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BOXED WARNINGS CLINICAL PHARMACOLOGY: noglycoside may be resistant to one or more other in body sites where the drug is physiologically con- when penicillins or other less potentially toxic After intramuscular (IM) administration of gentamicin aminoglycosides. The following bacteria are usually centrated. This category also provides a buffer zone drugs are contraindicated and bacterial sus- Patients treated with aminoglycosides should sulfate, peak serum concentrations usually occur resistant to the aminoglycosides, including gentami- that prevents small uncontrolled technical factors ceptibility tests and clinical judgment indicate its be under close clinical observation because between 30 and 60 minutes and serum levels are cin: most streptococcal species (including Strepto- from causing major discrepancies in interpretation. use. It may also be considered in mixed infec- of the potential toxicity associated with their measurable for six to eight hours. When gentamicin coccus pneumoniae and the Group D streptococci), A report of “Resistant” indicates that the antimicrobial tions caused by susceptible strains of staphylo- use. is administered by intravenous (IV) infusion over a most enterococcal species (including Enterococcus is not likely to inhibit growth of the pathogen if the cocci and gram-negative organisms. As with other aminoglycosides, gentamicin two-hour period, the serum concentrations are faecalis, E. faecium, and E. durans), and anaerobic antimicrobial compound reaches the concentrations In the neonate with suspected bacterial sepsis injection is potentially nephrotoxic. The risk similar to those obtained by IM administration. organisms, such as Bacteroides species and Clos- usually achievable at the infection site; other therapy or staphylococcal pneumonia, a penicillin-type of nephrotoxicity is greater in patients with In patients with normal renal function, peak serum tridium species. should be selected. drug is also usually indicated as concomitant impaired renal function and in those who concentrations of gentamicin (mcg/mL) are usu- Aminoglycosides are known to be not effective Quality Control therapy with gentamicin. receive high dosage of prolonged therapy. ally up to four times the single IM dose (mg/kg); against Salmonella and Shigella species in patients. Standardized susceptibility test procedures require Neurotoxicity manifested by ototoxicity, both for example, a 1 mg/kg injection in adults may be Therefore, in vitro susceptibility test results should the use of laboratory controls to monitor and ensure CONTRAINDICATIONS: vestibular and auditory, can occur in patients expected to result in a peak serum concentration not be reported. the accuracy and precision of supplies and Hypersensitivity to gentamicin is a contraindication treated with gentamicin, primarily in those up to 4 mcg/mL; a 1.5 mg/kg dose may produce to its use. A history of hypersensitivity or serious Interactions with Other Antimicrobials reagents used in the assay, and the techniques of with pre-existing renal damage and in patients levels up to 6 mcg/mL. While some variation is to the individuals performing the test.1,2,3 Standard toxic reactions to other aminoglycosides may con- with normal renal function treated with higher be expected due to a number of variables such as In vitro studies show that an aminoglycoside com- traindicate use of gentamicin because of the known bined with an antibiotic that interferes with cell wall gentamicin powder should provide the following doses and/or for longer periods than age, body temperature, surface area and physiologic range of MIC values provided in Table 2. For the dif- cross-sensitivity of patients to drugs in this class. recommended. Aminoglycoside-induced differences, the individual patient given the same synthesis may act synergistically against some enterococcal strains. The combination of gentamicin fusion technique using the 10-mcg gentamicin disk ototoxicity is usually irreversible. Other dose tends to have similar levels in repeated deter- the criteria provided in Table 2 should be achieved. WARNINGS: manifestations of neurotoxicity may include minations. Gentamicin administered at 1 mg/kg and penicillin G has a synergistic bactericidal effect (See BOXED WARNINGS.) numbness, skin tingling, muscle twitching every eight hours for the usual 7 to 10 day treat- against strains of Enterococcus faecalis, E. faecium Table 2: Acceptable Quality Control Ranges Contains sodium metabisulfite, a sulfite that may and convulsions. ment period to patients with normal renal func- and E. durans. An enhanced killing effect against for Susceptibility Testing cause allergic-type reactions including anaphy- Renal and eighth cranial nerve function tion does not accumulate in the serum. many of these strains has also been shown in vitro lactic symptoms and life-threatening or less severe should be closely monitored, especially in Gentamicin, like all aminoglycosides, may accu- with combinations of gentamicin and ampicillin, Minimum asthmatic episodes in certain susceptible peo- carbenicillin, nafcillin or oxacillin. Inhibitory patients with known or suspected reduced mulate in the serum and tissues of patients treated Concentrations Zone Diameter ple. The overall prevalence of sulfite sensitivity in renal function at onset of therapy and also in with higher doses and/or for prolonged periods, The combined effect of gentamicin and carbenicil- Quality Control Organism (mcg/mL) (mm) the general population is unknown and probably those whose renal function is initially normal particularly in the presence of impaired renal func- lin is synergistic for many strains of Pseudomonas low. Sulfite sensitivity is seen more frequently in aeruginosa. In vitro synergism against other Gram- Escherichia coli but who develop signs of renal dysfunction tion. In adult patients, treatment with gentamicin ATCC 25922 0.25 to 1 19 to 26 asthmatic than in non-asthmatic people. during therapy. Urine should be examined for dosages of 4 mg/kg/day or higher for 7 to 10 days negative organisms has been shown with combina- Aminoglycosides can cause fetal harm when decreased specific gravity, increased excre- may result in a slight, progressive rise in both tions of gentamicin and cephalosporins. Pseudomonas aeruginosa administered to a pregnant woman. Aminoglycoside tion of protein and the presence of cells or peak and trough concentrations. In patients with Gentamicin may be active against clinical isolates ATCC 27853 0.5 to 2 16 to 21 antibiotics cross the placenta, and there have casts. Blood urea nitrogen (BUN), serum cre- impaired renal function, gentamicin is cleared from of bacteria resistant to other aminoglycosides. Staphylococcus aureus been several reports of total irreversible bilateral atinine or creatinine clearance should be deter- the body more slowly than in patients with normal Antibacterial Activity ATCC 25923 Not Applicable 19 to 27 congenital deafness in children whose mothers mined periodically. When feasible, it is recom- renal function. The more severe the impairment, Gentamicin has been shown to be active against Staphylococcus aureus received streptomycin during pregnancy. Serious mended that serial audiograms be obtained the slower the clearance. (Dosage must be adjusted.) most of the following bacteria, both in vitro and in ATCC 29213 0.12 to 1 Not Applicable side effects to mother, fetus or newborn have not in patients old enough to be tested, particu- Since gentamicin is distributed in extra-cellular clinical infections (see INDICATIONS AND USAGE). been reported in the treatment of pregnant women larly high-risk patients. Evidence of ototoxicity Enterococcus faecalis with other aminoglycosides. Animal reproduction fluid, peak serum concentrations may be lower ATCC 29212 4 to 16 Not Applicable (dizziness, vertigo, tinnitus, roaring in the ears than usual in adult patients who have a large vol- Gram-Positive Bacteria studies conducted on rats and rabbits did not or hearing loss) or nephrotoxicity requires dos- ume of this fluid. Serum concentrations of genta- Staphylococcus species Note: For control organisms for gentamicin high-level reveal evidence of impaired fertility or harm to age adjustment or discontinuance of the drug. micin in febrile patients may be lower than those aminoglycoside screen tests for enterococci, see Table the fetus due to gentamicin sulfate. Gram-Negative Bacteria 3 As with the other aminoglycosides, on rare in afebrile patients given the same dose. When 2D Supplemental Table 1 in CLSI document M100-S23 It is not known whether gentamicin sulfate can occasions changes in renal and eighth cra- Citrobacter species cause fetal harm when administered to a preg- body temperature returns to normal, serum con- Enterobacter species INDICATIONS AND USAGE: nial nerve function may not become manifest centrations of the drug may rise. Febrile and ane- nant woman or can affect reproduction capacity. until soon after completion of therapy. Escherichia coli To reduce the development of drug-resistant If gentamicin is used during pregnancy or if the mic states may be associated with a shorter than Klebsiella species

