Tobramycin

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Nephrotoxicity [see Boxed Warning and Warnings and Precautions ( 5.1 )] Ototoxicity [see Boxed Warning and Warnings and Precautions ( 5.2 )] Embryo-Fetal Toxicity [see Boxed Warning and Warnings and Precautions ( 5.3 )] Allergic Reactions [see Warnings and Precautions ( 5.4 )] Neuromuscular Blockade [see Warnings and Precautions ( 5.5 )] The following adverse reactions associated with the use of Tobramycin for Injection were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: anemia, granulocytopenia, leukopenia, leukocytosis, eosinophilia and thrombocytopenia Ear and Labyrinth Disorders: Tinnitus, hearing loss, vertigo Gastrointestinal Disorders: nausea, vomiting, diarrhea General Disorders and Administration Site Conditions: fever, lethargy, pain at the injection site Immune system disorders: Anaphylaxis, hypersensitivity reactions Laboratory Investigations: elevated blood urea nitrogen, elevated serum creatinine, hyponatremia, hypokalemia, hypomagnesemia, hypocalcemia, hypophosphatemia, urinary casts, increased serum transaminases (AST, ALT); increased serum LDH and bilirubin Nervous System Disorders: headache, numbness, paresthesia, muscle twitching, convulsions, mental confusion, and disorientation Skin and Subcutaneous Tissue Disorders: rash, itching, urticaria Most common adverse reactions are ototoxicity and nephrotoxicity. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

4 CONTRAINDICATIONS Tobramycin for Injection is contraindicated in patients with a history of hypersensitivity to tobramycin or any other aminoglycoside [see Warnings and Precautions ( 5.4 )] . A history of hypersensitivity or serious toxic reactions to any aminoglycoside ( 4 ).

11 DESCRIPTION Tobramycin sulfate, a water-soluble aminoglycoside antibacterial, drug derived from the actinomycete Streptomyces tenebrarius. Tobramycin for Injection, USP is supplied as a sterile powder in a pharmacy bulk package vial for intravenous use. It is intended for reconstitution with 30 mL of Sterile Water for Injection, USP. Each vial contains tobramycin sulfate equivalent to 1.2 g of tobramycin. After reconstitution, the solution will contain 40 mg of tobramycin per mL. The product contains no preservative or sodium bisulfite. Tobramycin sulfate is O -3-amino-3-deoxy-α-D-glucopyranosyl-(1→4)- O -[2,6-diamino-2,3,6-trideoxy-α-D- ribo -hexopyranosyl-(1→6)]-2-deoxy-L-streptamine, sulfate (2:5)(salt) and has the molecular formula (C 18 H 37 N 5 O 9 ) 2 •5H 2 SO 4 . The molecular weight is 1425.42 g/mol. The molecular weight of the free base is 467.51 g/mol. The structural formula of tobramycin, free base, is as follows: Figure 2: Tobramycin Structure Figure 2: Tobramycin Structure

