CATTLE PRODUCTS AND SERVICES

U.S. BEEF AND DAIRY ZOETIS CATTLE PRODUCTS ANTIMICROBIALS

ADVOCIN® Sterile Injectable Solution (danofloxacin injection) ...... 5 ALBON® Boluses (sulfadimethoxine) ...... 5 DRAXXIN® Injectable Solution (tulathromycin) ...... 5 DRAXXIN® 25 Injectable Solution (tulathromycin injection) ...... 6 EXCEDE® Sterile Suspension (ceftiofur crystalline free acid) ...... 6 EXCENEL® RTU EZ Sterile Suspension (ceftiofur hydrochloride) ...... 7 LINCO-SPECTIN® Sterile Solution (lincomycin hydrochloride and spectinomycin sulfate tetrahydrate) . . 7 LIQUAMYCIN® LA-200® (oxytetracycline) ...... 8 NAXCEL® Sterile Powder (ceftiofur sodium) ...... 8

CALF SCOURS VACCINES, TREATMENTS AND SUPPORT

CALF-GUARD® ...... 9 ENTROLYTE® H .E ...... 9 RE-SORB® ...... 9 SCOURGUARD® 4K ...... 10 SCOURGUARD® 4KC ...... 10 TERRAMYCIN® Scours Tablets ...... 10

CLOSTRIDIAL VACCINES

ONE SHOT ULTRA® 7 ...... 11 ONE SHOT ULTRA® 8 ...... 11 ULTRABAC® 7 ...... 12 ULTRABAC® 8 ...... 12 ULTRABAC® 7/SOMUBAC® ...... 12 ULTRABAC® CD ...... 12 ULTRACHOICE® CD ...... 13 ULTRACHOICE® 7 ...... 13 ULTRACHOICE® 8 ...... 13

FOOTBATH

HOOF-TECTM Copper-Shot ...... 14 HOOF-TECTM Organic Footbath Concentrate ...... 14 HOOF-TECTM Organic Topical Spray ...... 14 HOOF-TECTM Copper-Cutter Dry Mix ...... 14 HOOF-TECTM Copper-Free Dry Mix ...... 14 HOOF-TEC Complete® ...... 14 HOOF-TECTM 1000 Footbath Concentrate ...... 14

1 ZOETIS CATTLE PRODUCTS GENETICS

CLARIFIDE®/CLARIFIDE® Ultra ...... 15 CLARIFIDE® Plus/CLARIFIDE® Ultra Plus ...... 15 Genetic Condition Testing - beef cattle ...... 16 HD 50K ...... 16 i50K® ...... 16 GeneMax® Advantage ...... 17 GeneMax® Focus ...... 17 PredicGENTM ...... 18 SireTRACE® ...... 18

GROWTH IMPLANTS

SYNOVEX® C ...... 19 SYNOVEX® H ...... 19 SYNOVEX® S ...... 19 SYNOVEX CHOICE® ...... 19 SYNOVEX PLUS® ...... 20 SYNOVEX® ONE FEEDLOT ...... 20 SYNOVEX® ONE GRASS ...... 20 MASTITIS PREVENTION AND TREATMENT

Dry Cow ALBADRY PLUS® Suspension ...... 21 ENVIRACOR® J-5 ...... 21 ORBESEAL® ...... 21 SPECTRAMAST® DC Sterile Suspension (ceftiofur hydrochloride) ...... 22 Lactating Cow PIRSUE® Sterile Solution (pirlimycin hydrochloride) ...... 23 SPECTRAMAST® LC Sterile Suspension (ceftiofur hydrochloride) ...... 23

MEDICATED FEED ADDITIVES

ACTOGAINTM 45 ...... 24 AUREO S 700® ...... 24 AUREOMYCIN® ...... 25 BOVATEC® ...... 25 BOVATEC® 2 .2 ...... 26 CHLORMAX® ...... 26 DECCOX® ...... 27 MGA® 200 ...... 27 MGA® 500 ...... 28

2 ZOETIS CATTLE PRODUCTS PARASITICIDES

DECTOMAX® 1% Injectable ...... 29 DECTOMAX® Pour-On ...... 29 VALBAZEN® Suspension ...... 30

REPRODUCTIVE MANAGEMENT

EAZI-BREED™ CIDR® Cattle Insert ...... 31 FACTREL® Injection (gonadorelin injection) ...... 31 LUTALYSE® Injection (dinoprost tromethamine injection) ...... 32 LUTALYSE® HighCon Injection (dinoprost tromethamine injection) ...... 32

RESPIRATORY-REPRODUCTIVE VACCINES

BOVI-SHIELD GOLD® BVD ...... 33 BOVI-SHIELD GOLD® IBR-BVD ...... 33 BOVI-SHIELD GOLD® 4 ...... 34 BOVI-SHIELD GOLD® 5 ...... 34 BOVI-SHIELD GOLD FP® 5 ...... 35 BOVI-SHIELD GOLD FP® 5 L5 ...... 35 BOVI-SHIELD GOLD FP® 5 VL5 ...... 36 BOVI-SHIELD GOLD FP® 5 L5 HB ...... 37 BOVI-SHIELD GOLD ONE SHOT® ...... 37 BOVI-SHIELD GOLD FP® 5 VL5 HB ...... 38 BOVI-SHIELD® IBR ...... 38 CATTLEMASTER GOLD FP® 5 ...... 39 CATTLEMASTER GOLD FP® 5 L5 ...... 39 CATTLEMASTER® 4+VL5 ...... 40 INFORCETM 3 ...... 40 LEPTOFERM-5® ...... 41 ONE SHOT® ...... 41 ONE SHOT® BVD ...... 41 ONE SHOT ULTRA® 7 ...... 42 ONE SHOT ULTRA® 8 ...... 42 PREGGUARD GOLD FP® 10 ...... 43 RESVAC® 4/SOMUBAC® ...... 43 SOMUBAC® ...... 43

3 ZOETIS CATTLE PRODUCTS

RESPIRATORY-REPRODUCTIVE VACCINES CONTINUED

SPIROVAC® ...... 44 SPIROVAC® L5 ...... 44 SPIROVAC® VL5 ...... 44 STAYBRED® VL5 ...... 45 TSV-2® ...... 45 VIBRIN® ...... 45

OTHER HEALTH MANAGEMENT

THERABLOAT® ...... 46

OTHER VACCINE SOLUTIONS

SRP® SALMONELLA ...... 47 SolidBac® Pinkeye IR/PR® ...... 47 ESCHERICHIA COLI BACTERIAL EXTRACT VACCINE with SRP® technology . . . . 47

SERVICES

PEOPLEFIRSTTM Human Capital ...... 48

PRESCRIBING INFORMATION

ADVOCIN® Sterile Injectable Solution (danofloxacin injection) ...... 50 DRAXXIN® Injectable Solution (tulathromycin) ...... 51 DRAXXIN® 25 Injectable Solution (tulathromycin injection) ...... 53 EXCEDE® Sterile Suspension (ceftiofur crystalline free acid) ...... 55 EXCENEL® RTU EZ Sterile Suspension (ceftiofur hydrochloride) ...... 59 FACTREL® Injection (gonadorelin injection) ...... 61 LUTALYSE® Injection (dinoprost tromethamine injection) ...... 62 LUTALYSE® HighCon Injection (dinoprost tromethamine injection) ...... 64 NAXCEL® Sterile Powder (ceftiofur sodium) ...... 66 PIRSUE® Sterile Solution (pirlimycin hydrochloride) ...... 68 SPECTRAMAST® DC Sterile Suspension (ceftiofur hydrochloride) ...... 69 SPECTRAMAST® LC Sterile Suspension (ceftiofur hydrochloride) ...... 70

4 ANTIMICROBIALS

ADVOCIN® Sterile Injectable Solution DRAXXIN® Injectable Solution (danofloxacin injection) (tulathromycin)

USES: USES: Treatment and control of bovine For use in beef and nonlactating respiratory disease (BRD) dairy cattle for the treatment associated with Mannheimia and control of respiratory haemolytica and Pasteurella disease in cattle at high risk multocida . of developing BRD associated with Mannheimia haemolytica, SUPPLIED: Pasteurella multocida, Histophilus 100-mL and 250-mL vials . somni and Mycoplasma bovis . KEY FACTS: DRAXXIN® Injectable Solution is also indicated for the • ADVOCIN® provides one more treatment and control treatment of infectious bovine keratoconjunctivitis (IBK) option for BRD in a subcutaneous, single dose at 2 associated with Moraxella bovis and foot rot associated mL/100 lb . of body weight . with Fusobacterium necrophorum and Porphyromonas levii in beef and nonlactating dairy cattle . • A four-day withdrawal time provides increased flexibility For use in suckling calves, dairy calves and veal calves for to treat animals during the entire feeding period . the treatment of bovine respiratory disease associated • The single dose therapy provides convenience for all with Mannheimia haemolytica, Pasteurella multocida, operations and requires less handling of cattle . Histophilus somni and Mycoplasma bovis . IMPORTANT SAFETY INFORMATION: SUPPLIED: Extra-label use of ADVOCIN in food-producing animals 50-mL, 100-mL, 250-mL and 500-mL vials . is prohibited . Do not use in cattle intended for dairy production or in calves to be processed for veal . ADVOCIN KEY FACTS: has a pre-slaughter withdrawal time of four days . See full • Highly effective in the treatment and control of four Prescribing Information, attached . major BRD-causing bacteria . • Approved for the treatment of pinkeye and footrot . ALBON® Boluses (sulfadimethoxine) • Provides up to 14 days of therapy in a single dose . • Approved for treatment of BRD in suckling, veal and USES: dairy calves . Oral treatment of shipping fever complex, bacterial pneumonia, calf diphtheria and IMPORTANT SAFETY INFORMATION: foot rot . DRAXXIN has a pre-slaughter withdrawal time of 18 days . Do not use in female dairy cattle 20 months of age or SUPPLIED: older . Do not use in animals known to be hypersensitive 5-g or 15-g scored boluses, 50 ct . to the product . See full Prescribing Information, attached . KEY FACTS: • Long-acting sulfonamide bolus . • Low dose provides rapid, sustained blood levels at higher levels than most other long-acting sulfonamides . • Low toxicity . • Approved for use in lactating dairy cows . • Given at 25 mg/lb . body weight for first day, 12 5. mg/lb . for three to four subsequent days . ALBON BOLUS has a 60 hour milk withhold period, and a pre-slaughter withdrawal time of seven days . Do not use in calves to be processed for veal . Treatment should not be continued beyond five days .

Antimicrobials 5 DRAXXIN® 25 Injectable Solution EXCEDE® Sterile Suspension (tulathromycin injection) (ceftiofur crystalline free acid)

USES: USES: A lower concentration of DRAXXIN® Treatment of bovine respiratory (tulathromycin injection) Injectable disease (BRD), shipping fever, Solution for the treatment of bovine pneumonia) associated with respiratory disease (BRD) associated Mannheimia haemolytica, with Mannheimia haemolytica, Pasteurella multocida and Histophilus somni in beef, non- Pasteurella multocida, Histophilus lactating dairy and lactating somni and Mycoplasma bovis in dairy cattle . EXCEDE® Sterile suckling, dairy and veal calves . Suspension is also indicated for the control of respiratory SUPPLIED: disease in beef and nonlactating dairy cattle that are at 100-mL and 250-mL vials . high risk of developing BRD associated with Mannheimia haemolytica, Pasteurella multocida and Histophilus somni . KEY FACTS: EXCEDE is also indicated for the treatment of bovine • A lower concentration of DRAXXIN to treat BRD in foot rot (interdigital necrobacillosis) associated with suckling, dairy and veal calves . Fusobacterium necrophorum and Porphyromonas levii in • More accurate and convenient dosing for smaller calves . beef, nonlactating dairy and lactating dairy cattle . EXCEDE is also indicated for treatment of acute metritis (0-10 days • Offers broad-spectrum treatment against all four major postpartum) associated with bacterial organisms susceptible BRD-causing bacteria . to ceftiofur in lactating dairy cattle . IMPORTANT SAFETY INFORMATION: SUPPLIED: DRAXXIN 25 has a pre-slaughter withdrawal time of 22 100-mL and 250-mL vials . days in calves . Do not use in ruminating cattle . Do not use KEY FACTS: in animals known to be hypersensitive to the product . See • Approved for use in lactating dairy cows . full Prescribing Information, attached . • Convenient, single-dose treatment protocol for BRD and foot rot . • Zero milk discard means no trips to the hospital pen, maximizing performance and productivity from the fresh cow program . • Two doses 72 hours apart are required for treatment of acute metritis . • Advanced, sustained-release formulation provides extended therapy in a single dose versus multiple daily doses required for other treatments . • Ready-to-use formulation . • A single-dose treatment protocol improves antimicrobial treatment compliance . • Unique base-of-ear site of administration contributes to better carcass quality . • No milk withhold, 13 day pre-slaughter withdrawal . IMPORTANT SAFETY INFORMATION: People with known hypersensitivity to penicillin or cephalosporins should avoid exposure to EXCEDE . EXCEDE is contraindicated in animals with known allergy to ceftiofur or to the β-lactam group (penicillins and cephalosporins) of antimicrobials . Inadvertent intra- arterial injection is possible and fatal . Do not use in calves to be processed for veal . Pre-slaughter withdrawal time is 13 days following the last dose . See full Prescribing Information, attached .

6 Antimicrobials EXCENEL® RTU EZ Sterile Suspension LINCO-SPECTIN® Sterile Solution (ceftiofur hydrochloride) (lincomycin HCl and spectinomycin sulfate tetrahydrate) USES: Treatment of acute metritis USES: (0-14 days postpartum) For use in semen extenders to protect associated with bacterial against contamination . organisms susceptible to ceftiofur . Treatment of bovine SUPPLIED: respiratory disease (BRD), 20-mL vials . shipping fever, pneumonia) KEY FACTS: associated with Mannheimia • Dual antibiotic formulation protects haemolytica, Pasteurella valuable bull semen, which is multocida and Histophilus nonsterile when collected . somni . EXCENEL RTU EZ is also • Each mL contains 50 mg lincomycin HCl and indicated for the treatment of 100 mg spectinomycin sulfate tetrahydrate . bovine foot rot (interdigital necrobacillosis) associated with Fusobacterium necrophorum and Bacteroides • Not for drug use . melaninogenicus . SUPPLIED: 100-mL and 250-mL vials . KEY FACTS: • When used according to label directions, milk won’t have to be discarded . No wasted milk ensures a better return on investment . • Short, four-day pre-slaughter withdrawal time, one of the shortest withdrawal times of any treatment in its class . • Zero milk discard means no trips to the hospital pen, maximizing performance and productivity from the fresh cow program . • No special preparations, no mixing, no disruptions to the milking routine − ready to use right out of the bottle . IMPORTANT SAFETY INFORMATION: People with known hypersensitivity to penicillin or cephalosporins should avoid exposure to EXCENEL RTU EZ . Do not use in animals found to be hypersensitive to the product . Do not slaughter cattle for 4 days following last treatment . Do not use in calves to be processed for veal . See full Prescribing Information, attached .

Antimicrobials 7 LIQUAMYCIN® LA-200® NAXCEL® Sterile Powder (oxytetracycline) (ceftiofur sodium)

USES: USES: For use in the treatment of the NAXCEL® is indicated following diseases in beef and dairy for treatment of bovine cattle; including suckling, dairy and respiratory disease veal calves: BRD due to Pasteurella (BRD), shipping fever, spp . and Hemophilus (Histophilus) pneumonia) associated spp ;. pinkeye caused by Moraxella with Mannheimia bovis; foot rot and diptheria caused haemolytica, by Fusobacterium necrophorum; Pasteurella multocida bacterial enteritis (scours, colibacillosis) caused by and Histophilus somni . NAXCEL also is indicated for Escherichia coli; wooden tongue caused by Actinobacillus treatment of acute bovine interdigital necrobacillosis ligniersii; leptospirosis caused by Leptospira pomona; (foot rot, pododermatitis) associated with Fusobacterium wound infections and acute metritis caused by necrophorum and Bacteroides melaninogenicus . staphylococci and streptococci organisms sensitive to oxytetracycline . SUPPLIED: 20-mL, 1-g and 80-mL, 4-g vials . SUPPLIED: KEY FACTS: 100-mL, 250-mL and 500-mL vials . • Fast and effective, reaches therapeutic KEY FACTS: blood concentrations within minutes . • Broad-spectrum oxytetracycline is effective against • Broad-spectrum — effective against a broad range of various bacterial diseases . pneumonia pathogens, including those that produce • Ready to use . No mixing, refrigeration or special beta-lactamase that deactivates penicillins such as handling needed . ampicillin and amoxicillin . • One dose delivers three days of sustained therapy . • Zero milk discard means no trips to the hospital pen, Fewer injections mean less labor and animal stress . maximizing performance and productivity from the fresh cow program . • Beef-friendly subcutaneous (SC) option is available to minimize risk of carcass blemish . • Has a flexible (12 mL per 100 lbs . body weight) low- volume dose via subcutaneous (SC) or intramuscular • Approved for use in lactating dairy cows . (IM) administration . • Administered by SC or intravenous (IV) injection to beef • Short pre-slaughter withdrawal — when used according and dairy cattle and calves, including pre-ruminating to label directions, you have the confidence of a four- veal calves . day meat withholding time • Single dosage of 9 mg/lb . is recommended for IMPORTANT SAFETY INFORMATION: treatment of bacterial pneumonia (shipping fever) People with known hypersensitivity to penicillin or associated with Pasteurella spp . and Histophilus cephalosporins should avoid exposure to NAXCEL . spp . in calves and yearlings or infectious bovine NAXCEL has a pre-slaughter withdrawal time of four days . keratoconjunctivitis (pinkeye) caused by Moraxella Do not use in animals found to be hypersensitive to the bovis . For treatment of foot rot and other indicated product . See full Prescribing Information, attached . diseases, a dosage of 3-5 mg/lb . body weight per day is recommended . Discontinue treatment with LIQUAMYCIN® LA-200® at least 28 days prior to slaughter . Discard milk for 96 hours after the last treatment . Do not exceed the highest recommended level of drug per pound of body weight per day .

8 Antimicrobials CALF SCOURS VACCINES, TREATMENT AND SUPPORT

CALF-GUARD® ENTROLYTE® H.E. Bovine Rota-Coronavirus Vaccine (Oral Nutrient Powder for Calves) (Modified-Live Virus) USES: USES: To provide a source of For vaccination of healthy electrolytes and energy that newborn calves or pregnant are typically lost in cases of cows as an aid in preventing scours . diarrhea (scours) caused by bovine rotavirus and SUPPLIED: coronavirus . Twin 178-g pouches per packet, 20 packets per carton . SUPPLIED: 1-dose vials . KEY FACTS: • High dextrose content provides more energy per dose KEY FACTS: and ensures palatability . • For oral vaccination of newborn calves or intramuscular • Provides a rapidly absorbed source of critical (IM) vaccination of pregnant cows . electrolytes lost as a result of calf scours . • Cow vaccination stimulates maternal antibodies, which • Easy to mix and use − powder dissolves quickly in warm are transferred to nursing calves via colostrum and milk . water . • Aids in preventing two of the most prevalent forms of • Conveniently packaged in pre-measured twin-pouch viral scours . packets for mixing in ½-gallon quantities . • Oral vaccination of calves with a single 3-mL dose • Contents of both pouches are mixed with ½-gallon should occur as soon as possible after birth and before (64 oz ). of warm water and given by nursing bottle or ingestion of colostrum . stomach tube . • Cows should receive two IM 3-mL doses administered three to six weeks apart during late pregnancy . Ideally, RE-SORB® the second dose should be administered within 30 days (Oral Hydration Electrolyte Product for Scouring prior to calving . Revaccinate cows annually with two Calves) doses during each subsequent pregnancy . USES: Fluid and electrolyte replacement associated with dehydration from diarrhea (scours) in calves . SUPPLIED: 2 .26-oz . (64-g) double-sided packets in boxes of 12 and buckets of 72 . KEY FACTS: • Rapidly replenishes lost electrolytes and fluids in the scouring calf . • Oral dosing permits fluid replacement at first signs of scours . • Easy to mix, dissolves rapidly, stays in solution . • Palatable formula tastes good, avoids stress of tube feeding . • Contents of one packet (both sides) are added to 2 quarts of water and fed as 2 quarts of solution twice daily for two days (four feedings) .

Calf Scours Vaccines, Treatment and Support 9 SCOURGUARD® 4K SCOURGUARD® 4KC Bovine Rota-Coronavirus Vaccine (Killed Virus) Bovine Rota-Coronavirus Vaccine (Killed Virus) Escherichia Coli Bacterin Clostridium Perfringens Type C-Escherichia Coli Bacterin-Toxoid USES: Used for vaccination USES: of healthy, pregnant Used for vaccination of healthy, cows and heifers as pregnant cows and heifers as an an aid in preventing aid in preventing diarrhea in their diarrhea in their calves caused by bovine rotavirus calves caused by (serotypes G6 and G10), bovine bovine rotavirus coronavirus, enterotoxigenic (serotypes G6 and G10), bovine coronavirus and strains of E. coli having the K99 pili enterotoxigenic strains of Escherichia coli (E. coli) having adherence factor and Clostridium the K99 pili adherence factor . perfringens Type C . SUPPLIED: SUPPLIED: 10- and 50-dose vials . 10- and 50-dose vials . KEY FACTS: KEY FACTS: • It is the first and only vaccine with label protection for • It is the first and only vaccine with label protection for both rotavirus G6 and G10 serotypes .* both rotavirus G6 and G10 serotypes *. • Helps protect calves from scours . • It significantly P( < 0 05). increases antibody • Compared with unvaccinated controls, SCOURGUARD concentrations to rotavirus G10 in the colostrum 1. has been shown to reduce mortality caused by E. coli by • Compared with unvaccinated controls, SCOURGUARD 95 percent . has been shown to reduce mortality caused by E. coli by • Administer two IM doses approximately three weeks 95% . apart to pregnant cows, with second dose given three to • Administer two IM doses approximately three weeks six weeks before calving . apart to pregnant cows, with the second dose given *As indicated by USDA label claims . three to six weeks before calving . *As indicated by USDA label claims . TERRAMYCIN® Scours Tablets 1 Data on file, Study Report No . 2134H-60-02-010, Zoetis Inc . (oxytetracycline hydrochloride)

USES: Oral antibiotic for control and treatment of bacterial enteritis and pneumonia in beef and dairy calves . SUPPLIED: Boxes of 24 and 100 tablets (250 mg/ tablet) . KEY FACTS: • For antibacterial treatment of shipping fever complex caused by Pasteurella multocida and enteritis (scours) caused by E. coli (colibacillosis) and Salmonella typhimurium in beef and dairy calves . • Readily absorbed from digestive tract . • Dosage is 1 or 2 tablets per 100 pounds of body weight every 12 hours for up to four consecutive days . TERRAMYCIN has a pre-slaughter withdrawal time of 7 days . Do not use in lactating dairy cattle . Do not use in calves to be processed for veal .

10 Calf Scours Vaccines, Treatment and Support CLOSTRIDIAL VACCINES

ONE SHOT ULTRA® 7 ONE SHOT ULTRA® 8 Clostridium Chauvoei-Septicum-Novyi-Sordellii- Clostridium Chauvoei-Septicum-Haemolyticum- Perfringens Types C & D-Mannheimia Novyi-Sordellii-Perfringens Types C & D- Haemolytica Bacterin-Toxoid Mannheimia Haemolytica Bacterin-Toxoid

USES: USES: Aids in the prevention of Aids in the prevention diseases caused by the of diseases caused by clostridial agents indicated the clostridial agents above and bovine indicated above and pneumonia caused by bovine pneumonia Mannheimia (Pasteurella) caused by Mannheimia haemolytica Type A1 . (Pasteurella) haemolytica Type A1 . SUPPLIED: 10- and 50-dose vials . SUPPLIED: 10- and 50-dose vials . KEY FACTS: • Helps prevent seven clostridial diseases (including KEY FACTS: diseases caused by Cl. perfringens Types B, C and D), • Helps prevent eight clostridial diseases (including which continue to be of economic importance in cattle . diseases caused by Cl. haemolyticum and Cl. perfringens Clostridium bacteria are universally present and produce Types B, C and D), which continue to be of economic potent toxins that can result in rapid death of otherwise importance in cattle . Clostridium bacteria are universally healthy animals . present and produce potent toxins that can result in • Helps protect against the primary cause of respiratory rapid death of otherwise healthy animals . death in cattle, shipping fever and pneumonia caused by • Helps protect against the primary cause of respiratory Mannheimia (Pasteurella) haemolytica Type A1 . death in cattle, shipping fever and pneumonia caused by • Produces leukotoxoid and whole-cell antibody Mannheimia (Pasteurella) haemolytica Type A1 . responses, helping provide protection needed to • Produces leukotoxoid and whole-cell antibody withstand Mannheimia haemolytica challenge . responses, helping provide protection needed to • Contains STIMUGEN®, a patented, water-soluble withstand Mannheimia haemolytica challenge . adjuvant that enhances the immune response with • Contains STIMUGEN, a patented, water-soluble adjuvant minimal risk of injection-site reactions . that enhances the immune response with minimal risk of • No age restrictions on use . injection-site reactions . • Subcutaneous (SC) dose is 2 mL followed by a second • No age restrictions on use . 2-mL dose of ULTRACHOICE® 7 four to six weeks later . • Subcutaneous (SC) dose is 2 mL followed by a second 2-mL dose of ULTRACHOICE 8 four to six weeks later . • For Cl. haemolyticum, repeat the dose every six months in animals subject to re-exposure .

Clostridial Vaccines 11 ULTRABAC® 7 ULTRABAC® 7/SOMUBAC® Clostridium Chauvoei-Septicum-Novyi-Sordellii- Clostridium Chauvoei-Septicum-Novyi-Sordellii- Perfringens Types C & D Bacterin-Toxoid Perfringens Types C & D-Haemophilus Somnus Bacterin-Toxoid USES: Aids in the prevention of diseases USES: caused by the clostridial agents Aids in the prevention of diseases indicated above . caused by the clostridial agents indicated above and Histophilus SUPPLIED: somni (Haemophilus somnus) . 10-, 50- and 200-dose vials . SUPPLIED: KEY FACTS: 10-, 50- and 200-dose vials . • Helps prevent seven clostridial diseases (including diseases KEY FACTS: caused by Cl. perfringens Types B, • Helps prevent seven clostridial C and D), which continue to be of diseases (including diseases caused economic importance in cattle . by Cl. perfringens Types B, C and D), Clostridium bacteria are universally present and produce which continue to be of economic importance in cattle . potent toxins that can result in rapid death of otherwise Clostridium bacteria are universally present and produce healthy animals . potent toxins that can result in rapid death of otherwise • Helps provide comprehensive clostridial protection in healthy animals . one vaccine . • Helps protect calves and adult cattle against H. somni, a • Subcutaneous (SC) dose is 5 mL followed by a second contributor to respiratory disease and the cause of dose given four to six weeks later . Annual revaccination thrombotic meningoencephalitis (TEME) and with a single dose is recommended . reproductive tract infection . • Subcutaneous (SC) dose is 5 mL followed by a second dose given four to six weeks later . Annual revaccination with a single dose is recommended . ULTRABAC® 8 Clostridium Chauvoei-Septicum-Haemolyticum- Novyi-Sordellii-Perfringens Types C & D Bacterin-Toxoid ULTRABAC® CD Clostridium Perfringens Types C & D USES: Bacterin-Toxoid Aids in the prevention of diseases caused by the clostridial agents USES: indicated above . Aids in the prevention of enterotoxemia and enteritis caused SUPPLIED: by Clostridium perfringens Types B, 10-, 50- and 200-dose vials . C and D . KEY FACTS: SUPPLIED: • Helps prevent eight clostridial 10- and 50-dose vials . diseases (including diseases caused by Cl. haemolyticum and KEY FACTS: Cl. perfringens Types B, C and D), • Helps prevent clostridial diseases, which continue to be of economic importance in cattle . which continues to be Clostridium bacteria are universally present and produce of economic importance in cattle . potent toxins that can result in rapid death of otherwise Clostridium bacteria are universally present and produce healthy animals . potent toxins that can result in rapid death of otherwise • Helps provide comprehensive clostridial protection in healthy animals . one vaccine . • Helps prevent enterotoxemia and enteritis caused by • Subcutaneous (SC) dose is 5 mL followed by a second Cl. perfringens Types B, C and D . dose given four to six weeks later . Annual revaccination • Subcutaneous (SC) dose is 2 mL followed by a second with a single dose is recommended . dose given four to six weeks later . Annual revaccination • For Cl. haemolyticum, repeat the dose every five to six with a single dose is recommended . months in animals subject to re-exposure .

12 Clostridial Vaccines ULTRACHOICE® CD ULTRACHOICE® 8 Clostridium Perfringens Types C & D Clostridium Chauvoei-Septicum-Haemolyticum- Bacterin-Toxoid Novyi-Sordellii-Perfringens Types C & D- Bacterin-Toxoid USES: Aids in the prevention of USES: enterotoxemia and enteritis Aids in the prevention of diseases caused by Clostridium perfringens caused by the clostridial agents Types B, C and D . indicated above . SUPPLIED: SUPPLIED: 50-dose vials . 10-, 50- and 200-dose vials . KEY FACTS: KEY FACTS: • Helps provide protection in a • Helps provide protection in a tissue-friendly 2-mL dose tissue-friendly 2-mL dose against against enterotoxemia and eight major clostridial diseases enteritis caused by Cl. perfringens Types B, C and D . (including diseases caused by Cl. • No age restrictions on use . haemolyticum and Cl. perfringens Types B, C and D), which continue to be of economic importance in cattle . • Subcutaneous (SC) dose is 2 mL followed by a second Clostridium bacteria are universally present and produce dose given four to six weeks later . Annual revaccination potent toxins that can result in rapid death of otherwise with a single dose is recommended . healthy animals . • No age restrictions on use . • Subcutaneous (SC) dose is 2 mL followed by a second dose given four to six weeks later . Annual revaccination ULTRACHOICE® 7 with a single dose is recommended . Clostridium Chauvoei-Septicum-Novyi-Sordellii- Perfringens Types C & D-Bacterin-Toxoid • For Cl. haemolyticum, repeat the dose every six months in animals subject to re-exposure . USES: Aids in the prevention of diseases caused by the clostridial agents indicated above . SUPPLIED: 10-, 50- and 250-dose vials . KEY FACTS: • Helps provide protection in a tissue-friendly 2-mL dose against seven clostridial diseases (including diseases caused by Cl. perfringens Types B, C and D), which continue to be of economic importance in cattle . Clostridium bacteria are universally present and produce potent toxins that can result in rapid death of otherwise healthy animals . • No age restrictions on use . • Subcutaneous (SC) dose is 2 mL followed by a second dose given four to six weeks later . Annual revaccination with a single dose is recommended .

Clostridial Vaccines 13 FOOTBATH

HOOF-TECTM COPPER-SHOT HOOF-TECTM COPPER-CUTTER TOPICAL SPRAY DRY MIX USES: USES: HOOF-TEC™ Copper-Shot Topical Spray HOOF-TEC™ Copper-Cutter Dry Mix is a provides a footbath in a bottle . This better alternative to traditional copper product is perfect for your heifers and dry cows or if you sulfate . It dissolves easily in water and don’t have a footbath system . Spray undiluted when you is more cost-effective than copper sulfate . It can be used need better management or dilute 1:1 with water to help with HOOF-TEC 1000 Footbath Concentrate . maintain hoof health . SUPPLIED: SUPPLIED: 50-lb . bags . 1-gal . and 5-gal . jugs, 15-gal . and 55-gal . drums, and a 250-gal . tote .

TM TM HOOF-TEC COPPER-FREE DRY MIX HOOF-TEC ORGANIC FOOTBATH USES: CONCENTRATE HOOF-TEC™ Copper-Free Dry Mix USES: allows you to completely replace HOOF-TEC™ Organic Footbath copper sulfate in your footbath and Concentrate is OMRI Listed® for use in dissolves easily in water with additional hoof conditioners . organic production or processing and It can be used with HOOF-TEC 1000 Footbath Concentrate . handling and offers organic dairy producers SUPPLIED: the same benefits and management options 50-lb . bags . as HOOF-TEC 1000 Footbath Concentrate . SUPPLIED: 15-gal . and 55-gal . drums . HOOF-TEC COMPLETE® HOOF-TECTM ORGANIC USES: HOOF-TEC Complete® is an all-in-one TOPICAL SPRAY footbath solution that is a combination of low pH copper sulfate and hoof-conditioning salts and USES: HOOF-TEC™ Organic Topical Spray minerals . Just mix HOOF-TEC Complete with water . No is OMRI Listed for use in organic need for additional copper sulfate . And it can be integrated production or processing and handling with your existing automated footbath system . and offers organic dairy producers the SUPPLIED: same benefits and management options as 55-gal . drum and a 250-gal . tote . HOOF-TEC Copper-Shot Topical Spray . SUPPLIED: 1-gal . and 5-gal . jugs and 15-gal . drum .

HOOF-TECTM 1000 FOOTBATH CONCENTRATE USES: HOOF-TEC™ 1000 Footbath Concentrate helps ionize copper ⎯ making it more available ⎯ so you can use up to 40% less .* Works with your current footbath procedure and may allow up to 200 more cows through each 50-gallon footbath . *Based on traditional copper sulfate dosage rate of 5% of footbath SUPPLIED: volume . Copper sulfate dosage with HOOF-TEC 1000 Footbath Concentrate is reduced to a rate of 3% of footbath volume . The 5-gal . jug, 15-gal . and 55-gal . drums, and a 250-gal . tote . change in deposit results in a 40% reduction of copper sulfate use .

14 Footbath GENETICS

CLARIFIDE®/ CLARIFIDE® PLUS/ CLARIFIDE® ULTRA CLARIFIDE® ULTRA PLUS A nearly 28,000 (28K called A low-density (28K called

® CLARIFIDE)- or 62,000 (62K ultra CLARIFIDE Plus) and higher density called CLARIFIDE Ultra)-marker (62K called CLARIFIDE Ultra Plus) DNA panel that provides genomic evaluation DNA panel that provides genomic evaluations for for dairy animals. Holsteins including wellness traits. USES: USES: For obtaining genomic predictions for over 50 production, CLARIFIDE® Plus (and the higher density CLARIFIDE® health and type traits, composite indexes, parentage Ultra Plus) is the first commercially available U .S -based. and inbreeding information, genetic conditions and milk genomic test that gives dairy producers the ability to protein components . Five (5) Holstein, two (2) Jersey, directly predict disease risk in Holstein cattle . and two (2) Brown Swiss haplotypes associated with CLARIFIDE Plus includes genomic predictions for fertility are also reported . Results provide insight into an wellness traits that provide direct indication of genetic animal’s future genetic potential and help dairy producers risk factors for six of the most common and costly make better decisions regarding which animals to raise animal health challenges on dairies . as replacements and informs breeding and reproductive strategies . For obtaining predictions for over 55 wellness, production, health and type traits, composite indexes, parentage and SAMPLES: inbreeding information, halotypes or genetic conditions Submit tissue-sampling units (TSUs), blood cards (one and milk protein components . Results provide insight blood card, not oversaturated) or whole blood (3 mL in into an animal’s future genetic potential and help dairy purple-top tubes, refrigerated) on animals of any age . For producers make better decisions regarding which animals animals older than 4 months, submit TSUs or hair (one hair to raise as replacements and breeding and reproductive collector with at least 20-30 intact hair bulbs) . Hair or TSU strategies . samples should be used for testing twins . SAMPLES: KEY FACTS: Submit tissue-sampling units (TSUs), blood cards (one • CLARIFIDE® is available for Holstein, Jersey and Brown blood card, not oversaturated) or whole blood (3 mL in Swiss, while CLARIFIDE® Ultra is only available for Jersey purple-top tubes, refrigerated) on animals of any age . For and Brown Swiss . animals older than 4 months, submit TSUs or hair (one hair • Assists dairy producers with breeding, selection and collector with at least 20-30 intact hair bulbs) . Hair or TSU other management decisions and helps speed up the samples should be used for testing twins . long-term genetic progress of a herd . KEY FACTS: • Genetic values are expressed as genomic predicted • For Holstein cattle only . transmitting abilities (GPTAs) and may be used to • Builds upon the same genetic offering as CLARIFIDE or evaluate dairy animals shortly after birth . CLARIFIDE Ultra, plus the inclusion of wellness traits . • Results are reported electronically in an Excel® Please see CLARIFIDE for further information . spreadsheet that contains multiple summary reports • CLARIFIDE Plus also includes an exclusive index of the information for simplified review and ease of called the Dairy Wellness Profit Index™ (DWP$™) that data analysis . incorporates all economically important traits including • Holstein producers can also order tests and view production, health, type and the new wellness traits results in ENLIGHT® at www.enlightdairy.com; an and the polled trait to make more comprehensive and online, comprehensive management tool designed to profitable genetic selection decisions due to greater help Holstein producers more efficiently manage herd genetic variation for profitability . genetics . • Includes the Wellness Trait Index™ (WT$™), a multitrait index that focuses solely on wellness traits (mastitis, lameness, metritis, retained placenta, displaced abomasum, ketosis plus the economic value of the polled gene) to directly estimate differences in expected profitability related to differences in genetic risk for disease . Genetics 15 Genetic Condition Testing - beef cattle HD 50K Testing for genetic conditions, including color, polled The beef industry’s most trusted arthrogryposis multiplex (AM), contractural arachnodactyly genomic solution that includes (CA), developmental duplication (DD), neuropathic genomic predictions for 19 traits plus hydrocephalus (NH), osteopetrosis (OS), tibial hemimelia parentage verification. (TH), pulmonary hypoplasia with anasarca (PHA) and USES: idiopathic epilepsy (IE) Helps registered seedstock producers confidently select, mate and market bulls and females for better production USES: For DNA diagnostic testing of genetic defects in suspect animals, potential and profitability . Greatly increases accuracy of or those known to be carriers of recessive genes, to determine predictions for young bulls and females with limited or whether the individual is a carrier . no progeny, and allows producers to make earlier, more accurate decisions that accelerate genetic progress . SAMPLES: SAMPLES: Submit whole blood (in purple-top tubes), blood cards, semen Submit blood cards (one FTA card, not oversaturated) for samples or hair follicles (at least 25 follicles with bulb intact) for animals of any age for testing . testing . Customers are advised to check with their respective breed association for specific ordering and sample submission KEY FACTS: instructions . • For Black Angus breeders, samples should be submitted to Angus Genetics, Inc . (AGI), a wholly owned subsidiary KEY FACTS: of the American Angus Association in St . Joseph, • Test results may be used to confirm carriers or recessive- Missouri . free animals, advance breeding decisions, eliminate the • For Red Angus breeders, samples should be sumbitted expression of the recessive conditions and facilitate to the Red Angus Association of America, and for marketing decisions . Limousin and Lim-Flex breeders, samples should be • Once carrier females are identified, producers can: submitted to the North American Limousin Foundation . – Eliminate carriers from the herd • For Brangus and Beefmaster breeders, co-branded – Breed carriers to recessive-free animals order forms and samples should be submitted to Zoetis – Use carriers as embryo transfer recipients Genetics Laboratory in Kalamazoo, Michigan . • Results reported as genomic-enhanced expected progeny differences (GE-EPDs) . • The resulted GE-EPD accuracy is generally equivalent to tested bulls having an initial progeny proof of roughly i50K® a dozen or more calves/carcasses/daughters with The beef industry’s newest, most cost-effective genomic performance data contributing to their EPD . Includes parentage verification and progeny Sire Match for solution with effectively the same accuracy as HD 50K. GeneMax® tested commercial Angus females . USES: i50K® is a reliable, cost-effective genomic test that enables GE-EPDs to help seedstock breeders make more informed selection, mating and marketing decisions . SAMPLES: Submit blood cards (one FTA card, not oversaturated) and completed order forms for animals of any age for testing according to the key facts provided above for different breeds of seedstock offering HD 50K . Twins should have hair or tissue samples used . KEY FACTS: • i50K provides Angus, Red Angus, Brangus, Beefmaster and Limousin breeders with more accurate and complete GE-EPDs for economically relevant traits leveraging cost-effective genotyping platforms . • i50K uses a process called imputation to infer 50K genotypes from lower-density genotypes with a high degree of concordance, built upon the extensive foundation of reference genotypes from HD 50K . • i50K predictions utilize the same calibration or single step processes (depending on breed) as HD 50K, and the resulting GE-EPD accuracies are unchanged .

16 Genetics GeneMax® Advantage GeneMax® Focus A genomic test created from a A genomic test created collaboration between Angus from a collaboration Genetics, Inc. (AGI), Certified Angus Beef and Zoetis between Angus Genetics, Inc. (AGI), Certified Angus for commercial replacement females (75% Angus or Beef and Zoetis for predicting feedlot gain and marbling, greater). as well as Sire Match (75% Angus or greater). USES: USES: Allows producers to select, mate and market commercial This test predicts genetic merit for weaning weight, post- Angus heifers with ease and confidence by reliably weaning gain, carcass weight, grade (marbling) and Sire identifying females with more desirable genetic merit for Match information to make informed feeder/fed cattle maternal, feedlot and carcass traits . Provides predictions marketing and/or replacement heifer decisions . for ten individual traits, three economic index scores, Smarter Outlier Reporting and Sire Match powered by HD SAMPLES: 50K and i50K® tested bull batteries . Submit blood cards (one card, not oversaturated) or Allflex tissue samples and completed order forms to AGI for SAMPLES: animals of any age for testing . Submit blood cards (one card, not oversaturated) or Allflex® tissue samples and completed order forms to AGI KEY FACTS: for animals of any age for testing . • On the ranch, GeneMax® Focus can assist with: − Making keep/cull decisions KEY FACTS: − Identifying the highest value replacement females •  Three economic index scores for easier, more − Making better breeding decisions, informing dependable decision-making: feeder cattle growth, carcass performance and − Cow Advantage: Predicts differences in associated value profitability from heifer development, pregnancy and calving to the sale of weaned progeny . • In the feedlot, GeneMax Focus helps: − Feeder Advantage: Predicts differences in the net − Manage risk by feeding more predictable gain and return of feeder calf progeny due to growth, feed grade potential efficiency and CAB carcass merit . − Earn more predictable premiums by grid marketing − Total Advantage: Predicts differences cattle with known marbling ability in profitability from genetic merit across all − Buy the right cattle with confidence economically relevant traits captured in the Cow and Feeder Advantage index scores . •  Smart Outlier Reporting may be customized for specific customer needs to identify animals that likely possess extreme unfavorable genetics for cow cost from size and milk, docility and tenderness . •  Sire Match matches tested females to registered and transferred HD 50K and i50K tested sires to empower better mating and management of inbreeding .

Genetics 17 PredicGEN™ SireTRACE® The genomic test for crossbred A DNA test to identify parentage British/Continental animals, and track progeny performance focusing on carcass traits to help USES: producers make selection or marketing decisions For tested animals and candidate parents, SireTRACE and improve carcass value. qualifies or excludes the sire and/or dam of record (typically for seedstock producers), or identifies the qualifying sire USES: from multi-sire breeding programs (typically for commercial PredicGEN™ provides valuable insight into key carcass producers) . SireTRACE authenticated pedigree information attributes associated with carcass premiums and enables contributes to more accurate genetic evaluation for better genetic management of antagonisms between seedstock animals, enables better management of mating marbling and yield grade in crossbred animals . This insight decisions for avoidance of inbreeding, and may be used empowers producers to make informed selection, mating, to facilitate evaluation of sires through SireTRACE enables management and marketing decisions to help ensure progeny performance . improved carcass merit . SAMPLES: SAMPLES: Submit blood (3 mL in purple-top tubes) or blood cards (one Submit blood cards (one FTA card, not oversaturated) or card, not oversaturated) for animals of any age for testing . AllFlex tissue samples for animals of any age for testing . Hair (with at least 20 to 30 visible hair bulbs each) collected Twins should have hair or tissue samples used . after the animal has reached 4 months of age, and semen KEY FACTS: (one straw) may also be submitted . • PredicGEN provides accurate predictions of genetic KEY FACTS: merit for key carcass traits — marbling score, USDA yield • Progeny performance data, sorted by sires or groups grade and tenderness, as well as an index that predicts of sires, can determine which bulls produce calves with carcass grid value . superior and/or inferior performance across evaluated • PredicGEN has been validated for use in a broad range of traits . British and Continental breeds and their crosses . • Sire evaluations can continue throughout a bull’s • PredicGEN can be used to prioritize selection of productive lifetime, based on annual performance data replacements, as well as to differentiate the value of from his progeny . feeder calves on the basis of key outcomes defining • Bulls can be managed within the bull battery for more carcass value . successful breeding according to their differences in • PredicGEN can be used in bull batteries owned by apparent serving capacity, dominance, and documented commercial cow/calf producers to document genetic merit across evaluated traits . comparable across-breed carcass/consumer trait • Knowing the lineage of both sire and dam of retained genetic merit, and enable sire assignment for progeny replacement heifers can lend greater precision to tested with PredicGEN . future breeding decisions and accelerate genetic • PredicGEN can add $60 – $80 or more in progeny value progress . attributed to informed decisions .*

*Assuming typical herd variation in genetic merit for marbling and yield grade where half of replacement heifer candidates are selected based on grid merit with PredicGEN, the increase in average genetic merit in selected heifers would result in $10 – $11 additional carcass value per progeny. This is incremental and complementary to any increase in genetic merit associated with sire selection strategies. Over a typical commercial female’s lifetime, this represents an additional $60 – $80 or more in progeny value attributed to selection with PredicGEN. Assumes typical grid parameters with an $8 Choice-Select spread.

18 Genetics GROWTH IMPLANTS

SYNOVEX® C SYNOVEX® S 100 mg progesterone/10 mg estradiol benzoate 200 mg progesterone/20 mg estradiol benzoate

USES: USES: For increased rate of weight gain For increased rate of weight gain in suckling beef calves more and improved feed efficiency in than 45 days of age and up to steers 400 pounds or more . 400 pounds of body weight . For SUPPLIED: improvement in rate of weight gain One pouch contains 10 10-dose in steers weighing greater than 400 pounds and fed in cartridges (100 implants) . confinement for slaughter when used as part of a re- implant program in which an initial SYNOVEX® C implant KEY FACTS: is followed at approximately 70 days by Synovex S . • A growth-promoting implant containing 200 mg of progesterone and 20 mg of estradiol benzoate . SUPPLIED: One pouch contains 10 10-dose cartridges (100 implants) . • One implant (eight pellets) is administered to each steer by subcutaneous implantation in the middle one-third of the KEY FACTS: ear . • A growth-promoting implant containing 100 mg of • The 10-dose cartridge is designed for use exclusively progesterone and 10 mg of estradiol benzoate . with the fixed-needle SYNOVEX Revolver or with the • One implant (four pellets) is administered to each calf SX10 applicator with its unique retractable needle, which by subcutaneous implantation in the middle one-third of properly delivers the implant without crushing, bunching the ear . or dropping pellets . • May be used in suckling heifer and steer calves 45 days of age or older . • The 10-dose cartridge is designed for use exclusively SYNOVEX CHOICE® with the fixed-needle SYNOVEX Revolver or with the 100 mg trenbolone acetate/14 mg estradiol SX10 precision applicator with its unique retractable benzoate needle, which properly delivers the implant without crushing, bunching or dropping pellets . USES: For increased rate of weight gain in SYNOVEX® H steers fed in confinement for slaughter, 200 mg testosterone propionate/20 mg estradiol and for increased rate of weight gain and improved feed efficiency in heifers fed in benzoate confinement for slaughter . USES: SUPPLIED: For increased rate of weight gain One pouch contains 10 10-dose cartridges (100 implants) . and improved feed efficiency in KEY FACTS: heifers 400 pounds or more . • A growth-promoting implant containing 100 mg of SUPPLIED: trenbolone acetate and 14 mg of estradiol benzoate . One pouch contains 10 10-dose cartridges (100 implants) . • One implant (four pellets) is administered to each steer or KEY FACTS: heifer by subcutaneous implantation in the middle one- • A growth-promoting implant containing 200 mg of third of the ear . testosterone propionate and 20 mg of estradiol benzoate . • The 10-dose cartridge is designed for use exclusively • One implant (eight pellets) is administered to each heifer with the fixed-needle SYNOVEX Revolver or with the by subcutaneous implantation in the middle one-third of SX10 applicator with its unique retractable needle, which the ear . properly delivers the implant without crushing, bunching • The 10-dose cartridge is designed for use exclusively or dropping pellets . with the fixed-needle SYNOVEX Revolver or with the SX10 applicator with its unique retractable needle, which Do not use SYNOVEX products in veal calves . Refer to labels properly delivers the implant without crushing, bunching for complete directions for use, precautions, and warnings . or dropping pellets .