bacteria and maintain the effectiveness of m Serum concentrations of aminoglycosides usual serum half-life. (Dosage adjustment is usu- patient becomes pregnant while taking genta- should be monitored when feasible to assure Proteus species Gentamicin Injection, USP and other antibacterial micin, she should be apprised of the potential ally not necessary.) In severely burned patients, Serratia species drugs, Gentamicin Injection, USP should be used adequate levels and to avoid potentially toxic hazard to the fetus. the half-life may be significantly decreased and Pseudomonas aeruginosa only to treat or prevent infections that are proven levels. When monitoring gentamicin peak con- resulting serum concentrations may be lower than centrations, dosage should be adjusted so that or strongly suspected to be caused by susceptible PRECAUTIONS: anticipated from the mg/kg dose. Susceptibility Test Methods bacteria. When culture and susceptibility infor- prolonged levels above 12 mcg/mL are avoided. Protein binding studies have indicated that the When available, the clinical microbiology labora- General When monitoring gentamicin trough concen- mation are available, they should be considered Prescribing Gentamicin Injection, USP in the degree of gentamicin binding is low; depending tory should provide cumulative results of the in vitro in selecting or modifying antibacterial therapy. In trations, dosage should be adjusted so that upon the methods used for testing, this may be susceptibility tests for antimicrobial drugs used in absence of a proven or strongly suspected levels above 2 mcg/mL are avoided. Exces- the absence of such data, local epidemiology and bacterial infection or a prophylactic indication between 0 and 30%. local hospitals and practice areas to the physician susceptibility patterns may contribute to the sive peak and/or trough serum concentra- After initial administration to patients with nor- as periodic reports that describe the susceptibility is unlikely to provide benefit to the patient and tions of aminoglycosides may increase the empiric selection of therapy. increases the risk of the development of drug- mal renal function, generally 70% or more of the profile of nosocomial and community-acquired Gentamicin Injection, USP is indicated in the risk of renal and eighth cranial nerve toxicity. gentamicin dose is recoverable in the urine in 24 pathogens. These reports should aid the physician resistant bacteria. In the event of overdosage or toxic reac- treatment of serious infections caused by sus- Neurotoxic and nephrotoxic antibiotics may be hours; concentrations in urine above 100 mcg/mL in selecting the most effective antimicrobial. ceptible strains of the following microorganisms: tions, hemodialysis may aid in the removal of may be achieved. Little, if any, metabolic transfor- almost completely absorbed from body surfaces gentamicin from the blood, especially if renal Dilution Technique Pseudomonas aeruginosa, Proteus species (indole- (except urinary bladder) after local irrigation and mation occurs; the drug is excreted principally by Quantitative methods are used to determine anti- positive and indole-negative), Escherichia coli, function is, or becomes, compromised. The glomerular filtration. After several days of treat- after topical application during surgical procedures. rate of removal of gentamicin is considerably microbial minimal inhibitory concentrations (MICs). Klebsiella-Enterobacter-Serratia species, Citrobacter The potential toxic effects of antibiotics administered ment, the amount of gentamicin excreted in the These MICs provide estimates of the susceptibility species and Staphylococcus species (coagulase- lower by peritoneal dialysis than it is by urine approaches the daily dose administered. in this fashion (neuromuscular blockage, respiratory hemodialysis. of bacteria to antimicrobial compounds. The MICs positive and coagulase-negative). paralysis, oto- and nephrotoxicity) should be con- As with other aminoglycosides, a small amount of should be determined using a standardized test Clinical studies have shown gentamicin In the newborn infant, exchange transfu- the gentamicin dose may be retained in the tis- sidered (see BOXED WARNINGS). sions may also be considered. method.1,3 Standardized procedures are based injection to be effective in bacterial neonatal sep- Increased nephrotoxicity has been reported fol- sues, especially in the kidneys. Minute quantities sis; bacterial septicemia and serious bacterial Concurrent and/or sequential systemic or of aminoglycosides have been detected in the on a dilution method (broth or agar) or equivalent lowing concomitant administration of aminogly- topical use of other potentially neurotoxic and/or with standardized inoculum concentrations and infections of the central nervous system (menin- coside antibiotics and cephalosporins. urine weeks after drug administration was discon- gitis), urinary tract, respiratory tract, gastrointesti- nephrotoxic drugs, such as cisplatin, cepha- tinued. Renal clearance of gentamicin is similar standardized concentrations of gentamicin powder. Neuromuscular blockade and respiratory paral- The MIC values should be interpreted according to nal tract (including peritonitis), skin, bone and soft loridine, kanamycin, amikacin, neomycin, poly- to that of endogenous creatinine. ysis have been reported in the cat receiving high myxin B, colistin, paromomycin, streptomycin, the criteria provided in Table 1. tissue (including burns). Aminoglycosides, includ- doses (40 mg/kg) of gentamicin. The possibility In patients with marked impairment of renal func- ing gentamicin, are not indicated in uncomplicated tobramycin, vancomycin and viomycin, should tion, there is a decrease in the concentration of Diffusion Technique of these phenomena occurring in man should be 45855H/Revised: October 2013 be avoided. Other factors which may increase initial episodes of urinary tract infections unless considered if aminoglycosides are administered aminoglycosides in urine and in their penetration Quantitative methods that require measurement of the causative organisms are susceptible to these patient risk of toxicity are advanced age and into defective renal parenchyma. This decreased zone diameters also provide reproducible estimates by any route to patients receiving anesthetics, dehydration. antibiotics and are not susceptible to antibiotics or to patients receiving neuromuscular blocking drug excretion, together with the potential nephro- of the susceptibility of bacteria to antimicrobial having less potential for toxicity. The concurrent use of gentamicin with potent toxicity of aminoglycosides, should be considered compounds. One such standardized procedure agents, such as succinylcholine, tubocurarine GENTAMICIN diuretics, such as ethacrynic acid or furosemide, Specimens for bacterial culture should be or decamethonium, or in patients receiving when treating such patients who have urinary tract requires the use of standardized inoculum concen- obtained to isolate and identify causative organ- should be avoided, since certain diuretics by infections. trations and paper disks impregnated with 10 mcg massive transfusions of citrate-anticoagulated themselves may cause ototoxicity. In addition, isms and to determine their susceptibility to INJECTION, USP Probenecid does not affect renal tubular trans- of gentamicin.2,3 The disk diffusion values should blood. If neuromuscular blockade occurs, calcium when administered intravenously, diuretics may gentamicin. salts may reverse it. port of gentamicin. be interpreted according to the criteria provided Gentamicin injection may be considered as initial enhance aminoglycoside toxicity by altering the in Table 1. Aminoglycosides should be used with caution antibiotic concentration in serum and tissue. The endogenous creatinine clearance rate and therapy in suspected or confirmed gram-negative the serum creatinine level have a high correla- in patients with neuromuscular disorders, such Aminoglycosides can cause fetal harm when Table 1: Susceptibility Interpretive Criteria infections, and therapy may be instituted before as myasthenia gravis or parkinsonism, since these administered to a pregnant woman (see WARN- tion with the half-life of gentamicin in serum. Results obtaining results of susceptibility testing. The of these tests may serve as guides for adjusting for Gentamicin drugs may aggravate muscle weakness because INGS section). decision to continue therapy with this drug should of their potential curare-like effects on the neuro- dosage in patients with renal impairment (see Susceptibility Interpretive Criteria be based on the results of susceptibility tests, DOSAGE AND ADMINISTRATION). muscular junction. During or following gentamicin Minimal Inhibitory the severity of the infection and the important therapy, paresthesias, tetany, positive Chvostek DESCRIPTION: Following parenteral administration, gentamicin Concentration Zone Diameter additional concepts contained in the BOXED Gentamicin sulfate, a water-soluble antibiotic of can be detected in serum, lymph, tissues, spu- Pathogen (mcg/mL) (mm) and Trousseau signs and mental confusion have WARNINGS. If the causative