gentamicin 100 MG/ML Injectable Solution [Garasol]

INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of Gentamicin Sulfate in 0.9% Sodium Chloride Injection and other antibacterial drugs, Gentamicin Sulfate in 0.9% Sodium Chloride Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Gentamicin Sulfate in 0.9% Sodium Chloride Injection is indicated in the treatment of serious infections caused by susceptible strains of the following microorganisms: Pseudomonas aeruginosa , Proteus species (indole-positive and indole-negative), Escherichia coli , Klebsiella-Enterobacter- Serratia species, Citrobacter species, and Staphylococcus species (coagulase-positive and coagulase-negative). Clinical studies have shown gentamicin sulfate to be effective in bacterial neonatal sepsis; bacterial septicemia; and serious bacterial infections of the central nervous system (meningitis), urinary tract, respiratory tract, gastrointestinal tract (including peritonitis), skin, bone and soft tissue (including burns). Aminoglycosides, including gentamicin, are not indicated in uncomplicated initial episodes of urinary tract infections unless the causative organisms are susceptible to these antibiotics and are not susceptible to antibiotics having less potential for toxicity. Specimens for bacterial culture should be obtained to isolate and identify causative organisms and to determine their susceptibility to gentamicin. Gentamicin Sulfate in 0.9% Sodium Chloride Injection may be considered as initial therapy in suspected or confirmed gram-negative infections, and therapy may be instituted before obtaining results of susceptibility testing. The decision to continue therapy with this drug should be based on the results of susceptibility tests, the severity of the infection, and the important additional concepts contained in the boxed WARNINGS . If the causative organisms are resistant to gentamicin, other appropriate therapy should be instituted. In serious infections when the causative organisms are unknown, Gentamicin Sulfate in 0.9% Sodium Chloride Injection may be administered as initial therapy in conjunction with a penicillin-type or cephalosporin-type drug before obtaining results of susceptibility testing. If anaerobic organisms are suspected as etiologic agents, consideration should be given to using other suitable antimicrobial therapy in conjunction with gentamicin. Following identification of the organism and its susceptibility, appropriate antibiotic therapy should then be continued. Gentamicin injection has been used effectively in combination with carbenicillin for the treatment of life-threatening infections caused by Pseudomonas aeruginosa . It has also been found effective when used in conjunction with a penicillin-type drug for the treatment of endocarditis caused by group D streptococci. Gentamicin injection has also been shown to be effective in the treatment of serious staphylococcal infections. While not the antibiotic of first choice, gentamicin may be considered when penicillins or other less potentially toxic drugs are contraindicated and bacterial susceptibility tests and clinical judgement indicate its use. It may also be considered in mixed infections caused by susceptible strains of staphylococci and gram-negative organisms. In the neonate with suspected bacterial sepsis or staphylococcal pneumonia, a penicillin-type drug is also usually indicated as concomitant therapy with gentamicin (see PRECAUTIONS, Pediatric Use and DOSAGE AND ADMINISTRATION sections).

DOSAGE AND ADMINISTRATION Gentamicin Sulfate in 0.9% Sodium Chloride Injection is for intravenous use only . The patient’s pretreatment body weight should be obtained for calculation of correct dosage. The dosage of aminoglycosides in obese patients should be based on an estimate of the lean body mass. It is desirable to limit the duration of treatment with aminoglycosides to short term. Patients with Normal Renal Function Adults: The recommended dosage of Gentamicin Sulfate in 0.9% Sodium Chloride Injection for patients with serious infections and normal renal function is 3 mg/kg/day administered in three equal doses every eight hours (Table 3). For patients with life-threatening infections, dosages up to 5 mg/kg/day may be administered in three or four equal doses. The dosage should be reduced to 3 mg/kg/day as soon as clinically indicated (Table 3). It is desirable to measure both peak and trough serum concentrations of gentamicin to determine the adequacy and safety of the dosage. When such measurements are feasible, they should be carried out periodically during therapy to assure adequate but not excessive drug levels. For example, the peak concentration (at 30 to 60 minutes following cessation of infusion) is expected to be in the range of 4 to 6 mcg/mL. When monitoring peak concentrations, dosage should be adjusted so that prolonged levels above 12 mcg/mL are avoided. When monitoring trough concentrations (just prior to the next dose), dosage should be adjusted so that levels above 2 mcg/mL are avoided. Determination of the adequacy of a serum level for