Growth Implants 19 SYNOVEX PLUS® SYNOVEX® ONE FEEDLOT 200 mg trenbolone acetate/28 mg estradiol 200 mg trenbolone acetate/28 mg estradiol benzoate benzoate

USES: USES: For increased rate of weight gain and For increased rate of weight gain improved feed efficiency in steers and improved feed efficiency for up and for increased rate of weight gain to 200 days in steers and heifers fed in heifers fed in confinement for in confinement for slaughter . slaughter . SUPPLIED: SUPPLIED: One pouch contains 10 10-dose One pouch contains 10 10-dose cartridges (100 implants) . cartridges (100 implants) . KEY FACTS: KEY FACTS: • The patented pore-forming barrier coating steadily • A growth-promoting implant containing 200 mg of releases the trenbolone acetate and estradiol benzoate trenbolone acetate and 28 mg of estradiol benzoate . for 200 days of growth enhancement . • One implant (eight pellets) is administered to each steer • One implant (eight pellets) is administered to each steer or heifer by subcutaneous implantation in the middle or heifer by subcutaneous implantation in the middle one-third of the ear . one-third of the ear . • The 10-dose cartridge is designed for use exclusively • The 10-dose cartridge is designed for use exclusively with with the fixed-needle SYNOVEX Revolver or with the the SX10 precision applicator with its unique retractable SX10 applicator with its unique retractable needle, needle, which properly delivers the implant without which properly delivers the implant without crushing, crushing, bunching or dropping pellets . bunching or dropping pellets .

SYNOVEX® ONE GRASS 150 mg trenbolone acetate/21 mg estradiol benzoate

USES: For increased rate of weight gain for up to 200 days in pasture steers and heifers (stocker, feeder and slaughter) SUPPLIED: One pouch contains 10 10-dose cartridges (100 implants) . KEY FACTS: • The patented pore-forming barrier coating steadily releases the trenbolone acetate and estradiol benzoate for 200 days of weight gain enhancement . • One implant (six pellets) is administered to each steer or heifer by subcutaneous implantation in the middle one- third of the ear . • The 10-dose cartridge is designed for use exclusively with Do not use SYNOVEX products in veal calves . Refer the SX10 precision applicator with its unique retractable to labels for complete directions for use, precautions, needle, which properly delivers the implant without and warnings . crushing, bunching or dropping pellets .

20 Growth Implants MASTITIS PREVENTION AND TREATMENT

Dry Cow ALBADRY PLUS® Suspension ORBESEAL® (penicillin/novobiocin sodium) (bismuth subnitrate)

USES: USES: Indicated for the Indicated for treatment of subclinical prevention of new mastitis caused by mastitis infections susceptible strains of throughout the dry Staphylococcus aureus and period . Streptococcus agalactiae in dry cows . SUPPLIED: Pails of 144 SUPPLIED: disposable syringes Packs of 12 and 144 10-mL disposable syringes (400 mg with individually wrapped isopropyl alcohol pads . novobiocin and 200,000 IU procaine penicillin G per syringe) with individually wrapped isopropyl alcohol pads . KEY FACTS: • Inert, nonantibiotic internal teat sealant for KEY FACTS: intramammary infusion of nonlactating cows . • Provides synergistic antibiotic combination of penicillin and novobiocin . • Mimics the cow’s natural firstline of intramammary defense, the keratin plug . • Bactericidal activity against major Staphylococcus and Streptococcus mastitis pathogens . • Provides a safe, physical barrier between the teat canal and the environment . • Ideal duration of activity during the involution phase of the dry cow period (two to three weeks after milking • Contains bismuth subnitrate, a safe, inert sealant . stops), when the keratin plug has not formed and the • Contents of one syringe are infused into each teat cow is susceptible to infection . cistern after administering a dry cow antibiotic therapy • Contents of one syringe are infused into each quarter at at dry off . Follow labeled dry period instructions specific dry off . to the antibiotic . • If used alone, ORBESEAL® has zero milk withhold and Do not use ALBADRY PLUS® 30 days prior to calving . Milk zero pre-slaughter withdrawal . from treated cows must not be used for food during the • Refer to the ORBESEAL label for complete first 72 hours after calving . Treated animals must not be instructions on proper administration at dry off slaughtered for food for 30 days following udder infusion . and removal at freshening .

ENVIRACOR® J-5

USES: Aids in the control of clinical signs associated with E. coli mastitis . SUPPLIED: 20- and 50-dose vials . KEY FACTS: • Subcutaneous (SC) 5-mL dose given at dry off, 30 days later and within two weeks of freshening . • Patented adjuvant system for optimum immune response . • Particularly valuable in recently freshened, low-SCC and high-production cows, which may be more susceptible to infection by E. coli . • Three-dose vaccination program helps deliver protection and safety . • Millions of doses given with demonstrated safety and efficacy .

Mastitis Prevention and Treatment 21 SPECTRAMAST® DC Sterile Suspension (ceftiofur hydrochloride)

USES: Indicated for the treatment of subclinical mastitis in dairy cattle at the time of dry off associated with Staphylococcus aureus, Streptococcus dysgalactiae and Streptococcus uberis . SUPPLIED: Packs of 12 and 144 10-mL disposable syringes (500 mg ceftiofur hydrochloride per syringe) with individually wrapped isopropyl alcohol pads . KEY FACTS: • Extended-action oil base ensures long-lasting effectiveness . • Contents of one syringe are infused into each infected quarter at dry off . • Milk taken from cows completing a 30-day dry cow period may be used for food with no milk discard due to ceftiofur residues .

IMPORTANT SAFETY INFORMATION: People with known hypersensitivity to penicillin or cephalosporins should avoid exposure to SPECTRAMAST® DC . Product requires a 30-day dry cow period, and has a 16-day pre-slaughter withdrawal period following last treatment . Use of this product in a manner other than indicated on the label, or failure to adhere to the proper milk discard period, will result in violative residues . See full Prescribing Information, attached .

Following label use, no pre-slaughter withdrawal period is required for neonatal calves born from treated dams regardless of colostrum consumption .

22 Mastitis Prevention and Treatment Lactating Cow PIRSUE® Sterile Solution SPECTRAMAST® LC Sterile Suspension (pirlimycin hydrochloride) (ceftiofur hydrochloride)

USES: USES: Indicated for the treatment Indicated for use in lactating of clinical and subclinical dairy cattle for (1) the treatment mastitis in lactating dairy of clinical mastitis associated with cattle associated with coagulase-negative staphylococci, Staphylococcus species such Streptococcus dysgalactiae and as Staphylococcus aureus, and Escherichia coli and (2) the Streptococcus species such treatment of diagnosed subclinical as Streptococcus agalactiae, mastitis associated with coagulase- Streptococcus dysgalactiae negative staphylococci and and Streptococcus uberis . Streptococcus dysgalactiae . SUPPLIED: SUPPLIED: Packs of 12 and 144 10-mL disposable syringes (50 mg Packs of 12 and 144 10-mL pirlimycin hydrochloride per syringe) with individually disposable syringes (125 mg wrapped isopropyl alcohol pads . ceftiofur hydrochloride per syringe) with individually wrapped isopropyl KEY FACTS: alcohol pads . • For antibiotic treatment of clinical and subclinical mastitis in lactating dairy cattle . KEY FACTS: • Unique flexible therapy label (two to eight days) . • For antibiotic treatment of clinical and subclinical mastitis in lactating dairy cattle . • Pirlimycin is unique in the way it is absorbed into the blood, which provides a long lasting effect and allows • Effective when used for the treatment of environmental for once-per-day dosing . staph and strep as well as E. coli infections . • Once-per-day dosing allows you to optimize your • Once-a-day administration . hospital crew . • Unique flexible therapy label (maximum of 8 days of treatment) . IMPORTANT SAFETY INFORMATION: PIRSUE has a nine-day pre-slaughter withdrawal period IMPORTANT DIAGNOSTIC INFORMATION: and an extended therapy withdrawal period of 21 days SPECTRAMAST® LC is intended for use in lactating dairy following last treatment . Discard milk during treatment cattle only with the specified, labeled pathogens . To and for 36 hours after last treatment regardless of assure responsible antimicrobial drug use, it is expected treatment duration . Repeated infusion during extended that subclinical mastitis will be diagnosed using a positive duration therapy regimens can result in elevated somatic culture, or other pathogen-specific test, in addition to any cell counts and clinical mastitis, which can result in animal other, appropriate veterinary medical evaluation prior to death . If acute mastitis or other clinical signs of illness treatment . develop, discontinue therapy immediately and contact your veterinarian . See full Prescribing Information, IMPORTANT SAFETY INFORMATION: attached . People with known hypersensitivity to penicillin or cephalosporins should avoid exposure to SPECTRAMAST LC . Product requires a 72-hour milk discard period and a 2-day pre-slaughter withdrawal period following last treatment . Use of this product in a manner other than indicated on the label, or failure to adhere to the proper milk discard period, will result in violative residues . See full Prescribing Information, attached .

Mastitis Prevention and Treatment 23 MEDICATED FEED ADDITIVES

ACTOGAINTM 45 AUREO S 700® (ractopamine hydrochloride Type A (chlortetracycline, sulfamethazine Type A medicated article) medicated article)

USES: USES: Complete Feed: For increased As an aid in the maintenance rate of weight gain, improved feed of weight gain in the presence efficiency and increased carcass of respiratory disease such as leanness in cattle fed in confinement shipping fever when fed in a 28- for slaughter during the last 28 to 42 day program . days on feed . SUPPLIED: Top-dress Feed: For increased 50-lb . multiwall paper bag with rate of weight gain and improved protective barrier ply . feed efficiency in cattle fed in confinement for slaughter during the KEY FACTS: last 28 to 42 days on feed . • Established product with more than 40 years of safe and effective use . SUPPLIED: • Granular formulation gives uniform distribution in feed 25-lb . plastic bag . and minimizes carryover potential . KEY FACTS: • Potent combination of two antibacterials . TM • Feeding ACTOGAIN 45 during the last 28 to 42 days of • Cost-effective . the finishing period redirects energy to make more lean • Readily absorbed delivering high blood and lung tissue muscle and less fat . concentrations . • ACTOGAIN contains ractopamine hydrochloride, the • A widely used feed medication in beef cattle starter diets . same beta agonist you’ve trusted for more than a decade . • In recent studies, ACTOGAIN delivered +17 lb . in live Withdraw AUREO® S 700 seven (7) days prior to slaughter . weight, +11 lb . in carcass weight, +15% improvement in Do not use in calves to be processed for veal . feed efficiency .1 Do not use ACTOGAIN in animals intended for breeding . Caution: Federal law restricts medicated feed containing Refer to label for complete directions for use, precautions, this veterinary feed directive (VFD) drug to use by or on and warnings . the order of a licensed veterinarian.

1 Data on file, Study Report No . A131R-US-13-204, Zoetis Inc .

24 Medicated Feed Additives AUREOMYCIN® BOVATEC® (chlortetracycline Type A medicated article) (lasalocid Type A medicated article)

USES: USES: Treatment and control of bacterial For improved feed efficiency pneumonia caused by Pasteurella and increased rate of weight spp . Treatment of bacterial gain when used in medicated enteritis caused by Escherichia feeds for cattle fed in coli . Control of active infection confinement for slaughter . of anaplasmosis caused by For increased rate of weight Anaplasma marginale . Reduction gain when used in medicated of liver condemnations due to liver feeds for pasture cattle abscesses . (slaughter, stocker, feeder cattle, SUPPLIED: and dairy and beef replacement 50-lb . multiwall paper bag with heifers) . Control of coccidiosis protective barrier ply . caused by Eimeria bovis and E. zuernii in cattle up to 800 pounds . KEY FACTS: •  Guaranteed potency and quality . SUPPLIED: 50-lb ., multiwall paper bag with protective barrier ply •  Broad spectrum, effective against a wide range of (BOVATEC® 91, 150 FP), or 50-lb . (7-gal .) plastic pails respiratory and enteric diseases . (BOVATEC Liquid 20) • Readily absorbed, delivering high blood and lung tissue concentrations . KEY FACTS: •  Increased rate of weight gain and feed efficiency . • Approved for use in combination with BOVATEC,® DECCOX,® and CATTLYST® . • Effectively controls coccidiosis . •  Versatile product with applications in all phases of beef • Consistent gain improvement in cattle grazing pasture or production, excluding veal . provided high-roughage diets . • Convenient treatment option when individual animal • Nutritional intake is not compromised and cattle adapt handling is not practical . easily (no step-up period) . • Available in both granular and meal form . • Wide range of free choice approvals (blocks, minerals, • Reduces incidence of liver abscesses . liquids, range cubes and tubs) . • Zero-day slaughter withdrawal . ® • High margin of safety . • Approved for use in combination with AUREOMYCIN, providing broad-spectrum health and performance Do not use AUREOMYCIN® in calves to be processed benefits . for veal . • Approved for use in combination with MGA® + Tylan® or MGA alone for feedlot heifers . Caution: Federal law restricts medicated feed containing this veterinary feed directive (VFD) drug to use by or on • BOVATEC Liquid 20 is the only liquid ionophore premix the order of a licensed veterinarian. available . Do not use BOVATEC in calves to be processed for veal . Do not allow horses or other equines access to feeds containing lasalocid, as ingestion may be fatal . Feeding undiluted or mixing errors resulting in excessive concentrations of lasalocid could be fatal to cattle and sheep .

Medicated Feed Additives 25 BOVATEC® 2.2 CHLORMAX® 50 (lasalocid Type C medicated feed) (chlortetracycline Type A medicated article)

USES: USES: For increased rate of weight gain in Treatment and control of bacterial pasture cattle (slaughter, stocker, pneumonia caused by Pasteurella feeder cattle, as well as dairy and spp . Treatment of bacterial enteritis beef replacement heifers) . caused by Escherichia coli . Control of active infection of anaplasmosis SUPPLIED: caused by Anaplasma marginale . 44-lb . block, contains 2 .2 g Reduction of liver condemnations lasalocid sodium per pound . due to liver abscesses .

KEY FACTS: SUPPLIED: • Convenient delivery of BOVATEC®; reduced labor and 50-lb multiwall paper bag with equipment cost . protective barrier ply . • Has shown consistent gain improvement regardless of pasture type . KEY FACTS: • Highest margin of safety among anticoccidial medication • Broad spectrum, effective against a range of respiratory options . and enteric diseases • Complements most nonmedicated supplement programs . • Readily absorbed, delivering high blood and lung tissue • No withdrawal period prior to slaughter is required . concentrations • Versatile product with applications in all phases of beef Do not use BOVATEC in calves to be processed for production, excluding veal calves . veal . Do not allow horses or other equines access to feeds containing lasalocid, as ingestion may be fatal . • High-quality meal formulation Feeding undiluted or mixing errors resulting in excessive • Reduces incidence of liver abscesses concentrations of lasalocid could be fatal to cattle and • Refer to product label for withdrawal times sheep . Contains copper . Do not feed to sheep . Do not feed CHLORMAX® 50 to calves to be processed for veal . Pre-slaughter withdrawal periods vary by indication . Consult product label for complete use directions and safety information including appropriate withdrawal period .

Caution: Federal law restricts medicated feed containing this veterinary feed directive (VFD) drug to use by or on the order of a licensed veterinarian.

26 Medicated Feed Additives DECCOX® MGA® 200 (decoquinate Type A medicated article) (melengestrol acetate Type A medicated article)

DECCOX®-L USES: (decoquinate Type B medicated feed) For increased rate of weight gain, DECCOX®-M improved feed efficiency and (decoquinate powder) suppression of estrus (heat) in heifers fed in confinement for slaughter . USES: For suppression of estrus in heifers For the prevention of coccidiosis intended for breeding . in ruminating and non-ruminating calves (including veal calves) and SUPPLIED: cattle caused by Eimeria bovis 50-lb . bags . and Eimeria zuernii . KEY FACTS: • MGA® 200 is used in dry feed . SUPPLIED: 50-lb . multiwall paper bag with • Contains the progestin hormone melengestrol acetate protective barrier ply . DECCOX®-L (MGA) for increased rate of weight gain, improved feed available in 50-lb . bags . efficiency and suppression of estrus . DECCOX-M available in 5- and • MGA may be fed in combination with BOVATEC® in a 50-lb . bags . single dry supplement with or without Tylan® . MGA may be fed with Zilmax®, ACTOGAIN™ or Optaflexx®, and KEY FACTS: Rumensin® in a single dry supplement with or without • Developed specifically for prevention of coccidiosis Tylan . MGA is also approved for use in combination with • A nonantibiotic anticoccidial oxytetracycline . • Effective in preventing coccidiosis by stopping the • MGA has no pre-slaughter withdrawal . development of coccidia early in the life cycle • Should be thoroughly mixed in the supplement of • Reduces treatment costs and performance losses feedlot heifers to provide 0 .25-0 .50 mg of MGA per associated with clinical outbreaks head per day . Consistent daily intake provides optimum • The only anticoccidial feed medication approved for use improvements in rate of gain and feed utilization and a in veal calves high degree of estrus suppression . Suppression of estrus • Versatile applications in dairy (milk replacer, whole milk, is maximized at the 0 .50-mg feeding level . complete feeds) and beef operations (top dress and complete feeds) • Approved for use in combination with AUREOMYCIN,® providing respiratory treatment and coccidiosis prevention Do not use DECCOX in cows producing milk for human consumption .

Medicated Feed Additives 27 MGA® 500 (melengestrol acetate Type A medicated article)

USES: Type A medicated article for mixing with non-medicated feed for increased rate of weight gain, improved feed efficiency and suppression of estrus (heat) . SUPPLIED: 40-lb . containers (4 627. gallons) . KEY FACTS: • MGA® 500 is a liquid formulation . • Contains the progestin hormone melengestrol acetate (MGA) for increased rate of weight gain, improved feed efficiency and suppression of estrus in heifers fed for slaughter . • MGA 500 Premix may be fed in combination with BOVATEC®, in combination with ACTOGAINTM and Rumensin®, with Zilmax® or Optaflexx®, and Rumensin® in a single liquid supplement with or without Tylan® . MGA is also approved for use in combination with oxytetracycline . • MGA has no pre-slaughter withdrawal . • Should be thoroughly mixed in liquid Type C medicated feed, which must be fed at 0 .5-2 0. lb . per head daily to provide 0 .25-0 .50 mg of MGA per head per day . Consistent daily intake provides optimum improvements in rate of gain and feed utilization and a high degree of estrus suppression . Suppression of estrus is maximized at the 0 .50-mg feeding level .

28 Medicated Feed Additives PARASITICIDES

DECTOMAX® Injectable DECTOMAX® Pour-On (doramectin) (doramectin)

USES: USES: Broad-spectrum treatment and Proven to effectively control infections control of internal and external and to protect cattle from reinfection parasites of cattle . with Cooperia oncophora and Ostertagia ostertagi for 28 days and Cooperia SUPPLIED: punctata for 35 days after treatment . 100-mL, 200-mL and 500-mL multidose vials . SUPPLIED: 1-liter multidose bottles, and KEY FACTS: 2 .5-L and 5-L multidose backpack containers . • For treatment and control of various species of gastrointestinal roundworms, lungworms, KEY FACTS: eyeworms, grubs, lice and mange mites . • For treatment and control of various species of • No other single product controls a broader spectrum of gastrointestinal roundworms, lungworms, eyeworms, internal and external parasites ⎯ including 36 stages of grubs, lice, horn flies and mange mites .

adult parasites, L4 larvae and inhibited larvae . • Controls 33 stages of internal and external parasites • Has extended activity against Ostertagia ostertagi with a single, convenient application . (21 days), Cooperia punctata (28 days) and C. oncophora • Provides seven-day persistent activity against horn flies . (14 days) . • Weatherproof formulation won’t wash off . • Safe for use in beef cattle, including pregnant cows, • Safe for use on any age or class of beef cattle, including newborn calves and bulls and dairy replacement heifers pregnant cows, calves and bulls and dairy replacement up to 20 months of age . heifers up to 20 months of age . • Tissue-friendly injectable solution permits precise • Dosage is 1 mL (5 mg doramectin) per 22 lb . body dosing . weight applied topically . • Dosage is 1 mL (10 mg doramectin) per 110 lb . body weight by either subcutaneous (SC) or intramuscular DECTOMAX Pour-On has a 45-day pre-slaughter (IM) injection . withdrawal period . Do not use in female dairy cattle 20 months of age or older . Do not use in calves to be DECTOMAX® Injectable has a 35-day pre-slaughter processed for veal . DECTOMAX has been developed withdrawal period . Do not use in female dairy cattle specifically for cattle and swine . Use in dogs may result in 20 months of age or older . Do not use in calves to be fatalities . processed for veal . DECTOMAX has been developed specifically for cattle and swine . Use in dogs may result in fatalities .

Parasiticides 29 VALBAZEN® Suspension (albendazole)

USES: Removal and control of stomach worms (including fourth-stage inhibited larvae of Ostertagia ostertagi), intestinal worms, lungworms, tapeworms and mature liver flukes . SUPPLIED: 500-mL, 1-L and 5-L bottles . KEY FACTS: • One product controls four major groups of parasitic worms ⎯ tapeworms, stomach worms, lungworms and liver flukes . • Kills inhibited fourth stage Ostertagia (brown stomach worm) larvae, the most important internal parasite of cattle . • Special drench gun makes administration fast and easy . • Dosage is 4 mL/100 lb . body weight .

Cattle must not be slaughtered within 27 days after the last treatment with VALBAZEN® . Do not use in female dairy cattle of breeding age . Do not administer to female cattle during the first 45 days of pregnancy or for 45 days after removal of bulls .

30 Parasiticides REPRODUCTIVE MANAGEMENT

EAZI-BREEDTM CIDR® Cattle Insert FACTREL® Injection (progesterone intravaginal insert) (gonadorelin injection)

USES: USES: Synchronization and advancement FACTREL® Injection is approved of estrus . for use with LUTALYSE® Injection (dinoprost tromethamine SUPPLIED: injection) or LUTALYSE® Each insert is impregnated with 1 .38 g HighCon Injection (dinoprost of progesterone in elastic silicone tromethamine injection) to molded over a nylon spine . Inserts synchronize estrous cycles to are packaged in a plastic pouch with allow for fixed-time artificial insemination (FTAI) in TM 10 inserts to a pouch . A special EAZI-BREED CIDR® lactating dairy cows . Applicator is available separately . FACTREL is also indicated for treatment of ovarian KEY FACTS: follicular cysts in cattle . When used in cattle with ovarian • More cows and heifers become pregnant earlier, follicular cysts, treatment effect is to reduce the number resulting in higher pregnancy rates . of days to next estrus . • Easier and more accurate heat detection . SUPPLIED: • More focused heat detection and easier artificial 20-mL vials (50 mcg/mL), insemination (AI) breeding within a narrower window of 50-mL vials (50 mcg/mL) . time . • Heifers freshening at a younger and more consistent KEY FACTS: age . • This gonadotropin-releasing hormone (GnRH) is a key component of a Food and Drug Administration- • Accurate breeding and calving dates . approved FTAI protocol when used in conjunction with • Improved efficiencies in labor management . LUTALYSE Injection in lactating dairy cattle .

Avoid contact with skin by wearing protective gloves • Backed by data with more than 12,000 combined cows when handling EAZI-BREED CIDR inserts . Do not use in studied in competitive trials which prove that FTAI heifers of insufficient size or age for breeding or in cattle with FACTREL and LUTALYSE provide an effective 1,2,3 with abnormal, immature, or infected genital tracts . Do method of synchronizing estrus . not use inserts more than once . • Flexible dosage treatment regimens to meet needs of individual operations and animals . • Improves breeding efficiency in a FTAI protocol .

IMPORTANT SAFETY INFORMATION: FACTREL is for use in cattle only . See full Prescribing Information, attached .

1 Data on File, Study Report No . 13PETREPRO01-08D, Zoetis Inc . 2 Poock S, Lucy M . Conception rate for postpartum dairy cows treated with different gonadorelin (GnRH) products for first or resynchronized timed AI . Presented at 2015 Midwest ADSA/ASAS Meeting, Des Moines, IA, March 16-18, 2015 . 3 Caldwell V, Tison N, Martineau R, Dubuc J, Des Côteaux L . Non- inferiority randomized field clinical trial of two GnRH commercial products used in a systematic double-ovsynch protocol at first breeding in dairy cows, in Proceedings . Proc Am Assoc Bov Pract Conf 2014 .

Reproductive Management 31 LUTALYSE® Injection LUTALYSE® HighCon Injection (dinoprost tromethamine injection) (dinoprost tromethamine injection)

USES: USES: Used to control the timing of estrous LUTALYSE® HighCon Injection and ovulation in estrus cattle that is a high-concentration have a corpus luteum, treatment of formula of LUTALYSE® pyometra . Injection (dinoprost tromethamine injection) and For use with FACTREL® Injection gives you the same results (gonadorelin injection) to synchronize as the LUTALYSE Injection estrous cycles to allow fixed-time you know and trust, in artificial inseminiation in lactating smaller, more convenient dairy cows . to administer 2-mL doses . LUTALYSE HighCon is the For use with EAZI-BREEDTM CIDR® Cattle Insert for first and only prostaglandin approved for subcutaneous synchronization of estrus in lactating dairy cows . administration . For use with EAZI-BREED CIDR Cattle Insert for LUTALYSE HighCon is approved for use with FACTREL synchronization of estrus in suckled beef cows and Injection (gonadorelin injection) to synchronize estrous replacement beef and dairy heifers, advancement of first cycles to allow for fixed-time artificial insemination (FTAI) postpartum estrus in suckled beef cows and advancement in lactating dairy cows . It also is approved for use with of first pubertal estrus in beef heifers . EAZI-BREED™ CIDR® Cattle Inserts in heifers and cows to improve breeding efficiency and pregnancy success . It’s SUPPLIED: important to note that LUTALYSE HighCon is approved 30-mL and 100-mL vials . for use in cattle only, not equine or swine like LUTALYSE. KEY FACTS: SUPPLIED: • Stimulate luteolysis, which naturally regresses the 20-mL vial contains 10 doses, corpus luteum . 100-mL vial contains 50 doses, • Effective in treatment of pyometra (chronic 250-mL vial contains 125 doses . endometritis) in cattle . KEY FACTS: • Treatment of unobserved (silent) estrus in lactating • Approved for a convenient 2-mL dose . dairy cattle . • The first and only prostaglandin with an Food and • An entirely natural prostaglandin . Drug Administration-approved subcutaneous claim in • A synchronized breeding program with LUTALYSE and addition to intramuscular administration . FACTREL can: • Now producers and veterinarians have flexible options • Improve pregnancy rates to choose a subcutaneous route of administration • Reduce time necessary for heat detection consistent with strict Beef Quality Assurance standards • Make more efficient use of labor and Dairy Animal Care and Quality Assurance . • Reduce cull rates • Available in three bottle sizes, allowing choices that best fit management needs for handling and administration . IMPORTANT SAFETY INFORMATION FOR LUTALYSE/ LUTALYSE HIGHCON: • An entirely natural prostaglandin . Women of childbearing age and persons with respiratory • Useful therapeutically for controlled breeding . problems should exercise extreme caution when handling • A synchronized breeding program with LUTALYSE/LUTALYSE HighCon . LUTALYSE/LUTALYSE LUTALYSE HighCon and FACTREL can: HighCon are readily absorbed through the skin and may • Improve pregnancy rates cause abortion and/or bronchiospasms, therefore spillage on the skin should be washed off immediately with soap • Reduce time necessary for heat detection and water . Aseptic techniques should be used to reduce • Make more efficient use of labor the possibility of post-injection clostridial infections . • Reduce cull rates Do not administer LUTALYSE/ LUTALYSE HighCon in pregnant cattle unless cessation of pregnancy is desired . See full Prescribing Information for LUTALYSE, attached . See full Prescribing Information for LUTALYSE HighCon, attached .

32 Reproductive Management RESPIRATORY-REPRODUCTIVE VACCINES

BOVI-SHIELD GOLD® BVD BOVI-SHIELD GOLD® IBR-BVD Bovine Virus Diarrhea Vaccine Bovine Rhinotracheitis-Virus Diarrhea Vaccine (Modified-Live Virus) (Modified-Live Virus)

USES: USES: Aids in preventing respiratory Prevents respiratory disease disease caused by bovine viral caused by infectious bovine diarrhea (BVD) virus Types 1 rhinotracheitis (IBR) virus, and 2, and when administered viremia caused by bovine viral subcutaneously, prevents diarrhea (BVD) virus Types 1 viremia caused by BVD Types 1 and 2, and aids in preventing and 2 viruses . respiratory disease caused by BVD Types 1 and 2 viruses when SUPPLIED: administered by the subcutaneous route of administration . 10- and 50-dose vials . When administered intramuscularly, BOVI-SHIELD GOLD® KEY FACTS: IBR-BVD aids in preventing respiratory disease caused by • Prevents BVD Types 1 and 2 viremia when administered IBR virus and BVD Types 1 and 2 viruses . subcutaneously . SUPPLIED: • Aids in the prevention of respiratory disease caused by 50-dose vials . BVD Types 1 and 2 viruses for at least 279 days when administered subcutaneously . KEY FACTS: • Prevents BVD Types 1 and 2 viremia when administered • Shown to be safe when given to pregnant cows or subcutaneously . calves nursing pregnant cows .* • Prevents respiratory disease caused by IBR virus for at • Single 2-mL intramuscular or subcutaneous dose . least 279 days when administered subcutaneously . Calves vaccinated before 6 months of age should be revaccinated after 6 months of age . • Aids in the prevention of respiratory disease caused by BVD Types 1 and 2 viruses for at least 279 days when administered subcutaneously . • Shown to be safe when given to pregnant cows or calves nursing pregnant cows .* *Do not use in pregnant cattle (abortions can result) • Single 2-mL subcutaneous or intramuscular dose . unless they were vaccinated, according to label Calves vaccinated before 6 months of age should be directions, with any BOVI-SHIELD GOLD FP® or revaccinated after 6 months of age . PREGGUARD GOLD FP® vaccine pre-breeding initially and within 12 months thereafter . Do not use in calves nursing pregnant cows unless their dams were vaccinated within the past 12 months as described above . To help ensure safety in pregnant cattle, heifers must receive at least 2 doses of any BOVI-SHIELD GOLD FP or PREGGUARD GOLD FP vaccine with the second dose administered approximately 30 days prebreeding.

Respiratory-Reproductive Vaccines 33 BOVI-SHIELD GOLD® 4 BOVI-SHIELD GOLD® 5 Bovine Rhinotracheitis-Virus Diarrhea- Bovine Rhinotracheitis-Virus Diarrhea- Parainfluenza 3 Vaccine (Modified-Live Virus) Parainfluenza 3-Respiratory Syncytial Virus Vaccine (Modified-Live Virus) USES: Prevents respiratory disease caused USES: by infectious bovine rhinotracheitis Prevents respiratory disease (IBR) virus, viremia caused by caused by infectious bovine bovine viral diarrhea (BVD) rhinotracheitis (IBR) virus, virus Types 1 and 2, and aids in viremia caused by bovine preventing respiratory disease viral diarrhea (BVD) virus caused by BVD virus Types 1 and 2, and respiratory Types 1 and 2, and aids in disease caused by parainfluenza 3 (PI3) virus preventing respiratory disease caused by BVD Types when administered by the subcutaneous route of 1 and 2 viruses, parainfluenza 3 (PI3) virus and bovine administration . When administered intramuscularly, respiratory syncytial virus (BRSV) when administered BOVI-SHIELD GOLD® 4 aids in preventing respiratory by the subcutaneous route of administration . When disease caused by IBR virus, BVD Types 1 and 2 viruses administered intramuscularly, BOVI-SHIELD GOLD® 5 aids and PI3 virus . in preventing respiratory disease caused by IBR virus, BVD Types 1 and 2 viruses, PI virus and BRSV . SUPPLIED: 3 10- and 50-dose vials . SUPPLIED: 5-, 10- and 50-dose vials . KEY FACTS: • Prevents BVD Types 1 and 2 viremia when administered KEY FACTS: subcutaneously . • Prevents BVD Types 1 and 2 viremia when administered • Prevents respiratory disease caused by IBR virus for at subcutaneously . least 279 days when administered subcutaneously . • Prevents respiratory disease caused by IBR virus for at • Aids in the prevention of respiratory disease caused by least 279 days when administered subcutaneously . BVD Types 1 and 2 viruses for at least 279 days when • Aids in the prevention of respiratory disease caused by administered subcutaneously . BVD Types 1 and 2 viruses for at least 279 days when • Aids in the prevention of respiratory disease caused by administered subcutaneously .

PI3 virus when administered either intramuscularly or • Aids in the prevention of respiratory disease caused by

subcutaneously . BRSV and PI3 virus when administered either • Shown to be safe when given to pregnant cows or calves intramuscularly or subcutaneously . nursing pregnant cows .* • Shown to be safe when given to pregnant cows or calves • Single 2-mL subcutaneous or intramuscular dose . nursing pregnant cows .* Calves vaccinated before 6 months of age should be • Single 2-mL subcutaneous or intramuscular dose . revaccinated after 6 months of age . Calves vaccinated before 6 months of age should be revaccinated after 6 months of age .

*Do not use in pregnant cattle (abortions can result) unless they were vaccinated, according to label directions, with any BOVI-SHIELD GOLD FP® or PREGGUARD GOLD FP® vaccine pre-breeding initially and within 12 months thereafter . Do not use in calves nursing pregnant cows unless their dams were vaccinated within the past 12 months as described above . To help ensure safety in pregnant cattle, heifers must receive at least 2 doses of any BOVI-SHIELD GOLD FP or PREGGUARD GOLD FP vaccine with the second dose administered approximately 30 days prebreeding.

34 Respiratory-Reproductive Vaccines BOVI-SHIELD GOLD FP® 5 BOVI-SHIELD GOLD FP® 5 L5 Bovine Rhinotracheitis-Virus Diarrhea- Bovine Rhinotracheitis-Virus Diarrhea- Parainfluenza 3-Respiratory Syncytial Virus Parainfluenza 3-Respiratory Syncytial Vaccine (Modified-Live Virus) Virus Vaccine (Modified-Live Virus)- Leptospira Canicola-Grippotyphosa-Hardjo- USES: Icterohaemorrhagiae-Pomona Bacterin Prevents persistently infected calves caused by bovine viral diarrhea (BVD) USES: virus Types 1 and 2 and respiratory Prevents persistently infected disease caused by infectious bovine calves caused by bovine viral rhinotracheitis (IBR) virus; aids in diarrhea (BVD) virus Types 1 and preventing abortion caused by IBR 2; aids in preventing abortion virus and respiratory disease caused by caused by infectious bovine

BVD Types 1 and 2 viruses, parainfluenza 3 (PI3) virus rhinotracheitis (IBR) virus and and bovine respiratory syncytial virus (BRSV) respiratory disease caused by and BVD Type 2 testicular infection when administered IBR virus, BVD Types 1 and 2 viruses, parainfluenza 3 (PI3) subcutaneously . When administered intramuscularly, virus and bovine respiratory syncytial virus (BRSV); BVD BOVI-SHIELD GOLD FP® 5 prevents persistently infected Type 2 testicular infection; and leptospirosis caused by calves caused by BVD virus Types 1 and 2 and aids in the fiveLeptospira serovars indicated above . preventing abortion caused by IBR virus; respiratory SUPPLIED: disease caused by IBR, BVD Types 1 and 2 viruses, PI3 virus and BRSV; and BVD Type 2 testicular infection . 5-, 10- and 50-dose vials . SUPPLIED: KEY FACTS: 10- and 50-dose vials . • Shown to be safe when given to pregnant cows or calves nursing pregnant cows *. KEY FACTS: • Helps prevents BVD Types 1 and 2 persistent infection for at • Helps prevent BVD Types 1 and 2 persistent infection for least 365 days . at least 365 days . • Aids in the prevention of IBR abortions for at least • Aids in the prevention of IBR abortions for at least 365 365 days . days . • Aids in the prevention of respiratory disease caused by • Prevents respiratory disease caused by IBR virus for at IBR virus, BVD Types 1 and 2 viruses, BRSV and PI3 virus . least 279 days .† • Aids in the prevention of leptospirosis caused by the five • Aids in the prevention of respiratory disease caused by serovars indicated above . BVD Types 1 and 2 viruses for at least 279 days †. • Single 2-mL intramuscular dose . • Aids in the prevention of respiratory disease caused by

BRSV and PI3 virus . • Shown to be safe when given to pregnant cows or calves nursing pregnant cows .* • Single 2-mL subcutaneous or intramuscular dose .

†Prevents IBR respiratory disease and IBR and BVD Types 1 and 2 respiratory DOI claims only apply to SC route of administration . *Do not use in pregnant cattle (abortions can result) unless they were vaccinated, according to label directions, with any BOVI-SHIELD GOLD FP® or PREGGUARD GOLD FP® vaccine pre-breeding initially and within 12 months thereafter . Do not use in calves nursing pregnant cows unless their dams were vaccinated within the past 12 months as described above . To help ensure safety in pregnant cattle, heifers must receive at least 2 doses of any BOVI-SHIELD GOLD FP or PREGGUARD GOLD FP vaccine with the second dose administered approximately 30 days prebreeding.

Respiratory-Reproductive Vaccines 35 BOVI-SHIELD GOLD FP® 5 VL5 Bovine Rhinotracheitis-Virus Diarrhea- Parainfluenza 3-Respiratory Syncytial Virus Vaccine (Modified-Live Virus)-Campylobacter Fetus-Leptospira Canicola-Grippotyphosa- Hardjo-Icterohaemorrhagiae-Pomona Bacterin

USES: Prevents persistently infected calves caused by bovine viral diarrhea (BVD) virus Types 1 and 2; aids in preventing abortion caused by infectious bovine rhinotracheitis (IBR) virus and respiratory disease caused by IBR virus, BVD Types

1 and 2 viruses, parainfluenza 3 (PI3) virus and bovine respiratory syncytial virus (BRSV); BVD Type 2 testicular infection; campylobacteriosis (vibrosis) caused by Campylobacter fetus and leptospirosis caused by the five Leptospira serovars indicated above . SUPPLIED: 10- and 50-dose vials . KEY FACTS: • Helps prevent BVD Types 1 and 2 persistent infection for at least 365 days . • Aids in the prevention of IBR abortions for at least 365 days . •  Aids in the prevention of respiratory disease caused by

IBR virus, BVD Types 1 and 2 viruses, BRSV and PI3 virus . •  Aids in the prevention of campylobacteriosis caused by C. fetus and leptospirosis caused by the five serovars indicated above . •  Shown to be safe when given to pregnant cows or calves nursing pregnant cows .* • Single 2-mL intramuscular dose followed by a single dose of VIBRIN/LEPTOFERM-5® three to four weeks later .

*Do not use in pregnant cattle (abortions can result) unless they were vaccinated, according to label directions, with any BOVI-SHIELD GOLD FP® or PREGGUARD GOLD FP® vaccine pre-breeding initially and within 12 months thereafter . Do not use in calves nursing pregnant cows unless their dams were vaccinated within the past 12 months as described above . To help ensure safety in pregnant cattle, heifers must receive at least 2 doses of any BOVI-SHIELD GOLD FP or PREGGUARD GOLD FP vaccine with the second dose administered approximately 30 days prebreeding.

36 Respiratory-Reproductive Vaccines BOVI-SHIELD GOLD FP® 5 L5 HB BOVI-SHIELD GOLD ONE SHOT® Bovine Rhinotracheitis-Virus Diarrhea- Bovine Rhinotracheitis-Virus Diarrhea- Parainfluenza 3-Respiratory Syncytial Virus Parainfluenza 3-Respiratory Syncytial Virus Vaccine Vaccine (Modified-Live Virus)-Leptospira (Modified-Live Virus), Mannheimia Haemolytica Canicola-Grippotyphosa-Hardjo- Toxoid Icterohaemorrhagiae-Pomona Bacterin USES: USES: Prevents respiratory disease Prevents persistently infected caused by infectious bovine calves caused by bovine rhinotracheitis (IBR) virus; viral diarrhea (BVD) virus prevents viremia caused by Types 1 and 2; aids in preventing bovine viral diarrhea (BVD) Types abortion caused by infectious 1 and 2 viruses; aids in prevention bovine rhinotracheitis (IBR) of respiratory disease caused virus and respiratory disease caused by IBR virus, BVD by BVD Types 1 and 2 viruses,

Types 1 and 2 viruses, parainfluenza 3 (PI3) virus and parainfluenza 3 (PI3) virus, and bovine respiratory syncytial bovine respiratory syncytial virus (BRSV); and BVD Type virus (BRSV); aids in prevention of bovine pneumonia 2 testicular infection . Prevents infection and urinary caused by Mannheimia haemolytica Type A1 . shedding caused by Leptospira borgpetersenii serovar Hardjo type hardjo-bovis (LHB) and aids in the prevention SUPPLIED: of diseases caused by L. pomona, L. grippotyphosa, L. 5-, 10- and 50-dose vials . canicola and L. icterohaemorrhagiae . KEY FACTS: SUPPLIED: • Convenient one dose administration . 5-, 10- and 50-dose vials . • The only combination vaccine that prevents three important bovine respiratory disease conditions while KEY FACTS: • Helps prevent BVD Types 1 and 2 persistent infection for also providing the strongest available protection against at least 365 days . Mannheimia haemolytica . • Prevents LHB kidney colonization and urinary shedding • Helps prevent bovine respiratory disease . for at least 365 days . • Prevents respiratory disease caused by IBR virus . • Prevents LHB genital tract colonization . • Prevents viremia caused by BVD Types 1 and 2 viruses . • Aids in the prevention of LHB fetal infections . • Aids in prevention of respiratory disease caused by BVD Types 1 and 2 viruses, PI virus and BRSV . • Prevents respiratory disease caused by IBR virus for 3 at least 279 days when administered subcutaneously . • Aid in prevention of bovine pneumonia caused by • Aids in the prevention of IBR abortion for at least Mannheimia haemolytica Type A1 . 365 days . • Single 2-mL subcutaneous administration in the • Aids in the prevention of respiratory disease caused neck region . by BVD Types 1 and 2 viruses for at least 279 days when administered subcutaneously . • Aids in the prevention of respiratory disease caused by

IBR virus, BVD Types 1 and 2 viruses, BRSV and PI3 virus when administered intramuscularly . *Do not use in pregnant cattle (abortions can result) unless they were vaccinated, according to label • Shown to be safe when given to pregnant cows or directions, with any BOVI-SHIELD GOLD FP® or calves nursing pregnant cows .* PREGGUARD GOLD FP® vaccine pre-breeding initially • Single 2-mL intramuscular or subcutaneous dose and within 12 months thereafter . Do not use in calves followed by a single dose of SPIROVAC® four to six nursing pregnant cows unless their dams were weeks later . Calves vaccinated before 6 months of age vaccinated within the past 12 months as described should be revaccinated after 6 months of age . above . To help ensure safety in pregnant cattle, heifers must receive at least 2 doses of any BOVI-SHIELD GOLD FP or PREGGUARD GOLD FP vaccine with the second dose administered approximately 30 days prebreeding.

Respiratory-Reproductive Vaccines 37 BOVI-SHIELD GOLD FP® 5 VL5 HB BOVI-SHIELD® IBR Bovine Rhinotracheitis-Virus Diarrhea- Bovine Rhinotracheitis Vaccine Parainfluenza 3-Respiratory Syncytial Virus Vaccine (Modified-Live Virus) (Modified-Live Virus)-Campylobacter Fetus- Leptospira Canicola-Grippotyphosa- USES: Hardjo-Icterohaemorrhagiae-Pomona Bacterin Prevents respiratory disease caused by infectious bovine USES: rhinotracheitis (IBR) virus Prevents persistently infected when administered by the calves caused by bovine viral subcutaneous route of diarrhea (BVD) virus Types administration . Aids in the 1 and 2; aids in preventing prevention of IBR when abortion caused by infectious administered by the intramuscular route . bovine rhinotracheitis (IBR) virus and respiratory SUPPLIED: disease caused by IBR virus, BVD Types 1 and 2 viruses, 50-dose vial . parainfluenza 3 (PI ) virus and bovine respiratory syncytial 3 KEY FACTS: virus (BRSV); and BVD Type 2 testicular infection . Prevents • Prevents respiratory disease caused by IBR virus for at infection and urinary shedding caused by Leptospira least 279 days when administered by the subcutaneous borgpetersenii serovar Hardjo type hardjo-bovis (LHB) and route . aids in the prevention of campylobacteriosis (vibriosis) caused by Campylobacter fetus and diseases caused by • Not for use in pregnant cows (abortions can result) . L. pomona, L grippotyphosa, L. canicola and • Single 2-mL subcutaneous dose or intramuscular . Calves L. icterohaemorrhagiae . vaccinated before 6 months of age should be revaccinated after 6 months of age . SUPPLIED: 10- and 50-dose vials . KEY FACTS: • Helps prevent BVD Types 1 and 2 persistent infection for at least 365 days . •  Prevents LHB kidney colonization and urinary shedding for at least 365 days . • Prevents LHB genital tract colonization . • Aids in the prevention of LHB fetal infections . •  Prevents respiratory disease caused by IBR virus for at least 279 days when administered subcutaneously . • Aids in the prevention of IBR abortion for at least 365 days . •  Aids in the prevention of respiratory disease caused by BVD Types 1 and 2 viruses for at least 279 days when administered subcutaneously . *Do not use in pregnant cattle (abortions can result) •  Aids in the prevention of respiratory disease caused by unless they were vaccinated, according to label BVD Types 1 and 2 viruses, BRSV, PI3 virus and IBR virus directions, with any BOVI-SHIELD GOLD FP® or when administered intramuscularly . PREGGUARD GOLD FP® vaccine pre-breeding initially •  Shown to be safe when given to pregnant cows or calves and within 12 months thereafter . Do not use in calves nursing pregnant cows .* nursing pregnant cows unless their dams were •  Single 5 mL intramuscular or subcutaneous dose followed vaccinated within the past 12 months as described by a single dose of SPIROVAC® VL5 four to six weeks above . To help ensure safety in pregnant cattle, heifers later . Calves vaccinated before 6 months of age should be must receive at least 2 doses of any BOVI-SHIELD GOLD revaccinated after 6 months of age . FP or PREGGUARD GOLD FP vaccine with the second dose administered approximately 30 days prebreeding.

38 Respiratory-Reproductive Vaccines CATTLEMASTER GOLD FP® 5 CATTLEMASTER GOLD FP® 5 L5 Bovine Rhinotracheitis-Virus Diarrhea- Bovine Rhinotracheitis-Virus Diarrhea-

Parainfluenza3-Respiratory Syncytial Virus Parainfluenza3-Respiratory Syncytial Virus Vaccine (Modified-Live and Killed Virus) Vaccine (Modified-Live and Killed Virus)- Leptospira Canicola-Grippotyphosa-Hardjo- USES: Icterohaemorrhagiae-Pomona Bacterin Aids in the prevention of abortion caused USES: by infectious bovine Aids in the prevention rhinotracheitis (IBR), of abortion caused persistently infected calves by infectious bovine caused by bovine viral rhinotracheitis (IBR) virus, diarrhea (BVD) virus Types persistently infected calves 1 and 2, and respiratory caused by bovine viral disease caused by IBR virus, BVD Types 1 and 2 viruses, diarrhea (BVD) virus Types parainfluenza 3 (PI3) virus and bovine respiratory syncytial 1 and 2, respiratory disease caused by IBR virus, BVD virus (BRSV) . Types 1 and 2 virus, parainfluenza 3 (PI3) virus and bovine respiratory syncytial virus (BRSV) and leptospirosis SUPPLIED: caused by the fiveLeptospira serovars indicated above . 5-, 10- and 25-dose vials . SUPPLIED: KEY FACTS: 5-, 10- and 25-dose vials . •  Helps provide demonstrated protection from the four most common viral respiratory diseases . KEY FACTS: •  Killed BVD Type 2 virus helps deliver exceptional •  Helps provide demonstrated protection from the four respiratory protection even against a lethal challenge 1. most common viral respiratory diseases, plus five-way leptospirosis protection . •  The only killed BVD vaccine line with the power to help deliver protection from BVD persistent infection and IBR •  Killed BVD Type 2 virus helps deliver exceptional 1 abortion .* respiratory protection even against a lethal challenge . •  The only killed BVD vaccine line with the power to help •  Demonstrated safe modified-live IBR virus, PI3 virus and BRSV protection . deliver protection from BVD persistent infection and IBR abortion .* • Adjuvant system stimulates the immune system for exceptional IBR and BVD protective levels . •  Demonstrated safe modified-live IBR virus, PI3 virus and BRSV protection . • Safe and convenient, vaccinate any calf, any cow, anytime . •  Adjuvant system stimulates the immune system for exceptional IBR and BVD protective levels . •  Beef-friendly subcutaneous injection . • Safe and convenient, vaccinate any calf, any cow,

1 Data on file, Study Report No . 3131R-60-02-251, Zoetis Inc . anytime . *Fetal Protection from BVD persistent infection when administered •  Beef-friendly subcutaneous injection . prior to breeding .

1 Data on file, Study Report No . 3131R-60-02-251, Zoetis Inc . *Fetal Protection from BVD persistent infection when administered prior to breeding .