organisms are resist- been described in patients with hypomagnesemia, the aminoglycoside group, is derived by the growth tum and in pleural, synovial and peritoneal fluids. (S) (I) (R) (S) (I) (R) ant to gentamicin, other appropriate therapy should hypocalcemia and hypokalemia. When this has of Micromonospora purpurea, an actinomycete. Concentrations in renal cortex sometimes may be instituted. a occurred in infants, tetany and muscle weakness It has the following structural formula. be eight times higher than the usual serum lev- Enterobacteriaceae ≤4 8 ≥16 ≥15 13 to 14 ≤12 In serious infections when the causative organ- els. Concentrations in bile, in general, have been has been described. Both adults and infants Pseudomonas isms are unknown, gentamicin injection may be required corrective electrolyte therapy. low and have suggested minimal biliary excre- aeruginosa ≤4 8 ≥16 ≥15 13 to 14 ≤12 administered as initial therapy in conjunction Elderly patients may have reduced renal func- To reduce the development of drug-resistant tion. Gentamicin crosses the peritoneal as well as Staphylococcus with a penicillin-type or cephalosporin-type drug bacteria and maintain the effectiveness of the placental membranes. Since aminoglycosides speciesb ≤4 8 ≥16 ≥15 13 to 14 ≤12 before obtaining results of susceptibility testing. tion which may not be evident in the results of Gentamicin Injection, USP and other antibacterial diffuse poorly into the subarachnoid space after If anaerobic organisms are suspected as etiologic routine screening tests such as BUN or serum S = Susceptible, I = Intermediate, R = Resistant creatinine. A creatinine clearance determination drugs, Gentamicin Injection, USP should be used parenteral administration, concentrations of agents, consideration should be given to using only to treat or prevent infections that are proven a For Salmonella and Shigella spp., aminoglycosides may be more useful. Monitoring of renal function gentamicin in cerebrospinal fluid are often low may appear active in vitro but are not effective clini- other suitable antimicrobial therapy in conjunc­ or strongly suspected to be caused by bacteria. and dependent upon dose, rate of penetration tion with gentamicin. Following identification of during treatment with gentamicin, as with other cally; the results should not be reported as susceptible aminoglycosides, is particularly important in such and degree of meningeal inflammation. There is b the organism and its susceptibility, appropriate For staphylococci that test susceptible, aminoglyco- patients. A Fanconi-like syndrome, with amino- minimal penetration of gentamicin into ocular sides are used only in combination with other active antibiotic therapy should then be continued. tissues following IM or IV administration. Gentamicin injection has been used effectively aciduria and metabolic acidosis has been reported agents that test susceptible in some adults and infants being given gentamicin Microbiology in combination with carbenicillin for the treat­­ Gentamicin injection is a sterile, nonpyrogenic A report of “Susceptible” indicates that the antimi- ment of life-threatening infections caused by injections. aqueous solution for parenteral administration. Mechanism of Action crobial is likely to inhibit growth of the pathogen if the Cross-allergenicity among aminoglycosides has Pseudomonas aeruginosa. It has also been Each mL contains: Gentamicin sulfate equiva- Gentamicin, an aminoglycoside, binds to the pro- antimicrobial compound reaches the concentration found effective when used in conjunction with a been demonstrated. lent to 40 mg gentamicin, methylparaben 1.8 mg karyotic ribosome, inhibiting protein synthesis in at the infection site necessary to inhibit growth of the penicillin-type drug for treatment of endocarditis Patients should be well hydrated during treatment. and propylparaben 0.2 mg as preservatives, sodium susceptible bacteria. It is bactericidal in vitro against pathogen. A report of “Intermediate” indicates that caused by group D streptococci. Although the in vitro mixing of gentamicin and metabisulfite 3.2 mg and edetate disodium Gram-positive and Gram-negative bacteria. the result should be considered equivocal, and if the Gentamicin injection has also been shown to carbenicillin results in a rapid and significant inac- 0.1 mg, Water for Injection q.s. Sodium hydroxide Drug Resistance microorganism is not fully susceptible to alternative be effective in the treatment of serious staphy- tivation of gentamicin, this interaction has not been and/or sulfuric acid may have been added for pH Bacterial resistance to gentamicin is generally clinically feasible drugs, the test should be repeated. lococcal infections. While not the antibiotic of first demonstrated in patients with normal renal func- Typesmiths Pi Font Pi Typesmiths adjustment. developed slowly. Bacteria resistant to one ami- This category implies possible clinical applicability choice, gentamicin injection may be considered tion who received both drugs by different routes (A)  Helvetica CrossTech–72869–Proof A1 CrossTech–72869–Proof M01 Form LLC USA, Kabi Fresenius 45855H No. 4500121296–Job No. P.O. 10/8/13–bw–O–Indd4 Fonts:

Reference ID: 3466754 5AV

of administration. A reduction in gentamicin serum PATIENTS WITH NORMAL recommended route of administration and dos- REFERENCES: half-life has been reported in patients with severe RENAL FUNCTION age schedule. 1. Clinical and Laboratory Standards Institute (CLSI). renal impairment receiving carbenicillin concom- Adults Methods for Dilution Antimicrobial Susceptibility itantly with gentamicin. The recommended dosage of gentamicin injec­tion PATIENTS WITH IMPAIRED Tests for Bacteria that Grow Aerobically; Approved Treatment with gentamicin may result in over- for patients with serious infections and normal RENAL FUNCTION Standard – Ninth Edition. CLSI document M07-A9, growth of nonsusceptible organisms. If this occurs, renal function is 3 mg/kg/day, administered in three Dosage must be adjusted in patients with impaired Clinical and Laboratory Standards Institute, 950 appropriate therapy is indicated. equal doses every eight hours (Table 3). renal function to assure therapeutically adequate, West Valley Road, Suite 2500, Wayne, Pennsyl- See BOXED WARNINGS regarding concurrent For patients with life-threatening infections, dos- but not excessive blood levels. Whenever possible vania 19087, USA, 2012. use of potent diuretics and regarding concurrent ages up to 5 mg/kg/day may be administered in serum concentration of gentamicin should be 2. Clinical and Laboratory Standards Institute (CLSI). and/or sequential use of other neurotoxic and/or three or four equal doses. This dosage should be monitored. One method of dosage adjustment is Performance Standards for Antimicrobial Disk for other essential information. reduced to 3 mg/kg/day as soon as clinically indi- to increase the interval between administration of Diffusion Susceptibility Tests; Approved Standard cated (Table 3). the usual doses. Since the serum creatinine con- – Eleventh Edition. CLSI document M02-A11, Clini- Information for Patients It is desirable to measure both peak and trough centration has a high correlation with the serum cal and Laboratory Standards Institute, 950 West Patients should be counseled that antibacterial serum concentrations of gentamicin to determine half-life of gentamicin, this laboratory test may Valley Road, Suite 2500, Wayne, Pennsylvania drugs including Gentamicin Injection, USP should the adequacy and safety of the dosage. When provide guidance for adjustment of the interval 19087, USA, 2012. only be used to treat bacterial infections. They do such measurements are feasible, they should be between doses. The interval between doses (in 3. Clinical and Laboratory Standards Institute (CLSI). not treat viral infections (e.g., the common cold). carried out periodically during therapy to assure hours) may be approximated by multiplying the Performance Standards for Antimicrobial Suscep- When Gentamicin Injection, USP is prescribed to adequate but not excessive drug levels. For exam- serum creatinine level (mg/100 mL) by 8. For tibility Testing; Twenty-third Informational Supple- treat a bacterial infection, patients should be told ple, the peak concentration (at 30 to 60 minutes example, a patient weighing 60 kg with a serum ment. CLSI document M100-S23, Clinical and that although it is common to feel better early in after IM injection) is expected to be in the range creatinine level of 2 mg/100 mL could be given Laboratory Standards Institute, 950 West Valley the course of therapy, the medication should of 4 to 6 mcg/mL. When monitoring peak con- 60 mg (1 mg/kg) every 16 hours (2 x 8). Road, Suite 2500, Wayne, Pennsylvania 19087, be taken exactly as directed. Skipping doses or centrations after IM or IV administration, dosage In patients with serious systemic infections and USA, 2013. not completing the full course of therapy may should be adjusted so that prolonged levels above renal impairment, it may be desirable to adminis- (1) decrease the effectiveness of the immediate 12 mcg/mL are avoided. When monitoring trough ter the antibiotic more