2 DOSAGE AND ADMINISTRATION PHARMACY BULK PACKAGE-Not for Direct Infusion: Dispense single doses to many patients in a pharmacy admixture program. Pharmacy bulk package vial must be reconstituted and diluted prior to intravenous administration ( 2.1 , 2.8 ) Recommended adult dosages are as follows: Serious Infections: Administer 3 mg/kg/day in 3 equal doses (i.e.1 mg/kg every 8 hours) Life-threatening Infections: Administer up to 5 mg/kg in 3 or 4 equal doses See full prescribing information for the recommended dosage for pediatric patients ( 2.3 ), patients with cystic fibrosis ( 2.5 ), patients with renal impairment ( 2.6 ), and obese patients ( 2.7 ). 2.1 Important Preparation and Administration Instructions Pharmacy Bulk Package-Not for Direct Infusion Tobramycin for Injection Pharmacy Bulk Package is intended for dispensing of single doses to many patients in a hospital pharmacy admixture service. It should only be prepared in an aseptic work area, such as a laminar flow hood. Tobramycin for Injection Pharmacy Bulk Package vial must be reconstituted and diluted prior to intravenous administration [see Dosage and Administration ( 2.8 )] . After reconstitution, the closure may be penetrated only one time using a suitable sterile transfer device or dispensing set, which allows measured dispensing of the contents. Use of a syringe and needle is not recommended as it may cause leakage. After penetration, the entire contents of the bulk vial must be dispensed within 24 hours. Do not administer Tobramycin for Injection as a direct, undiluted intravenous injection. 2.2 Dosage for Adult Patients with Normal Renal Function Tobramycin for Injection may be given intramuscularly or intravenously. Recommended dosages are the same for both routes. The recommended dosage is as follows: Adult Patients Adults with Serious Infections 3 mg/kg/day administered in 3 equal doses of 1 mg/kg every 8 hours. Adults with Life-Threatening Infections Up to 5 mg/kg/day may be administered in 3 or 4 equal doses (see Table 1 ). The dosage should be reduced to 3 mg/kg/day as soon as clinically indicated. To prevent increased toxicity due to excessive serum concentrations, dosage should not exceed 5 mg/kg/day unless serum concentrations are monitored [see Boxed Warning , Warnings and Precautions ( 5.2 )]. Table 1 DOSAGE SCHEDULE GUIDE FOR ADULTS WITH NORMAL RENAL FUNCTION (Dosage at 8-Hour Intervals) For Patient Weighing kg lb Usual Dose for Serious Infections 1 mg/kg Every 8 hours (h) (Total, 3 mg/kg/day) mg/dose mL/dose* q8h 120 264 120 mg 3 mL 115 253 115 mg 2.9 mL 110 242 110 mg 2.75 mL 105 231 105 mg 2.6 mL 100 220 100 mg 2.5 mL 95 209 95 mg 2.4 mL 90 198 90 mg 2.25 mL 85 187 85 mg 2.1 mL 80 176 80 mg 2 mL 75 165 75 mg 1.9 mL 70 154 70 mg 1.75 mL 65 143 65 mg 1.6 mL 60 132 60 mg 1.5 mL 55 121 55 mg 1.4 mL 50 110 50 mg 1.25 mL 45 99 45 mg 1.1 mL 40 88 40 mg 1 mL *Applicable to all product forms except the Tobramycin Injection, USP, (Pediatric). For Patient Weighing kg lb Maximum Dose for Life- Threatening Infections (Reduce as soon as possible) 1.66 mg/kg Every 8 hours (Total, 5 mg/kg/day) mg/dose mL/dose* Every 8h 120 264 200 mg 5 mL 115 253 191 mg 4.75 mL 110 242 183 mg 4.5 mL 105 231 175 mg 4.4 mL 100 220 166 mg 4.2 mL 95 209 158 mg 4 mL 90 198 150 mg 3.75 mL 85 187 141 mg 3.5 mL 80 176 133 mg 3.3 mL 75 165 125 mg 3.1 mL 70 154 116 mg 2.9 mL 65 143 108 mg 2.7 mL 60 132 100 mg 2.5 mL 55 121 91 mg 2.25 mL 50 110 83 mg 2.1 mL 45 99 75 mg 1.9 mL 40 88 66 mg 1.6 mL 2.3 Dosage for Pediatric Patients Pediatric Patients (Greater than 1 Week of Age): 6 to 7.5 mg/kg/day administered in 3 or 4 equally divided doses (2 to 2.5 mg/kg every 8 hours or 1.5 to 1.9 mg/kg every 6 hours). Premature or Full Term Neonates (1 Week of Age or Less): Up to 4 mg/kg/day may be administered in 2 equal doses every 12 hours. 2.4 Duration of Treatment for Adult and Pediatric Patients The usual duration of treatment for adult and pediatric patients is 7 to10 days. A longer course of therapy may be necessary in complicated infections. In such cases, monitoring of renal, auditory, and vestibular functions is advised, because neurotoxicity is more likely to occur when treatment is extended longer than 10 days. 2.5 Dosage in Patients with Cystic Fibrosis or Burns In patients with cystic fibrosis, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides. An initial dosing regimen of 10 mg/kg/day in 4 equally divided doses is suggested as a guide. The serum concentrations of tobramycin should be monitored during treatment due to wide inter-patient variability. Similarly, altered pharmacokinetics may result in reduced serum concentrations in patients with extensive burns. Monitoring tobramycin serum concentration in these patients is especially important as a basis for determination of appropriate dosage [see Dosage and Administration ( 2.9 ] . 2.6 Dosage for Patients with Renal Impairment Following a loading dose of 1 mg/kg, subsequent dosage in these patients must be adjusted, either with reduced doses administered at 8-hour intervals or with normal doses given at prolonged intervals. Both of these methods are suggested as guides and dose should be adjusted based on serum concentration. The dosage adjustment for patients with renal impairment are based on either the creatinine clearance level or the serum creatinine level of the patient because these values correlate with the half-life of tobramycin. The dosage schedule derived from either method should be used in conjunction with careful clinical and laboratory observations of the patient and serum tobramycin concentration monitoring and should be modified as necessary. Neither method should be used when dialysis is being performed. Reduced dosage at 8-hour intervals When the creatinine clearance rate is less than or equal to 70 mL per minute or when the serum creatinine value is known, the amount of the reduced dose can be determined by multiplying the normal dose in adult patients from Table 1 by the percent of the normal dosage from the accompanying nomogram in Figure 1 below. Figure 1: NOMOGRAM Figure 1 Normal dosage at prolonged intervals If the creatinine clearance rate is not available and the patient's condition is stable, a dosage frequency in hours for the recommended adult dose can be determined by multiplying the patient's serum creatinine by 6. 2.7 Dosage in Obese Patients The appropriate dose may be calculated by using the patient's estimated lean body weight plus 40% of the excess as the weight on which to determine the dose in mg/kg. 2.8 Instructions for Preparation and Intravenous Administration Tobramycin is supplied as a dry powder in a pharmacy bulk package vial that contains the equivalent of 1.2 g of tobramycin. The contents of the vial must be reconstituted and diluted prior to intravenous administration as follows: Reconstitute the contents of the pharmacy bulk package vial aseptically with 30 mL of Sterile Water for Injection, USP to provide a reconstituted solution containing 40 mg of tobramycin per mL. Dilute the reconstituted pharmacy bulk vial prior to intravenous administration by adding a specified volume of the reconstituted solution to 50 to 100 mL (for adult doses) of diluent (0.9% Sodium Chloride Injection or 5% Dextrose Injection) for each patient. For pediatric patients, the volume of diluent should be proportionately less than for adults. After penetration, entire contents of pharmacy bulk vial should be dispensed within 24 hours. Visually inspect for particulate matter and discoloration prior to administration The diluted solution should be intravenously infused over a period of 20 to 60 minutes. Intravenous infusion periods of less than 20 minutes are not recommended because peak serum concentrations may exceed 12 mcg/mL [see Dosage and Administration ( 2.9 )]. 2.9 Measurement of Serum Concentrations of Tobramycin Measure peak and trough serum tobramycin concentrations periodically during therapy to assure adequate concentrations and to avoid potentially toxic concentrations in all patients, especially in patients with renal impairment [see Dosage and Administration ( 2.6 )] . Avoid peak serum concentrations above 12 mcg/mL. Rising trough concentrations (above 2 mcg/mL) may indicate tissue accumulation. Such accumulation may result in ototoxicity and nephrotoxicity [Warnings and Precautions ( 5.1 , 5.2 ] . A useful guideline is to measure serum concentrations after 2 or 3 doses, so that the dosage could be adjusted if necessary, and at 3- to 4-day intervals during therapy. In the event of changing renal function, obtain more frequent serum tobramycin concentrations and adjust the dosage or dosage interval according to the guidelines provided [see Dosage and Administration ( 2.6 )]. In order to measure the peak concentration, a serum sample should be drawn about 30 minutes following intravenous infusion or 1 hour after an intramuscular injection. Trough concentrations are measured by obtaining serum samples at 8 hours or just prior to the next dose of tobramycin. These suggested time intervals are intended only as guidelines and may vary according to institutional practices. It is important, however, that there be consistency within the individual patient program unless computerized pharmacokinetic dosing programs are available in the institution. These serum-concentration assays may be especially useful for monitoring the treatment of severely ill patients with changing renal function or of those infected with less susceptible organisms or those receiving maximum dosage. 2.10 Drug Incompatibilities Tobramycin should not be physically premixed with other drugs but should be administered separately according to the recommended dose and route.