Respiratory-Reproductive Vaccines 39 CATTLEMASTER® 4+VL5 INFORCETM 3 Bovine Rhinotracheitis-Virus Diarrhea- Bovine Rhinotracheitis-Parainfluenza 3-Respiratory Parainfluenza 3-Respiratory Syncytial Virus Syncytial Virus Vaccine (Modified-Live Virus) Vaccine (Modified-Live and Killed Virus)- Campylobacter Fetus-Leptospira Canicola- USES: Grippotyphosa-Hardjo-Icterohaemorrhagiae- Prevents respiratory disease Pomona Bacterin caused by bovine respiratory syncytial virus (BRSV), USES: and aids in the prevention Aids in the prevention of of infectious bovine diseases caused by infectious rhinotracheitis (IBR) and bovine rhinotracheitis parainfluenza 3 (PI3) . (IBR) virus, bovine viral diarrhea (BVD) Type 1 virus, SUPPLIED: 1-, 10-, 25- and 50-dose vials . parainfluenza 3 (PI3) virus, bovine respiratory syncytial KEY FACTS: virus (BRSV), campylobacteriosis (vibrosis) caused by • First and only respiratory vaccine with the highest level Campylobacter fetus and the leptospirosis caused by the of disease prevention currently available against BRSV . fiveLeptospira serovars indicated above . • Developed for single nostril administration . SUPPLIED: • Provides at least six months of protection against IBR 5-, 10- and 25-dose vials . respiratory disease and at least 57 days of protection against BRSV respiratory disease after single nostril KEY FACTS: • Helps provide protection against four major viral administration . respiratory diseases of cattle, plus protection against • Contains proprietary, temperature-sensitive IBR and

campylobacteriosis (vibriosis) and five common causes PI3 strains, and a naturally temperature-sensitive BRSV of leptospirosis . strain that replicate effectively in the nasal passages . • Contains chemically altered, temperature-sensitive • Helps prime the immune system for a memory response

IBR and PI3 strains that do not grow outside the to subsequent disease challenges . upper respiratory tract and are incapable of systemic • Stimulates interferon release for protection . replication or fetal infection . • Safe and effective for use in all classes and types of • The nonshedding, nonimmunosuppressive and cattle in all management situations . nonabortigenic viral agents used in CATTLEMASTER® • Provides at least six months duration of immunity vaccines are safe for use in any cow, any calf, anytime . against IBR respiratory disease . • Intramuscular dose is 5-mL followed by a second dose given two to four weeks later . • Annual revaccination with a single dose is recommended . • Occasional hypersensitivity reactions may occur up to 18 hours post-vaccination . Owners should be advised to observe animals during this period . While this event appears to be rare overall, dairy cattle may be affected more frequently than other cattle .

40 Respiratory-Reproductive Vaccines LEPTOFERM-5® ONE SHOT® BVD Leptospira Canicola-Grippotyphosa-Hardjo- Bovine Virus Diarrhea Vaccine (modified-live virus) Icterohaemorrhagiae-Pomona Bacterin Mannheimia Haemolytica Toxoid

USES: USES: Aids in the prevention of leptospirosis Aids in the protection of caused by the five serovars indicated Mannheimia haemolytica above . and bovine viral diarrhea (BVD) Types 1 and 2 SUPPLIED: viruses, two of the major 10- and 50-dose vials . respiratory viruses that KEY FACTS: cause bovine respiratory • Helps provide protection against a disease (BRD) . Use contagious disease . ONE SHOT® BVD and INFORCE 3 concurrently for comprehensive respiratory protection . • Single intramuscular dose is 2-mL, with annual revaccination . SUPPLIED: 5-, 10- and 50-dose vials . KEY FACTS: • Helps young calves build the immunity they need prior ONE SHOT® to commingling of dairy calves and at turnout for beef Mannheimia Haemolytica Bacterin-Toxoid calves . • Helps provide a convenient and effective way to USES: combat BRD . Aids in the prevention of bovine pneumonia caused WARNING: by Mannheimia (Pasteurella) Do not use in pregnant cows (abortions can result) unless haemolytica Type A1 . they were vaccinated, according to label directions, with any BOVI-SHIELD GOLD FP® or PREGGUARD GOLD FP SUPPLIED: vaccine within the past 12 months . Do not use in calves 5-, 10- and 50-dose vials . nursing pregnant cows unless their dams were vaccinated KEY FACTS: within the past 12 months as described above . • Helps protect against the primary cause of respiratory death in cattle, shipping fever and pneumonia caused by Mannheimia (Pasteurella) haemolytica Type A1 . • Contains killed bacterial culture plus a toxoid . • Produces leukotoxoid and whole-cell antibody responses, helping provide protection needed to withstand Mannheimia haemolytica challenge . • Single subcutaneous dose is 2 mL .

Respiratory-Reproductive Vaccines 41 ONE SHOT ULTRA® 7 ONE SHOT ULTRA® 8 Clostridium Chauvoei-Septicum-Novyi-Sordellii- Clostridium Chauvoei-Septicum-Haemolyticum- Perfringens Types C & D-Mannheimia Novyi-Sordellii-Perfringens Types C & D-Mannheimia Haemolytica Bacterin-Toxoid Haemolytica Bacterin-Toxoid

USES: USES: Aids in the prevention Aids in the prevention of of diseases caused by diseases caused by the the clostridial agents clostridial agents indicated indicated above and above and bovine bovine pneumonia pneumonia caused by caused by Mannheimia Mannheimia (Pasteurella) (Pasteurella) haemolytica haemolytica Type A1 . Type A1 . SUPPLIED: SUPPLIED: 10- and 50-dose vials . 10- and 50-dose vials . KEY FACTS: KEY FACTS: • Helps prevent eight clostridial diseases (including • Helps prevent seven clostridial diseases (including diseases caused by Cl. haemolyticum and Cl. perfringens diseases caused by Cl. perfringens Types B, C and D), Types B, C and D), which continue to be of economic which continue to be of economic importance in cattle . importance in cattle . Clostridium bacteria are universally Clostridium bacteria are universally present and produce present and produce potent toxins that can result in potent toxins that can result in rapid death of otherwise rapid death of otherwise healthy animals . healthy animals . • Helps protect against the primary cause of respiratory • Helps protect against the primary cause of respiratory death in cattle, shipping fever and pneumonia caused by death in cattle, shipping fever and pneumonia caused by Mannheimia (Pasteurella) haemolytica Type A1 . Mannheimia (Pasteurella) haemolytica Type A1 . • Produces leukotoxoid and whole-cell antibody • Produces leukotoxoid and whole-cell antibody responses, helping provide protection needed to responses, helping provide protection needed to withstand Mannheimia haemolytica challenge . withstand Mannheimia haemolytica challenge . • Contains STIMUGEN, a patented, water-soluble adjuvant • Contains STIMUGEN®, a patented, water-soluble that enhances the immune response with minimal risk of adjuvant that enhances the immune response with injection-site reactions . minimal risk of injection-site reactions . • No age restrictions on use . • No age restrictions on use . • Subcutaneous dose is 2 mL followed by a second • Subcutaneous dose is 2-mL followed by a second 2-mL dose of ULTRACHOICE® 8 four to six weeks later . 2 mL dose of ULTRACHOICE® 7 four to six weeks later . • For Cl. haemolyticum, repeat the dose every six months in animals subject to re-exposure .

42 Respiratory-Reproductive Vaccines PREGGUARD GOLD FP® 10 RESVAC® 4/SOMUBAC® Bovine Rhinotracheitis-Virus Diarrhea- Bovine Rhinotracheitis-Virus Diarrhea- Parainfluenza 3 Vaccine (Modified-Live Virus)- Parainfluenza 3-Respiratory Syncytial Virus Campylobacter Fetus-Leptospira Canicola- Vaccine (Modified-Live Virus)-Haemophilus Grippotyphosa-Hardjo-Icterohaemorrhagiae- Somnus Bacterin Pomona Bacterin USES: USES: Aids in the prevention of Prevents persistently diseases caused by infected calves caused infectious bovine by bovine viral diarrhea rhinotracheitis virus, (BVD) virus Types bovine viral diarrhea Type 1 1 and 2 and aids in virus, parainfluenza 3 virus, preventing abortion bovine respiratory syncytial caused by infectious bovine rhinotracheitis (IBR) virus virus and Histophilus somni (Haemophilus somnus) . and respiratory disease caused by IBR virus, BVD Types 1 SUPPLIED: and 2 viruses, and parainfluenza 3 (PI3) virus; BVD Type 2 testicular infection; campylobacteriosis (vibriosis) caused 10- and 50-dose vials . by Campylobacter fetus and leptospirosis caused by the KEY FACTS: fiveLeptospira serovars indicated above . A 12-month • Helps provide protection against four of the most duration of immunity has been demonstrated against IBR common bovine viral respiratory diseases plus H. somni . induced abortion and persistently infected calves caused • Intramuscular dose is 2-mL . Administer two doses by BVD Types 1 and 2 viruses . two to four weeks apart . SUPPLIED: • Annual revaccination with a single dose is 10- and 50-dose vials . recommended . KEY FACTS: •  Helps prevent BVD Types 1 and 2 persistent infection for at least 365 days . SOMUBAC® Haemophilus Somnus Bacterin • Aids in the prevention of IBR abortions for at least 365 days . USES: •  Aids in the prevention of respiratory disease caused by Aids in the prevention of disease

IBR virus, BVD virus Types 1 and 2, and PI3 virus . caused by Histophilus somni •  Aids in the prevention of campylobacteriosis caused by (Haemophilus somnus) . C. fetus and leptospirosis caused by the five serovars SUPPLIED: indicated above . 10- and 50-dose vials . •  Shown to be safe when given to pregnant cows or calves nursing pregnant cows .* KEY FACTS: • Helps protect calves and adult •  Intramuscular dose is 2 mL, given to breeding cows cattle against H. somni, a and heifers approximately one month prior to breeding contributor to respiratory or being added to the herd, followed by a single dose of disease and the cause of thrombotic VIBRIN/LEPTOFERM-5® two to four weeks later to help meningoencephalitis (TEME) and reproductive provide primary C. fetus and Leptospira immunization . tract infection . *Do not use in pregnant cattle (abortions can result) • Contains three inactivated H. somni isolates ⎯ from unless they were vaccinated, according to label respiratory, reproductive and nervous tissue . directions, with any BOVI-SHIELD GOLD FP® or • Subcutaneous dose is 2 mL followed by a second PREGGUARD GOLD FP® vaccine pre-breeding initially dose two to four weeks later . and within 12 months thereafter . Do not use in calves • Annual revaccination with a single dose is nursing pregnant cows unless their dams were recommended . vaccinated within the past 12 months as described above . To help ensure safety in pregnant cattle, heifers must receive at least 2 doses of any BOVI-SHIELD GOLD FP or PREGGUARD GOLD FP vaccine with the second dose administered approximately 30 days prebreeding. Respiratory-Reproductive Vaccines 43 SPIROVAC® SPIROVAC® VL5 Leptospira Hardjo Bacterin Campylobacter Fetus-Leptospira Canicola- Grippotyphosa-Hardjo-Icterohaemorrhagiae- USES: Pomona Bacterin Prevention of infection caused by Leptospira USES: borgpetersenii serovar Prevention of infection caused Hardjo type hardjo-bovis, by Leptospira borgpetersenii including genital and renal serovar Hardjo type hardjo- tract colonization, and bovis, including genital and urinary shedding for up to renal tract colonization and 12 months . urinary shedding for up to 12 months . Aids in the prevention of diseases SUPPLIED: caused by L. pomona, L. grippotyphosa, L. canicola, 10- and 50-dose vials . L. icterohaemorrhagiae and Campylobacter fetus . KEY FACTS: SUPPLIED: • Provides 12-month duration of immunity, resulting in 10- and 50-dose vials . less time and labor required for vaccination . •  Safe for use in pregnant cows, enabling whole-herd KEY FACTS: vaccination . •  Provides 12 month duration of immunity against Leptospira borgpetersenii serovar Hardjo type hardjo- • Subcutaneous dose is 2 mL followed by a second bovis, resulting in less time and labor required for dose given four to six weeks later . vaccination . • Annual revaccination with a single dose is •  Safe for use in pregnant cows, enabling whole-herd recommended . vaccination . •  Subcutaneous or intramuscular dose is 5 mL followed SPIROVAC® L5 by a second dose given four to six weeks later . Leptospira Canicola-Grippotyphosa-Hardjo- Icterohaemorrhagiae-Pomona Bacterin • Annual revaccination with a single dose is recommended . USES: Prevention of infection caused by Leptospira borgpetersenii serovar hardjo type hardjo-bovis, including genital and renal tract colonization and urinary shedding for up to 12 months . Aids in the prevention of diseases caused by L. pomona, L. grippotyphosa, L. canicola and L. icterohaemorrhagiae . SUPPLIED: 10- and 50-dose vials . KEY FACTS: •  Provides 12 month duration of immunity against Leptospira borgpetersenii serovar Hardjo type hardjo- bovis, resulting in less time and labor required for vaccination . •  Safe for use in pregnant cows, enabling whole-herd vaccination . •  Subcutaneous or intramuscular dose is 2 mL followed by a second dose given four to six weeks later . • Annual revaccination with a single dose is recommended .

44 Respiratory-Reproductive Vaccines STAYBRED® VL5 TSV-2®

Campylobacter Fetus-Leptospira-Canicola- Bovine Rhinotracheitis-Parainfluenza3 Vaccine Grippotyphosa-Hardjo-Icterohaemorrhagiae- (Modified-Live Virus) Pomona Bacterin USES: USES: Aids in the prevention of Aids in the prevention of diseases diseases caused by infectious caused by Campylobacter fetus and bovine rhinotracheitis (IBR) the fiveLeptospira serovars indicated virus and parainfluenza 3 above . virus . SUPPLIED: SUPPLIED: 10- and 50-dose vials . 1-, 10-, 25- and 50-dose vials . KEY FACTS: KEY FACTS: • Vaccination is the most cost-effective method of • Intranasal (IN) administration results in rapid local controlling two of the most important bovine immunity at the site of natural infection . reproductive diseases ⎯ campylobacteriosis (vibriosis) • Stimulates local and systemic immunity . and leptospirosis ⎯ that can be difficult to detect, particularly in adult cattle . • Rapid protection makes TSV-2® a tool to use in the face of a potential IBR outbreak in young cattle or when • Intramuscular dose is 2 mL followed by a second receiving long-haul, high-risk calves . dose two to four weeks later given to all breeding-age cows and heifers 30 to 60 days before exposure or • Safe for use in pregnant cows . being added to the breeding herd . • Single IN dose is 2 mL, with annual revaccination . • Annual revaccination with a single dose is recommended . • Occasional hypersensitivity reactions may occur up to 18 hours post-vaccination . Owners should be advised to VIBRIN® observe animals during this period . While this event Campylobacter Fetus Bacterin appears to be rare overall, dairy cattle may be affected more frequently than other cattle . USES: Aids in the prevention of campylobacteriosis (vibriosis) caused by Campylobacter fetus . SUPPLIED: 50-dose vials . KEY FACTS: • Helps protect against campylobacteriosis, a common but difficult-to-detect reproductive disease of cattle . • A single dose is effective . • May be given as early as seven months before breeding, making it ideal for use at fall pregnancy check . • Single subcutaneous dose is 2 mL given to all breeding cows and heifers between 30 days and seven months before breeding .

Respiratory-Reproductive Vaccines 45 OTHER HEALTH MANAGEMENT

THERABLOAT® (poloxalene)

USES: To treat legume (alfalfa, clover) bloat in cattle . SUPPLIED: 2-fl . oz . (59 1-mL). vial containing 25 g of poloxalene per fl . oz . KEY FACTS: • Relieves legume bloat within minutes . • Contains the surfactant poloxalene, an antifoaming agent that works by collapsing gas bubbles that cause bloat . • May be used in lactating animals . • Provided in concentrated form for easy storage and handling . • For animals up to 500 lb ., 1 fl . oz . added to 1 pint of water is given in a drenching bottle . For animals over 500 lb ., 2 fl . oz . are used . • Do not use in humans .

46 Other Health Management OTHER VACCINE SOLUTIONS

SRP® SALMONELLA SolidBac® Pinkeye IR/PR® Salmonella Newport Vaccine with SRP Moraxella Bovis Bacterin (Siderophore Receptors and Porins) USES: USES: Aids in the prevention and control Aids in the control of disease and fecal of pinkeye (infectious bovine shedding caused by infection with keratoconjunctivitis) caused by Salmonella Newport . Moraxella bovis . SUPPLIED: SUPPLIED: 100-mL vial (50 doses) . Five 10-dose clips (50 doses) . KEY FACTS: KEY FACTS: • Helps control infection and fecal • Implant system delivers both initial and booster doses at shedding of Salmonella the same time for season-long pinkeye protection . Newport, resulting in reduced • Immediate release (IR) pellet helps provide protection disease incidence and improved herd performance 1. while programmed release (PR) pellet provides a slow- • The SRP antibodies generated by vaccination with release booster . SRP® SALMONELLA vaccine have been shown to • No more mixing, spillage or waste . recognize the SRPs of several common Salmonella • Flexible, tissue-friendly injection site locations . serotypes 2. • Administer 2 mL (1 dose) subcutaneously ahead of the shoulder . Revaccinate in two or four weeks . Dry cows ESCHERICHIA COLI BACTERIAL and bred heifers should be vaccinated twice before calving; whole-herd vaccination may be done at any EXTRACT VACCINE with SRP® stage of lactation as an aid to control salmonellosis . technology Revaccinate annually . E. Coli O157 vaccine with SRP

1 Hermesch DR, Thomson DU, Loneragan GH, Renter DR, White BJ . (Siderophore Receptors and Porins) Effects of a commercially available vaccine against Salmonella enterica serotype Newport on milk production, somatic cell count and shedding USES: of Salmonella organisms in female dairy cattle with no clinical signs of Helps reduce the amount of Escherichia salmonellosis . Am J Vet Res . 2008;69:1229-1234 . coli (E. coli) 0157 in the intestines of cattle 2 Data on file, Epitopix Study Report No . N-0005-136-142, Zoetis Inc . and helps decrease the amount shed in the feces to minimize E.ncoli 0157 exposure and infection of herdmates . SUPPLIED: 100-mL vial (50 doses) . KEY FACTS: • The first and only vaccine conditionally licensed to reduce the amount of E. coli 0157 in cattle . • Has been shown to help reduce the number of cattle testing positive for the bacteria by 85% 1. • Those animals still testing positive demonstrated a 98% reduction in concentrations of E. coli 1. * This product license is conditional . Efficacy and potency test studies are in progress .

1  Thomson DU, Loneragan GH, Thornton AB, et al . Use of a siderophore receptor and porin proteins-based vaccine to control the burden of Escherichia coli 0157:H7 in feedlot cattle . Foodborne Pathog Dis . 2009;6:871-877 .

Other Vaccine Solutions 47 SERVICES

PEOPLEFIRSTTM Human Capital Solutions

The industry’s first comprehensive human capital and business management solutions service Since 2009, PeopleFirst™ Human Capital Solutions provides owners, managers, supervisors and employees of agricultural operations, veterinary clinics and ranch and farm retail with comprehensive and strategic services to address leadership development, employee training and business objectives and strategies .

EMPLOYEE SERVICES: BUSINESS SERVICES: • Leadership Certificate Program — This course, delivered • Profit Solver® — The ultimate financial diagnostic tool for in English and Spanish, develops leadership skills for your veterinary practice . Profit Solver can increase clinic managers and supervisors to help improve how they run profitability by a scientific method of determining fair their operation, agribusiness or veterinary practice . service pricing . Practice-specific recommendations are • Learning Management Portal — Online technology made using your own labor, equipment and inventory automates and centralizes employee orientation to costs . Guaranteed to double your investment the first year, ensure everyone develops the right skills to achieve or your money back* . organizational objectives . The portal gives your • Strategic Planning — Custom and standard consulting organization the ability to provide continuous training, help create a strategic plan for your business by track/score completion and customize and formalize identifying your three-year objectives, aligning your team learning plans . around your strategic intent and creating an action plan to • Focused Leadership Principles — The next step in accomplish your goals . advancing leadership skills for managers in the agricultural • Succession Planning — We will work with you to develop industry . Designed for leaders who have an understanding a plan to transfer your assets . We are experts at facilitating of leadership fundamentals and best practices and want those difficult conversations, with family members or to further develop their leadership skills . business partners, to satisfy your goals . We’ll work with • Customized services — An array of consultative services your own lawyer and accountant to put the plan in place . can be customized to meet your needs, including full • Marketing Planning — We’ll work with your staff to organizational evaluations, engagement and 360-degree develop plans to help your business grow . feedback, leadership training, change management and • Customized services — An array of consultative services executive coaching . can be customized to meet your business needs, client surveys, scenario planning and action planning .

Please contact your local Zoetis representative to find out more about PeopleFirst .

*Zoetis guarantees that if you implement, follow and adhere to the recommendations agreed upon during the Profit Solver implementation, for the opportunities identified (e g. ., the customer must be willing to raise fees or reduce costs for services as agreed upon during the implementation) for one full year, then you will increase the profit from your business in an amount equivalent to at least twice the first year’s fees paid for Profit Solver . The guarantee does not apply if your goal is to maintain the existing profit level of the business rather than increase it .

48 Services PRESCRIBING INFORMATION To report adverse reactions or to obtain a copy of the Material Safety Data EFFECTIVENESS: The effectiveness of 8 mg/kg administered once and Sheet (MSDS), call 1-888-963-8471. the 6 mg/kg BW alternate day regimen was confirmed in 4 well-controlled PRECAUTIONS: The effects of danofloxacin on bovine reproductive studies of naturally acquired bacterial respiratory infections in feedlot age performance, pregnancy, and lactation have not been determined. cattle. These studies were conducted under commercial conditions at 4 locations in North America. Bacterial pathogens isolated in the clinical field Subcutaneous injection can cause a transient local tissue reaction that trial are provided in the Microbiology section. may result in trim loss of edible tissue at slaughter. Sterile Injectable Solution The effectiveness of ADVOCIN for the control of BRD in cattle at high risk of Quinolone-class drugs should be used with caution in animals with known developing BRD associated with Mannheimia haemolytica and Pasteurella Antimicrobial or suspected central nervous system (CNS) disorders. In such animals, multocida was demonstrated in a multi-site study conducted in North quinolones have, in rare instances, been associated with CNS stimulation, 180 mg of danofloxacin as the mesylate salt/mL America. The study enrolled a total of 1,480 commercial, crossbred-beef, which may lead to convulsive seizures. Holstein and Holstein-cross steer calves at high risk of developing BRD For subcutaneous use in beef cattle. Quinolone-class drugs have been shown to produce erosions of cartilage associated with M. haemolytica and P. multocida. At enrollment, calves Not for use in cattle intended for dairy production or in calves to be of weight-bearing joints and other signs of arthropathy in immature, rapidly were randomly administered a one-time subcutaneous injection of either processed for veal. growing animals of various species. Refer to Animal Safety for information ADVOCIN at a dosage rate of 8 mg/kg of body weight or an equivalent specific to danofloxacin. CAUTION: Federal law restricts this drug to use by or on the order of a volume of sterile saline. Cattle were observed daily for clinical signs of licensed veterinarian. Federal law prohibits the extra-label use of this drug ADVERSE REACTIONS: A hypersensitivity reaction was noted in 2 healthy BRD and were evaluated for clinical success on Day 10 post-treatment. in food-producing animals. calves treated with ADVOCIN in a laboratory study. In one location of a The treatment success rate of ADVOCIN-treated calves (86.0%) was multi-site field trial, one out of the 41 calves treated with 6 mg/kg q 48 hours statistically significantly (p=0.0068) greater than that of saline-treated DESCRIPTION: ADVOCIN is a sterile injectable solution containing showed lameness on Day 6 only. In this same field trial location one of 38 calves (76.3%) (based on back-transformed least squares means). No danofloxacin mesylate, a synthetic fluoroquinolone antimicrobial calves treated with 8 mg/kg once became lame 4 days after treatment and adverse events associated with ADVOCIN administration were reported agent. Danofloxacin mesylate is the non-proprietary designation for remained lame on the last day of the study (Day 10). Another calf in the in the study. (1S)-1cyclopropyl-6-fluoro-1,4-dihydro-7-(5-methyl-2,5-diazabicyclo [2.2.1] same treatment group developed lameness on the last day of the study. hept-2-yl)-4-oxo-3-quinolone carboxylic acid monomethanesulfonate. ANIMAL SAFETY: Safety studies were conducted in feeder calves using CLINICAL PHARMACOLOGY: single doses of 10, 20, or 30 mg/kg for 6 consecutive days and 18, 24, or The empirical formula is C19H20FN3O3 • CH3SO3H and the molecular weight is 453.49. (a) Pharmacokinetics: Danofloxacin distributes extensively throughout the 60 mg/kg for 3 consecutive days. No clinical signs of toxicity were observed body, as evidenced by a steady state volume of distribution (VDss) in cattle at doses of 10 and 20 mg/kg when administered for 6 days, nor at doses Figure 1. The chemical structure of danofloxacin mesylate. exceeding 1 L/kg. Danofloxacin concentrations in the lung homogenates of 18 and 24 mg/kg when administered for 3 days. Articular cartilage markedly exceed those observed in plasma, further suggesting extensive lesions, consistent with fluoroquinolone chondropathy, were observed distribution to the indicated site of infection. Danofloxacin is rapidly after examination of joints from animals as follows: one of 5 animals eliminated from the body (apparent terminal elimination T½ ranging from administered 18 mg/kg for 3 days; one of 6 animals administered 20 mg/kg 3–6 hours), and negligible accumulation was observed when animals were for 6 days; 5 of 6 animals administered 30 mg/kg for 6 days; and in all 4 dosed twice, 48 hours apart. animals administered 60 mg/kg for 3 days. Clinical signs of inappetence, transient lameness (2/6), ataxia (2/6), tremors (2/6), nystagmus (1/6), Danofloxacin is rapidly absorbed and is highly bioavailable when exophthalmos (1/6), and recumbency (2/6) were observed when a dose administered as a subcutaneous injection in the neck. Linear of 30 mg/kg was administered for 6 consecutive days. Recumbency and pharmacokinetics has been demonstrated when danofloxacin is depression were seen in one out of 4 animals administered 60 mg/kg for administered to cattle by subcutaneous injection at doses between 1.25 3 days. Swelling at the injection site was noted at each dose level. Each mL contains 180 mg of danofloxacin as the mesylate salt, 200 mg to 10 mg/kg. No statistically significant gender difference was observed in peak or total systemic exposure following a single subcutaneous Safety was also evaluated in 21-day-old calves. In one group, these 2-pyrrolidone, 50 mg polyvinyl pyrrolidone, 20.3 mg heavy magnesium immature animals were given injections of 6 mg/kg on study days 0, 2, 3, oxide, 2.5 mg phenol, 5 mg monothioglycerol, hydrochloric acid or sodium administration of danofloxacin to heifers and steers at a dose of 6 mg/kg body weight (Table 1). 5, 6, and 8. A second group of animals received injections of 18 mg/kg for hydroxide as needed to adjust pH, nitrogen headspace and water for a total of 2 injections 48 hours apart. The only treatment-related sign was injection, q.s. Table 1. Danofloxacin pharmacokinetic values in male and female cattle erythema of the nasal pad in 3 of 6 calves that received 18 mg/kg. One calf INDICATIONS: For the treatment of bovine respiratory disease (BRD) (n=6/group) after a single subcutaneous injection into the lateral neck in the 6 mg/kg group had pre-treatment scleral erythema, and developed associated with Mannheimia haemolytica and Pasteurella multocida in beef region at a dose of 6 mg danofloxacin/kg body weight nasal erythema after treatment that may or may not have been treatment- cattle and for the control of BRD in beef cattle at high risk of developing BRD Steers Heifers related. No changes in clinical pathology parameters were observed. associated with Mannheimia haemolytica and Pasteurella multocida. Mean %CVe Mean %CV No articular cartilage lesions were observed in the joints at any dosage. DOSAGE AND ADMINISTRATION: Care should be taken to dose accurately. An injection site study conducted in feeder calves demonstrated that the a AUC µg x hr/mL 9.4 10 8.8 9 Administered dose volume should not exceed 15 mL per injection site. 0-24 product can induce a transient local reaction in the subcutaneous tissue b F% 92 5 87 3 Single-Dose Therapy (BRD Treatment and Control in Cattle at High Risk): a and underlying tissue. Cmax µg/mL 1.25 16 1.27 13 Administer subcutaneously at 8 mg/kg of body weight (2 mL/100 lb) as a a,c TOXICOLOGY: Ninety-day oral toxicity studies in dogs and rats Tmax hr 3.2 42 1.7 31 one-time injection. d CL L/hr 0.54 12 0.62 9 established a no observable effect level (NOEL) of 2.5 mg/kg bw/day and Multi-Day Therapy (BRD Treatment): Administer subcutaneously at d VDss L/kg 2.7 7 2.6 4 2.4 mg/kg bw/day, respectively. Higher doses in juvenile dogs produced 6 mg/kg of body weight (1.5 mL/100 lb) with this treatment repeated once a T½ hr 4.8 18 4.2 7 arthropathy, a typical quinolone-associated side effect. In chronic rodent approximately 48 hours following the first injection. bioassays, no evidence of carcinogenicity was associated with long-term a AUC = area under the plasma concentration versus time curve from hr zero to hr 24 ADVOCIN Dosage and Treatment Schedule 0-24 danofloxacin administration in rats and mice. No teratogenic effects were postdose. Cmax = maximum observed concentration. Tmax = time to Cmax. observed in rodents at doses up to 50 mg/kg bw/day (mice) or 100 mg/kg Dose Volume (mL) b Bioavailability (F%) = extent of drug absorption following subcutaneous administration. Within subject F values were determined as the ratio of AUC values estimated bw/day (rats) or in rabbits at the highest dose tested of 15 mg/kg bw/day. Cattle Weight 6 mg/kg, given twice, 8 mg/kg given once 0-inf following a 6 mg/kg dose administered by either a subcutaneous or intravenous A three-generation rat reproductive toxicity study established a NOEL of (lb) 48 hours apart (treatment and control injection. 6.25 mg/kg bw/day. Microbial safety analyses indicate that danofloxacin (treatment) in cattle at high risk) c Statistically significant differences in Tmax were detected between genders. Given residues present in edible tissues of treated animals under the current the similarity in Cmax values, these differences are not expected to have any clinical use conditions would most likely not cause adverse effects on the human 50 0.75 1 relevance. 100 1.5 2 d Clearance (CL) and Volume of distribution at steady state (VDss) were determined from intestinal micro flora of the consumer. 150 2.25 3 data obtained after intravenous administration of a 6 mg/kg dose. e STORAGE INFORMATION: Store at or below 30°C (86°F). Protect from light. 200 3 4 Coefficient of variation % Protect from freezing. The color is yellow to amber and does not affect 250 3.75 5 (b) Microbiology: Danofloxacin exerts its activity by inhibiting the bacterial potency. 300 4.5 6 DNA gyrase enzyme, thereby blocking DNA replication. Inhibition of DNA HOW SUPPLIED: ADVOCIN (180 mg danofloxacin/mL) is supplied in 100- 400 6 8 gyrase is lethal to bacteria and danofloxacin has been shown to be rapidly and 250-mL, amber-glass, sterile, multi-dose vials. 500 7.5 10 bactericidal. Danofloxacin is active against gram-negative and gram- 600 9 12 positive bacteria. NADA #141-207, Approved by FDA 700 10.5 14 The Minimum Inhibitory Concentrations (MIC) of danofloxacin for Distributed by: 800 12 16* pathogens isolated in natural infections from various clinical studies Zoetis Inc. 900 13.5 18* in North America, 1996–1997, were determined using the standardized Kalamazoo, MI 49007 1000 15 20* microdilution technique (Sensititre/Alamar, Accumed International), and are * Administered dose volume should not exceed 15 mL per injection site. shown in Table 2. Use Only as Directed Clinical field studies indicate that ADVOCIN (danofloxacin injection) Sterile Table 2. Danofloxacin minimum inhibitory concentration (MIC) values* of CONTACT INFORMATION: To report suspected adverse effects and/or Injectable Solution is effective for the control of respiratory disease in beef indicated pathogens isolated from 1996-1997 pivotal BRD treatment field obtain a copy of the MSDS or for technical assistance, call Zoetis Inc. at cattle at high risk of developing BRD. Cattle at high risk of developing BRD studies in the U.S. 1-888-963-8471. For additional information about adverse drug experience typically experience one or more of the following risk factors: ** ** Indicated Number of MIC50 MIC90 MIC Range reporting for animal drugs, contact FDA at 1-888-FDA-VETS or online at • Commingling from multiple sale barns/sources Pathogen Isolates (µg/mL) (µg/mL) (µg/mL) http://www.fda.gov/AnimalVeterinary/SafetyHealth. • Extended transport times and shrink Mannheimia 106 0.06 0.06 ≤0.015 to 0.12 • Exposure to wet or cold weather conditions or wide temperature haemolytica swings Pasteurella 94 ≤0.015 0.06 ≤0.015 to 0.12 • Stressful arrival processing procedures (such as castration, dehorning, multocida or branding) * The correlation between in vitro susceptibility data and clinical effectiveness is • Recent weaning or poor vaccination history unknown. Revised: May 2014 ** The lowest MIC to encompass 50% and 90% of the most susceptible isolates, Made in France RESIDUE WARNINGS: Animals intended for human respectively. consumption must not be slaughtered within 4 days from 8713843A&P the last treatment. Do not use in cattle intended for dairy Table 3. Danofloxacin minimum inhibitory concentration (MIC) values* of production. A withdrawal period has not been established indicated pathogens isolated from 2013 pivotal field studies in the U.S. and for this product in preruminating calves. Canada for the control of BRD in cattle at high risk of developing BRD. ** ** Do not use in calves to be processed for veal. Indicated Number of MIC50 MIC90 MIC Range HUMAN WARNINGS: For use in animals only. Keep out of reach of children. Pathogen Isolates (µg/mL) (µg/mL) (µg/mL) Avoid contact with eyes. In case of contact, immediately flush eyes with Mannheimia 507 0.03 0.06 ≤0.008 to >8 copious amounts of water for 15 minutes. In case of dermal contact, wash haemolytica skin with soap and water. Consult a physician if irritation persists following Pasteurella 324 ≤0.008 0.12 ≤0.008 to 1.0 ocular or dermal exposures. Individuals with a history of hypersensitivity multocida to quinolones should avoid this product. In humans, there is a risk of * The correlation between in vitro susceptibility data and clinical effectiveness is unknown. user photosensitization within a few hours after excessive exposure to **The lowest MIC to encompass 50% and 90% of the most susceptible isolates, quinolones. If excessive accidental exposure occurs, avoid direct sunlight. respectively.

50 Table 1. DRAXXIN Cattle Dosing Guide the extracellular pathogen activity typically associated with the 1 ® Animal Weight Dose Volume macrolides. Markedly higher tulathromycin concentrations are (Pounds) (mL) observed in the lungs as compared to the plasma. The extent to (tulathromycin) 100 1.1 which lung concentrations represent free (active) drug was not Injectable Solution 200 2.3 examined. Therefore, the clinical relevance of these elevated 300 3.4 lung concentrations is undetermined. Antibiotic 400 4.5 Although the relationship between tulathromycin and the 100 mg of tulathromycin/mL 500 5.7 characteristics of its antimicrobial effects has not been For use in beef cattle (including suckling calves), non-lactating 600 6.8 characterized, as a class, macrolides tend to be primarily dairy cattle (including dairy calves), veal calves, and swine. Not 700 8.0 bacteriostatic, but may be bactericidal against some pathogens.2 for use in female dairy cattle 20 months of age or older. 800 9.1 They also tend to exhibit concentration independent killing; CAUTION: Federal (USA) law restricts this drug to use by or on 900 10.2 the rate of bacterial eradication does not change once serum the order of a licensed veterinarian. 1000 11.4 drug concentrations reach 2 to 3 times the minimum inhibitory concentration (MIC) of the targeted pathogen. Under these DESCRIPTION Swine conditions, the time that serum concentrations remain above DRAXXIN Injectable Solution is a ready-to-use sterile parenteral Inject intramuscularly as a single dose in the neck at a dosage the MIC becomes the major determinant of antimicrobial preparation containing tulathromycin, a semi-synthetic of 2.5 mg/kg (0.25 mL/22 lb) BW. Do not inject more than activity. Macrolides also exhibit a post-antibiotic effect (PAE), macrolide antibiotic of the subclass triamilide. Each mL of 2.5 mL per injection site. DRAXXIN contains 100 mg of tulathromycin as the free base in the duration of which tends to be both drug and pathogen a 50% propylene glycol vehicle, monothioglycerol (5 mg/mL), Table 2. DRAXXIN Swine Dosing Guide dependent. In general, by increasing the macrolide with citric and hydrochloric acids added to adjust pH. Animal Weight Dose Volume concentration and the exposure time, the PAE will increase to DRAXXIN consists of an equilibrated mixture of two isomeric (Pounds) (mL) some maximal duration. Of the two variables, concentration forms of tulathromycin in a 9:1 ratio. Structures of the isomers 15 0.2 and exposure time, drug concentration tends to be the most are shown below. 30 0.3 powerful determinant of the duration of PAE. 50 0.6 Figure 1. Tulathromycin is eliminated from the body primarily unchanged 70 0.8 via biliary excretion. 90 1.0 1 Carbon, C. 1998. Pharmacodynamics of Macrolides, Azalides, 110 1.3 and Streptogramins: Effect on Extracellular Pathogens. Clin. 130 1.5 Infect. Dis., 27:28-32. 150 1.7 2 Nightingale, C.J. 1997. Pharmacokinetics and Pharma- 170 1.9 codynamics of Newer Macrolides. Pediatr. Infect. Dis. J., 190 2.2 16:438-443. 210 2.4 230 2.6 Cattle 250 2.8 Following subcutaneous administration into the neck of feeder 270 3.1 calves at a dosage of 2.5 mg/kg BW, tulathromycin is rapidly The chemical names of the isomers are (2R,3S,4R,5R,8R,10R, 290 3.3 and nearly completely absorbed. Peak plasma concentrations 11R,12S,13S,14R)-13-[[2,6-dideoxy-3-C-methyl-3- -methyl- Ο generally occur within 15 minutes after dosing and product 4-C-[(propylamino) methyl]- -L-ribo-hexopyrano-syl]oxy]- CONTRAINDICATIONS α relative bioavailability exceeds 90%. Total systemic clearance 2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11- The use of DRAXXIN Injectable Solution is contraindicated in is approximately 170 mL/hr/kg. Tulathromycin distributes [[3,4,6-trideoxy-3-(dimethylamino)- -D-xylo-hexopyrano- animals previously found to be hypersensitive to the drug. β extensively into body tissues, as evidenced by volume of syl]-oxy]-1-oxa-6-azacyclopentadecan-15-one and (2R,3R,6R, WARNINGS distribution values of approximately 11 L/kg in healthy rumi- 8R,9R,10S,11S,12R)-11-[[2,6-dideoxy-3-C-methyl-3- - Ο FOR USE IN ANIMALS ONLY. nating calves. 3 This extensive volume of distribution is largely methyl-4-C-[(propylamino)methyl]- -L-ribo-hexopyrano-syl] α NOT FOR HUMAN USE. responsible for the long elimination half-life of this compound oxy]-2-[(1R,2R)-1,2-dihydroxy-1-methylbutyl]-8-hydroxy- KEEP OUT OF REACH OF CHILDREN. [approximately 2.75 days in the plasma (based on quantifiable 3,6,8,10,12-pentamethyl-9-[[3,4,6-trideoxy-3-(dimethylamino)- NOT FOR USE IN CHICKENS OR TURKEYS. terminal plasma drug concentrations) versus 8.75 days for -D-xylo-hexopyranosyl]oxy]-1-oxa-4-azacyclotridecan-13- β RESIDUE WARNINGS total lung concentrations (based on data from healthy one, respectively. Cattle animals)]. Linear pharmacokinetics are observed with INDICATIONS Cattle intended for human consumption must not be subcutaneous doses ranging from 1.27 mg/kg BW to Beef and Non-Lactating Dairy Cattle slaughtered within 18 days from the last treatment. 5.0 mg/kg BW. No pharmacokinetic differences are observed BRD – DRAXXIN Injectable Solution is indicated for the Do not use in female dairy cattle 20 months of age in castrated male versus female calves. treatment of bovine respiratory disease (BRD) associated or older. 3 Clearance and volume estimates are based on intersubject with Mannheimia haemolytica, Pasteurella multocida, Swine comparisons of 2.5 mg/kg BW administered by either Histophilus somni, and Mycoplasma bovis; and for the control Swine intended for human consumption must not be subcutaneous or intravenous injection. of respiratory disease in cattle at high risk of developing BRD slaughtered within 5 days from the last treatment. Swine associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis. PRECAUTIONS Following intramuscular administration to feeder pigs at a IBK – DRAXXIN Injectable Solution is indicated for the Cattle dosage of 2.5 mg/kg BW, tulathromycin is completely and treatment of infectious bovine keratoconjunctivitis (IBK) The effects of DRAXXIN on bovine reproductive performance, rapidly absorbed (Tmax ~0.25 hour). Subsequently, the drug associated with Moraxella bovis. pregnancy, and lactation have not been determined. rapidly distributes into body tissues, achieving a volume of Foot Rot – DRAXXIN Injectable Solution is indicated for the Subcutaneous injection can cause a transient local tissue distribution exceeding 15 L/kg. The free drug is rapidly cleared treatment of bovine foot rot (interdigital necrobacillosis) reaction that may result in trim loss of edible tissue at from the systemic circulation (CLsystemic = 187 mL/hr/kg). associated with Fusobacterium necrophorum and slaughter. However, it has a long terminal elimination half-life (60 to 90 Porphyromonas levii. Swine hours) owing to its extensive volume of distribution. Although Suckling Calves, Dairy Calves, and Veal Calves The effects of DRAXXIN on porcine reproductive performance, pulmonary tulathromycin concentrations are substantially BRD - DRAXXIN Injectable Solution is indicated for the pregnancy, and lactation have not been determined. higher than concentrations observed in the plasma, the clinical treatment of BRD associated with M. haemolytica, P. multocida, Intramuscular injection can cause a transient local tissue significance of these findings is undetermined. There are no H. somni, and M. bovis. reaction that may result in trim loss of edible tissue at gender differences in swine tulathromycin pharmacokinetics. Swine slaughter. MICROBIOLOGY DRAXXIN Injectable Solution is indicated for the treatment ADVERSE REACTIONS Cattle of swine respiratory disease (SRD) associated with Cattle Tulathromycin has demonstrated in vitro activity against Actinobacillus pleuropneumoniae, Pasteurella multocida, In one BRD field study, two calves treated with DRAXXIN at Mannheimia haemolytica, Pasteurella multocida, Histophilus Bordetella bronchiseptica, Haemophilus parasuis, and 2.5 mg/kg BW exhibited transient hypersalivation. One of these somni, and Mycoplasma bovis, four pathogens associated Mycoplasma hyopneumoniae; and for the control of SRD calves also exhibited transient dyspnea, which may have been with BRD; against Moraxella bovis associated with IBK; and associated with Actinobacillus pleuropneumoniae, Pasteurella related to pneumonia. against Fusobacterium necrophorum and Porphyromonas levii multocida, and Mycoplasma hyopneumoniae in groups of pigs Swine associated with bovine foot rot. where SRD has been diagnosed. In one field study, one out of 40 pigs treated with DRAXXIN at The MICs of tulathromycin against indicated BRD and IBK DOSAGE AND ADMINISTRATION 2.5 mg/kg BW exhibited mild salivation that resolved in less pathogens were determined using methods recommended by Cattle than four hours. the Clinical and Laboratory Standards Institute (CLSI, M31-A2). Inject subcutaneously as a single dose in the neck at a dosage CLINICAL PHARMACOLOGY The MICs against foot rot pathogens were also determined of 2.5 mg/kg (1.1 mL/100 lb) body weight (BW). Do not inject At physiological pH, tulathromycin (a weak base) is using methods recommended by the CLSI (M11-A6). All MIC more than 10 mL per injection site. approximately 50 times more soluble in hydrophilic than values were determined using the 9:1 isomer ratio of this hydrophobic media. This solubility profile is consistent with compound.