frequently but in reduced treatment and (2) increase the likelihood that concentrations (just prior to the next dose), dos- dosage. In such patients, serum concentrations bacteria will develop resistance and will not be age should be adjusted so that levels above of gentamicin should be measured so that ade- treatable by Gentamicin Injection, USP or other 2 mcg/mL are avoided. Determination of the ade- quate but not excessive levels result. A peak and antibacterial drugs in the future. quacy of a serum level for a particular patient trough concentration measured intermittently dur- must take into consideration the susceptibility of ing therapy will provide optimal guidance for Pregnancy Category D the causative organism, the severity of the infec- adjusting dosage. After the usual initial dose, a See WARNINGS section. tion and the status of the patient’s host-defense rough guide for determining reduced dosage at mechanisms. eight-hour intervals is to divide the normally ADVERSE REACTIONS: In patients with extensive burns, altered phar- recommended dose by the serum creatinine level Nephrotoxicity macokinetics may result in reduced serum con- (Table 4). For example, after an initial dose of Adverse renal effects, as demonstrated by the centrations of aminoglycosides. In such patients 60 mg (1 mg/kg), a patient weighing 60 kg with a presence of casts, cells or protein in the urine or treated with gentamicin, measurement of serum serum creatinine level of 2 mg/100 mL could be by rising BUN, NPN, serum creatinine or oliguria, concentrations is recommended as a basis for given 30 mg every eight hours (6042). It should dosage adjustment. be noted that the status of renal function may be have been reported. They occur more frequently in patients with a history of renal impairment changing over the course of the infectious process. (especially if dialysis is required) and in patients TABLE 3 It is important to recognize that deteriorating treated for longer periods or with larger doses DOSAGE SCHEDULE GUIDE renal function may require a greater reduction in than recommended. FOR ADULTS WITH NORMAL dosage than that specified in the above guide- RENAL FUNCTION lines for patients with stable renal impairment. Neurotoxicity (Dosage at Eight-Hour Intervals) Serious adverse effects on both vestibular and 40 mg per mL TABLE 4 auditory branches of the eighth nerve have been DOSAGE ADJUSTMENT GUIDE Dose for m reported, primarily in patients with renal impair- Life-Threatening FOR PATIENTS WITH RENAL IMPAIRMENT ment (especially if hemodialysis is required) Usual Dose for Infections (Reduce (Dosage at Eight-Hour Intervals and in patients on high doses and/or prolonged Serious As Soon As After the Usual Initial Dose) therapy. Symptoms include dizziness, vertigo, tin- Patient’s Infections Clinically Indicated) nitus, roaring in the ears and also hearing loss, Weight * 1 mg/kg q8h 1.7 mg/kg q8h** Approximate which, as with the other aminoglycosides, may kg (lb) (3 mg/kg/day) (5 mg/kg/day) Serum Creatinine Percent of Creatinine Clearance Rate Usual Doses be irreversible. Hearing loss is usually manifested mg/dose mL/dose mg/dose mL/dose (mg %) (mL/min/1.73m2) Shown Above initially by diminution of high-tone acuity. Other q8h q8h factors which may increase the risk of toxicity 140 (188) 140 1.11 166 1.61 ≤ 1.0-1.1 >100 -111 100 include excessive dosage, dehydration and pre- 145 (199) 145 1.11 175 1.91 1.1 to 1.3 170 to 100 180 vious exposure to other ototoxic drugs. 150 (110) 150 1.25 183 2.11 1.4 to 1.6 155 to 701 165 Peripheral neuropathy or encephalopathy, includ- 155 (121) 155 1.41 191 2.25 1.7 to 1.9 1 45 to 551 155 160 (132) 160 1.51 100 2.51 2 to 2.2 1 40 to 451 150 ing numbness, skin tingling, muscle twitching, 2.3 to 2.5 1 35 to 401 140 convulsions and a myasthenia gravis-like syn- 165 (143) 165 1.61 108 2.71 170 (154) 170 1.75 116 2.91 2.6 to 3.0 130 to 351 135 drome have been reported. 3.1 to 3.5 1 25 to 301 130 NOTE: The risk of toxic reactions is low in patients 175 (165) 175 1.91 125 3.11 180 (176) 180 2.11 133 3.31 3.6 to 4.0 1 20 to 251 125 with normal renal function who did not receive 185 (187) 185 2.11 141 3.51 4.1 to 5.1 1 15 to 201 120 gentamicin sulfate at higher doses or for longer 190 (198) 190 2.25 150 3.75 5.2 to 6.6 110 to 151 115 periods of time than recommended. 195 (209) 195 2.41 158 4.11 6.7 to 8.0 <10-111 110 Other reported adverse reactions possibly related 100 (220) 100 2.51 166 4.21 to gentamicin include: respiratory depression, leth- In adults with renal failure undergoing hemodial- **The dosage of aminoglycosides in obese patients should ysis, the amount of gentamicin removed from the argy, confusion, depression, visual disturbances, be based on an estimate of the lean body mass. decreased appetite, weight loss and hypotension **for q6h schedules, dosage should be recalculated. blood may vary depending upon several factors and hypertension; rash, itching, urticaria, gener- including the dialysis method used. An eight-hour alized burning, laryngeal edema, anaphylactoid Children hemodialysis may reduce serum concentrations reactions, fever and headache; nausea, vomiting, 6 to 7.5 mg/kg/day (2 to 2.5 mg/kg administered of gentamicin by approximately 50%. The recom- increased salivation and stomatitis; purpura, every eight hours). mended dosage at the end of each dialysis period is 1 to 1.7 mg/kg depending upon the severity of pseudotumor cerebri, acute organic brain syn- Infants and Neonates drome, pulmonary fibrosis, alopecia, joint pain, the infection. In children, a dose of 2 mg/kg may 7.5 mg/kg/day (2.5 mg/kg administered every eight be administered. transient hepatomegaly and splenomegaly. hours). Laboratory abnormalities possibly related to The above dosage schedules are not intended Premature or Full-Term Neonates One Week of as rigid recommendations but are provided as gentamicin include: increased levels of serum trans- Age or Less aminase (SGOT, SGPT), serum LDH and biliru- guides to dosage when measurement of gentamicin 5 mg/kg/day (2.5 mg/kg administered every serum level is not feasible. bin; decreased serum calcium, magnesium, sodium 12 hours). and potassium; anemia, leukopenia, granulocy- A variety of methods are available to measure For further information concerning the use of gentamicin concentrations in body fluids; these topenia, transient agranulocytosis, eosinophilia, gentamicin in infants and children, see gentamicin increased and decreased reticulocyte counts and include microbiologic, enzymatic and radioim- injection (pediatric) product information. munoassay techniques. thrombocytopenia. While clinical laboratory test The usual duration of treatment for all patients abnormalities may be isolated findings, they may Parenteral drug products should be inspected is 7 to 10 days. In difficult and complicated infec- visually for particulate matter and discoloration also be associated with clinically related signs tions, a longer course of therapy may be neces- and symptoms. For example, tetany and muscle prior to administration, whenever solution and sary. In such cases monitoring of renal, auditory container permit. weakness may be associated with hypomagnese- and vestibular functions is recommended, since mia, hypocalcemia and hypokalemia. toxicity is more apt to occur with treatment extended HOW SUPPLIED: While the local tolerance of gentamicin sulfate for more than 10 days. Dosage should be reduced Gentamicin Injection, USP, containing gentamicin is generally excellent, there has been an occa- if clinically indicated. 40 mg/mL is supplied as follows: sional report of pain at the injection site. Subcu- taneous atrophy or fat necrosis suggesting local FOR INTRAVENOUS ADMINISTRATION Product NDC irritation has been reported rarely. The IV administration of gentamicin may be par- No. No. Strength ticularly useful for treating patients with bacterial 1002 63323-010-02 80 mg/2 mL 2 mL fill in a OVERDOSAGE: septicemia or those in shock. It may also be the (40 mg/mL) 2 mL flip-top vial, in pack- In the event of overdosage or toxic reactions, preferred route of administration for some patients hemodialysis may aid in the removal of gentamicin with congestive heart failure, hematologic disor- ages of 25. from the blood, especially if renal function is, or ders, severe burns or those with reduced muscle 1020 63323-010-20 800 mg/20 mL 20 mL fill in a becomes, compromised. The rate of removal of mass. For intermittent IV administration in adults, (40 mg/mL) 20 mL flip-top gentamicin is considerably lower by peritoneal a single dose of gentamicin injection may be vial, in pack- dialysis than it is by hemodialysis. diluted in 50 to 200 mL of sterile isotonic saline ages of 25. solution or in a sterile solution of dextrose 5% in Also available, Gentamicin Injection (Pediatric), DOSAGE AND ADMINISTRATION: water; in infants and children, the volume of dilu- 10 mg/mL, supplied in 2 mL (20 mg) vials in pack- Gentamicin injection may be given IM or IV. The ent should be less. The solution may be infused ages of 25. patient’s pretreatment body weight should be over a period of one-half to two hours. The recommended dosage for IM and IV admin- Fresenius Kabi USA, LLC obtained for calculation of correct dosage. The Store at 20° to 25°C (68° to 77°F) [see USP dosage of aminoglycosides in obese patients should istration is identical. Controlled Room Temperature]. Lake Zurich, IL 60047 be based on an estimate of the lean body mass. It Gentamicin injection should not be physically is desirable to limit the duration of treatment with premixed with other drugs, but should be This container closure is not made with natural 45855H Typesmiths Pi Font Pi Typesmiths aminoglycosides to short term. administered separately in accordance with the rubber latex. Revised: October 2013 (A)  Helvetica CrossTech–72869–Proof 1 CrossTech–72869–Proof M02 Form LLC USA, Kabi Fresenius 45855H No. 4500121296–Job No. P.O. 10/7/13–hc–O–Indd4 Fonts:

