability{R-144}, oral ciprofloxacin should Not included in Canadian product labeling or product not commercially not be used in horses. available in Canada.

Strength(s) usually available: PARENTERAL DOSAGE FORMS U.S.— Note: Bracketed information in the Dosage Forms section refers to uses Veterinary-labeled product(s): that either are not included in U.S. product labeling or are for products Not commercially available. not commercially available in the U.S. Human-labeled product(s): 250 mg per 5 mL (5%) (Rx) [Cipro]. CIPROFLOXACIN INJECTION USP 500 mg per 5 mL (5%) (Rx) [Cipro]. Usual dose: Canada— Note: [Dogs]1—Although the safety and efﬁcacy have not been estab- Not commerically available. lished, an intravenous dose of 10 to 15 mg per kg of body weight, administered slowly every twenty-four hours has been recommended Packaging and storage: Prior to reconsitution, store below 25 C in the treatment of susceptible bacterial infections{R-81}. (77 F). Protect from freezing. After reconstitution, store below 30 C (86 F). Protect from freezing. Strength(s) usually available: Preparation of dosage form: To prepare the oral suspension, the small U.S.— bottle containing the microcapsules should be emptied into the large Veterinary-labeled product(s): bottle containing the diluent. Water should not be added to the Not commercially available. suspension. The large bottle should be closed and shaken vigorously Human-labeled product(s): for about 15 seconds. 200 mg per 20 mL (Rx) [Cipro I.V. (in sterile water for injection; requires dilution prior to administration)]. Stability: The suspension is stable for 14 days when stored in a refrig- 200 mg per 100 mL (Rx) [Cipro I.V. (in 5% dextrose injection; erator or at room temperature (below 30 C [86 F]). premixed)]. 400 mg per 40 mL (Rx) [Cipro I.V. (in sterile water for injection; USP requirements: Not in USP{R-105}. requires dilution prior to administration)].

400 mg per 200 mL (Rx) [Cipro I.V. (in 5% dextrose injection; where the Injection is labeled as being a concentrated form, its pH premixed)]. is between 3.3 and 3.9), Particulate matter, Limit of ciprofloxacin 1200 mg per 120 mL (Rx) [Cipro I.V. (in sterile water for injection; ethylenediamine analog (not more than 0.5%), Lactic acid content requires dilution prior to administration)]. (0.288–0.352 mg per mg of ciprofloxacin claimed on label, except Canada— that where the Injection is labeled as being a concentrated form, it Veterinary-labeled product(s): contains between 0.335 and 0.409 mg per mg of ciprofloxacin Not commerically available. claimed on the label), Dextrose content (if present), and Sodium Human-labeled product(s): chloride content (if present), and for Volume in Container under 200 mg per 20 mL (Rx) [Cipro I.V. (in sterile water for injection; Injections.{R-105}. requires dilution prior to administration)]. 1 400 mg per 40 mL (Rx) [Cipro I.V. (in sterile water for injection; Not included in Canadian product labeling or product not commercially requires dilution prior to administration)]. available in Canada.

Packaging and storage: Store in a cool place (between 8 and 15 C [46 and 59 F]) or at controlled room temperature (between 20 and DIFLOXACIN 25 C [68 and 77 F]), unless otherwise speciﬁed by manufacturer. Protect from light and freezing. ORAL DOSAGE FORMS

DIFLOXACIN HYDROCHLORIDE TABLETS Preparation of dosage form: To prepare a solution for intravenous Usual dose: Bacterial infections—Dogs: Oral, 5 to 10 mg per kg of body infusion, the concentrate in sterile water for injection should be weight every twenty-four hours{R-96; 99}. withdrawn aseptically from the vial and diluted to a final concentra- Note: The 5 mg per kg dose was found to be clinically effective in the tion of 1 to 2 mg per mL with a suitable intravenous solution (see treatment of susceptible skin, soft tissue, and urinary tract infec- manufacturer’s package insert). Solutions that come from the manufac- tions{R-99}. turer in 5% dextrose injection should not be diluted prior to intravenous For empiric treatment of probable Pseudomonas aeruginosa or Staph- infusion. The resulting solution should be infused over a period of at ylococcus infections in dogs, the higher end of the dosage range may least 60 minutes by direct infusion or through a Y-type intravenous be preferable, pending susceptibility results. infusion set. It is recommended that administration of any other solutions be discontinued during infusion of ciprofloxacin. Strength(s) usually available: U.S.{R-96}— Stability: When diluted with appropriate intravenous fluids (see man- Veterinary-labeled product(s): ufacturer’s package insert) to concentrations from 0.5 to 2 mg per mL, 11.4 mg (Rx) [Dicural Tablets]. solutions retain their potency for up to 14 days when refrigerated or 45.4 mg (Rx) [Dicural Tablets]. stored at room temperature. 136 mg (Rx) [Dicural Tablets]. Canada{R-99}— Incompatibilities: Ciprofloxacin is incompatible with aminophylline, Veterinary-labeled product(s): amoxicillin, cefepime, clindamycin, dexamethasone, floxacillin, furo- 11.4 mg (Rx) [Dicural Tablets]. semide, heparin, and phenytoin. 45.4 mg (Rx) [Dicural Tablets]. If ciprofloxacin is to be given concurrently with another medication, each 136 mg (Rx) [Dicural Tablets]. medication should be administered separately according to the recommended dosage and route of administration for each medication. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specified by USP requirements: Preserve in single-dose containers, preferably of manufacturer. Type I glass, in a cool place or at controlled room temperature. Avoid freezing and exposure to light. A sterile solution of Cipo- USP requirements: Not in USP{R-105}. floxacin in Sterile Water for Injection, in 5% Dextrose Injection, or in 0.9% Sodium Chloride Injection prepared with the aid of Lactic Acid. The label indicates whether the vehicle is Sterile Water for Injection, 5% Dextrose Injection, or 0.9% Sodium Chloride Injec- ENROFLOXACIN tion. Label the Injection that has Sterile Water for Injection as the vehicle to indicate that it is a concentrated form that must be SUMMARY OF DIFFERENCES diluted to appropriate strength (1 to 2 mg per ml) with 5% Dex- Pharmacology/pharmacokinetics: Biotransformation—Enrofloxacin is trose Injection or 0.9% Sodium Chloride Injection before adminis- de-ethylated to form ciprofloxacin; therapeutic concentrations of tration, and that the resulting solution is stable for up to 14 days ciprofloxacin can be reached with dosing calculated to achieve when stored in a cool place or at controlled room temperature. effective enrofloxacin concentrations. Contains the labeled amount, within ± 10%. Meets the require- Side/adverse effects: Cats—Retinal degeneration (acute blindness, mydri- ments for Color (where it is labeled as being in a concentrated asis) has been reported with enrofloxacin at doses higher than 5 mg form), Identification, Pyrogen, Sterility, pH (3.5–4.6, except that per kg of body weight a day.

ORAL DOSAGE FORMS following exposure. In human beings, there is a risk of user photo- Note: Bracketed information in the Dosage Forms section refers to uses sensitization within a few hours of signiﬁcant exposure to quinolones. that either are not included in U.S. product labeling or are for products USP requirements: Not in USP{R-105}. not commercially available in the U.S.

ENROFLOXACIN ORAL SOLUTION ENROFLOXACIN TABLETS Usual dose: Usual dose: Bacterial infections— 1 Escherichia coli infection —Chickens and turkeys: Oral, 25 to 50 parts Cats: Oral, 5 mg per kg of body weight a day{R-1}. The dose may be enrofloxacin per million parts water (ppm), administered as the only administered as a single daily dose or divided into two equal doses {R-3} source of drinking water for three to seven days . administered every twelve hours{R-1}. 1 Fowl cholera —Turkeys: Oral, 25 to 50 parts enrofloxacin per million Note: The above dose recommendation is based on risk of retinal parts water (ppm), administered as the only source of drinking water damage in cats administered doses higher than 5 mg/kg{R-1}. {R-3} for three to seven days . Dogs: Oral, 5 to 20 mg per kg of body weight a day{R-1}. The dose may Note: Medication should be initiated as soon after diagnosis as be administered as a single daily dose or divided into two equal doses {R-3} possible . The effects of environment and other factors on water administered every twelve hours{R-1}. {R-3} consumption should be considered . Note: For empiric treatment of probable Pseudomonas aeruginosa or Staphylococcus infections in dogs, the higher end of the dosage Strength(s) usually available: range may be preferable, pending susceptibility results. U.S.— Note: [Bustards]1—Although the safety and efficacy have not been Veterinary-labeled product(s): established, an oral dose of 10 mg per kg of body weight every twelve 32.3 mg per mL (Rx) [Baytril 3.23% Concentrate Solution]. hours has been suggested for the treatment of susceptible bacterial Canada— infections, based on pharmacokinetic data{R-41}. Veterinary-labeled product(s): Cats—Although the efficacy has not been established, if enrofloxacin is Not commercially available. used in the treatment of [Bartonella henselae]1 infection or [hemobartonellosis]1 in cats, the USP Veterinary Medicine Committee currently Withdrawal times: recommends the administration of 5 mg per kg of body weight a day. U.S.{R-3}— Limited research studies on the treatment of these infections have Withdrawal time sometimes led to recommendations for higher dosages; however, there

Species Meat (days) is concern about the occurrence of retinal degeneration when a dose of 20 mg/kg is administered to cats and the lack of information on relative Chickens, turkeys 2 risk of retinal damage at dosages between 5 and 20 mg/kg a day. Note: This product is not labeled for use in laying hens producing eggs for The following information is provided in the event other therapies human consumption{R-3}. have failed: [An oral dose of 5 to 8 mg per kg of body weight every twelve hours Packaging and storage: Store below 40 C (104 F), preferably be- (10 to 16 mg per kg a day) for four to six weeks has been tween 15 and 30 C (59 and 86 F), unless otherwise specified by recommended in the treatment of Bartonella henselae infection, based {R-72} 1 manufacturer. Store container in an upright position{R-3}. on efficacy trials .] [An oral dose of 5 to 10 mg per kg of body weight every twenty-four Preparation of dosage form: Product labeling recommends that stock hours for two weeks has been recommended in the treatment of solutions be prepared fresh daily{R-3}. Once stock solution or medicated hemobartonellosis{R-148}. Cats apparently completely cleared of infec- water is prepared, protect it from freezing or direct sunlight{R-3}. This tion were treated with the high end of this dosage range; however, the product should not be used in automatic water proportioners if the low end is the labeled dose.1 water hardness is greater than 196 parts per million (ppm){R-3}. Gal- Dogs—Although the efficacy has not been established, an oral dose of 5 vanized metal watering systems or containers should not be used to mg per kg of body weight every twenty-four hours for fifteen days has carry or store this product and chlorinators should not be operated been used in the treatment of [ehrlichiosis]1 in dogs, based on a while administering this medication{R-3}. comparative, randomized therapeutic trial{R-77}. An oral dose of 3 mg per kg of body weight every twelve hours for Additional information: Product labeling recommends that poultry seven days has been used in the treatment of [Rocky Mountain spotted litter from treated flocks spread on agricultural land be incorporated fever]1 in dogs, based on a controlled therapeutic trial using disease into the soil whenever possible{R-3}. It also recommends a 10- to 14- models{R-84}. day interval between flocks, top dressing with clean litter, and an [Ducks, pet or research]1—In the U.S., for use only in animals not to be increased frequency of removal of caked litter from each house{R-3}. used for food production: Although the safety and efficacy have not Poultry litter from treated flocks should not be used in cattle feed. been established, an oral dose of 10 mg per kg of body weight a day has been suggested for the treatment of susceptible bacterial infections Caution: Those who administer medication should avoid contact with in Muscovy ducks, based on pharmacokinetic data{R-42}. their eyes and skin. If contact occurs, immediately flush eyes with [Foals]1—Although the safety and efficacy have not been established, copious amounts of water for 15 minutes. In case of dermal contact, an oral dose of 2.5 mg per kg of body weight once a day for eight days wash skin with soap and water. Consult a physician if irritation persists has been recommended in the treatment of susceptible bacterial

infections in foals. Because of the potential for arthropathy in Intramuscular—2.5 mg per kg of body weight{R-86}. U.S. product immature animals, use is recommended in foals only when other labeling recommends that this be an initial single dose, to be antimicrobials are inappropriate{R-85}. followed by a dosage regimen using enrofloxacin tablets; this was [Horses]1—In the U.S., for use only in animals not to be used for food based on studies establishing the efficacy of 2.5 mg per kg of body production—Although the safety and efficacy have not been estab- weight every twelve hours{R-104}. Canadian product labeling lished, an oral dose of 7.5 to 10 mg per kg of body weight every recommends a maximum of six doses{R-102}. twenty-four hours has been recommended{R-24–27; 93}. Tablets have [Intravenous]1—5 to 20 mg per kg of body weight a day. The dose been crushed and suspended in water for administration{R-27} or may be administered as a single daily dose or divided into two ground into a powder and mixed in sugar syrup{R-25}. equal doses administered every twelve hours. To avoid adverse [Pacu, red]1—Although the safety and efficacy have not been effects, the drug should be diluted in a 2X volume of saline and established, administration of enrofloxacin by immersion of fish in a infused over 15 to 20 minutes. bath of a 2.5 mg per liter solution of enrofloxacin for five hours, every Note: For empiric treatment of probable Pseudomonas aeruginosa or twenty-four to forty-eight hours, has been suggested for the treatment Staphylococcus infections, the higher end of the dosage range may of susceptible bacterial infections in red pacu fish, based on pharma- be preferable, pending susceptibility results. cokinetic data{R-44}. [Cats]1: [Parrots, African grey]1—Although the safety and efficacy have not Intramuscular—2.5 mg per kg of body weight. For dogs, U.S. product been established, an oral dose of 7.5 to 30 mg per kg of body weight labeling recommends that this be an initial single dose, to be every twelve hours has been suggested in the treatment of susceptible followed by a dosage regimen using enrofloxacin tablets; this was bacterial infections in African grey parrots, based on pharmacokinetic based on studies establishing the efficacy of 2.5 mg per kg of body data{R-39}. The risk of side effects increases with higher doses; polyuria weight every twelve hours{R-104}. and polydipsia have been reported at the 30 mg per kg of body weight Intravenous—5 mg per kg of body weight a day. The dose may be dose{R-39}. administered as a single daily dose or divided into two equal doses [Rabbits, pet or research]1—In the U.S., for use only in animals not to be administered every twelve hours. To avoid adverse effects, the used for food production: Although the safety and efficacy have not been drug should be diluted in a 2X volume of saline and infused over established, an oral dose of 5 mg per kg of body weight every twelve 15 to 20 minutes. hours for fourteen days has been recommended in the treatment of Note: The above dosage recommendations are based on risk of retinal pasteurellosis in rabbits, based on clinical efficacy studies{R-67–69}. damage in cats administered doses higher than 5 mg/kg a day{R-1}. Bacterial pneumonia1—Cattle: Subcutaneous, 7.5 to 12.5 mg per kg of Strength(s) usually available: body weight as a single dose or 2.5 to 5 mg per kg of body weight U.S.— every twenty-four hours for three to five days{R-2}. Veterinary-labeled product(s): Note: Up to at least 1 week of age, calves eliminate enrofloxacin and 22.7 mg (Rx) [Baytril Tablets (film-coated){R-1}; Baytril Taste Tabs]. the active metabolite ciprofloxacin more slowly than do adult 68 mg (Rx) [Baytril Tablets (film-coated){R-1}; Baytril Taste Tabs]. cattle{R-13}. 136 mg (Rx) [Baytril Taste Tabs{R-1}]. Note: [Bustards]1—Although the safety and efficacy have not been Canada— established, a parenteral dose of 10 mg per kg of body weight every Veterinary-labeled product(s): twelve hours or 15 mg per kg of body weight every twenty-four hours 15 mg (Rx) [Baytril Tablets{R-102}]. has been suggested for the treatment of susceptible bacterial infections, 50 mg (Rx) [Baytril Tablets{R-102}]. based on pharmacokinetic data{R-41}. 150 mg (Rx) [Baytril Tablets{R-102}]. [Camels]1—Although the safety and efficacy have not been established, an intramuscular or subcutaneous dose of 2.5 mg per kg of body Packaging and storage: Store below 40 C (104 F), preferably be- weight every twelve hours has been suggested for the treatment of tween 15 and 30 C (59 and 86 F), unless otherwise specified by susceptible bacterial infections in camels, based on pharmacokinetic manufacturer. Store in a tight container. data{R-45}. [Ducks, pet or research]1—In the U.S., for use only in animals not to be USP requirements: Not in USP{R-105}. used for food production: Although the safety and efficacy have not been established, a parenteral dose of 10 mg per kg of body weight 1 Not included in Canadian product labeling or product not commercially every twenty-four hours has been suggested for the treatment of available in Canada. susceptible bacterial infections, based on pharmacokinetic data{R-42}. [Emus, pet or research]1—In the U.S., for use only in animals not to PARENTERAL DOSAGE FORMS be used for food production: Although the safety and efficacy have Note: Bracketed information in the Dosage Forms section refers to uses not been established, a parenteral dose of 2.2 mg per kg of body that either are not included in U.S. product labeling or are for products weight every twelve hours has been suggested for the treatment of not commercially available in the U.S. susceptible bacterial infections in emus, based on pharmacokinetic data{R-43}. 1 ENROFLOXACIN INJECTION [Horses] —In the U.S., for use only in animals not to be used for food Usual dose: production: Although the safety and efficacy have not been estab- Bacterial infections— lished, an intravenous dose of 5 mg per kg of body weight every Dogs: twenty-four hours has been used in the treatment of susceptible

bacterial infections in horses.{R-93} If a dose higher than 5 mg per kg of Note: The more concentrated enrofloxacin injection, 100 mg per mL, is body weight is administered, slow injection by indwelling catheter is labeled only for use in cattle{R-2}, while the less concentrated recommended to avoid adverse effects; dilution in 500 mL of sterile injection, 22.7 mg per mL, is labeled for use in dogs{R-104}. The saline solution may also be necessary{R-136}. product used for cattle contains different excipients than the [Llamas, pet or research]1—In the U.S., for use only in animals not to injectable solution for dogs; the safety of using the cattle product be used for food production: Although the safety and efficacy have not in other species has not been demonstrated{R-2}. been established, an intramuscular or subcutaneous dose of 5 mg per Canada— kg of body weight every twelve hours has been suggested for the Veterinary-labeled product(s): treatment of susceptible bacterial infections in llamas, based on 50 mg per mL (Rx) [Baytril Injectable Solution{R-102}]. pharmacokinetic data{R-45}. 1 [Oryx] —Although the safety and efficacy have not been established, a Withdrawal times: parenteral dose of 1.6 mg per kg of body weight every six to eight U.S.{R-2}—Federal law prohibits the extralabel use of enrofloxacin in hours has been suggested for the treatment of susceptible bacterial food-producing animals and restricts enrofloxacin to use by or on the {R-45} infections in oryx, based on pharmacokinetic data . order of a licensed veterinarian. [Pacu, red]1—Although the safety and efficacy have not been established, an intramuscular dose of 5 mg per kg of body weight Withdrawal time

every forty-eight hours has been suggested for the treatment of Species Meat (days) susceptible bacterial infections in the red pacu, based on pharmaco- Cattle 28 kinetic data{R-44}. [Parrots, African grey]1—Although the safety and efficacy have not Note: Not labeled for use in cattle intended for dairy production or in been established, an intramuscular dose of 7.5 to 30 mg per kg of body calves to be processed for veal{R-2}. Subcutaneous injection can cause a weight every twelve hours has been suggested in the treatment of local tissue reaction that is transient but can cause trim loss of edible susceptible bacterial infections in African grey parrots, based on tissue at slaughter{R-2}. pharmacokinetic data{R-39}. The risk of side effects increases with Canada—There is no established withdrawal time for cattle in Canada higher doses; polyuria and polydipsia have been reported with the 30 because enrofloxacin is not labeled for use in cattle. mg per kg of body weight dose{R-39}. [Pigs, potbellied and minature]1—In the U.S., for use only in animals not to be used in food production: Although the safety and efficacy Packaging and storage: Store below 40 C (104 F), preferably between have not been established, an oral dose of 10 mg per kg of body weight 15 and 30 C (59 and 86 F), unless otherwise specified by manufac- every 24 hours has been recommended for pigs in the treatment of turer. Protect from direct sunlight{R-1; 2}. Do not freeze{R-1; 2}. susceptible bacterial infections, based on pharmacokinetic data{R-25}. See also the Withdrawal times section. Caution: Those who administer medication should avoid contact with [Pythons]1—Although the safety and efficacy have not been estab- their eyes and skin. If contact occurs, immediately flush eyes with lished, an intramuscular dose of 10 mg per kg of body weight as a copious amounts of water for 15 minutes. In case of dermal contact, loading dose followed by 5 mg per kg of body weight every forty-eight wash skin with soap and water. A physician should be consulted if hours has been suggested for the treatment of susceptible bacterial irritation persists following exposure. In human beings, there is a risk infections in pythons{R-48}. For the treatment of Pseudomonas species of user photosensitization within a few hours of significant exposure to infections, 10 mg per kg of body weight every forty-eight hours has quinolones. been suggested, based on pharmacokinetic data{R-48}. [Rabbits, pet or research]1—In the U.S., for use only in animals not to {R-105} be used in food production: Although the safety and efficacy have not USP requirements: Not in USP . been established, a subcutaneous dose of 5 mg per kg of body weight 1 every twelve hours for fourteen days has been recommended in the Not included in Canadian product labeling or product not commercially control of pasteurellosis in rabbits{R-33; 67–69}. available in Canada. [Sheep, pet or research]1—In the U.S., for use only in animals not to be used in food production—Although the safety and efficacy have not been established, an intramuscular or intravenous dose of 2.5 to MARBOFLOXACIN 5 mg per kg of body weight every twenty-four hours has been recommended for sheep in the treatment of susceptible bacterial ORAL DOSAGE FORMS {R-28} infections , based on pharmacokinetic data. See also the MARBOFLOXACIN TABLETS Withdrawal times section. Usual dose: Bacterial infections—Cats and dogs: Oral, 2.75 to 5.5 mg per kg of body weight every twenty-four hours{R-97; 101}. Note: The 2.75 mg per kg dose was found to be clinically effective in Strength(s) usually available: the treatment of susceptible skin, soft tissue, and urinary tract U.S.— infections{R-97}. Veterinary-labeled product(s): For empiric treatment of probable Pseudomonas aeruginosa or Staph- 22.7 mg per mL (Rx) [Baytril Injectable Solution 2.27%{R-104}]. ylococcus infections, the higher end of the dosage range may be 100 mg per mL (Rx) [Baytril 100 Injectable Solution{R-2}]. preferable, pending susceptibility results.

Strength(s) usually available: Note: [Horses]1—In the U.S., for use only in animals not to be used U.S.{R-97}— for food production: Although the safety and efﬁcacy have not Veterinary-labeled product(s): been established, an oral dose of 5 to 7.5 mg per kg of body 25 mg (Rx) [Zeniquin Tablets]. weight every twenty-four hours has been recommended for the 50 mg (Rx) [Zeniquin Tablets]. treatment of susceptible bacterial infections in adult horses{R-133}. 100 mg (Rx) [Zeniquin Tablets]. Tablets have been crushed and suspended in water for adminis- 200 mg (Rx) [Zeniquin Tablets]. tration{R-133}. Canada{R-101}— Veterinary-labeled product(s): Strength(s) usually available: 25 mg (Rx) [Zeniquin Tablets]. U.S.{R-98}— 50 mg (Rx) [Zeniquin Tablets]. Veterinary-labeled product(s): 100 mg (Rx) [Zeniquin Tablets]. 5.7 mg (Rx) [Orbax Tablets]. 200 mg (Rx) [Zeniquin Tablets]. 22.7 mg (Rx) [Orbax Tablets]. 68 mg (Rx) [Orbax Tablets]. Packaging and storage: Store below 40 C (104 F), preferably Canada{R-100}— between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by Veterinary-labeled product(s): manufacturer. 5.7 mg (Rx) [Orbax Tablets]. 22.7 mg (Rx) [Orbax Tablets]. USP requirements: Not in USP{R-105}. 68 mg (Rx) [Orbax Tablets].

ORBIFLOXACIN Packaging and storage: Store between 2 and 30 C (36 and 86 ORAL DOSAGE FORMS F){R-98}, unless otherwise speciﬁed by manufacturer. Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products USP requirements: Not in USP{R-105}. not commercially available in the U.S.

1 ORBIFLOXACIN TABLETS Not included in Canadian product labeling or product not commercially available in Canada. Usual dose: Bacterial infections—Cats and dogs: Oral, 2.5 to 7.5 mg per kg of body weight every twenty-four hours{R-98}. Note: For empiric treatment of probable Pseudomonas aeruginosa or Developed: 02/17/00 Staphylococcus infections, the higher end of the dosage range may be Revised: 09/30/02 preferable, pending susceptibility results. Interim revision: 03/28/03

Table 1. Pharmacology/Pharmacokinetics—Intravenous administration.

Compound Elimination half-life VolD VolD, Steady state Clearance Species Dose (mg/kg) measured (hours) Area (L/kg) (L/kg) (mL/min/kg)

CIPROFLOXACIN Dogs{R-117} 2.5 to 10 2.2 3.06 ± 0.75 O.26 ± 0.11 ENROFLOXACIN Birds Bustards{R-41} 10 Enrofloxacin 5.63 ± 0.54 2.82 ± 0.37 2.98 ± 0.32 5.71 ± 0.41 Chickens{R-30} 10 Enrofloxacin 4.16 ± 0.19 2.20 ± 0.17 2.43 ± 0.19 2.2 ± 0.09 Chickens{R-31} 10 Enrofloxacin 10.29 ± 0.45 4.31 ± 0.15 2.77 ± 0.09 4.8 ± 0.17 Emus{R-43} 2.2 Enrofloxacin 3.33 1.49 ± 0.52 1.62 ± 1.04 6.00 ± 3.17 Calves{R-13} One day of age 2.5 Enrofloxacin 6.61 ± 1.12 1.81 ± 0.1 3.16 ± 0.5 2.5 Ciprofloxacin 9.19 ± 1.46 One week old 2.5 Enrofloxacin 4.87 ± 0.68 2.28 ± 0.14 6.5 ± 1 2.5 Ciprofloxacin 8.19 ± 0.85 Cattle, lactating{R-11} 5 Enrofloxacin 1.68 ± 0.18 > 1 {R-15} 5 Enrofloxacin 1.09 2.1 21 5 Ciprofloxacin 2.67 Camels{R-45} 2.5 Enrofloxacin 3.6 ± 0.89 1.13 ± 0.126 4.61 ± 1.03 Cats{R-22} 5 Enrofloxacin 6.7 ± 2.3 4.0 ± 0.3 9.5 ± 0.7 Ciprofloxacin 6.1 ± 1.3 Dogs{R-5} 1.25 to 5 Enrofloxacin > 3 9 {R-16} 5 Enrofloxacin 2.4 ± 0.87 7.0 ± 6.4 27.1 ± 16.2 5 Ciprofloxacin 3.9 ± 1.3 {R-18} 5.8 Enrofloxacin 4.4 ± 1 3.7 ± 0.6 10.88 ± 0.68 5.8 Ciprofloxacin 5.2 ± 0.4

Table 1. (Contd.)

Elimination half-life VolD VolD, Steady state Clearance Species Dose (mg/kg) (hours) Area (L/kg) (L/kg) (mL/min/kg)

Fish Salmon{R-37} 10 Enrofloxacin 34.2 6.1 2.3 Trout, rainbow{R-36} 5 Enrofloxacin 24.4 3.22 2.77 1.52 10 Enrofloxacin 30.4 2.56 2.34 0.97 Foals{R-85} 5 Enrofloxacin 17.10 ± 0.09 2.49 ± 0.43 2.47 ± 0.04 1.73 ± 0.001 Horses{R-27} 2.5 Enrofloxacin 5.94 1.22 ± 0.07 2.33 ± 0.17 5 Enrofloxacin 6.09 0.77 ± 0.11 1.50 ± 0.17 {R-24} 5 Enrofloxacin 4.4 2.3 ± 0.5 0.51 ± 0.11 Ciprofloxacin 5.1 ± 2.1 Llamas{R-46} 5 Enrofloxacin 3.38 ± 2.13 3.46 ± 0.98 11.7 ± 3.5 Oryx (antelope){R-47} 1.3 Enrofloxacin 0.69 ± 0.46 0.80 ± 0.3 12.07 ± 7.12 Pigs{R-29} 5 Enrofloxacin 3.9 ± 0.5 6.17 ± 1.83 Neonatal rabbits {R-35} 1 day of age 7.5 (IP) Enrofloxacin 5.01 2.03 4.7 8 days 7.5 (IP) Enrofloxacin 8.5 2.02 2.7 16 days 7.5 (IP) Enrofloxacin 6.1 2.52 4.8 30 days 7.5 (IP) Enrofloxacin 2 6.52 33.8 Rabbits{R-32} 5 Enrofloxacin 2.19 ± 0.29 4.4 ± 1.4 3.4 ± 0.9 22.8 ± 6.8 {R-33} 5 Enrofloxacin 2.5 2.12 0.93 10.1 {R-33} 7.5 Enrofloxacin 1.9 3.97 ± 0.9 23.9 ± 3.5 Sheep{R-46} 2.5 Enrofloxacin 3.73 ± 0.44 3.02 ± 0.22 9.17 ± 2.3 MARBFLOXACIN Dogs{R-108} 2 10.8 ± 1.3 1.33 ± 0.10 1.60 ± 0.21 {R-115} 2 12.4 ± 2.6 1.90 ± 0.76 1.37 ± 0.19 {R-97} 5.5 9.5 ± 0.7 1.19 ± 0.08 1.56 ± 0.13 ORBIFLOXACIN Cats{R-98} 2.5 4.5 ± 1.8 1.3 ± 0.13 Dogs{R-98} 2,5 5.4 ± 1.1 1.2 ± 0.2

Note: IP = Intraperitoneal

Table 2. Pharmacology/Pharmacokinetics: Other systemic data

Dose Peak Time to peak (mg/kg)/Route, Absorption serum serum Half-life, Water Compound half-life concentration concentration terminal Bioavailability Species temperature Number of doses measured (hours) (mcg/mL) (hours) (hours) (%)

CIPROFLOXACIN Dogs{R-134} 10/PO Single 1.4 (fr. graph) 2(fr. graph) 4.91 ± 1.26 20/PO Single 2.8 (fr. graph) 2(fr. graph) 5.30 ± 1.15 40/PO Single 6.6 (fr. graph) 6(fr. graph) 8.86 ± 2.78 {R-118} 11/PO Single 4.65 Every 12 hours 7.48 for 7 doses 23/PO Single 3.95 Every 12 hours 5.68 ± 0.54 1.53 ± 0.52 4.48 for 7 doses DIFLOXACIN Dogs{R-96} 5/PO Single 1.8 2.8 9.3 >80 {R-113} 5/PO Single 1.11 ± 0.07 2.84 ± 0.31 6.94 ± 0.54 {R-116} 5/PO Every 24 hours 1.79 ± 0.11 2.17 ± 0.26 8.52 ± 0.84 for 5 days ENROFLOXACIN Birds Bustards{R-41} 10/IM Single Enrofloxacin 0.23 ± 0.07 2.75 ± 0.11 1.72 ± 0.19 6.39 ± 1.49 97 10/PO Single Enrofloxacin 0.17 ± 0.02 1.84 ± 0.16 0.66 ± 0.05 6.80 ± 0.79 62 Chickens{R-30} 10/IM Single Enrofloxacin 1.83 ± 0.04 2.45 ± 0.1 1.43 ± 0.02 4.06 ± 0.06 88 10/PO Single Enrofloxacin 0.92 ± 0.05 1.69 ± 0.08 2.52 ± 0.08 4.29 ± 0.1 60 10/SC Single Enrofloxacin 0.36 ± 0.02 2.41 ± 0.06 1.46 ± 0.06 4.48 ± 0.04 81 Chickens{R-31} 10/PO Single Enrofloxacin 0.67 ± 0.05 2.44 ± 0.64 1.64 ± 0.04 14.23 ± 0.46 64 Ducks{R-42} 10/IM Single Enrofloxacin 1.67 ± 0.29 0.94 ± 0.18 10/PO Single Enrofloxacin 0.99 ± 0.08 1.38 ± 0.18 Parrots{R-39} 15/IM Single Enrofloxacin 3.87 ± 0.27 1 2.31 ± 0.09 3/PO Single Enrofloxacin 0.31 ± 0.11 4 2.59 ± 0.36 48 15/PO Single Enrofloxacin 1.12 ± 0.11 2 2.52 ± 0.33 30/PO Single Enrofloxacin 1.69 ± 0.23 4 2.74 ± 0.37

Table 2. (Contd.)

Camels{R-45} 2.5/IM Single Enrofloxacin 0.76 ± 0.46 1.44 ± 0.8 1 6.36 ± 2.03 85 2.5/PO Single Enrofloxacin Not detected 2.5/SC Single Enrofloxacin 0.5 ± 0.12 1.23 ± 0.27 1 10.58 ± 6.78 92 Cats {R-22} 5/PO Every 24 hours Enrofloxacin 0.2 ± 0 1.67 ± 0.11 0.6 ± 0.1 for 10 days 5/PO Every 24 hours Ciprofloxacin 0.13 ± 0.01 2.3 ± 0.5 for 10 days Cattle, lactating 5/IM Single Enrofloxacin 0.73 ± 0.12 2.4 ± 0.68 5.9 ± 1.44 82 {R-45} 5/SC Single Enrofloxacin 0.98 ± 0.2 3.2 ± 1.09 5.55 ± 0.52 137 Dogs{R-8} 1.25/IM Single Enrofloxacin 1.09 0.5 {R-5} 1.25/PO Single Enrofloxacin 0.25 (from graph) 1 > 3 2.5/PO Single Enrofloxacin 1 (from graph) 1 > 3 5/PO Single Enrofloxacin 1.5 (from graph) 1 > 3 {R-16} 5/PO Single Enrofloxacin 1.16 ± 0.6 0.9 ± 0.8 2.4 ± 0.5 5/PO Single Ciprofloxacin 0.29 ± 0.19 3.6 ± 0.3 3.9 ± 3.2 {R-17} 2.75/PO Every 12 hours Enrofloxacin 1.03 ± 0.28 1.88 ± 0.72 3.07 ± 1 for 7 doses 5.5/PO Every 12 hours Enrofloxacin 2.45 ± 0.84 1.55 ± 0.56 4.04 ± 0.78 for 7 doses 11/PO Every 12 hours Enrofloxacin 4.56 ± 0.49 2.31 ± 0.82 4.26 ± 1.03 for 7 doses {R-18} 5.8/PO Every 12 hours Enrofloxacin 1.43 ± 0.12 1.8 ± 0.2 83 for 15 days 5.8/PO Every 12 hours Ciprofloxacin 0.36 ± 0.03 2.2 ± 0.3 for 15 days {R-21} 2.5/SC Single Active drug* 0.6 ± 0.03 2.25 ± 0.09 2.61 ± 0.15 25/SC Single Active drug 5.77 ± 0.41 3.92 ± 0.16 6.42 ± 0.29 Fish Pacu{R-44} 5/IM Single Enrofloxacin 1.64 ± 0.92 4 28.9 Ciprofloxacin 0.05 ± 0.01 4 53 5/PO Single Enrofloxacin 0.8 ± 1.17 36 Ciprofloxacin 0.02 ± 0.008 36 2.5 mg per Single 5 hour Enrofloxacin 0.17 ± 0.04 2 Liter/bath dose Ciprofloxacin 0.024 ± 0.001 2 immersion Salmon{R-38} 5/PO, 9.7 C Single Enrofloxacin 0.53 2.87 48.2 46 10/PO, 9.7 C Single Enrofloxacin 0.27 0.42 105.1 49 {R-37} 10/PO (in feed), Single Enrofloxacin 1.54 6 56 10 C Trout{R-36} 5/PO, 10 C Single Enrofloxacin 0.37 24 44.2 35 10/PO, 10 C Single Enrofloxacin 0.55 6 29.5 24 50/PO, 10 C Single Enrofloxacin 1.93 6 29.5 17 Foals{R-85} 10/PO Single Enrofloxacin 2.12 ± 0.51 2.20 ± 2.17 18.4 ± 0.06 42 Horses{R-24} 5/IM Single Enrofloxacin 9.9 {R-5} 2.5/PO Every 12 hours Enrofloxacin 0.89 2.62 ± 0.61 1 ± 0.35 57 for 3 days 5/PO Every 12 hours Enrofloxacin 0.8 5.97 ± 1.56 1.25 ± 0.43 63 for 3 days {R-5} 5/PO Single Enrofloxacin 1.85 ± 0.86 0.92 ± 0.59 7.75 Mice{R-21} 1.56/SC Single Active drug 0.57 ± 0.06 0.37 ± 0.02 0.3 ± 0.03 25/SC Single Active drug 6.44 ± 0.46 0.54 ± 0.06 0.54 ± 0.04 Pigs{R-39} 10/PO Single Enrofloxacin 1.4 ± 0.5 4.8 ± 1.9 83 Pythons{R-24} 5/IM Single Enrofloxacin 1.66 ± 0.42 5.75 ± 1.47 6.37 5/IM Single Ciprofloxacin 0.35 ± 0.21 13 ± 5.9 Rabbits{R-32} 5/IM Single Enrofloxacin 0.07 ± 0.02 3.04 ± 0.34 0.17 1.81 ± 0.3 92 {R-33} 5/PO Single Enrofloxacin 0.452 2.3 2.41 61 5/SC Single Enrofloxacin 2.07 0.9 72 Sheep{R-28} 2.5/IM Single Enrofloxacin 0.78 ± 0.07 1.25 ± 0.11 3.65 ± 0.31 85 2.5/IM Single Ciprofloxacin 0.14 ± 0.02 5 ± 0.45 9.98 ± 2.33 MARBOFLOXACIN Cats{R-97} 6.2/PO Single 4.8 ± 0.7 1.2 ± 0.6 12.7 ± 1.1 Dogs{R-115} 1/PO Single 0.38 ± 0.35 0.83 ± 0.26 1.7 ± 1.2 14.7 ± 4.9 100 2/PO Single 0.53 ± 0.24 1.38 ± 0.40 2.5 ± 1.2 14.0 ± 4.9 4/PO Single 0.68 ± 0.59 2.93 ± 0.58 2.0 ± 1.1 12.5 ± 2.7

Table 2. (Contd.)

Dogs 1/SC Single 0.20 ± 0.11 0.78 ± 0.08 1.0 ± 0.6 11.5 ± 1.9 100 2/SC Single 0.20 ± 0.07 1.52 ± 0.13 0.9 ± 0.2 13.0 ± 3.3 4/SC Single 0.25 ± 0.12 3.04 ± 0.24 1.3 ± 0.61 13.4 ± 2.8 {R-113} 2/PO Single 1.47 ± 0.09 1.83 ± 0.17 9.07 ± 1.90 {R-108} 2/PO Every 24 hours 1.37 ± 0.21 1.97 ± 0.97 for 8 days {R-108} 2.7/PO Single 2.0 ± 0.2 1.5 ± 0.3 10.7 ± 1.6 5.6/PO Single 4.2 ± 0.5 1.8 ± 0.3 10.9 ± 0.6 94 ORBIFLOXACIN Cats{R-98} 2.5/PO Single 2.06 ± 0.6 1 ± 0.45 5.52 ± 2.66 Dogs{R-98} 2.5/PO Single 2.3 ± 0.3 0.77 ± 0.45 5.6 ± 1.1 97 {R-113} 2.5/PO Single 1.37 ± 0.01 2.42 ± 0.36 7.14 ± 0.42 Mares{R-133} 7.5/PO Single 2.41 ± 0/03 1.5 9.06 ± 1.33

Note IM¼Intramuscular administration, PO¼Oral administration, SC¼Subcutaneous administration. *These agar plate diffusion assays used bacillus subtills or Klebsiella pneumoniae as the test organism and, therefore, measured enrofloxacin, cigrofloxacin, and any other unidentified metabolites with antimicrobial activity against it.

REFERENCES 16. Kung K, Riond JL, Wanner M. Pharmacokinetics of enrofloxacin and its 1. Enrofloxacin tablets package insert (Baytril, Bayer—US), Rev 11/00, Rec metabolite ciprofloxacin after intravenous and oral administration of 6/10/02. enrofloxacin in dogs. J Vet Pharmacol Ther 1993; 16: 462–8. 2. Enrofloxacin injection package insert (Baytril [cattle], Bayer—US), Rev 17. Walker RD, Stein GE, Hauptman JG, et al. Pharmacokinetic evaluation of 2/99. In: Entriken TL, editor. Veterinary pharmaceuticals and biologicals, enrofloxacin administered orally to healthy dogs. Am J Vet Res 1992 Dec; 12th ed. Lenexa, KS: Veterinary Healthcare Communications. 2001. 53(12): 2315–9. p. 1131. 18. Monlouis JD, De Jong A, Limet A, et al. Plasma pharmacokinetics and urine 3. Enrofloxacin 3.23% Concentrate Antimicrobial Solution (Baytril, Bayer—US), concentrations of enrofloxacin after oral administration of enrofloxacin in Rev 7/99. In: Entriken TL, editor. Veterinary pharmaceuticals and biologicals, dogs [abstract]. J Vet Pharmacol Ther 1997; 20 (Suppl 1): 61–3. 12th ed. Lenexa, KS: Veterinary Healthcare Communications. 2001. 19. Dorfman M, Barsanti J, Budsberg SC. Enrofloxacin concentrations in dogs p. 1131–3. with normal prostate and dogs with chronic bacterial prostatitis. Am J Vet 4. Freedom of Information summary. NADA 140–828 (supplement). Baytril Res 1995 Mar; 56(3): 386–90. (enrofloxacin) 3.23% Concentrate Antimicrobial Solution. Sponsor: Bayer 20. Hawkins EC, Boothe DM, Guinn A, et al. Concentration of enrofloxacin and Corporation. October 4, 1996. its active metabolite in alveolar macrophages and pulmonary epithelial 5. Freedom of Information summary. NADA 140–441 (original). Baytril lining fluid of dogs. J Vet Pharmacol Ther 1998; 21: 18–23. (enrofloxacin). Sponsor: Bayer Corporation. December 27, 1988. 21. Meinen JB, McClure JT, Rosin E. Pharmacokinetics of enrofloxacin in 6. Freedom of Information summary. NADA 140–441 (supplemental). Baytril clinically normal dogs and mice and drug pharmacodynamics in neutropenic (enrofloxacin). Sponsor: Bayer Corporation. June 6, 1990. mice with Escherichia coli and staphylococcal infections. Am J Vet Res 1995 7. USP dictionary of USAN and international drug names, 2002 ed. Rockville, Sep; 56(9): 1219–24. MD: The United States Pharmacopeial Convention, Inc.; 2002. 22. Richez P, Monlouis JD, Dellac B, et al. Validation of a therapeutic regimen for 8. Freedom of Information summary. NADA 140–913 (original). Baytril enrofloxacin in cats on the basis of pharmacokinetic data [abstract]. J Vet (enrofloxacin) injectable solution. Sponsor: Bayer Corporation. May 4, 1990. Pharmacol Ther 1997; 20 (Suppl 1): 152–3. 9. Brown SA. Fluoroquinolones in animal health. J Vet Pharmacol Ther 1996; 23. Cester CC, Toutain PL. A comprehensive model for enrofloxacin to 19: 1–14. ciprofloxacin transformation and disposition in dog. J Pharm Sci 1997 Oct; 10. Vancutsem PM, Babish JG, Schwark WS. The fluoroquinolone antimicrobi- 86(10): 1148–55. als: structure, antimicrobial activity, pharmacokinetics, clinical use in 24. Kaartinen L, Panu S, Pyorala S. Pharmacokinetics of enrofloxacin in horses domestic animals and toxicity. Cornell Vet 1990; 80(2): 173–86. after single intravenous and intramuscular administration. Equine Vet J 11. Kaartinen L, Salonen M, Alli L, et al. Pharmacokinetics of enrofloxacin after 1997 Sep; 29(5): 378–81. single intravenous, intramuscular, and subcutaneous injections in lactating 25. Langston VC, Sedrish S, Boothe DM. Disposition of single-dose oral cows. J Vet Pharmacol Ther 1995; 18: 357–62. enrofloxacin in the horse. J Vet Pharmacol Ther 1996; 19: 316–9. 12. Villa R, Prandini E, Caloni F, et al. Serum protein binding of 26. Giguere S, Belanger M. Concentration of enrofloxacin in equine tissues some sulphonamides, quinolones and fluoroquinolones in farm and after long term oral administration. J Vet Pharmacol Ther 1997; 20: 402–4. domestic animals [abstract]. J Vet Pharmacol Ther 1997; 20 (Suppl 1): 27. Giguere S, Sweeney RW, Belanger M. Pharmacokinetics of enrofloxacin in 21–86. adult horses and concentration of the drug in serum, body fluids, and 13. Kaartinen L, Pyorala S, Moilanen M, et al. Pharmacokinetics of enrofloxacin endometrial tissues after repeated intragastrically administered doses. Am J in newborn and one-week-old calves. J Vet Pharmacol Ther 1997; 20: 479– Vet Res 1996 Jul; 57(7): 1025–30. 82. 28. Mengozzi G, Intorre L, Bertini S, et al. Pharmacokinetics of enrofloxacin and 14. Tyczkowska KL, Voyksner RD, Anderson KL, et al. Simultaneous determi- its metabolite ciprofloxacin after intravenous and intramuscular adminis- nation of enrofloxacin and its primary metabolite ciprofloxacin in bovine tration in sheep. Am J Vet Res 1996 Jul; 57(7): 1040–3. milk and plasma by ion-pairing liquid chromatography. J Chromatogr B 29. Nielsen P, Gyrd-Hansen M. Bioavailability of enrofloxacin after oral 1994; 658: 341–8. administration to fed and fasted pigs. Pharmacol Toxicol 1997; 80(5): 15. Malbe M, Salonen M, Fang W, et al. Disposition of enrofloxacin (Batyril) into 246–50. the udder after intravenous and intra-arterial injections into dairy cows. 30. Abd el-Aziz MI, Aziz MA, Soliman FA, et al. Pharmacokinetic evaluation of Zentralbl Veterinarmed A 1996 Aug; 43(6): 377–86. enrofloxacin in chickens. Br Poult Sci 1997; 38: 164–8.

31. Anadon A, Martinez-Larranaga MR, Diaz MJ, et al. Pharmacokinetics 55. Endtz HP, Ruijs GJ, van Klingeren B, et al. Quinolone resistance in and residues of enrofloxacin in chickens. Am J Vet Res 1995 Apr; 56(4): campylobacter isolated from man and poultry following the introduction of 501–6. fluoroquinolones in veterinary medicine. J Antimicrob Chemother 1991; 27: 32. Cabanes A, Arboix M, Garcia Anton JM, et al. Pharmacokinetics of 199–208. enrofloxacin after intravenous and intramuscular injection in rabbits. Am 56. Griggs DJ, Hall MC, Jin YF, et al. Quinolone resistance in veterinary isolates J Vet Res 1992 Nov; 53(11): 2090–3. of Salmonella. J Antimicrob Chemother 1994; 33: 1173–89. 33. Broome RL, Brooks DL, Babish JG, et al. Pharmacokinetic properties of 57. Lekeux P, Art T. Effect of enrofloxacin therapy on shipping fever pneumonia enrofloxacin in rabbits. Am J Vet Res 1991 Nov; 52(11): 1835–41. in feedlot cattle. Vet Rec 1988 Aug 20; 123(8): 205. 34. Aramayona JJ, Mora J, Fraile LJ, et al. Penetration of enrofloxacin and 58. Pellerin JL, Bourdeau P, Sebbag H, et al. Epidemiosurveillance of antimicro- ciprofloxacin into breast milk, and pharmacokinetics of the drugs in lactating bial compound resistance of Staphylococcus intermedius clinical isolates rabbits and neonatal offspring. Am J Vet Res 1996 Apr; 57(4): 547–53. from canine pyodermas. Comp Immunol Microbial Infect Dis 1998 Apr; 35. Fraile LJ, Martinez C, Aramayona JJ, et al. Limited capacity of neonatal 21(2): 115–33. rabbits to eliminate enrofloxacin and ciprofloxacin. Vet Q 1997; 19: 162–7. 59. Novotny MJ, Shaw DH. Effect of enrofloxacin on digoxin clearance 36. Bowser PR, Wooster GA, St Leger J, et al. Pharmacokinetics of enrofloxacin and steady-state serum concentrations in dogs. Can J Vet Res 1991; 55: in fingerling rainbow trout (Oncorhynchus mykiss). J Vet Pharmacol Ther 113–6. 1992; 15: 62–71. 60. Shlosberg A, Ershov E, Bellaiche M, et al. The effects of enrofloxacin on 37. Martinsen B, Horsberg TE. Comparative single-dose pharmacokinetics of four hepatic microsomal mixed function oxidases in broiler chickens. J Vet quinolones, oxolinic acid, flumequine, sarafloxacin, and enrofloxacin, in Pharmacol Ther 1995; 18: 311–3. Atlantic salmon (Salmo salar) held in seawater at 10 C. Antimicrob Agents 61. Intorre L, Mengozzi G, Maccheroni M, et al. Enrofloxacin-theophylline Chemother 1995 May; 39(5): 1059–64. interaction: influence of enrofloxacin on theophylline steady-state pharma- 38. Stoffregen DA, Wooster GA, Bustos PS, et al. Multiple route and dose cokinetics in the beagle dog. J Vet Pharmacol Ther 1995; 18: 352–6. pharmacokinetics of enrofloxacin in juvenile Atlantic salmon. J Vet 62. Vancutsem PM, Babish JG. Effects of ciprofloxacin and enrofloxacin on Pharmacol Ther 1997; 20: 111–23. zoxazolamine kinetics, plasma concentration and sleeping times in mice. 39. Flammer K, Aucoin DP, Whitt DA. Intramuscular and oral disposition of Toxicol Lett 1993; 69: 1–14. enrofloxacin in African grey parrots following single and multiple doses. J 63. Aramayona JJ, Garcia MA, Fraile LJ, et al. Placental transfer of enrofloxacin Vet Pharmacol Ther 1991; 14: 359–66. and ciprofloxacin in rabbits. Am J Vet Res 1994 Sep; 55(9): 1313–8. 40. Flammer K, Aucoin DP, Whitt DA, et al. Plasma concentrations of 64. Butaye P, Ducatelle R, De Backer P, et al. In vitro activities of doxycycline enrofloxacin in African grey parrots treated with medicated water. Avian and enrofloxacin against European Chlamydia psittaci strains from turkeys. Dis 1990; 34: 1017–22. Antimicrob Agents Chemother 1997 Dec; 41(12): 2800–1. 41. Bailey TA, Sheen RS, Silvanose C, et al. Pharmacokinetics of enrofloxacin 65. Gutierrez CB, Piriz S, Vadillo S, et al. In vitro susceptibility of actinobacillus after intravenous, intramuscular, and oral administration in houbara pleuropneumoniae strains to 42 antimicrobial agents. Am J Vet Res 1993 bustard (Chlamydotis undulata macqueenii). J Vet Pharmacol Ther 1998; Apr; 54(4): 546–50. 21: 288–97. 66. Prescott JF, Yielding KM. In vitro susceptibility of selected veterinary 42. Intorre L, Mengozzi G, Bertini S, et al. The plasma kinetics and tissue bacterial pathogens to ciprofloxacin, enrofloxacin and norfloxacin. Can J Vet distribution of enrofloxacin and its metabolite ciprofloxacin in the Muscovy Res 1990; 54: 195–7. duck. Vet Res Commun 1997; 21: 127–36. 67. Suckow MA, Martin BJ, Bowersock TL, et al. Derivation of Pasteurella 43. Helmick KE, Boothe DM, Jensen JM. Disposition of single-dose intravenously multocida-free rabbit litters by enrofloxacin treatment. Vet Microbiol 1996; administered enrofloxacin in emus (Dromaius novaehollandiae). J Zoo Wildl 51: 161–8. Med 1997; 28(1): 43–8. 68. Mahlet M, Stunkel S, Ziegowski C, et al. Inefficacy of enrofloxacin in 44. Lewbart G, Vaden S, Deen J, et al. Pharmacokinetics of enrofloxacin in the the elimination of Pasteurella multocida in rabbits. Lab Anim 1995; 29: red pacu (Colossoma brachypomum) after intramuscular, oral and bath 192–9. administration. J Vet Pharmacol Ther 1997; 20: 124–8. 69. Broome RL, Brooks DL. Efficacy of enrofloxacin in the treatment of 45. Gavrielli R, Yagil R, Ziv G, et al. Effect of water deprivation on the disposition respiratory pasteurellosis in rabbits. Lab Anim Sci 1991 Dec; 41(6): 572–6. kinetics of enrofloxacin in camels. J Vet Pharmacol Ther 1995; 18: 333–9. 70. Banish LD, Sins R, Bush M, et al. Clearance of Shigella flexneri carriers in a 46. Christensen JM, Smith BB, Murdane SB, et al. The disposition of five zoologic collection of primates. J Am Vet Med Assoc 1993 Jul 1; 203(1): 133–6. therapeutically important antimicrobial agents in llamas. J Vet Pharmacol 71. Line AS, Paul-Murphy J, Aucoin DP, et al. Enrofloxacin treatment of long- Ther 1996; 19: 431–8. tailed macaques with acute bacillary dysentery due to multiresistant Shigella 47. Gamble KC, Boothe DM, Jensen JM, et al. Pharmacokinetics of a single flexneri IV. Lab Anim Sci 1992 Jun; 42(3): 240–4. intravenous enrofloxacin dose in a scimitar-horned oryx (Oryx Dammah). J 72. Kordick DL, Papich MG, Breitschwerdt EB. Efficacy of enrofloxacin or Zoo Wildl Med 1997; 28(1): 36–42. doxycycline for treatment of Bartonella henselae or Bartonella clarridgeiae 48. Young LA, Schumacher J, Papich MG, et al. Disposition of enrofloxacin and infection in cats. Antimicrob Agents Chemother 1997 Nov; 41(11): 2448–55. its metabolite ciprofloxacin after intramuscular injection in juvenile burmese 73. Regnery RL, Rooney JA, Johnson AM, et al. Experimentally induced pythons (Python molurus bivittatus). J Zoo Wildl Med 1997; 28(1): 71–9. Bartonella henselae infections followed by challenge exposure and antimi- 49. Charleston B, Gate JJ, Aitken IA, et al. Comparison of the efficacies of three crobial therapy in cats. Am J Vet Res 1996 Dec; 57(12): 1214–9. fluoroquinolone antimicrobial agents, given as continuous or pulsed-water 74. Schroder J. Enrofloxacin: a new antimicrobial agent. J S Afr Vet Assoc 1989 medication, against Escherichia coli infection in chickens. Antimicrob Jun; 60(2): 122–4. Agents Chemother 1998 Jan; 42(1): 83–7. 75. Studdert VP, Hughes KL. Treatment of opportunistic mycobacterial infec- 50. Jacobs-Reitsma WF, Koenraad PMFJ, Bolder NM, et al. In vitro tions with enrofloxacin in cats. J Am Vet Med Assoc 1992 Nov 1; 201(9): susceptibility of campylobacter and salmonella isolates from broilers to 1388–90. quinolones, ampicillin, tetracycline, and erythromycin. Vet Q 1994; 16(4): 76. White PD, Kowalski JJ. Enrofloxacin-responsive cutaneous atypical myco- 206–8. bacterial infection in two cats. Proceedings of the 7th meeting of the 51. Barbour EK, Hamadeh S, Talhouk, et al. Evaluation of an enrofloxacin- American College of Veterinary Dermatology. 1991. p. 95. treatment program against Mycoplasma gallisepticum infection in broilers. 77. Kontos VJ, Athanasiou LV. Use of enrofloxacin in the treatment of acute Prev Vet Med 1998 May; 35(2): 91–9. canine ehrlichiosis. Canine Pract 1998; 23(3): 10–4. 52. Sumano LH, Ocampo CL, Brumbaugh GW, et al. Effectiveness of two 78. Giguere S, Sweeney RW, Habecker PL, et al. Tolerability of orally fluoroquinolones for the treatment of chronic respiratory disease outbreak in administered enrofloxacin in adult horses: a pilot study. J Vet Pharmacol broilers. Br Poult Sci 1998 Mar; 39(1): 42–6. Ther 1999; 22: 343–7. 53. Jordan FTW, Horrocks BK, Froyman R. A model for testing the efficacy of 79. Rodger LD, Carlson GP, Moran ME, et al. Resolution of a left ureteral stone enrofloxacin (Baytril) administered to turkey hens in the control of using electrohydraulic lithotripsy in a thoroughbred colt. J Vet Int Med 1995 Mycoplasma iowae infection in eggs and embryos. Avian Dis 1993; 37: Jul/Aug; 9(4): 280–2. 1057–61. 80. Heath SE, Townsend HGG, Pharr J, et al. Chronic pleuritis in a horse. Can 54. Hannan PCT, Windsor GD, De Jong A, et al. Comparative susceptibilities of Vet J 1989 Jan; 30: 69. various animal-pathogenic mycoplasmas to fluoroquinolones. Antimicrob 81. Committee consensus, 8/26/02. Agents Chemother 1997 Sept; 41(9): 2037–40. 82. Manufacturer comment, 8/13/02.

83. Winter RB. Using quinolones to treat haemobartonellosis [letter]. Vet Med 112. Spreng M, Deleforge J, Thomas V, et al. Antibacterial activity of marboflox- Small Animal Clin 1993 Apr; 306–7. acin. A new fluoroquinolone for veterinary use against canine and feline 84. Breitschwerdt EB, Davidson MG, Aucoin DP, et al. Efficacy of chloramphe- isolates. J Vet Pharmacol Ther 1995; 18: 284–9. nicol, enrofloxacin, and tetracycline for treatment of experimental Rocky 113. Heinen E. Comparative serum pharmacokinetics of the fluoroquinolones Mountain spotted fever in dogs. Antimicrob Agents Chemother 1991 Nov; enrofloxacin, difloxacin, marbofloxacin, and orbifloxacin in dogs after single 35(11): 2375–81. oral administration. J Vet Pharmacol Ther 2002; 25(1): 1–5. 85. Bermingham E, Papich MG, Vivrette SL. Pharmacokinetics of enrofloxacin 114. Bryant RE, Mazza JA. Effect of the abscess environment on the antimicrobial administered intravenously and orally to foals. Am J Vet Res 2000 Jun; activity of ciprofloxacin. Am J Med 1989; 87(Suppl 5A): 23–17S. 61(6): 706–9. 115. Schneider M, Thomas V, Boisrame B, et al. Pharmacokinetics of marboflox- 86. Panel comment, Rec 8/5/99. acin in dogs after oral and parenteral administration. J Vet Pharmacol Ther 87. New breakpoints of enrofloxacin (dogs/cats) approved by NCCLS. Bayer 1996; 19(1): 56–61. Animal Health paper. 116. Frazier DL, Thompson L, Trettien A, et al. Comparison of fluoroquinolone 88. National Committee for Clinical Laboratory Standards. M-31 Document: pharmacokinetic parameters after treatment with marbofloxacin, enroflox- Performance Standards for Antimicrobial Disk and Dilution Susceptibility acin, and difloxacin in dogs. J Vet Pharmacol Ther 2000; 23(5): 293–302. Tests for bacteria isolated from animals. Vol 19 No. 11 June 1999. 117. Abadia AR, Aramayona JJ, Munoz MJ, et al. Disposition of ciprofloxacin 89. Panel comment, Rec 7/21/99. following intravenous administration in dogs. J Vet Pharmacol Ther 1994; 90. Martinez-Martinez L, Pascual A, Jacoby GA. Quinolone resistance from a 17(5): 384–8. transferable plasmid. Lancet 1998; 351: 797–9. 118. Walker RD, Stein GE, Hauptman JG, et al. Serum and tissue cage fluid 91. Smith KE, Besser JM, Hedberg CW, et al. Quinolone resistant Campylobacter concentrations of ciprofloxacin after oral administration of the drug to jejuni infections in Minnesota, 1992–1998. New Eng J Med 1999; 340(20): healthy dogs. Am J Vet Res 1990; 51(6): 896–900. 1525–32. 119. Gelatt KN, van der Woerdt A, Ketring KL, et al. Enrofloxacin-associated 92. Panel comment, Rec 12/29/99. retinal degeneration in cats. Vet Ophthalmol 2001 Jun; 4(2): 99–106. 93. Panel consensus, 1/6/00. 120. Ozturk F, Kurt E, Inan UU, et al. Penetration of topical and oral ofloxacin into 94. Office of the Federal Register. Code of Federal Regulations. 21 Parts 500 to the aqueous and vitreous humor of inflamed rabbit eyes. Int J Pharm 2000 599. April 1, 1999. US Government Printing Office: Washington, D.C. 1999. Aug 25; 204(1–2): 91–5. p. 329. 121. Garcia-Saenz MC, Arias-Puente A, Fresnadillo-Martinez MJ, et al. Human 95. Papich MG, Riviere JE. Fluoroquinolone antimicrobial drugs. In: Adams HR, aqueous humor levels of oral ciprofloxacin, levofloxacin, and moxifloxacin. J editor. Veterinary Pharmacology and Therapeutics, 8th ed. Ames: Iowa State Cataract Refract Surg 2001 Dec; 27(12): 1969–74. University Press, 2001. p. 898–912. 122. Hanioglu-Kargi S, Basci N, Soysal H, et al. The penetration of ofloxacin into 96. Difloxacin Tablets package insert (Dicural, Fort Dodge—US). Downloaded human aqueous humor given by various routes. Eur J Ophthalmol 1998 from www.wyeth.com/divisions/fort_dodge.asp on 6/10/02. Jan-Mar; 8(1): 33–6. 97. Marbofloxacin Tablets package insert (Zeniquin, Pfizer—US). Downloaded 123. Donnenfeld ED, Perry HD, Snyder RW, et al. Intracorneal, aqueous humor, from www.zeniquin.com on 6/10/02. and vitreous humor penetration of topical and oral ofloxacin. 98. Orbifloxacin Tablets package insert (Orbax, Schering-Plough—US). Down- Arch Ophthalmol 1997 Feb; 115(2): 173–6. loaded from www.spah.com on 6/10/02. 124. Fiscella RG, Nguyen TK, Cwik MJ, et al. Aqueous and vitreous penetration of 99. Difloxacin Tablets package insert (Dicural, Ayerst—Canada). In: Arrioja- levofloxacin after oral administration. Ophthalmology 1999 Dec; 106(12): Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, 2286–90. MI: North American Compendiums, Inc. 2002. 125. Cekic O, Batman C, Yasar U, et al. Subretinal fluid levels of topical, oral, and 100. Orbifloxacin Tablets package insert (Orbax, Schering-Plough—Canada). In: combined administered ciprofloxacin in humans. Br J Ophthalmol 2000: 84: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port 1061–3. Huron, MI: North American Compendiums, Inc. 2002. 126. Saez-Llorens X, McCoig C, Feris JM, et al. Trovan Meningitis Study Group. 101. Marbofloxacin Tablets package insert (Orbax, Schering-Plough—Canada). Quinolone treatment for pediatric bacterial meningitis: A comparative study In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. of trovafloxacin and ceftriaxone with or without vancomycin. The Pediatric Port Huron, MI: North American Compendiums, Inc. 2002. Infectious Disease Journal 2002; 21(1): 14–22. 102. Enrofloxacin package insert (Baytril, Bayer—Canada). In: Arrioja-Dechert A, 127. Rodriguez-Cerrato V, McCoig CC, Michelow IC, et al. Pharmacodynamics and editor. Compendium of veterinary products, CD ed. Port Huron, MI: North bactericidal activity of moxifloxacin in experimental Escherichia coli menin- American Compendiums, Inc. 2002. gitis. Antimicrob Agents Chemother 2001; 45(11): 3092–97. 103. Fluoroquinolone therapy for cats: Concerns about altered vision. (Pfiz- 128. Destache CJ, Pakiz CB, Larsen, C, et al. Cerebrospinal fluid penetration and er—US), 2001. pharmacokinetics of levofloxacin in an experimental rabbit meningitis 104. Enrofloxacin injection package insert (Baytril [dogs], Bayer—US), Rev model. J Antimicrob Chemother. 2001; 47: 611–5. 8/00. In: Entriken TL, editor. Veterinary pharmaceuticals and biologicals, 129. Scotton PG, Pea F, Giobbia M, et al. Cerebrospinal fluid penetration of 12th ed. Lenexa, KS: Veterinary Healthcare Communications. 2001. levofloxacin in patients with spontaneous acute bacterial meningitis. Clin P. 1131–3. Infect Dis 2001; 33: 109–11. 105. The United States pharmacopeia. The national formulary. USP 26th revision 130. Lipman J, Allworth A, Wallis SC. Cerebrospinal fluid penetration of high (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United doses of intravenous ciprofloxacin in meningitis. Clin Infect Dis 2000; 31: States Pharmacopeial Convention, Inc., 2002. p. 458–61, 2555. 1131–3. 106. AMDUCA fluoroquinolone and glycopeptide prohibition: analysis of com- 131. Krcmery V, Filka J, Uher J, et al. Ciprofloxacin in treatment of nosocomial ments. May 14, 1998. Food and Drug Administration Center for Veterinary meningitis in neonates and in infants: report of 12 cases and review. Elsevier Medicine. Downloaded from www.fda.gov/cvm on 4/11/02. Science Inc., 1999. p. 75–80. 107. Klasco RK, editor. USP DI Drug information for the healthcare professional. 132. D’Antuono VS, Brown I. Successful treatment of enterobacter meningitis Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. with ciprofloxacin. Clin Infect Dis 1998; 26: 206–7. 108. Lefebvre HP, Schneider M, Dupouy V, et al. Effect of experimental renal 133. Haines GR, Brown MP, Gronwall RR, et al. Pharmacokinetics of orbifloxacin impairment on disposition of marbofloxacin and its metabolites in the dog. J and its concentration in body fluids and in endometrial tissues of mares. Can Vet Pharmacol Ther 1998 Dec; 21(6): 453–61. J Vet Res 2001 Jul; 65(3): 181–7. 109. Dicural Tablets freedom of information summary. NADA 141–096. 134. Abadia AR, Aramayona JJ, Munoz MJ, et al. Ciprofloxacin pharmacokinetics Approval date: November 20, 1997. Sponsor: Fort Dodge Animal Health. in dogs following oral administration. J Vet Med A 1995; 42: 505–11. Downloaded from www.fda.gov/cvm on 6/7/02. 135. Haines GR, Brown MP, Gronwall RR, et al. Serum concentrations and 110. Riddle C, Lemons CL, Papich MG, et al. Evaluation of ciprofloxacin as a pharmacokinetics of enrofloxacin after intravenous and intragastric admin- representative of veterinary fluoroquinolones in susceptibility testing. J Clin istration to mares. Can J Vet Res 2000; 64: 171–7. Microbiol 2000; 38(4): 1636–7. 136. Bertone AL, Tremaine WH, Macoris DG, et al. Effect of long-term admin- 111. Matsumoto S, Takahashi M, Kitadai N, et al. A study of metabolites isolated istration of an injectable enrofloxacin solution on physical and musculo- from the urine samples of cats and dogs administered orbifloxacin. J Vet Med skeletal variables in adult horses. J Am Vet Med Assoc 2000; 217(10): Sci 1998; 60(11): 1259–61. 1514–21.

137. Agalar C, Usubutun S, Turkyilmaz R. Ciprofloxacin and rifampicin versus 144. Dowling PM, Wilson RC, Tyler JW, et al. Pharmacokinetics of ciprofloxacin doxycycline and rifampicin in the treatment of brucellosis. Eur J Clin in ponies. J Vet Pharmacol Ther 1995, 18(1): 7–12. Microbiol Infect Dis. 1999; 18: 535–8. 145. Manufacturer comment, Rec 6/26/02. 138. Neer TM, Eddlestone SM, Gaunt SD, et al. Efficacy of enrofloxacin for the 146. Kay-Mugford PA, Ramsey DT, Dubielzig RR, et al. Ocular effects of orally treatment of experimentally induced ehrlichia canis infection. J Vet Intern administered orbifloxacin in cats. Proceedings 32nd Annual Meeting Med 1999; 13: 501–4. American College of Veterinary Ophthalmology 2001. p. 56. 139. Nicoletti P. Further studies on the use of antibiotics in canine brucellosis. The 147. National Committee for Clinical Laboratory Standards documents M31-A2 compendium. Small animal. 1991 June; 13(6): 944–7. and M37-A2. May 2002. 140. Corbel MJ. Brucellosis: an overview. Emerging Infect Dis 1997 April-June; 148. Dowers KL, Olver C, Radecki SV, et al. Use of enrofloxacin for treatment of 3(2): 213–21. large-form Haemobartonella felis in experimentally infected cats. J Am Vet 141. Mycobacteriosis. In: Ettinger SJ, Feldman EC, editors. Textbook of Veterinary Med Assoc 2002 Jul 15; 221(2): 250–3. Internal Medicine, 5th ed. Philadelphia: W.B. Saunders, 2000. p. 393–4. 149. Neer TM, Breitschwerdt EB, Greene RT, et al. Consensus statement on 142. Malik R, Hunt GB, Goldsmid SE, et al. Diagnosis and treatment of ehrlichial disease of small animals from the Infectious Disease Study Group of pyogranulomatous panniculitis due to Mycobacterium smegmatis in cats. the ACVIM. J Vet Intern Med 2002; 16: 309–15. J Small Anim Pract 1994; 35: 524–30. 143. Hannan PC, Windsor GD, de Jong A, et al. Comparative susceptibilities of various animal-pathogenic mycoplasmas to fluoroquinolones. Antimicrob Agents Chemother 1997 Sep; 41(9): 2037–40.

LINCOSAMIDES Veterinary—Systemic This monograph includes information on the following: Clindamycin; ACCEPTED Lincomycin. Dysentery, swine (treatment)—Pigs: Lincomycin hydrochloride for medicated feed and soluble powder are indicated in the treatment and Some commonly used brand names are: control of swine dysentery caused by susceptible organisms.{R-21; 28; For veterinary-labeled products— 38; 41; 63} AmTech Clindamycin Hydrochloride Lincomix 50 Feed Medication Enteritis, necrotic (treatment)—Chickens: Lincomycin hydrochloride for Capsules [Clindamycin] [Lincomycin] medicated feed1 and soluble powder are indicated in the control of AmTech Clindamycin Hydrochloride Lincomix Injectable Oral Liquid [Clindamycin] [Lincomycin] necrotic enteritis in chickens caused by susceptible organisms, such as Antirobe [Clindamycin] Lincomix Injectable Solution [Lincomycin] Clostridium perfringens.{R-22; 28; 38; 41; 42; 56} Antirobe Aquadrops [Clindamycin] Lincomix 44 Premix [Lincomycin] Growth promotion and feed efficiency, increased—Chickens and pigs1: Clincaps [Clindamycin] Lincomix 110 Premix [Lincomycin] ClindaCure [Clindamycin] Lincomix Soluble Powder [Lincomycin] Lincomycin hydrochloride for medicated feed is indicated for increased Clinda-Guard [Clindamycin] Lincomycin 44 Premix [Lincomycin] weight gain in growing-finishing pigs and for increased weight gain Clindrops [Clindamycin] Lincomycin 44G Premix [Lincomycin] and feed efficiency in broiler chickens.{R-38; 63} Lincocin [Lincomycin] Lincomycin 110 Premix [Lincomycin] Joint infections (treatment)—Pigs: Lincomycin injection is indicated in Lincocin Aquadrops [Lincomycin] Lincomycin 110G Premix [Lincomycin] Lincocin Injectable [Lincomycin] Lincomycin Soluble [Lincomycin] the treatment of infectious arthritis caused by susceptible organisms, Lincocin Sterile Solution Moorman’s LN 10 including susceptible Staphylococcus species, Streptococcus species, [Lincomycin] [Lincomycin] Erysipelothrix rhusiopathiae, and Mycoplasma species.{R-4; 5} Lincomix 20 Feed Medication nvClindamycin Capsules 1 [Lincomycin] [Clindamycin] Metritis (treatment) —Dogs: Lincomycin injection, syrup, and tablets are indicated in the treatment of metritis caused by susceptible organ- {R-3} Note: For a listing of dosage forms and brand names by country isms. availability, see the Dosage Forms section(s). Osteomyelitis (treatment)—Dogs: Clindamycin capsules and oral solution are indicated in the treatment of osteomyelitis caused by susceptible CATEGORY: organisms,{R-1; 2} such as Staphylococcus aureus.{R-35; 36; 62} Antibacterial (systemic). Periodontal infections (treatment)— Cats: Clindamycin oral solution is indicated in the treatment of {R-2; 30; 62} INDICATIONS periodontal infections caused by susceptible bacteria . Note: Bracketed information in the Indications section refers to uses that Dogs: Clindamycin capsules and oral solution are indicated in either are not included in U.S. product labeling or are for products not the treatment of periodontal infections caused by susceptible {R-1; 2; 62} commercially available in the U.S. bacteria. Porcine proliferative enteropathies (treatment)1—Pigs: Lincomycin hydrochloride for medicated feed is indicated in the control of porcine prolif- GENERAL CONSIDERATIONS erative enteropathies (ileitis) caused by Lawsonia intracellularis{R-38}. The lincosamides have activity against many gram-positive bacteria and Pneumonia, bacterial (treatment)—Pigs: Lincomycin injection1 and many anaerobic bacteria, but are not effective against most gram- lincomycin hydrochloride for medicated feed are indicated in the negative organisms. treatment of pneumonia caused by susceptible Mycoplasma species.{R-4; Lincomycin has been shown to have efficacy against Staphylococcus 5; 63} species, Streptococcus species (except Streptococcus faecalis), Erysipelo- Respiratory tract infections (treatment)1— {R-3; 4} thrix insidiosa, Leptospira pomona, and Mycoplasma species. The Cats: Lincomycin injection, syrup, and tablets are indicated in the activity of lincomycin against obligate anaerobes is seldom addressed treatment of respiratory tract infections caused by susceptible in published literature. According to the National Committee for organisms.{R-3} Clinical Laboratory Standards in the United States, clindamycin is the Dogs: Lincomycin injection, syrup, and tablets are indicated in the class antibiotic for the lincosamide family and the clindamycin disk is treatment of respiratory tract infections caused by susceptible used in in vitro testing to assess susceptibility to both clindamycin and organisms.{R-3} {R-31} lincomycin . Therefore, it is presumed that most anaerobes Skin infections (treatment)1—Dogs: Lincomycin injection, syrup, and susceptible to clindamycin would likewise be susceptible to lincomycin, tablets are indicated and [clindamycin]{R-20} is effective in the provided compensations for potency and kinetic disposition are treatment of skin infections, such as pustular dermatitis, caused by {R-39} made . susceptible organisms.{R-3} To assure efficacy in the treatment of skin Clindamycin has a spectrum of activity that includes Staphylococcus infections, underlying primary disorders, such as allergic inhalant species, Streptococcus species (except Streptococcus faecalis), and Myco- dermatitis, should be identified and controlled{R-1; 30}. plasma species, as well as anaerobic organisms, such as Bacteroides Soft tissue infections (treatment)— species, Fusobacterium species, Clostridium perfringens (but not neces- Cats: Clindamycin oral solution and lincomycin injection1, syrup1, and sarily other clostridia), Actinomyces species, Peptostreptococcus species, tablets1 are indicated in the treatment of soft tissue infections, {R-1} and many Propionibacterium species. including abscesses, caused by susceptible organisms.{R-2; 3; 30; 62}

Dogs: Clindamycin capsules and oral solution, and lincomycin injec- Canada— tion1, syrup1, and tablets1 are indicated in the treatment of soft tissue Withdrawal times have been established for the use of lincomycin in infections, including abscesses and infected wounds, caused by chickens and pigs (see the Dosage Forms section). Lincomycin is not susceptible organisms.{R-1–3; 62} labeled for use in chickens producing eggs for human consumption.{R-6; 41} ACCEPTANCE NOT ESTABLISHED Metritis (treatment)—Dogs: There are insufficient data to confirm CHEMISTRY specifically the efficacy of [clindamycin]1 in the treatment of metritis Source: {R-27} in dogs; however, because lincomycin is indicated for this use, Clindamycin hydrochloride—7(S)-Chloro derivative of lincomycin. clindamycin can be expected to be at least equally effective{R-15}. Lincomycin hydrochloride—Produced by the growth of a member of the Osteomyelitis (treatment)—[Cats]1: There are insufficient data to confirm lincolnensis group of Streptomyces lincolnensis (family Streptomyceta- {R-3} specifically the efficacy of clindamycin in the treatment of osteomyelitis ceae). in cats; however, the safety and predicted antimicrobial efficacy are Chemical name: l d supported by research.{R-24; 53; 54; 57} Clindamycin hydrochloride— -threo-alpha- -galacto-octopyranoside, Respiratory tract infections (treatment)—Cats and dogs: There are methyl 7-chloro-6,7,8-trideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl)- {r-25} insufficient data to confirm specifically the efficacy of [clindamycin]1 carbonyl]amino]-1-thio-, (2s-trans)-, monohydrochloride. d d in the treatment of respiratory infections in cats and dogs; however, Lincomycin hydrochloride— -erythro-alpha- -galacto-octopyranoside, because lincomycin is indicated for this use, clindamycin can be methyl 6,8-dideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl)carbonyl]- {r-25} expected to be at least equally effective{R-15}. amino]-1-thio-, monohydrochloride, monohydrate, (2s-trans)-. [Abscesses, laryngeal (treatment)]1—Cattle: There are insufficient data to Molecular formula: {R-25} confirm the efficacy and safety of lincomycin injection in the treatment Clindamycin hydrochloride—C18H33ClN2O5S Æ HCl. {R-25} of laryngeal abscesses in cattle. Reports of three cases showed a good Lincomycin hydrochloride—C18H34N2O6SÆHCl Æ H2O. response in laryngeal abscesses treated{R-44}. Molecular weight: {R-25} [Arthritis, septic (treatment)]1—Cattle and sheep: There are insufficient Clindamycin hydrochloride—461.44. {R-25} data to confirm the efficacy and safety of lincomycin injection in the Lincomycin hydrochloride—461.01. treatment of septic arthritis in cattle and sheep. Case reports of a dozen Description: cases show a resolution of clinical signs in approximately one-half of Clindamycin Hydrochloride USP—White or practically white, crystalline refractory joint infections treated (mixed infections of streptococci, powder. Is odorless or has a faint mercaptan-like odor. Is stable in the staphylococci, and Corynebacterium pyogenes).{R-44} presence of air and light. Its solutions are acidic and are dextrorota- {R-26} [Mastitis (treatment)]1—Cattle: There are insufficient data to confirm the tory. efficacy and safety of parenteral lincomycin in the treatment of mastitis Lincomycin Hydrochloride USP—White or practically white, crystalline in cattle; however, there is evidence of distribution into milk in powder. Is odorless or has a faint odor. Is stable in the presence of air {R-26} ruminants in concentrations sufficient to treat susceptible infections and light. Its solutions are acid and are dextrorotatory. that are refractory to other antimicrobials.{R-14; 58} Although no Lincomycin Hydrochloride Injection USP—Clear, colorless to slightly {R-26} studies have been performed to demonstrate the efficacy of lincomycin yellow solution, having a slight odor. against gram-positive mastitis pathogens such as Staphylococcus or pKa: {R-14} Corynebacterium, given lincomycin’s distribution and the susceptibility Clindamycin—7.7. {R-14} patterns of these organisms, lincomycin therapy may be a legitimate Lincomycin—7.6. choice when other conventional treatments are deemed unlikely to be Solubility: effective. Clindamycin Hydrochloride USP—Freely soluble in water, in dimethyl- [Toxoplasmosis (treatment)]1—Cats: There are insufficient data to formamide, and in methanol; soluble in alcohol; practically insoluble {R-26} establish the efficacy of clindamycin in the treatment of Toxoplasma in acetone. gondii infection in cats; however, it is considered to have fewer side Lincomycin Hydrochloride USP—Freely soluble in water; soluble in {R-26} effects and perhaps to be more effective in treating some aspects of the dimethylformamide; very slightly soluble in acetone. disease than is pyrimethamine{R-17–19; 34; 59}. Clindamycin may not effectively clear organisms from areas such as the central nervous system in chronically infected animals{R-18} and, in some cases, may PHARMACOLOGY/PHARMACOKINETICS be ineffective in resolving clinical signs involving the eye.{R-17} Mechanism of action/effect: The lincosamides inhibit protein 1Not included in Canadian product labeling or product not commercially synthesis in susceptible bacteria by binding to the 50 S ribosomal available in Canada. subunits of bacterial ribosomes and preventing peptide bond formation.{R-43} The lincosamides are usually considered bacteriostatic{R-43}; REGULATORY CONSIDERATIONS however, when clindamycin is present at sufficient concentra- U.S.— tions, it may act as a bactericidal antibiotic against sensitive organ- Withdrawal times have been established for the use of lincomycin in isms.{R-43} chickens and pigs (see the Dosage Forms section). Lincomycin is not labeled for use in chickens producing eggs for human consump- Other actions/effects: Clindamycin may interfere with the attachment tion.{R-4; 38; 42} and entry of Toxoplasma gondii tachyzoites into host cells.{R-33}

Absorption: Oral absorption of the lincosamides is rapid, but orally Clindamycin phosphate—Dogs: Intramuscular—1 hour (dose of 11 mg/ administered lincomycin is less well absorbed than clindamycin. kg).{R-16} Clindamycin—Oral absorption of clindamycin is high{R-1}and is Lincomycin hydrochloride— unaffected by food. Dogs: Lincomycin—Oral absorption of lincomycin may be greatly reduced by Intramuscular—10 minutes to 2 hours (dose of 22 mg/kg).{R-3} the presence of food in the stomach.{R-48} Oral—2 to 4 hours (dose of 22 mg/kg).{R-3} Oral absorption: Sheep: Intramuscular—1 hour (dose of 20 mg/kg).{R-14} Pigs—20 to 50%.{R-49} Rats—45 to 60%.{R-49} Serum concentrations: Intramuscular absorption: Lincomycin hydrochloride is rapidly ab- Peak serum concentration— sorbed after intramuscular administration.{R-3} Clindamycin hydrochloride: Sheep—Intramuscular: 13.8 mcg/mL (single dose of 20 mg/kg).{R-14} Distribution: Clindamycin and lincomycin are widely distributed into Clindamycin phosphate: Dogs—Intramuscular: 5.3 mcg/mL (dose of most tissues, including respiratory tissue, soft tissue, bones, and 11 mg/kg){R-16}. joints{R-13; 23; 24}. The lincosamides are weak bases (commercial Lincomycin: Sheep—Intramuscular: 12.6 mcg/mL (dose of 20 mg/ preparations are acidic) and are very lipid soluble at physiologic pH kg).{R-14} (7.4). Tissue concentrations may be higher than serum concentra- Serum concentration after multiple dosing—Clindamycin hydrochloride tions.{R-48} Small amounts are distributed into pancreatic and prostatic (sample 12 hours after the last dose of an every-twelve-hour oral dose secretions.{R-48} There is evidence that clindamycin hydrochloride for 10 days): Cats—{R-53} accumulates in polymorphonuclear granulocytes.{R-20} The lincosa- 3.5 mcg/mL (dose of 5.5 mg/kg). mides do not penetrate cerebrospinal fluid (CSF) well;{R-24} however, in 5.4 mcg/mL (dose of 11 mg/kg). healthy cats, concentrations of clindamycin in brain tissue after 10 6.5 mcg/mL (dose of 22 mg/kg). days of therapy were 10 to 20% of serum concentration and were consistently higher than CSF concentrations.{R-24} Duration of action: Volume of distribution (area)—Intravenous administration: Clindamycin—Cats and dogs:{R-15} Clindamycin phosphate—Dogs: 1.4 L per kg (L/kg).{R-16} 12 hours, with an oral dose of 11 mg/kg. Lincomycin—Calves: 24 hours, with an oral dose of 22 mg/kg. 6 weeks of age—1 to 1.2 L/kg (healthy calves or calves with induced Lincomycin—Dogs: Oral—For gram-positive organisms: 6 to 8 hours (22 Pasteurella haemolytica pneumonia).{R-46; 47} mg/kg dose).{R-3} 9 months of age—1.3 L/kg.{R-47} Note: Efficacy studies based on a 22 mg/kg dose every 12 hours for 3 weeks in dogs show that duration of action for lincomycin is sufficient Protein binding: for it to be effective when administered every twelve hours{R-20}. Clindamycin—Sheep: Moderate (40 to 50%).{R-14; 51} Lincomycin— Elimination: Cows—Low to moderate (26 to 46%).{R-52} Parent drug and metabolites are primarily excreted in the urine and the Sheep—Low (30 to 40%).{R-14; 51} bile.{R-1; 3; 24; 48; 49} Small amounts are excreted in intestinal contents Note: Human protein binding of lincomycin decreases with increased and pancreatic and prostatic fluids.{R-48} plasma concentrations; the range of protein binding varies from low When lincomycin is administered orally to dogs, 77% of the dose is to high. excreted in the feces and 14% of the dose is excreted in the urine. When administered intramuscularly, 38% of the dose is excreted in the Biotransformation: feces and 49% is excreted in the urine.{R-3} Clindamycin—Active metabolites of clindamycin measured in urine Less clindamycin than lincomycin is excreted in the urine.{R-50} along with parent compound include N-demethylclindamycin and Clearance—Intravenous administration: clindamycin sulfoxide.{R-1} Clindamycin phosphate—Dogs: 5.3 mL per minute per kg (mL/min/ Lincomycin—The percentage of administered lincosamide metabolized kg).{R-16} by the liver is unknown.{R-49} Lincomycin—Calves: 6 weeks of age—3.9 to 8.1 mL/min/kg.{R-46} Half-life: Elimination—Intravenous administration: 9 months of age—4.4 mL/min/kg.{R-46} Clindamycin phosphate—Dogs: 3.2 hours.{R-16} Lincomycin: PRECAUTIONS TO CONSIDER Calves, newborn to 2 weeks of age—3 hours.{R-47} Calves, 4 weeks to 9 months of age—2 to 2.5 hours.{R-46; 47} CROSS-SENSITIVITY AND RELATED PROBLEMS Animals sensitive to clindamycin may be sensitive to lincomycin and the Time to peak concentration: reverse may also be true. Clindamycin hydrochloride— Dogs: Oral—1.3 hours (single dose of 5.5 to 11 mg per kg of body SPECIES SENSITIVITY {R-1} weight [mg/kg]). Chinchillas, guinea pigs, hamsters, horses, ponies, and rabbits:{R-7–9; 11} The {R-14} Sheep: Intramuscular—1 hour (dose of 20 mg/kg). use of oral clindamycin or lincomycin is generally contraindicated in

these species because of the risk of altering the gastrointestinal » Neuromuscular blocking agents microflora and causing serious or fatal enterocolitis and diarrhea. (concurrent use of these medications with clindamycin or lincomycin Overgrowth of organisms such as Clostridium or Salmonella species has may enhance the neuromuscular blockade, resulting in respiratory been suspected as the cause in many species. Cecal Escherichia coli, but depression or paralysis;{R-1; 48} caution is also recommended during not Clostridium species, have been cultured from rabbits showing surgery or the postoperative period; treatment with cholinesterase adverse effects after lincomycin exposure.{R-9} Contamination of feed agents or calcium salts may help reverse the blockade{R-48}) with lincomycin at or below feed additive concentrations used for pigs has caused severe or fatal diarrhea in rabbits, ponies, and HUMAN DRUG INTERACTIONS{R-61} horses.{R-7–9} In addition to the above drug interactions reported in animals, the Ruminants: Ruminants exposed to oral lincomycin have also been following drug interactions have been reported in humans, and are reported to have side effects such as anorexia, ketosis, and sometimes included in the human monographs Clindamycin (Systemic) and severe diarrhea,{R-10; 12; 55} possibly caused by overgrowth of Lincomycin (Systemic) in USP DI Volume I; these drug interactions nonsusceptible bacteria; however, case reports and research studies are intended for informational purposes only and may or may not be using parenteral lincomycin have reported that only a small percent- applicable to the use of clindamycin and lincomycin in the treatment of age of treated animals developed diarrhea and/or decreased milk animals: production.{R-44–47} Antidiarrheals, adsorbent Feeds contaminated with 3 to 24 parts per million (ppm) of lincomycin (concurrent use of kaolin- or attapulgite-containing antidiarrheals have caused ketosis and diarrhea in dairy cows{R-12}. After treatment with oral lincomycin may significantly decrease absorption of oral with oral lincomycin for Campylobacter, two thirds of a range flock of lincomycin; concurrent use with oral clindamycin may delay sheep died; however, the flock had a history of Salmonella infections absorption; concurrent use should be avoided or patients should be and grazed in an area with some oxalate-containing range plants, both advised to take adsorbent antidiarrheals not less than 2 hours before of which were believed to play a role in the losses.{R-10} or 3 to 4 hours after oral lincosamides) Antidiarrheals, antiperistaltic PREGNANCY/REPRODUCTION (antiperistaltic agents, such as opiates, difenoxin, diphenoxylate, or The safety of clindamycin in pregnant or breeding animals has not been loperamide, may prolong or worsen pseudomembranous colitis by established.{R-1; 2; 13} delaying toxin elimination) When lincomycin was given to pregnant dogs at 50 mg per kg of body Antimyasthenics weight (mg/kg) per day, no evidence of teratogenic effects on the (concurrent use of medications with neuromuscular blocking action embryos was seen.{R-3} Also, 75 mg of lincomycin per kg a day may antagonize the effect of antimyasthenics on skeletal muscle; administered to breeding male and female rats during a breeding cycle temporary dosage adjustments of antimyasthenics may be necessary had no observed effect on breeding or teratogenic effects on to control symptoms of myasthenia gravis during and following offspring.{R-3} concurrent use) Chloramphenicol or LACTATION Erythromycins (may displace clindamycin or lincomycin from or prevent their Clindamycin and lincomycin are distributed into milk{R-14} in therapeu- binding to 50 S subunits of bacterial ribosomes, thus antagonizing tic concentrations.{R-40} With constant serum lincomycin concentra- the effects of the lincosamides; concurrent use is not recommended) tions, milk concentrations range from 2.5 to 6.2 times the serum Opioid (narcotic) analgesics concentration, depending on the pH of the milk.{R-14} (respiratory depressant effects of drugs with neuromuscular blocking activity may be additive to central respiratory depressant effects of PEDIATRICS opioid analgesics, possibly leading to increased or prolonged respi- No evidence of side effects was noted in newborn puppies and rats given ratory depression or paralysis [apnea]; caution and careful monitor- lincomycin at doses of 30 to 90 mg/kg a day.{R-3} ing of the patient are recommended)

DRUG INTERACTIONS AND/OR RELATED PROBLEMS LABORATORY VALUE ALTERATIONS The following drug interactions and/or related problems have been The following have been selected on the basis of their potential clinical selected on the basis of their potential clinical significance (possible significance (possible effect in parentheses where appropriate)—not mechanism in parentheses where appropriate)—not necessarily inclu- necessarily inclusive (» = major clinical significance): sive (» = major clinical significance): Note: No significant laboratory value alterations have been reported in Note: Combinations containing any of the following medications, animals. Human laboratory value alterations have been reported and depending on the amount present, may also interact with this are included in this monograph. medication. {R-61} » Anesthetics, hydrocarbon inhalation, such as: HUMAN LABORATORY VALUE ALTERATIONS Enflurane The following laboratory value alterations have been reported in Halothane humans, and are included in the human monographs Clindamycin Isoflurane (Systemic) and Lincomycin (Systemic) in USP DI Volume I; these Methoxyflurane, or laboratory value alterations are intended for informational purposes

only and may or may not be applicable to the use of clindamycin and Cats and dogs lincomycin in the treatment of animals: Anorexia; diarrhea; vomiting{R-1; 3; 54} With physiology/laboratory test values Note: Anorexia, diarrhea, and vomiting in cats and dogs are believed to Alanine aminotransferase (ALT [SGPT]), serum, and result from local irritation because side effects have not been seen Alkaline phosphatase, serum, and with parenteral treatment. Side effects are more likely with higher Aspartate aminotransferase (AST [SGOT]), serum doses.{R-54} (values may be increased) Ruminants With lincomycin— Anorexia; decreased milk production; diarrhea; ketosis MEDICAL CONSIDERATIONS/CONTRAINDICATIONS Note: Anorexia, decreased milk production, ketosis, and severe diarrhea The medical considerations/contraindications included have been have been reported to be most likely in ruminants administered selected on the basis of their potential clinical significance (reasons lincomycin orally.{R-10; 12} However, some animals may develop given in parentheses where appropriate)—not necessarily inclusive (» adverse effects with parenterally administered lincomycin.{R-45} = major clinical significance). Incidence unknown Risk-benefit should be considered when the following medical All species problems exist: Hypersensitivity reactions{R-1; 3} » Hepatic function impairment, severe (because clindamycin and lincomycin are metabolized by the liver{R-1; 49}, it is possible that severe hepatic function impairment THOSE INDICATING NEED FOR MEDICAL ATTENTION could prolong the half-lives of these medications; adjustments in ONLY IF THEY CONTINUE OR ARE BOTHERSOME dosage might be required{R-37}) Incidence more frequent » Hypersensitivity to clindamycin or lincomycin{R-1; 3} Cats (sensitivity or cross-sensitivity may occur) Lip smacking—with clindamycin oral solution{R-53}; saliva- » Renal function impairment, severe tion—with clindamycin oral solution{R-53} (lincomycin is eliminated by the kidneys of dogs to a greater degree Incidence less frequent or rare than is clindamycin{R-50}; very severe renal impairment may require Pigs dosage adjustments) Anal swelling{R-41; 42}; diarrhea{R-41; 42}—transient; irritable behavior{R-41; 42}; skin reddening{R-41; 42} PATIENT MONITORING Note: Anal swelling, diarrhea, irritable behavior, and skin reddening are generally self-limiting within 5 to 8 days. The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance): HUMAN SIDE/ADVERSE EFFECTS{R-61} Culture and susceptibility, in vitro, and In addition to the above side/adverse effects reported in animals, the Minimum inhibitory concentration (MIC) following side/adverse effects have been reported in humans, and are (in vitro cultures and MIC tests should be done on samples collected included in the human monographs Clindamycin (Systemic) and prior to lincosamide administration to determine pathogen suscep- Lincomycin (Systemic) in USP DI Volume I; these side/adverse effects tibility) are intended for informational purposes only and may or may not be Note: The clindamycin disk is used for in vitro susceptibility testing to applicable to the use of clindamycin and lincomycin in the treatment of assess susceptibility to both clindamycin and lincomycin{R-31}. animals: Incidence more frequent SIDE/ADVERSE EFFECTS Gastrointestinal disturbances; pseudomembranous colitis Note: The pseudomembranous colitis reported in people as an adverse Incidence less frequent reaction to lincosamides as well as the colitis and diarrhea side effects Fungal overgrowth; hypersensitivity; neutropenia; thrombocy- reported in chinchillas, guinea pigs, horses, rabbits, and ruminants are topenia considered to be caused by overgrowth of resistant organisms. Indicating possible pseudomembranous colitis and the need for medical Resistant Clostridium species are suspected, but other organisms or attention if they occur after medication is discontinued even other mechanisms may also be involved.{R-8–11; 48} Abdominal or stomach cramps and pain, severe; abdominal The following side/adverse effects have been selected on the basis of their tenderness; diarrhea, watery and severe, which may also be potential clinical significance (possible signs and, for humans, symp- bloody; fever toms in parentheses where appropriate)—not necessarily inclusive:

THOSE INDICATING NEED FOR MEDICAL ATTENTION OVERDOSE Incidence more frequent For information in cases of overdose or unintentional ingestion, contact Chinchillas, guinea pigs, hamsters, horses, ponies, and rabbits{R-7–9; 11} the American Society for the Prevention of Cruelty to Animals Enterocolitis (anorexia; collapse; dehydration; diarrhea, watery and (ASPCA) National Animal Poison Control Center (888-426-4435 sometimes hemorrhagic) or 900-443-0000; a fee may be required for consultation) and/or the Incidence less frequent drug manufacturer.

CLIENT CONSULTATION Apparatus 1 at 100 rpm), Uniformity of dosage units, and Water (not {R-26} Medication should be administered for the full length of time prescribed. more than 7.0%). Any signs of anorexia, diarrhea, or vomiting should be reported to the veterinarian. CLINDAMYCIN HYDROCHLORIDE ORAL SOLUTION USP Usual dose: Osteomyelitis; or 1 CLINDAMYCIN [Skin infections] —Dogs: See Clindamycin Hydrochloride Capsules USP. Periodontal infections and soft tissue infections— SUMMARY OF DIFFERENCES Cats: Oral, 11 to 33 mg (base) per kg of body weight every twenty- Indications: Has wider spectrum of activity than does lincomycin. four hours{R-1}. Indicated in the treatment of osteomyelitis, periodontal infections, and Dogs: Oral, 5.5 to 33 mg (base) per kg of body weight every twelve soft tissue infections. Used in the treatment of skin infections. hours{R-1}. Pharmacology/pharmacokinetics: Highly absorbed after oral administra- Note: Cats—Based on dosing studies, the following dosages have been tion. Absorption is unaffected by the presence of food in the stomach. used in cats for treatment of [osteomyelitis]1 and [skin infections]1: Staphylococcal infections—Oral, 5.5 mg (base) per kg of body weight {R-53} ORAL DOSAGE FORMS every twelve hours. Note: Bracketed information in the Dosage Forms section refers to uses Anaerobic bacterial infections—Oral, 11 mg (base) per kg of body that either are not included in U.S. product labeling or are for products weight every twelve hours or 22 mg per kg of body weight every {R-53} not commercially available in the U.S. twenty-four hours. The dosing and strengths of the dosage forms available are expressed Based on clinical efﬁcacy and pharmacokinetic studies, the following 1 in terms of the clindamycin base (not the hydrochloride salt). dose has been used in cats for the treatment of [toxoplasmosis] —Oral, 12.5 to 25 mg (base) per kg of body weight every twelve hours for two {R-17; 18; 53; 54; 57; 59} CLINDAMYCIN HYDROCHLORIDE CAPSULES USP to four weeks. Usual dose: Strength(s) usually available: Osteomyelitis—Dogs: Oral, 11 to 33 mg (base) per kg of body weight U.S.{R-6}— every twelve hours{R-1}. Veterinary-labeled product(s): Periodontal infections and soft tissue infections—Dogs: Oral, 5.5 to 33 25 mg (base) per mL (Rx) [AmTech Clindamycin Hydrochloride Oral mg (base) per kg of body weight every twelve hours{R-1}. Liquid; Antirobe Aquadrops; ClindaCure; Clinda-Guard; Clindrops; [Skin infections]1—Dogs: Oral, 11 mg (base) per kg of body weight generic]. every twenty-four hours.{R-20} Canada{R-6}— Note: The above dose for the treatment of skin infections in dogs is Veterinary-labeled product(s): based upon a clinical comparative efﬁcacy study of clindamycin 25 mg (base) per mL (Rx) [Antirobe Aquadrops]. and lincomycin{R-20}.

Packaging and storage: Store below 40 C (104 F), preferably Strength(s) usually available: ° ° between 15 and 30 C (59 and 86 F), unless otherwise specified by U.S.{R-1; 6}— ° ° manufacturer. Protect from freezing. Veterinary-labeled product(s): 25 mg (base) (Rx) [AmTech Clindamycin Hydrochloride Capsules; USP requirements: Preserve in tight containers. Label oral solution to Antirobe; Clincaps; generic]. indicate that it is intended for veterinary use only. Contains the 75 mg (base) (Rx) [AmTech Clindamycin Hydrochloride Capsules; equivalent of the labeled amounts, within ±10%. Meets the require- Antirobe; Clincaps; generic]. ments for Identification, Uniformity of dosage units, Deliverable vol- 150 mg (base) (Rx) [AmTech Clindamycin Hydrochloride Capsules; ume, and pH (3.0–5.5){R-26}. Antirobe; Clincaps; generic]. 300 mg (base) (Rx) [Antirobe]. 1Not included in Canadian product labeling or product not commercially {R-2; 6} Canada — available in Canada. Veterinary-labeled product(s): 25 mg (base) (OTC) [Antirobe; nvClindamycin Capsules]. 75 mg (base) (OTC) [Antirobe; nvClindamycin Capsules]. LINCOMYCIN 150 mg (base) (OTC) [Antirobe; nvClindamycin Capsules]. SUMMARY OF DIFFERENCES Packaging and storage: Store below 40 °C (104 °F), preferably be- Indications: Indicated in the treatment of swine dysentery; growth tween 15 and 30 °C (59 and 86 °F), unless otherwise specified by promotion and feed efficiency in chickens and pigs; joint infections in manufacturer. Preserve in tight containers. pigs; metritis in dogs; pneumonia in pigs; respiratory tract infections in cats and dogs; skin infections in dogs; and soft tissue infections in cats USP requirements: Preserve in tight containers. Contain an amount of and dogs. Indicated in the control of necrotic enteritis in chickens. clindamycin hydrochloride equivalent to the labeled amount of clin- Pharmacology/pharmacokinetics: Oral lincomycin is less well absorbed damycin, within –10% to +20%. Meet the requirements for Identifi- than intramuscular lincomycin; dosages are adjusted to compensate. cation, Dissolution (80% in 30 minutes in phosphate buffer [pH 6.8] in Elimination of lincomycin is affected to a greater extent by severe renal

function impairment than is clindamycin. Absorption is reduced by the Withdrawal time presence of food in the stomach. Species Meat (days)

ORAL DOSAGE FORMS Chickens 0 Note: The dosing and strengths of the dosage forms available are Pigs 0 expressed in terms of lincomycin base (not the hydrochloride salt). When mixed at 110 or 220 grams (base) of lincomycin per metric ton of feed for pigs: LINCOMYCIN HYDROCHLORIDE FOR MEDICATED FEED

Usual dose: Withdrawal time Growth promotion— Chickens: Oral, 2 to 4 grams (base) per ton of feed, fed as the only Species Meat (days) {R-38} ration. Pigs 2 Pigs1: Oral, 20 grams (base) per ton of feed, fed as the only ration.{R-38} Mycoplasma pneumonia—Pigs: Oral, 200 grams (base) per ton of feed, Packaging and storage: Store below 40 °C (104 °F), preferably fed as the only ration for twenty-one days.{R-38} between 15 and 30 °C (59 and 86 °F), unless otherwise speciﬁed by {R-42} Necrotic enteritis1—Chickens: Oral, 2 grams (base) per ton of feed, fed manufacturer. Store in a dry place. as the only ration.{R-48} Porcine proliferative enteropathies (control)1—Pigs: Oral, 100 grams Preparation of dosage form: Premix should be mixed into the com- (base) per ton of feed, fed as the only ration for twenty-one days or plete feed following manufacturer’s directions to produce 2, 3, 4, 20, until signs of disease disappear. A dose of 40 grams (base) per ton of 40, 100, or 200 grams of lincomycin (base) per ton of feed. feed, fed as the only ration, may follow the above dose or be used in place of the 100-gram dose in animals that have not yet had Additional information: {R-38; 42} symptoms{R-38}. Not for use in breeding swine or laying chickens. Swine dysentery—Pigs: In preparing feeds, appropriate cleanout procedures should be followed to {R-42} Control—Oral, 40 grams (base) per ton of feed, fed as the only prevent cross-contamination of other feeds. ration.{R-38; 42} {R-26} Treatment—Oral, 100 grams (base) per ton of feed (approximately USP requirements: Not in USP . 4.4 to 8.8 mg [base] per kg of body weight), fed as the only ration for twenty-one days or until signs of disease disappear.{R-38; 42} LINCOMYCIN HYDROCHLORIDE SOLUBLE POWDER USP Strength(s) usually available: Usual dose: U.S.{R-6}— Necrotic enteritis—Chickens: Oral, 64 mg (base) per gallon of water, {R-22; Veterinary-labeled product(s): administered as the only source of drinking water for seven days. 28; 41; 56} 10 grams (base) per pound of premix (OTC) [Moorman’s LN 10]. 20 grams (base) per pound of premix (OTC) [Lincomix 20 Feed Swine dysentery—Pigs: Oral, 250 mg (base) per gallon of water Medication]. (approximately 8.4 mg [base] per kg of body weight) a day, 50 grams (base) per pound of premix (OTC) [Lincomix 50 Feed administered as the only source of drinking water for ﬁve to ten {R-28; 41} Medication]. days . Canada{R-6}— Veterinary-labeled products: Strength(s) usually available: {R-6} 44 grams (base) per kg of premix (OTC) [Lincomix 44 Premix; U.S.— Lincomycin 44 Premix; Lincomycin 44G Premix]. Veterinary-labeled product(s): 110 grams (base) per kg of premix (OTC) [Lincomix 110 Premix; 400 mg (base) per gram of powder (OTC) [Lincomix Soluble Powder; Lincomycin 110 Premix; Lincomycin 110G Premix]. Lincosol Soluble Powder; generic]. Canada—{R-6} Withdrawal times: Veterinary-labeled product(s): {R-38; 42} U.S. — 400 mg (base) per gram of powder (OTC) [Lincomix Soluble Powder; generic]. Withdrawal time

Species Meat (days) Withdrawal times: U.S.—{R-41} Chickens 0 Pigs 0 or 6, depending on product Withdrawal time

Canada{R-63}— Species Meat (days) When mixed at 2.2 grams of lincomycin (base) per metric ton (1000 kg) Chickens 0 of feed for chickens and 44 grams (base) of lincomycin per metric ton Pigs 0 or 6, depending on product of feed for pigs:

Canada—{R-28} LINCOMYCIN HYDROCHLORIDE TABLETS When mixed at concentrations of 16 mg of lincomycin (base) per liter Usual dose: of water (61 mg per gallon) for chickens or 33 mg of lincomycin Metritis1;or (base) per liter of water (125 mg per gallon) for pigs: Skin infections1—Dogs: Oral, 22 mg (base) per kg of body weight every twelve hours or 15.4 mg (base) per kg of body weight every eight Withdrawal time hours.{R-3} 1 Species Meat (days) Respiratory tract infections —Cats and dogs: Oral, 22 mg (base) per kg of body weight every twelve hours or 15.4 mg (base) per kg of body Chickens 0 weight every eight hours{R-3}. Pigs 1 Soft tissue infections1—Cats and dogs: Oral, 22 mg (base) per kg of body weight every twelve hours or 15.4 mg (base) per kg of body Packaging and storage: Store below 40 °C (104 °F), preferably be- weight every eight hours.{R-3} tween 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Strength(s) usually available: U.S.—{R-3; 6} Preparation of dosage form: Powder should be mixed into the Veterinary-labeled product(s): drinking water following manufacturer’s directions to produce 61, 64, 100 mg (base) (Rx) [Lincocin]. 125, or 250 mg (base) per gallon. Fresh stock solutions should be 200 mg (base) (Rx) [Lincocin]. prepared on the day of use and unused medicated water discarded after 500 mg (base) (Rx) [Lincocin]. 2 days. Canada—{R-6} Veterinary-labeled product(s): USP requirements: Preserve in tight containers. Label it to indicate Not commercially available. that it is for veterinary use only. Contains an amount of Lincomycin Hydrochloride equivalent to the labeled amount of lincomycin, within Packaging and storage: Store below 40 °C (104 °F), preferably be- ±10%. Meets the requirements for Identification, Water, and Minimum tween 15 and 30 °C (59 and 86 °F), unless otherwise specified by {R-26} fill . manufacturer.

LINCOMYCIN HYDROCHLORIDE SYRUP USP USP requirements: Not in USP{R-26}. Usual dose: 1 Metritis ;or 1Not included in Canadian product labeling or product not commercially 1 Skin infections —Dogs: Oral, 22 mg (base) per kg of body weight every available in Canada. twelve hours or 15.4 mg (base) per kg of body weight every eight hours.{R-3} PARENTERAL DOSAGE FORMS Respiratory tract infections1—Cats and dogs: Oral, 22 mg (base) per kg Note: Bracketed information in the Dosage Forms section refers to uses of body weight every twelve hours or 15.4 mg (base) per kg of body that either are not included in U.S. product labeling or are for products weight every eight hours{R-3}. not commercially available in the U.S. Soft tissue infections1—Cats and dogs: Oral, 22 mg (base) per kg of The dosing and strengths of the dosage forms available are expressed body weight every twelve hours or 15.4 mg (base) per kg of body in terms of lincomycin base (not the hydrochloride salt). weight every eight hours.{R-3} LINCOMYCIN INJECTION USP Strength(s) usually available: Usual dose: U.S.{R-3; 6}— Joint infections; or Veterinary-labeled product(s): Mycoplasma pneumonia1—Pigs: Intramuscular, 11 mg (base) per kg of 50 mg (base) per mL (Rx) [Lincocin Aquadrops]. body weight every twenty-four hours for three to seven days.{R-4} Canada{R-6}— Metritis1;or Veterinary-labeled product(s): Skin infections1—Dogs: Intramuscular or intravenous, 22 mg (base) Not commercially available. per kg of body weight every twenty-four hours or 11 mg (base) per {R-3} Packaging and storage: Store between 15 and 30 °C (59 and 86 °F), kg of body weight every twelve hours. 1 unless otherwise specified by manufacturer.{R-33} Store in a tight Respiratory tract infections ;or 1 container. Soft tissue infections —Cats and dogs: Intramuscular or intravenous, 22 mg (base) per kg of body weight every twenty-four hours or 11 USP requirements: Preserve in tight containers. Contains an amount mg (base) per kg of body weight every twelve hours.{R-3} of Lincomycin Hydrochloride equivalent to the labeled amount of Note: For intravenous administration, the injection should be diluted lincomycin, within –10% to +20%, and one or more suitable colors, with 5% glucose or normal saline and administered as a drip flavors, preservatives, and sweeteners in water. Meets the require- infusion.{R-3} ments for Uniformity of dosage units (for syrup packaged in single-unit Note: [Cattle]1—Although the safety and efficacy have not been containers), Deliverable volume (for syrup packaged in multiple-unit established for treatment of laryngeal abscesses, mastitis, or septic {R-26} containers), and pH (3–5.5). arthritis in cattle, a dose of 5 mg (base) lincomycin per kg of body

weight every twenty-four hours, administered intramuscularly for five 1Not included in Canadian product labeling or product not commercially to seven days, has been used.{R-44; 45; 60} For deep-seated or severe available in Canada. infections, a dose of 10 mg (base) per kg of body weight every twelve hours has been recommended{R-46; 48}. [Sheep]1—Although the safety and efficacy have not been established Developed: 07/17/96 for treatment of septic arthritis in sheep, cases have been reported that Interim revision: 05/07/97; 10/15/99; 09/30/02; 04/04/03 responded to 5 mg (base) per kg of body weight, administered intramuscularly every twenty-four hours for three to five days.{R-44} REFERENCES Strength(s) usually available: 1. Clindamycin package insert (Antirobe, Pharmacia Animal Health—US), Rev {R-6} 2/02. Downloaded from www.pharmaciaah.com on 8/9/02. U.S. — 2. Clindamycin package insert (Antirobe, Pharmacia Animal Health—Canada). Veterinary-labeled product(s): In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port 25 mg (base) per mL (OTC) [Lincocin Injectable; Lincocin Sterile Huron, MI: North American Compendiums, Inc. 2002. 3. Lincomycin package insert (Lincocin [cat and dog], Pharmacia Animal Solution; Lincomix Injectable]. Health—US), Rev 10/00. Downloaded from www.pharmaciaah.com on 100 mg (base) per mL [Lincocin Sterile Solution [cats and dogs] (Rx); 8/9/02. Lincocin Sterile Solution [pigs] (OTC); Lincomix Injectable (OTC)]. 4. Lincomycin package insert (Lincomix [swine], Pharmacia Animal 300 mg (base) per mL (OTC) [Lincocin Injectable; Lincocin Sterile Health—US), Rev 8/99. Downloaded from www.pharmaciaah.com on 8/9/02. 5. Lincomycin product overview for pigs (Lincomix 100, Pharmacia—Canada). Solution; Lincomix Injectable]. Downloaded 2/26/03 from www. pharmaciaah.ca. {R-6} Canada — 6. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Veterinary-labeled product(s): Huron, MI: North American Compendiums, Inc. 2002. 7. Thilstead JP, Newton WM, Crandell RA, et al. Fatal diarrhea in rabbits 100 mg (base) per mL (OTC) [Lincomix Injectable Solution]. resulting from the feeding of antibiotic-contaminated feed. J Am Vet Med Assoc Withdrawal times: 1981; 179(4): 360–2. Note: There are no established withdrawal times for cattle or sheep in the 8. Raisbeck MF, Holt GR, Osweiler GD. Lincomycin-associated colitis in horses. J Am Vet Med Assoc 1981; 179(4): 362–3. United States or Canada because lincomycin is not approved for use in 9. Maiers JD, Mason SJ. Lincomycin-associated enterocolitis in rabbits. J Am Vet these species. Med Assoc 1984 Sep 15; 185(6): 670–2. If lincomycin is administered to cattle at the dose of 5 mg (base) per kg of 10. Bulgin MS. Losses related to the ingestion of lincomycin-medicated feed in a body weight for four days, evidence has been compiled by the Food Animal range sheep flock. J Am Vet Med Assoc 1988 Apr 15; 192(8): 1083–6. 11. Staempfli JR, Prescott JF, Brash ML. Lincomycin-induced severe colitis in Residue Avoidance Databank (FARAD) that suggests a milk withholding ponies: association with Clostridium cadaveris. Can J Vet Res 1992; 56(2): {R-45; 60} {R-60} time of 96 hours and a meat withdrawal time of 7 days 168–9. would be sufficient to avoid residues. There is no available information to 12. Rice DA, McMurray CH. Ketosis in dairy cows caused by low levels of make recommendations for withdrawal times when lincomycin is lincomycin in concentrated feed. Vet Rec 1983; 113: 495–6. 13. Havari J, Lincoln J. Pharmacologic features of clindamycin in dogs and cats. administered to cattle concurrently with other medications or when doses J Am Vet Med Assoc 1989 Jul 1; 195(1): 124–5. greater than 5 mg (base) per kg of body weight every twenty-four hours are 14. Ziv G, Sulman FG. Penetration of lincomycin and clindamycin into milk in administered. Also, no recommendations can be made for withdrawal ewes. Br Vet J 1973; 129: 83. 15. Panel comment, 4/25/96. times when lincomycin is administered to sheep. If it is necessary to 16. Budsberg SC, Kemp DT, Wolski N. Pharmacokinetics of clindamycin phosphate administer these doses, extended withdrawal times are recommended. in dogs after single intravenous and intramuscular administrations. Am J Vet Res 1992 Dec; 53(12): 2333–6. {R-4} U.S.— 17. Lappin MR, Greene CE, Winston S, et al. Clinical feline toxoplasmosis. J Vet Int Med 1989 Jul/Sep; 3(3): 139–43. Withdrawal time 18. Greene CE, Cook JR, Mahaffey EA. Clindamycin for treatment of Toxoplasma polymyositis in a dog. J Am Vet Med Assoc 1985 Sep 15; 187(6): 631–4. Species Meat (days) 19. Dubey JP, Yeary RA. Anticoccidial activity of 2-sulfa-moyl-4,4-diaminophe- nylsulfone, sulfadiazine, pyrimethamine and clindamycin in cats infected with Pigs 2 toxoplasma gondii. Can Vet J 1977 Mar; 18(3): 51–7. 20. Harvey RG, Noble WC, Ferguson EA. A comparison of lincomycin hydrochlo- Canada—{R-6} ride and clindamycin hydrochloride in the treatment of superficial pyoderma in dogs. Vet Rec 1993; 132: 351–3. Withdrawal time 21. Hamdy AH, Kratzer DD. Therapeutic effects of parenteral administration of lincomycin on experimentally transmitted swine dysentery. Am J Vet Res Species Meat (days) 1981 Feb; 42(2): 178–82. 22. Hamdy AH, Thomas RW, Yancey RJ. Therapeutic effect of optimal lincomycin Pigs 2 concentration in drinking water on necrotic enteritis in broilers. Poult Sci 1983 Apr; 62(4): 589–91. Packaging and storage: Store below 40 °C (104 °F), preferably 23. Swenson GH, Barbiers AR. The distribution and depletion of lincomycin in swine following parenteral administration. International Pig Veterinary between 15 and 30 C (59 and 86 F), unless otherwise specified by ° ° Society Proceedings, 4th ed.; 1976: B.5. manufacturer. 24. Brown SA, Zaya MJ, Dieringer TM, et al. Tissue concentrations of clindamycin after multiple oral doses in normal cats. J Vet Pharm Ther 1990; 13(3): USP requirements: Preserve in single-dose or in multiple-dose con- 270–7. tainers, preferably of Type I glass. Contains benzyl alcohol as a pre- 25. USP dictionary of USAN and international drug names, 2002 ed. Rockville, servative. Contains an amount of Lincomycin Hydrochloride in Water MD: The United States Pharmacopeial Convention, Inc.; 2002. 26. The United States pharmacopeia. The national formulary. USP 26th revision for Injection equivalent to the labeled amount of lincomycin, within – (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United 10% to +20%. Meets the requirements for Bacterial endotoxins, States Pharmacopeial Convention, Inc.; 2002. p. 471, 472, 1082, 1083, Sterility, pH (3.0–5.5), and Particulate matter, and for Injections.{R-26} 2555, 2567.