51 BRD - The MICs of tulathromycin were determined for BRD EFFECTIVENESS normal respiration, and rectal temperature of < 104°F on Day 7. isolates obtained from calves enrolled in therapeutic and at-risk Cattle The treatment success rate was significantly greater (P ≤ 0.05) field studies in the U.S. in 1999. In the therapeutic studies, BRD – In a multi-location field study, 314 calves with naturally in DRAXXIN-treated pigs (70.5%) compared to saline-treated isolates were obtained from pre-treatment nasopharyngeal occurring BRD were treated with DRAXXIN. Responses to pigs (46.1%). M. hyopneumoniae was isolated from 106 swabs from all study calves, and from lung swabs or lung tissue treatment were compared to saline-treated controls. A cure was saline-treated and non-treated sentinel pigs in this study. of saline-treated calves that died. In the at-risk studies, isolates defined as a calf with normal attitude/activity, normal respiration, Two induced infection model studies were conducted to confirm were obtained from nasopharyngeal swabs of saline-treated and a rectal temperature of ≤ 104°F on Day 14. The cure rate the effectiveness of DRAXXIN against M. hyopneumoniae. Ten non-responders, and from lung swabs or lung tissue of saline- was significantly higher (P≤ 0.05) in DRAXXIN-treated calves days after inoculation intranasally and intratracheally with a field treated calves that died. The results are shown in Table 3. (78%) compared to saline-treated calves (24%). There were two strain of M. hyopneumoniae, 144 pigs were treated with either IBK - The MICs of tulathromycin were determined for Moraxella BRD-related deaths in the DRAXXIN-treated calves compared to DRAXXIN (2.5 mg/kg BW) intramuscularly or an equivalent volume of saline. Pigs were euthanized and necropsied 10 days bovis isolates obtained from calves enrolled in IBK field studies nine BRD-related deaths in the saline-treated calves. post-treatment. The mean percentage of gross pneumonic in the U.S. in 2004. Isolates were obtained from pre-treatment Fifty-two DRAXXIN-treated calves and 27 saline-treated calves lung lesions was statistically significantly lower (P < 0.0001) conjunctival swabs of calves with clinical signs of IBK enrolled in from the multi-location field BRD treatment study had Mycoplasma bovis identified in cultures from pre-treatment for DRAXXIN-treated pigs than for saline-treated pigs in both the DRAXXIN and saline-treated groups. The results are shown studies (8.52% vs. 23.62% and 11.31% vs. 26.42%). in Table 3. nasopharyngeal swabs. Of the 52 DRAXXIN-treated calves, 37 (71.2%) calves were categorized as cures and 15 (28.8%) The effectiveness of DRAXXIN for the control of SRD was Foot Rot - The MICs of tulathromycin were determined for calves were categorized as treatment failures. Of the 27 saline- evaluated in a multi-location natural infection field study. When Fusobacterium necrophorum and Porphyromonas levii obtained treated calves, 4 (14.8%) calves were categorized as cures and at least 15% of the study candidates showed clinical signs of from cattle enrolled in foot rot field studies in the U.S. and 23 (85.2%) calves were treatment failures. SRD, all pigs were enrolled and treated with DRAXXIN (226 pigs) Canada in 2007. Isolates were obtained from pre-treatment A Bayesian meta-analysis was conducted to compare the BRD or saline (227 pigs). Responses to treatment were evaluated interdigital biopsies and swabs of cattle with clinical signs of treatment success rate in young calves (calves weighing 250 on Day 7. Success was defined as a pig with normal attitude, foot rot enrolled in the DRAXXIN and saline-treated groups. lbs or less and fed primarily a milk-based diet) treated with normal respiration, and rectal temperature of < 104°F. The The results are shown in Table 3. DRAXXIN to the success rate in older calves (calves weighing treatment success rate was significantly greater (P < 0.05) in Table 3. Tulathromycin minimum inhibitory concentration (MIC) more than 250 lbs and fed primarily a roughage and grain-based DRAXXIN-treated pigs compared to saline-treated pigs (59.2% values* for indicated pathogens isolated from field studies diet) treated with DRAXXIN. The analysis included data from four vs. 41.2%). evaluating BRD and IBK in the U.S. and from foot rot field BRD treatment effectiveness studies conducted for the approval ANIMAL SAFETY studies in the U.S. and Canada. of DRAXXIN in the U.S. and nine contemporaneous studies Cattle conducted in Europe. The analysis showed that the BRD Indicated Date No. of MIC ** MIC ** MIC range Safety studies were conducted in feeder calves receiving a single 50 90 treatment success rate in young calves was at least as good pathogen isolated isolates (μg/mL) (μg/mL) (μg/mL) subcutaneous dose of 25 mg/kg BW, or 3 weekly subcutaneous as the BRD treatment success rate in older calves. As a result, doses of 2.5, 7.5, or 12.5 mg/kg BW. In all groups, transient Mannheimia DRAXXIN is considered effective for the treatment of BRD haemolytica 1999 642 2 2 0.5 to 64 indications of pain after injection were seen, including head associated with M. haemolytica, P. multocida, H. somni, and shaking and pawing at the ground. Injection site swelling, Pasteurella M. bovis in suckling calves, dairy calves, and veal calves. discoloration of the subcutaneous tissues at the injection multocida 1999 221 0.5 1 0.25 to 64 In another multi-location field study with 399 calves at high risk site and corresponding histopathologic changes were seen in Histophilus 1999 36 4 4 1 to 4 of developing BRD, administration of DRAXXIN resulted in a animals in all dosage groups. These lesions showed signs of somni significantly reduced incidence of BRD (11%) compared to resolving over time. No other drug-related lesions were observed Mycoplasma ≤ 0.063 saline-treated calves (59%). Effectiveness evaluation was based macroscopically or microscopically. bovis 1999 43 0.125 1 to > 64 on scored clinical signs of normal attitude/activity, normal An exploratory study was conducted in feeder calves receiving Moraxella bovis 2004 55 0.5 0.5 0.25 to 1 respiration, and a rectal temperature of ≤ 104°F on Day 14. a single subcutaneous dose of 10, 12.5, or 15 mg/kg BW. Fusobacterium ≤ 0.25 2007 116 2 64 There were no BRD-related deaths in the DRAXXIN-treated Macroscopically, no lesions were observed. Microscopically, necrophorum to > 128 calves compared to two BRD-related deaths in the saline-treated minimal to mild myocardial degeneration was seen in one of Porphyromonas ≤ 0.25 calves. Fifty saline-treated calves classified as non-responders 2007 103 8 128 six calves administered 12.5 mg/kg BW and two of six calves levii to > 128 in this study had Mycoplasma bovis identified in cultures of administered 15 mg/kg BW. post-treatment nasopharyngeal swabs or lung tissue. * The correlation between in vitro susceptibility data and clinical A safety study was conducted in preruminant calves 13 to 27 effectiveness is unknown. Two induced infection model studies were conducted to confirm days of age receiving 2.5 mg/kg BW or 7.5 mg/kg BW once ** The lowest MIC to encompass 50% and 90% of the most the effectiveness of DRAXXIN against Mycoplasma bovis. subcutaneously. With the exception of minimal to mild injection susceptible isolates, respectively. A total of 166 calves were inoculated intratracheally with field site reactions, no drug-related clinical signs or other lesions strains of Mycoplasma bovis. When calves became pyrexic and were observed macroscopically or microscopically. Swine had abnormal respiration scores, they were treated with either Swine In vitro activity of tulathromycin has been demonstrated against DRAXXIN (2.5 mg/kg BW) subcutaneously or an equivalent Actinobacillus pleuropneumoniae, Pasteurella multocida, volume of saline. Calves were observed for signs of BRD for 14 Safety studies were conducted in pigs receiving a single Bordetella bronchiseptica, Haemophilus parasuis, and days post-treatment, then were euthanized and necropsied. In intramuscular dose of 25 mg/kg BW, or 3 weekly intramuscular Mycoplasma hyopneumoniae. both studies, mean lung lesion percentages were statistically doses of 2.5, 7.5, or 12.5 mg/kg BW. In all groups, transient significantly lower in the DRAXXIN-treated calves compared with indications of pain after injection were seen, including restless- The MICs of tulathromycin against indicated SRD pathogens ness and excessive vocalization. Tremors occurred briefly in were determined using methods recommended by the Clinical saline-treated calves (11.3% vs. 28.9%, P = 0.0001 and 15.0% vs. 30.7%, P < 0.0001). one animal receiving 7.5 mg/kg BW. Discoloration and edema of and Laboratory Standards Institute (CLSI, M31-A and M31-A3). injection site tissues and corresponding histopathologic changes MICs for Haemophilus parasuis were determined using IBK – Two field studies were conducted evaluating DRAXXIN were seen in animals at all dosages and resolved over time. No Veterinary Fastidious Medium and were incubated up to 48 for the treatment of IBK associated with Moraxella bovis in 200 other drug-related lesions were observed macroscopically or naturally-infected calves. The primary clinical endpoint of these hours at 35 to 37°C in a CO2-enriched atmosphere. All MIC microscopically. values were determined using the 9:1 isomer ratio of this studies was cure rate, defined as a calf with no clinical signs of IBK and no corneal ulcer, assessed on Days 5, 9, 13, 17, and STORAGE CONDITIONS compound. Isolates obtained in 2000 and 2002 were from lung Store at or below 25°C (77°F) samples from saline-treated pigs and non-treated sentinel pigs 21. Time to improvement, defined as the first day on which HOW SUPPLIED enrolled in Treatment of SRD field studies in the U.S. and a calf had no clinical signs of IBK in both eyes, provided that DRAXXIN Injectable Solution is available in the following Canada. Isolates obtained in 2007 and 2008 were from lung those scores were maintained at the next day of observation, was assessed as a secondary variable. At all time points, in package sizes: samples from saline-treated and DRAXXIN-treated pigs enrolled both studies, the cure rate was significantly higher (P < 0.05) 50 mL vial in the Control of SRD field study in the U.S. and Canada. The for DRAXXIN-treated calves compared to saline-treated calves. 100 mL vial results are shown in Table 4. Additionally, time to improvement was significantly less 250 mL vial Table 4. Tulathromycin minimum inhibitory concentration (MIC) (P < 0.0001) in both studies for DRAXXIN-treated calves 500 mL vial values* for indicated pathogens isolated from field studies compared to saline-treated calves. NADA 141-244, Approved by FDA evaluating SRD in the U.S. and Canada. Foot Rot - The effectiveness of DRAXXIN for the treatment of Distributed by: Indicated Date No. of MIC50 ** MIC 90** MIC range bovine foot rot was evaluated in 170 cattle in two field studies. Zoetis Inc. Kalamazoo, MI 49007 pathogen isolated isolates (μg/mL) (μg/mL) (μg/mL) Cattle diagnosed with bovine foot rot were enrolled and treated Actinobacillus 2000-2002 135 16 32 16 to 32 with a single subcutaneous dose of DRAXXIN (2.5 mg/kg BW) or To report a suspected adverse reaction or to request a safety pleuropneumoniae 2007-2008 88 16 16 4 to 32 an equivalent volume of saline. Cattle were clinically evaluated 7 days after treatment for treatment success, which was based on data sheet call 1-888-963-8471. For additional information Haemophilus 0.25 about adverse drug experience reporting for animal drugs, parasuis 2000-2002 31 1 2 to > 64 defined decreases in lesion, swelling, and lameness scores. In both studies, the treatment success percentage was statistically contact FDA at 1-888-FDA-VETS or online at Pasteurella 2000-2002 55 1 2 0.5 to > 64 http://www.fda.gov/AnimalVeterinary/SafetyHealth. multocida 2007-2008 40 1 2 ≤ 0.03 to 2 significantly higher in DRAXXIN-treated calves compared with For additional DRAXXIN product information call: 1-888-DRAXXIN Bordetella saline-treated calves (60% vs. 8%, P < 0.0001 and 83.3% vs. or go to www.DRAXXIN.com bronchiseptica 2000-2002 42 4 8 2 to 8 50%, P = 0.0088). Swine * The correlation between in vitro susceptibility data and clinical effectiveness is unknown. In a multi-location field study to evaluate the treatment of naturally occurring SRD, 266 pigs were treated with DRAXXIN. ** The lowest MIC to encompass 50% and 90% of the most 032908ZOA&P susceptible isolates, respectively. Responses to treatment were compared to saline-treated controls. Success was defined as a pig with normal attitude, Made in Brazil Revised: February 2014

52 ADVERSE REACTIONS Swine In one field study, one out of 40 pigs treated with DRAXXIN Injectable Solution (100 mg/mL) at 2.5 mg/kg BW exhibited mild salivation that resolved in less than four hours. (tulathromycin injection) Calves In one BRD field study, two calves treated with DRAXXIN Injectable Solution (100 mg/mL) at 2.5 mg/kg BW Injectable Solution exhibited transient hypersalivation. One of these calves also exhibited transient dyspnea, which may have been Antibiotic related to pneumonia. 25 mg of tulathromycin/mL For use in suckling calves, dairy calves, veal calves, and swine. Not for use in ruminating cattle. Post Approval Experience The following adverse events are based on post approval adverse drug experience reporting for DRAXXIN Injectable CAUTION: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. Solution (100 mg/mL). Not all adverse events are reported to the FDA CVM. It is not always possible to reliably estimate the adverse event frequency or establish a causal relationship to product exposure using these data. The DESCRIPTION following adverse events are listed in decreasing order of reporting frequency in cattle: Injection site reactions and DRAXXIN 25 Injectable Solution is a ready-to-use sterile parenteral preparation containing tulathromycin, a semi- anaphylaxis/anaphylactoid reactions. For a complete listing of adverse reactions for DRAXXIN Injectable Solution or synthetic macrolide antibiotic of the subclass triamilide. Each mL of DRAXXIN 25 contains 25 mg of tulathromycin DRAXXIN 25 Injectable Solution reported to the CVM see: http://www.fda.gov/AnimalVeterinary. as the free base in a 50% propylene glycol vehicle, monothioglycerol (5 mg/mL), citric acid (4.8 mg/mL) with hydrochloric acid and sodium hydroxide added to adjust pH. DRAXXIN 25 consists of an equilibrated mixture of CLINICAL PHARMACOLOGY two isomeric forms of tulathromycin in a 9:1 ratio. At physiological pH, tulathromycin (a weak base) is approximately 50 times more soluble in hydrophilic than lipophilic media. This solubility profile is consistent with the extracellular pathogen activity typically associated with The chemical names of the isomers are (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[[2,6-dideoxy-3-C-methyl-3-Ο- the macrolides.1 Markedly higher tulathromycin concentrations are observed in the lung parenchyma as compared methyl-4-C-[(propylamino) methyl]-α-L-ribohexopyrano-syl]oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexam- to the plasma, and these elevated concentrations can remain in lung tissue for several days beyond that which can ethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]-oxy]-1-oxa-6-azacyclopentadecan-15-one be measured in the plasma. However the clinical relevance of these elevated lung concentrations is undetermined. and (2R,3R,6R,8R,9R,10S,11S,12R)-11-[[2,6-dideoxy-3-C-methyl-3-Ο-methyl-4-C-[(propylamino)methyl]-α-L-ri- 2 bohexopyrano-syl]oxy]-2-[(1R,2R)-1,2-dihydroxy-1-methylbutyl]-8-hydroxy-3,6,8,10,12-pentamethyl-9-[[3,4,6-tri- As a class, macrolides tend to be primarily bacteriostatic, but may be bactericidal against some pathogens. When acting as a cidal compound, they tend to exhibit concentration independent killing; the rate of bacterial eradication deoxy-3-(dimethylamino)-β-D-xylohexopyranosyl]oxy]-1-oxa-4-azacyclotridecan-13-one, respectively. does not change once serum drug concentrations reach 2 to 3 times the minimum inhibitory concentration (MIC) of INDICATIONS the targeted pathogen. Under these conditions, the time that serum concentrations remain above the MIC becomes Swine the major determinant of antimicrobial activity. Macrolides also exhibit a post-antibiotic effect (PAE), the duration of which tends to be both drug and pathogen dependent. In general, by increasing the macrolide concentration and DRAXXIN 25 Injectable Solution is indicated for the treatment of swine respiratory disease (SRD) associated 3 with Actinobacillus pleuropneumoniae, Pasteurella multocida, Bordetella bronchiseptica, Haemophilus parasuis, the exposure time, the PAE will increase to some maximal duration. Tulathromycin is eliminated from the body primarily unchanged via biliary excretion. and Mycoplasma hyopneumoniae; and for the control of SRD associated with Actinobacillus pleuropneumoniae, 1 Pasteurella multocida, and Mycoplasma hyopneumoniae in groups of pigs where SRD has been diagnosed. Carbon, C. 1998. Pharmacodynamics of Macrolides, Azalides, and Streptogramins: Effect on Extracellular Patho- gens. Clin. Infect. Dis., 27:28-32. 2 Suckling Calves, Dairy Calves, and Veal Calves Nightingale, C.J. 1997. Pharmacokinetics and Pharmacodynamics of Newer Macrolides. Pediatr. Infect. Dis. J., 16:438-443. BRD - DRAXXIN 25 Injectable Solution is indicated for the treatment of bovine respiratory disease (BRD) associated 3 with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis. Andes D, Anon J, Jacobs MR, Craig WA. (2004). Application of pharmacokinetics and pharmacodynamics to antimicrobial therapy of respiratory tract infections. Clin Lab Med., 24:477-502. DOSAGE AND ADMINISTRATION Swine Swine Following intramuscular (IM) administration to feeder pigs at a dosage of 2.5 mg/kg BW, tulathromycin is nearly Inject intramuscularly as a single dose in the neck at a dosage of 2.5 mg/kg (1 mL/22 lb) Body Weight (BW). completely absorbed, with peak plasma concentrations achieved within ~0.25 hr. The volume of distribution Do not inject more than 4 mL per injection site. exceeds 15 L/kg, which is consistent with extensive tissue binding. This large distribution volume results in a long terminal elimination half- life (60 to 90 hours) despite a rapid systemic free drug clearance (187 mL/kg/hr). There Table 1. DRAXXIN 25 Swine Dosing Guide (25 mg/mL) are no gender differences in swine tulathromycin pharmacokinetics. Animal Weight Dose Volume (Pounds) (mL) Comparative Bioavailability Summary 4 0.2 Despite slightly lower peak concentrations with DRAXXIN 25 Injectable Solution, a single IM dose of 2.5 mg 10 0.5 tulathromycin/kg BW of either DRAXXIN Injectable Solution (100 mg/mL) or DRAXXIN 25 Injectable Solution 15 0.7 (25 mg/mL) resulted in comparable tulathromycin total systemic exposure. Therefore, DRAXXIN 25 Injectable 20 0.9 Solution is considered to be therapeutically equivalent to DRAXXIN Injectable Solution when administered to swine 22 1.0 by IM injection at a dose of 2.5 mg tulathromycin/kg BW. 25 1.1 30 1.4 Calves 50 2.3 Following subcutaneous (SC) administration into the neck of feeder calves at a dosage of 2.5 mg/kg BW, tulath- 70 3.2 romycin is nearly completely absorbed, with peak plasma concentrations achieved within ~0.25 hr. The volume 4 90 4.0 of distribution exceeds 11 L/kg , which is consistent with extensive tissue binding. This large distribution volume results in a long terminal elimination half- life of more than 100 hours, despite a rapid systemic free drug clearance (170 mL/kg/hr). No pharmacokinetic differences are observed in castrated male versus female calves. Calves Inject subcutaneously as a single dose in the neck at a dosage of 2.5 mg/kg (1 mL/22 lb) body weight (BW). Do not Comparative Bioavailability Summary inject more than 11.5 mL per injection site. Despite lower peak concentrations with DRAXXIN 25 Injectable Solution, a single SC dose of 2.5 mg tulathromycin/kg BW of either DRAXXIN Injectable Solution (100 mg/mL) or DRAXXIN 25 Injectable Solution (25 mg/mL) resulted Table 2. DRAXXIN 25 Calf Dosing Guide (25 mg/mL) in comparable total systemic tulathromycin exposure. Therefore, DRAXXIN 25 Injectable Solution is considered to Animal Weight Dose Volume be therapeutically equivalent to DRAXXIN Injectable Solution when administered to calves by SC injection at a dose (Pounds) (mL) of 2.5 mg tulathromycin/kg BW. 50 2.3 4 Clearance and volume estimates are based on intersubject comparisons of 2.5 mg/kg BW administered by either 75 3.4 subcutaneous or intravenous injection. 100 4.5 150 7.0 MICROBIOLOGY 200 9.0 Swine 250 11.5 Tulathromycin has demonstrated in vitro activity against A. pleuropneumoniae, P. multocida, B. bronchiseptica, H. parasuis, and M. hyopneumoniae. The MICs of tulathromycin against indicated pathogens collected from field CONTRAINDICATIONS studies were determined using methods recommended by the Clinical and Laboratory Standards Institute (CLSI, The use of DRAXXIN 25 Injectable Solution is contraindicated in animals previously found to be hypersensitive M31-A and M31-A3). MICs for H. parasuis were determined using Veterinary Fastidious Medium and were incu- to the drug. bated up to 48 hours at 35 to 37°C in a CO2-enriched atmosphere. These values are represented in Table 3, below.

WARNINGS Table 3. Tulathromycin minimum inhibitory concentration (MIC) values* for indicated pathogens isolated from FOR USE IN ANIMALS ONLY. field studies evaluating SRD in the U.S. and Canada. NOT FOR HUMAN USE. Indicated Date No. of MIC50** MIC90** MIC KEEP OUT OF REACH OF CHILDREN. pathogen isolated isolates (μg/mL) (μg/mL) range NOT FOR USE IN CHICKENS OR TURKEYS. (μg/mL) RESIDUE WARNINGS Actinobacillus 2000-2002 135 16 32 16 to 32 Swine pleuropneumoniae 2007-2008 88 16 16 4 to 32 Swine intended for human consumption must not be slaughtered within 5 days from the last treatment. Haemophilus 2000-2002 31 1 2 0.25 to > 64 Calves parasuis Calves intended for human consumption must not be slaughtered within 22 days from the last treatment Pasteurella 2000-2002 55 1 2 0.5 to> 64 with DRAXXIN 25 Injectable Solution. This drug is not for use in ruminating cattle. multocida 2007-2008 40 1 2 ≤ 0.03 to 2 Bordetella 2000-2002 42 4 8 2 to 8 PRECAUTIONS bronchiseptica Swine *The correlation between in vitro susceptibility data and clinical effectiveness is unknown. The effects of Draxxin 25 Injectable Solution on porcine reproductive performance, pregnancy, and lactation have ** The lowest MIC to encompass 50% and 90% of the most susceptible isolates, respectively. not been determined. Intramuscular injection can cause a transient local tissue reaction that may result in trim loss of edible tissue at slaughter. Calves Cattle Tulathromycin has demonstrated in vitro activity against M. haemolytica, P. multocida, H. somni, and M. bovis, The effects of Draxxin 25 Injectable Solution on bovine reproductive performance, pregnancy, and lactation have four pathogens associated with BRD. The MICs of tulathromycin against indicated pathogens collected from field not been determined. Subcutaneous injection can cause a transient local tissue reaction that may result in trim loss studies using DRAXXIN Injectable Solution (100 mg/mL) were determined using methods recommended by the of edible tissue at slaughter. CLSI (M31-A2). These values are represented in Table 4, below. 53 Table 4. Tulathromycin minimum inhibitory concentration (MIC) values* for indicated pathogens isolated from Calves field studies evaluating BRD in the U.S. Plasma concentrations of tulathromycin administered as DRAXXIN Injectable Solution (100 mg/mL) or as DRAXXIN 25 Injectable Solution were demonstrated to be therapeutically equivalent (see CLINICAL PHARMACOLOGY, Indicated Date No. of MIC50** MIC90** MIC pathogen isolated isolates (μg/mL) (μg/mL) range Comparative Bioavailability Summary). Therefore effectiveness studies conducted with DRAXXIN Injectable Solution (μg/mL) support the effectiveness for DRAXXIN 25 Injectable Solution. Mannheimia 1999 642 2 2 0.5 to 64 A safety study was conducted in feeder calves receiving DRAXXIN Injectable Solution (100 mg/mL) as a single haemolytica subcutaneous dose of 25 mg/kg BW, or 3 weekly subcutaneous doses of 2.5, 7.5, or 12.5 mg/kg BW. In all groups, Pasteurella 1999 221 0.5 1 0.25 to 64 transient indications of pain after injection were seen, including head shaking and pawing at the ground. Injection multocida site swelling, discoloration of the subcutaneous tissues at the injection site and corresponding histopathologic Histophilus 1999 36 4 4 1 to 4 changes were seen in animals in all dosage groups. These lesions showed signs of resolving over time. No other somni drug-related lesions were observed macroscopically or microscopically. Mycoplasma 1999 43 0.125 1 ≤ 0.063 to An exploratory study was conducted in feeder calves receiving DRAXXIN Injectable Solution (100 mg/mL) as a bovis > 64 single subcutaneous dose of 10, 12.5, or 15 mg/kg BW. Macroscopically, no lesions were observed. Microscopically, minimal to mild myocardial degeneration was seen in one of six calves administered 12.5 mg/kg BW and two of * The correlation between in vitro susceptibility data and clinical effectiveness is unknown. six calves administered 15 mg/kg BW. ** The lowest MIC to encompass 50% and 90% of the most susceptible isolates, respectively. A safety study was conducted in preruminant calves 13 to 27 days of age receiving DRAXXIN Injectable Solution EFFECTIVENESS (100 mg/mL) at 2.5 mg/kg BW or 7.5 mg/kg BW once subcutaneously. With the exception of minimal to mild Swine injection site reactions, no drug-related clinical signs or other lesions were observed macroscopically or micro- Plasma concentrations of tulathromycin administered as DRAXXIN Injectable Solution (100 mg/mL) or as scopically. DRAXXIN 25 Injectable Solution were demonstrated to be therapeutically equivalent (see CLINICAL PHARMACOLOGY, Comparative Bioavailability Summary). Therefore effectiveness studies conducted with DRAXXIN Injectable Solution Sixteen growing cattle were injected with either saline (eight animals) as a single injection of 11.5 mL or DRAXXIN (100 mg/mL) support the effectiveness for DRAXXIN 25 Injectable Solution. 25 Injectable Solution (eight animals) as a single injection of either 2.5 mg/kg BW or a dose volume of 11.5 mL (whichever volume was higher). One calf in the DRAXXIN 25-treated group was observed to have firmness at the In a multi-location field study to evaluate the treatment of naturally occurring SRD, 266 pigs were treated with injection site for a single day. Two DRAXXIN 25-treated calves exhibited injection site swelling. In one calf, the DRAXXIN Injectable Solution (100 mg/mL). Responses to treatment were compared to saline-treated controls. swelling resolved within 48 hours. In the other calf, the swelling was observed over a three-day period, after which Success was defined as a pig with normal attitude, normal respiration, and rectal temperature of < 104°F on Day 7. the calf underwent a scheduled necropsy, preventing further injection site observations. No injection site swelling The treatment success rate was significantly greater (P≤ 0.05) in DRAXXIN-treated pigs (70.5%) compared to was observed in saline-treated animals. At necropsy, three of the saline-treated calves and five of the DRAXXIN saline-treated pigs (46.1%). M. hyopneumoniae was isolated from 106 saline-treated and non-treated sentinel 25-treated calves had altered tissue present at the injection site. The gross and microscopic findings in the DRAXXIN pigs in this study. 25-treated group were consistent with inflammatory changes induced by injections, were considered to be mild to marked, and progressed to macroscopic resolution and microscopic resolution by Day 42 post-injection. Two induced infection model studies were conducted to confirm the effectiveness of DRAXXIN Injectable Solution (100 mg/mL) against M. hyopneumoniae. Ten days after inoculation intranasally and intratracheally with a field STORAGE CONDITIONS: strain of M. hyopneumoniae, 144 pigs were treated with either DRAXXIN (2.5 mg/kg BW) intramuscularly or an Store at or below 25°C (77°F). Use within 90 days of first vial puncture. equivalent volume of saline. Pigs were euthanized and necropsied 10 days post-treatment. The mean percentage of gross pneumonic lung lesions was statistically significantly lower (P < 0.0001) for DRAXXIN-treated pigs than for HOW SUPPLIED saline-treated pigs in both studies (8.52% vs. 23.62% and 11.31% vs. 26.42%). DRAXXIN 25 Injectable Solution is available in the following package sizes: The effectiveness of DRAXXIN Injectable Solution (100 mg/mL) for the control of SRD was evaluated in a multi- 50 mL vial location natural infection field study. When at least 15% of the study candidates showed clinical signs of SRD, 100 mL vial all pigs were enrolled and treated with DRAXXIN (226 pigs) or saline (227 pigs). Responses to treatment were 250 mL vial evaluated on Day 7. Success was defined as a pig with normal attitude, normal respiration, and rectal temperature of < 104°F. The treatment success rate was significantly greater (P < 0.05) in DRAXXIN-treated pigs compared to NADA 141-349, Approved by FDA saline-treated pigs (59.2% vs. 41.2%). Distributed by: Calves Zoetis Inc. Plasma concentrations of tulathromycin administered as DRAXXIN Injectable Solution (100 mg/mL) or as DRAXXIN Kalamazoo, MI 49007 25 Injectable Solution were demonstrated to be therapeutically equivalent (see CLINICAL PHARMACOLOGY, Comparative Bioavailability Summary). Therefore effectiveness studies conducted with DRAXXIN Injectable Solution To report a suspected adverse reaction or to request a safety data sheet call 1-888-963-8471. For additional (100 mg/mL) support the effectiveness for DRAXXIN 25 Injectable Solution. information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or online at http://www.fda.gov/AnimalVeterinary/SafetyHealth. BRD - In a multi-location field study, 314 calves with naturally occurring BRD were treated with DRAXXIN Injectable For additional DRAXXIN 25 product information call: 1‑888‑DRAXXIN or go to www.DRAXXIN.com Solution (100 mg/mL). Responses to treatment were compared to saline-treated controls. A cure was defined as a calf with normal attitude/activity, normal respiration, and a rectal temperature of ≤ 104°F on Day 14. The cure rate was significantly higher (P≤ 0.05) in DRAXXIN-treated calves (78%) compared to saline-treated calves (24%). There were two BRD-related deaths in the DRAXXIN-treated calves compared to nine BRD-related deaths in the saline-treated calves. 060005AAA&P Made in Brazil Revised: September 2014 Fifty-two DRAXXIN Injectable Solution (100 mg/mL)-treated calves and 27 saline-treated calves from the multi- location field BRD treatment study had Mycoplasma bovis identified in cultures from pre-treatment nasopharyngeal swabs. Of the 52 DRAXXIN-treated calves, 37 (71.2%) calves were categorized as cures and 15 (28.8%) calves were categorized as treatment failures. Of the 27 saline-treated calves, 4 (14.8%) calves were categorized as cures and 23 (85.2%) calves were treatment failures. A Bayesian meta-analysis was conducted to compare the BRD treatment success rate in young calves (calves weighing 250 lbs or less and fed primarily a milk-based diet) treated with DRAXXIN Injectable Solution (100 mg/mL) to the success rate in older calves (calves weighing more than 250 lbs and fed primarily a roughage and grain- based diet) treated with DRAXXIN. The analysis included data from four BRD treatment effectiveness studies conducted for the approval of DRAXXIN Injectable Solution (100 mg/mL) in the U.S. and nine contemporaneous studies conducted in Europe. The analysis showed that the BRD treatment success rate in young calves was at least as good as the BRD treatment success rate in older calves. As a result, DRAXXIN Injectable Solution (100 mg/mL) was considered effective for the treatment of BRD associated with M. haemolytica, P. multocida, H. somni, and M. bovis in suckling calves, dairy calves, and veal calves. Two induced infection model studies were conducted to confirm the effectiveness of DRAXXIN Injectable Solution (100 mg/mL) against Mycoplasma bovis. A total of 166 calves were inoculated intratracheally with field strains of Mycoplasma bovis. When calves became pyrexic and had abnormal respiration scores, they were treated with either DRAXXIN (2.5 mg/kg BW) subcutaneously or an equivalent volume of saline. Calves were observed for signs of BRD for 14 days post-treatment, then were euthanized and necropsied. In both studies, mean lung lesion per- centages were statistically significantly lower in the DRAXXIN-treated calves compared with saline-treated calves (11.3% vs. 28.9%, P = 0.0001 and 15.0% vs. 30.7%, P < 0.0001).

ANIMAL SAFETY Swine Plasma concentrations of tulathromycin administered as DRAXXIN Injectable Solution (100 mg/mL) or as DRAXXIN 25 Injectable Solution were demonstrated to be therapeutically equivalent (see CLINICAL PHARMACOLOGY, Comparative Bioavailability Summary). Therefore systemic target animal safety studies conducted with DRAXXIN Injectable Solution support the systemic safety for DRAXXIN 25 Injectable Solution. Safety studies were conducted in pigs receiving a single intramuscular dose of 25 mg/kg BW, or 3 weekly intramus- cular doses of 2.5, 7.5, or 12.5 mg/kg BW (both studies utilized DRAXXIN Injectable Solution (100 mg/mL)). In all groups, transient indications of pain after injection were seen, including restlessness and excessive vocalization. Tremors occurred briefly in one animal receiving 7.5 mg/ kg BW. Discoloration and edema of injection site tissues and corresponding histopathologic changes were seen in animals at all dosages and resolved over time. No other drug-related lesions were observed macroscopically or microscopically. Sixteen growing pigs were injected with either saline or DRAXXIN 25 Injectable Solution as a single injection of 4 mL. Injection site observations included two instances of erythema in the DRAXXIN 25-treated group on Day 1 post-injection. No heat, sensitivity, firmness, necrosis, drainage, or swelling was observed at any injection sites in either treatment group. The gross and microscopic findings in the DRAXXIN 25-treated group were consistent with inflammatory changes induced by injections and were considered to be mild or moderate with progression to macroscopic resolution by Day 28 post-injection and microscopic resolution by Day 42 post-injection. 54 ADMINISTRATION ADMINISTRATION FOR THE MIDDLE THIRD OF THE EAR • Shake well before using. Please read the complete package insert before administering EXCEDE Sterile Suspension subcutaneously in the posterior ear of cattle. (Ceftiofur Crystalline Free Acid) • Deposit as a single subcutaneous injection in the middle third of the posterior aspect of the ear, Sterile Suspension avoiding all blood vessels. See Figures 2 and 3. • Adjust the needle insertion point to avoid any blood vessels, previous implants, ear tags or ear tag For subcutaneous injection in the posterior aspect of the ear where it attaches to the head (base holes. Do not administer intra-arterially. of the ear) in lactating dairy cattle. For subcutaneous injection in the middle third of the posterior • Deliver the entire contents of the syringe. aspect of the ear or in the posterior aspect of the ear where it attaches to the head (base of the • When administered correctly, a subcutaneous bleb of EXCEDE Sterile Suspension will appear. ear) in beef and non-lactating dairy cattle. Not for use in calves to be processed for veal. • When withdrawing the needle, apply pressure to the needle insertion point, and massage toward the CAUTION base of the ear. Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. Federal Law prohibits extra-label use of this drug in cattle for disease prevention purposes; at unapproved doses; Figure 2. Subcutaneous administration of EXCEDE Sterile Suspension in the middle third of the frequencies, durations, or routes of administration; and in unapproved major food producing species/ posterior aspect of the ear. production classes. DESCRIPTION EXCEDE Sterile Suspension is a ready-to-use formulation that contains the crystalline free acid of ceftiofur, which is a broad spectrum cephalosporin antibiotic active against Gram-positive and Gram- negative bacteria including ß-lactamase-producing strains. Like other cephalosporins, ceftiofur is bactericidal, in vitro, resulting from inhibition of cell wall synthesis. Each mL of this ready-to-use sterile suspension contains ceftiofur crystalline free acid equivalent to 200 mg ceftiofur, in a caprylic/capric triglyceride (Miglyol®) and cottonseed oil based suspension. Figure 1. Structure of ceftiofur crystalline free acid:

Figure 3. Diagram of the approximate locations of the major arteries of the posterior ear and the Chemical name of ceftiofur crystalline free acid: recommended needle insertion locations. Administration of EXCEDE Sterile Suspension into ear 7-[[2-(2-Amino-4-thiazolyl)-2-(methoxyimino)acetyl]amino]- 3-[[(2-furanylcarbonyl)thio] methyl]-8- arteries is likely to be fatal. oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene 2-carboxylic acid INDICATIONS EXCEDE Sterile Suspension is indicated for treatment of bovine respiratory disease (BRD, shipping fever, pneumonia) associated with Mannheimia haemolytica, Pasteurella multocida, and Histophilus locations for somni in beef, non-lactating dairy, and lactating dairy cattle. injections EXCEDE Sterile Suspension is also indicated for the control of respiratory disease in beef and non-lactating dairy cattle which are at high risk of developing BRD associated with M. haemolytica, P. multocida, and H. somni. EXCEDE Sterile Suspension is also indicated for the treatment of bovine foot rot (interdigital necrobacillosis) associated with Fusobacterium necrophorum and Porphyromonas levii in beef, non- lactating dairy, and lactating dairy cattle. EXCEDE Sterile Suspension is also indicated for treatment of acute metritis (0-10 days post-partum) main ear associated with bacterial organisms susceptible to ceftiofur in lactating dairy cattle. arteries (avoid) large vein DOSAGE (avoid) Treatment of BRD and bovine foot rot Administer as a single subcutaneous injection in the posterior aspect of the ear where it attaches to the head (base of the ear) to cattle at a dosage of 3.0 mg ceftiofur equivalents (CE)/lb (6.6 mg CE/kg) ADMINISTRATION FOR BASE OF THE EAR body weight (BW) (1.5 mL sterile suspension per 100 lb BW). In lactating dairy cattle the injection techniques for subcutaneous (SC) injection in the posterior In beef and non-lactating dairy cattle, EXCEDE Sterile Suspension may also be administered as a aspect of the ear where it attaches to the head (base of the ear) can be made by the rostral or ventral single subcutaneous injection in the middle third of the posterior aspect of the ear at a dosage of injection techniques. 3.0 mg CE/lb (6.6 mg CE/kg) BW (1.5 mL sterile suspension per 100 lb BW). In beef and non-lactating dairy cattle the SC injection in the base of the ear can be made by the rostral, Most animals will respond to treatment within three to five days. If no improvement is observed, the ventral or toward the opposite eye injection techniques. diagnosis should be reevaluated. • Shake well before using. Please read the complete package insert before administering EXCEDE Control of BRD Sterile Suspension subcutaneously in the posterior aspect of the ear where it attaches to the head Administer as a subcutaneous injection either in the middle third of the posterior aspect of the ear (base of the ear). or in the posterior aspect of the ear where it attaches to the head (base of the ear) to beef and non- • The subcutaneous (SC) injection may be made using the toward the opposite eye, rostral, or ventral lactating dairy cattle at a dosage of 3.0 mg CE/lb (6.6 mg CE/kg) BW (1.5 mL sterile suspension per techniques. Hold the syringe and needle and insert the needle as described below. 100 lb BW). • Deliver the entire contents of the syringe. Clinical studies indicate that administration of EXCEDE Sterile Suspension is effective for the control • Do not administer EXCEDE Sterile Suspension in the neck. of respiratory disease in beef and non-lactating dairy cattle at “high risk” of devel oping BRD. One or Administration for the Base of the Ear: Toward the Opposite Eye Technique more of the following factors typically characterizes calves on arrival at high risk of developing BRD. • Hold the syringe and needle behind the ear to be dosed so the needle and syringe point in the • Cattle are from multiple farm origins, direction of an imaginary line that would pass through the head toward the animal’s opposite eye. • cattle have had extended transport times (that may have included few if any rest stops), See Figures 4 and 5. • ambient temperature change from origin to arrival of 30° F or more, • Insert the needle through the loose skin in the posterior aspect of the ear where it attaches to the • cattle have had continued exposure to extremely wet or cold weather conditions, head (base of the ear) while maintaining this angle. See Figure 4. • cattle have experienced excessive shrink or excessive arrival processing procedures (such as castration, dehorning). Figure 4. Subcutaneous administration of EXCEDE Sterile Suspension in the posterior aspect of the Treatment of Acute Metritis ear where it attaches to the head (base of the ear). Administer as a subcutaneous injection in the posterior aspect of the ear where it attaches to the head (base of the ear) to lactating dairy cattle at a dosage of 3.0 mg CE/lb (6.6 mg CE/kg) BW (1.5 mL sterile suspension per 100 lb BW). Repeat this dose in the contra-lateral (opposite) ear approximately 72 hours following the initial dose. Table 1. Dosing Schedule for EXCEDE Sterile Suspension. Weight Dose Volume Weight Dose Volume (lb) (mL) (lb) (mL) 100 1.5 1100 16.5 200 3.0 1200 18.0 300 4.5 1300 19.5 400 6.0 1400 21.0 500 7.5 1500 22.5 600 9.0 1600 24.0 700 10.5 1700 25.5 800 12.0 1800 27.0 900 13.5 1900 28.5 1000 15.0 2000 30.0 55 Figure 5. Injection location for the subcutaneous administration of EXCEDE Sterile Suspension in ANTIBACTERIAL WARNINGS the posterior aspect of the ear where it attaches to the head (base of the ear). Use of antibacterial drugs in the absence of a susceptible bacterial infection is unlikely to provide benefit to treated animals and may increase the risk of the development of drug-resistant bacteria. PRECAUTIONS Following subcutaneous injection in the middle third of the posterior aspect of the ear, thickening and swelling (characterized by aseptic cellular infiltrate) of the ear may occur. As with other parenteral injections, localized post-injection bacterial infections may result in abscess formation. Attention to hygienic procedures can minimize their occurrence. Following injection in the posterior aspect of the ear where it attaches to the head (base of the ear), areas of discoloration and signs of inflammation may persist at least 13 days post administration resulting in trim loss of edible tissue at slaughter. Injection of volumes greater than 20 mL, in the middle third of the ear, may result in open draining lesions in a small percentage of cattle. The effects of ceftiofur on bovine reproductive performance, pregnancy, and lactation have not been location for injection determined. ADVERSE EFFECTS Administration for the Base of Ear: Toward the Same Eye Technique or Rostral Direction Intra-arterial injection may occur during administration of EXCEDE Sterile Suspension via middle third • Hold the syringe and needle behind the ear to be dosed so the needle and syringe point in the of the ear injection or base of the ear injection directed towards the opposite eye. Intra-arterial injection direction of an imaginary line that would pass through the head toward the eye on the same side of of EXCEDE Sterile Suspension is likely to result in sudden death of the animal. During the conduct of the head. See Figures 5 and 6. clinical studies, there was a low incidence of acute death (see ANIMAL SAFETY) confirmed to be the • Insert the needle through the loose skin in the posterior aspect of the ear where it attaches to the result of inadvertent intra-arterial injection. No other adverse systemic effects were noted for either the head (base of the ear) while maintaining the needle position. See Figure 6. antibiotic or formulation during any of the clinical and target animal safety studies. CLINICAL PHARMACOLOGY Figure 6. Diagram of head showing the direction for the base of ear injections administered Ceftiofur administered as either ceftiofur sodium (NAXCEL® Sterile Powder), ceftiofur hydrochloride rostrally toward the eye on the same side of the head into the loose skin in the caudal aspect of the (EXCENEL® RTU Sterile Suspension), or ceftiofur crystalline free acid (EXCEDE Sterile Suspension) is base of the ear. metabolized rapidly to desfuroylceftiofur, the primary metabolite. Subcutaneous administration of ceftiofur crystalline free acid, either in the middle third of the posterior aspect of the ear (middle third of the ear, MOE) of beef and non-lactating dairy cattle, or in the posterior aspect of the ear where it attaches to the head (base of the ear, BOE) of beef, non-lactating dairy, and lactating dairy cattle, provides therapeutic concentrations of ceftiofur and desfuroylceftiofur-related metabolites in plasma above the lowest minimum inhibitory concentration to encompass 90% of the most susceptible isolates (MIC90) for the labeled BRD pathogens, Pasteurella multocida, Mannheimia haemolytica and Histophilus somni, for generally not less than 150 hours after a single administration (See Figure 8). Single Dose Regimen The pharmacokinetic parameters for the two subcutaneous locations of injection (MOE and BOE) are found in Table 2. Statistical analyses of the data from these two subcutaneous injection sites (MOE and BOE) demonstrate that they are therapeutically equivalent. Figure 8. Average (n=12/group) plasma concentrations of ceftiofur and desfuroylceftiofur-related metabolites after administration of EXCEDE Sterile Suspension at 3.0 mg CE/lb (6.6 mg CE/kg) BW via subcutaneous injection into one of two different locations of the ear, middle third of the ear (MOE Administration for Base of the Ear: Ventral Technique Cattle) and base of the ear (BOE Cattle) in beef cattle as well into the base of the ear (BOE Lactating) • Hold the syringe and needle above the ear to be dosed so that the needle and syringe are pointing in lactating dairy cattle. ventrally toward the base of the ear. The needle will be inserted into the loose skin in the posterior aspect of the ear where it attaches to the head (base of the ear) while pointing ventrally. Care should be taken to not insert the needle through the cartilage of the ear. See Figure 7. • Insert the needle through the loose skin in the posterior aspect of the ear where it attaches to the head (base of the ear) while maintaining needle position. See Figure 7. Figure 7. Diagram of head showing the direction of base of ear injections when administered ventrally into the loose skin in the caudal aspect of the base of the ear. its metabolites (μg/mL) Concentration of ceftiofur and

Day Table 2. Average (n = 12/group) pharmacokinetic parameters for ceftiofur and desfuroylceftiofur metabolites calculated after a single subcutaneous administration of 3.0 mg CE/lb (6.6 mg CE/kg) BW of EXCEDE Sterile Suspension in either the middle third of the ear or the base of the ear.

CONTRAINDICATIONS Pharmacokinetic Beef - Middle Beef - Base of Dairy Cow - As with all drugs, the use of EXCEDE Sterile Suspension is contraindicated in animals pre viously Parameter Third of the Ear the Ear Base of the Ear Mean Value ± Mean Value ± Mean Value ± found to be hypersensitive to the drug. Standard Standard Standard WARNINGS Deviation Deviation Deviation FOR USE IN ANIMALS ONLY. NOT FOR HUMAN USE. KEEP OUT OF REACH OF CHILDREN. Penicillins and cephalosporins can cause allergic reactions in sensitized individuals. Topical exposures Cmax (μg CE/mL) 6.90 ± 2.68 6.39 ± 1.79 4.44 ± 1.65 to such antimicrobials, including ceftiofur, may elicit mild to severe allergic reactions in some individuals. tmax (h) 12.0 ± 6.2 19.8 ± 5.81 19.00 ± 8.02 Repeated or prolonged exposure may lead to sensitization. Avoid direct contact of the product with the AUC 0-LOQ (μg•h/mL) 376 ± 66.1 412 ± 67.3 313 ± 85.5 skin, eyes, mouth and clothing. Sensitization of the skin may be avoided by wearing protective gloves. t>0.2, model (h) 183 ± 40.8 NE NE Persons with a known hypersensitivity to penicillin or cephalosporins should avoid exposure to this t>0.2, nca (h) 246 ± 48.5 218 ± 45.5 205 ± 35.7 product. t (h) 62.3 ± 13.5 40.7 ± 11.2 43.92 ± 9.84 In case of accidental eye exposure, flush with water for 15 minutes. In case of accidental skin exposure, 1/2 wash with soap and water. Remove contaminated clothing. If allergic reaction occurs (e.g., skin rash, Cmax (μg CE/mL) = maximum plasma concentration (in μg CE/mL). hives, difficult breathing), seek medical attention. tmax (h) = the time after injection when Cmax occurs (in hours). The material safety data sheet contains more detailed occupational safety information. To obtain a AUC 0-LOQ (μg•h/mL) = the area under the plasma concentration vs. time curve from time of injection to the limit of material safety data sheet or to report any adverse event please call 1-888-963-8471. quantitation of the assay (0.15 μg CE/mL). Intra-arterial injection may occur during administration of EXCEDE Sterile Suspension via middle t>0.2, model (h) = the time plasma concentrations remain above 0.2 μg CE/mL (in hours), estimated using third of the ear injection or base of the ear injection directed towards the opposite eye. Intra-arterial compartmental pharmacokinetic techniques. injection of EXCEDE Sterile Suspension is likely to result in sudden death of the animal. t>0.2, nca (h) = the time plasma concentrations remain above 0.2 μg CE/mL (in hours), estimated using noncompartmental pharmacokinetic techniques. RESIDUE WARNINGS t1/2 (h) = terminal phase biological half life (in hours) • Following label use as either a single-dose or 2-dose regimen, a 13-day pre-slaughter NE = Not estimated withdrawal period is required after the last treatment. • Following label use as either a single-dose or 2-dose regimen, no milk discard period Two-Dose Regimen is required for this product. A two-dose regimen of 6.6 mg CE/kg BW administered 72 hours apart is required for the treatment • Use of dosages in excess of 3.0 mg CE/lb (6.6 mg CE/kg) BW or administration by of acute metritis in lactating cows. The mean plasma concentration vs. time profile for ceftiofur and unap proved routes (subcutaneous injection in the neck or intramuscular injection) desfuroylceftiofur-related metabolites for the 2-dose regimen in 12 cows is shown in Figure 9 below. may cause violative residues. The pharmacokinetic parameters for the 2-dose regimen are provided in Table 3. • A withdrawal period has not been established for this product in pre-ruminating calves. • Do not use in calves to be processed for veal. 56 Figure 9. LS-Mean DCA Plasma Concentration Time Profile Following Two Subcutaneous Injections The effectiveness of EXCEDE Sterile Suspension for the treatment of bovine foot rot was evaluated in a of EXCEDE 72 hours apart at a Dose of 3.0 mg CE/lb (6.6 mg CE/kg) BW in 12 lactating cows. six-location field effectiveness study. Cattle diagnosed with bovine foot rot were enrolled and treated with EXCEDE Sterile Suspension, administered by subcutaneous injection in the base of the ear as a single dose of 3.0 mg CE/lb (6.6 mg CE/kg) BW or an equivalent volume of a vehicle control. Cattle were clinically evaluated 7 days post-treatment for treatment success, which was based on defined decreases in lesion, swelling and lameness scores. A total of 169 beef and dairy cattle were included in the analysis. There was a statistically significant difference (p = 0.0054) in treatment success for EXCEDE-treated cattle (58.4%) compared to vehicle-treated control cattle (13.2%). The effectiveness of EXCEDE Sterile Suspension for the treatment of acute metritis was evaluated in a 15-location field effectiveness study. A total of 1023 cows with a fetid vaginal discharge and a rectal temperature of ≥ 103 °F were enrolled in the study and treated with either a two-dose regimen of EXCEDE (6.6 mg CE/BW) or an equivalent volume of vehicle control, administered approximately 72 hours apart

its metabolites (μg/mL) its metabolites at the base of opposite ears. At 14 days post-treatment, each cow remaining in the study was examined its metabolites (μg/mL)