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CLINICAL PHARMACOLOGY: ­tissues following intramuscular or intravenous A report of “Susceptible” indicates that the antimi- aeruginosa. It has also been found effective when BOXED WARNINGS After intramuscular administration of gentamicin administration. crobial is likely to inhibit growth of the pathogen if the used in conjunction with a penicillin-type drug Patients treated with aminoglycosides should ­sulfate, peak serum concentrations usually occur Microbiology antimicrobial compound reaches the concentration for the treatment of endocarditis caused by group be under close clinical observation because of between 30 and 60 minutes and serum levels are Mechanism of Action at the infection site necessary to inhibit growth of the D streptococci. the potential toxicity associated with their use. measurable for 6 to 8 hours. In infants, a single Gentamicin, an aminoglycoside, binds to the pro- pathogen. A report of “Intermediate” indicates that Gentamicin Injection has also been shown to As with other aminoglycosides, Gentamicin dose of 2.5 mg/kg usually provides a peak serum karyotic ribosome, inhibiting protein synthesis in the result should be considered equivocal, and if the be effective in the treatment of serious staphylo- Injection is potentially nephrotoxic. The risk level in the range of 3 to 5 mcg/mL. When genta- susceptible bacteria. It is bactericidal in vitro against microorganism is not fully susceptible to alternative coccal infections. While not the antibiotic of first of nephrotoxicity is greater in patients with micin is administered by intravenous infusion over Gram-positive and Gram-negative bacteria. clinically feasible drugs, the test should be repeated. choice, gentamicin may be considered when impaired renal function and in those who a two-hour period, the serum concentrations This category implies possible clinical applicability ­penicillins or other less potentially toxic drugs are receive high dosage or prolonged therapy. are similar to those obtained by intramuscular Drug Resistance in body sites where the drug is physiologically con- ­contraindicated and bacterial susceptibility­ tests Neurotoxicity manifested by ototoxicity, both admin­istration. Age markedly affects the peak Bacterial resistance to gentamicin is generally centrated. This category also provides a buffer zone and clinical judgment indicate its use. It may also vestibular and auditory, can occur in patients concentrations: in one report, a 1 mg/kg dose pro- developed slowly. Bacteria resistant to one ami- that prevents small uncontrolled technical factors be considered in mixed infections caused by treated with gentamicin, primarily in those duced mean peak concentrations of 1.58, 2.03, and noglycoside may be resistant to one or more other from causing major discrepancies in interpretation. A ­susceptible strains of staphylococci and gram- with pre-existing renal damage and in patients 2.81 mcg/mL in patients six months to five years old, aminoglycosides. The following bacteria are usu- report of “Resistant” indicates that the antimicrobial negative organisms. with normal renal function treated with higher 5 to 10 years old, and over 10 years old, respectively. ally resistant to the aminoglycosides, including is not likely to inhibit growth of the pathogen if the In the neonate with suspected bacterial sepsis or doses and/or for longer periods than recom- In infants one week to six months of age, the gentamicin: most streptococcal species (includ- antimicrobial compound reaches the concentrations staphylococcal pneumonia, a penicillin-type drug 1 ing Streptococcus pneumoniae and the Group D mended. Aminoglycoside-induced ototoxicity half-life is 3 to 3 ⁄2 hours. In full-term and large usually achievable at the infection site; other therapy is also usually indicated as concomitant ther­apy is usually irreversible. Other manifestations ­premature infants less than one week old, the streptococci), most enterococcal species (including should be selected. with gentamicin. 1 Enterococcus faecalis, E. faecium, and E. durans), of neurotoxicity may include numbness, skin approximate serum half-life of gentamicin is 5 ⁄2 Quality Control tingling, muscle twitching and convulsions. hours. In small premature infants, the half-life is and anaerobic organisms, such as Bacteroides CONTRAINDICATIONS: species and Clostridium species. Standardized susceptibility test procedures require Hypersensitivity to gentamicin is a contraindication Renal and eighth cranial nerve function inversely related to birth weight. In premature the use of laboratory controls to monitor and ensure should be closely monitored, especially in infants weighing less than 1,500 grams, the half- Aminoglycosides are known to be not effective to its use. A history of hypersensitivity or serious 1 against Salmonella and Shigella species in patients. the accuracy and precision of supplies and toxic reactions to other aminoglycosides may con­ patients with known or suspected reduced life is 11 ⁄2 hours; in those weighing 1,500 to 2,000 Therefore, in vitro susceptibility test results should reagents used in the assay, and the techniques of traindicate use of gentamicin because of the renal function at onset of therapy, and also in grams, the half-life is eight hours; in those weigh- the individuals performing the test.1,2,3 Standard those whose renal function is initially normal ing over 2,000 grams, the half-life is approximately not be reported. known cross-sensitivity of patients to drugs in this gentamicin powder should provide the following class. but who develop signs of renal dysfunction five hours. While some variation is to be expected Interactions with Other Antimicrobials range of MIC values provided in Table 2. For the dif- ­during therapy. Urine should be examined for due to a number of variables such as age, body In vitro studies show that an aminoglycoside com- fusion technique using the 10-mcg gentamicin disk WARNINGS: decreased specific gravity, increased excre- ­temperature, surface area and physiologic differ- bined with an antibiotic that interferes with cell wall the criteria provided in Table 2 should be achieved. (See BOXED WARNINGS.) tion of protein, and the presence of cells or ences, the individual patient given the same dose synthesis may act synergistically against some Aminoglycosides can cause fetal harm when casts. Blood urea nitrogen (BUN), serum cre­ tends to have similar levels in repeated determi- enterococcal strains. The combination of gentamicin Table 2: Acceptable Quality Control Ranges administered to a pregnant woman. Aminoglyco- atinine, or creatinine clearance should be nations. and penicillin G has a synergistic bactericidal effect for Susceptibility Testing side antibiotics cross the placenta, and there have determined periodically. When feasible, it is Gentamicin, like all aminoglycosides, may accu­- against strains of Enterococcus faecalis, E. faecium been several reports of total irreversible bilateral ­recommended that serial audiograms be ob- mulate in the serum and tissues of patients treated and E. durans. An enhanced killing effect against Minimum Inhibitory congenital deafness in ­children whose mothers tained in patients old enough to be tested, with higher doses and/or for prolonged periods, many of these strains has also been shown in vitro Concentrations Zone Diameter received streptomycin during pregnancy. Serious particularly high-risk patients. Evidence of ­particularly in the presence of impaired or imma- with combinations of gentamicin and ampicillin, Quality Control Organism (mcg/mL) (mm) side effects to mother, fetus, or newborn have not ototoxicity (dizziness, vertigo, tinnitus, roar- ture renal function. In patients with immature or carbenicillin, nafcillin or oxacillin. been reported in the treatment of pregnant women Escherichia coli ing in the ears or hearing loss) or nephrotox- impaired renal function, gentamicin is cleared The combined effect of gentamicin and carbenicil- ATCC 25922 0.25 to 1 19 to 26 with other aminoglycosides. Animal reproduction icity requires dosage adjustment or discon- from the body more slowly than in patients with lin is synergistic for many strains of Pseudomonas studies conducted on rats and rabbits did not tinuance of the drug. As with the other amino- ­normal renal function. The more severe the impair­ aeruginosa. In vitro synergism against other Gram- Pseudomonas aeruginosa reveal