27. Clindamycin package insert (Cleocin HCL, Pharmacia—US), Rev 9/02, Rec 47. Burrows GE, Barto PB, Martin B, et al. Comparative pharmacokinetics of 1/14/03. antibiotics in newborn calves: chloramphenicol, lincomycin, and tylosin. Am J 28. Lincomycin product overview for poultry and pigs (Lincomix Soluble Powder, Vet Res 1983 Jun; 44(6): 1053–7. Pharmacia—Canada). Downloaded 2/26/03 from www. pharmaciaah.ca. 48. Burrows GE. Pharmacotherapeutics of macrolides, lincomycins and spectino- 29. Veterinary Advisory Panel meeting, 2/1/96. mycin. J Am Vet Med Assoc 1980 May 15; 176(10): 1072–7. 30. Telecommunication (Upjohn—US), 1/30/96. 49. Hornish RE, Gosline RE, Nappier JM. Comparative metabolism of lincomycin in 31. National Committee for Clinical Laboratory Standards publication. Villanova, the swine, chicken and rat. Drug Metab Rev 1987; 18(2 & 3): 177–214. PA: NCCLS, 1983; 3(14): M2-T3, M31-P. 50. Brown RB, Barza M, Brusch JL, et al. Pharmacokinetics of lincomycin and 32. DSD comment, 8/91. clindamycin phosphate in a canine model. J Infect Dis 1975 Mar; 131(3): 33. Blais J, Tardif C, Chamberland S. Effect of clindamycin on intracellular 252–60. replication, protein synthesis, and infectivity of Toxoplasma gondii. Antimic- 51. Ziv G, Sulman FG. Binding of antibiotics to bovine and ovine serum. rob Agents Chemother 1993 Dec; 37(12): 2571–7. Antimicrob Agents Chemother 1972 Sep; 2(3): 206–13. 34. Peterson JL, Willard MD, Lees GE, et al. Toxoplasmosis in two cats with inflam- 52. Gyrd-Hansen N, Rasmussen F. Renal og mammaer ekskretion af lincomycin matory intestinal disease. J Am Vet Med Assoc 1991 Aug 15; 199(4): 473–6. hos hoer. Nordisk Veterinaermedicin 1967; 19: 11–6. 35. Braden TD, Johnson CA, Wakerell P, et al. Efficacy of clindamycin in the 53. Brown SA, Dieringer TM, Hunter RP, et al. Oral clindamycin disposition after treatment of Staphylococcus aureus osteomyelitis in dogs. J Am Vet Med Assoc single and multiple doses in normal cats. J Vet Pharm Ther 1989; 12: 1988 Jun 15; 192(12): 1721–5. 209–16. 36. Braden TD, Johnson CA, Gabel CL, et al. Posologic evaluation of clindamycin, 54. Greene CE, Lappin MR, Marks A. Effect of clindamycin on clinical, hemato- using a canine model of post-traumatic osteomyelitis. Am J Vet Res 1987; logical and biochemical parameters in clinically healthy cats. J Am Anim Hosp 48(7): 1101–5. Assoc 1992 Jul/Aug; 28: 323–6. 37. Mann HJ, Townsend RJ, Fuhs DW, et al. Decreased hepatic clearance of 55. Vomand KC, Sumano H. Adverse drug reactions in cattle. J Am Vet Med Assoc clindamycin in critically ill patients with sepsis. Clin Pharm 1987 Feb; 6: 154–60. 1990 Oct; 197(7): 899–905. 38. Lincomycin package insert (Lincomix 50, Pharmacia Animal Health—US). 56. Hamdy AH, Thomas RW, Kratzer DD, et al. Lincomycin dose response for Downloaded from www.pharmaciaah.com on 8/9/02. treatment of necrotic enteritis in broilers. Poult Sci 1983; 62: 585–8. 39. Panel comment, 4/17/96. 57. Jacobs G, Lappin M, Marks A, et al. Effect of clindamycin on Factor-VII activity 40. Panel comment, 11/17/95. in healthy cats. Am J Vet Res 1989 Mar; 50(3): 393–5. 41. Lincomycin package insert (Lincomix Soluble Powder, Pharmacia Animal 58. Brown MB, Scasserra AE. Antimicrobial resistance in streptococcal species Health—US). Downloaded from www.pharmaciaah.com on 8/9/02. isolated from bovine mammary glands. Am J Vet Res 1990 Dec; 51(12): 42. Lincomycin package insert (Lincomix 44, Pharmacia Animal Health—- 2015–8. Canada). In: Arrioja-Dechert A, editor. Compendium of veterinary products, 59. Lappin MR, Roberts SM, Davidson MG, et al. Enzyme-linked immunosorbent CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. assays for the detection of Toxoplasma gondii-specific antibodies and antigens 43. Barragry TB. Veterinary drug therapy. Baltimore: Lea & Febiger; 1994. in the aqueous humor of cats. J Am Vet Med Assoc 1992 Oct 1; 201(7): p. 251–62. 1010–4. 44. Plenderleith RWJ. Treatment of cattle, sheep, and horses with lincomycin: case 60. Panel comment, 11/28/95. studies. Vet Rec 1988; 122: 112–3. 61. Klasco RK, editor. USP DI Drug information for the healthcare professional. 45. Pearson A. Determination of milk withholding time in cattle following use of Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. intramuscular lincomycin. Vet Rec 1989; 125(24): 601. 62. Clindamycin product overview for cats and dogs (Clindamycin, Pharma- 46. Burrows GE, Barto PB, Weeks BR. Chloramphenicol, lincomycin and oxytet- cia—Canada). Downloaded 2/26/03 from www. pharmaciaah.ca. racycline disposition in calves with experimental pneumonic pasteurellosis. 63. Lincomycin product overview for poultry and pigs (Lincomix 44, Pharma- J Vet Pharm Ther 1986; 9: 213–22. cia—Canada). Downloaded 2/26/03 from www. pharmaciaah.ca.

MACROLIDES Veterinary—Systemic

This monograph includes information on the following: Azithromycin; anaerobes, but Bacteroides fragilis is usually resistant. Some strains Clarithromycin; Erythromycin; Tilmicosin; Tylosin. of Actinomyces and Chlamydia are inhibited by erythromycin.{R-1; 2} Most Pseudomonas, Escherichia coli, and Klebsiella strains are resistant Some commonly used brand names are: to erythromycin{R-2}. Cross-resistance to the other macrolides can For veterinary-labeled products— also occur{R-1}. Erymycin-100 [Erythromycin Tylan 10 [Tylosin Phosphate] Thiocyanate] Tilmicosin has in vitro activity against gram-positive organisms and Erythro-200 [Erythromycin Base] Tylan 40 [Tylosin Phosphate] mycoplasma and is active against certain gram-negative organisms{R-53}, Gallimycin [Erythromycin Phosphate] Tylan 50 [Tylosin Base] such as Haemophilus somnus{R-89}, Mannheimia (Pasteurella) haemoly- Gallimycin-50 [Erythromycin Tylan 100 [Tylosin Phosphate] {R-53} Thiocyanate] tica, and Pasteurella multocida. However, M. haemolytica is more Gallimycin-100 [Erythromycin Base] Tylan 200 [Tylosin Base] sensitive than P. multocida to tilmicosin. Other gram-negative organ- Gallimycin-200 [Erythromycin Base] Tylan Soluble [Tylosin Tartrate] isms tested{R-91}, including Enterobacter aerogenes, Escherichia coli, Gallimycin PFC [Erythromycin Tylocine 200 [Tylosin Base] Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella{R-99}, and Phosphate] {R-91} Gallistat [Erythromycin Phosphate] Tylosin 10 Premix [Tylosin Phosphate] Serratia species, are very resistant to tilmicosin . Some strains of Micotil [Tilmicosin Phosphate] Tylosin 40 Premix [Tylosin Phosphate] Actinomyces also are extremely resistant to tilmicosin{R-99}. Pulmotil 90 [Tilmicosin Phosphate] Tyloved [Tylosin Base] Tylosin has a spectrum of activity similar to that of erythromycin but is Pulmotil Premix [Tilmicosin Phosphate] more active than erythromycin against certain mycoplasmas{R-51; For human-labeled products— 105}. Apo-Erythro [Erythromycin Base] Ery-Tab [Erythromycin Base] Azithromycin, a macrolide labeled for human use, has some advan- Apo-Erythro E-C [Erythromycin Base] Erythro [Erythromycin Ethylsuccinate] tages over erythromycin in the treatment of infections in animals, Apo-Erythro-ES [Erythromycin Erythrocin [Erythromycin Lactobionate; Ethylsuccinate] Erythromycin Stearate] including better oral absorption, a longer half-life, and a broader Apo-Erythro-S [Erythromycin Stearate] Erythrocot [Erythromycin Stearate] spectrum of activity than erythromycin{R-120; 122}. However, the Biaxin [Clarithromycin] Erythromid [Erythromycin Base] activity of azithromycin against staphylococci is not as good as that Biaxin XL [Clarithromycin] Ilosone [Erythromycin Estolate] E-Base [Erythromycin Base] Ilotycin [Erythromycin Base; of erythromycin. Azithromycin concentrates in tissues, particularly Erythromycin Gluceptate] in leukocytes, macrophages and fibroblasts and is slowly released E.E.S. [Erythromycin Ethylsuccinate] My-E [Erythromycin Stearate] from leukocytes{R-119; 121}. The intracellular reservoir of azithromy- E-Mycin [Erythromycin Base] Novo-Rythro [Erythromycin cin apparently produces effective drug concentrations in interstitial Ethylsuccinate] Erybid [Erythromycin Base] Novo-rythro [Erythromycin Estolate; fluids even after the plasma concentrations have declined below Erythromycin Stearate] detectable levels; plasma pharmacokinetic parameters have little ERYC [Erythromycin Base] Novo-rythro Encap [Erythromycin Base] correlation to the in vivo efficacy of azithromycin. Azithromycin ERYC-250 [Erythromycin Base] PCE [Erythromycin Base] ERYC-333 [Erythromycin Base] Wintrocin [Erythromycin Stearate] can be delivered to infected tissues and early abscesses via {R-119} EryPed [Erythromycin Ethylsuccinate] Zithromax [Azithromycin] leukocytes. Clarithromycin, also labeled for human use, is tolerated better than Note: For a listing of dosage forms and brand names by country erythromycin by human patients, has a broader spectrum of activity availability, see the Dosage Forms section(s). than erythromycin, and, like azithromycin, it also concentrates in CATEGORY: leukocytes. In dogs, clarithromycin has a shorter half-life than azithromycin{R-119; 124} and there is limited information for its clinical Antibacterial (systemic). use in animals. INDICATIONS Note: Bracketed information in the Indications section refers to uses that ACCEPTED either are not included in U.S. product labeling or are for products not Abscesses, hepatic (prophylaxis)1—Cattle, beef: Tylosin phosphate for commercially available in the U.S. medicated feed is indicated for reduction in incidence of hepatic abscesses caused by susceptible Fusobacterium necrophorum and Acti- GENERAL CONSIDERATIONS nomyces pyogenes.{R-48; 49} Macrolides are considered bacteriostatic at therapeutic concentrations Atrophic rhinitis (treatment)1—Pigs: Tylosin phosphate for medicated but they can be slowly bactericidal, especially against streptococcal feed is indicated for maintaining weight gain and feed efficiency in the bacteria; their bactericidal action is described as time-dependent. The presence of atrophic rhinitis infections.{R-49} antimicrobial action of some macrolides is enhanced by a high pH and Arthritis, infectious (treatment)1—Pigs: Tylosin injection is indicated in suppressed by low pH, making them less effective in abscesses, necrotic the treatment of swine arthritis caused by susceptible Mycoplasma tissue, or acidic urine.{R-119} hyosynoviae.{R-51; 52} Erythromycin is an antibiotic with activity primarily against gram- Coryza, infectious (prophylaxis)—Chickens: Erythromycin thiocyanate for positive bacteria, such as Staphylococcus and Streptococcus species, medicated feed1 and [erythromycin phosphate powder for oral including many that are resistant to penicillins by means of beta- solution] are indicated as aids in the prevention of infectious coryza lactamase production. Erythromycin is also active against myco- caused by susceptible organisms.{R-9; 54} plasma and some gram-negative bacteria, including Campylobacter Coryza, infectious (treatment)—Chickens: Erythromycin phosphate pow- and Pasteurella species.{R-1; 10–12} It has activity against some der for oral solution is indicated as an aid in the control of infectious

coryza caused by susceptible organisms, including Haemophilus galli- Pigs: Erythromycin injection is indicated in the treatment of narum.{R-3; 9} respiratory syndrome (pneumonia, bronchitis, and rhinitis){R-7; Diphtheria (treatment)1—Cattle, beef and nonlactating dairy: Tylosin 111}. Tilmicosin for medicated feed is indicated in the control of injection is indicated in the treatment of diphtheria caused by swine respiratory disease associated with Actinobacillus pleuropneu- susceptible Fusobacterium necrophorum.{R-51; 52} moniae and Pasteurella multocida{R-107}; however, parenteral tilmic- Dysentery, swine (prophylaxis)—Pigs: Tylosin phosphate for medicated osin should not be administered to pigs because of the risk of feed is indicated in the prevention of swine dysentery{R-48; 49}. cardiovascular toxicity{R-53}. Tylosin injection is indicated in the Dysentery, swine (treatment)—Pigs: Tylosin phosphate for medicated treatment of pneumonia caused by susceptible bacteria, including feed is indicated in the control of swine dysentery caused by susceptible P. multocida.{R-51; 52} organisms.{R-48; 49} Tylosin injection is indicated in the treatment of [Calves]: Tilmicosin injection is indicated in Canadian product labeling acute swine dysentery caused by susceptible Treponema hyodysenteriae, for the treatment of bovine respiratory disease associated with when followed by appropriate feed or water medication.{R-51; 52} susceptible M. haemolytica or Pasteurella multocida during the first 30 Tylosin tartrate powder for oral solution is indicated in the control and days in the feedlot{R-65; 112}. treatment of swine dysentery{R-50; 66}. [Foals]1: Erythromycin is used in the treatment of pneumonia caused Enteritis (treatment)— by Rhodococcus equi{R-83}. Some clinicians recommend the use of Piglets, one week of age or older: Erythromycin injection is indicated in rifampin in combination with erythromycin in the treatment of this the treatment of scours, caused by susceptible organisms, in young infection{R-4; 13; 14}; however, comparative efficacy studies of pigs{R-7; 111}. erythromycin administered with and without rifampin have not Turkeys: Erythromycin phosphate powder for oral solution is indicated been performed. See also Pneumonia under Acceptance not established in the control of enteritis (bluecomb) caused by susceptible organ- below. isms.{R-3; 9} [Lambs]: Tilmicosin injection is indicated in Canadian product labeling Enterotoxemia (prophylaxis)—Lambs, newborn: Erythromycin injection for the treatment of pneumonic pasteurellosis in lambs associated is indicated in the prevention of dysentery in lambs{R-7; 111}. with susceptible M. haemolytica{R-65; 112}. Erysipelas (treatment)—Pigs: Tylosin injection is indicated in the Pododermatitis (treatment)1—Cattle, beef and nonlactating dairy: Eryth- treatment of erysipelas caused by susceptible Erysipelothrix rhusiopa- romycin injection and tylosin injection are indicated in the treatment thiae{R-51; 52}; however, penicillin is considered the primary treatment of pododermatitis caused by susceptible organisms.{R-7; 51; 52; 111} of choice for this indication{R-88}. Proliferative enteropathy, porcine (prophylaxis and treatment)1—Pigs: Feed efficiency, improvement of1;or Tylosin phosphate for medicated feed is indicated in the prevention and Weight gain, increased rate1— control of porcine proliferative enteropathy (ileitis) associated with Chickens, including laying chickens: Tylosin phosphate for medicated susceptible Lawsonia intracellularis{R-49}. feed is indicated for increased rate of weight gain and improving feed Respiratory disease, chronic (prophylaxis)1—Chickens and turkeys: Eryth- efficiency.{R-49} romycin thiocyanate for medicated feed and [erythromycin phosphate Pigs: Tylosin phosphate for medicated feed is indicated for improving powder for oral solution] are indicated as aids in the prevention of feed efficiency and growth promotion{R-48; 49}. chronic respiratory disease.{R-54} Leptospirosis—Sows, farrowing: Erythromycin injection is indicated in Respiratory disease, chronic (treatment)— the management of leptospirosis in sows at farrowing time{R-7; 111}. Chickens, broiler and replacement: Erythromycin thiocyanate for Metritis (treatment)— medicated feed and erythromycin phosphate powder for oral solution Cattle, beef and nonlactating dairy: Erythromycin injection and tylosin are indicated in the control of chronic respiratory disease in chickens injection are indicated in the treatment of metritis caused by due to susceptible Mycoplasma gallisepticum.{R-3; 9; 54; 64} Tylosin susceptible organisms{R-7; 51; 52; 111}; however, therapeutic regi- tartrate powder for oral solution{R-50; 66} is indicated in the control mens often emphasize evacuation of uterine contents as the primary of and as an aid in the treatment of chronic respiratory disease, and treatment. tylosin phosphate for medicated feed1 is indicated as an aid in the Sows, at farrowing time: Erythromycin injection is indicated in the control of chronic respiratory disease caused by susceptible treatment of metritis caused by susceptible organisms{R-7; 111}; M. gallisepticum.{R-49} however, therapeutic regimens often emphasize evacuation of Turkeys: Erythromycin thiocyanate for medicated feed1 and [erythro- uterine contents as the primary treatment. mycin phosphate powder for oral solution] are indicated for Pneumonia, bacterial (treatment)— reduction of lesions and to decrease the severity of chronic Cattle: Erythromycin injection is indicated in the treatment of respiratory disease.{R-9; 54; 64} pneumonia and bovine respiratory disease caused by susceptible Respiratory tract infections, bacterial (treatment)— bacteria, including Pasteurella multocida.{R-6; 7; 111} Tylosin injection Pigs: Erythromycin injection is indicated in the treatment of respiratory is indicated in the treatment of pneumonia and bovine respiratory syndrome (bronchitis, pneumonia, and rhinitis){R-7; 111}. Tilmicosin disease caused by susceptible bacteria, including Pasteurella multocida for medicated feed is indicated in the control of swine respiratory and Actinomyces pyogenes.{R-51} Tilmicosin injection is indicated in disease associated with Actinobacillus pleuropneumoniae and Pasteu- the control of bovine respiratory disease in cattle at high risk for rella multocida{R-107}; however, parenteral tilmicosin should not infection and in the treatment of bovine respiratory disease caused by be administered to pigs because of the risk of cardiovascular susceptible bacteria, including Mannheimia haemolytica{R-53}. In some toxicity{R-53}. regions, tilmicosin has been more effective than oxytetracycline{R-75} Sheep: Erythromycin injection is indicated in the treatment of upper in clinical resolution of calf pneumonia. respiratory tract infections{R-7; 111}.

Sinusitis, infectious (treatment)—Turkeys: Tylosin tartrate powder for Streptococcus species; however, studies have shown that erythromycin oral solution is indicated to maintain weight gain and feed efficiency in is distributed into milk at antimicrobial concentrations under certain the presence of infectious sinusitis caused by susceptible M. gallisept- pH conditions and may be clinically effective{R-45–47}. icum.{R-50} [Pneumonia, bacterial, (treatment)]1—Foals: Although there is insuffi- [Enteritis, Campylobacter (treatment)]1—Dogs: Erythromycin stearate is cient evidence to establish efficacy, pharmacokinetic studies suggest used in the treatment of diarrhea believed to be caused by susceptible that azithromycin may be as effective as erythromycin, with less Campylobacter species. Erythromycin treatment stops the shedding of frequent dosing and fewer side effects, in the treatment of pneumonia Campylobacter in the feces; however, shedding often recurs shortly after caused by Rhodococcus equi in foals{R-121; 122}. discontinuation of therapy.{R-10–12} See also Enteritis, Campylobacter [Respiratory tract infections (treatment)]1, including, under Acceptance not established below. [Bronchitis (treatment)]1 [Pyoderma (treatment)]1—Dogs: Erythromycin tablets are used in the [Laryngitis (treatment)]1 treatment of pyoderma caused by susceptible Staphylococcus species. [Pneumonia (treatment)]1 However, because drug-induced vomiting is a common side effect of [Tracheobronchitis (treatment)]1,or administration, erythromycin is not considered the treatment of [Tracheitis (treatment)]1—Cats and dogs: Although at one time choice.{R-42–44} Canadian tylosin tablets were available for the treatment of [Synovitis, infectious (prophylaxis)]—Chickens and turkeys: Erythromycin pneumonia and tracheobronchitis{R-56}, and the use of tylosin phosphate powder for oral solution is indicated in the management of injection in the treatment of respiratory tract infections in cats infectious synovitis{R-9}. and dogs has been approved by the U.S. Food and Drug Administration{R-108}, these uses are not included in United States ACCEPTANCE NOT ESTABLISHED or Canadian product labeling for tylosin. Studies performed during the original approval process showed that tylosin injection can be [Chlamydial infections (treatment)]1—Cats: There are no clinical studies effective in the treatment of bronchitis, laryngitis, pneumonia, to document the effectiveness of azithromycin in the treatment of tracheobronchitis, or tracheitis in dogs and upper respiratory tract chlamydial infections in cats. In vitro studies and clinical trials of infections or pneumonitis in cats when the infection is caused by azithromycin in urinary and respiratory tract chlamydial infections in susceptible organisms{R-108}. human patients have demonstrated efficacy{R-33–35; 113} and a [Rocky Mountain spotted fever]1—Dogs: There are insufficient data at pharmacokinetic study of azithromycin in cats allows for prediction this time to establish the efficacy of azithromycin in the treatment of of potentially effective dosing regimens{R-120}. Rocky Mountain spotted fever in dogs. A comparative therapeutic [Colitis, chronic (treatment)]1—Dogs: There are insufficient data to study of induced Rocky Mountain spotted fever in dogs showed that establish the efficacy of tylosin in the treatment of chronic colitis in azithromycin, when given for a 3-day treatment regimen, was effective dogs and there is no available information on the mechanism of action in improving platelet counts, slowing vascular leakage, and reducing for alleviation of colitis. However, tylosin tartrate powder for oral fever; however, retinal vascular lesions remained unchanged. Overall, solution has been used in the U.S. in the treatment of chronic colitis in the response was not as good as the administration of doxycycline for 7 dogs. The use of tylosin in the treatment of colitis is typically reserved days. If azithromycin is administered to dogs for the treatment of for patients that are not responsive to other forms of therapy, such as Rocky Mountain spotted fever, longer term treatment may be be more diet change, and for patients with chronic colitis for which specific effective.{R-123–125} causes have been ruled out.{R-84–86; 101; 102} [Cryptosporidiosis (treatment)]1—Cats and dogs: There is no treatment 1Not included in Canadian product labeling or product not commercially that has been clearly demonstrated to eradicate Cryptosporidium available in Canada. species infection in human beings{R-32; 40} or animals; the zoonotic potential of this organism should be considered. Azithromycin can be administered to shorten the length of time oocysts are shed in cats and REGULATORY CONSIDERATIONS dogs; however, there are no clinical studies in these species to U.S.— document efficacy in the treatment of cryptosporidiosis. There are Erythromycin thiocyanate and tylosin tartrate are not labeled for use studies of immunocompromised, human immunodeficiency virus in chickens or turkeys producing eggs for human consump- (HIV)-positive patients that show some evidence of the efficacy of tion.{R-8; 50; 54} Tilmicosin is not labeled for use in female dairy cattle azithromycin in prevention, remission, and possibly eradication of 20 months of age or older{R-53}, veal calves, calves less than 1 month infection with long-term administration{R-41; 97}. Because of insuffi- of age, or calves fed an all-milk diet. Tylosin injection is not labeled cient data, it is not possible at this time to recommend long-term for use in lactating dairy cattle or preruminating calves.{R-51; 52} dosing regimens that might be useful in the treatment of this infection Withdrawal times have been established for erythromycin injection, in cats and dogs. erythromycin phosphate powder for oral solution, erythromycin [Enteritis, Campylobacter (treatment)]1—Dogs: In vitro studies have thiocyanate, tilmicosin phosphate, tylosin injection, tylosin phos- demonstrated that azithromycin may have up to 6 times the activity phate, and tylosin tartrate (see the Dosage Forms section). of erythromycin against susceptible Campylobacter strains, making it a Azithromycin and clarithromycin are not labeled for use in animals. potential treatment for this type of enteritis in dogs; however, no Canada— clinical studies have been performed{R-57; 110}. Erythromycin phosphate, erythromycin thiocyanate, and tylosin [Mastitis (treatment)]1— Cattle: There are insufficient data to establish tartrate are not labeled for use in chickens or turkeys producing the efficacy of systemic erythromycin in the treatment of acute eggs for human consumption.{R-8; 9} Neither tilmicosin nor tylosin and peracute mastitis caused by susceptible Staphylococcus and base injection is labeled for use in lactating dairy cattle.{R-55; 65}

Withdrawal times have been established for erythromycin injection, Clarithromycin—747.95{R-16}. erythromycin phosphate powder for oral solution, erythromycin Erythromycin—733.93{R-16}. thiocyanate, tilmicosin phosphate, tylosin injection, tylosin phos- Erythromycin estolate—1056.39{R-16}. phate, and tylosin tartrate (see the Dosage Forms section). Erythromycin ethylsuccinate—862.05{R-16}. Azithromycin and clarithromycin are not labeled for use in animals. Erythromycin gluceptate—960.11{R-16}. Erythromycin lactobionate—1092.22{R-16}. Erythromycin stearate—1018.40{R-16}. CHEMISTRY Tilmicosin phosphate—967.13{R-16}. Source: Tylosin—916.1{R-100}. Azithromycin and clarithromycin—Semisynthetically derived from Description: erythromycin{R-116; 119}. Azithromycin dihydrate—White, crystalline powder{R-116}. Erythromycin—Produced from a strain of Saccharopolyspora erythraeus{R-7}. Clarithromycin USP—White to off-white, crystalline powder{R-22}. Tilmicosin—Produced semisynthetically{R-53} by chemical modiﬁcations Erythromycin USP—White or slightly yellow, crystalline powder. Is of desmycosin{R-1}. odorless or practically odorless{R-22}. Tylosin—Produced by a strain of the actinomycete Streptomyces fradiae Erythromycin Estolate USP—White, crystalline powder. Is odorless or {R-55}. practically odorless{R-22}. Chemical group: Erythromycin Ethylsuccinate USP—White or slightly yellow crystalline Azalide antibiotic, a subclass of macrolides—Azithromycin{R-116}. powder. Is odorless or practically odorless{R-22}. Macrolide antibiotics (macrocyclic lactones){R-1; 117}—Clarithromycin, Erythromycin Gluceptate—White powder. Is odorless or practically erythromycin, tilmicosin, and tylosin. odorless, and is slightly hygroscopic. Its solution (1 in 20) is neutral Chemical name: or slightly acid. Azithromycin—1-Oxa-6-azacyclopentadecan-15-one, 13-[(2,6-dideoxy- Erythromycin Lactobionate for Injection USP—White or slightly yellow 3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10- crystals or powder, having a faint odor. Its solution (1 in 20) is neutral trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dim- or slightly alkaline{R-22}. ethylamino)-beta-D-xylo-hexopyranosyl]oxy]-, dihydrate, [2R-(2R*, Erythromycin Stearate USP—White or slightly yellow crystals or powder. 3S*,4R*,5R*,8R*,10R*,11R*,12S*,13S*,14R*)]-{R-16}. Is odorless or may have a slight, earthy odor{R-22}. Clarithromycin—Erythromycin, 6-O-methyl-{R-16}. Tilmicosin USP—White to off-white amorphous solid{R-22}. Erythromycin—Erythromycin{R-16}. Tylosin USP—White to buff-colored powder{R-22}. Erythromycin estolate—Erythromycin, 2¢-propanoate, dodecyl sulfate pKa: (salt){R-16}. Erythromycin base—8.8{R-18; 19}. Erythromycin ethylsuccinate—Erythromycin 2¢-(ethyl butanedio- Tilmicosin—7.4; 8.6{R-94}. ate){R-16}. Tylosin—7.1{R-5; 58}. Erythromycin gluceptate—Erythromycin monoglucoheptonate Solubility: (salt){R-16}. Azithromycin—39 mg soluble per mL of water (pH 7.4 ) at 37 C{R-118}. Erythromycin lactobionate—Erythromycin mono(4-O-beta-D-galacto- Clarithromycin USP—Soluble in acetone; slightly soluble in dehy- pyranosyl-D-gluconate) (salt){R-16}. drated alcohol, in methanol, and in acetonitrile; practically insoluble Erythromycin stearate—Erythromycin octadecanoate (salt){R-16}. in water. Slightly soluble in phosphate buffer at pH values of 2 Tilmicosin phosphate—Tylosin, 4A-O-de(2,6-dideoxy-3-C-methyl-alpha- to 5{R-22}. L-ribo-hexopyranosyl)-20-deoxo-20-(3,5-dimethyl-1-piperidinyl)-, Erythromycin USP—Slightly soluble in water; soluble in alcohol, in [20(cis)]-, phosphate (1:1) (salt){R-16}. chloroform, and in ether{R-22}. Tylosin—(10E,12E)-(3R,4S,5S,6R,8R,14S,15R)-14-[(6-deoxy-2,3-di- Erythromycin Estolate USP—Soluble in alcohol, in acetone, and in O-methyl-beta-D-allopyranosyl)oxymethyl]-5-[[3,6-dideoxy-4-O-(2,6- chloroform; practically insoluble in water{R-22}. dideoxy-3-C-methyl-alpha-L-ribo-hexopyranosyl)-3-dimethylamino- Erythromycin Ethylsuccinate USP—Very slightly soluble in water; freely beta-D-glycopyranosyl]oxy]-6-formylmethyl-3-hydroxy-4,8,12-tri- soluble in alcohol, in chloroform, and in polyethylene glycol methyl-9-oxoheptadeca-10,12-dien-15-olide{R-100}. 400{R-22}. Molecular formula: Erythromycin Gluceptate—Freely soluble in water, in alcohol, and in {R-16} Azithromycin—C38H72N2O12Æ2H2O . methanol; slightly soluble in acetone and in chloroform; practically {R-16} Clarithromycin—C38H69NO13 . insoluble in ether. {R-16} Erythromycin—C37H67NO13 . Erythromycin Lactobionate for Injection USP—Freely soluble in water, in {R-16} Erythromycin estolate—C40H71NO14ÆC12H26O4S . alcohol, and in methanol; slightly soluble in acetone and in chloro- {R-16} {R-22} Erythromycin ethylsuccinate—C43H75NO16 . form; practically insoluble in ether . {R-16} Erythromycin gluceptate—C37H67NO13ÆC7H14O8 . Erythromycin Stearate USP—Practically insoluble in water; soluble in {R-16} {R-22} Erythromycin lactobionate—C37H67NO13ÆC12H22O12 . alcohol, in chloroform, in methanol, and in ether . {R-16} {R-22} Erythromycin stearate—C37H67NO13ÆC18H36O2 . Tilmicosin USP—Slightly soluble in water and in n-hexane . {R-16} Tilmicosin phosphate—C46H80N2O13ÆH3O4P . Tylosin USP—Freely soluble in methanol; soluble in alcohol, in amyl {R-100} Tylosin—C46H77NO17 . acetate, in chloroform, and in dilute mineral acids; slightly soluble in Molecular weight: water{R-22}. Azithromycin—785.02{R-16}. Tylosin tartrate—Readily soluble in water, up to 600 mg per mL{R-61}.

PHARMACOLOGY/PHARMACOKINETICS Foals: Azithromycin peak concentration in polymorphonuclear leuko- Note: See also Table 1. Pharmacology/Pharmacokinetics at the end of this cytes (PMN) was 27.3 mcg per mL (mcg/mL) while peak plasma monograph. concentration was 0.72 mcg/mL after a single 10 mg/kg oral dose. The drug persisted in PMNs for 120 hours while it was only detected {R-121} Mechanism of action/effect: Bacteriostatic, with potential for a time- in plasma for about 24 hours. dependent bactericidal action, particularly with high concentrations{R- Clarithromycin—Widely distributed into tissues and enters leukocytes {R-115} 1; 5; 119}. The macrolides are thought to enter the cell and reversibly and macrophages . bind to the 50 S ribosomal subunit, inhibiting translocation of pep- Erythromycin—In the calf, lung tissue erythromycin concentrations tides, thereby inhibiting protein synthesis.{R-5} Bacterial resistance were found to be approximately three times higher than serum occurs by alteration of the ribosome receptor site and/or by prevention concentrations from 8 to 24 hours after intramuscular administra- {R-28} of the antibiotic from entering the cell. Although macrolides bind to tion . mitochondrial ribosomes, as does chloramphenicol, macrolides are Tilmicosin and tylosin—Tylosin concentrations in lung tissue are many unable to cross the mitochondrial membrane and so do not produce times higher than in serum from 2 to 36 hours after a single {R-70} bone marrow suppression in mammals{R-119}. intramuscular administration ; tilmicosin concentrations in lung tissue are many times higher than in serum for at least 96 hours after {R-104} Absorption: a single subcutaneous administration . Azithromycin—Oral administration: Shown to be fairly well absorbed Half-life: Azithromycin in leukocytes— orally in cats (bioavailability of 58%), dogs (bioavailability of >90%), Foals: 49.2 hours{R-121}. and foals (bioavailability of 39 to 56%){R-120–123}. Human data: 34 to 57 hours{R-115}. Erythromycin—Oral administration: Many oral erythromycin base preparations are coated to prevent Elimination: degradation in the stomach. The higher pH of the intestine then Azithromycin— permits absorption.{R-1; 2} However, absorption of enteric-coated and Cats: More than 50% of the drug is eliminated unchanged in the bile. delayed-release dosage forms can be unpredictable in animals{R-21}. One major metabolite resulting from N-demethylation and two Erythromycin estolate and erythromycin ethylsuccinate are absorbed minor metabolites also appear in the bile{R-120}. as inactive esters from the duodenum and then undergo hydrolysis to Human information: More than 50% of the drug is eliminated the free base. The stearate salt dissociates in the duodenum and is unchanged through biliary excretion while 4 to 14%, depending absorbed as the free base. It has been suggested that erythromycin on route of administration, is eliminated unchanged in the phosphate also dissociates and is absorbed as the free base. Food in urine{R-115}. the stomach does not seem to affect signiﬁcantly the absorption of Clarithromycin—Human information: 20 to 40% is eliminated unchanged the base or salt. in the urine{R-115}. It is unclear whether any of the oral erythromycin preparations is Erythromycin—Primarily hepatic; metabolite and a small amount of absorbed more effectively than any other when administered to active drug are excreted to a large degree in the bile but are also animals{R-1}; however, it does appear that oral absorption in excreted in urine and milk. After oral administration, high concen- horses may be different from human absorption. In horses, oral trations of erythromycin may be eliminated in the feces.{R-1; 29} erythromycin stearate and erythromycin phosphate produced Tilmicosin—Cattle: Of the total subcutaneous dose administered, 24% peak plasma concentrations more quickly than did the ester has been recovered in the urine and 68% in the feces.{R-53} formulations; the effect is the opposite of that seen in human studies.{R-18} Duration of action: Tylosin—Intramuscular administration: Bioavailability—Goats: 72.6% Tilmicosin—Cattle, healthy or acutely pneumonic: 3 days, minimum (15 mg per kg of body weight [mg/kg] dose){R-72}. (based on maintenance of >3.12 mcg/mL lung concentration [minimum inhibitory concentration 95% for M. haemolytica] with a Distribution: subcutaneous dose of 10 mg/kg){R-53; 103; 104}. Widely distributed in the body{R-1; 68}. Ion trapping and the high lipid Tylosin—Goats: 12 hours (based on maintenance of >1 mcg/mL serum solubility of the macrolides generally causes tissue concentrations to be concentration with an intramuscular dose of 15 mg/kg).{R-72} higher (often many times higher) than serum concentrations.{R-1; 70} Azithromycin—Tissue concentrations can be as much as 100 times serum concentrations and concentrations in leukocytes can be 200 to PRECAUTIONS TO CONSIDER 300 times serum concentrations{R-115; 119}. Cats: Azithromycin appears to distribute well, although sometimes SPECIES SENSITIVITY slowly, into a variety of tissues. High tissue to plasma ratios are Erythromycin: produced. In one study, lung, femur, eye, skin, and brain tissue Cattle—Oral administration of erythromycin phosphate or erythromy- concentrations of azithromycin were still rising when the last sample cin stearate has caused severe diarrhea in ruminating calves.{R-28} was taken, 72 hours after the dose{R-120}. Because of this adverse effect and poor absorption, oral erythromycin Dogs: A single dose of azithromycin produced high tissue concentra- administration in cattle is not recommended. tions, often with a tissue to serum ratio of 100 to one; azithromycin Horses—In foals treated with erythromycin, mild self-limiting diarrhea concentrations in eye and brain tissue exceeded serum concentra- may develop.{R-26} In adult horses, the risk of severe diarrhea makes tions by 20- and 1.2-fold, respectively{R-123}. the use of erythromycin controversial.{R-2}

Tilmicosin: estolate has been associated with reversible hepatotoxicity in some All species—To avoid cardiotoxicity, tilmicosin should not be admin- women during pregnancy. istered intravenously{R-81}. Tilmicosin{R-53} and tylosin: Safety in breeding or pregnant animals has Human—Injection of tilmicosin may be lethal. Although there is little not been established. information on the effects of tilmicosin in people, a variable susceptibility to cardiotoxic reactions in other species warrants LACTATION caution with human exposure and close monitoring of the cardio- Clarithromycin is excreted into milk{R-117}. The distribution of azithro- vascular system, particularly after accidental injection{R-81}.A mycin into milk has not yet been demonstrated{R-116}. physician should be consulted immediately in cases of accidental Erythromycin, tilmicosin, and tylosin concentrations in milk can be injection.{R-53} much higher than concentrations in serum.{R-26; 72; 74} Dogs—In laboratory dogs, tachycardia and decreased cardiac contrac- In cattle, tilmicosin is distributed into milk at effective antibacterial tility have been noted in response to tilmicosin injection{R-100}. concentrations for susceptible pathogens, but detectable concentra- Goats—Administration of tilmicosin to goats at intramuscular or tions in milk are maintained for many weeks (up to 42 days){R-87}. subcutaneous doses >10 mg per kg of body weight (mg/kg) is likely Tilmicosin should not be administered to lactating dairy cattle because to lead to toxicity{R-81; 100}. of impractical withdrawal times.{R-74} Horses—Administration of tilmicosin to horses at intramuscular In mastitis-free cattle, systemic tylosin is distributed into milk at or subcutaneous doses >10 mg/kg is likely to lead to concentrations that are therapeutic for some mastitis pathogens; toxicity{R-81; 100}. however, tylosin is distributed into milk more readily as the pH of milk Pigs—Injection of tilmicosin into swine can be fatal as a result of decreases. The pH of mastitic milk can approach 7.4 and decrease the cardiovascular toxicity. Administration of epinephrine to treat diffusion of tylosin, interfering with the medication’s ability to reach cardiovascular toxicity due to intravenous tilmicosin administration therapeutic concentrations in milk against some organisms{R-79; 80}. has been associated with an increased risk of death.{R-53; 100} Tylosin: Horses—Injection of tylosin has been fatal to horses.{R-51; 52} PEDIATRICS CROSS-SENSITIVITY AND/OR RELATED PROBLEMS In animals up to 1 month of age, the hepatic clearance of macrolides may {R-1} Patients that are hypersensitive to one macrolide may be hypersensitive be slower than in adult animals . to a different macrolide{R-116; 117}. DRUG INTERACTIONS AND/OR RELATED PREGNANCY/REPRODUCTION PROBLEMS Azithromycin: The following drug interactions and/or related problems have been Fertility and reproduction—Rats and mice given azithromycin at doses selected on the basis of their potential clinical significance (possible of up to 200 mg/kg a day have shown no evidence of impaired mechanism in parentheses where appropriate)—not necessarily inclu- fertility or harm to the fetus{R-116}. sive (» = major clinical significance): FDA human pregnancy category B. Note: Combinations containing any of the following medications, depend- Clarithromycin: ing on the amount present, may also interact with this medication. Fertility and reproduction—Male and female rats administered up to Beta-adrenergic antagonists, such as 160 mg/kg a day have shown no effect on estrous cycle, fertility, Propranolol parturition, or viability of offspring{R-117}. (propranolol and other beta-adrenergic antagonists exacerbate the Pregnancy—Monkeys administered oral doses of 150 mg/kg a day had negative inotrophy of tilmicosin-induced tachycardia in embryonic loss, which was attributed to marked maternal toxicity at dogs{R-53}) this dose. In utero fetal loss occurred in rabbits given intravenous » Chloramphenicol or doses of 33 mg per square meter of body surface area, which is » Florfenicol or equivalent to 17 times less than the maximum recommended human » Lincosamides or daily dose. » Macrolide antibiotics, other Clarithromycin was not found to be teratogenic in four rat studies or (chloramphenicol, florfenicol, and the lincosamides have mechanisms in two rabbit studies. Two additional studies in a different rat strain of action similar to the macrolides; they may be prevented from demonstrated a low incidence of cardiovascular anomalies at oral binding, or prevent a macrolide from binding, to the 50 S subunits of doses of 150 mg/kg a day administered during gestation days 6 bacterial ribosomes; concurrent use is not recommended{R-1}) through 15. Cleft palate was seen at doses of 500 mg/kg a day. Fetal » Epinephrine growth retardation was seen in monkeys given an oral dose of 70 (in pigs, the intravenous administration of epinephrine potentiates the mg/kg a day, which produced plasma concentrations that were lethality of intravenously administered tilmicosin{R-53}) equivalent to two times the human serum concentrations. Phenobarbital or FDA human pregnancy category C{R-115}. Medications metabolized by microsomal mixed-function oxidases, other Erythromycin: Erythromycin crosses the placenta; however, there is no (concurrent use with erythromycin may decrease the effects of these evidence of teratogenicity or other effects when female rats are fed medications because of induction of hepatic microsomal enzy- erythromycin base during pregnancy.{R-17} In people, erythromycin mes{R-87})

HUMAN DRUG INTERACTIONS{R-115} adjustment of the xanthines may be necessary during and after In addition to the above drug interactions reported in animals, the therapy with macrolides) following drug interactions have been reported in humans, and are (concurrent administration of theophylline with clarithromycin included in the human monographs Azithromycin (Systemic), Clari- has been shown to increase the area under the plasma concentra- thromycin (Systemic), or Erythromycins (Systemic) in USP DI Volume I; tion–time curve [AUC] of theophylline by 17%; monitoring of these drug interactions are intended for informational purposes only theophylline serum concentrations is recommended in patients and may or may not be applicable to the use of macrolides in the receiving high doses of theophylline or in patients with theophyl- treatment of animals: line serum concentrations in the upper therapeutic range) Note: There are no tilmicosin or tylosin products labeled for use in people. (with erythromycin, this effect may be more likely to occur after 6 Anticoagulants, coumarin- or indanedione-derivative or days of concurrent therapy because the magnitude of theophylline Warfarin clearance reduction is proportional to the peak serum erythromycin (concurrent administration with macrolide antibiotics has been concentrations) associated with increased anticoagulant effects; prothrombin time For azithromycin should be monitored carefully in patients receiving anticoagulants Antacids, aluminum- and magnesium-containing and macrolides concurrently) (concurrent use with antacids decreases the peak serum concentra- Carbamazepine or tion [Cmax] of azithromycin by approximately 24%, but has no effect Cyclosporine or on the area under the plasma concentration–time curve [AUC]; oral Digoxin or azithromycin should be administered at least 1 hour before or 2 Hexobarbital or hours after aluminum- and magnesium-containing antacids) Phenytoin or For clarithromycin Valproic acid Pimozide (concurrent use with macrolide antibiotics has been associated with (concurrent administration of pimozide with clarithromycin has increased serum concentration of these medications; monitoring of resulted in cardiac arrhythmias, including QTc-interval prolonga- serum concentrations of medications administered concurrently is tion, ventricular tachycardia, ventricular fibrillation, and torsades de recommended to avoid toxicity) pointes; fatalities have also occurred; the most likely cause is the (although no clinical cases of toxicity have been reported, inhibition of hepatic metabolism of pimozide by clarithromycin; concurrent use of oral antibiotics may increase serum digoxin concurrent use is contraindicated) concentrations in some individuals; in these individuals, alteration Zidovudine of gut flora by antibiotics may diminish digoxin conversion to (concurrent administration with clarithromycin causes a decrease in inactive metabolites, resulting in increased serum digoxin concen- the steady state concentration of zidovudine; doses of clarithromycin trations; although limited data are available, this interaction has and zidovudine should be taken at least 4 hours apart) been reported with oral use of erythomycins, neomycin, and For erythromycin tetracyclines) Hepatotoxic medications, other Midazolam or (concurrent use of other hepatotoxic medications with erythromycin Triazolam may increase the potential for hepatotoxicity) (concurrent use with macrolide antibiotics may decrease the Ototoxic medications, other clearance of these medications, increasing the pharmacologic effect (concurrent use with high-dose erythromycin in patients with renal of midazolam or triazolam) function impairment may increase the potential for ototoxicity) Penicillins (since bacteriostatic drugs may interfere with the bactericidal effect LABORATORY VALUE ALTERATIONS of penicillins in the treatment of meningitis or in other situations in The following have been selected on the basis of their potential clinical which a rapid bactericidal effect is necessary, it is best to avoid significance (possible effect in parentheses where appropriate)—not concurrent therapy) necessarily inclusive (» = major clinical significance): Rifabutin or Note: Laboratory value alterations relating specifically to use of macro- Rifampin lides in animals are rarely described. Human laboratory value (concurrent use of rifabutin with azithromycin causes a 15% alterations have been reported for erythromycin and are included in decrease in serum concentration of rifabutin{R-116}) the following section. (concurrent use of rifabutin or rifampin with clarithromycin causes a {R-115} decrease in the serum concentration of clarithromycin by greater HUMAN LABORATORY VALUE ALTERATIONS than 50%) The following laboratory value alterations have been reported in Xanthines, such as: humans, and are included in the human monographs Azithromycin Aminophylline (Systemic), Clarithromycin (Systemic), or Erythromycins (Systemic) in Caffeine USP DI Volume I; these laboratory value alterations are intended for Oxtriphylline informational purposes only and may not be applicable to the use of Theophylline macrolides in the treatment of animals: (concurrent use of the xanthines [except dyphylline] with Note: There are no tilmicosin or tylosin products labeled for use in people. macrolides may decrease hepatic clearance of xanthines, result- For azithromycin ing in increased serum concentrations and/or toxicity; dosage With physiology/laboratory test values

Alanine aminotransferase (ALT [SGPT]) and Minimum inhibitory concentration (MIC) Aspartate aminotransferase (AST [SGOT]) and (in vitro cultures and MIC tests should be done on samples collected Creatine kinase and prior to macrolide administration to determine pathogen suscepti- Gamma-glutamyltransferase and bility) Lactate dehydrogenase (serum values may be increased) SIDE/ADVERSE EFFECTS Bilirubin, serum and The following side/adverse effects have been selected on the basis of their Potassium, serum potential clinical significance (possible signs and, for humans, symp- (concentrations may be increased) toms in parentheses where appropriate)—not necessarily inclusive: For clarithromycin With physiology/laboratory test values THOSE INDICATING NEED FOR MEDICAL Alanine aminotransferase (ALT [SGPT]) and ATTENTION Aspartate aminotransferase (AST [SGOT]) Incidence unknown (rarely, serum values may be increased) All species Blood urea nitrogen (BUN) Allergic reactions—considered rare{R-1} (rarely, concentration may be elevated) Cats and dogs For erythromycin Gastrointestinal effects (anorexia, diarrhea, vomiting)—particularly With diagnostic test results with erythromycin{R-1; 2; 96} Aspartate aminotransferase (AST [SGOT]) Note: In dogs, it has been shown that intravenous erythromycin (use of erythromycin may interfere with AST [SGOT] determina- produces an increase in the electrical and motor activity of the tions if azonefast violet B or diphenylhydrazine colorimetric tests stomach; this effect most likely occurs through cholinergic pathways. are used) The effect produces an abrupt, powerful increase in gastric motility Catecholamines, urinary causing retrograde contractions leading to gastrointestinal effects, (erythromycin may produce false elevations of urinary catechol- such as vomiting and retching.{R-59; 60} In one survey, 41% of pet amines because of interference with the fluorometric determina- owners reported that their dogs (19 of 46) vomited following tion) administration of oral erythromycin stearate.{R-96} This increase in With physiology/laboratory test values gastric motility has not been shown to occur in response to tylosin{R-67} Alanine aminotransferase (ALT [SGPT]) and and, although vomiting may occur in response to tylosin adminis- Alkaline phosphatase and tration, it occurs infrequently. Aspartate aminotransferase (AST [SGOT]) and Cattle Bilirubin, serum Diarrhea—associated with oral erythromycin dosage forms{R-28} (values may be increased by all erythromycins, but more Horses commonly by erythromycin estolate) Diarrhea, severe—with erythromycin; considered more likely in adult horses{R-2} MEDICAL CONSIDERATIONS/CONTRAINDICATIONS Pigs {R-51} The medical considerations/contraindications included have been Diarrhea, erythema, and pruritis—with tylosin; edema, {R-2; 51} selected on the basis of their potential clinical significance (reasons rectal, and partial anal prolapse —with erythromycin and given in parentheses where appropriate)—not necessarily inclusive tylosin (» = major clinical significance). Risk-benefit should be considered when the following medical THOSE INDICATING NEED FOR MEDICAL problems exist: ATTENTION ONLY IF THEY CONTINUE OR ARE Hepatic function impairment BOTHERSOME {R-29} (macrolides are hepatically metabolized ; although hepatotoxic- All species ity has not been reported in animals, erythromycin estolate has, on Pain and/or swelling at the site of injection—with subcutaneous uncommon occasions, been associated with hepatotoxicity in people; injection in cattle, swelling is transient and usually mild{R-2; 29; 53} therefore, consideration of risk is recommended{R-1}) Renal function impairment, severe HUMAN SIDE/ADVERSE EFFECTS{R-115} (clarithromycin elimination is reduced in human patients with renal In addition to the above side/adverse effects reported in animals, the function impairment, particularly those with a creatinine clearance following side/adverse effects have been reported in humans, and are < 30 mL per minute; it is recommended that the dose be reduced by included in the human monographs Azithromycin (Systemic), Clari- one-half or that the dosage interval be doubled{R-115}) thromycin (Systemic), or Erythromycins (Systemic) in USP DI Volume I; these side/adverse effects are intended for informational purposes only PATIENT MONITORING and may or may not be applicable to the use of macrolides in the The following may be especially important in patient monitoring (other treatment of animals: tests may be warranted in some patients, depending on condition; » = Note: There are no tilmicosin or tylosin products labeled for use in people. major clinical significance): For azithromycin Culture and susceptibility in vitro and Incidence more frequent—for injection form only

Thrombophlebitis the mild evidence of myocardial necrosis seen with three 50 mg/kg Incidence less frequent doses administered 72 hours apart{R-53} was not found with a 30 mg/ Gastrointestinal disturbances kg dosage regimen. Repeated subcutaneous doses of 150 mg/kg every Incidence rare 3 days resulted in one death following the third treatment and one Acute interstitial nephritis; allergic reactions; dizziness; head- death following the fourth treatment in cattle{R-53; 100}. In contrast, ache; pseudomembranous colitis three of four pigs administered a 20 mg/kg intramuscular dose of For clarithromycin tilmicosin and four of four pigs given a 30 mg/kg dose died. In goats Incidence less frequent and horses, subcutaneous or intramuscular doses above 10 mg/kg Abnormal sensation of taste; gastrointestinal disturbances; may cause signs of toxicosis{R-81; 100}. headache Oral tilmicosin caused no ill effects in pigs when they were administered Incidence rare 2000 parts per million (ppm) in the only ration for 42 days or 4000 Hepatotoxicity; hypersensitivity reaction; pseudomembranous ppm for 21 days{R-107}. Oral doses of 4 mg/kg a day administered to colitis; thrombocytopenia dogs for up to a year caused no observable adverse effects{R-107}. The For erythromycin median lethal dose of oral tilmicosin in fasted rats is 800 mg/kg and in Incidence more frequent nonfasted rats is 2250 mg/kg{R-107}. Gastrointestinal disturbances Incidence less frequent CLINICAL EFFECTS OF OVERDOSE Hepatotoxicity; hypersensitivity; inﬂammation or phlebitis at The following effects have been selected on the basis of their potential the injection site—with parenteral erythromycins only; oral clinical signiﬁcance (possible signs in parentheses where appropri- candidiasis; vaginal candidiasis ate)—not necessarily inclusive: Incidence rare For tilmicosin—in order of their appearance Cardiac toxicity, especially QT prolongation and torsades de Dogs pointes; loss of hearing, usually reversible; pancreatitis Cardiovascular changes, including sinus tachycardia, myocar- Note: Hepatotoxicity has been associated rarely with all erythromycin dial depression, and reduced arterial pulse pressure (tremors, salts, but more frequently with erythromycin estolate. Reports rapid respiration, convulsions, and in severe cases, death)—noted suggest that a hypersensitivity mechanism may be involved. Liver with an intravenous dose of 2.5 mcg/kg{R-81}. function tests often indicate cholestasis. Symptoms typically appear within a few days to 1 or 2 weeks after the start of continuous therapy and are reversible when erythromycin is discontinued. TREATMENT OF OVERDOSE However, hepatotoxicity reappears promptly on readministration to For tilmicosin: The treatment of tilmicosin-induced cardiotoxicosis is not sensitive patients. yet well established. Tachycardia is believed to result in part from Loss of hearing is more likely to occur with administration of high stimulation of cardiac beta-receptors. In dogs, this effect is partially doses (‡ 4 grams per day) in patients with renal or hepatic disease blocked by propranolol; however, propranolol also potentiates the and/or in elderly patients. It appears to be related to high peak decreased cardiac contractility induced by tilmicosin{R-81}. Dobuta- plasma concentrations, usually exceeding 12 mcg per mL. Hearing mine may partially remedy the cardiac depression in dogs{R-81}. loss is usually reversible, although irreversible deafness has Epinephrine potentiated the lethality of intravenously administered occurred. It occurs 36 hours to 8 days after treatment is started tilmicosin in pigs{R-53}. and begins to dissipate within 1 to 14 days after erythromycin is discontinued. VETERINARY DOSING INFORMATION OVERDOSE Activity of the macrolides is highest in tissues and in environments with For more information in cases of overdose or unintentional ingestion, elevated pH.{R-1} contact the American Society for the Prevention of Cruelty to Organisms that develop resistance to one macrolide antibiotic may also Animals (ASPCA) National Animal Poison Control Center (888- be resistant to other macrolide antibiotics; this cross-resistance should 426-4435 or 900-443-0000; a fee may be required for consultation) be considered when alternative antibacterials are chosen{R-1}. Bacte- and/or the drug manufacturer. rial resistance to erythromycin seems to be more of a problem with

For azithromycin: Mice and rats—The LD50 for oral administration is repeated or continuous use; resistance decreases rapidly when 3000 to 4000 mg/kg{R-118}. medication is discontinued.{R-1} For tilmicosin: Greater susceptibility to toxicity from parenterally administered tilmicosin has been shown in goats, horses, and pigs FOR ORAL DOSAGE FORMS ONLY than in cattle.{R-81}. In all species tested, the primary toxic effect is Tylosin is more stable than erythromycin in acid environments cardiotoxicity{R-53; 81}. and therefore can be administered orally without enteric coating.{R-58} Intravenous administration of tilmicosin is not recommended for use in any species because an intravenous dose of 10 mg or less per kg of body weight (mg/kg) causes signs of toxicity and, in some cases, death FOR PARENTERAL DOSAGE FORMS ONLY in calves, cattle, goats, horses, and sheep{R-81}. Subcutaneous doses of Only the gluceptate and the lactobionate salts of erythromycin can be up to 30 mg/kg every 3 days for a total of three doses in cattle have administered intravenously. Other parenteral dosage forms must be been speciﬁed as the highest nontoxic dose in healthy cattle because administered by the intramuscular route only.

Cattle: The intramuscular route of administration for erythromycin is [Foals]1—Although the safety and efﬁcacy have not been established, recommended to avoid the poor absorption and intestinal side effects an oral dose of 10 mg per kg of body weight every twenty-four hours for associated with oral dosing and the poor absorption and more severe ﬁve days, followed by 10 mg per kg of body weight every forty-eight local reactions associated with subcutaneous administration{R-28}. hours has been recommended in the treatment of Rhodococcus equi Even with intramuscular injection, the effect of erythromycin on edible pneumonia, based on pharmacokinetic data{R-121; 122}. Erythromycin tissues should be considered before administration{R-95}. High-dose has typically been used in combination with rifampin in the treatment intravenous administration should be avoided unless the gluceptate or of R. equi pneumonia and the same might be expected for azithromycin; lactobionate forms are used{R-82} because immediate side effects have however, many clinicians are administering azithromycin without been reported with such administration. rifampin in the treatment of this infection.

Strength(s) usually available{R-116}: FOR TREATMENT OF ADVERSE EFFECTS U.S.— For anaphylaxis Veterinary-labeled product(s): Recommended treatment consists of the following: Not commercially available. • Parenteral epinephrine. Human-labeled product(s): • Oxygen administration and breathing support. 20 mg per mL (when reconstituted according to manufacturer’s • Parenteral fluid administration as needed. instruction) (available in 300-mg bottles) (Rx) [Zithromax (sucrose)]. Note: Parenteral epinephrine is not recommended treatment for 40 mg per mL (when reconstituted according to manufacturer’s tilmicosin toxicity because of adverse effects noted in pigs (see instruction) (available in 600-, 900-, and 1200-mg bottles) (Rx) {R-53} Overdose section); however, epinephrine is not contraindicated [Zithromax (sucrose)]. {R-100} for anaphylaxis due to tilmicosin . Canada— Veterinary-labeled product(s): Not commercially available. AZITHROMYCIN Human-labeled product(s): SUMMARY OF DIFFERENCES 20 mg per mL (when reconstituted according to manufacturer’s Pharmacology/pharmacokinetics: Distribution—Azithromycin concen- instruction) (available in 300-mg bottles) (Rx) [Zithromax trates in tissues, particularly in leukocytes, macrophages and fibroblasts (sucrose)]. and is slowly released from leukocytes{R-120; 121}. The intracellular 40 mg per mL (when reconstituted according to manufacturer’s reservoir of azithromycin produces effective drug concentrations in instruction) (available in 600- and 900-mg bottles) (Rx) [Zithro- interstitial fluids even after the plasma concentrations have declined max (sucrose)]. below detectable levels{R-121}. Azithromycin can be delivered to infected tissues and early abscesses via leukocytes{R-119}. Packaging and storage: Prior to reconstitution, store between 5 and 30 C (41 and 86 F) in a ORAL DOSAGE FORMS tight container. Note: Bracketed information in the Dosage Forms section refers to uses After reconstitution, the pediatric oral suspension should be stored that either are not included in U.S. product labeling or are for products between 5 and 30 C (41 and 86 F) and used within 10 days. not commercially available in the U.S. Preparation of dosage form: For the pediatric suspension, add the AZITHROMYCIN FOR ORAL SUSPENSION USP volume of water indicated on manufacturer’s product labeling to the Usual dose: bottle and shake well. Note: Dosing recommendations for the use of azithromycin in the treatment of animals are given with some caution advised. Unlike USP requirements: Preserve in tight containers. A dry mixture of other antibiotics for which there is limited clinical efficacy and safety Azithromycin and one or more buffers, sweeteners, diluents, antica- data, the ability of azithromycin to concentrate in tissues makes the king agents, and flavors. Contains the labeled amount, within ±10%. typical dosing estimation based on pharmacokinetic data more Meets the requirements for Identification, Uniformity of dosage units challenging. The following are current recommendations for dosing; (for solid packaged in single-unit containers), Deliverable volume, pH however, these may be supplanted as knowledge about azithromycin (9.0–11.0 [for solid packaged in single-unit containers], 8.5–11.0 [for increases: solid packaged in multiple-unit containers], in the suspension con- [Cats]1 and [dogs]1—Although the safety and efficacy have not been stituted as directed in the labeling), and Water not more than established, an oral dose of 3 to 5 mg per kg of body weight every 1.5%).{R-22} twenty-four hours for three to four days has been used to treat susceptible bacterial infections, based on pharmacokinetic data{R-120; AZITHROMYCIN TABLETS 123; 125–7}. For infections that require longer-term treatment, Usual dose: See Azithromycin For Oral Suspension USP. azithromycin has been administered for a maximum of 3 or 4 days a week; this is done either by administering the 3 to 5 mg per kg dose Strength(s) usually available{R-116}: every other day or by administering the same dose once on three U.S.— subsequent days (Monday, Tuesday, and Wednesday) each week, Veterinary-labeled product(s): with no treatment on the other four days of the week. Not commercially available.

Human-labeled product(s): CLARITHROMYCIN 250 mg (Rx) [Zithromax]. 500 mg (Rx) [Zithromax]. ORAL DOSAGE FORMS Canada— Note: Bracketed information in the Dosage Forms section refers to uses Veterinary-labeled product(s): that either are not included in U.S. product labeling or are for products Not commercially available. not commercially available in the U.S. Human-labeled product(s): CLARITHROMYCIN FOR ORAL SUSPENSION USP 250 mg (Rx) [Zithromax]. Usual dose: 500 mg (Rx) [Zithromax]. Note: Dosing recommendations for the use of clarithromycin in the treatment of animals are given with caution advised. Unlike other Packaging and storage: Store below 40 C (104 F), preferably be- antibiotics for which there is limited clinical efﬁcacy and safety data, tween 15 and 30 C (59 and 86 F), in a well-closed container. the ability of clarithromycin to concentrate in tissues makes the typical dosing estimation based on pharmacokinetic data more USP requirements: Not in USP{R-22}. challenging. One pharmacokinetic study suggested that 10 mg per kg a day may be an effective dose for [dogs]1, but did not attempt to 1Not included in Canadian product labeling or product not commercially recommend duration of therapy{R-124}. There are no reports of available in Canada. speciﬁc dosing regimens in common usage.

Strength(s) usually available{R-115}: When reconstituted according to PARENTERAL DOSAGE FORMS manufacturer’s instructions— U.S.: AZITHROMYCIN FOR INJECTION Veterinary-labeled product(s)— Not commercially available. Usual dose: Human-labeled product(s)— Note: There are no data at this time to recommend dosing for 25 mg per mL (Rx) [Biaxin]. parenteral azithromycin in animals. 50 mg per mL (Rx) [Biaxin]. Canada: Strength(s) usually available{R-115}: Veterinary-labeled product(s)— U.S.— Not commercially available. Veterinary-labeled product(s): Human-labeled product(s)— Not commercially available. 25 mg per mL (Rx) [Biaxin]. Human-labeled product(s): 50 mg per mL (Rx) [Biaxin]. 500 mg (Rx) [Zithromax]. Canada— Packaging and storage: Store between 15 and 30 C (59 and 86 F), Veterinary-labeled product(s): in a well-closed container. Protect from light. Not commercially available. Human-labeled product(s): Preparation of dosage form: Add the total volume of water indicated 500 mg (Rx) [Zithromax]. on manufacturer’s product labeling, in two portions, shaking well after each addition.

Packaging and storage: Store below 40 C (104 F), preferably be- Stability: After reconstitution, suspension retains its potency for 14 tween 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by days. Do not refrigerate. manufacturer.

USP requirements: Preserve in tight containers. A dry mixture of Preparation of dosage form: To prepare the initial solution for Clarithromycin, dispersing agents, diluents, preservatives, and flavor- intravenous infusion, add 4.8 mL of sterile water for injection to each ings. Contains the labeled amount, within –10 to +15%, labeled 500-mg vial and shake until all of the medication is dissolved. Further amount being 25 mg or 50 mg per mL when constituted as directed in dilute this solution by transferring it into 250 or 500 mL of a suitable the labeling. Meets the requirements for Identification, pH (4.0–5.4, in diluent (see manufacturer’s package insert) to provide a final con- the suspension constituted as directed in the labeling), Loss on drying centration of 2 or 1 mg per mL, respectively. (not more than 2.0%), and Deliverable volume.{R-22}

Stability: After reconstitution with sterile water for injection, the solu- CLARITHROMYCIN TABLETS USP tion is stable for 24 hours when stored below 30 C (86 F). After Usual dose: See Clarithromycin for Oral Suspension USP. dilution to 1 or 2 mg per mL in suitable diluent, solutions are stable for 24 hours at or below room temperature (30 C [86 F]), or for 7 days if Strength(s) usually available{R-115}: stored at 5 C (41 F). U.S.— Veterinary-labeled product(s): USP requirements: Not in USP{R-22}. Not commercially available.

Human-labeled product(s): Strength(s) usually available: 250 mg (Rx) [Biaxin]. U.S.— 500 mg (Rx) [Biaxin]. Veterinary-labeled product(s): Canada— Not commercially available. Veterinary-labeled product(s): Human-labeled product(s): Not commercially available. 250 mg (Rx) [ERYC; generic]. Human-labeled product(s): Canada— 250 mg (Rx) [Biaxin]. Veterinary-labeled product(s): 500 mg (Rx) [Biaxin]. Not commercially available. Human-labeled product(s): Packaging and storage: Store between 15 and 30 C (59 and 86 F), 250 mg (Rx) [Apo-Erythro E-C; ERYC-250; Novo-rythro Encap]. unless otherwise specified by the manufacturer. Protect from light. 333 mg (Rx) [Apo-Erythro E-C; ERYC-333]. Preserve in tight containers. Packaging and storage: Store below 40 C (104 F), preferably be- USP requirements: Preserve in tight containers. Contain the labeled tween 15 and 30 C (59 and 86 F), unless otherwise specified by amount, within ±10%. Meet the requirements for Identification, Dis- manufacturer. Store in a tight container. solution (80% in 30 minutes in 0.1 M Sodium acetate buffer in Apparatus 2 at 50 rpm), Uniformity of dosage units, and Loss on USP requirements: Preserve in tight containers. Contain the labeled drying (not more than 6.0%).{R-22} amount, within –10% to +15%. Meet the requirements for Identifi- cation, Drug release (Method B: 80% in 60 minutes for Acid stage and CLARITHROMYCIN EXTENDED-RELEASE TABLETS 60 minutes for Buffer stage in Apparatus 1 at 50 rpm), and Water (not Usual dose: more than 7.5%).{R-22} Note: There is no specific evidence that human extended-release dosage forms are completely absorbed by animals; therefore, reliable ERYTHROMYCIN TABLETS USP 1 dose recommendations cannot be made. Usual dose: [Pyoderma] —Dogs: Oral, 10 to 20 mg per kg of body weight every eight to twelve hours.{R-30; 42–44; 60} Strength(s) usually available{R-115}: Note: The above dose recommendation is based on current clinical practice U.S.— rather than specific canine pharmacokinetic data. The absorption of {R-21} Veterinary-labeled product(s): enteric-coated tablets in dogs can be unpredictable. Not commercially available. Strength(s) usually available: Human-labeled product(s): U.S.— 500 mg (Rx) [Biaxin XL]. Veterinary-labeled product(s): Canada— Not commercially available. Veterinary-labeled product(s): Human-labeled product(s): Not commercially available. 250 mg (Rx) [generic]. Human-labeled product(s): 500 mg (Rx) [generic]. 500 mg (Rx) [Biaxin XL]. Canada— Veterinary-labeled product(s): Packaging and storage: Store between 15 and 30 C (59 and 86 F), Not commercially available. unless otherwise specified by the manufacturer. Protect from light. Human-labeled product(s): 250 mg (Rx) [Apo-Erythro; Erythromid]. USP requirements: Not in USP.{R-22}

Packaging and storage: Store below 40 C (104 F), preferably be- 1Not included in Canadian product labeling or product not commercially tween 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by available in Canada. manufacturer. Store in a tight container.

USP requirements: Preserve in tight containers. Contain the labeled ERYTHROMYCIN BASE amount, within –10% to +20%. Meet the requirements for Identiﬁ- cation, Dissolution (70% in 60 minutes in 0.05 M phosphate buffer ORAL DOSAGE FORMS [pH 6.8] in Apparatus 2 at 50 rpm), Uniformity of dosage units, and Note: Bracketed information in the Dosage Forms section refers to uses Loss on drying (not more than 5.0%).{R-22} that either are not included in U.S. product labeling or are for products Note: Tablets that are enteric-coated meet the requirements for not commercially available in the U.S. Erythromycin Delayed-release Tablets.{R-22}

ERYTHROMYCIN DELAYED-RELEASE CAPSULES USP ERYTHROMYCIN DELAYED-RELEASE TABLETS USP Usual dose: Usual dose: Note: There is no speciﬁc evidence that human delayed-release dosage Note: There is no speciﬁc evidence that human delayed-release dosage forms are completely absorbed by animals; therefore, reliable dose forms are completely absorbed by animals; therefore, reliable dose recommendations cannot be made. recommendations cannot be made.

Strength(s) usually available: Note: The above dose is higher than those stated on U.S. or U.S.— Canadian product labeling. Veterinary-labeled product(s): Pigs (treatment of respiratory syndrome): Intramuscular, 1.1 to 3.3 Not commercially available. mg per kg of body weight every twenty-four hours{R-111}. Human-labeled product(s): Note: Injections should be made deep into the muscle.{R-6} Erythro- 250 mg (Rx) [E-Mycin; Ery-Tab; Ilotycin; generic]. mycin injection should not be administered intravenously or 333 mg (Rx) [E-Base; E-Mycin; Ery-Tab; PCE; generic]. subcutaneously. 500 mg (Rx) [E-Base; Ery-Tab; PCE]. Pododermatitis—Cattle: Intramuscular, 1.1 to 2.2 mg per kg of body Canada— weight every twenty-four hours{R-111}. Veterinary-labeled product(s): Respiratory tract infections, bacterial (treatment)— Not commercially available. Pigs (treatment of respiratory syndrome): Intramuscular, 1.1 to 3.3 Human-labeled product(s): mg per kg of body weight every twenty-four hours{R-111}. 250 mg (Rx) [E-Mycin; generic]. Sheep (treatment of upper respiratory tract infections): Intramus- 333 mg (Rx) [PCE]. cular, 1.1 mg per kg of body weight every twenty-four 500 mg (Rx) [Erybid]. hours{R-111}.

Packaging and storage: Store below 40 C (104 F), preferably Strength(s) usually available: between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by U.S.—{R-6; 8} manufacturer. Store in a tight container. Veterinary-labeled product(s): 100 mg per mL (OTC) [Gallimycin-100]. USP requirements: Preserve in tight containers. The label indicates 200 mg per mL (OTC) [Gallimycin-200]. that Erythromycin Delayed-release Tablets are enteric-coated. The Canada—{R-7; 8} labeling indicates the Drug Release Test with which the product Veterinary-labeled product(s): complies. Contain the labeled amount, within –10% to +20%. Meet the 200 mg per mL (OTC) [Erythro-200; Gallimycin-200]. requirements for Identiﬁcation, Drug Release (Method B: 75% in 60 Withdrawal times: minutes for Acid stage and 60 minutes for Buffer stage in Apparatus 1 U.S.— at 100 rpm for Test 1 and in Apparatus 2 at 75 rpm for Test 2), For Gallimycin-200{R-6}: Uniformity of dosage units, and Water (not more than 6.0%).{R-22} Withdrawal time 1 Not included in Canadian product labeling or product not commercially Species Meat (days) available in Canada. Cattle 6

PARENTERAL DOSAGE FORMS Note: Product labeling listing the above withdrawal time states that it Note: Bracketed information in the Dosage Forms section refers to uses applies to a dose of 8.8 mg per kg of body weight every 24 hours that either are not included in U.S. product labeling or are for products and a course of therapy not exceeding 5 days. Higher doses or not commercially available in the U.S. longer duration of treatment may increase withdrawal times. This product is not labeled for use in lactating dairy cattle. To avoid ERYTHROMYCIN INJECTION USP excessive trim, cattle should not be slaughtered for 21 days after the Usual dose: last injection. Enteritis (scours)—Piglets, one week of age or older: Intramuscular, 11 For Gallimycin-100{R-111}: mg per kg of body weight every twenty-four hours{R-111}. Withdrawal time Enterotoxemia (lamb dysentery) (prophylaxis)—Lambs, newborn: Intramuscular, 5.5 mg per kg of body weight every twenty-four Species Meat (day) Milk (hours) {R-111} hours, as soon after birth as is practical . Cattle 14 72 Leptospirosis—Sows, farrowing: Intramuscular, 1.1 to 3.3 mg per kg of Pigs 7 body weight every twenty-four hours{R-111}. Sheep 3 Metritis— Cattle: Intramuscular, 1.1 to 2.2 mg per kg of body weight every Note: Product labeling listing the above withdrawal times states that they twenty-four hours{R-111}. apply to a dose of 1.1 to 2.2 mg per kg of body weight for cattle, 1.1 to Sows, farrowing: Intramuscular, 1.1 to 3.3 mg per kg of body weight 3.3 mg per kg of body weight for pigs, and 1.1 mg per kg of body every twenty-four hours{R-111}. weight for sheep. {R-7} Pneumonia, bacterial— Canada— Cattle: Intramuscular, 2.2{R-111} to 8.8{R-6} mg per kg of body weight Withdrawal time every twenty-four hours. Species Meat (day) Milk (hours) Note: See product labeling for the above dosing recommendations with applicable withdrawal times. Cattle 14 72 Pigs 7 For pneumonic pasteurellosis—[Intramuscular, 15 mg per kg of body Sheep 3 weight every twelve hours.{R-24; 28}]1

Canada— Note: Product labeling listing the above withdrawal times states that the Veterinary-labeled product(s): recommended withdrawal times apply to doses of 2.2 to 4.4 mg per kg Not commercially available. of body weight in cattle, 22 mg per kg of body weight in piglets, 2.2 to Human-labeled product(s): 6.6 mg per kg of body weight in pigs, 11 mg per kg of body weight in 250 mg (base) (Rx) [Ilosone; Novo-rythro]. lambs, and 2.2 mg per kg of body weight in sheep; administered every 24 hours in each species. To avoid excessive trim, cattle should not be Packaging and storage: Store below 40 C (104 F), preferably slaughtered for 21 days after the last injection; for pigs and sheep, the between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by waiting period is 10 days. manufacturer. Store in a tight container.

Packaging and storage: Store below 40 C (104 F), preferably be- USP requirements: Preserve in tight containers. Contain an amount of tween 15 and 30 C (59 and 86 F), unless otherwise specified by erythromycin estolate equivalent to the labeled amount of erythro- manufacturer. Protect from freezing. mycin, within –10% to +15%. Meet the requirements for Identifica- tion, Disintegration (30 minutes), Uniformity of dosage units, and {R-22} USP requirements: Preserve in multiple-dose containers. A sterile Water (not more than 5.0%). solution of Erythromycin in a polyethylene glycol vehicle. Label it to indicate that it is for veterinary use only. Label it to state that it is for ERYTHROMYCIN ESTOLATE ORAL SUSPENSION USP intramuscular administration only. Contains the labeled amount, Usual dose: See Erythromycin Estolate Capsules USP. within –10% to +20%. Meets the requirements for Identification, Strength(s) usually available: Water (not more than 1.0%), and Sterility, and for Injections.{R-22} U.S.— Veterinary-labeled product(s): 1Not included in Canadian product labeling or product not commercially Not commercially available. available in Canada. Human-labeled product(s): 25 mg (base) per mL (Rx) [Ilosone; generic]. ERYTHROMYCIN ESTOLATE 50 mg (base) per mL (Rx) [Ilosone; generic]. Canada— SUMMARY OF DIFFERENCES Veterinary-labeled product(s): Pharmacology/pharmacokinetics: Absorption—Erythromycin estolate is Not commercially available. absorbed as the ester from the duodenum and is hydrolyzed to free base Human-labeled product(s): in the body.{R-1; 18} 25 mg (base) per mL (Rx) [Ilosone; Novo-rythro]. Side/adverse effects: In humans, erythromycin estolate has been asso- 50 mg (base) per mL (Rx) [Ilosone; Novo-rythro]. ciated with an increased risk of subclinical hepatotoxicity during pregnancy and an increased risk of cholestatic jaundice at any time. Packaging and storage: Store between 2 and 8 C (36 and 46 F). These effects have not been reported in animals; however, periodic Store in a tight container. liver function tests for animals receiving long-term erythromycin estolate therapy have been recommended.{R-2} Auxiliary labeling: • Refrigerate. • Shake well. ORAL DOSAGE FORMS Note: Bracketed information in the Dosage Forms section refers to uses USP requirements: Preserve in tight containers, in a cold place. Con- that either are not included in U.S. product labeling or are for products tains one or more suitable buffers, colors, diluents, dispersants, and not commercially available in the U.S. flavors. Contains an amount of erythromycin estolate equivalent to the The dosing and strengths of the dosage forms available are expressed labeled amount of erythromycin, within –10% to +15%. Meets the in terms of erythromycin base (not the estolate salt). requirements for Identification, Uniformity of dosage units (single-unit containers), Deliverable volume, and pH (3.5–6.5){R-22}. ERYTHROMYCIN ESTOLATE CAPSULES USP Usual dose: [Rhodococcus equi pneumonia]1—Foals: Oral, 25 mg (base) ERYTHROMYCIN ESTOLATE TABLETS USP {R-13; 14; 26} per kg of body weight every six hours. Usual dose: See Erythromycin Estolate Capsules USP. Note: The above dose has also been administered concurrently with 5 mg rifampin per kg of body weight.{R-13; 14} The doses recommended are Strength(s) usually available. based on pharmacokinetic and clinical efficacy studies in foals.{R-13; 14; U.S.— 26} Veterinary-labeled product(s): Not commercially available. Strength(s) usually available: Human-labeled product(s): U.S.— 250 mg (base) (Rx) [generic]. Veterinary-labeled product(s): 500 mg (base) (Rx) [Ilosone]. Not commercially available. Canada— Human-labeled product(s): Veterinary-labeled product(s): 250 mg (base) (Rx) [Ilosone; generic]. Not commercially available.

Human-labeled product(s): USP requirements: Preserve in tight containers, and store in a cold 500 mg (base) (Rx) [Ilosone]. place. A suspension of Erythromycin Ethylsuccinate containing one or more suitable buffers, colors, dispersants, flavors, and preservatives. Packaging and storage: Store below 40 C (104 F), preferably be- Contains an amount of erythromycin ethylsuccinate equivalent to the tween 15 and 30 C (59 and 86 F), unless otherwise specified by the labeled amount of erythromycin, within –10% to +20%. Meets the manufacturer. Store in a tight container. requirements for Identification, Uniformity of dosage units (single-unit containers), Deliverable volume, and pH (6.5–8.5).{R-22} USP requirements: Preserve in tight containers. Label Tablets to indicate whether they are to be chewed before swallowing. Contain an ERYTHROMYCIN ETHYLSUCCINATE FOR ORAL amount of erythromycin estolate equivalent to the labeled amount of SUSPENSION USP erythromycin, within –10% to +20% (+15%, if chewable). Meet the Usual dose: See Erythromycin Ethylsuccinate Oral Suspension USP. requirements for Identification, Disintegration (30 minutes [Note: Chewable tablets are exempt from this requirement]), Uniformity of Strength(s) usually available: When reconstituted according to dosage units, and Water (not more than 5.0%; if chewable, not more manufacturer’s instructions— than 4.0%).{R-22} U.S.: Veterinary-labeled product(s): 1Not included in Canadian product labeling or product not commercially Not commercially available. available in Canada. Human-labeled product(s): 40 mg per mL (Rx) [E.E.S.; EryPed; generic]. 80 mg per mL (Rx) [EryPed; generic]. ERYTHROMYCIN ETHYLSUCCINATE Canada: Veterinary-labeled product(s): SUMMARY OF DIFFERENCES Not commercially available. Pharmacology/pharmacokinetics: Absorption— Human-labeled product(s): {R-1} Absorbed as the ester, then hydrolyzed to free base in the body. 20 mg per mL (Rx) [Novo-Rythro]. Pigeons: Orally administered erythromycin ethylsuccinate has a 40 mg per mL (Rx) [E.E.S.; Novo-Rythro]. {R-27} relative bioavailability of less than 10%. 80 mg per mL (Rx) [E.E.S.].

ORAL DOSAGE FORMS Packaging and storage: Prior to reconstitution, store below 40 C Note: The strengths of the dosage forms available are expressed in terms (104 F), preferably between 15 and 30 C (59 and 86 F), unless of the ethylsuccinate salt. In people, 400 mg of erythromycin otherwise specified by manufacturer. Store in a tight container. ethylsuccinate produces approximately the same blood concentrations Stability: After reconstitution, depending on the manufacturer or the as 250 mg of erythromycin base. specific product, suspensions do not require refrigeration if used within 1.17 grams of erythromycin ethylsuccinate equal 1 gram of erythro- 14 days. mycin base{R-90}. USP requirements: Preserve in tight containers. A dry mixture of ERYTHROMYCIN ETHYLSUCCINATE ORAL Erythromycin Ethylsuccinate with one or more suitable buffers, colors, SUSPENSION USP diluents, dispersants, and flavors. Contains an amount of erythromy- Usual dose: cin ethylsuccinate equivalent to the labeled amount of erythromycin, Note: There are no dose recommendations specific to animals for this within –10% to +20%. Meets the requirements for Identification, dosage form. Uniformity of dosage units (single-unit containers), Deliverable volume, pH (7.0–9.0, in the suspension constituted as directed in the Strength(s) usually available: labeling), and Loss on drying (not more than 1.0%).{R-22} U.S.— Veterinary-labeled product(s): ERYTHROMYCIN ETHYLSUCCINATE TABLETS USP Not commercially available. Usual dose: See Erythromycin Ethylsuccinate Oral Suspension USP. Human-labeled product(s): 40 mg per mL (Rx) [E.E.S.; Erythro; generic]. Strength(s) usually available. 80 mg per mL (Rx) [E.E.S.; Erythro; generic]. U.S.— Canada— Veterinary-labeled product(s): Not commercially available. Not commercially available. Human-labeled product(s): Packaging and storage: Store between 2 and 8 C (36 and 46 F). 400 mg (Rx) [E.E.S.; generic]. Store in a tight container. Canada— Veterinary-labeled product(s): Stability: After dispensing, suspensions do not require refrigeration if Not commercially available. used within 14 days. Some manufacturers recommend storage in Human-labeled product(s): light-resistant containers to prevent discoloration.{R-36} 600 mg (Rx) [Apo-Erythro-ES; E.E.S.].

Packaging and storage: Store below 40 C (104 F), preferably be- STERILE ERYTHROMYCIN GLUCEPTATE USP tween 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by Usual dose: [Antibacterial]1—Foals: Intravenous, 5 mg (base) per kg of manufacturer. Store in a tight container. body weight every four to six hours.{R-26}

USP requirements: Preserve in tight containers. Label the chewable Size(s) usually available: Tablets to indicate that they are to be chewed before swallowing. U.S.— Contain an amount of erythromycin ethylsuccinate equivalent to the Veterinary-labeled product(s): labeled amount of erythromycin, within –10% to +20%. Meet the Not commercially available. requirements for Identiﬁcation, Dissolution (75% in 45 minutes in Human-labeled product(s): 0.01 N hydrochloric acid in Apparatus 2 at 50 rpm for nonchewable 1 gram (base) (Rx) [Ilotycin]. tablets and 75% in 60 minutes in 0.1 M acetate buffer [pH 5.0] in Canada— Apparatus 2 at 75 rpm for Tablets labeled as chewable), Uniformity of Veterinary-labeled product(s): dosage units, Loss on drying (not more than 4.0% [Note: Chewable Not commercially available. Tablets are exempt from this requirement]), and Water (Chewable Human-labeled product(s): Tablets only, not more than 5.0%).{R-22} 500 mg (base) (Rx) [Ilotycin]. 1 gram (base) (Rx) [Ilotycin]. ERYTHROMYCIN ETHYLSUCCINATE TABLETS Packaging and storage: Prior to reconstitution, store below 40 C (CHEWABLE) USP (104 F), preferably between 15 and 30 C (59 and 86 F), unless Usual dose: See Erythromycin Ethylsuccinate Oral Suspension USP. otherwise speciﬁed by manufacturer.

Strength(s) usually available: Preparation of dosage form:{R-37} U.S.— To prepare solution, add at least 10 mL of sterile water for injection to Veterinary-labeled product(s): each 500-mg vial and at least 20 mL of diluent to each 1-gram vial. Not commercially available. After initial dilution, solution may be further diluted to a concentration of Human-labeled product(s): 1 gram per L in 0.9% sodium chloride injection or 5% dextrose 200 mg (Rx) [EryPed]. injection for slow, continuous infusion. 400 mg (Rx) [Erythro]. Stability: After reconstitution, initial dilutions (25 to 50 mg per mL) Canada— retain their potency for 7 days if refrigerated.{R-37} Veterinary-labeled product(s): Not commercially available. USP requirements: Preserve in Containers for Sterile Solids. It is Human-labeled product(s): Erythromycin Gluceptate suitable for parenteral use. Has a potency 200 mg (Rx) [E.E.S. (scored); EryPed]. equivalent to not less than 600 mcg of erythromycin per mg, calculated on the anhydrous basis. In addition, where packaged for dis- Packaging and storage: Store below 40 C (104 F), preferably be- pensing, contains an amount of erythromycin gluceptate equivalent to tween 15 and 30 C (59 and 86 F), unless otherwise specified by the labeled amount of erythromycin, within –10% to +15%. Meets the manufacturer. Store in a tight container. requirements for Identification, Bacterial endotoxins, Sterility, pH (6.0–8.0, in a solution containing 25 mg per mL), Water (not more USP requirements: Preserve in tight containers. Label the chewable than 5.0%), and Particulate matter, and, where packaged for dis- Tablets to indicate that they are to be chewed before swallowing. pensing, Uniformity of dosage units, Constituted solutions, and Contain an amount of erythromycin ethylsuccinate equivalent to the Labeling under Injections.{R-22} labeled amount of erythromycin, within –10% to +20%. Meet the requirements for Identification, Dissolution (75% in 45 minutes in 1Not included in Canadian product labeling or product not commercially 0.01 N hydrochloric acid in Apparatus 2 at 50 rpm for nonchewable available in Canada. tablets and 75% in 60 minutes in 0.1 M acetate buffer [pH 5.0] in Apparatus 2 at 75 rpm for Tablets labeled as chewable), Uniformity of ERYTHROMYCIN LACTOBIONATE dosage units, Loss on drying (not more than 4.0% [Note: Chewable Tablets are exempt from this requirement]), and Water (Chewable PARENTERAL DOSAGE FORMS Tablets only, not more than 5.0%).{R-22} Note: The strengths of the dosage forms available are expressed in terms of erythromycin base (not the lactobionate salt).

ERYTHROMYCIN LACTOBIONATE FOR INJECTION USP ERYTHROMYCIN GLUCEPTATE Usual dose: Note: There are no dose recommendations speciﬁc to animals for this PARENTERAL DOSAGE FORMS dosage form. Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products Size(s) usually available: not commercially available in the U.S. U.S.—{R-39} The dosing and strengths of the dosage forms available are expressed Veterinary-labeled product(s): in terms of erythromycin base (not the gluceptate salt). Not commercially available.

Human-labeled product(s): Enteritis—Turkeys: Oral, 500 mg per gallon of water, administered as 500 mg (base) (Rx) [Erythrocin; generic]. the only source of drinking water for seven days.{R-3} 1 gram (base) (Rx) [Erythrocin; generic]. Note: Dosage ranges for birds are approximate, based on variable water Canada— consumption and animal size. Veterinary-labeled product(s): Strength(s) usually available: Not commercially available. U.S.—{R-3; 6; 8} Human-labeled product(s): Veterinary-labeled product(s): 500 mg (base) (Rx) [Erythrocin]. 260 mg (231.2 mg erythromycin base) per gram (OTC) [Gallimycin 1 gram (base) (Rx) [Erythrocin]. PFC]. {R-8; 9} Packaging and storage: Prior to reconstitution, store below 40 C Canada— (104 F), preferably between 15 and 30 C (59 and 86 F), unless Veterinary-labeled product(s): otherwise specified by manufacturer. 130 mg (115.6 mg base) per gram (OTC) [Gallimycin; Gallistat]. 260 mg (231.2 mg base) per gram (OTC) [Gallimycin PFC]. Preparation of dosage form: See manufacturer’s product labeling. Withdrawal times: {R-3; 9} Stability: U.S. and Canada— After reconstitution, initial dilutions (50 mg per mL) retain their potency Withdrawal time for 14 days if refrigerated, or for 24 hours at room temperature. Species Meat (days) Infusions prepared in piggyback infusion bottles retain their potency for 8 hours at room temperature, for 24 hours if refrigerated, or for 30 days Chickens and turkeys 1 if frozen. Acidic infusions are unstable and lose potency rapidly. A pH of at least Note: Products are not labeled for use in birds producing eggs for human {R-3; 9} 5.5 is recommended for final dilutions, which should be administered consumption or in replacement pullets over 16 weeks of age . completely within 8 hours after dilution. Canadian product labeling lists the dose as 116 mg (base) per liter of water for chickens and turkeys. USP requirements: Preserve in Containers for Sterile Solids. A sterile, dry mixture of erythromycin lactobionate and a suitable preservative. Con- Packaging and storage: Store below 40 C (104 F), preferably be- tains an amount of erythromycin lactobionate equivalent to the labeled tween 15 and 30 C (59 and 86 F), unless otherwise specified by amount of erythromycin, within –10% to +20%. Meets the requirements manufacturer. for Constituted solution, Identification, Bacterial endotoxins, pH (6.5– Stability: Solutions should be discarded after 3 days.{R-8} 7.5, in a solution containing the equivalent of 50 mg of erythromycin per {R-22} mL), Water (not more than 5.0%), Particulate matter, and Heavy metals USP requirements: Not in USP . (not more than 0.005%), and for Injections.{R-22} ERYTHROMYCIN STEARATE ERYTHROMYCIN PHOSPHATE SUMMARY OF DIFFERENCES SUMMARY OF DIFFERENCES Pharmacology/pharmacokinetics: Absorption—Erythromycin stearate dissociates in the duodenum and is absorbed as the free base.{R-18} Pharmacology/pharmacokinetics: Absorption— Erythromycin phosphate is presumed to dissociate in the duodenum and be absorbed as the free base.{R-18} ORAL DOSAGE FORMS Horses: Erythromycin phosphate is absorbed at least as well as Note: Bracketed information in the Dosage Forms section refers to uses erythromycin estolate when administered orally.{R-18} that either are not included in U.S. product labeling or are for products not commercially available in the U.S. The dosing and strengths of the dosage forms available are expressed ORAL DOSAGE FORMS in terms of erythromycin base (not the stearate salt). Note: The dosing and strengths of the dosage form available are expressed in terms of erythromycin phosphate (not erythromycin base). ERYTHROMYCIN STEARATE ORAL SUSPENSION 1.12 grams of erythromycin phosphate equal 1 gram of erythromycin Usual dose: [Enteritis, Campylobacter]1—Dogs: Oral, 10 mg (base) per {R-8} base . kg of body weight every eight hours.{R-10}

ERYTHROMYCIN PHOSPHATE POWDER FOR ORAL Strength(s) usually available: SOLUTION U.S.— Usual dose: Not commercially available. Chronic respiratory disease—Chickens: Oral, 500 mg per gallon of Canada— water, administered as the only source of drinking water every Veterinary-labeled product(s): twenty-four hours for ﬁve days{R-3}. Not commercially available. Coryza, infectious—Chickens: Oral, 500 mg per gallon of water, Human-labeled product(s): administered as the only source of drinking water for seven 25 mg (base) per mL (Rx) [Erythrocin; Novo-rythro]. days.{R-3} 50 mg (base) per mL (Rx) [Erythrocin; Novo-rythro].

Packaging and storage: Store below 40 C (104 F), preferably Respiratory disease, chronic (treatment)—Chickens and turkeys1: Oral, between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by 200 grams (185 grams of base) per ton of feed, fed as the only manufacturer. Store in a tight container. ration.{R-54}

Auxiliary labeling: Strength(s) usually available: • Refrigerate. U.S.—{R-8; 54} • Shake well. Veterinary-labeled product(s): 220 grams (203 grams of base) per kg of premix (OTC) [Erymycin-100]. {R-22} USP requirements: Not in USP. Canada—{R-8; 64} Veterinary-labeled product(s): ERYTHROMYCIN STEARATE TABLETS USP 110 grams (102 grams of base) per kg of premix (OTC) [Gallimycin-50]. Usual dose: See Erythromycin Stearate Oral Suspension. Withdrawal times: U.S.—{R-54} Strength(s) usually available: With a dose of 200 grams (185 grams of base) per ton of feed: U.S.— Veterinary-labeled product(s): Withdrawal time Not commercially available. Species Meat (days) Human-labeled product(s): Chickens 2 250 mg (base) (Rx) [Erythrocin; Erythrocot; My-E; Wintrocin; generic]. Turkeys 0 500 mg (base) (Rx) [Erythrocin; generic]. Canada— Note: Product is not labeled for use in birds producing eggs for human Veterinary-labeled product(s): consumption{R-54}. Not commercially available. Human-labeled product(s): With a dose of 100 grams (93 grams of base) per ton of feed: 250 mg (base) (Rx) [Apo-Erythro-S; Erythrocin; Novo-rythro]. Withdrawal time 500 mg (base) (Rx) [Apo-Erythro-S; Erythrocin]. Species Meat (days) Packaging and storage: Store below 40 C (104 F), preferably be- Chickens 1 tween 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by Turkeys 0 manufacturer. Store in a tight container. Note: Some manufacturers recommend storage in light-resistant con- Note: Product is not labeled for use in birds producing eggs for human tainers to prevent discoloration. consumption{R-54}. Canada— USP requirements: Preserve in tight containers. Contain an amount of Withdrawal time erythromycin stearate equivalent to the labeled amount of erythromycin, within –10% to +20%. Meet the requirements for Identiﬁca- Species Meat (days) tion, Dissolution (75% in 120 minutes in 0.05 M phosphate buffer [pH Chickens 1 6.8] in Apparatus 2 at 100 rpm), Uniformity of dosage units, and Loss {R-22} on drying (not more than 5.0%). Note: Product labeling listing the above withdrawal time states that it applies to a dose of 220 grams per metric ton (1000 kg) of feed, fed as 1 Not included in Canadian product labeling or product not commercially the only ration, to chickens.{R-64} available in Canada. Not labeled for use in chickens producing eggs for human consumption.

Packaging and storage: Store below 40 C (104 F), preferably between ERYTHROMYCIN THIOCYANATE 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by manufacturer.

ORAL DOSAGE FORMS USP requirements: Not in USP.{R-22} Note: 1.08 grams of thiocyanate salt equal 1 gram of erythromycin base{R-54}. 1Not included in Canadian product labeling or product not commercially available in Canada. ERYTHROMYCIN THIOCYANATE FOR MEDICATED FEED Usual dose: TILMICOSIN PHOSPHATE Coryza, infectious (prophylaxis)1—Chickens: Oral, 100 grams (93 grams of base) per ton of feed, fed as the only ration for seven to ADDITIONAL DOSING INFORMATION fourteen days.{R-54} Tilmicosin injection should be given only by subcutaneous administra- Respiratory disease, chronic (prophylaxis)1—Chickens and turkeys: Oral, tion because intravenous administration is fatal with doses as low as 5 100 grams (93 grams of base) per ton of feed, fed as the only ration from mg per kg of body weight.{R-53} two days before stress until three to six days after stress.{R-54} Parenteral administration of tilmicosin to pigs by any route often is fatal.{R-53}

ORAL DOSAGE FORMS Note: Tilmicosin should not be administered intravenously. Intramus- Note: The dosing and strengths of the dosage form available are cular administration should be avoided. No more than 15 mL should {R-53} expressed in terms of tilmicosin base (not the phosphate salt). be administered per injection site.

TILMICOSIN FOR MEDICATED FEED Strength(s) usually available{R-8}: Usual dose: Pneumonia, bacterial—Pigs: Oral, 181 to 383 grams per U.S.— ton of feed, fed as the only ration for twenty-one days, beginning Veterinary-labeled product(s): approximately seven days before an anticipated disease outbreak, if 300 mg (base) per mL (Rx) [Micotil]. possible{R-107; 114}. Canada— Veterinary-labeled product(s): {R-8} Strength(s) usually available : 300 mg (base) per mL (Rx) [Micotil]. U.S.— Veterinary-labeled product(s): Withdrawal times: 200 grams (base) per kg (90.7 grams [base] per pound) of premix U.S.— (Rx) [Pulmotil 90]. Withdrawal time Canada— Veterinary-labeled product(s): Species Meat (days)

200 grams (base) per kg (OTC) [Pulmotil Premix]. Cattle 28 Withdrawal times: U.S.{R-107}— Note: Product labeling listing the above withdrawal time states that it

Withdrawal time applies to a dose of 10 mg (base) per kg of body weight administered once to cattle. Species Meat (days) Not labeled for use in lactating cattle. Pigs 7 Tilmicosin should not be used in lactating dairy cows because of its extended antimicrobial activity in milk. A single subcutaneous Canada{R-114}— tilmicosin dose of 10 mg per kg of body weight resulted in tilmicosin concentrations detectable in milk for 19 to 31 days when measured by Withdrawal time high performance liquid chromatography or 14 to 21 days when {R-74} Species Meat (days) measured by Bacillus stearothermophilus assay . Canada— Pigs 7 Withdrawal time

Packaging and storage: Store below 40 C (104 F), preferably be- Species Meat (days)

tween 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by Calves, cattle, lambs 28 manufacturer.

Preparation of dosage form: Tilmicosin should not be mixed in con- Note: Product labeling listing the above withdrawal time states that it centrates or feeds containing bentonite because bentonite may reduce applies to a dose of 10 mg (base) per kg of body weight administered the efﬁcacy of tilmicosin{R-107}. Premix should be thoroughly mixed in once to cattle or lambs{R-112}. feed before administration{R-107}. Not labeled for use in lactating dairy cattle, veal calves, calves weighing less than 70 kg, or lactating sheep{R-92}. Caution: Inhalation, oral exposure, and direct contact with eyes should {R-107} be avoided . Packaging and storage: Store at or below 30 C (86 F). Protect from light.{R-53} USP requirements: Not in USP.{R-22} Caution: Injection of tilmicosin in humans may be fatal. Caution should PARENTERAL DOSAGE FORMS be exercised to avoid self-injection. An automatically powered syringe Note: Bracketed information in the Dosage Forms section refers to uses should not be used for administration.{R-53} that either are not included in U.S. product labeling or are for products not commercially available in the U.S. Auxiliary labeling: The dosing and strengths of the dosage form available are expressed in • Keep out of the reach of children. terms of tilmicosin base (not the phosphate salt). • Avoid contact with eyes.

TILMICOSIN INJECTION USP USP requirements: Preserve in light-resistant Containers for Injec- Usual dose: Pneumonia, bacterial— tions. Store at or below 30. A sterile solution of Tilmicosin in a Cattle: Subcutaneous, 10 mg (base) per kg of body weight as a single mixture of Propylene Glycol and Water for Injection, solubilized with dose{R-53}. the aid of Phosphoric Acid. Label the Injection to indicate that it is for [Calves] and [lambs]: Subcutaneous, 10 mg (base) per kg of body veterinary use only. Contains the labeled amount, within ±10%. Meets weight as a single dose{R-65; 112}. the requirements for Identiﬁcation, Bacterial endotoxins, Sterility, pH

(5.5–6.5), Particulate matter, and Content of propylene glycol (within If tylosin-medicated drinking water is used as a follow-up treatment for ±20% of labeled amount){R-22}. swine dysentery, feed containing 40 to 100 grams of tylosin phosphate for medicated feed per ton of feed is recommended to assure depletion TYLOSIN BASE of tissue residues.{R-51; 52} Canada—{R-55} SUMMARY OF DIFFERENCES Withdrawal time Pharmacology/pharmacokinetics: Tylosin is stable enough in acid envi- {R-58} ronments to be administered orally without enteric coating. Species Meat (days)

PARENTERAL DOSAGE FORMS Cattle 21 Pigs 14 Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products Note: Product labeling listing the above withdrawal times states that they not commercially available in the U.S. apply to a dose of 17.6 mg per kg of body weight (mg/kg) for cattle and 2.2 to 8.8 mg/kg every 24 hours for pigs. Not for use in lactating dairy TYLOSIN INJECTION cattle. Usual dose: To avoid excessive trim, swine should not be slaughtered for 21 days Arthritis, infectious1; after treatment; cattle should not be slaughtered for 42 days after Erysipelas; or treatment.{R-55} Swine dysentery—Pigs: Intramuscular, 8.8 mg per kg of body weight every twelve hours{R-51}. Packaging and storage: Store below 40 C (104 F), preferably Note: When used to treat swine dysentery, tylosin injection should be between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by followed by administration of medication in feed or drinking manufacturer. water.{R-51} Diphtheria1; Incompatibilities: To avoid precipitation, tylosin injection should not Metritis; or be mixed with other injectables.{R-51} Pododermatitis1—Cattle, beef and nonlactating dairy: Intramuscular, 17.6 mg per kg of body weight every twenty-four hours.{R-51; 52; 55}. Caution: Pneumonia, bacterial— Contact with human skin should be avoided. Cattle, beef and nonlactating dairy: Intramuscular, 17.6 mg per kg of Injection into pigs weighing less than 6.25 pounds should not be attempted body weight every twenty-four hours{R-51; 55}. unless the syringe is capable of accurately delivering 0.1 mL. Adverse Pigs: Intramuscular, 8.8 mg per kg of body weight every twelve reactions may occur from overdosage in piglets.{R-51; 52} hours{R-51}. Note: In pigs, no more than 5 mL per injection site is recommended; USP requirements: Not in USP.{R-22} in cattle, no more than 10 mL per injection site.{R-51; 52} Note: [Cats]1 and [dogs]1—A dose of 6.6 to 11 mg per kg of body weight 1Not included in Canadian product labeling or product not commercially every twelve to twenty-four hours has been used in the treatment of available in Canada. respiratory tract infections in cats and dogs{R-108}.

Strength(s) usually available{R-8}: U.S.— TYLOSIN PHOSPHATE Veterinary-labeled product(s): ORAL DOSAGE FORMS 50 mg per mL (OTC) [Tylan 50]. generic 200 mg per mL (OTC) [Tylan 200; TyloVed; ]. TYLOSIN GRANULATED USP Canada—{R-55} Usual dose: Veterinary-labeled product(s): Abscesses, hepatic (prophylaxis)1—Cattle, beef: Oral, 8 to 10 grams per 200 mg per mL (OTC) [Tylan 200; Tylocine 200]. ton of feed (approximately 60 to 90 mg per animal a day), fed as the only ration{R-49}. Withdrawal times: Atrophic rhinitis1—Pigs: Oral, 100 grams per ton of feed, fed as the U.S.—{R-51; 52} only ration{R-49}. Withdrawal time Dysentery, swine—Pigs: Prophylaxis—Oral, 100 grams per ton of feed, fed as the only ration Species Meat (days) for at least three weeks, followed by 40 grams per ton of feed, fed Cattle 21 as the only ration{R-49}. Pigs 14 Treatment—Oral, 40 to 100 grams per ton of feed, fed as the only ration for two to six weeks{R-48; 49}. Note: Product labeling listing the above withdrawal times states that they Note: The dose shown for treatment with tylosin phosphate for apply to a maximum treatment period of 5 days in cattle and medicated feed should follow an initial treatment with tylosin maximum treatment period of 3 days in pigs{R-51; 52}. Not for use in powder for oral solution in the drinking water for three to ten lactating dairy cattle{R-51} or preruminant calves. days{R-49; 100}.

Feed efficiency, improvement of1;or tartrate in drinking water, a withdrawal time of two days is Increased weight gain1— necessary. Chickens: Oral, 4 to 50 grams per ton of feed, fed as the only ration{R- 49}. Packaging and storage: Store below 40 C (104 F), preferably be- Chickens, laying: Oral, 20 to 50 grams per ton of feed, fed as the only tween 15 and 30 C (59 and 86 F), unless otherwise specified by ration{R-49}. manufacturer. Pigs: Oral, 10 to 40 grams per ton of feed, fed as the only ration{R-48; 49}. Preparation of dosage form: Medication should be thoroughly mixed Proliferative enteropathy, porcine (prophylaxis and treatment)1—Pigs: in feed before use. It should not be used in any feed containing more Oral, 100 grams per ton of feed, fed as the only ration for three than 2% bentonite.{R-49} weeks{R-49}. Respiratory disease, chronic1— Caution: When handling and mixing medication, protective clothing Chickens, broiler: Oral, 800 to 1000 grams per ton of feed, fed as the and impervious gloves should be used. Contact with human skin only ration. should be avoided.{R-49} Chickens, replacement: Oral, 1000 grams per ton of feed, fed as the only ration. USP requirements: Preserve in well-closed, polyethylene-lined or Note: Medication should be administered in feed to chickens up to 5 polypropylene-lined containers, protected from moisture and excessive days of age, then administered again for twenty-four to forty-eight heat. Contains tylosin phosphate mixed with suitable carriers and hours to chickens 3 to 5 weeks of age. inactive ingredients. Label it to indicate that it is for animal use only. Label it also to indicate that it is for manufacturing, processing, or {R-8} Strength(s) usually available : repackaging. Contains the labeled amount, within ± 20%. Meets the U.S.— requirement for Identification, Loss on drying (not more than 12.0%), Veterinary-labeled product(s): Powder fineness, and Content of tylosins.{R-22} 22 grams per kg (10 grams per pound) of premix (OTC) [Tylan 10]. 88 grams per kg (40 grams per pound) of premix (OTC) [Tylan 40]. 1Not included in Canadian product labeling or product not commercially 220 grams per kg (100 grams per pound) of premix (OTC) [Tylan 100]. available in Canada. Canada— Veterinary-labeled product(s): 22 grams per kg of premix (OTC) [Tylan 10; Tylosin 10 Premix]. TYLOSIN TARTRATE 88 grams per kg of premix (OTC) [Tylan 40; Tylosin 40 Premix]. ORAL DOSAGE FORMS 220 grams per kg of premix (OTC) [Tylan 100]. Note: Bracketed information in the Dosage Forms section refers to uses Withdrawal times: that either are not included in U.S. product labeling or are for products U.S.{R-49; 100}— not commercially available in the U.S. When fed at doses of 10 to 100 grams of tylosin phosphate per ton of 1.1 grams of tylosin tartrate equals 1 gram of tylosin base{R-90}. The feed: dosing and strengths of the dosage forms available are expressed in

Withdrawal time terms of the base.

Species Meat (days) TYLOSIN TARTRATE POWDER FOR ORAL SOLUTION Pigs 0 Usual dose: Dysentery, swine—Pigs: Oral, 250 mg per gallon of water, as the only source of drinking water for three to ten days.{R-50} When fed at doses of 800 to 1000 grams of tylosin phosphate per ton of Respiratory disease, chronic—Chickens: Oral, 2 grams (base) per gallon feed: (approximately, 110 mg per kg of body weight a day) in the only Withdrawal time source of drinking water for three to five days.{R-50} Species Meat (days) Sinusitis, infectious—Turkeys: Oral, 2 grams per gallon (approximately 132 mg per kg of body weight a day) in the only source of drinking Chickens 5 water for three to five days.{R-50} Note: [Dogs]1—There are insufficient data to establish the efficacy of Canada— tylosin in the treatment of chronic colitis in dogs; however, an oral When fed at a dose of 110 grams of tylosin phosphate per metric ton dose of 11 mg per kg of body weight every eight hours has been (1000 kg) of feed: recommended{R-84}. {R- Withdrawal time Note that reformulation is necessary for administration to dogs 109}. Species Meat (days)

{R-8; 50} Pigs 0 Size(s) usually available : U.S.— Note: Product labeling listing the above withdrawal time states that Veterinary-labeled product(s): when tylosin premix is administered concurrently with tylosin 100 grams (base) of powder (OTC) [Tylan Soluble].

Canada— Note: Product labeling listing the above withdrawal times states that Veterinary-labeled product(s): they apply to a dose of 1 gram per 4 L (approximately 1 gallon) of 100 grams (base) of powder (OTC) [Tylan Soluble]. drinking water for 3 to 10 days for pigs, 2 grams per 4 L of drinking water for 3 to 5 days for chickens, and 2 grams per 4 L of drinking Withdrawal times{R-8}: water for 3 to 5 days for turkeys.{R-66} U.S.—

Withdrawal time Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by Species Meat (days) manufacturer. Chickens 1 Turkeys 5 Preparation of dosage form: A fresh solution of tylosin tartrate should be prepared every 3 days. Water should be added to powder (not Note: Product labeling listing the above withdrawal times states that they powder added to water) when preparing the solution.{R-50} apply to a dose of 250 mg per gallon of drinking water for pigs and 2 Caution: Contact with human skin should be avoided. Protective grams per gallon of drinking water for chickens and turkeys. Product clothing and impervious gloves should be worn when mixing and is not labeled for use in birds producing eggs for human consump- handling solutions.{R-50} tion{R-50}. Canada— USP requirements: Not in USP.{R-22}

Withdrawal time 1Not included in Canadian product labeling or product not commercially Species Meat (days) available in Canada.

Chickens 1 Developed: 07/22/97 Pigs 2 Turkeys 3 Revised: 09/30/02 Interim revision: 11/21/99; 04/04/03

Table 1. Pharmacology/pharmacokinetics.

Protein Elimination Volume of

binding half-life distribution Clearance Route; Dose Tmax Cmax Bioavailablity Drug (%) (hr) (L/kg) (mL/min/kg) (mg/kg) (hr) (mcg/mL) (%)

Azithromycin Cats{R-120} Terminal: 35 Steady state: 23 10.7 IV; 5 PO; 5 0.85 0.97 58 Dogs (beagles) 16–26* 29 Steady state: 12 IV; 24 0.33 4.2 97 {R-123} PO; 24 Foals, 8- to 14- 16 Area: 12.4 10 IV; 5 weeks{R-121} Terminal: 16.3 Steady state: 11.6 PO; 10 1.4 0.72 39 Foals, 6- to 10- 20.3 Area: 22.3 10.4 IV; 10 weeks{R-122} Steady state: 18.6 PO; 10 1.8 0.57 56 Human data{R-115} 7–50 11 to 14 Steady state: 33 PO: 500 mg 2 to 3 0.4 37 total dose Rats{R-123} 14–29* 32 Steady state: 84 IV; 20 PO; 20 2.0 0.29 46

Clarithromycin Dogs (crossbred Terminal: 3.9 Steady state: 1.4 4.3 IV; 10 beagles){R-124} Fed PO; 10 1.6 3.3 70 Fasted PO; 10 1.7 3.5 79

Erythromycin Calves{R-23} 2.2 Area: 1.5 7.8 IV; 15 Cattle{R-21} 18 IV/IM; 20 {R-25} 3.2 Area: 0.79 2.9 IV; 12.5 Dogs{R-62} 1.7 Steady state: 2.7 21 IV; 10 Horses, foals{R-26} 1 Area: 2.3 to 7.2 IV; 5 to 20 Mice{R-62} 0.7 Steady state: 3.6 77 IV; 10 Pigeons{R-27} 0.9 IV; 20 PO; 100 10 Rabbits{R-62} 0.7 Steady state: 6.8 53 IV; 10 Rats{R-62} 0.7 Steady state: 9.3 73 IV; 25 Sheep{R-21} 23 IV/IM; 20

Table 1. (Contd.)

Protein Elimination Volume of Binding Half-life Distribution Clearance Route; Dose Tmax Cmax Bioavailablity Drug (%) (hr) (L/kg) (mL/min/kg) (mg/kg) (hr) (mcg/mL) (%)

Tilmicosin Cattle{R-91} SC; 10 1.8 0.13 {R-104} SC; 10 1 0.71

Tylosin Calves, 2.3 Area: 4.4 24.5 IV; 10 newborn{R-73} Calves, 1 week 1 to 15 Area: 3.6 to 4.4 32 to 48 IV: 10 to 9 months Calves, 7 1.2 Area: 2.5 23.7 IV; 10 weeks{R-69} Chickens{R-71} 30 Cattle{R-20} 33.5 IV/IM; 20 {R-25; 80} 1.6 Area: 1.1 7.8 IV; 12.5 {R-79} 2.1 IV; 20 Dogs{R-68} 0.9 Area: 1.7 22 IV; 10 IM; 10 0.5 1.5 Goats{R-72} 38 3 Area: 1.7 6.8 IM; 15 4.2 2.4 73 Sheep{R-20} 38 IV/IM; 20 {R-79} 2.1 IV; 20

*Protein binding is concentration dependent, reported as increasing with decreasing concentration from 10 to 0.02 mg/L. Protein binding is concentration dependent, reported as increasing with decreasing concentration from 1 to 0.2 mcg/mL.

REFERENCES 18. Ewing PJ, Burrows G, Macallister C, et al. Comparison of oral erythromycin 1. Barragry TB. Veterinary drug therapy. Philadelphia: Lea & Febiger, 1994: formulations in the horse using pharmacokinetic proﬁles. J Vet Pharmacol 224-6, 251–62. Ther 1994; 17: 17–23. 2. Plumb DC. Veterinary drug handbook. White Bear Lake, MN: PharmaVet 19. Clarke CR, Barron SJ, Ayalew S, et al. Response of Pasteurella haemolytica to Publishing, 1991: 513. erythromycin and dexamethasone in calves with established infection. Am J 3. Erythromycin phosphate product information (Gallimycin-PFC, Bimeda—US), Vet Res 1992; 53(5): 684–7. Rec 2/12/03. 20. Ziv G, Sulman FG. Binding of antibiotics to bovine and ovine serum. 4. Beech J. Drug therapy of respiratory disorders. Vet Clin North Am Equine Antimicrobial Agents and Chemotherapy 1972 Sep: 206–13. Pract 1987; 3(1): 59–80. 21. Nap RC, Breen DJ, Lam TJGM, DeBruyne JJ. Gastric retention of enteric-coated 5. Prescott JF, Baggot JD, editors. Antimicrobial therapy in veterinary medicine. aspirin tablets in beagle dogs. J Vet Pharmacol Ther 1990; 13: 148–53. 2nd ed. Ames, IA: Iowa State University Press, 1993: 119–26; 187–203. 22. The United States pharmacopeia. The national formulary. USP 26th revision 6. Erythromycin base package insert (Gallimycin-200, Bimeda—US), Rec 7/01/ (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United 02. States Pharmacopeial Convention, Inc., 2002. p. 200, 201, 465, 466, 728, 7. Erythromycin base package insert (Gallimycin-200, A.P.A. of Vetoqui- 729, 731–4, 737–9, 741, 1838, 2555, 2560, 2584, 2586. nol—Canada) In: Arrioja-Dechert A, editor. Compendium of veterinary 23. Burrows GE. Effects of experimentally induced Pasteurella haemolytica products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. pneumonia on the pharmacokinetics of erythromycin in the calf. Am J Vet 8. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Res 1985; 46(4): 798–803. Huron, MI: North American Compendiums, Inc. 2002. 24. Burrows GE, Griffen DD, Pippin A, et al. A comparison of the various routes of 9. Erythromycin phosphate package insert (Gallimycin PFC, A.P.A. of Vetoqu- administration of erythromycin in cattle. J Vet Pharmacol Ther 1989; 12: inol—Canada) In: Arrioja-Dechert A, editor. Compendium of veterinary 289–95. products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. 25. Baggot JD, Gingerich DA. Pharmacokinetic interpretation of erythromycin 10. Monfort JD, Donahoe JP, Stills HF, et al. Efﬁcacies of erythromycin and and tylosin activity in serum after intravenous administration of a single dose chloramphenicol in extinguishing fecal shedding of Campylobacter jejuni in to cows. Res Vet Sci 1976; 21: 318–23. dogs. J Am Vet Med Assoc 1990; 196(7): 1069–72. 26. Prescott JF, Hoover DJ, Dohoo IR. Pharmacokinetics of erythromycin in foals 11. Smith JA, Isaac-Renton JL, Jellett JF, et al. Inhibitory and lethal activities of and in adult horses. J Vet Pharmacol Ther 1983; 6: 67–74. rosaramicin, erythromycin, and clindamycin against Campylobacter fetus 27. Vanhaecke E, De Backer P, Remon JP, et al. Pharmacokinetics and susp jejuni and intestinalis. Am J Vet Res 1983; 44(8): 1605–6. bioavailability of erythromycin in pigeons (Columba livia). J Vet Pharmacol 12. Fox JG, Moore R, Ackerman JI. Campylobacter jejuni-associated diarrhea in Ther 1990; 13: 356–60. dogs. J Am Vet Med Assoc 1983; 183(12): 1430–3. 28. Burrows GE, Gentry M, Ewing BS. Serum and tissue concentrations of 13. Hillidge CJ. Use of erythromycin-rifampin combination in treatment of erythromycin in calves with induced pneumonic pasteurellosis. Am J Vet Res Rhodococcus equi pneumonia. Vet Microbiol 1987; 14: 337–42. 1989; 50(7): 1166–9. 14. Sweeney CR, Sweeney RW, Divers TJ. Rhodococcus equi pneumonia in 48 29. Huber WB. In: Booth NH, McDonald LE. Veterinary pharmacology and foals: response to antimicrobial therapy. Vet Microbiol 1987; 14: 329–36. therapeutics. 5th ed. Ames, IA: Iowa State University Press, 1968. 15. Kenney DG, Robbins SC, Prescott, et al. Development of reactive arthritis and 30. Kirk RW, Bonagura JD, editors. Current veterinary therapy small animal resistance to erythromycin and rifampin in a foal during treatment for practice. Philadelphia: W.B. Saunders Company, 1992. p. 1238. Rhodococcus equi pneumonia. Equine Vet J 1994; 25(3): 246–8. 31. Erythromycin base (ERYC, PD). In: Krogh CME, editor. CPS Compendium of 16. USP dictionary of USAN and international drug names, 2002 ed. Rockville, pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical MD: The United States Pharmacopeial Convention, Inc.; 2002. Association, 1994: 458–9. 17. Erythromycin base (E-mycin, Boots). In: PDR Physicians’ desk reference. 32. Mead JR. Cryptosporidiosis and the challenges of chemotherapy. Drug Resist 49th ed. Montvale, NJ: Medical Economics Data Production Company, 1994: Updat 2002 Feb; 5(1): 47–57. 651–3.