a particular patient must take into consideration the susceptibility of the causative organism, the severity of the infection, and the status of the patient’s host-defense mechanisms. In patients with extensive burns, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides. In such patients treated with gentamicin, measurement of serum concentrations is recommended as a basis for dosage adjustment. Table 3: Dosage Schedule Guide for Adults With Normal Renal Function (Dosage at Eight-Hour Intervals) Patient’s Weight The dosage of aminoglycosides in obese patients should be based on an estimate of the lean body mass. Usual Dose for Serious Infections 1 mg/kg q8h (3 mg/kg/day) Dose for Life-Threatening Infections (Reduce as Soon as Clinically Indicated) 1.7 mg/kg q8h For q6h schedules, dosage should be recalculated. (5 mg/kg/day) kg (lb) mg/dose q8h mg/dose q8h 40 ( 88) 40 66 45 ( 99) 45 75 50 (110) 50 83 55 (121) 55 91 60 (132) 60 100 65 (143) 65 108 70 (154) 70 116 75 (165) 75 125 80 (176) 80 133 85 (187) 85 141 90 (198) 90 150 95 (209) 95 158 100 (220) 100 166 Children : 6 to 7.5 mg/kg/day (2 to 2.5 mg/kg administered every eight hours). Infants and Neonates : 7.5 mg/kg/day (2.5 mg/kg administered every eight hours). Premature or Full-Term Neonates One Week of Age or Less : 5 mg/kg/day (2.5 mg/kg administered every 12 hours). NOTE: For further information concerning the use of gentamicin in infants and children, see Pediatric Gentamicin Sulfate Injection product information. The usual duration of treatment for all patients is seven to ten days. In difficult and complicated infections, a longer course of therapy may be necessary. In such cases monitoring of renal, auditory, and vestibular functions is recommended, since toxicity is more apt to occur with treatment extended for more than ten days. Dosage should be reduced if clinically indicated. For Intravenous Administration The intravenous administration of gentamicin may be particularly useful for treating patients with bacterial septicemia or those in shock. It may also be the preferred route of administration for some patients with congestive heart failure, hematologic disorders, severe burns, or those with reduced muscle mass. For intermittent intravenous administration in adults, a single dose of Gentamicin Sulfate in 0.9% Sodium Chloride Injection may be administered according to individual patient requirements from the appropriate premixed container. The solution may be infused over a period of one-half to two hours. Gentamicin Sulfate Injection should not be physically premixed with other drugs, but should be administered separately in accordance with the recommended route of administration and dosage schedule. Patients with Impaired Renal Function Dosage must be adjusted in patients with impaired renal function to assure therapeutically adequate, but not excessive blood levels. Whenever possible, serum concentrations of gentamicin should be monitored. One method of dosage adjustment is to increase the interval between administration of the usual doses. Since the serum creatinine concentration has a high correlation with the serum half-life of gentamicin, this laboratory test may provide guidance for adjustment of the interval between doses. The interval between doses (in hours) may be approximated by multiplying the serum creatinine level (mg/100 mL) by 8. For example, a patient weighing 60 kg with a serum creatinine level of 2 mg/100 mL could be given 60 mg (1 mg/kg) every 16 hours (2 x 8). In patients with serious systemic infections and renal impairment, it may be desirable to administer the antibiotic more frequently but in reduced dosage. In such patients, serum concentrations of gentamicin should be measured so that adequate, but not excessive levels result. A peak and trough concentration measured intermittently during therapy will provide optimal guidance for adjusting dosage. After the usual initial dose, a rough guide for determining reduced dosage at eight-hour intervals is to divide the normally recommended dose by the serum creatinine level (Table 4). For example, after an initial dose of 60 mg (1 mg/kg), a patient weighing 60 kg with a serum creatinine level of 2 mg/100 mL could be given 30 mg every eight hours (60 ÷ 2). It should be noted that the status of renal function may be changing over the course of the infectious process. It is important to recognize that deteriorating renal function may require a greater reduction of dosage than that specified in the above guidelines for patients with stable renal impairment. This container system may be inappropriate for the dosage requirements of children, infants, and neonates. Other dosage forms may be more appropriate. Table 4: Dosage Adjustment Guide For Patients With Renal Impairment (Dosage at Eight-Hour Intervals After the Usual Initial Dose) Serum Creatinine (mg %) Approximate Creatinine Clearance (mL/min/1.73 m 2 Percent of Usual Doses Shown in Table 3 ≤1 >100 100 1.1 - 1.3 70 - 100 80 1.4 - 1.6 55 - 70 65 1.7 - 1.9 45 - 55 55 2 - 2.2 40 - 45 50 2.3 - 2.5 35 - 40 40 2.6 - 3 30 - 35 35 3.1 - 