evidence of impaired fertility or harm to the glycosides, on rare occasions changes in renal ment, the slower the clearance. (Dosage must be negative organisms has been shown with combina- ATCC 27853 0.5 to 2 16 to 21 fetus due to ­gentamicin sulfate. and eighth cranial nerve function may not adjusted.) tions of gentamicin and cephalosporins. Staphylococcus aureus It is not known whether gentamicin sulfate can become manifest until soon after completion Since gentamicin is distributed in extracellular Gentamicin may be active against clinical isolates ATCC 25923 Not Applicable 19 to 27 cause fetal harm when administered to a preg- of therapy. of bacteria resistant to other aminoglycosides. fluid, peak serum concentrations may be lower Staphylococcus aureus nant woman or can affect reproduction capacity. Serum concentrations of aminoglycosides than usual in patients who have a large volume Antibacterial Activity ATCC 29213 0.12 to 1 Not Applicable If gentamicin is used during pregnancy or if the should be monitored when feasible to assure of this fluid. Serum concentrations of genta- Gentamicin has been shown to be active against patient becomes pregnant while taking genta- m adequate levels and to avoid potentially toxic micin in febrile patients may be lower than those Enterococcus faecalis most of the following bacteria, both in vitro and ATCC 29212 4 to 16 Not Applicable micin, she should be apprised of the potential levels. When monitoring gentamicin peak con- in afebrile patients given the same dose. When body in clinical infections (see INDICATIONS AND hazard to the fetus. centrations, dosage should be adjusted so that temperature returns to normal, serum con- USAGE). Note: For control organisms for gentamicin high-level Preserved Gentamicin Injection contains prolonged levels above 12 mcg/mL are avoided. centrations of the drug may rise. Febrile and ane­ aminoglycoside screen tests for enterococci, see Table sodium metabisulfite, a sulfite that may cause When monitoring gentamicin trough con- Gram-Positive Bacteria 2D Supplemental Table 1 in CLSI document M100-S233 mic states may be associated with a shorter than Staphylococcus species allergic-type reactions including anaphylactic centrations, dosage should be adjusted so that usual serum half-life. (Dosage adjustment is usu- INDICATIONS AND USAGE: symptoms and life-threatening or less severe asth­ levels above 2 mcg/mL are avoided. Exces- ally not necessary.) In severely burned patients, Gram-Negative Bacteria To reduce the development of drug-resistant matic episodes in certain susceptible people. The sive peak and/or trough serum concentra- the half-life may be significantly decreased and Citrobacter species ­bacteria and maintain the effectiveness of Gentamicin overall prevalence of sulfite sensitivity in the gen- tions of aminoglycosides may increase the resulting serum concentrations may be lower than Enterobacter species Injection, USP and other antibacterial drugs, eral population is unknown and probably low. Sul­- risk of renal and eighth cranial nerve toxicity. anticipated from the mg/kg dose. Escherichia coli Gentamicin Injection, USP should be used only fite sensitivity is seen more frequently in asthmatic In the event of overdose or toxic reactions, Protein-binding studies have indicated that the Klebsiella species to treat or prevent infections that are proven or than in nonasthmatic people. hemodialysis may aid in the removal of gen- degree of gentamicin binding is low, depending Proteus species strongly suspected to be caused by susceptible tamicin from the blood, especially if renal func- Serratia species PRECAUTIONS: upon the methods used for testing, this may be bacteria. When culture and susceptibility infor­ General tion is, or becomes, compromised. The rate between 0 and 30%. Pseudomonas aeruginosa mation are available, they should be considered of removal of gentamicin is considerably less Prescribing Gentamicin Injection in the absence In neonates less than three days old, approx- Susceptibility Test Methods in selecting or modifying antibacterial therapy. In of a proven or strongly suspected bacterial infec- by peritoneal dialysis than by hemodialysis. imately 10% of the administered dose is excreted When available, the clinical microbiology labora- the absence of such data, local epidemiology In the newborn infant, exchange transfu- tion or a prophylactic indication is unlikely to pro- in 12 hours; in infants 5 to 40 days old, approxi- tory should provide cumulative results of the in vitro and susceptibility patterns may contribute to the vide benefit to the patient and increases the risk of sions may also be considered. mately 40% is excreted over the same period. susceptibility tests for antimicrobial drugs used in empiric selection of therapy. Concurrent and/or sequential systemic or the development of drug-resistant bacteria. Excretion of gentamicin correlates with postnatal local hospitals and practice areas to the physician Gentamicin Injection is indicated in the treat- Neurotoxic and nephrotoxic antibiotics may be topical use of other potentially neurotoxic age and creatinine clearance. Thus, with increas­ as periodic reports that describe the susceptibility ment of serious infections caused by susceptible and/or nephrotoxic drugs, such as cisplatin, almost completely absorbed from body surfaces ing postnatal age and concomitant increase in profile of nosocomial and community-acquired strains of the following microorganisms: (except the urinary bladder) after local irrigation cephaloridine, kanamycin, amikacin, neomy­ renal maturity, gentamicin is excreted more rap- pathogens. These reports should aid the physician Pseudomonas aeruginosa, Proteus species cin, polymyxin B, colistin, paromomycin, strep- and after topical application during surgical pro- idly. Little, if any, metabolic transformation occurs; in selecting the most effective antimicrobial. (indole-positive and indole-negative), Escherichia cedures. The potential toxic effects of antibiotics tomycin, tobramycin, vancomycin, and vio- the drug is excreted principally by glomerular coli, Klebsiella-Enterobacter-Serratia species, ­­­mycin, should be avoided. Other factors Dilution Technique administered in this fashion (neuromuscular block- filtration. After several days of treatment, the Quantitative methods are used to determine anti- Citrobacter species, and Staphylococcus species ade, respiratory paralysis, oto- and nephrotoxicity) which may increase patient risk of toxicity are amount of gentamicin excreted in the urine 45814J/Revised: October 2013 microbial minimal inhibitory concentrations (MICs). (coagulase-positive and coagulase-negative). should be considered (see BOXED WARNINGS). advanced age and dehydration. approaches, but does not equal, the daily dose Clinical studies have shown Gentamicin Injec- The concurrent use of gentamicin with These MICs provide estimates of the susceptibility Increased nephrotoxicity has been reported fol­ administered. As with other aminoglycosides, a of bacteria to antimicrobial compounds. The MICs tion to be effective in bacterial neonatal sepsis; lowing concomitant administration of aminogly- potent diuretics, such as ethacrynic acid or small amount of the gentamicin dose may be ­bacterial septicemia; and serious bacterial infec- furosemide, should be avoided, since certain should be determined using a standardized test coside antibiotics and cephalosporins. retained in the tissues, especially in the kidneys. 1,3 tions of the central nervous system (meningitis), GENTAMICIN diuretics by themselves may cause ototoxicity. method. Standardized procedures are based Neuromuscular blockade and respiratory paral­- Minute quantities of aminoglycosides have been on a dilution method (broth or agar) or equivalent ­urinary tract, respiratory tract, gastrointestinal ysis have been reported in the cat receiving high In addition, when administered intravenously, detected in the urine of some patients weeks after tract (including peritonitis), skin, bone and soft INJECTION, USP (Pediatric) diuretics may enhance aminoglycoside tox- with standardized inoculum concentrations and doses (40 mg/kg) of gentamicin. The possibility drug administration was discontinued. Renal clear- standardized concentrations of gentamicin powder. ­tissue (including burns). Aminoglycosides, includ- of these phenomena occurring in man should be icity by altering the antibiotic concentration in ance of gentamicin is similar to that of endogenous ing gentamicin, are not indicated in uncompli- serum and tissue. The MIC values should be interpreted according to considered if aminoglycosides are administered creatinine. the criteria provided in Table 1. cated initial episodes of urinary tract infec­tions by any route to patients receiving anesthetics, or Aminoglycosides can cause fetal harm In patients with marked impairment of renal func­ unless the causative organisms are suscep­tible when administered to a pregnant woman Diffusion Technique to patients receiving neuromuscular blocking tion, there is a decrease in the concentration of to these antibiotics and are not susceptible to agents, such as succinylcholine, tubocurarine or (see WARNINGS