33. Fraser-Hurt N, Bailey RL, Cousens S, et al. Efﬁcacy of oral azithromycin versus 65. Tilmicosin phosphate (Micotil, Provel—Canada). In: Arrioja–Dechert A, topical tetracycline in mass treatment of endemic trachoma. Bulletin of the editor. Compendium of veterinary products, CD ed. Port Huron, MI: North World Health Organization 2001; 79: 632–40. American Compendiums, Inc. 2002. 34. Samra Z, Rosenberg S, Soffer Y, et al. In vitro susceptibility of recent clinical 66. Tylosin package insert (Tylocine Soluble Powder, Elanco—Canada). In: isolates of Chlamydia trachomatis to macrolides and tetracyclines. Diagnostic Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Microbiology and Infectious Disease 2001; 39: 177–9. Huron, MI: North American Compendiums, Inc. 2002. 35. Niki Y, Kimura M, Miyashita N, et al. In vitro and in vivo activities of 67. Itoh Z, Suzuki T, Nayaka M, et al. Structure-activity relation among azithromycin, a new azalide antibiotic, against chlamydia. Antimicrob Agents macrolide antibiotics in initiation of interdigestive migrating contractions in Chemo 1994 Oct; 38(10): 2296–9. the canine gastrointestinal tract. Am J Physiol 1985 Mar; 248(3 Pt 1): G320– 36. Erythromycin ethylsuccinate (E.E.S., Abbott). In: PDR Physicians’ desk 5. reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data Production 68. Weisel MK, Powers JD, Powers TE, et al. A pharmacokinetic analysis of tylosin Company, 1995. p. 423–4. in the normal dog. Am J Vet Res 1977 Feb; 33: 273–5. 37. Erythromycin gluceptate (Ilotycin, Dista). In: PDR Physicians’ desk reference. 69. Burrows GE, Barto PB, Martin B. Antibiotic disposition in experimental 49th ed. 1995. Montvale, NJ: Medical Economics Data Production Company, pneumonic pasteurellosis: gentamicin and tylosin. Can J Vet Res 1986; 50: 1995. p. 937–8. 193–9. 38. Robinson NE, editor. Current therapy in equine medicine 3. Philadelphia: 70. Van Duyn RL, Folkberts TM. Concentrations of tylosin in blood and lung W.B. Saunders Company, 1992. p. 817. tissue from calves given single and repeated daily intramuscular doses. Vet 39. Erythromycin lactobionate package insert (Elkins-Sinn, Inc.—US), Rev 8/91, Med Small Anim Clin 1979 Mar: 375–9. Rec 5/92. 71. Ziv G. Preliminary clinical pharmacological investigations of tylosin and 40. Chen X, Keithly JS, Paya CV, et al. Cryptosporidiosis. N Engl J Med 2002, May tiamulin in chickens. Vet Q 1980 Oct; 2(4): 206–10. 30; 346(22): 1723–31. 72. Atef M, Youssef AH, Atta AH, et al. Disposition of tylosin in goats. Br Vet J 41. Dionisio D, Orsi A, Sterrantino G, et al. Chronic cryptosporidiosis in patients 1991; 147: 207. with AIDS: stable remission and possible eradication after long term, low dose 73. Burrows GE, Barto PB, Martin B, et al. Comparative pharmacokinetics of azithromycin. J Clin Path 1998; 51: 138–42. antibiotics in newborn calves: chloramphenicol, lincomycin, and tylosin. Am 42. Medleau L, Lang RE, Brown J, et al. Frequency and antimicrobial suscepti- J Vet Res 1983 Jun; 44 (6): 1053–7. bility of Staphylococcus species isolated from canine pyodermas. Am J Vet Res 74. Helton-Groce SL, Thomson TD, Readnour RS. A study of tilmicosin residues in 1986 Feb; 47(2): 229–31. milk following subcutaneous administration to lactating dairy cows. Can Vet J 43. Hill PB, Moriello KA. Canine pyoderma. J Am Vet Med Assoc 1994 Feb; 1993 Oct; 34: 619–21. 204(3): 334–40. 75. Laven R, Andrews AH. Long-acting antibiotic formulations in the treatment 44. Mason I. Selection and use of antibacterial agents in canine pyoderma. In of calf pneumonia: a comparative study of tilmicosin and oxytetracycline. Vet Pract 1993 May; 15(3): 129–34. Rec 1991; 129: 109–11. 45. Swarbrick O. The use of parenteral erythromycin in the treatment of bovine 76. Ose EE, Tonkinson LV. Single dose treatment of neonatal calf pneumonia with mastitis. Vet Rec 1966 Oct; 79(18): 508–12. the new macrolide antibiotic tilmicosin. Vet Rec 1988 Oct; 123: 367–9. 46. Ziv G. Drug selection and use in mastitis: systemic vs local therapy. J Am Vet 77. Scott PR. Field study of undifferentiated respiratory disease in housed beef Med Assoc 1980 May 15; 176(10): 1109–15. calves. Vet Rec 1994 Mar; 134: 325–7. 47. MacDiarmid SC. Antibacterial drugs used against mastitis in cattle by the 78. Picavet T, Muylle E, Devriese LA, et al. Efﬁcacy of tilmicosin in treatment of systemic route. N Z Vet J 1978; 26: 290–5. pulmonary infections in calves. Vet Rec 1991; 129: 400–3. 48. Tylosin package insert (Tylosin 10 Premix, Bio-Agri-Mix—Canada), Rec 7/7/ 79. Ziv G, Sulman FG. Serum and milk concentrations of spectinomycin and 95. tylosin in cows and ewes. Am J Vet Res 1973 Mar; 34 (3): 329–33. 49. Tylosin package insert (Tylan 40, Elanco—US), Rec 1/13/97. 80. Gingerich DA, Baggot JD, Kowalski JJ. Tylosin antimicrobial activity and 50. Tylosin package insert (Tylan Soluble, Elanco—US), Rev 3/98. Downloaded pharmacokinetics in cows. Can Vet J 1977 Apr; 18 (4): 96–100. 2/17/03 from www.elanco.com. 81. Jordan WH, Byrd RA, Cochrane RI, et al. A review of the toxicity of the 51. Tylosin package insert (Tylan 50, Elanco—US), Rev 11/4/93, Rec 8/4/95. antibiotic Micotil 300. Vet Hum Toxicol 1993 Apr; 35(2): 151–8. 52. Tylosin package insert (Tylosin Injection, Boehringer-Ingelheim—US). Down- 82. Panel comment, Rec 3/26/96. loaded 2/17/03 from www.bi-vetmedica.com. 83. Panel comment, Rec 4/15/96. 53. Tilmicosin package insert (Micotil injection, Elanco—US), Rev 6/1/2000. 84. Panel comment, Rec 4/1/96. Downloaded 2/12/03 from www.elanco.com. 85. Panel comment, Rec 4/18/96. 54. Erythromycin package insert (Erymycin-100, Bimeda—US), Rec 7/12/02. 86. Leib M, Matz ME. Diseases of the large intestine. In: Ettinger SJ, Feldman EC, 55. Tylocine 200, Provel. In: Arrioja-Dechert A, editor. Compendium of veter- editors. Textbook of veterinary internal medicine, 4th ed. Philadelphia, PA: inary products, CD ed. Port Huron, MI: North American Compendiums, Inc. W.B. Saunders, 1995. 2002. 87. Panel comment, Rec 4/2/96. 56. Tylosin base (Tylocine tablets, MTC—Canada), Rev 5/91, Rec 12/10/96 88. Panel comment, Rec 3/19/96. [discontinued product]. 89. Panel comment, Rec 4/1/96. 57. Taylor DE, Chang N. In vitro susceptibilites of campylobacter jejuni and 90. Reynolds JEF, editor. Martindale, the extra pharmacopeia. 30th ed. London: campylobacter coli to azithromycin and erythromycin. Antimicrob Agents The Pharmaceutical Press, 1993: 220–1. Chemo 1991 Sep; 35(9): 1917–8. 91. Ziv G, Shem-Tov M, Glickman A, et al. Tilmicosin antibacterial activity and 58. Riviere J, Craigmill AL, Sundlof SF. Handbook of comparative pharmacoki- pharmacokinetics in cows. J Vet Pharmacol Ther 1995; 18: 340–5. netics and residues of veterinary antimicrobials. CRC Press, Inc: Boca Raton, 92. Manufacturer comment, Rec 5/24/96. FL 1991. p. 229–61. 93. Kunkle GA. New considerations for rational antibiotic therapy of cutaneous 59. Holle GE, Seinbach E, Forth W. Effects of erythromycin in the dog upper staphylococcal infection in the dog. Semin Vet Med Surg Small Anim 1987; 2: gastrointestinal tract. Am J Physiology 1992; 263 (1): G52–9. 212–20. 60. Panel comment, Rec 6/16/95. 94. Manufacturer comment, Rec 5/24/96. 61. Brander GC, Pugh DM, Bywater RJ, Jenkins WL. Veterinary applied 95. Panel comment, Rec 5/24/96. pharmacology & therapeutics, 5th ed. Philadelphia: Bailliere Tindall 1991. 96. Kunkle GA, Sundlof S, Keisling K. Adverse side effects of oral antibacterial p. 463–5. therapy in dogs and cats: an epidemiologic study of pet owners’ observations. 62. Duthu GS. Interspecies correlation of the pharmacokinetics of erythromycin, J Am Anim Hosp Assoc 1995; 31: 46–55. oleandomycin, and tylosin. J Pharm Sci Sep 1985; 74 (9): 943–6. 97. Holmberg SD, Moorman AC, Von Bargen JC, et al. Possible effectiveness of 63. Christie PJ, Davidson JN, Novick RP, et al. Effects of tylosin feeding on the clarithromycin and rifabutin for cryptosporidiosis chemoprophylaxis in HIV antibiotic resistance of selected gram-positive bacteria in pigs. Am J Vet Res disease. J Am Med Assoc 1998 Feb; 279(5): 384–6. Jan 1983; 44 (1): 126–8. 98. Panel comment, Rec 5/24/96. 64. Erythromycin thiocyanate (Gallimycin–50, A.D.A—Canada). In: Arrioja- 99. Ose EE. In vitro antibacterial properties of EL-870, a new semisynthetic Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, macrolide antibiotic. J Antibiot 1987 Feb; 40(2): 190–4. MI: North American Compendiums, Inc. 2002. 100. Manufacturer comment, Rec 10/30/96.

101. Veterinary Supplemental New Drug Submission. Health and Welfare Canada. 114. Tilmicosin package insert (Pulmotil Premix, Elanco—Canada), In: Arrioja- Health Protection Branch. The use of tylosin in the treatment of chronic Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, colitis in dogs and cats. Provel. DIN 0919660. MI: North American Compendiums, Inc. 2002. 102. Van Kruiningen HJ. Clinical efficacy of tylosin in canine inflammatory bowel 115. Klasco RK, editor. USP DI Drug information for the healthcare professional. disease. J Am Anim Hosp Assoc 1976; 12(4): 498–501. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 103. Thomson TD, Laudert SB, Chamberland S, et al. Micotil—pharmacokinetics of 116. Azithromycin package insert (Zithromax, Pfizer—US). Downloaded from tilmicosin, a semisythetic macrolide antibiotic in acutely pneumonic cattle www.zithromax.com on 7/2/02. and primary bovine alveolar macrophages. In: European Association for 117. Clarithromycin package insert (Biaxin, Abbott Laboratories—US). Down- Veterinary Pharmacology and Toxicology. Proceedings of the 6th Interna- loaded from www.biaxin.com on 7/2/02. tional Congress; Aug 8, 1994. Edinburgh UK: Blackwell Scientific Publica- 118. McEvoy GK, editor. AHFS Drug Information. Bethesda: American Society of tions. August 7–11, 1994; O12: 31. Health-System Pharmacists. 2001. p. 288–312. 104. Thomson TD, Lawrence K. Micotil: pharmacokinetics of tilmicosin, a 119. Adams HR, editor. Veterinary Pharmacology and Therapeutics, 8th ed. Ames: semisynthetic macrolide antibiotic in cattle. In: European Association for Iowa State University Press. 2001. p. 876–882. Veterinary Pharmacology and Toxicology. Proceedings of the 6th Interna- 120. Hunter RP, Lynch MJ, Ericson JF, et al. Pharmacokinetics, oral bioavailability tional Congress. Edinburgh, UK: Blackwell Scientific Publications. August and tissue distribution of azithromycin in cats. J Vet Pharmacol Ther 1995; 7–11, 1994; P31; 55. 18: 38–46. 105. Kato H, Murakami T, Takase S, et al. Sensitivities in vitro to antibiotics of 121. Davis JL, Gardner SY, Jones SL, et al. Pharmacokinetics of azithromycin in mycoplasma isolated from canine sources. Jap J Vet Sci 1972; 34: 197–206. foals after i.v. and oral dose and disposition into phagocytes. J Vet Pharmacol 106. Manufacturer comment, Rec 1/13/97. Ther 2002; 25(2): 99–104. 107. Tilmicosin package insert (Pulmotil, Elanco—US). Downloaded 2/12/03 from 122. Jacks S, Giguere S, Gronwall RR, et al. Pharmacokinetics of azithromycin and www.elanco.com. concentration in body fluids and bronchoalveolar cells in foals. Am J Vet Res 108. Tylosin injection (21 CFR 522.2640[a]). Federal Register. April 1, 1995. 2001; 62(12): 1870–5. 109. Veterinary Medicine Advisory Panel meeting, 4/28/97. 123. Shepard RM, Falkner FC. Pharmacokinetics of azithromycin in rats and dogs. 110. Gomex-Garces JL, Cogollos R, Alos JI. Susceptibilities of fluoroquinolone- Antimicrob Chemother 1990; 25(Suppl A): 49–60. resistant strains of Campylobacter jejuni to 11 oral antimicrobial agents. 124. Vilmanyi E, Kung K, Riond JL, et al. Clarithromycin pharmacokinetics after Antimicrob Agents Chemo 1995 Feb; 39(2): 542–4. oral administration with or without fasting in crossbred beagles. J Small Anim 111. Erythromycin package insert (Gallimycin-100, Bimeda—US), Rec 7/18/02. Pract 1996; 37(11): 535–9. 112. Tilmicosin package insert (Micotil, Provel—Canada), Rec 10/21/98. 125. Breitschwerdt EB, Papich MG, Hegarty BC, et al. Efficacy of doxycycline, 113. Martin DH, Mroczkowski TF, Dalu ZA, et al. A controlled trial of a single dose azithromycin, or trovafloxacin for treatment of experimental Rocky of azithromycin for the treatment of chlamydial urethritis and cervicitis. New Mountain spotted fever in dogs. Antimicrob Agents Chemo 1999 Apr; England J Med 1992 Sep; 327(13): 921–5. 43(4): 813–21.

METRONIDAZOLE Veterinary—Systemic

Some commonly used brand names for human-labeled products are: Apo- bacterial colitis caused by susceptible organisms, including Clostridium Metronidazole; Flagyl; Flagyl I.V.; Flagyl I.V. RTU; Metric 21; Metro I.V.; difficile{R-10–12}. Novonidazol; Protostat; and Trikacide. [Encephalopathy, hepatic (treatment)] —Cats and dogs: Although there Note: For a listing of dosage forms and brand names by country are insufficient data to establish efficacy, metronidazole is used to availability, see the Dosage Forms section(s). reduce gastrointestinal bacterial production of ammonia thought to contribute to clinical signs in hepatic encephalopathy. 1 CATEGORY: [Endometritis (treatment)] —Horses: Although there are insufficient data to establish efficacy, metronidazole is used in combination with other Antibacterial (systemic); antiprotozoal. antibiotics in the treatment of endometritis, including infections caused by penicillinase-producing anaerobic bacteria{R-13}. INDICATIONS [Helicobacter species infections (treatment)]1—Cats and dogs: Although Note: In other USP DI monographs, bracketed information in the the treatment of Helicobacter pylori in human gastrointestinal disease Indications section refers to uses that are not included in U.S. product has had major clinical impact, there is currently little evidence to labeling, and superscript 1 refers to uses that are not included in suggest that these organisms significantly affect gastrointestinal Canadian product labeling. However, since metronidazole is not function in cats and dogs or that metronidazole, in combination specifically approved for veterinary use, there is no product labeling with another antibiotic and bismuth subsalicylate or subcitrate, identifying approved indications. will produce long-term eradication of Helicobacter species in these species{R-22–26}. 1 GENERAL CONSIDERATIONS [Infections, bacterial (treatment)] , including [Bone and joint infections (treatment)]1; Metronidazole is effective in the treatment of systemic and enteric [Central nervous system infections (treatment)]1; obligate anaerobic bacterial infections, including Clostridium species, [Intra-abdominal infections (treatment)]1; Fusobacterium species{R-1}, and penicillinase-producing strains of [Perioperative infections, colorectal (prophylaxis)]1; Bacteroides{R-2; 3}. Surgical therapy may be necessary to completely [Respiratory tract infections, lower (treatment)]1; resolve isolated infections{R-3}. [Septicemia, bacterial (treatment)]1;or Metronidazole is not clinically effective against facultative anaerobes or [Skin and soft tissue infections (treatment)]1—Cats, dogs, and horses: obligate aerobes{R-1; 4}. However, it is often combined with another Although there are insufficient clinical research data to establish antibiotic or antibiotics effective against aerobes to treat mixed efficacy, metronidazole is used in the treatment of many types of bacterial infections{R-2}. anaerobic bacterial infections in animals. In human patients, Metronidazole is considered effective in the treatment of some protozoal metronidazole is indicated, usually in combination with other infections in animals. antibiotics, in the prevention of perioperative infections during colorectal surgery and in the treatment of bone and joint infections; ACCEPTED central nervous system infections; intraoperative infections; lower [Giardiasis (treatment)]1—Cats and dogs: Metronidazole is used to respiratory tract infections, including pleuropneumonia and eliminate shedding of giardial cysts and treat associated diarrhea in lung abscess; septicemia; and skin and soft tissue infections cats and dogs{R-6; 7; 36}. Environmental eradication is necessary for caused by susceptible species, including Bacteroides and Clostridium {R-1; 4} effective treatment. The infection may not be completely cleared in all species . There are limited pharmacokinetic data and case animals{R-7}. reports available pertaining to the use of metronidazole in the treatment of these types of infections in animals{R-8; 9; 12; 14; 16; 19–21; 28}. [Periodontal infections (treatment)]1—Cats and dogs: Metronida- ACCEPTANCE NOT ESTABLISHED zole is used in the treatment of periodontal infections in cats and [Amebiasis, intestinal (treatment)]1; dogs{R-15; 17; 18} It may be administered for destructive periodontal [Balantidiasis, intestinal (treatment)]1;or diseases as part of a treatment plan that also includes one or more of [Trichomoniasis, intestinal (treatment)]1—Cats and dogs: In human the following: dental scaling, gingival crevicular lavage, periodontal patients, metronidazole is used in the treatment of susceptible Balan- surgery, or regular teeth cleaning{R-17}. tidium coli, Entamoeba histolytica, and Trichomonas species{R-1; 4; 5}. Metronidazole is also recommended in the treatment of enteric protozoal infections in cats and dogs, although the relationship REGULATORY CONSIDERATIONS between infection and clinical signs can be difficult to define. U.S.— [Bowel disease, inflammatory (treatment)]1—Cats and dogs: Although The Food and Drug Administration has not approved the use of there are insufficient data to establish efficacy, metronidazole is used in metronidazole in animals. The use of nitroimidazoles in food animals the treatment of inflammatory bowel disease. is strictly prohibited.{R-27} [Colitis, antibiotic-associated (treatment)]1;or Canada— [Colitis, clostridial (treatment)]1—Horses: Although there are insufficient Metronidazole is not approved for use in food-producing animals. data to establish efficacy, metronidazole is used in the treatment of There are no established withdrawal times.

CHEMISTRY PRECAUTIONS TO CONSIDER Chemical group: Nitroimidazoles. CARCINOGENICITY/MUTAGENICITY Chemical name: Metronidazole has been shown to be a carcinogen in mice and rats with Metronidazole—1H-Imidazole-1-ethanol, 2-methyl-5-nitro-.{R-29} chronic oral administration. It has also been shown to be mutagenic in Metronidazole hydrochloride—1H-Imidazole-1-ethanol, 2-methyl-5- in vitro assays.{R-1; 4} nitro-, hydrochloride.{R-29} Molecular formula: {R-29} Metronidazole—C6H9N3O3. PREGNANCY/REPRODUCTION {R-29} Metronidazole hydrochloride—C6H9N3O3 Æ HCl. Pregnancy—Metronidazole readily crosses the placenta and enters the Molecular weight: fetal circulation{R-1}. No teratogenic effects were seen in the pups of rats Metronidazole—171.15.{R-29} that had received 250 mg per kg of body weight (mg/kg) a day for 1 to Metronidazole hydrochloride—207.61.{R-29} 12 days, or 100 mg/kg a day for 40 days. However, spermatogenesis in Description: Metronidazole USP—White to pale yellow, odorless crys- male rats was affected by the administration of 100 mg/kg a day. tals or crystalline powder. Is stable in air, but darkens on exposure to light.{R-30} LACTATION Solubility: Metronidazole USP—Sparingly soluble in water and in alco- Metronidazole is distributed into milk at concentrations similar to plasma hol; slightly soluble in ether and in chloroform.{R-30} concentrations{R-1; 4}. Risk-beneﬁt should be considered carefully when metronidazole is used in nursing animals. PHARMACOLOGY/PHARMACOKINETICS

Mechanism of action/effect: Metronidazole is reduced as it enters the DRUG INTERACTIONS AND/OR RELATED PROBLEMS target cell where it interacts with bacterial or protozoal DNA, causing The following drug interactions and/or related problems have been selected a loss of helical structure and strand breakage in the DNA; these effects on the basis of their potential clinical significance (possible mechanism in inhibit nucleic acid synthesis and cause death of the cell. parentheses where appropriate)—not necessarily inclusive: Note: Combinations containing any of the following medications, depend- Absorption: Metronidazole is moderately well absorbed from the gas- ing on the amount present, may also interact with metronidazole. trointestinal tract.{R-21; 33; 37} Cimetidine (hepatic metabolism of metronidazole may be decreased when Distribution: Horses—In one pharmacokinetic study of horses, peak metronidazole and cimetidine are used concurrently, possibly resulting metronidazole concentrations in peritoneal fluid, synovial fluid, and in delayed elimination and increased serum metronidazole concen- cerebrospinal fluid were 65%, 92%, and 30% of peak serum concentrations{R-5}; dosage of metronidazole may need to be adjusted) trations.{R-21} With an oral dose of 7.5 mg/kg every 6 hours, endo- Phenobarbital metrial penetration was poor{R-21}. (phenobarbital may induce microsomal liver enzymes, increasing metronidazole’s metabolism and resulting in a decrease in half-life Biotransformation: Hepatic, metabolized primarily by side-chain and plasma concentration{R-5}; dosage of metronidazole may need to oxidation and glucuronide synthesis. be adjusted)

Pharmacokinetic data: SIDE/ADVERSE EFFECTS Table 1. Intravenous administration. The following side/adverse effects have been selected on the basis of their potential clinical signiﬁcance (possible signs and, for humans, symp- Half-life of Volume of Clearance toms in parentheses where appropriate)—not necessarily inclusive: Species elimination (hours) distribution (L/kg) (mL/kg/min)

Dogs{R-37} 4.48 ± 0.89 Area: 0.95 ± 0.10 2.49 ± 0.54 THOSE INDICATING NEED FOR MEDICAL ATTENTION Horses{R-33} 2.9 Area: 1.70 ± 0.24 6.67 ± 0.83 Neurologic disturbances (ataxia, nystagmus, seizures, tremors, {R-21} 3.11 ± 0.21 Area: 0.74 ± 0.01 2.8 ± 0.18 {R-31; 32} Steady state: 0.69 ± 0.01 weakness)—with high dosage in cats, dogs, and horses {R-39} 3.27 ± 0.65 Steady state: 0.68 ± 0.16 2.8 ± 0.8 THOSE INDICATING NEED FOR MEDICAL ATTENTION Table 2. Oral administration. ONLY IF THEY CONTINUE OR ARE BOTHERSOME Anorexia; neutropenia; vomiting Dose Cmax Tmax Bioavailability Species (mg/kg) (mcg/mL) (hour) (%) THOSE NOT INDICATING NEED FOR MEDICAL {R-37} Dogs 44 42* 1* 59 to 100 ATTENTION Horses{R-33} 25 12.6 ± 2.4 1 to 2 85.0 ± 18.6 {R-39} 20 22 ± 8 1.1 ± 0.6 74 ± 18 Reddish brown urine {R-21} 15 13.9 ± 2.18 0.67 97 ± 5.7 HUMAN SIDE/ADVERSE EFFECTS{R-5} *Read from graph. Two horses with pleuropneumonia yielded similar kinetic results to that of healthy In addition to the above side/adverse effects reported in animals, the mares in this study. following side/adverse effects have been reported in humans, and are

included in the human monograph Metronidazole (Systemic) in USP DI Horses: Oral, 15 to 25 mg (base) per kg of body weight every six Volume I; these side/adverse effects are intended for informational hours{R-33}. purposes only and may or may not be applicable to the use of Note: Anorexia may occur in horses treated with the above dose; metronidazole in the treatment of animals: therefore, some clinicians recommend use of a lower oral dose of Incidence more frequent 10 mg per kg of body weight every twelve hours{R-40}. Central nervous system (CNS) effects; gastrointestinal distur- For susceptible gram-negative anaerobic infections in horses, one bance study recommended an alternative dosage regimen of 15 mg per Incidence less frequent or rare kg of body weight as an initial dose, followed by 7.5 mg per kg of Change in taste sensation; CNS toxicity, including ataxia and body weight every six hours{R-21}. encephalopathy; dark urine; dryness of mouth; hypersensitiv- Contents of the capsule can be mixed with molasses or adminis- ity; leukopenia; pancreatitis; peripheral neuropathy—usually tered via nasogastric tube.{R-31; 33; 34} with high doses or prolonged use; seizures—usually with high doses; [Hepatic encephalopathy]1;or thrombocytopenia—reversible; thrombophlebitis; unpleasant or [Inﬂammatory bowel disease]1—Cats and dogs: Oral, 7.5 mg (base) per sharp metallic taste; urinary tract effects, including frequent kg of body weight every twelve hours. or painful urination and inability to control urine ﬂow; vaginal candidiasis Strength(s) usually available: U.S.— OVERDOSE Veterinary product(s): For information in cases of overdose or unintentional ingestion, contact Not commercially available. the American Society for the Prevention of Cruelty to Animals Human product(s): (ASPCA) National Animal Poison Control Center (888-426-4435 375 mg (base) (Rx) [Flagyl]. or 900-443-0000; a fee may be required for consultation) and/or the Canada— drug manufacturer. Veterinary-labeled product(s): Lethal dose—Dogs: 250 mg per kg of body weight (mg/kg) a day induced Not commercially available. central nervous system dysfunction within 4 to 6 days and death Human-labeled product(s): within a week of onset of signs{R-32}. 500 mg (base) (Rx) [Flagyl; Trikacide].

Packaging and storage: Store below 40 °C (104 °F), preferably between CLINICAL EFFECTS OF OVERDOSE 15 and 30 °C (59 and 86 °F), in a well-closed container, unless other- The following effects have been selected on the basis of their potential wise specified by manufacturer. Store in a light-resistant container. clinical significance—not necessarily inclusive: Dogs, with doses of 65 to 129 mg/kg a day.{R-32} USP requirements: Not in USP{R-30}. Ataxia; head tilt; nystagmus (spontaneous, positional, vertical); seizures METRONIDAZOLE TABLETS USP Note: Ataxia and nystagmus were noted consistently in a report on five Usual dose: See Metronidazole Capsules. cases of toxicosis. Signs appeared within 7 to 12 days of initiating Note: Cats—The typical way to give 15 mg per kg of body weight to a therapy. In dogs that survived complications of neurologic dysfunc- nine-pound cat is to administer one-fourth of a 250-mg tablet. tion, signs gradually resolved over 1 to 2 weeks after ending metronidazole administration{R-32}. Strength(s) usually available: U.S.— Veterinary-labeled product(s): ORAL DOSAGE FORMS Not commercially available. Note: In other USP DI monographs, bracketed uses in the Dosage Forms Human-labeled product(s): section refer to categories of use and/or indications that are not 250 mg (base) (Rx) [Flagyl; Metric 21; Protostat (scored; lactose)]. included in U.S. product labeling, and superscript 1 refers to categories 500 mg (base) (Rx) [Flagyl; Protostat (scored; lactose)]. of use and/or indications that are not included in Canadian product Canada— labeling. However, since metronidazole is not specifically approved for Veterinary-labeled product(s): veterinary use, there is no product labeling identifying approved Not commercially available. indications. Human-labeled product(s): The dosing and strengths of the dosage forms available are expressed 250 mg (base) (Rx) [Apo-Metronidazole; Flagyl; Novonidazol (scored); in terms of metronidazole base. Trikacide].

METRONIDAZOLE CAPSULES Packaging and storage: Store below 40 °C (104 °F), preferably between Usual dose: 15 and 30 °C (59 and 86 °F), in a well-closed container, unless other- [Bacterial infections, anaerobic]1;or wise speciﬁed by manufacturer. Store in a light-resistant container. [Protozoal infections]1— Cats and dogs: Oral, 15 mg (base) per kg of body weight every twelve Additional information: For cats, tablets should not be crushed for hours{R-38}. administration, because metronidazole is bitter and often unpalatable.

USP requirements: Preserve in well-closed, light-resistant containers. METRONIDAZOLE HYDROCHLORIDE FOR INJECTION Contain the labeled amount, within ±10%. Meet the requirements Usual dose: See Metronidazole Injection USP. for Identification, Dissolution (85% in 60 minutes in 0.1 N hydrochloric acid in Apparatus 1 at 100 rpm), and Uniformity of dosage Size(s) usually available: {R-30} units . U.S.— Veterinary-labeled product(s): Not commercially available. PARENTERAL DOSAGE FORMS Human-labeled product(s): Note: In other USP DI monographs, bracketed uses in the Dosage Forms 500 mg (base) (Rx) [Flagyl I.V.]. section refer to categories of use and/or indications that are not Canada— included in U.S. product labeling, and superscript 1 refers to categories Not commercially available. of use and/or indications that are not included in Canadian product labeling. However, since metronidazole is not specifically approved for Packaging and storage: Prior to reconstitution, store below 30 °C veterinary use, there is no product labeling identifying approved (86 °F), in a light-resistant container, unless otherwise specified by indications. manufacturer. The dosing and strengths of the dosage forms available are expressed in terms of metronidazole base. Preparation of dosage form: Metronidazole hydrochloride for injection must not be given by direct METRONIDAZOLE INJECTION USP intravenous injection, since the initial dilution has an extremely low Usual dose: pH (0.5 to 2.0). It must be diluted further and neutralized prior to Note: Reliable dosing information is not available for the use of administration.{R-35} parenteral metronidazole in animals. However, for situations in To prepare initial dilution for intravenous infusion, add 4.4 mL of sterile which oral administration is not a viable option, injectable forms are water for injection, bacteriostatic water for injection, 0.9% sodium used by following dosing regimens similar to oral dosage forms. chloride injection, or bacteriostatic sodium chloride injection to each 500-mg vial, to provide a concentration of 100 mg per mL (pH 0.5 to Strength(s) usually available: 2.0). The resulting solution should be further diluted in 100 mL of U.S.— 0.9% sodium chloride injection, 5% dextrose injection, or lactated Veterinary-labeled product(s): Ringer’s injection. The final dilution must be neutralized with Not commercially available. approximately 5 mEq of sodium bicarbonate injection per 500 mg of Human-labeled product(s): metronidazole (final pH 6 to 7). Since carbon dioxide gas is produced 500 mg (base) per 100 mL (Rx) [Flagyl I.V. RTU; Metro I.V.; during neutralization, it may be necessary to relieve the pressure in the generic]. final container. The final concentration should not exceed 8 mg per Canada— mL, since neutralization decreases the solubility of metronidazole and {R-35} Veterinary-labeled product(s): precipitation may occur. Not commercially available. Human-labeled product(s): Stability: 500 mg (base) per 100 mL (Rx) [Flagyl; generic]. After reconstitution, solutions retain their potency for 96 hours if stored below 30 °C (86 °F) in room light. Diluted and neutralized solutions Withdrawal times: There are no established withdrawal times since retain their potency for 24 hours. metronidazole is not approved for use in food-producing animals. Neutralized solutions should not be refrigerated, because precipitation may occur. Packaging and storage: Store below 40 °C (104 °F), preferably {R-35} between 15 and 30 °C (59 and 86 °F), unless otherwise specified by Incompatibilities: manufacturer. Protect from light. Protect from freezing. Metronidazole should not be used with aluminum (needles or hubs) that would come into contact with the medication. Incompatibilities: Intravenous admixtures of metronidazole and other Intravenous admixtures of metronidazole with other medications are not medications are not recommended.{R-35} recommended.

{R-30} Additional information: Metronidazole Injection USP is an isotonic USP requirements: Not in USP . (297 to 310 mOsm per L), ready-to-use solution, requiring no dilution or buffering prior to administration.{R-35} Revised: 07/28/94; 09/30/02 Interim revision: 06/05/95; 06/20/96; 05/19/97; 7/21/98 USP requirements: Preserve in single-dose containers of Type I or Type 04/05/03 II glass, or in suitable plastic containers, protected from light. A sterile, isotonic, buffered solution of Metronidazole in Water for Injection. REFERENCES Contains the labeled amount, within ±10%. Meets the requirements 1. Flagyl 375 (capsules) package insert (Pharmacia—US), Rev 9/01. Downloaded from www.pharmacia.com on 4/15/02. for Identiﬁcation, Bacterial endotoxins, pH (4.5–7.0), and Particulate 2. Boothe DM. Anaerobic infections in small animals. Probl Vet Med 1990 Jun; {R-30} matter, and for Injections . 2(2): 330–47.

3. Dow SW. Management of anaerobic infections. Vet Clin North Am Small Anim 23. Perkins SE, Yan LL, Shen Z, et al. Use of PCR and culture to detect Helicobacter Pract 1988 Nov; 18(6): 1167–82. pylori in naturally infected cats following triple antimicrobial therapy. 4. Flagyl tablets package insert (Pharmacia—US), Rev 9/01. Downloaded from Antimicrob Agents Chemother 1996 Jun; 40(6): 1486–90. www.pharmacia.com on 4/15/02. 24. Happonen I, Linden J, Westermarck EJ. Effect of triple therapy on eradication of 5. Klasco RK, editor. USP DI Drug information for the healthcare professional. canine gastric helicobacters and gastric disease. Small Anim Pract 2000 Jan; Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 41(1): 1–6. 6. Zimmer JF. Treatment of feline giardiasis with metronidazole. Cornell Vet 1987 25. Simpson KW, Strauss-Ayali D, McDonough PL, et al. Gastric function in dogs Oct; 77(4): 383–8. with naturally acquired gastric Helicobacter spp. infection. J Vet Intern Med 7. Zimmer JF, Burrington DB. Comparison of four protocols for the treatment of 1999 Nov-Dec; 13(6): 507–15. canine giardiasis. J Am Anim Hosp Assoc 1986; 22: 168–72. 26. Cornetta AM, Simpson KW, Strauss-Ayali D, et al. Use of a [13C]urea breath 8. Tisdall PL, Hunt GB, Beck JA, et al. Management of perianal fistulae in five test for detection of gastric infection with Helicobacter spp in dogs. Am J Vet dogs using azathioprine and metronidazole prior to surgery. Aust Vet J 1999 Res 1998 Nov; 59(11): 1364–9. Jun; 77(6): 374–8. 27. Extralabel drug use in animals. Fed Regist 1996 Nov 7; 61(217): 57731–46. 9. Carlson GP, O’Brien MA. Anaerobic bacterial pneumonia with septicemia in 28. Bartlett JG, Louie TJ, Gorbach SL, et al. Therapeutic efficacy of 29 antimicrobial two racehorses. J Am Vet Med Assoc 1990 Mar 15; 196(6): 941–3. regimens in experimental intra-abdominal sepsis. Rev Infect Dis 1981 May- 10. Jones RL. Clostridial enterocolitis. Vet Clin North Am Equine Pract 2000 Dec; Jun; 313: 535–42. 16(3): 471–85. 29. USP dictionary of USAN and international drug names, 2002 ed. Rockville, 11. Weese JS, Parsons DA, Staempfli HR. Association of Clostridium difficile with MD: The United States Pharmacopeial Convention, Inc., 2002. enterocolitis and lactose intolerance in a foal. J Am Vet Med Assoc 1999 Jan 30. The United States pharmacopeia. The national formulary. USP 26th revision 15; 214(2): 229–32, 205. (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United 12. McGorum BC, Dixon PM, Smith DG. Use of metronidazole in equine acute States Pharmacopeial Convention, Inc., 2002. p. 1227, 1228, 2570. idiopathic toxaemic colitis. Vet Rec 1998 Jun 6; 142(23): 635–8. 31. Panel comment, Rec. 5/93. 13. Ricketts SW, Mackintosh ME. Role of anaerobic bacteria in equine endome- 32. Dow SW, LeCouteur RA, Poss ML, et al. Central nervous system toxicosis tritis. J Reprod Fertil Suppl 1987; 35(2): 343–51. associated with metronidazole treatment of dogs: five cases (1984–1987). J Am 14. Mair TS. The medical management of eight horses with grade 3 rectal tears. Vet Med Assoc 1989; 195(3): 365–8. Equine Vet J Suppl 2000 Jun; 16(32): 104–7. 33. Sweeny RW, Sweeney CR, Soma LR, et al. Pharmacokinetics of metronidazole 15. Heijl L, Lindhe J. Effect of selective antimicrobial therapy on plaque and given to horses by intravenous and oral routes. Am J Vet Res 1986 Aug; gingivitis in the dog. J Clin Periodontol 1980 Dec; 7(6): 463–78. 47(5): 1726–9. 16. Sweeney RW, Sweeney CR, Weiher J. Clinical use of metronidazole in horses: 34. Sweeny RW, Sweeney CR, Weiher J. Clinical use of metronidazole in horses: 200 cases (1984-1989). J Am Vet Med Assoc 1991 Mar 15; 198(6): 1045–8 200 cases (1984-1989). J Am Vet Med Assoc 1991; 198(6): 1045–8. 17. Norris JM, Love DN. In vitro antimicrobial susceptibilities of three Porphyro- 35. Flagyl IV and IV RTU package insert (SCS Pharmaceuticals—US), Rev 7/16/ monas spp and in vivo responses in the oral cavity of cats to selected 98. In: PDR Physician’s Desk Reference. 54th ed. 2000. Montvale, NJ: Medical antimicrobial agents. Aust Vet J 2000 Aug; 78(8): 533–7. Economics Company, 2000. p. 2878–80. 18. Heijl L, Lindhe J. The effect of metronidazole on established gingivitis and 36. Kirkpatrick CE, Farrell JP. Feline giardiasis: observations on natural and plaque in beagle dogs. J Periodontol 1982 Mar; 53(3): 180–7. induced infections. Am J Vet Res 1984 Oct; 45(10): 2182–8. 19. Chou S, Richards GK, Brown RA. A new approach to antibiotic therapy in 37. Neff-Davis CA, Davis LE, Gillette EL. Metronidazole: a method for its colon surgery based on bioassay tissue concentrations. Can J Surg 1982 Sep; determination in biological fluids and its disposition kinetics in the dog. J Vet 25(5): 527–31. Pharmacol Ther 1981; 4: 121–7. 20. Piek CJ, Robben JH. Pyothorax in nine dogs. Vet Q 2000 Apr; 22(2): 107–11. 38. Committee comment, Rec. 5/27/02. 21. Specht TE, Brown MP, Gronwall RR, et al. Pharmacokinetics of metronidazole 39. Steinman A, Gips M, Lavy E, et al. Pharmacokinetics of metronidazole in and its concentration in body fluids and endometrial tissues of mares. Am J Vet horses after intravenous, rectal, and oral administration. J Vet Pharmacol Ther Res 1992 Oct; 53(10): 1807–12. 2000; 23: 353–7. 22. Neiger R, Seiler G, Schmassmann A. Use of a urea breath test to evaluate short- 40. Panel comment, Rec. 11/29/94. term treatments for cats naturally infected with Helicobacter heilmannii. Am J Vet Res 1999 Jul; 60(7): 880–3.

PENICILLIN G Veterinary—Intramammary-Local Some commonly used brand names for veterinary-labeled products are PHARMACOLOGY/PHARMACOKINETICS Go-dry and Masti-Clear. Note: For a listing of dosage forms and brand names by country Mechanism of action/effect: The penicillins produce their bactericidal availability, see the Dosage Forms section(s). effect by inhibiting cross-linkages during bacterial cell wall synthesis.{R-9} Pencillin G must penetrate the cell wall to attach to speciﬁc proteins on Not commercially available in Canada. the inner surface of the bacterial cell membrane. In actively growing CATEGORY: cells, the binding of penicillin within the cell wall leads to interference Antibacterial (intramammary-local). with production of cell wall peptidoglycans and subsequent lysis of the cell in a hypo- or iso-osmotic environment.{R-9; 13}

Distribution: Medications infused into a teat are considered to be fairly INDICATIONS evenly distributed in that quarter of the healthy mammary gland; GENERAL CONSIDERATIONS however, in an udder affected by moderate to severe mastitis, the The spectrum of activity of penicillin G includes many aerobic and presence of edema, blockage of milk ducts, and reduced blood circu- anaerobic gram-positive organisms. Penicillin G is highly susceptible to lation causes uneven distribution.{R-14} After penicillin G procaine is beta-lactamases and has little activity against organisms that can infused into a mammary gland, it is also partially distributed into the produce these enzymes. In addition, penicillin G is ineffective against other quarters of the gland,{R-4; 15} into the local lymph circulation, bacteria that are resistant by certain other mechanisms, such as having and to some degree into the plasma and other tissues.{R-16} a relatively impermeable cell wall. Therefore, penicillin G has little activity against many staphylococci and most gram-negative bacteria. Peak serum concentration: In healthy animals, after intramammary administration of 400 mg (404,000 Units) of penicillin G procaine in combination with the same amount of dihydrostreptomycin sulfate, ACCEPTED the peak serum concentration of penicillin G is 0.07 mcg/mL at 4 1 Mastitis (treatment) —Cattle: Penicillin G is indicated in the treatment of hours.{R-16} mastitis in cattle{R-1; 2; 7} caused by susceptible organisms such as Streptococcus agalactiae{R-7; 20}. Intramammary therapy alone is indicated only in the treatment of subacute mastitis manifested by mild PRECAUTIONS TO CONSIDER inflammatory changes in the milk or udder. Acute or peracute mastitis, PATIENT MONITORING in which gross inflammatory changes in the milk or udder or systemic The following may be especially important in patient monitoring (other signs appear, requires administration of other medications also, which tests may be warranted in some patients, depending on condition; » = {R-5} may include systemic antibiotics and/or supportive therapy. major clinical significance): Bacteriologic pathogen identification in milk 1Not included in Canadian product labeling or product not commercially (milk samples should be tested 3 weeks after the end of treatment; available in Canada. mastitis is not considered bacteriologically cured until samples show REGULATORY CONSIDERATIONS an absence of the mastitis-causing organisms{R-2}) U.S.— Clinical signs Withdrawal times have been established for penicillin G procaine (although a resolution of clinical signs of mastitis is not an indication {R-18} intramammary infusion (see the Dosage Forms section{R-1}). that a bacteriologic cure has been achieved , monitoring of the clinical condition of the mammary gland, teat, and milk produced CHEMISTRY can aid in diagnosis of a recurrence of mastitis or initial diagnosis of Source: Produced by the mold Penicillium.{R-8} mastitis in another cow in the herd) Chemical group: Beta-lactam antibiotics.{R-8; 9} Somatic cell count Chemical name: Penicillin G procaine—4-Thia-1-azabicyclo[3.2.0]hep- (somatic cell counts performed on milk to monitor the dairy herd are tane-2-carboxylic acid, 3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-, used primarily to maintain milk quality, but also to approximately [2S-(2 alpha,5 alpha,6 beta)]-, compd. with 2-(diethylamino)ethyl assess the overall effectiveness of mastitis control programs that may {R-5} 4-aminobenzoate (1:1) monohydrate.{R-10} include antibiotic treatment of cows) Molecular formula: Penicillin G procaine {R-10} SIDE/ADVERSE EFFECTS C16H18N2O4S Æ C13H20N2O2 Æ H2O. Molecular weight: Penicillin G procaine—588.72.{R-10} The following side/adverse effects have been selected on the basis of their Description: Penicillin G Procaine USP—White crystals or white, very potential clinical significance (possible signs and, for humans, symp- fine, microcrystalline powder. Is odorless or practically odorless, and is toms in parentheses where appropriate)—not necessarily inclusive: relatively stable in air. Its solutions are dextrorotary. Is rapidly inactivated by acids, by alkali hydroxides, and by oxidizing agents{R-17}. THOSE INDICATING NEED FOR MEDICAL ATTENTION pKa: 2.7.{R-11; 12} Incidence unknown Solubility: Penicillin G Procaine USP—Slightly soluble in water; soluble Cows in alcohol and in chloroform{R-17}. Allergic reactions—theoretically possible locally or systemically

OVERDOSE Withdrawal times: {R-1; 2} For information in cases of overdose or unintentional ingestion, contact U.S. — the American Society for the Prevention of Cruelty to Animals Withdrawal time (ASPCA) National Animal Poison Control Center (888-426-4435 or 900-443-0000; a fee may be required for consultation) and/or the Species Meat (days) Milk (hours) drug manufacturer. Cows Nonlactating 14 72 CLIENT CONSULTATION Lactating 3 60 Treatment of mastitis in dairy cattle is best achieved by a comprehensive mastitis control program in which herd management is the primary focus. The program should include good maintenance of milking equipment and constant evaluation of milking procedures and teat Packaging and storage: Store between 15 and 30 C (59 and 86 F), {R-1; 2} health as well as strategic treatment of clinical cases of mastitis.{R-7} unless otherwise speciﬁed by manufacturer.

VETERINARY DOSING INFORMATION USP requirements: Preserve in well-closed disposable syringes. A suspension of Penicillin G Procaine in a suitable vegetable oil vehicle. Antibiotic therapy in the dry cow is measurably more effective than Label it to indicate that it is for veterinary use only. Contains an treatment during lactation.{R-7; 18} amount of penicillin G procaine equivalent to the labeled amount of Choice of antibiotic for treatment of mastitis should be based on penicillin G, within –10% to +15%. Meets the requirements for Iden- knowledge of culture and sensitivity of pathogens causing mastitis in tification and Water (not more than 1.4%).{R-17} the cow and the dairy herd.{R-19} Before administration of intramammary penicillin G procaine, the 1 following steps should be performed:{R-1} Not included in Canadian product labeling or product not commercially • The udder should be milked out completely and the teats washed available in Canada. with warm water and a disinfectant. Care should be taken to avoid {R-6} washing excess dirt down from the udder onto the teat ends. Developed: 03/08/95 The area should be dried thoroughly. An effective germicidal teat dip Interim revision: 04/24/96; 05/19/97; 07/08/98; 10/15/99; 06/30/02 should be applied for one minute and then each teat wiped with a 02/28/03 separate cotton ball soaked with an antiseptic such as 70% alcohol. • Persons performing the treatment should wash and dry their hands REFERENCES before each treatment. 1. Go-dry (G.C. Hanford Mfg. Co—US), Rev 10/92, Rec 7/22/94. • The tip of the syringe should be inserted into the teat end as little as 2. Masti-Clear (G.C. Hanford Mfg. Co—US), Rec 2/19/03. 3. Arrioja-Dechert A, editor. Compendium of veterinary products, CD edition. possible{R-6} and the contents of the syringe should be injected into Port Huron, MI: North American Compendiums, Inc., 2002. each streak canal while the teat is held firmly. The medication 4. Hawkins GE, Cannon RY, Paar CF. Concentration of penicillin in milk from should then be gently massaged up the teat canal into the udder. noninfused quarters following infusion of one quarter. J Dairy Sci 1962; 45: An effective teat dip is recommended on all teats following treatment. 1020–2. 5. Heath SE. Bovine mastitis. In: Howard JL. Current veterinary therapy 3 food For the lactating cow, treated quarters should not be milked for at least animal practice. Philadelphia: W.B. Saunders, 1993. p. 762–9. six hours after treatment but should be milked at regular intervals 6. Panel comment, Rec 12/6/94. thereafter.{R-2} 7. Hady PJ, Lloyd JW, Kaneene JB. Antibacterial use in lactating dairy cattle. J Am Vet Med Assoc 1993 Jul; 203(2): 210–20. 8. Watson ADJ. Penicillin G and the alternatives. Vet Annu. 1985; 25: 277–83. INTRAMAMMARY DOSAGE FORMS 9. Donowitz GR, Mandell GL. Beta-lactam antibiotics. N Engl J Med 1988; 318: 419–26. 10. USP dictionary of USAN and international drug names, 2002 ed. Rockville, PENICILLIN G PROCAINE INTRAMAMMARY MD: The United States Pharmacopeial Convention, Inc.; 2002. INFUSION USP 11. Prescott JF, Baggot JD. Antimicrobial therapy in veterinary medicine, 2nd ed. Usual dose: Antibacterial1—Cattle: Ames, IA: Iowa State University Press, 1993. p. 81–9. 12. Ziv G, et al. Pharmacokinetic evaluation of penicillin and cephalosporin Dry cow (nonlactating)—Intramammary, 100,000 Units into each derivatives in serum and milk of lactating cows and ewes. Am J Vet Res 1973; {R-1} quarter of the udder at the time of drying-off. 34(12): 1561–5. Lactating cow—Intramammary, 100,000 Units into each affected 13. Wright AJ, Wilkowski CJ. The penicillins. Mayo Clin Proc 1983: 58: 21–32. quarter of the udder every twelve hours for a maximum of three 14. Jarp J, Bugge HP, Larsen S. Clinical trial of three therapeutic regimens for {R-2} bovine mastitis. 1989; 124: 630–4. doses. 15. Anifantakis EM. Excretion rates of antibiotics in milk of sheep and their effect on yogurt production. J Dairy Sci 1982; 65: 426–9. Strength(s) usually available: 16. Franklin A, Rantzien M, Obel N, et al. Concentrations of penicillin, strepto- U.S.—{R-1; 2} mycin, and spiramycin in bovine udder tissue liquids. Am J Vet Res 1986 Apr; 47(4): 804–7. Veterinary-labeled product(s): 17. The United States pharmacopeia. The national formulary. USP 26th revision 100,000 Units per 10 mL (OTC) [Go-dry (dry cow only); Masti-Clear (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United (lactating cow only)]. States Pharmacopeial Convention, Inc., 2002. p. 1415, 2573. Canada—{R-3} 18. Craven N. Efficacy and financial value of antibiotic treatment of bovine clinical mastitis during lactation—a review. Br Vet J 1987; 143: 410–22. Veterinary-labeled product(s): 19. Panel comment , Rec 11/18/94. Not commercially available. 20. Panel comment, Rec 11/18/94.

PENICILLIN G Veterinary—Systemic

Some commonly used brand names are: which pathogens other than Actinomyces species are not yet For veterinary-labeled products—Agri-cillin; Ambi-pen; Aquacillin; Benz- involved.{R-6; 14} apro; Combicillin; Combicillin AG; Depocillin; Derapen SQ/LA; Duo-Pen; [Arthritis, septic (treatment)]—Cattle, horses, pigs, and sheep:{R-6} Peni- Duplocillin LA; Durapen; Hi-Pencin 300; Longisil; Microcillin; Pen- cillin G is indicated in the treatment of septic arthritis caused by Aqueous; Pen G Injection; Penmed; Penpro; Pot-Pen; Propen LA; R-Pen; susceptible bacteria in cattle, horses, pigs, and sheep.{R-15; 16} Twin-pen; and Ultrapen LA. [Leptospirosis (treatment)]—Cattle,{R-6} dogs{R-6; 17}, horses1{R-18}, and For human-labeled products—Pfizerpen. pigs:{R-6} Penicillin G is indicated in the treatment of acute leptospirosis in cattle, dogs, horses, and pigs. The chronic shedding stage of CATEGORY: leptospirosis is often treated with tetracycline; penicillin G adminis- Antibacterial (systemic). tered alone will not clear the carrier state.{R-73; 85} [Malignant edema (treatment)]—Cattle:{R-6} Penicillin G is indicated in INDICATIONS the treatment of malignant edema caused by susceptible Clostridium Note: Bracketed information in the Indications section refers to uses that septicum in cattle. either are not included in U.S. product labeling or are for products not [Metritis (treatment)]—Cattle, horses, pigs, and sheep:{R-6} Penicillin G is commercially available in the U.S. indicated in the treatment of metritis caused by susceptible organisms in cattle, horses, pigs, and sheep{R-20; 21}; however, therapeutic regimens often emphasize evacuation of uterine contents as the GENERAL CONSIDERATIONS primary treatment.{R-85} The spectrum of activity of penicillin G includes many aerobic and [Pyelonephritis (treatment)]—Cattle: Penicillin G is indicated in the anaerobic gram-positive organisms. Aerobes susceptible to penicillin treatment of pyelonephritis caused by susceptible organisms such as G include most beta-hemolytic streptococci, beta-lactamase-negative Corynebacterium renale in cattle.{R-6; 22; 23} staphylococci, Actinomyces species, some Bacillus anthracis, Coryne- [Skin and soft tissue infections (treatment)]— bacterium species, and Erysipelothrix rhusiopathiae. Most species of Cattle: Penicillin G is indicated in the treatment of skin and soft tissue anaerobes, including Clostridium species, but excluding beta-lactam- infections caused by susceptible organisms, including those associ- ase-producing Bacteroides species, are also susceptible to penicillin G. ated with calf diphtheria, foot rot, the umbilicus, and wounds.{R-10}. Penicillin G is easily inactivated by beta-lactamases and has little Horses: Penicillin G is indicated in the treatment of skin and soft tissue efficacy against organisms that can produce these enzymes. In infections caused by susceptible organisms, including those associ- addition, penicillin G is ineffective against those bacteria that are ated with the umbilicus and with wounds.{R-6} resistant by other mechanisms, such as having a relatively Pigs: Penicillin G is indicated in the treatment of skin and soft tissue impermeable cell wall. Therefore, penicillin G has little activity infections caused by susceptible organisms, including those associ- against many staphylococci and most gram-negative bacteria.{R-3; 4} ated with the umbilicus.{R-6} Sheep: Penicillin G is indicated in the treatment of skin and soft tissue infections caused by susceptible organisms, including those associ- ACCEPTED ated with post-surgical tail docking and castration site infections, Blackleg (treatment)—Cattle and [sheep]: Penicillin G is indicated in the and also those associated with the umbilicus.{R-6; 10} treatment of blackleg caused by susceptible organisms such as [Tetanus (treatment)]—Cats, cattle, dogs, horses, and pigs1: Penicillin G is {R-5; 6} Clostridium chauvoei in cattle and sheep. indicated in the treatment of Clostridium tetani in cats, cattle, dogs, Erysipelas (treatment)—Pigs and turkeys: Penicillin G is indicated in the horses, and pigs in conjunction with tetanus antitoxin and supportive treatment of infections caused by Erysipelothrix rhusiopathiae (insidiosa) therapy.{R-6} in pigs and turkeys.{R-6–9} Pharyngitis (treatment); or 1Not included in Canadian product labeling or product not commercially Rhinitis (treatment)—Cattle: Penicillin G is indicated in the treatment of available in Canada. bacterial rhinitis or pharyngitis caused by susceptible organisms such as Actinomyces pyogenes.{R-5} REGULATORY CONSIDERATIONS Pneumonia, bacterial (treatment)—Cattle,{R-6; 7} sheep{R-6; 7},[horses]{R-6}, U.S.— and [pigs]{R-10}: Penicillin G is indicated in the treatment of bacterial Administration of penicillin G procaine to animals may produce pneumonia caused by susceptible organisms in cattle, sheep, [horses], procaine concentrations in the blood and urine that violate equine and [pigs]; however, for bacterial pneumonia in cattle, sheep, and pigs, and greyhound racing commission prohibitions.{R-91; 92} penicillin G is not considered the drug of first choice pending culture and Penicillin G is not for use in turkeys producing eggs for human sensitivity results.{R-85; 87} consumption or for use in horses intended for food.{R-7; 8} Strangles (treatment)—Horses: Penicillin G is indicated in the treatment Penicillin G Benzathine and Penicillin G Procaine Injectable Suspen- of strangles caused by Streptococcus equi;{R-7} however, it may be sion USP combination is not labeled for use in lactating cattle or effective only during the acute phase of the infection.{R-13} preruminating calves.{R-5} [Actinomycosis (treatment)]—Cattle: Penicillin G is indicated in the Some brands of Penicillin G Procaine Injectable Suspension USP are treatment of actinomycosis, and may be most effective for infections in not labeled for use in preruminating cattle.{R-53}

Withdrawal times have been established for Penicillin G Potassium Penicillin G Sodium USP—Colorless or white crystals or white to slightly USP, Penicillin G Benzathine and Penicillin G Procaine Injectable yellow, crystalline powder. Is odorless or practically odorless, and is Suspension USP, and Penicillin G Procaine Injectable Suspension moderately hygroscopic. Its solutions are dextrorotatory. Is relatively USP (see the Dosage Forms section).{R-5; 7; 8; 26} stable in air, but is inactivated by prolonged heating at about 100 C, Canada— especially in the presence of moisture. Its solutions lose potency fairly Administration of penicillin G procaine to animals may produce rapidly at room temperature, but retain substantially full potency for procaine concentrations in the blood and urine that violate equine several days at temperatures below 15 C. Its solutions are rapidly and greyhound racing commission prohibitions.{R-84} inactivated by acids, alkali hydroxides, oxidizing agents, and penicil- Penicillin G is not labeled for use in turkeys producing eggs for human linase.{R-51} consumption.{R-9} pKa: 2.7.{R-2; 32} Penicillin G Benzathine and Penicillin G Procaine Injectable Solubility: Suspension USP combination is not labeled for use in lactating Penicillin G Benzathine USP—Very slightly soluble in water; sparingly cattle.{R-27; 28} soluble in alcohol.{R-51} Withdrawal times have been established for Penicillin G Potassium Penicillin G Potassium USP—Very soluble in water, in saline TS, and in USP, Penicillin G Benzathine and Penicillin G Procaine Injectable dextrose solutions; sparingly soluble in alcohol.{R-51} Suspension USP, and Penicillin G Procaine Injectable Suspension Penicillin G Procaine USP—Slightly soluble in water; soluble in alcohol USP (see the Dosage Forms section).{R-9; 27; 28} and in chloroform.{R-51}

CHEMISTRY PHARMACOLOGY/PHARMACOKINETICS Source: Produced by the mold Penicillium.{R-1} See also Table 1. Pharmacokinetic Parameters at the end of this Chemical group: Beta-lactam antibiotics.{R-1; 29} monograph. Chemical name: Note: With the exception of information in Table 1, pharmacokinetic data Penicillin G benzathine—4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic in this section are based on intravenous administration of potassium or acid, 3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-, [2S-(2alpha,5alpha, sodium penicillin G. 6beta)]-, compd. with N,N’-bis(phenylmethyl)-1,2-ethanediamine (2:1), tetrahydrate.{R-30} Mechanism of action/effect: The penicillins produce their bactericidal Penicillin G potassium—4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic effect by inhibition of bacterial cell wall synthesis.{R-29} Pencillin G acid, 3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-, monopotassium must penetrate the cell wall to attach to speciﬁc proteins on the inner salt, [2S-(2alpha,5alpha,6beta)]-.{R-30} surface of the bacterial cell membrane. In actively growing cells, the Penicillin G procaine—4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic binding of penicillin within the cell wall leads to interference with acid, 3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-, [2S-(2alpha,5alpha, production of cell wall peptidoglycans and subsequent lysis of the cell 6beta)]-, compd. with 2-(diethylamino)ethyl 4-aminobenzoate (1:1) in a hypo- or iso-osmotic environment.{R-4; 29; 33} monohydrate.{R-30} Penicillin G sodium—4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic Absorption: acid, 3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-, [2S-(2alpha, Gastric absorption of penicillin G is poor in many species because it is 5alpha,6beta)]-, monosodium salt.{R-30} rapidly hydrolyzed in the acid environment of the stomach or Molecular formula: abomasum.{R-4} Only 15 to 30% of penicillin G may be absorbed by {R-30} Penicillin G benzathine—(C16H18N2)4S)2ÆC16H20N2Æ4H2O. the oral route in a fasted animal and that percent decreases when {R-30} {R-34} Penicillin G potassium—C16H17KN2O4S. there is food in the stomach. {R-30} Penicillin G procaine—C16H18N2O4SÆC13H20N2O2ÆH2O. The sodium and potassium salts of penicillin G are the only dosage forms {R-30} Penicillin G sodium—C16H17N2NaO4S. that are suitable for intravenous administration. They are also the Molecular weight: most quickly absorbed from intramuscular or subcutaneous sites of Penicillin G benzathine—981.19.{R-30} administration.{R-4; 34; 35} Procaine penicillin G is more slowly Penicillin G potassium—372.48.{R-30} absorbed from intramuscular administration than are the sodium or Penicillin G procaine—588.72.{R-30} potassium salts and so produces more sustained but lower plasma Penicillin G sodium—356.37.{R-30} concentrations.{R-4; 35} Benzathine penicillin G is the least soluble of Description: the dosage forms and so is the most slowly absorbed; the longest Penicillin G Benzathine USP—White, odorless, crystalline powder.{R-51} sustained but lowest plasma concentrations of penicillin G are Penicillin G Potassium USP—Colorless or white crystals, or white, produced.{R-4; 35} The rate of absorption from intramuscular injections crystalline powder. Is odorless or practically so, and is moderately of some penicillin dosage forms, such as procaine penicillin G, can vary hygroscopic. Its solutions are dextrorotatory. Its solutions retain depending on the injection site; injections into the neck muscle in substantially full potency for several days at temperatures below 15 C, cattle and horses produce more rapid absorption and higher plasma but are rapidly inactivated by acids, by alkali hydroxides, by glycerin, concentrations than do injections into the gluteal muscle. Also, and by oxidizing agents.{R-51} procaine penicillin G is more completely absorbed in steers when Penicillin G Procaine USP—White crystals or white, very ﬁne, micro- injected intramuscularly than when administered subcutaneously. crystalline powder. Is odorless or practically odorless, and is relatively stable in air. Its solutions are dextrorotatory. Is rapidly inactivated by Distribution: Volume of distribution— acids, by alkali hydroxides, and by oxidizing agents.{R-51} Dromedaries: 0.34 ± 0.079 liter per kg (L/kg).{R-59}

Horses: 0.72 ± 0.16 L/kg.{R-44} PEDIATRICS {R-59} Sheep: 0.604 ± 0.205 L/kg. In neonates that have not yet developed full renal function, excretion of penicillin G occurs at a slower rate than it does in a mature Protein binding: animal.{R-60; 75} Cattle—Low (28.5%).{R-38; 39} Dogs—Moderate (60%).{R-40} Horses—Moderate (52–54%).{R-39; 41} DRUG INTERACTIONS AND/OR RELATED Rabbits—Low (35%).{R-39; 42} PROBLEMS Sheep—Low (30.4%).{R-38; 39} The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible Half-life: Elimination— mechanism in parentheses where appropriate)—not necessarily inclu- Calves, newborn to 15 days: 26.6 minutes.{R-60} sive (» = major clinical significance): Dogs: 30 minutes.{R-39} Note: Combinations containing any of the following medications, depend- Dromedaries: 49 minutes.{R-59} ing on the amount present, may also interact with this medication. Horses: 48 to 53 minutes.{R-41; 57} Antibacterials, bacteriostatic, such as: Sheep: 42 minutes.{R-59} Chloramphenicol or Turkeys: 30 minutes.{R-62} Tetracycline (because penicillin G acts only on cells that are actively reproducing, Elimination: Primarily renal{R-2; 4}; active renal tubular secretion bacteriostatic antibiotics such as chloramphenicol or tetracycline occurs.{R-89} From 60 to 100% of the dose is recoverable from urine may decrease the efficacy of penicillin G by depressing the activity of following injection of an aqueous solution of penicillin G.{R-43} target cells{R-43}; however, the clinical significance of this interfer- Total clearance— ence is not well documented{R-66}) Dromedaries: 4.87 ± 0.63 mL/min/kg.{R-59} Phenylbutazone Horses: 8.5 ± 1.33 mL/min/kg.{R-44} (the concomitant administration of phenylbutazone with penicillin G Sheep: 9.17 ± 1.39 mL/min/kg.{R-59} may cause higher plasma concentrations of penicillin G, resulting in Calves: lower distribution of penicillin G to the tissues{R-44}) Newborn—2.98 ± 0.52 mL/min/kg.{R-60} Five days—4.83 ± 1.45 mL/min/kg.{R-60} Ten days—3.11 ± 1 mL/min/kg.{R-60} MEDICAL CONSIDERATIONS/CONTRAINDICATIONS Fifteen days—4.65 ± 1.18 mL/min/kg.{R-60} The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)—not necessarily inclusive (» PRECAUTIONS TO CONSIDER = major clinical significance). Except under special circumstances, this medication should not be CROSS-SENSITIVITY AND/OR RELATED PROBLEMS used when the following medical problems exist: In humans, patients allergic to other penicillins may also be allergic to » Hypersensitivity to penicillin penicillin G; in addition, patients allergic to cephalosporins may be (some reactions, such as hemolytic anemia in horses{R-49}, may be allergic to penicillin G.{R-52} The incidence of these occurrences in much more likely to occur in an animal that has had a previous animals is unknown, but it is recommended that penicillin use be reaction to penicillin G) avoided in animals that have had a previous severe reaction.{R-2} » Hypersensitivity to procaine{R-6} Animals allergic to procaine or other ester-type local anesthetics may (some sources recommend intradermal procaine testing of animals also be allergic to penicillin G procaine.{R-6; 75} suspected of procaine sensitivity before administering procaine penicillin G{R-6}) PREGNANCY/REPRODUCTION Penicillins have been shown to cross the placenta; however, no Risk-benefit should be considered when the following medical teratogenic problems have been associated with the use of penicillin problems exist: G during pregnancy in studies of mice, rabbits, and rats, or during Erysipelas in pigs clinical use in many species. No well-controlled studies have been (administration of procaine penicillin has caused recurrence or performed for most species.{R-75} exacerbation of signs of erysipelas including abortion, cyanotic ears, fever of 39.5 to 41 C, inappetance, lassitude, vomiting, and LACTATION shivering{R-50}) Penicillin G is distributed into milk{R-2}; in food animals the distribution is Renal function impairment sufficient to cause violative residues. However, the concentrations of (because penicillin G is primarily excreted by the kidneys, unneces- penicillin produced in milk are subtherapeutic for most bacteria.{R-85} sary accumulation of medication in the plasma and tissues may In sheep, 0.11% of an intramuscular injection of sodium penicillin G occur{R-45}; also, the sodium or potassium content of intravenous was distributed into the milk.{R-31} penicillin G dosage forms should be considered)

PATIENT MONITORING Gastrointestinal reactions; headache; oral candidiasis; vaginal The following may be especially important in patient monitoring (other candidiasis tests may be warranted in some patients, depending on condition; » = Incidence less frequent major clinical significance): Allergic reactions, specifically anaphylaxis; exfoliative derma- Culture and susceptibility, in vitro, and titis; serum sickness–like reactions; skin rash, hives, or itching Minimum inhibitory concentration (MIC) Incidence rare (in vitro cultures and MIC test should be done on samples collected Clostridium difficile colitis; hepatotoxicity; interstitial nephri- prior to penicillin administration to determine pathogen susceptibil- tis; leukopenia or neutropenia; mental disturbances; pain at site ity) of injection; platelet dysfunction or thrombocytopenia; seizures Potassium or sodium, serum Note: Clostridium difficile colitis may occur up to several weeks after (determination of concentrations of serum sodium or potassium may discontinuation of these medications. be necessary in animals receiving high doses or long-term therapy Interstitial nephritis is seen primarily with methicillin, and to a lesser with potassium or sodium penicillin G, particularly in those patients degree with nafcillin and oxacillin, but may occur with any penicillin. with severe renal function impairment, other pre-existing electrolyte Mental disturbances are toxic reactions to the procaine content of imbalance, or congestive heart failure{R-75}) penicillin G procaine; this reaction may be seen in patients who receive a large single dose of the medication, as in the treatment of SIDE/ADVERSE EFFECTS gonorrhea. Seizures are more likely to occur in patients receiving high doses of a The following side/adverse effects have been selected on the basis of their penicillin and/or patients with severe renal function impairment. potential clinical significance (possible signs and, for humans, symptoms in parentheses where appropriate)—not necessarily inclusive: OVERDOSE For information in cases of overdose or unintentional ingestion, contact THOSE INDICATING NEED FOR MEDICAL ATTENTION the American Society for the Prevention of Cruelty to Animals Incidence unknown (ASPCA) National Animal Poison Control Center (888-426-4435 All species or 900-443-0000; a fee may be required for consultation) and/or the Allergic reactions, specifically anaphylaxis,{R-6} contact derma- drug manufacturer. titis,{R-6} serum sickness–like syndromes,{R-6} and urticaria{R-6}; overgrowth of nonsusceptible organisms{R-7}; procaine toxicity—with procaine-containing dosage forms only VETERINARY DOSING INFORMATION Note: Multiple cases of procaine toxicity have been reported in pig herds FOR PARENTERAL DOSAGE FORMS ONLY {R-50; 77} being treated for erysipelas . Signs included abortion, To prevent procaine toxicity, keeping procaine penicillin at proper cyanotic ears, fever of 39.5 to 41 C, inappetance, lassitude, storage temperature and following shelf life recommendations are vomiting, and shivering. recommended to avoid any degradation of the product.{R-48} Horses Allergic reactions, specifically anaphylaxis{R-6; 48} (hemorrhagic enterocolitis, progressive respiratory distress from coughing to dyspnea FOR TREATMENT OF ADVERSE EFFECTS to apnea);{R-48} immune-mediated hemolytic anemia (icterus, Recommended treatment consists of the following: inappetance, listlessness, paleness of mucous membranes, red-brown For anaphylaxis {R-6} urine, splenomegaly, tachycardia);{R-49} procaine toxicity (signs in • Parenteral epinephrine. reported order of occurrence: fright, sudden backing, aimless galloping, • Oxygen administration and respiratory support. {R-76} loss of coordination, muscle tremors, apnea, cardiac arrest)—with For procaine toxicity {R-48} high doses of procaine-containing dosage forms{R-48} • If seizures occur, sedation with diazepam and/or barbiturates{R-6}. • Oxygen administration and respiratory support as needed. THOSE INDICATING NEED FOR MEDICAL ATTENTION • Treatment for cardiovascular collapse if necessary. ONLY IF THEY CONTINUE OR ARE BOTHERSOME Incidence more frequent ORAL DOSAGE FORMS All species Pain at site of injection—with higher doses{R-69} PENICILLIN G POTASSIUM FOR ORAL SOLUTION USP Usual dose: Antibacterial—Turkeys: Oral, administered as the sole {R-47} HUMAN SIDE/ADVERSE EFFECTS source of drinking water at a concentration of 1,500,000 Units per In addition to the above side/adverse effects reported in animals, the gallon (395,000 Units per L) for five days.{R-8} following side/adverse effects have been reported in humans, and are included in the human monograph Penicillins (Systemic) in USP DI Size(s) usually available{R-46}: Volume I; these side/adverse effects are intended for informational U.S.—{R-8} purposes only and may or may not be applicable to the use of penicillin Veterinary-labeled product(s): G in the treatment of animals: 384,000,000 Units (OTC) [R-Pen]. Incidence more frequent 500,000,000 Units (OTC) [R-Pen; generic].

Canada—{R-9} Strength(s) usually available{R-46}: Veterinary-labeled product(s): U.S.— 100,000,000 Units (OTC) [Pot-Pen]. Veterinary-labeled product(s): 500,000,000 Units (OTC) [Pot-Pen; generic]. 150,000 Units of penicillin G benzathine and 150,000 Units of 15,000,000,000 Units (OTC) [generic]. penicillin G procaine per mL (Rx) [Ambi-pen; Combicillin; Combicillin AG; Duo-Pen; Durapen; Twin-Pen; generic]. Withdrawal times: Canada— U.S.{R-8; 26} and Canada{R-9}— Veterinary-labeled product(s): 150,000 Units of penicillin G benzathine and 150,000 Units of Withdrawal time penicillin G procaine per mL (Rx) [Benzapro; Duplocillin LA; Species Meat (days) Longisil].

Turkeys 1 Withdrawal times: U.S.—{R-26} Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by Withdrawal time the manufacturer. Store in a tight container. Species Meat (days)

Preparation of dosage form: Cattle, beef 30 U.S.—Dissolve 384,000,000 Units in 256 Gallons (969 L) to produce the Note: Products bearing labeling listing the above withdrawal time state final 1,500,000 Units per Gallon (3.8 L) solution.{R-8} that it is based on a dose of 4400 Units of penicillin G benzathine and Canada—Dissolve 100,000,000 Units in 88.7 Gallons (337 L) to produce 4400 Units of penicillin G procaine per kg (2000 Units of each per the final 1,128,600 Units per Gallon (3.8 L) solution.{R-9} pound) of body weight administered subcutaneously every 48 hours for two treatments and is not applicable to higher doses or longer Stability: Gravity flow water systems require preparation of fresh solu- administration.{R-5} tions every 12 hours. Automatic watering systems require fresh {R-8} solution preparation every 24 hours. Canada—{R-27; 28}

USP requirements: Preserve in tight containers. A dry mixture of Withdrawal time Penicillin G Potassium and one or more suitable buffers, colors, dilu- Species Meat (days) ents, flavors, and preservatives. Contains the labeled number of Peni- cillin G Units when constituted as directed in the labeling, within –10% Cattle, beef 14 to +30%. Meets the requirements for Identification, Uniformity of Note: Products bearing labeling listing the above withdrawal time state dosage units (single-unit containers), Deliverable volume (multiple- that it is based on a dose of 4286 to 4500 Units of penicillin G unit containers), pH (5.5–7.5, in the solution constituted as directed in benzathine and 4286 to 4500 Units of penicillin G procaine per kg of the labeling), and Water (not more than 1.0%).{R-51} body weight administered intramuscularly and is not applicable to higher doses or longer administration.{R-27; 28; 63} PARENTERAL DOSAGE FORMS Note: Bracketed information in the Dosage Forms section refers to uses Packaging and storage: Store between 2 and 8 C (36 and 46 F). {R-5} that either are not included in U.S. product labeling or are for products Protect from freezing. not commercially available in the U.S. Preparation of dosage form: The vial should be warmed to room tem- {R-5} PENICILLIN G BENZATHINE AND PENICILLIN G perature and shaken well to insure a uniform suspension. PROCAINE INJECTABLE SUSPENSION USP Note: Penicillin G benzathine and penicillin G procaine combination has USP requirements: Preserve in single-dose or in multiple-dose con- been replaced by other more effective medications. Although products tainers, preferably of Type I or Type III glass. A sterile suspension of containing penicillin G procaine and penicillin G benzathine combined Penicillin G Benzathine and Penicillin G Procaine or when labeled for may be effective in the treatment of extremely sensitive organisms, the veterinary use only, of Penicillin G Benzathine and Penicillin G Pro- plasma concentration of penicillin G produced by the administration of caine, in Water for Injection. Where it is intended for veterinary use recommended doses of penicillin G benzathine drops to such a low level only, it is so labeled. May contain one or more suitable buffers, pre- after 12 to 48 hours that it becomes ineffective in the treatment of servatives, and suspending agents. Contains the labeled amounts, most systemic infections.{R-78; 79} No dosage of these penicillin G within –10% to +15%. Meets the requirements for Identification, procaine and penicillin G benzathine combinations can be recom- Crystallinity, pH (5.0–7.5), Limit of soluble penicillin G and procaine mended as likely to be effective for many infections caused by (where it is prepared from penicillin G procaine and is labeled for penicillin-sensitive organisms.{R-88} Even when administered at label veterinary use only, not more than 1%), and for Bacterial endotoxins, doses, the risk exists for residues, which are 30 to 60 times the and Sterility under Penicillin G Procaine Suspension, and for Injec- maximum limit, to occur at the injection site.{R-80} tions.{R-51}

PENICILLIN G POTASSIUM FOR INJECTION USP Citrate, of which not more than 0.15% may be replaced by Citric Acid. Usual dose: [Antibacterial]1— Has a potency of the labeled number of Penicillin G Units, within –10% Cats and dogs: Intravenous or intramuscular, 20,000 to 40,000 Units to +20%. In addition, where it contains Sodium Citrate it has a po- per kg of body weight every six to eight hours.{R-54} tency of not less than 1335 and not more than 1595 Penicillin G Units Horses: Intravenous or intramuscular, 20,000 Units per kg of body per mg. Meets the requirements for Constituted solution, Identification, weight every six to eight hours.{R-57; 65} Crystallinity, Bacterial endotoxins, Sterility, pH (6.0–8.5, in a solution containing 60 mg per mL or, where packaged for dispensing, in the Size(s) usually available: solution constituted as directed in the labeling), Loss on drying (not U.S.—{R-66; 67} more than 1.5%), and Particulate matter, and for Uniformity of dosage {R-51} Veterinary-labeled product(s): units and Labeling under Injections. Not commercially available. Human-labeled product(s): PENICILLIN G PROCAINE INJECTABLE SUSPENSION 1,000,000 Units (Rx) [generic]. USP 5,000,000 Units (Rx) [Pfizerpen; generic]. Usual dose: Antibacterial— 10,000,000 Units (Rx) [generic]. [Cats] and [dogs]: Intramuscular, 20,000 to 40,000 Units per kg of {R-54} 20,000,000 Units (Rx) [Pfizerpen; generic]. body weight every twelve to twenty-four hours. {R-36; 79} Canada—{R-68} Cattle, pigs, and sheep: Intramuscular, [24,000 to 66,000 Veterinary-labeled product(s): Units per kg of body weight every twenty-four hours]. Not commercially available. Horses: Intramuscular, [20,000 Units per kg of body weight every {R-56; 58; 65; 69} Human-labeled product(s): twelve to twenty-four hours. ] 1,000,000 Units (Rx) [generic]. Note: Penicillin G procaine should not be administered subcutaneously {R-80} 5,000,000 Units (Rx) [generic]. at high doses because doing so produces significant local {R-82} 10,000,000 Units (Rx) [generic]. inflammation and hemorrhage, as well as medication deposits that can contribute to residue problems. The maximum dose Packaging and storage: Prior to reconstitution, store below 40 C per injection site of penicillin G procaine should be 3,000,000 Units (104 F), preferably between 15 and 30 C (59 and 86 F), unless (10 mL); injection sites should be different for each succeeding {R-7; 53} otherwise specified by manufacturer. treatment. Penicillin G procaine should never be administered intravenously. Preparation of dosage form: {R-46} To prepare initial dilution for intramuscular or intravenous use, see Strength(s) usually available : manufacturer’s labeling. U.S.— To prepare for further dilution for intravenous use, see manufacturer’s Veterinary-labeled product(s): labeling. 300,000 Units per mL (OTC) [Agri-cillin; Aquacillin; Microcillin; Pen- Aqueous; generic]. Stability: After reconstitution, solutions retain their potency for 24 Canada— hours at room temperature or for 7 days if refrigerated.{R-66; 68} Veterinary-labeled product(s): 300,000 Units per mL (OTC) [Depocillin; Derapen SQ/LA; Hi-Pencin 300; Pen-Aqueous; Pen G Injection; Penmed; Penpro; Propen LA; Incompatibilities: Ultrapen LA; generic]. Penicillin G potassium is rapidly inactivated by oxidizing and reducing Note: Some Canadian products, such as Derapen SQ/LA, Propen LA, and agents, such as alcohols and glycols.{R-68} Ultrapen LA, list their strengths and dosing in terms of milligrams Extemporaneous admixtures of beta-lactam antibacterials (penicillins rather than international units (IU){R-46}; procaine penicillin G and cephalosporins) and aminoglycosides may result in substantial contains 1009 penicillin G IU per mg{R-25}. mutual inactivation. Do not mix these antibacterial agents in the same {R-69} intravenous bag, bottle, or tubing. Withdrawal times: U.S.—{R-7; 26; 53} Additional information: Human guidelines recommend that daily doses of 10,000,000 Units or Withdrawal time more should be administered by slow intravenous infusion or by Species Meat (days) Milk (hours) intermittent piggyback infusion to avoid causing or exacerbating possible electrolyte imbalance.{R-68} Cattle 448 The potassium content and sodium content (derived from sodium citrate Calves (nonruminating) 7 Sheep 8 buffer) of penicillin G potassium for injection are approximately Swine 6 1.7 mEq (66.3 mg) and 0.3 mEq (6.9 mg), respectively, per 1,000,000 Units of penicillin G.{R-66} Note: Products bearing labeling with the above withdrawal times list a dose of 6600 Units per kg of body weight administered intramuscu- USP requirements: Preserve in Containers for Sterile Solids. It is sterile larly once every 24 hours. Treatment should not exceed five days in Penicillin G Potassium or a sterile, dry mixture of Penicillin G Potas- lactating cattle or seven days in sheep, swine, or nonlactating cattle for {R-7; 26} sium with not less than 4.0% and not more than 5.0% of Sodium these withdrawal times to apply.

Withdrawal time dose in cattle or a single intramusuclar dose in pigs. The dose may be repeated in seventy-two hours. Species Meat (days) Milk (hours) Packaging and storage: Store between 2 and 8 C (36 and 46 F). Cattle 10 48 {R-53; 70} Sheep 9 Protect from freezing. Swine 7 Preparation of dosage form: The vial should be warmed to room {R-53} Note: Products bearing labeling with the above withdrawal times list a temperature and shaken well to insure a uniform suspension. dose of 6600 Units per kg of body weight administered intramuscu- Additional information: larly once every 24 hours. Treatment should not exceed four days for Some animals may develop procaine toxicity, which can result in acute these withdrawal times to apply. These products are not labeled for use neurologic signs{R-48}. in pre-ruminating calves.{R-26; 53; 70} Administration of penicillin G procaine to racing horses may pro- Canada—{R-6; 81} duce violative procaine concentrations in urine for more than two When administered at a dose of 6670 Units per kg of body weight weeks.{R-91; 92} every twenty-four hours{R-81}:

Withdrawal time USP requirements: Preserve in single-dose or in multiple-dose containers, preferably of Type I or Type III glass, in a refrigerator. A Species Meat (days) Milk (hours) sterile suspension of Penicillin G Procaine or, where labeled for

Cattle 572 veterinary use only, of sterile penicillin G procaine, in Water for Injection and contains one or more suitable buffers, dispersants, or When administered at a dose of 15,000 Units per kg of body weight suspending agents, and a suitable preservative. It may contain {R-93} every twenty-four hours : procaine hydrochloride in a concentration not exceeding 2.0%. Where it is intended for veterinary use, the label so states. Contains Withdrawal time an amount of penicillin G procaine equivalent to the labeled amount Species Meat (days) of penicillin G, within –10% to +15%, the labeled amount being not less than 300,000 Penicillin G Units per mL or per container. Meets Pigs 8 the requirements for Identiﬁcation, Crystallinity, Bacterial endotoxins, Sterility, pH (5.0–7.5), and Penicillin G and procaine contents, When administered at a dose of 21,000 Units per kg of body weight {R-51} and for Injections. every twenty-four hours{R-93}:

Withdrawal time PENICILLIN G SODIUM FOR INJECTION USP Species Meat (days) Milk (hours) Usual dose: [Antibacterial]1—See Penicillin G Potassium for Injection USP. Cattle 10 96 Sheep 10 — Strength(s) usually available: U.S.— Note: The Canadian Bureau of Veterinary Drugs has published results of Veterinary-labeled product(s): tissue residue studies and calculated withdrawal times for use of Not commercially available. penicillin G procaine administered at doses that are higher than U.S. Human-labeled product(s): label doses{R-80; 82; 83}. Some of these withdrawal times are now listed 5,000,000 Units (Rx) [generic]. in the labeling of Canadian products, as shown above, with the Canada— exception of the withdrawal calculated for the highest dose. If penicillin Veterinary-labeled product(s): G is administered at the extra-label dose of 60,000 Units per kg of body Not commercially available. weight every 24 hours, there is some evidence to suggest that a Human-labeled product(s): withdrawal time of 21 days would be sufﬁcient to avoid residues in 1,000,000 Units (Rx) [generic]. sheep and non-lactating cattle and that a withdrawal time of 15 days 5,000,000 Units (Rx) [generic]. would be sufﬁcient for pigs. 10,000,000 Units (Rx) [generic]. For Derapen SQ/LA, Propen LA, and Ultrapen LA:

Withdrawal time Packaging and storage: Prior to reconstitution, store below 40 C

Species Meat (days) (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by the manufacturer. Cattle Intramuscular dose 21 Subcutaneous dose 14 Preparation of dosage form: To prepare initial dilution for intramus- Pigs 10 cular or intravenous use, see manufacturer’s labeling for instructions.

Note: Products bearing labeling with the above withdrawal times list 20 Stability: After reconstitution, solutions retain their potency for 24 mg per kg of body weight as a single intramusuclar or subcutaneous hours at room temperature or for 7 days if refrigerated.{R-68}

Incompatibilities: and not less than 4.0% and not more than 5.0% of Sodium Citrate, Penicillin G sodium is rapidly inactivated by acids, alkalies, and oxidizing of which not more than 0.15% may be replaced by Citric Acid. agents and in carbohydrate solutions at alkaline pH. Contains the labeled amount of Penicillin G, within –10% to +20%, Extemporaneous admixtures of beta-lactam antibacterials (penicillins and where it contains Sodium Citrate it has a potency of not less and cephalosporins) and aminoglycosides may result in substantial than 1420 and not more than 1667 Penicillin G Units per mg. Meets mutual inactivation. Do not mix these antibacterials in the same the requirements for Constituted solution, Identiﬁcation, Crystallinity, intravenous bag, bottle, or tubing.{R-29; 71} Bacterial endotoxins, Sterility, pH (6.0–7.5, in a solution containing 60 mg per mL), Loss on drying (not more than 1.5%), and Partic- Additional information:{R-68} ulate matter, and for Uniformity of dosage units and Labeling under Human guidelines recommend that daily doses of 10,000,000 Units or Injections.{R-51} more should be administered by slow intravenous infusion to avoid causing or exacerbating electrolyte imbalance. 1Not included in Canadian product labeling or product not commercially The sodium content is approximately 2 mEq (2 mmol) per 1,000,000 available in Canada. Units of penicillin G. This should be considered in patients on a restricted sodium intake. Developed: 04/27/95 Interim revision: 07/19/95; 07/11/96; 7/15/98; 11/5/99; 09/30/02; USP requirements: Preserve in Containers for Sterile Solids. It is 04/05/03 sterile Penicillin G Sodium or a sterile mixture of penicillin G sodium

Table 1. Pharmacokinetic parameters.

Disappearance

Penicillin G Dose Route/site of Cmax Tmax Duration of Target minimum serum rate constant Species dosage form (Units/kg) administration* (mcg/mL) (hours) action (hours) conc.(mcg/mL) (hour–1)

Calves (6–9 mo.) Potassium{R-55} 10,000 IM/neck 4.71 ± 3.86 1 to 1.5 – – – Procaine{R-55} 30,000 IM/neck 1.55 ± 0.33 1.5 to 6 – – –

Cattle Procaine{R-36} 66,000 IM/neck 4.24 ± 1.08 6.00 ± 0.00 – – 0.08 ± 0.03 66,000 SC/neck 1.85 ± 0.27 5.33 ± 0.67 – – 0.04 ± 0.01 After 5-day Procaine{R-36} 24,000 IM/gluteal 0.99 ± 0.04 5.33 ± 0.67 – – 0.04 ± 0.01 administration 66,000 IM/gluteal 2.63 ± 0.27 6.00 ± 0.00 – – 0.04 ± 0.00 During 7-day Benzathine with 11,000 IM/not stated 0.72 2 administration: Procaine{R-69}

Horses Sodium{R-57} 10,000 IV/jugular 1.68 0.5 20,000 IV/jugular 2.92 0.5 40,000 IV/jugular 3.90 0.5 Procaine{R-57} 10,000 IM/gluteal 4.90 0.5 20,000 IM/gluteal 18.75 0.5 40,000 IM/gluteal >24 0.5 Procaine{R-56} 22,000 IM/gluteal 1.42 ± 0.22 3

Foals (0–7 days) Procaine{R-58} 22,000 IM/semimem- 2.17 ± 0.27 2 branous

*Legend: IM = intramuscular; IV = intravenous; SC = subcutaneous. The durations of action in this study were based on a speciﬁc minimum target serum concentration considered by that researcher to be a value high enough to treat penicillin-susceptible organisms.

This study gave the stated dose once every 24 hours and monitored serum concentrations for 7 days. The Cmax shown here was the highest measured; values stayed below 0.31 after the ﬁrst day and went as low as 0.12 mcg/mL.

REFERENCES 8. Penicillin G Potassium USP package labeling (Solvay Animal Health—US), Rec 1. Watson ADJ. Penicillin G and the alternatives. Vet Annu 1985; 25: 8/1/94. 277–83. 9. Pot-Pen package labeling (Sanofi Sante Animale—Canada), Rec 7/22/94. 2. Prescott JF, Baggot JD. Antimicrobial therapy in veterinary medicine. 2nd ed. 10. Penicillin procaine G package insert (Pfizer Sante Animale—Canada), Rec 8/2/ Ames, IA: Iowa State University Press, 1993: 81–9. 94. 3. Barragry TB. Veterinary drug therapy. Baltimore, MD: Lea & Febiger, 1994: 11. Bateman KG, et al. An evaluation of antimicrobial therapy for undifferentiated 224–6, 701–10. bovine respiratory disease. Can Vet J 1990 Oct; 31: 689–96. 4. Papich MG. The beta-lactam antibiotics: clinical pharmacology and recent 12. Mechor GD, Jim GK, Janzen ED. Comparison of penicillin, oxytetracycline, and developments. Compend Contin Educ Pract Vet 1987; 9(1): 68–74. trimethoprim-sulfadoxine in the treatment of acute undifferentiated bovine 5. Sterile penicillin G benzathine and penicillin G procaine in aqueous suspension respiratory disease. Can Vet J 1988 May; 29: 438–43. package insert (G.C. Hanford Manufacturing Company—US), Rev 12/93, Rec 13. Taylor FGR. Strangles. In: Robinson NE. Current therapy in equine medicine 3. 9/7/94. Philadelphia: W.B. Saunders, 1992: 324–6. 6. Penpro package insert (Sanofi Sante Animale—Canada), Rec 7/22/94. 14. Walker RD. Actinobacillosis and Actinomycosis. In: Howard JL. Current 7. Microcillin product information (Anthony—US). In: Arrioja-Dechert A, editor. veterinary therapy 3 food animal practice. Philadelphia: W.B. Saunders Compendium of veterinary products, CD ed. Port Huron, MI: North American Company, 1993: 534–7. Compendiums, Inc. 2002.

15. Wagner PC, Watrous BJ, Darien BJ. Septic arthritis and osteomyelitis. In: 49. Blue JT, Dinsmore RP, Anderson KL. Immune-mediated hemolytic anemia Robinson NE. Current therapy in equine medicine 3. Philadelphia: W.B. induced by penicillin in horses. Cornell Vet 1987; 77: 263–76. Saunders, 1992: 460. 50. Embrechts E. Procaine penicillin toxicity in pigs. Vet Rec 1982 Oct; 111: 314. 16. St. Jean G. Septic arthritis. In: Howard JL. Current veterinary therapy 3 food 51. The United States pharmacopeia. The national formulary. USP 26th revision animal practice. Philadelphia: W.B. Saunders Company, 1993: 873–4. (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United 17. Rentko VT, Ross LA. Canine leptospirosis. In: Kirk RW, Bonagura JD. Current States Pharmacopeial Convention, Inc., 2002. p. 1409, 1410, 1412, 1415, veterinary therapy XI small animal practice. Philadelphia: W.B. Saunders, 1421, 2573. 1992: 260–3. 52. Amoxicillin package insert (Trimox, Apothecon—US), Rev 4/90, Rec 7/93. 18. Bernard WV. Leptospirosis. Vet Clin North Am Equine Pract 1993 Aug; 9(2): 53. Agri-cillin package insert (Agri Laboritories Ltd.—US), Rec 8/28/94. 435–44. 54. Kirk RW, Bonagura JD, editors. Current veterinary therapy XI small animal 19. Jarp J, Bugge HP, Larsen S. Clinical trial of three therapeutic regimens for practice. Philadelphia: W.B. Saunders, 1992: 1244. bovine mastitis. Vet Rec 1989; 124: 630–4. 55. Bengtsson AF, Luthman J, Jacobsson O. Concentrations of sulphadimidine, 20. Richarson GF. Metritis and endometritis. In: Howard JL. Current veterinary oxytetracycline and penicillin G in serum, synovial fluid and tissue cage fluid therapy 3 food animal practice. Philadelphia: W.B. Saunders Company, 1993: after parenteral administration to calves. J Vet Pharmacol Ther 1989; 12: 37– 770–2. 45. 21. Timoney PJ. Contagious equine metritis. In: Robinson NE. Current therapy in 56. Stover SM, et al. Aqueous procaine penicillin G in the horse: serum, synovial, equine medicine 3. Philadelphia: W.B. Saunders, 1992: 757–60. peritoneal, and urine concentrations after single-dose intramuscular admin- 22. Muckle CA, Menzies PI. Corynebacterium species infections in food animals. In: istration. Am J Vet Res 1981; 42: 629–31. Howard JL. Current veterinary therapy 3 food animal practice. Philadelphia: 57. Love DN, et al. Serum concentrations of penicillin in the horse after W.B. Saunders Company, 1993: 537–41. administration of a variety of penicillin preparations. Equine Vet J 1983; 23. Rebhun WC, et al. Pyelonephritis in cows: 15 cases (1982–1986). J Am Vet 15(1): 43–8. Med Assoc 1989 Apr; 194(7): 953–5. 58. Brown MP, et al. Aqueous procaine penicillin G in foals: Serum concentrations 24. Ettinger SJ. Textbook of veterinary internal medicine. 2nd ed. Philadelphia: and pharmacokinetics after a single intramuscular dose. Equine Vet J 1984; W.B. Saunders, 1983; 350, 359. 16(4): 374–5. 25. Hardman JG, Limbird LE, Gilman AG, editors. Goodman & Gilman’s The 59. Oukessou M, et al. Comparative benzylpenicillin pharmacokinetics in the Pharmacological Basis of Therapeutics, 10th ed. McGraw-Hill Professional dromedary Camelus dromedarius and in sheep. J Vet Pharmacol Ther 1990; 13: Publishing. August 13, 2001. 298–303. 26. Code of federal regulations. Washington, D.C.: Office of the Federal Register. 60. Short CR, et al. Clearance of penicillin G in the newborn calf. J Vet Pharmacol April 1, 1993; 21(parts 500 to 599). Ther 1984; 7: 45–8. 27. Derapen package insert (Ayerst Laboratories—Canada), Rev 94, Rec 8/17/ 61. Ziv G, Shani J, Sulman FG. Pharmacokinetic evaluation of penicillin and 94. cephalosporin derivatives in serum and milk of lactating cows and ewes. Am J 28. Longisil package labeling (Sanofi Sante Animale—Canada), Rec 8/17/94. Vet Res 1973; 34(12): 1561–5. 29. Donowitz GR, Mandell GL. Beta-lactam antibiotics. N Engl J Med 1988; 318: 62. Hirsh, et al. Pharmacokinetics of penicillin G in the turkey. Am J Vet Res 1978; 419–26. 39(7): 1219–21. 30. USP dictionary of USAN and international drug names, 2002 ed. Rockville, 63. Penlong XL. In: Bennett K, editor. Compendium of veterinary products. 2nd ed. MD: The United States Pharmacopeial Convention, Inc., 2002. Port Huron, MI: North American Compendiums Inc., 1993: 398. 31. Anifantakis EM. Excretion rates of antibiotics in milk of sheep and their effect 64. Howard JL. Current veterinary therapy 3 food animal practice. Philadelphia: on yogurt production. J Dairy Sci 1982; 65: 426–9. W.B. Saunders Company, 1993: 932. 32. Ziv G, et al. Pharmacokinetic evaluation of penicillin and cephalosporin 65. Wilcke J, editor. Practice formulary. In: Veterinary values. 2nd ed. U.S.: derivatives in serum and milk of lactating cows and ewes. Am J Vet Res 1973; AgResources, Inc. 1985: 196–7. 34(12): 1561–5. 66. Penicillin G potassium (Pfizerpen, Roerig). In: PDR Physicians’ desk reference. 33. Wright AJ, Wilkowski CJ. The penicillins. Mayo Clin Proc 1983: 58: 21–32. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production Company, 34. Plumb DC. Veterinary drug handbook. White Bear Lake, MN: PharmaVet 1994: 1985–7. Publishing, 1991: 470–1. 67. Penicillin G potassium, Apothecon. Red Book 1994. Montvale, NJ: Medical 35. Watson ADJ. Penicillin G and the alternatives. Vet Ann 1985; 25: 277–83. Economics Data, 1994: 311. 36. Papich MG, et al. A study of the disposition of procaine penicillin G in feedlot 68. Penicillin G (generic, Wyeth-Ayerst). In: Krogh CME, editor. CPS Compendium steers following intramuscular and subcutaneous injection. J Vet Pharmacol of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Ther 1993; 16: 317–27. Association, 1994: 997–8. 37. Firth EC. Effect of the injection site on the pharmacokinetics of procaine 69. Sullins KE, Messer NT, Nelson L. Serum concentration of penicillin in the horse penicillin G in horses. Am J Vet Res 1986 Nov; 47(11): 2380–4. after repeated intramuscular injections of procaine penicillin G alone or in 38. Ziv G, Sulman FG. Binding of antibiotics to bovine and ovine serum. combination with benzathine penicillin and/or phenylbutazone. Am J Vet Res Antimicrob Agents Chemother 1972 Sep: 206–13. 1984 May; 45(5): 1003–7. 39. Powers TE, Garg RC. Pharmacotherapeutics of newer penicillins and cepha- 70. Penicillin G Procaine Aqueous Suspension (G.C. Hanford Mfg. Co—US), Rev losporins. J Am Vet Med Assoc 1980 May; 176(10): 1054–60. 9/93, Rec 8/1/94. 40. Peterson LR, et al. Prediction of peak penicillin and cephalosporin concentra- 71. St Peter WL, Redic-Kill KA, Halstenson CE. Clinical pharmacokinetics of tions in canine serum as derived from in vitro serum and tissue quantitative antibiotics in patients with impaired renal function. Clin Pharmacokinet 1992; protein binding. J Antimicrobial Chemotherapy 1979; 5: 219–27. 22(3): 169–210. 41. Durr A. Comparison of the pharmacokinetics of penicillin G and ampicillin in 72. English PB. Serum penicillin concentrations in the bovine with fortified the horse. Res Vet Sci 1976; 20: 24–9. benzathine. Aust Vet J 1959 Aug; 35: 353–8. 42. Rolinson GN, Sutherland R. The binding of antibiotics to serum proteins. Br J 73. Prescott JF. Leptospirosis. In: Howard JL. Current veterinary therapy 3 food Pharmacol 1965; 25: 638–50. animal practice. Philadelphia: W.B. Saunders, 1993. p. 541–6. 43. Huber WG. Penicillins. In: Booth NH, McDonald LE. Veterinary pharmacology 74. Smith MC, Sherman DM. Goat medicine. Philadelphia, PA: Lea & Febiger, and therapeutics. 5th ed. Ames, IA: Iowa State University Press, 1988: 796– 1994. p. 206–8. 812. 75. Penicillin G procaine (Pfizerpen-AS, Roerig). In: PDR Physicians’ desk 44. Firth EC, et al. The effect of phenylbutazone on the plasma disposition of reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production penicillin G in the horse. J Vet Pharmacol Ther 1990; 13: 179–85. Company, 1994. p. 1987–9. 45. Riviere JE, Coppoc GL. Dosage of antimicrobial drugs in patients with renal 76. Kirk RW, Bistner SI. Handbook of veterinary procedures and emergency insufficiency. J Am Vet Med Assoc 1981 Jan; 178(1): 70–2. treatment. 3rd ed. Philadelphia: W.B. Saunders, 1981. p. 155–6. 46. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port 77. Nurmio P. Penicillin G procaine: a possible cause of embryonic death in swine. Huron, MI: North American Compendiums, Inc. 2002. Vet Rec 1980 Feb; 106 (5): 97–8. 47. Klasco RK, editor. USP DI Drug information for the healthcare professional. 78. Papich MG. Disposition of penicillin G after administration of benzathine Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. penicillin G, or a combination of benzathine penicillin G and procaine penicillin 48. Nielsen IL, et al. Adverse reaction to procaine penicillin G in horses. Aust Vet J G in cattle. Am J Vet Res 1994; 55(6): 825–30. 1988 Jun; 65(6): 181–4. 79. Panel comment, 11/4/94.

80. Korsrud GO, et al. Depletion of penicillin G residues in tissues and injection 86. Heath SE. Bovine mastitis. In: Howard JL. Current veterinary therapy 3 food sites of yearling beef steers dosed with benzathine penicillin G alone or in animal practice. Philadelphia: W.B. Saunders, 1993. p. 762–8. combination with procaine penicillin G. Food additives and contaminants 87. Panel comment, 11/15/94. 1994; 11(1): 1–6. 88. Panel comment, 11/29/94. 81. Penmed product information (Medprodex—Canada). In: Arrioja-Dechert A, 89. Panel comment, 11/17/94. editor. Compendium of veterinary products, CD ed. Port Huron, MI: North 90. Bengtsson B, et al. Distribution of penicillin-G and spiramycin to tissue cages American Compendiums, Inc. 2002. and subcutaneous tissue ﬂuid in calves. Res Vet Sci 1991; 50: 301–7. 82. Bureau of Veterinary Drugs Overview 1993–94. Food Directorate/Health 91. Panel comment, 11/15/94. Protection Branch/Health Canada. Minister of National Health and Welfare: 92. Tobin T. Drugs and the performance horse. Charles Thomas, Publishers, 1981. Minister of Supplies and Services Canada 1994. p. 270–2. 83. Ritter L. Withholding times for procaine penicillin G in cattle [letter]. Can Vet J 93. Depocillin product information (Intervet—Canada). In: Arrioja-Dechert A, 1991; 32: 647. editor. Compendium of veterinary products, CD ed. Port Huron, MI: North 84. Race track division schedule of drugs 1991. Agriculture Canada. American Compendiums, Inc. 2002. 85. Panel comment, 11/21/94.

PIRLIMYCIN Veterinary—Intramammary-Local

Some commonly used brand names are Pirsue Aqueous Gel and Pirsue Absorption: Almost one half of the dose is absorbed systemically after Sterile Solution{R-1}. intramammary administration.{R-5} Note: For a listing of dosage forms and brand names by country availability, see the Dosage Forms section(s). Distribution: Pirlimycin is lipophilic and diffuses readily across tissue membranes.{R-3} CATEGORY: Antibacterial (intramammary-local). Biotransformation: Pirlimycin is eliminated primarily as parent drug when administered by the intramammary route; however, 4% of the dose is oxidized by the liver to pirlimycin sulfoxide{R-5}. INDICATIONS Peak concentrations: Based on two intramammary doses of 50 mg GENERAL CONSIDERATIONS each, given 24 hours apart— Pirlimycin is a lincosamide antibiotic with activity primarily against Blood: 0.025 mcg per mL (mcg/mL) 2 and 6 hours after the second gram-positive organisms, including Staphylococcus and Streptococcus 50-mg intramammary dose{R-14; 15}. species.{R-1} It is considered more active than clindamycin against Mammary tissue: 10 mcg per gram (mcg/gram) 10 hours after the Staphylococcus aureus.{R-5} Pirlimycin is not active against gram- second dose{R-4}. negative bacteria, such as Escherichia coli.{R-10} Milk: > 150 mcg/mL in the first assay sample, taken 4 hours after each dose{R-4}. ACCEPTED Mastitis (treatment)—Cows, lactating: Pirlimycin is indicated in the Liver concentration: treatment of clinical and subclinical mastitis caused by Staphylococcus Total—The concentration of pirlimycin and metabolites (primarily aureus, Streptococcus agalactiae, Streptococcus dysgalactiae, and Strepto- pirlimycin sulfoxide) in the liver 4 days after the second 50-mg coccus uberis.{R-1} intramammary dose is 2.18 mcg/gram{R-11; 13; 14}. In refractory cases of chronic Staphylococcus aureus mastitis, adminis- Parent compound (marker residue)—The concentration of pirlimycin in tration of intramammary pirlimycin at recommended doses is sufficient the liver 2 days after the second 50-mg intramammary dose is 2.33 to control but not eliminate the pathogen.{R-4} Intramammary therapy mcg/gram; the concentration falls below 0.5 mcg/gram by 21 days alone is indicated only in the treatment of subacute or subclinical after the second dose{R-11; 14}. mastitis manifested by mild changes in the milk or udder. Cows with acute or peracute mastitis, which involves gross changes in the milk Mammary tissue concentration: Based on two intramammary or udder or systemic signs, should be given other medications also, doses of 50 mg each, given 24 hours apart—The mammary which may include systemic antibiotics and/or supportive therapy.{R-6} tissue concentration 4 days after the second dose is 0.927 mcg/ gram{R-14; 15}. REGULATORY CONSIDERATIONS U.S. and Canada— Milk concentration: Based on a 50-mg intramammary dose at 0 and Withdrawal times have been established for cattle. See the Dosage 24 hours, the milk pirlimycin concentration 12 hours after the second Forms section.{R-1} infusion of medication is measured to be 8 to 18 mcg/mL and by 36 hours the concentration is less than 1 mcg/mL{R-11}. CHEMISTRY Source: Semisynthetic derivative of lincomycin.{R-3} Elimination: When pirlimycin is administered by the intramammary Chemical group: Lincosamide antibiotic. route, approximately 51% of the original dose is distributed into the Chemical name: Pirlimycin hydrochloride—L-threo-alpha-D-galacto- milk, 10% into the urine, and 24% into the feces.{R-5} Of the total dose, Octopyranoside, methyl 7-chloro-6,7,8-trideoxy-6-[[(4-ethyl-2-piperi- 68% is recovered as unchanged pirlimycin.{R-5} dinyl)carbonyl]amino]-1-thio-, monohydrochloride, monohydrate, (2S-cis).{R-2} Molecular formula: Pirlimycin hydrochloride— PRECAUTIONS TO CONSIDER C H ClN O S Æ HCl Æ H O.{R-2} 17 31 2 5 2 PATIENT MONITORING Molecular weight: Pirlimycin hydrochloride—465.43{R-2}. The following may be especially important in patient monitoring (other pKa: 8.5.{R-3} tests may be warranted in some patients, depending on condition; » = major clinical significance): PHARMACOLOGY/PHARMACOKINETICS Bacteriologic pathogens in milk (milk samples should be tested three weeks after treatment with Mechanism of action/effect: Pirlimycin is bacteriostatic at therapeu- pirlimycin is discontinued; mastitis is not considered bacterio- tic concentrations.{R-3} The lincosamides inhibit protein synthesis in logically cured until samples show an absence of the mastitis- susceptible bacteria by binding to the 50 S ribosomal subunits of causing organism; for refractory Staphylococcus aureus mastitis, bacterial ribosomes and preventing peptide bond formation.{R-7} in which control, but not elimination, is achieved, S. aureus

can reappear in milk cultures by 10 hours after the second Strength(s) usually available: treatment{R-4}) U.S.—{R-1; 18; 19} Veterinary-labeled product(s): SIDE/ADVERSE EFFECTS 5 mg per mL (Rx) [Pirsue Sterile Solution]. Canada—{R-12; 18} Note: All clinical efﬁcacy and toxicity studies performed with intramam- Veterinary-labeled product(s): mary pirlimycin in cows have shown it to be nonirritating{R-11}.No 5 mg per mL (Rx) [Pirsue Aqueous Gel]. serious adverse effects associated with the use of pirlimycin in cows have been documented. The Food and Drug Administration Adverse Withdrawal times: {R-17–19} Drug Experience reporting program has received only one report of U.S.— urticaria, possibly drug-related, in three cows that responded well to Withdrawal time treatment for the urticaria{R-16}. Species Meat (days) Milk (hours) OVERDOSE Cows 9 36 For information in cases of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to Animals Canada—{R-12; 18} (ASPCA) National Animal Poison Control Center (888-426-4435 or 900-443-0000; a fee may be required for consultation) and/or the Withdrawal time drug manufacturer. Species Meat (days) Milk (hours)

Cows 28 48 CLIENT CONSULTATION Treatment of mastitis in dairy cattle is best achieved by a comprehensive mastitis control program in which herd management is the Packaging and storage: Store at 25 C (77 F) or less, unless otherwise primary focus. The program should include good maintenance of specified by manufacturer. Protect from freezing.{R-1} milking equipment and constant evaluation of milking procedures and teat health as well as strategic treatment of clinical cases of USP requirements: Not in USP{R-20}. mastitis.{R-9} Developed: 07/09/96 Revised: 02/27/98 VETERINARY DOSING INFORMATION Interim revision: 06/30/02; 02/28/03 The choice of antibiotic for the treatment of mastitis should be based on knowledge of the culture and sensitivity of the pathogens causing REFERENCES mastitis in the cow and the dairy herd. 1. Pirsue Sterile Solution (Pharmacia—US), Rev 1/03. Downloaded 2/17/03 Before administration of intramammary pirlimycin, the following steps from www.pharmaciaah.com. should be performed: 2. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention Inc; 2002. • The udder should be milked out completely and the teats washed 3. Henke CL, Chester ST, Dame KJ, et al. New developments in lactating cow with warm water and a disinfectant. Care should be taken to avoid preparations—the efficacy of three blind labeled intramammary infusion washing excess dirt down from the udder onto the teat ends. The formulae in the treatment of clinical mastitis. Proceedings of the 31st annual meeting of the National Mastitis Council, Inc.; 1992 Feb 10–12; Arlington, area should be dried thoroughly. An effective germicidal teat dip Virginia. Arlington, VA: National Mastitis Council; 1992. should be applied for one minute and then each teat wiped with a 4. Owens WE, Nickerson SC, Watts JL, et al. Milk, serum, and mammary tissue separate cotton ball soaked with an antiseptic such as 70% isopropyl concentration of pirlimycin following intramuscular, intramammary or alcohol. combination therapy of chronic Staphyloccus aureus mastitis. Agri-Practice 1994 Mar; 15(3): 19–23. • Persons performing the treatment should wash and dry their hands 5. Hornish RE, Arnold TS, Baczynskyj L, et al. Pirlimycin in the dairy cow: before each treatment. metabolism and residues. Proceedings of the 202nd national meeting of the • To administer pirlimycin, the tip of the syringe should be inserted American Chemical Society; 1991 Aug 25–30; New York. Washington, DC: American Chemical Society; 1992. into the teat end as little as possible and the contents of the syringe 6. Heath SE. Bovine mastitis. In: Howard JL, editor. Current veterinary therapy 3. should be injected into each streak canal while the teat is held Food animal practice. Philadelphia: WB Saunders Co; 1993. p. 762–9. firmly. 7. Barragry TB. Veterinary drug therapy. Baltimore: Lea & Febiger; 1994. The medication should then be gently massaged up the teat canal into p. 251–62. 8. Jarp J, Bugge JP, Larsen S. Clinical trial of three therapeutic regimens for the gland cistern. bovine mastitis. Vet Rec 1989; 124: 630–4. Following treatment, an effective teat dip is recommended on all teats. 9. Hady PJ, Lloyd JW, Kaneene JB. Antibacterial use in lactating dairy cattle. J Am Vet Med Assoc 1993; 203(2): 219–20. 10. Thornsberry C, Marler JK, Watts JL, et al. Activity of pirlimycin against INTRAMAMMARY DOSAGE FORMS pathogens from cows with mastitis and recommendations for disk diffusion tests. Antimicrob Agents Chemother 1993; 37: 1122–6. 11. Freedom of Information Summary. Pirlimycin hydrochloride for intramam- PIRLIMYCIN INTRAMAMMARY INFUSION mary treatment of clinical or subclinical mastitis in lactating dairy cattle. Usual dose: Mastitis—Cows, lactating: Intramammary, 50 mg admin- NADA 141–036. The Upjohn Company. Office of Consumer Affairs, Food and Drug Administration, Rockville, MD. istered into each affected quarter, followed by a second dose admin- 12. Pirsue Aqueous Gel package insert (Pharmacia—Canada), Rev 1/01, Rec istered twenty-four hours later.{R-1; 17} 1/30/02.

13. Manufacturer comment, Rec 6/25/96. 17. Freedom of Information Summary. Pirsue Sterile Solution (new formulation 14. Manufacturer comment, Rec 7/22/96. and withdrawal period). NADA 141-036. Sponsor: Pharmacia & Upjohn 15. Upjohn Technical Report (TR) 782-7926-92-002. Metabolism study 2. Company. September 7, 2000. In: Freedom of Information Report. Pirlimycin hydrochloride for intramam- 18. Arrioja-Dechert A, editor. Compendium of veterinary products, CD edition. mary treatment of clinical or subclinical mastitis in lactating dairy cattle. Port Huron, MI: North American Compendiums, Inc., 2002. NADA 141-036. The Upjohn Company. Ofﬁce of Consumer Affairs, Food and 19. Entriken TL, editor. Veterinary pharmaceuticals and biologicals, 12th ed. Drug Administration, Rockville, MD. Lenexa, KS: Veterinary Healthcare Communications, 2001. p. 1892–3. 16. The Food and Drug Administration Center for Veterinary Medicine Adverse 20. The United States pharmacopeia. The national formulary. USP 26th revision Drug Experience Summaries, Center for Veterinary Medicine, Food and Drug (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United Administration, Rockville, MD. 10/18/96. States Pharmacopeial Convention, Inc., 2002.

POTENTIATED SULFONAMIDES Veterinary—Systemic This monograph includes information on the following: Ormetoprim and CATEGORY: Sulfadimethoxine; Pyrimethamine and Sulfaquinoxaline*; Sulfadiazine Antibacterial (systemic); antiprotozoal (systemic). and Trimethoprim; Sulfadoxine and Trimethoprim*; Sulfamethoxazole and Trimethoprim. INDICATIONS Some commonly used brand names are: Note: Bracketed information in the Indications section refers to uses that For veterinary-labeled products— are either not included in U.S. product labeling or are for products not Bimotrim [Sulfadoxine Tribrissen 120 [Sulfadiazine commercially available in the U.S. and Trimethoprim] and Trimethoprim] Borgal [Sulfadoxine Tribrissen 480 [Sulfadiazine Information identified by a superscript 1 refers to uses that are either and Trimethoprim] and Trimethoprim] not included in Canadian product labeling or are for products not Potensulf [Sulfadoxine Tribrissen 960 [Sulfadiazine commercially available in Canada. and Trimethoprim] and Trimethoprim] Primor 120 [Ormetoprim Tribrissen 24% [Sulfadiazine and Sulfadimethoxine] and Trimethoprim] GENERAL CONSIDERATIONS Primor 240 [Ormetoprim Tribrissen 48% [Sulfadiazine and Sulfadimethoxine] and Trimethoprim] The combined and synergistic activities of the two agents in each type Primor 600 [Ormetoprim Tribrissen 400 Oral Paste of potentiated sulfonamide produce antibacterial activity against a and Sulfadimethoxine] [Sulfadiazine and Trimethoprim] wide range of infections caused by gram-positive and gram-negative Primor 1200 [Ormetoprim Tribrissen Piglet Suspension bacteria, some protozoa{R-3}, and some anaerobes under certain and Sulfadimethoxine] [Sulfadiazine and Trimethoprim] {R-44} Quinnoxine-S [Ormetoprim Tribrissen 40% Powder conditions . The minimum inhibitory concentrations against and Sulfadimethoxine] [Sulfadiazine and Trimethoprim] specific susceptible bacteria for each antibiotic are generally lowered Rofenaid 40 [Ormetoprim Trimidox [Sulfadoxine when the antibiotics are administered in the potentiated sulfonamide and Sulfadimethoxine] and Trimethoprim] combination. The resistance developed to the potentiated sulfona- Romet 30 [Ormetoprim Trivetrin [Sulfadoxine {R-20; 23} and Sulfadimethoxine] and Trimethoprim] mides is lower than that to each individual agent ; this Romet-30 [Ormetoprim Tucoprim Powder [Sulfadiazine is an important benefit because of the common resistance to and Sulfadimethoxine] and Trimethoprim] sulfonamides and rapid development of resistance to diaminopyri- Sulfaquinoxaline-S [Pyrimethamine Uniprim Powder [Sulfadiazine {R-20} and Sulfadimethoxine] and Trimethoprim] midines when used alone. Cross-resistance between sulfona- Tribrissen 30 [Sulfadiazine mides is considered complete{R-94} and often occurs between and Trimethoprim] pyrimidines{R-25}.