3.5 25 - 30 30 3.6 - 4 20 - 25 25 4.1 - 5.1 15 - 20 20 5.2 - 6.6 10 - 15 15 6.7 - 8 <10 10 In adults with renal failure undergoing hemodialysis, the amount of gentamicin removed from the blood may vary depending upon several factors including the dialysis method used. An eight hour hemodialysis may reduce serum concentrations of gentamicin by approximately 50%. The recommended dosage at the end of each dialysis period is 1 to 1.7 mg/kg depending upon the severity of infection. In children, a dose of 2 mg/kg may be administered. The above dosage schedules are not intended as rigid recommendations but are provided as guides to dosage when the measurement of gentamicin serum levels is not feasible. A variety of methods are available to measure gentamicin concentrations in body fluids; these include microbiologic, enzymatic and radioimmunoassay techniques. Gentamicin Sulfate in 0.9% Sodium Chloride Injection is a ready-to-use isotonic solution. No dilution or buffering is required. If the prescribed dose is exactly 60, 80, or 100 mg use the appropriate container. If the prescribed dose is higher or lower than that of the supplied container adjustments can be made. If the dose is higher than the contents of a 100 mg container the additional amount shoul

WARNINGS: (See BOXED WARNINGS .) Preserved Gentamicin Injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. Aminoglycosides can cause fetal harm when administered to a pregnant woman. Aminoglycoside antibiotics cross the placenta, and there have been several reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Serious side effects to mother, fetus, or newborn have not been reported in the treatment of pregnant women with other aminoglycosides. Animal reproduction studies conducted on rats and rabbits did not reveal evidence of impaired fertility or harm to the fetus due to gentamicin sulfate. It is not known whether gentamicin sulfate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. If gentamicin is used during pregnancy or if the patient becomes pregnant while taking gentamicin, she should be apprised of the potential hazard to the fetus. Risk of Ototoxicity Due to Mitochondrial DNA Variants Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene ( MT-RNR1 ), particularly the m.1555A>G variant. Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. Mitochondrial DNA variants are present in less than 1% of the general US population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

CONTRAINDICATIONS: Hypersensitivity to gentamicin is a contraindication to its use. A history of hypersensitivity or serious toxic reactions to other aminoglycosides may contraindicate use of gentamicin because of the known cross-sensitivity of patients to drugs in this class.

CLINICAL PHARMACOLOGY: After intramuscular (IM) administration of gentamicin sulfate, peak serum concentrations usually occur between 30 and 60 minutes and serum levels are measurable for six to eight hours. When gentamicin is administered by intravenous (IV) infusion over a two-hour period, the serum concentrations are similar to those obtained by IM administration. In patients with normal renal function, peak serum concentrations of gentamicin (mcg/mL) are usually up to four times the single IM dose (mg/kg); for example, a 1 mg/kg injection in adults may be expected to result in a peak serum concentration up to 4 mcg/mL; a 1.5 mg/kg dose may produce levels up to 6 mcg/mL. While some variation is to be expected due to a number of variables such as age, body temperature, surface area and physiologic differences, the individual patient given the same dose tends to have similar levels in repeated determinations. Gentamicin administered at 1 mg/kg every eight hours for the usual 7 to 10 day treatment period to patients with normal renal function does not accumulate in the serum. Gentamicin, like all aminoglycosides, may accumulate in the serum and tissues of patients treated with higher doses and/or for prolonged periods, particularly in the presence of impaired renal function. In adult patients, treatment with gentamicin dosages of 4 mg/kg/day or higher for 7 to 10 days may result in a slight, progressive rise in both peak and trough concentrations. In patients with impaired renal function, gentamicin is cleared from the body more slowly than in patients with normal renal function. The more severe the impairment, the slower the clearance. (Dosage must be adjusted.) Since gentamicin is distributed in extra-cellular fluid, peak serum concentrations may be lower than usual in adult patients who have a large volume of this fluid. Serum concentrations of gentamicin in febrile patients may be lower than those in afebrile patients given the same dose. When body temperature returns to normal, serum concentrations of the drug may rise. Febrile and anemic states may be associated with a shorter than usual serum half-life. (Dosage adjustment is usually not necessary.) In severely burned patients, the half-life may be significantly decreased and resulting serum concentrations may be lower than anticipated from the mg/kg