1 INDICATIONS AND USAGE Tobramycin for Injection, is an aminoglycoside antibacterial indicated for the treatment of serious bacterial infections caused by susceptible isolates of the designated bacteria in the diseases listed below: Tobramycin for Injection, is an aminoglycoside antibacterial indicated for the treatment of serious bacterial infections caused by susceptible isolates of the designated bacteria in the diseases listed below: Septicemia in the pediatric patient and adults caused by P. aeruginosa , E. coli , and Klebsiella species (spp). Lower respiratory tract infections caused by P. aeruginosa, Klebsiella spp, Enterobacter spp, Serratia spp, E. coli, and S. aureus Serious central nervous system infections (meningitis) caused by susceptible organisms. Intra-abdominal infections, including peritonitis, caused by E. coli, Klebsiella spp., and Enterobacter spp. Skin, bone, and skin structure infections caused by P. aeruginosa, Proteus spp, E. coli, Klebsiella spp., Enterobacter spp., and S. aureus. Complicated urinary tract infections caused by P. aeruginosa , Proteus spp., (indole-positive and indole-negative), E. coli , Klebsiella spp., Enterobacter spp., Serratia spp., S. aureus , Providencia spp., and Citrobacter spp. To reduce the development of drug-resistant bacteria and maintain the effectiveness of Tobramycin for Injection and other antibacterial drugs, Tobramycin for Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria ( 1.2 ). 1.1 Septicemia Tobramycin for Injection is indicated for the treatment of septicemia caused by susceptible isolates of P. aeruginosa, E. coli, and Klebsiella spp., in adult and pediatric patients. 1.2 Lower Respiratory Tract Infections Tobramycin for Injection is indicated for the treatment of lower respiratory tract infections caused by susceptible isolates of P. aeruginosa, Klebsiella spp., Enterobacter spp., Serratia spp., E. coli, and S. aureus in adult and pediatric patients. 1.3 Central Nervous System Infections (Meningitis) Tobramycin for Injection is indicated for the treatment of bacterial meningitis caused by susceptible bacteria in adult and pediatric patients. 1.4 Intra-abdominal Infections Tobramycin for Injection is indicated for the treatment of intra-abdominal infections, including peritonitis, caused by susceptible isolates of E. coli, Klebsiella spp., and Enterobacter spp. in adult and pediatric patients. 1.5 Skin and Skin Structure Infections Tobramycin for Injection is indicated for the treatment of skin and skin structure infections caused by susceptible isolates of P. aeruginosa, Proteus spp., E. coli, Klebsiella spp., Enterobacter spp., and S. aureus in adult and pediatric patients. 1.6 Bone Infections Tobramycin for Injection is indicated for the treatment of bone infections caused by susceptible isolates of P. aeruginosa, Proteus spp., E. coli, Klebsiella spp., Enterobacter spp., and S. aureus in adult and pediatric patients 1.7 Complicated and Recurrent Urinary Tract Infections Tobramycin for Injection is indicated for the treatment of complicated urinary tract infections caused by susceptible isolates of P. aeruginosa, Proteus spp., (indole-positive and indole-negative), E. coli, Klebsiella spp., Enterobacter spp., Serratia spp., S. aureus, Providencia spp., and Citrobacter spp. in adult and pediatric patients 1.8 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Tobramycin for Injection and other antibacterial drugs, Tobramycin for 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.