For human-labeled products— ACCEPTED Apo-Sulfatrim [Sulfamethoxazole Nu-Cotrimox DS [Sulfamethoxazole Coccidiosis (prophylaxis)— and Trimethoprim] and Trimethoprim] 1{R-6} Apo-Sulfatrim DS [Sulfamethoxazole Roubac [Sulfamethoxazole Chickens: Ormetoprim and sulfadimethoxine premix is indicated and Trimethoprim] and Trimethoprim] in the prevention of coccidiosis caused by susceptible Eimeria Bactrim [Sulfamethoxazole Septra [Sulfamethoxazole acervulina, E. brunetti, E. maxima, E. mivati, E. necatrix, and E. tenella. and Trimethoprim] and Trimethoprim] {R-17} Bactrim DS [Sulfamethoxazole Septra DS [Sulfamethoxazole [Pyrimethamine and sulfaquinoxaline combination is indicated and Trimethoprim] and Trimethoprim] in the prevention of coccidiosis, caused by susceptible organisms.] Bactrim I.V. [Sulfamethoxazole Septra Grape Suspension Potentiated sulfonamides may be more effective in the treatment of and Trimethoprim] [Sulfamethoxazole E. acervulina than of E. tenella{R-71}. and Trimethoprim] 1 Bactrim Pediatric [Sulfamethoxazole Septra I.V. [Sulfamethoxazole Partridges, chukar : Ormetoprim and sulfadimethoxine premix is and Trimethoprim] and Trimethoprim] indicated in the prevention of coccidiosis caused by susceptible Cofatrim Forte [Sulfamethoxazole Septra Suspension [Sulfamethoxazole Eimeria kofoidi and E. legionensis {R-6; 125}. and Trimethoprim] and Trimethoprim] Turkeys: Ormetoprim and sulfadimethoxine premix1{R-6} is indicated in Cotrim [Sulfamethoxazole Sulfatrim [Sulfamethoxazole and Trimethoprim] and Trimethoprim] the prevention of coccidiosis caused by susceptible Eimeria adenoeides, Cotrim DS [Sulfamethoxazole Sulfatrim DS [Sulfamethoxazole E. gallopavonis, and E. meleagridis. [Pyrimethamine and sulfaquinox- and Trimethoprim] and Trimethoprim] aline combination{R-17} is indicated in the prevention of coccidiosis Cotrim Pediatric [Sulfamethoxazole Sulfatrim Pediatric [Sulfamethoxazole and Trimethoprim] and Trimethoprim] caused by susceptible organisms.] Novo-Trimel [Sulfamethoxazole Sulfatrim S/S [Sulfamethoxazole [Coccidiosis (treatment)]—Chickens and turkeys: Pyrimethamine and and Trimethoprim] and Trimethoprim] sulfaquinoxaline oral solution{R-17} is indicated to aid in the treatment Novo-Trimel D.S. [Sulfamethoxazole Sulfatrim Suspension [Sulfamethoxazole of susceptible coccidia. and Trimethoprim] and Trimethoprim] 1 Nu-Cotrimox [Sulfamethoxazole Colibacillosis (prophylaxis) —Chickens, broiler and replacement, and and Trimethoprim] ducks: Ormetoprim and sulfadimethoxine premix{R-6} is indicated in the prevention of colibacillosis caused by susceptible Escherichia coli. Note: For a listing of dosage forms and brand names by country Colibacillosis (treatment)— 1 {R-6} availability, see the Dosage Forms section(s). Ducks : Ormetoprim and sulfadimethoxine premix is indicated in the control of colibacillosis caused by susceptible E. coli. [Cattle]: Sulfadoxine and trimethoprim injection{R-13; 14} is indicated in *Not commercially available in the U.S. the treatment of colibacillosis caused by susceptible organisms.

[Pigs]: Sulfadiazine and trimethoprim oral suspension{R-10} and Urinary tract infections (treatment)—Dogs: Ormetoprim and sulfadime- sulfadoxine and trimethoprim injection{R-13} are indicated in the thoxine tablets{R-126} and sulfadiazine and trimethoprim tablets1{R-2} treatment of neonatal colibacillosis caused by susceptible E. coli are indicated in the treatment of acute urinary tract infections caused {R-10}. by susceptible organisms. Enteric septicemia (treatment)1—Catfish: Ormetoprim and sulfadime- Urogenital tract infections (treatment)1—Horses: Sulfadiazine and tri- thoxine premix{R-7; 16} is indicated in the control of enteric septicemia methoprim injection{R-96; 146}, oral paste, and oral powder{R-4} are caused by susceptible Edwardsiella ictaluri. indicated in the treatment of acute urogenital tract infections{R-3}. Fowl cholera (prophylaxis)1—Chickens and turkeys: Ormetoprim and [Arthritis, bacterial (treatment)]—Pigs: Sulfadoxine and trimethoprim sulfadimethoxine premix{R-6} is indicated in the prevention of fowl injection{R-13–15} is indicated in the treatment of bacterial arthritis cholera caused by susceptible Pasteurella multocida. caused by susceptible organisms. Fowl cholera (treatment)1—Ducks: Ormetoprim and sulfadimethoxine [Enteritis, bacterial (treatment)]— premix{R-6} is indicated in the control of fowl cholera caused by Cattle: Sulfadoxine and trimethoprim injection{R-13; 14} is indicated susceptible Pasteurella multocida. in the treatment of enteritis caused by susceptible E. coli or Furunculosis (treatment)—Salmon and trout: Ormetoprim and sulfadime- Salmonella. thoxine premix{R-7; 16} is indicated in the control of furunculosis Pigs: Sulfadiazine and trimethoprim oral suspension{R-10} and sulfa- caused by susceptible Aeromonas salmonicida. doxine and trimethoprim injection{R-13; 14} are indicated in the Gastrointestinal tract infections, bacterial (treatment)—Treatment of treatment of post-weaning scours caused by susceptible E. coli. gastroenteritis with antimicrobials should rely on a specific diagnosis [Mastitis (treatment)]; or and knowledge of pathogen susceptibility. [Metritis (treatment)]—Sows: Sulfadoxine and trimethoprim injec- Dogs: Sulfadiazine and trimethoprim [injection]{R-8; 95} and tablets1{R- tion{R-13–15} is indicated in the treatment of mastitis-metritis-agalactia 2; 11} are indicated in the treatment of acute gastrointestinal tract syndrome caused by susceptible organisms. infections. [Perioperative infections (treatment)]—Horses: Sulfadiazine and trimeth- [Cats]: Sulfadiazine and trimethoprim injection{R-8} and tablets1{R-11} oprim oral paste{R-18} and injection{R-9} are indicated in the treatment are indicated in the treatment of acute gastrointestinal tract of postoperative bacterial infections caused by susceptible organisms. infections. [Pneumonia, bacterial (treatment)]— Infectious coryza (prophylaxis)1—Chickens: Ormetoprim and sulfadime- Cattle: Sulfadoxine and trimethoprim injection{R-13; 14} is indicated in thoxine premix{R-6} is indicated in the prevention of infectious coryza the treatment of bacterial pneumonia, including bovine pneumonic caused by susceptible Haemophilus gallinarum. pasteurellosis (shipping fever), caused by susceptible organisms. New duck disease (treatment)1—Ducks: Ormetoprim and sulfadimethox- Pigs: Sulfadoxine and trimethoprim combination{R-14; 15} is indicated ine premix{R-6} is indicated in the control of new duck disease in the treatment of bacterial pneumonia caused by susceptible (infectious serositis) caused by susceptible Riemerella anatipestifer. organisms. Respiratory tract infections, bacterial (treatment)— [Pododermatitis (treatment)]—Cattle: Sulfadoxine and trimethoprim Dogs: Sulfadiazine and trimethoprim [injection{R-8; 95}] and tablets1{R- injection{R-13; 14} is indicated in the treatment of pododermatitis 2} are indicated in the treatment of acute bacterial respiratory tract caused by susceptible organisms. infections caused by susceptible organisms. [Septicemia (treatment)]— Horses: Sulfadiazine and trimethoprim injection{R-9; 96; 146}, oral Cattle: Sulfadoxine and trimethoprim injection{R-13; 14} is indicated in paste{R-3; 18}, and oral powder1{R-4} are indicated in the treatment of the treatment of septicemia caused by susceptible organisms. respiratory tract infections caused by susceptible organisms. Dogs: Sulfadiazine and trimethoprim injection1{R-95} is used in the [Cats]: Sulfadiazine and trimethoprim injection{R-8} and tablets1{R-11} treatment of septicemia caused by susceptible organisms. are indicated in the treatment of respiratory tract infections caused [Vibrio anguillarum infection]—Salmon: Sulfadiazine and trimethoprim by susceptible organisms. combination oral powder{R-22} is indicated in the treatment of Skin and soft tissue infections (treatment)— infections caused by susceptible Vibrio anguillarum{R-64}. Dogs: Ormetoprim and sulfadimethoxine tablets1{R-5} are indicated in the treatment of skin and soft tissue infections caused by susceptible E. coli and Staphylococcus intermedius. Sulfadiazine and trimetho- ACCEPTANCE NOT ESTABLISHED prim [injection]{R-8} and tablets1{R-2; 11} are indicated in the Distemper, canine (treatment)—Dogs: Although U.S. product labeling treatment of abscesses and infected wounds caused by susceptible includes the use of sulfadiazine and trimethoprim in the treatment of organisms. secondary bacterial infections associated with canine distemper{R-2}, Horses: Sulfadiazine and trimethoprim injection{R-9; 96; 146}, oral and this use may be appropriate in bacterial infections that are paste{R-3; 18}, and oral powder1{R-4} are indicated in the treatment of susceptible to this medication, the use of these antimicrobials in the abscesses and infected wounds caused by susceptible organisms. treatment of distemper-associated infections is not considered more [Cats]: Sulfadiazine and trimethoprim injection{R-8} and tablets1{R-11} appropriate or more generally accepted than in the treatment of are indicated in the treatment of bacterial infections, such as bacterial infections associated with other viral infections. abscesses and wounds, caused by susceptible organisms. Bacterial infections (treatment)—Horses: There are insufficient controlled Strangles (treatment)—Horses: Sulfadiazine and trimethoprim injec- studies to support the efficacy and safety of [sulfamethoxazole and tion{R-9; 96; 146}, oral paste{R-3; 18}, and oral powder1{R-4} are trimethoprim combination]1 in the treatment of bacterial infections in indicated in the treatment of acute strangles caused by susceptible foals and horses; however, based on pharmacokinetic data, the organisms. combination is used in the treatment of susceptible infections{R-31–33}.

[Coccidiosis (treatment)]1—Cats and dogs: There are insufficient data to that these trimethoprim and sulfonamide combinations are distributed support the efficacy of sulfadiazine and trimethoprim or ormetoprim and into prostate fluid at therapeutic concentrations{R-48}. Ormetoprim and sulfadimethoxine{R-136} in the treatment of enteric coccidiosis in cats sulfadimethoxine combination also could be effective in the treatment and dogs; however, these medications are used to reduce the shedding of prostatitis, based on a pharmacokinetic profile similar to that of of oocysts and may aid in the natural elimination of Isospora species. trimethoprim with sulfadiazine or sulfamethoxazole{R-138}. [Equine infectious arthritis (treatment)]1—Horses: There are insufficient data to support the efficacy and safety of sulfadiazine and trimethoprim 1Not included in Canadian product labeling or product not commercially combination in the treatment of equine infectious arthritis; however, available in Canada. pharmacokinetic and clinical studies do lend support to its efficacy in the treatment of experimentally-induced Staphylococcus aureus joint infections{R-41; 42}. REGULATORY CONSIDERATIONS [Equine protozoal myeloencephalitis (treatment)]1;or U.S.— [Protozoal infections (treatment)]1—Horses: There are insufficient con- Withdrawal times have been established for ormetoprim and sulfa- trolled studies to support the efficacy and safety of sulfamethoxazole dimethoxine for medicated feed (see the Dosage Forms section). and trimethoprim combination in the treatment of protozoal infections Canada— in foals and horses; however, based on pharmacokinetic data, the Withdrawal times have been established for ormetoprim and sulfa- combination is used in the treatment of susceptible infections dimethoxine for medicated feed; pyrimethamine and sulfaquinoxa- {R-31–33}. Prior to the availability of approved products (ponazuril, line oral solution; sulfadiazine and trimethoprim boluses, oral paste, toltrazuril) to treat equine protozoal myeloencephalitis, administration oral powder, and oral suspension; and sulfadoxine and trimethoprim of sulfamethoxazole and trimethoprim in combination with pyrimeth- injection (see the Dosage Forms section). amine was clinically useful in treating horses with this disease{R-147}. In vitro studies also show efficacy of potentiated sulfonamides against CHEMISTRY Sarcocystis neurona{R-148}. Chemical group: [Meningitis, bacterial (treatment)]1—Dogs: There are insufficient data to Ormetoprim, pyrimethamine, and trimethoprim—Diaminopyrimidines. support the efficacy of sulfadiazine and trimethoprim combination in Sulfadiazine, sulfadimethoxine, sulfadoxine, sulfamethoxazole, and sulf- the treatment of bacterial meningitis in dogs; however, it has been aquinoxaline—Sulfonamides. used for this indication{R-38}. Chemical name: [Nocardiosis (treatment)]1—Cats and dogs: There are insufficient data to Ormetoprim—2,4-Pyrimidinediamine,5-[(4,5-dimethoxy-2-methylphenyl) support the efficacy of sulfadiazine and trimethoprim or sulfamethox- methyl]-{R-1}. azole and trimethoprim in the treatment of nocardiosis in cats and Pyrimethamine—2,4-Pyrimidinediamine, 5-(4-chlorophenyl)-6-ethyl-{R-1}. dogs; however, these medications are used in the treatment of Sulfadiazine—Benzenesulfonamide, 4-amino-N-2-pyrimidinyl-{R-1}. nocardial infections. Sulfonamides have been considered the treatment Sulfadimethoxine—Benzenesulfonamide, 4-amino-N-(2,6-dimethoxy-4- of choice and there is some evidence{R-128–133} to suggest that pyrimidinyl)-{R-1}. sulfadiazine and trimethoprim or sulfamethoxazole and trimethoprim Sulfadoxine—Benzenesulfonamide, 4-amino-N-(5,6-dimethyoxy-4-pyri- are efficacious in the treatment of these infections{R-128; 131; 133}. midinyl)-{R-1}. Ormetoprim and sulfadimethoxine combination could also be effective Sulfamethoxazole—Benzenesulfonamide, 4-amino-N-(5-methyl-3-isoxaz- in the treatment of nocardiosis, based on a pharmacokinetic profile olyl)-{R-1}. similar to that of trimethoprim with sulfadiazine or sulfamethoxaz- Sulfaquinoxaline—N1-2-Quinoxalinylsulfanilamide{R-1}. ole{R-138}. Because of a variability in the susceptibility of Nocardia Trimethoprim—2,4-Pyrimidinediamine, 5-[(3,4,5-trimethoxyphenyl) species, culture and sensitivity tests should be performed, if possible. methyl]-{R-1}. Surgical drainage should be provided for any abscesses or draining Molecular formula: {R-130; 131} {R-1} tracts . Sulfonamide and trimethoprim combination admin- Ormetoprim—C16H18N4O2 . {R-1} istered alone may not be effective in the treatment of cerebral Pyrimethamine—C12H13ClN4 . {R-132} {R-1} nocardiosis . Sulfadiazine—C10H10N4O2S . 1 {R-1} [Pneumonia (treatment)] —Calves, nonruminating: Until recently, Cana- Sulfadimethoxine—C12H14N4O4S . {R-1} dian sulfadiazine and trimethoprim boluses were labeled for use in the Sulfadoxine—C12H14N4O4 . {R-12} {R-1} treatment of bacterial pneumonia in calves . Such a product has Sulfamethoxazole—C10H11N3O3S . {R-1} not been available in the United States. Although there are no Sulfaquinoxaline—C14H12N4O2S . {R-1} sulfadiazine and trimethoprim products labeled for use in calves in the Trimethoprim—C14H18N4O3 . United States or Canada at this time, oral sulfadiazine and trimeth- Molecular weight: oprim tablets might be used in the treatment of susceptible infections, Ormetoprim—274.32{R-1}. such as bacterial pneumonia, in calves. For more information, see Pyrimethamine—248.71{R-1}. Sulfadiazine and Trimethoprim Tablets in the Dosage Forms section of Sulfadiazine—250.28{R-1}. this monograph. Sulfadimethoxine—310.34{R-1}. [Prostate infection (treatment)]1—Dogs: There are insufficient data to Sulfadoxine—310.33{R-1}. support the efficacy of trimethoprim in combination with sulfadiazine Sulfamethoxazole—253.28{R-1}. or sulfamethoxazole in the treatment of prostate infections caused by Sulfaquinoxaline—300.34{R-1}. susceptible organisms in dogs; however, pharmacokinetic studies show Trimethoprim—290.32{R-1}.

Description: compete with para-aminobenzoic acid (PABA) for incorporation into Ormetoprim—White powder{R-5}. dihydrofolic acid{R-20}. By replacing the PABA molecule in dihydrofolic Pyrimethamine USP—White, odorless, crystalline powder{R-117}. acid, they prevent formation of folic acid required for nucleic acid Sulfadiazine USP—White or slightly yellow powder. Odorless or nearly synthesis and multiplication of the bacterial cell{R-94; 101}. Sulfona- odorless and stable in air, but slowly darkens on exposure to mides are effective only in cells that must produce their own folic acid; light{R-117}. mammalian cells do not synthesize folic acid, but get it from outside Sulfadimethoxine USP—Practically white, crystalline powder{R-117}. sources. Sulfadoxine—White or yellowish-white crystalline powder, melting at Diaminopyrimidines—Ormetoprim{R-5} and trimethoprim{R-23} are bac- 197–200 C{R-118}. teriostatic antimicrobials that block a step in folate production just Sulfamethoxazole USP—White to off-white, practically odorless, crystal- subsequent to that affected by the sulfonamides. Bacterial production line powder{R-117}. of tetrahydrofolic acid from dihydrofolate is interrupted by the Sulfaquinoxaline—Yellow, odorless powder{R-118}. diaminopyrimidine as it reversibly binds and inhibits dihydrofolate Trimethoprim USP—White to cream-colored, odorless crystals, or reductase. Because the conversion of dihydrofolic acid to tetrahydro- crystalline powder{R-117}. folic acid is blocked, folate cannot be produced. Pyrimethamine causes pKa: the same inhibition of dihydrofolate reductase in protozoa{R-20}. Like Sulfadiazine—6.4{R-25}. bacteria and protozoa, animal cells also reduce folic acid to tetrahy- Sulfadimethoxine—6.2{R-97; 98}. drofolic acid; however, bacterial and protozoal dihydrofolate reductase Sulfadoxine—6.3{R-25}. is significantly more tightly bound by trimethoprim than is human Sulfamethoxasole—5.7{R-25}. dihydrofolate reductase{R-2}. Sulfaquinoxaline—5.5{R-99; 100}. Potentiated sulfonamides—Because the diaminopyrimidines exert their Trimethoprim—7.6{R-73; 90}. effect on folate biosynthesis at a step immediately subsequent to the Solubility: one at which the sulfonamides act, the combination of a sulfonamide Pyrimethamine USP—Practically insoluble in water; slightly soluble in and diaminopyrimidine produces a synergistic effect that deprives the acetone, in alcohol, and in chloroform{R-117}. cell of essential nucleic acids and proteins. The potentiated sulfonamide Sulfadiazine USP—Practically insoluble in water; freely soluble in dilute combination produces an antimicrobial effect that is bacteriostatic and mineral acids, in solutions of potassium and sodium hydroxides, and in sometimes bactericidal against certain bacteria under optimum ammonia TS; sparingly soluble in alcohol and in acetone; slightly conditions.{R-2; 23; 24} The minimal effective ratio of sulfonamide to soluble in human serum at 37 C{R-117}. diaminopyrimidine in the target tissue is 20 to 1 for synergism. At Sulfadimethoxine USP—Soluble in 2 N sodium hydroxide; spar- equimolar quantities, other ratios are equally effective, depending on ingly soluble in 2 N hydrochloric acid; slightly soluble in alcohol, in the strain of organism and the minimum inhibitory concentration ether, in chloroform, and in hexane; practically insoluble in (MIC) for each drug. Therefore, 16 to 1, 10 to 1, and other ratios may water{R-117}. be effective, but combinations are formulated to achieve at least 20 to Sulfadoxine—Very slightly soluble in water; slightly soluble in alco- 1 in vivo{R-20}. hol and in methyl alcohol; practically insoluble in ether. Dissolves in solutions of alkali hydroxides and in dilute mineral acids{R-118}. Absorption: Oral— Sulfamethoxazole USP—Practically insoluble in water, in ether, and in Ormetoprim and sulfadimethoxine: chloroform; freely soluble in acetone and in dilute solutions of sodium Calves, 6 weeks of age—The bioavailability of oral ormetoprim is very hydroxide; sparingly soluble in alcohol{R-117}. poor in ruminating calves{R-86}; the bioavailability of oral sulfa- Sulfaquinoxaline—Practically insoluble in water; very slightly soluble in dimethoxine in calves is slow but complete and unaffected by alcohol; practically insoluble in ether; freely soluble in aqueous ruminant status{R-81}. solutions of alkalis{R-118}. Dogs—Ormetoprim and sulfadimethoxine are rapidly and well Trimethoprim USP—Very slightly soluble in water; soluble in benzyl absorbed after oral administration{R-5}. alcohol; sparingly soluble in chloroform and in methanol; slightly Horses—Oral absorption of ormetoprim and sulfadimethoxine is soluble in alcohol and in acetone; practically insoluble in ether and in variable. Sulfadimethoxine appears to be more efficiently absorbed carbon tetrachloride{R-117}. than ormetoprim{R-35; 36}. Sulfadimethoxine administered alone: Bioavailability— Catfish, channel: 40 mg/kg dose—{R-68} PHARMACOLOGY/PHARMACOKINETICS Free base: 31%. Note: Unless otherwise noted, pharmacokinetic values are based on Sodium salt: 34%. administration of a single intravenous dose and concurrent adminis- Trout, rainbow: tration of a diaminopyrimidine and a sulfonamide. 42 mg/kg dose—{R-67} When sulfamethoxazole and trimethoprim are administered concur- Free base: 34%. rently to horses, the pharmacokinetics of each drug appears to be Sodium salt: 63%. unaffected by the presence of the other{R-30; 32}. 126 mg/kg dose—Sodium salt: 50%{R-67}. Sulfadiazine and trimethoprim: Mechanism of action/effect: Calves, 6 weeks of age—The bioavailability of oral trimethoprim is Sulfonamides—The sulfonamides are bacteriostatic antimicrobials that greatly reduced in ruminating calves as compared to preruminating interfere with the biosynthesis of folic acid in bacterial cells; they calves. Therapeutic serum concentrations (> 0.1 mcg/mL) were not

achieved with oral administration of 25 mg of sulfadiazine and 5 mg Sulfadimethoxine and trimethoprim: After 4-day dosing in mares, of trimethoprim in combination to ruminating calves{R-81}. The trimethoprim was measured in CSF at 50% of serum concentrations, bioavailability of oral sulfadiazine in calves is slow but complete and but sulfadimethoxine was measured at 2.7% of serum concentra- unaffected by rumen status{R-81}. tions{R-35}. Dogs—Sulfadiazine and trimethoprim are rapidly and well absorbed Sulfamethoxazole and trimethoprim: A single dose of 36 mg of following oral administration{R-76}. However, absorption can be sulfamethoxazole and 7.5 mg of trimethoprim per kg of body weight, variable among dogs and between different doses given to the same administered intravenously to mares, reached concentrations in dog{R-46}. serum sufficient to exceed the minimum inhibitory concentrations Horses—The absorption of trimethoprim is delayed when a horse has (MICs) of common bacterial and protozoal pathogens{R-33}. After free access to feed{R-27}. Initial serum concentrations will be lower in repeated doses, sulfamethoxazole, unlike trimethoprim, accumulated a fed horse than in a fasted horse; however, the effect is greatly in the CSF{R-31}. decreased by the third day of treatment{R-27}. Fish—Sulfadimethoxine administered alone: Pigs—Bioavailability: Dose of 40 mg of sulfadiazine and 4 mg of In channel catfish, sulfadimethoxine is distributed into the muscle at trimethoprim per kg—Fasted or fed: the highest concentration immediately after administration, but Sulfadiazine—85 to 89%{R-91}. within 48 to 96 hours the highest concentrations are in the Trimethoprim—90 to 92%{R-91}. bile{R-68}. At any point in time there can be wide variation in Sheep—Absorption of sulfadiazine in sheep is comparable to that in tissue residues among fish{R-69}. dogs; however, trimethoprim is not as well absorbed orally in sheep In rainbow trout, sulfadimethoxine is distributed at the highest as in dogs{R-76}. concentrations into the bile, followed by the intestine, liver, blood, Sulfamethoxazole and trimethoprim: Bioavailability—Quail: Dose of skin, kidney, spleen, gill, muscle, and fat.{R-67}

50 mg of sulfamethoxazole and 10 mg of trimethoprim per kg of Volume of distribution (VolD): body weight— Ormetoprim and sulfadimethoxine—Horses:{R-35} Sulfamethoxazole: 81%{R-93}. Ormetoprim— Trimethoprim: 41%{R-93}. Area: 1.7 Liters per kg (L/kg). Steady state: 1.2 L/kg. Distribution: Potentiated sulfonamides are widely distributed Sulfadimethoxine— throughout body tissues{R-2; 3}. In general, the diaminopyrimidine Area: 0.28 L/kg. concentration in plasma peaks early and is quickly found in high Steady state: 0.27 L/kg. concentrations in tissues{R-76}; therefore, concentrations are generally Sulfadiazine and trimethoprim— higher in the tissues than in the serum{R-25}. The sulfonamide com- Calves: Area— ponent generally is found at higher concentrations in plasma for a Sulfadiazine: much longer time and tissue distribution is slower{R-76}. Initial con- 1 day of age—0.72 L/kg{R-79}. centrations of sulfonamides in tissues are generally lower than those in 1 week of age—0.66 L/kg{R-79; 80}. plasma{R-25}. 6 weeks of age—0.58 L/kg{R-79}. Calves, preruminating—Sulfadiazine and trimethoprim are distributed Ruminating—0.85 L/kg{R-77}. well into cerebrospinal fluid (CSF){R-79} and synovial fluid{R-80}. Trimethoprim: Dogs—Potentiated sulfonamides are rapidly and widely distributed in 1 day of age—1.69 L/kg{R-79}. the tissues. Trimethoprim and sulfadiazine are distributed into the 1 week of age—2.2 to 2.5 L/kg{R-79; 80}. aqueous and vitreous humors of the eye at concentrations that are 30 6 weeks of age—2.27 L/kg{R-79}. to 50% of serum concentrations{R-45}. Trimethoprim is distributed into Ruminating—1.97 L/kg{R-77}. prostatic fluid at concentrations that are up to three times the serum Horses: Steady state— concentration and are higher when trimethoprim is administered Sulfadiazine: 0.58 L/kg{R-43}. concurrently with sulfadiazine or sulfamethoxazole{R-48}. Sulfadiazine Trimethoprim: 1.68 L/kg{R-43}. and sulfamethoxazole are distributed into prostatic fluid at about 10% Pigs: Steady state— of the concurrent serum concentration{R-48}. Sulfadiazine: 0.54 L/kg{R-91}. Horses—Distribution of potentiated sulfonamides has been broadly Trimethoprim: 1.8 L/kg{R-91}. investigated in the horse. Ormetoprim and sulfadimethoxine{R-35}, Sulfadimethoxine administered alone—Steady state: sulfadiazine and trimethoprim{R-29}, and sulfamethoxazole and Catfish, channel—0.66 L/kg{R-68}. trimethoprim{R-31; 33} are all well distributed into peritoneal fluid, Trout, rainbow—0.42 to 0.5 L/kg{R-67; 70}. CSF, synovial fluid, and urine. Ormetoprim and sulfadimethoxine also Sulfadoxine and trimethoprim— have been shown to be well distributed into the endometrium{R-35}. Cows: Apparent— Inflammation in the meninges or synovium does not significantly Sulfadoxine: 0.37 L/kg{R-82}. affect distribution into the respective fluids{R-31}. Trimethoprim: 1.14 L/kg{R-82}. Ormetoprim and sulfadimethoxine: Equine endometrial tissue and Goats: Apparent— synovial and peritoneal fluid concentrations of ormetoprim were Sulfadoxine: 0.27 L/kg{R-72}. similar to concurrent serum concentrations and concentrations of Trimethoprim: 1.2 L/kg{R-72}. sulfadimethoxine in those fluids were 25 to 30% of serum concen- Horses: Apparent— tration{R-35}. Sulfadoxine: 0.39 L/kg{R-30}.

{R-30} {R-105–108} Trimethoprim: 1.5 L/kg . the animal .N4-acetyl metabolites have no antimicrobial Sulfamethoxazole and trimethoprim— activity and hydroxymetabolites have 2.5 to 39.5% of the activity of Foals: the parent compound{R-109}. Metabolites may compete with the parent Sulfamethoxazole—Area and steady state: 0.73 L/kg{R-32}. drug for involvement in folic acid synthesis. They have little Trimethoprim—Area and steady state: 2.2 L/kg{R-32}. detrimental effect on the bacterial cell, so their presence could decrease Horses: the activity of the remaining parent drug{R-109}. Sulfamethoxazole— Sulfadiazine—Calves: Sulfadiazine is excreted primarily as unchanged drug Area: 0.36 L/kg{R-31}. in the urine; the percentage of unchanged drug excreted increases from 1 Steady state: 0.33 L/kg{R-31}; 0.5 L/kg{R-33}. day of age to 42 days of age, changing from 22 to 50%{R-79}. Trimethoprim— Sulfadimethoxine: Area: 2.27 L/kg{R-31}. Catfish, channel—Metabolized primarily by the liver; acetylation is the Steady state: 1.62 L/kg{R-31}; 2.79 L/kg{R-33}. major pathway{R-68}. Quail: Dogs—Sulfadimethoxine is not acetylated in the dog as it is in other Sulfamethoxazole—Area: 0.48 L/kg{R-93}. species, and it is excreted primarily as unchanged drug{R-5}. Trimethoprim—Area: 3.9 L/kg{R-93}. Salmon—Metabolism occurs primarily in the liver{R-66}. Diaminopyrimidines—Trimethoprim: In many species, including {R-79} Protein binding: In general, the binding of sulfonamides to proteins is cows , goats, and pigs, trimethoprim is extensively {R-25} concentration-dependent{R-25; 30} and, in general, trimethoprim pro- metabolized . tein binding is independent of plasma concentration{R-25; 30}. There appears to be no interference in protein binding between sulfadoxine Half-life: and trimethoprim{R-30}; this may also be true for other potentiated Absorption—Horses: Oral—Sulfadiazine and trimethoprim: Dose of sulfonamides. 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body {R-43} Sulfadiazine— weight (mg/kg) — Cattle: Moderate (50%) (concentration not specified){R-75}. Sulfadiazine: 0.35 hour. Sulfadimethoxine— Trimethoprim: 0.44 hour. Cats: High (87.5%) (50 mcg/mL plasma concentration){R-102}. Distribution—Horses: Oral—Sulfadiazine and trimethoprim: Dose of Catfish, channel: Low (18%), not concentration-dependent{R-68}. 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body {R-43} Chickens: Average binding over a range of concentrations— weight — Moderate (40%), at serum concentrations of 2 to 10 mcg/ Sulfadiazine: 0.27 hour. mL{R-103}. Trimethoprim: 0.15 hour. Dogs: High (> 75%), at plasma concentrations of 50 to 150 mcg/mL{R-104}. Elimination— Goats: Very high (94%), at plasma concentration of 100 micromole/ Ormetoprim and sulfadimethoxine: Horses— {R-35} L{R-98}. Ormetoprim: 1.7 hours . {R-35} Trout, rainbow: Low (17%), not concentration-dependent{R-67}. Sulfadimethoxine: 7.9 hours . Sulfadoxine— Sulfadiazine and trimethoprim: Horses: Calves— High (72%), at serum concentration of 50 mcg/mL{R-30}. 1 day of age: {R-79} Moderate (40%), at serum concentration of 150 mcg/mL{R-30}. Sulfadiazine—5.7 hours . {R-79} Low (14%), at serum concentration of 450 mcg/mL{R-30}. Trimethoprim—8.4 hours . Cows: 1 week of age: {R-79; 80} High (65 to 80%), at serum concentration of 100 mcg/mL or Sulfadiazine—4.4 hours . {R-79; 80} below{R-82; 83}. Trimethoprim—2.1 hours . Moderate (44 to 51%), at serum concentration of 150 mcg/mL or 6 weeks of age: {R-79} more{R-82; 83}. Sulfadiazine—3.6 hours . {R-79} Trimethoprim— Trimethoprim—0.9 hour . Cows: Moderate (57%){R-83}. Calves, ruminating— {R-77} {R-78} Goats: Moderate (48%){R-73}. Sulfadiazine: 3.25 hours ; 4 hours . {R-78} {R-77} Horses: Moderate (50%){R-30}. Trimethoprim: 1 hour ; 3.44 hours . Pigs: Moderate (33 to 54%){R-90}. Horses— Sulfadiazine: 2.7 hours{R-29};4.65hours{R-43}; 7 hours{R-3}. Biotransformation: Trimethoprim: 2 to 3 hours{R-3; 29; 32; 43}. Sulfonamides—Sulfonamides are metabolized primarily in the liver, but Sulfadoxine and trimethoprim: metabolism also occurs in other tissues. Biotransformation occurs by Cows, lactating— acetylation, glucuronide conjugation, and aromatic hydroxylation in Sulfadoxine: many species{R-94}. The types of metabolites formed and the amount of Alpha phase (up to 4 hours postadministration)—0.9 each varies depending on the specific sulfonamide administered; the hour{R-82}. species, age, diet, and environment of the animal; the presence of Beta phase (between 4 and 48 hours postadministration)—10.8 disease; and, with the exception of pigs and ruminants, the gender of hours{R-82}.

Trimethoprim: 1.18 hours{R-82}. Sulfadiazine and trimethoprim—Oral: Goats— Calves— 2 days of age: 1 week of age: 11.9 mcg of sulfadiazine per mL at 12 hours and 0.41 Sulfadoxine—16.5 hours{R-72}. mcg of trimethoprim per mL at 3 hours (dose of 25 mg of sulfadiazine Trimethoprim—3 hours{R-72}. and 5 mg of trimethoprim per kg){R-81}. 40 days of age to adult: 6 weeks of age: Sulfadoxine—11.7 hours{R-72}. Milk-fed—17.3 mcg of sulfadiazine per mL at 3 hours and 0.43 Trimethoprim—0.8 hour{R-72}. mcg of trimethoprim per mL at 1.5 hours (dose of 25 mg sulfadiazine Horses— and 5 mg of trimethoprim per kg of body weight){R-81}. Sulfadoxine: 14 hours{R-30}; 9.7 hours{R-37}. Grain and fiber–fed—14.9 mcg of sulfadiazine per mL at 8 Trimethoprim: 3.2 hours{R-30}; 1.9 hours{R-37}. hours and < 0.1 mcg of trimethoprim per mL (below test limit) for Sheep— entire trial (dose of 25 mg of sulfadiazine and 5 mg of 1 week of age: trimethoprim per kg of body weight){R-81}. Sulfadoxine—15.3 hours{R-84}. Dogs— Trimethoprim—2.5 hours{R-84}. 12.4 mcg of sulfadiazine per mL at 4 hours and 1.7 mcg of 4 months of age to adult: trimethoprim per mL at 1 hour (dose of 20 mg of sulfadiazine and Sulfadoxine—11.5 hours{R-84}. 4 mg of trimethoprim per kg of body weight){R-49}. Trimethoprim—0.75 hour{R-74; 84}. 30.1 mcg of sulfadiazine per mL{R-19} and 1.52 mcg of trimethoprim Sulfamethoxazole and trimethoprim: per mL{R-2; 19} at 3 hours (dose of 25 mg of sulfadiazine and 5 mg Horses— of trimethoprim per kg of body weight). Sulfamethoxazole: 3.5 hours{R-31}; 4.8 hours{R-33}. After 2 days of dosing every 12 hours: 67.4 mcg of sulfadiazine per Trimethoprim: 1.9 hours{R-31}; 3.4 hours{R-33}. mL and 2.98 mcg of trimethoprim per mL at 2 hours{R-46} (dose of Horse foals— 25 mg of sulfadiazine and 5 mg of trimethoprim per kg). Sulfamethoxazole: 9.9 hours{R-32}. After 4 days of dosing every 24 hours: 84.7 mcg of sulfadiazine at 3 Trimethoprim: 1.6 hours{R-32}. hours and 2.55 mcg of trimethoprim per mL at 2 hours{R-46} (dose Pony foals— of 25 mg of sulfadiazine and 5 mg of trimethoprim per kg). Sulfamethoxazole: 5.8 hours{R-32}. Horses— Trimethoprim: 2.8 hours{R-32}. Fasted: 9 to 13 mcg of sulfadiazine per mL at 3 hours and 1 to 1.5 Quail: mcg of trimethoprim per mL at 1 to 2 hours (dose of 25 to 29 mg Sulfamethoxazole—2.9 hours{R-93}. of sulfadiazine and 5 to 6 mg of trimethoprim per kg of body Trimethoprim—2.38 hours{R-93}. weight){R-27–29} Sulfadiazine: Administered alone orally—Dogs: 9.84 hours{R-49}. Fed: 10 mcg of sulfadiazine per mL and 0.5 mcg of trimethoprim per Sulfadimethoxine: Administered alone— mL at 6 hours (dose of 29.2 mg of sulfadiazine and 5.8 mg of Cats: 10.2 hours{R-102}. trimethoprim per kg of body weight){R-27}. Dogs: 13.1 hours{R-104}. Pigs— Trout, rainbow: 16 hours{R-67; 70}. Fasted: 32 mcg of sulfadiazine per mL at 4.3 hours and 1.9 mcg of Trimethoprim: Administered alone— trimethoprim per mL at 2.1 hours (oral dose of 40 mg of sulfadiazine Dogs: Based on oral dosing—2.5 hours{R-30; 49}. and 8 mg of trimethoprim per kg of body weight){R-91}. Pigs: 2.4 hours{R-89}. Fed: 25 mcg of sulfadiazine per mL at 3.2 hours and 1.5 mcg of trimethoprim per mL at 3.4 hours (oral dose of 40 mg of sulfadiazine and 8 mg of trimethoprim per kg of body weight){R-91}. Peak serum concentration: Salmon—20.3 mcg of sulfadiazine per mL at 24 hours and 3.25 mcg of Sulfadimethoxine—Administered alone: Oral— trimethoprim per mL at 12 hours (oral dose of 83.3 mg of Catfish, channel: 7.83 to 11 mcg/mL at 3 to 6 hours (after 5 days of sulfadiazine and 16.7 mg of trimethoprim per kg of body weight of {R-68; 69} dosing 40 to 42 mg/kg every 24 hours) . fish at 8 C){R-63}. {R- Chickens: 106.3 mcg/mL at 12 hours (single dose of 100 mg/kg). Sulfadoxine and trimethoprim—Cattle: Intramuscular administra- 103} tion—30.3 mcg of sulfadoxine per mL at 2 hours and 0.7 mcg of {R-111} Cows: 114 ± 10 mcg/mL at 10 hours (dose of 107 mg/kg). trimethoprim per mL at 0.75 to 1 hour (dose of 13.3 mg of sulfadoxine {R-104} Dogs: 67 ± 16 mcg/mL at 3.75 hours (dose of 55 mg/kg). and 2.7 mg of trimethoprim per kg of body weight){R-85}. Ormetoprim and sulfadimethoxine—Oral: Sulfamethoxazole and trimethoprim—Horses: Oral administration—0.26 Foals, 1 to 3 days of age—0.65 mcg of ormetoprim per mL at 2 hours mcg/mL of trimethoprim at 0.75 hour and 13.7 mcg/mL of sulfame- and 54.6 mcg of sulfadimethoxine per mL at 8 hours (dose of 3.5 mg thoxazole at 1.5 hours (dose of 12.5 mg of sulfamethoxazole and 2.5 of ormetoprim and 17.5 mg of sulfadimethoxine per kg of body mg of trimethoprim per kg of body weight){R-31}. weight){R-36}. Horses—80 mcg of sulfadimethoxine per mL at 8 hours and 0.92 mcg Duration of action: Duration of action may be estimated by the length of ormetoprim per mL at 0.5 hour postadministration (loading dose of time target serum concentrations are maintained; however, duration of 9.2 mg of ormetoprim and 45.8 mg of sulfadimethoxine per kg of of action for the potentiated sulfonamides is difficult to estimate from body weight){R-25}. target serum concentrations{R-78} because of the rapid movement of the

diaminopyrimidines into the tissues and the possibly wide range of local azine and trimethoprim are administered concurrently, neither sulfonamide to diaminopyrimidine concentration ratios believed to be antibiotic interferes with the excretion of the other{R-3; 4}. effective and synergistic. Target concentrations should be viewed as Dogs: Two-thirds of the total dose is eliminated in the urine as parent estimates only, and clinical response should be considered one of the drug in the first 24 hours{R-19}. measurements of activity of the medication. Some sources consider Total clearance— bacteria susceptible if their minimum inhibitory concentration (MIC) is Ormetoprim and sulfadimethoxine: Horses— 0.5 mcg/mL for trimethoprim and 9.5 mcg/mL for sulfonamide{R-25}. Ormetoprim: 11.1 mL per minute per kg (mL/min/kg){R-35}. However, the National Committee for Clinical Laboratory Standards Sulfadimethoxine: 0.42 mL/min/kg{R-35}. (NCCLS) in the U.S. lists MIC breakpoints for animal isolates and tri- Sulfadiazine and trimethoprim: methoprim/sulfamethoxazole as £ 2 mcg per mL/38 mcg per mL for Calves— susceptible organisms and ‡ 4 mcg per mL/76 mcg per mL for resistant Sulfadiazine: organisms{R-141}. Organisms testing between these values are consid- 1 day of age—1.43 mL/min/kg{R-79}. ered intermediate and may or may not be inhibited in certain body sites 1 week of age—1.7 mL/min/kg{R-79; 80}. or with certain antimicrobials with low toxicity in which high concen- 6 weeks of age—1.88 mL/min/kg{R-79}. trations can be achieved{R-141}. These breakpoints are also used to test Trimethoprim: for susceptibility to sulfadiazine and trimethoprim or ormetoprim and 1 day of age—2.8 mL/min/kg{R-79}. sulfadimethoxine combination{R-141}. 1 week of age—12 mL/min/kg{R-79; 80}. Sulfadiazine and trimethoprim—Calves: 6 weeks of age—28.9 mL/min/kg{R-79}. 1 day of age—A single intravenous dose of 25 mg of sulfadiazine and Calves, ruminating— 5 mg of trimethoprim produced therapeutic serum concentrations Sulfadiazine: 3.15 mL/min/kg{R-77}. > 2 mcg of sulfadiazine per mL of serum for 24 hours and > 0.1 Trimethoprim: 6.6 mL/min/kg{R-77}. mcg of trimethoprim per mL for 15 hours{R-79}. Horses— 7 to 42 days of age—A single intravenous dose of 25 mg of sulfadiazine Sulfadiazine: 1.92 mL/min/kg{R-43}. and 5 mg of trimethoprim produced therapeutic serum concentra- Trimethoprim: 8.49 mL/min/kg{R-43}. tions of > 2 mcg of sulfadiazine per mL of serum for 15 hours and Pigs— > 0.1 mcg/mL of trimethoprim for 6 to 8 hours{R-79}. Sulfadiazine: 2.3 mL/min/kg{R-91}. Sulfadoxine and trimethoprim—Cattle: Sulfadoxine serum concentra- Trimethoprim: 9.1 mL/min/kg{R-91}. tions exceeded 9.5 mcg/mL from 12 minutes to 10 hours postinjec- Sulfamethoxazole and trimethoprim: tion and trimethoprim serum concentrations exceeded 0.5 mcg/mL Horses— from 15 minutes to 2 hours (intramuscular dose of 13.3 mg of Sulfamethoxazole: 1.3 mL/min/kg{R-31; 33}. sulfadoxine and 2.7 mg of trimethoprim per kg of body weight) Trimethoprim: 11.3 mL/min/kg{R-33}; 14.8 mL/min/kg{R-31}. postinjection{R-85}. Horse foals— Sulfamethoxazole: 0.83 mL/min/kg{R-32}. Trimethoprim: 17.1 mL/min/kg{R-32}. Elimination: Pony foals— Sulfonamides—Renal excretion is the primary route of elimination for Sulfamethoxazole: 1.1 mL/min/kg{R-32}. most nonenteric sulfonamides and it occurs by glomerular filtration of Trimethoprim: 11.7 mL/min/kg{R-32}. parent drug, tubular excretion of unchanged drug and metabolites, Sulfadimethoxine: Administered alone— and passive reabsorption of nonionized drug.{R-94; 110} Alkalization of Cats: 0.32 mL/min/kg{R-102}. the urine increases the fraction of the dose that is eliminated in the Dogs: 0.36 mL/min/kg{R-104}. urine.{R-110} In general, the metabolites of the parent drug are more Trout, rainbow: 0.36 mL/min/kg{R-70}. quickly eliminated by the kidney than is the original sulfonamide{R-75}, but the proportions of metabolites formed can vary depending on many factors. PRECAUTIONS TO CONSIDER Sulfadimethoxine: SPECIES SENSITIVITY Cattle—Sulfadimethoxine is metabolized to a great degree, so that 40 Dogs: An idiosyncratic sulfonamide toxicosis can occur in any breed of dog, to 60% of the administered dose is excreted as metabolites in the but this reaction has been reported more frequently in the Doberman {R-111} urine . Pinscher than in other breeds. This specific type of drug reaction includes Dogs—Sulfadimethoxine is slowly excreted renally because of a high blood dyscrasias, nonseptic polyarthritis, and skin rash{R-53; 54}. See also {R-5} degree of tubular reabsorption . the Side Adverse Effects section in this monograph. Sulfadoxine: Horses—Sulfadoxine is excreted by glomerular filtration Horses: Trimethoprim with sulfadiazine or with sulfadoxine infused into {R-34} and reabsorption . The clearance of sulfadoxine increases with the uterus of horses can cause endometrial inflammation, straining, and {R-34} increasing pH . expulsion of the medication. Conception rates may be lowered. Because Trimethoprim—Renal excretion occurs by glomerular filtration, active there is good distribution of these medications when administered by {R-25; 89} tubular secretion, and reabsorption . systemic routes, intrauterine administration is not recommended.{R-27}. Horses: It is believed that a large percentage of trimethoprim is metabolized before elimination in urine (46%) and feces (52%){R-25; CROSS-SENSITIVITY AND/OR RELATED PROBLEMS 26; 30}. The clearance of trimethoprim is affected by urine pH, plasma Patients allergic to one sulfonamide may be allergic to other sulfona- concentration, and extent of diuresis{R-34}; however, when sulfadi- mides also.

PREGNANCY/REPRODUCTION thrombocytopenic effects; if concurrent use is required, close Sulfonamides and diaminopyrimidines cross the placenta in pregnant observation for myelotoxic effects should be considered) animals{R-110} and some teratogenic effects have been seen with very Cyclosporine high doses given to pregnant mice and rats{R-110}. (concurrent use with sulfonamides or trimethoprim may increase the Ormetoprim and sulfadimethoxine: Dogs—Safety in breeding or pregnant metabolism of cyclosporine, resulting in decreased plasma concentrations animals has not been established{R-5}. and potential transplant rejection, and additive nephrotoxicity; plasma Sulfadiazine and trimethoprim: cyclosporine concentrations and renal function should be monitored) Dogs—The recommended dose of 25 mg of sulfadiazine and 5 mg of Dapsone trimethoprim per kg of body weight administered during pregnancy (concurrent use with trimethoprim will usually increase the plasma had no apparent effect on offspring{R-2; 19}. concentrations of both dapsone and trimethoprim, possibly due to an Horses—Safety in pregnant animals has not been established{R-4}. inhibition in dapsone metabolism, and/or competition for renal With administration of recommended doses, no changes in sper- secretion between the two medications; increased serum dapsone matogenesis in stallions were apparent{R-4}. concentrations may increase the number and severity of side effects, especially methemoglobinemia) LACTATION Folate antagonists, other Sulfonamides are distributed into milk, with 0.5 to 2% of the total dose (concurrent use with trimethoprim or use of trimethoprim between found in the milk{R-114; 115}. For example, the milk-to-plasma courses of other folic acid antagonists is not recommended because of concentration ratio for sulfadiazine and sulfadoxine was measured to the possibility of an increased risk of megaloblastic anemia) be 0.5 in cows{R-75; 82}. Hemolytics, other Trimethoprim is distributed into milk{R-35}. Trimethoprim concentrations (concurrent use with sulfonamides may increase the potential for in milk were found to be 1.3 to 3.5 times the plasma concentration toxic side effects) measured at the same time in goats{R-73}. The concentration of Hepatotoxic medications, other trimethoprim in the milk of cows is 1 to 3 times higher than in (concurrent use with sulfonamides may result in an increased plasma{R-82; 83} and the concentration of trimethoprim in the milk of incidence of hepatotoxicity; patients, especially those on prolonged pigs is 1.3 to 3.5 times higher than in plasma{R-90}. administration or those with a history of liver disease, should be carefully monitored) DRUG INTERACTIONS AND/OR RELATED PROBLEMS Methenamine (in acid urine, methenamine breaks down into formaldehyde, which The following drug interactions and/or related problems have been may form an insoluble precipitate with certain sulfonamides, selected on the basis of their potential clinical significance (possible especially those that are less soluble in urine, and may also increase mechanism in parentheses where appropriate)—not necessarily inclu- the danger of crystalluria; concurrent use is not recommended) sive (» = major clinical significance): Methotrexate or Note: Combinations containing the following medication, depending on Phenylbutazone or the amount present, may also interact with this medication. Sulfinpyrazone Detomidine (the effects of methotrexate may be potentiated during concurrent (a trimethoprim and sulfonamide combination administered to a use with sulfonamides because of displacement from plasma protein detomidine-anesthetized horse can lead to arrhythmias, hypotension, binding sites; phenylbutazone and sulfinpyrazone may displace and death; it is suspected that the antimicrobial potentiates the sulfonamides from plasma protein binding sites, increasing sulfon- cardiac changes reported with detomidine{R-25; 120}). amide concentrations) HUMAN DRUG INTERACTIONS{R-149} Phenytoin (trimethoprim may inhibit the hepatic metabolism of phenytoin, In addition to the above drug interactions reported in animals, the increasing the half-life of phenytoin by up to 50% and decreasing its following drug interactions have been reported in humans and are clearance by 30%) included in the human monographs Sulfonamides (Systemic) and Procainamide Trimethoprim (Systemic) in USP DI Volume I; these drug interactions (concurrent use with trimethoprim may increase the plasma are intended for informational purposes only and may or may not be concentration of both procainamide and its metabolite NAPA by applicable to the use of sulfonamides in the treatment of animals: decreasing their renal clearance) Note: Combinations containing any of the following medications, depend- Rifampin ing on the amount present, may also interact with this medication. (concurrent use may significantly increase the elimination and Anticoagulants, coumarin- or indandione-derivative, or shorten the elimination half-life of trimethoprim) Anticonvulsants, hydantoin, or Warfarin Antidiabetic agents, oral (trimethoprim may potentiate the anticoagulant activity of warfarin (these medications may be displaced from protein binding sites and/ by inhibiting its metabolism) or their metabolism may be inhibited by some sulfonamides, resulting in increased or prolonged effects and/or toxicity; dosage adjustments may be necessary during and after sulfonamide therapy) LABORATORY VALUE ALTERATIONS Bone marrow depressants The following have been selected on the basis of their potential clinical (concurrent use of bone marrow depressants with sulfonamides significance (possible effect in parentheses where appropriate)—not or aminopyrimidines may increase the leukopenic and/or necessarily inclusive (» = major clinical significance):

With diagnostic test results (slight to moderate reduction in hematopoietic activity has been Thyrotropin stimulation tests or reported with long-term high dosing of potentiated sulfona- {R-99} Total serum thyroxine (T4) mides ) (thyroid function tests may be lowered in dogs with administration of » Hypersensitivity to diaminopyrimidines or sulfonamides{R-5; 10; 18; 19} sulfamethoxazole and trimethoprim combination at high doses [25 (animals that have had a previous reaction may be much more likely mg of sulfamethoxazole and 5 mg of trimethoprim per kg of body to react on subsequent administration) weight every 12 hours for 6 weeks]{R-62} or ormetoprim and Risk-benefit should be considered when the following medical sulfadimethoxine{R-21} [8 weeks of medication with the labeled dose problems exist: {R-5; 10; 18; 19; 25} or with three to five times the labeled dose]; the T4 and thyrotropin Hepatic function impairment {R-61} stimulation tests, but not T3, may be significantly reduced ; this (delayed biotransformation may increase the risk of adverse effects) effect was not shown with labeled doses of sulfadiazine and Renal function impairment{R-25} trimethoprim{R-62}) (delayed elimination could cause accumulation of sulfonamide and With physiology/laboratory test values metabolites, increasing the risk of adverse effects) Cholesterol, serum Urolithiasis{R-25} (cholesterol concentrations can be elevated with administration of (sulfonamides can crystallize in the renal system under certain sulfonamides, including ormetoprim and sulfadimethoxine combina- conditions{R-25}) tion; however, this effect is reversible{R-5}) PATIENT MONITORING The following may be especially important in patient monitoring (other {R-149} HUMAN LABORATORY VALUE ALTERATIONS tests may be warranted in some patients, depending on condition; » = In addition to the above laboratory value alterations reported in animals, major clinical significance): the following laboratory value alterations have been reported in Complete blood count (CBC), including platelet count humans, and are included in the human monographs Sulfonamides (some animals have had reductions in hematopoietic activity when (Systemic) and Trimethoprim (Systemic) in USP DI Volume I; these administered potentiated sulfonamides; periodic CBC and platelet laboratory value alterations are intended for informational purposes counts are recommended if it is necessary to administer long-term only and may or may not be applicable to the use of sulfonamides in treatment with potentiated sulfonamides{R-3; 19}) the treatment of animals: Culture and susceptibility, in vitro, and With diagnostic test results Minimum inhibitory concentration (MIC) Benedict’s test (in vitro cultures and MIC test should be done on samples collected (sulfonamides may produce a false-positive Benedict’s test for urine prior to potentiated sulfonamide administration to determine path- glucose) ogen susceptibility) Creatinine determinations Schirmer’s tear test (sulfamethoxazole or trimethoprim may interfere with the Jaffe´ (periodic Schirmer’s tear tests during potentiated sulfonamide alkaline picrate reaction assay for creatinine, resulting in creatinine therapy in dogs may be warranted to monitor for early keratocon- values that are approximately 10% higher than actual values) junctivitis sicca{R-124}) Sulfosalicylic acid test (sulfonamides may produce a false-positive sulfosalicylic acid test SIDE/ADVERSE EFFECTS for urine protein) The following side/adverse effects have been selected on the basis of their Urine urobilinogen test strip (e.g., Urobilistix) potential clinical significance (possible signs and, for humans, symptoms (sulfonamides may interfere with the Urobilistix test for urinary in parentheses where appropriate)—not necessarily inclusive: urobilinogen) With physiology/laboratory test values THOSE INDICATING NEED FOR MEDICAL ATTENTION Alanine aminotransferase (ALT [SGPT]), serum, and Incidence unknown Aspartate aminotransferase (AST [SGOT]), serum For all species (values may be increased) Crystallization in the urinary tract{R-5}; hypersensitivity, spe- Bilirubin, serum, and cifically anaphylaxis{R-4; 5} Blood urea nitrogen (BUN) and Note: Crystallization of sulfonamides is theoretically possible with Creatinine, serum administration of potentiated sulfonamides; however, the lower (concentrations may be increased) doses of sulfonamide used in the potentiated sulfonamide combination makes crystallization less likely to occur than with sulfonamide MEDICAL CONSIDERATIONS/CONTRAINDICATIONS administered alone. Sulfonamides can crystallize in the kidneys or The medical considerations/contraindications included have been urine in animals with aciduria, with high doses of sulfonamide, or selected on the basis of their potential clinical significance (reasons with dehydration. The amount of drug in the acetylated metabolite given in parentheses where appropriate)—not necessarily inclusive (» form also can affect solubility. Because dogs do not produce = major clinical significance). acetylated metabolites, they may be less susceptible to this adverse Except under special circumstances, this medication should not be effect{R-123}. Crystallization also can be minimized in susceptible used when the following medical problems exist: animals by maintaining a high urine flow and, if necessary, » Blood dyscrasias{R-25; 99} alkalinizing the urine.

Dogs Pigs Anemia, hemolytic{R-5; 19}; anemia, nonregenerative{R-23; 51}; Thyroid hyperplasia—in gilts, sows and piglets; believed to be in anorexia{R-5; 19}; cutaneous drug eruption, including erythema response to the sulfadimethoxine component of ormetoprim and multiforme, perforating folliculitis, and pustular dermati- sulfadimethoxine combination{R-92} tides{R-54; 60}; diarrhea{R-5; 19}; facial swelling{R-5; 19}; fever{R-5; For sulfaquinoxaline 19}; hepatitis{R-5; 19; 52; 54}; hypothyroidism{R-21; 61; 62}; idiosyn- Chickens and dogs cratic toxicosis{R-53; 54; 57–60} (blood dyscrasias, including anemia, Hemorrhagic syndrome (anorexia, epistaxis, hemoptysis, lethargy, leukopenia, or thrombocytopenia; fever; focal retinitis; lymphadenop- pale mucous membranes, death){R-100; 112; 113; 121; 122} athy; nonseptic polyarthritis; polymyositis; skin rash); keratocon- Note: Hemorrhagic syndrome has been reported in chickens and dogs junctivitis sicca{R-5; 19; 55; 56}; neurologic disorders{R-19} but may occur in other species. It is most often reported with the (aggression, ataxia, behavioral changes, hyperexcitability, seizures); addition of sulfaquinoxaline to feed for chickens, but in dogs, polyarthritis{R-5; 19}; polydipsia/polyuria{R-5; 19}; thrombocyto- reports follow administration of products labeled for poultry but penia—one case reported without other blood lines affected{R-116}; administered to dogs in the water supply.{R-112; 113; 121; 122} urticaria{R-5; 19}; vomiting{R-5; 19}. Sulfaquinoxaline is a vitamin K antagonist that inhibits vitamin K Note: Idiosyncratic toxicosis can occur 8 to 20 days after starting epoxide and vitamin K quinone reductase and causes an effect treatment and is believed to be caused by either an immune-mediated similar to that of coumarin anticoagulants.{R-100} Rapid hypopro- syndrome or by an idiosyncratic reaction in dogs, perhaps due to toxic thrombinemia occurs in dogs and an additional adverse effect of metabolites of the sulfonamide. Of 22 reported cases compiled in one sulfaquinoxaline on speciﬁc cell types may explain why supple- study, 7 were Doberman Pinschers and it has been theorized that they mentation of chicken feeds with vitamin K has not always are more susceptible than other breeds to this toxicosis{R-53; 54}.A prevented the syndrome in chickens.{R-100; 112} Rapid discontin-

large majority of the animals in which idiosyncratic toxicosis occurs uation of medication and initiation of therapy with vitamin K1 have had a previous exposure to a sulfonamide{R-54}. When sulfon- may reverse the effects. amide therapy is discontinued, recovery generally occurs within 2 to 5 days.{R-54; 60} Keratoconjunctivitis sicca is considered a possible side/adverse effect in THOSE INDICATING NEED FOR MEDICAL ATTENTION any dog administered sulfonamides; it can occur at any time after ONLY IF THEY CONTINUE OR ARE BOTHERSOME therapy is initiated. The most frequent reports have been with Incidence more frequent {R-55; sulfasalazine or trimethoprim and sulfonamide combination Cats 56} , perhaps because these medications are most commonly used for Salivation—with uncoated tablets or broken tablets{R-11}; thyroid long-term therapy in dogs. As many as 15% (5 out of 33 in one function changes—with prolonged dosages{R-11}; vomiting, tran- study) of dogs treated with sulfadiazine and trimethoprim may sient—up to 1 hour after administration of sulfadiazine and trimeth- {R-124} develop keratoconjunctivitis sicca . While increased risk has oprim combination{R-23} not been linked to higher dose or longer treatment, dogs weighing Cattle, horses, or pigs {R-124} less than 12 kg may be at increased risk . Lacrimation may Local pain and swelling—with intramuscular injection of sulfon- return to normal after discontinuation of sulfonamide treatment. amide and trimethoprim{R-9; 13; 14} The nonregenerative anemias seen in response to long-term adminis- Pigs tration of sulfadiazine and trimethoprim combination are, in some Irritant reactions—with intramuscular injections{R-14}; vomit- cases, believed to be related to folate reduction with long-term, high- ing—with oral suspension of sulfadiazine and trimethoprim combi- {R-23} dose administration (60 to 120 mg/kg a day for many weeks ) nation{R-10} of potentiated sulfonamide{R-23; 50}; these anemias generally respond {R-23} well to withdrawal of the medication . In the event an animal HUMAN SIDE/ADVERSE EFFECTS{R-149} does not respond to medication withdrawal, folinic or folic acid In addition to the above side/adverse effects reported in animals, the supplementation may be necessary{R-137; 138}. following side/adverse effects have been reported in humans and are Iatrogenic hypothyroidism may occur and thyroid function test included in the human monographs Sulfonamides (Systemic) and results may be lowered with administration of sulfamethoxazole and Trimethoprim (Systemic) in USP DI Volume I; these side/adverse effects trimethoprim combination at high doses (25 mg of sulfamethoxazole are intended for informational purposes only and may or may not be and 5 mg of trimethoprim per kg every 12 hours for 6 weeks){R-62} applicable to the use of potentiated sulfonamides in the treatment of or ormetoprim and sulfadimethoxine{R-21} (8-week medication with animals: the labeled dose or with three to five times the labeled dose). Results For sulfonamides— of the T and thyrotropin stimulation tests, but not T , may show 4 3 Incidence more frequent significant reduction{R-61}; this effect was not shown with labeled Central nervous system (CNS) effects; gastrointestinal distur- doses of sulfadiazine and trimethoprim (12.5 mg of sulfadiazine and bances; hypersensitivity; photosensitivity 2.5 mg of trimethoprim per kg every 12 hours for 4 weeks){R-62}. Incidence less frequent Horses Blood dyscrasias; hepatitis; Lyell’s syndrome (difficulty in Diarrhea, transient—approximately 3% of horses treated in one swallowing; redness, blistering, peeling, or loosening of skin); study{R-3; 139}; hypersensitivity reactions (anorexia; decreased Stevens-Johnson syndrome (aching joints and muscles; redness, hematopoiesis{R-3}; loose stool; or muscle tremors)—with intravenous blistering, peeling, or loosening of skin; unusual tiredness or administration of potentiated sulfonamides{R-25; 26; 35} weakness)

Incidence rare VETERINARY DOSING INFORMATION CNS toxicity; Clostridium difficile colitis; crystalluria or Although the minimum inhibitory concentrations (MICs) of potentiated hematuria; goiter or thyroid function disturbance; interstitial sulfonamides are important in determining therapeutic regimens, they nephritis or tubular necrosis can be misleading because the actual concentrations of drugs at the Note: Fatalities have occurred, although rarely, due to severe reactions therapeutic site can be difficult to pinpoint at any one time. such as Stevens-Johnson syndrome, fulminant hepatic necrosis, agran- Trimethoprim goes rapidly into tissues, and sulfonamides often have ulocytosis, aplastic anemia, and other blood dyscrasias. Therapy measurable serum concentrations for longer periods. The ratio of should be discontinued at the first appearance of skin rash or any sulfonamide to trimethoprim concentrations necessary at the site for serious side/adverse effects or if signs of folic acid deficiency occur. efficacy may vary from the goal of 20 to 1, depending on the tissue and Crystalluria is more likely to occur with a less soluble sulfonamide, the local concentrations of other factors, such as thymidine.{R-24}. such as sulfadiazine. It occurs most often with the administration of Clinical efficacy also should be considered, once pathogen susceptibility high doses, and can be minimized by maintaining a high urine flow has been determined{R-24; 31}. and alkalinizing the urine. The National Committee for Clinical Laboratory Standards (NCCLS) in C. difficile colitis may occur up to several weeks after discontinuation the U.S. lists MIC breakpoints for animal isolates and trimethoprim/ of these medications. sulfamethoxazole as £ 2 mcg per mL/38 mcg per mL for susceptible For trimethoprim— organisms and ‡ 4 mcg per mL/76 mcg per mL for resistant Incidence less frequent organisms{R-141}. Organisms testing between these values are consid- Gastrointestinal disturbances; headache; pruritis; skin rash ered intermediate and may or may not be inhibited in certain body Incidence rare sites in which high concentrations can be achieved or with certain Anaphylaxis; aseptic meningitis; blood dyscrasias, such as antimicrobial agents with low toxicity{R-141}. These breakpoints are leukopenia or neutropenia, megaloblastic anemia, and throm- also used to test for susceptibility to sulfadiazine and trimethoprim or bocytopenia; glossitis; methemoglobinemia; phototoxicity; se- ormetoprim and sulfadimethoxine combination{R-141}. vere skin reactions, such as erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal FOR ORAL DOSAGE FORMS ONLY necrolysis [Lyell’s syndrome] Horses: The oral administration of 25 to 100 mg of sulfadiazine and 5 to OVERDOSE 20 mg of trimethoprim per kg of body weight a day for 5 days does not cause the increase in coliform bacteria and Clostridium perfringens type For more information in cases of overdose or unintentional ingestion, A associated with induced colitis. Healthy horses do not appear to contact the American Society for the Prevention of Cruelty to develop watery stools within this dosage range. At the highest dose, a Animals (ASPCA) National Animal Poison Control Center (888- slight decrease in coliform count is noted in healthy horses.{R-40} 426-4435 or 900-443-0000; a fee may be required for consultation) Having free access to feed does not significantly affect the horse’s and/or the drug manufacturer. ability to absorb sulfadiazine during administration of oral sulfadiazine Acute toxicities appear to be difficult to induce; those reported below are and trimethoprim combination. The absorption of trimethoprim is in response to a dose five times the loading dose and ten times the delayed so initial serum concentrations will be lower in a fed horse maintenance dose on the product label. than in a fasted horse; however, this effect is greatly decreased by the third day of treatment{R-27}. CLINICAL EFFECTS OF OVERDOSE The following effects have been selected on the basis of their potential FOR TREATMENT OF ADVERSE EFFECTS clinical significance (possible signs in parentheses where appropri- Recommended treatment consists of the following: ate)—not necessarily inclusive: For anaphylaxis For ormetoprim and sulfadimethoxine{R-21} • Parenteral epinephrine. Dogs (53 mg ormetoprim and 267 mg sulfadimethoxine per kg of body • Oxygen administration and respiratory support. weight dose or 160 mg ormetoprim per kg administered alone) Convulsions; hyperglycemia, mild ORMETOPRIM AND SULFADIMETHOXINE TREATMENT OF OVERDOSE ORAL DOSAGE FORMS Recommended treatment consists of the following: Note: Bracketed information in the Dosage Forms section refers to uses • Discontinuing medication. that either are not included in U.S. product labeling or are for products • Administering intravenous diazepam or other acute antiseizure not commercially available in the U.S. medication as needed. • Providing fluid replacement therapy as required. ORMETOPRIM AND SULFADIMETHOXINE FOR MEDICATED FEED CLIENT CONSULTATION Usual dose: Dosage and length of treatment recommendations should be followed. Coccidiosis (prophylaxis)1— High doses or long-term use can increase the risk of side effects. Chickens and partridges, chukar: Oral, 68.1 grams of ormetoprim and Animals should have a good water supply and should be monitored to 113.5 grams of sulfadimethoxine per ton of feed, fed as the only insure their adequate water consumption during treatment. ration{R-6; 125}.

Turkeys: Oral, 34 grams of ormetoprim and 56.8 grams of Withdrawal time sulfadimethoxine per ton of feed, fed as the only ration{R-6}. Colibacillosis (prophylaxis)1—Chickens: Oral, 68.1 grams of ormeto- Species Meat (days) prim and 113.5 grams of sulfadimethoxine per ton of feed, fed as the Catfish 3 {R-6} only ration . Salmon, trout 42 Colibacillosis (treatment)1—Ducks: Oral, 272.4 grams of ormetoprim and 454 grams of sulfadimethoxine per ton of feed, fed as the only Canada{R-16}— ration for seven days{R-6}. Enteric septicemia1—Catfish: Oral, 8 mg of ormetoprim and 42 mg of Withdrawal time sulfadimethoxine per kg of body weight a day, administered in the Species Meat (days) feed and fed as the only ration for five days{R-7; 16}. Fowl cholera (prophylaxis)1— Salmon, trout 42 Chickens: Oral, 68.1 grams of ormetoprim and 113.5 grams of sulfadimethoxine per ton of feed, fed as the only ration{R-6}. Note: Product labeling with the above withdrawal time states that it Turkeys: Oral, 34 grams of ormetoprim and 56.8 grams of applies to a dose of 15 mg per kg of body weight a day when the water sulfadimethoxine per ton of feed, fed as the only ration{R-6}. temperature is ‡ 10 C. Fowl cholera (treatment)1—Ducks: Routine—Oral, 136.2 grams of ormetoprim and 227 grams of Packaging and storage: Store below 40 C (104 F), preferably be- sulfadimethoxine per ton of feed, fed as the only ration for seven tween 15 and 30 C (59 and 86 F), unless otherwise specified by the days{R-6}. manufacturer. Severe—Oral, 272.4 grams of ormetoprim and 454 grams of sulfadimethoxine per ton of feed, fed as the only ration for seven Additional information: Canadian labeling states that the product days{R-6}. should not be used when the water temperature is below 10 C{R-16}. Furunculosis—Salmon and trout: Oral, 8 mg of ormetoprim and 42 mg of sulfadimethoxine per kg of body weight a day, administered in the USP requirements: Not in USP. feed, and fed as the only ration for five days{R-7; 16}. Infectious coryza (prophylaxis)1—Chickens: Oral, 68.1 grams of ormetoprim and 113.5 grams of sulfadimethoxine per ton of feed, ORMETOPRIM AND SULFADIMETHOXINE TABLETS {R-6} Usual dose: fed as the only ration . 1 1 Skin and soft tissue infections ;or New duck disease —Ducks: Oral, 272.4 grams of ormetoprim and 454 Urinary tract infections1—Dogs: Oral, 9.2 mg of ormetoprim and 45.8 grams of sulfadimethoxine per ton of feed, fed as the only ration for {R-6} mg of sulfadimethoxine per kg of body weight as an initial dose, seven days . followed by 4.6 mg of ormetoprim and 22.9 mg of trimethoprim per kg of body weight every twenty-four hours{R-5}. Administration for more than twenty-one days is not recommended{R-5}. Strength(s) usually available{R-150}: Note: Dogs—Although the efficacy has not been established, a dose U.S.— of 11 mg of ormetoprim and 55 mg of sulfadimethoxine a day Veterinary-labeled product(s): has been used in the treatment of [enteric coccidiosis]1 in dogs. This 50 grams of ormetoprim and 250 grams of sulfadimethoxine per kg therapy may reduce shedding of oocysts and relieve symp- of premix (OTC) [Romet 30 (catfish and salmonids)]. toms{R-136}. 150 grams of ormetoprim and 250 grams of sulfadimethoxine per kg of premix (OTC) [Rofenaid 40 (chickens, ducks, partridges, and Strength(s) usually available{R-150}: turkeys)]. U.S.{R-5}— Canada— Veterinary-labeled product(s): Veterinary-labeled product(s): 20 mg of ormetoprim and 100 mg of sulfadimethoxine (Rx) [Primor 120]. 50 grams of ormetoprim and 250 grams of sulfadimethoxine per kg 40 mg of ormetoprim and 200 mg of sulfadimethoxine (Rx) [Primor of premix (Rx) [Romet-30 (salmonids)]. 240]. 100 mg of ormetoprim and 500 mg of sulfadimethoxine (Rx) [Primor Withdrawal times: 600]. {R-6; 7} U.S. — 200 mg of ormetoprim and 1000 mg of sulfadimethoxine (Rx) [Primor 1200]. Withdrawal time Canada— Species Meat (days) Veterinary-labeled product(s): Not commercially available. Chickens, ducks, partridges, turkeys 5

Packaging and storage: Store below 40 C (104 F), preferably be- Note: Product labeling with the above withdrawal times states that this tween 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by the combination is not for use in birds producing eggs for food or for manufacturer. chickens over 16 weeks of age{R-6}.

USP requirements: Not in USP. Note: Horses—Based on pharmacokinetic studies, disease models of infectious arthritis, and the relatively short half-life of trimethoprim 1Not included in Canadian product labeling or product not commercially in the horse, an [oral dose of 25 mg of sulfadiazine and 5 mg of available in Canada trimethoprim per kg of body weight every twelve hours has been used to treat susceptible infections in horses{R-25}, including equine infectious arthritis]1, in which case the dose is administered for three PYRIMETHAMINE AND SULFAQUINOXALINE to six weeks{R-41; 42}. ORAL DOSAGE FORMS The administration of oral sulfadiazine and trimethoprim combi- Note: Bracketed information in the Dosage Forms section refers to uses nation while a horse has free access to feed does not signiﬁcantly {R-25; 27; 28} that either are not included in U.S. product labeling or are for products affect the absorption of the sulfadiazine ; however, the not commercially available in the U.S. absorption of trimethoprim is delayed so that initial serum concentrations will be lower in a fed horse than in a fasted horse. PYRIMETHAMINE AND SULFAQUINOXALINE ORAL This effect is greatly decreased by the third day of treatment{R-27}. SOLUTION For horses being treated for less severe, susceptible infections, Usual dose: [Coccidiosis (prophylaxis and treatment)]—Chickens and allowing free access to food is recommended to decrease the risk of {R-25} turkeys: Oral, 14.7 mg of pyrimethamine and 48.8 mg of sulfaqui- diarrhea . noxaline per liter of water, administered as the only source of drinking Strength(s) usually available{R-150}: water for two days. Treatment is stopped for three days and then U.S.{R-3}— repeated as necessary to control infection. For existing infection, Veterinary-labeled product(s): treatment should be repeated until symptoms of disease have disap- 333 mg of sulfadiazine and 67 mg of trimethoprim per gram of paste peared{R-17}. (Rx) [Tribrissen 400 Oral Paste]. {R-18} Strength(s) usually available{R-150}: Canada — U.S.— Veterinary-labeled product(s): Veterinary-labeled product(s): Not commercially available. Not commercially available. Withdrawal times: {R-17} Canada — U.S.—Sulfadiazine and trimethoprim oral paste is not labeled for use in Veterinary-labeled product(s): food-producing animals, including horses intended for food produc- 9.8 grams of pyrimethamine and 32.5 grams of sulfaquinoxaline per tion. See Sulfadiazine and Trimethoprim Tablets for more information. liter of solution (OTC) [Quinnoxine-S; Sulfaquinoxaline-S]. Packaging and storage: Store between 15 and 30 C (59 and 86 F), Withdrawal times: unless otherwise speciﬁed by the manufacturer{R-3}. Canada{R-17}—

Withdrawal time USP requirements: Not in USP.

Species Meat (days) SULFADIAZINE AND TRIMETHOPRIM ORAL Chickens, turkeys 4 POWDER Usual dose: Packaging and storage: Store below 23 C (73 F), unless otherwise Respiratory tract infections1; speciﬁed by the manufacturer. Protect from freezing{R-17}. Skin and soft tissue infections1; 1 USP requirements: Not in USP. Strangles ;or Urogenital infections1—Horses: Oral, 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body weight every twenty-four hours{R-4}. SULFADIAZINE AND TRIMETHOPRIM Note: Based on pharmacokinetic studies, an [oral dose of 25 mg of ORAL DOSAGE FORMS sulfadiazine and 5 mg of trimethoprim per kg of body weight every 1 {R-25} Note: Bracketed information in the Dosage Forms section refers to uses twelve hours] has also been used in horses . that either are not included in U.S. product labeling or are for products The administration of oral sulfadiazine and trimethoprim combi- not commercially available in the U.S. nation while a horse has free access to feed does not signiﬁcantly affect the absorption of the sulfadiazine{R-25; 27; 28}; however, the SULFADIAZINE AND TRIMETHOPRIM ORAL PASTE absorption of trimethoprim is delayed so initial serum concentra- Usual dose: tions will be lower in a fed horse than in a fasted horse. This Respiratory tract infections; effect is greatly decreased by the third day of treatment{R-27}. For Skin and soft tissue infections; horses being treated for less severe, susceptible infections, allowing Strangles; free access to food is recommended to decrease the risk of 1 Urogenital infections ;or diarrhea{R-25}. [Perioperative infections]—Horses: Oral, 25 mg of sulfadiazine and [Vibrio anguillarum infection]—Salmon: Oral, 25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body weight every twenty-four 5 mg of trimethoprim per kg of body weight a day, administered in {R-3; 18} hours . the feed, and fed as the only ration for seven to ten days{R-22}.

Strength(s) usually available{R-150}: SULFADIAZINE AND TRIMETHOPRIM TABLETS U.S.— Usual dose: Veterinary-labeled product(s): Gastrointestinal tract infections1; 333 mg of sulfadiazine and 67 mg of trimethoprim per gram of Respiratory tract infections1;or powder (Rx) [Tucoprim Powder; Uniprim Powder (horses)]. Skin and soft tissue infections1{R-46}—Dogs and [cats]: Oral, 12.5 mg of Canada— sulfadiazine and 2.5 mg of trimethoprim per kg of body weight every Veterinary-labeled product(s): twelve hours{R-2; 11; 19} or, less commonly, 25 mg of sulfadiazine 333 mg of sulfadiazine and 67 mg of trimethoprim per gram of and 5 mg of trimethoprim per kg of body weight every twenty-four powder (Rx) [Tribrissen 40% Powder (salmon)]. hours. Note: Only intact tablets should be administered to cats, to avoid Withdrawal times: excessive salivation caused by contact of the medication with oral U.S.—Sulfadiazine and trimethoprim oral powder is not labeled for use in mucosa{R-11}. food-producing animals, including horses intended for food produc- Urinary tract infections1—Dogs: Oral, 12.5 mg of sulfadiazine and tion. See Sulfadiazine and Trimethoprim Tablets for more information. 2.5 mg of trimethoprim per kg of body weight every twelve hours or, Canada{R-22}— less commonly, 25 mg of sulfadiazine and 5 mg of trimethoprim per {R-11} Withdrawal time kg of body weight every twenty-four hours . Note: For [bacterial prostatitis in dogs, 25 mg of sulfadiazine and 5 mg Species Meat (days) of trimethoprim per kg of body weight every twelve hours for two 1 {R-23; 47; 48} Salmon 80 to four weeks] is recommended , based on pharmacokinetic data. Note: The half-lives of sulfadiazine and trimethoprim in the deepest layer Product labeling states that administration for more than fourteen {R-65} of marine sediments can be ninety days or longer . days is not recommended{R-2; 11; 19}. Note: Although the efficacy has not been established, doses up to [37.5 to Packaging and storage: Store below 40 C (104 F), preferably 50 mg of sulfadiazine and 7.5 to 10 mg of trimethoprim per kg of body between 15 and 30 C (59 and 86 F), in a tight container, unless weight every twelve hours for three to six months have been used in the {R-22} otherwise specified by the manufacturer. Protect from light . treatment of nocardiosis]1 in cats and dogs{R-23; 130; 132}. For organisms susceptible to both sulfadiazine and trimethoprim, USP requirements: Not in USP. once-daily dosing is likely to be efficacious for cats and dogs. However, for organisms that may be resistant to one of the SULFADIAZINE AND TRIMETHOPRIM ORAL antimicrobials, twice-daily dosing as above is recommended. For SUSPENSION infections for which susceptibility is unknown or when life-threat- Usual dose: ening infections are present, 25 mg of sulfadiazine and 5 mg of [Colibacillosis]; or trimethoprim per kg of body weight every twelve hours has been [Enteritis, bacterial]—Piglets: Oral, 22.8 mg of sulfadiazine and 4.6 mg of used, based on current information about the pharmacokinetics of {R-23} trimethoprim per kg of body weight every twenty-four hours{R-10}. this medication in the dog . Note: [Calves, nonruminating]1—Until recently, Canadian sulfadiazine Strength(s) usually available{R-150}: and trimethoprim boluses were labeled for use in the treatment of {R-12} U.S.— bacterial pneumonia in calves . Although there are no sulfadia- Veterinary-labeled product(s): zine and trimethoprim products labeled for use in calves in the United Not commercially available. States or Canada at this time, oral sulfadiazine and trimethoprim Canada— tablets might be used in the treatment of susceptible infections, such as Veterinary-labeled product(s): pneumonia, in calves. 45.5 mg of sulfadiazine and 9.1 mg of trimethoprim per mL (Rx) Tablets are not recommended for use in ruminating animals because of {R-81} [Tribrissen Piglet Suspension]. poor bioavailability and subsequent lack of efficacy as calves progress to the ruminant state{R-12}. In ruminating calves, therapeutic Withdrawal times: serum concentrations of trimethoprim have not been reached with Canada{R-10}— oral administration{R-81}. Increased rate of elimination and decreased absorption of the medication as calves mature lead to a decrease Withdrawal time in resulting serum antibiotic concentration that is measurable at Species Meat (days) 6 weeks of age in milk-fed calves and becomes so pronounced with onset of rumination that this medication cannot be administered Piglets 5 effectively{R-79; 81; 143}. According to some researchers{R-24; 81; 143}, many pathogens Packaging and storage: Store below 40 C (104 F), preferably be- important in calfhood diseases, including Escherichia coli, Salmonella tween 15 and 30 C (59 and 86 F), unless otherwise specified by the species, and Haemophilus species, have minimum inhibitory concen- manufacturer. Protect from freezing. trations (MICs) that range from 3 to 10 mcg per mL (mcg/mL) for sulfonamides and 0.1 to 0.5 mcg/mL for trimethoprim. Researchers USP requirements: Not in USP. have suggested that, in calves less than 1 week of age, oral

administration of 12.5 mg of sulfadiazine and 2.5 mg of trimethoprim PARENTERAL DOSAGE FORMS per kg of body weight every 24 hours would be appropriate in the Note: Bracketed information in the Dosage Forms section refers to uses {R-81} treatment of infections caused by these organisms . They note that either are not included in U.S. product labeling or are for products that in animals older than 1 week of age, an oral dose of 25 mg of not commercially available in the U.S. sulfadiazine and 5 mg of trimethoprim per kg of body weight, administered every 12 hours, has been necessary to maintain SULFADIAZINE AND TRIMETHOPRIM INJECTION therapeutic concentrations{R-81}. However, the National Committee Usual dose: for Clinical Laboratory Standards (NCCLS) lists the breakpoints as Respiratory tract infections; or £ 38/2 mcg/mL for sulfonamide and trimethoprim, respectively{R-141}. Skin and soft tissue infections— It is possible for an organism to be classified as sensitive yet have MICs [Cats] and [dogs]: Subcutaneous, 12.5 mg of sulfadiazine and 2.5 mg above the plasma concentration achieved by the above dosages{R-145}. of trimethoprim per kg of body weight every twelve hours or, less Based on pharmacokinetic calculations, an oral dosage of 37.5 mg of commonly, 25 mg of sulfadiazine and 5 mg of trimethoprim per kg sulfadiazine and 7.5 mg of trimethoprim per kg of body weight every 12 of body weight every twenty-four hours{R-8; 95}. hours in calves older than 1 week of age but younger than 6 weeks of Horses: Intramuscular or intravenous, 20 mg of sulfadazine and 4 mg age may be needed to consistently maintain concentrations greater than of trimethoprim per kg of body weight every twenty-four hours{R-9}. or equal to the NCCLS breakpoints, but the safety and efficacy of such a Strangles; or dose has not been tested in calves{R-144; 145}. Urogenital tract infections1—Horses: Intramuscular or intravenous, Strength(s) usually available{R-150}: 20 mg of sulfadiazine and 4 mg of trimethoprim per kg of body {R-9} U.S.— weight every twenty-four hours . Veterinary-labeled product(s): [Gastrointestional tract infections]—Cats and dogs: Subcutaneous, 25 mg of sulfadiazine and 5 mg of trimethoprim (Rx) [Tribrissen 30]. 12.5 mg of sulfadiazine and 2.5 mg of trimethoprim per kg of body 100 mg of sulfadiazine and 20 mg of trimethoprim (Rx) [Tribrissen weight every twelve hours or, less commonly, 25 mg of sulfadiazine 120]. and 5 mg of trimethoprim per kg of body weight every twenty-four {R-8} 400 mg of sulfadiazine and 80 mg of trimethoprim (Rx) [Tribrissen 480]. hours . 800 mg of sulfadiazine and 160 mg of trimethoprim (Rx) [Tribrissen Note: Although Canadian labeling recommends intramuscular or 960]. intravenous administration of sulfadiazine and trimethoprim combi- Canada— nation and there are few reports in the literature of adverse reactions Veterinary-labeled product(s): to intravenous administration of this combination, some sources Not commercially available. recommend caution when administering these medications intravenously to horses{R-25}. Withdrawal times: Product labeling states that administration for more than fourteen U.S. and Canada—Sulfadiazine and trimethoprim tablets are not labeled days in cats and dogs and more than seven days in horses is not for use in food-producing animals. recommended{R-8; 9}. There is no established withdrawal time for calves in the U.S. and, in Canada, where a sulfadiazine and trimethoprim bolus was once {R-150} available, there is no longer any product labeled for use in calves. If a Strength(s) usually available : sulfadiazine and trimethoprim combination product available in the U.S.— U.S. is administered to 1-week-old calves at a dose of 12.5 mg of Veterinary-labeled product(s): sulfadiazine and 2.5 mg of trimethoprim every twelve hours, there is 400 mg of sulfadiazine and 80 mg of trimethoprim per mL (Rx) some evidence to suggest that a meat withdrawal time of 10 days, the [Tribrissen 48% (horses)]. discontinued Canadian product label withdrawal time, would be Canada— sufficient to avoid residues that would violate U.S. standards{R-12; 79; Veterinary-labeled product(s): 80; 81; 140; 142}. Estimates for a withdrawal time for dosages larger 200 mg of sulfadiazine and 40 mg of trimethoprim per mL (Rx) than 12.5 mg of sulfadiazine and 2.5 mg of trimethoprim every twelve [Tribrissen 24% (cats and dogs)]. hours are not available. It should be considered that substitution of one 400 mg of sulfadiazine and 80 mg of trimethoprim per mL (Rx) oral dosage form for another may result in differences in pharmaco- [Tribrissen 48% (horses)]. {R-140} {R- kinetic results. Available residue studies and pharmacokinetic Withdrawal times: 81} studies for oral products were performed in calves using boluses U.S. and Canada—Products are not labeled for use in horses to be used and tablets, respectively. for food production{R-9}.

Packaging and storage: Store below 40 C (104 F), preferably be- Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by the tween 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by the manufacturer. manufacturer.

USP requirements: Not in USP. USP requirements: Not in USP.

1Not included in Canadian product labeling or product not commercially 1Not included in Canadian product labeling or product not commercially available in Canada. available in Canada.

SULFADOXINE AND TRIMETHOPRIM SULFAMETHOXAZOLE AND TRIMETHOPRIM ORAL SUSPENSION USP PARENTERAL DOSAGE FORMS Usual dose: Note: Bracketed information in the Dosage Forms section refers to uses Note: [Dogs]1—Although the safety and efficacy have not been that either are not included in U.S. product labeling or are for products established, an oral dose of 25 mg of sulfamethoxazole and 5 mg not commercially available in the U.S. of trimethoprim per kg of body weight every twelve hours for two to SULFADOXINE AND TRIMETHOPRIM INJECTION four weeks has been used in the treatment of bacterial prostatitis in {R-47; 48} Usual dose: dogs, based on pharmacokinetic data . 1 [Bacterial enteritis]; [Horses] —Although the safety and efficacy have not been estab- [Bacterial pneumonia]; or lished, an oral dose of 25 mg of sulfamethoxazole and 5 mg of [Colibacillosis]—Cattle and pigs: Intramuscular or slow intravenous, trimethoprim per kg of body weight every twelve hours has been 13.3 mg of sulfadoxime and 2.7 mg of trimethoprim per kg of body used in the treatment of bacterial infections, based on pharmacoki- {R-31} weight, every twenty-four hours for five days{R-13–15}. netic studies . Note: [Cattle]—Based on pharmacokinetic studies, a dose of 13.3 mg Strength(s) usually available: of sulfadoxine and 2.7 mg of trimethoprim per kg of body weight U.S.— every twelve hours1 may be necessary to treat infections in cattle Veterinary-labeled product(s): caused by organisms that are less than very sensitive to sulfadox- Not commercially available. ine and trimethoprim{R-85}. Human-labeled product(s):{R-119} [Bacterial arthritis]; 40 mg of sulfamethoxazole and 8 mg of trimethoprim per mL (Rx) [Mastitis]; or [Bactrim Pediatric; Cotrim Pediatric; Septra Grape Suspension; Septra [Metritis]—Pigs: Intramuscular or slow intravenous, 13.3 mg of Suspension; Sulfatrim Pediatric; Sulfatrim Suspension; generic]. sulfadoxine and 2.7 mg of trimethoprim per kg of body weight every Canada— twenty-four hours for five days{R-13–15}. Veterinary-labeled product(s): [Pododermatitis]; or Not commercially available. [Septicemia]—Cattle: Intramuscular or slow intravenous, 13.3 mg of Human-labeled product(s): sulfadoxine and 2.7 mg of trimethoprim per kg of body weight, every 40 mg of sulfamethoxazole and 8 mg of trimethoprim per mL (Rx) twenty-four hours for five days{R-13–15}. [Apo-Sulfatrim; Bactrim; Novo-Trimel; Nu-Cotrimox; Septra]. Strength(s) usually available{R-150}: U.S.— Packaging and storage: Store below 40 C (104 F), preferably be- Veterinary-labeled product(s): tween 15 and 30 C (59 and 86 F), unless otherwise specified by the Not commercially available. manufacturer. Store in a tight, light-resistant container. Protect from Canada— freezing. Veterinary-labeled product(s): 200 mg of sulfadoxine and 40 mg of trimethoprim per mL (Rx) USP requirements: Preserve in tight, light-resistant containers. Con- [Bimotrim; Borgal; Potensulf; Trimidox; Trivetrin]. tains the labeled amounts, within ±10%. Meets the requirements for Identification, pH (5.0–6.5), Chromatographic purity, and Alcohol Withdrawal times: content (not more than 0.5%){R-117}. Canada{R-13–15}—

Withdrawal time SULFAMETHOXAZOLE AND TRIMETHOPRIM TABLETS

Species Meat (days) Milk (hours) USP Usual dose: See Sulfamethoxazole and Trimethoprim Oral Suspension USP. Cattle 10 96 Pigs 10 Strength(s) usually available: U.S.— Packaging and storage: Store below 40 C (104 F), preferably be- Veterinary-labeled product(s): tween 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by the Not commercially available. manufacturer. Protect from freezing. Human-labeled product(s):{R-119} USP requirements: Not in USP. 400 mg of sulfamethoxazole and 80 mg of trimethoprim (Rx) [Bactrim; Cotrim; Septra; Sulfatrim; Sulfatrim S/S]. 1Not included in Canadian product labeling or product not commercially 800 mg of sulfamethoxazole and 160 mg of trimethoprim (Rx) available in Canada. [Bactrim DS; Cofatrim Forte; Cotrim DS; Septra DS; Sulfatrim DS]. Canada— SULFAMETHOXAZOLE AND TRIMETHOPRIM Veterinary-labeled product(s): ORAL DOSAGE FORMS Not commercially available. Note: Bracketed information in the Dosage Forms section refers to uses Human-labeled product(s): that either are not included in U.S. product labeling or are for products 100 mg of sulfamethoxazole and 20 mg of trimethoprim (Rx) [Apo- not commercially available in the U.S. Sulfatrim].

400 mg of sulfamethoxazole and 80 mg of trimethoprim (Rx) [Apo- Preparation of dosage form: The contents of each vial (5 mL) must be Sulfatrim; Bactrim; Novo-Trimel; Nu-Cotrimox; Septra]. diluted to 75 to 125 mL with 5% dextrose injection prior to admin- 800 mg of sulfamethoxazole and 160 mg of trimethoprim (Rx) [Apo- istration by intravenous infusion. The resulting solution should be Sulfatrim DS; Bactrim DS; Novo-Trimel D.S.; Nu-Cotrimox DS; administered by intravenous infusion over a sixty- to ninety-minute Roubac; Septra DS]. period.

Packaging and storage: Store below 40 C (104 F), preferably be- Stability: After initial dilution with 75 or 125 mL of 5% dextrose tween 15 and 30 C (59 and 86 F), unless otherwise specified by the injection, infusion should be administered within two or six hours, manufacturer. Store in a well-closed, light-resistant container. respectively. The solution should not be used if it is cloudy or contains a precipitate. The solution should not be mixed with other medications USP requirements: Preserve in well-closed, light-resistant containers. or solutions. Contain the labeled amounts, within ±7%. Meet the requirements for Identification, Dissolution (70% of each active ingredient in 60 min- USP requirements: Preserve in single-dose, light-resistant containers, utes in 0.1 N hydrochloride acid in Apparatus 2 at 75 rpm), and preferably of Type I glass. May be packaged in 50-mL multiple-dose Uniformity of dosage units{R-117}. containers. A sterile solution of Sulfamethoxazole and Trimethoprim in Water for Injection which, when diluted with Dextrose Injection, is suitable for intravenous infusion. Label it to indicate that it is to be 1Not included in Canadian product labeling or product not commercially diluted with 5% Dextrose Injection prior to administration. Contains available in Canada. the labeled amounts, within ±10%. Meets the requirements for Iden- tification, Pyrogen, pH (9.5–10.5), Particulate matter, and Related PARENTERAL DOSAGE FORMS compounds, and for Injections.{R-117} Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. 1Not included in Canadian product labeling or product not commercially available in Canada. SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION USP Developed: 6/10/98 Usual dose: Revised: 6/30/02 Note: [Foals]1 and [horses]1—Although the efficacy and safety have not Interim revision: 11/10/99; 4/10/03 been established, a slow intravenous dose of 12.5 mg of sulfamethoxasole and 2.5 mg of trimethoprim per kg of body weight every twelve hours has been used in the treatment of susceptible bacterial and protozoal infections in foals and horses, based on pharmacokinetic REFERENCES 1. USP dictionary of USAN and international drug names, 2002 ed. Rockville, data{R-31; 32}. However, to reach effective concentrations in the MD: The United States Pharmacopeial Convention, Inc. 2002. cerebrospinal fluid (CSF) for bacterial and protozoal infections, higher 2. Sulfadiazine and trimethoprim product information (Tribrissen tablets, doses are required; distribution studies show that an intravenous Schering-Plough—US). Downloaded from www.spah.com on 2/21/03. dose of 36 mg of sulfamethoxazole and 7.5 mg of trimethoprim per 3. Sulfadiazine and trimethoprim product information (Tribrissen 400 Oral Paste, Schering-Plough—US). Downloaded from www.spah.com on 2/21/03. kg of body weight will produce CSF concentrations sufficient to treat 4. Sulfadiazine and trimethoprim package insert (Tucoprim, Pharmacia—US), {R-31; 33} susceptible bacterial and protozoal infections . Rev 4/01. Downloaded from www.pharmaciaah.com on 2/21/03. Intravenous doses should be administered slowly. 5. Ormetoprim and sulfadimethoxine package insert (Primor, Pfizer—US), Rev 3/94. Downloaded from www.pfizer.com on 2/21/03. Strength(s) usually available: 6. Ormetoprim and sulfadimethoxine package insert (Rofenaid 40 Premix, Roche—US), Rev 92, Rec 10/30/95. U.S.— 7. Ormetoprim and sulfadimethoxine package insert (Romet B, Roche—US), Rev Veterinary-labeled product(s): 87, Rec 10/30/95. Not commercially available. 8. Sulfadiazine and trimethoprim product information (Tribrissen 24% Injection, Schering-Plough—Canada). Downloaded from Schering-Plough Animal Human-labeled product(s):{R-119} Health Product Label Retrieval Service on 2/21/03. 80 mg of sulfamethoxazole and 16 mg of trimethoprim per mL (Rx) 9. Sulfadiazine and trimethoprim product information (Tribrissen 48% Injection, [Bactrim I.V.; Septra I.V.]. Schering-Plough—Canada). Downloaded from Schering-Plough Animal Canada— Health Product Label Retrieval Service on 2/21/03. 10. Sulfadiazine and trimethoprim package insert (Tribrissen Piglet Suspension, Veterinary-labeled product(s): Mallinckrodt—Canada), Rec 6/1/95. Not commercially available. 11. Sulfadiazine and trimethoprim package insert (Tribrissen Tablets, Mallinck- Human-labeled product(s): rodt—Canada), Rec 6/1/95 [discontinued product]. 12. Sulfadiazine and trimethoprim package insert (Tribrissen Boluses, Mallinck- 80 mg of sulfamethoxazole and 16 mg of trimethoprim per mL (Rx) rodt—Canada), Rec 6/1/95 [discontinued product]. [Septra]. 13. Sulfadoxine and trimethoprim product information (Trivetrin Injection, Schering-Plough—Canada). Downloaded from Schering-Plough Animal Packaging and storage: Store below 40 C (104 F), preferably be- Health Product Label Retrieval Service on 2/21/03. tween 15 and 30 C (59 and 86 F), unless otherwise specified by the 14. Sulfadoxine and trimethoprim package insert (Borgal Injection, Hoes- chst—Canada), Rec 7/5/95. manufacturer. Store in a light-resistant container. Should not be 15. Sulfadoxine and trimethoprim package insert (Trimidox, Sanofi—Canada), refrigerated. Rec 5/19/95.

16. Romet-30, Hoffman-LaRoche. In: Bennett K, editor. Compendium of veter- experimentally induced infectious arthritis. Am J Vet Res 1988 Oct; 49(10): inary products. 4th ed. Hensall, Ontario: North American Compendiums, Ltd.; 1681–7. 1995. p. 572. 43. Van Duijkeren E, Vulto AG, Sloet Van Oldruitenborgh-Oosterbaan MM, et al. 17. Pyrimethamine and sulfaquinoxaline product label (Quinnoxine-S, A.P.A./ A comparative study of the pharmacokinetics of intravenous and oral Sanofi—Canada), Rec 10/27/95. trimethoprim/sulfadiazine formulations in the horse. J Vet Pharmacol Ther 18. Sulfadiazine and trimethoprim package insert (Tribrissen Oral Paste, Mal- 1994; 17: 440–6. linckrodt—Canada), Rec 6/1/95. 44. Indiveri MC, Hirsh DC. Susceptibility of obligate anaerobes to trimethoprim- 19. Sulfadiazine and trimethoprim package insert (Ditrim, Syntex—US), Rev 5/ sulfamethoxazole. J Am Vet Med Assoc 1986 Jan; 188(1): 46–8. 93, Rec 3/1/96. 45. Sigel CW, Macklin AW, Grace ME, et al. Trimethoprim and sulfadiazine 20. Van Miert ASGPAM. The sulfonamide-diaminopyridine story. J Vet Pharma- concentrations in aqueous and vitreous humors of the dog. Vet Med Small col Ther 1994; 17: 309–16. Anim Clin 1981 Jul; 76(7): 991–3. 21. Freedom of information summary. Primor tablets. New Animal Drug 46. Pohlenz-Zertuche HO, Brown MP, Gronwall R, et al. Serum and skin Application (NADA) 100–929. Hoffman-LaRoche Inc. concentrations after multiple-dose oral administration of trimethoprim- 22. Sulfadiazine and trimethoprim product information (Tribrissen 40% Powder, sulfadiazine in dogs. Am J Vet Res 1992 Jul; 53(7): 1273–6. Schering-Plough—Canada). Downloaded from Schering-Plough Animal 47. Rogers KS, Lees GE, Simpson RB. Effects of single-dose and three-day Health Product Label Retrieval Service on 2/21/03. trimethoprim-sulfadiazine and amikacin treatment of induced Escherichia coli 23. Wilcke JR. Therapeutic application of sulfadiazine/trimethoprim in dogs and urinary tract infections in dogs. Am J Vet Res 1988; 49(3): 345–9. cats: a review. Companion Anim Pract 1988 Sep: 3–8. 48. Robb CA, Carroll PT, Tippett LO, et al. The diffusion of selected sulfonamides, 24. Bushby SRM. Sulfonamide and trimethoprim combinations. J Am Vet Med trimethoprim, and diaveridine into prostatic fluid of dogs. Invest Urol 1971; Assoc 1980 May; 176(10): 1049–53. 8(6): 679–85. 25. Van Duijkeren E, Vulto AG, Van Miert ASGPAM. Trimethoprim/sulfonamide 49. Sigel CW, Ling GV, Bushbuy SRM, et al. Pharmacokinetics of trimethoprim combinations in the horse: a review. J Vet Pharmacol Ther 1994; 17: 64–73. and sulfadiazine in the dog: urine concentrations after oral administration. 26. Alexander F, Collett RA. Trimethoprim in the horse. Equine Vet J 1975 Oct; Am J Vet Res 1981 Jun; 42(6): 996–1001. 7(4): 203–6. 50. Fox LE, Ford S, Alleman AR, et al. Aplastic anemia associated with prolonged 27. Sigel CW, Byars TD, Divers TJ, et al. Serum concentrations of trimethoprim high-dose trimethoprim-sulfadiazine administration in two dogs. Vet Clin and sulfadiazine following oral paste administration to the horse. Am J Vet Path 1993 Sep; 22(3): 89–92. Res 1981 Nov; 42 (11): 2002–5. 51. Weiss DJ, Klausner JS. Drug-associated aplastic anemia in dogs: eight cases 28. Bogan JA, Galbraith A, Baxter NM, et al. Effect of feeding on the fate of orally (1984–1988). J Am Vet Med Assoc 1990 Feb; 196(3): 472–5. administered phenylbutazone, trimethoprim and sulphadiazine in the horse. 52. Rowland PH, Center SA, Dougherty SA. Presumptive trimethoprim-sulfadi- Vet Rec 1984; 115: 599–600. azine-related hepatotoxicosis in a dog. J Am Vet Med Assoc 1992 Feb; 200(3): 29. Brown MP, Kelly RH, Stover SM, et al. Trimethoprim-sulfadiazine in the 348–50. horse: serum, synovial, peritoneal, and urine concentrations after single-dose 53. Cribb AE, Spielberg SP. An in vitro investigation of predisposition to intravenous administration. Am J Vet Res 1983 Apr; 44(4): 540–3. sulphonamide idiosyncratic toxicity in dogs. Vet Res Commun 1990; 14: 30. Rasmussen F, Gelsa H, Nielsen P. Pharmacokinetics of sulphadoxine and 241–52. trimethoprim in horses. Half-life and volume of distribution of sulphadoxine 54. Cribb AE. Idiosyncratic reactions to sulfonamides in dogs. J Am Vet Med Assoc and trimethoprim and cumulative excretion of [14C]-trimethoprim. J Vet 1989 Dec; 195(11): 1615. Pharmacol Ther 1979; 2: 245–55. 55. Collins BK, Moore CP, Hagee JH. Sulfonamide-associated keratoconjunctivitis 31. Brown MP, Gronwall R, Castro L. Pharmacokinetics and body fluid and sicca and corneal ulceration in a dysuric dog. J Am Vet Med Assoc 1986 Oct; endometrial concentrations of trimethoprim-sulfamethoxazole in mares. Am J 189(8): 924–6. Vet Res 1988 Jun; 49(6): 918–22. 56. Morgan RV, Bachrach A. Keratoconjunctivitis sicca associated with sulfon- 32. Brown MP, McCartney JH, Gronwall R, et al. Pharmacokinetics of trimeth- amide therapy in dogs. J Am Vet Med Assoc 1982; 180: 432–4. oprim-sulphamethoxazole in two-day-old foals after a single intravenous 57. Giger U, Werner LL, Millichamp NJ, et al. Sulfadiazine-induced allergy in six injection. Equine Vet J 1990; 22(1): 51–3. Doberman Pinschers. J Am Vet Med Assoc 1995 Mar; 186(5): 479–84. 33. Green SL, Mayhew IG, Brown MP, et al. Concentrations of trimethoprim 58. Werner LL, Bright JM. Drug-induced hypersensitivity disorders in two dogs and sulfamethoxazole in cerebrospinal fluid and serum in mares with and treated with trimethoprim sulfadiazine: case reports and drug challenge without a dimethyl sulfoxide pretreatment. Can J Vet Res 1990 Apr; 54(2): studies. J Am Anim Hosp Assoc 1983 Sep/Oct; 19(5): 783–90. 215–22. 59. Lees GE, Rogers KS, Troy GC. Polyarthritis associated with sulfadiazine 34. Gelsa J. The renal clearance of inulin, creatinine, trimethoprim and administration in a Labrador retriever dog. Southwest Vet 1986; 37(1): sulphadoxine in horses. J Vet Pharmacol Ther 1979; 2: 257–64. 14–7. 35. Brown MP, Gronwall RR, Houston AE. Pharmacokinetics and body fluid and 60. Medleau L, Shanley KJ, Rakich PM, et al. Trimethoprim-sulfonamide- endometrial concentrations of ormetoprim-sulfadimethoxine in mares. Can J associated drug eruptions in dogs. J Am Anim Hosp Assoc 1990 May/Jun; Vet Res 1989; 53: 12–6. 26(3): 305–11. 36. Brown MP, Gronwall RR, Cook LK, et al. Serum concentrations of 61. Hall IA, Campbell KL, Chambers MD, et al. Effect of trimethoprim/sulfameth- ormetoprim/sulphadimethoxine in 1–3-day-old foals after a single dose of oxazole on thyroid function in dogs with pyoderma. J Am Vet Med Assoc oral paste combination. Equine Vet J 1993; 25: 73–4. 1993 Jun; 202(12): 1959–62. 37. Boyd EH, Allen WE. Absorption of two trimethoprim/sulphonamide combi- 62. Panciera DL, Post K. Effect of oral administration of sulfadiazine and nations from the uterus of pony mares. J Vet Pharmacol Ther 1989 Dec; trimethoprim in combination on thyroid function in dogs. Can J Vet Res 12(4): 438–43. 1992; 56: 349–52. 38. Carli S, Sonzogni O, Villa R. Pharmacokinetic profile of sulphamonomethox- 63. Hormazabal V, Rogstad A. Simultaneous determination of sulphadiazine and ine-trimethoprim in horses after intravenous, intramuscular and oral trimethoprim in plasma and tissues of cultured fish for residual and administration. Res Vet Sci 1993; 54: 184–8. pharmacokinetic studies. J Chromatogr 1992 Dec; 583(2): 201–7. 39. Van Duijkeren E, Vulto AG, Sloet Van Oldruitenborgh-Oosterbaan MM, et al. 64. Kimura T, Yoshimizu M, Wada M. In vitro antibacterial activity of the Pharmacokinetics of trimethoprim/sulphachlorpyridazine in horses after oral, combination of sulphadiazine and trimethoprim on bacterial fish pathogens. nasogastric and intravenous administration. J Vet Pharmacol Ther 1995; 18: J Fish Dis 1983 Nov; 6(6): 525–32. 47–53. 65. Hektoen H, Berge JA, Hormazabal V, et al. Persistence of antibacterial agents 40. White G, Prior SD. Comparative effects of oral administration of trimetho- in marine sediments. Aquaculture 1995 Jun; 133(3–4): 175–84. prim/sulphadiazine or oxytetracycline on the faecal flora of horses. Vet Rec 66. Zheng M, Liu H, Hall SF, et al. High-performance liquid chromatographic 1982; 111: 316–8. analysis of Romet-30 in Chinook salmon (Oncorhynchus tshawytscha): 41. Bertone AL, McIlwraith CW, Jones RL, et al. Comparison of various wash-out time, tissue distribution in muscle, liver and skin, and metabolism of treatments for experimentally induced equine arthritis. Am J Vet Res 1987 sulfadimethoxine. J Chromatogr 1994; 670: 77–88. Mar; 48(3): 519–29. 67. Kleinow KM, Lech JJ. A review of the pharmacokinetics and metabolism of 42. Bertone AL, Jones RL, McIlwraith CW. Serum and synovial fluid steady- sulfadimethoxine in the rainbow trout (Salmo gairdneri). Vet Hum Toxicol state concentrations of trimethoprim and sulfadiazine in horses with 1988; 30 (Suppl. 1): 26–30.

68. Squibb KS, Michel CMF, Zelikoff JT, et al. Sulfadimethoxine pharmacokinetics 93. Lashev LD, Mihailov R. Pharmacokinetics of sulphamethoxazole and and metabolism in the channel catfish (Ictalurus punctatus). Vet Hum trimethoprim administered intravenously and orally to Japanese quails. Toxicol 1988; 30 (Suppl. 1): 31–5. J Vet Pharmacol Ther 1994; 17: 327–30. 69. Walker CC, Thune RL, Barker SA. Plasma/muscle ratios of sulfadimethoxine 94. Prescott JF, Baggott JD, editors. Antimicrobial therapy in veterinary medicine, residues in channel catfish (Ictalurus punctatus). J Vet Pharmacol Ther 1995; 2nd ed. Ames, Iowa: Iowa State University Press; 1993. p. 119–26. 18: 306–10. 95. Tribrissen 24% Injection. In: Code of Federal Regulations 522.2610 70. Kleinow KM, James MO, Lech JJ. Drug pharmacokinetics and metabolism in Trimethoprim and sulfadiazine sterile suspension. NADA 105–093. food-producing fish and crustaceans: methods and examples. In: Hutson DH, 96. Tribrissen 48% Injection. In: Code of Federal Regulations 522.2610 Hawkins DR, Paulson GD, et al, editors. Xenobiotics and food-producing Trimethoprim and sulfadiazine sterile suspension. New Animal Drug Appli- animals: metabolism and residues. Proceedings of the American Chemical cation (NADA) 105–965. Society. American Chemical Society, New York, NY, 1991; Aug 25–30; 97. Van Gogh H, Van Deurzen JM, Van Duin CTM, et al. Influence of gestation on 1992. p. 98–130. the pharmacokinetics of four sulphonamides in goats. Res Vet Sci 1990; 48: 71. Mathis GF, McDougald LR, McMurray B. Effectiveness of therapeutic 152–7. anticoccidial drugs against recently isolated coccidia. Poult Sci 1984; 63: 98. Van Gogh H. Pharmacokinetics of nine sulphonamides in goats. J Vet 1149–53. Pharmacol Ther 1980; 3: 69–81. 72. Nielsen P, Rasmussen F. Influence of age on half-life of trimethoprim and 99. Riviere J, Craigmill AL, Sundlof SF. Handbook of comparative pharmacoki- sulphadoxine in goats. Acta Pharmacol Toxicol 1976; 38: 113–9. netics and residues of veterinary antimicrobials. Boca Raton, FL: CRC Press, 73. Rasmussen F. Renal and mammary excretion of trimethoprim in goats. Vet Inc.; 1991. p. 339–407. Rec 1970 Jul; 87(1): 14–8. 100. Preusch PC, Hazelett SE, Lemasters KK. Sulfaquinoxaline inhibition of vitamin 74. Atef M, Al-Khayyat AA, Fahd K. Pharmacokinetics and tissue distribution K epoxide and quinone reductase. Arch Biochem Biophys 1989 Feb 15; of trimethoprim in sheep. Zentralbl Veterinarmed Reine A 1978 Sep; 25(7): 269(1): 18–24. 579–84. 101. Appelgate J. Clinical pharmacology of sulfonamides. Mod Vet Pract 1983: 75. Nouws JFM, Mevius D, Vree TB, et al. Pharmacokinetics, metabolism, and 667–9. renal clearance of sulfadiazine, sulfamerazine, and sulfamethazine and of 102. Baggot JD. Pharmacokinetics of sulfadimethoxine in cats. Aust J Exp Biol Med their N4-acetyl and hydroxy metabolites in calves and cows. Am J Vet Res Sci 1977; 55(6): 663–70. 1988 Jul; 49(7): 1059–65. 103. Bajwa RS, Singh J. Studies on the levels of sulphadimethoxine and 76. Piercy DWT. Distribution of trimethoprim/sulphadiazine in plasma, tissue and sulphamethoxypyridazine in blood of poultry. Indian J Anim Sci 1977 Sep; synovial fluids. Vet Rec 1978 Jun; 102(24): 523–4. 47(9): 549–53. 77. Clarke CR, Short CR, Corstvet RE, et al. Effect of pasteurella haemolytica 104. Baggot JD, Ludden TM, Powers TE. The bioavailability, disposition kinetics infection on the distribution of sulfadiazine and trimethoprim into tissue and dosage of sulphadimethoxine in dogs. Can J Comp Med 1976 Jul; 40: chambers implanted subcutaneously in cattle. Am J Vet Res 1989 Sep; 50(9): 310–7. 1551–6. 105. Witkamp RF, Yun HI, vant Klooster GAE, et al. Comparative aspects and sex 78. White G, Piercy WT, Gibbs HA. Use of a calf salmonellosis model to evaluate differentiation of plasma sulfamethazine elimination and metabolite forma- the therapeutic properties of trimethoprim and sulphadiazine and their tion in rats, rabbits, dwarf goats, and cattle. Am J Vet Res 1992 Oct; 53(10): mutual potentiation in vivo. Res Vet Sci 1981; 31: 27–31. 1830–5. 79. Shoaf SE, Schwark WS, Guard CL. Pharmacokinetics of sulfadiazine/trimeth- 106. Paulson GD. The effect of dietary nitrite and nitrate on the metabolism of oprim in neonatal male calves: effect of age and penetration into cerebrospinal sulphamethazine in the rat. Xenobiotica 1986; 16(1): 53–61. fluid. Am J Vet Res 1989 Mar; 50(3): 396–403. 107. Struble LB, Paulson GD. The metabolism and deamination of [14C]-sulpha- 80. Shoaf SE, Schwark WS, Guard CL, et al. Pharmacokinetics of trimethoprim/ methazine in a germ-free pig: the influence of nitrate and nitrite. Food Chem sulfadiazine in neonatal calves: influence of synovitis. J Vet Pharmacol Ther Toxicol 1988 May; 26: 797–801. 1986 Dec; 9(4): 446–54. 108. Nouws JFM, Vree TB, Baakman M, et al. Age and dosage dependency in the

81. Shoaf SE, Schwark WS, Guard CL. The effect of age and diet on sulfadiazine/ plasma disposition and the renal clearance of sulfamethazine and its N4-acetyl trimethoprim disposition following oral and subcutaneous administration to and hydroxy metabolites in calves and cows. Am J Vet Res 1986 Mar; 47(3): calves. J Vet Pharmacol Ther 1987 Dec; 10(4): 331–45. 642–9. 82. Davitiyananda D, Rasmussen F. Half-lives of sulphadoxine and trimethoprim 109. Nouws JFM, Firth EC, Vree TB, et al. Pharmacokinetics and renal clearance

after a single intravenous infusion in cows. Acta Vet Scand 1974; 15: 356–65. of sulfamethazine, sulfamerazine, and sulfadiazine and their N4-acetyl 83. Davitiyananda D, Rasmussen F. Mammary and renal excretion of sulpha- and hydroxy metabolites in horses. Am J Vet Res 1987 Mar; 48(3): 392– doxine and trimethoprim in cows. Acta Vet Scand 1974; 15: 340–55. 402. 84. Atef M, Al-Samarrae SA, Abdel Hamid YM. Half-life and volume of 110. Plumb DC. Veterinary drug handbook. White Bear Lake, MN: PharmaVet distribution of trimethoprim and sulphadoxine in sheep and its relation to Publishing; 1991. p. 520–9. age and weight. Zentralbl Veterinarmed A 1979; 26: 31–6. 111. Bourne DWA, Bialer M, Dittert LW, et al. Disposition of sulfadimethoxine in 85. Conlon PD, Butler DG, Burger JP, et al. Evaluation of route and frequency of cattle: inclusion of protein binding factors in a pharmacokinetic model. J administration of three antimicrobial drugs in cattle. Can Vet J 1993 Oct; 34: Pharm Sci 1981 Sep; 79(9): 1068–72. 606–10. 112. Daft BM, Bickford AA, Hammarlund MA. Experimental and ﬁeld sulfaqui- 86. Wilson WD, George LW, Baggot JD, et al. Ormetoprim-sulfadimethoxine noxaline toxicosis in leghorn chickens. Avian Dis 1989; 33: 30–4. in cattle: pharmacokinetics, bioavailability, distribution to the tears, and in 113. Brown MJ. Adverse reactions to sulfaquinoxaline in coyote pups. J Am Vet vitro activity against Moraxella bovis. Am J Vet Res 1987 Mar; 48(3): 407– Med Assoc 1982; 181(11): 1419–20. 14. 114. Roudaut B, Moretain JP. Sulphonamide residues in milk of dairy cows 87. Bateman KG, Martin SW, Shewen PE, et al. An evaluation of antimicrobial following intravenous injection. Food Addit Contam 1990; 7(4): 527–33. therapy for undifferentiated bovine respiratory disease. Can Vet J 1990 Oct; 115. Paulson GD, Feil VJ, Giddings JM, et al. Lactose conjugation of sulphonamide 31: 689–96. drugs in the lactating dairy cow. Xenobiotica 1992; 22(8): 925–39. 88. Kee Jim G, Booker CW, Guichon PT. A comparison of trimethoprim- 116. Sullivan PS, Arrington K, West R, et al. Thrombocytopenia associated with sulfadoxine and ceftiofur sodium for the treatment of respiratory disease in administration of trimethoprim/sulfadiazine in a dog. J Am Vet Med Assoc feedlot calves. Can Vet J 1992 Apr; 33: 245–50. 1992 Dec; 201(11): 1741–4. 89. Nielsen P, Rasmussen F. Half-life and renal excretion of trimethoprim in 117. The United States pharmacopeia. The national formulary. USP 26th swine. Acta Pharmacol Toxicol 1975; 36: 123–31. revision (Jan 1, 2003). NF 21st ed (Jan 1, 2003). Rockville, MD: The 90. Atef M. Trimethoprim in sheep: inﬂuence of pH and protein binding on United States Pharmacopeial Convention, Inc.; 2002. p. 1738–40, 2579, mammary and renal excretion. Zentralbl Veterinarmed Reine A 1979 Jan; 2582, 2585. 26(1): 37–43. 118. USP DI Drug information for the healthcare professional. Volume III. 91. Nielsen P, Gyrd-Hansen N. Oral bioavailability of sulphadiazine and trimeth- Greenwood Village, CO: MICROMEDEX, Inc.; 2003. oprim in fed and fasted pigs. Res Vet Sci 1994; 56: 48–52. 119. Bactrim (Roche). In: PDR Physicians desk reference. 49th ed. 1995. 92. Blackwell TE, Werdin RE, Eisenmenger MC, et al. Goitrogenic effects in Montvale, NJ: Medical Economics Company, 1995. p. 2026–30. offspring of swine fed sulfadimethoxine and ormetoprim in late gestation. 120. Taylor PM, Rest RJ, Duckham TN, et al. Possible potentiated sulphonamide J Am Vet Med Assoc 1989 Feb; 194(4): 519–23. and detomidine interactions. Vet Rec 1988; 122: 143.