dose. Protein binding studies have indicated that the degree of gentamicin binding is low; depending upon the methods used for testing, this may be between 0 and 30%. After initial administration to patients with normal renal function, generally 70% or more of the gentamicin dose is recoverable in the urine in 24 hours; concentrations in urine above 100 mcg/mL may be achieved. Little, if any, metabolic transformation occurs; the drug is excreted principally by glomerular filtration. After several days of treatment, the amount of gentamicin excreted in the urine approaches the daily dose administered. As with other aminoglycosides, a small amount of the gentamicin dose may be retained in the tissues, especially in the kidneys. Minute quantities of aminoglycosides have been detected in the urine weeks after drug administration was discontinued. Renal clearance of gentamicin is similar to that of endogenous creatinine. In patients with marked impairment of renal function, there is a decrease in the concentration of aminoglycosides in urine and in their penetration into defective renal parenchyma. This decreased drug excretion, together with the potential nephrotoxicity of aminoglycosides, should be considered when treating such patients who have urinary tract infections. Probenecid does not affect renal tubular transport of gentamicin. The endogenous creatinine clearance rate and the serum creatinine level have a high correlation with the half-life of gentamicin in serum. Results of these tests may serve as guides for adjusting dosage in patients with renal impairment (see DOSAGE AND ADMINISTRATION ). Following parenteral administration, gentamicin can be detected in serum, lymph, tissues, sputum and in pleural, synovial and peritoneal fluids. Concentrations in renal cortex sometimes may be eight times higher than the usual serum levels. Concentrations in bile, in general, have been low and have suggested minimal biliary excretion. Gentamicin crosses the peritoneal as well as the placental membranes. Since aminoglycosides diffuse poorly into the subarachnoid space after parenteral administration, concentrations of gentamicin in cerebrospinal fluid are often low and dependent upon dose, rate of penetration and degree of meningeal inflammation. There is minimal penetration of gentamicin into ocular tissues following IM or IV administration. Microbiology Mechanism of Action Gentamicin, an aminoglycoside, binds to the prokaryotic ribosome, inhibiting protein synthesis in susceptible bacteria. It is bactericidal in vitro against Gram-positive and Gram-negative bacteria. Mechanism of Resistance Bacterial resistance to gentamicin is generally developed slowly. Bacteria resistant to one aminoglycoside may be resistant to one or more other aminoglycosides. The following bacteria are usually resistant to the aminoglycosides, including gentamicin: most streptococcal species (including Streptococcus pneumoniae and the Group D streptococci), most enterococcal species (including Enterococcus faecalis , E. faecium , and E. durans ), and anaerobic organisms, such as Bacteroides species and Clostridium species. Aminoglycosides are known to be not effective against Salmonella and Shigella species in patients. Therefore, in vitro susceptibility test results should not be reported. Interactions with Other Antimicrobials In vitro studies show that an aminoglycoside combined with an antibiotic that interferes with cell wall synthesis may act synergistically against some enterococcal strains. The combination of gentamicin and penicillin G has a synergistic bactericidal effect against strains of Enterococcus faecalis , E. faecium and E. durans . An enhanced killing effect against many of these strains has also been shown in vitro with combinations of gentamicin and ampicillin, carbenicillin, nafcillin or oxacillin. The combined effect of gentamicin and carbenicillin is synergistic for many strains of Pseudomonas aeruginosa . In vitro synergism against other Gram-negative organisms has been shown with combinations of gentamicin and cephalosporins. Gentamicin may be active against clinical isolates of bacteria resistant to other aminoglycosides. Antibacterial Activity Gentamicin has been shown to be active against most of the following bacteria, both in vitro and in clinical infections (see INDICATIONS AND USAGE ). Gram-Positive Bacteria Staphylococcus species Gram-Negative Bacteria Citrobacter species Enterobacter species Escherichia coli Klebsiella species Proteus species Serratia species Pseudomonas aeruginosa Susceptibility Test Methods When available, the clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility tests for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antimicrobial drug for treatment. Dilution Technique Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method. 1, 3 Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of gentamicin powder. The MIC values should be interpreted according to the criteria provided in Table 1. Diffusion Technique Quantitative methods that require measurement of zone diameters also provide reproduc