section). aminoglycosides in urine and in their penetration Quantitative methods that require measurement of antibiotics having less potential for toxicity. zone diameters also provide reproducible estimates decamethonium, or in patients receiving massive into defective renal parenchyma. This decreased Specimens for bacterial culture should be ob- transfusions of citrate-anticoagulated blood. If neu- drug excretion, together with the potential nephro- of the susceptibility of bacteria to antimicrobial tained to isolate and identify causative organisms DESCRIPTION: compounds. One such standardized procedure romuscular blockade occurs, calcium salts may Gentamicin sulfate, a water-soluble antibiotic of toxicity of aminoglycosides, should be considered and to determine their susceptibility to gentamicin. reverse it. when treating such patients who have urinary tract requires the use of standardized inoculum concen- Gentamicin may be considered as initial ther- the aminoglycoside group, is derived from trations and paper disks impregnated with 10 mcg Aminoglycosides should be used with caution infections. apy in suspected or confirmed gram-negative in patients with neuromuscular disorders, such Micro­monospora purpurea, an actinomycete. of gentamicin.2,3 The disk diffusion values should It has the following structural formula: Probenecid does not affect renal tubular trans- infections, and therapy may be instituted before as myasthenia gravis, since these drugs may aggra­ port of gentamicin. be interpreted according to the criteria provided obtaining results of susceptibility testing. The deci- vate muscle weakness because of their potential The endogenous creatinine clearance rate and in Table 1. sion to continue therapy with this drug should be curare-like effects on the neuromuscular junction. the serum creatinine level have a high correla- Table 1: Susceptibility Interpretive Criteria based on the results of susceptibility tests, the During or following gentamicin therapy, paresthe- To reduce the development of drug-resistant bac- tion with the half-life of gentamicin in serum. for Gentamicin severity of the infection, and the important addi- sias, tetany, positive Chvostek and Trousseau signs, teria and maintain the effectiveness of Gentamicin Results of these tests may serve as guides for Susceptibility Interpretive Criteria tional concepts contained in the BOXED WARN- and mental confusion have been described in Injection, USP and other antibacterial drugs, adjusting dosage in patients with renal impairment Minimal Inhibitory INGS above. If the causative organisms are resis- patients with hypomagnesemia, hypocalcemia, (see DOSAGE AND ADMINISTRATION). ­Gentamicin Injection, USP should be used only to Concentration Zone Diameter tant to gentamicin, other appropriate therapy and hypokalemia. When this has occurred in treat or prevent infections that are proven or strongly Following parenteral administration, gentamicin Pathogen (mcg/mL) (mm) should be instituted. infants, tetany and muscle weakness have been suspected to be caused by bacteria. can be detected in serum, lymph, tissues, spu- (S) (I) (R) (S) (I) (R) In serious infections when the causative organ­ described. Both adults and infants required appro­ tum, and in pleural, synovial, and peritoneal fluids. isms are unknown, gentamicin may be adminis- priate corrective electrolyte therapy. Concentrations in renal cortex sometimes may Enterobacteriaceaea ≤4 8 ≥16 ≥15 13 to 14 ≤12 tered as initial therapy in conjunction with a A Fanconi-like syndrome, with amino-aciduria be eight times higher than the usual serum lev- Pseudomonas penicillin-type or cephalosporin type drug before and metabolic acidosis, has been reported in some els. Concentrations in bile, in general, have been aeruginosa ≤4 8 ≥16 ≥15 13 to 14 ≤12 obtaining results of susceptibility testing. If anaer- adults and infants being given gentamicin Gentamicin Injection is a sterile, nonpyro- low and have suggested minimal biliary excre- Staphylococcus obic organisms are suspected as etiologic agents, injections. tion. Gentamicin crosses the peritoneal as well as speciesb ≤4 8 ≥16 ≥15 13 to 14 ≤12 genic, aqueous solution for parenteral admin- consideration should be given to using other suit- Cross-allergenicity among aminoglycosides has istration and is available both with and without­ the placental membranes. Since aminoglycosides S = Susceptible, I = Intermediate, R = Resistant able antimicrobial therapy in conjunction with been demonstrated. ­preservatives. diffuse poorly into the subarachnoid space after a For Salmonella and Shigella spp., aminoglycosides gentamicin. Following identification of the organ- Patients should be well hydrated during treat- Each mL of the preservative free product con- ­parenteral administration, concentrations of may appear active in vitro but are not effective clini- ism and its susceptibility, appropriate antibiotic ment. tains: Gentamicin sulfate, equivalent to gentamicin gentamicin in cerebrospinal fluid are often low cally; the results should not be reported as susceptible therapy should then be continued. Although the in vitro mixing of gentamicin and 10 mg; Water for Injection q. s. Sulfuric acid and/or and dependent upon dose, rate of penetration, b For staphylococci that test susceptible, aminoglyco- Gentamicin has been used effectively in com- ­carbenicillin results in a rapid and significant inac- and degree of meningeal inflammation. There is Typesmiths Pi Font Pi Typesmiths sodium hydroxide may have been added for pH sides are used only in combination with other active bination with carbenicillin for the treatment of life- tivation of gentamicin, this interaction has not been (A)  Helvetica adjustment (3 to 5.5). minimal penetration of gentamicin into ocular agents that test susceptible threatening infections caused by Pseudomonas demonstrated in patients with normal renal func- CrossTech–72868–Proof A1 CrossTech–72868–Proof M01 Form LLC USA, Kabi Fresenius 45814J No. 4500121296–Job P.O. 10/8/13–bw–O–Indd4 Fonts:

Reference ID: 3466754 5AV

tion who received both drugs by different routes mate of the lean body mass. It is desirable to TABLE 3 of administration. A reduction in gentamicin serum limit the duration of treatment with aminogly- DOSAGE ADJUSTMENT GUIDE half-life has been reported in patients with severe cosides to short term. FOR PATIENTS WITH RENAL IMPAIRMENT renal impairment receiving carbenicillin con- DOSAGE FOR PATIENTS (Dosage at Eight-Hour Intervals comitantly with gentamicin. After the Usual Initial Dose) Treatment with gentamicin may result in over- WITH NORMAL RENAL FUNCTION

growth of nonsusceptible organisms. If this occurs, Children: 6 to 7.5 mg/kg/day. (2 to 2.5 mg/kg Approximate appropriate therapy is indicated. administered every 8 hours.) Serum Creatinine Percent of Do not administer unless solution is clear and Creatinine Clearance Rate Usual Doses Infants and Neonates: 7.5 mg/kg/day. (2.5 mg/kg 2 package undamaged. administered every 8 hours.) (mg %) (mL/min/1.73m ) Shown Above See BOXED WARNINGS regarding concur- ≤ 1.0-1.1 >100-111 100 rent use of potent diuretics and regarding con- Premature or Full-term Neonates One Week of 1.1 to 1.3 170 to 100 180 current and/or sequential use of other neurotoxic Age or Less: 5 mg/kg/day. (2.5 mg/kg administered 1.4 to 1.6 155 to 701 165 and/or nephrotoxic antibiotics and for other every 12 hours.) 1.7 to 1.9 1 45 to 551 155 essential information. It is desirable to measure periodically both peak 2 to 2.2 1 40 to 451 150 Information for Patients and trough serum concentrations of gentamicin 2.3 to 2.5 1 35 to 401 140 Patients should be counseled that antibacterial when feasible during therapy to assure adequate 2.6 to 3.0 130 to 351 135 drugs including Gentamicin Injection should but not excessive drug levels. For example, the 3.1 to 3.5 1 25 to 301 130 peak concentration (at 30 to 60 minutes after intra- 3.6 to 4.0 1 20 to 251 125 only be used to treat bacterial infections. They 4.1 to 5.1 1 15 to 201 120 do not treat viral infections (e.g., the common muscular injection) is expected to be in the range of 3 to 5 mcg/mL. When monitoring peak con- 5.2 to 6.6 110 to 151 115 cold). When Gentamicin Injection is prescribed 6.7 to 8.0 <10-111 110 to treat a bacterial infection, patients should be centrations after intramuscular or intravenous told that although it is common to feel better administration, dosage should be adjusted so that prolonged levels above 12 mcg/mL are avoided. In patients with renal failure undergoing hemo- early in the course of therapy, the medication dialysis, the amount of gentamicin removed from should be taken exactly as directed. Skipping When monitoring trough concentrations (just prior to the next dose), dosage should be adjusted so the blood may vary depending upon several fac- doses or not completing the full course of ther- tors including the dialysis method used. An eight- apy may (1) decrease the effectiveness of the that levels above 2 mcg/mL are avoided. Deter- mination of the adequacy of a serum level for a hour hemodialysis may reduce serum concen- immediate treatment and (2) increase the likeli- trations of gentamicin by approximately 50%. In hood