121. Osweiler GD, Green RA. Canine hypoprothrombinemia resulting from 137. Castles TR, Kintner LD, Lee C. The effects of folic or folinic acid on the toxicity sulfaquinoxaline administration. Vet Hum Tox 1978 Jun; 20(3): 190–2. of pyrimethamine in dogs. Toxicol Appl Pharmacol 1971; 20: 447–59. 122. Neer TM, Savant RL. Hypoprothrombinemia secondary to administration of 138. Panel consensus, 4/28/97. sulfaquinoxaline to dogs in a kennel setting. J Am Vet Med Assoc 1992 May; 139. Wilson DA, MacFadden KE, Green EM, et al. Case control and historical 200(9): 1344–5. cohort study of diarrhea associated with administration of trimethoprim- 123. Panel comment on Sulfonamides (Veterinary-Systemic), 6/96. potentiated sulfonamides to horses and ponies. J Vet Intern Med 1996; 10(4): 124. Berger SL, Scagliotti RH, Lund EM. A quantitative study of the effects of 258–64. Tribrissen on canine tear production. J Am Anim Hosp Assoc 1995 May/Jun; 140. Bennett EE, Craig GR, Pitfield N, et al. The persistence and elimination of 31: 236–41. residues of trimethoprim and sulphadiazine in the tissues of calves treated 125. FDA. Sulfadimethoxine and ormetoprim. Freedom of Information Summary. with ‘Tribrissen Boluses’. Mallinkrodt Canada product report series. June 14, Public Master File Number 5157. 1972. 126. Ormetoprim and sulfadimethoxine package insert (Primor tablets, Pfiz- 141. National Committee for Clinical Laboratory Standards. Performance stan- er—US), Rev 5/96, Rec 12/20/96. dards for antimicrobial disk and dilution susceptibility tests for bacteria 127. Bushby SRM. Sulfonamide and trimethoprim combinations. J Am Vet Med isolated from animals; proposed standards. NCCLS document M31-P (ISBN 1- Assoc 1980 May 15; 10(2): 1049–53. 56238-258-6). Villanova, PA: National Committee for Clinical Laboratory 128. Itkin RJ, Krawiec DR, Cloran JA, et al. Ulcerative urocystitis in a dog. J Am Standards; 1994. p. 5–6, 34–7. Anim Hosp 1994; 30(3): 296–9. 142. Code of Federal Regulation. 21 CFR Chapter 1. Washington, D.C.: U.S. 129. Buoro IBJ, Mande JD, Nyamwange SB. Isolation of Nocardia asteroides Government Printing Office 1994 Apr 1. 556.490, 556.630, 556.640, from a dog with haemorrhagic cystitis. J Small Anim Pract 1993; 34: 99– 556.650, 556.660, 556.670, 556.680, 556.690. 102. 143. Guard CL, Schwark WS, Friedman DS, et al. Age-related alterations in 130. Marino DJ, Jaggy A. Nocardiosis: a literature review with selected case reports trimethoprim-sulfadiazine disposition following oral or parenteral adminis- in two dogs. J Vet Intern Med 1993 Jan–Feb; 7(1): 4–11. tration in calves. Can J Vet Res 1986; 50: 342–6. 131. Kirpensteijn J, Fingland RB. Cutaneous actinomycosis and nocardiosis in 144. Panel comment, 10/97. dogs: 48 cases (1980–1990). J Am Vet Med Assoc 1992 Sep 15; 201(6): 145. Panel comment, 10/97. 917–20. 146. Sulfadiazine and trimethoprim product information (Tribrissen 48%, Scher- 132. Gombert ME, duBouchet L, Aulicino TM, et al. Antimicrobial synergism in the ing-Plough—US). Downloaded from www.spah.com on 2/17/03. therapy of experimental cerebral nocardiosis. J Antimicrob Chemother 1989; 147. Fenger CK, Granstrom DE, Langemeir JL. Epizootic of equine protozoal 23: 39–43. myeloencephalomyelitis on a farm. J Am Vet Med Assoc 1997, 210(7): 923– 133. Davenport DJ, Johnson GC. Cutaneous nocardiosis in a cat. J Am Vet Med 927. Assoc 1986; 188(7): 728–9. 148. Lindsaya DS, Dubeyb JP. Determination of the activity of pyrimethamine, 134. Meric SM. Canine meningitis: a changing emphasis. J Vet Intern Med 1988 trimethoprim, sulfonamides, and combinations of pyrimethamine and Jan–Mar; 2(1): 26–35. sulfonamides against Sarcocystis neurona in cell cultures. Vet Parasit April 135. Fenner WR. Treatment of central nervous system infections in small animals. 1999, 82(3): 205–210. J Am Vet Med Assoc 1989 Nov 15; 185(10): 1176–80. 149. Klasco RK, editor. USP DI Drug information for the healthcare professional. 136. Dunbar MR, Foreyt WJ. Prevention of coccidiosis in domestic dogs and captive Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. coyotes (Canis latrans) with sulfadimethoxine-ormetoprim combination. Am 150. Arrioja-Dechert A, editor. Compendium of veterinary products, CD edition. J Vet Res 1985 Se; 46(9): 1899–902. Port Huron, MI: North American Compendiums, Inc., 2002.

PYRIMETHAMINE Veterinary—Systemic

A commonly used brand name for a human-labeled product is Daraprim. in which clinical signs of the infection had not yet progressed to rigid Note: For a listing of dosage forms and brand names by country hindlimb paralysis{R-12; 14; 15}. availability, see the Dosage Forms section(s). [Toxoplasmosis (treatment)]1—Cats: Although the efficacy and safety have not been established, pyrimethamine is used in combination with CATEGORY: sulfadiazine in the treatment of toxoplasmosis in cats{R-18–20}. Side Antiprotozoal (systemic). effects associated with the administration of pyrimethamine and sulfadiazine have led clinicians to search for other treatments. INDICATIONS However, this therapy may have some value in the treatment of Note: In other USP DI monographs, bracketed information in the infection with nonencysted organisms in cats that can tolerate the Indications section refers to uses that are not included in U.S. product medications. labeling, and superscript 1 refers to uses that are not included in Canadian product labeling. However, since pyrimethamine is not REGULATORY CONSIDERATIONS specifically approved for veterinary use, there is no product labeling U.S. and Canada—Pyrimethamine is not labeled for use in animals, identifying approved indications. including food-producing animals; therefore, there are no established withdrawal times. GENERAL CONSIDERATIONS Pyrimethamine is a folic acid antagonist{R-1}, active against protozoal CHEMISTRY dihydrofolate reductase. It is considered most effective against path- Chemical group: A diaminopyrimidine; structurally related to tri- {R-6} ogenic protozoa when administered in combination with a sulfon- methoprim . amide{R-11; 16; 20}. Chemical name: 2,4-Pyrimidinediamine, 5-(4-chlorophenyl)-6- {R-2} The ready availability of combination products containing trimethoprim ethyl- . {R-2} and sulfadiazine or trimethoprim and sulfamethoxazole may have Molecular formula: C12H13ClN4 . {R-2} contributed to the frequency of their concurrent administration with Molecular weight: 248.71 . pyrimethamine. While trimethoprim does not increase the efficacy of Description: Pyrimethamine USP—White, odorless, crystalline pow- {R-3} therapy against protozoa{R-30}, it is suspected to increase the incidence der . {R-5} of side effects due to folate reduction{R-1; 21}. Whenever possible, pka: 7.34 . pyrimethamine should be administered in combination with a sulfon- Solubility: Pyrimethamine USP—Practically insoluble in water; slightly {R-3} amide alone in the treatment of susceptible infections. soluble in acetone, in alcohol, and in chloroform . The development of resistant organisms has been stimulated in in vitro experiments, and cross-resistance by these cultures to other dihydro- PHARMACOLOGY/PHARMACOKINETICS folate inhibitors has been shown. However, when pyrimethamine was Mechanism of action/effect: Pyrimethamine reversibly binds to and combined with a sulfonamide in the treatment of pyrimethamine- inhibits the enzyme dihydrofolate reductase in protozoa. This inhibi- resistant Neospora cultures, the combination was completely effec- tion prevents the production of tetrahydrofolic acid from dihydrofolate tive{R-11}. and thereby prevents the metabolism of folate{R-6}. Like protozoa, In the case of equine protozoal myeloencephalitis, resistance may occur mammalian cells reduce folic acid to tetrahydrofolic acid; however, the within an individual horse if inadequate treatment is administered; therapeutic action of pyrimethamine relies on a greater selectivity for however, transmission of resistance to the Sarcocystis neurona protozoal dihydrofolate reductase than for the mammalian enzyme{R-1; population outside the individual is not considered a problem because 16}. Pyrimethamine is generally administered in conjunction with a the horse is an aberrant host and does not shed infectious sulfonamide to take advantage of the sequential inhibition of enzy- organisms{R-21; 29}. matic steps in folate synthesis provided by the combination{R-1}.

Absorption: Oral—Human beings: Pyrimethamine is well absorbed ACCEPTED orally{R-1}. [Equine protozoal myeloencephalitis (treatment)]1—Horses: Pyrimeth- amine is used in combination with a sulfonamide, such as sulfadiazine Bioavailability: Oral—Horses: Average, 56% (range, 39 to 78%){R-5}. or sulfamethoxazole{R-9}, in the treatment of protozoal myeloencephalitis{R-7; 8; 21}. Distribution: Rapidly and extensively distributed after intravenous administration{R-5}. ACCEPTANCE NOT ESTABLISHED Horses—Cerebrospinal ﬂuid (CSF) concentrations reached 25 to 50% of [Neospora caninum infection (treatment)]1—Dogs: Although the efﬁcacy the serum concentrations but did not appear to accumulate in horses and safety have not been established, pyrimethamine is used in administered daily oral doses of 1 mg per kg of body weight (mg/kg) combination with sulfonamides, most typically sulfadiazine, in the for 10 days{R-6}. treatment of Neospora caninum infection. This use is based on evidence Pigs—Distribution occurs in two phases after a 10 mg/kg intravenous of in vitro pathogen susceptibility{R-11; 13} and case reports of dose; the fast phase has a half-life of 0.11 hour, and the slow phase successful treatment outcomes in some dogs, particularly in puppies has a half-life of 1.6 hours{R-10}.

Rats—Mean CSF concentration was 27% of the plasma concentration PREGNANCY/REPRODUCTION during the first 48 hours after a single oral dose of 2.9 mg/kg (1 mg Reproduction: Rats—The fertility index of rats treated with pyrimeth- {R-24} per rat) . amine is lowered only by the highest doses administered. This suggests Volume of distribution—Intravenous administration: a toxic effect on the whole animal or the conceptus{R-1}. {R-5} Horses—Steady-state: 1.52 liters per kg (L/kg) . Pregnancy: {R-10} Pigs—Area: 12.1 ± 2 L/kg . Hamsters—Single doses of 20 mg per pregnant hamster caused malformation or death in less than 10% of fetuses{R-1}. Protein binding: Horses—In a group of horses treated with oral pyrimethamine at 1 mg {R-24} Dogs—High (85%) . per kg of body weight (mg/kg) a day, sulfadiazine at 16.7 mg/kg {R-24} Human beings—High (87%) . every twelve hours, and trimethoprim at 3.3 mg/kg every twelve {R-24} Mice—High (78%) . hours, the three horses that were pregnant during therapy aborted {R-10} Pigs—High (85%), independent of serum concentration . during the second or third month of treatment{R-21}. Each of the {R-6} Rats—High (78%) . aborted fetuses was in the fifth month of gestation{R-21}. It is not certain which of the medications might have caused the abortions. Biotransformation: Less than 5% of administered doses are excreted The horses’ diets had not been supplemented with folate at the time {R-10} {R-24} as unchanged drug in the urine in pigs and rats ; five of the abortions{R-21}. hours after administration of radiolabeled pyrimethamine to a rat, The administration of oral folic acid to pregnant mares being treated less than 50% of radioactivity in the blood was intact parent for equine protozoal myeloencephalitis may not protect the fetus {R-24} drug . Therefore, it is believed that pyrimethamine is extensively from the effects of folate deficiency. Reports have been made of metabolized, although metabolites have not been identified in animals. mares delivering foals with congenital defects after oral administra- In human beings, pyrimethamine is believed to be hepatically tion during pregnancy of pyrimethamine, 0.5 to 1 mg/kg a day, {R-24; 28} metabolized . with sulfadiazine, 25 mg/kg a day; or sulfamethoxazole, 12.5 mg/ kg day, and trimethoprim, 2.5 mg/kg{R-35}. Two of the three Half-life: Elimination—Intravenous administration: reported mares had been treated in the last 3 months of gestation {R-5} Horses—12 ± 3.7 hours . and one for 2 years before foaling. These mares had also been {R-10} Pigs—13.3 ± 4.9 hours . supplemented with oral folic acid, 40 mg as a total daily dose, and vitamin E, 8000 Units as a total daily dose, during the period of Concentrations: antibiotic treatment. Each of three mares on this dosage regimen Peak serum concentration—Oral administration: Horses— produced a foal with renal hypoplasia or nephrosis and bone Single dose: 0.18 ± 0.03 mcg per mL of serum (mcg/mL) with marrow aplasia or hypoplasia{R-35}. In both mares and foals, serum {R-5} administration of 1 mg/kg . folate concentrations were below the laboratory reference range and Multiple doses: 0.32 ± 0.11 mcg/mL after the 5th dose and 0.26 ± in two foals, folate was less than 30% of the minimum reference {R-6} 0.07 mcg/mL after the 10th dose of 10 daily doses of 1 mg/kg . range{R-35}. The risk of congenital defects should be considered Time to peak concentration—Oral administration: Horses— when treating pregnant mares with pyrimethamine and sulfon- {R-5} Single dose: 2.9 ± 2.1 hours after administration of 1 mg/kg . amide. Multiple doses: 2.2 hours after the 5th dose and 2.7 hours after the Miniature pigs—A high incidence of malformations (70%), such as cleft {R-6} 10th dose of 10 daily doses of 1 mg/kg . palate, club foot, and micrognathia, was seen in offspring when Serum concentrations, other—Oral administration: Horses— pregnant sows were administered pyrimethamine, 3.6 mg/kg a day, Single dose: 0.09 mcg/mL 24 hours after administration of from days 11 to 35 of gestation; however, no abnormalities were {R-5} 1 mg/kg . noted in the offspring of sows administered 0.9 to 1.8 mg/kg a day Multiple doses: Plasma steady state was reached at the 5th day of 10 during the same period of gestation{R-1; 4}. daily doses of 1 mg/kg; at that time the serum concentrations Rats—Fetal resorption and stunted growth in fetuses have been seen in fluctuated approximately 65% over each 24-hour period, with the pregnant rats given pyrimethamine{R-1}. Rats administered 12.5 mg/ {R-6} peak at approximately 0.32 mcg/mL . kg from days 7 to 9 of gestation had 66% of fetuses resorbed and 33% stunted, while a dose of 0.5 to 1 mg/kg from days 4 to 13 of Elimination: Pigs—Only about 3% of an intravenous dose of pyri- gestation caused resorption of 8 to 15% of fetuses and stunted methamine is excreted in the urine as unchanged drug, although up to growth in 7 to 17% of fetuses{R-1}. 90% of the dose is eliminated in that time{R-10}. Total clearance— {R-5} Horses: 1.6 ± 0.32 mL per minute per kg (mL/min/kg) . LACTATION {R-10} Pigs: 0.68 ± 0.16 mL/min/kg . Pyrimethamine is distributed into human milk{R-1}. Distribution into milk in lactating animals has not been determined. PRECAUTIONS TO CONSIDER CARCINOGENICITY PEDIATRICS Mice: A significant increase in the number of lung tumors per mouse has Dogs: Pyrimethamine has been administered at a dose of 1 mg per kg of been reported with doses of 25 mg per kg of body weight (mg/kg), body weight a day for 4 weeks in 8- to 17-week-old puppies, without administered intraperitoneally{R-1}. any apparent harmful effects{R-14}.

DRUG INTERACTIONS AND/OR RELATED PROBLEMS Complete blood counts (CBCs){R-19; 21; 23} and The following drug interactions and/or related problems have been Platelet counts selected on the basis of their potential clinical significance (possible (should be performed on a regular basis, particularly with long-term mechanism in parentheses where appropriate)—not necessarily inclu- or high-dose therapy; periodic packed cell volume evaluation is sive (» = major clinical significance): recommended in horses being treated for equine protozoal myeloen- {R-29} Note: Drug interactions relating specifically to the use of pyrimethamine cephalitis to monitor for anemia ) in animals are rarely reported in veterinary literature. Human drug interactions have been reported and are included in the following SIDE/ADVERSE EFFECTS section. The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and, for humans, HUMAN DRUG INTERACTIONS AND/OR RELATED symptoms in parentheses where appropriate)—not necessarily PROBLEMS{R-37} inclusive: The following drug interactions have been reported in humans, and are Note: It is assumed that animals have the same tendency as people to included in the human monograph Pyrimethamine (Systemic) in USP develop signs of folate deficiency with long-term use or high doses of DI Volume I; these drug interactions are intended for informational folic acid antagonists such as pyrimethamine. Signs of folate deficiency purposes only and may or may not be applicable to the use of have been reported frequently in the human literature and include pyrimethamine in the treatment of animals: agranulocytosis, megaloblastic anemia, and thrombocytopenia{R-16}. Note: Combinations containing any of the following medications, Similar signs have been noted in cats, dogs, and horses{R-19; 21; 26}.It depending on the amount present, may also interact with this should be considered that signs of folate deficiency may occur in any medication. species administered pyrimethamine. When administering pyrimeth- Bone marrow depressants amine with a sulfonamide, the risk of sulfonamide-related side effects (concurrent use of pyrimethamine with bone marrow depressants should be considered. See the Sulfonamides (Veterinary— may increase the leukopenic and/or thrombocytopenic effects; if Systemic) monograph for further information. concurrent use is required, the possibility of increased myelotoxic effects should be considered, especially when pyrimethamine is used in large doses, such as those required in the treatment of toxoplas- THOSE INDICATING NEED FOR MEDICAL ATTENTION mosis) Incidence unknown Folate antagonists, other Cats (concurrent use of other folate antagonists with pyrimethamine or Leukopenia—seen with a dose of 1 mg per kg of body weight (mg/ kg) use of pyrimethamine between courses of other folate antagonists is a day for 6 days{R-19} not recommended because of the possible development of megalob- Horses lastic anemia) Anemia{R-21}; congenital defects in offspring (bone marrow aplasia or hypoplasia; renal nephrosis or hypoplasia; skin lesions){R-35}; {R-21} {R-21} MEDICAL CONSIDERATIONS/CONTRAINDICATIONS diarrhea ; leukopenia The medical considerations/contraindications included have been

selected on the basis of their potential clinical significance (reasons {R-37} given in parentheses where appropriate)—not necessarily inclusive HUMAN SIDE/ADVERSE EFFECTS In addition to the above side/adverse effects reported in animals, the (» = major clinical significance). following side/adverse effects have been reported in humans, and are Except under special circumstances, this medication should not be included in the human monograph Pyrimethamine (Systemic) in USP used when the following medical problems exist: DI Volume I; these side/adverse effects are intended for informational » Anemia or purposes only, and may or may not be applicable to the use of Bone marrow suppression pyrimethamine in the treatment of animals: (pyrimethamine may cause folate deficiency, resulting in megalob- Incidence less frequent lastic anemia and blood dyscrasias, including agranulocytosis and Agranulocytosis, leukopenia, or thrombocytopenia; atrophic thrombocytopenia{R-19; 21; 26}) glossitis; gastrointestinal disturbances (anorexia, diarrhea, nau- » Hepatic function impairment, severe sea, and vomiting) (in human beings, pyrimethamine is metabolized in the liver) Incidence rare Risk-benefit should be considered when the following medical Erythema multiforme and/or Stevens-Johnson syndrome; problem exists: hypersensitivity Pregnancy (the risk of teratogenesis should be considered in planning treatment with pyrimethamine{R-35}) OVERDOSE For more information in cases of overdose or unintentional ingestion, PATIENT MONITORING contact the American Society for the Prevention of Cruelty The following may be especially important in patient monitoring (other to Animals (ASPCA) National Animal Poison Control Center tests may be warranted in some patients, depending on condition; » = (888-426-4435 or 900-443-0000; a fee may be required for consul- major clinical significance): tation) and/or the drug manufacturer.

CLINICAL EFFECTS OF OVERDOSE mechanism of action of the drug{R-9; 21}; however, neither oral The following effects have been selected on the basis of their potential supplement has been clearly proven to be effective. Only limited clinical significance (possible signs in parentheses where appropri- information on the effectiveness of folic acid or folinic acid in the ate)—not necessarily inclusive: prevention of folate deficiency caused by pyrimethamine is avail- Dogs—with a dose of 5 to 10 mg per kg of body weight (mg/kg) a day for able. 10 to 21 days{R-26} Cats and dogs: No definitive studies are available to confirm that folic Chronic effects acid or folinic acid supplementation should be used to prevent signs of Anorexia and/or decreased appetite; ataxia; bone marrow folate deficiency that may occur during treatment with pyrimeth- {R-36} suppression, including leukopenia and reticulocytopenia; dehy- amine . Monitoring animals for signs of folate deficiency is dration; gastrointestinal toxicity (diarrhea, occasionally bloody; recommended during treatment with pyrimethamine (see the Patient {R-36} vomiting); weakness; weight loss monitoring and Side/Adverse Effects sections) . Note: Bone marrow suppression has been demonstrated by biopsy Horses: An oral folic acid dose of 0.09 to 0.18 mg per kg of body in a few dogs receiving extremely high doses of pyrimethamine weight mg/kg) (40 to 80 mg per horse) every twenty-four hours {R-29; 31} (6 mg/kg a day for 10 to 15 days){R-26}. Three of eight dogs has been used ; however, case reports have shown that a treated had bone marrow suppression, particularly of the erythroid total dose of 40 mg of folic acid a day given to pregnant mares elements{R-26}. being treated with pyrimethamine and sulfonamide is sometimes In dogs, vomiting was reported to be common within 2 to 5 hours of not effective in preventing congenital defects in foals caused by {R-35} administration of 7.5 to 10 mg/kg, but vomiting was seen only folate deficiency . Fresh grass has more than twice the total {R-32} occasionally in dogs receiving 5 mg/kg a day for 10 to 21 days{R-26}. folacin concentration of hay , and serum folate concentrations Intestinal lesions, including inflammation, mucoid degeneration, tend to be much higher in pastured horses than in permanently {R-33; 34} shortened villi and mucosal atrophy, are visible on histopathologic stabled horses or horses in training . It has been examination after administration of 6.2 mg/kg a day for 10 days to recommended that horses be maintained on feeds containing high {R-29} dogs{R-26}. folacin concentrations during pyrimethamine therapy . Rather Respiratory depression and circulatory collapse, as well as neuro- than supplementing horses with folic acid, some clinicians recom- toxicity leading to seizures, have been reported in people receiving mend monitoring the packed-cell volume to detect developing total doses of 250 to 300 mg of pyrimethamine{R-1}. These specific anemias. signs have not been reported in animals; however, one of four dogs Some clinicians have used the in vitro minimum inhibitory concentration administered 5 mg/kg a day died on the 17th day of therapy; the (MIC) of pyrimethamine considered necessary to inhibit Toxoplasma {R-5; 21} specific cause of death was not reported{R-26}. gondii or the MIC of pyrimethamine necessary to inhibit Neospora caninum{R-11} as guidelines for target cerebrospinal fluid concentrations for control of the Sarcocystis species responsible for TREATMENT OF OVERDOSE{R-1} equine protozoal myeloencephalitis.{R-5} • Gastric lavage. • Control of central nervous system stimulation by administration of benzodiazepines or short-acting barbiturates, if necessary. DIET/NUTRITION • Respiratory assistance, if necessary. Horses: Pyrimethamine should be administered 1 hour prior to feeding • Administration of folate to prevent hematopoietic changes (see hay{R-9}. Veterinary Dosing Information). Human beings: Information from human product labeling includes the statement that anorexia and vomiting induced by pyrimethamine may CLIENT CONSULTATION be minimized by administering it with food{R-1}. Clients should be advised to watch for signs such as loss of appetite, weakness, pale mucous membranes or pinpoint blood spots in membranes, or noticeable bruising. ORAL DOSAGE FORMS Note: In other USP DI monographs, bracketed information in the Dosage VETERINARY DOSING INFORMATION Forms section refers to categories of use and/or indications that are not The administration of sulfadiazine and trimethoprim products labeled for included in U.S. product labeling, and superscript 1 refers to categories use in animals in combination with human-labeled pyrimethamine of use and/or indications that are not included in Canadian product tablets is commonly discussed in veterinary literature. However, the labeling. However, since pyrimethamine is not specifically approved for low affinity of protozoal dihydrofolate for trimethoprim suggests poor veterinary use, there is no product labeling identifying approved {R-30} efficacy of trimethoprim in the treatment of protozoal infections . indications. The concurrent administration of trimethoprim with pyrimethamine offers no known benefit and may increase the risk of adverse effects associated with these dihydrofolate reductase inhibitors{R-1; 9; 21}. PYRIMETHAMINE TABLETS USP Whenever possible, pyrimethamine should be administered in combi- Usual dose: nation with a sulfonamide alone in the treatment of susceptible [Equine protozoal myeloencephalitis]1—Horses: Oral, 1 mg per kg of infections. body weight every twenty-four hours{R-5} in combination with 16.7 mg The administration of folic acid or folinic acid supplements during of sulfadiazine or sulfamethoxazole per kg of body weight every twelve treatment with pyrimethamine may help to prevent adverse effects hours{R-5; 8; 9; 21} has been used. The average duration of treat- associated with folate deficiency, which occur as an extension of the ment necessary to clear the organism may be as long as 130 days

or more{R-21}. Testing cerebrospinal fluid for Sarcocystis neurona USP requirements: Preserve in tight, light-resistant containers. Con- antibodies may help determine when to discontinue treatment{R-21}. tain the labeled amount, within ± 7%. Meet the requirements for Note: The above dose is based on clinical case reports with successful Identification, Dissolution (75% in 45 minutes in 0.01 N hydrochloric outcomes that also included the concurrent administration of 3.3 mg acid in Apparatus 2 at 50 rpm), and Uniformity of dosage units{R-3}. of trimethoprim per kg of body weight. However, the administration Developed: 07/01/98 of pyrimethamine concurrently with trimethoprim generally is not Interim revision: 10/14/99; 9/30/02; 03/28/03 recommended. To decrease the risk of toxicity, the administration of pyrimethamine with sulfadiazine alone is preferred, but there are no REFERENCES specific reports of the efficacy of this combination. 1. Pyrimethamine package insert (Daraprim, Burroughs Wellcome—US), Rev 1 [Neospora caninum infection] —Dogs: Although the efficacy and safety 4/94, Rec 10/13/94. have not been established, an oral dose of 1 mg of pyrimethamine per 2. USP dictionary of USAN and international drug names, 2002 ed. Rockville, kg of body weight every twenty-four hours{R-14} in combination with MD: The United States Pharmacopeial Convention, Inc., 2002. 3. The United States pharmacopeia. The national formulary. USP 26th revision 12.5 mg of sulfadiazine per kg of body weight every twelve hours{R-14} (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United for four weeks has been used. States Pharmacopeial Convention, Inc., 2002. p. 1602, 2579. Note: The above dose is based on clinical case reports with successful 4. Misawa J, Kanda S, Kokue E, et al. Teratogenic activity of pyrimethamine in outcomes that also included the concurrent administration of 2.5 Gottingen minipig. Toxicol Lett 1982; 10(1): 51–4. 5. Clarke CR, Burrows GE, MacAllister CG, et al. Pharmacokinetics of intrave- mg of trimethoprim per kg of body weight. However, the admin- nously and orally administered pyrimethamine in horses. Am J Vet Res 1992 istration of pyrimethamine concurrently with trimethoprim gener- Dec; 53(12): 2292–5. ally is not recommended. To decrease the risk of toxicity, the 6. Clarke CR, Burrows GE, MacAllister CG, et al. Pharmacokinetics, penetration into cerebrospinal fluid, and hematologic effects after multiple oral adminis- administration of pyrimethamine with sulfadiazine alone is pre- trations of pyrimethamine to horses. Am J Vet Res 1992 Dec; 53(12): 2296–9. ferred, but there are no reports of the efficacy of this combination. 7. Boy MG, Galligan DT, Divers TJ. Protozoal encephalomyelitis in horses: 82 [Toxoplasmosis]1—Cats: Although the efficacy and safety have not been cases (1972-1986). J Am Vet Med Assoc 1990 Feb; 196(4): 632–4. established, an oral dose of 1 mg of pyrimethamine per kg of body 8. Brewer B, Mayhew IG. Multifocal neurologic disease in a horse. J Equine Vet {R-18} Sci 1988 Jul/Aug; 8(4): 302–4. weight every twenty-four hours in combination with 25 mg of 9. Bertone JJ. Update on equine protozoal myeloencephalitis. FDA Vet 1996 {R-18} sulfadiazine per kg of body weight every twelve hours for May/Jun; XI(III): 7–9. fourteen to twenty-eight days has been used. 10. Shimoda M, Kokue E, Kurebayashi Y, et al. Three-compartment model for Note: The above dose was extrapolated from studies evaluating the pyrimethamine disposition in the pig. J Vet Pharmacol Ther 1981 Jun; 4(2): 165–70. efficacy of pyrimethamine and sulfadiazine in ending or reducing shed- 11. Lindsay DS, Butler JM, Rippey NS, et al. Demonstration of synergistic effects of ding of oocysts{R-18; 19} as well as preventing tissue infection{R-19}. sulfonamides and dihydrofolate reductase/thymidylate synthase inhibitors Because pyrimethamine is only available in 25-mg tablets, some against Neospora caninum tachyzoites in cultured cells, and characterization of mutants resistant to pyrimethamine. Am J Vet Res 1996 Jan; 57(1): 68–72. clinicians will arrange for capsules to be formulated in smaller 12. Knowler C, Wheeler SJ. Neospora caninum infection in three dogs. J Small strengths for easier administration of the unpalatable medication to Anim Pract 1995; 36: 172–7. cats. Consultation with an experienced pharmacist is recommended. 13. Lindsay DS, Rippey NS, Cole RA, et al. Examination of the activities of 43 chemotherapeutic agents against Neospora caninum tachyzoites in cultured cells. Am J Vet Res 1994 Jul; 55(7): 976–81. Strength(s) usually available: 14. Mayhew IG, Smith KC, Dubey JP, et al. Treatment of encephalomyelitis due to U.S.— Neospora caninum in a litter of puppies. J Small Anim Pract 1991; 32: 609– Veterinary-labeled product(s): 12. Not commercially available. 15. Hay WH, Shell LG, Lindsay DS, et al. Diagnosis and treatment of Neospora {R-1} caninum infection in a dog. J Am Vet Med Assoc 1990 Jul 1; 197(1): 87–8. Human-labeled product(s) : 16. St. Georgiev V. Opportunistic/nosocomial infections. Treatment and develop- 25 mg (Rx) [Daraprim (scored)]. mental therapeutics. Toxoplasmosis. Med Res Rev 1993 Sep; 13(5): 529–68. Canada— 17. Davidson MG, Lappin MR, Rottman JR, et al. Paradoxical effect of clindamycin in experimental, acute toxoplasmosis in cats. Antimicrob Agents Chemother Veterinary-labeled product(s): 1996 Jun; 40(6): 1352–9. Not commercially available. 18. Sheffield HG, Melton ML. Effects of pyrimethamine and sulfadiazine on the Human-labeled product(s): intestinal development of Toxoplasma gondii in cats. Am J Trop Med Hyg 1976 25 mg (Rx) [Daraprim (scored)]. May; 25(3): 379–83. 19. Dubey JP, Yeary RA. Anticoccidial activity of 2-sulfa-moyl-4,4-diaminodiphe- Withdrawal times: nylsulfone, sulfadiazine, pyrimethamine and clindamycin in cats infected with Toxoplasma gondii. Can Vet J 1977 Mar; 18(3): 51–7. U.S. and Canada—Pyrimethamine is not labeled for use in animals, 20. Mack DG, McLeod R. New micromethod to study the effect of antimicrobial including food-producing animals; therefore, there are no established agents on Toxoplasma gondii: comparison of sulfadoxine and sulfadiazine withdrawal times. individually and in combination with pyrimethamine and study of clindamycin, metronidazole, and cyclosporin A. Antimicrob Agents Chemother 1984 Jul; 26(1): 26–30. Packaging and storage: Store below 40 C (104 F), preferably 21. Fenger CK, Granstom DE, Langemeier JL, et al. An epizootic of equine protozoal between 15 and 30 C (59 and 86 F), unless otherwise specified by myeloencephalitis on a farm. J Am Vet Med Assoc 1997 Apr 1; 210(7): 923–7. manufacturer. Store in a tight, light-resistant container. 22. McCabe RE, Oster S. Current recommendations and future prospects in the treatment of toxoplasmosis. Drugs 1989 Dec; 38(6): 973–87. 23. Peterson JL, Willard MD, Lees GE, et al. Toxoplasmosis in two cats with inflammatory intestinal disease. J Am Vet Med Assoc 1991 Aug; 199(4): Auxiliary labeling: • Keep out of the reach of children{R-1}. 473–6. 24. Cavallito JC, Nichol CA, Brenckman WD, et al. Lipid-soluble inhibitors Caution: Potential danger of accidental overdose{R-1}. of dihydrofolate reductase. I. Kinetics, tissue distribution, and extent of

metabolism of pyrimethamine, metoprine, and etoprine in the rat, dog, and 31. Reviewer comment, Rec 6/18/97. man. Drug Metab Dispos 1978; 6: 329–37. 32. National Research Council. Nutrient requirements of horses. Washington, 25. Bygbjerg IC, Lund JT, Hording M. Effect of folic and folinic acid on cytopenia D.C.: National Academy Press, 1989. p. 29–30. occurring during cotrimoxazole treatment of pneumocystis carinii pneumonia. 33. Roberts MC. Serum and red cell folate and serum levels in horses. Aust Vet J Scand J Infect Dis 1988; 20: 685–6. 1983 Apr; 60(4): 106–11. 26. Castles TR, Kintner LD, Lee C. The effects of folic or folinic acid on the toxicity 34. Allen BV. Serum folate levels in horses, with particular reference to the English of pyrmethamine in dogs. Toxicol Appl Pharmacol 1971; 20: 447–59. thoroughbred. Vet Rec 1978; 103: 257–9. 27. Plumb DC. Veterinary drug handbook, 2nd ed. Ames, IA: Iowa University 35. Toribio RE, Bain FT, Mrad OR, et al. Congenital defects in newborn foals of Press, 1995. p. 541–3. mares treated for equine protozoal myeloencephalitis during pregnancy. J Am 28. Weiss LM, Harris C, Berger M, et al. Pyrimethamine concentrations in serum Vet Med Assoc 1998 Mar 1; 212(5): 697–701. and cerebrospinal ﬂuid during treatment of acute toxoplasma encephalitis in 36. Panel consensus, 5/5/98. patients with AIDS. J Infect Dis 1988 Mar; 157(3): 580–3. 37. Klasco RK, editor. USP DI Drug information for the healthcare professional. 29. Reviewer comment, Rec 7/11/97. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 30. Panel comment, Rec 6/22/97.

RIFAMPIN Veterinary—Systemic

Some commonly used brand names for human-labeled products are: antimicrobial was not very effective{R-51} and in vivo efficacy against Rifadin; Rifadin IV; Rimactane; and Rofact. induced infections in mice was only weakly significant{R-52}. Resistance to rifampin can develop quickly; therefore, it is most often used CATEGORY: in combination with other antimicrobials{R-2; 11; 54}. Resistant mutants Antibacterial (systemic). may be concentration-sensitive and contain RNA polymerases with one of a variety of sensitivities to rifampin{R-12}. Resistance may occur as a INDICATIONS single-step mutation of the DNA-dependent RNA polymerase; therefore, Note: In other USP DI monographs, bracketed information in the initial susceptibility can rapidly diminish as small populations of Indications section refers to uses that are not included in U.S. product resistant cells soon outnumber susceptible cells{R-2}. This effect is labeling, and superscript 1 refers to uses that are not included in diminished when combination antibiotic treatment is administered{R-2; Canadian product labeling. However, since rifampin is not specifically 4}. One case of the development of resistant Rhodococcus equi in a foal approved for veterinary use, there is no product labeling identifying treated with erythromycin and rifampin has been reported{R-39}. Cross- approved indications. resistance to other antibiotics{R-2} or transfer of resistance to other local microorganisms has not been reported{R-4}. GENERAL CONSIDERATIONS Rifampin is a broad-spectrum antibiotic, with activity against many ACCEPTED {R-7} gram-positive and some gram-negative aerobic bacteria as well as [Pneumonia, Rhodococcus equi (treatment adjunct)]1 ;or {R-53; 60} facultative anaerobic organisms . However, for clinical [Extrapulmonary infection, Rhodococcus equi (treatment adjunct)]1 — purposes, rifampin generally should not be considered broad-spectrum Foals: Rifampin is used in combination with erythromycin in the until proven so in each case. Most gram-negative bacteria should be treatment of pneumonia caused by Rhodococcus (Corynebacterium) equi considered resistant or to have unpredictable susceptibilities until infection in foals{R-33; 34; 36}. Although the lung appears to be most {R-11} susceptibility data are available . Because many infections involve vulnerable to Rhodococcus equi infection, in some cases susceptible foals more than one species of bacterium and because resistance can have been found to have abdominal or subcutaneous abscesses, develop quickly, rifampin is most often administered in combination bacterial endocarditis, diskospondylitis, gastrointestinal infections, with other antimicrobial agents. osteomyelitis, or septicemia{R-37–42}. In many, but not all, of these Rifampin is considered especially active in the treatment of staphylo- cases the foal has a concomitant pneumonia{R-37–42}. R. equi are coccal infections and in the eradication of pathogens located in susceptible in vitro to erythromycin alone{R-66; 67}, and erythromycin {R-20; difficult to reach target areas, such as inside phagocytic cells alone has been effective in the treatment of this infection{R-36; 67; 75}. 62} {R-62} . The ability of rifampin to reach intracellular bacteria can However, no studies have been performed to compare the efficacy of make it difficult to predict in vivo therapy results based on in vitro erythromycin alone with the combination of erythromycin and {R-49} sensitivity tests . rifampin in foals. The in vitro evidence of synergistic activity for the Rifampin has been shown to have in vitro activity against equine combination of erythromycin and rifampin against R. equi{R-10} and {R-7} {R-6; 7} Corynebacterium pseudotuberculosis , Rhodococcus equi , Staph- the volume of case reports supporting the efficacy of the combination {R-7} {R-6; 7} {R-7} ylococcus species , Streptococcus equi , S. equisimilis , make treatment with a combination of erythromycin and rifampin {R-6; 7} and S. zooepidemicus isolates. Susceptibility has been variable more commonly recommended for this indication than erythromycin for the equine gram-negative nonenteric bacteria. It has shown alone{R-32}. moderate activity against Actinobacillus suis, A. equuli, Bordetella bronchiseptica,andPasteurella species isolates{R-6; 7}. Equine isolates of Pseudomonas aeruginosa, Escherichia coli, Enterobacter cloacae, Klebsiella ACCEPTANCE NOT ESTABLISHED pneumoniae, Proteus species, and Salmonella species were found to be [Infections, bacterial (treatment)]1—Although the safety and efficacy resistant{R-7}. have not been established, rifampin is used in combination with other Strains of the porcine pathogen Actinobacillus pleuropneumoniae, isolated antimicrobials in the treatment of susceptible bacterial infections, and in Spain, were found to be susceptible to rifampin in vitro at a in particular, staphylococcal infections{R-20} in animals. Rifampin is concentration of 1 mcg/mL or less{R-50}. Rifampin also had activity particularly suited for the treatment of organisms that are resistant to against Pasteurella multocida species isolated from pigs with pneumonia other therapies by nature of their intracellular location{R-20; 62}. in Spain{R-55}. Because the pharmacokinetics of rifampin have been well-studied in Some strains of Mycobacterium paratuberculosis were found to be sensitive horses{R-6; 7; 13} and minimal side effects have been reported in foals{R- to rifampin in in vitro tests{R-43}. 33; 34; 36}, the treatment of these infections in horses may be more Anaerobes found to be susceptible in vitro include 132 strains of well-defined than for other species. The use of rifampin in other Bacteroides species and 25 strains of Fusobacterium species isolated from animals could be based on available pharmacokinetic data for calves{R- goats in Spain; with blood concentrations of 2 mcg/mL, only 18% of 19}, dogs{R-4; 65}, foals{R-16}, rabbits{R-18}, and sheep{R-22}; knowledge strains were resistant{R-53}. Although in vitro tests showed rifampin to of bacterial susceptibility; case reports describing treatment of infec- be active against Clostridium perfringens type A isolates{R-52}, when tions in a cat{R-58}, a deer{R-60}, and dogs{R-57}; and also efficacy higher concentrations of pathogens per milliliter were tested, the studies that have been performed in rats{R-54; 59}. However, there is

limited knowledge about the safety of rifampin use in species other CHEMISTRY than horses. Source: Semisynthetic derivative of rifamycin B{R-2}, a natural 1 [Brucellosis (treatment)] —Dogs: Although the safety and efficacy have fermentation product of Nocardia (Streptomyces) mediterranei{R-4; 6}. not been established, rifampin in combination with doxycycline has Chemical group: Macrocyclic antibiotic{R-13}. been recommended in the treatment of brucellosis in dogs. This Chemical name: Rifamycin,3-[[(4-methyl-1-piperazinyl)imino]methyl]- recommendation is based on demonstrated efficacy in the treatment of {R-1}. {R-68–72} {R-1} human brucellosis and evidence of possible canine pathogen Molecular formula: C43H58N4O12 . {R-73} susceptibility to rifampin . There are no controlled studies in dogs. Molecular weight: 822.94{R-1}. 1 [Paratuberculosis (treatment)] —Cattle, goats, and sheep: For use in Description: Rifampin USP—Red-brown, crystalline powder{R-3}. animals not to be used in food production—Although the safety and pKa: 7.9{R-22}. efficacy have not been established, rifampin has been administered in Solubility: Rifampin USP—Very slightly soluble in water; freely soluble conjunction with isoniazid in the alleviation of signs associated with in chloroform; soluble in ethyl acetate and in methanol{R-3}. paratuberculosis (Mycobacterium paratuberculosis infection or Johne’s disease){R-23; 43}. The addition of an aminoglycoside to the regimen PHARMACOLOGY/PHARMACOKINETICS has also been used in the initial weeks of severe infection{R-23; 44}. The use of rifampin is based on in vitro culture and sensitivity results{R-43} Mechanism of action/effect: Rifampin inhibits DNA-dependent RNA and on case reports of clinical improvement for extended periods of polymerase; however, at therapeutic doses, it inhibits the enzyme in time{R-23; 44}; however, internal lesions and fecal shedding of the bacteria, while not affecting mammalian polymerase{R-2; 4}. Rifampin organism are rarely controlled. It should be noted that semen from is bactericidal and is active against extracellular organisms as well as bulls with paratuberculosis have been found to contain M. paratuber- against susceptible intracellular organisms{R-2; 49}, including intra- culosis even after freezing and processing. Placental infection of a fetus leukocytic organisms{R-20}. Rifampin can enter neutrophils and mac- also can occur in infected cows.{R-23} It is not known if rifampin and rophages to kill intracellular bacteria{R-4; 20}, while not interfering isoniazid therapy can prevent transmission in semen or transplacen- with phagocytosis{R-20}. tally. The cost of rifampin therapy, as well as the inability to Rifampin appears to penetrate the outer membrane of gram-positive completely clear infection and prevent spread of disease, limits bacteria more easily than that of gram-negative bacteria{R-4}. This is treatment only to valuable quarantined animals{R-23; 44}. reflected in the significantly lower minimum inhibitory concentrations [Potomac horse fever (treatment)]1—Horses: Although the efficacy is (MIC) required for gram-positive bacteria (0.01 mcg per mL of serum) not established, rifampin is used in combination with erythromycin compared with gram-negative bacteria (8 to 32 mcg per mL){R-4}. in the treatment of Potomac horse fever (equine ehrlichial colitis){R-56}. It is as effective as oxytetracycline in the resolution of Absorption: Rifampin is rapidly absorbed after oral administration to clinical signs, with the exception that rifampin and erythromycin will people, calves, dogs, and horses{R-4; 19}, although bioavailability is not not reduce fever as quickly as oxytetracycline, taking up to 12 hours high in horses and sheep. Administration with food can prolong the longer to return the body temperature to normal{R-56}. Rifampin and time to peak serum concentration in adult horses and people{R-4; 14}. erythromycin have the advantage of being available in oral dosage Adult sheep appear to have prolonged absorption, possibly because of forms. prolonged movement through the rumen{R-4; 20}. Bioavailability— UNACCEPTED Oral: [Mycobacterial infections (treatment)]1—Current therapeutic regimens Horses— for mycobacterial infections cannot guarantee that an animal is no 48.8%, with a single dose of 10 mg per kg of body weight longer contagious during treatment. Treatment of Mycobacterium (mg/kg){R-6}. tuberculosis, Mycobacterium bovis, and other mycobacterial species 39.5%, with a single dose of 10 mg/kg, administered in the feed{R-13}. transmissible to human beings is nearly always considered inappro- Note: An unpublished study of horses receiving a dose of 5 mg/kg priate{R-45; 47}. The treatment of tuberculosis in cattle is not permitted found a bioavailability of 68% when rifampin was administered in Canada or the U.S.{R-64}. The treatment of mycobacterial infections 1 hour before feeding and 26% when it was administered 1 hour that do not cause human tuberculosis, such as atypical mycobacterial after feeding{R-15}. Because rifampin is most often administered infections in cats, may be acceptable{R-45–48} although there is with feed, recommended dosages compensate for the decreased insufficient evidence of efficacy at this time. absorption. Sheep— REGULATORY CONSIDERATIONS 36.6 ± 3.2%, with a dose of 10 mg/kg, as an oral drench{R-19}. U.S. and Canada— 3 to 32%, with a dose of 20 mg/kg, in a gel capsule{R-21}. Rifampin is not labeled in the United States or Canada for use in 14 to 122%, with a dose of 50 mg/kg, in a gel capsule{R-21}. animals, including food-producing animals. There are no established Note: The study performed using gel capsules of rifampin in sheep withdrawal times. found that absorption was incomplete and still continuing by the The treatment of tuberculosis in cattle is not permitted in Canada or end of the study, producing extremely variable results{R-21}. the U.S.{R-64} Absorption was also relatively low and variable with the oral

drench but not to the same extent as with gel capsules; the 50 mg/kg intraperitoneally every 12 hours for 6 days did not show medication may have been administered directly into the aboma- induction of liver microsomal enzyme activity against substances sum and would therefore have been rapidly and consistently tested{R-26}, but mice administered the same dose showed significant absorbed{R-21}. induction of the hepatic mixed-function oxidase system and enzymatic Intramuscular—Horses: 59.8 ± 3.2%, with a dose of 10 mg/kg{R-13}. activity{R-26}. In horses, enzyme induction has generally not been seen with less than 5 days of therapy, but once there is an increase in Distribution: Rifampin is highly lipid-soluble and is widely distributed hepatic enzyme activity, the increase may last for more than 2 weeks {R-17} in tissues{R-4; 6}. Antimicrobial concentrations are approached in all after discontinuation of treatment . However; several factors may tissue compartments throughout the body, including milk{R-22}, modify the therapeutic levels of rifampin, such as the variability in its bone{R-54}, cerebrospinal fluid{R-18}, exudates, ascitic fluid, and soft absorption in horses when given alone, and the possible change in tissues{R-4}. Rifampin crosses the blood-brain barrier{R-6; 18} and, in pharmacokinetics due to interactions with other medications that rabbits, the cerebrospinal fluid to plasma concentration ratio ranged often are administered with rifampin; data are insufficient for from 0.52 to 1.17, from 30 minutes to 12 hours after an oral dose determining whether the increased elimination of rifampin due to of 10 mg/kg{R-18}. Rifampin can penetrate phagocytic cells to kill hepatic enzyme induction during prolonged dosing may be corrected susceptible intracellular bacteria{R-6; 7; 20}. In many species, as has for by a dose modification. been documented in dogs and human beings, feces, saliva, sweat, tears, and urine may be discolored red-orange by rifampin and its metabolites{R-4}. Half-life: Volume of distribution— Absorption— Horses: Intramuscular administration: Horses—6.7 ± 1.5 hours, with a dose of Area—0.93 ± 0.29 liter per kg (L/kg){R-7}; 0.63 ± 0.06 L/kg{R-13}. 10 mg/kg{R-13}. Steady state—0.76 L/kg{R-6}. Oral, with food: Horses— Sheep: Steady state—0.45 ± 0.06 L/kg{R-21}. 4.2 ± 1.2 hours, with a dose of 10 mg/kg{R-13}. 2.6 ± 1.3 hours, with a dose of 25 mg/kg{R-13}. Protein binding: Distribution—Intravenous: Horses—13.8 ± 5.2 minutes, with a dose of Horses—High (78%), with serum concentrations of 2 to 20 micrograms 10 mg/kg{R-13}. per milliliter (mcg/mL){R-6}. Elimination— Human beings—High (80%){R-4}. Intravenous: Sheep—High (84%){R-22}. Horses—8.1 hours{R-6}; 7.3 hours{R-7}; 6 hours{R-13}. Sheep— {R-19} {R-21} Biotransformation: Nonlactating: 2.9 hours ; 4.56 hours . {R-22} The biotransformation and elimination of rifampin in animals is not well Lactating: 3.3 hours . defined. Induction of hepatic enzymes occurs in response to admin- Intramuscular (terminal elimination)— {R-13} istration of rifampin in many species{R-17; 25; 26}, but major metab- Horses: 7.3 hours, with a dose of 10 mg/kg . {R-22} olites of the parent drug in most animals have not yet been traced{R-6; Sheep: 11 hours, with a dose of 20 mg/kg . 21}. In human studies, it was found that the primary metabolite of Oral (terminal elimination)— rifampin is 25-desacetylrifampin, which is bioactive{R-4}. Human Single dose: {R-4; 65} desacetylrifampin is more profusely secreted in the bile compared with Dogs—8 hours, with a dose of 10 mg/kg . rifampin, but is less concentrated in the serum than the parent drug{R-4}. Foals— And while rifampin undergoes extensive human enterohepatic 1 week of age: 25.4 ± 1.2 hours, with a dose of 10 mg/ {R-14} recycling, desacetylrifampin is poorly absorbed and therefore is not kg . recycled{R-6}. 10 weeks of age: 7.9 ± 1.5 hours, with a dose of 10 mg/ {R-14} Horses—Desacetylrifampin was not detected in serum samples after kg . {R-6} an intravenous dose of 10 mg/kg or oral doses of 10 mg/kg every Horses—13.3 hours, with a dose of 10 mg/kg . {R-21} 12 hours for seven doses{R-6}. The metabolite was measured in Sheep—6.42 hours, with a dose of 20 mg/kg . urine, but the parent compound was much more predominant{R-6}; Multiple doses: Horses—7.99 hours, after the seventh dose of 10 mg/ {R-6} however, only 6.82% of the total dose was recovered in the urine as kg, administered every 12 hours . either rifampin or desacetylrifampin{R-6}. Note: Multiple doses result in lower peak serum concentrations and a {R-4} Rats—Desacetylrifampin is formed in extremely low quantities in decreased half-life, because of autoinduction of hepatic enzymes . rats{R-25}. Sheep—Desacetylrifampin was not found in serum samples from sheep Concentrations: administered either intravenous or oral rifampin{R-21}. Rifampin and Time to peak concentration— metabolites have not been measured in sheep urine. Intramuscular administration: Rifampin can induce hepatic enzymes, including increasing its own Horses—4.2 ± 0.2 hours, with a dose of 10 mg/kg{R-13}. hepatic biotransformation with multiple doses{R-17; 25}. Induction has Sheep—3 hours, with a dose of 20 mg/kg{R-22}. been shown to occur in many species, including dogs{R-27}, horses{R- Oral: 17}, pigs{R-30}, and rabbits{R-28; 29}. The dose needed to induce an Calves, 2 to 3 weeks of age—4 to 8 hours, with a dose of 10 mg/kg{R- increase in hepatic enzymes varies among species. Rats administered 19}.

Dogs—2 to 4 hours, with a dose of 10 mg/kg{R-4; 65}. Horses: Serum concentrations greater than 2 mcg/mL were reached 45 Foals, 6 to 8 weeks of age—4 hours, with a dose of 10 mg/kg{R-16}. minutes after intragastric rifampin administration of 20 mg/kg and Horses— concentrations were maintained at greater than 3 mcg/mL for at least 3 hours{R-6}; 1.6 ± 0.5 hours{R-14}, with a single dose of 10 mg/kg. 24 hours. 3.7 ± 1.2 hours{R-13}; 3.5 ± 1.7 hours{R-14}, with a single dose of 10 mg/kg, administered with food{R-13}. Elimination: Horses: Only 6.82% of the intravenous dose of 10 mg/kg 2.5 hours, with an intragastric dose of 20 mg/kg of oral was recovered in the urine as rifampin or desacetylrifampin, an active suspension{R-7}. metabolite{R-6}. It is not known if the rifampin not recovered is pre- 3.5 hours, with a dose of 25 mg/kg, administered with food{R-13}. dominately sequestered in the tissue or perhaps excreted in bile pri- Sheep—4 to 8 hours{R-19}; 8 to 24 hours{R-21}. marily as desacetylrifampin, a more polar and more easily bile-excreted Peak serum concentration—Autoinduction of hepatic enzymes can cause compound{R-6}. multiple doses of rifampin to result in lower peak serum concentrations Total clearance— than expected, if based on single dose measurements{R-4; 19}. Horses: 1.14 mL/min/kg{R-6}; 1.34 mL/min/kg{R-13}. Intramuscular: Sheep: 1.16 ± 0.21 mL/min/kg{R-21}; 5.17 mL/min/kg{R-19}. Horses—4 ± 0.3 mcg/mL, with a dose of 10 mg/kg{R-13}. Sheep—Approximately 8 mcg/mL (from graph), with a dose of 20 mg/kg{R-22}. Oral: PRECAUTIONS TO CONSIDER Calves, 2 to 3 weeks of age—11.7 to 24.6 mcg/mL, with a dose of 10 SPECIES SENSITIVITY mg/kg{R-19}. Dogs: There is very little information about the effects of rifampin in small Dogs—40 mcg/mL, with a dose of 10 mg/kg{R-4; 65}. animals; however, there is anecdotal information warning that up to Foals, 6 to 8 weeks of age—6.7 mcg/mL, with a dose of 10 mg/ 20% or more of dogs receiving 5 to 10 mg per kg of body weight kg{R-16}. (mg/kg) a day will develop increases in hepatic enzymes that may lead Horses— to clinical hepatitis{R-4}. Because one study found peak serum 3.9 mcg/mL{R-6}; 4.5 ± 1.1 mcg/mL{R-14}, with a dose of 10 mg/kg. concentrations in dogs that were four times that of horses after a 2.9 ± 0.4 mcg/mL{R-13}; 3.3 ± 2.9 mcg/mL{R-14}, with a dose of 10 standard dose of 10 mg/kg, it has been suggested that the incidence of mg/kg, administered with food. side effects in dogs may be due to overdosage{R-4; 65}. Some clinicians 13.3 ± 2.7 mcg/mL, with intragastric administration of 20 mg/kg have noted lethargy, bilirubinemia, and bilirubinuria in dogs admin- of oral suspension{R-7}. istered rifampin, but there is no information on incidence of adverse 9.8 ± 1.9 mcg/mL, with a dose of 25 mg/kg, administered with effects, dosage administered, pretreatment liver evaluation, or other food{R-13}. factors{R-57}. Sheep— 0.6 to 2.4 mcg/mL, with a dose of 10 mg/kg{R-19}. 3.27 ± 1.43, with a dose of 20 mg/kg{R-21}. TUMORGENICITY Other concentrations— Studies in female mice of a strain known to be particularly susceptible to Cerebrospinal fluid: Rabbits—1.3 to 1.6 mcg/mL from 30 minutes to the spontaneous development of hepatomas have shown that rifampin, 12 hours after an oral dose of 10 mg/kg{R-18}. given in doses of 2 to 10 times the maximum human dose (20 mg per Serum: kg of body weight, up to 600 mg every 12 hours) for 1 year, causes a Dogs—9 to 10 mcg/mL, 24 hours after an oral dose of 10 mg/ significant increase in the development of hepatomas. However, kg{R-65}. studies in male mice of the same strain, in other strains of male or Horses— female mice, and in rats have not shown that rifampin is tumori- 6.86 ± 1.69 mcg/mL, 12 hours after an intragastric dose of 20 mg/ genic{R-2}. kg of oral suspension{R-7}. 3.83 ± 0.87 mcg/mL, 24 hours after an intragastric dose of 20 mg/ PREGNANCY/REPRODUCTION kg of oral suspension{R-7}. Mice and rats: Oral doses of 150 to 250 mg/kg during pregnancy Rabbits—Ranged from 1.8 to 2.5 mcg/mL from 30 minutes to 12 produced dose-dependent teratogenic effects in offspring, including hours after an oral dose of 10 mg/kg{R-18}. cleft palate in the mouse and spina bifida in the rat{R-2}. Sheep—0.97 ± 0.61 mcg/mL, 24 hours after an oral dose of 20 mg/ Human information: Rifampin has caused postnatal hemorrhage in kg in a gelatin capsule{R-21}. the mother and infant when administered during the last weeks of pregnancy{R-2}. Treatment with vitamin K may be Duration of action: The National Committee for Clinical Laboratory indicated{R-2}. Standards (NCCLS) in the United States lists minimum inhibitory concentration (MIC) breakpoints for animal isolates and rifampin as £ 1 mcg/mL for susceptible organisms and ‡ 4 mcg/mL for resistant LACTATION organisms{R-8}. Sheep: Rifampin is well-distributed into milk, with a milk to serum concentration ratio of 0.9 to 1.28 in sheep given an intramuscular Dogs: Serum concentration was 9 to 10 mcg/mL 24 hours after a single dose of 10 mg/kg{R-22}. oral dose of 10 mg/kg{R-65}.

DRUG INTERACTIONS AND/OR RELATED PROBLEMS Barbiturates The following drug interactions and/or related problems have been (concurrent use with rifampin may enhance the metabolism of selected on the basis of their potential clinical significance (possible hexobarbital by induction of hepatic microsomal enzymes, result- mechanism in parentheses where appropriate)—not necessarily inclu- ing in lower serum concentrations; there are conflicting data on sive (» = major clinical significance): rifampin’s effect on phenobarbital; dosage adjustment may be Note: Combinations containing any of the following medications, required) depending on the amount present, may also interact with this Beta-adrenergic blocking agents, systemic medication. (concurrent use of metoprolol or propranolol with rifampin has Drugs metabolized by hepatic microsomal enzymes, including: resulted in reduced plasma concentrations of these two beta- Ciprofloxacin{R-29} or adrenergic blocking agents due to enhanced metabolism of hepatic Corticosteroids{R-4} or microsomal enzymes by rifampin; although not documented, other Digitalis glycosides{R-4} or beta-adrenergic blocking agents may also interact with rifampin) Itraconazole{R-30} or Bone marrow depressants Ketoconazole{R-4} or (concurrent use of bone marrow depressants with rifampin may Phenobarbital{R-5} or increase the leukopenic and/or thrombocytopenic effects; if con- Phenylbutazone{R-17} or current use is required, close observation for myelotoxic effects Warfarin{R-4; 31} should be considered) (rifampin causes induction of hepatic enzymes in dogs{R-27}, Chloramphenicol mice{R-26}, horses{R-5; 17}, pigs{R-30}, and rabbits{R-28; 29}, poten- (concurrent use with rifampin may enhance the metabolism of tially increasing metabolism{R-5} and thereby decreasing serum chloramphenicol by induction of hepatic microsomal enzymes, concentrations{R-4} of the above medications; there is some resulting in significantly lower serum chloramphenicol concen- selectivity in enzyme induction so that not every drug that is trations; dosage adjustment may be necessary) oxidized by the system is affected{R-29}; in guinea pigs and rats, Clofazimine hepatic metabolism does not appear to be significantly induced by (concurrent use with rifampin has resulted in reduced absorption commonly administered dosages of rifampin{R-26; 27} but can be of rifampin, delaying its time to peak concentration, and increas- by extremely high doses{R-25}; phenobarbital will also increase the ing its half-life) metabolism of rifampin by enzyme induction{R-17}) Corticosteroids, glucocorticoid and mineralocorticoid (concurrent use with rifampin may enhance the metabolism of HUMAN DRUG INTERACTIONS AND/OR RELATED corticosteroids by induction of hepatic microsomal enzymes, PROBLEMS{R-79} resulting in a considerable decrease in corticosteroid plasma concentrations; dosage adjustment may be required; rifampin has In addition to the above drug interactions reported in animals, the also counteracted endogenous cortisol and produced acute adrenal following drug interactions have been reported in humans, and are insufficiency in patients with Addison’s disease) included in the human monograph Rifampin (Systemic) in USP DI Cyclosporine Volume I; these drug interactions are intended for informational (rifampin may enhance metabolism of cyclosporine by induction of purposes only and may or may not be applicable to the use of rifampin hepatic microsomal enzymes and intestinal cytochrome P450 in the treatment of animals: enzymes; dosage adjustment may be required) Aminophylline or Dapsone Oxtriphylline or (concurrent use with rifampin may decrease the effect of dapsone Theophylline because of increased metabolism resulting from stimulation of (rifampin may increase metabolism of theophylline, oxtriphylline, hepatic microsomal enzyme activity; dapsone concentrations may and aminophylline by induction of hepatic microsomal enzymes, be decreased by half; dapsone dosage adjustments are not required resulting in increased theophylline clearance) during concurrent therapy with rifampin for leprosy) Anesthetics, hydrocarbon inhalation, except isoflurane Diazepam (chronic use of hepatic enzyme–inducing agents prior to anesthe- (concurrent use with rifampin may enhance the elimination of sia, except isoflurane, may increase anesthetic metabolism, leading diazepam, resulting in decreased plasma concentrations; whether to increased risk of hepatotoxicity) this effect applies to other benzodiazepines has not been deter- Anticoagulants, coumarin- or indandione-derivative mined; dosage adjustment may be necessary) (concurrent use with rifampin may enhance the metabolism of Disopyramide or these anticoagulants by induction of hepatic microsomal enzymes, Mexiletine or resulting in a considerable decrease in the activity and effective- Propafenone or ness of the anticoagulants; prothrombin time determinations may Quinidine or be required as frequently as once a day; dosage adjustments of Tocainide anticoagulants may be required before and after rifampin therapy) (concurrent use with rifampin may enhance the metabolism of Azole antifungals these antiarrhythmics by induction of hepatic microsomal (concurrent use may increase the metabolism of the azole enzymes, resulting in significantly lower serum antiarrhythmic antifungals, lowering their plasma concentrations; depending on concentrations; serum antiarrhythmic concentrations should be the clinical situation, the dose of an azole antifungal may need to monitored and dosage adjustment may be necessary) be increased during concurrent use with rifampin)

Estramustine or With diagnostic test results Estrogens Indocyanine green and (concurrent use of estramustine or estrogens with rifampin may Sulfobromophthalein sodium excretion test (BSP) result in significantly reduced estrogenic effect because of stimu- (in rats, plasma clearances of indocyanine green and sulfobromoph- lation of estrogen metabolism or reduction in enterohepatic thalein sodium were increasingly and significantly delayed after 200 circulation of estrogens) mg per kg of body weight a day was administered for 1 to 7 days{R-25}; Hepatotoxic medications, other the impact of recommended doses, such as 20 mg/kg a day, on these (concurrent use of rifampin and other hepatotoxic medications excretion tests has not been measured) may increase the potential for hepatotoxicity; patients should be With physiology/laboratory test values monitored closely for signs of hepatotoxicity) Alkaline phosphatase{R-57} Human immunodeficiency virus (HIV) protease inhibitors, such as (in the dog, mild increases in serum alkaline phosphatase levels are Amprenavir or common and are not considered significant unless accompanied by Indinavir or elevations in other hepatic enzymes{R-4; 54}) Nelfinavir or Ritonavir or {R-79} Saquinavir HUMAN LABORATORY VALUE ALTERATIONS (rifampin accelerates the metabolism of protease inhibitors The following laboratory value alterations have been reported in through induction of hepatic P450 cytochrome oxidases, resulting humans, and are included in the human monograph Rifampin in subtherapeutic levels of the protease inhibitors; in addition, (Systemic) in the USP DI Volume I; these laboratory value alterations protease inhibitors retard the metabolism of rifampin, resulting in are intended for informational purposes only and may or may not be increased serum levels of rifampin and the likelihood of increased applicable to the use of rifampin in the treatment of animals: drug toxicity; concurrent use of HIV protease inhibitors with With diagnostic test results rifampin is only recommended under specific circumstances as Coombs’ (antiglobulin) tests, direct (may become positive rarely outlined by the Centers for Disease Control and Prevention [CDC]) during rifampin therapy) Isoniazid Dexamethasone suppression test (concurrent use of isoniazid with rifampin may increase the risk of (rifampin may prevent the inhibitory action of a standard hepatotoxicity, especially in patients with preexisting hepatic dexamethasone dose administered for the overnight suppression function impairment and/or in fast acetylators of isoniazid; test, rendering the test abnormal; it is recommended that rifampin patients should be monitored closely for signs of hepatotoxicity therapy be discontinued 15 days before administering the dexa- during the first 3 months of therapy) methasone suppression test) Phenytoin Folate determinations, serum and (concurrent use with rifampin may stimulate the hepatic metab- Vitamin B12 determinations, serum olism of phenytoin, increasing its elimination and thus counter- (therapeutic concentrations of rifampin may interfere with stan- acting its anticonvulsant effects; careful monitoring of serum dard microbiological assays for serum folate and vitamin B12; hydantoin concentrations and dosage adjustments may be neces- alternate methods must be considered when determining serum sary before and after rifampin therapy) folate and vitamin B12 concentrations in patients taking rifampin) Probenecid Sulfobromophthalein (BSP) uptake and excretion (may compete with rifampin for hepatic uptake when used (hepatic uptake and excretion of BSP in liver function tests may be concurrently, resulting in increased and more prolonged rifampin delayed by rifampin, resulting in BSP retention; the BSP test serum concentrations and/or toxicity; however, the effect on should be performed prior to the daily dose of rifampin to avoid rifampin serum concentrations is inconsistent, and concurrent use false-positive test results) of probenecid to increase rifampin serum concentrations is not Urinalyses based on spectrometry or color reaction recommended) (rifampin may interfere with urinalyses that are based on Trimethoprim spectrometry or color reaction due to rifampin’s reddish-orange (concurrent use with rifampin may significantly increase the to reddish-brown discoloration of urine) elimination and shorten the elimination half-life of trimethoprim) With physiology/laboratory test values Verapamil, oral Alanine aminotransferase (ALT [SGPT]) and (rifampin has been found to accelerate the metabolism of oral Alkaline phosphatase and doses of verapamil, resulting in a significant decrease in serum Aspartate aminotransferase (AST [SGOT]) verapamil concentration, and thereby reversing its cardiovascular (values may be increased) effects; concurrent use of intravenous verapamil with rifampin Bilirubin, serum and was found to have only minor effects on verapamil’s clearance and Blood urea nitrogen (BUN) and no significant effect on cardiovascular effects) Uric acid, serum (concentrations may be increased) LABORATORY VALUE ALTERATIONS The following have been selected on the basis of their potential clinical MEDICAL CONSIDERATIONS/CONTRAINDICATIONS significance (possible effect in parentheses where appropriate)—not The medical considerations/contraindications included have been necessarily inclusive (» = major clinical significance): selected on the basis of their potential clinical significance (reasons

given in parentheses where appropriate)—not necessarily inclusive Volume I; these side/adverse effects are intended for informational (» = major clinical significance). purposes only and may or may not be applicable to the use of rifampin Risk-benefit should be considered when the following medical in the treatment of animals: problem exists: Incidence more frequent » Hepatic function impairment, severe Gastrointestinal disturbances; reddish-orange to reddish- (in dogs, hepatic function impairment may predispose to major side brown discoloration of urine, feces, saliva, sputum, sweat, effects, and the risk should be carefully considered{R-4}; in any species, and tears dosage adjustments may be necessary with hepatic dysfunction and Incidence less frequent avoiding use of rifampin should be considered{R-4; 6}) Flu-like syndrome (chills; difficult breathing; dizziness; fever; headache; muscle and bone pain; shivering); fungal overgrowth; hyper- PATIENT MONITORING sensitivity The following may be especially important in patient monitoring (other Incidence rare tests may be warranted in some patients, depending on condition; » = Blood dyscrasias; hepatitis; hepatitis prodromal symptoms; major clinical significance): interstitial nephritis Hepatic enzyme tests Note: Intermittent use of rifampin may increase the chance of a patient (particularly in dogs, hepatic enzymes should be monitored during developing the flu-like syndrome, as well as acute hemolysis or renal rifampin therapy) failure. These reactions are thought to be immunologically mediated, and intermittent use of the medication should be limited to SIDE/ADVERSE EFFECTS those conditions in which its safety and efficacy have been The following side/adverse effects have been selected on the basis of their established. potential clinical significance (possible signs and, for humans, symptoms in parentheses where appropriate)—not necessarily inclusive: OVERDOSE For more information in the case of overdose or unintentional ingestion, contact the American Society for the Prevention of Cruelty to THOSE INDICATING NEED FOR MEDICAL ATTENTION Animals (ASPCA) National Animal Poison Control Center (888- Incidence more frequent 426-4435 or 900-443-0000; a fee may be required for consultation) Foals and/or the manufacturer. Diarrhea, self-limiting{R-34}—often occurs in the first week of The lethal dose for 50% of test animals (LD50) is approximately 885 mg therapy and resolves without treatment{R-34} per kg of body weight (mg/kg) in the mouse, 1720 mg/kg in the rat, Incidence unknown and 2120 mg/kg in the rabbit{R-2}. Dogs Hepatotoxicity{R-4} Horses CLINICAL EFFECTS OF OVERDOSE With intravenous administration (dimethylsulfoxide vehicle) In human beings, overdose can cause mental changes, nausea and Allergic reactions, specifically anaphylactoid reactions{R-17}; vomiting, angioedema, generalized pruritus, and red-orange discolor- central nervous system depression, generalized{R-13}; decreased ation of the mucous membranes, sclera, and skin{R-63}. Signs of appetite{R-13}; signs of distress (apprehension, pawing with forefeet, overdose specific to animals are not known. shifting of weight-bearing from one side to another){R-14}; sudden {R-14} {R-14} defecation ; weakness or unsteadiness TREATMENT OF OVERDOSE Note: Hemolysis was seen grossly in blood samples of some horses From the human therapeutic literature{R-2; 63}: administered intravenous rifampin at a dose of 10 mg/kg{R-13}. To decrease absorption— The signs listed above have been reported with administration of Evacuating stomach contents using ipecac syrup or gastric lavage. rifampin in a dimethylsulfoxide vehicle; therefore, it is unclear Administering an activated charcoal slurry to help adsorb residual whether some effects, such as allergic-like reactions or hemolysis, rifampin in the gastrointestinal tract. were caused by the vehicle or by rifampin{R-78}. Supportive therapy.

THOSE INDICATING NEED FOR MEDICAL ATTENTION CLIENT CONSULTATION ONLY IF THEY CONTINUE OR ARE BOTHERSOME Notify your veterinarian of any medications your animal is already Incidence more frequent receiving before treatment or any medications that may be initiated Horses during treatment with rifampin because drug interactions can occur{R-4}. Sweating, mild to moderate—may occur with parenteral adminis- It is important to be sure that the animal receives the full course of {R-13; 14} tration, more prominent with intravenous administration . treatment prescribed. However, if new signs occur, such as decreased appetite, depression, diarrhea, or jaundice{R-13; 14; 34}, contact your HUMAN SIDE/ADVERSE EFFECTS{R-79} veterinarian. In addition to the above side/adverse effects reported in animals, the Reddish-orange to reddish-brown discoloration of urine, stools, saliva, following side/adverse effects have been reported in humans, and are sputum, sweat, and tears may occur as a typical effect of the {R-63; 64} included in the human monograph Rifampin (Systemic) in USP DI medication, but is not harmful .

VETERINARY DOSING INFORMATION [Potomac horse fever]1—Horses: Oral, 10 mg per kg of body weight every The National Committee for Clinical Laboratory Standards (NCCLS) in twelve hours in combination with 25 mg of erythromycin estolate or the United States lists minimum inhibitory concentration (MIC) erythromycin ethylsuccinate per kg of body weight every twelve {R-56} breakpoints of animal isolates for rifampin as £ 1 mcg/mL for hours . 1 susceptible organisms and ‡ 4 mcg/mL for resistant organisms{R-8}. Note: [Horses] —Although the safety and efficacy of rifampin have not Organisms testing between these values are considered intermediate been established, an oral dose of 10 mg rifampin per kg of body weight {R-6; 7} and may or may not be inhibited{R-8}. every twelve hours has been used in the treatment of susceptible Specifically for Rhodococcus equi, one study of nine strains found minimum bacterial infections, such as staphylococcal infections in horses, based on inhibitory concentrations (MICs) for rifampin to be 0.0078 to 0.0625 pharmacokinetic data. It is usually administered in combination with {R-6; 7} mcg/mL{R-10}. In another study, a MIC of less than or equal to 0.25 mcg/ another antimicrobial, such as erythromycin or penicillin . 1 1 1 mL was found for 18 Rhodococcus equi isolates{R-7}; 83% of these isolates [Cattle] ,[goats] , and [sheep] —For use in animals not to be used in had an MIC of 0.0625 or less{R-7}. food production: Although the safety and efficacy of rifampin have not Other equine organisms have also been found to have MICs of less than been established, an oral dose of 20 mg per kg of body weight every 0.25 mcg/mL, including coagulase-positive Staphylococcus species (MIC twenty-four hours has been used in the treatment of susceptible {R-23} {R-19; 20} of 0.0625 or less), Streptococcus zooepidemicus (MIC of 0.0625 or less), bacterial infections in cattle and sheep , based on S. equi (MIC of 0.0625 or less), S. equisimilis (MIC of 0.125 or less), and pharmacokinetic data. For the treatment of paratuberculosis in cattle, Corynebacterium pseudotuberculosis (MIC of 0.0156 or less){R-7}. Gram- goats, and sheep, an oral dose of 20 mg per kg of body weight every negative organisms have been found to be variably susceptible or twenty-four hours, administered in conjunction with 20 mg of oral resistant{R-7}. The MICs of 19 Actinobacillus isolates from horses ranged isoniazid per kg of body weight every twenty-four hours, has been used {R-23} from 1 to 4 mcg/mL{R-7}. to control signs, based on case reports and the pharmacokinetics {R-19; 21} The possibility of mixed infections involving both gram-positive and known ; however, clinical improvement only occurs for a short gram-negative organisms should be considered in some situations, period of time and does not prevent spread of the infection to other {R-23; 44} such as young horses with respiratory tract infections{R-7; 36}. animals . 1 Because nonenteric gram-negative organisms can have variable [Dogs] —If rifampin is administered to dogs, dosing of rifampin should susceptibility, susceptibility data should be used to determine the generally be kept below 10 mg per kg of body weight a day, based on {R-4} appropriate therapy{R-7}. The possibility of mixed infections and limited pharmacokinetic data and reports of hepatic toxicity in dogs . the rapid rise of resistance to rifampin make combination therapy A single oral dose of 10 mg per kg appears to produce much higher the most logical recourse in many cases{R-7}. Rifampin has been serum concentrations than the same dose administered to other {R-4; 65} shown in in vitro tests to have synergistic activity with erythromycin species , with a possibly increased risk of toxicity. The best dose or trimethoprim and to have an additive effect with ampicillin or for maximum safety and efficacy has not been established. penicillin G{R-7; 9; 10}. However, rifampin’s activity in in vitro tests can be antagonistic to those of other antimicrobials, such as Strength(s) usually available: gentamicin{R-10}; it is not certain how this interaction might affect U.S.— in vivo activity. Veterinary-labeled product(s): Not commercially available. Human-labeled product(s): FOR ORAL DOSAGE FORMS ONLY {R-2} 150 mg (Rx) [Rifadin ]. Administration with food reduces the rate of absorption and prolongs the 300 mg (Rx) [Rifadin{R-2}; Rimactane{R-24}; generic]. time to peak concentration in adult horses{R-4}. Canada— Veterinary-labeled product(s): ORAL DOSAGE FORMS Not commercially available. Note: In other USP DI monographs, bracketed uses in the Dosage Forms Human-labeled product(s): section refer to categories of use and/or indications that are not 150 mg (Rx) [Rifadin; Rimactane; Rofact]. included in U.S. product labeling, and superscript 1 refers to categories 300 mg (Rx) [Rifadin; Rimactane; Rofact]. of use and/or indications that are not included in Canadian product labeling. However, since rifampin is not specifically approved for Withdrawal times: veterinary use, there is no product labeling identifying approved U.S. and Canada—The use of rifampin in food-producing animals has not indications. been approved by the Food and Drug Administration or the Canadian Health Protection Branch; therefore, there are no established with- RIFAMPIN CAPSULES USP drawal times. Usual dose: The issue of whether rifampin should be used in food animals is [Pneumonia, Rhodococcus equi]1 ;or complicated by its link to hepatic tumors in one strain of female mice (see [Extrapulmonary infection, Rhodococcus equi]1—Foals: Oral, 5 mg per kg Tumorgenicity under Precautions in this monograph). The significance of of body weight every twelve hours in combination with 25 mg of this link is not known, but any residue of a known carcinogen in animal erythromycin estolate or erythromycin ethylsuccinate per kg of body products for human consumption is considered a violation of the Food, weight every six to eight hours{R-34; 36}. Therapy may be continued for Drug, and Cosmetic Act. As such, the USP Veterinary Medicine Advisory four to nine weeks or until radiographs and complete blood counts are Panel has concluded that rifampin should not be administered to normal{R-66}. animals intended for production of products for human consumption.

Packaging and storage: Store below 40 C (104 F), in a tight Prior to intravenous infusion, the amount calculated for administration container, unless otherwise specified by the manufacturer{R-2; 3}. is added to 500 mL or, in some cases, 100 mL of infusion medium and Protect from light{R-3}. mixed well before administration{R-3}. Dextrose 5% for Injection is recommended for infusion medium, but sterile saline may also be used with a slight reduction in stability{R-2}. Preparation of dosage form: Human product labeling suggests the preparation of an extemporaneous oral 1% w/v suspension with Stability: The reconstituted 60 mg/mL solution is stable for 24 hours at preprepared syrups when necessary{R-2}. room temperature{R-2}. Once mixed with infusion medium to produce a 100 mL or 500 mL solution, the product should be administered within USP requirements: Preserve in tight, light-resistant containers, pro- 4 hours; precipitation of rifampin may occur after this time{R-2}. tected from excessive heat. Contain the labeled amount, within ±10%. Meet the requirements for Identification, Dissolution (75% in 45 minutes in 0.1 N hydrochloric acid in Apparatus 1 at 100 rpm), Uniformity USP requirements: Preserve in Containers for Sterile Solids. Contains of dosage units, and Loss on drying (not more than 3.0%){R-3}. the labeled amount, within –10% to +15%. Meets the requirements for Identification, Bacterial endotoxins, Sterility, pH (7.8–8.8, in a solution containing 60 mg of rifampin per mL), Water (not more than 1.0%), PARENTERAL DOSAGE FORMS and Particulate matter{R-3}. Note: In other USP DI monographs, bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included Developed: 11/05/99 in U.S. product labeling, and superscript 1 refers to categories of use Interim revision: 09/30/02; 03/28/03 and/or indications that are not included in Canadian product labeling. However, since rifampin is not specifically approved for veterinary use, REFERENCES there is no product labeling identifying approved indications. 1. USP dictionary of USAN and international drug names, 2002 ed. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 2002. 2. Rifadin and Rifadin I.V. package insert (Hoechst Marion Roussel, Inc—US), RIFAMPIN FOR INJECTION USP Rev 2/96, Rec 2/4/97. Note: Although parenteral pharmacokinetic studies have been performed 3. The United States pharmacopeia. The national formulary. USP 26th revision in horses{R-6; 7; 13} and sheep{R-19; 21; 22}, rifampin is generally (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, Maryland: The United States Pharmacopeial Convention, Inc.; 2002. p. 1640–2, 2579. administered by the oral route in animals. 4. Frank LA. Clinical pharmacology of rifampin. J Am Vet Med Assoc 1990 Jul 1; See Rifampin Capsules USP; however, also note that oral dosing for 197(1): 114–7. horses is adjusted for poor bioavailability. Use of oral dosing for 5. Burrows GE, MacAllister CG, Tripp P, et al. Interactions between chloram- parenteral administration of rifampin could result in overdosage. phenicol, acepromazine, phenylbutazone, rifampin, and thiamylal in the horse. Equine Vet J 1989; 21(1): 34–8. Parenteral rifampin should be administered only by the intravenous 6. Kohn CW, Sams R, Kowalske JJ, et al. Pharmacokinetics of single intravenous route, not intramuscularly or subcutaneously. and single and multiple dose oral administration of rifampin in mares. J Vet Pharmacol Ther 1993; 16: 119–31. Strength(s) usually available: 7. Wilson WD, Spensley MS, Baggot JD, et al. Pharmacokinetics, bioavailability, and in vitro antibacterial activity of rifampin in the horse. Am J Vet Res 1988 U.S.— Dec; 49(12): 2041–6. Veterinary-labeled product(s): 8. The National Committee for Clinical Laboratory Standards (NCCLS). Perfor- Not commercially available. mance standards for antimicrobial disk and dilution susceptibility tests for bacteria isolated from animals; proposed standards. NCCLS document M31-P Human-labeled product(s): (ISBN 1-56238-258-6). Villanova, PA: National Committee for Clinical {R-2} 600 mg (Rx) [Rifadin IV] . Laboratory Standards; 1994. p. 5–6, 34–7. Canada— 9. Kerry DW, Hamilton-Miller JMT, Brumfitt W. Trimethoprim and rifampicin: Veterinary-labeled product(s): in vitro activities separately and in combination. J Antimicrob Chemother 1975; 1: 417–27. Not commercially available. 10. Prescott JF, Nicholson VM. The effects of combinations of selected antibiotics Human-labeled product(s): on the growth of Corynebacterium equi. J Vet Pharmacol Ther 1984; 7: 61–4. Not commercially available. 11. Thornsberry C, Hill BC, Swenson JM, et al. Rifampin: spectrum of antibacterial activity. Rev Infect Dis 1983 Jul/Aug; 5(Suppl. 3): S412–S417. 12. Wehrli W. Rifampin: mechanisms of action and resistance. Rev Infect Dis 1983 Withdrawal times: Jul/Aug; 5(Suppl 3): S407–S411. U.S. and Canada—The use of rifampin in food-producing animals has not 13. Burrows GE, MacAllister CG, Beckstrom DA, et al. Rifampin in the horse: been approved by the Food and Drug Administration or the Canadian comparison of intravenous, intramuscular, and oral administrations. Am J Vet Res 1985 Feb; 46(2): 442–6. Health Protection Branch; therefore, there are no established with- 14. Burrows GE, MacAllister CG, Ewing P, et al. Rifampin disposition in the horse: drawal times. effects of age and method of oral administration. J Vet Pharmacol Ther 1992; 15: 124–32. 15. Baggot JD. Bioavailability and bioequivalence of veterinary drug dosage forms, Packaging and storage: Store below 40 C (104 F), preferably with particular reference to horses: an overview. J Vet Pharmacol Ther 1992 between 15 and 30 C (59 and 86 F), in a tight container, unless Jun; 15(2): 160–73. otherwise specified by the manufacturer. Protect from light{R-2}. 16. Castro LA, Brown MP, Gronwall R, et al. Pharmacokinetics of rifampin given as a single oral dose in foals. Am J Vet Res 1986 Dec; 47(12): 2584–6. Preparation of dosage form: Human product labeling recommends 17. Burrows GE, MacAllister CG, Ewing P, et al. Rifampin disposition in the horse: that 600 mg of rifampin powder be reconstituted with 10 mL of sterile effects of repeated dosage of rifampin or phenylbutazone. J Vet Pharmacol Ther 1992; 15: 305–8. water for injection to produce a 60 mg per mL (mg/mL) solution{R-2}.

18. Chan K. Rifampicin concentrations in cerebrospinal fluid and plasma of the 49. Zak O, Tosch W, Sande MA. Correlation of antibacterial activities of antibiotics rabbit by high performance liquid chromatography. Methods Find Exp Clin in vitro and in animal models of infection. J Antimicrob Chemother 1985 Jan; Pharmacol 1986 Dec; 8(12): 721–6. 25(Suppl A): 273–82. 19. Sweeney RW, Divers TJ, Benson C, et al. Pharmacokinetics of rifampin in 50. Guitierrez CB, Piriz S, Vadillo S, et al. In vitro susceptibility of Actinobacillus calves and adult sheep. J Vet Pharmacol Ther 1988 Dec; 11(4): 413–6. pleuropneumoniae strains to 42 antimicrobial agents. Am J Vet Res 1993 Apr; 20. Lobo MC, Mandell GL. Treatment of experimental staphylococcal infection 54(4): 546–50. with rifampin. Antimicrob Agents Chemother 1972 Sep; 2(3): 195–200. 51. Stevens DL, Laine BM, Mitten JE. Comparison of single and combination anti- 21. Jernigan AD, St-Jean GD, Rings DM, et al. Pharmacokinetics of rifampin in microbial agents for prevention of experimental gas gangrene caused by Clos- adult sheep. Am J Vet Res 1991 Oct; 52(10): 1626–9. tridium perfringens. Antimicrob Agents Chemother 1987 Feb; 31(2): 312–6. 22. Ziv G, Sulman FG. Evaluation of rifamycin SV and rifampin kinetics in 52. Traub WH. Chemotherapy of experimental (murine) Clostridium perfringens lactating ewes. Antimicrob Agents Chemother 1974 Feb; 5(2): 139–42. type A gas gangrene. Chemotherapy 1988; 34(6): 472–7. 23. St-Jean G, Jernigan AD. Treatment of Mycobacterium paratuberculosis 53. Duran SP, Manzano JV, Valera RC, et al. In-vitro antimicrobial susceptibility of infection in ruminants. Vet Clin North Am Food Anim Pract 1991 Nov; Bacteroides and Fusobacterium isolated from footrot in goats. Br Vet J 1990; 7(3): 793–804. 146(5): 437–42. 24. Physicians desk reference, 51st ed. Montvale, NJ: Medical Economics Data 54. O’Reilly T, Kunz S, Sande E, et al. Relationship between antibiotic concentra- Production; 1995. p. 896. tion in bone and efficacy of treatment of staphylococcal osteomyelitis in rats: 25. Adachi Y, Nanno T, Yamashita M, et al. Induction of rat liver bilirubin- azithromycin compared with clindamycin and rifampin. Antimicrob Agents conjugating enzymes and glutathione S-transferase by rifampicin. Gastro- Chemother 1992 Dec; 36(12): 2693–7. enterol Jpn 1985 Apr; 20(2): 104–10. 55. Gutierrez Martin CB, Rodriguez Ferri EF. In vitro susceptibility of Pasteurella 26. Benedetti MS, Dostert P. Induction and autoinduction properties of rifamycin multocida subspecies multocida strains isolated from swine to 42 antimicrobial derivatives: a review of animal and human studies. Environ Health Perspect agents. Zentralbl Bakteriol 1993 Aug; 279(3): 387–93. 1994 Nov; 102(Suppl 9): 101–5. 56. Palmer JE, Benson CE. Effect of treatment with erythromycin and rifampin 27. Abramson FP, Lutz MP. The kinetics of induction by rifampin of alpha1-acid during the acute stages of experimentally induced equine ehrlichial colitis. glycoprotein and antipyrine clearance in the dog. Drug Metab Dispos 1986; Am J Vet Res 1992 Nov; 53(11): 2071–6. 14(1): 46–51. 57. Ackerman L. Cutaneous bacterial granuloma (botryomycosis) in five dogs: 28. Whitehouse LW, Iverson F, Wong LT. Effects of rifampin pretreatment on treatment with rifampin. Mod Vet Pract 1987 Jul/Aug; 68(7/8): 404–9. hepatic parameters in the rabbit. Toxicol Lett 1985 Feb-Mar; 24(2-3): 131–6. 58. Beck DM. Can rifampin help manage CNS infections and internal abscesses in 29. Barriere SL, Kaatz GW, Seo SM. Enhanced elimination of ciprofloxacin after cats? Vet Med 1987 Dec; 1239–40. multiple-dose administration of rifampin to rabbits. Antimicrob Agents 59. Renneberg J, Karlsson E, Nilsson B, et al. Interactions of drugs acting against Chemother 1989 Apr; 33(4): 589–90. Staphylococcus aureus in vitro and in a mouse model. J Infect 1993 May; 30. Kaltenback G, Leveque D, Peter J, et al. Pharmacokinetic interaction between 26(3): 265–77. itraconazole and rifampin in Yucutan miniature pigs. Antimicrob Agents 60. St-Jean G, Smeak DD, Hubbell JAE, et al. Resolution of pyothorax in a white- Chemother 1996 Sep; 40(9): 2043–6. tailed deer by thoracotomy, tube drainage and lavage. Can Vet J 1990 Feb; 31: 31. Wells PS, Holbrook AM, Crowther NR, et al. Interactions of warfarin with 110–2. drugs and food. Ann Intern Med 1994 Nov 1; 121(9): 676–83. 61. Gezon HM, Bither HD, Gibbs HC, et al. Identification and control of 32. Prescott JF, Sweeney CR. Treatment of Corynebacterium equi pneumonia of paratuberculosis in a large herd. Am J Vet Res 1988 Nov; 49(11): 1817–23. foals: a review. J Am Vet Med Assoc 1985 Oct; 187(7): 725–8. 62. Sanchez MS, Ford CW, Yancey RJ. Evaluation of antibiotic effectiveness against 33. Knottenbelt DC. Rhodococcus equi infection in foals: a report of an outbreak on Staphylococcus aureus surviving within the bovine mammary gland macro- a thoroughbred stud in Zimbabwe. Vet Rec 1993 Jan 23; 132(4): 79–85. phage. J Antimicrob Chemother 1988 Jun; 21(6): 773–86. 34. Hillidge CJ. Use of erythromycin-rifampin combination in treatment of 63. Wong P. Acute rifampin overdose: a pharmacokinetic study and review of the Rhodococcus equi pneumonia. Vet Microbiol 1987 Aug; 14(3): 337–42. literature. J Pediatr 1984; 104(5): 781–3. 35. Hillidge CJ. Review of Corynebacterium (Rhodococcus) equi lung abscesses in 64. Essey MA, Koller MA. Status of bovine tuberculosis in North America. Vet foals; pathogenesis, diagnosis, and treatment. Vet Rec 1986 Sep 13; 119: 261–4. Microbiol 1994; 40: 15–22. 36. Sweeney CR, Sweeney RW, Divers TJ. Rhodococcus equi pneumonia in 48 foals: 65. Finel JM, Pittillo RF, Mellett LB. Flourometric and microbiological assays for response to antimicrobial therapy. Vet Microbiol 1987 Aug; 14(3): 329–36. rifampicin and the determination of serum levels in the dog. Chemotherapy 37. Nay TS. Extrapulmonary Rhodococcus equi in a thoroughbred foal. Can Vet J 1971; 16: 380–8. 1996 Oct; 37(10): 623–4. 66. Prescott JF. Rhodococcus equi: an animal and human pathogen. Clin Microbiol 38. Chaffin MK, Honnas CM, Crabill MR, et al. Cauda equina syndrome, Rev 1991 Jan; 4(1): 20–34. diskospondylitis, and a paravertebral abscess caused by rhodococcus equi in 67. Giguere S, Prescott JF. Clinical manifestations, diagnosis, treatment, and a foal. J Am Vet Med Assoc 1995 Jan 15; 206(2): 215–20. prevention of Rhodococcus equi infections in foals. Vet Microbiol 1997 June 39. Kenney DG, Robbins SC, Prescott JF, et al. Development of reactive arthritis 16; 56(3-4): 313–34. and resistance to erythromycin and rifampin in a foal during treatment for 68. Molik GM. Early clinical response to different therapeutic regimens for human Rhodococcus equi pneumonia. Equine Vet J 1994; 25(3): 246–8. brucellosis. Am J Trop Med Hyg 1998; 58(2): 190–1. 40. Collatos C, Clark ES, Reef VB, et al. Septicemia, atrial fibrillation, cardiomegaly, 69. Solera J, Rodriquez-Zopoto M, Geijo P, et al. Doxycycline-rifampin versus left atrial mass, and Rhodococcus equi septic osteoarthritis in a foal. J Am Vet doxycycline-streptomycin in treatment of human brucellosis due to Brucella Med Assoc 1990 Oct 15; 197(8): 1039–42. melitensis. Antimicrob Agents Chemother 1995 Sep; 39(9): 2061–7. 41. Desjardins MR, Vachon AM. Surgical management of Rhodococcus equi 70. Colmenero Costillo JD, Alonso A, Ruis Diaz F, et al. Comparative trial of metaphysitis in a foal. J Am Vet Med Assoc 1990 Sep 1; 197(5): 608–12. doxycycline plus steptomycin versus doxycycline plus rifampin for the therapy 42. Perdrizet JA, Scott DW. Cellulitis and subcutaneous abscesses caused by of human brucellosis. Chemotherapy 1989; 35(2): 146–52. Rhodococcus equi infection in a foal. J Am Vet Med Assoc 1987 Jun 15; 71. Acocello G, Bertrand A, Beytout J, et al. Comparison of three different regimens 190(12): 1559–61. in the treatment of acute brucellosis; a multicenter multinational study. 43. Chiodini RJ. Biochemical characteristics of various strains of Mycobacterium J Antimicrob Chemother 1989; 23(3): 433–9. paratuberculosis. Am J Vet Res 1986 Jul; 47(7): 1442–5. 72. Ariza J, Fernandez-Viladrich P, Rufi G, et al. Comparative trial of rifampin- 44. Slocombe RF. Combined streptomycin-isoniazid-rifampin therapy in the doxycycline versus tetracycline-streptomycin in the therapy of human treatment of Johnes disease in a goat. Can Vet J 1982 May; 23(5): 160–3. brucellosis. Antimicrob Agents Chemother 1985 Oct; 28(4): 548–51. 45. Gunn-Moore DA, Jenkins PA, Lucke VM. Feline tuberculosis: a literature 73. Mateu-de-Antonio EM, Martin M. In vitro efficacy of several antimicrobial review and discussion of 19 cases caused by an unusual mycobacterial combinations against Brucella canis and Brucella melitensis strains isolated variant. Vet Rec 1996 Jan 20; 138(3): 53–8. from dogs. Vet Microbiol 1995 Jun; 45(1): 1–10. 46. de Bolla GJ. Tuberculosis in a cat [letter]. Vet Rec 1994 Mar 26; 134(13): 336. 74. Decre D, Bergogne-Berezin E, Phillippon A, et al. In vitro susceptibility of 47. Wilesmith JW, Clifton-Hadley RS. Tuberculosis in cats [comment]. Vet Rec Rhodococcus equi to 27 antibiotics [letter]. J Antimicrob Chemother 1991 1994 Apr 2; 134(14): 359. Aug; 28(2): 311–3. 48. Greth A, Flamand JR, Delhomme A. An outbreak of tuberculosis in a captive 75. Verville TD, Slater LN, Kuhls TL, et al. Rhodococcus equi infections of humans: herd of Arabian oryx (Orys leucorys): management. Vet Rec 1994 Feb 12; 12 cases and a review of the literature. Medicine (Baltimore) 1994 May; 73(3): 134(7): 165–7. 119–32.

76. Nordmann P, Kerestedjion J, Ronco E. Therapy of Rhodococcus equi 78. Panel comment, Rec 6/24/99. disseminated infections in nude mice. Antimicrob Agents Chemother 1992 79. Klasco RK, editor. USP DI Drug information for the healthcare professional. Jan; 36(6): 1244–8. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 77. Arlotti M, Zoboli G, Moscatelli GL, et al. Rhodococcus equi infection in HIV- positive subjects: a retrospective analysis of 24 cases. Scand J Infect Dis 1996; 28: 463–7.

SPECTINOMYCIN Veterinary—Systemic

Some commonly used brand names for veterinary-labeled products are: Paratyphoid (treatment)1—Chicks, newly hatched: Spectinomycin hydro- Adspec Sterile Solution; AmTech Spectam Scour-Halt; Bovispec Sterile chloride injection is indicated in the control of mortality and to lessen Solution; Spectam; Spectam Injectable; Spectam Oral Solution; Spectam severity of infections caused by Salmonella typhimurium{R-17}. Scour-Halt; Spectam Soluble Powder; and Spectam Water Soluble. Pneumonia, bacterial (treatment)—Cattle: Spectinomycin sulfate injec- Note: For a listing of dosage forms and brand names by country tion is indicated in the treatment of pneumonia (bovine respiratory availability, see the Dosage Forms section(s). disease) associated with M. haemolytica, P. multocida, and H. somnus in cattle{R-21; 25}. 1 CATEGORY: Salmonella infantis infection (treatment) —Chicks, newly hatched: Spec- Antimicrobial (systemic). tinomycin hydrochloride injection is indicated in the control of mortality and to lessen severity of infections caused by S. infantis{R-17}; INDICATIONS: however, S. infantis is not considered to be a major pathogen in the Note: Bracketed information in the Indications section refers to uses that poultry industry. either are not included in U.S. product labeling or are for products not Synovitis (prophylaxis)—Chickens, broiler: Spectinomycin powder for oral commercially available in the U.S. solution is indicated to aid in the prevention of mortality associated with infectious synovitis due to susceptible Mycoplasma synoviae{R-2; 18}. GENERAL CONSIDERATIONS Synovitis (treatment)— Spectinomycin is an antibiotic that is active against a variety of Chickens, broiler1: Spectinomycin powder for oral solution is indicated aerobic gram-negative and gram-positive organisms{R-3; 4} as well to aid in the control of mortality associated with infectious synovitis as Mycoplasma species{R-7}. Spectinomycin is used clinically, due to susceptible M. synoviae{R-18}. primarily for its activity against gram-negative organisms; some Chicks, newly hatched1: Spectinomycin hydrochloride injection is gram-positive organisms may also be susceptible to this agent. It indicated in the control of mortality and to lessen severity of has in vitro and in vivo activity against Mannheimia (Pasteurella) infections caused by susceptible M. synoviae{R-17}. haemolytica, Pasteurella multocida, and Haemophilus somnus{R-25}. [Fowl cholera (treatment)]—Turkeys: Spectinomycin hydrochloride injec- Anaerobic organisms are generally resistant{R-7}. Spectinomycin is tion is indicated to reduce mortality due to fowl cholera caused by usually bacteriostatic at therapeutic doses{R-5}. As an aminocyclitol sensitive strains of Pasteurella multocida{R-1}. antibiotic, spectinomycin is structurally and functionally similar to the aminoglycoside antibiotics, which are also aminocyclitols. ACCEPTANCE NOT ESTABLISHED Spectinomycin lacks the toxic effects of the aminoglycoside antibi- Colibacillosis (treatment)1—[Ducklings]: There are insufficient data to otics; however, its use is limited by the ready development of establish the safety and efficacy of spectinomycin in the treatment of bacterial resistance{R-5}. colibacillosis in ducklings; however, in one study, subcutaneous administration of spectinomycin reduced the mortality and improved weight {R-10} ACCEPTED gain in 1-day-old ducklings experimentally infected with E. coli . Infections, bacterial (treatment), including Air sacculitis (treatment)1—Turkey poults, 1- to 3-day-old: Spectinomycin Respiratory tract infections (treatment)—[Pigs]1: There are insufficient hydrochloride injection is indicated to aid in the control of air sacculitis data to establish the safety and efficacy of spectinomycin injection in associated with Mycoplasma meleagridis sensitive to spectinomycin the treatment of respiratory infections and systemic infections due to {R-17}. susceptible organisms in pigs; however, the parenteral administra- Chronic respiratory disease (CRD) (prophylaxis)—Chickens, broiler: tion of spectinomycin to pigs has been used in clinical practice to Spectinomycin powder for oral solution is indicated to aid in the treat these infections{R-5}. prevention of mortality due to CRD associated with susceptible Mycoplasma gallisepticum{R-2; 18}. 1Not included in Canadian product labeling or product not commercially Chronic respiratory disease (CRD) (treatment)— available in Canada. Turkey poults, 1- to 3-day-old1: Spectinomycin hydrochloride injection is indicated to aid in the control of CRD associated with Escherichia coli{R-17}. REGULATORY CONSIDERATIONS Chickens, broiler: Spectinomycin powder for oral solution is indicated to U.S.— aid in the control of mortality due to CRD associated with susceptible Spectinomycin oral solution is labeled for use in piglets younger than 4 Mycoplasma gallisepticum{R-2; 18}. weeks of age or weighing < 6.8 kg{R-3; 4}. Colibacillosis (treatment)1—Chicks, newly hatched: Spectinomycin Spectinomycin injection is labeled for use only in newly hatched chicks hydrochloride injection is indicated in the control of mortality and to and in 1- to 3-day-old turkey poults{R-17}. lessen severity of infections caused by E. coli{R-17}. Spectinomycin is not labeled for use in birds producing eggs for human Enteritis, bacterial (treatment)—Piglets: Spectinomycin oral solution is consumption{R-18}. indicated in the treatment of bacterial enteritis (white scours) Withdrawal times have been established for the use of spectinomy- associated with E. coli in piglets younger than 4 weeks of age{R-3; 4}. cin in newly hatched chicks{R-17}, broiler chickens{R-18},1-to

3-day-old turkey poults{R-17}, and piglets{R-4}(see the Dosage Forms administration of spectinomycin{R-7}. Tissue/serum ratios of spectino- section). mycin usually do not exceed 0.25 to 0.5 and are much lower in brain, Canada— aqueous humor, and bone{R-22}.

Spectinomycin is not labeled for use in birds producing eggs for human Volume of distribution (VolD): consumption{R-1}. Cows—0.295 Liter per kg (L/kg){R-13}. Spectinomycin injection is not labeled for use in turkeys weighing Ewes—0.307 L/kg{R-13}. < 0.5 kg{R-1}. Withdrawal times have been established for the use of spectinomycin Protein binding: Cows—Low (approximately 10%){R-13}. in broiler chickens{R-2}, piglets{R-3}, and turkeys{R-1}(see the Dosage Forms section). Biotransformation: Spectinomycin does not appear to undergo any signiﬁcant metabolism. In swine, it is excreted unchanged in the urine CHEMISTRY following intramuscular administration{R-7}. Source: Spectinomycin is a product of Streptomyces spectabilis{R-5; 25}. Chemical group: Aminocyclitol{R-5}. Half-life: Elimination— Chemical name: Cows: 1.01{R-13} to 1.2 hours{R-7}. Spectinomycin hydrochloride—4H-Pyrano[2,3-b][1,4]benzodioxin-4-one, Ewes: 1.01 hours{R-13}. decahydro-4a,7,9-trihydroxy-2-methyl-6,8-bis(methylamino)-, dihy- Pigs: 0.98 hour{R-7}. drochloride, pentahydrate{R-6}. Spectinomycin sulfate tetrahydrate—Decahydro-4a,7,9-trihydroxy- Peak serum concentration/Time to peak serum concentration: 2-methyl-6,8-bis(methylamino)-4H-pyrano[2,3-b][1,4]benzodioxin- Calves, preruminating—20 mcg/mL between 0.33 and 0.67 hours 4-one sulfate, tetrahydrate{R-25}. following an intramuscular dose of 10 mg/mL{R-7}.

Molecular formula: Spectinomycin hydrochloride—C14H24N2O7 Æ Cows—Approximately 55 micrograms per mL (mcg/mL) at 1 hour {R-6} 2HCl Æ 5H2O . following an intramuscular dose of 20 mg per kg of body weight Molecular weight: Spectinomycin hydrochloride—495.35{R-6}. (mg/kg){R-13}. Description: Spectinomycin Hydrochloride USP—White to pale-buff Dogs— crystalline powder{R-16}. Intramuscular: 78 mcg/mL 40 minutes following an intramuscular pKa: 6.95 and 8.70{R-23}. dose of 40 mg/kg. Solubility: Spectinomycin Hydrochloride USP—Freely soluble in Oral{R-7}: water; practically insoluble in alcohol, in chloroform, and in 22 mcg/mL approximately 4 hours following a dose of ether{R-16}. 100 mg/kg. 80 mcg/mL approximately 4 hours following a dose of 500 mg/kg. PHARMACOLOGY/PHARMACOKINETICS Ewes—Approximately 53 mcg/mL at 1 hour following an intramuscular Note: Unless otherwise noted, pharmacokinetic data in this section are dose of 20 mg/kg{R-13}. based on a single intravenous injection of spectinomycin. The pharmacokinetics and detection of spectinomycin do not appear to Elimination: be inﬂuenced by administration in combination with lincomycin{R-7}; Following intramuscular administration—Spectinomycin is rapidly some of the pharmacokinetic data in this section are derived from absorbed, then quickly eliminated from plasma and tissues studies in which lincomycin and spectinomycin were administered through renal excretion{R-7}. Because of this rapid excretion, drug concomitantly{R-7}. accumulation is not observed following repeated administration{R-7}. Renal impairment may cause accumulation of the active Mechanism of action/effect: Spectinomycin binds to the 30S ribo- drug{R-22}. somal subunit of the microorganism and inhibits protein synthesis by Following oral administration—Because spectinomycin is poorly preventing elongation of the polypeptide chain at the translocation absorbed from the gastrointestinal tract, it is excreted mostly in the step{R-5}. feces{R-7}.

Absorption: Spectinomycin is only slightly absorbed from the gas- {R-7} trointestinal tract ; however, it is rapidly absorbed following PRECAUTIONS TO CONSIDER intramuscular administration{R-7}. In cattle, spectinomycin is completely bioavailable following intramuscular administration{R-7}. LACTATION Repeated administration in cattle does not appear to result in tis- Cows: In one experimental study, the milk-to-serum ratio of spectino- sue concentrations higher than those achieved with a single mycin concentrations ranged from 0.44 to 1.12 in mastitic cows dose{R-7}. receiving one intramuscular dose of 20 mg per kg of body weight (mg/ kg), followed by three intramuscular doses of 10 mg/kg at hourly Distribution: Twelve hours following intramuscular administration intervals{R-13}. Spectinomycin levels in milk from dairy cows receiving and 24 hours following oral administration, concentrations of specti- an intramuscular dose of 20 mg/kg two times a day for 3 consecutive nomycin are found in the following swine tissues in decreasing con- days were below 0.2 mcg/mL at the ﬁfth milking after the last centrations: kidney, liver, lung, muscle, and fat{R-7}. An identical injection{R-7}. No residues of spectinomycin were detectable at the proﬁle is seen in cattle 24 and 72 hours following intramuscular seventh milking{R-7}.

SIDE/ADVERSE EFFECTS VETERINARY DOSING INFORMATION The following side/adverse effects have been selected on the basis of SAFETY CONSIDERATIONS their potential clinical signiﬁcance (possible signs and, for humans, Some individuals who handle spectinomycin develop serious reactions symptoms in parentheses where appropriate)—not necessarily involving skin, nails, and eyes{R-1; 9}. Individuals who have experi- inclusive: enced a rash or other evidence of allergic reaction should avoid further contact with spectinomycin{R-2}. THOSE INDICATING NEED FOR MEDICAL ATTENTION Incidence unknown ORAL DOSAGE FORMS All species Note: The dosing and strengths of the dosage forms available are Anaphylactic reactions{R-25}; neuromuscular blockade{R-5} expressed in terms of spectinomycin base (not the hydrochloride salt).

SPECTINOMYCIN HYDROCHLORIDE ORAL SOLUTION THOSE INDICATING NEED FOR MEDICAL ATTENTION Usual dose: Enteritis, bacterial—Piglets, younger than 4 weeks of age: ONLY IF THEY CONTINUE OR ARE BOTHERSOME For piglets weighing < 4.5 kg—Oral, 50 mg (base) as a total dose per Incidence unknown animal two times a day for three to five days{R-3; 4}. Cattle For piglets weighing 4.5 kg to 6.8 kg—Oral, 100 mg (base) as a total Discoloration of tissue at the injection site;{R-25} swelling at the dose per animal two times a day for three to five days{R-3; 4}. injection site, mild{R-25} Note: If improvement is not seen within forty-eight hours of initiating treatment, the diagnosis or choice of therapy should be reconsidered{R- 3; 4}. HUMAN SIDE/ADVERSE EFFECTS{R-15} Strength(s) usually available: In addition to the above side/adverse effects reported in animals, the U.S.— following side/adverse effects have been reported in humans, and are For veterinary-labeled product(s): included in the human monograph Spectinomycin (Systemic) in USP DI 50 mg (base) per mL (OTC) [AmTech Spectam Scour-Halt; Spectam Volume I; these side/adverse effects are intended for informational Scour-Halt]. purposes only and may or may not be applicable to the use of Canada— spectinomycin in the treatment of animals: For veterinary-labeled product(s): Incidence rare 50 mg (base) per mL (OTC) [Spectam Oral Solution; Spectam Scour-Halt]. Dizziness; gastrointestinal disturbance; hypersensitivity; pain at site of injection Withdrawal times: U.S. and Canada{R-3; 4; 19}— OVERDOSE Withdrawal time For more information in cases of overdose or unintentional ingestion, Species Meat (days) contact the American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (888- Pigs 21 426-4435 or 900-443-0000; a fee may be required for consultation) and/or the drug manufacturer. Note: The above withdrawal time applies when medication is administered Cattle: When cattle were administered 150 mg per kg a day (10 times at a total dose of 50 mg (base) two times a day for piglets weighing less the labeled dose) for 5 days, the effects seen at the end of the than 4.5 kg or 100 mg (base) two times a day for piglets weighing 4.5 kg {R-3; 4} treatment period included increased relative kidney weights{R-25}. to 6.8 kg, for a maximum duration of five days . Urinalysis was performed only on steers. Urinary pH was decreased and squamous and transitional cells were found in the urine{R-25} Packaging and storage: Store below 23 °C (73 °F). Do not freeze {R-3; 4}.

CLINICAL EFFECTS OF OVERDOSE Auxiliary labeling: When not in use, the plastic doser should be Note: The following effects have been selected on the basis of their removed and the original cap replaced on bottle{R-3; 4}. The plastic potential clinical signiﬁcance (possible signs in parentheses where doser should be rinsed with water after each use. appropriate)—not necessarily inclusive (» = major clinical signiﬁ- {R-16} cance): USP requirements: Not in USP . Acute effects— Turkey poults{R-1} SPECTINOMYCIN HYDROCHLORIDE POWDER FOR Ataxia{R-1}; coma{R-1} ORAL SOLUTION Note: Clinical signs of ataxia and coma following a single, subcutaneous dose of 90 mg per poult were transient, resolving after 4 Usual dose: hours{R-1}; a single, subcutaneous injection of up to 50 mg per Chronic respiratory disease (prophylaxis and treatment)—Chickens, poult caused no detectable ill effects{R-1}. broiler: Oral, administered as the sole source of drinking water at a

concentration of 0.5 mg (base) per mL (2 grams [base] per gallon) of Chronic respiratory disease (treatment)1—Turkey poults, 1- to 3-day- water for the first three days of life and for one day following each old: Subcutaneous in cervical area, 5 mg (base) as a single, total dose vaccination{R-2; 18; 24}. per poult{R-17}. Dilution with sterile physiologic saline is recom- Synovitis (prophylaxis and treatment1)—Chickens, broiler: Oral, admin- mended to facilitate accurate dosing{R-17}. istered as the sole source of drinking water at a concentration of 0.26 Colibacillosis (treatment)1; mg (base) per mL (1 gram [base] per gallon) of water for the first three Paratyphoid (treatment)1; to five days of life{R-18; 24}. Salmonella infantis infection (treatment)1;or Note: Canadian labeling lists a dose of 0.5 mg (base) per mL (2 grams Synovitis (treatment)1—Chicks, newly hatched: Subcutaneous in [base] per gallon) of water for this indication{R-2}. cervical area, 2.5 to 5 mg (base) as a single, total dose per chick{R-17}. Dilution with sterile physiologic saline is recommended so that the total Strength(s) usually available: volume administered is 0.2 mL{R-17}. U.S.— [Fowl cholera (treatment)]—Turkeys: Subcutaneous in dorsal cervical Veterinary-labeled product(s): area, 11 to 22 mg (base) per kg of body weight as a single injection. 500 mg (base) per gram of water-soluble powder (OTC) [Spectam The entire flock should be treated as soon as symptoms of fowl Water Soluble]. cholera are observed{R-1}. Treatment must not be repeated within Canada— five days of the initial treatment{R-1}. Veterinary-labeled product(s): Note: [Ducklings]1—For use in animals not to be used in food production: 500 mg (base) per gram of water-soluble powder (OTC) [Spectam Although there are insufficient data to establish safety and efficacy, a Soluble Powder]. single, subcutaneous, total dose of 5 mg (base) per duckling has been shown to reduce mortality and improve weight gain in one-day-old Withdrawal times: ducklings experimentally infected with E. coli{R-10}. U.S. and Canada{R-2; 18; 24}— [Pigs]1—Although there are insufficient data to establish safety and efficacy, the intramuscular administration of spectinomycin to pigs, Withdrawal time at doses ranging from 6.6 to 22 mg (base) per kg of body weight {R-11} Species Meat (days) every twelve to twenty-four hours , has been used in clinical practice to treat respiratory infections and systemic infections caused by Chickens 5 organisms sensitive to spectinomycin{R-5}. Strength(s) usually available{R-22}: Note: The above withdrawal time applies when medication is adminis- U.S.— tered in the drinking water up to a maximum concentration of 0.5 mg {R-2; 18} Veterinary-labeled product(s): (base) per mL for up to a maximum duration of 5 days . {R-17} 100 mg (base) per mL (OTC) [GENERIC] . Products are not labeled for use in poultry laying eggs for human Canada— consumption{R-24}. Veterinary-labeled product(s): 100 mg (base) per mL (OTC) [Spectam; Spectam Injectable]{R-1}. Packaging and storage: Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by Withdrawal times: manufacturer. Note: Pigs—Because injectable spectinomycin is not labeled for use in pigs, there are no established withdrawal times in the U.S. or Canada. If Preparation of dosage form: Water-soluble powder should be mixed spectinomycin is administered intramuscularly at a dose of 20 mg per kg with drinking water according to the manufacturer’s directions. of body weight, evidence has been compiled by the Food Animal Residue Avoidance Databank (FARAD) that suggests a meat withdrawal time of USP requirements: Not in USP{R-16}. thirty days would be sufficient to avoid violative residues{R-7; 14}. U.S.{R-17}— 1Not included in Canadian product labeling or product not commercially available in Canada. Withdrawal time

Species Meat (days)

PARENTERAL DOSAGE FORMS Chicks, newly hatched 0 Note: Bracketed information in the Dosage Forms section refers to uses Turkey poults, 1- to 3-day-old 0 that either are not included in U.S. product labeling or are for products not commercially available in the U.S. Note: The above withdrawal time applies when medication is adminis- The dosing and strengths of the dosage forms available are expressed tered up to a maximum dose of 5 mg per animal in chicks and 10 mg in terms of spectinomycin base (not the hydrochloride or sulfate salt). per animal in turkey poults as a single injection{R-17}. Canada{R-1}— SPECTINOMYCIN HYDROCHLORIDE INJECTION Withdrawal time Usual dose: Air sacculitis (treatment)1—Turkey poults, 1- to 3-day-old: Subcuta- Species Meat (days) neous in cervical area, 10 mg (base) as a single, total dose per Turkeys 5 poult{R-17}.

Note: The above withdrawal time applies when medication is adminis- Package and storage: Store at 20 to 25 °C (68 to 77 °F), unless tered up to a maximum dose of 22 mg per kg of body weight as a single otherwise speciﬁed by the manufacturer{R-25}. Protect from freezing. {R-1} injection. USP requirements: Not in USP{R-16}.