Concentration of ceftiofur and Concentration and rectal temperature and vaginal discharge score were recorded. Cows with a non-fetid discharge, and Concentration of ceftiofur and a rectal temperature < 103 °F, and that did not require alternate (“escape”) therapy during the 14_day observation period were classified as a cure. The cure rate was significantly higher (p < 0.0001) in EXCEDE- treated cows (362/493, 74.3%) than in vehicle-treated cows (271/489, 55.3%). One cow died 15 to 20 minutes after the second administration of EXCEDE. Necropsy findings determined the probable cause of death to be intra-arterial injection. Table 3. Average (n = 12) Pharmacokinetic Parameters Following Two Subcutaneous Injections of ANIMAL SAFETY EXCEDE Sterile Suspension at a Dose 3.0 mg CE/lb (6.6 mg CE/kg) BW at a 72 Hour Interval. Systemic Safety Studies After parenteral administration, ceftiofur crystalline free acid (as EXCEDE Sterile Suspension), PK Parameter Mean ± Standard Deviation ceftiofur sodium and ceftiofur hydrochloride are rapidly metabolized to desfuroylceftiofur. Therefore, AUC0-LOQ (μg•h/mL) 651 ± 119 studies conducted with ceftiofur sodium are adequate to evaluate the systemic safety of EXCEDE Sterile t½ (h) 55.7 ± 4.84 Suspension. Results from a five-day tolerance study conducted with ceftiofur sodium in normal feeder calves indicated that ceftiofur was well tolerated at 25 mg CE/lb/day for five consecutive days, approx- t>0.2 (h) 341 ± 34.0 imately 8 times the approved dose of EXCEDE Sterile Suspension 3.0 mg CE/lb (6.6 mg CE/kg) BW. Tmax (h) 77.1 ± 33.4 Ceftiofur administered parenterally had no adverse systemic effects. Cmax (μg/mL) 5.98 ± 2.51 In a 15-day safety/toxicity study, five steer and five heifer calves per group were adminis tered ceftiofur sodium intramuscularly at 0 (vehicle control), 1, 3, 5 or 10 mg CE/lb/day thus, evaluating MICROBIOLOGY up to 3.3 times the approved dose of EXCEDE Sterile Suspension of 3.0 mg CE/lb/day (6.6 mg CE/kg) Ceftiofur has demonstrated in vitro activity against Mannheimia haemolytica, Pasteurella multocida, BW. There were no adverse systemic effects, indicating that ceftiofur has a wide margin of safety when and Histophilus somni, three major pathogens associated with BRD, and against Fusobacterium injected intramuscularly into feeder calves. Local tissue tolerance to subcutaneous injection of EXCEDE necrophorum and Porphyromonas levii associated with bovine foot rot. Sterile Suspension in the posterior ear of cattle was evaluated in a separate study. A summary of the susceptibility of BRD and foot rot pathogens is presented in Table 4. BRD isolates The systemic safety of ceftiofur concentrations resulting from product administration at the base of were obtained from cattle enrolled in a field study conducted in the United States that were diagnosed the ear was established via a pharmacokinetic comparison of the two routes of administration (base of with BRD. Foot rot isolates were obtained from cattle enrolled in a field study conducted in the United the ear versus middle third of the ear). Based upon the results of this relative bioavailability study, it was States and Canada that were diagnosed with foot rot. Susceptibility testing was conducted according to determined that the two routes of administration are therapeutically equivalent. the Clinical and Laboratory Standards Institute (CLSI) M7-A3 and M11-A6 standards for BRD and foot To support systemic target animal safety for the 2-dose metritis regimen, five projected daily doses rot isolates, respectively. of NAXCEL Sterile Powder (ceftiofur sodium) at 2.2 mg/kg BW were compared pharmacokinetically with Table 4. Ceftiofur minimum inhibitory concentration (MIC) values* of indicated pathogens isolated EXCEDE administered 2 times at a 72 hour interval at 6.6 mg/kg BW. The peak concentration (Cmax) and from cattle with naturally occurring BRD or foot rot. the extent of exposure (AUC) after two doses of EXCEDE were statistically no higher than the exposure following five daily doses of NAXCEL Sterile Powder in beef cattle. Indicated Year of Number of MIC50** MIC90** MIC range Investigation of Intra-Arterial and Intravenous Injection pathogen isolation isolates (μg/mL) (μg/mL) (μg/mL) In approximately 6000 animals enrolled in the BRD clinical studies, nine animals died following Mannheimia haemolytica 1996 to 1997 75 0.008 0.015 0.001 to 0.015 injection of EXCEDE Sterile Suspension. All deaths were within 30 minutes of the time of injection. The Pasteurella multocida 1996 to 1997 43 0.004 0.004 0.001 to 0.015 exact cause was confirmed in three animals. These deaths resulted from inadvertent intra-arterial injection of this oil-based suspension into one of the two major auricular (ear) arteries. Intra-arterial Histophilus somni 1996 to 1997 11 0.004 0.004 0.002 to 0.015 injection at this location resulted in direct administration of the oil-based formula tion into the arterial Fusobacterium necrophorum 2006 to 2007 148 ≤ 0.25 0.5 ≤ 0.25 to >128 blood supply of the brain resulting in embolism and death. Porphyromonas levii 2006 to 2007 141 ≤ 0.25 2.0 ≤ 0.25 to 16 Since intra-arterial injection was confirmed in three animals that died following injection of EXCEDE * The correlation between in vitro susceptibility data and clinical effectiveness is unknown. Sterile Suspension, the consequences of purposeful intra-arterial injection of EXCEDE Sterile ** The lowest MIC to encompass 50% and 90% of the most susceptible isolates, respectively. Suspension were investigated in feeder cattle. Two heifers (body weight approximately 225 kg) were given a single 3.0 mg CE/lb (6.6 mg CE/kg) BW bolus dose of EXCEDE Sterile Suspension in the middle Based on pharmacokinetic and clinical effectiveness studies of ceftiofur in cattle after a single auricular artery. Both heifers collapsed immediately and died within approximately eight minutes of administration of 3.0 mg CE/lb (6.6 mg CE/kg) BW and the MIC and susceptibility data, the following injection. Intra-arterial injection of EXCEDE Sterile Suspension in the ear will result in death and must breakpoints are recommended for BRD pathogens by CLSI. be avoided. Table 5. CLSI-accepted interpretive criteria* for ceftiofur against cattle respiratory pathogens. Since subcutaneous injection in the ear may potentially result in inadvertent intravenous administration of an injectable product, the consequences of purposeful intravenous injection of Pathogen Disk Zone diameter MIC breakpoint EXCEDE Sterile Suspension were investigated in feeder cattle. Three heifers and three steers (body potency (mm) (μg/mL) weight range 197-223 kg) were given a single 3.0 mg CE/lb (6.6 mg CE/kg) BW bolus dose of EXCEDE S I R S I R Sterile Suspension in the jugular vein and were monitored for adverse effects following injection. One steer and one heifer had transient (2 to 5 minutes) increases in heart rate without any other untoward Mannheimia haemolytica signs in these or the other cattle. Intravenous injection of EXCEDE Sterile Suspension is an unacceptable Pasteurella multocida 30 μg ≥ 21 18 to 20 ≤ 17 ≤ 2.0 4.0 ≥ 8.0 route of administration. Histophilus somni Safety Studies in Beef Cattle S – Susceptible Middle of the ear injection: A study was designed and conducted to specifically address tissue tolerance in cattle when EXCEDE I – Intermediate Sterile Suspension was administered as a single subcutaneous injection into the posterior aspect of the R – Resistant ear of cattle at the recommended dose of 3.0 mg CE/lb (6.6 mg CE/kg) BW. Results from this study * These interpretive criteria are only intended for use when CLSI M31-A2 performance standards are used to determine indicate that the subcutaneous injection of EXCEDE Sterile Suspension into the middle third of the antimicrobial susceptibility. Interpretive criteria for bovine foot rot pathogens have not been established. posterior aspect of the ear of cattle is well tolerated and characterized by a biphasic thickening of the ear. The initial increase in thickness is attributed to the space required for the volume of injected EFFECTIVENESS material. Additional increases in thickness were observed through Day 14 after injection. After Day 14, A field dose confirmation study for the treatment of BRD evaluated the effectiveness of single doses post injection ear thickness decreased in all animals. One animal carried an injected ear in a drooping of 2.0 and 3.0 mg CE/lb (4.4 or 6.6 mg CE/kg) BW for the treatment of the bacterial component of BRD position for 7 days post injection. At necropsy, subcutaneous areas of discoloration and some foci of under field conditions. All treatments were administered subcutaneously in the middle third of the hemorrhage were observed in ears of injected cattle. The discoloration was markedly reduced in size by posterior aspect of the ear. Cattle were clinically evaluated on Days 2 to 4, 14 and 28 and were observed the end of the study. Ears are inedible tissues in the US (9 CFR 301.2). No signs of irritation were on all other study days. The 3.0 mg CE/lb (6.6 mg CE/kg) BW EXCEDE Sterile Suspension dose observed on the edible portions of the carcass around the base of the ear. significantly (p ≤0.05) increased Day 14 treatment success rate, defined as animals that did not require The local tolerance of the ear of cattle to a single subcutaneous injection of EXCEDE Sterile Suspension any ancillary treatment and had a rectal temperature of <104°F, normal respiration index, and had no or was also evaluated in a large multi-location effectiveness study. None of the 1927 animals treated with mild depression on that day. EXCEDE Sterile Suspension were removed from this trial due to ear irritation although swelling was The effectiveness of a single dose of EXCEDE Sterile Suspension for the control of BRD in feedlot noted at some injection sites. Leak back and/or bleeding from the injection site was observed in a small cattle was evaluated in a nine-location field effectiveness study. In addition to standard processing on fraction of the treated animals immediately after administration. It was concluded that administration arrival at feedlots, cattle (n=3911) considered to be at high risk for BRD were assigned to one of four of EXCEDE Sterile Suspension in the posterior aspect of the ear was well tolerated and was acceptable arrival treatments, including EXCEDE Sterile Suspension at 2.0 or 3.0 mg CE/lb (4.4 or 6.6 mg CE/kg) under feedlot conditions. BW or negative control. Effectiveness evaluation was based on the incidence of clinical BRD within 28 A study evaluated the 56-day feedlot performance of beef steers administered EXCEDE Sterile days following arrival processing. Administration of a single dose of EXCEDE Sterile Suspension Suspension alone, EXCEDE Sterile Suspension with a growth promoting implant, growth promoting administered subcutaneously in the middle third of the posterior aspect of the ear at arrival processing implant alone, or neither product, in a total of 207 Angus and Angus cross-bred steers. The significantly reduced the incidence of BRD in high-risk feedlot cattle in the 28-day period after arrival administration of EXCEDE Sterile Suspension in the posterior aspect of the ear with or without growth processing compared to negative controls. promoting implants was well tolerated by cattle and did not adversely affect feedlot cattle performance. Base of the ear administration (beef and non-lactating dairy cattle) and middle third of the ear Based upon the results of this study, the location of implants administered after EXCEDE Sterile administration (lactating dairy cattle) were compared to the middle third of the ear pharmacoki netic Suspension may need to be adjusted slightly within the boundaries of the middle third of the ear in some data for beef and non-lactating dairy cattle and were found to be therapeutically equivalent. animals. 57 Base of the ear injection: The local tolerance of the ear to a single subcutaneous injection at the base of the ear of EXCEDE Sterile Suspension was evaluated in a multi-location field study in 2926 beef cattle. Normal restraint was adequate for adminis tration of EXCEDE Sterile Suspension for 99.8% of cattle. No post injection problems (exces sive bleeding or leak back) were observed in 99.8% of cattle. On Days 28 and 56 post- injec tion, 97.8% and 98.9% of the cattle had “normal” (no observed swelling) ears. In a residue study, 72 beef cattle were injected in the base of the ear with EXCEDE Sterile Suspension at a dose rate of 3.0 mg CE/lb (6.6 mg CE/kg) BW. Injection sites were observed daily from treatment to necropsy (4, 7, 10, or 13 days post-injection) for swelling and drooping, and evaluated grossly at necropsy, using skinning and trimming procedures similar to slaughterhouse practices. All animals had injection site swelling during the study; swelling resolved prior to euthanasia in 23 of 72 animals. None of the animals showed ear drooping. At necropsy, signs of inflammation (hemorrhage, congestion, and firmness of tissue) and presence of drug material were seen in the area around the injection site and on the carcass. At 13 days post-injection, gross lesions were found in the inedible portions of the base of the ear in all 18 animals, and in the exposed carcass tissue in 11 of 18 animals. The ventral base of the ear injection technique was evaluated in a conditions of use study in 200 beef cattle. Each animal received a single injection of EXCEDE Sterile Suspension at a dose of 6.6 mg CE/kg BW at the base of the ear using the ventral injection technique. Normal restraint was adequate for 95.5% of animals in the study. Injection site scores were normal for 65.3% and 92.5% of cattle on Days 14 and 28, respectively. One animal had an unusually large swelling on Day 7 which reduced to a size comparable to other study animals by Day 14. Safety Studies in Lactating Dairy Cattle The local tolerance of the ear to a single subcutaneous injec tion at the base of the ear of EXCEDE Sterile Suspension was evaluated in a multi-location field study in 114 adult dairy cattle. Successful injection in the base of the ear was achieved in 97.4% of cattle using nor mal facilities and restraint equipment. No leak back or excessive bleeding was observed following injection for 99.1% of cattle, with injection volumes ranging from 15 to 30 mL. On Days 28 and 56 following injection of EXCEDE Sterile Suspension in the base of the ear, 95.6% and 100% of ears, respectively, were observed as normal with no injection site swelling. In a residue study, six dairy cows were injected in the base of the ear at a dose rate of 3.0 mg CE/lb (6.6 mg CE/kg) BW of EXCEDE Sterile Suspension. No animals exhibited drooping ears at any time after treatment but all animals had signs of swelling at the injection site at all observation times after treatment. Cows were slaughtered 10 days after injection. At necropsy, all six cows showed evidence of injection site inflammation (discoloration of fat tissue/fascia) and four of six cows had discoloration of tissue dorsal and posterior to the ear canal on the carcass. In addition to discoloration, tan nodules and a milky white fluid exudate were also present at the sectioned surface. Injection site safety for base of the ear administration was evaluated in the metritis effectiveness study described above. Normal restraint was adequate for ≥ 97.8% of injections administered. Injection site scores were normal in 50.3%, 73.2%, and 96.4% at 2 or 3, 11, and 54±3 days after the second injection, respectively. The ventral and rostral base of the ear injection techniques were compared with the toward the opposite eye technique in a conditions of use study in 197 lactating dairy cattle. Normal restraint was adequate for 89.8% (ventral), 98% (rostral), and 100% (opposite eye) of animals in the study. Injection site scores were normal for 32% (rostral), 46.9% (ventral), and 47.9% (opposite eye) of cattle on Day 14, and 73% (rostral), 87.8% (ventral), and 64.6% (opposite eye) of cattle on Day 28, respectively. TISSUE AND MILK RESIDUE DEPLETION A radiolabeled residue metabolism study established tolerances for ceftiofur residues in cattle kidney, liver and muscle. A separate study established the tolerance for ceftiofur residues in milk. The tolerances for ceftiofur residues are 0.4 ppm in kidney, 2.0 ppm in liver, 1.0 ppm in muscle and 0.1 ppm in milk. A pivotal tissue residue decline study was conducted in dairy cattle. In this study, cows received a single injection of 3.0 mg CE/lb (6.6 mg CE/kg) BW. Ceftiofur residues in tissues were less than the tolerances for ceftiofur residues in tissues such as the kidney, liver and muscle by 13 days after dosing. These data collectively support a 13-day pre-slaughter withdrawal period. A pivotal milk residue decline study was conducted in lactating dairy cattle. In this study, cows received a single injection of 3.0 mg CE/lb (6.6 mg CE/kg) BW. Ceftiofur residues in milk were less than tolerances at all time points after treatment. These data collectively support that no milk discard period is required for this product. Two-Dose Residue Decline Studies A pivotal tissue residue decline study was conducted in dairy cattle. In this study, cows received two injections of 3.0 mg CE/lb (6.6 mg CE/kg) BW with a 72 hour interval between injections. Ceftiofur residues in tissues were less than the tolerances for ceftiofur residues in the kidney by 13 days after the second dose. These data collectively continue to support a 13-day pre-slaughter withdrawal period after the last dose. A pivotal milk residue decline study was conducted in lactating dairy cattle. In this study, cows received two injections of 3.0 mg CE/lb (6.6 mg CE/kg) BW with a 72 hour interval between injections. Milk residue decline data from this study supports that no milk discard period is required for this product. STORAGE CONDITIONS Store at controlled room temperature 20° to 25°C (68° to 77°F). Shake well before using. Contents should be used within 12 weeks after the first dose is removed. HOW SUPPLIED EXCEDE Sterile Suspension is available in the following package sizes: 100 mL vial 250 mL vial NADA #141-209, Approved by FDA

Distributed by: Zoetis Inc. Kalamazoo, MI 49007 www.EXCEDE.com or call 1-888-963-8471 Revised: August 2013 10423902A&P 58 WARNINGS Cmax - maximum plasma concentration NOT FOR HUMAN USE. KEEP OUT OF REACH OF CHILDREN. AUC0-LOQ - the area under the plasma concentration vs. time curve from time of injection to the limit of quantification of the assay Penicillins and cephalosporins can cause allergic reactions in t - the time after initial injection to when C occurs sensitized individuals. Topical exposures to such antimicrobials, max max t - the plasma half life of the drug including ceftiofur, may elicit mild to severe allergic reactions in some 1/2 For intramuscular injection in swine. For t - the time plasma concentrations remain above 0.2 µg/mL. intramuscular and subcutaneous injection in cattle. individuals. Repeated or prolonged exposure may lead to sensitization. >0.2 This product may be used in lactating dairy cattle. Avoid direct contact of the product with the skin, eyes, mouth and The standard bioequivalence (BE) criteria, based upon the Not for use in calves to be processed for veal. clothing. exponentiated 90% confidence bounds about the ratio of treatment means, were met for the pivotal bioequivalence parameters, AUC CAUTION: Federal (USA) law restricts this drug to use Persons with a known hypersensitivity to penicillin or cephalosporins 0-LOQ and C , when each formulation was administered to swine IM at a by or on the order of a licensed veterinarian. Federal law prohibits should avoid exposure to this product. max dose rate of 2.27 mg CE/lb (5.0 mg CE/kg) BW (Table 2). extra-label use of this drug in cattle and swine for disease prevention In case of accidental eye exposure, flush with water for 15 minutes. In Table 2: Back-transformed least squares (LS) means and 90% purposes; at unapproved doses, frequencies, durations, or routes of case of accidental skin exposure, wash with soap and water. Remove confidence interval (CI) for the two pivotal pharmacokinetic administration; and in unapproved major food producing species/ contaminated clothing. If allergic reaction occurs (e.g., skin rash, hives, parameters, C and AUC in swine following an IM production classes. difficult breathing), seek medical attention. max 0-LOQ administration of 2.27 mg CE/lb (5.0 mg CE/kg) BW, as either DESCRIPTION The material safety data sheet contains more detailed occupational EXCENEL RTU (reference article) or as EXCENEL RTU EZ Sterile EXCENEL RTU EZ Sterile Suspension is a ready to use formulation safety information. To obtain a material safety data sheet (MSDS) or to Suspension (test article). that contains the hydrochloride salt of ceftiofur, which is a broad report any adverse event please call 1-888-963-8471. LS Mean spectrum cephalosporin antibiotic. Each mL of this ready-to-use For additional information about adverse drug experience reporting PK Parameter 90% CI BE† Difference sterile suspension contains ceftiofur hydrochloride equivalent to 50 mg for animal drugs, contact FDA at 1-888-FDA-VETS or online at ceftiofur, 2.50 mg polyoxyethylene sorbitan monooleate (polysorbate http://www.fda.gov/AnimalVeterinary/SafetyHealth. Cmax 1.10 1.03 to 1.18 Yes 80), 6.5 mg water for injection in a caprylic/capric triglyceride (Miglyol® RESIDUE WARNINGS: AUC0-LOQ 1.03 0.99 to 1.06 Yes 812) suspension. Swine: When used according to label indications, † If the 90% CI of the LS mean difference is within the limits of 0.80 Figure 1. Structure: dosage and route of administration, treated swine must to 1.25, then the results support bioequivalence of treatment groups not be slaughtered for 4 days following the last treatment. In another comparative bioavailability PK study (previously Use of dosages in excess of those indicated or by reviewed under NADA 140-890), comparable plasma concentrations unapproved routes of administration may result in illegal of ceftiofur, administered as EXCENEL RTU Sterile Suspension or residues in edible tissues. as NAXCEL Sterile Powder, were demonstrated when each product Cattle: When used according to label indications, was administered intramuscularly at the upper end of the label dose dosage and route of administration, treated cattle range [2.27 mg CE/lb (5.0 mg CE/kg) BW]. The bioequivalence criteria

must not be slaughtered for 4 days following the last were met for the AUC0-LOQ, Cmax, and t>0.2 when both products were treatment. When used according to label indications, administered by an intramuscular injection to swine at a dose rate of dosage and route of administration, a milk discard time 5.0 mg CE/kg BW. is not required. Uses of dosages in excess of those Cattle: Ceftiofur administered as either ceftiofur sodium or ceftiofur indicated or by unapproved routes of administration, hydrochloride is metabolized rapidly to desfuroylceftiofur, the primary such as intra mammary, may result in illegal residues in metabolite. Administration of ceftiofur to cattle as either the sodium or Chemical Name of Ceftiofur Hydrochloride: 5-Thia-1-azabicyclo[4,2.0] edible tissues and/or milk. A withdrawal period has not hydrochloride salt provides effective concentrations of ceftiofur and oct-2-ene-2-carboxylic acid, 7-[[(2-amino-4-thiazolyl)(methoxyimino)- been established in pre-ruminating calves. Do not use in desfuroylceftiofur metabolites in plasma above the MIC90 for the label acetyl]amino]-3-[[(2-furanyl car bon yl)thio]methyl]-8-oxo-,hydrochloride calves to be processed for veal. BRD pathogens Mannheimia haemolytica, Pasteurella multocida and salt [6R-[6 ,7 (Z)]]- α β PRECAUTIONS Histophilus somni for at least 48 hours. The relationship between plasma INDICATIONS The effects of ceftiofur on cattle and swine reproductive performance, concentrations of ceftiofur and desfuroylceftiofur meta bolites above the Swine: EXCENEL RTU EZ Sterile Suspension is indicated for treatment/ pregnancy and lactation have not been determined. MIC90 in plasma and effectiveness has not been established for the control of swine bacterial respiratory disease (swine bacterial treatment of bovine interdigital necrobacillosis (foot rot) associated with Intramuscular and subcutaneous injection in cattle and intramuscular pneumonia) associated with Actinobacillus pleuropneumoniae, Fusobacterium necrophorum and Bacteroides melaninogenicus. injection in swine can cause a transient local tissue reaction that may Pasteurella multocida, Salmonella Choleraesuis and Streptococcus suis. result in trim loss of edible tissue at slaughter. Comparative Bioavailability Summary Cattle: EXCENEL RTU EZ Sterile Suspension is indicated for treatment CLINICAL PHARMACOLOGY The current EXCENEL RTU EZ Sterile Suspension formulation of the following bacterial diseases: replaces a previously approved formulation. The previously approved Swine: Ceftiofur administered as either ceftiofur sodium or ceftiofur — Bovine respiratory disease (BRD, shipping fever, pneumonia) EXCENEL RTU EZ product was a reformulation of another ceftiofur hydrochloride is metabolized rapidly to desfuroylceftiofur, the primary associated with Mannheimia haemolytica, Pasteurella multocida and hydrochloride injectable product, EXCENEL RTU Sterile Suspension metabolite. Administration of ceftiofur to swine as either the sodium Histophilus somni. (NADA 140-890). Comparable plasma concentrations of ceftiofur or hydrochloride salt provides effective concentrations of ceftiofur administered as EXCENEL RTU Sterile Suspension and the — Acute bovine interdigital necrobacillosis (foot rot, pododermatitis) and desfuroylceftiofur metabolites in plasma above the lowest reformulated EXCENEL RTU EZ Sterile Suspension were demonstrated associated with Fuso bacterium necrophorum and Bacteroides minimum inhibitory concentration to encompass 90% of the most in two comparative two-treatment, two-period crossover relative melaninogenicus. susceptible isolates (MIC90) for the labeled pathogens: Actinobacillus bioavailability studies in cattle. Products were administered via pleuropneumoniae, Pasteurella multocida, Streptococcus suis and — Acute metritis (0 to 14 days post-partum) associated with bacterial intramuscular (IM) or subcutaneous (SC) injection, using alternating Salmonella Choleraesuis for the 24 hour period between the dosing organisms susceptible to ceftiofur. sides of the neck during periods 1 and 2. A summary of average intervals. The MIC for Salmonella Choleraesuis (1.0 µg/mL) is higher DOSAGE AND ADMINISTRATION 90 plasma pharmacokinetic (PK) parameters in cattle after a single IM and than the other three pathogens and plasma concentrations exceed this SC administration of EXCENEL RTU Sterile Suspension and EXCENEL Shake well before using. value for the entire dosing interval only after the 2.27 mg/lb (5.0 mg/ RTU EZ Sterile Suspension at a dose of 1.0 mg CE/lb (2.2 mg CE/kg) Swine: Administer intramuscularly at a dosage of 1.36 to 2.27 mg kg) BW dose. BW is provided in Table 3. ceftiofur equivalents (CE)/lb (3 to 5 mg CE/kg) body weight (BW) (1 mL Comparative Bioavailability Summary of sterile suspension per 22 to 37 lb BW). Treatment should be repeated Table 3: Comparative treatment values (arithmetic mean ± SD) The current EXCENEL RTU EZ Sterile Suspension formulation at 24 hour intervals for a total of three consecutive days. Do not inject for the plasma PK estimates of total ceftiofur (parent compound replaces a previously approved formulation. The previously approved more than 5 mL per injection site. plus desfuroylceftiofur metabolites) in cattle following an IM or EXCENEL RTU EZ product was a reformulation of another ceftiofur SC administration of 1.0 mg CE/lb (2.2 mg CE/kg) BW, as either Cattle: hydrochloride injectable product, EXCENEL RTU Sterile Suspension EXCENEL RTU (reference article) or as EXCENEL RTU EZ Sterile — For bovine respiratory disease and acute bovine interdigital (NADA 140-890). Comparable plasma concentrations of ceftiofur Suspension (test article). necrobacillosis: administer by intramuscular or subcutaneous administered as EXCENEL RTU Sterile Suspension or the reformulated administration at the dosage of 0.5 to 1 mg CE/lb (1.1 to 2.2 mg CE/ EXCENEL RTU EZ Sterile Suspension were demonstrated in a IM SC PK kg) BW (1 to 2 mL sterile suspension per 100 lb BW). Administer daily comparative two-treatment, two-period crossover relative bioavailability Parameter EXCENEL EXCENEL EXCENEL EXCENEL at 24 hour intervals for a total of three consecutive days. Additional study in swine. Products were administered via intramuscular (IM) RTU RTU EZ RTU RTU EZ treatments may be administered on Days 4 and 5 for animals which injection into the neck, using alternating sides during periods 1 and do not show a satisfactory response (not recovered) after the initial C (μg/ 2. A summary of average plasma pharmacokinetic (PK) parameters max 8.58 ± 1.50 9.25 ± 1.73 8.40 ± 1.42 9.19 ± 1.65 three treatments. In addition, for BRD only, administer intramuscularly in swine after a single IM administration of EXCENEL RTU Sterile mL) or subcutaneously 1 mg CE/lb (2.2 mg CE/kg) BW every other day on Suspension and EXCENEL RTU EZ Sterile Suspension at a dose of 2.27 AUC 0-LOQ 89.4 ± 13.8 88.5 ±17.0 86.7 ± 20.3 91.0 ± 20.2 Days 1 and 3 (48 hour interval). Do not inject more than 15 mL per mg CE/lb (5.0 mg CE/kg) BW is provided in Table 1. (μg*h/mL) injection site. Table 1: Comparative treatment values (arithmetic mean ± SD) t (h) 2.08 ± Selection of dosage level (0.5 to 1 mg CE/lb) and regimen/duration for the plasma PK estimates of total ceftiofur (parent compound max 1.71 ± 0.706 1.73 ± 0.489 2.25 ± 0.872 0.670 (daily or every other day for BRD only) should be based on an plus desfuroylceftiofur metabolites) in swine following an IM assessment of the severity of disease, pathogen susceptibility and administration of 2.27 mg CE/lb (5.0 mg CE/kg) BW, as either t1/2 (h) 32.0 ± 8.48 29.3 ± 7.35 34.0 ± 8.52 32.9 ± 6.91 clinical response. EXCENEL RTU (reference article) or as EXCENEL RTU EZ Sterile t>0.2 (h): 42.2 ± 6.20 41.2 ± 6.11 40.5 ± 5.28 41.5 ± 7.32 — For acute post-partum metritis: administer by intramuscular or Suspension (test article). C - maximum plasma concentration subcutaneous administration at the dosage of 1 mg CE/lb (2.2 mg CE/ max AUC - the area under the plasma concentration vs. time curve from kg) BW (2 mL sterile suspension per 100 lb BW). Administer at 24 hour PK Parameter EXCENEL RTU EXCENEL RTU EZ 0-LOQ time of injection to the limit of quantification of the assay intervals for five consecutive days. Do not inject more than 15 mL per Cmax (μg/mL) 18.2 ± 4.09 19.7 ± 3.39 t - the time after initial injection to when C occurs injection site. max max AUC (μg*h/mL) 257 ± 57.1 263 ± 54.8 t1/2 - the plasma half life of the drug CONTRAINDICATIONS 0-LOQ t>0.2 - the time plasma concentrations remain above 0.2 µg/mL t (h) 1.5 ± 0.49 1.5 ± 0.73 As with all drugs, the use of EXCENEL RTU EZ Sterile Suspension max The standard bioequivalence (BE) criteria, based upon the is contraindicated in animals previously found to be hypersensitive to t (h) 20.0 ± 1.56 20.0 ± 1.82 exponentiated 90% confidence bounds about the ratio of treatment the drug. 1/2 means, were met for the pivotal bioequivalence parameters, AUC0-LOQ t (h) 83.1 ± 10.3 82.5 ± 10.5 >0.2 and Cmax, when each formulation was administered to cattle IM or SC at a dose rate of 1.0 mg CE/lb (2.2 mg CE/kg) BW (Table 4). 59 Table 4: Back-transformed least squares (LS) means and 90% ANIMAL SAFETY HOW SUPPLIED confidence intervals (CI) for the two pivotal pharmacokinetic Swine: Evaluation of target animal safety in swine was based on EXCENEL RTU EZ Sterile Suspension is available in 100 mL and parameters, Cmax and AUC0-LOQ in cattle following an IM and SC a PK comparison between the reformulated EXCENEL RTU EZ 250 mL vials. administration of 1.0 mg CE/lb (2.2 mg CE/kg) BW, as either EXCENEL Sterile Suspension and EXCENEL RTU Sterile Suspension. Ceftiofur NADA 141-288, Approved by FDA RTU (reference article) or as EXCENEL RTU EZ Sterile Suspension administered to swine as the reformulated EXCENEL RTU EZ (test article). Sterile Suspension at a dose of 5 mg CE/kg BW by IM injection was demonstrated to be bioequivalent to a corresponding IM injection of Revised: March 2013 IM SC PK EXCENEL RTU Sterile Suspension based upon comparability of their LS Mean LS Mean Parameter 90% CI 90% CI respective AUC0-LOQ and Cmax values (see EFFECTIVENESS section). Difference Difference Because of the demonstrated blood level bioequivalence, this study Distributed by: confirms the systemic safety of the reformulated EXCENEL RTU EZ Cmax 1.08 1.00 to 1.16 1.09 1.02 to 1.18 Zoetis Inc. Sterile Suspension in swine when administered by IM injection at a Kalamazoo, MI 49007 AUC0-LOQ 0.984 0.94 to 1.03 1.06 0.99 to 1.13 dose of 5 mg CE/kg BW for three consecutive days. In another comparative bioavailability PK study (previously reviewed Injection site tissue tolerance and resolution were evaluated after under NADA 140-890), comparable plasma concentrations of ceftiofur administering EXCENEL RTU EZ Sterile Suspension by intramuscular administered as EXCENEL RTU Sterile Suspension or as NAXCEL Sterile injection to 8 young pigs with at least the maximum proposed volume Powder were demonstrated when each product was administered of 5 mL per injection site once daily for three consecutive days. Each intramuscularly or subcutaneously at the approved dose range of injection was administered in a different location on the neck, and ceftiofur sodium [0.5 to 1.0 mg CE/lb (1.1 to 2.2 mg CE/kg) BW]. injection sites alternated between the left and right sides. General health and injection sites were evaluated through 42 days after the first MICROBIOLOGY treatment. No test article-related health issues were observed. Mild EXCENEL RTU EZ Sterile Suspension is a ready-to-use formulation swelling, erythema, and firmness was observed in a very small number that contains the hydrochloride salt of ceftiofur. Ceftiofur is a broad- of occasions (≤ 2% of total observations). No swelling was observed spectrum cephalosporin antibiotic active against Gram-positive from 3 days after the last injection through the end of the study. Grossly and Gram-negative bacteria. Like other cephalosporins, ceftiofur is visible discoloration of the injection site and histopathologic changes predominantly bactericidal in vitro, resulting in the inhibition of cell consistent with inflammation were noted in treated pigs necropsied wall synthesis. In vitro activity of ceftiofur has been demonstrated 7 days or 14 days after injection. against Actinobacillus pleuropneumoniae, Pasteurella multocida, and Cattle: Evaluation of target animal safety in cattle was based on Salmonella Choleraesuis, three pathogens associated with swine two PK studies comparing the reformulated EXCENEL RTU EZ respiratory disease. Similarly, in vitro activity of ceftiofur has been Sterile Suspension and EXCENEL RTU Sterile Suspension (one demonstrated against Mannheimia haemolytica, Pasteurella multocida, study comparing IM administration and one study comparing and Histophilus somni, the three major pathogens associated with SC administration). In both studies, ceftiofur, when administered bovine respiratory disease, and against Fusobacterium necrophorum to cattle at a dose of 2.2 mg CE/kg BW of the reformulated and Bacteroides melaninogenicus, pathogenic anaerobic bacteria EXCENEL RTU EZ Sterile Suspension, was demonstrated to be associated with bovine foot rot. bioequivalent to a 2.2 mg CE/kg BW dose of EXCENEL RTU Sterile Utilizing data that included isolates from swine and cattle affected Suspension (see EFFECTIVENESS section). Because of the by respiratory disease, zone diameter and minimum inhibitory demonstrated blood-level bioequivalence, these studies confirm concentration (MIC) breakpoints were determined using standardized systemic safety of the reformulated EXCENEL RTU EZ Sterile procedures from the Clinical and Laboratory Standards Institute (CLSI, Suspension when administered either IM or SC at a dose of 2.2 mg CE/ formerly National Committee of Clinical Laboratory Standards) M31-A2. kg BW for five consecutive days. The CLSI-accepted interpretive criteria for ceftiofur against these Injection site tissue tolerance and lesion resolution were evaluated Gram-negative pathogens are shown in Table 5. after administration of the reformulated EXCENEL RTU EZ Sterile Table 5: CLSI-accepted interpretive criteria for ceftiofur against Suspension by intramuscular and subcutaneous injections to 16 swine and cattle respiratory pathogens.* growing cattle (8 cattle for each route) at the maximum volume of 15 mL per injection site, once daily for five consecutive days. Each injection Zone diameter was administered in a different location on the neck and injection interpretive MIC breakpoint sites alternated between the left and right sides. General health and Disk Pathogen standards (μg/mL) injection sites were evaluated through necropsy (up to 42 days after potency (mm) the first dose). Animals were euthanized on Day 7, 14, 28, or 42 (two calves at each time point). No test article-related health issues were S I R S I R observed. Injection site reactions consisted of firmness and swelling Actinobacillus at the injection sites. Injection site swelling was observed in 4/1030 pleuropneumoniae (0.4%) of IM injection site observations and in 606/1029 (58.9%) of SC Pasteurella injection site observations. Swelling progressively decreased over time, multocida and was still present in both animals injected SC that were necropsied Salmonella on Day 42. Grossly visible discoloration of the injection site and/or Choleraesuis 18 to histopathologic changes consistent with inflammation were noted 30 μg ≥ 21 ≤ 17 ≤ 2.0 4.0 ≥ 8.0 20 through Day 42 in SC and IM injection sites. Mannheimia TISSUE RESIDUE DEPLETION haemolytica Swine: Radiolabeled residue metabolism studies established Pasteurella tolerances for ceftiofur residues in swine kidney, liver and muscle. The multocida tolerances for ceftiofur residues are 0.25 ppm in kidney, 3.0 ppm in liver Histophilus somni and 2.0 ppm in muscle. S – Susceptible A pivotal tissue residue decline study was conducted in swine. In I – Intermediate this study, pigs received 2.27 mg of ceftiofur per lb body weight (5 mg R – Resistant of ceftiofur per kg body weight) per day for three consecutive days. Ceftiofur residues in tissues were less than the tolerances for ceftiofur * These interpretive criteria are only intended for use when residues in tissues such as kidney and muscle by 4 days after dosing. CLSI M31-A2 performance standards are used to determine These data collectively support a 4-day pre-slaughter withdrawal antimicrobial susceptibility. period in swine when used according to label directions. EFFECTIVENESS Cattle: A radiolabeled residue metabolism study established Swine: Plasma concentrations of ceftiofur administered as EXCENEL tolerances for ceftiofur residues in cattle kidney, liver and muscle. A RTU Sterile Suspension or as EXCENEL RTU EZ Sterile Suspension separate study established the tolerance for ceftiofur residues in milk. following intramuscular administration in swine were compared and found The tolerances for ceftiofur residues are 0.4 ppm in kidney, 2.0 ppm in to be bioequivalent for AUC0-LOQ and Cmax. Therefore, EXCENEL RTU EZ liver, 1.0 ppm in muscle and 0.1 ppm in milk. Sterile Suspension has the same effectiveness profile as previously Two pivotal tissue residue decline studies were conducted in cattle. established for EXCENEL RTU Sterile Suspension. Because the Cattle received either a subcutaneous injection or intramuscular injection effectiveness of cephalosporin antibiotics is dependent upon time above of 1.0 mg of ceftiofur per lb body weight (2.2 mg per kg body weight). In MIC, EXCENEL RTU EZ Sterile Suspension is considered effective for the both studies, ceftiofur residues in tissues were less than the tolerances treatment/control of swine respiratory disease. for ceftiofur residues in tissues such as the kidney and muscle by Cattle: Plasma concentrations of ceftiofur administered as EXCENEL 4 days after dosing. These data collectively support a 4-day pre- RTU Sterile Suspension or as EXCENEL RTU EZ Sterile Suspension slaughter withdrawal period when used according to label directions. following intramuscular or subcutaneous administration in cattle STORAGE CONDITIONS were compared and found to be bioequivalent for AUC0-LOQ and Store at controlled room temperature 20° to 25°C (68° to 77°F); Cmax. Therefore, EXCENEL RTU EZ Sterile Suspension has the same effectiveness profile as previously established for EXCENEL RTU excursions permitted 15° to 40°C (59° to 104°F). Protect from freezing. Sterile Suspension. Because the effectiveness of cephalosporin Shake well before using. Contents should be used within 42 days after antibiotics is dependent upon time above MIC, EXCENEL RTU EZ the first dose is removed. Sterile Suspension is considered effective for the labeled indications.

60 NADA 139-237, Approved by FDA WARNINGS AND PRECAUTIONS For use in animals only. Not for human use. Keep out of reach of children. ® RESIDUE WARNINGS Factrel Injection No withdrawal period or milk discard time is required when used according to labeling. (gonadorelin injection) EFFECTIVENESS 50 mcg gonadorelin per mL (as gonadorelin hydrochloride) Solution For the treatment of ovarian follicular cysts in lactating dairy cows, beef cows, and for Intramuscular Injection. replacement dairy and beef heifers: The treatment effect of FACTREL Injection when used in lactating dairy cows, beef For use in cattle only cows, and replacement dairy and beef heifers is a reduction in the number of days to first estrus. CAUTION There were no significant differences in days from treatment to conception, Federal (USA) law restricts this drug to use by or on the order of a licensed frequency of cows conceiving at first or subsequent heats, or conception rates veterinarian. among treated or non-treated control animals, when FACTREL Injection was used DESCRIPTION alone for treatment of cystic ovaries. FACTREL Injection is a sterile solution containing 50 micrograms of synthetic For use with LUTALYSE (dinoprost tromethamine injection) Injection to synchronize gonadorelin (as hy dro chloride) per mL in aqueous formulation containing 0.6% estrous cycles to allow fixed-time artificial insemination (FTAI) in lactating dairy sodium chloride and 2% benzyl alcohol (as a preservative). cows: Gonadorelin is the gonad otropin releasing hormone (GnRH) which is produced A field study was conducted to compare control (0 mL FACTREL Injection) to two by the hypothalamus and causes the release of the gonado tro pin luteinizing doses of 2, 3 or 4 mL FACTREL Injection (100-200 mcg gonadorelin) for use with hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary. LUTALYSE Injection to synchronize estrous cycles to allow FTAI in lactating dairy FACTREL Injection has the identical amino acid sequence as endo genous cows under field conditions. Cows were examined prior to study start and only clinically normal cows were enrolled. A total of 1142 cows were enrolled at 6 gonadorelin; 5-oxo Pro-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 with identical phys iological activities. The molecular weight of gonadorelin is 1182 with a commercial dairies. Cows were assigned randomly in blocks of 4 cows to each of molecular formula of C H N O . The corresponding values for gonado relin 4 treatment groups consisting of: 55 75 17 13 Day 0: 2, 3 or 4 mL dose of FACTREL Injection or no injection (Control) hydrochloride are 1219 (1 HCI) expressed as C55H75N17O13HCI, or 1255 (2 HCI) expressed as C H N O 2HCI. Day 7: 5 mL LUTALYSE Injection (all treatment groups) 55 75 17 13 Day 9: 2, 3 or 4 mL dose of FACTREL Injection or no injection (Control) INDICATIONS FOR USE Day 10: Fixed-time artificial insemination For the treatment of ovarian follicular cysts in lactating dairy cows, beef cows, and On Day 9 the second dose of FACTREL Injection (cows received the same dose replacement dairy and beef heifers. The treatment effect of FACTREL Injection as for first treatment) was given either 48 or 56 hours after the dose of LUTALYSE when used in lactating dairy cows, beef cows, and replacement dairy and beef Injection and FTAI was conducted 24 or 17 hours later, respectively. For control heifers is a reduction in the number of days to first estrus. cows FTAI was performed 72 hours after the LUTALYSE Injection dose was For use with LUTALYSE® (dinoprost tromethamine injection) Injection to administered. All treatment groups had significantly greater pregnancy rates to synchronize estrous cycles to allow fixed-time artificial insemination (FTAI) in FTAI than cows administered LUTALYSE Injection alone, and were 17.1, 27.3, 29.1 lactating dairy cows. and 32.2% for cows receiving 0 (Control), 2, 3 or 4 mL FACTREL Injection, respectively. DOSAGE For the treatment of ovarian follicular cysts in lactating dairy cows, beef cows, and SAFETY AND TOXICITY replacement dairy and beef heifers: Administer 2 mL of FACTREL Injection as a In cows the intramuscular administration of up to 12.5 times maximum single intramuscular injection. recommended dosage (2,500 mcg/day) of FACTREL Injection for 3 days did not For use with LUTALYSE (dinoprost tromethamine injection) Injection to synchronize affect any physiological or clinical parameter. Likewise, single intramuscular doses estrous cycles to allow fixed-time artificial insemination (FTAI) in lactating dairy of 500 mcg did not interfere with pregnancy. No evidence of irritation at injection cows: Administer 2 to 4 mL FACTREL Injection (100-200 mcg gonadorelin) per site was found in any animal. cow as an intramuscular injection in a treatment regimen with the following A total of 1142 cows were enrolled in the previously noted field study that evaluated framework: the effectiveness of two doses of 2, 3 or 4 mL of FACTREL Injection for use with • Administer the first dose of FACTREL Injection (2-4 mL) at Day 0 LUTALYSE Injection to synchronize estrous cycles to allow FTAI in lactating dairy • Administer LUTALYSE (25 mg dinoprost, as dinoprost tromethamine cows. Cows were observed daily for abnormal clinical signs. Over the course of injection) Injection by intramuscular injection 6-8 days after the first dose of the study there were 148 adverse health events documented in 118 cows. These FACTREL Injection. adverse health events were common conditions in dairy cows (mastitis, lameness • Administer a second dose of FACTREL Injection (2-4 mL) 30 to 72 hours and pneumonia) and are not considered related to treatment. after the LUTALYSE injection. • Perform FTAI 0 to 24 hours after the second dose of FACTREL Injection, or ADVERSE REACTIONS inseminate cows on detected estrus using standard herd practices. To report suspected adverse events, for technical assistance or to obtain a copy Below are three examples of treatment regimens for FTAI that fit within the dosage of the Material Safety Data Sheet (MSDS) contact Zoetis Inc. at 1-888-963-8471. regimen framework described immediately above: For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or online at http://www.fda.gov/ Example 1 Example 2 Example 3 AnimalVeterinary/SafetyHealth. Day 0 (Monday) 1st FACTREL 1st FACTREL 1st FACTREL HOW SUPPLIED FACTREL Injection (gonadorelin injection), 50 mcg/mL is available in 20 mL and Day 7 (the LUTALYSE LUTALYSE LUTALYSE 50 mL multi-dose vials (box of one). following Monday) STORAGE CONDITIONS Store at refrigerator temperature 2° to 8°C (36° to 46°F). Use contents within Day 9 2nd FACTREL + 2nd FACTREL 2nd FACTREL 1 month of first vial puncture. (Wednesday) FTAI at 48 hours 48 hours after 56 hours after NADA 139-237, Approved by FDA after LUTALYSE LUTALYSE LUTALYSE

Day 10 FTAI FTAI (Thursday) 24 hours after 2nd 18 hours after 2nd Distributed by: Zoetis Inc. FACTREL FACTREL Kalamazoo, MI 49007 MECHANISM OF ACTION Follicular cysts are enlarged non-ovulatory follicles resulting from a malfunction of the neuroendocrine mechanism controlling follicular maturation and ovulation. Exogenous administration of agents possessing luteinizing hormone (LH) activity, such as pituitary extracts or human chorionic gonadotropin, often causes ovulation or regression of follicular cysts. FACTREL Injection induces release of endogenous luteinizing hormone (LH) to produce this same effect. Gonadorelin, through release of LH has been demonstrated to induce ovulation of dominant ovarian follicles present on the bovine ovary during the estrous cycle. Administration of FACTREL Injection has the same effect. Revised: May 2015 40004714A&P

61 Below are three examples of treatment regimens for FTAI that fit within the dosage regimen framework described Lutalyse® Injection immediately above: (dinoprost tromethamine injection) Example 1 Example 2 Example 3 5 mg dinoprost/mL as dinoprost tromethamine Day 0 (Monday) 1st FACTREL 1st FACTREL 1st FACTREL Caution: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. Day 7 (the following LUTALYSE LUTALYSE LUTALYSE Monday) DESCRIPTION Day 9 2nd FACTREL 2nd FACTREL 2nd FACTREL LUTALYSE® Injection (5 mg dinoprost/mL) is a sterile solution containing the naturally occurring prostaglandin (Wednesday) + FTAI at 48 hours after 56 hours after F alpha (dinoprost) as the tromethamine salt. Each mL contains dinoprost tromethamine equivalent to 5 mg 2 at 48 hours after LUTALYSE LUTALYSE dinoprost: also, benzyl alcohol, 16.5 mg added as preservative and water for injection. LUTALYSE When necessary, pH was adjusted with sodium hydroxide and/or hydrochloric acid. Dinoprost tromethamine is a white or slightly off-white crystalline powder that is readily soluble in water at room temperature in concentrations Day 10 FTAI FTAI to at least 200 mg/mL. (Thursday) 24 hours after 18 hours after 2nd FACTREL 2nd FACTREL INDICATIONS FOR USE 6. For use with EAZI-BREED™ CIDR® (progesterone intravaginal insert) Cattle Insert for Synchronization of Estrus in Cattle: LUTALYSE Injection is indicated as a luteolytic agent. LUTALYSE Injection is effective only in those cattle having a corpus luteum, i.e., those which ovulated at least five days prior to treatment. Lactating Dairy Cows: Future reproductive performance of animals that are not cycling will be unaffected by injection of LUTALYSE • Administer one EAZI-BREED CIDR Cattle Insert per animal and remove 7 days later (for example if Injection. administered on a Monday remove the following Monday). • For estrus synchronization in beef cows, beef heifers and replacement dairy heifers • Administer 5 mL LUTALYSE Injection at the time of removal of the EAZI-BREED CIDR Cattle Insert. • For unobserved (silent) estrus in lactating dairy cows with a corpus luteum • Observe animals for signs of estrus on Days 2 to 5 after removal of the EAZI-BREED CIDR Cattle Insert and inseminate animals found in estrus following normal herd practices. • For treatment of pyometra (chronic endometritis) in cattle • For abortion in beef cows, beef heifers and replacement dairy heifers 7. For use with EAZI-BREED™ CIDR® (progesterone intravaginal insert) Cattle Insert for synchronization of estrus • For use with FACTREL (gonadorelin injection) Injection to synchronize estrous cycles to allow fixed-time artificial in suckled beef cows and replacement beef and dairy heifers, advancement of first postpartum estrus in suckled insemination (FTAI) in lactating dairy cows beef cows, and advancement of first pubertal estrus in beef heifers: • Administer one EAZI-BREED CIDR Cattle Insert per animal for 7 days (for example, if administered on a • For use with EAZI-BREEDTM CIDR® (progesterone intravaginal insert) Cattle Insert for synchronization of estrus in Monday remove on the following Monday). lactating dairy cows • Inject 5 mL LUTALYSE Injection (equivalent to 5 mg/mL dinoprost) 1 day prior to EAZI-BREED CIDR Cattle • For use with EAZI-BREEDTM CIDR® (progesterone intravaginal insert) Cattle Insert for synchronization of estrus Insert removal, on Day 6 of the 7 day administration period. in suckled beef cows and replacement beef and dairy heifers, advancement of first postpartum estrus in suckled beef cows, and advancement of first pubertal estrus in beef heifers • Observe animals for signs of estrus on Days 1 to 3 after removal of the EAZI-BREED CIDR Cattle Insert and inseminate animals about 12 hours after onset of estrus. Swine: • For parturition induction in swine Swine: For Parturition Induction in Swine: For intramuscular use for parturition induction in swine. Mares: LUTALYSE Injection is indicated for parturition induction in swine when injected within 3 days of normal • For controlling the timing of estrus in estrous cycling mares predicted farrowing. The response to treatment varies by individual animals with a mean interval from • For difficult-to-breed mares (clinically anestrous mares that have a corpus luteum) administration of 2 mL LUTALYSE Injection (10 mg dinoprost) to parturition of approximately 30 hours. This can

MANAGEMENT CONSIDERATIONS be employed to control the time of farrowing in sows and gilts in late gestation. Many factors contribute to success and failure of reproduction management, and these factors are important also Management Considerations: Several factors must be considered for the successful use of LUTALYSE Injection when time of breeding is to be regulated with LUTALYSE Injection. Some of these factors are: for parturition induction in swine. The product must be administered at a relatively specific time (treatment a. Cattle must be ready to breed—they must have a corpus luteum and be healthy; earlier than 3 days prior to normal predicted farrowing may result in increased piglet mortality). It is important b. Nutritional status must be adequate as this has a direct effect on conception and the initiation of estrus in that adequate records be maintained on (1) the average length of gestation period for the animals on a specific heifers or return of estrous cycles in cows following calving; location, and (2) the breeding and projected farrowing dates for each animal. This information is essential to determine the appropriate time for administration of LUTALYSE Injection. c. Physical facilities must be adequate to allow cattle handling without being detrimental to the animal; d. Estrus must be detected accurately if timed Al is not employed; Mares: LUTALYSE Injection is indicated for its luteolytic effect in mares. Administer a single intramuscular injection e. Semen of high fertility must be used; of 1 mg per 100 lbs (45.5 kg) body weight which is usually 1 mL to 2 mL LUTALYSE Injection. This luteolytic effect f. Semen must be inseminated properly. can be utilized to control the timing of estrus in estrous cycling and clinically anestrous mares that have a corpus luteum in the following circumstances: A successful breeding program can employ LUTALYSE Injection effectively, but a poorly managed breeding program will continue to be poor when LUTALYSE Injection is employed unless other management deficiencies are remedied 1. Controlling Time of Estrus of Estrous Cycling Mares: Mares treated with LUTALYSE Injection during diestrus (4 or first. Cattle expressing estrus following LUTALYSE Injection are receptive to breeding by a bull. Using bulls to breed more days after ovulation) will return to estrus within 2 to 4 days in most cases and ovulate 8 to 12 days after large numbers of cattle in heat following LUTALYSE Injection will require proper management of bulls and cattle. treatment. This procedure may be utilized as an aid to scheduling the use of stallions.