that bacteria will develop resistance and ­particular patient must take into consideration the susceptibility of the causative organism, the sever- ­children, the recommended dose at the end of will not be treatable by Gentamicin Injection or each dialysis period is 2 to 2.5 mg/kg depending other antibacterial drugs in the future. ity of the infection, and the status of the patient’s host-defense mechanisms. upon the severity of the infection. Pregnancy Category D In patients with extensive burns, altered The above dosage schedules are not intended See WARNINGS section. pharmacokinetics may result in reduced serum as rigid recommendations but are provided as ADVERSE REACTIONS: concentrations of aminoglycosides. In such guides to dosage when the measurement of Nephrotoxicity patients treated with gentamicin, measurement gentamicin serum levels is not feasible. Adverse renal effects, as demonstrated by the of serum concentrations is recommended as a A variety of methods are available to measure presence of casts, cells, or protein in the urine or basis for dosage adjustment. gentamicin concentrations in body fluids; these by rising BUN, NPN, serum creatinine or oliguria, The usual duration of treatment is 7 to 10 days. include microbiologic, enzymatic and radio- have been reported. They occur more frequently In difficult and complicated infections, a longer immunoassay techniques. in patients treated for longer periods or with larger course of therapy may be necessary. In such cases Parenteral drug products should be inspected dosages than recommended. monitoring of renal, auditory, and vestibular func- visually for particulate matter and discoloration tions is recommended, since toxicity is more apt prior to administration, whenever solution and con- Neurotoxicity tainer permit. Serious adverse effects on both vestibular and to occur with treatment extended for more than auditory branches of the eighth nerve have been 10 days. Dosage should be reduced if clinically HOW SUPPLIED: indicated. Gentamicin Injection, USP (Preservative Free) is

reported, primarily in patients with renal impair- m ment (especially if dialysis is required), and in For Intravenous Administration supplied as: patients on high doses and/or prolonged therapy. The intravenous administration of gentamicin may Product NDC Symptoms include dizziness, vertigo, tinnitus, roar- be particularly useful for treating patients with No. No. Strength ing in the ears and hearing loss, which, as with ­bacterial septicemia or those in shock. It may also 17302 63323-173-02 20 mg/2 mL 2 mL fill in a other aminoglycosides, may be irreversible. Hear­ing be the preferred route of administration for some (10 mg/mL) 2 mL single loss is usually manifested initially by diminu- patients with congestive heart failure, hemato- dose vial, tion of high-tone acuity. Other factors which may logic disorders, severe burns, or those with packaged increase the risk of toxicity include excessive reduced muscle mass. in 25. dosage, dehydration and previous exposure to For intermittent intravenous administration, a other ototoxic drugs. single dose of Gentamicin Injection may be Store at 20° to 25°C (68° to 77°F) [see USP Controlled Peripheral neuropathy or encephalopathy, diluted in 0.9% Sodium Chloride Injection or in Room Temperature]. including numbness, skin tingling, muscle twitch- 5% Dextrose Injection. The solution may be ing, convulsions and a myasthenia gravis-like This container closure is not made with natural infused over a period of one-half to two hours. rubber latex. ­syndrome, have been reported. The recommended dosage for intravenous and Note: The risk of toxic reactions is low in neo- intramuscular administration is identical. REFERENCES: nates, infants and children with normal renal func­­- Gentamicin Injection should not be physically tion who do not receive Gentamicin Injection at 1. Clinical and Laboratory Standards Institute (CLSI). premixed with other drugs, but should be admin- Methods for Dilution Antimicrobial Susceptibility higher doses or for longer periods of time than istered separately in accordance with the recom- recommended. Tests for Bacteria that Grow Aerobically; Approved mended route of administration and dos­age Standard – Ninth Edition. CLSI document M07-A9, Other reported adverse reactions possibly schedule. related to gentamicin include: respiratory depres­ Clinical and Laboratory Standards Institute, 950 sion, lethargy, confusion, depression, visual dis- DOSAGE FOR PATIENTS West Valley Road, Suite 2500, Wayne, Pennsyl- turbances, decreased appetite, weight loss, hypo- WITH IMPAIRED RENAL FUNCTION vania 19087, USA, 2012. tension and hypertension; rash, itching, urticaria, Dosage must be adjusted in patients with impaired 2. Clinical and Laboratory Standards Institute (CLSI). generalized burning, laryngeal edema, anaphylac­- renal function to assure therapeutically adequate Performance Standards for Antimicrobial Disk toid reactions, fever and headache; nausea, vomit- but not excessive, blood levels. Whenever possi- Diffusion Susceptibility Tests; Approved Standard ing, increased salivation and stomatitis; purpura, ble, serum concentrations of gentamicin should – Eleventh Edition. CLSI document M02-A11, Clini- pseudotumor cerebri, acute organic brain syn- be monitored. One method of dosage adjustment cal and Laboratory Standards Institute, 950 West drome, pulmonary fibrosis, alopecia, joint pain, is to increase the interval between administration Valley Road, Suite 2500, Wayne, Pennsylvania ­transient hepatomegaly and splenomegaly. of the usual doses. Since the serum creatinine 19087, USA, 2012. Laboratory abnormalities possibly related to concentration has a high correlation with the 3. Clinical and Laboratory Standards Institute (CLSI). gentamicin include: increased levels of serum serum half-life of gentamicin, this laboratory test Performance Standards for Antimicrobial Suscep- transaminase (SGOT, SGPT), serum LDH and bili­ may provide guidance for adjustment of the inter­ tibility Testing; Twenty-third Informational Supple- rubin, decreased serum calcium, magnesium, val between doses. In adults, the interval between ment. CLSI document M100-S23, Clinical and sodium and potassium; anemia, leukopenia, doses (in hours) may be approximated by multi- Laboratory Standards Institute, 950 West Valley granulocytopenia, transient agranulocytosis, eosin­ plying the serum creatinine level (mg/100 mL) by Road, Suite 2500, Wayne, Pennsylvania 19087, ophilia, increased and decreased reticulocyte 8. For example, a patient weighing 60 kg with a USA, 2013. counts and thrombocytopenia. While clinical lab- serum creatinine level of 2 mg/100 mL could be oratory test abnormalities may be isolated find- given 60 mg (1 mg/kg) every 16 hours (2 x 8). ings, they may also be associated with clinically These guidelines may be considered when related signs and symptoms. For example, tetany treating infants and children with serious renal and muscle weakness may be associated with impairment.­ hypomagnesemia, hypocalcemia, and hypoka- In patients with serious systemic infections and lemia. renal impairment, it may be desirable to adminis- While local tolerance of Gentamicin Injection ter the antibiotic more frequently but in reduced is generally excellent, there has been an occa- dosage. In such patients, serum concentrations sional report of pain at the injection site. Subcu­ of gentamicin should be measured so that ade- taneous atrophy or fat necrosis suggesting local quate but not excessive levels result. irritation has been reported rarely. A peak and trough concentration measured OVERDOSAGE: intermittently during therapy will provide optimal In the event of overdose or toxic reactions, hemo- guidance for adjusting dosage. After the usual dialysis may aid in the removal of gentamicin from ­initial dose, a rough guide for determining reduced the blood, and is especially important if renal func- dosage at eight-hour intervals is to divide the nor­ tion is, or becomes, compromised. The rate of mally recommended dose by the serum creati- removal of gentamicin is considerably less by peri­ nine level (Table 3). For example, after an initial toneal dialysis than it is by hemodialysis. In the dose of 20 mg (2 mg/kg), a child weighing 10 kg ­newborn infant, exchange transfusions may also with a serum creatinine level of 2 mg/100 mL be considered. could be given 10 mg every eight hours (20 4 2). It

should be noted that the status of renal function DOSAGE AND ADMINISTRATION: may be changing over the course of the infec- Gentamicin Injection may be given intramuscu- tious process. It is important to recognize that Fresenius Kabi USA, LLC

larly or intravenously. The patient’s pretreatment deteriorating renal function may require a greater Lake Zurich, IL 60047 body weight should be obtained for calculation­ of reduction in dosage than that specified in the ­correct dosage. The dosage of aminoglycosides above guidelines for patients with stable renal 45814J Typesmiths Pi Font Pi Typesmiths in obese patients should be based on an esti- impairment. Revised: October 2013 (A)  Helvetica

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Reference ID: 3466754