Preparation of dosage form: 1 Dilution with sterile physiologic saline according to product labeling is Not included in Canadian product labeling or product not commercially recommended when administering total doses <5 mg and is appropri- available in Canada. ate when large flocks are being treated{R-17}. Aseptic technique must be {R-17} employed and unused diluted solution should be discarded . Developed: 07/08/98 Packaging and storage: Store below 40 °C (104 °F), preferably be- Interim revision: 10/15/99; 09/30/02; 04/05/03 tween 15 and 30 °C (59 and 86 °F), unless otherwise specified by REFERENCES manufacturer. Protect from freezing{R-17}. 1. Spectam Injectable package insert (Vetoquinol—Canada). In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North Auxiliary labeling: Injection site should be disinfected prior to injection American Compendiums, Inc. 2002. and precautions should be taken to prevent contamination of the 2. Spectam Soluble Powder package insert (Vetoquinol—Canada). In: Arrioja- contents of the bottle{R-1; 17}. Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. USP requirements: Not in USP{R-16}. 3. Spectam Scour-Halt package insert (Vetoquinol—Canada). In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. SPECTINOMYCIN SULFATE INJECTION 4. Spectam Scour Halt package labeling (Agrilabs/Durvet—US). In: Arrioja- Usual dose: Pneumonia—Cattle: Subcutaneous, 10 to 15 mg (base) per kg Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: of body weight every twenty-four hours for three to five days{R-25}. North American Compendiums, Inc. 2002. 5. Prescott JF, Baggot JD, editors. Antimicrobial therapy in veterinary medicine. Note: It is recommended that this medication be administered Ames, IA: Iowa State University Press; 1993. p. 174–8. subcutaneously in the neck and that not more than 50 mL be given 6. USP Dictionary of USAN and international drug names, 2002 ed. Rockville, per site{R-25}. MD: The United States Pharmacopeial Convention, Inc; 2002. 7. Cuerpo L, Livingston RC. Spectinomycin. In: Residues of some veterinary drugs Strength(s) usually available{R-21; 22; 25}: in animals and foods. Monographs prepared by the forty-second meeting of the joint FAO/WHO expert committee on food additives. FAO Food Nutr Pap 1994; U.S.— 41(6): 1–86. Veterinary-labeled product(s): 8. Genetzky R, Zeman D, Miskimins D, et al. Intravenous spectinomycin- 100 mg (base) per mL (Rx) [Adspec Sterile Solution; Bovispec Sterile associated deaths in feedlot cattle. J Vet Diagn Invest 1994; 5: 266–9. Solution]. 9. Monte AD, Laffi G, Mancini G. Occupational contact dermatitis due to spectinomycin. Contact Dermatitis 1994; 31: 204–5. Canada— 10. Freed M, Clarke JP, Bowersock TL, et al. Effect of spectinomycin on Escherichia Veterinary-labeled product(s): coli infection in 1-day-old ducklings. Avian Dis 1993; 37: 763–6. 100 mg (base) per mL (Rx) [Adspec Sterile Solution]. 11. Panel comment, Rec 2/97. 12. Hjerpe CA. The bovine respiratory disease complex. In: Howard JL, editor. Withdrawal times: Current veterinary therapy 3: food animal practice. Philadelphia: WB U.S.— Saunders; 1993. p. 653–64. 13. Ziv G, Sulman FG. Serum and milk concentrations of spectinomycin and Withdrawal time tylosin in cows and ewes. Am J Vet Res 1973; 34: 329–33. 14. Food Animal Residue Avoidance Databank recommendations. Personal Species Meat (days) communications, J. E. Riviere, Prof Vet Pharmacol, N.C. State Univ. School of Vet. Med., 6/12/96. Cattle 11 15. Klasco RK, editor. USP DI Drug information for the healthcare professional. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 16. The United States pharmacopeia. The national formulary. USP 26th revision Note: Product labeling listing the above withdrawal time states that (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United withdrawal times have not been established for preruminating calves States Pharmacopeial Convention, Inc; 2002. or for lactating dairy cattle and that it should not be used in female 17. Spectinomycin Injectable package labeling (Durvet—US). In: Arrioja-Dechert dairy cattle 20 months of age or older or in calves to be procesed for A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. {R-25} veal . 18. Spectam Water Soluble Concentrate package labeling (Rhone Merieux—US), Discoloration of tissue at the injection site may last more than 11 days, Rec 6/20/96. making it necessary to trim the site and surrounding tissue at 19. Spectam Scour-Halt package labeling (Rhone Merieux—US), Rec 6/20/96. 20. Jenkins WL. Clinical pharmacology of antibacterials used in bacterial slaughter{R-25}. bronchopneumonia in cattle. Mod Vet Pract 1985; 66: 264–8. {R-21} Canada — 21. Adspec Sterile Solution product information (Pharmacia Animal Health— Canada). Downloaded from www.pharmaciaah.ca on 2/19/03. Withdrawal time 22. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Compendiums, Inc. 2002. Species Meat(days) 23. O’Neil MJ, editor. The Merck index. An encyclopedia of chemicals, drugs, and biologicals. 13th ed. Whitehouse Station, NJ: Merck & Co., Inc; 2001. p. 1558. Cattle 11 24. Spectinomycin Water Soluble (Bimeda—US). In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North American Note: Product labeling listing the above withdrawal time states that it Compendiums, Inc. 2002. applies to a dosage of 10 mg per kg of body weight every twenty-four 25. Adspec Sterile Solution package insert (Pharmacia Animal Health—US), Rev 8/00. Downloaded from www.pharmaciaah.com on 8/13/02. hours for three to five days.

SULFONAMIDES Veterinary—Systemic

This monograph includes information on the following: as coccidia.{R-17; 18} They are considered ineffective against most Sulfachlorpyridazine , Sulfadimethoxine, Sulfamethazine, Sulfanil- obligate anaerobes{R-86; 90; 93} and should not be used to treat amide*, Sulfaquinoxaline, Sulfathiazole*. serious anaerobic infections. However, they may affect aerobic Some commonly used brand names are: organisms that contribute to the lowered oxygen tension in the For veterinary-labeled products— microenvironment and, as such, they may be useful in certain diseases involving Fusobacteria, although the organism itself is often Albon Boluses [Sulfadimethoxine] Sulfa-Max III Calf Bolus [Sulfamethazine] Albon 12.5% Concentrated Solution Sulfa-Max III Cattle Bolus resistant. The activity of sulfonamides is very sensitive to environ- [Sulfadimethoxine] [Sulfamethazine] ment, and this limitation affects the activity of sulfonamides in Albon Injection 40% [Sulfadimethoxine] 2 Sulfamed [Sulfamethazine and particular ﬂuids and tissues, such as purulent material, as well as the Sulfathiazole] ability of laboratories to standardize minimum inhibitory concentra- Albon Oral Suspension 5% Sulfa-MT [Sulfamethazine and [Sulfadimethoxine] Sulfathiazole] tions (MIC) of sulfonamides necessary in vivo to inhibit speciﬁc Albon SR [Sulfadimethoxine] Sulfa-Q 20% [Sulfaquinoxaline] cultured bacteria.{R-17} Albon Tablets [Sulfadimethoxine] Sulfasol [Sulfadimethoxine] Resistance of animal pathogens to sulfonamides is widespread as a result AmTech Sulfadimethoxine Injection-40% Sulfa 2 Soluble Powder {R-17; 19} [Sulfadimethoxine] [Sulfamethazine and Sulfathiazole] of more than 50 years of therapeutic use and this limits their AmTech Sulfadimethoxine 12.5% Sulfasure SR Calf Bolus effectiveness; however, sulfonamides are still widely used in combina- Oral Solution [Sulfadimethoxine] [Sulfamethazine] tion with other medications, as in the case of the potentiated AmTech Sulfadimethoxine Soluble Sulfasure SR Calf Tablets sulfonamides. They are also utilized in herd management of disease Powder [Sulfadimethoxine] [Sulfamethazine] Calfspan [Sulfamethazine] Sulfasure SR Cattle Bolus and some individual animal applications. Cross-resistance between [Sulfamethazine] sulfonamides is considered complete.{R-17} Di-Methox Injection-40% Sulforal [Sulfadimethoxine] [Sulfadimethoxine] Di-Methox 12.5% Oral Solution Sulmet Drinking Water Solution 12.5% [Sulfadimethoxine] [Sulfamethazine] ACCEPTED Di-Methox Soluble Powder Sulmet Oblets [Sulfamethazine] Coccidiosis (treatment)—Resistance to sulfonamides by coccidia has been [Sulfadimethoxine] reported in several species, including cattle, chickens{R-22}, and Optimed [Sulfaquinoxaline] Sulmet Soluble Powder [Sulfamethazine] {R-106} Powder 21 [Sulfamethazine 31.92% Sul-Q-Nox [Sulfaquinoxaline] sheep . It also should be noted that sulfonamides aid in reducing and Sulfathiazole] the number of oocysts shed, but they may not alter the clinical course S-125 [Sulfadimethoxine] Suprasulfa III Calf Bolus [Sulfamethazine] of a susceptible coccidial infection{R-106}. S-250 [Sulfadimethoxine] Suprasulfa III Cattle Bolus {R-11} [Sulfamethazine] Calves and cattle: Sulfamethazine extended-release tablets are SDM Injection [Sulfadimethoxine] Sustain III [Sulfamethazine] indicated in the treatment of Eimeria bovis and Eimeria zuernii. SDM Powder [Sulfadimethoxine] Sustain III Calf Bolus [Sulfamethazine] Sulfaquinoxaline1{R-14} is indicated in the control and treatment of SDM Solution [Sulfadimethoxine] Sustain III Cattle Bolus [Sulfamethazine] susceptible E. bovis and E. zuernii. S-M-T [Sulfamethazine Triple Sulfa Bolus [Sulfamethazine, 1{R-2} and Sulfathiazole] Sulfanilamide, and Sulfathiazole] Chickens: Sulfadimethoxine oral solution and powder for oral Sulfa ‘‘25’’ [Sulfamethazine] Vetisulid Boluses [Sulfachlorpyridazine] solution1{R-4} are indicated in the treatment of outbreaks of Sulfa 25% [Sulfamethazine] Vetisulid Injection [Sulfachlorpyridazine] coccidiosis caused by susceptible coccidia. Sulfamethazine oral Sulfalean Powder [Sulfamethazine Vetisulid Powder [Sulfachlorpyridazine] {R-12} 1{R-9} and Sulfathiazole] solution and powder for oral solution are indicated in the control of susceptible Eimeria necatrix and Eimeria tenella. Sulfaquinoxaline{R-14} is indicated in the control of outbreaks of coccidiosis caused by susceptible Eimeria acervulina, Eimeria brunetti, *Not commercially available in the U.S. Eimeria maxima, E. necatrix, and E. tenella. Not commercially available in Canada. Dogs: Sulfadimethoxine injection{R-3}, oral suspension, and tablets{R-6} are indicated in the treatment of enteritis associated with coccidiosis caused by susceptible organisms. Turkeys: Sulfadimethoxine oral solution1{R-2} and powder for oral CATEGORY: solution1{R-4} are indicated in the treatment of outbreaks of Antibacterial (systemic); antiprotozoal. coccidiosis caused by susceptible coccidia. Sulfamethazine oral solution{R-12} and powder for oral solution1{R-9} are indicated in INDICATIONS the control of susceptible Eimeria adenoeides and Eimeria melea- Note: Bracketed information in the Indications section refers to uses that grimitis. Sulfaquinoxaline{R-14} is indicated in the control of either are not included in U.S. product labeling or are for products not outbreaks of susceptible E. adenoeides and E. meleagrimitis.{R-14} commercially available in the U.S. Coryza, infectious (treatment)—Chickens: Sulfadimethoxine oral solu- tion1{R-2} and powder for oral solution1{R-4} are indicated in the treatment of outbreaks of infectious coryza caused by susceptible GENERAL CONSIDERATIONS Haemophilus gallinarum. Sulfamethazine oral solution{R-12} and powder Sulfonamides are broad-spectrum antimicrobials inhibiting both gram- for oral solution1{R-9} are indicated in the control of infectious coryza positive and gram-negative bacteria, as well as some protozoa, such caused by susceptible H. gallinarum.

Cystitis, bacterial (treatment)—Cats and dogs: Sulfadimethoxine injec- Fowl typhoid (treatment)—Chickens and turkeys: Sulfaquinoxaline is tion1, oral suspension1, and tablets{R-3; 6} are indicated in the indicated in the control of acute fowl typhoid caused by susceptible treatment of cystitis caused by susceptible organisms; however, the Salmonella gallinarum.{R-14} potentiated sulfonamides and other antimicrobials have generally Pneumonia, bacterial (treatment)— replaced sulfonamides administered alone. Calves: Sulfamethazine tablets{R-13} and extended-release tablets{R-7; Diphtheria (treatment)—Cattle: Sulfonamides are not directly effective 10; 11} are indicated in the treatment of pneumonia and bovine against most obligate anaerobes{R-86; 90; 93}, but may affect aerobic respiratory disease complex caused by susceptible Pasteurella species. organisms that create the microenvironment in which Fusobacteria However, in vitro studies have shown high levels of resistance to thrive; therefore, sulfonamides may be useful in the treatment of sulfamethazine by Mannheimia (Pasteurella) haemolytica and diphtheria but are not recommended in advanced or serious infections. P. multocida{R-23}; therefore, sulfamethazine generally has been Sulfadimethoxine tablets1{R-1}, oral solution1{R-2}, injection1{R-3}, replaced by antimicrobials known to be effective against the specific powder for oral solution1{R-4}, and extended-release tablets1{R-5}; and pathogens involved. sulfamethazine tablets, oral solution, powder for oral solution1, and Cats and dogs: Sulfadimethoxine injection1{R-3}, oral suspension1, and extended-release tablets{R-7; 9; 10; 12; 13} are indicated in the tablets{R-6} are indicated in the treatment of bacterial pneumonia treatment of calf diphtheria caused by susceptible Fusobacterium caused by susceptible organisms; however, sulfadimethoxine gener- necrophorum. [Sulfamethazine, sulfanilamide, and sulfathiazole ally has been replaced by antimicrobials known to be effective combination is indicated as an aid in the treatment of diphtheria in against the specific pathogens involved. calves{R-97}.] Cattle: Sulfamethazine oral solution{R-12}, powder for oral solution1{R-9}, Enteritis, bacterial (treatment)—The primary treatment for enteritis in and extended-release tablets{R-10}; and sulfadimethoxine tab- many cases, including those involving colibacillosis in calves, is lets1{R-1}, oral solution1{R-2}, injection1{R-3}, powder for oral solu- aggressive fluid replacement. Treatment of enteritis with antimicrobi- tion1{R-4}, and extended-release tablets1{R-5}; and [sulfamethazine als should rely on a specific diagnosis and knowledge of pathogen and sulfathiazole combination{R-15; 96}] are indicated in the treat- susceptibility. ment of bacterial pneumonia and bovine respiratory disease complex Calves, less than 1 month of age1: Sulfachlorpyridazine injection and caused by susceptible organisms. [Sulfamethazine, sulfanilamide, tablets are indicated in the treatment of diarrhea caused or and sulfathiazole combination is indicated as an aid in the treatment complicated by Escherichia coli{R-89}. of pneumonia{R-97}.] However, in vitro studies have shown high Calves and cattle: Sulfamethazine tablets, oral solution, powder for oral levels of resistance to sulfamethazine by M. haemolytica and solution1, and extended-release tablets;{R-7; 9; 10; 12; 13} and P. multocida{R-23}, and the sulfonamides generally have been [sulfamethazine and sulfathiazole combination{R-15}] are indicated replaced by antimicrobials known to be effective against the specific in the treatment of enteritis (colibacillosis, scours) caused by pathogens involved. susceptible E. coli. [Sulfamethazine, sulfanilamide, and sulfathiazole Foals: Sulfamethazine tablets{R-13} are indicated in the treatment of combination{R-97} is indicated as an aid in the treatment of enteritis pneumonia caused by susceptible Pasteurella species; however, caused by susceptible organisms.] sulfamethazine generally has been replaced by antimicrobials known Dogs: Sulfadimethoxine injection1{R-3}, oral suspension1, and tablets{R-6} to be effective against the specific pathogens involved. are indicated in the treatment of enteritis caused by susceptible Pigs: Sulfamethazine oral solution{R-12} and powder for oral solu- Salmonella species. tion1{R-9} are indicated in the treatment of pneumonia caused by Foals: Sulfamethazine tablets are indicated in the treatment of enteritis susceptible organisms; however, sulfamethazine generally has been caused by susceptible E. coli.{R-13} replaced by antimicrobials known to be effective against the specific Pigs: Sulfachlorpyridazine powder for oral solution1{R-89}, and sulfa- pathogens involved. methazine oral solution{R-12} and powder for oral solution1{R-9} are Pododermatitis, necrotic (treatment)—Cattle: Sulfonamides are not indicated in the treatment of enteritis caused by susceptible E. coli. directly effective against most obligate anaerobes{R-86; 90; 93}, but [Sulfamethazine and sulfathiazole combination is indicated to aid in may affect aerobic organisms that create the microenvironment in the treatment of enteritis.{R-15}] which Fusobacteria thrive; therefore, they may be useful in the [Sheep]: Sulfamethazine oral solution{R-16} is indicated in the treatment treatment of pododermatitis but are not recommended in advanced of enteritis caused by susceptible organisms. or serious infections. Sulfadimethoxine tablets1{R-1}, oral solu- Fowl cholera (treatment)— tion1{R-2}, injection1{R-3}, powder for oral solution1{R-4}, and Chickens: Sulfadimethoxine oral solution1{R-2} and powder for oral extended-release tablets1{R-5}; and sulfamethazine oral solu- solution1{R-4} are indicated in the treatment of acute fowl cholera tion{R-12}, powder for oral solution1{R-9}, and extended-release caused by susceptible Pasteurella multocida. Sulfamethazine oral tablets{R-10} are indicated in the treatment of pododermatitis solution{R-12} and powder for oral solution1{R-9}, and sulfaquinox- caused by susceptible Fusobacterium necrophorum. [Sulfamethazine aline{R-14} are indicated in the control of acute fowl cholera caused and sulfathiazole combination{R-15; 96} and sulfamethazine, sulfa- by susceptible P. multocida. nilamide, and sulfathiazole combination{R-97} are indicated as aids Turkeys: Sulfadimethoxine oral solution1{R-2} and powder for oral in the treatment of necrotic pododermatitis caused by susceptible solution1{R-4} are indicated in the treatment of acute fowl cholera F. necrophorum.] caused by susceptible P. multocida. Sulfaquinoxaline{R-14} is indicated Pullorum disease (treatment)—Chickens: Sulfamethazine oral solution{R- in the control of acute fowl cholera caused by susceptible 12} and powder for oral solution1{R-9} are indicated in the control of P. multocida. susceptible Salmonella pullorum.

Respiratory infections, bacterial (treatment)— Withdrawal times have been established for sulfachlorpyridazine, sul- Cats and dogs: Sulfadimethoxine injection{R-3}, oral suspension, and fadimethoxine, sulfamethazine, and sulfaquinoxaline. See the Dosage tablets{R-6} are indicated in the treatment of respiratory infections, Forms section. such as bronchitis, caused by susceptible organisms. Federal law restricts the use of some forms of sulfadimethoxine and [Pigs]: Sulfamethazine and sulfathiazole combination is indicated as an sulfamethazine to use by or on the order of a licensed veterinarian. aid in the treatment of respiratory infections caused by susceptible See the Dosage Forms section. organisms.{R-15} Canada— [Sheep]: Sulfamethazine oral solution is indicated in the treatment Withdrawal times have been established for sulfamethazine; sulfa- of acute respiratory infections caused by susceptible organ- methazine and sulfathiazole combination; and sulfamethazine, isms{R-16}. sulfanilamide, and sulfathiazole combination. See the Dosage Forms Skin and soft tissue infections (treatment)—Cats and dogs: Sulfadime- section. thoxine injection1, oral suspension1, and tablets{R-3; 6} are indicated in the treatment of skin and soft tissue infections; however, sulfonamides CHEMISTRY are not effective in infections associated with purulent debris, such as Chemical name: abscesses. Sulfachlorpyridazine—N1-(6-Chloro-3-pyridazinyl)sulfanilamide{R-36}. Sulfadimethoxine—Benzenesulfonamide, 4-amino-N-(2,6-dimethoxy-4- pyrimidinyl)-{R-36}. ACCEPTANCE NOT ESTABLISHED Sulfamethazine—Benzenesulfonamide, 4-amino-N-(4,6-dimethyl-2-pyri- Cats, cattle, dogs, and sheep: Although product labeling in the U.S. and midinyl)-{R-36}. Canada includes the use of sulfonamides in the treatment of metritis in Sulfanilamide—p-Aminobenzenesulfonamide{R-36}. cats, dogs, and cattle, and pyometra{R-3; 6; 9; 10; 15; 16} in cats and dogs, Sulfaquinoxaline—N1-2-Quinoxalinylsulfanilamide{R-36}. and Canadian labeling also includes the treatment of metritis in sheep, Sulfathiazole—Benzenesulfonamide, 4-amino-N-2-thiazolyl-{R-36}. the efficacy of these uses is not established based on current Molecular formula: knowledge. Sulfonamides are poorly distributed into the uterus and {R-36} Sulfachlorpyridazine—C10H9ClNO2S . their activity may be decreased in the presence of purulent debris; {R-36} Sulfadimethoxine—C12H14N4O4S . sulfonamides therefore rarely are recommended in the treatment of {R-36} {R-103} Sulfamethazine—C12H14N4O2S . metritis . {R-36} Sulfanilamide—C6H8N2O2S . Cattle and sheep: Although product labeling in the U.S. and Canada for {R-36} Sulfaquinoxaline—C14H12N4O2S . cattle and in Canada for sheep includes use of sulfonamides in the {R-36} Sulfathiazole—C9H9N3O2S2 . treatment of mastitis{R-3; 6; 9; 10; 12; 13; 15; 16; 97}, the efficacy of this Molecular weight: use is not established based on current knowledge. Many sulfona- Sulfachlorpyridazine—284.72{R-36}. mides, including most of those labeled for treatment of mastitis, are Sulfadimethoxine—310.34{R-36}. poorly distributed into milk. Considering also the high incidence of Sulfamethazine—278.33{R-36}. pathogen resistance reported, sulfonamides rarely are recommended in Sulfanilamide—172.21{R-36}. the treatment of mastitis{R-103}. Sulfaquinoxaline—300.34{R-36}. Horses: Although product labeling in the U.S. and Canada includes the Sulfathiazole—255.32{R-36}. use of sulfonamides in the treatment of equine strangles (Streptococcus Description: equi infection), the efficacy of this use is not established based on Sulfadimethoxine USP—Practically white, crystalline powder{R-56}. current knowledge. The activity of sulfonamides may be decreased in Sulfamethazine USP—White to yellowish white powder, which may the presence of purulent debris; therefore, they rarely are recom- darken on exposure to light. Practically odorless.{R-56} mended in the treatment of strangles{R-103; 107}. Sulfanilamide—White, odorless, crystalline powder{R-98}. Sulfaquinoxaline—Yellow, odorless powder{R-94}. 1Not included in Canadian product labeling or product not commercially Sulfathiazole USP—Fine, white or faintly yellowish white, practically available in Canada. odorless powder{R-56}. pKa: REGULATORY CONSIDERATIONS Sulfadimethoxine—6.15{R-33; 35}. {R-19} U.S.— Sulfamethazine—2.65, 7.4 . {R-19; 35} The presence of sulfonamide residues in food for human consumption Sulfanilamide—10.5 . {R-19; 46} has been a concern in recent years. After a variety of efforts to Sulfaquinoxaline—5.5 . {R-19} control residues, the incidence of violative sulfonamide residues Sulfathiazole—7.1 . recently was reported to be as low as 1% in the U.S.{R-24}; however, Solubility: because of a study linking moderate to high doses of sulfamethazine, Sulfadimethoxine USP—Soluble in 2 N sodium hydroxide; sparingly directly or by a secondary mechanism, to the production of thyroid soluble in 2 N hydrochloric acid; slightly soluble in alcohol, in ether, in {R-56} tumors in mice, concern about residues continues.{R-24; 51} chloroform, and in hexane; practically insoluble in water . The use of sulfonamides in lactating dairy cattle, other than those Sulfamethazine USP—Very slightly soluble in water and in ether; soluble {R-56} medications specifically approved for use, has been specified by the in acetone; slightly soluble in alcohol . Food and Drug Administration as a high priority for regulatory Sulfanilamide—Slightly soluble in water, in alcohol, in acetone, in attention{R-104}. glycerin, in propylene glycol, in hydrochloric acid, and in solutions of

potassium and sodium hydroxide; practically insoluble in chloroform, Pigs—Area: 0.5{R-66; 67}; 0.77 ± 0.06 L/kg{R-70}. in ether, and in petroleum ether{R-98}. Administered in conjunction with sulfathiazole: Area—1.01 ± Sulfaquinoxaline—Practically insoluble in water; very slightly soluble in 0.12 L/kg{R-70}. alcohol; practically insoluble in ether; freely soluble in aqueous Sheep—Area: 0.4 L/kg{R-62; 63}; 0.6 L/kg{R-58}. solutions of alkalis{R-94}. Sulfanilamide: Goats—Area: 1.3 ± 0.13 L/kg{R-35}. Sulfathiazole USP—Very slightly soluble in water; soluble in acetone, in Sulfathiazole: Pigs—Area: 1.16 ± 0.16 L/kg{R-70}. dilute mineral acids, in solutions of alkali hydroxides, and in 6 N ammonium hydroxide; slightly soluble in alcohol{R-56}. Protein binding: Binding can vary depending on serum concentration{R-43} and other factors. Sulfachlorpyridazine—Cows: High (80 to 85%){R-34}. PHARMACOLOGY/PHARMACOKINETICS Sulfadimethoxine— Note: Unless otherwise noted, pharmacokinetic values are based on a Cats: High (87.5%){R-42}. single intravenous administration of medication. Chickens: Moderate (40%){R-43}. Dogs: High (>75%){R-39}. {R-35} Mechanism of action: Bacteriostatic. Sulfonamides interfere with the Goats: High (94%) . biosynthesis of folic acid in bacterial cells; they compete with para- Sulfamethazine— aminobenzoic acid (PABA) for incorporation in the folic acid molecule. Cows: By replacing the PABA molecule and preventing the folic acid for- When plasma concentration is less than 50 mcg per mL {R-79} mation required for DNA synthesis, the sulfonamides prevent multi- (mcg/mL)—High (79%) . plication of the bacterial cell. Susceptible organisms must synthesize When plasma concentration is more than 50 mcg/mL— {R-79} their own folic acid; mammalian cells use preformed folic acid and, Moderate (51%) . {R-35} therefore, are not susceptible. Cells that produce excess PABA or Goats: High (86%) . {R-37} environments with PABA, such as necrotic tissues, allow for resistance Horses: High (70%) . {R-58} by competition with the sulfonamide{R-17; 18}. Sheep: High (77%) . Sulfanilamide—Cows: Low (<20%){R-34}. Sulfathiazole—Cows: High (65 to 76%){R-34}. Absorption: Most sulfonamides are well absorbed orally with the exception of the enteric sulfonamides, such as sulfaquinoxaline, which Biotransformation: Sulfonamides are primarily metabolized in the liver are minimally absorbed{R-19}. Delays in absorption may occur in adult but metabolism also occurs in other tissues. Biotransformation occurs ruminants or when sulfonamides are administered with food to mainly by acetylation, glucuronide conjugation, and aromatic hydrox- monogastric animals{R-17; 20}. ylation in many species{R-17}. The types of metabolites formed and the amount of each varies depending on the specific sulfonamide adminis- Bioavailability: Oral— tered; the species, age, diet, and environment of the animal; the presence Sulfadimethoxine: of disease; and, with the exception of pigs and ruminants, even the sex of {R-44} Cattle—59% (107 mg per kg of body weight [mg/kg] dose) . the animal{R-53; 54; 71; 79}. Dogs are considered to be unable to acetylate {R-41} Dogs—48.8% (55 mg/kg dose) . sulfonamides to any significant degree{R-108}. Sulfamethazine: N4-acetyl metabolites have no antimicrobial activity and hydroxymetab- {R-66} Pigs—86% (50 mg/kg dose) . olites have 2.5 to 39.5% of the activity of the parent compound{R-37}. {R-57} Ponies—84% (160 mg/kg dose) . Metabolites may compete with the parent drug for involvement in folic acid synthesis but have little detrimental effect on the bacterial cell, and {R-37} Distribution: Sulfonamides are widely distributed throughout the body. so could lower the activity of the remaining parent drug. They cross the placenta, and a few penetrate into the cerebrospinal In pigs, sulfamethazine is metabolized into N4-acetylsulfamethazine, fluid{R-20}. Sulfonamides may be distributed into milk; however, they desaminosulfamethazine and the N4-glucose conjugate of sulfameth- {R-72} vary greatly in their ability to do so. The process depends on several azine . In general, metabolites of sulfonamides are cleared more {R-78} factors, including protein binding and pKa values{R-102}. quickly than the parent drug ; however, the desaminosulfameth- Volume of distribution— azine half-life of elimination can vary from 1 to 9 days, while Sulfadimethoxine: sulfamethazine and other metabolites have a shorter half-life of 10 to {R-73} Goats—Area: 0.49 ± 0.095 L/kg{R-35}. 20 hours . It has been theorized that diets containing nitrate, Pigs—Area: which is then reduced by bacteria to nitrite, will greatly increase the Suckling (1 to 2 weeks)—0.483 ± 0.078 L/kg{R-45}. amount of sulfamethazine biotransformed to the desaminosulfameth- {R-71} Growing (11 to 12 weeks)—0.345 ± 0.016 L/kg{R-45}. azine metabolite and prolong tissue residues of metabolite , but Rabbits—Steady state: 0.213 ± 0.007 L/kg{R-40}. there is no conclusive evidence. Sulfamethazine: Buffalo—Area: 0.44 ± 0.17 L/kg{R-55}. Half-life: Cattle—Extrapolated: 0.35 L/kg{R-82}. Absorption—Sulfadimethoxine: Dogs—Oral dose of 55 mg/kg: 1.9 Goats—Area: 0.28 to 0.39 L/kg; 0.44 L/kg{R-35}. hours{R-39}. Horses—Steady state: 0.63 ± 0.074 L/kg{R-57}. Elimination— Lambs—Area: 0.334 ± 0.031 L/kg{R-61}. Sulfachlorpyridazine: Cows—1.2 hours{R-34}.

Sulfadimethoxine: concentration of at least 50 mcg/mL from 18 hours to at least Cats—10.2 hours{R-42}. 120 hours after start of treatment.{R-76} Cattle—12.5 hours{R-38}. Oral dose of 142.9 mg/kg a day (1028 mg/L of water) administered Dogs—13.1 hours{R-39}. in the only source of drinking water maintained a serum Goats—8.6 hours{R-34}. concentration of at least 50 mcg/mL from 24 to 180 hours after Pigs— the start of treatment.{R-76} Single dose: Oral dose of 71.4 mg/kg a day (572 mg/L of water) administered in Suckling pig (1 to 2 weeks of age)—16.2 hours{R-45}. the only source of drinking water maintained a serum concentra- Growing pig (11 to 12 weeks of age)—9.4 hours{R-45}. tion of at least 50 mcg/mL from only 72 to 96 hours after the start After 5 days of once-daily intravenous dosing: 9.2 hours{R-40}. of treatment.{R-76} Rabbits—After 6 days of once-daily intravenous dosing: 5.2 hours{R-40}. Oral (extended-release tablets): Sulfamethazine: Calves, 3 to 5 days of age: An oral dose of 396 mg/kg, administered Buffalo—5.5 hours{R-55}. as a single extended-release tablet, maintained a serum concen- Calves, 2 to 3 months of age—5.2 to 5.7 hours{R-78; 79}. tration of at least 50 mcg/mL from 4 to 96 hours post- Cattle—5 to 11.3 hours{R-34; 78; 79; 82}. administration.{R-80} Goats—2.4 to 4.1 hours{R-35}; 8.5 to 9.6 hours{R-35; 82}. Calves and cattle: An oral dose of 264 mg/kg maintained a serum Horses—5.4 hours{R-37}; 11.4 hours{R-57}. concentration greater than 50 mcg/mL from 12 to 48 or 72 hours Lambs—7.2 hours{R-61}. post-administration.{R-81} Pigs—9.8 hours{R-70}; 16.9 hours{R-66; 67}. Sheep—4.5 hours{R-58}; 9.5 to 10.8 hours{R-62; 63}. Elimination: Renal excretion is the primary route of elimination for Sulfanilamide: most nonenteric sulfonamides and it occurs by glomerular ﬁltration Cows—6.2 hours{R-34}. of parent drug, tubular excretion of unchanged drug and metabolites, Goats—7.7 hours{R-34}. and passive reabsorption of nonionized drug.{R-17; 20} Alkalization of Sulfathiazole: the urine increases the fraction of the dose that is eliminated in the Cows—1.5 hours{R-34}. urine.{R-20} In general, the metabolites of the parent drug are more Pigs—9 hours{R-70}. quickly eliminated by the kidney than the original sulfonamide Sheep—1.3 hours{R-84}. is{R-78}, but the proportions of metabolites formed can vary, depending on many factors. Peak serum concentration: Sulfonamides are also distributed in relatively small amounts into milk, Sulfadimethoxine—Oral: saliva, and into the gastrointestinal tract.{R-77; 79} Chickens—106.3 mcg/mL at 12 hours (100 mg/kg dose).{R-43} Sulfadimethoxine—Cattle: 17.9% of an intravenous dose of 107 mg Cattle—114 ± 10 mcg/mL at 10 hours (107 mg/kg dose).{R-44} per kg of sulfadimethoxine is excreted into the urine unchanged and Dogs—67 ± 16 mcg/mL of serum at 3.75 hours (55 mg/kg dose).{R-39} at least 58.4% is excreted as metabolites into urine.{R-44} Only 6.3% Sulfamethazine—Oral: Ponies—301.4 mcg/mL of serum at 0.83 hour of an oral dose of 107 mg of sulfadimethoxine per kg is excreted (160 mg/kg dose).{R-57} unchanged in the urine and 37.7% as metabolites in the urine.{R-44} Duration of action: Total clearance: The sulfonamides have been loosely categorized according to their Cats—0.31 mL per minute per kg (mL/min/kg).{R-42} duration of action:{R-19} Dogs—0.36 mL/min/kg.{R-39} Short-acting—Sulfathiazole. Goats—0.65 mL/min/kg.{R-35} Intermediate-acting—Sulfachlorpyridazine, sulfamethazine. Pigs— Intermediate- to long-acting—Sulfadimethoxine. Suckling pig (1 to 2 weeks): 0.35 mL/min/kg.{R-45} Note: Duration of action may be estimated by the length of time target Growing pig (11 to 12 weeks): 0.44 mL/min/kg.{R-45} serum concentrations are maintained. Target concentrations are Sulfamethazine— generally based on minimum inhibitory concentrations for each Cattle: 11 to 37% of a dose of sulfamethazine is excreted into the urine organism. Many sources use 50 mcg sulfonamide per mL (5 mg per as parent drug.{R-78; 82} decaliter) of blood as the minimum effective concentration for Horses: Only 43% of the administered dose is eliminated in the urine sulfonamides in animals.{R-64; 76; 80} and only 7.8% of it is in the form of parent drug.{R-37} Sulfadimethoxine—Oral: Chickens—A single dose of 100 mg per kg of Pigs: 24.5% of a sulfamethazine dose is excreted in the urine as body weight (mg/kg) maintained plasma concentration of greater unchanged drug and 52.1% as measured metabolites.{R-67} than or equal to 50 mcg/mL for 36 hours.{R-43} Sheep: 18% of a sulfamethazine dose is excreted into the urine as Sulfamethazine— parent compound and 53% as metabolites.{R-64} Intravenous: Lambs—An intravenous dose of 107.3 mg/kg main- Total clearance: tained a plasma concentration of greater than 50 mcg/mL for 18 Buffalo—0.93 mL/min/kg{R-55}. to 24 hours.{R-64} Calves, 5 days of age—0.33 mL/min/kg{R-79}. Oral (powder for oral solution): Calves, 8 months of age—{R-76} Calves, 2 to 3 months of age—0.57 mL/min/kg{R-79}. Oral dose of 214.3 mg/kg a day (1848 mg/L of water) administered Cows—0.73 mL/min/kg{R-79}. in the only source of drinking water maintained a serum Goats—0.55 to 0.65 mL/min/kg; 1.13 to 1.4 mL/min/kg{R-35}.

Horses—0.92 mL/min/kg{R-37}. DRUG INTERACTIONS AND/OR RELATED PROBLEMS {R-66} Pigs—0.35 mL/min/kg . The following drug interactions and/or related problems have been {R-57} Ponies—0.7 mL/min/kg . selected on the basis of their potential clinical significance (possible {R-58} Sheep—1.6 mL/min/kg . mechanism in parentheses where appropriate)—not necessarily inclu- {R-70} Sulfathiazole—Total clearance: Pigs—1.5 mL/min/kg . sive (» = major clinical significance): Note: Drug interactions relating specifically to the use of sulfonamides in animals are rarely reported in veterinary literature. Human drug PRECAUTIONS TO CONSIDER interactions have been reported and are included in the following section. SPECIES SENSITIVITY Dogs: An idiosyncratic sulfonamide toxicosis can occur in any breed of dog, but has been reported more frequently in the Doberman HUMAN DRUG INTERACTIONS{R-69} Pinscher than in other breeds. This specific type of drug reaction The following drug interactions have been reported in humans, and are includes blood dyscrasias, nonseptic polyarthritis, and skin rash.{R- included in the human monograph Sulfonamides (Systemic) in USP DI 26; 27} Dogs given sulfonamides may also develop cutaneous Volume I; these drug interactions are intended for informational eruptions, hepatitis, or keratitis sicca.{R-17; 27} Dogs are reported purposes only and may or may not be applicable to the use of to develop a hemorrhagic syndrome when doses of sulfaquinoxaline sulfonamides in the treatment of animals: that are tolerated by many chickens are administered in their Note: Combinations containing any of the following medications, drinking water.{R-47–50} depending on the amount present, may also interact with this medication. Anticoagulants, coumarin- or indandione-derivative, or CROSS-SENSITIVITY AND/OR RELATED PROBLEMS Anticonvulsants, hydantoin, or Patients allergic to one sulfonamide may be allergic to other sulfona- Antidiabetic agents, oral mides also. (these medications may be displaced from protein binding sites and/ or their metabolism may be inhibited by some sulfonamides, result- CARCINOGENICITY ing in increased or prolonged effects and/or toxicity; dosage adjustments may be necessary during and after sulfonamide therapy) For sulfamethazine—High doses have been shown to induce follicular Bone marrow depressants cell hyperplasia of the thyroid gland and splenic changes in specific– (concurrent use of bone marrow depressants with sulfonamides pathogen-free mice. When the highest doses (4800 parts per million may increase the leukopenic and/or thrombocytopenic effects; if in the diet) were fed for 24 months, 26 to 33% of the mice concurrent use is required, close observation for myelotoxic effects developed thyroid gland adenomas.{R-51} The applicability of these should be considered) results to other species with recommended doses is unclear at this Cyclosporine time. (concurrent use with sulfonamides may increase the metabolism of cyclosporine, resulting in decreased plasma concentrations and PREGNANCY/REPRODUCTION potential transplant rejection, and additive nephrotoxicity; plasma Sulfonamides cross the placenta in pregnant animals.{R-20; 60} Some cyclosporine concentrations and renal function should be moni- teratogenic effects have been seen when very high doses were given to tored) pregnant mice and rats.{R-20} Hemolytics, other (concurrent use with sulfonamides may increase the potential for toxic side effects) LACTATION Hepatotoxic medications, other Sulfonamides are distributed into milk; however, the sulfonamides that (concurrent use with sulfonamides may result in an increased are clinically relevant to food-producing animals are distributed into incidence of hepatotoxicity; patients, especially those on prolonged milk in concentrations too low to be therapeutic but high enough to administration or those with a history of liver disease, should be produce residues{R-103; 105}. Sulfadiazine and sulfanilamide are more carefully monitored) efficiently distributed into milk than most sulfonamides, but are not Methenamine used in dairy cattle{R-103}. For many sulfonamides, 0.5 to 2% of the (in acid urine, methenamine breaks down into formaldehyde, total dose is found in the milk.{R-31; 32} Distribution into milk varies which may form an insoluble precipitate with certain sulfonamides, depending on the amount of non–protein-bound sulfonamide present especially those that are less soluble in urine, and may also increase in the blood and the amount of the nonionized and therefore the danger of crystalluria; concurrent use is not recommended) liposoluble form of the medication present. Sulfonamides with higher Methotrexate or pKa values produce a higher proportion of drug in the blood that is Phenylbutazone non-ionized{R-31}, and if other factors, such as the rate of biotransfor- (the effects of methotrexate may be potentiated during concurrent mation, also support it, may be distributed more easily into milk. For use with sulfonamides because of displacement from plasma lactating dairy cattle, concentration of the active parent compound of protein binding sites; phenylbutazone may displace sulfonamides sulfamethazine, measured at a specific time in milk, is about 20% of from plasma protein binding sites, increasing sulfonamide con- the concentration in the blood.{R-77} centrations)

Penicillins Hepatic function impairment (since bacteriostatic drugs may interfere with the bactericidal effect (systemically absorbed sulfonamides are metabolized by the liver; of penicillins in the treatment of meningitis or in other situations delayed biotransformation may increase the risk of adverse effects) where a rapid bactericidal effect is necessary, it is best to avoid Renal function impairment concurrent therapy) (systemically absorbed sulfonamides are renally excreted; delayed elimination could cause accumulation of sulfonamide and metabo- LABORATORY VALUE ALTERATIONS lites, increasing the risk of adverse effects) The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not PATIENT MONITORING necessarily inclusive (» = major clinical significance): The following may be especially important in patient monitoring (other Note: Laboratory value alterations relating specifically to the use of tests may be warranted in some patients, depending on condition; » = sulfonamides in animals are rarely reported in veterinary literature. major clinical significance): Human laboratory value alterations have been reported and are Culture and susceptibility, in vitro, and included in the following section. Minimum inhibitory concentration (MIC) (in vitro cultures and MIC test should be done on samples collected prior to sulfonamide administration to determine pathogen suscep- {R-69} HUMAN LABORATORY VALUE ALTERATIONS tibility) The following laboratory value alterations have been reported in humans, and are included in the human monograph Sulfonamides SIDE/ADVERSE EFFECTS (Systemic) in USP DI Volume I; these laboratory value alterations are The following side/adverse effects have been selected on the basis of their intended for informational purposes only and may or may not be potential clinical significance (possible signs and, for humans, symp- applicable to the use of sulfonamides in the treatment of animals: toms in parentheses where appropriate)—not necessarily inclusive: With diagnostic test results Benedict’s test (sulfonamides may produce a false-positive Benedict’s test for urine THOSE INDICATING NEED FOR MEDICAL ATTENTION glucose) Incidence unknown Jaffe´ alkaline picrate reaction assay All species (sulfamethoxazole may interfere with the Jaffe´ alkaline picrate Crystallization in the urinary tract reaction assay for creatinine, resulting in overestimations of Note: Crystallization of sulfonamides can occur in the kidneys or urine approximately 10% in the normal values for creatinine) with high doses of sulfonamide or when an animal is dehydrated. Sulfosalicylic acid test Solubility in the urine is dependent on the concentration of drug in the (sulfonamides may produce a false-positive sulfosalicylic acid test urine, urinary pH (less soluble in an acidic pH), the patient’s hydration, for urine protein) and the amount of drug in the acetylated form. Because dogs do not Urine urobilinogen test strip (e.g., Urobilistix) produce acetylated metabolites, they may be less susceptible to this {R-85} (sulfonamides may interfere with the urine urobilinogen [Urobi- adverse effect . It can be minimized in susceptible animals by listix] test for urinary urobilinogen) maintaining a high urine flow and, if necessary, alkalinizing the urine. With physiology/laboratory test values Dogs {R-27} {R-100; Alanine aminotransferase (ALT [SGPT]), serum, and Cutaneous drug eruption ; hepatitis; hypothyroidism 101} {R-26; 27} Aspartate aminotransferase (AST [SGOT]), serum, and ; idiosyncratic toxicosis (blood dyscrasias, including Bilirubin, serum anemia, leukopenia or thrombocytopenia; fever; focal retinitis; lymph- (values may be increased) adenopathy; nonseptic polyarthritis; polymyositis; skin rash); kerato- {R-28–30} Blood urea nitrogen (BUN) and conjunctivitis sicca Creatinine, serum Note: Iatrogenic hypothyroidism may occur and thyroid function test {R-100; (concentrations may be increased) values may be lowered in dogs administered sulfonamides 101}. Although studies have looked at this reaction with potentiated sulfonamides{R-100; 101}, sulfonamides administered alone have been MEDICAL CONSIDERATIONS/CONTRAINDICATIONS reported to impair thyroid function{R-100}. With administration of The medical considerations/contraindications included have been sulfamethoxazole and trimethoprim combination at high doses or of selected on the basis of their potential clinical significance (reasons ormetoprim and sulfadimethoxine, thyrotropin stimulation test given in parentheses where appropriate)—not necessarily inclusive values and serum thyroxine values have been significantly (» = major clinical significance). reduced{R-100}. Sulfadiazine and trimethoprim combination, admin- Except under special circumstances, this medication should not be istered at labeled doses (25 mg of sulfadiazine and 5 mg of used when the following medical problem exists: trimethoprim per kg every 24 hours), has not affected thyroid test » Hypersensitivity to sulfonamides values in studies performed. (animals that have had a previous reaction to sulfonamides may be Idiosyncratic toxicosis can occur 8 to 20 days after initiation of much more likely to react on subsequent administration) treatment and is believed to be caused either by an immune- Risk-benefit should be considered when the following medical mediated syndrome or by an idiosyncratic reaction in dogs, perhaps problems exist: due to toxic metabolites of the sulfonamide. Of 22 reported cases

compiled in one study, 7 involved Doberman Pinschers, and it has and other blood dyscrasias. Therapy should be discontinued at been theorized that they are more susceptible to this toxicosis{R-26}. the first appearance of skin rash or any serious side/adverse A large majority of the animals in which idiosyncratic toxicosis effects. occurs have had a previous exposure to a sulfonamide. Most cases The multiorgan toxicity of sulfonamides is thought to be the result involve a trimethoprim and sulfonamide combination{R-27}. When of the way sulfonamides are metabolized in certain patients. It is sulfonamide therapy is discontinued, recovery generally occurs probably due to the inability of the body to detoxify reactive within 2 to 5 days.{R-27} metabolites. Sulfonamides are metabolized primarily by acetyla- Keratoconjunctivitis sicca is considered a possible side/adverse effect in tion. Patients can be divided into slow and fast acetylators. Slow any dog on sulfonamide therapy for more than a month; however, it can acetylation of sulfonamides makes more of the medication occur at any time after therapy is initiated. Reports conflict over whether available for metabolism by the oxidative pathways of the this is a dose-related or idiosyncratic reaction{R-108}. The most frequent cytochrome P450 system. These pathways produce reactive toxic reports have been with sulfasalazine or trimethoprim and sulfonamide metabolites, such as hydroxylamine and nitroso compounds. The combination{R-28–30}, perhaps because these medications are most metabolites are normally detoxified by scavengers, such as commonly used for long-term therapy in dogs. Lacrimation may not glutathione. However, some populations, such as human immu- return to normal after discontinuation of sulfonamide treatment. nodeficiency virus (HIV)–infected patients, have low concentra- For sulfaquinoxaline tions of glutathione and these metabolites accumulate, producing Chickens and dogs toxicity. Patients who are slow acetylators have a higher incidence Hemorrhagic syndrome (anorexia, epistaxis, hemoptysis, lethargy, of sulfonamide hypersensitivity reactions, although severe toxicity pale mucous membranes, possibly death){R-46–50} has also been seen in fast acetylators. Acetylation status alone Note: Hemorrhagic syndrome has been reported in chickens and dogs cannot fully explain sulfonamide toxicity since approximately 50% but may occur in other species. It is most often reported with the of North American blacks and whites are slow acetylators and addition of sulfaquinoxaline to feed for chickens, but in dogs has been severe reactions occur in less than 1% of patients treated with reported to follow administration in the water supply of products sulfonamides. However, decreased acetylation may increase the labeled for poultry.{R-47–50} Sulfaquinoxaline is a vitamin K antag- amount of sulfonamide metabolized to toxic metabolites. onist that inhibits vitamin K eposide and vitamin K quinone reductase and causes an effect similar to that of coumarin antico- OVERDOSE agulants.{R-46} Rapid hypoprothrombinemia occurs in dogs, and For more information in cases of overdose or unintentional ingestion, sulfaquinoxaline may have an additional adverse effect on specific contact the American Society for the Prevention of Cruelty to cell types; this may explain why supplementation of chicken feeds Animals (ASPCA) National Animal Poison Control Center (888- with vitamin K has not always prevented the syndrome in 426-4435 or 900-443-0000; a fee may be required for consultation) chickens.{R-46–47} Rapid discontinuation of medication and initiation and/or the drug manufacturer.

of therapy with vitamin K1 may reverse the effects. Toxicities secondary to acute overdose of sulfonamides are not typically reported. Side effects may be more likely to occur with high doses and HUMAN SIDE/ADVERSE EFFECTS{R-69} long-term administration, but are seen at recommended doses as well. In addition to the above side/adverse effects reported in animals, the CLIENT CONSULTATION following side/adverse effects have been reported in humans, and are Dosage and length of treatment recommendations should be followed; included in the human monograph Sulfonamides (Systemic) in USP DI high doses or long-term use can increase the risk of side effects. Volume I; these side/adverse effects are intended for informational Animals should have a good water supply and should be monitored to purposes only and may or may not be applicable to the use of ensure adequate water consumption during treatment. sulfonamides in the treatment of animals: Incidence more frequent Central nervous system effects; gastrointestinal disturbances; VETERINARY DOSING INFORMATION hypersensitivity; photosensitivity Residue avoidance: Management practices can affect depletion of residues Incidence less frequent in pigs. When pigs have environmental access to urine and manure Blood dyscrasias; hepatitis; Lyell’s syndrome (difficulty in swal- from pigs treated with sulfamethazine, the residues are easily recycled lowing; redness, blistering, peeling, or loosening of skin); Stevens- and can cause these animals to have positive urine tests for Johnson syndrome (aching joints and muscles; redness, blistering, sulfonamide and violative tissue residues. Hot or cold environmental peeling, or loosening of skin; unusual tiredness or weakness) temperatures do not appear to inactivate sulfamethazine in the Incidence rare environment.{R-70; 74} Central nervous system toxicity; Clostridium difficile colitis; crystalluria or hematuria; goiter or thyroid function disturbance; interstitial nephritis or tubular necrosis FOR ORAL DOSAGE FORMS ONLY Note: C. difficile colitis may occur up to several weeks after Intestinal parasites, among other factors, can affect the pharmacokinetics discontinuation of these medications. of sulfamethazine in lambs and probably in other species also. In Fatalities have occurred, although rarely, due to severe reactions parasitized lambs given a single dose of 99 mg per kg of body weight such as Stevens-Johnson syndrome, toxic epidermal necrolysis, (mg/kg), sulfamethazine’s half-life of elimination and time to peak fulminant hepatic necrosis, agranulocytosis, aplastic anemia, concentration were doubled.{R-65}

FOR TREATMENT OF ADVERSE EFFECTS Canada— Recommended treatment consists of the following: Veterinary-labeled product(s): For anaphylaxis Not commercially available. Parenteral epinephrine. • Withdrawal times:{R-88} Oxygen administration and respiratory support. • U.S.— Withdrawal time

Species Meat (days) SULFACHLORPYRIDAZINE Calves, ruminating 7 SUMMARY OF DIFFERENCES Pharmacology/pharmacokinetics: Intermediate duration of action.{R-19} Note: Product labeling listing the above withdrawal time states that it applies when medication is administered for a maximum of ﬁve days. No withdrawal times have been established for use in preruminating ORAL DOSAGE FORMS calves.{R-88}

SULFACHLORPYRIDAZINE POWDER FOR ORAL Packaging and storage: Store below 40 C (104 F), preferably bet- SOLUTION ween 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by Usual dose: Enteritis (diarrhea associated with E. coli)1— manufacturer. Avoid excessive heat.{R-88} Calves, less than 1 month of age: Oral, 33 to 49.5 mg per kg of body Additional information: Animals should maintain an adequate water {R-89} weight every twelve hours. intake during the treatment period. Pigs: Oral, 22 to 38.5 mg per kg of body weight, administered as a USP requirements: Not in USP. drench every twelve hours or 44 to 77 mg per kg of body weight a {R-89} day administered in the only source of drinking water. 1Not included in Canadian product labeling or product not commercially available in Canada. Strength(s) usually available{R-92}: U.S.— PARENTERAL DOSAGE FORMS Veterinary-labeled product(s): {R-89} 50 grams per bottle (OTC) [Vetisulid Powder]. SULFACHLORPYRIDAZINE INJECTION Canada— Usual dose: Enteritis (diarrhea associated with E. coli)1—Calves, less Veterinary-labeled product(s): than 1 month of age: Intravenous, 33 to 49.5 mg per kg of body Not commercially available. weight every twelve hours.{R-87}

Withdrawal times:{R-89} Strength(s) usually available: U.S.— U.S.— Veterinary-labeled product(s): Withdrawal time 200 mg per mL (OTC) [Vetisulid Injection]. Species Meat (days) Canada— Veterinary-labeled product(s): Calves 7 Not commercially available. Pigs 4 Withdrawal times: Packaging and storage: Store below 40 C (104 F), preferably bet- U.S.— ween 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by Withdrawal time manufacturer. Species Meat (days)

Additional information: Animals should maintain an adequate water Calves, ruminating 5 intake during the treatment period. Note: Product labeling listing the above withdrawal time states that it USP requirements: Not in USP. applies when medication is administered for a maximum of ﬁve days. No withdrawal times have been established for use in preruminating calves. SULFACHLORPYRIDAZINE TABLETS Packaging and storage: Store below 40 C (104 F), preferably 1 Usual dose: Enteritis (diarrhea associated with Escherichia coli) —Calves, between 15 and 30 C (59 and 86F), unless otherwise speciﬁed by less than 1 month of age: Oral, 33 to 49.5 mg per kg of body weight manufacturer. Protect from light. Protect from freezing{R-87}. every twelve hours.{R-88} Additional information: Animals should maintain an adequate water intake during the treatment period. Strength(s) usually available{R-92}: USP requirements: Not in USP. U.S.— Veterinary-labeled product(s): 1Not included in Canadian product labeling or product not commercially 2 grams (OTC) [Vetisulid Boluses]. available in Canada.

SULFADIMETHOXINE Stability: Freezing or discoloration does not affect stability. Medication should be thawed before using.{R-2} SUMMARY OF DIFFERENCES Pharmacology/pharmacokinetics: Intermediate to long duration of Preparation of dosage form: Prepare fresh drinking water daily. action{R-19}. Additional information: Animals should maintain an adequate water ORAL DOSAGE FORMS intake during the treatment period.

SULFADIMETHOXINE ORAL SOLUTION USP requirements: Not in USP. Usual dose: 1 Calf diphtheria ; SULFADIMETHOXINE ORAL SUSPENSION USP Pneumonia, bacterial1;or Usual dose: Necrotic pododermatitis1—Calves and cattle: Oral, 55 mg per kg of body Bacterial pneumonia and other respiratory infections1; weight (2.4 to 3.75 grams per gallon of water) as an initial dose, Cystitis1;or followed by 27.5 mg per kg of body weight (1.2 to 1.8 grams per Skin and soft tissue infections1—Cats and dogs: Oral, 55 mg per kg of gallon of water) a day for four days.{R-2} body weight as an initial dose, followed by 27.5 mg per kg of body Coccidiosis1;or weight every twenty-four hours.{R-6} Fowl cholera1— Enteritis associated with coccidiosis or Salmonella1—Dogs: Oral, 55 mg Chickens, broiler and replacement: Oral, 1875 mg per gallon of water per kg of body weight as an initial dose, followed by 27.5 mg per kg (0.05% solution), administered as the only source of drinking of body weight every twenty-four hours.{R-6} water for six days{R-2}. Turkeys: Oral, 938 mg per gallon of water (0.025% solution), Strength(s) usually available{R-92}: administered as the only source of drinking water for six U.S.— days{R-2}. Veterinary-labeled product(s): Infectious coryza outbreaks1—Chickens, broiler and replacement: Oral, 50 mg per mL (Rx) [Albon Oral Suspension 5%]. 1875 mg per gallon of water (0.05% solution), administered as the Canada— only source of drinking water for six days{R-2}. Veterinary-labeled product(s): Note: Administration of sulfadimethoxine for longer than the recom- Not commercially available. mended time can result in slowed growth rates and other adverse effects.{R-83} Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by Strength(s) usually available{R-92}: manufacturer. U.S.— Veterinary-labeled product(s): Additional information: Animals should maintain an adequate water 125 mg per mL (OTC) [Albon 12.5% Concentrated Solution; AmTech intake during the treatment period. Sulfadimethoxine 12.5% Oral Solution; Di-Methox 12.5% Oral Solution; SDM Solution; Sulforal; generic]. USP requirements: Preserve in tight, light-resistant containers, and Canada— store at controlled room temperature. Label it to indicate that it is for Veterinary-labeled product(s): veterinary use only. Contains the labeled amount, within ±10%. Meets Not commercially available. the requirements for Identiﬁcation and pH (5.0–7.0){R-56}.

Withdrawal times: U.S.— SULFADIMETHOXINE SOLUBLE POWDER USP Withdrawal time Usual dose: Bacterial pneumonia1; Species Meat (days) Calf diphtheria1;or 1 Cattle 7 Necrotic pododermatitis —Calves and cattle: Oral, 55 mg per kg of Chickens, turkeys 5 body weight (2.4 to 3.3 grams per gallon) as an initial dose, followed by 27.5 mg per kg of body weight (1.2 grams per gallon) every Note: Product labeling listing the above withdrawal times states that they twenty-four hours for four days.{R-4} are not labeled for use in chickens older than 16 weeks of age, turkeys Coccidiosis1;or older than 24 weeks of age, preruminating calves, or lactating dairy Fowl cholera1— cattle.{R-2} Chickens, broiler and replacement: Oral, 1892 mg per gallon of water (0.05% solution), administered as the only source of drinking Packaging and storage: Store below 40 C (104 F), preferably bet- water for six days{R-4}. ween 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by Turkeys: Oral, 946 mg per gallon of water (0.025% solution), manufacturer. Protect from light.{R-2} administered as the only source of drinking water for six days{R-4}.

Infectious coryza outbreaks1—Chickens, broiler and replacement: Oral, 5000 mg (5 grams) (OTC) [Albon Boluses]. 1892 mg per gallon of water (0.05% solution), administered as the 15,000 mg (15 grams) (OTC) [Albon Boluses]. only source of drinking water for six days{R-4}. Note: The 125-mg, 250-mg, and 500-mg tablets listed above are labeled for use only in cats and dogs, while the 5-gram and 15-gram Strength(s) usually available{R-92}: tablets are labeled for use only in cattle. U.S.— Canada{R-19}— Veterinary-labeled product(s): Veterinary-labeled product(s): 28.3 grams per ounce of powder (OTC) [AmTech Sulfadimethoxine Sol- 125 mg (OTC) [S-125]. uble Powder; Di-Methox Soluble Powder; SDM Powder; Sulfasol; generic]. 250 mg (OTC) [S-250]. Canada— Veterinary-labeled product(s): Withdrawal times:{R-1} Not commercially available. U.S.—

Withdrawal time Withdrawal times: U.S.— Species Meat (days) Milk (hours)

Withdrawal time Cattle 760

Species Meat (days) Note: Product labeling listing the above withdrawal times states that they Cattle 7 are not labeled for use in preruminating calves. Chickens, turkeys 5 Additional information: Animals should maintain an adequate water Note: Product labeling listing the above withdrawal times states that they intake during the treatment period{R-1}. are not labeled for use in preruminating calves, lactating dairy cattle, Packaging and storage: Store below 40 C (104 F), preferably between chickens older than 16 weeks of age, or turkeys older than 24 weeks of 15 and 30 C(59and86F), unless otherwise speciﬁed by manufacturer. age.

Packaging and storage: Store below 40 C(104F), preferably between USP requirements: Preserve in tight, light-resistant containers, and 15 and 30 C(59and86F), unless otherwise speciﬁed by manufacturer. store at controlled room temperature. Label the Tablets to indicate that they are for veterinary use only. Contains the labeled amount, within Additional information: Animals should maintain an adequate water ±10%. Meets the requirements for Identiﬁcation, Disintegration (30 intake during the treatment period. minutes), and Uniformity of dosage units{R-56}.

USP requirements: Preserve in tight, light-resistant containers, and SULFADIMETHOXINE EXTENDED-RELEASE TABLETS store at controlled room temperature. Label it to indicate that it is for Usual dose: veterinary use only. Contains the labeled amount, within ±10%. Meets Bacterial pneumonia1; the requirements for Identification, Minimum fill, and pH (7.0–8.0, in Calf diphtheria1;or a solution [1 in 20]){R-56}. Pododermatitis1—Cattle: Oral, 137.5 mg per kg of body weight as a single dose.{R-5} SULFADIMETHOXINE TABLETS USP Note: To maintain sustained release of medication, tablets should not Usual dose: be divided; it is recommended that animals should receive a tablet for Bacterial pneumonia and other respiratory infections; the nearest 91 kg (200 pounds) of body weight.{R-5} Cystitis; or Strength(s) usually available{R-92}: Skin and soft tissue infections—Cats and dogs: Oral, 55 mg per kg of U.S.— body weight as an initial dose, followed by 27.5 mg per kg of body Veterinary-labeled product(s): weight every twenty-four hours{R-6}. 12.5 grams (Rx) [Albon SR]. Calf diphtheria1; Canada— Pneumonia, bacterial1;or Veterinary-labeled product(s): Pododermatitis1—Cattle: Oral, 55 mg per kg of body weight as the Not commercially available. initial dose, followed by 27.5 mg per kg of body weight every twenty- four hours for five days{R-1}. Withdrawal times: Enteritis associated with coccidiosis or Salmonella—Dogs: Oral, 55 mg U.S.— per kg of body weight as an initial dose, followed by 27.5 mg per kg of body weight every twenty-four hours.{R-6} Withdrawal time

Strength(s) usually available{R-92}: Species Meat (days) U.S.— Cattle 21 Veterinary-labeled product(s): 125 mg (Rx) [Albon Tablets]. Note: Product labeling listing the above withdrawal time states that they 250 mg (Rx) [Albon Tablets]. are not labeled for use in lactating dairy cattle or preruminating 500 mg (Rx) [Albon Tablets]. calves.{R-5}

Packaging and storage: Store below 40 C (104 F), preferably bet- Packaging and storage: Store below 40 C (104 F), preferably ween 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by manufacturer. manufacturer. Protect from light.

Additional information: Animals should maintain an adequate water USP requirements: Not in USP. intake during the treatment period. 1Not included in Canadian product labeling or product not commercially USP requirements: Not in USP. available in Canada. 1Not included in Canadian product labeling or product not commercially available in Canada. SULFAMETHAZINE SUMMARY OF DIFFERENCES {R-19} PARENTERAL DOSAGE FORMS Pharmacology/pharmacokinetics: Intermediate duration of action . ORAL DOSAGE FORMS SULFADIMETHOXINE INJECTION Note: Bracketed information in the Dosage Forms section refers to uses Usual dose: that either are not included in U.S. product labeling or are for products Bacterial respiratory infections1; not commercially available in the U.S. Cystitis1;or Skin and soft tissue infections1—Cats and dogs: Intravenous or subcu- SULFAMETHAZINE ORAL SOLUTION taneous, 55 mg per kg of body weight as an initial dose, followed by Usual dose: 27.5 mg per kg of body weight every twenty-four hours.{R-3} Calf diphtheria; or Calf diphtheria1; Necrotic pododermatitis—Calves and cattle: Oral, 247.5 mg per kg of Pneumonia, bacterial1;or body weight as an initial dose, followed by 123.8 mg per kg of body Necrotic pododermatitis1—Cattle: Intravenous, 55 mg per kg of body weight every twenty-four hours for three days, administered in the weight as an initial dose, followed by 27.5 mg per kg of body weight only source of drinking water{R-12}. every twenty-four hours.{R-3} Coccidiosis— Enteritis associated with coccidiosis or Salmonella1—Dogs: Intravenous Chickens: Oral, 134 to 196 mg per kg of body weight a day for two or subcutaneous, 55 mg per kg of body weight as an initial dose, days, followed by 67 to 98 mg per kg of body weight for four days, followed by 27.5 mg per kg of body weight every twenty-four administered in the only source of drinking water{R-12}. hours.{R-3} Turkeys: Oral, 117 to 286 mg per kg of body weight a day for two Note: Intramuscular injection can cause local pain and inﬂammation days, followed by 58.5 to 143 mg per kg of body weight for four and result in lower serum concentrations of sulfadimethoxine.{R-3} days, administered in the only source of drinking water{R-12}. Enteritis, bacterial— {R-92} Strength(s) usually available : Calves, cattle, and pigs: Oral, 247.5 mg per kg of body weight as an U.S.— initial dose, followed by 123.8 mg per kg of body weight every Veterinary-labeled product(s): twenty-four hours for three days, administered in the only source 400 mg per mL (Rx) [Albon Injection 40%; AmTech Sulfadime- of drinking water{R-12}. thoxine Injection-40%; Di-Methox Injection-40%; SDM Injection; [Sheep]: Oral, 225 mg per kg of body weight the ﬁrst day, followed by generic]. 112.5 mg per kg of body weight for three days, administered in the Canada— only source of drinking water{R-16}. Veterinary-labeled product(s): Fowl cholera, acute; or Not commercially available. Pullorum disease—Chickens: Oral, 134 to 196 mg per kg of body weight a day for six days, administered in the only source of drinking Withdrawal times: water{R-12}. U.S.—{R-3} Infectious coryza—Chickens: Oral, 134 to 196 mg per kg of body weight a day for two days, administered in the only source of Withdrawal time drinking water{R-12}. Species Meat (days) Milk (hours) Pneumonia, bacterial—Calves, cattle, and pigs: Oral, 247.5 mg per kg

Cattle 560 of body weight as an initial dose, followed by 123.8 mg per kg of body weight every twenty-four hours for three days, administered in {R-12} Note: Product labeling listing the above withdrawal times states that the only source of drinking water . withdrawal times have not been established for use in preruminating Respiratory infections, bacterial—[Sheep]: Oral, 225 mg per kg of body calves. weight the ﬁrst day, followed by 112.5 mg per kg of body weight for three days, administered in the only source of drinking water{R-16}. Additional information: Animals should maintain an adequate water {R-92} intake during the treatment period. Strength(s) usually available : U.S.— Stability: Crystallization does not change the potency of sulfadime- Veterinary-labeled product(s): thoxine injection.{R-3} 125 mg per mL (OTC) [Sulmet Drinking Water Solution 12.5%].

Canada— Fowl cholera, acute1;or Veterinary-labeled product(s): Pullorum disease1—Chickens: Oral, 128 to 187 mg per kg of body 125 mg per mL (OTC) [generic]. weight a day for six days, administered in the only source of drinking 250 mg per mL (OTC) [Sulfa ‘‘25’’; Sulfa 25%; generic]. water{R-9}. Infectious coryza1—Chickens: Oral, 128 to 187 mg per kg of body Withdrawal times: weight a day for two days, administered in the only source of U.S.— drinking water{R-9}.

Withdrawal time Strength(s) usually available{R-92}: Species Meat (days) U.S.— Cattle, chickens, turkeys 10 Veterinary-labeled product(s): Pigs 15 453.5 grams of sulfamethazine powder per packet (OTC) [Sulmet Soluble Powder]. Note: Product labeling listing the above withdrawal times states that Canada— they apply when administered for a maximum of ﬁve days in cattle Veterinary-labeled product(s): or pigs. Products are not labeled for use in chickens and turkeys Not commercially available. producing eggs for human consumption, calves less than 1 month of age or fed an all-milk diet, or dairy cows 20 months of age or Withdrawal times: older. U.S.{R-9}— Canada—

Withdrawal time Withdrawal time

Species Meat (days) Milk (hours) Species Meat (days)

Cattle 10 or 12, depending on product 96 Calves, cattle, chickens, turkeys 10 Calves, pigs, sheep 10 or 12, depending on product Pigs 15 Chickens, turkeys 12 Note: Product labeling listing the above withdrawal times states that Note: Product labeling listing the above withdrawal times states that they they apply when administered for a maximum of ﬁve days in cattle are not labeled for use in laying birds or for use in swine feeds. or pigs. Products are not labeled for use in chickens and turkeys producing eggs for human consumption, calves less than 1 month Packaging and storage: Store below 40 C (104 F), preferably be- of age or fed all-milk diets, or dairy cows 20 months of age or tween 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by older. manufacturer. Protect from freezing.

Packaging and storage: Store below 40 C (104 F), preferably be- Additional information: Animals should maintain an adequate water tween 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by intake during the treatment period. manufacturer.

USP requirements: Not in USP. Preparation of dosage form: Fresh solutions should be prepared daily.{R-12} SULFAMETHAZINE POWDER FOR ORAL SOLUTION Usual dose: Calf diphtheria1;or Additional information: Animals should maintain an adequate water Necrotic pododermatitis1—Cattle: Oral, 237.6 mg per kg of body weight intake during the treatment period. as an initial dose, followed by 118.8 mg per kg of body weight every twenty-four hours for three days, administered as an individual USP requirements: Not in USP. animal drench or in the only source of drinking water{R-9}. Coccidiosis1— Chickens: Oral, 128 to 187 mg per kg of body weight a day for two SULFAMETHAZINE TABLETS days, followed by 64 to 93.5 mg per kg of body weight for four days, Usual dose: administered in the only source of drinking water{R-9}. Calf diphtheria—Calves: Oral, 220 mg per kg of body weight as an Turkeys: Oral, 110 to 273 mg per kg of body weight a day for two initial dose, followed by 110 mg per kg of body weight every twenty- days, followed by 55 to 136.5 mg per kg of body weight for four four hours{R-13}. days, administered in the only source of drinking water{R-9}. Enteritis associated with Escherichia coli—Calves and foals: Oral, 220 Enteritis, bacterial1;or mg per kg of body weight as an initial dose, followed by 110 mg per Pneumonia, bacterial1—Cattle and pigs: Oral, 237.6 mg per kg of body kg of body weight every twenty-four hours{R-13}. weight as an initial dose, followed by 118.8 mg per kg of body weight Pneumonia, bacterial—Calves and foals: Oral, 220 mg per kg of body every twenty-four hours for three days, administered as an individ- weight as an initial dose, followed by 110 mg per kg of body weight ual animal drench or in the only source of drinking water{R-9}. every twenty-four hours{R-13}.

Strength(s) usually available{R-92}: Strength(s) usually available{R-92}: U.S.— U.S.{R-7; 10; 11}— Veterinary-labeled product(s): Veterinary-labeled product(s): 2.5 grams (OTC) [Sulmet Oblets]. 8 grams (OTC) [Sulfa-Max III Calf Bolus; Sustain III Calf Bolus]. 5 grams (OTC) [Sulmet Oblets]. 8.25 grams (OTC) [Sulfasure SR Calf Bolus; Suprasulfa III Calf Bolus]. Canada— 30 grams (OTC) [Sulfasure SR Cattle Bolus; Suprasulfa III Cattle Bolus]. Veterinary-labeled product(s): 32.1 grams (OTC) [Sulfa-Max III Cattle Bolus; Sustain III Cattle Bolus] 15 grams (OTC) [generic]. Canada— 15.6 grams (OTC) [generic]. Veterinary-labeled product(s): 8 grams (OTC) [Calfspan]. Withdrawal times: 8.25 grams (OTC) [Sulfasure SR Calf Tablets]. U.S.— 32.1 grams (OTC [Sustain III]. Withdrawal time Withdrawal times: Species Meat (days) U.S.{R-7; 10}—

Calves, cattle 10 Withdrawal time

Note: Product labeling listing the above withdrawal time states that it Species Meat (days) applies to a maximum of ﬁve days treatment. Products are not labeled for Calves, ruminating and cattle 8 or 12, depending on product use in calves less than 1 month of age or those fed an all-milk diet, female dairy cattle 20 months of age or older, or horses intended for food. Note: Product labeling listing the above withdrawal times states that they Canada— apply to animals given a maximum of two doses. Products are not Withdrawal time labeled for use in calves less than 1 month of age, calves fed an all-milk diet, or dairy cattle 20 months of age or older. Species Meat (days) Milk (hours) Canada— Calves, cattle{R-8} 10 96 Withdrawal time Note: Product labeling listing the above withdrawal times states that they Species Meat (days) apply to a maximum of ﬁve days treatment. Products are not labeled for use in calves less than 1 month of age or those fed an all-milk diet, Cattle 8, 12, or 28, depending on or horses intended for food. product

Note: Product labeling listing the above withdrawal times states that they Packaging and storage: Store below 40 C (104 F), preferably bet- are not labeled for use in lactating dairy cattle. ween 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by manufacturer. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by Additional information: Animals should maintain an adequate water manufacturer. intake during the treatment period. Additional information: Animals should maintain an adequate water intake during the treatment period. USP requirements: Not in USP. USP requirements: Not in USP.

1 SULFAMETHAZINE EXTENDED-RELEASE TABLETS Not included in Canadian product labeling or product not commercially available in Canada. Usual dose: Calf diphtheria; Coccidiosis; SULFAMETHAZINE, SULFANILAMIDE, AND Enteritis, bacterial; or SULFATHIAZOLE Pneumonia, bacterial— ORAL DOSAGE FORMS Calves, 1 month of age or older: Oral, 350 to 400 mg per kg of body Note: Bracketed information in the Dosage Forms section refers to uses weight, administered as a single dose{R-7; 11}. The dose may be that either are not included in U.S. product labeling or are for products repeated in three days, if necessary{R-7; 11}. not commercially available in the U.S. Cattle: Oral, 330 to 350 mg per kg of body weight as a single dose{R-10}. The dose may be repeated in three days, if necessary{R-11}. SULFAMETHAZINE, SULFANILAMIDE, Necrotic pododermatitis—Cattle: Oral, 330 to 350 mg per kg of body AND SULFATHIAZOLE TABLETS weight as a single dose{R-10}. The dose may be repeated in three days, Usual dose: if necessary{R-11}. [Bacterial enteritis]; Note: Tablets can be broken at the score line, but should not be [Bacterial pneumonia]; crushed. [Calf diphtheria]; or

[Necrotic pododermatitis]—Cattle: Oral, 48.8 mg sulfamethazine, 73 Strength(s) usually available{R-92}: mg sulfanilamide, and 73 mg sulfathiazole per kg of body weight as U.S.— an initial dose, followed by 24.4 mg sulfamethazine, 36.5 mg Veterinary-labeled product(s): sulfanilamide, and 36.5 mg sulfathiazole per kg of body weight, Not commercially available. administered twelve hours later.{R-97} Canada— Veterinary-labeled product(s): {R-92} Strength(s) usually available : 630 mg sulfamethazine and 315 mg of sulfathiazole per gram of U.S.— powder (OTC) [2 Sulfamed; S-M-T; Sulfa-MT]. Veterinary-labeled product(s): 641 mg sulfamethazine and 320 mg of sulfathiazole per gram of Not commercially available. powder (OTC) [Sulfalean Powder]. {R-97} Canada— 667 mg of sulfamethazine and 333 mg of sulfathiazole per gram of Veterinary-labeled product(s): powder (OTC) [Powder 21; Sulfa 2 Soluble Powder]. 3.9 grams sulfamethazine, 5.85 grams sulfanilamide, and 5.85 grams sulfathiazole (OTC) [Triple Sulfa Bolus]. Withdrawal times: Canada— Withdrawal times: Canada— Withdrawal time Species Meat (days) Milk (hours) Withdrawal time Cattle 10 96 Species Meat (days) Milk (hours) Pigs 10 Cattle 10 96 Note: Some products are not labeled for use in lactating dairy cattle. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by Packaging and storage: Store below 40 C (104 F), preferably be- manufacturer. Protect from moisture. tween 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by manufacturer. Protect from moisture.{R-15} Additional information: Animals should maintain an adequate water Additional information: Animals should maintain an adequate water intake during the treatment period. intake during the treatment period. These products should not be administered in animal feeds. USP requirements: Not in USP. USP requirements: Not in USP.

SULFAMETHAZINE AND SULFATHIAZOLE

ORAL DOSAGE FORMS SULFAQUINOXALINE Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products SUMMARY OF DIFFERENCES not commercially available in the U.S. Pharmacology/pharmacokinetics: Sulfaquinoxaline is minimally absorbed systemically and is referred to as an enteric sulfonamide.{R-19} SULFAMETHAZINE AND SULFATHIAZOLE POWDER Side/adverse effects: Clotting disorders similar to those resulting from FOR ORAL SOLUTION coumarin anticoagulants have been reported in chickens and {R-46–50} Usual dose: dogs. [Enteritis]—Cattle and pigs: Oral, 144 mg of sulfamethazine and 72 mg of sulfathiazole per kg of body weight as an initial dose, followed by 72 mg of sulfamethazine and 36 mg of sulfathiazole per kg of body ORAL DOSAGE FORMS weight a day for three days, administered as an individual animal drench or in the only source of drinking water{R-15}. SULFAQUINOXALINE ORAL SOLUTION USP [Pneumonia, bacterial]; or Usual dose: [Pododermatitis]—Cattle: Oral, 144 mg of sulfamethazine and 72 mg Acute fowl cholera; or of sulfathiazole per kg of body weight as an initial dose, followed by Acute fowl typhoid—Chickens and turkeys: Oral, a 0.04% solution, 72 mg of sulfamethazine and 36 mg of sulfathiazole per kg of body administered in the only source of drinking water for two to three weight a day for three days, administered as an individual animal days{R-14}. drench or in the only source of drinking water{R-15}. Coccidiosis— [Respiratory infections, bacterial]—Pigs: Oral, 144 mg of sulfameth- Calves1 and cattle1: Oral, 13.2 mg per kg of body weight a day, azine and 72 mg of sulfathiazole per kg of body weight as an initial administered in the only source of drinking water as a 0.015% dose, followed by 72 mg of sulfamethazine and 36 mg of sulfathiazole solution for three to ﬁve days{R-14}. per kg of body weight a day for three days, administered as an Chickens: Oral, a 0.04% solution, administered in the only source of individual animal drench or in the only source of drinking drinking water for two to three days{R-14}. Treatment should be water{R-15}. stopped for three days, then the medication readministered as a

0.025% solution for two to four more days. The schedule may be drinking water for more than twenty-four to thirty-six hours may repeated, if necessary{R-14}. result in reduced growth rate from decreased feed or water consump- Turkeys: Oral, a 0.025% solution of sulfaquinoxaline, administered as tion.{R-14; 95} the only source of drinking water for two days. Treatment should be stopped for three days, then the medication readministered as a USP requirements: Preserve in tight, light-resistant containers. Label 0.025% solution for two days; treatment is then stopped for three it to indicate that it is for veterinary use only. Contains the equivalent days, then medication is readministered as the 0.025% solution for of the labeled concentration of sulfaquinoxaline, within ±10%. Meets two final days. The complete schedule may be repeated, if the requirements for Identification, Deliverable volume and pH (not necessary{R-14}. less than 12){R-56}. Note: For treatment of coccidiosis in chickens and turkeys, it is recommended that litter not be changed until absolutely necessary. 1Not included in Canadian product labeling or product not commercially available in Canada. Strength(s) usually available{R-92}: U.S.— Developed: 07/01/97 Veterinary-labeled product(s): Interim revision: 07/10/98; 11/10/99; 06/30/02; 04/05/03 200 mg per mL (OTC) [Sulfa-Q 20%; generic]. 319.2 mg per mL (OTC) [Optimed; 31.92% Sul-Q-Nox]. Canada— REFERENCES Veterinary-labeled product(s): 1. Sulfadimethoxine package insert (Albon bolus, Roche—US), Rec 1/16/96. generic 2. Sulfadimethoxine product information (Albon 12.5% Drinking Water Solu- 192 mg per mL (OTC) [ ]. tion, SmithKline Beecham—US), Rev 9/93, Rec 11/27/95. 3. Sulfadimethoxine product information (Albon Injection 40%, SmithKline Withdrawal times: Beecham—US), Rev 9/93, Rec 11/27/95. U.S.— 4. Sulfadimethoxine product information (Albon Soluble Powder, SmithKline Beecham—US), Rev 9/93, Rec 11/27/95. Withdrawal time 5. Sulfadimethoxine package label (Albon SR, Roche—US), Rec 1/16/96. 6. Sulfadimethoxine product information (Albon Tablets and Oral Suspension, Species Meat (days) SmithKline Beecham—US), Rev 9/93, Rec 11/27/95. 7. Sulfamethazine package insert (Calfspan, Solvay—US), Rec 10/19/95. Calves, cattle, chickens, turkeys 10 8. Sulfamethazine product information (Sulfamethazine bolus, PVL—Canada), Rec 12/1/95. Note: Products are not labeled for use in chickens and turkeys laying 9. Sulfamethazine package insert (Sodium Sulfamethazine Soluble Powder, Durvet—US), Rec 10/19/95. eggs for human consumption, preruminant calves, or lactating dairy 10. Sulfamethazine package insert (Sustain III, Durvet—US), Rec 10/19/95. cattle. 11. Sulfamethazine package insert (Sulfasure SR, Fermenta—US), Rec 10/27/95. Canada— 12. Sulfamethazine package insert (Sulmet Drinking Water Solution, Cyan- amid—US), Rec 11/13/95. Withdrawal time 13. Sulfamethazine package insert (Sulmet Oblets, Fort Dodge—US), Rec 11/13/ 95. Species Meat (days) 14. Sulfaquinoxaline product information (31.95% Sul-Q-Nox, Alpharma—US). In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Chickens, turkeys 12 Port Huron, MI: North American Compendiums, Inc., 2002. 15. Sulfamethazine and sulfathiazole package insert (S-M-T, Sanofi—Canada), Note: Products are not labeled for use in chickens and turkeys laying eggs Rec 10/27/95. for human consumption. 16. Sulfamethazine product information (Sodium sulfamethazine solution, PVL—Canada), Rev 10/92, Rec 12/1/95. 17. Prescott JF, Baggott, JD, editors. Antimicrobial therapy in veterinary Preparation of dosage form: Fresh solutions should be prepared medicine, 2nd ed. Ames, IA: Iowa State University Press, 1993. p. 119–26. daily. To help avoid toxic reactions, the medication should be evenly 18. Appelgate J. Clinical pharmacology of sulfonamides. Mod Vet Pract 1983: mixed in drinking water. 667–9. 19. Riviere J, Craigmill AL, Sundlof SF. Handbook of comparative pharmacoki- Caution: People who handle this medication should avoid contact with netics and residues of veterinary antimicrobials. Boca Raton, FL: CRC Press, Inc., 1991. p. 339–407. eyes, skin, or clothing to prevent eye and skin burns. In case of con- 20. Plumb DC. Veterinary drug handbook. White Bear Lake, MN: PharmaVet tact, the areas affected should be flushed for at least fifteen minutes; Publishing, 1991. p. 520–9. medical attention should be sought for eye exposure.{R-14} Keep out of 21. Vree TB, Reekers-Ketting JJ, Hekster CA, et al. Acetylation and deacetylation of sulphonamides in dogs. J Vet Pharmacol Ther 1983; 6: 153–6. the reach of children.{R-14} 22. Mathis GF, McDougald LR. Drug responsiveness of field isolates of chicken coccidia. Poultry Sci 1982; 61: 38–45. Packaging and storage: Store below 40 C (104 F), preferably be- 23. Watts JL, Yancey RJ, Salmon SA, et al. A 4-year survey of antimicrobial tween 15 and 30 C (59 and 86 F), unless otherwise specified by susceptibility trends for isolates from cattle with bovine respiratory disease in manufacturer. Protect from moisture.{R-15} North America. J Clin Microbiol 1994 Mar; 32(3): 725–31. 24. Barragry TB. Veterinary drug therapy. Baltimore, MD: Lea & Febiger, 1994. p. 295–313. Additional information: Animals should maintain an adequate water 25. Charm SE, Zoner E, Salter R. Confirmation of widespread sulfonamide intake during the treatment period. contamination in Northeast United States market milk. J Food Prod 1988 Chickens: Prolonged administration of sulfaquinoxaline may result in Dec; 51(12): 920–4. 26. Cribb AE, Spielberg SP. An in vitro investigation of predisposition to deposition of crystals in the kidney or interference with normal blood sulphonamide idiosyncratic toxicity in dogs. Vet Res Comm 1990; 14: clotting.{R-14; 95} Sulfaquinoxaline levels of greater than 0.012% in 241–52.

27. Cribb AE. Idiosyncratic reactions to sulfonamides in dogs. J Am Vet Med 55. Khan FH, Nawaz M, Anwar-Ul-Hasson S. Pharmacokinetics of sulfameth- Assoc 1989 Dec; 195(11): 1615. azine in buffaloes. Ann Rech Vet 1980; 11(1): 9–12. 28. Collins BK, Moore CP, Hagee JH. Sulfonamide-associated keratoconjunctivitis 56. The United States pharmacopeia. The national formulary. USP 26th revision sicca and corneal ulceration in a dysuric dog. J Am Vet Med Assoc 1986 Oct; (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United 189(8): 924–6. States Pharmacopeial Convention, Inc., 2002. p. 1732, 1733, 1742, 2582, 29. Sansom J, Barnett KC, Long RD. Keratoconjunctivitis sicca in the dog 2583. associated with the administration of salicylazosulphapyridine (sulphasal- 57. Wilson RC, Hammond LS, Clark CH, et al. Bioavailability and pharmacoki- azine). Vet Rec 1985; 116: 391–3. netics of sulfamethazine in the pony. J Vet Pharmacol Ther 1989; 12: 30. Morgan RV, Bachrach A. Keratoconjunctivitis sicca associated with sulfon- 99–102. amide therapy in dogs. J Am Vet Med Assoc 1982; 180: 432–4. 58. Srivastava AK, Rampal S. Disposition kinetics and dosage regimen of 31. Roudaut B, Moretain JP. Sulphonamide residues in milk of dairy cows sulphamethazine in sheep (ovis aries). Br Vet J 1990; 146: 239–42. following intravenous injection. Food Addit Contam 1990; 7(4): 527–33. 59. Siddique AB, Simunek J. Blood-brain barrier to sulfamethazine in rat and 32. Paulson GD, Feil VJ, Giddings JM, et al. Lactose conjugation of sulphonamide sheep fetus. Acta Vet Brno 1977; 46: 101–9. drugs in the lactating dairy cow. Xenobiotica 1992; 22(8): 925–39. 60. Siddique AB, Simunek J. Placental transfer of sulfamethazine in sheep at 33. Van Gogh H, Van Deurzen JM, Van Duin CTM, et al. Influence of gestation on different stages of gestation. Acta Vet Brno 1977; 46: 95–100. the pharmacokinetics of four sulphonamides in goats. Res Vet Sci 1990; 48: 61. Bourne DWA, Bevill RG, Sharma RM, et al. Disposition of sulfonamides in 152–7. food-producing animals: pharmacokinetics of sulfamethazine in lambs. Am J 34. Nielsen P, Rasmussen F. Half-life, apparent volume of distribution, and protein- Vet Res 1977; 38(7): 967–72. binding for some sulphonamides in cows. Res Vet Sci 1977; 22: 205–8. 62. Bulgin MS, Lane VM, Archer TE, et al. Pharmacokinetics, safety, and tissue 35. Van Gogh H. Pharmacokinetics of nine sulphonamides in goats. J Vet residues of sustained-release sulfamethazine in sheep. J Vet Pharmacol Ther Pharmacol Ther 1980; 3: 69–81. 1991; 14: 36–45. 36. USP dictionary of USAN and international drug names, 2002 ed. Rockville, 63. Abdel Hamid Youssef S, El-Gendi AYI, El-Sayed MGA, et al. Some pharma- MD: The United States Pharmacopeial Convention, Inc., 2002. cokinetic and biochemical aspects of sulphadiazine and sulphadimidine in 37. Nouws JFM, Firth EC, Vree TB, et al. Pharmacokinetics and renal clearance of ewes. J Vet Pharmacol Ther 1981; 4: 173–82. sulfamethazine, sulfamerazine, and sulfadiazine and their N4-acetyl and 64. Bevill RF, Rajinder MS, Meachum SH, et al. Disposition of sulfonamides in hydroxy metabolites in horses. Am J Vet Res 1987 Mar; 48(3): 392–402. food-producing animals: concentrations of sulfamethazine and its metabolites 38. Boxenbaum HG, Fellig J, Hansen LJ, et al. Pharmacokinetics of sulphadime- in plasma, urine, and tissues of lambs following intravenous administration. thoxine in cattle. Res Vet Sci 1977; 23: 24–8. Am J Vet Res 1977 Jul; 30(7): 873–7. 39. Baggot JD, Ludden TM, Powers TE. The bioavailability, disposition kinetics 65. Righter HF, Showalter DH, Teske RH. Comparative plasma kinetics of orally and dosage of sulphadimethoxine in dogs. Can J Comp Med 1976 Jul; 40: administered sulfamethazine in clinically parasitized and parasitism-treated 310–7. lambs. J Vet Pharmacol Ther 1979; 2: 203–8. 40. Ladefoged O, Christiansen SE. A computer method for the calculation of 66. Sweeney RW, Bordalaye PC, Smith CM, et al. Pharmacokinetic model for pharmacokinetic parameters after repetitive drug administration, and its use predicting sulfamethazine disposition in pigs. Am J Vet Res 1993 May; 54(5): in calculations of kinetic parameters of sulphadimethoxine in pigs and 750–4. rabbits. J Vet Pharmacol Ther 1979; 2: 95–9 67. Duffee NE, Bevill RF, Thurman JC, et al. Pharmacokinetics of sulfamethazine 41. Sams RA, Baggot JD. Bioavailability, disposition kinetics, and dosage of in male, female, and castrated male swine. J Vet Pharmacol Ther 1984; 7: sulfadimethoxine in dogs—a correction. Can J Comp Med 1977 Oct; 41(4): 203–11. 479–80. 68. Ashworth RB, Epstein RL, Thomas MH, et al. Sulfamethazine blood/tissue 42. Baggot JD. Pharmacokinetics of sulfadimethoxine in cats. Aust J Exp Biol Med correlation study in swine. Am J Vet Res 1986 Dec; 47(12): 2596–603. Sci 1977; 55(6): 663–70. 69. Klasco RK, editor. USP DI Drug information for the healthcare professional. 43. Bajwa RS, Singh J. Studies on the levels of sulphadimethoxine and Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. sulphamethoxypyridazine in blood of poultry. Indian J Anim Sci 1977 Sep; 70. Van Poucke LSG, Van Peteghem CH. Pharmacokinetic and tissue residues of 47(9): 549–53. sulfathiazole and sulfamethazine in pigs. L Food Protect 1994 Sep; 57(9): 44. Bourne DWA, Bialer M, Dittert LW, et al. Disposition of sulfadimethoxine in 796–801. cattle: inclusion of protein binding factors in a pharmacokinetic model. 71. Struble LB, Paulson GD. The metabolism and deamination of [14C]-sulpha- J Pharm Sci 1981 Sep; 79(9): 1068–72. methazine in a germ-free pig: the influence of nitrate and nitrite. Food Chem 45. Righter JF, Showalter DH, Teske RH. Pharmacokinetic study of sulfadime- Toxicol 1988 May; 260: 797–801. thoxine depletion in suckling and growing pigs. Am J Vet Res 1979; 40(5): 72. Mitchell AD, Paulson GD, Saylskie RG. Steady state kinetics of 14C- 713–5. sulfamethazine {4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzene[U-14C]sul- 46. Preusch PC, Hazelett SE, Lemasters KK. Sulfaquinoxaline inhibition of fonamide} metabolism in swine. Drug Metab Dispos 1986; 14(2): 155–60. vitamin K epoxide and quinone reductase. Arch Biochem Biophys 1989 73. Mitchell AD, Paulson GD. Depletion kinetics of 14C-sulfamethazine in swine. Feb 15; 269(1): 18–24. Drug Metab Dispos 1986; 14(2): 161–7. 47. Daft BM, Bickford AA, Hammarlund MA. Experimental and field sulfaqui- 74. Whipple DM, Samuelson G, Heath GE, et al. Tissue residue depletion and noxaline toxicosis in leghorn chickens. Avian Dis 1989; 33: 30–4. recycling of sulfamethazine in swine. J Am Vet Med Assoc 1980; 176(12): 48. Brown MJ. Adverse reactions to sulfaquinoxaline in coyote pups. J Am Vet 1348–52. Med Assoc 1982; 181(11): 1419–20. 75. Kuiper HA, Aerts RMC, Haagsma N, et al. Case study of the depletion of 49. Osweiler GD, Green RA. Canine hypoprothrombinemia resulting from sulfamethazine from plasma and tissues upon oral administration to piglets sulfaquinoxaline administration. Vet Hum Tox 1978 Jun; 20(3): 190–2. affected with atrophic rhinitis. J Agric Food Chem 1988; 36: 822–5. 50. Neer TM, Savant RL. Hypoprothrombinemia secondary to administration of 76. Church TL, Janzen ED, Sisodia CS, et al. Blood levels of sulfamethazine sulfaquinoxaline to dogs in a kennel setting. J Am Vet Med Assoc 1992 May; achieved in beef calves on medicated drinking water. Can Vet J 1979; 20: 41– 200(9): 1344–5. 4. 51. Littlefield NA, Gaylor DW, Blackwell BN, et al. Chronic toxicity/carcinoge- 77. Paulson GD, Feil VJ, Zaylskie RG, et al. Depletion of residues from milk and nicity studies of sulphamethazine in B6C3F1 mice. Food Chem Toxicol 1989; blood of cows dosed orally and intravenously with sulfamethazine. J Assoc Off 27(7): 455–63. Anal Chem 1994; 77(4): 895–900. 52. Paulson G, Struble C, Mitchell A. Comparative metabolism of sulfamethazine 78. Nouws JFM, Mevius D, Vree TB, et al. Pharmacokinetics, metabolism, and [4-Amino-N-(4,6 dimethyl-2-pyrimidinyl)benzenesulfonamide] in the rat, renal clearance of sulfadiazine, sulfamerazine, and sulfamethazine and of

chicken, pig, and sheep. 5th International Congress of Pesticide Chemistry their N4-acetyl and hydroxy metabolites in calves and cows. Am J Vet Res 1983: 375–80. 1988 Jul; 49(7): 1059–65. 53. Witkamp RF, Yun HI, van’t Klooster GA, et al. Comparative aspects and sex 79. Nouws JFM, Vree TB, Baakman M, et al. Age and dosage dependency in the

differentiation of plasma sulfamethazine elimination and metabolite forma- plasma disposition and the renal clearance of sulfamethazine and its N4-acetyl tion in rats, rabbits, dwarf goats, and cattle. Am J Vet Res 1992 Oct; 53(10): and hydroxy metabolites in calves and cows. Am J Vet Res 1986 Mar; 47(3): 1830–5. 642–9. 54. Paulson GD. The effect of dietary nitrite and nitrate on the metabolism of 80. Murphy J, Wong M, Ray WH. The advantages of a timed-release sulfameth- sulphamethazine in the rat. Xenobiotica 1986; 16(1): 53–61. azine bolette for calves. Vet Med 1986 Sep; 8(9): 882–5.

81. Miller GE, Stowe CM, Jegers A, et al. Blood concentration studies of a 94. Reynolds JEF, editor. Martindale, the extra pharmacopeia. 29th ed. London: sustained release form of sulfamethazine in cattle. J Am Vet Med Assoc 1969; The Pharmaceutical Press, 1989. p. 301. 154: 773–8. 95. Sulfaquinoxaline package label (34% Sul-Q-Nox, Russell—US), Rec 10/23/95. 82. Bevill RF, Dittert LW, Bourne DWA. Disposition of sulfonamides in food- 96. Sulfamethazine and sulfathiazole combination product information (Powder producing animals IV: pharmacokinetics of sulfamethazine in cattle following 21, PVL—Canada), Rev 9/94, Rec 12/1/95. administration of an intravenous dose and 3 oral dosage forms. J Pharm Sci 97. Sulfamethazine, sulfanilamide, and sulfathiazole product information (Triple 1977 May; 66(5): 619–23. sulfa bolus, PVL—Canada), Rev 8/92, Rec 12/1/95. 83. Bajwa RS, Singh J. Studies on the effect of prolonged administration of 98. AVC (Marion Merrell Dow), Rev 4/91. In: PDR Physicians’ desk reference. sulphadimethoxine and sulphamethoxypyridazine on the growth rate and 49th ed. 1995. Montvale, NJ: Medical Economics Data Production Company, hematology of chicks. Indian J Anim Sci 1977 Oct; 47(10): 692–3. 1995. p. 1394–5. 84. Koritz D, Bourne DWA, Dittert LW, et al. Disposition of sulfonamides in food- 99. Reece RL, Barr DA, Gould JA. Poisoning in a chicken ﬂock caused by producing animals: pharmacokinetics of sulfathiazole in sheep. Am J Vet Res sulphachloropyrazine. Vet Rec 1986; 119: 324–5. 1977; 38(7): 979–82. 100. Hall IA, Campbell KL, Chambers MD, et al. Effect of trimethoprim/ 85. Panel comment, Rec 6/20/96. sulfamethoxazole on thyroid function in dogs with pyoderma. J Am Vet 86. National Committee for Clinical Laboratory Standards publication. Villanova, Med Assoc 1993 Jun 15; 202(12): 1959–62. PA: NCCLS, 1983; 3(14): M2–T3. 101. Panciera DL, Post K. Effect of oral administration of sulfadiazine and 87. Sulfachlorpyridazine package label (Vetisulid injection, Solvay—US), Rec 11/ trimethoprim in combination on thyroid function in dogs. Can J Vet Res 3/95. 1992; 56: 349–52. 88. Sulfachlorpyridazine package label (Vetisulid boluses, Solvay—US), Rec 11/3/ 102. Rasmussen F. Mammary excretion of sulphonamides. Acta Pharmacol 95. Toxicol 1958; 15: 139–48. 89. Sulfachlorpyridazine package label (Vetisulid powder, Solvay—US), Rec 11/ 103. Panel comment, 5/8/96. 3/95. 104. Extra-label use of drugs in food-producing animals (Compliance Policy Guide 90. Duran SP, Valera RC, Manzano JV, et al. Comparative in-vitro susceptibility of 7125.06). Rev 7/20/92. Food and Drug Administration Center for Veterinary Bacteroides and Fusobacterium isolated from footrot in sheep to 28 Medicine. antimicrobial agents. J Vet Pharmacol Ther 1991; 14: 185–92. 105. Langston VC, Davis LE. Factors to consider in the selection of antimicrobial 91. Sulfadimethoxine package insert (S-125, Sanoﬁ—Canada), Rec 10/27/95. drugs for therapy. Compend Contin Educ Pract Vet 1989 Mar; 11(3): 355– 92. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port 63. Huron, MI: North American Compendiums, Inc., 2002. 106. Panel comment, 5/21/96. 93. Stowe CM, Sisodia CS. The pharmacologic properties of sulfadimethoxine in 107. Panel comment, 5/23/96. dairy cattle. Am J Vet Res 1963; 24: 525–35. 108. Panel comment, 5/21/96.

TETRACYCLINES Veterinary—Systemic

This monograph includes information on the following: Chlortetracy- Oxy-110 [Oxytetracycline] Terra-Vet Soluble Powder 343 cline; Doxycycline; Oxytetracycline; Tetracycline. [Oxytetracycline] Oxy-220 [Oxytetracycline] Tet-324 [Tetracycline] Some commonly used brand names are: Oxy 250 [Oxytetracycline] Tetra 55 [Tetracycline] For veterinary-labeled products— Oxy-440 [Oxytetracycline] Tetra 250 [Tetracycline] Oxy 1000 [Oxytetracycline] Tetra 1000 [Tetracycline] Agrimycin 100 [Oxytetracycline] Oxytet-250 Concentrate [Oxytetracycline] Oxybiotic-100 [Oxytetracycline] Tetra 4000 [Tetracycline] Agrimycin 200 [Oxytetracycline] Oxytetra-A [Oxytetracycline] Oxybiotic-200 [Oxytetracycline] Tetra Bac 324 [Tetracycline] Agrimycin-343 [Oxytetracycline] Oxytetracycline 50 [Oxytetracycline] Oxy 500 Calf Bolus [Oxytetracycline] Tetrabol [Tetracycline] Alamycin LA [Oxytetracycline] Oxytetracycline 100 [Oxytetracycline] Oxy 1000 Calf Bolus [Oxytetracycline] Tetracycline 250 [Tetracycline] AmTech Chlortetracycline HCL Oxytetracycline 200 [Oxytetracycline] Oxycure 100 [Oxytetracycline] Tetracycline 1000 [Tetracycline] Soluble Powder [Chlortetracycline] Oxycure 200 [Oxytetracycline] Tetracycline 250 Concentrate AmTech Maxim-100 [Oxytetracycline] Oxytetracycline 100LP [Oxytetracycline] Soluble Powder [Tetracycline] AmTech Maxim-200 [Oxytetracycline] Oxy Tetra Forte [Oxytetracycline] Oxy LA [Oxytetracycline] Tetracycline 62.5 Soluble Powder Oxytetramycin 100 [Oxytetracycline] [Tetracycline] AmTech Oxytetracycline HCL Oxytet-25-S [Oxytetracycline] Oxy LP [Oxytetracycline] Tetradure LA 300 [Oxytetracycline] Soluble Powder [Oxytetracycline] Oxy-Mycin 100 [Oxytetracycline] Tetraject LA [Oxytetracycline] AmTech Oxytetracycline HCL Oxytet Soluble [Oxytetracycline] Oxy-Mycin 200 [Oxytetracycline] Tetraject LP [Oxytetracycline] Soluble Powder-343 [Oxytetracycline] Oxymycine LA [Oxytetracycline] Tetramed 250 [Tetracycline] AmTech Tetracycline Hydrochloride Oxytet-SP [Oxytetracycline] Oxymycine LP [Oxytetracycline] Tetramed 1000 [Tetracycline] Soluble Powder-324 [Tetracycline] Oxyshot LA [Oxytetracycline] Tetrasol Soluble Powder [Tetracycline] Aureomycin 110G [Chlortetracycline] Oxytet-343 Water Soluble Powder Oxysol-62.5 [Oxytetracycline] Tetravet-CA [Oxytetracycline] [Oxytetracycline] Oxysol-110 [Oxytetracycline] Tet-Sol 10 [Tetracycline] Aureomycin 220G [Chlortetracycline] Oxyvet 200 LA [Oxytetracycline] Oxysol-220 [Oxytetracycline] Tet-Sol 324 [Tetracycline] Aureomycin 50 Granular Oxyvet 100 LP [Oxytetracycline] Oxysol-250 [Oxytetracycline] Tetroxy-100 [Oxytetracycline] [Chlortetracycline] Oxysol-440 [Oxytetracycline] Tetroxy HCA Soluble Powder Aureomycin 90 Granular Panmycin Aquadrops [Tetracycline] [Oxytetracycline] [Chlortetracycline] Oxysol-1000 [Oxytetracycline] 5-Way Calf Scour Bolus [Tetracycline] Aureomycin 100 Granular Pennchlor 50ÆG [Chlortetracycline] [Chlortetracycline] For human-labeled products— Aureomycin Soluble Powder Pennchlor 90 G [Chlortetracycline] Æ Achromycin V [Tetracycline] Novo-Doxylin [Doxycycline] [Chlortetracycline] Alti-Doxycycline [Doxycycline] Novo-Tetra [Tetracycline] Aureomycin Soluble Powder Pennchlor 100 Hi-Flo Meal Apo-Doxy [Doxycycline] Nu-Doxycycline [Doxycycline] Concentrate [Chlortetracycline] [Chlortetracycline] Apo-Doxy-Tabs [Doxycycline] Nu-Tetra [Tetracycline] Aureomycin Uterine Oblets Pennchlor 50 Meal [Chlortetracycline] Apo-Tetra [Tetracycline] Vibramycin [Doxycycline] [Chlortetracycline] Doryx [Doxycycline] Vibra-Tabs [Doxycycline] Biomycin 200 [Oxytetracycline] Pennchlor 70 Meal [Chlortetracycline] Doxycin [Doxycycline] Vibra-Tabs C-Pak [Doxycycline] Calf Scour Bolus Antibiotic Pennchlor 100 MR [Chlortetracycline] Doxytec [Doxycycline] [Tetracycline] Chlor 50 [Chlortetracycline] Pennchlor 64 Soluble Powder Note: For a listing of dosage forms and brand names by country [Chlortetracycline] availability, see the Dosage Forms section(s). Chlor 100 [Chlortetracycline] Pennox 100 Hi-Flo Meal [Oxytetracycline] CATEGORY: ChlorMax 50 [Chlortetracycline] Pennox 200 Hi-Flo Meal [Oxytetracycline] Chlorosol-50 [Chlortetracycline] Pennox 200 Injectable [Oxytetracycline] Antibacterial (systemic); antiprotozoal; antirickettsial. CLTC 100 MR [Chlortetracycline] Pennox 50 Meal [Oxytetracycline] CTC 50 [Chlortetracycline] Pennox 100-MR [Oxytetracycline] INDICATIONS CTC Soluble Powder Concentrate Pennox 343 Soluble Powder [Chlortetracycline] [Oxytetracycline] Note: Bracketed information in the Indications section refers to uses that Duramycin 10 [Tetracycline] PolyOtic Soluble Powder [Tetracycline] either are not included in U.S. product labeling or are for products not Duramycin 72-200 [Oxytetracycline] Promycin 100 [Oxytetracycline] commercially available in the U.S. Duramycin 100 [Oxytetracycline] Solu-Tet [Tetracycline] Duramycin-324 [Tetracycline] Solu-Tet 324 [Tetracycline] Foul Brood Mix [Oxytetracycline] Terramycin 50 [Oxytetracycline] GENERAL CONSIDERATIONS Geomycin 200 [Oxytetracycline] Terramycin 100 [Oxytetracycline] Kelamycin [Oxytetracycline] Terramycin 200 [Oxytetracycline] The tetracyclines are broad-spectrum antibiotics with activity against Liquamycin LA-200 [Oxytetracycline] Terramycin-50 [Oxytetracycline] gram-positive and gram-negative bacteria, including some anaerobes. Maxim-200 [Oxytetracycline] Terramycin-100 [Oxytetracycline] They are also active against chlamydia, mycoplasmas, some proto- Onycin 62.5 [Tetracycline] Terramycin-200 [Oxytetracycline] zoa{R-28; 133}, and several rickettsiae, including Anaplasma, Ehrlichia, Onycin 250 [Tetracycline] Terramycin-Aqua [Oxytetracycline] Onycin 1000 [Tetracycline] Terramycin 100 For Fish and Haemobartonella. The activity range of the tetracyclines also [Oxytetracycline] includes Escherichia coli, Klebsiella species, Pasteurella species, Salmo- OT 200 [Oxytetracycline] Terramycin Scours Tablets nella species, Staphylococcus species, and Streptococcus species{R-4}. [Oxytetracycline] OTC 50 [Oxytetracycline] Terramycin Soluble Powder Susceptibility testing has demonstrated that some coliforms, myco- [Oxytetracycline] plasma, streptococci, and staphylococci have developed resistance to OXTC 50 [Oxytetracycline] Terramycin-343 Soluble Powder tetracyclines{R-21; 150}. However, the breakpoints used to classify these [Oxytetracycline] organisms as susceptible or resistant are not validated for animal OXTC 100 [Oxytetracycline] Terra-Vet 100 [Oxytetracycline] OXTC 200 [Oxytetracycline] Terra-Vet Soluble Powder indications. Susceptibility testing should not be the sole basis for [Oxytetracycline] selecting tetracyclines for therapy{R-65}.

ACCEPTED [Chickens]: Oxytetracycline soluble powder{R-54} and chlortetracycline Abortion, vibrionic (prophylaxis)1—Sheep: Chlortetracycline for medi- for medicated feed are indicated in the treatment of susceptible E. coli cated feed{R-16; 152} is indicated to aid in reduction of the incidence of involved in the development of enteritis. {R-26} vibrionic abortion caused by susceptible Campylobacter fetus. [Lambs]: Oxytetracycline for medicated feed is indicated in Abscesses, cervical (prophylaxis)1—Pigs: Chlortetracycline for medicated the reduction of bacterial enteritis in creep-fed suckling lambs. 1 feed{R-152} is indicated for reduction of the incidence of cervical Escherichia coli infections (treatment) —Chickens: Chlortetracycline for {R-16; 115; 152} abscesses caused by susceptible organisms. medicated feed is indicated as an aid in reducing Abscesses, hepatic (prophylaxis)1—Cattle: Chlortetracycline for medi- mortality due to E. coli infections. cated feed{R-16; 152} is indicated as an aid in the prevention of hepatic Feed efficiency, improved; or 1 1 1 abscesses in cattle. Weight gain, increased rate—Calves , cattle , chickens, pigs, sheep , and {R-16; 152} Actinobacillosis (treatment)1—Cattle: Oxytetracycline injection{R-45} is turkeys: Chlortetracycline for medicated feed and oxy- 1{R-117} indicated in the treatment of actinobacillosis (wooden tongue) caused tetracyline for medicated feed are indicated for growth promo- by susceptible Actinobacillus lignieresii. tion and feed efficiency. {R-117} Anaplasmosis (treatment)1—Cattle: Chlortetracycline for medicated Foul brood (treatment)—Bees: Oxytetracycline for medicated feed {R-61; 117} feed{R-16; 152} is indicated in the control of active infection caused and soluble powder are indicated in the treatment of by susceptible Anaplasma marginale. American and European foul brood caused by susceptible organisms. Diphtheria (treatment)1—Cattle: Oxytetracycline injection{R-24; 45} is Fowl cholera (prophylaxis)—Chickens: Oxytetracycline for medicated {R-122} 1{R-61; 122} indicated in the treatment of diphtheria (necrotic laryngitis, necrotic feed and soluble powder are indicated in the necrophorus stomatitis) caused by susceptible Fusobacterium necropho- prevention of fowl cholera caused by susceptible organisms. rum. Fowl cholera (treatment)— 1 Enteritis, bacterial (treatment)—The treatment of enteritis should be Chickens: Chlortetracycline soluble powder and oxytetracycline for 1{R-117} {R-11} dependent on a specific diagnosis and knowledge of pathogen medicated feed and soluble powder are indicated in the susceptibility to tetracyclines. Some pathogens associated with enter- control of mortality from fowl cholera caused by susceptible {R-80} {R-18} itis, such as Escherichia coli, are found to be resistant to the Pasteurella multocida . [Tetracycline soluble powder is tetracyclines. indicated in the treatment of fowl cholera caused by susceptible Calves: Chlortetracycline soluble powder1, oxytetracycline tablets{R- organisms.] 1 {R-152} 60}, and tetracycline boluses and soluble powder{R-1} are indicated Ducks : Chlortetracycline for medicated feed is indicated as an in the control of bacterial enteritis (scours) caused by suscep- aid in the control and treatment of fowl cholera caused by susceptible tible E. coli. Chlortetracycline for medicated feed{R-16; 152} and Pasteurella multocida. soluble powder; oxytetracycline for medicated feed{R-117}, injection, Furunculosis (treatment)—Salmonids (salmon and trout): Oxytetracy- {R-62; 124} soluble powder, and tablets1{R-23; 24; 60; 61}; and tetracycline cline for medicated feed is indicated in the control of bolus and soluble powder{R-1; 18} are indicated in the treatment of furunculosis caused by susceptible Aeromonas salmonicida. {R-27; bacterial enteritis caused by susceptible E. coli and Salmonella Gaffkemia (treatment)—Lobsters: Oxytetracycline for medicated feed 124} species. is indicated in the treatment of gaffkemia caused by susceptible Cattle: Chlortetracycline for medicated feed1{R-16; 152} and oxy- Aerococcus viridans. 1 tetracycline for medicated feed1{R-117}, injection1{R-45}, and soluble Gastroenteritis (treatment) —Cats and dogs: Tetracycline oral suspen- {R-4} powder{R-61} are indicated in the treatment of bacterial enteritis sion is indicated in the treatment of bacterial gastroenteritis, but caused by susceptible E. coli and Salmonella{R-11}. use should be reserved for treatment of organisms known to be Pigs: Chlortetracycline soluble powder1{R-17}, oxytetracycline soluble susceptible. 1 powder{R-11; 54}, and tetracycline powder for oral solution{R-18} are Hemorrhagic septicemia, bacterial (treatment) —Catfish and salmonids: {R-62; 124} indicated in the control and treatment of bacterial enteritis caused Oxytetracycline for medicated feed is indicated in the control by susceptible E. coli. Chlortetracycline for medicated feed{R-16; 152} of hemorrhagic septicemia caused by susceptible Aeromonas hydrophila, {R-173} and oxytetracycline injection{R-24; 45} and for medicated feed{R-117} A. sobia, and Pseudomonas species . are indicated in the treatment of bacterial enteritis (scours) caused Hexamitiasis (treatment)—Turkeys: Chlortetracycline for medicated 1{R-16; 152} 1{R-117} by susceptible E. coli and Salmonella. feed and oxytetracycline for medicated feed are Sheep: Oxytetracycline for medicated feed1{R-117} and soluble pow- indicated in the control of hexamitiasis, and oxytetracycline soluble 1{R-11; 61} {R-18} der{R-54; 61} and [tetracycline soluble powder]{R-18} are indicated in powder and [tetracycline soluble powder] are indicated the treatment of enteritis caused by susceptible organisms. in the treatment of hexamitiasis caused by susceptible Hexamita Turkeys, growing: Chlortetracycline soluble powder1{R-17} and oxytet- meleagridis. racycline soluble powder{R-11; 54} are indicated in the control of Keratoconjuntivitis, infectious (treatment)—Cattle: Long-acting oxytet- {R-45} susceptible organisms involved in the development of enteritis racycline injection is indicated in the treatment of keratocon- (bluecomb). junctivitis caused by susceptible Moraxella bovis. Turkeys: Chlortetracycline for medicated feed{R-16; 152} and [powder for Leptospirosis (treatment)— 1{R-16; 152} oral solution]{R-17} and tetracycline soluble powder{R-18; 19} are Pigs: Chlortetracycline for medicated feed and oxytetracy- {R-122} indicated in the control and treatment of enteritis caused by cline for medicated feed are indicated to aid in reducing the susceptible organisms. Oxytetracycline for medicated feed{R-117} is shedding of leptospirosis and the incidence of abortion. Oxytetracy- indicated in the treatment of susceptible E. coli involved in the cline for medicated feed is indicated as an aid in the reduction of development of enteritis (bluecomb). abortion and urinary shedding of leptospirosis, production of

healthier newborn pigs, and maintenance of weight gains in the Pseudomonas disease (treatment)1—Catfish and salmonids: Oxytetracy- presense of leptospirosis{R-122}. Oxytetracycline injection{R-24; 45} cline for medicated feed{R-62} is indicated in the control of pseudomo- and soluble powder{R-11} are indicated in the treatment of leptospi- nas disease caused by susceptible organisms. rosis caused by susceptible Leptospira pomona. Oxytetracycline can Psittacosis (treatment)1—Cockatoos, macaws, and parrots: Chlortetracy- reduce the incidence of abortions and shedding of leptospira;{R-11} cline for medicated feed{R-152} is indicated in the treatment of however, it can be ineffective in eliminating the organism{R-113}. psittacosis caused by susceptible Chlamydia psittaci. Cattle: Oxytetracycline injection{R-24; 45} is indicated in the treatment Respiratory disease, bacterial, chronic (prophylaxis)—Chickens: Oxytet- of leptospirosis caused by susceptible Leptospira pomona. racycline for medicated feed{R-122} is indicated in the prevention of Paratyphoid (treatment)1—Turkeys, less than 4 weeks of age: Chlortet- chronic respiratory disease caused by susceptible organisms. racycline for medicated feed{R-16; 152} is indicated as an aid in reducing Respiratory disease, bacterial, chronic (treatment)—Chickens: Chlortet- mortality from paratyphoid infection caused by susceptible Salmonella racycline for medicated feed and soluble powder1{R-16; 17; 152}, typhimurium. oxytetracycline for medicated feed1 and soluble powder{R-11; 22}, and Pneumonia, bacterial (prophylaxis)—Cattle: Oxytetracycline for medi- tetracycline soluble powder{R-18; 127} are indicated in the control of cated feed1{R-117; 122} is indicated in the prevention of pneumonia and respiratory disease, including air sac disease, caused by susceptible as an aid in the reduction of losses due to bovine respiratory disease Mycoplasma gallisepticum and E. coli. Chlortetracycline for medicated complex. feed{R-16; 115} and powder for oral solution{R-17} are indicated in the Pneumonia, bacterial (treatment)— treatment of chronic respiratory disease caused by susceptible organ- Calves: Chlortetracycline soluble powder1, oxytetracycline tablets1{R-60}, isms. and tetracycline boluses{R-1} are indicated in the control of Skeletal tissue marking1—Salmon, Pacific: Oxytetracycline for medicated pneumonia and bovine respiratory disease complex caused by feed{R-117} is indicated to mark skeletal tissue in Pacific salmon. susceptible organisms, including Pasteurella species. Chlortetracy- Skin and soft tissue infections (treatment)1—Cattle:{R-45} Oxytetracycline cline soluble powder; oxytetracycline injection, soluble powder, and injection is indicated in the treatment of wounds infected by tablets1{R-60; 61}; and tetracycline boluses and soluble powder{R-1; susceptible Staphylococcus species or Streptococcus species. 18} are indicated in the treatment of pneumonia caused by Synovitis, infectious (treatment)—Chickens and turkeys: Chlortetracycline susceptible organisms, including Pasteurella species. However, due for medicated feed1{R-16; 152} and soluble powder1{R-17}, oxytetracy- to resistance{R-51; 171; 180} by pathogens, the tetracyclines may no cline for medicated feed{R-117} and soluble powder{R-11}, and tetracy- longer be effective in the treatment of some types of bacterial cline soluble powder{R-3} are indicated in the control of infectious pneumonia. synovitis caused by susceptible Mycoplasma synoviae. Chlortetracycline Cattle: Chlortetracycline for medicated feed{R-152} is indicated in the powder for oral solution{R-17} is indicated in the treatment of infectious control1 and treatment of pneumonia caused by susceptible organ- synovitis caused by susceptible M. synoviae. isms. Oxytetracycline{R-24; 45; 61} is indicated in the treatment of Ulcer disease (treatment)—Salmonids (salmon, trout): Oxytetracycline for pneumonia and shipping fever complex caused by susceptible medicated feed{R-62; 124} is indicated in the control of ulcer disease Pasteurella and Haemophilus species. Increasing resistance to tetra- caused by susceptible Haemophilus piscium. cyclines by strains of organisms involved in bovine pneumonia is Urinary tract infections (treatment)1—Cats and dogs: Tetracycline oral reported{R-51; 171; 180}. suspension{R-4} is indicated in the treatment of urinary tract infections Pigs: Chlortetracycline soluble powder1{R-17} is indicated in the control caused by susceptible Staphylococcus species and E. coli. Also, concen- of pneumonia caused by susceptible Actinobacillus pleuropneumoniae trations of tetracycline in urine are high enough to be effective against (Haemophilus species), Pasteurella species, and Klebsiella species. Pseudomonas species{R-150}. Chlortetracycline for medicated feed1{R-152} and oxytetracycline Uterine infections, acute (treatment)— soluble powder are indicated in the treatment of pneumonia caused Cattle: Oxytetracycline injection{R-24; 45} is indicated in the treatment by susceptible Pasteurella multocida. Chlortetracycline soluble pow- of acute metritis caused by susceptible strains of Staphylococcus and der{R-17}, oxytetracycline injection{R-24; 45}, and tetracycline soluble Streptococcus species. powder{R-1; 18} are indicated in the treatment of pneumonia caused [Pigs]: Oxytetracycline injection{R-24} is indicated in the treatment of by susceptible Actinobacillus pleuropneumonia (Haemophilus species), acute metritis caused by susceptible organisms. Klebsiella, and Pasteurella species. Increasing resistance to tetracy- [Sheep]: Oxytetracycline injection{R-24; 121} is indicated in the treat- cline by strains of organisms involved in porcine pneumonia is ment of uterine infections. reported{R-50}. [Arthritis, bacterial (treatment)]—Cattle and sheep: Oxytetracycline Sheep: Oxytetracycline for medicated feed1{R-117}, [injection]{R-24; 121}, injection{R-24; 25} is indicated in the treatment of septic arthritis (joint and soluble powder{R-6; 13}, and [tetracycline soluble powder]{R-18} ill) caused by susceptible organisms. are indicated in the treatment of pneumonia caused by susceptible [Atrophic rhinitis (treatment)]—Pigs: Oxytetracycline for medicated organisms. feed{R-122} is indicated for use as an aid in maintaining weight gain Pododermatitis (treatment)—Cattle: Long-acting oxytetracycline injec- in pigs infected with atrophic rhinitis. tion{R-24; 45} is indicated in the treatment of pododermatitis (‘foot rot’) [Blackleg (treatment)]; or caused by susceptible Fusobacterium necrophorum. Signs may not be [Malignant edema (treatment)]—Cattle: Oxytetracycline injection{R-24; completely resolved by oxytetracycline alone and other treatment or 25; 121} is indicated in the treatment of infections caused by susceptible surgery may be required. Clostridia species.