DOSAGE AND ADMINISTRATION 2. Difficult-to-Breed Mares: In extended diestrus there is failure to exhibit regular estrous cycles which is different As with any multi-dose vial, practice aseptic techniques in withdrawing each dose to decrease the possibility of from true anestrus. Many mares described as anestrus during the breeding season have serum progesterone post-injection bacterial infections. Adequately clean and disinfect the vial stopper prior to entry with a sterile levels consistent with the presence of a functional corpus luteum. A proportion of “barren”, maiden, and needle and syringe. Use only sterile needles, and use each needle only once. lactating mares do not exhibit regular estrous cycles and may be in extended diestrus. Following abortion, early fetal death and resorption, or as a result of “pseudopregnancy”, there may be serum progesterone levels No vial stopper should be entered more than 20 times. For this reason, the 100 mL bottle should only be used for consistent with a functional corpus luteum. Treatment of such mares with LUTALYSE Injection usually results cattle. The 30 mL bottle may be used for cattle, swine, or mares. in regression of the corpus luteum followed by estrus and/or ovulation. Treatment of “anestrous” mares which Cattle: abort subsequent to 36 days of pregnancy may not result in return to estrus due to presence of functional 1. For Estrus Synchronization in Beef Cows, Beef Heifers and Replacement Dairy Heifers. endometrial cups. LUTALYSE Injection is used to control the timing of estrus and ovulation in estrous cycling cattle that have a corpus luteum. Inject a dose of 5 mL LUTALYSE Injection (25 mg dinoprost) intramuscularly either once or twice WARNINGS AND PRECAUTIONS at a 10 to 12 day interval. With the single injection, cattle should be bred at the usual time relative to estrus. With User Safety: Not for human use. Keep out of the reach of children. Women of childbearing age, asthmatics, and the two injections cattle can be bred after the second injection either at the usual time relative to detected estrus persons with bronchial and other respiratory problems should exercise extreme caution when handling this or at about 80 hours after the second injection of LUTALYSE Injection. Estrus is expected to occur 1 to 5 days after product. In the early stages, women may be unaware of their pregnancies. Dinoprost tromethamine is readily injection if a corpus luteum was present. Cattle that do not become pregnant to breeding at estrus on days 1 to absorbed through the skin and can cause abortion and/or bronchiospasms. Accidental spillage on the skin should 5 after injection will be expected to return to estrus in about 18 to 24 days. be washed off immediately with soap and water.

2. For Unobserved (Silent) Estrus in Lactating Dairy Cows with a Corpus Luteum. Inject a dose of 5 mL To report suspected adverse events, for technical assistance or to obtain a copy of the Safety Data Sheet (SDS) LUTALYSE Injection (25 mg dinoprost) intramuscularly. Breed cows as they are detected in estrus. If estrus has contact Zoetis Inc. at 1-888-963-8471. For additional information about adverse drug experience reporting for not been observed by 80 hours after injection, breed at 80 hours. If the cow returns to estrus, breed at the usual animal drugs, contact FDA at 1-888-FDA-VETS or online at http://www.fda.gov/AnimalVeterinary/SafetyHealth. time relative to estrus. Residue Warnings: No milk discard or preslaughter drug withdrawal period is required for labeled uses in cattle. 3. For Treatment of Pyometra (chronic endometritis) in Cattle. Inject a dose of 5 mL LUTALYSE Injection No preslaughter drug withdrawal period is required for labeled uses in swine. Use of this product in excess of the (25 mg dinoprost) intramuscularly. approved dose may result in drug residues. Do not use in horses intended for human consumption.

4. For Abortion in Beef Cows, Beef Heifers and Replacement Dairy Heifers. LUTALYSE Injection is indicated for its Animal Safety Warnings: Severe localized clostridial infections associated with injection of LUTALYSE Injection have abortifacient effect in beef cows, beef heifers and replacement dairy heifers during the first 100 days of gestation. been reported. In rare instances, such infections have resulted in death. Inject a dose of 25 mg dinoprost (5 mL) intramuscularly. Aggressive antibiotic therapy should be employed at the first sign of infection at the injection site whether Cattle that abort will abort within 35 days of injection. localized or diffuse. Do not administer intravenously (IV) as this route may potentiate adverse reactions.

5. For use with FACTREL® (gonadorelin injection) Injection to synchronize estrous cycles to allow Non-steroidal anti-inflammatory drugs may inhibit prostaglandin synthesis; therefore this class of drugs should not fixed-time artificial insemination (FTAI) in lactating dairy cows: Administer 2 to 4 mL FACTREL Injection (100-200 be administered concurrently. Do not administer to pregnant cattle, unless abortion is desired. Cattle administered mcggonadorelin) per cow as an intramuscular injection in a treatment regimen with the following framework: a progestin would be expected to have a reduced response to LUTALYSE Injection. Do not administer to sows and/or • Administer the first dose of FACTREL Injection (2-4 mL) at Day 0 gilts prior to 3 days of normal predicted farrowing as an increased number of stillbirths and postnatal mortality • Administer LUTALYSE (25 mg dinoprost, as dinoprost tromethamine) Injection by intramuscular injection may result. In mares, LUTALYSE Injection is ineffective when administered prior to day-5 after ovulation. 6-8 days after the first dose of FACTREL Injection. Mare pregnancy status should be determined prior to treatment since LUTALYSE Injection has been reported to • Administer a second dose of FACTREL Injection (2-4 mL) 30 to 72 hours after the LUTALYSE injection. induce abortion and parturition when sufficient doses were administered. Mares should not be treated if they • Perform FTAI 0 to 24 hours after the second dose of FACTREL Injection, or inseminate cows on detected suffer from either acute or subacute disorders of the vascular system, gastrointestinal tract, respiratory system, or estrus using standard herd practices. reproductive tract. 62 ADVERSE REACTIONS Additional studies investigated the effects in the mare of single intramuscular doses of 0, 0.25, 1.0, 2.5, 3.0, 5.0, and Limited salivation has been reported in some instances. 10.0 mg dinoprost tromethamine. Heart rate, respiration rate, rectal temperature, and sweating were measured Cattle: at 0, 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, and 6.0 hr. after injection. Neither heart rate nor respiration rates were Swine: The most frequently observed side effects were erythema and pruritus, slight incoordination, nesting significantly altered (P > 0.05) when compared to contemporary control values. Sweating was observed for 0 of behavior, itching, urination, defecation, abdominal muscle spasms, tail movements, hyperpnea or dyspnea, 9, 2 of 9, 7 of 9, 9 of 9, and 8 of 9 mares injected with 0.25, 1.0, 2.5, 3.0, 5.0, or 10.0 mg dinoprost tromethamine, increased vocalization, salivation, and at the 100 mg (10x) dose only, possible vomiting. These side effects are respectively. Sweating was temporary in all cases and was mild for doses of 3.0 mg or less but was extensive (beads transitory, lasting from 10 minutes to 3 hours, and were not detrimental to the health of the animal. of sweat over the entire body and dripping) for the 10 mg dose. Sweating after the 5.0 mg dose was intermediate between that seen for mares treated with 3.0 and 10.0 mg. Sweating began within 15 minutes after injection and Mares: The most frequently observed side effects are sweating and decreased rectal temperature. However, these have been transient in all cases observed and have not been detrimental to the animal. ceased by 45 to 60 minutes after injection. Rectal temperature was decreased during the interval 0.5 until 1.0, 3 to 4, or 5 hours after injection for 0.25 and 1.0 mg, 2.5 and 3.0, or 5.0 and 10.0 mg dose groups, respectively. Average Other reactions seen have been increase in heart rate, increase in respiration rate, some abdominal discomfort, rectal temperature during the periods of decreased temperature was on the order of 97.5 to 99.6, with the greatest locomotor incoordination, and lying down. These effects are usually seen within 15 minutes of injection and decreases observed in the 10 mg dose group. disappear within one hour. Mares usually continue to eat during the period of expression of side effects. One anaphylactic reaction of several hundred mares treated with LUTALYSE Injection was reported but was not EFFECTIVENESS confirmed. Cattle: Contact Information: To report adverse reactions call Zoetis Inc. at 1-888-963-8471. For Treatment of Pyometra (chronic endometritis) in Cattle: In studies conducted with LUTALYSE Injection, pyometra CLINICAL PHARMACOLOGY was defined as presence of a corpus luteum in the ovary and uterine horns containing fluid but not a conceptus based on palpation per rectum. Return to normal was defined as evacuation of fluid and return of the uterine horn General Biologic Activity: Prostaglandins occur in nearly all mammalian tissues. Prostaglandins, especially PGE’s size to 40mm or less based on palpation per rectum at 14 and 28 days. Most cattle that recovered in response to and PGF’s, have been shown, in certain species, to 1) increase at time of parturition in amniotic fluid, maternal LUTALYSE Injection recovered within 14 days after injection. After 14 days, recovery rate of treated cattle was no placenta, myometrium, and blood, 2) stimulate myometrial activity, and 3) to induce either abortion or parturition. different than that of non-treated cattle. Prostaglandins, especially PGF2α, have been shown to 1) increase in the uterus and blood to levels similar to levels achieved by exogenous administration which elicited luteolysis, 2) be capable of crossing from the uterine vein to For Abortion in Beef Cows, Beef Heifers and Replacement Dairy Heifers: Commercial cattle were palpated per rectum the ovarian artery (sheep), 3) be related to IUD induced luteal regression (sheep), and 4) be capable of regressing for pregnancy in six feedlots. The percent of pregnant cattle in each feedlot less than 100 days of gestation ranged the corpus luteum of most mammalian species studied to date. Prostaglandins have been reported to result in between 26 and 84; 80% or more of the pregnant cattle were less than 150 days of gestation. The abortion rates release of pituitary tropic hormones. Data suggest prostaglandins, especially PGE’s and PGF’s, may be involved in following injection of LUTALYSE Injection increased with increasing doses up to about 25 mg. As examples, the the process of ovulation and gamete transport. Also PGF2α has been reported to cause increase in blood pressure, abortion rates, over 7 feedlots on the dose titration study, were 22%, 50%, 71%, 90% and 78% for cattle up to 100 bronchoconstriction, and smooth muscle stimulation in certain species. days of gestation when injected IM with LUTALYSE Injection doses of 0,1 (5 mg), 2 (10 mg), 4 (20 mg) and 8 (40 mg) mL, respectively. The statistical predicted relative abortion rate based on the dose titration data, was about 93% for Metabolism: A number of metabolism studies have been done in laboratory animals. The metabolism of tritium the 5 mL (25 mg) LUTALYSE Injection dose for cattle injected up to 100 days of gestation. labeled dinoprost (3H PGF2 alpha) in the rat and in the monkey was similar. Although quantitative differences were observed, qualitatively similar metabolites were produced. For use with FACTREL® (gonadorelin injection) Injection to synchronize estrous cycles to allow fixed-time artificial For a full description of the studies conducted for the use of FACTREL 3 3 insemination (FTAI) in lactating dairy cows: A study demonstrated that equimolar doses of H PGF2 alpha Tham and H PGF2 alpha free acid administered Injection and LUTALYSE Injection, please refer to the labeling for FACTREL Injection. intravenously to rats demonstrated no significant differences in blood concentration of dinoprost. An interesting observation in the above study was that the radioactive dose of 3H PGF2 alpha rapidly distributed in tissues and Mares: dissipated in tissues with almost the same curve as it did in the serum. The half-life of dinoprost in bovine blood has For Difficult-to-Breed Mares: In one study with 122 Standardbred and Thoroughbred mares in clinical anestrus for been reported to be on the order of minutes. A complete study on the distribution of decline of 3H PGF2 alpha Tham an average of 58 days and treated during the breeding season, behavioral estrus was detected in 81 percent at an in the tissue of rats was well correlated with the work done in the cow. Cattle serum collected during 24 hours after average time of 3.7 days after injection with 5 mg LUTALYSE Injection; ovulation occurred an average of 7.0 days doses of 0 to 250 mg dinoprost have been assayed by RIA for dinoprost and the 15-keto metabolites. These data after treatment. Of those mares bred, 59% were pregnant following an average of 1.4 services during that estrus. support previous reports that dinoprost has a half-life of minutes. Dinoprost is a natural prostaglandin. All systems associated with dinoprost metabolism exist in the body; therefore, no new metabolic, transport, excretory, binding HOW SUPPLIED or other systems need be established by the body to metabolize injected dinoprost. LUTALYSE Injection is available in 30 and 100 mL vials.

TARGET ANIMAL SAFETY STORAGE, HANDLING, AND DISPOSAL Store at controlled room temperature 20° to 25°C (68° to 77°F). Dinoprost was non-teratogenic in rats when administered orally at 1.25, 3.2, 10.0 and Laboratory Animals: Use contents within 12 weeks of first vial puncture. Protect from freezing. 20.0 mg dinoprost/kg/day from day 6th-15th of gestation or when administered subcutaneously at 0.5 and 1.0 mg/kg/day on gestation days 6, 7 and 8 or 9, 10 and 11 or 12, 13 and 14. Dinoprost was non-teratogenic in the rabbit when administered either subcutaneously at doses of 0.5 and 1.0 mg dinoprost/kg/day on gestation days 6, NADA 108-901, Approved by FDA 7 and 8 or 9, 10 and 11 or 12, 13 and 14 or 15, 16 and 17 or orally at doses of 0.01, 0.1 and 1.0 mg dinoprost/kg/day on days 6-18 or 5.0 mg/kg/day on days 8-18 of gestation. A slight and marked embryo lethal effect was observed in dams given 1.0 and 5.0 mg dinoprost/kg/day respectively. This was due to the expected luteolytic properties of the drug. Distributed by: A 14-day continuous intravenous infusion study in rats at 20 mg PGF2α per kg body weight indicated Zoetis Inc. prostaglandins of the F series could induce bone deposition. However, such bone changes were not observed in Kalamazoo, MI 49007 monkeys similarly administered LUTALYSE Injection at 15 mg dinoprost per kg body weight for 14 days. Made in Spain Cattle: In cattle, evaluation was made of clinical observations, clinical chemistry, hematology, urinalysis, organ weights, and gross plus microscopic measurements following treatment with various doses up to 250 mg dinoprost administered twice intramuscularly at a 10 day interval or doses of 25 mg administered daily for 10 days. There Revised: August 2015 was no unequivocal effect of dinoprost on the hematology or clinical chemistry parameters measured. Clinically, a slight transitory increase in heart rate was detected. Rectal temperature was elevated about 1.5˚ F through the 6th P1208-678US/11-14A&P hour after injection with 250 mg dinoprost, but had returned to baseline at 24 hours after injection. No dinoprost associated gross lesions were detected. There was no evidence of toxicological effects. Thus, dinoprost had a safety factor of at least 10X on injection (25 mg luteolytic dose vs. 250 mg safe dose), based on studies conducted with cattle. At luteolytic doses, dinoprost had no effect on progeny. If given to a pregnant cow, it may cause abortion; the dose required for abortion varies considerably with the stage of gestation. Induction of abortion in feedlot cattle at stages of gestation up to 100 days of gestation did not result in dystocia, retained placenta or death of heifers in the field studies. The smallness of the fetus at this early stage of gestation should not lead to complications at abortion. However, induction of parturition or abortion with any exogenous compound may precipitate dystocia, fetal death, retained placenta and/or metritis, especially at latter stages of gestation.

Swine: In pigs, evaluation was made of clinical observations, food consumption, clinical pathologic determinations, body weight changes, urinalysis, organ weights, and gross and microscopic observations following treatment with single doses of 10, 30, 50 and 100 mg dinoprost administered intramuscularly. The results indicated no treatment related effects from dinoprost treatment that were deleterious to the health of the animals or to their offspring.

Mares: Dinoprost tromethamine was administered to adult mares (weighing 320 to 485 kg; 2 to 20 years old), at the rates of 0, 100, 200, 400, and 800 mg per mare per day for 8 days. Route of administration for each dose group was both intramuscularly (2 mares) and subcutaneously (2 mares). Changes were detected in all treated groups for clinical (reduced sensitivity to pain; locomotor incoordination; hypergastromotility; sweating; hyperthermia; labored respiration), blood chemistry (elevated cholesterol, total bilirubin, LDH, and glucose), and hematology (decreased eosinophils; increased hemoglobin, hematocrit, and erythrocytes) measurements. The effects in the 100 mg dose, and to a lesser extent, the 200 mg dose groups were transient in nature, lasting for a few minutes to several hours. Mares did not appear to sustain adverse effects following termination of the side effects. Mares treated with either 400 mg or 800 mg exhibited more profound symptoms. The excessive hyperstimulation of the gastrointestinal tract caused a protracted diarrhea, slight electrolyte imbalance (decreased sodium and potassium), dehydration, gastrointestinal irritation, and slight liver malfunction (elevated SGOT, SGPT at 800 mg only). Heart rate was increased but pH of the urine was decreased. Other measurements evaluated in the study remained within normal limits. No mortality occurred in any of the groups. No apparent differences were observed between the intramuscular and subcutaneous routes of administration. Luteolytic doses of dinoprost tromethamine are on the order of 5 to 10 mg administered on one day, therefore, LUTALYSE Injection was demonstrated to have a wide margin of safety. Thus, the 100 mg dose gave a safety margin of 10 to 20X for a single injection or 80 to 160X for the 8 daily injections. 63 4. For Abortion in Beef Cows, Beef Heifers and Replacement Dairy Heifers. LUTALYSE HighCon Injection is indicated for its abortifacient effect in beef cows, beef heifers and replacement dairy heifers during the first 100 days of gestation. Inject a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection. Cattle that abort will abort within 35 days of injection. 5. For use with FACTREL® (gonadorelin injection) Injection to synchronize estrous cycles Lutalyse® HighCon to allow fixed-time artificial insemination (FTAI) in lactating dairy cows: Administer 2 to Injection 4 mL FACTREL Injection (100-200 mcg gonadorelin) per cow as an intramuscular injection in a treatment regimen with the following framework: (dinoprost tromethamine injection) • Administer the first dose of FACTREL Injection (2-4 mL) at Day 0 12.5 mg dinoprost/mL as dinoprost tromethamine • Administer a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection 6-8 days after the first dose of FACTREL Injection. For use in cattle only. • Administer a second dose of FACTREL Injection (2-4 mL) 30 to 72 hours after the LUTALYSE Not for use in horses and swine. HighCon Injection. Caution: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. • Perform FTAI 0 to 24 hours after the second dose of FACTREL Injection, or inseminate cows DESCRIPTION on detected estrus using standard herd practices. LUTALYSE® HighCon Injection (12.5 mg dinoprost/mL) is a sterile solution containing the naturally Below are three examples of treatment regimens for FTAI that fit within the dosage regimen occurring prostaglandin F2 alpha (dinoprost) as the tromethamine salt. Each mL contains dinoprost framework described immediately above: tromethamine equivalent to 12.5 mg dinoprost: also, benzyl alcohol, 16.5 mg added as preservative Example 1 Example 2 Example 3 and water for injection. When necessary, pH was adjusted with sodium hydroxide and/or hydrochloric st st st acid. Dinoprost tromethamine is a white or slightly off-white crystalline powder that is readily soluble Day 0 (Monday) 1 FACTREL 1 FACTREL 1 FACTREL in water at room temperature in concentrations to at least 200 mg/mL. Day 7 LUTALYSE LUTALYSE LUTALYSE (the following HighCon HighCon HighCon INDICATIONS FOR USE Monday) LUTALYSE HighCon Injection is indicated as a luteolytic agent. LUTALYSE HighCon Injection is Day 9 2nd FACTREL 2nd FACTREL 2nd FACTREL effective only in those cattle having a corpus luteum, i.e., those which ovulated at least five days (Wednesday) + FTAI 48 hours 56 hours prior to treatment. at 48 hours after after • For estrus synchronization in beef cows, beef heifers and replacement dairy heifers after LUTALYSE LUTALYSE • For unobserved (silent) estrus in lactating dairy cows with a corpus luteum LUTALYSE HighCon HighCon • For treatment of pyometra (chronic endometritis) in cattle HighCon • For abortion in beef cows, beef heifers and replacement dairy heifers Day 10 FTAI FTAI • For use with FACTREL (gonadorelin injection) Injection to synchronize estrous cycles to allow (Thursday) 24 hours 18 hours nd nd fixed-time artificial insemination (FTAI) in lactating dairy cows after 2 after 2 FACTREL FACTREL • For use with EAZI-BREED™ CIDR® (progesterone intravaginal insert) Cattle Insert for synchronization of estrus in lactating dairy cows 6. For use with EAZI-BREED™ CIDR® (progesterone intravaginal insert) Cattle Insert for • For use with EAZI-BREED™ CIDR® (progesterone intravaginal insert) Cattle Insert for synchronization Synchronization of Estrus in Lactating Dairy Cows: of estrus in suckled beef cows and replacement beef and dairy heifers, advancement of first • Administer one EAZI-BREED CIDR Cattle Insert per animal and remove 7 days later (for postpartum estrus in suckled beef cows, and advancement of first pubertal estrus in beef heifers example if administered on a Monday remove the following Monday). • Administer a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular MANAGEMENT CONSIDERATIONS or subcutaneous injection at the time of removal of the EAZI-BREED CIDR Cattle Insert. Many factors contribute to success and failure of reproduction management, and these factors are • Observe animals for signs of estrus on Days 2 to 5 after removal of the EAZI-BREED CIDR important also when time of breeding is to be regulated with LUTALYSE HighCon Injection. Some of Cattle Insert and inseminate animals found in estrus following normal herd practices. these factors are: a. Cattle must be ready to breed—they must have a corpus luteum and be healthy; 7. For use with EAZI-BREED™ CIDR® (progesterone intravaginal insert) Cattle Insert for b. Nutritional status must be adequate as this has a direct effect on conception and the synchronization of estrus in suckled beef cows and replacement beef and dairy heifers, initiation of estrus in heifers or return of estrous cycles in cows following calving; advancement of first postpartum estrus in suckled beef cows, and advancement of first pubertal estrus in beef heifers: c. Physical facilities must be adequate to allow cattle handling without being detrimental to • Administer one EAZI-BREED CIDR Cattle Insert per animal for 7 days (for example, if the animal; administered on a Monday remove on the following Monday). d. Estrus must be detected accurately if timed Al is not employed; • Administer a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or e. Semen of high fertility must be used; subcutaneous injection 1 day prior to EAZI-BREED CIDR Cattle Insert removal, on Day 6 of the f. Semen must be inseminated properly. 7 day administration period. A successful breeding program can employ LUTALYSE HighCon Injection effectively, but a poorly • Observe animals for signs of estrus on Days 1 to 3 after removal of the EAZI-BREED CIDR managed breeding program will continue to be poor when LUTALYSE HighCon Injection is employed Cattle Insert and inseminate animals about 12 hours after onset of estrus. unless other management deficiencies are remedied first. Cattle expressing estrus following WARNINGS AND PRECAUTIONS LUTALYSE HighCon Injection are receptive to breeding by a bull. Using bulls to breed large numbers User Safety: Not for human use. Keep out of the reach of children. Women of childbearing age, of cattle in heat following LUTALYSE HighCon Injection will require proper management of bulls asthmatics, and persons with bronchial and other respiratory problems should exercise extreme and cattle. Future reproductive performance of animals that are not cycling will be unaffected by caution when handling this product. In the early stages, women may be unaware of their injection of LUTALYSE HighCon Injection. pregnancies. Dinoprost tromethamine is readily absorbed through the skin and can cause abortion DOSAGE AND ADMINISTRATION and/or bronchiospasms. Accidental spillage on the skin should be washed off immediately with As with any multi-dose vial, practice aseptic techniques in withdrawing each dose to decrease the soap and water. possibility of post-injection bacterial infections. Adequately clean and disinfect the vial stopper prior Residue Warnings: No milk discard or preslaughter drug withdrawal period is required for labeled to entry with a sterile needle and syringe. Use only sterile needles, and use each needle only once. uses in cattle. Use of this product in excess of the approved dose may result in drug residues. No vial stopper should be entered more than 20 times. Animal Safety Warnings: Severe localized clostridial infections associated with injection of 1. For Estrus Synchronization in Beef Cows, Beef Heifers and Replacement Dairy Heifers. LUTALYSE Injection have been reported. In rare instances, such infections have resulted in death. LUTALYSE HighCon Injection is used to control the timing of estrus and ovulation in estrous Aggressive antibiotic therapy should be employed at the first sign of infection at the injection site cycling cattle that have a corpus luteum. Inject a dose of 2 mL LUTALYSE HighCon Injection (25 mg whether localized or diffuse. Do not administer intravenously (IV) as this route may potentiate adverse dinoprost) intramuscularly or subcutaneously either once or twice at a 10 to 12 day interval. With reactions. Non-steroidal anti-inflammatory drugs may inhibit prostaglandin synthesis; therefore this the single injection, cattle should be bred at the usual time relative to estrus. With the two injections class of drugs should not be administered concurrently. Do not administer to pregnant cattle, unless cattle can be bred after the second injection either at the usual time relative to detected estrus or abortion is desired. Cattle administered a progestin would be expected to have a reduced response at about 80 hours after the second injection of LUTALYSE HighCon Injection. Estrus is expected to to LUTALYSE Injection. occur 1 to 5 days after injection if a corpus luteum was present. Cattle that do not become pregnant to breeding at estrus on days 1 to 5 after injection will be expected to return to estrus in about ADVERSE REACTIONS 18 to 24 days. Limited salivation has been reported in some instances. Contact Information: To report suspected adverse events, for technical assistance or to obtain a 2. For Unobserved (Silent) Estrus in Lactating Dairy Cows with a Corpus Luteum. Inject a copy of the Safety Data Sheet (SDS) contact Zoetis Inc. at 1-888-963-8471. For additional information dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or online injection. Breed cows as they are detected in estrus. If estrus has not been observed by at http://www.fda.gov/AnimalVeterinary/SafetyHealth. 80 hours after injection, breed at 80 hours. If the cow returns to estrus, breed at the usual time relative to estrus. CLINICAL PHARMACOLOGY 3. For Treatment of Pyometra (chronic endometritis) in Cattle. Inject a dose of 2 mL LUTALYSE General Biologic Activity: Prostaglandins occur in nearly all mammalian tissues. Prostaglandins, HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection. especially PGE’s and PGF’s, have been shown, in certain species, to 1) increase at time of parturition in amniotic fluid, maternal placenta, myometrium, and blood, 2) stimulate myometrial activity, and 3) to induce either abortion or parturition. Prostaglandins, especially PGF2α, have been shown to 1) increase 64 in the uterus and blood to levels similar to levels achieved by exogenous administration which elicited changes were not observed in monkeys similarly administered 15 mg dinoprost per kg body luteolysis, 2) be capable of crossing from the uterine vein to the ovarian artery (sheep), 3) be related weight for 14 days. to IUD induced luteal regression (sheep), and 4) be capable of regressing the corpus luteum of most Cattle: In cattle, evaluation was made of clinical observations, clinical chemistry, hematology, mammalian species studied to date. Prostaglandins have been reported to result in release of pituitary urinalysis, organ weights, and gross plus microscopic measurements following treatment with tropic hormones. Data suggest prostaglandins, especially PGE’s and PGF’s, may be involved in the various doses up to 250 mg dinoprost administered twice intramuscularly at a 10 day interval or process of ovulation and gamete transport. Also PGF2α has been reported to cause increase in blood doses of 25 mg administered daily for 10 days. There was no unequivocal effect of dinoprost on pressure, bronchoconstriction, and smooth muscle stimulation in certain species. the hematology or clinical chemistry parameters measured. Clinically, a slight transitory increase Metabolism: A number of metabolism studies have been done in laboratory animals. The metabolism in heart rate was detected. Rectal temperature was elevated about 1.5˚ F through the 6th hour of tritium labeled dinoprost (3H PGF2 alpha) in the rat and in the monkey was similar. Although after injection with 250 mg dinoprost, but had returned to baseline at 24 hours after injection. No quantitative differences were observed, qualitatively similar metabolites were produced. A study dinoprost associated gross lesions were detected. There was no evidence of toxicological effects. demonstrated that equimolar doses of 3H PGF2 alpha Tham and 3H PGF2 alpha free acid administered Thus, dinoprost had a safety factor of at least 10X on injection (25 mg luteolytic dose vs. 250 mg intravenously to rats demonstrated no significant differences in blood concentration of dinoprost. safe dose), based on studies conducted with cattle. At luteolytic doses, dinoprost had no effect An interesting observation in the above study was that the radioactive dose of 3H PGF2 alpha rapidly on progeny. If given to a pregnant cow, it may cause abortion; the dose required for abortion distributed in tissues and dissipated in tissues with almost the same curve as it did in the serum. The varies considerably with the stage of gestation. Induction of abortion in feedlot cattle at stages half-life of dinoprost in bovine blood has been reported to be on the order of minutes. A complete study of gestation up to 100 days of gestation did not result in dystocia, retained placenta or death of on the distribution of decline of 3H PGF2 alpha Tham in the tissue of rats was well correlated with the heifers in the field studies. The smallness of the fetus at this early stage of gestation should not lead work done in the cow. Cattle serum collected during 24 hours after doses of 0 to 250 mg dinoprost have to complications at abortion. However, induction of parturition or abortion with any exogenous been assayed by RIA for dinoprost and the 15-keto metabolites. These data support previous reports compound may precipitate dystocia, fetal death, retained placenta and/or metritis, especially at that dinoprost has a half-life of minutes. Dinoprost is a natural prostaglandin. All systems associated latter stages of gestation. with dinoprost metabolism exist in the body; therefore, no new metabolic, transport, excretory, binding Injection Site Safety Summary: Eight non-lactating, non-pregnant dairy cows were injected or other systems need be established by the body to metabolize injected dinoprost. with saline and eight animals were injected with LUTALYSE HighCon (12.5 mg dinoprost/mL Relative Bioavailability Study: The requirement for substantial evidence of effectiveness was @ 25 mg/animal) twice, at an interval of ten days. The first injection was administered in the left neck fulfilled by a pharmacokinetic study comparing the relative bioavailability of the subcutaneous on Day 0 and the second injection was administered in the right neck on Day 10. Clinical observations (SC) administration of 25 mg of LUTALYSE HighCon Injection (12.5 mg dinoprost/mL) to the were conducted on Days -14, -1, 0, 1, 2, 10, and 11, and injection site observations were conducted on approved intramuscular (IM) administration of 25 mg of LUTALYSE Injection (5 mg dinoprost/mL). all animals once on Days -14, -1, and once daily from Day 0 until Day 11. Animals were euthanized on The effectiveness data for LUTALYSE Injection at doses of 25 and 35 mg IM were used to support an Day 11. There were no abnormal clinical observations or general health observations related to drug adjusted Test/Reference (T/R) ratio of 1.4 and 90% Confidence Intervals of 80 - 164% for Cmax and AUC administration during the conduct of the study. Injection site observations revealed no findings of to demonstrate therapeutic equivalence. erythema, heat, or sensitivity. No hardness was noted at the injection sites in any control animal post The pivotal relative bioavailability study was a randomized, non-replicated, three treatment, three treatment administration. In the treated group, two animals had hardness noted on the right neck on period, six sequence crossover study in 24 cows (4 cows per sequence). Each cow received a single Day 11. This hardness was probably a result of test article administration at that site on the previous dose of 25 mg dinoprost administered as 5 mL of LUTALYSE Injection IM, 5 mL of LUTALYSE Injection day. No abnormal skin appearance was noted in any animal during this study. Swelling with a volume SC, or 2 mL of LUTALYSE HighCon SC, with a washout period of 48 hours between doses. Plasma of 3.53 cm3 was observed on Day 11 in the right neck in one treated animal. At necropsy discoloration samples were collected at 60 and 10 minutes prior to dose administration, and at 5, 10, 15, 20, 30, (variations of dark red, tan, gray, or yellow mottled) in the subcutaneous tissue was observed at all 75 minutes, and at 2, 3, 4.5, 6, 7.5, and 12 hours after each dose. Samples were analyzed by UPLC-MS/MS dinoprost injection sites. More discolored subcutaneous tissue was present at the Day 10 injection for PGF2α (dinoprost) and PGFm (metabolite) concentrations. PGFm was chosen as the analyte of sites compared to the Day 0 injection sites. There was no discoloration observed in the deep muscle interest because its concentrations are reflective of exogenously administered dinoprost (after tissue. In summary, this study demonstrated that subcutaneous injection of LUTALYSE HighCon was subtraction of endogenous concentrations), and it has a longer half-life and therefore less blood well tolerated when injected subcutaneously into dairy cows at a dose of 25 mg dinoprost/cow twice level fluctuations than PGF2α. The results of the relative bioavailability study are summarized in at an interval of 10 days. Table 1. The Cmax and AUClast of LUTALYSE HighCon were within the adjusted 90% Confidence Intervals. EFFECTIVENESS Therefore, the SC administration of 25 mg of LUTALYSE HighCon was considered to be equivalent to The requirement for substantial evidence of effectiveness was fulfilled by a pharmacokinetic study the IM administration of 25 mg of LUTALYSE Injection. comparing the relative bioavailability of the SC administration of 25 mg of LUTALYSE HighCon Table 1: Relative Bioavailability Results for LUTALYSE HighCon Injection Injection (12.5 mg dinoprost/mL) to the approved IM administration of 25 mg of LUTALYSE Injection (5 mg dinoprost/mL) (see CLINICAL PHARMACOLOGY, Relative Bioavailability Study). This study Parameter Product/ LSMean Ratio Lower Upper demonstrated the equivalence of the SC administration of 25 mg of LUTALYSE HighCon to the IM Route T/R† 90% CI 90% CI administration of 25 mg of LUTALYSE Injection. Therefore, the effectiveness studies conducted with LUTALYSE LUTALYSE Injection support the effectiveness of LUTALYSE HighCon Injection. Injection 41.26 (IM)* For Treatment of Pyometra (chronic endometritis) in Cattle: In studies conducted with LUTALYSE Injection, pyometra was defined as presence of a corpus luteum in the ovary and uterine horns C LUTALYSE max containing fluid but not a conceptus based on palpation per rectum. Return to normal was defined (ng/mL) Injection 50.80 1.23 110.99 136.60 as evacuation of fluid and return of the uterine horn size to 40mm or less based on palpation per (SC) rectum at 14 and 28 days. Most cattle that recovered in response to LUTALYSE Injection recovered LUTALYSE within 14 days after injection. After 14 days, recovery rate of treated cattle was no different than that HighCon 55.12 1.34 120.42 148.20 of non-treated cattle. Injection For Abortion in Beef Cows, Beef Heifers and Replacement Dairy Heifers: Commercial cattle (SC) were palpated per rectum for pregnancy in six feedlots. The percent of pregnant cattle in each LUTALYSE feedlot less than 100 days of gestation ranged between 26 and 84; 80% or more of the pregnant Injection 66.85 cattle were less than 150 days of gestation. The abortion rates following injection of LUTALYSE (IM)* Injection increased with increasing doses up to about 25 mg. As examples, the abortion rates,

AUClast LUTALYSE over 7 feedlots on the dose titration study, were 22%, 50%, 71%, 90% and 78% for cattle up to (hr*ng/mL) Injection 67.25 1.00 96.26 105.12 100 days of gestation when injected IM with LUTALYSE Injection doses of 0, 1 (5 mg), 2 (10 mg), (SC) 4 (20 mg) and 8 (40 mg) mL, respectively. The statistical predicted relative abortion rate based on the LUTALYSE dose titration data was about 93% for the 5 mL (25 mg) LUTALYSE Injection dose for cattle injected up to 100 days of gestation. HighCon 65.81 0.98 94.20 102.87 For use with FACTREL® (gonadorelin injection) Injection to synchronize estrous cycles to Injection allow fixed-time artificial insemination (FTAI) in lactating dairy cows: For a full description of (SC) the studies conducted for the use of FACTREL Injection and LUTALYSE Injection, please refer to the Cmax - maximum plasma concentration labeling for FACTREL Injection. AUClast - the area under the plasma concentration vs. time curve from time of injection to the limit of quantification of the assay HOW SUPPLIED * Reference product and route of administration LUTALYSE HighCon Injection is available in 20, 100 and 250 mL vials. † Geometric means STORAGE, HANDLING AND DISPOSAL TARGET ANIMAL SAFETY Store below 25°C (77°F), with brief excursions between 0°C and 40°C (32°F and 104°F). Use contents Laboratory Animals: Dinoprost was non-teratogenic in rats when administered orally at 1.25, 3.2, 10.0 within 12 weeks of first vial puncture. Stopper may be punctured a maximum of 20 times. and 20.0 mg dinoprost/kg/day from day 6th-15th of gestation or when administered subcutaneously NADA #141-442, Approved by FDA at 0.5 and 1.0 mg/kg/day on gestation days 6, 7 and 8 or 9, 10 and 11 or 12, 13 and 14. Dinoprost was non-teratogenic in the rabbit when administered either subcutaneously at doses of 0.5 and 1.0 mg dinoprost/kg/day on gestation days 6, 7 and 8 or 9, 10 and 11 or 12, 13 and 14 or 15, 16 and 17 or Distributed by: orally at doses of 0.01, 0.1 and 1.0 mg dinoprost/kg/day on days 6-18 or 5.0 mg/kg/day on days 8-18 Zoetis Inc. of gestation. A slight and marked embryo lethal effect was observed in dams given 1.0 and 5.0 mg Kalamazoo, MI 49007 dinoprost/kg/day respectively. This was due to the expected luteolytic properties of the drug. A 14-day continuous intravenous infusion study in rats at 20 mg PGF2α per kg body weight Made in Spain indicated prostaglandins of the F series could induce bone deposition. However, such bone Revised: August 2015 P1207-669US/06-15A&P 65 24-hour intervals for a total of three consecutive days. Additional treatments Table 1. Ceftiofur MIC Values of Bacterial Isolates from Clinical Field ® may be given on days four and five for animals which do not show a satisfactory Studies in the USA Naxcel response (not recov ered) after the initial three treatments. Selection of dosage Animal Organism Number Date MIC90* MIC Range brand of ceftiofur sodium (0.5 to 1.0 mg/lb) should be based on the practitioner’s judgement of severity Tested Tested (µg/mL) (µg/mL) sterile powder of disease (i.e., extent of elevated body temperature, depressed physical appearance, increased respiratory rate, coughing and/or loss of appetite). Bovine Mannheimia haemolytica 461 1988-1992 0.06 ≤0.03-0.13 Pharmacokinetic data indicate that elimination of the drug is more rapid in Mannheimia haemolytica 42 1993 0.015 ≤0.003-0.03 For intramuscular and subcutaneous injection in cattle only. For intramuscular lactating does. For lactating does, the high end of the dose range is recommended. Pasteurella multocida 318 1988-1992 0.06 ≤0.03-0.25 injection in swine, sheep, goats, and horses. For subcutaneous injection ≤ ≤ only in dogs, day-old chickens and day-old turkey poults. This product may Horses Pasteurella multocida 48 1993 0.003 0.003-0.015 be used in lactating dairy cattle, sheep, and goats. Administer to horses by intramuscular injection at the dosage of 1.0 to 2.0 Histophilus somni 109 1988-1992 0.06 ≤0.03-0.13 mg ceftiofur per pound (2.2 to 4.4 mg/kg) of body weight (2-4 mL reconstituted Histophilus somni 59 1993 ≤0.0019 no range CAUTION: Federal (USA) law restricts this drug to use by or on the order of a sterile solution per 100 lbs body weight). A maximum of 10 mL may be Fusobacterium licensed veterinarian. Federal law prohibits extra-label use of this drug in cattle, administered per injection site. Treatment should be repeated at 24-hour necrophorum 17 1994 ≤0.06 no range swine, chickens and turkeys for disease prevention purposes; at unapproved intervals, continued for 48 hours after clinical signs have disappeared and should doses, frequencies, durations, or routes of administration; and in unapproved not exceed 10 days. Swine Actinobacillus pleuropn. 83 1993 ≤0.03 ≤0.03-0.06 major food producing species/production classes. Dogs Pasteurella multocida 74 1993 ≤0.03 ≤0.03-0.06 Streptococcus suis 94 1993 0.25 ≤0.03-1.0 DESCRIPTION Administer to dogs by subcutaneous injection at the dosage of 1.0 mg ceftiofur NAXCEL Sterile Powder contains the sodium salt of ceftiofur which is a broad per pound (2.2 mg/kg) of body weight (0.1 mL reconstituted sterile solution per Salmonella choleraesuis 50 1993 1.0 1.0-2.0 spectrum cephalosporin antibiotic active against gram-positive and gram- 5 lbs body weight). Treatment should be repeated at 24-hour intervals for 5-14 days. beta-hemolytic negative bacteria including β-lactamase-producing strains. Like other Reconstituted NAXCEL Sterile Powder is to be administered to dogs by Streptococcus spp. 24 1993 ≤0.03 ≤0.03-0.06 cephalosporins, ceftiofur is bactericidal in vitro, resulting from inhibition of cell subcutaneous injection. No vial closure should be entered more than 20 times. Actinobacillus suis 77 1998 0.0078 0.0019-0.0078 wall synthesis. Therefore, only the 1 gram vial is approved for use in dogs. Haemophilus parasuis 76 1998 0.06 0.0039-0.25 Each mL of the reconstituted drug contains ceftiofur sodium equivalent to Day-Old Chicks Sheep Mannheimia haemolytica 39 1992 0.13 ≤0.03-0.13 50 mg ceftiofur. The pH was adjusted with sodium hydroxide and mono basic Administer by subcutaneous injection in the neck region of day-old chicks at potassium phosphate. the dosage of 0.08 to 0.20 mg ceftiofur/chick. One mL of the 50 mg/mL Pasteurella multocida 23 1992 ≤0.03 no range Chemical Structure of Ceftiofur Sodium reconstituted solution will treat approximately 250 to 625 day-old chicks. Canine Escherichia coli 44 1992 4.0 0.06-64.0 Reconstituted NAXCEL Sterile Powder is to be administered by subcutaneous Escherichia coli 18 1990 0.25 0.13-0.5 injection only. A sterile 26 gauge needle and syringe or properly cleaned Proteus mirabilis 17 1990 ≤0.06 ≤0.06-0.5 automatic injection machine should be used. Proteus mirabilis 23 1992 1.0 ≤0.06-4.0 Day-Old Turkey Poults Administer by subcutaneous injection in the neck region of day-old turkey Turkey Escherichia coli 1204 1995 1.0 0.13->32.0 poults at the dosage of 0.17 to 0.5 mg ceftiofur/poult. One mL of the 50 mg/mL *Minimum inhibitory concentration (MIC) for 90% of the isolates. reconstituted solution will treat approximately 100 to 294 day-old turkey poults. Chemical Name of Ceftiofur Sodium Reconstituted NAXCEL Sterile Powder is to be administered by subcutaneous Table 2. Ceftiofur MIC Values of Bacterial Isolates from Diagnostic 5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2-amino-4- injection only. Laboratories in the USA and Canada* thiazolyl)(methoxy imino)-acetyl]amino]-3-[[(2-furanylcarbonyl)thio] methyl]- CONTRAINDICATIONS 8-oxo-, monosodium salt, [6R-[6α,7β(Z)]]- Animal Organism Number Date MIC90** MIC Range As with all drugs, the use of NAXCEL Sterile Powder is contraindicated in Tested Tested (µg/mL) (µg/mL) RECONSTITUTION OF THE STERILE POWDER animals previously found to be hypersensitive to the drug. Bovine Mannheimia haemolytica 110 1997-1998 0.06 ≤0.03-0.25 NAXCEL Sterile Powder should be reconstituted as follows: WARNINGS 1 gram vial–Reconstitute with 20 mL Sterile Water for Injection. Each mL Mannheimia haemolytica 139 1998-1999 ≤0.03 ≤0.03-0.5 NOT FOR HUMAN USE. KEEP OUT OF REACH OF CHILDREN. Mannheimia haemolytica 209 1999-2000 ≤0.03 ≤0.03-0.12 of the resulting solution contains ceftiofur sodium equivalent to 50 mg Penicillins and cephalosporins can cause allergic reactions in sensitized ≤ ≤ ceftiofur. individuals. Topical exposures to such antimicrobials, including ceftiofur, may Mannheimia haemolytica 189 2000-2001 0.03 0.03-0.12 4 gram vial–Reconstitute with 80 mL Sterile Water for Injection. Each mL elicit mild to severe allergic reactions in some individuals. Repeated or prolonged Pasteurella multocida 107 1997-1998 ≤0.03 ≤0.03-0.25 of the resulting solution contains ceftiofur sodium equivalent to 50 mg exposure may lead to sensitization. Avoid direct contact of the product with the Pasteurella multocida 181 1998-1999 ≤0.03 ≤0.03-0.5 ceftiofur. skin, eyes, mouth, and clothing. Pasteurella multocida 208 1999-2000 ≤0.03 ≤0.03-0.12 Shake thoroughly prior to use. Persons with a known hypersensitivity to penicillin or cephalosporins should Pasteurella multocida 259 2000-2001 ≤0.03 ≤0.03-0.12 INDICATIONS avoid exposure to this product. Histophilus somni 48 1997-1998 ≤0.03 ≤0.03-0.25 Cattle In case of accidental eye exposure, flush with water for 15 minutes. In case Histophilus somni 87 1998-1999 ≤0.03 ≤0.03-0.125 of accidental skin exposure, wash with soap and water. Remove contaminated NAXCEL Sterile Powder is indicated for treatment of bovine respiratory Histophilus somni 77 1999-2000 ≤0.03 ≤0.03-0.06 clothing. If allergic reaction occurs (e.g., skin rash, hives, difficult breathing), disease (shipping fever, pneumonia) associated with Mannheimia haemolytica, Histophilus somni 129 2000-2001 ≤0.03 ≤0.03-0.12 Pasteurella multocida and Histophilus somni. NAXCEL Sterile Powder is also seek medical attention. Bacteroides fragilis group 29 1994 16.0 ≤0.06->16.0 indicated for treatment of acute bovine interdigital necrobacillosis (foot rot, The material safety data sheet contains more detailed occupational safety pododermatitis) associated with Fusobacterium necrophorum and Bacteroides information. To obtain a material safety data sheet (MSDS) or to report any Bacteroides spp., non-fragilis group 12 1994 16.0 0.13->16.0 melaninogenicus. adverse event please call Zoetis Inc. at 1-888-963-8471. RESIDUE WARNINGS: Peptostreptococcus Swine anaerobius 12 1994 2.0 0.13-2.0 NAXCEL Sterile Powder is indicated for treatment/control of swine bacterial Cattle: When used according to label indications, dosage and respiratory disease (swine bacterial pneumonia) associated with Actinobacillus routes of administration, treated cattle must not be slaughtered Swine Actinobacillus pleuropn. 97 1997-1998 ≤0.03 no range (Haemophilus) pleuropneu moniae, Pasteurella multocida, Salmonella for 4 days following the last treatment. When used according to Actinobacillus pleuropn. 111 1998-1999 ≤0.03 ≤0.03-0.25 choleraesuis and Streptococcus suis. label indications, dosage and routes of administration, a milk Actinobacillus pleuropn. 126 1999-2000 ≤0.03 ≤0.03-0.06 Sheep discard time is not required. Use of dosages in excess of those Actinobacillus pleuropn. 89 2000-2001 ≤0.03 ≤0.03-0.06 NAXCEL Sterile Powder is indicated for treatment of sheep respiratory disease indicated or by unapproved routes of administration, such as Pasteurella multocida 114 1997-1998 ≤0.03 ≤0.03-1.0 (sheep pneumonia) associated with Mannheimia haemolytica and Pasteurella intramammary, may result in illegal residues in edible tissues Pasteurella multocida 147 1998-1999 ≤0.03 ≤0.03-0.5 and/or in milk. multocida. Pasteurella multocida 173 1999-2000 ≤0.03 ≤0.03-0.06 Swine: When used according to label indications, dosage and Goats Pasteurella multocida 186 2000-2001 ≤0.03 ≤0.03-0.12 route of administration, treated pigs must not be slaughtered for NAXCEL Sterile Powder is indicated for treatment of caprine respiratory Streptococcus suis 106 1997-1998 0.5 ≤0.03-4.0 disease (goat pneumonia) associated with Mannheimia haemolytica and 4 days following the last treatment. Use of dosages in excess of Streptococcus suis 142 1998-1999 0.25 ≤0.03-1.0 Pasteurella multocida. those indicated or by unapproved routes of administration may result in illegal residues in edible tissues. Streptococcus suis 146 1999-2000 0.06 ≤0.03-4.0 Horses Streptococcus suis 167 2000-2001 0.06 ≤0.03-4.0 NAXCEL Sterile Powder is indicated for treatment of respiratory infections in Sheep: Neither a pre-slaughter drug withdrawal interval nor horses associated with Streptococcus zooepidemicus. a milk discard time is required when this product is used Salmonella choleraesuis 96 1999-2000 1.0 0.03->4.0 according to label indications, dosage, and route of Salmonella choleraesuis 101 2000-2001 1.0 0.5-2.0 Dogs administration. Use of dosages in excess of those indicated or NAXCEL Sterile Powder is indicated for the treatment of canine urinary tract by unapproved routes of administration, such as Equine Streptococcus equi subsp. equi 12 1994 ≤0.0019 no range infections associated with Escherichia coli and Proteus mirabilis. intramammary, may result in illegal residues in edible tissues Day-Old Chicks and/or in milk. Streptococcus equi subsp. equi 29 2002 ≤0.03 ≤0.03-0.05 NAXCEL Sterile Powder is indicated for the control of early mortality, Goats: Neither a pre-slaughter drug withdrawal interval nor associated with E. coli organisms susceptible to ceftiofur, in day-old chicks. Streptococcus a milk discard time is required when this product is used zooepidemicus 48 1994 ≤0.0019 no range Day-Old Turkey Poults according to label indications, dosage, and route of Streptococcus NAXCEL Sterile Powder is indicated for the control of early mortality, associated administration. Use of dosages in excess of those indicated or zooepidemicus 59 2002 ≤0.03 ≤0.03-0.25 with E. coli organisms susceptible to ceftiofur, in day-old turkey poults. by unapproved routes of administration, such as Rhodococcus equi 66 1998 4.0 ≤0.03-16.0 DOSAGE AND ADMINISTRATION intramammary, may result in illegal residues in edible tissues and/or in milk. Rhodococcus equi 42 2002 8.0 ≤0.03->32.0 Cattle Horses: Do not use in horses intended for human consumption. Bacteroides fragilis group 32 1995 >16.0 0.13->16.0 Administer to cattle by intramuscular or subcutaneous injection at the dosage Bacteroides spp., of 0.5 to 1.0 mg ceftiofur per pound (1.1 to 2.2 mg/kg) of body weight (1-2 mL PRECAUTIONS non-fragilis group 12 1995 4.0 0.25-4.0 reconstituted sterile solution per 100 lbs body weight). Treatment should be The effects of ceftiofur on the reproductive performance, pregnancy, and Fusobacterium repeated at 24-hour intervals for a total of three consecutive days. Additional lactation of cattle, swine, sheep, and goats have not been determined. necrophorum 16 1995 ≤0.06 no range treatments may be given on days four and five for animals which do not show Cattle Canine Escherichia coli 26 2000 32 0.25->32 a satisfactory response (not recov ered) after the initial three treatments. Following subcutaneous administration of ceftiofur sodium in the neck, small Proteus mirabilis 14 2000 0.25 0.06-0.25 Selection of dosage (0.5 to 1.0 mg/lb) should be based on the practitioner’s areas of discoloration at the site may persist beyond five days, potentially judgement of severity of disease (i.e., for respiratory disease, extent of elevated resulting in trim loss of edible tissues at slaughter. Turkey Escherichia coli 17 1998-1999 1.0 0.25-1.0 body temperature, depressed physical appearance, increased respiratory rate, As with any parenteral injection, localized post-injection bacterial infections Escherichia coli 25 1999-2000 0.50 0.12-0.5 coughing and/or loss of appetite; and for foot rot, extent of swelling, lesion and may result in abscess formation. Attention to hygienic procedures can minimize Escherichia coli 20 2000-2001 2.0 0.12-16.0 severity of lameness). their occurrence. Citrobacter spp. 37 1995 32.0 0.5->32.0 Swine Swine Enterobacter spp. 51 1995 >32.0 0.13->32.0 Administer to swine by intramuscular injection at the dosage of 1.36 to 2.27 The safety of ceftiofur has not been determined for swine intended for Klebsiella spp. 100 1995 1.0 0.13-2.0 mg ceftiofur per pound (3.0 to 5.0 mg/kg) of body weight (1 mL of reconstituted breeding. sterile solution per 22 to 37 lbs body weight). Treatment should be repeated at Proteus spp. 19 1995 1.0 0.06-32.0 Horses Pseudomonas spp.*** 31 1995 >32.0 0.06->32.0 24-hour intervals for a total of three consecutive days. The safety of ceftiofur has not been determined for horses intended for Salmonella spp. 24 1995 1.0 0.5-1.0 Sheep breeding. The administration of antimicrobials to horses under conditions of Administer to sheep by intramuscular injection at the dosage of 0.5 to 1.0 stress may be associated with acute diarrhea that could be fatal. If acute diarrhea Staphylococcus spp. (coagulase positive) 17 1995 2.0 1.0-2.0 mg ceftiofur per pound (1.1 to 2.2 mg/kg) of body weight (1-2 mL reconstituted is observed, discontinue use of this antimicrobial and initiate appropriate sterile solution per 100 lbs body weight). Treatment should be repeated at therapy. Staphylococcus spp. (coagulase negative) 26 1995 8.0 0.13->32.0 24-hour intervals for a total of three consecutive days. Additional treatments Dogs may be given on days four and five for animals which do not show a satisfactory The safety of ceftiofur has not been determined for dogs intended for Chicken Escherichia coli 62 1997-1998 0.50 0.25-2.0 response (not recov ered) after the initial three treatments. Selection of dosage breeding, or pregnant dogs. Escherichia coli 53 1998-1999 4.0 0.25->4.0 (0.5 to 1.0 mg/lb) should be based on the practitioner’s judgement of severity Escherichia coli 67 1999-2000 0.50 0.12-16.0 of disease (i.e., extent of elevated body temperature, depressed physical ADVERSE REACTIONS ≤ appearance, increased respiratory rate, coughing and/or loss of appetite). The use of ceftiofur may result in some signs of immediate and transient local Escherichia coli 90 2000-2001 1.0 0.03-8.0 Goats pain to the animal. * The following in vitro data are available but their clinical significance is unknown. Administer to goats by intramuscular injection at the dosage of 0.5 to 1.0 mg ** Minimum inhibitory concentration (MIC) for 90% of the isolates. CLINICAL MICROBIOLOGY *** MIC is 32 µg/mL ceftiofur per pound (1.1 to 2.2 mg/kg) of body weight (1-2 mL reconstituted Summaries of MIC data are presented in Tables 1 and 2. Testing followed 50 sterile solution per 100 lbs body weight). Treatment should be repeated at Clinical and Laboratory Standards Institute (CLSI) Guidelines.