[Bloat]—Cattle: Oxytetracycline for medicated feed{R-26} is indicated as an that specific dosage regimens may be successful in treating the aid in reducing the incidence of bloat in young cattle on pasture and in infection{R-160}. No controlled studies are available. feedlots. [Chlamydial infection (treatment)]1;or [Cold water disease (treatment)]—Salmonids:{R-124} Oxytetracycline for [Respiratory tract infections, bacterial (treatment)]1—Cats: There are medicated feed is indicated in the treatment of cold water disease insufficient data to establish the safety and efficacy of doxycycline in caused by susceptible Cytophaga psychrophilia. the treatment of chlamydial infections or bacterial respiratory infec- [Columnaris disease (treatment)]—Salmonids: Oxytetracycline for medi- tions in cats; however, it is used in the treatment of infections caused cated feed{R-124} is indicated in the treatment of columnaris disease by susceptible organisms{R-151; 177}. caused by susceptible Chondrococcus (Flexibacter) columnaris. [Ehrlichiosis (treatment)]1—Dogs: There are insufficient data to establish [Egg production, increased]; or the efficacy of doxycycline in the treatment of ehrlichiosis in dogs. [Egg hatchability, increased]—Chickens and turkeys: Chlortetracycline for Clinical signs are often resolved by administration of doxycycline or medicated feed is indicated for use in increasing egg production or egg tetracycline{R-40; 41; 43; 139}, but it is uncertain whether the organism hatchability. is cleared from dogs treated{R-40; 139}. Serum Ehrlichia canis antibody [Ehrlichiosis, equine (treatment)]1—Horses: Oxytetracycline is used in the titers can remain increased in some dogs for over 2 years after the treatment of ehrlichiosis caused by susceptible Ehrlichia equi{R-46; 138}. resolution of clinical signs during treatment with tetracycline{R-139}; [Enteric redmouth disease (treatment)]—Salmonids: Oxytetracycline for also, in some dogs, blood and tissue cultures have tested positive for medicated feed{R-124} is indicated in the treatment of enteric red- Ehrlichia canis 2 months after treatment with doxycycline{R-40}. mouth disease caused by susceptible Yersinis ruckeri. [Flexural limb deformities (treatment)]1—Foals: There are insufficient [Enterotoxemia (treatment)]—Lambs: Chlortetracycline for medicated data to establish the efficacy of oxytetracycline in the treatment of feed and oxytetracycline for medicated feed{R-26} are indicated in the flexural limb deformities in foals; however, studies show that oxytet- reduction of losses due to enterotoxemia in feedlot lambs. racycline can cause a short-term moderate improvement in meta- [Erysipelas (treatment)]—Pigs: Oxytetracycline injection{R-24; 25; 121} is carpophalangeal joint angle and an increase in range of joint motion indicated in the treatment of erysipelas caused by susceptible organ- in newborn foals as compared to untreated foals{R-157; 158}. The isms. available studies were performed in healthy foals rather than foals with [Mastitis (treatment)]—Cattle, pigs, and sheep: Oxytetracycline injec- deformities and both the ideal dose and actual short- and long-term tion{R-24; 25} is indicated in the treatment of mastitis caused by benefits and risks of this treatment are unknown. susceptible organisms. Oxytetracycline, administered at the dosage [Haemobartonella felis infection (treatment)]1—Cats: There are insufficient recommended in product labeling, does not appear to be effective data to establish the safety and efficacy of doxycycline in the treatment for the cure of Staphylococcus aureus infections in the dry of feline infectious anemia, caused by susceptible Haemobartonella felis; cow{R-103}. however, it is used in the treatment of acute infections{R-147}.If [Omphalophlebitis (treatment)]—Cattle: Oxytetracycline injection{R-24; considered clinically necessary, corticosteroids{R-149} and blood trans- 25} is indicated in the treatment of omphalophlebitis (navel ill) caused fusions are used concurrently with doxycycline in the treatment of this by susceptible organisms. infection{R-147}. Acutely infected cats may clinically recover without [Peritonitis (treatment)]—Cattle: Oxytetracycline injection{R-25; 121} is treatment{R-147; 159}, although it is believed that the organism is not indicated in the treatment of peritonitis caused by susceptible cleared from these animals; there is also some question about the organisms. efficacy of doxycycline or other tetracyclines in completely clearing the [Pododermatitis (prophylaxis)]—Cattle: Chlortetracycline for medicated organism from infected cats{R-148}. Controlled clinical efficacy trials feed is indicated as an aid in the prevention of pododermatitis{R-116}. have not been conducted for any medication; however, a tetracycline [Potomac horse fever (treatment)]1—Horses: Oxytetracycline is used in is usually administered when a cat is diagnosed and doxycycline is the treatment of Potomac horse fever (equine ehrlichial colitis) caused considered the tetracycline of choice{R-147} because of an expectation by susceptible Ehrlichia risticii{R-47; 48}. Treatment of exposed animals of fewer side effects. Cats with serious underlying viral infections, such to prevent development of disease is not recommended; the incubation as feline leukemia virus, are not expected to respond well to therapy. period will be increased but the disease is not prevented{R-48}. [Leptospirosis (treatment)]1—Dogs: Although doxycyline is proposed in [Rocky Mountain spotted fever (treatment)]1—Dogs: Tetracycline or dox- some veterinary references for use in the clearance of the leptospirosis ycycline{R-151} is used in the treatment of Rocky Mountain spotted carrier state in dogs, there are insufficient data showing clearance or fever caused by susceptible Rickettsia rickettsii{R-140; 141}. prevention of a potential carrier state to support this use as an [Sinusitis, infectious (prophylaxis)]—Turkeys: Chlortetracycline for med- established indication. icated feed is indicated in the prevention of sinusitis caused by [Lyme disease (treatment)]1—Dogs: There are insufficient data to susceptible organisms. establish the efficacy of tetracyclines in the treatment of Lyme [Sinusitis, infectious (treatment)]—Turkeys: Oxytetracycline for medi- borreliosis. Doxycycline has been effective in the resolution of early cated feed{R-26; 122} and tetracycline soluble powder are indicated in Borrelia burgdorferi infection in people{R-163}; therefore, doxycycline the control of sinusitis caused by susceptible organisms, such as and tetracycline are used to treat the infection in dogs{R-164; 165}; susceptible Mycoplasma gallisepticum. however, it is uncertain whether this is the best medication to produce long-term resolution of the infection{R-163}. ACCEPTANCE NOT ESTABLISHED [Thromboembolic meningoencephalitis (treatment)]1—Cattle: There are [Brucellosis (treatment)]1—Dogs: There are insufficient data to establish insufficient data to establish the efficacy of oxytetracycline in the the efficacy of tetracycline administered concurrently with strepto- treatment of thromboembolic meningoencephalitis; however, if cattle mycin in the treatment of brucellosis in dogs; however, studies suggest are diagnosed in the early stages of the disease, before recumbency,

treatment can be effective against susceptible Haemophilus som- 1,11-dioxo-, monohydrochloride, compd. with ethanol (2:1), mono- nus{R-161; 166}. hydrate, [4S-(4 alpha, 4a alpha, 5 alpha, 5a alpha, 6 alpha, 12a [Uterine infections, bacterial (treatment)]—Cattle, horses, pigs, and sheep: alpha)]-{R-114}. Although Canadian product labeling includes the use of intrauterine Oxytetracycline—2-Naphthacenecarboxamide, 4-(dimethylamino)-1,4,- chlortetracycline, oxytetracycline, and tetracycline in the treatment of 4a,5,5a,6,11,12a-octahydro-3,5,6,10,12,12a-hexahydroxy-6-methyl- uterine infections, there are insufficient available data concerning the 1,11-dioxo-, [4S-(4 alpha,4a alpha,5 alpha,5a alpha,6 beta,12a efficacy and safety of this use. Intrauterine tetracycline treatment can alpha)]-, dihydrate{R-114}. reduce the incidence of putrefaction of retained fetal membranes and Oxytetracycline hydrochloride—2-Naphthacenecarboxamide, 4-(dimeth- fever associated with infection in cattle, but because it is believed to ylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,6,10,12,12a-hexa- penetrate only into the endometrium from infusion into the hydroxy-6-methyl-1,11-dioxo-, monohydrochloride, [4S-(4 alpha,4a uterus{R-104; 130}, parenteral antibiotics are recommended for those alpha,5 alpha,5a alpha,6 beta,12a alpha)]-{R-114}. animals that have evidence of infection or develop signs of septice- Tetracycline—2-Naphthacenecarboxamide, 4-(dimethylamino)-1,4,4a, mia{R-144}. The intrauterine administration of tetracyclines for the 5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-6-methyl-1,11- treatment of uterine infections such as endometritis or treatment of dioxo-, [4S-(4 alpha,4a alpha,5a alpha,6 beta,12a alpha)]-{R-114}. infection associated with retained placentas in cattle is not effective in Tetracycline hydrochloride—2-Naphthacenecarboxamide, 4-(dimethyla- shortening the interval from parturition to conception, increasing mino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy- pregnancy rates, or reducing culling rates{R-144–146}. Considering 6-methyl-1,11-dioxo-, monohydrochloride, [4S-(4 alpha,4a alpha,5a costs, risks of residues{R-129}, and a lack of significant change in long- alpha,6 beta,12a alpha)]-{R-114}. term fertility in cattle, there is no evidence to support the routine use of Molecular formula: {R-114} intrauterine tetracyclines in cattle, horses, pigs, and sheep. Chlortetracycline hydrochloride—C22H23ClN2O83 Æ HCl . {R-114} Doxycycline—C22H24N2O8 Æ H2O . {R-114} Doxycycline hyclate—(C22H24N2O8ÆHCl)2 Æ C2H6O Æ H2O . 1 {R-114} Not included in Canadian product labeling or product not commercially Oxytetracycline—C22H24N2O9 Æ 2H2O . {R-114} available in Canada. Oxytetracycline hydrochloride—C22H24N2O9 Æ HCl . {R-114} Tetracycline—C22H24N2O8 . {R-114} Tetracycline hydrochloride—C22H24N2O8 Æ HCl . REGULATORY CONSIDERATIONS Molecular weight: U.S.— Chlortetracycline hydrochloride—515.34{R-114}. Withdrawal times have been established for chlortetracycline for Doxycycline—462.45{R-114}. medicated feed and soluble powder; oxytetracycline soluble powder, Doxycycline hyclate—1025.87{R-114}. for medicated feed, tablets, and injection; and tetracycline soluble Oxytetracycline—496.46{R-114}. powder and boluses. See the Dosage Forms section. Oxytetracycline hydrochloride—496.89{R-114}. Canada— Tetracycline—444.43{R-114}. Withdrawal times have been established for chlortetracycline for Tetracycline hydrochloride—480.90{R-114}. medicated feed, and uterine tablets; oxytetracycline soluble powder, Description: for medicated feed, uterine infusion, and injection; and tetracycline Chlortetracycline Hydrochloride USP—Yellow, crystalline powder. Is soluble powder, boluses, and uterine tablets. See the Dosage Forms odorless. Is stable in air, but is slowly affected by light{R-128}. section. Doxycycline USP—Yellow, crystalline powder{R-128}. Doxycycline Hyclate USP—Yellow, crystalline powder{R-128}. CHEMISTRY Oxytetracycline USP—Pale yellow to tan, odorless, crystalline powder. Is Source: stable in air, but exposure to strong sunlight causes it to darken. It Chlortetracycline—Isolated from the fungus Streptomyces aureofac- loses potency in solutions of pH below 2, and is rapidly destroyed by iens{R-22}. alkali hydroxide solutions{R-128}. Doxycycline—Produced semisynthetically.{R-22} Oxytetracycline Hydrochloride USP—Yellow, odorless, crystalline pow- Oxytetracycline—Isolated from the fungus Streptomyces rimosus{R-22}. der. Is hygroscopic. Decomposes at a temperature exceeding 180 C, Tetracycline—Produced by some streptomyces strains; however, it is and exposure to strong sunlight or to temperatures exceeding 90 Cin manufactured by hydrogenolysis of chlortetracycline{R-113}. moist air causes it to darken. Its potency is diminished in solutions Chemical name: having a pH below 2, and is rapidly destroyed by alkali hydroxide Chlortetracycline hydrochloride—2-Naphthacenecarboxamide, 7-chloro- solutions{R-128}. 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a- Tetracycline USP—Yellow, odorless, crystalline powder. Is stable in air, pentahydroxy-6-methyl-1,11-dioxo-, monohydrochloride [4S-(4 alpha, but exposure to strong sunlight causes it to darken. It loses potency in 4a alpha,5a alpha,6 beta,12a alpha)]-{R-114}. solutions of pH below 2, and is rapidly destroyed by alkali hydroxide Doxycycline—2-Naphthacenecarboxamide, 4-(dimethylamino) - 1,4,4a, solutions{R-128}. 5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- Tetracycline Hydrochloride USP—Yellow, odorless, crystalline powder. Is 1,11-dioxo-, [4S-(4 alpha,4a alpha,5 alpha,5a alpha,6 alpha,12a moderately hygroscopic. Is stable in air, but exposure to strong alpha)]-, monohydrate{R-114}. sunlight in moist air causes it to darken. It loses potency in solution Doxycycline hyclate—2-Naphthacenecarboxamide, 4-(dimethylamino)- at a pH below 2, and is rapidly destroyed by alkali hydroxide 1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- solutions{R-128}.

2003 Thomson MICROMEDEX All rights reserved 230 TETRACYCLINES Veterinary—Systemic pKa: interference with oral absorption by calcium or other substances{R- Chlortetracycline: 3.3, 7.4, 9.3{R-133}. 133}. See the Drug interactions section. Oxytetracycline: 3.3, 3.7, 9.1{R-156}. Parenteral—Oxytetracycline: As with other parenteral medications, the Tetracycline: 8.3, 10.2{R-133}. absorption and bioavailability of intramuscularly administered oxytet- Solubility: racycline can vary depending on the site of administration. Oxytetra- Chlortetracycline Hydrochloride USP—Sparingly soluble in water; solu- cycline is more bioavailable when administered intramuscularly into ble in solutions of alkali hydroxides and carbonates; slightly soluble in the shoulder of calves than when administered intramuscularly into alcohol; practically insoluble in acetone, in chloroform, in dioxane, the neck or particularly into the buttock.{R-94} and in ether{R-128}. The absorption of the long-acting formulations of oxytetracycline (with Doxycycline USP—Very slightly soluble in water; freely soluble in dilute 2-pyrrolidone excipient) administered intramuscularly has been acid and in alkali hydroxide solutions; sparingly soluble in alcohol; described as having a rapid phase of 48 minutes for 14% of the dose practically insoluble in chloroform and in ether{R-128}. and a slow phase of 18 hours for 38% of the dose in cattle administered Doxycycline Hyclate USP—Soluble in water and in solutions of alkali a 20 mg/kg dose{R-99}. With a 10 mg/kg dose, the rapid phase is 16 hydroxides and carbonates; slightly soluble in alcohol; practically minutes and the slow phase is 11 hours.{R-100} insoluble in chloroform and in ether{R-128}. Oxytetracycline USP—Very slightly soluble in water; freely soluble in 3 N Bioavailability: hydrochloric acid and in alkaline solutions; sparingly soluble in Oral— alcohol{R-128}. Chlortetracycline: Oxytetracycline Hydrochloride USP—Freely soluble in water, but crystals Chickens—1% (25 mg per kg of body weight [mg/kg] dose).{R-78; 79} of oxytetracycline base separate as a result of partial hydrolysis of the Pigs—Fasted or fed: 18 to 19%{R-77}. hydrochloride. Sparingly soluble in alcohol and in methanol, and even Turkeys—6% (15 mg/kg dose).{R-78; 80} less soluble in dehydrated alcohol; insoluble in chloroform and in Doxycycline: ether{R-128}. Chickens—41.3% (20 mg/kg dose).{R-64} Tetracycline USP—Very slightly soluble in water; freely soluble in dilute Human value—90 to 95%{R-169}. acid and in alkali hydroxide solutions; sparingly soluble in alcohol; Oxytetracycline: practically insoluble in chloroform and in ether{R-128}. Pigs—4.8% (50 mg/kg dose).{R-109} Tetracycline Hydrochloride USP—Soluble in water and in solutions of Piglets, weaned, 10 weeks of age— alkali hydroxides and carbonates; slightly soluble in alcohol; practi- By drench: 9% (20 mg/kg dose).{R-82} cally insoluble in chloroform and in ether{R-128}. In medicated feed for 3 days: 3.7% (400 parts per million [ppm] of feed).{R-82} PHARMACOLOGY/PHARMACOKINETICS Trout, rainbow (Oncorhynchus mykiss)—5.6% (75 mg/kg dose).{R-89} Note: Unless otherwise noted, pharmacokinetic values are based on a Turkeys— single intravenous dose of medication. Fasted: 47.6% (10 mg/kg dose).{R-85} Fed: 9.4% (10 mg/kg dose).{R-85} Mechanism of action/effect: Tetracycline: Pigs, fasted—23% (22 mg/kg dose).{R-74} Tetracyclines are broad-spectrum bacteriostatic agents that inhibit Intramuscular— protein synthesis by binding reversibly to receptors of the 30 S Oxytetracycline, conventional formulation: ribosomal subunit of susceptible microorganisms. The binding of a Buffalo—63.2% (22 mg/kg dose).{R-87} tetracycline to the subunit blocks the binding of the aminoacyl-tRNA Calves, 17 days of age—61% (20 mg/kg dose){R-99}. to the acceptor site on the mRNA-ribosomal complex and prevents the Calves, 3 months of age—76 hours postinjection of 18 mg/kg dose: addition of new amino acids to the peptide chain, inhibiting protein Buttock administration—83.1%.{R-94} synthesis.{R-22} Neck administration—93.3%.{R-94} Tetracyclines must enter the target cell to be effective. Uptake appears Shoulder administration—99.4%.{R-94} to depend on passive diffusion and active transport, with the Catﬁsh, African, and trout, rainbow—85% (60 mg/kg dose).{R-90} exception of doxycycline, which enters the cell by passive diffu- Cows—80.8% (8 mg/kg dose){R-95}; 95% (20 mg/kg dose){R-174}. sion{R-28}. Susceptible cells concentrate the antibiotic; resistant Goats—65.5% (20 mg/kg dose).{R-81} strains appear to carry an R-factor that inhibits uptake of Oxytetracycline, long-acting formulation: drug.{R-22} Camels—93.7% (10 mg/kg dose).{R-88} Cattle—51%; 78.5%; 95% (20 mg/kg dose).{R-98; 99; 174} Absorption: Goats—79.4% (20 mg/kg dose).{R-81} Oral—Doxycycline: Generally is more completely absorbed from the gastrointestinal tract than are the tetracyclines developed less Distribution: Tetracyclines are lipid soluble and are well distributed to recently{R-40; 64; 74}, which can be poorly and variably absorbed. most tissues. Doxycycline is the most lipid soluble and shows the Human studies have shown that the absorption of oxytetracycline or greatest degree of tissue penetration.{R-28; 71} tetracycline is decreased when either is administered with food; the Volume of distribution— effect of food on doxycycline absorption is insigniﬁcant. Doxycycline is Chlortetracycline: also less likely than the older tetracyclines to form chelation complexes Calves, ruminating—Area volume of distribution: 1.93 ± 0.15 liters with divalent and trivalent metals and, therefore, there is less per kg (L/kg).{R-76}

Pigs—Steady state volume of distribution: Tetracycline— Fasted—0.97 ± 0.21 L/kg.{R-77} Cows: Low to moderate (31 to 41%).{R-67} Fed—1.39 ± 0.31 L/kg.{R-77} Sheep: Low (28 to 32%).{R-67} Turkeys—Area: 0.23 ± 0.05 L/kg.{R-78} Doxycycline: Biotransformation: All species—The tetracyclines are not known to be Calves—Steady state: biotransformed to any signiﬁcant extent before elimination.{R-28; 68–70} Preruminating—1.81 ± 0.24 L/kg.{R-68} Ruminating—1.31 ± 0.11 L/kg.{R-68} Cats—Steady state: 0.34 ± 0.03 L/kg.{R-70} Half-life: Elimination— Dogs—Steady state: 0.93 ± 0.14 L/kg.{R-70} Chlorotetracycline: Pigs—Steady state: 0.53 ± 0.04 L/kg.{R-69} Calves, ruminant—8.3 hours.{R-76} Oxytetracycline: Turkeys—0.88 hour.{R-78} Buffalo—Area: 0.28 to 0.45 L/kg.{R-87} Doxycycline: Calves, newborn to 8 months—Area: 1.67 L/kg.{R-93; 100} Calves— Camels—Steady state: 0.71 L/kg.{R-88} Preruminant: 9.8 hours.{R-68} Cows—Area: 0.80 ± 0.03 L/kg.{R-95} Ruminant: 14.2 hours.{R-68} Dogs—Area: 2.10 ± 0.42 L/kg.{R-84} Cats—4.6 hours.{R-70} Donkeys— Chickens—4.8 hours.{R-64} Area: 0.78 L/kg{R-92}. Dogs—7 to 10.4 hours.{R-63; 70} Steady state: 0.65 L/kg{R-92}. Horses—Oral administration (apparent half-life): 8.7 ± 1.6 Foals— hours{R-131}. Area: 2.19 L/kg.{R-154} Pigs—3.9 hours.{R-69} Steady state: 2.17 L/kg.{R-154} Oxytetracycline: Goats—Area: 1.44 L/kg.{R-81} Buffalo—2.8 to 3.6 hours.{R-87} Horses— Calves— Apparent: 1.35 L/kg.{R-96} Newborn: 11.2 hours.{R-93} Area: 0.67 L/kg.{R-92} 6 weeks of age: 3.5 to 7.2 hours.{R-93; 100; 106} Steady state: 0.34 L/kg.{R-92} 6 weeks of age with induced Mannheimia (Pasteurella) haemolytica Pigs—Area: pneumonia: 2.5 hours.{R-106} Adult—1.8 L/kg.{R-83} 8 months of age: 6.3 hours.{R-93} Adult with pneumonia—1.53 L/kg.{R-83} Camels—7.7 hours.{R-88} Ponies— Catﬁsh, African—80.3 hours.{R-90} Area: 1.05 L/kg.{R-92} Cows—10 hours.{R-95} Steady state: 0.47 L/kg.{R-92} Dogs—6 hours.{R-84} Rabbits—0.86 L/kg.{R-86} Donkeys—6.5 hours.{R-92} Rats—Area: 0.79 L/kg.{R-91} Foals—6.7 to 7.3 hours.{R-154} Tetracycline: Goats—6.5 hours.{R-81} Chickens—Steady state: 0.17 L/kg.{R-73} Horses—13 hours{R-92}; 15.7 hours{R-175}. Pigs—Area: 4.5 ± 1.1 L/kg.{R-74} Pigs— Rabbits—Area: 1.05 ± .88 L/kg.{R-72} 10 weeks of age, weaned: 11.6 to 17.2 hours.{R-82} Adult: 3.8 to 6.7 hours.{R-77; 83} Protein binding: Adult, with pneumonia: 5.1 to 5.2 hours.{R-83} Chlortetracycline— Ponies—15 hours.{R-92} Cows: Moderate (47 to 51%).{R-67} Rabbits—1.3 hours.{R-86} Sheep: Moderate (46 to 50%).{R-67} Trout, rainbow— Doxycycline— Oncorhynchus mykiss: 60.3 hours.{R-89} Calves: Very high (92%).{R-68} Salmo gairdneri: 89.5 hours.{R-90} Cats: Very high (98%);{R-70} albumin binding—76%.{R-70} Turkeys—0.73 hour.{R-85} Dogs: Very high (91%);{R-70} albumin binding—54%.{R-70} Tetracycline: Pigs: Very high (93%).{R-69} Cats—2.5 hours.{R-75} Sheep: High (84 to 90%).{R-67} Chickens—2.8 hours.{R-73} Oxytetracycline— Dogs—1.6 to 2 hours.{R-75} Buffalo: Moderate (42%).{R-87} Pigs—16 hours.{R-74} Cows: Low (18 to 22%){R-67}. Rabbits—2 hours.{R-72} Horses and cows: Combined results—Moderate (50%).{R-96} Pigs, weaned, 10 weeks of age: High (75.5%).{R-82} Time to peak concentation/Peak serum concentration: Sheep: Low (21 to 25%).{R-67} Chlortetracycline—Oral: Trout, rainbow: Moderate (55%).{R-89} Calves (22 mg/kg dose)—

Milk fed: 15.7 ± 0.33 hours to a peak serum concentration of 1.86 ± Tetracycline—Oral: Pigs—72 hours to a peak serum concentration of 0.6 0.54 mcg per mL (mcg/mL).{R-76} mcg/mL (dose of 0.55 gram per kg of feed).{R-74} Ruminant: 13.3 ± 2.67 hours to a peak serum concentration of 0.67 ± 0.24 mcg/mL.{R-76} Turkeys—2.5 hours to a peak serum concentration of 0.6 mcg/mL (15 Duration of action: mg/kg dose).{R-80} Note: Duration of action may be estimated by the time target serum Doxycycline—Oral: concentrations are maintained. Target concentrations are generally Single dose— based on minimum inhibitory concentrations (MIC) for each organ- Chickens—0.35 ± 0.02 hour to a peak serum concentration of 54.6 ism. While 0.5 mcg/mL has been considered the MIC of oxytetracy- ± 2.4 mcg/mL (20 mg/kg dose).{R-64} cline for many pathogens in the past and research studies were based Horses— on that target, there are now many pathogens with MICs of 4 to 16 1 hour to a peak serum concentration of 0.22 mcg/mL (3 mg/kg mcg/mL. Duration of action may be minimal or nonexistent for these dose){R-131}. isolates. 1 hour to a peak serum concentration of 0.32 mcg/mL (dose of 10 Chlortetracycline— mg/kg){R-131}. Pigs: When administered 110 mg chlortetracycline per kg of feed, fed Multiple dosing: Horses—2 hours postadministration to a serum as the only ration, therapeutic plasma or tissue concentrations were concentration of 0.42 mcg/mL at 2 hours after the ﬁfth dose (ﬁve not produced{R-155}. intragastric doses of 10 mg/kg administered at twelve hour Turkeys: A single oral dose of 15 mg/kg produces serum concentrations intervals){R-131}. above 0.4 mcg/mL for 8 to 10 hours.{R-80}

Note: The MIC90 of doxycycline has been reported as £1 mcg/mL for Doxycycline—Dogs: An intravenous dose of 5 mg/kg produces serum Streptococcus zooepidemicus and 0.25 mcg/mL for Staphylococcus concentrations above 2 mcg/mL for 8 hours.{R-63} aureus in horses{R-131}. Oxytetracycline— Oxytetracycline— Oral: Oral: Pigs, weaned, 10 weeks of age— Pigs—A single oral 50 mg/kg dose produces >0.5 mcg/mL serum 30 hours after start of administration to a peak serum concentration concentrations for at least 8 hours.{R-109} of 0.2 ± 0.06 mcg/mL (dose of 400 parts per million in feed for 3 Pigs, after challenge with Actinobacillus pleuropneumonia—A single days).{R-82} oral 50 mg/kg dose produces >0.5 mcg/mL serum concentrations 1 to 5 hours to a peak serum concentration of 1.18 to 1.41 mcg/mL for at least 24 hours.{R-109} (20 mg per kg single dose). Pigs—When administered 550 mg of oxytetracycline per kg of feed, Intramuscular: fed as the only diet, plasma concentrations peaked at 0.4 mcg/ Conventional formulation— mL{R-107}. Calves, 14 weeks of age: 6 hours to a peak serum concentration of Note: These results may vary by size of pig and amount of feed 5.5 ± 1.25 mcg/mL (dose of 18 mg/kg in the neck).{R-95} intake. Catﬁsh, African: 7 hours to a peak serum concentration of 43.4 Intramuscular: mcg/mL (60 mg/kg dose).{R-90} Conventional formulation— Cows: 6.7 hours to a peak serum concentration of 5.7 ± 2.39 mcg/ Calves: A single dose of 18 mg/kg maintains serum concentrations mL (dose of 8 mg/kg in the neck).{R-95} > 1 mcg/mL for at least 32 hours.{R-94} Pigs: 1.5 hours to a peak serum concentration of 6.7 ± 3.4 (dose of Cows: A single dose of 20 mg/kg in the hindquarters maintains 20 mg/kg in the hindquarter).{R-107} serum concentrations of > 0.5 mcg/mL for 52 hours{R-98}. Trout, rainbow: 4 hours to a peak serum concentration of 56.9 mcg/ Pigs: A single dose of 20 mg/kg maintains serum concentrations mL (60 mg/kg dose).{R-90} > 0.5 mcg/mL for 28 to 36 hours.{R-107; 174} Long-acting formulation— Long-acting formulation— Calves, nonruminating, 5 weeks of age: 1 to 1.5 hours to a peak Calves, milk fed: A single dose of 10 mg/kg maintains serum serum concentration of 4 mcg/mL (dose of 20 mg/kg in the gluteal concentrations > 0.5 mcg/mL for 12 to 24 hours.{R-100} muscles).{R-99} Calves, ruminating: A single dose of 40 mg/kg maintains serum Calves, nonruminating, 6 weeks of age: 4.01 ± 2.84 hours to a peak concentrations > 2 mcg/mL for 48 hours;{R-101} also lung serum concentration of 3.01 ± 0.72 mcg/mL (dose of 10 mg/kg in concentrations produced are 2 mcg/mL at 48 hours.{R-101} the hindquarter).{R-100} Camels: A single dose of 10 mg/kg maintains serum concentrations Calves, ruminating: 7.6 ± 4 hours to a peak serum concentration of > 0.5 mcg/mL for 72 hours.{R-88} 9.6 ± 2.6 mcg/mL (dose of 40 mg/kg in the hindquarter).{R-101} Cows: Camels: 7.3 ± 3.5 hours to a peak serum concentration of 3.49 ± A single dose of 10 mg/kg in the neck maintains > 0.5 mcg/mL 0.44 mcg/mL (10 mg/kg dose).{R-88} serum concentrations for 48 to 70 hours and milk concentrations Cows: 5 to 10 hours to a peak serum concentration of 4.5 to 6.8 for 33 to 49 hours.{R-97} mcg/mL (dose of 10 mg/kg in the neck).{R-97} A single dose of 20 mg/kg in the hindquarters maintains serum Pigs: 0.5 hour to a peak serum concentration of 6 ± 2.2 mcg/mL concentrations of > 0.5 mcg/mL for 86 hours.{R-98} (dose of 20 mg/kg in the hindquarters).{R-107} A single dose of 20 mg/kg in the gluteal muscles maintains serum Steers: 8 hours to a peak serum concentration of 3.13 mcg/mL concentrations > 4 mcg/mL for 12 hours; also lung concentra- (dose of 20 mg/kg in the hindquarters).{R-98} tions are > 0.5 mcg/mL for 65 hours.{R-99}

Pigs: A single dose of 20 mg/kg produces serum concentrations > 0.5 Some studies have linked the cardiovascular effects of intravenous mcg/mL for 35 to 48 hours{R-107; 174}; however, the use of the administration in calves to the propylene glycol vehicle in some long-acting formulation does not produce significantly different preparations{R-33; 170}; however, adverse cardiovascular effects and plasma oxytetracycline concentrations from those produced by the collapse have been shown to occur after intravenous administration of conventional formulation{R-107}. tetracycline without propylene glycol vehicle{R-34}; the electrocardio- Tetracycline—Pigs: A ration containing 0.55 gram of tetracycline graphic abnormalities may be due to chelation of free calcium ions{R-34}. hydrochloride per kg of feed, fed as the only ration, produces 0.3 to Tetracyclines ideally should be diluted in fluids and administered 0.4 mcg/mL serum concentrations for the 96 hours that it is fed.{R-74} slowly if given by the intravenous route{R-176}. If this is not possible, Note: These results may vary by size of pig and amount of feed intake. intravenous injections should be made as a slow push, with the dose Elimination: administered over 1 to 2 minutes. Chlortetracycline—Total clearance: Horses: While rapid intravenous administration of tetracyclines causes Calves, ruminating—2.70 ± 0.17 mL per minute per kg (mL/min/ reactions in many species, doxycycline in particular can lead to severe kg).{R-76} cardiovascular dysfunction and death when administered intrave- {R-35} Pigs, fasted—2.75 ± 0.92 mL/min/kg.{R-77} nously at any rate to horses. Pigs, fed—5.12 ± 0.88 mL/min/kg.{R-77} Administration of tetracyclines can also lead to severe diarrhea in some Turkeys—3.77 ± 0.77 mL/min/kg.{R-78} horses. However, oral, multiple-dose administration of doxycycline {R-131} Doxycycline—Doxycycline differs from the other tetracyclines in that a large to horses without observed side effects has been reported . percentage is excreted into the intestines and is inactive there.{R-133} Dogs: 90% of a single intravenous dose is eliminated within 48 hours PREGNANCY/REPRODUCTION in nonmetabolized form. Of the 90%, 16% is eliminated in urine, Tetracyclines have been shown to cross the placenta{R-22} and may affect <5% in the bile, and the remainder in the intestines.{R-63} fetal bone formation.{R-135} Total clearance: Calves— Preruminant: 2.20 mL/min/kg.{R-68} LACTATION {R-68} Ruminant: 1.07 mL/min/kg. Tetracyclines are distributed into milk. Cats—1.09 ± 0.21 mL/min/kg.{R-70} Dogs—1.7 mL/min/kg{R-63; 70}. Pigs—1.67 ± 0.18 mL/min/kg.{R-69} PEDIATRICS Oxytetracycline—Calves, cows, dogs, pigs, and turkeys: The conventional Use of tetracyclines during tooth development (the last 2 to 3 weeks of formulation of oxytetracycline is eliminated primarily by glomerular pregnancy to 1 month of age){R-22} may cause discoloration of the filtration; only a small amount (1 to 2% in pigs and turkeys) is bones and teeth.{R-4} In neonates that have not yet developed full renal eliminated in the bile.{R-63; 82; 85; 93; 97} function, excretion of chlortetracycline, oxytetracycline, and tetracy- Total clearance: cline may occur more slowly than in a mature animal. One exception Oxytetracycline— is that 4-day-old foals have a faster elimination half-life and more rapid Buffalo: 1.02 to 1.45 mL/min/kg.{R-87} clearance of oxytetracycline compared to adults{R-154}. Calves, 6 to 8 weeks of age: 1.66 to 1.88{R-93}; 2.67 to 4.67 mL/ min/kg.{R-100} Camels: 1.26 mL/min/kg{R-88}. DRUG INTERACTIONS AND/OR RELATED PROBLEMS Dogs: 4.23 ± 1.29 mL/min/kg.{R-84} The following drug interactions and/or related problems have been Donkeys: 1.52 mL/min/kg.{R-92} selected on the basis of their potential clinical significance (possible Foals, 4 to 5 days of age: 3.17 mL/min/kg{R-154}. mechanism in parentheses where appropriate)—not necessarily inclu- Goats: 2.67 mL/min/kg.{R-81} sive (» = major clinical significance): Horses: 0.66 mL/min/kg.{R-92} Note: Although methoxyflurane has been suspected of increasing the Pigs, 10 weeks of age: 4.17 mL/min/kg.{R-82} potential for tetracycline-induced nephrotoxicity in people, this has not Pigs, adult: 3.5 mL/min/kg.{R-83} been shown to be true in dogs.{R-137} Ponies: 1.01 mL/min/kg.{R-92} Combinations containing any of the following medications, depending Rabbits: 7.23 mL/min/kg.{R-86} on the amount present, may also interact with this medication. Rats: 2.79 mL/min/kg.{R-91} » Antacids or Tetracycline—Total clearance: » Calcium supplements, such as calcium carbonate, or Chickens—1.63 ± 0.18 mL/min/kg.{R-73} » Iron supplements or Pigs—3.08 ± 0.4 mL/min/kg.{R-74} » Magnesium-containing laxatives or Rabbits—6.1 ± 0.6 mL/min/kg.{R-72} Sodium bicarbonate (concurrent use with tetracyclines may result in formation of non- PRECAUTIONS TO CONSIDER absorbable complexes; also, concurrent use within 1 to 3 hours of antacid or sodium bicarbonate administration may result in decreased SPECIES SENSITIVITY absorption of oral tetracyclines because of increased intragastric pH) All species: Rapid intravenous administration of tetracyclines can result in Phenobarbital or cardiovascular dysfunction and collapse in any species{R-33–35; 169}. Microsomal enzyme inducers, other

(concurrent use with doxycycline may result in decreased doxycy- MEDICAL CONSIDERATIONS/CONTRAINDICATIONS cline serum concentrations due to induction of microsomal enzyme The medical considerations/contraindications included have been activity; adjustment of doxycycline dosage or substitution of another selected on the basis of their potential clinical significance (reasons tetracycline may be necessary) given in parentheses where appropriate)—not necessarily inclusive Tereftalic acid (» = major clinical significance). (blood concentrations of chlortetracycline are increased when it is Risk-benefit should be considered when the following medical {R-156} administered concurrently with tereftalic acid ) problem exists: Renal function impairment, severe (chlortetracycline, oxytetracycline, and tetracycline are eliminated HUMAN DRUG INTERACTIONS AND/OR RELATED primarily by the kidney and can accumulate in animals with severe {R-132} PROBLEMS renal dysfunction; doxycycline is only partially eliminated renally In addition to the above drug interactions reported in animals, the and is much less likely to accumulate{R-71}) following drug interactions have been reported in humans, and are included in the human monograph Tetracyclines (Systemic) in USP DI Volume I; these drug interactions are intended for informational PATIENT MONITORING purposes only and may or may not be applicable to the use of The following may be especially important in patient monitoring (other tetracyclines in the treatment of animals: tests may be warranted in some patients, depending on condition; » = Cholestyramine major clinical significance): (concurrent use with cholestyramine may result in binding of oral Culture and susceptibility, in vitro, and tetracyclines, thus impairing their absorption; an interval of several Minimum inhibitory concentration (MIC) hours between administration of cholestyramine and oral tetracy- (in vitro cultures and MIC test should be done on samples collected clines is recommended) prior to administration of tetracyclines to determine pathogen Vitamin A susceptibility) (concurrent use with tetracycline has been reported to cause benign intracranial hypertension) SIDE/ADVERSE EFFECTS The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and, for humans, symp- LABORATORY VALUE ALTERATIONS toms in parentheses where appropriate)—not necessarily inclusive: The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance): THOSE INDICATING NEED FOR MEDICAL ATTENTION With physiology/laboratory test values Incidence rare Urinalysis All species {R-32; 45} (transient hemoglobinuria has been reported in cattle given paren- Hypersensitivity reactions, specifically anaphylaxis teral oxytetracycline){R-38; 45; 56} (defecation; eruption of skin plaques; frothing from the mouth; glassy-eyed appearance; labored breathing; muscle trembling; piloe- rection; prostration; restlessness; swelling of eyelids, ears, muzzle, {R-132} HUMAN LABORATORY VALUE ALTERATIONS anus, vulva or scrotum and sheath){R-45}; photosensitization{R-39} The following laboratory value alterations have been reported in Cattle, dogs, and horses humans, and are included in the human monograph Tetracyclines Nephrotoxicosis{R-29–31; 112; 168}—with high doses, concurrent (Systemic) in USP DI Volume I; these laboratory value alterations are debilitating conditions, or use of outdated tetracyclines intended for informational purposes only and may or may not be Incidence unknown applicable to the use of tetracyclines in the treatment of animals: All species With diagnostic test results Overgrowth of nonsusceptible organisms Catecholamine determinations, urine Cats, cattle, dogs, horses, monkeys, rabbits, rats, and sheep{R-33–35} (may produce false elevations of urinary catecholamines because Cardiovascular dysfunction, including atrioventricular block, of interfering fluorescence) atrial tachycardia, ventricular bradycardia, hypotension (in With physiology/laboratory test values order of appearance—agitation or nervousness, dyspnea, muscle Alanine aminotransferase (ALT [SGPT]) and fasciculations, urination, defecation, collapse, death)—a dose-depen- Alkaline phosphatase and dent effect{R-34} with rapid intravenous administration; cardiovascu- Amylase and lar dysfunction, including hypertension, arterial{R-35}—in horses Aspartate aminotransferase (AST [SGOT]) and given doxycycline Bilirubin Note: Although the propylene glycol vehicle of some oxytetracycline (serum concentrations may be increased) preparations has been shown to have some cardiovascular effects Blood urea nitrogen (BUN) when administered intravenously{R-33}, the calcium-binding nature (antianabolic effect of tetracyclines [except doxycycline] may of the tetracyclines has been implicated in cardiovascular dysfunction increase BUN concentrations; in patients with significantly and sudden collapse in cattle and sheep after intravenous admin- impaired renal function, increased serum concentrations of tetra- istration of tetracyclines.{R-34; 35} Although pretreatment with cyclines may lead to azotemia, hyperphosphatemia, and acidosis) calcium borogluconate has been considered before intravenous

administration{R-34}, specific postreaction therapy for possible women, in patients receiving high-dose intravenous therapy, and hypocalcemia has not been recommended. in patients with renal function impairment. However, hepatotox- In horses, doses of doxycycline as low as 0.2 to 0.4 mg per kg of icity has also occurred in patients without these predisposing body weight administered intravenously have caused cardiovascular conditions. Tetracycline-induced pancreatitis has also been de- dysfunction, collapse, and death. Instead of hypotension, hyper- scribed in association with hepatotoxicity, and without associated tension is reported in horses given intravenous doxycycline and liver disease. is associated with the other signs of cardiovascular dysfunction seen with rapid intravenous tetracycline administration in other OVERDOSE species. For more information in cases of overdose or unintentional ingestion, Cats contact the American Society for the Prevention of Cruelty to Fever (anorexia, sometimes diarrhea)—usually resolves within 48 Animals (ASPCA) National Animal Poison Control Center (888- hours of discontinuing oxytetracycline or tetracycline{R-39} 426-4435 or 900-443-0000; a fee may be required for consultation) Cattle and/or the drug manufacturer. Hemoglobinuria, transient{R-38; 45; 56} (brownish-red urine)—with Overdose of tetracyclines in animals is unusual because very high doses are parenteral administration of oxytetracycline; hepatitis with fatty often tolerated; however, effects that have been associated with overdose degeneration and/or bile stasis{R-168}—with repeated high doses or in animals include nephrotoxicosis and possible hepatotoxicity. concurrent debilitating conditions Acute toxicity of intravenously-administered tetracyclines{R-33; 34} in Horses many species is most often seen with rapid administration; however, Colitis; diarrhea, severe intravenous doxycycline administration in horses has caused collapse Psittacine birds (cockatoos, macaws, and parrots) even when administered over a 3- to 7-minute period. This reaction to Aspergillosis, increased risk of—may occur with prolonged chlor- intravenous tetracyclines is dose-dependent, but is not only associated tetracycline treatment{R-152} with high doses. Rabbits Administration of repeated high doses of intravenous or intramuscular Anorexia; diarrhea—with doses administered that are two times the oxytetracycline to calves or cattle can result in renal cortical tubular recommended dose{R-86} nephrosis. While a single intramuscular dose of 40 mg of an oxytetracycline per kg (in a 2-pyrrolidine formulation) administered to healthy calves produced no significant toxicity{R-101}, studies have THOSE INDICATING NEED FOR MEDICAL ATTENTION shown that 33 to 44 mg of oxytetracycline per kg of body weight a day ONLY IF THEY CONTINUE OR ARE BOTHERSOME administered intravenously or intramuscularly for 2 or more days can Incidence more frequent produce renal protein casts, tubular necrosis, and death in calves with All species respiratory disease{R-30; 168}. A similar dose of 33 mg oxytetracycline Discoloration of teeth in young animals (yellow, brown, or grey per kg of body weight administered intravenously for 3 days produces discoloration)—when administered during late pregnancy or during a rise in blood urea nitrogen and the appearance of renal casts in the period of tooth development{R-39}; local tissue irritation at site of urine of normal heifers{R-167}. The vehicles used in formulations, such injection—with intramuscular administration{R-37; 101} as propylene glycol, have been linked to reduced renal blood flow and Cats and dogs have been suspected of exacerbating adverse effects{R-29; 33}. Tetra- Nausea or vomiting—with oral administration{R-39}, in particular, cycline and its degradation products have been reported to also cause with doxycycline on an empty stomach{R-156} nephrotoxicity in cattle and foals{R-29; 112}. Serious toxicity can be expected to be more likely in animals that are already compromised by disease or dehydration. HUMAN SIDE/ADVERSE EFFECTS{R-132} Hepatotoxicity has been reported as a human side effect of tetracyclines {R-167} In addition to the above side/adverse effects reported in animals, the and may be more common in pregnant women . Hepatic fatty following side/adverse effects have been reported in humans, and are degeneration has been observed in people and has been induced in included in the human monograph Tetracyclines (Systemic) in USP DI mice and rats given extremely high doses (100 to 300 mg of Volume I; these side/adverse effects are intended for informational tetracycline per kg of body weight); however, fatty infiltration of the purposes only and may or may not be applicable to the use of liver was also observed in calves that had respiratory disease and tetracyclines in the treatment of animals: that developed renal tubular necrosis after administration of two Incidence more frequent doses of 33 mg of oxytetracycline per kg of body weight 24 hours {R-168} Central nervous system toxicity; staining of infants’ or apart . children’s teeth; gastrointestinal disturbances; photosensitivity Incidence less frequent VETERINARY DOSING INFORMATION Fungal overgrowth; hypertrophy of the papillae; nephrogenic diabetes insipidus; pigmentation of skin and mucous mem- FOR ORAL DOSAGE FORMS ONLY branes For some tetracyclines, serum concentrations from animal to animal Incidence rare vary more widely when administered in drinking water than when Benign intracranial hypertension; hepatotoxicity; pancreatitis administered in feed.{R-59} Note: Tetracycline-induced hepatotoxicity is usually seen as a fatty Unlike other tetracyclines, doxycycline can be used without dosage degeneration of the liver. It is more likely to occur in pregnant adjustment in animals with renal function impairment.

FOR PARENTERAL DOSAGE FORMS ONLY Canada— Care should be taken to administer intravenous tetracyclines slowly and/ Veterinary-labeled products: or dilute them in ﬂuids to avoid cardiovascular side effects.{R-33–35} 500 mg (OTC) [Aureomycin Uterine Oblets]. Intramuscular injection of oxytetracycline will affect the quality of meat for a prolonged period. Whenever possible, subcutaneous administra- Withdrawal times: tion should be chosen{R-65}. Canada—

Withdrawal time DIET/NUTRITION Species Meat (days) Oral tetracyclines are absorbed more efficiently when administered without food, particularly without foods containing divalent or Cattle, pigs, sheep 0 trivalent metals, such as milk or milk replacer. Doxycycline absorption appears to be less affected than other tetracyclines. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specified by manufacturer. FOR TREATMENT OF ADVERSE EFFECTS Recommended treatment consists of the following: USP requirements: Not in USP. For anaphylaxis • Parenteral epinephrine. ORAL DOSAGE FORMS • Oxygen administration and respiratory support. Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products FOR TREATMENT OF ACUTE REACTIONS TO not commercially available in the U.S. INTRAVENOUS ADMINISTRATION Recommended treatment consists of the following: CHLORTETRACYCLINE HYDROCHLORIDE SOLUBLE • Intravenous fluids. POWDER USP • Oxygen administration and respiratory support. Usual dose: Note: Because the specific causes of acute reactions may be difficult to Calves1 and pigs1— immediately determine, an electrocardiogram should be monitored Bacterial enteritis; or when possible to identify cardiac arrythmias and direct the course of Bacterial pneumonia: Oral, 22 mg per kg of body weight a day, therapy. administered in the only source of drinking water.{R-17} Chickens1— Chronic respiratory disease: Oral, 400 to 800 mg per gallon of {R-17} CHLORTETRACYCLINE water (approximately 22 to 59 mg per kg of body weight a day{R-143}), administered in the only source of drinking ADDITIONAL DOSING INFORMATION water.{R-17} When possible, oral chlortetracycline should be administered 1 hour Fowl cholera: Oral, 1000 mg (1 gram) per gallon of water, before or 2 hours after milk replacer.{R-1} administered in the only source of drinking water. Synovitis: Oral, 200 to 400 mg per gallon of water (approximately MUCOSAL DOSAGE FORMS 11 to 29.5 mg per kg of body weight a day), administered in the only source of drinking water.{R-17; 143} Note: Bracketed information in the Dosage Forms section refers to uses Turkeys, growing1— that either are not included in U.S. product labeling or are for products Enteritis: Oral, 55 mg per kg of body weight a day, administered in not commercially available in the U.S. the only source of drinking water.{R-17} Infectious synovitis: Oral, 400 mg per gallon of water CHLORTETRACYCLINE UTERINE TABLETS (approximately 7 to 37 mg per kg of body weight a day), Usual dose: administered in the only source of drinking water.{R-143} Note: [Cattle]—Although the efficacy and safety are not currently Note: Environmental and health conditions may affect the intake of established, an intrauterine dose of 500 to 1000 mg administered as a water and the amount of medication consumed.{R-17} {R-118} single dose after parturition for the treatment of acute uterine Administration of medication in food or water to animals with infections is included in Canadian product labeling. pneumonia or other infections can be affected by reduced feed and [Ewes] and [sows]—Although the efficacy and safety are not currently water intake{R-109}. established, an intrauterine dose of 250 to 500 mg administered as a single dose after parturition{R-118} for the treatment of acute uterine Strength(s) usually available{R-58}: infections is included in Canadian product labeling. U.S.—{R-17} Veterinary-labeled products: Strength(s) usually available{R-58}: 25 grams per pound of powder (OTC) [Aureomycin Soluble Powder]. U.S.— 64 grams per pound of powder (OTC) [AmTech Chlortetracycline HCL Veterinary-labeled products: Soluble Powder; Aureomycin Soluble Powder Concentrate; CTC Soluble Not commercially available. Powder Concentrate; Pennchlor 64 Soluble Powder].

Canada— Cattle— Veterinary-labeled products: Anaplasmosis (treatment)1: Not commercially available. Cattle weighing < 700 pounds—Oral, 350 mg per animal a day, administered in the feed and fed as the only ration{R-16; 152}. Withdrawal times: Cattle weighing ‡ 700 pounds—Oral 1.1 mg per kg of body Note: With chlortetracycline soluble powder, withdrawal times vary weight a day, administered in the feed and fed as the only greatly from product to product and may differ from those listed below. ration{R-152}. See also individual manufacturer’s labeling. Bacterial enteritis1; or bacterial pneumonia (treatment)1: Oral, 22 U.S.—{R-17; 58} mg per kg of body weight a day, administered in the feed and fed as the only ration{R-152}. 1 Withdrawal time Bacterial pneumonia (control) : Oral, 350 mg per animal a day administered in the feed, fed as the only ration.{R-16; 152} Species Meat (days) Improved feed efficiency and increased rate of weight gain1;or Calves, chickens, and turkeys 1 hepatic abscesses (prophylaxis)1: Oral, 70 mg a day per animal Pigs 1 or 5, depending on product administered in the feed, fed as the only ration.{R-16; 152} [Pododermatitis (prophylaxis)]: Oral, 0.22 mg per kg of body weight Note: Product labeling with the above withdrawal time listed for poultry a day or 70 mg per animal a day, administered in the feed and fed {R-116} states that it applies when the medication is mixed at 1000 mg of as the only ration . chlortetracycline per gallon of drinking water. Chickens— Product labeling with the above withdrawal times states that they Chronic respiratory disease: Oral, 200 to 400 grams per ton of feed, {R-16; 152} apply when cattle and pigs are treated for a maximum of five days and fed as the only ration. 1 chickens and turkeys are treated for a maximum of fourteen days. Escherichia coli infections : Oral, 500 grams per ton of feed, fed as the {R-16; 115} Not labeled for use in laying hens, preruminating calves, or lactating only ration. dairy cattle. Improved feed efficiency and increased rate of weight gain: Oral, 10 to 50 grams per ton of feed, fed as the only ration.{R-152} 1 Packaging and storage: Store below 40 C (104 F), preferably Synovitis : Oral, 100 to 200 grams per ton of feed, fed as the only {R-152} between 15 and 30 C (59 and 86 F), in a tight container, unless ration . otherwise specified by manufacturer. Protect from light. [Enteritis; or increased egg production or hatchability]: Oral, 100 to 200 grams per ton of feed (110 to 220 grams per metric ton [1000 Preparation of dosage form: Fresh solutions should be prepared every kg] of feed), fed as the only ration. 24 hours. When administered in a galvanized waterer, fresh solutions Note: Canadian product labeling also lists the above dose for feed should be prepared every 12 hours. efficiency. Cockatoos, macaws, and parrots—Psittacosis1: Oral, 10 mg per gram of Incompatibilities: Administration 1 hour before or 2 hours after giving mash or feed, administered continuously for 45 days as the only {R-152} milk or milk replacers is recommended. Chlortetracycline hydrochlo- ration . 1 ride soluble powder should not be mixed with milk replacers. Ducks —Fowl cholera: Oral, 200 to 400 grams per ton of feed (approximately 17.6 to 61.6 mg per kg of body weight a day) {R-16; 152} USP requirements: Preserve in tight containers, protected from administered in the feed, fed as the only ration. light. Label it to indicate that it is intended for oral veterinary Pigs— 1 use only. Contains the labeled amount, within –10% to +25%. Cervical abscesses (prophylaxis) : Oral, 50 to 100 grams per ton of {R-115} Meets the requirement for Loss on drying (not more than feed, fed as the only ration. 1 2.0%).{R-128} Bacterial enteritis; or bacterial pneumonia : Oral, 22 mg per kg of body weight a day, administered in the only ration{R-152}. CHLORTETRACYCLINE FOR MEDICATED FEED Improved feed efficiency and increased rate of weight gain: Oral, 10 {R-152} Usual dose: to 50 grams per ton of feed, fed as the only ration. Calves— For reducing the shedding of leptospirosis and the incidence of 1 Improved feed efficiency and increased weight gain for calves associated abortion : Oral, 400 grams per ton of feed, fed as the {R-152} weighing up to 250 pounds1: Oral, 0.22 mg per kg of body only ration for fourteen days. weight a day administered in the feed, fed as the only ration.{R-16; Note: Canadian product labeling lists a dose in the treatment of 152} enteritis and for increasing feed efficiency and improving weight Improved feed efficiency and increased weight gain for calves gain of 50 to 100 grams per ton of feed (55 to 110 grams per {R-116} weighing 250 to 400 pounds1: Oral, 25 to 70 mg per animal a metric ton [1000 kg] of feed), fed as the only ration . 1 day administered in the feed, fed as the only ration.{R-16; 152} Sheep—Vibrionic abortion (prophylaxis) : Oral, 80 mg per animal a Enteritis: Oral, 22 mg per kg of body weight a day, administered in day administered in the feed, fed as the only ration continuously {R-16; 152} the feed and fed as the only ration{R-152}. during pregnancy. 1 Note: Products made to add to calf milk replacer are indicated for Sheep, growing —Improved feed efficiency and increased rate of 1 treatment of bacterial enteritis and for improved feed efficiency and weight gain : Oral, 20 to 50 grams per ton of feed, fed as the only {R-16} increased weight gain only. ration.

Turkeys— a day, and to cattle at a dose of 350 mg per animal a day or 1.1 mg per Bacterial enteritis: Oral, 55 mg per kg of body weight a day, kg of body weight a day in feed, to chickens at 500 grams or more per administered in the only ration{R-16; 152}. ton of feed for a maximum of five days, to pigs at 400 grams or less per Note: Canadian product labeling lists a dose in the treatment of ton of feed or 22 mg per kg of body weight a day for up to fourteen enteritis of 100 to 200 grams per ton of feed (110 to 220 grams per days, and to sheep when fed 80 mg per animal a day or 20 to 50 metric ton [1000 kg] of feed), fed as the only ration{R-116}. grams per ton of feed. Hexamitiasis1: Oral, 400 grams per ton of feed, fed as the only Not labeled for use in preruminating calves, lactating dairy cows, or ration{R-16; 152}. horses to be used for food.{R-16} Synovitis1: Oral, 200 grams per ton of feed, fed as the only Some products are not labeled for use in chickens, ducks, or turkeys ration{R-16; 152}. producing eggs for human consumption.{R-152} [Increased egg production; or sinusitis (prophylaxis)]: Oral, 100 to When fed at 22 mg per kg of body weight a day: 200 grams per ton of feed (110 to 220 grams per metric ton [1000 kg] of feed), fed as the only ration. Withdrawal time 1 Turkeys, growing, less than 4 weeks of age—Paratyphoid : Oral, 400 Species Meat (days) grams per ton of feed, fed as the only ration.{R-115} Calves, cattle 0 or 10, depending on product Turkeys, growing—Improved efficiency or; increased rate of weight gain: Oral 10 to 50 grams per ton of feed, fed as the only ration{R-16; Note: Not labeled for use in lactating dairy cows.{R-16} 152}. [Lambs]—Enterotoxemia: Oral, 20 grams per ton of feed (22 grams per Canada— metric ton [1000 kg] of feed), fed as the only ration. Withdrawal time Note: Environmental and health conditions may affect the intake of Species Meat (days) water and the amount of medication consumed.{R-17} Administration of medication in food or water to animals with Calves, cattle 5 Chickens, pigs, turkeys 7 pneumonia or other infections can be affected by reduced feed and Lambs 4 water intake{R-109}. Note: Product labeling listing the above withdrawal times states that they Strength(s) usually available{R-58}: apply when the product is fed to chickens and turkeys at 55 to 220 mg U.S.— per kg of feed, to pigs at 55 to 110 mg per kg of feed, to calves at 55 mg Veterinary-labeled products: per kg of feed, to lambs at 22 mg per kg of feed, and to cattle at 0.22 110 grams per kg of premix (OTC) [Aureomycin 50 Granular; mg per kg of body weight or 70 mg per animal. ChlorMax 50; CTC 50; Pennchlor 50ÆG; Pennchlor 50 Meal]. Not labeled for use in lactating diary cows. 154 grams per kg of premix (OTC) [Pennchlor 70 Meal]. 198 grams per kg of premix (OTC) [Aureomycin 90 Granular; Packaging and storage: Store below 40 C (104 F), preferably Pennchlor 90ÆG]. between 15 and 30 C (59 and 86 F), unless otherwise specified by 220 grams per kg of premix (OTC) [Aureomycin 100 Granular; CLTC manufacturer. 100 MR; Pennchlor 100 Hi-Flo Meal; Pennchlor 100MR]. Canada— USP requirements: Not in USP. Veterinary-labeled products: 110 grams per kg of premix (OTC) [Aureomycin 110G; Chlor 50; Chlorosol-50]. 1Not included in Canadian product labeling or product not commercially 220 grams per kg of premix (OTC) [Aureomycin 220G; Chlor 100]. available in Canada. Withdrawal times{R-58}: Note: With chlortetracycline oral premix, withdrawal times vary greatly from product to product and may differ from those listed below. DOXYCYCLINE See also individual manufacturer’s labeling. SUMMARY OF DIFFERENCES U.S.—{R-123} Pharmacology/pharmacokinetics: More completely absorbed from the

Withdrawal time gastrointestinal tract than the tetracyclines developed earlier and absorption is less likely to be affected by food or calcium or other Species Meat (days) Eggs (hours) divalent or trivalent metals. Doxycycline is also more lipid-soluble than Calves, cattle 0, 1, or 2, depending other tetracyclines. In dogs, doxycycline is eliminated primarily on product and dose through intestinal excretion.{R-63} Chickens 0 or 1, depending on 0 for some products Precautions: Medical considerations—Doxycycline is only partially product and dose Pigs, sheep, turkeys 0 eliminated renally and is less likely to accumulate in animals with renal function impairment; it can be used without dosage adjustment. Note: Product labeling listing the above withdrawal times states that they Side/adverse effects: Horses—Intravenous administration can lead to {R-34} apply when product is fed to calves at a dose of up to 70 mg per animal cardiovascular dysfunction and death.

ORAL DOSAGE FORMS volume, pH (5.0–6.5, in the suspension constituted as directed in the {R-128} Note: Bracketed information in the Dosage Forms section refers to uses labeling), and Water (not more than 3.0%). that either are not included in U.S. product labeling or are for products not commercially available in the U.S. DOXYCYCLINE CALCIUM ORAL SUSPENSION USP The dosing and strengths of the dosage forms available are expressed Usual dose: See Doxycycline for Oral Suspension USP. in terms of doxycycline base. Strength(s) usually available: DOXYCYCLINE FOR ORAL SUSPENSION USP U.S.— Usual dose: [Rocky Mountain spotted fever]1—Dogs: Oral, 5 mg per kg Veterinary-labeled products: of body weight every twelve hours{R-151} for fourteen days. Not commercially available. Note: [Cats]1—Although the efficacy has not been established, an oral Human-labeled products: dose of 5 mg per kg of body weight every twelve hours for twenty-one 10 mg (base) per mL (Rx) [Vibramycin]. days has been used in the treatment of feline infectious anemia{R-147; Canada— 151}. For chlamydial infections or respiratory infections in cats, a dose of 5 Veterinary-labeled products: mg per kg of body weight every twelve hours or 10 mg per kg of body Not commercially available. weight every twenty-four hours has been used{R-151}. Human-labeled products: [Dogs]1—Although the efficacy has not been established, an oral dose Not commercially available. of 10 mg per kg of body weight every twelve hours for two to three weeks has been used for the treatment of ehrlichiosis; this regimen is Packaging and storage: Store below 40 C (104 F), preferably between based on a clinical trial that found, however, that only two out of five 15 and 30 C (59 and 86 F), unless otherwise specified by manufac- dogs treated with the above dose and a twenty-four-hour dosing turer. Store in a tight, light-resistant container. Protect from freezing. interval for one week were cleared of Ehrlichia canis, as shown by negative blood and tissue cultures{R-40}. A dose of 5 mg per kg of Auxiliary labeling: body weight every twelve hours for six to eight weeks has been used in • Shake well. the treatment of ehrlichiosis to decrease the risk of side effects{R-176}; however, the efficacy of this regimen has not been confirmed. Retesting USP requirements: Preserve in tight, light-resistant containers. Pre- serum immunoflourescent antibody for E. canis two months posttreat- pared from Doxycycline Hyclate, and contains one or more suitable ment is recommended, and retreatment should be started if values buffers, colors, diluents, flavors, and preservatives. Contains an have not dropped significantly.{R-40} amount of doxycycline calcium equivalent to the labeled amount of doxycycline, within –10% to +25%. Meets the requirements for Strength(s) usually available: Identification, Uniformity of dosage units (single-unit containers), {R-128} U.S.— Deliverable volume, and pH (6.5–8.0). Veterinary-labeled products: Not commercially available. DOXYCYCLINE HYCLATE CAPSULES USP Human-labeled products: Usual dose: See Doxycycline for Oral Suspension USP. 5 mg (base) per mL, when reconstituted according to manufacturer’s instructions (Rx) [Vibramycin]. Strength(s) usually available: Canada— U.S.—{R-135} Veterinary-labeled products: Veterinary-labeled products: Not commercially available. Not commercially available. Human-labeled products: Human-labeled products: Not commercially available. 50 mg (base) (Rx) [Vibramycin; generic]. 100 mg (base) (Rx) [Vibramycin; generic]. Packaging and storage: Prior to reconstitution, store below 40 C (104 Canada— F), preferably between 15 and 30 C (59 and 86 F), unless otherwise Veterinary-labeled products: specified by manufacturer. Store in a tight, light-resistant container. Not commercially available. Human-labeled products: Stability: After reconstitution, suspensions retain their potency for 14 100 mg (base) (Rx) [Alti-Doxycycline; Apo-Doxy; Doxycin; Doxytec days at room temperature. (lactose); Novo-Doxylin; Nu-Doxycycline; Vibramycin].

Auxiliary labeling: Packaging and storage: Store below 40 C (104 F), preferably • Shake well. between 15 and 30 C (59 and 86 F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container. USP requirements: Preserve in tight, light-resistant containers. Con- tains one or more suitable buffers, colors, diluents, flavors, and pre- USP requirements: Preserve in tight, light-resistant containers. Con- servatives. Contains the labeled amount, within –10% to +25% when tain an amount of doxycycline hyclate equivalent to the labeled constituted as directed. Meets the requirements for Identification, amount of doxycycline, within –10% to +20%. Meet the require- Uniformity of dosage units (single-unit containers), Deliverable ments for Identification, Dissolution (80% in 30 minutes in water in

Apparatus 2 at 75 rpm), Uniformity of dosage units, and Water (not amount of doxycycline, within –10% to +20%. Meet the requirements more than 8.5%).{R-128} for Identiﬁcation, Dissolution (85% in 90 minutes in water in Appa- ratus 2 at 75 rpm), Uniformity of dosage units, and Water (not more DOXYCYCLINE HYCLATE DELAYED-RELEASE than 5.0%).{R-128} CAPSULES USP Note: Delayed-release capsules must be swallowed whole and, in general, 1 absorption of delayed-release dosage forms is unpredictable in animals. Not included in Canadian product labeling or product not commercially Doxycycline Hyclate Delayed-release Capsules USP are not recom- available in Canada. mended for use in animals.

Strength(s) usually available: PARENTERAL DOSAGE FORMS U.S.— Note: Bracketed information in the Dosage Forms section refers to uses Veterinary-labeled products: that either are not included in U.S. product labeling or are for products Not commercially available. not commercially available in the U.S. Human-labeled products: The dosing and strengths of the dosage forms available are expressed 100 mg (base) (Rx) [Doryx (lactose)]. in terms of doxycycline base (not the hyclate salt). Canada— Veterinary-labeled products: DOXYCYCLINE FOR INJECTION USP Not commercially available. Usual dose: Human-labeled products: Note: [Dogs]1—Although the efficacy has not been established, an Not commercially available. intravenous dose of 3 to 5 mg (base) per kg of body weight every twelve hours has been used in the treatment of susceptible bacterial Packaging and storage: Store below 40 C (104 F), preferably infections.{R-70} between 15 and 30 C (59 and 86 F), unless otherwise specified by This dose is based on pharmacokinetic studies. manufacturer. Store in a tight, light-resistant container. Size(s) usually available: USP requirements: Preserve in tight, light-resistant containers. The U.S.— label indicates that the contents of the Capsules are enteric-coated. Veterinary-labeled products: Contain an amount of doxycycline hyclate equivalent to the labeled Not commercially available. amount of doxycycline, within –10% to +20%. Meet the requirements Human-labeled products: for Identification, Drug release (Acid stage: 50% [Level 1 and Level 2] 100 mg (base) (Rx) [Vibramycin]. in 20 minutes in 0.06 N hydrochloric acid in Apparatus 1 at 50 rpm; 200 mg (base) (Rx) [Vibramycin]. Buffer stage: 85% in 30 minutes in neutralized phthalate buffer [pH Canada— 5.5] in Apparatus 1 at 50 rpm), Uniformity of dosage units, and Water Veterinary-labeled products: {R-128} (not more than 5.0%). Not commercially available. Human-labeled products: DOXYCYCLINE HYCLATE TABLETS USP Not commercially available. Usual dose: See Doxycycline for Oral Suspension USP. Packaging and storage: Prior to reconstitution, store below 40 C Strength(s) usually available: (104 F), preferably between 15 and 30 C (59 and 86 F), unless U.S.—{R-135} otherwise specified by manufacturer. Protect from light. Veterinary-labeled products: Not commercially available. Human-labeled products: Preparation of dosage form: To prepare initial dilution for intrave- 100 mg (base) (Rx) [Vibra-Tabs; generic]. nous use, 10 mL of sterile water for injection or other suitable diluent Canada— (see manufacturer’s package insert) should be added to each 100-mg Veterinary-labeled products: vial or 20 mL of diluent should be added to each 200-mg vial. The Not commercially available. resulting solution containing the equivalent of 100 to 200 mg of Human-labeled products: doxycycline may be further diluted in 100 to 1000 mL or in 200 to 100 mg (base) (Rx) [Alti-Doxycycline; Apo-Doxy-Tabs; Doxycin; Novo- 2000 mL of suitable diluent, respectively. Doxylin; Nu-Doxycycline; Vibra-Tabs; Vibra-Tabs C-Pak].

Packaging and storage: Store below 40 C (104 F), preferably Stability: between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by After reconstitution, intravenous infusions of doxycycline hyclate retain manufacturer. Store in a tight, light-resistant container. their potency for twelve hours at room temperature or for seventy-two hours if refrigerated at concentrations of 100 mcg (0.1 mg) to 1 mg USP requirements: Preserve in tight, light-resistant containers. Con- per mL in suitable ﬂuids (see manufacturer’s package insert). Intra- tain an amount of doxycycline hyclate equivalent to the labeled venous infusions of doxycycline hyclate retain their potency for six

hours at room temperature at concentrations of 100 mcg (0.1 mg) to 1 Withdrawal times: mg per mL in lactated Ringer’s injection or 5% dextrose and lactated Canada— Ringer’s injection. Infusions must be protected from direct sunlight Withdrawal time during administration. Species Meat (days) Milk (hours) If frozen immediately after reconstitution with sterile water for injection, solutions at concentrations of 10 mg per mL retain their potency for up Cows 18 24 to eight weeks at –20 C (–4 F). Once thawed, solutions should not be refrozen. Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specified by Additional information: manufacturer. Concentrations of less than 100 mcg (0.1 mg) per mL or greater than 1 mg per mL are not recommended. Preparation of dosage form: Warm to body temperature to ease Infusions may be administered over a one- to four-hour period. Rapid administration.{R-12} administration should be avoided. Intramuscular or subcutaneous administration is not recommended. Stability: Preparation may darken on standing, but the potency {R-12} USP requirements: Preserve in Containers for Sterile Solids, protected remains unaffected. from light. Contains an amount of doxycycline hyclate equivalent to the labeled amount of doxycycline, within –10% to +20%. Meets the USP requirements: Not in USP. requirements for Constituted solution, Identification, Bacterial endotoxins, Sterility, pH (1.8–3.3, in the solution constituted as directed in the labeling), Loss on drying (not more than 4.0%), and Particulate ORAL DOSAGE FORMS {R-128} matter. Note: Bracketed information in the Dosage Forms section refers to uses that either are not included in U.S. product labeling or are for products not commercially available in the U.S. 1Not included in Canadian product labeling or product not commercially available in Canada. OXYTETRACYCLINE HYDROCHLORIDE SOLUBLE POWDER USP OXYTETRACYCLINE Usual dose: Bees—American and European foul brood: Oral, 200 mg per colony ADDITIONAL DOSING INFORMATION once every four to five days for three treatments in the spring When possible, oral oxytetracycline should be administered 1 hour before and/or fall. Powder is dusted on the outer parts of the frames or or 2 hours after milk replacer.{R-1} mixed as a syrup and fed in feeder pails or in the combs.{R-6; 61; 134} Note: Honey from infected colonies should not be used for the MUCOSAL DOSAGE FORMS preparation of medicated syrup. Note: Bracketed information in the Dosage Forms section refers to uses Calves and cattle— that either are not included in U.S. product labeling or are for products Bacterial enteritis: Oral, 22 mg per kg of body weight every twenty- not commercially available in the U.S. four hours, administered in the only source of drinking water or as a drench.{R-61} 1 OXYTETRACYCLINE HYDROCHLORIDE UTERINE Bacterial pneumonia : Oral, 22 mg per kg of body weight every twenty-four hours, administered in the only source of drinking SUSPENSION water or as a drench.{R-61} Usual dose: Chickens— Note: [Cows]—Although the efficacy and safety are not currently Chronic respiratory disease; or fowl cholera: Oral, 400 to 800 mg per established, an intrauterine dose of 3.9 to 4.4 mg per kg of body gallon of water (approximately 22 to 59 mg per kg of body weight weight, administered as a single dose{R-12}, is included in Canadian a day), administered as the only source of drinking water.{R-11} product labeling for the treatment of uterine infections. Synovitis1: Oral, 200 to 400 mg per gallon of water, administered as the only source of drinking water.{R-11; 13; 61} Strength(s) usually available{R-58}: [Bacterial enteritis]: Oral, 200 to 400 mg per gallon of water, U.S.— administered as the only source of drinking water. Veterinary-labeled products: Pigs— Not commercially available. Bacterial enteritis: Oral, 22 mg per kg of body weight, administered Canada—{R-12} in the only source of drinking water.{R-11; 13; 61} Veterinary-labeled products: Bacterial pneumonia: Oral, 22 mg per kg of body weight, admin- 50 mg per mL (Rx) [Kelamycin]. istered in the only source of drinking water{R-6; 13}.

Leptospirosis1: Oral, 22 mg per kg of body weight, administered in Withdrawal time the only source of drinking water{R-6; 13}. Sheep— Species Meat (days) Bacterial enteritis: Oral, 22 mg per kg of body weight every Calves, cattle, sheep 5 twenty-four hours, administered in the only source of drinking Chickens 0 water.{R-61} Pigs 0, 5, or 13, depending on product Turkeys 0 or 5, depending on product Bacterial pneumonia1: Oral, 22 mg per kg of body weight every twenty-four hours, administered in the only source of drinking Note: Product labeling listing the above withdrawal times states that water{R-13}. treatment of calves, cattle, pigs, and sheep should be for a maximum of Turkeys, growing—Bacterial enteritis: Oral, 55 mg per kg of body ﬁve days and chickens and turkeys for a maximum of fourteen days. weight a day for seven to fourteen days.{R-7; 11; 13} Not labeled for use in lactating dairy cattle, preruminating calves, or Turkeys— birds producing eggs for human consumption. Hexamitiasis1: Oral, 200 to 400 mg per gallon of water (approxi- Canada—{R-54} mately 3.5 to 37 mg per kg of body weight a day), administered as the only source of drinking water.{R-11} Withdrawal time 1 Synovitis : Oral, 400 mg per gallon of water (7 to 37 mg per kg of Species Meat (days) body weight a day), administered as the only source of drinking {R-7; 11; 13} Calves, pigs, sheep 10 water. Chickens, turkeys 7 Note: Environmental and health conditions may affect the intake of {R-17} water and the amount of medication consumed. Administra- Note: Product labeling listing the above withdrawal times states that they tion of medication by food or water to animals with pneumonia or apply to doses of 5 to 10 mg per kg of body weight every twelve hours other infections can be affected by reduced feed and water for three to ﬁve days for calves, 10 mg per kg of body weight every {R-109} intake . twelve hours for three or four days for pigs, 50 mg per L of drinking water for three or four days for chickens and turkeys, and 5 mg per kg of body weight every twelve hours for three or four days for sheep. Strength(s) usually available{R-58}: These products are not labeled for use in lactating dairy cattle or birds U.S.— producing eggs for human consumption{R-54}. Veterinary-labeled products:

25 grams per pound of powder (OTC) [AmTech Oxytetracycline HCL Withdrawal time Soluble Powder; Terramycin Soluble Powder; Terra-Vet Soluble Powder]. Species Meat (days) Milk (hours) Eggs (hours) 166 grams per pound of powder (OTC) [Oxytet Soluble; Tetravet-CA; Cattle 10 60 or 96, Tetroxy HCA Soluble Powder]. depending 343 grams per pound of powder (OTC) [Agrimycin-343; AmTech on product Chickens, 7 60 or 120, Oxytetracycline HCL Soluble Powder-343; Oxytet-343 Water Soluble turkeys depending Powder; Pennox 343 Soluble Powder; Terramycin-343 Soluble on product Powder; Terra-Vet Soluble Powder 343; generic]. Pigs, sheep 10

Canada— Note: Some products are not labeled for use in lactating cattle and some Veterinary-labeled products: are not labeled for use in poultry laying eggs for human consumption. 11 mg per gram of powder (OTC) [Foul Brood Mix]. Product labeling listing the above withdrawal times states that they 55 mg per gram of powder (OTC) [Oxytetra-A; Oxytet-25-S]. apply to doses of 22 mg per kg of body weight a day for ﬁve days for 62.5 mg per gram of powder (OTC) [Oxysol-62.5; Oxytet-SP]. calves and cattle, 33 mg per kg of body weight a day for pigs, and 111 220 mg per gram of powder (OTC) [Oxy Tetra Forte]. mg per L of water for chickens and turkeys. 250 mg per gram of powder (OTC) [Oxy 250; Oxysol-250; Oxytet- 250 Concentrate]. Packaging and storage: Store below 40 C (104 F), preferably 1 gram per gram of powder (OTC) [Oxy 1000; Oxysol-1000]. between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by manufacturer.

Withdrawal times{R-58}: Preparation of dosage form: Note: With oxytetracycline soluble powder, withdrawal times vary Oxytetracycline soluble powder can be mixed with water and adminis- greatly from product to product and may differ from those listed below. tered as a drench. Fresh drinking water and drench solutions should be See also individual manufacturer labeling. prepared daily as recommended by the manufacturer.{R-11} Bees: To avoid contamination of honey, oxytetracycline hydrochloride For bees, medication is mixed with powdered sugar and dusted on the soluble powder should be fed early in the spring or fall before the main frames or mixed with sugar and water to form a paste or syrup and honey ﬂow begins. Honey stored during treatment should be applied as recommended by manufacturer.{R-54} removed following last medication and cannot be used for human food.{R-61} Stability: Stable for twenty-four hours.{R-11}

Incompatibilities: Milk replacer—Oxytetracycline is bound to milk Chronic respiratory disease (control): Oral, 400 grams per ton of replacer at a rate of 63%; this is a binding that is not readily revers- feed, fed as the only ration{R-117}. ible.{R-111} Administration of oral oxytetracycline in milk replacer will Note: Canadian labeling lists a dose of 100 grams per ton (110 result in lower bioavailability.{R-111} grams per metric ton [1000 kg]) in the treatment of chronic respiratory disease{R-26}. USP requirements: Preserve in well-closed containers. A mixture of Fowl cholera1; or synovitis: Oral, 100 to 200 grams per ton of feed, Oxytetracycline Hydrochloride and one or more suitable excipients. fed as the only ration{R-117}. Label it to indicate that it is for oral veterinary use only. Contains Improved feed efficiency1 and increased weight gain1: Oral, 10 to 50 the labeled amount, within ±10%. Meets the requirements for grams per ton of feed, fed as the only ration{R-117}. Identification, pH (1.5–3.0, in the solution obtained as directed in Lobsters—Gaffkemia: Oral, 2.2 grams per kg of feed, fed as the only the labeling), Loss on drying (not more than 3.0%, and Minimum ration{R-27; 124}. fill.{R-128} Pigs— Bacterial enteritis: Oral, 22 mg per kg of body weight a day, OXYTETRACYCLINE FOR MEDICATED FEED administered in the feed and fed as the only ration{R-117}. Usual dose: Note: Canadian labeling lists a dose of 100 grams per ton (110 Bees, honey—Foul brood: Oral, 200 mg per colony of bees every four to grams per metric ton [1000 kg]) in the treatment of bacterial five days in the spring and/or fall{R-117}. Powder is dusted on the enteritis{R-26}. outer parts of the frames or mixed as a syrup and fed in feeder pails or For reducing the shedding of leptospirosis and reducing the incidence in the combs{R-117}. of associated abortions: Oral, 22 mg per kg of body weight per Note: Honey from infected colonies should not be used for the animal a day, administered in the feed and fed as the only ration{R- preparation of medicated syrup{R-117}. 117}. Calves— Note: Canadian labeling lists a dose of 500 grams per ton (550 Bacterial enteritis: Oral, 22 mg per kg of body weight a day{R-117}. grams per metric ton [1000 kg]) in the treatment of leptospi- Note: Canadian labeling lists a dose of 50 grams per ton (55 grams rosis{R-26}. per metric ton [1000 kg]) in the treatment of bacterial Improved feed efficiency and increased weight gain1: Oral, 10 to 50 enteritis{R-26}. grams per ton of feed, fed as the only ration{R-117}. Improved feed efficiency1; or increased weight gain1 in calves [Atrophic rhinitis]: Oral, 50 grams per ton (55 grams per metric ton weighing less than 113.6 kg (250 pounds): Oral 0.11 to 0.22 mg [1000 kg]) of feed, fed as the only ration{R-26}. per kg of body weight a day, administered in the feed and fed as the Note: Different feeding regimens will result in differences in actual mg only ration{R-117}. of oxytetracycline per kg of body weight consumed by individual Improved feed efficiency1; or increased weight gain1 in calves pigs{R-110}. weighing 113 to 181 kg (250 to 400 pounds): Oral, 25 mg Therapeutic serum concentrations of > 0.5 mcg/mL were not per animal a day, administered in the feed and fed as the only produced when 550 mg of oxytetracycline per kg of feed was ration{R-117}. administered to 30-kg pigs in one study{R-107}. Note: According to product labeling, when administered in milk An oral dose of 54 to 108 mg per kg of body weight a day replacer, the 22 mg per kg of body weight dose is indicated in the (concentrations of 1600 and 2400 mg of oxytetracycline per kg of treatment of bacterial enteritis only{R-117}. feed) was reported to be required to produce 1 mcg per mL serum Catfish1—Hemorrhagic septicemia; or pseudomonas disease: Oral 55 to concentrations in pigs{R-110}. 82.5 mg per kg of body weight a day for a maximum of ten days, Salmon, Pacific1—Marking of skeletal tissue: Oral, 250 mg per kg of administered in the feed and fed as the only ration{R-27}. body weight a day{R-27}. Cattle— Salmonids—[Cold water disease]; [columnaris disease]; [enteric red- Bacterial enteritis1: Oral, 22 mg per kg of body weight a day{R-117}. mouth disease]; furunculosis; hemorrhagic septicemia1; pseudo- Bacterial pneumonia, acute (prophylaxis and treatment)1: Oral, 500 monas disease1; or ulcer disease: Oral, 55 to 82.5 mg per kg of to 2000 mg (2 grams) per animal a day, administered in the feed body weight a day, administered in the feed and fed as the only and fed as the only ration for three to five days prior to shipping ration{R-27; 124}. and three to five days after shipping{R-122; 117}. Sheep1— Bacterial pneumonia (treatment)1: Oral, 22 mg per kg of body weight Bacterial enteritis; or bacterial pneumonia: Oral 22 mg per kg of a day, administered in feed and fed as the only ration for seven to body weight per animal a day, administered in the feed and fed as fourteen days{R-117}. the only ration{R-117}. Improved feed efficiency1; or increased weight gain1, in growing Improved feed efficacy and increased weight gain: Oral, 10 to 20 cattle weighing over 400 pounds: Oral, 75 mg per animal a day, grams per ton of feed, fed as the only ration{R-117}. administered in the feed and fed as the only ration{R-117}. Turkeys— [Bloat]—Oral, 75 mg per animal a day, administered in the feed and Bacterial enteritis (bluecomb): Oral, 55 mg per kg of body weight fed as the only ration{R-26}. a day, administered in the feed and fed as the only ration{R-117}. Chickens— Note: Canadian labeling lists a dose of 100 grams per ton (110 grams Chronic respiratory disease, specifically air sacculitis, reduction in per metric ton [1000 kg]) of feed, fed as the only ration{R-26}. associated mortality1: Oral, 500 grams per ton of feed, fed as the Hexamitiasis1: Oral, 100 grams per ton of feed, fed as the only only ration{R-117}. ration{R-117}.

Improved feed efficiency1 and increased weight gain1: Oral, 10 to 50 When fed up to 200 grams per ton of feed: grams per ton of feed, fed as the only ration{R-117}. Synovitis: Oral, 200 grams per ton of feed, fed as the only Withdrawal time {R-26} ration . Species Meat (days) [Sinusitis]: Oral, 100 grams per ton (110 grams per metric ton [1000 Turkeys 0 kg]) of feed, fed as the only ration{R-26}. [Lambs]— Note: Not labeled for turkeys producing eggs for human consump- Bacterial enteritis: Oral, 100 grams per ton (110 grams per metric tion{R-117}. ton [1000 kg]) of feed, fed as the only ration{R-26}. When fed to turkeys at 200 grams or more per ton of feed, and to cattle, Enterotoxemia: Oral, 20 grams per ton (22 grams per metric ton pigs, and sheep at 22 mg/kg: [1000 kg]) of feed, fed as the only ration{R-26}. Note: Environmental and health conditions may affect the intake of water Withdrawal time and the amount of medication consumed.{R-17} Administration of Species Meat (days) medication by food or water to animals with pneumonia or other infections can be affected by reduced feed and water intake{R-109}. Bees 42 (honey) Catfish 21 Calves (some products), 5 {R-58} Strength(s) usually available : cattle, sheep, turkeys U.S.—{R-62; 122} Lobsters 30 Veterinary-labeled products: Pacific salmon 7 Pigs 0 or 5, depending on product 110 grams per kg of premix (OTC) [OTC 50; OXTC 50; Pennox 50 Salmonids 21 Meal; Terramycin 50]. 220 grams per kg of premix (OTC) [OXTC 100; Pennox 100 Hi-Flo Note: Not labeled for poultry producing eggs for human consump- Meal; Pennox 100-MR; Terramycin 100; Terramycin 100 For Fish]. tion{R-117}. A withdrawal time has not been established for prerumi- 440 grams per kg of premix (OTC) [OXTC 200; Pennox 200 Hi-Flo nating calves for some products{R-117}. Meal; Terramycin 200]. Canada{R-26; 55}— Canada—{R-26; 55} Note: Bees—Withdraw medication 4 weeks prior to honey flow. Veterinary-labeled products: 110 grams per kg of premix (OTC) [Oxy-110; Oxysol-110; Oxytet- Withdrawal time

racycline 50; Terramycin-50]. Species Meat (days) 220 grams per kg of premix (OTC) [Oxy-220; Oxysol-220; Oxytet- Bees 28 (honey) racycline 100; Terramycin-100]. Calves, cattle 5 440 grams per kg of premix (OTC) [Oxy-440; Oxysol-440; Oxytet- Chickens, pigs, turkeys 7 racycline 200; Terramycin-200; Terramycin-Aqua]. Lambs 4 Lobsters 30 Withdrawal times{R-58}: Salmonids, 10 C or warmer 40 Note: Bees—To avoid contamination of honey, oxytetracycline hydro- Salmonids, below 10 C80 chloride soluble powder should be fed early in the spring or fall before Note: Not labeled for chickens producing eggs for human consumption{R- the main honey ﬂow begins. Honey stored during therapy should be 117}. Withdrawal time has not been established for preruminating removed following the last medication and should not be used for calves{R-117}. human food{R-117}. U.S.—{R-27; 186} Packaging and storage: Store below 40 C (104 F), preferably When fed 500 grams per ton of feed: between 15 and 30 C (59 and 86 F), unless otherwise speciﬁed by Withdrawal time manufacturer. Species Meat (days) Preparation of dosage form: For use in dry feeds only, as indi- Chickens 1 cated on manufacturer’s labeling. Should not be used without If fed low-calcium feed 3 diluting.{R-122} Note: Not labeled for chickens producing eggs for human consumption{R- 117}. Incompatibilities: Salmonid and lobster feeds having a high ash content (calcium, copper, iron, or zinc) may bind oxytetracycline and When fed up to 400 grams per ton of feed: prevent absorption. Oxytetracycline also should not be administered Withdrawal time with feeds containing bentonite.{R-124}

Species Meat (days) Additional information: U.S.—For ﬁsh, this medication should not be Chickens 0 If fed low-calcium feed 3 used when water temperature is below 16.7 C (62 F) for catﬁsh or below 9 C (48.2 F) for salmonids.{R-62} Note: Not labeled for chickens producing eggs for human consumption{R-117}. USP requirements: Not in USP.

OXYTETRACYCLINE TABLETS USP For pneumonia caused by Pasteurella, an [intravenous dose of 11 mg 1 Usual dose: per kg of body weight every twelve hours] has been recommended, Bacterial enteritis1;or based on pharmacokinetic changes in calves with induced pneumo- {R-106} Bacterial pneumonia1—Calves: nia ; however, this regimen is usually reserved for serious Control—Oral, 5.5 mg per kg of body weight every twelve hours.{R-2; cases. The shortened dosing interval will require an extended 60} withdrawal time{R-14}. 1 Treatment—Oral, 11 mg per kg of body weight every twelve hours for For [thromboembolic meningoencephalitis] , a dose of 11 mg per kg of up to four days.{R-2; 60} body weight every twenty-four hours has been recommended; however, there are no specific research data to support the efficacy {R-178; 179} Strength(s) usually available{R-58}: of this use . U.S.—{R-2; 60} [Pigs]—Bacterial enteritis; bacterial pneumonia; erysipelas; lepto- Veterinary-labeled products: spirosis; mastitis; or uterine infections: Intramuscular or intra- 250 mg (OTC) [Terramycin Scours Tablets]. venous, 6.6 to 11 mg per kg of body weight every twenty-four {R-10} 500 mg (OTC) [Oxy 500 Calf Bolus]. hours. 1000 mg (OTC) [Oxy 1000 Calf Bolus]. Note: No more than 10 mL should be injected per site in adult cattle and Canada— no more than 5 mL per site in pigs. Less mature animals should have Veterinary-labeled products: decreasing volumes injected per site (but not total mg per kg of body Not commercially available. weight) so that small animals receive 0.5 to 2 mL per injection site. Intravenously administered oxytetracycline should be injected slow- {R-21} Withdrawal times: ly. Intramuscularly administered oxytetracycline causes a nota- U.S.—{R-60} ble tissue reaction (see note on slaughter trim below under Withdrawal times). Withdrawal time [Horses]1—Ehrlichiosis (Ehrlichiosis equi); or Potomac horse fever (Ehr- Species Meat (days) lichiosis risticii): Intravenous, 10 mg per kg of body weight every {R-46–48; 92; 138} Calves 0 or 7, depending on product twenty-four hours. Note: Gastrointestinal side effects are possible following oxytetracycline Note: Product labeling with the above withdrawal time states that it administration to horses. applies when calves are treated for up to four days. The above dose is based on clinical trials and retrospective dose- Products are not labeled for use in preruminating calves{R-58}. response studies. [Foals]1—Although the efficacy and safety have not been established, USP requirements: Preserve in tight, light-resistant containers. Contain a single intravenous dose of 44 mg of oxytetracycline per kg of body the labeled amount, within –10% to +20%. Meet the requirements for weight has been used in the treatment of flexural limb deformities in {R-157; Identification, Dissolution (75% in 45 minutes in 0.1 N hydrochloric acid newborn foals, based on controlled studies in healthy foals 158} in Apparatus 1 at 100 rpm), Uniformity of dosage units, and Water (not . The dose is most often administered as a single intravenous dose {R-158} more than 7.5%).{R-128} of 2 to 3 grams per foal or as an intravenous dose of 1.5 grams per foal, repeated in twenty-four hours. In some cases, clinicians 1Not included in Canadian product labeling or product not commercially have repeated an initial 2- to 3-gram dose twenty-four hours {R-20; 157} available in Canada. following the initial dose . Studies have demonstrated the safety, including lack of renal toxicity, of doses of up to 54.5 to 75 mg per kg of body weight, PARENTERAL DOSAGE FORMS administered two times, twenty-four hours apart, to twenty {R-20; 158} Note: Bracketed information in the Dosage Forms section refers to uses newborn foals ; however, because high doses of oxytet- that either are not included in U.S. product labeling or are for products racyclines have been associated with renal toxicity in many {R-15} not commercially available in the U.S. species , some clinicians prefer to test renal function before treatment. It is recommended that this high dose of oxytetracycline not be administered to foals with any systemic illness or OXYTETRACYCLINE INJECTION USP disorder predisposing to renal compromise, including dehydration or endotoxemia. Usual dose: [Sheep]—Bacterial arthritis; bacterial pneumonia; mastitis; or uterine Cattle—Actinobacillosis1; [bacterial arthritis]; bacterial enteritis; [black- infections: Intramuscular or intravenous, 6.6 mg per kg of body leg/malignant edema]; diphtheria1; [leptospirosis]; [mastitis]; [ompha- weight every twenty-four hours{R-24; 121}. lophlebitis]; [peritonitis]; pneumonia and bovine respiratory disease complex; pododermatitis; skin and soft tissue infections1; or uterine infections: Intramuscular or intravenous, 6.6 to 11 mg per kg of body Strength(s) usually available{R-58}: weight every twenty-four hours.{R-24; 121} U.S.— Note: For uterine infections in cattle, an [intravenous dose of 11 mg per Veterinary-labeled products: kg of body weight every eight to twelve hours]1 has been 100 mg per mL (OTC) [Agrimycin 100; AmTech Maxim-100; recommended, based on distribution studies{R-104}. The shortened Duramycin 100; Oxybiotic-100; Oxycure 100; Oxy-Mycin 100; dosing interval will require an extended withdrawal time{R-14}. Promycin 100; Terra-Vet 100; Tetroxy-100].

Canada— intramuscular injection, when they are administered at the same Veterinary-labeled products: dose.{R-107; 162}. As such, use of the long-acting formulations at 100 mg per mL (OTC) [Oxy LP; Oxymycine LP; Oxytetracycline standard doses of 6 to 11 mg per kg of body weight may not result in a 100LP; Oxytetramycin 100; Oxyvet 100 LP; Tetraject LP]. prolonged duration of action. Also, there is no difference in duration of action between conventional and long-acting formulations when they {R-58} Withdrawal times : are administered intravenously{R-99; 151}. {R-21; 56} U.S.— Usual dose: 1 1 Withdrawal time Cattle—Actinobacillosis ; bacterial enteritis ; bacterial pneumonia and bovine respiratory disease complex; diphtheria1; keratoconjunctivi- Species Meat (days) tis; leptospirosis; metritis, acute1; pododermatitis; or skin and soft Cattle 18, 19, 20, or 22, depending tissue infections1: Intramuscular, intravenous, or, when labeled, on product subcutaneous, 6.6 to 11 mg per kg of body weight every twenty-four hours for four days{R-3; 45}. Note: Product labeling listing the above withdrawal times states that they Note: When it is impractical to give cattle more than a single dose for apply to a dose of 6.6 to 11 mg per kg of body weight a day in cattle for the treatment of keratoconjunctivitis or pneumonia, an intramus- a maximum of four days. cular or, when labeled, subcutaneous dose of 20 mg per kg of body Not labeled for use in lactating cattle or preruminating calves. weight administered as a single dose is recommended.{R-45} Cattle slaughtered within 20 days of intramuscular administration of In calves, [40 mg per kg of body weight as a single dose]1 has been oxytetracycline may require trimming of the injection sites and used in the treatment of bacterial pneumonia that is unresponsive to surrounding tissues during dressing procedure. 20 mg per kg of body weight, based on pharmacokinetic and Canada—{R-24} toxicity data{R-95; 101}; however, the clinical efficacy was not Withdrawal time established in this study. This higher dose should not be repeated {R-30; 167; 168} Species Meat (days) Milk (hours) because of the risk of adverse effects . For [thromboembolic meningoencephalitis]1 in cattle, a dose of 11 mg Cattle 18 60 or 72, depending per kg of body weight every twenty-four hours has been on product Pigs, sheep 18 recommended; however, there are no specific research data to support the efficacy of this use{R-178; 179}. 1 Note: The above withdrawal times are based on Canadian labeling that Pigs—Bacterial enteritis ; bacterial pneumonia; or leptospirosis: Intra- lists a dose of 6.6 mg per kg of body weight a day for a maximum of muscular, 6.6 to 11 mg per kg of body weight every twenty-four {R-45} two to three days.{R-24} hours for four days. Note: When it is impractical to give pigs more than a single dose for the Packaging and storage: Store below 40 C (104 F), preferably treatment of pneumonia, an intramuscular dose of 20 mg per kg of between 15 and 30 C (59 and 86 F), unless otherwise specified by body weight administered as a single dose is recommended.{R-45} manufacturer. Protect from light. Protect from freezing. Sows—Bacterial enteritis in suckling pigs: Intramuscular, 6.6 mg per kg of body weight, administered once eight hours before farrowing or Preparation of dosage form: For intravenous administration, dilution immediately after farrowing.{R-45} in water for injection or physiological saline is recommended. Doses of Note: No more than 10 mL should be administered intramuscularly at up to 2500 mg (50 mL) can be diluted in 250 mL of diluent, and larger any one site in adult cattle. No more than 5 mL should be injected doses in 500 mL of diluent. intramuscularly at any one site in adult pigs.{R-45} Injections should be administered deep into the fleshy part of the muscle.{R-25} Less mature Stability: Diluted medication should be used or discarded immediately animals should have size-dependent decreasing volumes injected per after mixing.{R-21} Solution may darken on standing but this color site so that small calves receive only 1 to 2 mL per injection site. change does not affect the potency of the medication. Strength(s) usually available{R-58}: USP requirements: Preserve in single-dose or in multiple-dose con- U.S.—{R-3; 45} tainers, protected from light. A sterile solution of Oxytetracycline with Veterinary-labeled products: or without one or more suitable anesthetics, antioxidants, buffers, 200 mg per mL (OTC) [Agrimycin 200; AmTech Maxim-200; complexing agents, preservatives, and solvents. Contains the labeled Biomycin 200; Duramycin 72-200; Geomycin 200; Liquamycin amount, within –10% to +20%. Meets the requirements for Identifi- LA-200; Maxim-200; OT 200; OxyBiotic-200; Oxycure 200; Oxy- cation, Bacterial endotoxins, Sterility, and pH (8.0–9.0).{R-128} Mycin 200; Oxyshot LA; Pennox 200 Injectable]. Note: The above products contain the following viscosity excipients: OXYTETRACYCLINE INJECTION USP (LONG-ACTING) Biomycin 200 contains polyethylene glycol; Duramycin 72-200, Note: The formulations listed below have a viscosity excipient intended to Liquamycin LA-200, Maxim-200; and Pennox 200 contain 2- prolong therapeutic serum antibiotic concentrations. These products pyrrolidone; and Oxyshot LA contains N-methylpyrrolidone. are believed to differ from other oxytetracycline injection products Canada—{R-25; 120} only in the rate of absorption from intramuscular injection; moreover, Veterinary-labeled products: some studies using oxytetracycline products with 2-pyrrolidone 200 mg per mL (OTC) [Alamycin LA; Biomycin 200; Liquamycin LA- viscosity excipient have failed to show that the duration of action is 200; Oxy LA; Oxymycine LA; Oxyvet 200 LA; Tetraject LA]. significantly prolonged over that of the conventional formulation after 300 mg per mL (OTC) [Tetradure LA 300].

Withdrawal times{R-58}: TETRACYCLINE U.S.—{R-3; 5; 45; 153} Note: If oxytetracycline injection is administered to calves as a single ADDITIONAL DOSING INFORMATION intramusuclar dose of 40 mg per kg of body weight, there is some When possible, oral tetracycline should be administered 1 hour before or {R-1} evidence to suggest that a withdrawal time of 49 days would be 2 hours after milk replacer. sufﬁcient to avoid residues, based on tissue depletion studies of the parent drug{R-101}. MUCOSAL DOSAGE FORMS Note: Bracketed information in the Dosage Forms section refers to uses Withdrawal time that either are not included in U.S. product labeling or are for products Species Meat (days) not commercially available in the U.S. Cattle 28 Pigs 28 or 42, depending on product TETRACYCLINE UTERINE TABLETS Usual dose: Note: Some products are not labeled for use in lactating dairy cattle and Note: [Cows] and [mares]—Although the efﬁcacy and safety are not list the above withdrawal times. currently established, the use of a 4-gram bolus administered as a Product labeling listing the above withdrawal times states that they single intrauterine dose is included in Canadian product labeling{R-9} apply to a dose of 6.6 to 11 mg per kg of body weight a day for a for the treatment of uterine infections. The dose may be repeated in maximum of four days or 20 mg per kg of body weight administered as a two days if necessary.{R-9} single dose. Strength(s) usually available: Withdrawal time U.S.— Species Meat (days) Milk (hours) Veterinary-labeled products:

Cattle 28 96 Not commercially available. {R-9} Pigs 28 Canada— Veterinary-labeled products: Note: Product labeling listing the above withdrawal times states that they 4 grams (OTC) [Tetra 4000; Tetrabol]. apply to a dose of 6.6 to 11 mg per kg of body weight a day for a maximum of four days or 20 mg per kg of body weight administered as Withdrawal times: a single dose. Canada—{R-9} {R-25; 120} Canada— Withdrawal time Withdrawal time Species Meat (days) Milk (hours)

Species Meat (days) Cows 18 72 Cattle and pigs Intramuscular injection 21 or 28, depending on product Cattle Packaging and storage: Store below 40 C (104 F), preferably be- Subcutaneous injection 48 tween 15 and 30 C (59 and 86 F), in a tight container, unless otherwise speciﬁed by manufacturer. Note: Product labeling listing the above withdrawal times states that they apply to a dose of 20 mg per kg of body weight administered once. Not Auxiliary labeling: Protect from excessive moisture.{R-9} labeled for use in lactating dairy cattle. One product recommends a 42-day withdrawal to avoid excess trim at USP requirements: Not in USP. the injection site{R-58}. ORAL DOSAGE FORMS Packaging and storage: Store between 15 and 30 C (59 and 86 F), Note: Bracketed information in the Dosage Forms section refers to uses unless otherwise speciﬁed by manufacturer. Protect from light. Protect that either are not included in U.S. product labeling or are for products from freezing.{R-45} not commercially available in the U.S.

Preparation of dosage form: Warm to room temperature before TETRACYCLINE BOLUSES USP administration. Usual dose: Bacterial enteritis; or bacterial pneumonia—Calves: Oral, USP requirements: Preserve in single-dose or in multiple-dose con- 11 mg per kg of body weight every twelve hours for ﬁve days.{R-1} tainers, protected from light. A sterile solution of Oxytetracycline with or without one or more suitable anesthetics, antioxidants, buffers, Strength(s) usually available{R-58}: complexing agents, preservatives, and solvents. Contains the labeled U.S.—{R-1} amount, within –10% to +20%. Meets the requirements for Identiﬁ- Veterinary-labeled products: cation, Bacterial endotoxins, Sterility, and pH (8.0–9.0).{R-128} 500 mg (OTC) [Calf Scour Bolus Antibiotic; 5-Way Calf Scour Bolus]. Canada—{R-9} 1Not included in Canadian product labeling or product not commercially Veterinary-labeled products: available in Canada. 4 grams (OTC) [Tetra 4000; Tetrabol].

Withdrawal times{R-58}: Human-labeled products: U.S.—{R-1} 250 mg (Rx) [Achromycin V; generic]. generic Withdrawal time 500 mg (Rx) [Achromycin V; ]. Canada— Species Meat (days) Veterinary-labeled products: Calves 12, 14 or 24, depending on Not commercially available. product Human-labeled products: 250 mg (Rx) [Apo-Tetra; Novo-Tetra; Nu-Tetra]. Canada—{R-9}

Withdrawal time Packaging and storage: Store below 40 C (104 F), preferably be- Species Meat (days) tween 15 and 30 C (59 and 86 F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container. Calves 5 Cattle 18 USP requirements: Preserve in tight, light-resistant containers. Con- Note: Product labeling with the above withdrawal times state that they tain the labeled amount, within )10% to +25%. Meet the require- apply to a dose of 20 mg per kg of body weight a day for three to five ments for Identification, Dissolution (80% in 60 minutes, 90 minutes days. for 500-mg capsules, in water in Apparatus 2 at 75 rpm), Uniformity of dosage units, Loss on drying (not more than 4.0%), and Limit of Packaging and storage: Store below 40 C (104 F), preferably be- 4-epianhydrotetracycline (not more than 3.0%).{R-128} tween 15 and 30 C (59 and 86 F), unless otherwise specified by manufacturer. Store in a tight container. TETRACYCLINE HYDROCHLORIDE SOLUBLE POWDER USP Auxiliary labeling: {R-9} Usual dose: • Protect from excessive moisture. Calves and pigs—Bacterial enteritis; or bacterial pneumonia: Oral, 11 mg per kg of body weight every twelve hours, administered in the USP requirements: Preserve in tight containers. Label Boluses to only source of drinking water for three to five days.{R-19} indicate that they are intended for veterinary use only. Contain the Chickens—Chronic respiratory disease; or infectious synovitis: Oral, equivalent of the labeled amount of tetracycline hydrochloride, within 27.5 mg per kg of body weight every twelve hours, administered in –10% to +20%. Meet the requirements for Identification, Uniformity of the only source of drinking water for seven to fourteen days.{R-19} dosage units, and Loss on drying (not more than 3.0%; or for Boluses Turkeys—Infectious synovitis; or bacterial enteritis: Oral, 27.5 mg per greater than 15 mm in diameter, not more than 6.0%).{R-128} kg of body weight every twelve hours, administered in the only source of drinking water for seven to fourteen days.{R-19} TETRACYCLINE HYDROCHLORIDE CAPSULES USP [Sheep]—Bacterial enteritis; or respiratory tract diseases: Oral, 40 mg Usual dose: [Rocky Mountain spotted fever]1—Dogs: Oral, 22 mg per per kg of body weight every twelve hours for four to five days{R-18}. kg of body weight every eight hours for fourteen days.{R-140; 141} Note: Environmental and health conditions may affect the intake of water Note: [Dogs]1—The above dose is based on clinical trials and and the amount of medication consumed.{R-17} Administration of retrospective dose-response studies. The same dosage regimen has medication by food or water to animals with pneumonia or other also been used in the treatment of ehrlichiosis in dogs{R-43; 139}, infections can be affected by reduced feed and water intake{R-109}. although the efficacy of this treatment has not been confirmed. A dose of 22 mg per kg of body weight every six to eight hours has Strength(s) usually available{R-58}: also been used in the treatment of other susceptible bacterial U.S.—{R-8; 19} infections in dogs. Veterinary-labeled products: Dosing trials suggest that 30 mg of oral tetracycline per kg of body 25 grams per pound of powder (OTC) [Duramycin 10; PolyOtic Soluble weight every twelve hours for twenty-eight days, administered in Powder; Solu-Tet; Tet-Sol 10]. conjunction with 20 mg of intramuscular streptomycin every 324 grams per pound of powder (OTC) [AmTech Tetracycline Hydro- twenty-four hours for the first fourteen days, may be successful in chloride Soluble Powder-324; Duramycin-324; Solu-Tet 324; Tet-324; resolving brucellosis in dogs. It has been recommended that all dogs Tetra Bac 324; Tetrasol Soluble Powder; Tet-Sol 324; generic]. be treated in a population in which some have tested positive for Canada—{R-18} brucellosis; good management practices are recommended and Veterinary-labeled products: repeated follow-up testing is needed for several months to confirm 55 mg per gram of powder (OTC) [Tetra 55; generic]. {R-160} that all dogs remain seronegative . 62.5 mg per gram of powder (OTC) [Onycin 62.5; Tetracycline 62.5 See also Tetracycline Oral Suspension USP. Soluble Powder]. 250 mg per gram of powder (OTC) [Onycin 250; Tetra 250; Strength(s) usually available: Tetracycline 250; Tetracycline 250 Concentrate Soluble Powder; U.S.— Tetramed 250]. Veterinary-labeled products: 1000 mg per gram of powder (OTC) [Onycin 1000; Tetra 1000; Not commercially available. Tetracycline 1000; Tetramed 1000].

Withdrawal times: Auxiliary labeling: {R-8; 19} {R-4} U.S.— • Shake well before each dose .

Withdrawal time USP requirements: Preserve in tight, light-resistant containers. It is

Species Meat (days) Tetracycline with or without one or more suitable buffers, preservatives, stabilizers, and suspending agents. Contains the equivalent of Calves 4 or 5, depending on product the labeled amount of tetracycline hydrochloride, within –10% to Chickens, pigs, turkeys 4 or 7, depending on product +25%. Meets the requirements for Identiﬁcation, Uniformity of dos- Note: Products are not labeled for use in preruminating calves or poultry age units (single-unit containers), Deliverable volume, pH (3.5–6.0), {R-128} producing eggs for human consumption{R-58}. and Limit of 4-epianhydrotetracycline (not more than 5.0%). Canada—{R-18} 1Not included in Canadian product labeling or product not commercially Withdrawal time available in Canada. Species Meat (days) Developed: 07/17/96 Calves, chickens, pigs, 5 sheep, turkeys Revised: 7/14/98; 10/12/99; 6/30/02; 04/05/03

Note: Product labeling with the above withdrawal time states that it applies to a dose of 20 to 40 mg per kg of body weight every twelve hours for a REFERENCES maximum of five days for calves, pigs, and sheep and a dose of 200 mg 1. Tetracycline package insert (5-Way Calf Scour Bolus, Agrilabs—US), Rev 91, Rec 4/4/95. per liter of water for three to five days for chickens and turkeys. 2. Oxytetracycline package insert (Oxy 500 Calf Bolus, Boehringer Ingel- Although a milk withdrawal time is included on one product label, heim—US). Downloaded 2/26/03 from www.bi-vetmedica.com. these products are not specifically labeled for use in lactating 3. Oxytetracycline package insert (Biomycin 200, Boehringer Ingelheim—US). dairy cows in Canada. Products are not labeled for use in laying Downloaded 2/26/03 from www.bi-vetmedica.com. {R-18; 58} 4. Tetracycline package insert (Panmycin Aquadrops, Pharmacia—US), Rev hens . 11/01. 5. Liquamycin LA-200 Freedom of Information Summary. NADA 113-232 Packaging and storage: Store below 40 C (104 F), preferably (Supplement). Sponsor: Pfizer, Inc. July 21, 1998. 6. Terramycin Soluble Powder Freedom of Information Summary. NADA 008- between 15 and 30 C (59 and 86 F), in a tight container, unless 622 (Supplement). Sponsor: Pfizer Inc. July 7, 1993. otherwise specified by manufacturer. 7. Oxytetracycline Freedom of Information Summary. NADA number 200–247. Sponsor: Phoenix Scientific Inc. 2/10/99. Preparation of dosage form: Fresh solutions should be prepared every 8. Tetracycline package label (Solu-Tet 324, Alpharma—US). 9. Tetracycline package insert (Tetrabol, Vetoquinol—Canada). 24 hours when administered in plastic or stainless steel waterers and 10. Oxytetracycline package label (Oxybiotic-P, Vedco—US), discontinued pro- every 12 hours when administered in galvanized waterers. duct. 11. Oxytetracycline package label (Oxytet Soluble, Alpharma—US). 12. Oxytetracycline package label (Kelamycin, PVL—Canada). Stability: Solutions are stable for 24 hours.{R-8} 13. Oxytetracycline product labeling (Pennox 343, Pennfield—US), Rec 5/7/99. 14. Panel consensus, on monograph revision of 3/97. USP requirements: Preserve in tight containers. Label it to indicate 15. Vivrette S, Cowgill LD, Pascoe J, et al. Hemodialysis for treatment of that it is intended for veterinary use only. Contains the labeled oxytetracycline-induced acute renal failure in a neonatal foal. J Am Vet Med Assoc 1993 Jul 1: 203(1): 105–7. amount, within –10% to +25%. Meets the requirements for Identifi- 16. Chlortetracycline package insert (Pennchlor 50, Pennfield—US), Rev 4/97, {R-128} cation and Loss on drying (not more than 2.0%). Rec 6/18/98. 17. Chlortetracycline pacakage insert (CTC Soluble Powder, Agri Labs—US). TETRACYCLINE ORAL SUSPENSION USP 18. Tetracycline package insert (Onycin 250, Vetoquinol—Canada). 19. Tetracycline package insert (Duramycin-324, Durvet—US). 1 1 Usual dose: Bacterial gastroenteritis or urinary tract infections —Cats 20. Wright AK, Petrie L, Papich MG, et al. Effect of high dose oxytetracycline on and dogs: Oral, 14 to 22 mg per kg of body weight every six to eight renal parameters in neonatal foals. In: Caddel LB, editor. Proceedings of the hours.{R-177} 38th Annual Convention of the American Association of Equine Practitio- ners. Orlando, FL; 1993. p. 297–8. See also Tetracycline Hydrochloride Capsules USP. 21. Oxytetracycline package insert (Oxytetracycline hydrochloride injection, Vedco—US), Rec 8/1/95. Strength(s) usually available: 22. Barragry TB. Veterinary drug therapy. Baltimore: Lea & Febiger, 1994: U.S.—{R-4} 264–92. 23. Oxytetracycline package insert (Oxysol-220, A.P.A.—Canada). Veterinary-labeled products: 24. Oxytetracycline package insert (Oxyvet 100 LP, Vetoquinol—Canada). 100 mg per mL (Rx) [Panmycin Aquadrops]. 25. Oxytetracycline package insert (Oxyvet 200 LA, Vetoquinol—Canada). Canada—{R-126} 26. Oxytetracycline package insert (Oxysol-110, A.P.A—Canada). 27. Oxytetracycline supplemental approval (Terramycin Type A Medicated Veterinary-labeled products: Article Pfizer—US). NADA 008-804. Approved Animal Drug Products (Green Not commercially available. Book). Virginia Tech: Blacksburg, VA. 1996 Nov 15: 8.43. 28. Aronson AL. Pharmacotherapeutics of the newer tetracyclines. J Am Vet Med Packaging and storage: Store between 15 and 30 C (59 and 86 F), Assoc 1980 May 15; 176(10): 1061–8. 29. Vaala WE, Ehren SJ, Divers TJ. Acute renal failure associated with in a tight container, unless otherwise specified by manufacturer. administration of excessive amounts of tetracycline in a cow. J Am Vet Med Protect from light. Assoc 1987 Dec 15; 191(12): 1601–3.

30. Lairmore MD, Alexander AF, Powers DE, et al. Oxytetracycline-associated 61. Oxytetracycline product information (Terramycin Soluble Powder, Pfiz- nephrotoxicosis in feedlot calves. J Am Vet Med Assoc 1984; 185(7): er—US), Rec 12/14/95. 793–5. 62. Oxytetracycline product information (TM 100F, Pfizer—US), Rec 12/14/95. 31. Riond J, Riviere JE. Effects of tetracyclines on the kidney in cattle and dogs. J 63. Wilson RC, Kemp DT, Kutzman JV, et al. Pharmacokinetics of doxycycline in Am Vet Med Assoc 1989 Oct 1; 195(7): 995–7. dogs. Can J Vet Res 1988; 52: 12–4. 32. Ward GS, Guiry CC, Alexander LL. Tetracycline-induced anaphylactic shock 64. Anadon A, Martinez Larranga MR, Diaz MJ, et al. Pharmacokinetics of in a dog. J Am Vet Med Assoc 1982 Apr 1; 180(7): 770–1. doxycycline in broiler chickens. Avian Pathol 1994; 23(1): 79–90. 33. Gross DR, Dodd KT, Williams JD, et al. Adverse cardiovascular effects of 65. Committee comment, Rec 2/14/02. oxytetracycline preparations and vehicles in intact awake calves. Am J Vet 66. Riond JL, Riviere JE. Doxycycline binding to plasma albumin of several Res 1981 Aug; 42(8): 1371–7. species. J Vet Pharmacol Ther 1989; 12: 253–60. 34. Gyrd-Hansen N, Rasmussen F, Smith M. Cardiovascular effects of intravenous 67. Ziv G, Sulman G. Binding of antibiotics to bovine and ovine serum. administration of tetracycline in cattle. J Vet Pharmacol Ther 1981; 4: 15– Antimicrobial agents and chemotherapy 1972 Sep; 2(3): 206–13. 25. 68. Riond J, Tyczkowska K. Riviere J. Pharmacokinetics and metabolic inertness 35. Riond JL, Riviere JE, Duckett WM, et al. Cardiovascular effects and fatalities of doxycycline in calves with mature or immature rumen function. Am J Vet associated with intravenous administration of doxycycline to horses and Res 1989 Aug; 50(8); 1329–33. ponies. Equine Vet J 1992; 24(1): 41–5. 69. Riond J. Riviere JE. Pharmacokinetics and metabolic inertness of doxycycline 36. Kaufman AG, Greene CE. Increased alanine transaminase activity associated in young pigs. Am J Vet Res 1990 Aug; 51(8): 1271–5. with tetracycline administration in a cat. J Am Vet Med Assoc 1993 Feb 15; 70. Riond JL, Vaden SL, Riviere JE. Comparative pharmacokinetics of doxycycline 202(4): 628–30. in cats and dogs. J Vet Pharmacol Ther 1990; 13: 415–24. 37. Immelman A, Botha WS, Grib D. Muscle irritation caused by different 71. Shaw DH, Rubin SI. Pharmacologic activity of doxycline. J Am Vet Med Assoc products containing oxytetracycline. J S Afr Vet Assoc 1978; 49(2): 103–5. 1986; 189(7): 808–10. 38. Anderson WI, Wilson RC, Goetsch DD. Hemoglobinuria in cattle given long- 72. Percy DH, Black W. Pharmacokinetics of tetracycline in the domestic rabbit acting oxytetracycline. Mod Vet Pract 1983 Dec; 64(12): 997–8. following intravenous or oral administration. Can J Vet Res 1988; 52: 5–11. 39. Longhofer SL. Chemotherapy of rickettsial, protozoal, and chlamydial 73. Anadon A. Pharmacokinetics of tetracycline in chickens after intravenous diseases. Vet Clin North Am Small Anim Pract 1988 Nov; 18(6): 1183–96. administration. Poult Sci 1985; 64: 2273–9. 40. Iqbal Z, Rikihisa Y. Reisolation of Ehrlichia canis from blood and tissues of 74. Kniffen TS, Bane DP, Hall WF, et al. Bioavailability, pharmacokinetics, and dogs after doxycycline treatment. J Clin Microbiol 1994; 32(7): 1644–9. plasma concentration of tetracycline fed to swine. Am J Vet Res 1989 Apr; 41. Waddle JR, Littman MP. A retrospective study of 27 cases of naturally 50(4): 518–21. occurring canine ehrlichiosis. J Am Anim Hosp Assoc 1988 Nov/Dec; 24(6): 75. Kietzman M, Nolte I, Mischke R. Pharmacokinetics and bioavailability of 615–20. orally-administered tetracycline in dogs and cats. Kleintierpraxis 1995 Apr; 42. Ogunkoya AB, Adeyanju JB, Abduhllahi R. Experimental and clinical trials of 40(4): 253. long acting oxytetracycline in the treatment of canine erhlichiosis. Vet Q 76. Bradley BD, Allen EH, Showalter DH, et al. Comparative pharmacokinetics of 1985 Apr; 7(2): 158–61. chlortetracycline in milk fed versus conventionally fed calves. J Vet 43. Magnorelli LA, Litwin HJ, Holland CJ, et al. Canine ehrlichiosis in Connect- Pharmacol Ther 1982; 5: 267–78. icut. J Clin Microbiol 1990 Feb; 28(2): 366–7. 77. Kilroy CR, Hall WF, Bane DP, et al. Chlortetracycline in swine-bioavailability 44. George LW. Antibiotic treatment of infectious bovine keratoconjunctivitis. and pharmacokinetics in fasted and fed pigs. J Vet Pharmacol Ther 1990; 13: Cornell Vet 1990 Jul; 80(3): 229–34. 49–58. 45. Oxytetracycline package insert (Duramycin 72–200, Durvet—US), Rev 2/95, 78. Dyer DC. Pharmacokinetics of chlortetracycline in the turkey: evaluation of Rec 8/11/95. biliary secretion. Am J Vet Res 1988 Jan; 49(1): 36–7. 46. Madigan JE, Gribble D. Equine ehrlichiosis in northern California: 49 cases 79. Pollet RA, Glatz CE, Dyer DC, et al. Pharmacokinetics of chlortetracycline (1968–81). J Am Vet Med Assoc 1987 Feb 15; 190(4): 445–8. potentiation with citric acid in the chicken. Am J Vet Res 1983 Sep; 44(9): 47. Palmer JE, Benson CE, Whitlock RH. Effect of treatment with oxytetracycline 1718–21. during the acute stages of experimentally induced equine ehrlichial colitis in 80. Pollet RA, Glatz CE, Dyer DC. The pharmacokinetics of chlortetracycline ponies. Am J Vet Res 1992 Dec; 53(12): 2300–4. orally administered to turkeys: influence of citric acid and Pasteurella 48. Palmer JE, Whitlock RH, Benson CE. Equine ehrlichial colitis: effect of multocida infection. J Pharmacokinet Biopharm 198; 13: 243–64. oxytetracycline treatment during the incubation period of Ehrlichia risticii 81. Escudero E, Carceles CM, Serrano JM. Pharmacokinetics of oxytetracycline in infection in ponies. J Am Vet Med Assoc 1988; 192: 343–5. goats: modifications induced by a long-acting formulation. Vet Rec 1994; 49. Eidson M, Thistead JP, Rollag OJ. Clinical, clinicopathologic and pathologic 135: 548–52. features of plague in cats: 119 cases (1977–1988). J Am Vet Med Assoc 1991 82. Mevius DJ, Vellenga L, Breukink HJ. Pharmacokinetics and renal clearance of Nov 1; 199(9): 1191–7. oxytetracycline in piglets following intravenous and oral administration. Vet 50. Gutierrez CB, Piriz S, Vadillo S, et al. In vitro susceptibility of Actinobacillus Q 1986 Oct; 8(4): 74–85. pleuropneumoniae strains to 42 antimicrobial agents. Am J Vet Res 1993 83. Pijpers A, Schoevers EJ, Van Gogh J, et al. The pharmacokinetics of Apr; 54(4): 546–50. oxytetracycline following intravenous administration in healthy and diseased 51. Watts JL, Yancey RJ, Salmon SA, et al. A 4-year survey of antimicrobial pigs. J Vet Pharmacol Ther 1989; 13: 320–6. susceptibility trends for isolates from cattle with bovine respiratory disease in 84. Baggot JD, Powers TE, Powers JD, et al. Pharmacokinetics and dosage of North America. J Clin Microbiol 1994 Mar; 32(3): 725–31. oxytetracycline in dogs. Res Vet Sci 1977; 24: 77–81. 52. Cairoli F, Ferrario L, Carli S, et al. Efficiency of oxytetracycline and 85. Dyer DC. Pharmacokinetics of oxytetracycline in the turkey: evaluation of tetracycline-benzydamine in the prevention of infection after placental biliary and urinary excretion. Am J Vet Res 1989 Apr; 50(4): 522–4. retention in cattle. Vet Rec 1993; 133: 394–5. 86. McElroy DE, Ravis WR, Clark CH. Pharmacokinetics of oxytetracycline 53. Timms LM, Marshall RN, Breslin MF. Evaluation of the efficacy of chlortet- hydrochloride in rabbits. Am J Vet Res 1987; 48(8): 1261–3. racycline for the control of chronic respiratory disease caused by Escherichia 87. Varma KJ, Paul BS. Pharmacokinetics and plasma protein binding (in vitro) of coli and Mycoplasma gallisepticum. Res Vet Sci 1989; 47: 377–82. oxytetracycline in buffalo (Bubalus bubalis). Am J Vet Res 1983 Mar; 44(3): 54. Oxytetracycline package insert (Oxysol-62.5, A.P.A.—Canada). 497–8. 55. Oxytetracycline package insert (Oxysol-220, Sanofi—Canada), Rec 8/14/95. 88. Oukessou M, Uccelli-Thomas V, Toutain P. Pharmacokinetics and local 56. Oxytetracycline package insert (Oxy-Tet 100, Vedco—US), discontinued tolerance of a long acting oxytetracycline formulation in camels. Am J Vet Res product. 1992 Sep; 53(9): 1658–62. 57. Chlortetracycline package insert (Calf Scour Bolus, Durvet—US), Rec 8/4/95. 89. Bjorklund HV, Bylund G. Comparative pharmacokinetics and bioavailability 58. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port of oxilinic acid and oxytetracycline in rainbow trout (Onchorhynchus Huron, MI: North American Compendiums, Inc. 2002. mykiss). Xenobiotica 1991; 21(11): 1511–20. 59. Kung K, Wanner M. Pharmacokinetics of doxycycline in turkey and 90. Grondel JL, Nouws JFM, Schutte AR, et al. Comparative pharamockinetics of comparison between feed and water medication. Archiv Fur Geflugelkunde oxytetracycline in rainbow trout (Salmo Gairdneri) and African catfish 1994 Apr; 58(2): 84–8. (Clarias gariepinus). J Vet Pharmacol Ther 1989; 12: 157–62. 60. Oxytetracycline product information (Terramycin Scours Tablets, Pfizer—US), 91. Curl JL, Curl JS, Harrison JK. Pharmacokinetics of long acting oxytetracycline Rev 3/98. in the laboratory rat. Lab Anim Sci 1988; 38(4): 430–4.

92. Hospool CJI, McKellar QA. Disposition of oxytetracycline in horses, ponies, and 119. Hunneman WA, Pijpers A, Lommerse J, et al. Prophylaxis of pleuropneumo- donkeys after intravenous administration. Equine Vet J 1990; 22(4): 284–5. nia in pigs by in-feed medication with oxytetracycline and the subsequent 93. Burrows GE, Barto PB, Martin B. Comparative pharmacokinetics of gentami- transmission of infection. Vet Rec 1994 Feb; 134(9): 215–8. cin, neomycin, and oxytetracycline in newborn calves. J Vet Pharmacol Ther 120. Oxytetracycline package insert (Biomycin 200, Boehringer Ingelheim 1987; 10: 54–63. Ltd.—Canada). 94. Nouws JFM, Vree TB. Effect of injection site on the bioavailability of an 121. Oxytetracycline package insert (Oxytetracycline 100, A.P.A.—Canada). oxytetracycline formulation in ruminant calves. Vet Q 1983; 5(4): 165–70. 122. Oxytetracycline product information (OXTC 100, Pfizer—US), Rev 93, Rec 95. Nouws JFM, Van Ginneken CAM, Ziv G. Age-dependent pharmacokinetics of 12/15/95. oxytetracycline in ruminants. J Vet Pharmacol Ther 1983; 6: 59–66. 123. Aureomycin Type A Medicated Article Freedom of Information Summary. 96. Pilloud M. Pharmacokinetics, plasma protein binding and dosage of oxytet- NADA 48–761. Sponsor: Roche Vitamins Inc. July 31, 1998. racycline in cattle and horses. Res Vet Sci 1973; 15: 224–30. 124. Oxytetracycline product label (Terramycin-Aqua, Pfizer—Canada), Rec 12/5/ 97. Mevius DJ, Nouws JFM, Breukink JF, et al. Comparative pharmacokinetics, 95. bioavailability and renal clearance of five parenteral oxytetracycline-20% 125. Oxytetracycline (Oxytetra-A, Dominion). In: Bennett K, editor. Compendium formulations in dairy cows. Vet Q 1986; 8(4): 285–94. of veterinary products. 4th ed. Hensall, ON: North American Compendiums 98. Davey LA, Ferber MT, Kaye B. Comparison of the serum pharmacokinetics of Inc., 1995: 483. a long acting and a conventional oxytetracycline injection. Vet Rec 1985; 126. Tetracycline hydrochloride package insert (Panmycin Aquadrops, Upjohn—- 117: 426–9. Canada), discontinued product. 99. Toutain PL, Raynaud JP. Pharmacokinetics of oxytetracycline in young 127. Tetracycline hydrochloride package insert (Onycin 62.5, Sanofi—Canada), cattle: comparison of conventional versus long-acting formulations. Am J Vet Rec 4/11/95. Res 1983 Jul; 44(7): 1203–9. 128. The United States pharmacopeia. The national formulary. USP 26th revision 100. Schifferli K, Galeazzi RL, Nicolet J, et al. Pharmacokinetics of oxytetracycline (January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United and therapeutic implications in veal calves. J Vet Pharmacol Ther 1982; 5: States Pharmacopeial Convention, Inc., 2002. p. 439, 440, 667-71, 1378, 247–57. 1379, 1382, 1790-2, 1794, 2554, 2559, 2572, 2573, 2583, 2584. 101. Terhune TN, Upson DW. Oxytetracycline pharmacokinetics, tissue depletion, 129. Dinsmore RP, Stevens RD, Cattell MB, et al. Oxytetracycline residues in milk and toxicity after administration of a long acting preparation at double the after intrauterine treatment of cows with retained fetal membranes. J Am Vet label dosage. J Am Vet Med Assoc 1989 Apr; 194(7): 911–7. Med Assoc 1996 Nov 15; 209(10): 1753–5. 102. Anderson KL, Moats WA, Rushing JE, et al. Potential for oxytetracycline 130. Masera J, Gustafsson BK, Afiefy MM, et al. Disposition of oxytetracycline in administration by three rates to cause milk residues in lactating cows, as the bovine genital tract: systemic vs. intrauterine administration. J Am Vet detected by radioimmunoassay (Charm II) and high-performance liquid Med Assoc 1980 May 15; 176(10): 1099–102. chromatography test methods. Am J Vet Res 1995 Jan; 56(1): 70–7. 131. Bryant JE, Brown MP, Gronwall RR, et al. Study of intragastric administration 103. Soback S, Ziv G, Winkler M, et al. Systemic dry cow therapy—a preliminary of doxycycline: pharmacokinetics including body fluid, endometrial and report. J Dairy Sci 1990; 73: 661–6. minimum inhibitory concentrations, Equine Veterinary Journal 2000; 32: 104. Bretzlaff KN, Ott RS, Koritz GD, et al. Distribution of oxytetracycline in genital 233–238. tract tissues of postpartum cows given the drug by intravenous and 132. Klasco RK, editor. USP DI Drug information for the healthcare professional. intrauterine routes. Am J Vet Res 1983 May; 44(5): 764–9. Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003. 105. Bretzlaff KN, Ott RS, Koritz GD. Distribution of oxytetracycline in the healthy 133. Riviere J, Craigmill AL, Sundlof SF. Handbook of comparative pharmacoki- and diseased postpartum genital tract of cows. Am J Vet Res 1983 May; netics and residues of veterinary antimicrobials. Boca Raton, FL: CRC Press, 44(5): 760–3. Inc, 1991: 175–226. 106. Burrows GE, Barto PB, Weeks BR. Chloramphenicol, lincomycin, and 134. Oxytetracycline (Foul Brood Mix, Medivet). In: Bennett K, editor. Compen- oxytetracycline disposition in calves with experimental pneumonic pasteu- dium of veterinary products. 4th ed. Hensall, ON: North American Compen- rellosis. J Vet Pharmacol Ther 1986; 9: 213–22. diums Inc., 1995: 324. 107. Hall WF, Kniffen TS, Bane DP, et al. Plasma concentrations of oxytetracycline 135. Doxycycline hyclate package insert (Novo-Doxylin, Novopharm—Canada), in swine after administration of the drug intramuscularly and orally in feed. Rev 3/2/95, Rec 7/18/95. J Am Vet Med Assoc 1989 May; 194(9): 1265–8. 136. Doxycycline hyclate package insert (Doxy 100 & 200, Lymphomed—US), Rev 108. Banting AD, Duval M, Gregoire S. A comparative study of serum kinetics of 5/92, Rec 1/94. oxytetracycline in pigs and calves following intramuscular administration. 137. Pedersoli WM, Jackson JA. Tetracycline, methoxyflurane anesthesia and J Vet Pharmacol Ther 1985; 8: 418–20. severe renal failure in dogs. J Am Anim Hosp Assoc 1973; 9(1): 57–65. 109. Pijpers A, Schoevers EJ, Van Gogh FH, et al. The influence of disease on feed 138. Nyindo MBA, Ristic M, Lewis G, et al. Immune response of ponies to and water consumption and on pharmacokinetics of orally administered experimental infection with Ehrlichia equi. Am J Vet Res 1978; 39(1): oxytetracycline in pigs. J Anim Sci 1991; 69: 2947–54. 15–8. 110. Pijpers A, Schoevers EJ, Haagsma N, et al. Plasma levels of oxytetracycline, 139. Davidson DE, Dill GS, Tingpalapong M, et al. Prophylactic and therapeutic use doxycycline, and minocycline in pigs after oral administration in feed. J Anim of tetracycline during an epizootic among military dogs. J Am Vet Med Assoc Sci 1991; 69: 4512–22. 1978 Mar; 172(6): 697–700. 111. Palmer GH, Bywater RJ, Stanton A. Absorption in calves of amoxicillin, 140. Breitschwerdt EB, Davidson MG, Aucoin DP, et al. Efficacy of chloramphe- ampicillin, and oxytetracycline given in milk replacer, water, or an oral nicol, enrofloxacin, and tetracycline for treatment of experimental Rocky rehydration formulation. Am J Vet Res 1983 Jan; 44(1): 68–71. Mountain spotted fever in dogs. Antimicrob Agents Chemother 1991 Nov; 112. Vivrette S, Cowgil LD, Pascoe J, et al. Hemodialysis for treatment of 35(11): 2375–81. oxytetracycline-induced acute renal failure in a neonatal foal. J Am Vet 141. Greene CE, Burgdorfer W, Caragnolo R, et al. Rocky Mountain spotted fever in Med Assoc 1993 Jul; 203(1): 105–7. dogs and its differentiation from canine ehrlichiosis. J Am Vet Med Assoc 113. Ketterer PJ, Dunster PJ. Failure to eliminate Leptospira pomona from pigs by 1985; 186(5): 465–72. treatment with long acting oxytetracycline. Aust Vet J 1985 Oct; 62(10): 142. Oxytetracycline (TM 50, Pfizer). In: Bennett K, editor. Compendium of 348–9. veterinary products. 4th ed. Port Huron, MI: North American Compendiums 114. USP dictionary of USAN and international drug names, 2002 ed. Rockville, Inc., 1995: 1100–1. MD: The United States Pharmacopeial Convention, Inc., 2002. 143. Chlortetracycline (Fermycin Soluble, Fermenta) In: Bennett K, editor. 115. Chlortetracycline package insert (Aureomycin 50 Granular Type A Medicated Compendium of veterinary products. 4th ed. Port Huron, MI: North American Article, Hoffman LaRoche—US), Rec 6/18/98. Compendiums Inc., 1995: 491. 116. Chlortetracycline package insert (Chlor 50, Bio-Agri-Mix Ltd—Canada), Rec 144. Stevens RD, Dinsmore RP, Cattell MB. Evaluation of the use of intrauterine 8/29/95. infusions of oxytetracycline, subcutaneous injections of fenprostalene, or a 117. Oxytetracycline product literature (Oxytetracycline 50, Pennfield—US), Rev combination of both, for the treatment of retained fetal membranes in dairy 11/95, Rec 11/30/96. cows. J Am Vet Med Assoc 1995 Dec 15; 207(12): 1612–5. 118. Chlortetracycline (Aureomycin Uterine Oblets, Wyeth). In: Compendium of 145. Thurmond MC, Jameson CM, Picanso JP. Effect of intrauterine antimicrobial veterinary products, CD ed. Hensall, Ontario: North American Compendiums treatment in reducing calving-to-conception interval in cows with endome- Inc., 2003. tritis. J Am Vet Med Assoc 1993 Dec 1; 203(11): 1576–8.

146. Heinonen M, Heinonen K. Retained placenta in cattle: the effect of treatment 162. Xia W, Nielsen P, Gyrd-Hansen N. Oxytetracyclines in cattle: a comparison or nontreatment on puerperal diseases and subsequent fertility. Acta Vet between a conventional and a long-acting preparation. Acta Vet Scand 1983; Scand 1989; 30: 425–9. 24: 120–8. 147. Carney HC, England JJ. Feline hemobartonellosis. Vet Clin North Am Small 163. Dersten A, Poitschek C, Rauch S, et al. Effects of penicillin, cetriaxone, and Anim Prac 1993 Jan; 23(1): 79–80. doxycycline on morphology of Borrelia burgdorferi. Antimicrob Agents 148. Bobade PA, Nash AS, Rogerson P. Feline haemobartonellosis: clinical, Chemother 1995 May; 39(5): 1127–33. haematological and pathological studies in natural infections and the 164. Appel MJG. Lyme disease in dogs and cats. Compend Contin Ed Pract Vet relationship to infection with feline leukemia virus. Vet Rec 1988; 122: 32–6. Small Anim 1990 May; 12(5): 617–25. 149. Harvey JW, Gaskin JM. Feline haemobartonellosis: attempts to induce relapses 165. Greene RT. Canine Lyme borreliosis. Vet Clin North Am Small Anim Pract of clinical disease in chronically infected cats. J Am Anim Hosp Assoc 1978; 1991 Jan; 21(1): 51–64. 14: 453–6. 166. Garcia-Delgado GA, Little PB, Barnum DA. A comparison of various 150. Panel comment, Rec 3/1/96. Haemophilus somnus strains. Can J Comp Med 1977 Oct; 41: 380–8. 151. Panel comment, Rec 2/23/96. 167. Griffen DD, Morter RL, Amstutz HE, et al. Experimental oxytetracycline 152. Freedom of Information Summary. NADA 48–761 Aureomycin Type A toxicity in feedlot heifers. Bovine Practitioner 1979; 14: 37–40. Medicated Article. Sponsor: Hoffman-LaRoche. 168. Griffen DD, Amstutz HE, Morter RL, et al. Oxytetracycline toxicity associated 153. Oxytetracycline package insert (Maxim-200, Phoenix—US), Rev 6/94, Rec 2/ with bovine respiratory disease therapy. Bovine Practitioner 1979; 14: 29– 5/96. 35. 154. Papich MG, Wright AK, Patrie L, et al. Pharmacokinetics of oxytetracycline 169. Riond J, Riviere JE. Pharmacology and toxicology of doxycycline. Vet Hum administered intravenously to 4 to 5-day-old foals. J Vet Pharmacol Ther Toxicol 1988 Oct; 30(5): 431–43. 1995; 18: 375–8. 170. Gross DR, Kitzman JV, Adams HR. Cardiovascular effects of intravenous 155. Korsrud GO, Papich MG, Fesser ACE, et al. Residue depletion in tissues and administration of propylene glycol and of oxytetracycline in propylene glycol ﬂuids from swine fed sulfamethazine, chlortetracycline, and penicillin G in in calves. Am J Vet Res 1979; 40: 783–91. combination. Food Addit Contam 1996 Apr; 13(3): 287–92. 171. Panel comment, Rec 3/14/96. 156. Panel comment, Rec 3/5/96. 172. Panel comment, Rec 3/14/96. 157. Kasper CA, Clayton HM, Wright AK, et al. Effects of high doses of 173. Panel comment, Rec 2/5/96. oxytetracycline on metacarpophalangeal joint kinematics in neonatal foals. 174. Xia W, Gyrd-Hansen N, Nielsen P. Comparison of pharmacokinetic param- J Am Vet Med Assoc 1995, Jul 1; 207(1): 71–3. eters for two oxytetracycline preparations in pigs. J Vet Pharmacol Ther 158. Madison JB, Garber JL, Rice B, et al. Effect of oxytetracycline on metacarpo- 1983; 6: 113–20. phalangeal and distal interphalangeal joint angles in newborn foals. J Am Vet 175. Teske RH, Rollins LD, Condon RJ, et al. Serum oxytetracycline concentrations Med Assoc 1994 Jan 15; 204(2): 246–9. after intravenous and intramuscular administration in horses. J Am Vet Med 159. Harvey JW, Gaskin JM. Feline haemobartonellosis. J Am Anim Hosp Assoc Assoc 1973; 162: 119. 1977; 13: 28–38. 176. Panel comment, Rec 3/26/96. 160. Nicoletti P. Further studies on the use of antibiotics in canine brucellosis. 177. Panel consensus, 5/16/96. Compend Contin Educ Pract Vet 1991 Jun; 13(6): 944–7. 178. Panel comment, Rec 5/21/ 96. 161. Smith BP, Biberstein EL. Septicemia and meningoencephalitis in pastured 179. Manufacturer comment, Rec 5/10/96. cattle caused by a Haemophilus-like organism (‘‘Haemophilus somnus’’). 180. Panel comment, Rec 5/24/96. Cornell Vet 1977; 67(3): 327–32.

Indications Index

Note: Both labeled and extra-labeled indications are included in this index Penicillin G, 151 without differentiation. Please consult the individual monograph Tetracyclines, 227 Indications section for US and Canadian product labeling status for Bloat each species and for more information on when use is appropriate. Tetracyclines, 228 This reference does not include every antimicrobial product available; Bone and joint infections (treatment) therefore, it should not be assumed that all medications appropriate for Aminoglycosides, 2 a given indication are listed or that those not listed are inappropriate. Bovine respiratory disease (treatment)—See Pneumonia and Respiratory Because clinical variables play an important role in choice of tract infections antimicrobial treatment, it cannot be assumed that the agents listed Bowel disease, inﬂammatory (treatment) for any indication are interchangeable in a particular situation. Metronidazole, Not estab, 144 Indications may be found under more than one Indications subheading Brucellosis (treatment) (Accepted, Acceptance not established, Unaccepted) when recommended Fluoroquinolones, Not estab, 88 for more than one species or medication within a monograph. Tetracyclines, Not estab, 228 Indications below can be found under the Accepted subheading of the Chlamydial infections (treatment) listed monograph’s Indications section for at least one species unless Fluoroquinolones, Not estab, 88 ‘‘Not estab’’ is stated. ‘‘Not estab’’ signiﬁes a drug monograph in which Macrolides, Not estab, 121 the indication is listed under the Acceptance not established subheading. Rifampin, Not estab, 192 Unaccepted uses have not been indexed. Listing as Accepted, Acceptance Tetracyclines, Not estab, 228 not established, or Unaccepted in a monograph is not meant to signify Chronic respiratory disease (CRD) (prophylaxis) label versus extra-label status. Macrolides, 120 Spectinomycin, 202 Abortion, vibrionic (prophylaxis) Chronic respiratory disease (CRD) (treatment) Tetracyclines, 226 Macrolides, 120 Abscesses, cervical (prophylaxis) Spectinomycin, 202 Tetracyclines, 226 Tetracyclines, 227 Abscesses, hepatic (prophylaxis) Coccidiosis (prophylaxis) Macrolides, 119 Potentiated Sulfonamides, 164 Tetracyclines, 226 Coccidiosis (treatment) Abscesses, laryngeal (treatment) Potentiated Sulfonamides, 164 Lincosamides, Not estab, 110 Potentiated Sulfonamides, Not estab, 166 Actinobacillosis (treatment) Sulfonamides, 207 Tetracyclines, 226 Cold water disease (treatment) Actinomycosis (treatment) Tetracyclines, 228 Penicillin G, 151 Colibacillosis (prophylaxis) Air sacculitis (treatment) Potentiated Sulfonamides, 164 Spectinomycin, 202 Colibacillosis (treatment) Amebiasis, intestinal (treatment) Fluoroquinolones, 87 Metronidazole, Not estab, 144 Potentiated Sulfonamides, 164 Anaplasmosis (treatment) Spectinomycin, 202 Tetracyclines, 226 Spectinomycin, Not estab, 202 Arthritis, bacterial (treatment) Colitis, antibiotic-associated (treatment) Lincosamides, Not estab, 110 Metronidazole, Not estab, 144 Macrolides, 119 Colitis, chronic (treatment) Penicillin G, 151 Macrolides, Not estab, 121 Potentiated Sulfonamides, 165 Colitis, clostridial (treatment) Tetracyclines, 227 Metronidazole, Not estab, 144 Atrophic rhinitis (treatment) Columnaris disease (treatment) Macrolides, 119 Tetracyclines, 228 Tetracyclines, 227 Coryza, infectious (prophylaxis) Bacteremia (treatment) Macrolides, 119 Aminoglycosides, 2 Coryza, infectious (treatment) Balantidiasis, intestinal (treatment) Macrolides, 119 Metronidazole, Not estab, 144 Sulfonamides, 207 Bartonella infections (treatment) Cryptosporidiosis (treatment) Fluoroquinolones, Not estab, 88 Macrolides, Not estab, 121 Blackleg (treatment)

Cystitis (treatment) Tetracyclines, 228 Fluoroquinolones, 87 Escherichia coli infection (treatment) Sulfonamides, 208 Aminoglycosides, 2 Dermatitis, bacterial (treatment) Cephalosporins, 51 Aminopenicillins, 36 Tetracyclines, 226 Diphtheria (treatment) Feed efﬁciency, improved Macrolides, 120 Macrolides, 120 Sulfonamides, 208 Tetracyclines, 226 Tetracyclines, 226 Flexural limb deformities (treatment) Distemper, canine (treatment) Tetracyclines, Not estab, 228 Aminoglycosides, Not estab 3 Foul brood (treatment) Potentiated Sulfonamides, Not estab, 165 Tetracyclines, 226 Dysentery, swine (prophylaxis) Fowl cholera (prophylaxis) Macrolides, 120 Potentiated Sulfonamides, 165 Dysentery, swine (treatment) Tetracyclines, 226 Lincosamides, 109 Fowl cholera (treatment) Macrolides, 120 Fluoroquinolones, 87 Egg hatchability, increased Potentiated Sulfonamides, 165 Tetracyclines, 228 Spectinomycin, 202 Egg production, increased Sulfonamides, 208 Tetracyclines, 228 Tetracyclines, 226 Ehrlichiosis, canine (treatment) Fowl typhoid (treatment) Tetracyclines, Not estab, 228 Sulfonamides, 208 Ehrlichiosis, equine (treatment) Furunculosis (treatment) Tetracyclines, 228 Florfenicol, 81 Encephalopathy, hepatic (treatment) Potentiated Sulfonamides, 165 Metronidazole, Not estab, 144 Tetracyclines, 226 Endometritis (treatment) Gaffkemia (treatment) Metronidazole, Not estab, 144 Tetracyclines, 226 Endophthlalmitits, bacterial (treatment) Gastroenteritis/Gastrointestinal infections, bacterial (treatment) Fluoroquinolones, Not estab, 88 Aminoglycosides, Not estab, 3 Enteric redmouth disease (treatment) Aminopenicillins, 36 Tetracyclines, 228 Potentiated Sulfonamides, 165 Enteric septicemia (treatment) Tetracyclines, 226 Potentiated Sulfonamides, 165 Genitourinary tract infections, bacterial (treatment) Enteritis, bacterial (treatment) Aminopenicillins, 36 Aminoglycosides, 2 Giardiasis (treatment) Macrolides, 120 Metronidazole, 144 Potentiated Sulfonamides, 165 Growth promotion and feed efﬁciency, increased Spectinomycin, 202 Lincosamides, 109 Sulfonamides, 208 Haemobartonella felis infection (treatment) Tetracyclines, 226 Fluoroquinolones, Not estab, 88 Enteritis, Campylobacter (treatment) Tetracyclines, Not estab, 228 Macrolides, 121 Helicobacter species infections (treatment) Enteritis, necrotic (treatment) Metronidazole, Not estab, 144 Lincosamides, 109 Hemorrhagic septicemia, bacterial (treatment) Enterotoxemia (prophylaxis) Tetracyclines, 226 Macrolides, 120 Hexamitiasis (treatment) Enterotoxemia (treatment) Tetracyclines, 226 Tetracyclines, 228 Infections, bacterial (treatment) Equine infectious arthritis (treatment) Aminoglycosides, Not estab, 3 Potentiated Sulfonamides, Not estab, 166 Aminopenicillins, Not estab, 36 Equine protozoal myeloencephalitis (treatment) Cephalosporins, Not estab, 52 Potentiated Sulfonamides, Not estab, 166 Fluoroquinolones, 87 Pyrimethamine, 185 Metronidazole, Not estab, 144 Erysipelas (treatment) Potentiated Sulfonamides, Not estab, 165 Macrolides, 120 Rifampin, Not estab, 191 Penicillin G, 151 Spectinomycin, Not estab, 202

Infectious coryza (prophylaxis) Aminoglycosides, Not estab, 3 Potentiated Sulfonamides, 165 Paracolon (treatment) Joint infections (treatment) Aminoglycosides, 2 Lincosamides, 109 Paratuberculosis (treatment) Keratoconjunctivitis (treatment) Rifampin, Not estab, 192 Florfenicol, 81 Paratyphoid (treatment) Tetracyclines, 226 Spectinomycin, 202 Leptospirosis (treatment) Tetracyclines, 227 Aminoglycosides, Not estab, 3 Pasteurellosis (treatment) Aminopenicillins, Not estab, 36 Fluoroquinolones, Not estab, 88 Macrolides, 120 Periodontal infections (treatment) Penicillin G, 151 Amoxicillin and Clavulanate, 46 Tetracyclines, 226 Lincosamides, 109 Lyme disease (treatment) Metronidazole, Not estab, 144 Tetracyclines, Not estab, 228 Perioperative infections (prophylaxis) Malignant edema (treatment) Cephalosporins, 52 Penicillin G, 151 Potentiated Sulfonamides, 165 Tetracyclines, 227 Peritonitis (treatment) Mastitis (treatment) Tetracyclines, 228 Aminoglycosides, Not estab, 3 Pharyngitis (treatment) Aminopenicillins (Intramammary), 33 Penicillin G, 151 Cephapirin (Intramammary), 71 Pneumonia, bacterial (prophylaxis) Erythromycin (Intramammary), 79 Tetracyclines, 227 Lincosamides, Not estab, 110 Pneumonia, bacterial (treatment) Macrolides, Not estab, 121 Aminopenicillins, 36 Penicillin G (Intramammary), 149 Florfenicol, 81 Pirlimycin (Intramammary), 161 Fluoroquinolones, 87 Potentiated Sulfonamides, 165 Lincosamides, 109 Tetracyclines, 228 Macrolides, 120 Meningitis, bacterial (treatment) Penicillin G, 151 Fluoroquinolones, Not estab, 88 Potentiated Sulfonamides, 165 Potentiated Sulfonamides, Not estab, 166 Potentiated Sulfonamides, Not estab, 166 Metritis (treatment) Spectinomycin, 202 Cephalosporins, 51 Sulfonamides, 208 Lincosamides, 109 Tetracyclines, 227 Macrolides, 120 Pneumonia, Rhodococcus equi (treatment) Penicillin G, 151 Macrolides, 120 Potentiated Sulfonamides, 165 Macrolides, Not estab, 121 Mycobacterial infections (treatment) Rifampin, 191 Fluoroquinolones, Not estab, 88 Pneumonitis (treatment) Mycoplasmal infections (treatment) Aminoglycosides, Not estab, 3 Fluoroquinolones, Not estab, 88 Pododermatitis (prophylaxis) Neospora caninum infection (treatment) Tetracyclines, 228 Pyrimethamine, Not estab, 185 Pododermatitis (treatment) New duck disease (treatment) Aminopenicillins, 36 Potentiated Sulfonamides, 165 Cephalosporins, 51 Nocardiosis (treatment) Florfenicol, 81 Potentiated Sulfonamides, Not estab, 166 Macrolides, 120 Omphalophlebitis (treatment) Potentiated Sulfonamides, 165 Tetracyclines, 228 Sulfonamides, 208 Osteomyelitis (treatment) Tetracyclines, 227 Amoxicillin and Clavulanate, Not estab, 46 Potomac horse fever (treatment) Lincosamides, 109 Rifampin, Not estab, 192 Otitis media (treatment) Tetracyclines, 228 Aminoglycosides, Not estab, 3 Proliferative enteropathy, porcine (prophylaxis and treatment) Pancreatitis (treatment) Lincosamides, 109 Aminoglycosides, Not estab, 3 Macrolides, 120 Panleukopenia (treatment) Prostate infection (treatment)

Potentiated Sulfonamides, Not estab, 166 Lincosamides, 109 Protozoal infections (treatment) Penicillin G, 151 Potentiated Sulfonamides, Not estab, 166 Potentiated Sulfonamides, 165 Pseudomonas aeruginosa infection (treatment) Sulfonamides, 209 Aminoglycosides, 2 Tetracyclines, 227 Pseudomonas disease (treatment) Strangles (treatment) Tetracyclines, 227 Aminopenicillins, 36 Psittacosis (treatment) Penicillin G, 151 Tetracyclines, 227 Potentiated Sulfonamides, 165 Pullorum disease (treatment) Swine dysentery (treatment) Sulfonamides, 208 Aminoglycosides, 3 Pyelonephritis (treatment) Synovitis, infectious (prophylaxis) Penicillin G, 151 Macrolides, 121 Pyoderma (treatment) Spectinomycin, 202 Macrolides, 121 Synovitis, infectious (treatment) Respiratory disease, bacterial, chronic (prophylaxis) Spectinomycin, 202 Tetracyclines, 227 Tetracyclines, 227 Respiratory tract infections, bacterial (treatment) Tetanus (treatment) Aminoglycosides, 3 Penicillin G, 151 Cephalosporins, 51 Thromboembolic meningoencephalitis (treatment) Fluoroquinolones, 87 Tetracyclines, Not estab, 228 Lincosamides, 109 Tonsillitis, bacterial (treatment) Macrolides, 120 Aminopenicillins, 36 Potentiated Sulfonamides, 165 Toxoplasmosis (treatment) Sulfonamides, 209 Lincosamides, Not estab, 110 Tetracyclines, Not estab, 228 Pyrimethamine, Not estab, 185 Rhinitis (treatment) Tracheobronchitis, bacterial (treatment) Penicillin G, 151 Aminopenicillins, 36 Rocky Mountain spotted fever Trichomoniasis, intestinal (treatment) Macrolides, Not estab, 121 Metronidazole, Not estab, 144 Tetracyclines, 228 Ulcer disease (treatment) Salmonella infantis infection (treatment) Tetracyclines, 227 Spectinomycin, 202 Upper respiratory tract infections (treatment) Salmonella typhimurium infection (treatment) Aminopenicillins, 36 Aminoglycosides, 2 Urinary tract infections, bacterial (treatment) Septicemia (treatment) Aminoglycosides, 3 Aminoglycosides, 2 Amoxicillin and Clavulanate, 46 Potentiated Sulfonamides, 165 Cephalosporins, 52 Sinusitis, infectious (prophylaxis) Potentiated Sulfonamides, 165 Tetracyclines, 228 Tetracyclines, 227 Sinusitis, infectious (treatment) Urogenital tract infections (treatment) Macrolides, 121 Potentiated Sulfonamides, 165 Tetracyclines, 228 Uterine infections, bacterial (treatment) Skeletal tissue marking Aminoglycosides, 3 Tetracyclines, 227 Tetracyclines, 227 Skin and soft tissue infections (treatment) Tetracyclines, Not estab, 229 Aminoglycosides, 3 Vibrio anguillarum infection Aminopenicillins, 36 Potentiated Sulfonamides, 165 Amoxicillin and Clavulanate, 46 Weight gain, increased rate Cephalosporins, 52 Macrolides, 120 Fluoroquinolones, 87 Tetracyclines, 226

Dosing Index

Note: Both labeled and extra-labeled dosage recommendations are included in Cats, dogs this index without differentiation. Please consult the individual mono- Cefadroxil For Oral Suspension, 57 graph for US and Canadian product labeling status for each species and Cefadroxil Tablets, 57 for more information on when use is appropriate. Cefazolin—Included in Cephalosporins (Veterinary—Systemic), 51 Dogs Amikacin—Included in Aminoglycosides (Veterinary—Systemic), 1 Cefazolin For Injection, 58 Cats, dogs, calves, donkeys, foals, goats, guinea pigs, hawks, parrots, ponies, Cefazolin Injection, 58 pythons, snakes, tortoises Cefixime—Included in Cephalosporins (Veterinary—Systemic), 51 Amikacin Sulfate Injection, 14 Dogs Horses Cefixime For Oral Suspension, 59 Amikacin Sulfate Injection, 14 Cefixime Tablets, 59 Amikacin Sulfate Uterine Solution, 13 Cefotaxime—Included in Cephalosporins (Veterinary—Systemic), Amoxicillin— 51 Included in Aminopenicillins (Veterinary—Intramammary-Local), Cats, dogs, foals 33 Cefotaxime For Injection, 60 Cows Cefotaxime Injection, 60 Amoxicillin Intramammary Infusion, 34 Cefotetan—Included in Cephalosporins (Veterinary—Systemic), 51 Included in Aminopenicillins (Veterinary—Systemic), 36 Dogs Calves Cefotetan For Injection, 60 Amoxicillin Tablets, 40 Cefoxitin—Included in Cephalosporins (Veterinary—Systemic), 51 Cats, dogs Dogs, horses Amoxicillin For Injectable Suspension, 41 Cefoxitin For Injection, 61 Amoxicillin For Oral Suspension, 40 Cefoxitin Injection, 61 Amoxicillin Tablets, 40 Ceftiofur—Included in Cephalosporins (Veterinary—Systemic), 51 Cattle Cattle, pigs Amoxicillin For Injectable Suspension, 41 Ceftiofur Hydrochloride Injection, 62 Amoxicillin and Clavulanate—Included in Amoxicillin and Clavu- Ceftiofur Sodium For Injection, 62 lanate (Veterinary—Systemic), 46 Chicks, dogs, goats, horses, sheep, turkey poults Cats, dogs Ceftiofur Sodium For Injection, 62 Amoxicillin and Clavulanate Potassium For Oral Suspension, 48 Cephalexin—Included in Cephalosporins (Veterinary—Systemic), Amoxicillin and Clavulanate Potassium Tablets, 49 51 Ampicillin—Included in Aminopenicillins (Veterinary—Systemic), Birds, dogs 36 Cephalexin Capsules, 63 Calves, cattle Cephalexin For Oral Suspension, 64 Ampicillin For Injectable Suspension, 42 Cephalexin Hydrochloride Tablets, 64 Cats, dogs Cephalexin Tablets, 64 Ampicillin Capsules, 42 Cephalothin—Included in Cephalosporins (Veterinary—Systemic), Ampicillin For Injectable Suspension, 42 51 Ampicillin For Injection, 43 Birds, dogs, horses Horses Cephalothin For Injection, 65 Ampicillin For Injection, 43 Cephapirin— Apramycin—Included in Aminoglycosides (Veterinary—Systemic), Included in Cephalosporins (Veterinary—Systemic), 51 1 Dogs, horses Pigs Cephapirin For Injection, 66 Apramycin Sulfate Powder For Oral Solution, 15 In Cephapirin (Veterinary—Intramammary-Local), 71 Azithromycin—Included in Macrolides (Veterinary—Systemic), Cows 119 Cephapirin Benzathine Intramammary Infusion, 72 Cats, dogs, foals Cephapirin Sodium Intramammary Infusion, 72 Azithromycin For Oral Suspension, 128 Cephradine— Azithromycin Tablets, 128 Included in Cephalosporins (Veterinary—Systemic), 51 Cefaclor—Included in Cephalosporins (Veterinary—Systemic), 51 Dogs, foals Dogs Cephradine Capsules, 66 Cefaclor Capsules, 56 Cephradine For Oral Suspension, 66 Cefaclor For Oral Suspension, 57 Chloramphenicol—In Chloramphenicol (Veterinary—Systemic), Cefadroxil—Included in Cephalosporins (Veterinary—Systemic), 74 51

Cats, dogs Dogs Chloramphenicol Capsules, 76 Doxycycline For Injection, 240 Chloramphenicol Palmitate Oral Suspension, 76 Enrofloxacin—Included in Fluoroquinolones (Veterinary—Syste- Chloramphenicol Sodium Succinate For Injection, 77 mic),87 Chloramphenicol Tablets, 77 Bustards, cats, dogs, ducks, horses, pacu, parrots, rabbits Horses Enrofloxacin Injection, 100 Chloramphenicol Capsules, 76 Enrofloxacin Tablets, 99 Chloramphenicol Sodium Succinate For Injection, 77 Camels, cattle, emus, llamas, oryx, potbellied and minature pigs, pythons, Chloramphenicol Tablets, 77 sheep Chlortetracycline—Included in Tetracyclines (Veterinary—Syste- Enrofloxacin Injection, 100 mic), 225 Chickens, turkeys Calves, chickens, pigs, turkeys Enrofloxacin Oral Solution, 99 Chlortetracycline For Medicated Feed, 237 Foals Chlortetracycline Hydrochloride Soluble Powder, 236 Enrofloxacin Tablets, 99 Cattle Erythromycin— Chlortetracycline For Medicated Feed, 237 Included in Erythromycin (Veterinary—Intramammary-Local), 79 Chlortetracycline Uterine Tablets, 236 Cows Cockatoos, ducks, lambs, macaws, parrots, sheep Erythromycin Intramammary Infusion, 80 Chlortetracycline For Medicated Feed, 237 Included in Macrolides (Veterinary—Systemic), 119 Ewes, sows Dogs Chlortetracycline Uterine Tablets, 236 Erythromycin Tablets, 130 Ciprofloxacin—Included in Fluoroquinolones (Veterinary—Syste- Cattle, lambs, pigs, piglets, sheep mic), 87 Erythromycin Injection, 131 Dogs Erythromycin Estolate—Included in Macrolides (Veterinary—Sys- Ciprofloxacin For Oral Suspension, 97 temic), 119 Ciprofloxacin Injection, 97 Foals Ciprofloxacin Tablets, 97 Erythromycin Estolate Capsules, 132 Horses Erythromycin Estolate Oral Suspension, 132 Ciprofloxacin For Oral Suspension, 97 Erythromycin Estolate Tablets, 132 Ciprofloxacin Tablets, 97 Erythromycin Gluceptate—Included in Macrolides (Veterinary— Clarithromycin—Included in Macrolides (Veterinary—Systemic), Systemic), 119 119 Foals Dogs Sterile Erythromycin Gluceptate, 134 Clarithromycin For Oral Suspension, 129 Erythromycin Phosphate—Included in Macrolides (Veterinary— Clarithromycin Tablets, 129 Systemic), 119 Clindamycin—Included in Lincosamides (Veterinary—Systemic), Chickens, turkeys 109 Erythromycin Phosphate Powder For Oral Solution, 135 Cats Erythromycin Stearate—Included in Macrolides (Veterinary—Sys- Clindamycin Hydrochloride Oral Solution, 114 temic), 119 Dogs Dogs Clindamycin Hydrochloride Capsules, 114 Erythromycin Stearate Oral Suspension, 135 Clindamycin Hydrochloride Oral Solution, 114 Erythromycin Stearate Tablets, 136 Difloxacin—Included in Fluoroquinolones (Veterinary—Systemic), Erythromycin Thiocyanate—Included in Macrolides (Veterinary— 87 Systemic), 119 Dogs Chickens, turkeys Difloxacin Hydrochloride Tablets, 98 Erythromycin Thiocyanate For Medicated Feed, 136 Dihydrostreptomycin—Included in Aminoglycosides (Veterinary Florfenicol—In Florfenicol (Veterinary—Systemic), 81 —Systemic), 1 Cattle Cattle, dogs, pigs Florfenicol Injection, 84 Dihydrostreptomycin Injection, 15 Salmon Doxycycline—Included in Tetracyclines (Veterinary—Systemic), Florfenicol For Medicated Feed, 84 225 Gentamicin—Included in Aminoglycosides (Veterinary—Systemic), Cats, dogs 1 Doxycycline Calcium Oral Suspension, 239 Cats, chicks, dogs, baboons, buffalo calves, budgerigars, calves, cattle, eagles, Doxycycline For Oral Suspension, 239 foals, goats, hawks, llamas, owls, pythons, turkey poults Doxycycline Hyclate Capsules, 239 Gentamicin Injection, 17 Doxycycline Hyclate Tablets, 240 Horses

Gentamicin Injection, 17 Dogs Gentamicin Uterine Infusion, 16 Ormetoprim and Sulfadimethoxine Tablets, 176 Pigs Oxytetracycline—Included in Tetracyclines (Veterinary—Syste- Gentamicin Injection, 17 mic), 225 Gentamicin Oral Solution, 16 Bees Gentamicin Powder For Oral Solution, 17 Oxytetracycline For Medicated Feed, 243 Hetacillin—Included in Aminopenicillins (Veterinary—Intramam- Oxytetracycline Hydrochloride Soluble Powder, 241 mary-Local), 33 Calves Cows Oxytetracycline For Medicated Feed, 243 Hetacillin Potassium Intramammary Infusion, 34 Oxytetracycline Hydrochloride Soluble Powder, 241 Kanamycin—Included in Aminoglycosides (Veterinary—Systemic), Oxytetracycline Tablets, 245 1 Catfish, lobsters, salmon, salmonids Cats, dogs Oxytetracycline For Medicated Feed, 243 Kanamycin Injection, 19 Cattle Lincomycin—Included in Lincosamides (Veterinary—Systemic), Oxytetracycline For Medicated Feed, 243 109 Oxytetracycline Hydrochloride Soluble Powder, 241 Cats and dogs Oxytetracycline Hydrochloride Uterine Suspension, 241 Lincomycin Hydrochloride Syrup, 116 Oxytetracycline Injection, 245 Lincomycin Hydrochloride Tablets, 116 Oxytetracycline Injection (Long-Acting), 246 Lincomycin Injection, 116 Chickens, turkeys Cattle Oxytetracycline For Medicated Feed, 243 Lincomycin Injection, 116 Oxytetracycline Hydrochloride Soluble Powder, 241 Chickens Horses Lincomycin Hydrochloride For Medicated Feed, 115 Oxytetracycline Injection, 245 Lincomycin Hydrochloride Soluble Powder, 115 Lambs Pigs Oxytetracycline For Medicated Feed, 243 Lincomycin Hydrochloride For Medicated Feed, 115 Pigs Lincomycin Hydrochloride Soluble Powder, 115 Oxytetracycline For Medicated Feed, 243 Sheep Oxytetracycline Hydrochloride Soluble Powder, 241 Lincomycin Injection, 116 Oxytetracycline Injection, 245 Marbofloxacin—Included in Fluoroquinolones (Veterinary—Syste- Oxytetracycline Injection (Long-Acting), 246 mic),87 Sheep Cats, dogs Oxytetracycline For Medicated Feed, 243 Marbofloxacin Tablets, 101 Oxytetracycline Hydrochloride Soluble Powder, 241 Metronidazole—In Metronidazole (Veterinary—Systemic), 144 Oxytetracycline Injection, 245 Cats, dogs, horses Sows Metronidazole Capsules, 146 Oxytetracycline Injection, 245 Metronidazole Injection, 147 Oxytetracycline Injection (Long-Acting), 246 Metronidazole Hydrochloride For Injection, 147 Penicillin G— Metronidazole Tablets, 146 Included in Penicillin G (Veterinary—Intramammary-Local), 149 Neomycin—Included in Aminoglycosides (Veterinary—Systemic), 1 Cows Cattle, goats, pigs, and sheep Penicillin G Procaine Intramammary Infusion, 150 Neomycin Sulfate For Medicated Feed, 19 Included in Penicillin G (Veterinary—Systemic), 151 Neomycin Sulfate Oral Solution, 19 Cats, dogs, horses Neomycin Sulfate Powder For Oral Solution, 20 Penicillin G Potassium For Injection, 156 Horses Penicillin G Procaine Injectable Suspension, 156 Neomycin Sulfate Oral Solution, 19 Penicillin G Sodium For Injection, 157 Neomycin Sulfate Powder For Oral Solution, 20 Cattle, pigs, sheep Turkeys Penicillin G Procaine Injectable Suspension, 156 Neomycin Sulfate Powder For Oral Solution, 20 Turkeys Orbifloxacin—Included in Fluoroquinolones (Veterinary—Syste- Penicillin G Potassium For Oral Solution, 154 mic),87 Pirlimycin—In Pirlimycin (Veterinary—Intramammary-Local), Cats, dogs, horses 161 Orbifloxacin Tablets, 102 Cows Ormetoprim and Sulfadimethoxine—Included in Potentiated Sul- Pirlimycin Intramammary Infusion, 162 fonamides (Veterinary—Systemic), 164 Pyrimethamine—In Pyrimethamine (Veterinary—Systemic), 185 Catfish, chickens, ducks, partridges, salmon, trout, turkeys Cats, dogs, horses Ormetoprim and Sulfadimethoxine For Medicated Feed, 175 Pyrimethamine Tablets, 188

Pyrimethamine and Sulfaquinoxaline—Included in Potentiated Sulfadoxine and Trimethoprim—Included in Potentiated Sulfona- Sulfonamides (Veterinary—Systemic), 164 mides (Veterinary—Systemic), 164 Chickens, turkeys Cattle, pigs Pyrimethamine and Sulfaquinoxaline Oral Solution, 177 Sulfadoxine and Trimethoprim Injection, 180 Rifampin—In Rifampin (Veterinary—Systemic), 191 Sulfamethazine—Included in Sulfonamides (Veterinary—Syste- Cattle, dogs, foals, goats, horses, sheep mic), 207 Rifampin Capsules, 198 Calves, cattle Spectinomycin—In Spectinomycin (Veterinary—Systemic), 202 Sulfamethazine Extended-Release Tablets, 220 Cattle Sulfamethazine Oral Solution, 218 Spectinomycin Sulfate Injection, 206 Sulfamethazine Powder For Oral Solution, 219 Chicks, ducklings, pigs, turkeys, turkey poults Sulfamethazine Tablets, 219 Spectinomycin Hydrochloride Injection, 205 Chickens, turkeys Chickens Sulfamethazine Oral Solution, 218 Spectinomycin Hydrochloride Powder For Oral Solution, 204 Sulfamethazine Powder For Oral Solution, 219 Piglets Foals Spectinomycin Hydrochloride Oral Solution, 204 Sulfamethazine Tablets, 219 Streptomycin—Included in Aminoglycosides (Veterinary—Syste- Pigs mic), 1 Sulfamethazine Oral Solution, 218 Calves, chickens, pigs Sulfamethazine Powder For Oral Solution, 219 Streptomycin Sulfate Oral Solution, 21 Sheep Sulfachlorpyridazine—Included in Sulfonamides (Veterinary—Sys- Sulfamethazine Oral Solution, 218 temic), 207 Sulfamethazine, Sulfanilamide, and Sulfathiazole—Included in Calves Sulfonamides (Veterinary—Systemic), 207 Sulfachlorpyridazine Injection, 215 Cattle Sulfachlorpyridazine Powder For Oral Solution, 215 Sulfamethazine, Sulfanilamide, and Sulfathiazole Tablets, 220 Sulfachlorpyridazine Tablets, 215 Sulfamethazine and Sulfathiazole—Included in Sulfonamides Pigs (Veterinary—Systemic), 207 Sulfachlorpyridazine Powder For Oral Solution, 215 Cattle, pigs Sulfadiazine and Trimethoprim—Included in Potentiated Sulfona- Sulfamethazine and Sulfathiazole Powder For Oral Solution, 221 mides (Veterinary—Systemic), 164 Sulfamethoxazole and Trimethoprim—Included in Potentiated Calves Sulfonamides (Veterinary—Systemic), 164 Sulfadiazine and Trimethoprim Tablets, 178 Dogs Cats, dogs Sulfamethoxazole and Trimethoprim Oral Suspension, 180 Sulfadiazine and Trimethoprim Injection, 179 Sulfamethoxazole and Trimethoprim Tablets, 180 Sulfadiazine and Trimethoprim Tablets, 178 Foals Horses Sulfamethoxazole and Trimethoprim Injection, 181 Sulfadiazine and Trimethoprim Injection, 179 Horses Sulfadiazine and Trimethoprim Oral Paste, 177 Sulfamethoxazole and Trimethoprim Injection, 181 Sulfadiazine and Trimethoprim Oral Powder, 177 Sulfamethoxazole and Trimethoprim Oral Suspension, 180 Piglets Sulfamethoxazole and Trimethoprim Tablets, 180 Sulfadiazine and Trimethoprim Oral Suspension, 178 Sulfaquinoxaline—Included in Sulfonamides (Veterinary—Syste- Salmon mic), 207 Sulfadiazine and Trimethoprim Oral Powder, 177 Calves, cattle, chickens, turkeys Sulfadimethoxine—Included in Sulfonamides (Veterinary—Syste- Sulfaquinoxaline Oral Solution, 221 mic), 207 Tetracycline—Included in Tetracyclines (Veterinary—Systemic), Calves, cattle 225 Sulfadimethoxine Extended-Release Tablets, 217 Calves Sulfadimethoxine Injection, 218 Tetracycline Boluses, 247 Sulfadimethoxine Oral Solution, 216 Tetracycline Hydrochloride Soluble Powder, 248 Sulfadimethoxine Soluble Powder, 216 Cats Sulfadimethoxine Tablets, 217 Tetracycline Oral Suspension, 249 Cats, dogs Chickens, pigs, sheep, turkeys Sulfadimethoxine Injection, 218 Tetracycline Hydrochloride Soluble Powder, 248 Sulfadimethoxine Oral Suspension, 216 Cows, mares Sulfadimethoxine Tablets, 217 Tetracycline Uterine Tablets, 247 Chickens, turkeys Dogs Sulfadimethoxine Oral Solution, 216 Tetracycline Hydrochloride Capsules, 248 Sulfadimethoxine Soluble Powder, 216 Tetracycline Oral Suspension, 249

Tilmicosin—Included in Macrolides (Veterinary—Systemic), 119 Tylosin Tartrate—Included in Macrolides (Veterinary—Systemic), Calves, cattle, and lambs 119 Tilmicosin Injection, 137 Chickens, dogs, pigs, turkeys Pigs Tylosin Tartrate Powder For Oral Solution, 139 Tilmicosin For Medicated Feed, 137 Withdrawal times, extra-label Tylosin Base—Included in Macrolides (Veterinary—Systemic), Note: Label and extra-label withdrawal recommendations can be found 119 in the Withdrawal times section for each dosage form. Cats, cattle, dogs, pigs Amoxicillin Tablets, 41 Tylosin Injection, 138 Lincomycin Injection, 116 Tylosin Phosphate—Included in Macrolides (Veterinary—Syste- Oxytetracycline Injection (Long-Acting), 246 mic), 119 Penicillin G Procaine Injectable Suspension, 156 Cattle, chickens, pigs Spectinomycin Hydrochloride Injection, 205 Tylosin Granulated, 138 Sulfadiazine and Trimethoprim Tablets, 178

Veterinary Brand and Generic Name Index

Note: Includes both United States and Canadian products. Chlortetracycline Hydrochloride Soluble Powder, 236 Clindamycin Hydrochloride Oral Solution, 114 Adspec Sterile Solution—Spectinomycin Sulfate Injection, 206 Gentamicin Injection, 17 Agri-cillin—Penicillin G Procaine Injectable Suspension, 156 Gentamicin Oral Solution, 16 Agrimycin 100—Oxytetracycline Injection, 245 Gentamicin Uterine Infusion, 16 Agrimycin 200—Oxytetracycline Injection (Long-Acting), 246 Neomycin Sulfate Oral Solution, 19 Agrimycin-343—Oxytetracycline Hydrochloride Soluble Powder, 241 Oxytetracycline Hydrochloride Soluble Powder, 241 Alamycin LA—Oxytetracycline Injection (Long-Acting), 246 Oxytetracycline Injection, 245 Albon Boluses—Sulfadimethoxine Tablets, 217 Oxytetracycline Injection (Long-Acting), 246 Albon 12.5% Concentrated Solution—Sulfadimethoxine Oral Solution, 216 Spectinomycin Hydrochloride Oral Solution, 204 Albon Injection 40%—Sulfadimethoxine Injection, 218 Sulfadimethoxine Injection, 218 Albon Oral Suspension 5%—Sulfadimethoxine Oral Suspension, 216 Sulfadimethoxine Oral Solution, 216 Albon SR—Sulfadimethoxine Extended-Release Tablets, 217 Sulfadimethoxine Soluble Powder, 216 Albon Tablets—Sulfadimethoxine Tablets, 217 Tetracycline Hydrochloride Soluble Powder, 248 Ambi-pen—Penicillin G Benzathine and Penicillin G Procaine Injectable Antirobe—Clindamycin Hydrochloride Capsules, 114 Suspension, 155 Antirobe Aquadrops—Clindamycin Hydrochloride Oral Solution, 114 Amifuse E—Amikacin Sulfate Uterine Solution, 13 Apralan—Apramycin Sulfate Powder For Oral Solution, 15 Amiglyde-V—Amikacin Sulfate Uterine Solution, 13 Apralan Soluble—Apramycin Sulfate Powder For Oral Solution, 15 Amiglyde-V Injection—Amikacin Sulfate Injection, 14 Apramycin (Apralan; Apralan Soluble) Amiglyde-V Intrauterine Solution—Amikacin Sulfate Uterine Solution, 13 See Aminoglycosides (Veterinary—Systemic), 1 Amiject D—Amikacin Sulfate Injection, 14 Powder For Oral Solution, 15 Amikacin C Injection—Amikacin Sulfate Injection, 14 Aquacillin—Penicillin G Procaine Injectable Suspension, 156 Amikacin E Solution—Amikacin Sulfate Uterine Solution, 13 Aquaflor—Florfenicol For Medicated Feed, 84 Amikacin (Amifuse E; Amiglyde-V; Amiglyde-V Injection; Amiglyde-V Aureomycin 110G, Aureomycin 220G—Chlortetracycline For Medicated Intrauterine Solution; Amiject D; Amikacin C Injection; Amikacin E Feed, 237 Solution; AmTech AmiMax C Injection; AmTech AmiMax E Solution; Aureomycin 50 Granular, Aureomycin 90 Granular, Aureomycin 100 CaniGlide; Equi-Phar EquiGlide) Granular—Chlortetracycline For Medicated Feed, 237 See Aminoglycosides (Veterinary—Systemic), 1 Aureomycin Soluble Powder—Chlortetracycline Hydrochloride Soluble Injection, 14 Powder, 236 Uterine Solution, 13 Aureomycin Soluble Powder Concentrate—Chlortetracycline Hydrochloride Amoxicillin (Amoxi-Drop; Amoxi-Inject; Amoxil Tablets; Amoxi-Tabs; Soluble Powder, 236 Biomox Oral Suspension; Biomox Tablets; Moxilean-50 Suspension; Aureomycin Uterine Oblets—Chlortetracycline Uterine Tablets, 236 Robamox-V Oral Suspension; Robamox-V Tablets) Azramycine S125, Azramycine S250—Chloramphenicol Palmitate Oral See Aminopenicillins (Veterinary—Systemic), 36 Suspension, 76 For Injectable Suspension, 41 Baytril 3.23% Concentrate Solution—Enrofloxacin Oral Solution, 99 For Oral Suspension, 40 Baytril Injectable Solution—Enrofloxacin Injection, 100 Tablets, 40 Baytril Injectable Solution 2.27%—Enrofloxacin Injection, 100 Amoxicillin, Intramammary (Amoxi-Mast) Baytril 100 Injectable Solution—Enrofloxacin Injection, 100 See Aminopenicillins (Veterinary—Intramammary-Local), 33 Baytril Tablets—Enrofloxacin Tablets, 99 Intramammary Infusion, 34 Baytril Taste Tabs—Enrofloxacin Tablets, 99 Amoxicillin and Clavulanate (Clavamox) Benzapro—Penicillin G Benzathine and Penicillin G Procaine Injectable See Amoxicillin and Clavulanate (Veterinary—Systemic), 46 Suspension, 155 For Oral Suspension, 48 Bimotrim—Sulfadoxine and Trimethoprim Injection, 180 Tablets, 49 Biomox Oral Suspension—Amoxicillin For Oral Suspension, 40 Amoxi-Drop—Amoxicillin For Oral Suspension, 40 Biomox Tablets—Amoxicillin Tablets, 40 Amoxi-Inject—Amoxicillin For Injectable Suspension, 41 Biomycin 200—Oxytetracycline Injection (Long-Acting), 246 Amoxi-Mast—Amoxicillin Intramammary Infusion, 34 Biosol Liquid—Neomycin Sulfate Oral Solution, 19 Amoxil Tablets—Amoxicillin Tablets, 40 Borgal—Sulfadoxine and Trimethoprim Injection, 180 Amoxi-Tabs—Amoxicillin Tablets, 40 Bovispec Sterile Solution—Spectinomycin Sulfate Injection, 206 Amphicol Film-coated Tablets—Chloramphenicol Tablets, 77 Calf Scour Bolus Antibiotic—Tetracycline Boluses, 247 Ampicillin (Polyflex) Calfspan—Sulfamethazine Extended-Release Tablets, 220 See Aminopenicillins (Veterinary—Systemic), 36 CaniGlide—Amikacin Sulfate Injection, 14 For Injectable Suspension, 42 Cefa-Dri—Cephapirin Benzathine Intramammary Infusion, 72 AmTech Cefa-Drops—Cefadroxil For Oral Suspension, 57 Amikacin Sulfate Injection, 14 Cefadroxil (Cefa-Drops; Cefa-Tabs) Amikacin Sulfate Uterine Solution, 13

See Cephalosporins (Veterinary—Systemic), 51 CTC Soluble Powder Concentrate—Chlortetracycline Hydrochloride Soluble For Oral Suspension, 57 Powder, 236 Tablets, 57 Depocillin—Penicillin G Procaine Injectable Suspension, 156 Cefa-Lak—Cephapirin Sodium Intramammary Infusion, 72 Derapen SQ/LA—Penicillin G Procaine Injectable Suspension, 156 Cefa-Tabs—Cefadroxil Tablets, 57 Dicural Tablets—Difloxacin Hydrochloride Tablets, 98 Ceftiofur (Excenel; Excenel RTU; Naxcel) Difloxacin (Dicural Tablets) See Cephalosporins (Veterinary—Systemic), 51 See Fluoroquinolones (Veterinary—Systemic), 87 Ceftiofur Hydrochloride Injection, 62 Tablets, 98 Ceftiofur Sodium For Injection, 62 Dihydrostreptomycin (Ethamycin)— Cephapirin (Cefa-Dri; Cefa-Lak; ToDay; ToMorrow) See Aminoglycosides (Veterinary—Systemic), 1 See Cephapirin (Veterinary—Intramammary-Local), 71 Injection, 15 Cephapirin Benzathine Intramammary Infusion, 72 Di-Methox Injection-40%—Sulfadimethoxine Injection, 218 Cephapirin Sodium Intramammary Infusion, 72 Di-Methox 12.5% Oral Solution—Sulfadimethoxine Oral Solution, 216 Chlor 50, Chlor 100—Chlortetracycline For Medicated Feed, 237 Di-Methox Soluble Powder—Sulfadimethoxine Soluble Powder, 216 Chlor 100, Chlor 250, Chlor 500, Chlor 1000—Chloramphenicol Tablets, Duo-Pen—Penicillin G Benzathine and Penicillin G Procaine Injectable 77 Suspension, 155 Chloramphenicol (Amphicol Film-Coated Tablets; Azramycine S125; Duplocillin LA—Penicillin G Benzathine and Penicillin G Procaine Azramycine S250; Chlor 100; Chlor 250; Chlor 500; Chlor 1000; Chlor Injectable Suspension, 155 Palm 125; Chlor Palm 250; Duricol; Karomycin Palmitate 125; Duramycin 10—Tetracycline Hydrochloride Soluble Powder, 248 Karomycin Palmitate 250; Viceton) Duramycin 72-200—Oxytetracycline Injection (Long-Acting), 246 See Chloramphenicol (Veterinary—Systemic), 74 Duramycin 100—Oxytetracycline Injection, 245 Capsules, 76 Duramycin-324—Tetracycline Hydrochloride Soluble Powder, 248 Oral Suspension, 76 Durapen—Penicillin G Benzathine and Penicillin G Procaine Injectable Tablets, 76 Suspension, 155 ChlorMax 50—Chlortetracycline For Medicated Feed, 237 Duricol—Chloramphenicol Capsules, 76 Chlorosol-50—Chlortetracycline For Medicated Feed, 237 Enrofloxacin (Baytril 3.23% Concentrate Solution; Baytril Injectable Chlor Palm 125, Chlor Palm 250—Chloramphenicol Palmitate Oral Solution; Baytril Injectable Solution 2.27%; Baytril 100 Injectable Suspension, 76 Solution; Baytril Tablets; Baytril Taste Tabs) Chlortetracycline (AmTech Chlortetracycline HCL Soluble Powder; See Fluoroquinolones (Veterinary—Systemic), 87 Aureomycin 110G; Aureomycin 220G; Aureomycin 50 Granular; Injection, 100 Aureomycin 90 Granular; Aureomycin 100 Granular; Aureomycin Soluble Oral Solution, 99 Powder; Aureomycin Soluble Powder Concentrate; Aureomycin Uterine Tablets, 99 Oblets; Chlor 50; Chlor 100; ChlorMax 50; Chlorosol-50; CLTC 100 MR; Equi-Phar EquiGlide—Amikacin Sulfate Uterine Solution, 13 CTC 50; CTC Soluble Powder Concentrate; Pennchlor 50ÆG; Pennchlor Erymycin-100—Erythromycin Thiocyanate For Medicated Feed, 136 90ÆG; Pennchlor 100 Hi-Flo Meal; Pennchlor 50 Meal; Pennchlor 70 Erythro-36—Erythromycin Intramammary Infusion, 80 Meal; Pennchlor 100 MR; Pennchlor 64 Soluble Powder) Erythro-200—Erythromycin Injection, 131 See Tetracyclines (Veterinary—Systemic), 225 Erythro-Dry Cow—Erythromycin Intramammary Infusion, 80 For Medicated Feed, 237 Erythromycin Base (Erythro-200; Gallimycin-100; Gallimycin-200) Soluble Powder, 236 See Macrolides (Veterinary—Systemic), 119 Uterine Tablets, 236 Injection, 131 Clavamox— Erythromycin, Intramammary (Erythro-36; Erythro-Dry Cow; Galli- Amoxicillin and Clavulanate Potassium For Oral Suspension, 48 mycin-36; Gallimycin-Dry Cow) Amoxicillin and Clavulanate Potassium Tablets, 49 See Erythromycin (Veterinary—Intramammary-Local), 79 Clincaps—Clindamycin Hydrochloride Capsules, 114 Intramammary Infusion, 80 ClindaCure—Clindamycin Hydrochloride Oral Solution, 114 Erythromycin Phosphate (Gallimycin; Gallimycin PFC; Gallistat) Clinda-Guard—Clindamycin Hydrochloride Oral Solution, 114 See Macrolides (Veterinary—Systemic), 119 Clindamycin (AmTech; Antirobe; Antirobe Aquadrops; Clincaps; ClindaCure; Powder For Oral Solution, 135 Clinda-Guard; Clindrops; nvClindamycin Capsules) Erythromycin Thiocyanate (Erymycin-100; Gallimycin-50) See Lincosamides (Veterinary—Systemic), 109 See Macrolides (Veterinary—Systemic), 119 Capsules, 114 For Medicated Feed, 136 Oral Solution, 114 Ethamycin—Dihydrostreptomycin Injection, 15 Clindrops—Clindamycin Hydrochloride Oral Solution114 Excenel—Ceftiofur Sodium For Injection, 62 CLTC 100 MR—Chlortetracycline For Medicated Feed, 237 Excenel RTU—Ceftiofur Hydrochloride Injection, 62 Combicillin—Penicillin G Benzathine and Penicillin G Procaine Injectable Florfenicol (Aquaflor; NuFlor) Suspension, 155 See Florfenicol (Veterinary—Systemic), 81 Combicillin AG—Penicillin G Benzathine and Penicillin G Procaine For Medicated Feed, 84 Injectable Suspension, 155 Injection, 84 CTC 50—Chlortetracycline For Medicated Feed, 237 Foul Brood Mix—Oxytetracycline Hydrochloride Soluble Powder, 241

Gallimycin—Erythromycin Phosphate Powder For Oral Solution, 135 Lincomix 44 Premix, Lincomix 110 Premix—Lincomycin Hydrochloride Gallimycin-36—Erythromycin Intramammary Infusion, 80 For Medicated Feed, 115 Gallimycin-50—Erythromycin Thiocyanate For Medicated Feed, 136 Lincomix Soluble Powder—Lincomycin Hydrochloride Soluble Powder, Gallimycin-100, Gallimycin-200—Erythromycin Injection, 131 115 Gallimycin-Dry Cow—Erythromycin Intramammary Infusion, 80 Lincomycin (Lincocin, Lincocin Aquadrops, Lincocin Injectable, Lincocin Gallimycin PFC—Erythromycin Phosphate Powder For Oral Solution, Sterile Solution, Lincomix 20 Feed Medication, Lincomix 50 Feed 135 Medication, Lincomix Injectable, Lincomix Injectable Solution, Lincomix Gallistat—Erythromycin Phosphate Powder For Oral Solution, 135 44 Premix, Lincomix 110 Premix, Lincomix Soluble Powder, Lincomycin Garacin Piglet Injection—Gentamicin Injection, 17 44 Premix, Lincomycin 110 Premix, Lincomycin 44G Premix, Lincomycin Garacin Pig Pump—Gentamicin Oral Solution, 16 110G Premix, Lincosol Soluble Powder, Moorman’s LN 10) Garacin Soluble Powder—Gentamicin Powder For Oral Solution, 17 See Lincosamides (Veterinary—Systemic), 109 Garasol Injection—Gentamicin Injection, 17 For Medicated Feed, 115 Garasol Pig Pump Oral Solution—Gentamicin Oral Solution, 16 Injection, 116 Garasol Solution Injectable—Gentamicin Injection, 17 Soluble Powder, 115 Gentamicin (AmTech GentaMax 100; AmTech Gentamicin Sulfate Pig Syrup, 116 Pump Oral Solution; AmTech Gentapoult; Garacin Piglet Injection; Garacin Tablets, 116 Pig Pump; Garacin Soluble Powder; Garasol Injection; Garasol Pig Pump Lincomycin 44 Premix, Lincomycin 110 Premix, Lincomycin 44G Premix, Oral Solution; Garasol Solution Injectable; Gen-Gard; Genta-fuse; Genta- Lincomycin 110G Premix—Lincomycin Hydrochloride For Medicated Max 100; GentaVed 50; GentaVed 100; Gentocin; Gentocin Solution; Feed, 115 Gentocin Solution Injectable; Gentozen; Legacy) Lincosol Soluble Powder—Lincomycin Hydrochloride Soluble Powder, 115 See Aminoglycosides (Veterinary—Systemic), 1 Liquamycin LA-200—Oxytetracycline Injection (Long-Acting), 246 Injection, 17 Longisil—Penicillin G Benzathine and Penicillin G Procaine Injectable Oral Solution, 16 Suspension, 155 Powder For Oral Solution, 17 Marboﬂoxacin (Zeniquin Tablets) Uterine Infusion, 16 See Fluoroquinolones (Veterinary—Systemic), 87 Gen-Gard—Gentamicin Powder For Oral Solution, 17 Tablets, 101 Genta-fuse—Gentamicin Injection, 17 Masti-Clear—Penicillin G Procaine Intramammary Infusion, 150 GentaMax 100—Gentamicin Uterine Infusion, 16 Maxim-100—Oxytetracycline Injection, 245 GentaVed 50—Gentamicin Injection, 17 Maxim-200—Oxytetracycline Injection (Long-Acting), 246 GentaVed 100—Gentamicin Uterine Infusion, 16 Micotil—Tilmicosin Injection, 137 Gentocin—Gentamicin Injection, 17 Microcillin—Penicillin G Procaine Injectable Suspension, 156 Gentocin Solution—Gentamicin Uterine Infusion, 16 Moorman’s LN 10—Lincomycin Hydrochloride For Medicated Feed, 115 Gentocin Solution Injectable—Gentamicin Injection, 17 Moxilean-50 Suspension—Amoxicillin For Oral Suspension, 40 Gentozen—Gentamicin Uterine Infusion, 16 Naxcel—Ceftiofur Sodium For Injection, 62 Geomycin 200—Oxytetracycline Injection (Long-Acting), 246 Neomycin (AmTech; Biosol Liquid; Neo-325; Neomed 325; Neomix 325; Go-dry—Penicillin G Procaine Intramammary Infusion, 150 Neomix AG 325; Neomix AG 325 Medicated Premix; Neomix Soluble Hetacillin (Hetacillin K Intramammary Infusion) Powder; Neomycin 200; Neomycin 325; Neo-Sol 50; Neosol-Oral; Neosol See Aminopenicillins (Veterinary—Intramammary-Local), 33 Soluble Powder; Neoved 200; Neovet 325/100; Neovet Neomycin Oral Intramammary Infusion, 34 Solution) Hetacillin K Intramammary Infusion—Hetacillin Potassium Intramam- See Aminoglycosides (Veterinary—Systemic), 1 mary Infusion, 34 For Medicated Feed, 19 Hi-Pencin 300—Penicillin G Procaine Injectable Suspension, 156 Oral Solution, 19 Kanamycin (Kantrim) Powder For Oral Solution, 20 See Aminoglycosides (Veterinary—Systemic), 1 Neo-325—Neomycin Sulfate Powder For Oral Solution, 20 Injection, 19 Neomed 325—Neomycin Sulfate Powder For Oral Solution, 20 Kantrim—Kanamycin Injection, 19 Neomix 325—Neomycin Sulfate Powder For Oral Solution, 20 Karomycin Palmitate 125, Karomycin Palmitate 250—Chloramphenicol Neomix AG 325—Neomycin Sulfate Powder For Oral Solution, 20 Palmitate Oral Suspension, 76 Neomix AG 325 Medicated Premix—Neomycin Sulfate For Medicated Kelamycin—Oxytetracycline Hydrochloride Uterine Suspension, 241 Feed, 19 Legacy—Gentamicin Uterine Infusion, 16 Neomix Soluble Powder—Neomycin Sulfate Powder For Oral Solution, 20 Lincocin—Lincomycin Hydrochloride Tablets, 116 Neomycin 200—Neomycin Sulfate Oral Solution, 19 Lincocin Aquadrops—Lincomycin Hydrochloride Syrup, 116 Neomycin 325—Neomycin Sulfate Powder For Oral Solution, 20 Lincocin Injectable—Lincomycin Injection, 116 Neo-Sol 50—Neomycin Sulfate Powder For Oral Solution, 20 Lincocin Sterile Solution—Lincomycin Injection, 116 Neosol-Oral—Neomycin Sulfate Oral Solution, 19 Lincomix 20 Feed Medication, Lincomix 50 Feed Medication —Lincomycin Neosol Soluble Powder—Neomycin Sulfate Powder For Oral Solution, 20 Hydrochloride For Medicated Feed, 115 Neoved 200—Neomycin Sulfate Oral Solution, 19 Lincomix Injectable—Lincomycin Injection, 116 Neovet 325/100—Neomycin Sulfate Powder For Oral Solution, 20 Lincomix Injectable Solution—Lincomycin Injection, 116 Neovet Neomycin Oral Solution—Neomycin Sulfate Oral Solution, 19

NuFlor—Florfenicol Injection, 84 mycin-Aqua; Terramycin 100 For Fish; Terramycin Scours Tablets; nvClindamycin Capsules—Clindamycin Hydrochloride Capsules, 114 Terramycin Soluble Powder; Terramycin-343 Soluble Powder; Terra-Vet Onycin 62.5, Onycin 250, Onycin 1000—Tetracycline Hydrochloride 100; Terra-Vet Soluble Powder; Terra-Vet Soluble Powder 343; Tetradure Soluble Powder, 248 LA 300; Tetraject LA; Tetraject LP; Tetravet-CA; Tetroxy-100; Tetroxy Optimed—Sulfaquinoxaline Oral Solution, 221 HCA Soluble Powder) Orbax Tablets—Orbiﬂoxacin Tablets, 102 See Tetracyclines (Veterinary—Systemic), 225 Orbiﬂoxacin (Orbax Tablets) For Medicated Feed, 243 See Fluoroquinolones (Veterinary—Systemic), 87 Injection, 245 Tablets, 102 Injection (Long-Acting), 246 Ormetoprim and Sulfadimethoxine (Primor 120; Primor 240; Primor Soluble Powder, 241 600; Primor 1200; Rofenaid 40; Romet 30; Romet-30) Tablets, 245 See Potentiated Sulfonamides (Veterinary—Systemic), 164 Uterine Suspension, 241 For Medicated Feed, 175 Oxytetracycline 50, Oxytetracycline 100, Oxytetracycline 200—Oxytetra- Tablets, 176 cycline For Medicated Feed, 243 OT 200—Oxytetracycline Injection (Long-Acting), 246 Oxytetracycline 100LP—Oxytetracycline Injection, 245 OTC 50—Oxytetracycline For Medicated Feed, 243 Oxy Tetra Forte—Oxytetracycline Hydrochloride Soluble Powder, 241 OXTC 50, OXTC 100, OXTC 200—Oxytetracycline For Medicated Feed, Oxytetramycin 100—Oxytetracycline Injection, 245 243 Oxytet-25-S—Oxytetracycline Hydrochloride Soluble Powder, 241 Oxy-110, Oxy-220, Oxy-440—Oxytetracycline For Medicated Feed, 243 Oxytet Soluble—Oxytetracycline Hydrochloride Soluble Powder, 241 Oxy 250, Oxy 1000—Oxytetracycline Hydrochloride Soluble Powder, Oxytet-SP—Oxytetracycline Hydrochloride Soluble Powder, 241 241 Oxytet-343 Water Soluble Powder—Oxytetracycline Hydrochloride Solu- Oxybiotic-100—Oxytetracycline Injection, 245 ble Powder, 241 Oxybiotic-200—Oxytetracycline Injection (Long-Acting), 246 Oxyvet 200 LA—Oxytetracycline Injection (Long-Acting), 246 Oxy 500 Calf Bolus, Oxy 1000 Calf Bolus—Oxytetracycline Tablets, 245 Oxyvet 100 LP—Oxytetracycline Injection, 245 Oxycure 100—Oxytetracycline Injection, 245 Panmycin Aquadrops—Tetracycline Oral Suspension, 249 Oxycure 200—Oxytetracycline Injection (Long-Acting), 246 Pen-Aqueous—Penicillin G Procaine Injectable Suspension, 156 Oxy LA—Oxytetracycline Injection (Long-Acting), 246 Pen G Injection—Penicillin G Procaine Injectable Suspension, 156 Oxy LP—Oxytetracycline Injection, 245 Penicillin G (Agri-cillin; Ambi-pen; Aquacillin; Benzapro; Combicillin; Oxy-Mycin 100—Oxytetracycline Injection, 245 Combicillin AG; Depocillin; Derapen SQ/LA; Duo-Pen; Duplocillin LA; Oxy-Mycin 200—Oxytetracycline Injection (Long-Acting), 246 Durapen; Hi-Pencin 300; Longisil; Microcillin; Pen-Aqueous; Pen G Oxymycine LA—Oxytetracycline Injection (Long-Acting), 246 Injection; Penmed; Penpro; Pot-Pen; Propen LA; R-Pen; Twin-pen; Ultrapen Oxymycine LP—Oxytetracycline Injection, 245 LA) Oxyshot LA—Oxytetracycline Injection (Long-Acting), 246 See Penicillin G (Veterinary—Systemic), 151 Oxysol-62.5, Oxysol-250, Oxysol-1000—Oxytetracycline Hydrochloride Benzathine and Procaine Injectable Suspension, 155 Soluble Powder, 241 Potassium For Oral Solution, 154 Oxysol-110, Oxysol-220, Oxysol-440—Oxytetracycline For Medicated Procaine Injectable Suspension, 156 Feed, 243 Penicillin G, Intramammary (Go-dry; Masti-Clear) Oxytet-250 Concentrate—Oxytetracycline Hydrochloride Soluble Powder, See Penicillin G (Veterinary—Intramammary-Local), 149 241 Intramammary Infusion, 150 Oxytetra-A—Oxytetracycline Hydrochloride Soluble Powder, 241 Penmed—Penicillin G Procaine Injectable Suspension, 156 Oxytetracycline (Agrimycin 100; Agrimycin 200; Agrimycin-343; Pennchlor 50ÆG, Pennchlor 90ÆG—Chlortetracycline For Medicated Feed, Alamycin LA; AmTech Maxim-100; AmTech Maxim-200; AmTech 237 Oxytetracycline HCL Soluble Powder; AmTech Oxytetracycline HCL Soluble Pennchlor 100 Hi-Flo Meal—Chlortetracycline For Medicated Feed, 237 Powder-343; Biomycin 200; Duramycin 72-200; Duramycin 100; Foul Pennchlor 50 Meal, Pennchlor 70 Meal—Chlortetracycline For Medicated Brood Mix; Geomycin 200; Kelamycin; Liquamycin LA-200; Maxim-200; Feed, 237 OT 200; OTC 50; OXTC 50; OXTC 100; OXTC 200; Oxy-110; Oxy-220; Pennchlor 100 MR—Chlortetracycline For Medicated Feed, 237 Oxy 250; Oxy-440; Oxy 1000; Oxybiotic-100; OxyBiotic-200; Oxy 500 Pennchlor 64 Soluble Powder—Chlortetracycline Hydrochloride Soluble Calf Bolus; Oxy 1000 Calf Bolus; Oxycure 100; Oxycure 200; Oxy LA; Powder, 236 Oxy LP; Oxy-Mycin 100; Oxy-Mycin 200; Oxymycine LA; Oxymycine Pennox 100 Hi-Flo Meal, Pennox 200 Hi-Flo Meal—Oxytetracycline For LP; Oxyshot LA; Oxysol-62.5; Oxysol-110; Oxysol-220; Oxysol-250; Medicated Feed, 243 Oxysol-440; Oxysol-1000; Oxytet-250 Concentrate; Oxytetra-A; Oxyte- Pennox 200 Injectable—Oxytetracycline Injection (Long-Acting), 246 tracycline 50; Oxytetracycline 100; Oxytetracycline 200; Oxytetracycline Pennox 50 Meal—Oxytetracycline For Medicated Feed, 243 100LP; Oxy Tetra Forte; Oxytetramycin 100; Oxytet-25-S; Oxytet Pennox 100-MR—Oxytetracycline For Medicated Feed, 243 Soluble; Oxytet-SP; Oxytet-343 Water Soluble Powder; Oxyvet 200 LA; Pennox 343 Soluble Powder—Oxytetracycline Hydrochloride Soluble Oxyvet 100LP; Pennox 100 Hi-Flo Meal; Pennox 200 Hi-Flo Meal; Powder, 241 Pennox 200 Injectable; Pennox 50 Meal; Pennox 100-MR; Pennox 343 Penpro—Penicillin G Procaine Injectable Suspension, 156 Soluble Powder; Promycin 100; Terramycin 50; Terramycin-50; Terra- Pirlimycin, Intramammary (Pirsue Aqueous Gel; Pirsue Sterile Solution) mycin 100; Terramycin-100; Terramycin 200; Terramycin-200; Terra- See Pirlimycin (Veterinary—Intramammary-Local), 161

Intramammary Infusion, 162 Injection, 215 Pirsue Aqueous Gel—Pirlimycin Intramammary Infusion, 162 Powder For Oral Solution, 215 Pirsue Sterile Solution—Pirlimycin Intramammary Infusion, 162 Tablets, 215 Polyﬂex—Ampicillin For Injectable Suspension, 42 Sulfadiazine and Trimethoprim (Tribrissen 30; Tribrissen 120; PolyOtic Soluble Powder—Tetracycline Hydrochloride Soluble Powder, Tribrissen 480; Tribrissen 960; Tribrissen 24%; Tribrissen 48%; Tribrissen 248 400 Oral Paste; Tribrissen Piglet Suspension; Tribrissen 40% Powder; Potensulf—Sulfadoxine and Trimethoprim Injection, 180 Tucoprim Powder; Uniprim Powder) Pot-Pen—Penicillin G Potassium For Oral Solution, 154 See Potentiated Sulfonamides (Veterinary—Systemic), 164 Powder 21—Sulfamethazine and Sulfathiazole Powder For Oral Solution, Injection, 179 221 Oral Paste, 177 Primor 120, Primor 240, Primor 600, Primor 1200—Ormetoprim and Oral Powder, 177 Sulfadimethoxine Tablets, 176 Oral Suspension, 178 Promycin 100—Oxytetracycline Injection, 245 Tablets, 178 Propen LA—Penicillin G Procaine Injectable Suspension, 156 Sulfadimethoxine (Albon 12.5% Concentrated Solution; Albon Injection Pulmotil 90—Tilmicosin For Medicated Feed, 137 40%; Albon Oral Suspension 5%; Albon SR; Albon Tablets; AmTech Pulmotil Premix—Tilmicosin For Medicated Feed, 137 Sulfadimethoxine Injection-40%; AmTech Sulfadimethoxine 12.5% Oral Pyrimethamine and Sulfaquinoxaline (Quinnoxine-S; Sulfaquinoxa- Solution; AmTech Sulfadimethoxine Soluble Powder; Di-Methox Injection- line-S) 40%; Di-Methox 12.5% Oral Solution; Di-Methox Soluble Powder; S-125; See Potentiated Sulfonamides (Veterinary—Systemic), 164 S-250; SDM Injection; SDM Powder; SDM Solution; Sulfasol; Sulforal) Oral Solution, 177 See Sulfonamides (Veterinary—Systemic), 207 Quinnoxine-S—Pyrimethamine and Sulfaquinoxaline Oral Solution, 177 Extended-Release Tablets, 217 Robamox-V Oral Suspension—Amoxicillin For Oral Suspension, 40 Injection, 218 Robamox-V Tablets—Amoxicillin Tablets, 40 Oral Solution, 216 Rofenaid 40—Ormetoprim and Sulfadimethoxine For Medicated Feed, Oral Suspension, 216 175 Soluble Powder, 216 Romet 30—Ormetoprim and Sulfadimethoxine For Medicated Feed, 175 Tablets, 217 R-Pen—Penicillin G Potassium For Oral Solution, 154 Sulfadoxine and Trimethoprim (Bimotrim; Borgal; Potensulf; Trimidox; S-125, S-250—Sulfadimethoxine Tablets, 217 Trivetrin) SDM Injection—Sulfadimethoxine Injection, 218 See Potentiated Sulfonamides (Veterinary—Systemic), 164 SDM Powder—Sulfadimethoxine Soluble Powder, 216 Injection, 180 SDM Solution—Sulfadimethoxine Oral Solution, 216 Sulfalean Powder—Sulfamethazine and Sulfathiazole Powder For Oral S-M-T—Sulfamethazine and Sulfathiazole Powder For Oral Solution, 221 Solution, 221 Solu-Tet—Tetracycline Hydrochloride Soluble Powder, 248 Sulfa-Max III Calf Bolus—Sulfamethazine Extended-Release Tablets, 220 Solu-Tet 324—Tetracycline Hydrochloride Soluble Powder, 248 Sulfa-Max III Cattle Bolus—Sulfamethazine Extended-Release Tablets, Spectam Injectable—Spectinomycin Hydrochloride Injection, 205 220 Spectam Oral Solution—Spectinomycin Hydrochloride Oral Solution, 204 2 Sulfamed—Sulfamethazine and Sulfathiazole Powder For Oral Solution, Spectam Scour-Halt—Spectinomycin Hydrochloride Oral Solution, 204 221 Spectam Soluble Powder—Spectinomycin Hydrochloride Powder For Oral Sulfamethazine (Calfspan; Sulfa ‘‘25’’; Sulfa 25%; Sulfa-Max III Calf Solution, 204 Bolus; Sulfa-Max III Cattle Bolus; Sulfasure SR Calf Bolus; Sulfasure SR Spectam Water Soluble—Spectinomycin Hydrochloride Powder For Oral Calf Tablets; Sulfasure SR Cattle Bolus; Sulmet Drinking Water Solution Solution, 204 12.5%; Sulmet Oblets; Sulmet Soluble Powder; Suprasulfa III Calf Bolus; Spectinomycin (Adspec Sterile Solution; AmTech Spectam Scour-Halt; Suprasulfa III Cattle Bolus; Sustain III; Sustain III Calf Bolus; Sustain III Bovispec Sterile Solution; Spectam; Spectam Injectable; Spectam Oral Cattle Bolus) Solution; Spectam Scour-Halt; Spectam Soluble Powder; Spectam Water See Sulfonamides (Veterinary—Systemic), 207 Soluble) Extended-Release Tablets, 220 See Spectinomycin (Veterinary—Systemic), 202 Oral Solution, 218 Hydrochloride Injection, 205 Powder For Oral Solution, 219 Hydrochloride Oral Solution, 204 Tablets, 219 Hydrochloride Powder For Oral Solution, 204 Sulfamethazine, Sulfanilamide, and Sulfathiazole (Triple Sulfa Bolus) Sulfate Injection, 206 See Sulfonamides (Veterinary—Systemic), 207 Streptomycin Tablets, 220 See Aminoglycosides (Veterinary—Systemic), 1 Sulfamethazine and Sulfathiazole (Powder 21; S-M-T; Sulfalean Oral Solution, 21 Powder; 2 Sulfamed; Sulfa-MT; Sulfa 2 Soluble Powder) Sulfa ‘‘25’’—Sulfamethazine Oral Solution, 218 See Sulfonamides (Veterinary—Systemic), 207 Sulfa 25%—Sulfamethazine Oral Solution, 218 Powder For Oral Solution, 221 Sulfachlorpyridazine (Vetisulid Boluses; Vetisulid Injection; Vetisulid Sulfa-MT—Sulfamethazine and Sulfathiazole Powder For Oral Solution, Powder) 221 See Sulfonamides (Veterinary—Systemic), 207 Sulfa-Q 20%—Sulfaquinoxaline Oral Solution, 221

Sulfaquinoxaline (Optimed; Sulfa-Q 20%; 31.92% Sul-Q-Nox) Soluble Powder, 248 See Sulfonamides (Veterinary—Systemic), 207 Uterine Tablets, 247 Oral Solution, 221 Tetracycline 250, Tetracycline 1000—Tetracycline Hydrochloride Soluble Sulfaquinoxaline-S—Pyrimethamine and Sulfaquinoxaline Oral Solution, Powder, 248 177 Tetracycline 250 Concentrate Soluble Powder—Tetracycline Hydrochloride Sulfasol—Sulfadimethoxine Soluble Powder, 216 Soluble Powder, 248 Sulfa 2 Soluble Powder—Sulfamethazine and Sulfathiazole Powder For Tetracycline 62.5 Soluble Powder—Tetracycline Hydrochloride Soluble Oral Solution, 221 Powder, 248 Sulfasure SR Calf Bolus—Sulfamethazine Extended-Release Tablets, 220 Tetradure LA 300—Oxytetracycline Injection (Long-Acting), 246 Sulfasure SR Calf Tablets—Sulfamethazine Extended-Release Tablets, 220 Tetraject LA—Oxytetracycline Injection (Long-Acting), 246 Sulfasure SR Cattle Bolus—Sulfamethazine Extended-Release Tablets, 220 Tetraject LP—Oxytetracycline Injection, 245 Sulforal—Sulfadimethoxine Oral Solution, 216 Tetramed 250, Tetramed 1000—Tetracycline Hydrochloride Soluble Sulmet Drinking Water Solution 12.5%—Sulfamethazine Oral Solution, Powder, 248 218 Tetrasol Soluble Powder—Tetracycline Hydrochloride Soluble Powder, Sulmet Oblets—Sulfamethazine Tablets, 219 248 Sulmet Soluble Powder—Sulfamethazine Powder For Oral Solution, 219 Tetravet-CA—Oxytetracycline Hydrochloride Soluble Powder, 241 31.92% Sul-Q-Nox—Sulfaquinoxaline Oral Solution, 221 Tetroxy-100—Oxytetracycline Injection, 245 Suprasulfa III Calf Bolus—Sulfamethazine Extended-Release Tablets, 220 Tetroxy HCA Soluble Powder—Oxytetracycline Hydrochloride Soluble Suprasulfa III Cattle Bolus—Sulfamethazine Extended-Release Tablets, Powder, 241 220 Tet-Sol 10, Tet-Sol 324—Tetracycline Hydrochloride Soluble Powder, Sustain III—Sulfamethazine Extended-Release Tablets, 220 248 Sustain III Calf Bolus—Sulfamethazine Extended-Release Tablets, 220 Tilmicosin (Micotil; Pulmotil 90; Pulmotil Premix) Sustain III Cattle Bolus—Sulfamethazine Extended-Release Tablets, 220 See Macrolides (Veterinary—Systemic), 119 Terramycin 50, Terramycin 100, Terramycin 200—Oxytetracycline For For Medicated Feed, 137 Medicated Feed, 243 Injection, 137 Terramycin-Aqua—Oxytetracycline For Medicated Feed, 243 ToDay—Cephapirin Sodium Intramammary Infusion, 72 Terramycin 100 For Fish—Oxytetracycline For Medicated Feed, 243 ToMorrow—Cephapirin Benzathine Intramammary Infusion, 72 Terramycin Scours Tablets—Oxytetracycline Tablets, 245 Tribrissen 30, Tribrissen 120, Tribrissen 480, Tribrissen 960—Sulfadiazine Terramycin Soluble Powder—Oxytetracycline Hydrochloride Soluble Pow- and Trimethoprim Tablets, 178 der, 241 Tribrissen 24%, Tribrissen 48%—Sulfadiazine and Trimethoprim Injec- Terramycin-343 Soluble Powder—Oxytetracycline Hydrochloride Soluble tion, 179 Powder, 241 Tribrissen 400 Oral Paste—Sulfadiazine and Trimethoprim Oral Paste, Terra-Vet 100—Oxytetracycline Injection, 245 177 Terra-Vet Soluble Powder—Oxytetracycline Hydrochloride Soluble Pow- Tribrissen Piglet Suspension—Sulfadiazine and Trimethoprim Oral Suspen- der, 241 sion, 178 Terra-Vet Soluble Powder 343—Oxytetracycline Hydrochloride Soluble Tribrissen 40% Powder—Sulfadiazine and Trimethoprim Oral Powder, Powder, 241 177 Tet-324—Tetracycline Hydrochloride Soluble Powder, 248 Trimidox—Sulfadoxine and Trimethoprim Injection, 180 Tetra 55, Tetra 250, Tetra 1000—Tetracycline Hydrochloride Soluble Triple Sulfa Bolus—Sulfamethazine, Sulfanilamide, and Sulfathiazole Powder, 248 Tablets, 220 Tetra 4000— Trivetrin—Sulfadoxine and Trimethoprim Injection, 180 Tetracycline Boluses, 247 Tucoprim Powder—Sulfadiazine and Trimethoprim Oral Powder, 177 Tetracycline Uterine Tablets, 247 Twin-pen—Penicillin G Benzathine and Penicillin G Procaine Injectable Tetra Bac 324—Tetracycline Hydrochloride Soluble Powder, 248 Suspension, 155 Tetrabol— Tylan 10, Tylan 40, Tylan 100—Tylosin Granulated, 138 Tetracycline Boluses, 247 Tylan 50, Tylan 200—Tylosin Injection, 138 Tetracycline Uterine Tablets, 247 Tylan Soluble—Tylosin Tartrate Powder For Oral Solution, 139 Tetracycline (AmTech Tetracycline Hydrochloride Soluble Powder-324; Calf Tylocine 200—Tylosin Injection, 138 Scour Bolus Antibiotic; Duramycin 10; Duramycin-324; Onycin 62.5; Tylosin Base (Tylan 50; Tylan 200; Tylocine 200; Tyloved) Onycin 250; Onycin 1000; Panmycin Aquadrops; PolyOtic Soluble See Macrolides (Veterinary—Systemic), 119 Powder; Solu-Tet; Solu-Tet 324; Tet-324; Tetra 55; Tetra 250; Tetra Injection, 138 1000; Tetra 4000; Tetra Bac 324; Tetrabol; Tetracycline 250; Tylosin Phosphate (Tylan 10; Tylan 40; Tylan 100; Tylosin 10 Premix; Tetracycline 1000; Tetracycline 250 Concentrate Soluble Powder; Tetra- Tylosin 40 Premix) cycline 62.5 Soluble Powder; Tetramed 250; Tetramed 1000; Tetrasol See Macrolides (Veterinary—Systemic), 119 Soluble Powder; Tet-Sol 10; Tet-Sol 324; 5-Way Calf Scour Bolus) Granulated, 138 See Tetracyclines (Veterinary—Systemic), 225 Tylosin 10 Premix, Tylosin 40 Premix—Tylosin Granulated, 138 Boluses, 247 Tylosin Tartrate (Tylan Soluble) Oral Suspension, 249 See Macrolides (Veterinary—Systemic), 119

Powder For Oral Solution, 139 Vetisulid Injection—Sulfachlorpyridazine Injection, 215 Tyloved—Tylosin Injection, 138 Vetisulid Powder—Sulfachlorpyridazine Powder For Oral Solution, 215 Ultrapen LA—Penicillin G Procaine Injectable Suspension, 156 Viceton—Chloramphenicol Tablets, 77 Uniprim Powder—Sulfadiazine and Trimethoprim Oral Powder, 177 5-Way Calf Scour Bolus—Tetracycline Boluses, 247 Vetisulid Boluses—Sulfachlorpyridazine Tablets, 215 Zeniquin Tablets—Marboﬂoxacin Tablets, 101

Human Brand and Generic Name Index

Note: Only human dosage forms considered by USP Veterinary Medicine Ceclor— Advisory Committees to be appropriate have been included in this Cefaclor Capsules, 56 publication. Cefaclor For Oral Suspension, 57 Includes both United States and Canadian products. Cefadyl—Cephapirin For Injection, 66 Cefazolin (Ancef; Kefzol) Achromycin V—Tetracycline Hydrochloride Capsules, 248 See Cephalosporins (Veterinary—Systemic), 51 Alti-Doxycycline— For Injection, 58 Doxycycline Hyclate Capsules, 239 Injection, 58 Doxycycline Hyclate Tablets, 240 Cefixime (Suprax) Ampicillin (Ampicin; Apo-Ampi; Novo-Ampicillin; Nu-Ampi; Omnipen; See Cephalosporins (Veterinary—Systemic), 51 Omnipen-N; Penbritin; Polycillin-N; Principen; Totacillin; Totacillin-N) For Oral Suspension, 59 See Aminopenicillins (Veterinary—Systemic), 36 Tablets, 59 Capsules, 42 Cefotan—Cefotetan For Injection, 60 For Injection, 43 Cefotaxime (Claforan) Ampicin—Ampicillin For Injection, 43 See Cephalosporins (Veterinary—Systemic), 51 Ancef— For Injection, 60 Cefazolin For Injection, 58 Injection, 60 Cefazolin Injection, 58 Cefotetan (Cefotan) Apo-Ampi—Ampicillin Capsules, 42 See Cephalosporins (Veterinary—Systemic), 51 Apo-Cefaclor— For Injection. 60 Cefaclor Capsules, 56 Cefoxitin (Mefoxin) Cefaclor For Oral Suspension, 57 See Cephalosporins (Veterinary—Systemic), 51 Apo-Cephalex—Cephalexin Tablets, 64 For Injection, 61 Apo-Doxy—Doxycycline Hyclate Capsules, 239 Injection, 61 Apo-Doxy-Tabs—Doxycycline Hyclate Tablets, 240 Cephalexin (Apo-Cephalex; Keflex; Keftab; Novo-Lexin; Nu-Cephalex; PMS- Apo-Erythro—Erythromycin Tablets, 130 Cephalexin) Apo-Erythro E-C—Erythromycin Delayed-Release Capsules, 130 See Cephalosporins (Veterinary—Systemic), 51 Apo-Erythro-ES—Erythromycin Ethylsuccinate Tablets, 133 Capsules, 63 Apo-Erythro-S—Erythromycin Stearate Tablets, 136 For Oral Suspension, 64 Apo-Metronidazole—Metronidazole Tablets, 146 Hydrochloride Tablets, 64 Apo-Sulfatrim— Tablets, 64 Sulfamethoxazole and Trimethoprim Oral Suspension, 180 Cephalothin (Ceporacin; Keflin) Sulfamethoxazole and Trimethoprim Tablets, 180 See Cephalosporins (Veterinary—Systemic), 51 Apo-Sulfatrim DS—Sulfamethoxazole and Trimethoprim For Injection, 65 Tablets, 180 Cephapirin (Cefadyl) Apo-Tetra—Tetracycline Hydrochloride Capsules, 248 See Cephalosporins (Veterinary—Systemic) Azithromycin (Zithromax) For Injection, 66 See Macrolides (Veterinary—Systemic), 119 Cephradine (Velosef) For Injection, 129 See Cephalosporins (Veterinary—Systemic), 51 For Oral Suspension, 128 Capsules, 66 Bactrim— For Oral Suspension, 66 Sulfamethoxazole and Trimethoprim Oral Suspension, 180 Ceporacin—Cephalothin For Injection, 65 Sulfamethoxazole and Trimethoprim Tablets, 180 Chloramphenicol (Chloromycetin; Novochlorocap) Bactrim DS—Sulfamethoxazole and Trimethoprim Tablets, 180 See Chlorampheniol (Veterinary—Systemic), 74 Bactrim I.V. —Sulfamethoxazole and Trimethoprim Injection, 181 Capsules, 76 Bactrim Pediatric—Sulfamethoxazole and Trimethoprim Oral Suspension, Sodium Succinate For Injection, 77 180 Chloromycetin—Chloramphenicol Sodium Succinate For Injection, 77 Biaxin— Cipro— Clarithromycin For Oral Suspension, 129 Ciprofloxacin For Oral Suspension, 97 Clarithromycin Tablets, 129 Ciprofloxacin Tablets, 97 Biaxin XL—Clarithromycin Extended-Release Tablets, 130 Ciprofloxacin (Cipro; Cipro I.V.) Cefaclor (Apo-Cefaclor; Ceclor) See Fluoroquinolones (Veterinary—Systemic), 87 See Cephalosporins (Veterinary—Systemic), 51 For Oral Suspension, 97 Capsules, 56 Injection, 97 For Oral Suspension, 57 Tablets, 97

Cipro I.V.—Ciprofloxacin Injection, 97 Tablets, 130 Claforan— Erythromycin Estolate (Ilosone; Novo-rythro) Cefotaxime For Injection, 60 See Macrolides (Veterinary—Systemic), 119 Cefotaxime Injection, 60 Capsules, 132 Clarithromycin (Biaxin; Biaxin XL) Oral Suspension, 132 See Macrolides (Veterinary—Systemic), 119 Tablets, 132 Extended-Release Tablets, 130 Erythromycin Ethylsuccinate (Apo-Erythro-ES; E.E.S.; EryPed; Ery- For Oral Suspension, 129 thro; Novo-Rythro) Tablets, 129 See Macrolides (Veterinary—Systemic), 119 Cofatrim Forte—Sulfamethoxazole and Trimethoprim Tablets, 180 For Oral Suspension, 133 Cotrim—Sulfamethoxazole and Trimethoprim Tablets, 180 Oral Suspension, 133 Cotrim DS—Sulfamethoxazole and Trimethoprim Tablets, 180 Tablets, 133, 134 Cotrim Pediatric—Sulfamethoxazole and Trimethoprim Oral Suspension, Erythromycin Gluceptate (Ilotycin) 180 See Macrolides (Veterinary—Systemic), 119 Daraprim—Pyrimethamine Tablets, 188 Sterile Erythromycin Gluceptate, 134 Doryx—Doxycycline Hyclate Delayed-Release Capsules, 240 Erythromycin Lactobionate (Erythrocin) Doxycin— See Macrolides (Veterinary—Systemic), 119 Doxycycline Hyclate Capsules, 239 Erythromycin Lactobionate For Injection, 134 Doxycycline Hyclate Tablets, 240 Erythromycin Stearate (Apo-Erythro-S; Erythrocin; Erythrocot; My-E; Doxycycline (Alti-Doxycycline; Apo-Doxy; Apo-Doxy-Tabs; Doryx; Dox- Novo-rythro; Wintrocin) ycin; Doxytec; Novo-Doxylin; Nu-Doxycycline; Vibramycin; Vibra-Tabs; See Macrolides (Veterinary—Systemic), 119 Vibra-Tabs C-Pak) Erythromycin Stearate Oral Suspension, 135 See Tetracyclines (Veterinary—Systemic), 225 Erythromycin Stearate Tablets, 136 For Oral Suspension, 239 Flagyl— Calcium Oral Suspension, 239 Metronidazole Capsules, 146 Capsules, 239 Metronidazole Injection, 147 Delayed-Release Capsules, 240 Metronidazole Tablets, 146 For Injection, 240 Flagyl I.V.—Metronidazole Hydrochloride For Injection, 147 Tablets, 240 Flagyl I.V. RTU—Metronidazole Injection, 147 Doxytec—Doxycycline Hyclate Capsules, 239 Keflex— E-Base—Erythromycin Delayed-Release Tablets, 130 Cephalexin Capsules, 63 E.E.S.— Cephalexin For Oral Suspension, 64 Erythromycin Ethylsuccinate For Oral Suspension, 133 Cephalexin Tablets, 64 Erythromycin Ethylsuccinate Oral Suspension, 133 Keflin—Cephalothin For Injection, 65 Erythromycin Ethylsuccinate Tablets, 133, 134 Keftab—Cephalexin Hydrochloride Tablets, 64 E-Mycin—Erythromycin Delayed-Release Tablets, 130 Kefzol—Cefazolin For Injection, 58 Erybid—Erythromycin Delayed-Release Tablets, 130 Ilosone— ERYC, ERYC-250, ERYC-333—Erythromycin Delayed-Release Capsules, Erythromycin Estolate Capsules, 132 130 Erythromycin Estolate Oral Suspension, 132 EryPed— Erythromycin Estolate Tablets, 132 Erythromycin Ethylsuccinate For Oral Suspension, 133 Ilotycin— Erythromycin Ethylsuccinate Tablets, 133, 134 Erythromycin Delayed-Release Tablets, 130 Ery-Tab—Erythromycin Delayed-Release Tablets, 130 Sterile Erythromycin Gluceptate, 134 Erythro— Mefoxin— Erythromycin Ethylsuccinate Oral Suspension, 133 Cefoxitin For Injection, 61 Erythromycin Ethylsuccinate Tablets, 134 Cefoxitin Injection, 61 Erythrocin— Metric 21—Metronidazole Tablets, 146 Erythromycin Lactobionate For Injection, 134 Metro I.V. —Metronidazole Injection, 147 Erythromycin Stearate Oral Suspension, 135 Metronidazole (Apo-Metronidazole; Flagyl; Flagyl I.V.; Flagyl I.V. RTU; Erythromycin Stearate Tablets, 136 Metric 21; Metro I.V.; Novonidazol; Protostat; Trikacide) Erythrocot—Erythromycin Stearate Tablets, 136 See Metronidazole (Veterinary—Systemic), 144 Erythromid—Erythromycin Tablets, 130 Capsules, 146 Erythromycin Base (Apo-Erythro; Apo-Erythro E-C; E-Base; E-Mycin; Hydrochloride For Injection, 147 Erybid; ERYC; ERYC-250; ERYC-333; Ery-Tab; Erythromid; Ilotycin; Injection, 147 Novo-rythro Encap; PCE) Tablets, 146 See Macrolides (Veterinary—Systemic), 119 My-E—Erythromycin Stearate Tablets, 136 Delayed-Release Capsules, 130 Novo-Ampicillin—Ampicillin Capsules, 42 Delayed-Release Tablets, 130 Novochlorocap—Chloramphenicol Capsules, 76

Novo-Doxylin— For Injection, 199 Doxycycline Hyclate Capsules, 239 Rimactane—Rifampin Capsules, 198 Doxycycline Hyclate Tablets, 240 Rofact—Rifampin Capsules, 198 Novo-Lexin— Roubac—Sulfamethoxazole and Trimethoprim Tablets, 180 Cephalexin Capsules, 63 Septra— Cephalexin For Oral Suspension, 64 Sulfamethoxazole and Trimethoprim Injection, 181 Cephalexin Tablets, 64 Sulfamethoxazole and Trimethoprim Oral Suspension, 180 Novonidazol—Metronidazole Tablets, 146 Sulfamethoxazole and Trimethoprim Tablets, 180 Novo-Rythro—Erythromycin Ethylsuccinate For Oral Suspension, 133 Septra DS—Sulfamethoxazole and Trimethoprim Tablets, 180 Novo-rythro— Septra Grape Suspension—Sulfamethoxazole and Trimethoprim Oral Erythromycin Estolate Capsules, 132 Suspension, 180 Erythromycin Estolate Oral Suspension, 132 Septra I.V.—Sulfamethoxazole and Trimethoprim Injection, 181 Erythromycin Stearate Oral Suspension, 135 Septra Suspension—Sulfamethoxazole and Trimethoprim Oral Suspension, Erythromycin Stearate Tablets, 136 180 Novo-rythro Encap—Erythromycin Delayed-Release Capsules, 130 Sulfamethoxazole and Trimethoprim (Apo-Sulfatrim; Apo-Sulfatrim Novo-Tetra—Tetracycline Hydrochloride Capsules, 248 DS; Bactrim; Bactrim DS; Bactrim I.V.; Bactrim Pediatric; Cofatrim Forte; Novo-Trimel— Cotrim; Cotrim DS; Cotrim Pediatric; Novo-Trimel; Novo-Trimel D.S.; Nu- Sulfamethoxazole and Trimethoprim Oral Suspension, 180 Cotrimox; Nu-Cotrimox DS; Roubac; Septra; Septra DS; Septra Grape Sulfamethoxazole and Trimethoprim Tablets, 180 Suspension; Septra I.V.; Septra Suspension; Sulfatrim; Sulfatrim DS; Novo-Trimel D.S.—Sulfamethoxazole and Trimethoprim Tablets, 180 Sulfatrim Pediatric; Sulfatrim S/S; Sulfatrim Suspension) Nu-Ampi— See Potentiated Sulfonamides (Veterinary—Systemic), 164 Ampicillin Capsules, 42 Injection, 181 Nu-Cephalex—Cephalexin Tablets, 64 Oral Suspension, 180 Nu-Cotrimox— Tablets, 180 Sulfamethoxazole and Trimethoprim Oral Suspension, 180 Sulfatrim—Sulfamethoxazole and Trimethoprim Tablets, 180 Sulfamethoxazole and Trimethoprim Tablets, 180 Sulfatrim DS—Sulfamethoxazole and Trimethoprim Tablets, 180 Nu-Cotrimox DS—Sulfamethoxazole and Trimethoprim Tablets, 180 Sulfatrim Pediatric—Sulfamethoxazole and Trimethoprim Oral Suspen- Nu-Doxycycline— sion, 180 Doxycycline Hyclate Capsules, 239 Sulfatrim S/S—Sulfamethoxazole and Trimethoprim Tablets, 180 Doxycycline Hyclate Tablets, 240 Sulfatrim Suspension—Sulfamethoxazole and Trimethoprim Oral Suspen- Nu-Tetra—Tetracycline Hydrochloride Capsules, 248 sion, 180 Omnipen—Ampicillin Capsules, 42 Suprax— Omnipen-N—Ampicillin For Injection, 43 Cefixime For Oral Suspension, 59 PCE—Erythromycin Delayed-Release Tablets, 130 Cefixime Tablets, 59 Penbritin—Ampicillin Capsules, 42 Tetracycline (Achromycin V; Apo-Tetra; Novo-Tetra; Nu-Tetra) Penicillin G (Pfizerpen) See Tetracyclines (Veterinary—Systemic), 225 See Penicillin G (Veterinary—Systemic), 151 Capsules, 248 Potassium For Injection, 156 Trikacide—Metronidazole Capsules, 146 Sodium For Injection, 157 Totacillin—Ampicillin Capsules, 42 Pfizerpen—Penicillin G Potassium For Injection, 156 Totacillin-N—Ampicillin For Injection, 43 PMS-Cephalexin— Velosef— Cephalexin For Oral Suspension, 64 Cephradine Capsules, 66 Cephalexin Tablets, 64 Cephradine For Oral Suspension, 66 Polycillin-N—Ampicillin For Injection, 43 Vibramycin— Principen—Ampicillin Capsules, 42 Doxycycline Calcium Oral Suspension, 239 Pyrimethamine (Daraprim) Doxycycline For Injection, 240 See Pyrimethamine (Veterinary—Systemic), 185 Doxycycline For Oral Suspension, 239 Tablets, 188 Doxycycline Hyclate Capsules, 239 Protostat—Metronidazole Tablets, 146 Vibra-Tabs—Doxycycline Hyclate Tablets, 240 Rifadin—Rifampin Capsules, 198 Vibra-Tabs C-Pak—Doxycycline Hyclate Tablets, 240 Rifadin IV—Rifampin For Injection, 199 Wintrocin—Erythromycin Stearate Tablets, 136 Rifampin (Rifadin; Rifadin IV; Rimactane; Rofact) Zithromax— See Rifampin (Veterinary—Systemic), 191 Azithromycin For Injection, 129 Capsules, 198 Azithromycin For Oral Suspension, 128