66 Based on the pharmacokinetic studies of ceftiofur in swine and cattle after a Sheep STORAGE CONDITIONS single intramuscular injection of 1.36 to 2.27 mg ceftiofur equivalents/lb In a 15-day safety/toxicity study in sheep, three wether and three ewe lambs Store unreconstituted product at controlled room temperature 20° to 25° C (3.0 to 5.0 mg/kg) BW (swine) or 0.5 to 1.0 mg ceftiofur equivalents/lb (1.1 to per group were given formulated ceftiofur sodium by the intramuscular route (68° to 77° F). 2.2 mg/kg) BW (cattle) and the MIC and disk (30 µg) diffusion data, the following 0 (sterile water vehicle), 1, 3 or 5 times the recommended dose of 1.0 mg/lb/ Store reconstituted product either in a refrigerator 2° to 8° C (36° to 46° F) breakpoints are recommended by CLSI. day for 3 times the recommended maximum duration of 5 days of treatment. for up to 7 days or at controlled room temperature 20° to 25° C (68° to 77° F) Zone Diameter (mm) MIC (µg/mL) Interpretation There were no adverse systemic effects indicating that formulated ceftiofur is for up to 12 hours. ≥ 21 ≤ 2.0 (S) Susceptible well tolerated and has a wide margin of safety in sheep. Based on examination Protect from light. Color of the cake may vary from off-white to a tan color. 18-20 4.0 (I) Intermediate of injection sites from study days 9, 11, 13 and 15, a low incidence of visual Color does not affect potency. changes and histopathologic findings of mild, reversible inflammation from all ≤ 17 ≥ 8.0 (R) Resistant ONE-TIME SALVAGE PROCEDURE FOR RECONSTITUTED PRODUCT groups including the controls indicated that the formulation is a slight muscle At the end of the 7-day refrigeration or 12-hour room temperature storage A report of “Susceptible” indicates that the pathogen is likely to be inhibited irritant. period following reconstitution, any remaining reconstituted product may be by generally achievable blood levels. A report of “Intermediate” is a technical Goats buffer zone and isolates falling into this category should be retested. Alternatively frozen for up to 8 weeks without loss in potency or other chemical properties. In a 15-day safety/toxicity study 5 lactating does, 5 dry does, and 5 wethers This is a one-time only salvage procedure for the remaining product. To use the organism may be successfully treated if the infection is in a body site where were given formulated ceftiofur by the intramuscular route with 11 mg/kg/day drug is physiologically concentrated. A report of “Resistant” indicates that the this salvaged product at any time during the 8-week storage period, hold the for 15 days. This con stitutes 5 times the recommended dose for 3 times the vial under warm running water, gently swirling the container to accelerate achievable drug concentrations are unlikely to be inhibitory and other therapy recommended maximum duration of 5 days of treatment. There were no should be selected. thawing, or allow the frozen material to thaw at room temperature. Rapid freezing adverse systemic effects indicating that formulated ceftiofur is well tolerated or thawing may result in vial breakage. Any product not used immediately upon Based on the pharmacokinetic studies of ceftiofur in horses after a single and has a wide margin of safety in goats. intramuscular injection of 1 mg ceftiofur equivalents/lb (2.2 mg/kg) BW, clinical thawing should be discarded. Horses effectiveness data and MIC data, the following breakpoint is recommended by HOW SUPPLIED CLSI. In a safety study, horses received a daily intramuscular injection of either 0 mg/lb/day (saline control), 1.0 mg/lb/day (50 mg/mL), 3.0 mg/lb/day (100 mg/ NAXCEL Sterile Powder is available in the following package sizes: Zone Diameter (mm) MIC (µg/mL) Interpretation mL), or 5.0 mg/lb/day (200 mg/mL) of an aqueous solution of ceftiofur sodium 1 gram vial ≥ 22 ≤ 0.25 (S) Susceptible for 30 or 31 days. Ceftiofur sodium was well tolerated when administered intra- 4 gram vial muscularly to male and female horses at doses up to 5.0 mg/lb/day for 30 or 31 The susceptible only category is used for populations of organisms (usually 1 days. No clinical evidence of irritation was noted at any dose. The drug-related Clinical and Laboratory Standards Institute (CLSI). Performance Standards one species) for which regression analysis (disk vs. MIC) cannot be performed. changes detected in this study were limited to a transient decrease in food for Anti microbial Disk and Dilution Susceptibility Tests for Bacteria Isolated These breakpoints will permit detection of strains with decreased susceptibility consumption in horses receiving 3.0 or 5.0 mg/lb/day ceftiofur, and general from Animals; Approved Standard – Second Edition. NCCLS document as compared to the original population. mild skeletal muscle irritation at the injection sites which resolved by regener- M31-A2. CLSI, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania Standardized procedures1 require the use of laboratory control organisms for ation of muscle fibers. 19087-1898, 2002. both stan dardized diffusion techniques and standardized dilution techniques. In a tolerance study, horses received a single daily intravenous infusion of The 30 µg ceftiofur sodium disk should give the following zone diameters and NADA # 140-338, Approved by FDA either 0 (saline), 10.0 or 25.0 mg/lb/day of an aqueous solution (50 mg/mL) of the ceftiofur sodium standard reference powder (or disk) should provide the ceftiofur for 10 days. The results indicated that ceftiofur administered intrave- following MIC values for the reference strain. Ceftiofur sodium disks or powder nously at a dose of 10.0 or 25.0 mg/lb/day apparently can change the bacterial reference standard is appropriate for both ceftiofur salts. flora of the large intestine thereby leading to inflammation of the large intestine Distributed by: Table 3. Acceptable quality control ranges for ceftiofur against Clinical with subsequent diarrhea and other clinical signs (loose feces, eating bedding and Laboratory Standards Institute recommended American Type straw, dehydration, rolling or colic and a dull, inactive demeanor). Decreased Zoetis Inc. Culture Collection (ATCC) reference strains food consumption, a loss of body weight, hematologic changes related to acute Kalamazoo, MI 49007 inflammation and stress, and serum chemistry changes related to decreased Organism Name (ATCC Number) Zone Diameter* MIC Range food consumption and diarrhea were also associated with treatment at these Revised: January 2014 (mm) (µg/mL) doses. The adverse effects were most severe a few days after dosing was Escherichia coli (25922) 26–31 0.25–1.0 initiated and tended to become less severe toward the end of the 10-day dosing 30146300A&P period. Staphylococcus aureus (29213) — 0.25–1.0 Dogs Staphylococcus aureus (25923) 27–31 — Ceftiofur sodium was well tolerated at the therapeutic dose and is safe for the treatment of urinary tract infections in dogs. In the acute safety study, Pseudomonas aeruginosa (27853) 14–18 16.0–64.0 ceftiofur was well tolerated by dogs at the recommended level (1.0 mg/lb) for Actinobacillus pleuropneumoniae 5-14 days. When administered subcutaneously for 42 consecutive days, one (27090) 34–42** 0.004–0.015*** of four females developed thrombocytopenia (15 days) and anemia (36 days). Histophilus somni (700025) 36–46** 0.0005–0.004*** Thrombocytopenia and anemia also occurred at the 3X and 5X dose levels. In the reversibility phase of the study (5X dose), the thrombocytopenia reversed * All testing performed using a 30µg disk. within 8 days, and of the two anemic animals the male recovered within ** Quality control ranges are applicable only to tests performed by disk diffusion 6 weeks and the female was sacrificed due to the severity of the anemia. In the 15-day tolerance study in dogs, high subcutaneous doses (25 and test using a chocolate Mueller-Hinton agar, incubated in 5-7% CO2 for 20-24 hours. 125 times the recommended therapeutic dose) produced a progressive and *** MIC quality control ranges are applicable only to tests performed by broth dose-related thrombocytopenia, with some dogs also exhibiting anemia and microdilution procedures using veterinary fastidious medium (VFM). bone marrow changes. The hematopoietic changes noted in dogs treated with ceftiofur were similar to those associated with long-term cephalosporin admin- ANIMAL SAFETY istration in dogs and also man. The hematopoietic effects are not expected to Cattle occur as a result of recommended therapy. Results from a five-day tolerance study in normal feeder calves indicated Day-Old Chicks that formulated ceftiofur was well tolerated at 25 times (25 mg/lb/day) the In an acute toxicity study of ceftiofur in day-old chicks, a total of 60 male and highest recommended dose of 1.0 mg/lb/day for five consecutive days. Ceftiofur 60 female chicks were each given single subcutaneous injections of 10, 100 administered intramuscularly had no adverse systemic effects. or 1,000 mg/kg of body weight. Treatment on day 1 was followed by 6 days In a 15-day safety/toxicity study, five steer and five heifer calves per group of observation; body weight was determined on days 1, 4 and 7; and selected were intramuscularly administered formulated ceftiofur at 0 (vehicle control), hematology parameters were evaluated on day 4. No meaningful differences 1, 3, 5 and 10 times the highest recommended dose of 1.0 mg/lb/day to determine were noted among the treated and control groups of chicks for the parameters the safety factor. There were no adverse systemic effects indicating that the evaluated. Histopathologic evaluation of all deaths and chicks surviving to formulated ceftiofur has a wide margin of safety when injected intramuscularly termination did not reveal a target organ or tissue of potential toxicity of into the feeder calves at 10 times (10 mg/lb/day) the recommended dose ceftiofur when administered at up to 20 times (100 mg/kg) the intended highest for three times (15 days) the recommended three to five days of therapy. use dosage. The formulation was shown to be a slight muscle irritant based on results of Day-Old Turkey Poults histopathological evaluation of the injection sites at 1 and 3 times the highest In an acute toxicity study of ceftiofur in day-old turkey poults, a total of recommended dose of 1.0 mg/lb/day. The histopathological evaluations were 30 male and 30 female poults were each administered single subcutaneous conducted at posttreatment days 1, 3, 7 and 14. injections of 100, 400 or 800 mg/kg body weight. Injection on day 1 was The injection of NAXCEL Sterile Powder at the recommended dose admin- followed by 6 days of observation; body weight on days 1, 4, and 7; and selected istered SC in the neck of cattle was well tolerated. However, a several square hematology parameters on day 4. No meaningful differences were noted centimeter area of yellow-red discoloration resulting from a single SC injection between the treated groups at 100 or 400 mg ceftiofur/kg and a negative persisted in many of the cattle beyond 4.5 days post-injection. Also, one of the control group for the parameters evaluated. Histopathologic evaluation of all animals developed an abscess at the injection site. deaths and poults surviving to termination did not reveal a target organ or Swine tissue of potential toxicity of ceftiofur when administered at up to 50 times Results from a five-day tolerance study in normal feeder pigs indicated that (400 mg/kg) the highest use dosage. A dose of 800 mg/kg (100 times the formulated ceftiofur was well tolerated when administered at 57 mg/lb (more intended highest use dosage) was toxic, resulting in clinical signs and deaths than 25 times the highest recommended daily dosage of 2.27 mg/lb of body accompanied by gross and microscopic morphologic tissue alterations. weight) for five consecutive days. Ceftiofur administered intramuscularly to pigs produced no overt adverse signs of toxicity. TISSUE RESIDUE DEPLETION To determine the safety factor and to measure the muscle irritancy Cattle potential in swine, a safety/toxicity study was conducted. Five barrows and A radiolabeled residue metabolism study established tolerances for ceftiofur five gilts per group were intramuscularly administered formulated ceftiofur at residues in cattle kidney, liver and muscle. These tolerances of ceftiofur residues 0, 2.27, 6.81 and 11.36 mg/lb of body weight for 15 days which is 0, 1, 3 are 0.4 ppm in kidney, 2.0 ppm in liver, 1.0 ppm in muscle, and 0.1 ppm in and 5 times the highest recommended dose of 2.27 mg/lb of body weight/ milk. day and 5 times the recommended treatment length of 3 days. There were A pivotal tissue residue decline study was conducted in cattle. In this study, no adverse systemic effects indicating that formulated ceftiofur has a wide cattle received an intramuscular injection of 1.0 mg of ceftiofur per lb body margin of safety when injected intramuscularly into feeder pigs at the highest weight (2.2 mg of ceftiofur per kg body weight) for five consecutive days. recommended dose of 2.27 mg/lb/day for 3 days or at levels up to 5 times the Ceftiofur residues in tissues were less than the tolerances for ceftiofur residues highest recommended dose for 5 times the recommended length of treatment. in tissues such as kidney, liver and muscle by 4 days after dosing. These data The formulation was shown to be a slight muscle irritant based on results of collectively support a 4-day pre-slaughter withdrawal period in cattle when histopathological evaluation of the injection sites at posttreatment days 1, 2, 3 used according to label directions. and 4. By day 10 post injection the muscle reaction was subsiding and at day Swine 15 post injection there was little evidence of muscle damage in any of the pigs Radiolabeled residue metabolism studies established tolerances for ceftiofur in any of the treatment groups. residues in swine kidney, liver, and muscle. These tolerances of ceftiofur residues are 0.25 ppm in kidney, 3.0 ppm in liver and 2.0 ppm in muscle. A pivotal tissue residue decline study was conducted in swine. In this study, pigs received 2.27 mg of ceftiofur per lb body weight (5 mg of ceftiofur per kg body weight) per day for three consecutive days. Ceftiofur residues in tissues were less than the tolerances for ceftiofur residues in tissues such as kidney, liver and muscle by 4 days after dosing. These data collectively support a 4-day pre-slaughter withdrawal period in swine when used according to label directions.

67 ® STORAGE CONDITIONS Store at Controlled Room Temperature 20 to 25°C (68 to 77°F). Pirsue Sterile Solution Store Plastets in Carton or Pail Until Used. HOW SUPPLIED (Pirlimycin hydrochloride) PIRSUE Sterile Solution is available in unbroken packages of 12-10 mL Plastet Disposable Syringes with 12 individually For Intramammary Infusion in Lactating Cows Only wrapped 70% isopropyl alcohol pads. The Plastet Disposable Syringes are packaged in Cartons (12-10 mL Plastet Disposable Syringes per carton) and in Pails (12 packages of 12-10 mL Plastet Disposable Syringes or 144 Plastets FOR USE IN ANIMALS ONLY - NOT FOR HUMAN USE per pail). NADA # 141-036, Approved by FDA CAUTION: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. PAA036273 DESCRIPTION Pirlimycin hydrochloride is a lincosaminide antibiotic. Distributed by: Chemical Structure of Pirlimycin Hydrochloride Zoetis Inc. Kalamazoo, MI 49007 CH H H 3 N HC Cl Revised: January 2013 C NH CH O O HO H HCl H H CH3CH2 OH H H SCH3 x H2O

H OH

Chemical Name of Pirlimycin Hydrochloride

Methyl(2S-Cis)-7-chloro-6,7,8-trideoxy-6[[(4-ethyl-2-piperidinyl)carbonyl]amino]-1-thio-L-threo-a-D-galacto-octo-pyranoside monohydrochloride hydrate.

PIRSUE Sterile Solution is a clear solution. Each 10 mL PLASTET® Disposable Syringe contains: Pirlimycin free base equivalents ………………………………………… 50 mg Aqueous vehicle ………………………………………………………………… q.s. INDICATIONS FOR USE PIRSUE Sterile Solution (pirlimycin hydrochloride) is indicated for the treatment of clinical and subclinical mastitis in lactating dairy cattle associated with Staphylococcus species such as Staphylococcus aureus and Streptococcus species such as Streptococcus agalactiae, Streptococcus dysgalactiae, and Streptococcus uberis. DOSAGE Infuse one (1) syringe into each affected quarter. Use proper teat end preparation and sanitation and proper intramammary infusion technique (see ADMINISTRATION). Repeat treatment after 24 hours. Daily treatment may be repeated at 24-hour intervals for up to 8 consecutive days. ADMINISTRATION Teat End Preparation: Wash teats thoroughly with water containing a suitable dairy antiseptic. Dry the teats thoroughly. Milk out the udder completely. Using the alcohol pad provided, wipe the teat end of the affected quarters, using a separate pad for each teat. Allow sufficient time (at least 5 to 10 seconds) for the alcohol to dry. Use of protective gloves by persons applying treatment is recommended as part of aseptic infusion technique. Important Considerations for Extended Therapy: For extended duration of therapy, infuse only quarters known to be infected with label pathogens. Do not concurrently infuse uninfected low SCC quarters of the same cow. Prepare the teats using the above instructions, and then infuse PIRSUE Sterile Solution using aseptic infusion technique and partial insertion (see diagram below). Sterile Solution

PIRSUE®

128/10ml FPO:

NO COPY AREA

FPO: 128/10ml Sterile Solution PIRSUE®

Infusion: The Plastet disposable syringe is designed to provide the choice of either insertion of the full cannula as has traditionally been practiced, or insertion of no more than 1/8 inch of the cannula, as reported by Eberhart, R.J., et. al., 1987. Current Concepts of Bovine Mastitis, 3rd Edition, National Mastitis Council, Arlington, VA. a. Full insertion: Remove the white end cap by pulling straight up as shown. Gently insert the full cannula into the teat canal. b. Partial insertion: Remove the white end cap by pulling straight up as shown. Gently insert the exposed white tip into the teat canal. b. a.

Choose the desired insertion length (full or partial) and gently insert the tip into the teat canal. Carefully push the plunger to infuse the entire contents, and then massage the quarter to distribute the solution into the milk cistern. Following infusion, dip all quarters with an antiseptic teat dip. Cows with systemic clinical signs caused by mastitis should receive other appropriate therapy under the direction of a licensed veterinarian. Reinfection: After treatment, reinfection may occur unless good herd management, sanitation, and mechanical safety measures are practiced. Affected cows should be watched carefully to detect recurrence and possible spread of infection to other animals. WARNING Repeated infusion during extended duration therapy regimens, even with adequate teat end preparation and sanitation, can result in elevated somatic cell counts and/or clinical mastitis, which can result in animal death. If acute clinical mastitis or other clinical signs of illness develop during extended duration therapy with PIRSUE, discontinue therapy immediately and contact your veterinarian.

Discard Empty Container; DO NOT REUSE KEEP OUT OF REACH OF CHILDREN

RESIDUE WARNINGS 1. Milk taken from animals during treatment and for 36 hours after the last treatment must not be used for food regardless of treatment duration. 2. Following infusion twice at a 24-hour interval, treated animals must not be slaughtered for 9 days. 3. Following any extended duration of therapy (infusion longer than twice at a 24-hour interval, up to 8 consecutive days), animals must not be slaughtered for 21 days. 4. Use of this product in a manner other than indicated under DOSAGE might result in violative residues. PRECAUTION When using extended duration therapy with PIRSUE Sterile Solution, failure to thoroughly clean quarters and to use aseptic infusion technique can result in the infusion of environmental mastitis pathogens not sensitive to pirlimycin. ADVERSE REACTIONS As demonstrated in the pivotal target animal safety study, even with adequate pre-treatment preparation, repeated infusion of PIRSUE Sterile Solution resulted in elevated SCC and clinical mastitis due to infection with Gram-negative environmental pathogens. For a complete listing of adverse reactions for pirlimycin reported to the Center for Veterinary Medicine (CVM) see http://www.fda.gov/cvm/ade_cum.htm. For technical assistance, to report suspected adverse reactions, or to request a Material Safety Data Sheet (MSDS), call 1-888-963-8471. MICROBIOLOGY Pirlimycin is a lincosaminide antibiotic that has activity against Gram-positive mastitis pathogens. Pirlimycin functions by binding to the 50S ribosomal subunit of bacterial ribonucleic acid, which interferes with protein synthesis within the bacteria. In vitro activity of pirlimycin has been demonstrated against Staphylococcus aureus, Streptococcus agalactiae, ® STORAGE CONDITIONS Streptococcus dysgalactiae, and StreptococcusStore at Controlled uberis, Roomfour pathogens Temperature associated 20 to 25°C with (68 clinical to 77°F). and subclinical mastitis Pirsue Sterile Solution in lactating dairy cattle. Store Plastets in Carton or Pail Until Used. (Pirlimycin hydrochloride) Utilizing data that included isolates fromHOW cows SUPPLIED with mastitis, zone diameter interpretive criteria and minimum inhibitory ® concentration (MIC) breakpoints werePIRSUESTORAGE determined Sterile CONDITIONS usingSolution standardized is available proceduresin unbroken frompackages the Clinicalof 12-10 and mL PlastetLaboratory Disposable Syringes with 12 individually Store at Controlled Room Temperature 20 to 25°C (68 to 77°F). For Intramammary Infusion in Lactating Cows Only Standards Institute (CLSI, formerly Nationalwrapped Committee 70% isopropyl of Clinical alcohol Laboratory pads. The Standards) Plastet Disposable M31-A2. The Syringes CLSI-accepted are packaged in Cartons (12-10 mL Plastet Pirsue Sterile Solution interpretive criteria for pirlimycin againstDisposableStore Gram-positive Plastets Syringes in Carton mastitis per or carton) pathogensPail Until and Used. arein Pails shown (12 in packagesTable 1. of 12-10 mL Plastet Disposable Syringes or 144 Plastets FOR USE IN ANIMALS ONLY - NOT FOR HUMAN USE HOWper pail). SUPPLIED (Pirlimycin hydrochloride) PIRSUE Sterile Solution is available in unbroken packages of 12-10 mL Plastet Disposable Syringes with 12 individually Table 1. CLSI-Accepted InterpretiveNADA Criteria# 141-036, for ApprovedPirlimycin by Against FDA Bovine Mastitis Pathogens* CAUTION:For Intramammary Federal Infusion (USA) law in Lactatingrestricts this Cows drug Only to use by or on the order of a licensed veterinarian. Pathogen wrappedDisk Potency 70% isopropyl alcoholZone Diameter pads. The Plastet DisposableMIC Breakpoint Syringes are packaged in Cartons (12-10 mL Plastet Disposable Syringes per carton) and in Pails (12 packages of 12-10 mL Plastet Disposable Syringes or 144 Plastets Interpretive Standards (mm) (mg/mL) PAA036273 DESCRIPTION FOR USE IN ANIMALS ONLY - NOT FOR HUMAN USE per pail). Pirlimycin hydrochloride is a lincosaminide antibiotic. S R S R NADADistributed # 141-036, by: Approved by FDA CAUTION: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. Staphylococcus aureus Chemical Structure of Pirlimycin Hydrochloride Zoetis Inc. Streptococcus agalactiae Kalamazoo, MI 49007 PAA036273 DESCRIPTION CH H H 3 Streptococcus dysgalactiae 2 mg ≥13 ≤12 ≤2.0 ≥4.0 Pirlimycin hydrochloride is a lincosaminide antibiotic. N HC Cl Streptococcus uberis Distributed by: ZoetisRevised: Inc. January 2013 Chemical StructureC of Pirlimycin Hydrochloride S - Susceptible NH CH Kalamazoo, MI 49007 O CH3 O R - Resistant H H HO H HCl H H CH3CH2 N HC Cl * These interpretive criteria are only intended for use when CLSI M31-A2 performance standards are used to deter- OH H mine antimicrobial susceptibility.Revised: January 2013 C NHH CH SCH3 x H2O EFFECTIVENESS O OHO HO H H HCl The effectiveness of pirlimycin was demonstrated in a field dose response study in lactating dairy cattle with clinical H H CH3CH2 mastitis. Three investigators enrolled 486 cows from 39 herds. Cows with abnormal milk (clots, flakes) and with or OH H without udder clinical signs (swelling, redness, or soreness) were enrolled and treated, regardless of the mastitis Chemical Name of Pirlimycin Hydrochloridex H O H SCH3 2 pathogen isolated or the pre-treatment somatic cell count. Cows were treated in the affected quarter(s) with 50, 100, or 200 mg of pirlimycin twice at a 24-hour interval. A non-treated control group was included. In this study, an individual Methyl(2S-Cis)-7-chloro-6,7,8-trideoxy-6[[(4-ethyl-2-piperidinyl)carbonyl]amino]-1-thio-L-threo-H OH a-D-galacto-octo-pyranoside quarter was cured if it had normal milk, no udder clinical signs, and if the milk was negative for any mastitis pathogen monohydrochloride hydrate. at 10 days post-treatment. If no bacteria were isolated pre-treatment, a decrease in somatic cell count was required. Chemical Name of Pirlimycin Hydrochloride A cow was cured if all enrolled quarters in that cow were cured. All three treatment levels had significantly greater cow PIRSUE Sterile Solution is a clear solution. cure rates than the non-treated control group. Based on this study, the dose of 50 mg of pirlimycin per quarter Each 10 mL PLASTET® Disposable Syringe contains: Methyl(2S-Cis)-7-chloro-6,7,8-trideoxy-6[[(4-ethyl-2-piperidinyl)carbonyl]amino]-1-thio-L-threo-a-D-galacto-octo-pyranoside administered twice at a 24-hour interval was determined to be the effective dose for the treatment of clinical mastitis. monohydrochloridePirlimycin free base hydrate. equivalents ………………………………………… 50 mg Aqueous vehicle ………………………………………………………………… q.s. ANIMAL SAFETY Two pivotal studies addressing the safety of pirlimycin administered at dosages of 50 mg or 200 mg (4X) into all four INDICATIONSPIRSUE Sterile FOR Solution USE is a clear solution. quarters twice at a 24-hour interval indicate that the formulation is safe and non-irritating to the bovine udder. Safety PIRSUEEach 10 mLSterile PLASTET® Solution Disposable(pirlimycin Syringehydrochloride) contains: is indicated for the treatment of clinical and subclinical mastitis in observations were also made during the clinical effectiveness study. No udder irritation was noted due to intramammary lactatingPirlimycin dairy free cattlebase equivalentsassociated with………………………………………… Staphylococcus species such as 50 Staphylococcus mg aureus and Streptococcus species infusion with pirlimycin during these studies. Aqueoussuch as Streptococcus vehicle ………………………………………………………………… agalactiae, Streptococcus dysgalactiae, and Streptococcus q.s. uberis. An additional study was conducted to determine the safety of extended duration therapy. Twenty lactating Holstein cows, INDICATIONSDOSAGE FOR USE first lactation or greater, at various milk production levels, and with no evidence of clinical mastitis were enrolled and PIRSUEInfuse one Sterile (1) Solutionsyringe into(pirlimycin each hydrochloride)affected quarter. is indicatedUse proper for theteat treatment end preparation of clinical and and sanitation subclinical and mastitis proper in treated with pirlimycin administered at a dosage of 50 mg/quarter in all four quarters daily for eight consecutive days. lactatingintramammary dairy cattleinfusion associated technique with (see Staphylococcus ADMINISTRATION). species suchRepeat as Staphylococcustreatment after 24aureus hours. and Daily Streptococcus treatment mayspecies be Cows were monitored for general health, changes in milk production and quality, and signs of udder irritation for a total repeatedsuch as Streptococcus at 24-hour intervals agalactiae, for up Streptococcus to 8 consecutive dysgalactiae, days. and Streptococcus uberis. of 14 days, beginning three days prior to the first treatment. Milk production was not affected by treatment. SCCs of tre- DOSAGEADMINISTRATION ated cows were statistically significantly increased post-treatment relative to the pre-treatment level. A total of 24 pirlimy- InfuseTeat End one Preparation: (1) syringe Wash into teatseach thoroughlyaffected quarter.with water Use containing proper ateat suitable end dairypreparation antiseptic. and Dry sanitation the teats andthoroughly. proper cin-treated quarters (32%) in 15 cows had increased SCCs (>200,000 cells/mL) for at least two consecutive milkings. intramammaryMilk out the udder infusion completely. technique Using (see theADMINISTRATION). alcohol pad provided, Repeat wipe treatment the teat after end 24of hours.the affected Daily treatmentquarters, usingmay be a Of these, six treated cows (8 quarters) had a concurrent bacterial infection attributable to a mastitis pathogen. Udder repeatedseparate padat 24-hour for each intervals teat. Allow for up sufficient to 8 consecutive time (at least days. 5 to 10 seconds) for the alcohol to dry. Use of protective gloves irritation occurred in seven pirlimycin-treated cows (10 quarters). Abnormal strip cup scores occurred in six pirlimycin- ADMINISTRATIONby persons applying treatment is recommended as part of aseptic infusion technique. treated cows (9 quarters). Most of the abnormal udder and strip cup observations were seen in quarters where bacte- TeatImportant End Preparation: Considerations Wash for teats Extended thoroughly Therapy: with water For containingextended durationa suitable of dairy therapy, antiseptic. infuse Dry only the quarters teats thoroughly. known to ria were also isolated. be infected with label pathogens. Do not concurrently infuse uninfected low SCC quarters of the same cow. Prepare Milk out the udder completely. Using the alcohol pad provided, wipe the teat end of the affected quarters, using a Corroborative data from field studies and field use reports indicate that although intramammary infusion of pirlimycin separatethe teats padusing for the each above teat. instructions,Allow sufficient and time then (at infuse least 5PIRSUE to 10 seconds) Sterile Solutionfor the alcohol using asepticto dry. Use infusion of protective technique gloves and partial insertion (see diagram below). hydrochloride at 50 mg/quarter administered from two to eight consecutive days was well tolerated, repeated infusion by persons applying treatment is recommended as part of aseptic infusion technique. with pirlimycin increases the potential for intramammary infections and subsequent clinical mastitis due to environmental Important Considerations for Extended Therapy: For extended duration of therapy, infuse only quarters known to bacteria, including coliform bacteria. Adverse reactions, including clinical signs of mastitis (udder swelling and abnor- be infected with label pathogens. Do not concurrently infuse uninfected low SCC quarters of the same cow. Prepare mal milk), increased SCCs, and death from coliform mastitis have been reported in cows following extended therapy the teats using the above instructions, and then infuse PIRSUE Sterile Solution using aseptic infusion technique and with pirlimycin. Some, but not all, adverse reactions were associated with failure to thoroughly clean quarters and to partial insertion (see diagram below). use aseptic infusion technique. MILK AND TISSUE RESIDUE DEPLETION The established tolerance of pirlimycin in milk is 0.40 ppm. Milk residue depletion studies were conducted in cows with clinical mastitis. In one study, cows were infused with 50 mg of pirlimycin twice at a 24-hour interval into all quarters regardless of the number of affected quarters. In a second study, cows with a single mastitic quarter were infused with Sterile Solution 50 mg of pirlimycin twice at a 24-hour interval into only the affected quarter. In a third study, normal cows were infused PIRSUE® with 50 mg of pirlimycin twice at a 24-hour interval into all four quarters. As a result of these three studies, milk taken from cows during treatment and for 36 hours following treatment must not be used for food and must be discarded. For

extended duration of therapy (once daily for up to 8 consecutive days), a milk residue study was conducted where cows

128/10ml FPO: FPO: Sterile Solution received 50 mg of pirlimycin per quarter into all four quarters for 8 consecutive days. This study confirmed that milk

PIRSUE® taken from cows during treatment and for 36 hours following the last treatment must not be used for food and must be discarded.

NO COPY AREA

128/10ml FPO: FPO: The established tolerance for pirlimycin in liver (the target tissue) is 0.5 ppm. A pivotal tissue residue study was conducted following administration of 50 mg of pirlimycin twice at a 24-hour interval into all four quarters. Following receipt of the 50 mg of pirlimycin twice at a 24-hour interval into all four quarters, the liver residue decline data from this study supports a 9-day pre-slaughter withdrawal period. NO COPY AREA For extended duration of therapy, a second tissue residue study was conducted. Each lactating cow received 50 mg pirlimycin per quarter into all four quarters, once daily for 8 consecutive days. Using the established tolerance for

FPO: 128/10ml Sterile Solution pirlimycin of 0.5 ppm in the liver, these data support a 21-day pre-slaughter withdrawal period for extended duration

PIRSUE® pirlimycin therapy. Extended duration of therapy is considered as any treatment period longer than 2 days (up to 8 consecutive days) of therapy.

EFFECT ON MILK MANUFACTURING STARTER CULTURES

FPO: 128/10ml Sterile Solution A study was conducted to examine the effect of varying concentrations of pirlimycin in milk on the growth of bacterial PIRSUE® starter cultures used to produce fermented milk products. Pirlimycin did not adversely affect bacterial starter cultures used for the production of fermented milk products at concentrations found following normal label use including proper milk discard periods. Violative levels of pirlimycin (>0.40 ppm) can adversely affect the growth of bacterial starter cultures.

® Infusion: The Plastet disposable syringe is designed to provide the choice of either insertion of the full cannula as has STORAGE CONDITIONS traditionally been practiced, or insertion of no more than 1/8 inch of the cannula, as reported by Eberhart, R.J., et. al., Store at Controlled Room Temperature 20 to 25°C (68 to 77°F). Pirsue Sterile1987. Current Concepts Solution of Bovine Mastitis, 3rd Edition, National Mastitis Council, Arlington, VA. Store Plastets in Carton or Pail Until Used. a. Full insertion: Remove the white end cap by pulling straight up as shown. Gently insert the full cannula into the HOW SUPPLIED (Pirlimycin hydrochloride)Infusion:teat canal. The Plastet disposable syringe is designed to provide the choice of either insertion of the full cannula as has PIRSUE Sterile Solution is available in unbroken packages of 12-10 mL Plastet Disposable Syringes with 12 individually traditionallyb. Partial insertion: been practiced, Remove or theinsertion white ofend no capmore by than pulling 1/8 straightinch of theup ascannula, shown. as Gently reported insert by theEberhart, exposed R.J., white et. al.,tip For Intramammary Infusion in Lactating Cows Only wrapped 70% isopropyl alcohol pads. The Plastet Disposable Syringes are packaged in Cartons (12-10 mL Plastet 1987.into the Current teat canal. Concepts of Bovine Mastitis, 3rd Edition, National Mastitis Council, Arlington, VA. Disposable Syringes per carton) and in Pails (12 packages of 12-10 mL Plastet Disposable Syringes or 144 Plastets a. Full insertion: Remove the white end cap by pulling straight up as shown. Gently insert the full cannula into the FOR USE IN ANIMALS ONLY - NOT FOR HUMAN USE b. per pail). teat canal. b. Partial insertion: Remove the white end cap by pullinga. straight up as shown. Gently insert the exposed white tip NADA # 141-036, Approved by FDA CAUTION: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. into the teat canal. PAA036273 DESCRIPTION b. Pirlimycin hydrochloride is a lincosaminide antibiotic. a. Distributed by: Chemical Structure of Pirlimycin Hydrochloride Zoetis Inc. Kalamazoo, MI 49007 CH H H 3 N HC Cl Choose the desired insertion length (full or partial) and gently insert the tip into the teat canal. Carefully push the plunger Revised: January 2013 to infuse the CentireNH CHcontents, and then massage the quarter to distribute the solution into the milk cistern. Following infusion, dip all quarters with an antiseptic teat dip. Cows with systemic clinical signs caused by mastitis should receive O O PAA036273A&P other appropriateHO therapy underH the directionHCl of a licensed veterinarian. H H CH3ChooseReinfection:CH2 the desired After treatment, insertion length reinfection (full or may partial) occur and unless gently good insert herd the management,tip into the teat sanitation, canal. Carefully and mechanical push the plunger safety measures are practiced.OH AffectedH cows should be watched carefully to detect recurrence and possible spread of infection Time/Date: PAA036273.indd 1 2/8/13 9:01 AM to infuse the entireH contents,SC andH3 then massagex H2O the quarter to distribute the solution into the milk cistern. Following infusion,to other animals. dip all quarters with an antiseptic teat dip. Cows with systemic clinical signs caused by mastitis should receive WARNINGother appropriate therapyH OH under the direction of a licensed veterinarian. Project No. Artwork Number Description Country RepeatedReinfection: infusion After duringtreatment, extended reinfection duration may therapy occur regimens,unless good even herd with management, adequate teat sanitation, end preparation and mechanical and sanitation, safety measures are practiced. Affected cows should be watched carefully to detect recurrence and possible spread of infection 11395 PAA036273 Pirsue USA canChemical result in Name elevated of Pirlimycin somatic Hydrochloridecell counts and/or clinical mastitis, which can result in animal death. If acute clinical mastitisto other animals.or other clinical signs of illness develop during extended duration therapy with PIRSUE, discontinue therapy Dimensions Drawing No. SKU No. Item immediately and contact your veterinarian. Methyl(2S-Cis)-7-chloro-6,7,8-trideoxy-6[[(4-ethyl-2-piperidinyl)carbonyl]amino]-1-thio-L-threo-WARNING a-D-galacto-octo-pyranoside monohydrochloride hydrate. Repeated infusion during extended duration therapy regimens, even with adequate teat end preparation and sanitation, 5” x 24” Folds to: 5” x 1.5” PD2194 1475000 Insert can result in elevated somatic cell countsDiscard and/or Empty clinical Container; mastitis, DO which NOT REUSEcan result in animal death. If acute clinical PIRSUE Sterile Solution is a clear solution.mastitis or other clinical signs of illnessKEEP develop OUT during OF REACH extended OF durationCHILDREN therapy with PIRSUE, discontinue therapy Additional Info: Colors: Each 10 mL PLASTET® Disposable immediatelySyringe contains: and contact your veterinarian. EDITOR’S COPY Pirlimycin free base equivalents ………………………………………… RESIDUE WARNINGS 50 mg Black Dieline GS: DATE: Aqueous vehicle ………………………………………………………………… 1. Milk taken from animals q.s. duringDiscard treatment Empty andContainer; for 36 hours DO NOT after REUSE the last treatment must not KEEP OUT OF REACH OF CHILDREN INDICATIONS FOR USE be used for food regardless of treatment duration. Mgr Rev GA PR GS / ART REV (LCA) GS / ART REV (FA) 2. Following infusion twice at a 24-hour interval, treated animals must not be slaughtered for C. Andrews PIRSUE Sterile Solution (pirlimycin hydrochloride) is indicated for the treatment of clinical and subclinical mastitis in CHANGES CHANGES CHANGES lactating dairy cattle associated with Staphylococcus RE9SIDUE days. species WARNINGS such as Staphylococcus aureus and Streptococcus species GS A. French/K.M. 3. Following any extended duration of therapy (infusion longer than twice at a 24-hour interval, 1 such as Streptococcus agalactiae, Streptococcus 1. Milk dysgalactiae, taken from and animals Streptococcus during treatment uberis. and for 36 hours after the last treatment must not GA D. Verschoof OK OK OK upbe toused 8 consecutive for food regardless days), animals of treatment must notduration. be slaughtered for 21 days. DOSAGE 2.4. FollowingUse of this infusion product twice in a mannerat a 24-hour other interval,than indicated treated under animals DOSAGE must not might be slaughtered result in violative for Infuse one (1) syringe into each affected quarter. Use proper teat end preparation and sanitation and proper residues.9 days. intramammary infusion technique (see ADMINISTRATION). Repeat treatment after 24 hours. Daily treatment may be 3. Following any extended duration of therapy (infusion longer than twice at a 24-hour interval, repeated at 24-hour intervals for up toPRECAUTION 8 consecutive days. When usingup extended to 8 consecutive duration days),therapy animals with PIRSUE must not Sterile be slaughtered Solution, forfailure 21 days.to thoroughly clean quarters and to use ADMINISTRATION aseptic infusion4. Use techniqueof this product can resultin a manner in the infusion other than of environmentalindicated under mastitis DOSAGE pathogens might result not sensitive in violative to pirlimycin. Teat End Preparation: Wash teats thoroughly withresidues. water containing a suitable dairy antiseptic. Dry the teats thoroughly. Milk out the udder completely. UsingADVERSE the alcohol REACTIONS pad provided, wipe the teat end of the affected quarters, using a separate pad for each teat. Allow sufficientAsPRECAUTION demonstrated time (at least in 5the to 10pivotal seconds) target for animal the alcohol safety to study,dry. Use even of protective with adequate gloves pre-treatment preparation, repeated by persons applying treatment is recommendedinfusionWhen using of PIRSUEas extended part of Sterile aseptic duration Solution infusion therapy resulted technique. with inPIRSUE elevated Sterile SCC Solution,and clinical failure mastitis to thoroughly due to infection clean quarterswith Gram-negative and to use Important Considerations for Extendedenvironmentalaseptic Therapy:infusion pathogens. technique For extended Forcan aresult durationcomplete in the of listing infusiontherapy, of adverseof infuse environmental onlyreactions quarters mastitis for pirlimycin known pathogens to reported not sensitiveto the Center to pirlimycin. for Veterinary be infected with label pathogens. DoADVERSEMedicine not concurrently (CVM) REACTIONS see infuse http://www.fda.gov/cvm/ade_cum.htm. uninfected low SCC quarters of For the technical same cow. assistance, Prepare to report suspected adverse reactions, the teats using the above instructions,Asor to demonstratedand request then ainfuse Material in PIRSUEthe Safety pivotal Sterile Data target SheetSolution animal (MSDS), using safety callaseptic study, 1-888-963-8471. infusion even with technique adequate and pre-treatment preparation, repeated partial insertion (see diagram below).infusionMICROBIOLOGY of PIRSUE Sterile Solution resulted in elevated SCC and clinical mastitis due to infection with Gram-negative environmentalPirlimycin is a pathogens.lincosaminide For antibiotic a complete that listing has activityof adverse against reactions Gram-positive for pirlimycin mastitis reported pathogens. to the Center Pirlimycin for Veterinary functions Medicineby binding (CVM) to the see 50S http://www.fda.gov/cvm/ade_cum.htm. ribosomal subunit of bacterial ribonucleic For technical acid, which assistance, interferes to report with suspected protein synthesis adverse reactions,within the bacteria.or to request In vitro a Material activity Safetyof pirlimycin Data Sheet has been (MSDS), demonstrated call 1-888-963-8471. against Staphylococcus aureus, Streptococcus agalactiae, MICROBIOLOGYStreptococcus dysgalactiae, and Streptococcus uberis, four pathogens associated with clinical and subclinical mastitis Pirlimycinin lactating is dairy a lincosaminide cattle. antibiotic that has activity against Gram-positive mastitis pathogens. Pirlimycin functions by binding to the 50S ribosomal subunit of bacterial ribonucleic acid, which interferes with protein synthesis within the bacteria.Utilizing dataIn vitro that activity included of pirlimycinisolates from has beencows demonstratedwith mastitis, zoneagainst diameter Staphylococcus interpretive aureus, criteria Streptococcus and minimum agalactiae, inhibitory Streptococcusconcentration (MIC)dysgalactiae, breakpoints and Streptococcuswere determined uberis using, four standardized pathogens associatedprocedures with from clinical the Clinicaland subclinical and Laboratory mastitis Standards Institute (CLSI, formerly National Committee of Clinical Laboratory Standards) M31-A2. The CLSI-accepted in lactating dairy cattle. Sterile Solution interpretive criteria for pirlimycin against Gram-positive mastitis pathogens are shown in Table 1. PIRSUE® Utilizing data that included isolates from cows with mastitis, zone diameter interpretive criteria and minimum inhibitory

concentration Table 1. (MIC)CLSI-Accepted breakpoints Interpretive were determined Criteria forusing Pirlimycin standardized Against procedures Bovine Mastitis from Pathogens*the Clinical and Laboratory

128/10ml Standards Pathogen Institute (CLSI, formerlyFPO: NationalDisk Potency Committee of ClinicalZone Laboratory Diameter Standards) MICM31-A2. Breakpoint The CLSI-accepted interpretive criteria for pirlimycin against Gram-positive mastitis pathogens are shown in Table 1. Interpretive Standards (mm) (mg/mL) 68 S R S R Table 1. CLSI-Accepted Interpretive Criteria for Pirlimycin Against Bovine Mastitis Pathogens* Staphylococcus aureus NO COPY AREA Pathogen Disk Potency Zone Diameter MIC Breakpoint Streptococcus agalactiae Interpretive Standards (mm) (mg/mL) Streptococcus dysgalactiae 2 mg ≥13 ≤12 ≤2.0 ≥4.0 S R S R Streptococcus uberis Staphylococcus aureus S - Susceptible Streptococcus agalactiae R - Resistant Streptococcus dysgalactiae 2 mg ≥13 ≤12 ≤2.0 ≥4.0

FPO: 128/10ml Sterile Solution * These interpretive criteria are only intended for use when CLSI M31-A2 performance standards are used to deter-

Streptococcus uberis PIRSUE® mine antimicrobial susceptibility. S - Susceptible EFFECTIVENESS R - Resistant The effectiveness of pirlimycin was demonstrated in a field dose response study in lactating dairy cattle with clinical mastitis.* These Three interpretive investigators criteria enrolled are only 486 intended cows from for use 39 whenherds. CLSI Cows M31-A2 with abnormalperformance milk standards (clots, flakes) are used and to with deter or- withoutmi udderne antimicrobial clinical signs susceptibility. (swelling, redness, or soreness) were enrolled and treated, regardless of the mastitis pathogenEFFECTIVENESS isolated or the pre-treatment somatic cell count. Cows were treated in the affected quarter(s) with 50, 100, orThe 200 effectiveness mg of pirlimycin of pirlimycin twice at awas 24-hour demonstrated interval. Ain non-treated a field dose control response group study was inincluded. lactating In dairythis study, cattle anwith individual clinical quartermastitis. was Three cured investigators if it had normal enrolled milk, 486 no cowsudder fromclinical 39 signs,herds. and Cows if the with milk abnormal was negative milk (clots, for any flakes) mastitis and pathogen with or atwithout 10 days udder post-treatment. clinical signs If (swelling,no bacteria redness, were isolated or soreness) pre-treatment, were enrolled a decrease and intreated, somatic regardless cell count of was the required. mastitis pathogenA cow was isolated cured if or all the enrolled pre-treatment quarters somaticin that cow cell werecount. cured. Cows All were three treated treatment in the levels affected had significantlyquarter(s) with greater 50, 100,cow Infusion: The Plastet disposable syringecureor 200 ratesis mg designed ofthan pirlimycin theto providenon-treated twice the at achoice 24-hourcontrol of group.interval.either insertionBased A non-treated onof thethis full controlstudy, cannula groupthe asdose washas ofincluded. 50 mg Inof thispirlimycin study, anper individual quarter traditionally been practiced, or insertionadministeredquarter of no was more cured twice than ifat it1/8 ahad 24-hour inch normal of theinterval milk, cannula, nowas udder determinedas reported clinical signs,toby beEberhart, theand effective if theR.J., milk et.dose wasal., for negative the treatment for any of mastitis clinical pathogen mastitis. 1987. Current Concepts of Bovine Mastitis,ANIMALat 10 days 3rd SAFETY Edition,post-treatment. National IfMastitis no bacteria Council, were Arlington, isolated VA. pre-treatment, a decrease in somatic cell count was required. a. Full insertion: Remove the whiteTwoA endcow pivotal capwas by curedstudies pulling if alladdressing straight enrolled up quartersthe as safety shown. in ofthat Gentlypirlimycin cow wereinsert administered cured. the full All cannula three at dosages treatment into the of levels50 mg hador 200 significantly mg (4X) greaterinto all cowfour teat canal. quarterscure rates twice than at thea 24-hour non-treated interval control indicate group. that Basedthe formulation on this study,is safe theand dose non-irritating of 50 mg to ofthe pirlimycin bovine udder. per quarterSafety b. Partial insertion: Remove the whiteobservationsadministered end cap weretwiceby pulling alsoat a made 24-hourstraight during intervalup asthe shown. clinicalwas determined Gentlyeffectiveness insert to be thestudy. the exposed effectiveNo udder white dose irritation tip for the was treatment noted due of to clinical intramammary mastitis. into the teat canal. ANIMALinfusion with SAFETY pirlimycin during these studies. AnTwo additional pivotal studies study wasaddressing conducted theb. to safety determine of pirlimycin the safety administered of extended at duration dosages therapy. of 50 mgTwenty or 200 lactating mg (4X) Holstein into all cows, four quartersfirst lactation twice or at greater, a 24-houra. at variousinterval milkindicate production that the levels, formulation and with is safeno evidence and non-irritating of clinical to mastitis the bovine were udder. enrolled Safety and observationstreated with pirlimycin were also administered made during atthe a clinicaldosage effectiveness of 50 mg/quarter study. in No all udderfour quarters irritation dailywas notedfor eight due consecutive to intramammary days. Cowsinfusion were with monitored pirlimycin forduring general these health, studies. changes in milk production and quality, and signs of udder irritation for a total ofAn 14 additional days, beginning study was three conducted days prior to determine to the first the treatment. safety of extendedMilk production duration was therapy. not affected Twenty by lactating treatment. Holstein SCCs ofcows, tre- afirstted lactationcows were or statisticallygreater, at significantlyvarious milk increased production post-treatment levels, and withrelative no toevidence the pre-treatment of clinical mastitislevel. A weretotal ofenrolled 24 pirlimy and- citreatedn-treated with quarters pirlimycin (32%) administered in 15 cows at hada dosage increased of 50 SCCs mg/quarter (>200,000 in all cells/mL) four quarters for at daily least for two eight consecutive consecutive milkings. days. OfCows these, were si monitoredx treated cows for general (8 quarters) health, had changes a concurrent in milk productionbacterial infection and quality, attributable and signs to aof mastitisudder irritation pathogen. for aUdder total ofirritation 14 days, occurred beginning in seven three pirlimycin-treated days prior to the cowsfirst treatment. (10 quarters). Milk productionAbnormal stripwas notcup affected scores occurredby treatment. in six SCCs pirlimycin- of tre- atreatedted co wscows were (9 statisticallyquarters). Mostsignificantly of the abnormalincreased udderpost-treatment and strip relative cup observations to the pre-treatment were seen level. in quarters A total ofwhere 24 pirlimy bacte- Choose the desired insertion length (fullcirian-treated were or partial) also quarters isolated.and gently (32%) insert in 15 the cows tip into had the increased teat canal. SCCs Carefully (>200,000 push cells/mL)the plunger for at least two consecutive milkings. to infuse the entire contents, and thenOfCorroborative these, massage six treatedthedata quarter from cows field to (8 distribute studiesquarters) and the had fieldsolution a concurrent use intoreports the bacterial indicatemilk cistern. infection that althoughFollowing attributable intramammary to a mastitis infusion pathogen. of pirlimycin Udder infusion, dip all quarters with an antisepticirritationhydrochloride teat occurred dip. at Cows 50 in mg/quarterseven with systemic pirlimycin-treated administered clinical signs cowsfrom caused two(10 toquarters). by eight mastitis consecutive Abnormal should receivedaysstrip cupwas scoreswell tolerated, occurred repeated in six pirlimycin- infusion other appropriate therapy under the directiontreatedwith pirlimycin cows of a licensed(9 increases quarters). veterinarian. the Most potential of the for abnormal intramammary udder andinfections strip cup and observations subsequent clinicalwere seen mastitis in quarters due to environmental where bacte- Reinfection: After treatment, reinfectionbacteria,ria were may alsoincluding occur isolated. unless coliform good bacteria. herd management, Adverse reactions, sanitation, including and mechanical clinical signs safety of mastitis (udder swelling and abnor- measures are practiced. Affected cows should be watched carefully to detect recurrence and possible spread of infection maCorroborativel milk), increased data from SCCs, field and studies death and from field coliform use reports mastitis indicate have beenthat althoughreported intramammaryin cows following infusion extended of pirlimycin therapy to other animals. withhydrochloride pirlimycin. at Some, 50 mg/quarter but not all, administered adverse reactions from two were to eight associated consecutive with failuredays was to thoroughly well tolerated, clean repeated quarters infusion and to WARNING usewith asepticpirlimycin infusion increases technique. the potential for intramammary infections and subsequent clinical mastitis due to environmental Repeated infusion during extended durationMILKbacteria, AND therapy including TISSUE regimens, coliform RESIDUE even bacteria. DEPLETION with adequateAdverse reactions, teat end preparation including clinical and sanitation, signs of mastitis (udder swelling and abnor- can result in elevated somatic cell countsThemal milk),established and/or increased clinical tolerance SCCs, mastitis, of andpirlimycin which death can infrom milk result coliform is 0.40in animal mastitisppm. death.Milk have residue Ifbeen acute depletion reported clinical studies in cows were following conducted extended in cows therapy with mastitis or other clinical signs of illnessclinicalwith pirlimycin.develop mastitis. during Some, In one extended but study, not cowsall,duration adverse were therapy infused reactions with with PIRSUE,were 50 mgassociated ofdiscontinue pirlimycin with therapytwicefailure at to a thoroughly24-hour interval clean intoquarters all quarters and to immediately and contact your veterinarian.regardlessuse aseptic of infusion the number technique. of affected quarters. In a second study, cows with a single mastitic quarter were infused with 50 mg of pirlimycin twice at a 24-hour interval into only the affected quarter. In a third study, normal cows were infused MILKDiscard AND Empty TISSUE Container; RESIDUE DO DEPLETION NOT REUSE Thewith established50 mg of pirlimycin tolerance twice of pirlimycin at a 24-hour in milk interval is 0.40 into ppm. all fourMilk quarters.residue depletion As a result studies of these were three conducted studies, in milkcows taken with KEEP OUT OF REACH OF CHILDREN clinicalfrom cows mastitis. during In treatment one study, and cows for 36 were hours infused following with treatment50 mg of mustpirlimycin not be twice used at for a food24-hour and interval must be into discarded. all quarters For regardlessextended duration of the number of therapy of affected (once daily quarters. for up Into a8 secondconsecutive study, days), cows a with milk a residue single mastiticstudy was quarter conducted were infusedwhere cows with RESIDUE WARNINGS 50received mg of 50pirlimycin mg of pirlimycintwice at a per24-hour quarter interval into intoall four only quarters the affected for 8 quarter. consecutive In a thirddays. study, This normalstudy confirmed cows were that infused milk 1. Milk taken from animals withtakenduring 50 from treatment mg cowsof pirlimycin andduring for treatment36twice hours at a afterand 24-hour forthe 36last interval hours treatment followinginto all must four the not quarters. last treatment As a resultmust notof these be used three for studies, food and milk must taken be be used for food regardlessfromdiscarded. of cows treatment during duration. treatment and for 36 hours following treatment must not be used for food and must be discarded. For 2. Following infusion twice atextended a 24-hour duration interval, of therapytreated animals(once daily must for not up be to slaughtered8 consecutive for days), a milk residue study was conducted where cows 9 days. Thereceived established 50 mg oftolerance pirlimycin for per pirlimycin quarter intoin liver all four(the quarterstarget tissue) for 8 consecutiveis 0.5 ppm. days.A pivotal This tissuestudy confirmedresidue study that milkwas 3. Following any extended durationconductedtaken from of therapyfollowingcows during (infusion administration treatment longer and thanof 50for twice mg36 hoursatof apirlimycin 24-hour following interval,twice the lastat a treatment24-hour interval must not into be allused four for quarters. food and Following must be up to 8 consecutive days),discarded.receipt animals of themust 50 not mg be of slaughtered pirlimycin twice for 21 at days. a 24-hour interval into all four quarters, the liver residue decline data from 4. Use of this product in a mannerthis study other supports than indicated a 9-day pre-slaughterunder DOSAGE withdrawal might result period. in violative residues. The established tolerance for pirlimycin in liver (the target tissue) is 0.5 ppm. A pivotal tissue residue study was conductedFor extended following duration administration of therapy, aof second 50 mg tissueof pirlimycin residue twice study at was a 24-hour conducted. interval Each into lactating all four cow quarters. received Following 50 mg PRECAUTION pirlimycin per quarter into all four quarters, once daily for 8 consecutive days. Using the established tolerance for When using extended duration therapyreceipt with of PIRSUE the 50 mgSterile of pirlimycin Solution, twicefailure at toa thoroughly24-hour interval clean intoquarters all four and quarters, to use the liver residue decline data from thispirlimycin study supportsof 0.5 ppm a 9-day in the pre-slaughter liver, these datawithdrawal support period. a 21-day pre-slaughter withdrawal period for extended duration aseptic infusion technique can resultpirlimycin in the infusion therapy. of environmental Extended duration mastitis of pathogens therapy is not considered sensitive asto pirlimycin.any treatment period longer than 2 days (up to 8 ADVERSE REACTIONS Forconsecutive extended days) duration of therapy. of therapy, a second tissue residue study was conducted. Each lactating cow received 50 mg As demonstrated in the pivotal targetpirlimycin animal persafety quarter study, into even all fourwith quarters,adequate oncepre-treatment daily for 8preparation, consecutive repeated days. Using the established tolerance for infusion of PIRSUE Sterile Solution pirlimycinEFFECTresulted inON of elevated 0.5MILK ppm MANUFACTURING SCC in the and liver, clinical these mastitis STARTER data supportdue CULTURES to infectiona 21-day with pre-slaughter Gram-negative withdrawal period for extended duration environmental pathogens. For a completepirlimycinA study listing was therapy. ofconducted adverse Extended reactionsto examine duration for thepirlimycin of effect therapy ofreported varyingis considered to concentrations the Center as any for treatmentofVeterinary pirlimycin period in milk longer on the than growth 2 days of bacterial(up to 8 Medicine (CVM) see http://www.fda.gov/cvm/ade_cum.htm.consecutivestarter cultures days) used of therapy. toFor produce technical fermented assistance, milk to reportproducts. suspected Pirlimycin adverse did reactions,not adversely affect bacterial starter cultures or to request a Material Safety Data Sheetused for (MSDS), the production call 1-888-963-8471. of fermented milk products at concentrations found following normal label use including proper milk discard periods. Violative levels of pirlimycin (>0.40 ppm) can adversely affect the growth of bacterial starter MICROBIOLOGY EFFECT ON MILK MANUFACTURING STARTER CULTURES cultures. Pirlimycin is a lincosaminide antibioticA study that haswas activityconducted against to examine Gram-positive the effect mastitis of varying pathogens. concentrations Pirlimycin of functions pirlimycin in milk on the growth of bacterial by binding to the 50S ribosomal subunitstarter of culturesbacterial used ribonucleic to produce acid, fermentedwhich interferes milk products. with protein Pirlimycin synthesis did withinnot adversely the affect bacterial starter cultures bacteria. In vitro activity of pirlimycinused has beenfor the demonstrated production of against fermented Staphylococcus milk products aureus, at concentrations Streptococcus found agalactiae, following normal label use including proper Streptococcus dysgalactiae, and Streptococcusmilk discard uberisperiods., four Violative pathogens levels associated of pirlimycin with clinical(>0.40 andppm) subclinical can adversely mastitis affect the growth of bacterial starter in lactating dairy cattle. cultures.

Utilizing data that included isolates from cows with mastitis, zone diameter interpretive criteria and minimum inhibitory concentration (MIC) breakpoints were determined using standardized procedures from the Clinical and Laboratory Standards Institute (CLSI, formerly National Committee of Clinical Laboratory Standards) M31-A2. The CLSI-accepted interpretive criteria for pirlimycin against Gram-positive mastitis pathogens are shown in Table 1.

Table 1. CLSI-Accepted Interpretive Criteria for Pirlimycin Against Bovine Mastitis Pathogens* Pathogen Disk Potency Zone Diameter MIC Breakpoint Interpretive Standards (mm) (mg/mL) S R S R Staphylococcus aureus Streptococcus agalactiae Streptococcus dysgalactiae 2 mg ≥13 ≤12 ≤2.0 ≥4.0 Streptococcus uberis S - Susceptible R - Resistant * These interpretive criteria are only intended for use when CLSI M31-A2 performance standards are used to deter- mine antimicrobial susceptibility. Time/Date: PAA036273.indd 1 2/8/13 9:01 AM EFFECTIVENESS The effectiveness of pirlimycin was demonstrated in a field dose response study in lactating dairy cattle with clinical Project No. Artwork Number Description Country mastitis. Three investigators enrolled 486 cows from 39 herds. Cows with abnormal milk (clots, flakes) and with or without udder clinical signs (swelling, redness, or soreness) were enrolled and treated, regardlessTime/Date: of thePAA036273.indd mastitis 11395 1 2/8/13 9:01 AMPAA036273 Pirsue USA pathogen isolated or the pre-treatment somatic cell count. Cows were treated in the affected quarter(s) with 50, 100, Dimensions Drawing No. SKU No. Item or 200 mg of pirlimycin twice at a 24-hour interval. A non-treated control group was included. In this study, an individual Project No. Artwork Number Description Country quarter was cured if it had normal milk, no udder clinical signs, and if the milk was negative for any mastitis pathogen 5” x 24” Folds to: 5” x 1.5” PD2194 1475000 Insert at 10 days post-treatment. If no bacteria were isolated pre-treatment, a decrease in somatic cell count was required. 11395 PAA036273 Pirsue USA A cow was cured if all enrolled quarters in that cow were cured. All three treatment levels had significantlyAdditional greater Info: cow Colors: cure rates than the non-treated control group. Based on this study, the dose of 50 mg of pirlimycin per quarter Dimensions Drawing No. SKU No. EDITOR’SItem COPY administered twice at a 24-hour interval was determined to be the effective dose for the treatment of clinical mastitis. 5” x 24” Folds to:Black 5” x 1.5”Dieline PD2194 1475000 GS: InDATE:sert ANIMAL SAFETY Two pivotal studies addressing the safety of pirlimycin administered at dosages of 50 mg or 200 mg (4X) into all four Additional Info: Colors:GA PR GS / ART REV (LCA) GS / ART REV (FA) quarters twice at a 24-hour interval indicate that the formulation is safe and non-irritating to the bovineMgr C.udder. Andrews Safety Rev EDITOR’S COPY observations were also made during the clinical effectiveness study. No udder irritation was noted due to intramammary CHANGES CHANGES CHANGES GS A. French/K.M. Black Dieline GS: DATE: infusion with pirlimycin during these studies. 1 GA D. Verschoof OK OK OK An additional study was conducted to determine the safety of extended duration therapy. Twenty lactating Holstein cows, GA PR GS / ART REV (LCA) GS / ART REV (FA) first lactation or greater, at various milk production levels, and with no evidence of clinical mastitisMgr wereC. enrolled Andrews and Rev treated with pirlimycin administered at a dosage of 50 mg/quarter in all four quarters daily for eightGS consecutiveA. French/K.M. days. CHANGES CHANGES CHANGES Cows were monitored for general health, changes in milk production and quality, and signs of udder irritation for a total 1 OK OK OK of 14 days, beginning three days prior to the first treatment. Milk production was not affected by treatment.GA D. SCCs Verschoof of tre- ated cows were statistically significantly increased post-treatment relative to the pre-treatment level. A total of 24 pirlimy- cin-treated quarters (32%) in 15 cows had increased SCCs (>200,000 cells/mL) for at least two consecutive milkings. Of these, six treated cows (8 quarters) had a concurrent bacterial infection attributable to a mastitis pathogen. Udder irritation occurred in seven pirlimycin-treated cows (10 quarters). Abnormal strip cup scores occurred in six pirlimycin- treated cows (9 quarters). Most of the abnormal udder and strip cup observations were seen in quarters where bacte- ria were also isolated. Corroborative data from field studies and field use reports indicate that although intramammary infusion of pirlimycin hydrochloride at 50 mg/quarter administered from two to eight consecutive days was well tolerated, repeated infusion with pirlimycin increases the potential for intramammary infections and subsequent clinical mastitis due to environmental bacteria, including coliform bacteria. Adverse reactions, including clinical signs of mastitis (udder swelling and abnor- mal milk), increased SCCs, and death from coliform mastitis have been reported in cows following extended therapy with pirlimycin. Some, but not all, adverse reactions were associated with failure to thoroughly clean quarters and to use aseptic infusion technique. MILK AND TISSUE RESIDUE DEPLETION The established tolerance of pirlimycin in milk is 0.40 ppm. Milk residue depletion studies were conducted in cows with clinical mastitis. In one study, cows were infused with 50 mg of pirlimycin twice at a 24-hour interval into all quarters regardless of the number of affected quarters. In a second study, cows with a single mastitic quarter were infused with 50 mg of pirlimycin twice at a 24-hour interval into only the affected quarter. In a third study, normal cows were infused with 50 mg of pirlimycin twice at a 24-hour interval into all four quarters. As a result of these three studies, milk taken from cows during treatment and for 36 hours following treatment must not be used for food and must be discarded. For extended duration of therapy (once daily for up to 8 consecutive days), a milk residue study was conducted where cows received 50 mg of pirlimycin per quarter into all four quarters for 8 consecutive days. This study confirmed that milk taken from cows during treatment and for 36 hours following the last treatment must not be used for food and must be discarded.

The established tolerance for pirlimycin in liver (the target tissue) is 0.5 ppm. A pivotal tissue residue study was conducted following administration of 50 mg of pirlimycin twice at a 24-hour interval into all four quarters. Following receipt of the 50 mg of pirlimycin twice at a 24-hour interval into all four quarters, the liver residue decline data from this study supports a 9-day pre-slaughter withdrawal period.

For extended duration of therapy, a second tissue residue study was conducted. Each lactating cow received 50 mg pirlimycin per quarter into all four quarters, once daily for 8 consecutive days. Using the established tolerance for pirlimycin of 0.5 ppm in the liver, these data support a 21-day pre-slaughter withdrawal period for extended duration pirlimycin therapy. Extended duration of therapy is considered as any treatment period longer than 2 days (up to 8 consecutive days) of therapy.

EFFECT ON MILK MANUFACTURING STARTER CULTURES A study was conducted to examine the effect of varying concentrations of pirlimycin in milk on the growth of bacterial starter cultures used to produce fermented milk products. Pirlimycin did not adversely affect bacterial starter cultures used for the production of fermented milk products at concentrations found following normal label use including proper milk discard periods. Violative levels of pirlimycin (>0.40 ppm) can adversely affect the growth of bacterial starter cultures.

Time/Date: PAA036273.indd 1 2/8/13 9:01 AM

Project No. Artwork Number Description Country 11395 PAA036273 Pirsue USA Dimensions Drawing No. SKU No. Item 5” x 24” Folds to: 5” x 1.5” PD2194 1475000 Insert Additional Info: Colors: EDITOR’S COPY Black Dieline GS: DATE:

Mgr C. Andrews Rev GA PR GS / ART REV (LCA) GS / ART REV (FA) GS A. French/K.M. CHANGES CHANGES CHANGES 1 GA D. Verschoof OK OK OK ® In case of accidental eye exposure, flush with water for 15 minutes. In case Table 4. Acceptable quality control ranges for SPECTRAMAST DC of accidental skin exposure, wash with soap and water. Remove contaminated ceftiofur against CLSI recommended American Type clothing. If allergic reaction occurs (e.g., skin rash, hives, difficult breathing), Culture Collection (ATCC) reference strains brand of ceftiofur seek medical attention. The material safety data sheet contains more detailed occupational safety Organism (ATCC No.) Zone MIC hydrochloride information. To report adverse effects in users, to obtain more information or to Diameter* range sterile suspension obtain a material safety data sheet, call Zoetis Inc. at 1-888-963-8471. (mm) (μg/mL) RESIDUE WARNINGS Escherichia coli (25922) 26 to 31 0.25 to 1.0 1. Milk taken from cows completing a 30-day dry cow Staphylococcus aureus (29213) --- 0.25 to 1.0 period may be used for food with no milk discard due to Staphylococcus aureus (25923) 27 to 31 --- For Intramammary Infusion in Dry Dairy ceftiofur residues. Cattle Only 2. Following label use, no pre-slaughter withdrawal period Pseudomonas aeruginosa (27853) 14 to 18 16.0 to 64.0 is required for neonatal calves born from treated cows *All testing performed using a 30 µg disk. FOR USE IN ANIMALS ONLY — NOT FOR HUMAN USE regardless of colostrum consumption. EFFECTIVENESS CAUTION: Federal (USA) law restricts this drug to use by or on the order of 3. Following intramammary infusion, a 16-day pre- slaughter withdrawal period is required for treated cows. The effectiveness of a single intramammary (IMM) infusion of ceftiofur a licensed veterinarian. Federal Law prohibits extra-label use of this drug in dry hydrochloride for the treatment of subclinical mastitis present at the time of dry dairy cattle for disease prevention purposes; at unapproved doses, frequencies, 4. Use of this product in a manner other than indicated under DOSAGE might result in violative residues. off was demonstrated in a randomized block design study. Nineteen veterinary durations, or routes of administration; and in unapproved major food producing investigators enrolled cows in 21 herds and from these 21 herds, 431 cows species/production classes. CLINICAL MICROBIOLOGY and 1708 quarters met enrollment criteria in the study and calved within a DESCRIPTION: Ceftiofur hydrochloride is a cephalosporin antibiotic. Ceftiofur is a broad-spectrum cephalosporin antibiotic that exerts its effect 45 to 60 day period following enrollment. The enrollment criteria were whole by inhibiting bacterial cell wall synthesis. Like other ß-lactam antimicrobial udder somatic cell counts greater than 400,000 cells/mL or a linear somatic Chemical Structure of agents, the cephalosporins inhibit cell wall synthesis by interfering with the cell count score greater than or equal to 5. Milk microbiologic samples were enzymes essential for peptidoglycan synthesis. This effect results in lysis of the obtained prior to treatment and at Days 3 and 5 post-calving. There were 5 Ceftiofur Hydrochloride bacterial cell and accounts for the bactericidal nature of these agents. Ceftiofur treatment groups including a negative control group. There were 43 cows in U-64279A has demonstrated in vitro activity against clinical isolates and isolates from the negative control group and 51 cows in the 500 mg ceftiofur group that had diagnostic laboratories. The results of susceptibility testing of these isolates a positive pre-treatment milk culture that were evaluated for treatment success. against ceftiofur are presented in Tables 1 and 2. Appropriate reference strains The primary decision variable was the microbiologic (therapeutic) cure in which were also susceptibility tested and their minimum inhibitory concentration bacteria isolated pre-treatment were absent from both post-treatment samples. Chemical Name of (MIC) values and zone of inhibition with a 30 µg disk are presented in Table 4. Ceftiofur Hydrochloride In another study in eleven study herds, 446 cows with a somatic cell count (SCC) greater than or equal to 400,000 cells/mL or a linear score greater 5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7 - [[2-(2- amino- Table 1. Ceftiofur MIC values for isolates from a multi than or equal to 5 were enrolled. Cows with a dry period of at least 45 days 4-thiazolyl) - 2 -(methoxyimino)acetyl]amino]-3-[[(2-furanyl-carbonyl)thio] -site clinical field studyevaluating subclinical mastitis were blocked by lactation (1st + 2nd or 3rd). A single quarter milk sample was methyl]-8-oxo, hydrochloride. ≥ in dry dairy cows in the U.S. during 2000 aseptically obtained from all four quarters for bacterial culture prior to treatment Ceftiofur Hydrochloride Sterile Suspension is an oil based sterile suspen- and on Days 3 and 5 post-calving. There were 4 treatment groups including sion. Organism No. MIC90* MIC range ® (µg/mL) (µg/mL) a negative control. There were 84 cows in the negative control and 73 in the Each 10 mL PLASTET Disposable Syringe Contains: 500 mg ceftiofur group that had a positive pre-treatment milk culture that were Ceftiofur Equivalents (as the hydrochloride salt) ...... 500 mg Staphylococcus aureus 300 1.0 ≤0.06 to 2.0 evaluated for treatment success. The primary decision variable was the microbi- Microcrystalline Wax...... 700 mg ologic (therapeutic) cure in which bac-teria isolated pre-treatment were absent Streptococcus dysgalactiae 55 ≤0.06 ≤0.06 to >64.0 Oleoyl Polyoxylglyceride ...... 500 mg from both post-treatment samples. Cottonseed Oil ...... q.s. Streptococcus uberis 58 1.0 ≤0.06 to 4.0 Ceftiofur was found to be effective against Staphylococcus aureus, INDICATIONS FOR USE *The MIC for 90% of the isolates. Streptococcus dysgalactiae, and Streptococcus uberis, when SPECTRAMAST® DC Ceftiofur Hydrochloride Sterile Suspension compared to negative controls. This intramammary ceftiofur formulation was is indicated for the treatment of subclinical mastitis in dair cattle at the time Table 2. Ceftiofur MIC values* for mastitis pathogens well tolerated. No adverse formulation related events were noted during the of dry off associated with Staphylo coc cus aureus, Streptococcus from diagnostic laboratories in the U.S. and Canada entire study. A large multi-location field dose confirmation study and a pilot ® study demonstrated that 500 mg of ceftiofur infused once per quarter at the time dysgalactiae, and Streptococcus uberis. SPECTRAMAST DC Organism No. Date MIC ** MIC range 90 of dry off was effective for the treatment of subclinical mastitis in dairy cattle at Ceftiofur Hydrochloride Sterile Suspension has been proven effective against isolated (µg/mL) (µg/mL) Staph y lo coc cus aureus, Streptococcus dysgalactiae, and the time of dry off. 135 1991–1992 1.0 0.13 to 2.0 Streptococcus uberis. ANIMAL SAFETY DOSAGE Staphylococcus 10 1993 1.0 0.25 to 1.0 An udder irritation study was conducted in 22 healthy lactating dairy cows Infuse one (1) syringe into each affected quarter at the time of dry off. aureus 107 1995 1.0 0.25 to 2.0 to assess udder irritation following a single intramammary infusion of a sterile oil-based suspension containing 500 mg of ceftiofur into all four quarters DIRECTIONS FOR USING THE PLASTET® 61 2000 1.0 ≤0.06 to 2.0 followed by milk-out 12 hours later. Throughout the 10 day post-treatment DISPOSABLE SYRINGE Coagulase (-) 139 2000–2001 1.0 ≤0.06 to 2.0 observation period there was a clinically insignificant rise in SCC to mean The syringe is designed to provide the choice of either insertion of the staphylococci levels <200,000 cells/mL from the pre-infusion level of <69,000 cells/mL. No full cannula as has traditionally been practiced, or insertion of no more than 15 1991–1992 1.0 ≤0.06 to 2.0 clinical signs of udder irritation (swelling, pain, or redness), changes in rectal

1/8 inch of the cannula, as reported by Eberhart, R.J., et. al. 1987. Current † temperature, or changes in milk production were noted in this study. Clinical Concepts of Bovine Mastitis, 3rd Edition, National Mastitis Council, Arlington, Streptococcus 15 1993 ≤0.0039 No range observations were made during a GLP residue depletion study of 36 cows VA. dysgalactiae 152 1997–1999 0.25 0.25 to 4.0 following a single intramammary infusion of a sterile oil based suspension a. Full insertion: Remove the red end cap by pulling straight up as 64 2000 ≤0.06 ≤0.06 to 0.5 containing 500 mg of ceftiofur into all four quarters at the end of lactation. shown. Gently insert the full cannula into the teat canal; carefully infuse the No report of udder irritation or adverse reaction was noted in the daily visual 22 1991–1992 0.5 0.06 to 4.0 product. ≤ observations over the 14 days immediately following treatment. Collectively, b. Partial insertion: Remove the red end cap by pulling straight up as Streptococcus 15 1993 0.03 ≤0.0039 to 0.06 these studies demonstrate that the intramammary infusion of an oil-based uberis sterile suspension containing 500 mg of ceftiofur once into all four quarters shown. Gently insert the exposed white tip into the teat canal; carefully 133 1997–1999 0.5 0.5 to 8.0 at the end of lactation is clinically safe and non-irritating to the udder of non- infuse the product. 20 2000 1.0 <0.06 to 2.0 lactating dairy cows. ADMINISTRATION 39 1991–1992 1.0 0.25 to 1.0 MILK AND TISSUE RESIDUE DEPLETION Escherichia coli 40 1993 0.5 0.13 to 1.0 A metabolism study in cattle using radiolabeled ceftiofur provided the data to establish tolerances for ceftiofur-related residues (as desfuroylceftiofur) in 52 2000 0.5 ≤0.06 to 1.0 tissue and milk. These tolerances of ceftiofur residues are 0.1 ppm in milk, 0.4 * The above in vitro data are available, but their clinical significance is unknown. ppm in kidney, 2.0 ppm in liver, and 1.0 ppm in muscle. ** The MIC for 90% of the isolates. Pivotal residue decline studies were conducted to assess the † No range, all isolates yielded the same value. depletion of ceftiofur-related residues, measured as desfuroylcef- Based on pharmacokinetic, milk residue and clinical effectiveness studies tio-fur using the official analytical method, in tissues of treated cows, in in dairy cattle following intramammary infusion of ceftiofur and the MIC and milk from treated cows, and in tissues of calves born to treated Treatment: Wash teats thoroughly with warm water containing a suitable disk (30 µg) diffusion data from mastitis pathogens, the following breakpoints cows. In these studies, non-mastitic cows received 500 mg of ceftiofur dairy antiseptic. Dry teats thoroughly. Milk out udder completely. Using an are recommended by the National Committee for Clinical Laboratory Standards per quarter into all four quarters once at dry off. The milk residue deple- alcohol pad provided, wipe off the end of the affected teat using a separate pad [now the Clinical and Laboratories Standards Institute (CLSI)] (Table 3). tion study demonstrated that milk produced at calving may be used for for each teat. Choose the desired insertion length (full or partial) and insert tip human consumption with no discard period when the treatment to calv- Table 3. Current recommended interpretive criteria ing interval is 30 days or more. The tissue depletion study measured into teat canal; push plunger to dispense entire contents, massage the quarter to established by CLSI for ceftiofur for Bovine Mastitis distribute the suspension into the milk cistern. residues in the tissues of treated cows and in the tissues of neonatal calves Reinfection: After successful treatment, reinfection may occur unless good born to treated cows. In neonatal calves born to treated cows, tissue residues herd management, sanitation, and mechanical safety measures are practiced. Bovine Mastitis Disk Zone MIC break- were less than the codified tolerances for kidney, liver and muscle. These data Affected cows should be watched carefully to detect recurrence of infection and Organisms Content Diameter point (μg/ support a zero day pre-slaughter withdrawal period for calves born to treated possible spread to other animals. (mm) mL) cows when the treatment to calving interval is 30 days or more, regardless of colostrum consumption. The tissue residue depletion data support a 16-day CONTRAINDICATIONS S I R S I R pre-slaughter withdrawal period following intramammary infusion for treated ® As with all drugs, the use of SPECTRAMAST DC Sterile Suspension Staphylococcus cows. is contraindicated in animals previously found to be hypersensitive to the drug. aureus Streptococcus STORAGE CONDITIONS Discard Empty Container: DO NOT REUSE dysgalactiae Store at controlled room temperature 20° to 25° C (68° to 77° F). Protect Streptococcus from light. Store plastets in carton until used. KEEP OUT OF REACH OF CHILDREN uberis 30 µg ≥21 18–20 ≤17 ≤2.0 4.0 ≥8.0 HOW SUPPLIED Streptococcus ® WARNINGS agalactiae SPECTRAMAST DC Sterile Suspension is available in cartons Penicillins and cephalosporins can cause allergic reactions in sensitized Escherichia coli containing 1 unbroken package of 12–10 mL PLASTET® Disposable Syringes individuals. Topical exposures to such antimicrobials, including ceftiofur, S–Susceptible I–Intermediate R–Resistant with 12 individually wrapped 70% isopropyl alcohol pads and in pails containing may elicit mild to severe allergic reactions in some individuals. Repeated 12 unbroken packages of 12-10 mL PLASTET Disposable Syringes with 144 Standardized procedures require the use of laboratory control organisms for individually wrapped 70% isopropyl alcohol pads. or prolonged exposure may lead to sensitization. Avoid direct contact of the both standardized diffusion techniques and standardized dilution techniques. product with the skin, eyes, mouth and clothing. Sen si ti za tion of the skin may The 30 µg ceftiofur sodium disk should give the following zone diameters and NADA# 141-239, Approved by FDA be avoided by wearing protective gloves. the ceftiofur sodium standard reference powder (or disk) should provide the Distributed by: Persons with a known hypersensitivity to penicillin or cephalosporins should following MIC values for the reference strain. The ceftiofur sodium disks or avoid exposure to this product. standard reference powder is appropriate for ceftiofur hydrochloride (Table 4). Zoetis Inc. Kalamazoo, MI 49007

www.spectramast.com or call 1-888-963-8471 Revised: September 2013 30150900A&P 69 ® CONTRAINDICATIONS SPECTRAMAST LC As with all drugs, the use of SPECTRAMAST® LC Sterile Suspension is (ceftiofur intramammary suspension) contraindicated in animals previously found to be hypersensitive to the drug. Sterile Suspension Discard Empty Container: DO NOT REUSE KEEP OUT OF REACH OF CHILDREN For Intramammary Infusion in Lactating Cows Only WARNINGS FOR USE IN ANIMALS ONLY — NOT FOR HUMAN USE Penicillins and cephalosporins can cause allergic reactions in sensitized individuals. Topical exposures to such antimicrobials, including ceftiofur, may elicit mild to severe allergic reactions in some individuals. Repeated or CAUTION: Federal (USA) law restricts this drug to use by or on the order of prolonged exposure may lead to sensitization. Avoid direct contact of the prod- a licensed veterinarian. Federal law prohibits extra-label use of this drug in uct with the skin, eyes, mouth and clothing. Sen si ti za tion of the skin may be lactating dairy cattle for disease prevention purposes; at unapproved doses, avoided by wearing protective gloves. frequencies, durations, or routes of administration; and in unapproved major Persons with a known hypersensitivity to penicillin or cephalosporins food producing species/production classes. should avoid exposure to this product. In case of accidental eye exposure, flush with water for 15 minutes. In case DESCRIPTION of accidental skin exposure, wash with soap and water. Remove contaminated Ceftiofur hydrochloride is a cephalosporin antibiotic. clothing. If allergic reaction occurs (e.g., skin rash, hives, difficult breathing), Chemical Structure of Ceftiofur Hydrochloride seek medical attention. NH 2 The safety data sheet contains more detailed occupational safety infor- S N mation. To report suspected adverse events, for technical assistance or to obtain a copy of the safety data sheet (SDS), contact Zoetis Inc. at C C NH S 1-888-963-8471. For additional information about adverse drug experience N O reporting for animal drugs, contact FDA at 1-888-FDA-VETS or online at OCH O N 3 CH2 SC http://www.fda.gov/AnimalVeterinary/SafetyHealth. COOH O O RESIDUE WARNINGS • HCl 1. Milk taken from cows during treatment (a maximum of eight U-64279A daily infusions) and for 72 hours after the last treatment must Chemical Name of Ceftiofur Hydrochloride not be used for human consumption. 5-Thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, 7 -[[2-(2- 2. Following label use for up to eight consecutive days, a 2-day amino-4-thiazolyl) - 2 -(methoxyimino)acetyl]amino]-3-[[(2-furanylcarbonyl) pre-slaughter withdrawal period is required. thio]methyl]-8-oxo, hydrochloride. 3. Use of this product in a manner other than indicated under SPECTRAMAST® LC Sterile Suspension is an oil based sterile suspension. DOSAGE might result in violative residues. Each 10 mL PLASTET® Disposable Syringe Contains: PRECAUTION Ceftiofur Equivalents (as the hydrochloride salt) ...... 125 mg Following intramammary infusion with antibiotics in lactating cows, milk Microcrystalline Wax ...... 700 mg obtained during treatment and during the milk discard period should be Oleoyl Polyoxylglyceride ...... 500 mg properly discarded and not fed to calves. SPECTRAMAST LC is intended Cottonseed Oil ...... q.s. for use in lactating dairy cattle with mastitis associated only with the speci- INDICATIONS FOR USE fied labeled pathogens. To assure responsible antimicrobial drug use, it is SPECTRAMAST® LC (ceftiofur intramammary suspension) Sterile expected that subclinical mastitis will be diagnosed using a positive culture Suspension is indicated for use in lactating dairy cattle for (1) the treatment of or other pathogen-specific test in addition to any other appropriate veteri- clinical mastitis associated with coagulase-negative staphylococci, nary medical evaluation prior to treatment. Cows with systemic clinical signs Streptococcus dysgalactiae, and Escherichia coli and (2) the treatment of caused by mastitis should receive other appropriate therapy under the direc- diagnosed subclinical mastitis associated with coagulase-negative staphylo- tion of a licensed veterinarian. After successful treatment, reinfection may cocci and Streptococcus dysgalactiae. occur unless good herd management, sanitation, and mechanical safety DOSAGE measures are practiced. Affected cows should be watched carefully to detect Infuse one (1) syringe into each affected quarter. Repeat this treatment recurrence of infection and possible spread to other animals. in 24 hours. For extended duration therapy, once daily treatment may be CLINICAL MICROBIOLOGY repeated for up to 8 consecutive days. Ceftiofur is a broad-spectrum cephalosporin antibiotic that exerts its effect by DIRECTIONS FOR USING THE PLASTET® DISPOSABLE SYRINGE inhibiting bacterial cell wall synthesis. Like other ß-lactam antimicrobial agents, The syringe is designed to provide the choice of either insertion of the full cephalosporins inhibit cell wall synthesis by interfering with the enzymes cannula as has traditionally been practiced, or insertion of no more than essential for peptidoglycan synthesis. This effect results in lysis of the bacte- 1/8 inch of the cannula, as reported by Eberhart, R.J., et. al. 1987. Current rial cell and accounts for the bactericidal nature of these agents. Ceftiofur Concepts of Bovine Mastitis, 3rd Edition, National Mastitis Council, Arlington, VA. has demonstrated in vitro activity against coagulase-negative staphylococci, Streptococcus dysgalactiae, and Escherichia coli. The minimum inhibitory a. Full insertion: Remove the red end cap by pulling straight up as shown. concentrations (MICs) of ceftiofur against indicated pathogens collected from Gently insert the full cannula into the teat canal; carefully infuse the field studies conducted in 2000 were determined using methods recommended product. by the National Committee for Clinical Laboratory Standards (NCCLS, M31-A) b. Partial insertion: Remove the red end cap by pulling straight up as and are represented in Table 1, below: shown. Gently insert the exposed white tip into the teat canal; carefully infuse the product. Table 1. Ceftiofur Minimum Inhibitory Concentrations (MIC) Values* of Isolates from Field Studies Evaluating Clinical b. Mastitis in Dairy Cows in the U.S. During 2000 a. Pathogen Number of MIC90** MIC Range isolates (µg/mL) (µg/mL) Coagulase-negative 33 1.0 ≤0.06–2.0 staphylococci (CNS) Streptococcus dysgalactiae 32 ≤0.06 ≤0.06–0.5 Escherichia coli 35 0.5 ≤0.06–1.0 * The correlation between in vitro susceptibility data and clinical effectiveness is unknown. ADMINISTRATION Treatment: Wash teats thoroughly with warm water containing a suitable ** The lowest MIC to encompass 90% of the most susceptible isolates. dairy antiseptic. Dry teats thoroughly. Milk out udder completely. Using an alcohol pad provided, wipe off the end of the affected teat using a separate pad for each teat. Choose the desired insertion length (full or partial) and insert tip into teat canal; push plunger to dispense entire contents, massage the quarter to distribute the suspension into the milk cistern.

70 EFFECTIVENESS ANIMAL SAFETY In 1999 to 2000, the efficacy of ceftiofur was demonstrated in a pivotal A pivotal GLP udder irritation study was conducted in 40 cows to assess multi-location field trial in lactating dairy cattle with clinical mastitis in one udder irritation following daily intramammary infusion of an oil-based suspen- quarter. Ceftiofur was formulated in stable cottonseed oil sterile suspension sion containing 125 mg of ceftiofur for up to 8 consecutive days. A transient manufactured under GMP guidelines. Cows with mastitis were enrolled in and clinically insignificant rise in SCC to levels <200,000 cell/mL was the study if visually abnormal milk (clots, flakes, or watery secretion) or if observed following infusion in normal cows with very low pre-infusion SCC udder swelling, heat, pain or redness were present and the milk was not yet (<10,000 cell/mL). This elevation is not unexpected with oil-based suspensions. visually abnormal but California Mastitis Test (CMT) gave results of 2 or The duration of therapy did not affect this elevation. No udder clinical signs greater. A total of 13 trial sites enrolled 352 cows in the study. Cows were of irritation (swelling, pain, or redness), changes in body temperature or in assigned to one of three treatment groups: non-treated con trol, 62.5 mg ceftiofur, milk production were noted during this study. This pivotal GLP study demon- and 125 mg ceftiofur. Each treatment group received an intramammary strated that this formulation is clinically safe and non-irritating to the udder of infusion twice at a 24-hour interval in the affected quarter. The non-treated lactating dairy cows. In two clinical field efficacy studies in 971 lactating controls received no therapy. Three different definitions for cure were used dairy cows, no reports of udder irritation or adverse events were noted for analysis purposes: 1) a clinical cure was defined as the milk and udder following infusion. Collectively, these three studies demonstrate that the returning to normal 14 days after the last treatment and remaining normal at intramammary infusion of an oil-based suspension containing 125 mg of the 21 day time point; 2) a bacterial cure was defined as the absence of ceftiofur once daily into all four quarters for up to 8 consecutive days is clinically the pre-treatment pathogen at 14 and 21 days post-treatment; 3) a protocol safe and non-irritating to the udder of lactating dairy cows. cure was defined as the absence of the pre-treatment pathogen at 14 and MILK AND TISSUE RESIDUE DEPLETION 21 days post-treatment and return to normal of the milk and udder 14 days A metabolism study in cattle using radiolabeled ceftiofur provided the data after the last treatment and remaining normal at the 21 day time point. Three to establish tolerances for ceftiofur-related residues (as desfuroylceftiofur) in hundred and thirty seven cows were analyzed for clinical cure rates, which tissue and milk. These tolerances are 0.1 ppm in milk, 0.4 ppm in kidney, were 54.7% (64/117) for the non-treated control group compared to 69.4% 2.0 ppm in liver, and 1.0 ppm in muscle. (75/108) for the 62.5 mg treatment group and 78.6% (88/112) for the 125 mg Two pivotal milk residue decline studies were conducted. In these studies, treatment group. The 125 mg treatment group’s clinical cure rate was signifi- non-mastitic cows received 125 mg of ceftiofur per quarter into all four quarters cantly greater than the non-treated control (P=0.002). One hundred and forty either twice at a 24-hour interval or once daily for 8 consecutive days. six cows were analyzed for bacterial cure rates, which were 41.3% (19/46) Regardless of treatment duration and using a tolerance of 0.10 ppm for for the non-treated control group, 45.6% (21/46) for the 62.5 mg treatment ceftiofur-related residues in milk, these studies demonstrate that milk taken group and 70.4% (38/54) for the 125 mg treatment group. The 125 mg treatment during treatment (a maximum of 8 consecutive daily infusions) and for group’s bacterial cure rate was significantly greater than the non-treated 72 hours after the last treatment must not be used for human consumption control group (P=0.006). One hundred and forty six cows were analyzed for and must be discarded. protocol cure rates, which were 63.0% (34/54) for the 125 mg treatment A pivotal tissue residue decline study in lactating dairy cattle provides tissue group, 41.3% (19/46) for the 62.5 mg treatment group and 23.9% (11/46) for residue decline data. In this study, the cattle received an intramammary infusion the non-treated control group. The 125 mg treatment group’s protocol cure of 125 mg of ceftiofur hydrochloride into each of four quarters once daily for rate was significantly better than the non-treated control (P<0.001) for treatment 8 consecutive days. Ceftiofur residues were determined in the kidney (the of clinical mastitis. Thus, 125 mg of ceftiofur administered via intramammary target tissue) using the official analytical method. Kidney residues were less infusion twice at a 24-hour interval was effective in the treatment of clinical than the established tolerance (0.4 ppm) by 2 days after the last infusion. mastitis in lactating dairy cows associated with coagulase-negative staphylococci, These data collectively support the assignment of a 2-day pre-slaughter (CNS), Streptococcus dysgalactiae, and Escherichia coli. withdrawal period regardless of treatment duration. The effectiveness of ceftiofur for the treatment of subclinical mastitis was STORAGE CONDITIONS demonstrated in a 10-site field study in lactating dairy cattle in 2013. Cows Store at controlled room temperature 20° to 25° C (68° to 77° F). Protect with subclinical mastitis were enrolled in the study if milk and udders were from light. Store syringes in carton or pail until used. visually normal, composite quantitative somatic cell count (SCC) was >400,000 HOW SUPPLIED cells/mL, and milk culture was positive for a mastitis-causing pathogen. Cows SPECTRAMAST® LC Sterile Suspension is available in cartons containing were assigned to one of two treatment groups: SPECTRAMAST LC (125 mg 1 unbroken package of 12–10 mL PLASTET® Disposable Syringes with 12 ceftiofur equivalents per dose) or an equivalent volume of saline. Each treatment individually wrapped 70% isopropyl alcohol pads and in pails containing 12 group received an intramammary infusion twice at a 24-hour interval in the unbroken packages of 12-10 mL PLASTET Disposable Syringes with 144 affected quarter. Treatment success (bacterial cure) was defined as the individually wrapped 70% isopropyl alcohol pads. absence of the pre-treatment pathogen at 14 and 20 days post-treatment. NADA# 141-238, Approved by FDA Three hundred thirty-six cows were analyzed for bacterial cure rates. There was a statistically significantly different (P < 0.0001) overall proportion of treatment successes in the SPECTRAMAST LC-treated group (44%, 75/164) compared with the saline-treated group (4%, 8/172). Additionally, a clinically- Distributed by: relevant ratio of clinical successes to failures was observed in the Zoetis Inc. SPECTRAMAST LC-treated group compared to the saline-treated group Kalamazoo, MI 49007 for evaluable cases of subclinical mastitis associated with CNS and with www.spectramast.com or call 1-888-963-8471 S. dysgalactiae. Revised: February 2015

30151801A&P

71 NOTES

72 NOTES

73 All trademarks are the property of Zoetis Services LLC or a related company or a licensor unless otherwise noted . Allflex is a registered trademark of Allflex USA, Inc . CIDR is a registered trademark of InterAg . Enlight is a U .S . registered trademark of Holstein Association and Zoetis Services LLC . Excel is a registered trademark of Microsoft Corporation . OMRI Listed is a registered trademark of Organic Materials Review Institute . Optaflexx, Rumensin and Tylan are registered trademarks of Eli Lilly and Company, its subsidiaries or affiliates . Profit Solver is the registered trademark of Fee Technology, Inc . SolidBac and IR/PR are registered trademarks of SolidTech Animal Health, Inc . Zilmax is a registered trademark of Intervet Inc . or an affiliate . © 2017 Zoetis Services LLC . All rights reserved . GCA-00214

CONTACT 888-ZOETIS1 (888-963-8471) www.zoetisUS.com