10 OVERDOSAGE 10.1 Signs and Symptoms Acute overdosage with Tobramycin for Injection can result in more severe manifestations of the types of toxicities known to occur with recommended doses, e.g., renal damage, ototoxicity, neuromuscular blockade. The severity of the signs and symptoms following a tobramycin overdose are dependent on the dose administered, the patient's renal function, state of hydration, age and whether or not other medications with similar toxicities are being administered concurrently. [see Warnings and Precautions ( 5.1 , 5.2 , 5.5 )] for signs and symptoms related to neurotoxicity, nephrotoxicity and neuromuscular blockade; and Adverse Reactions ( 6 )]. If tobramycin were ingested, toxicity would be less likely because aminoglycosides are minimally absorbed from an intact gastrointestinal tract. 10.2 Treatment In all cases of suspected overdosage, call your Regional Poison Control Center or the National Poison Control center at 1-800-222-1222 or www.poison.org to obtain the most up-to-date information about the treatment of overdose. This recommendation is made because, in general, information regarding the treatment of overdosage may change more rapidly than the package insert. Management of tobramycin overdosage is symptomatic and supportive. Maintain airway, provide adequate hydration and monitor renal function, serum electrolytes, and tobramycin concentrations until the serum tobramycin level falls below 2 mcg/mL. Tobramycin is removed by hemodialysis.

7 DRUG INTERACTIONS 7.1 Drugs with Nephrotoxic or Ototoxic Potential Avoid concurrent and/or sequential use of Tobramycin for Injection with other drugs with nephrotoxic and/or ototoxic potential. 7.2 Diuretics Some diuretics can enhance aminoglycoside toxicity by altering concentrations in serum and tissue and causing dehydration. Monitor serum concentrations, renal function, serum electrolytes, sodium, magnesium, calcium and phosphate, urine output and urinalysis, and signs of auditory or vestibular toxicity in patients concomitantly administered diuretics. 7.3 Drugs with Neuromuscular Blockade or Neurotoxic Potential Prolonged respiratory paralysis may occur in patients concomitantly receiving neuromuscular blocking agents with Tobramycin for Injection [see Boxed Warning , Warnings and Precautions ( 5.5 )] . If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts but mechanical assistance may be necessary. In addition, avoid concurrent and/or sequential use of Tobramycin for Injection with other neurotoxic drugs.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tobramycin sulfate is an aminoglycoside antibacterial drug [see Microbiology ( 12.4 )]. 12.3 Pharmacokinetics In patients with normal renal function, except neonates, tobramycin administered every 8 hours does not accumulate in serum. The serum elimination half-life in patients with normal renal function is 2 hours. However, in patients with renal impairment and in neonates, serum concentrations of the antibacterial are usually higher and can be measured for longer periods of time than in adults with normal renal function. Thus, the dosage of tobramycin for patients with renal impairment and neonates must be adjusted accordingly [see Dosage and Administration ( 2.3 , 2.6 )]. Absorption Following intramuscular administration, peak serum concentrations of tobramycin occur between 30 and 90 minutes. Following an intramuscular dose of 1 mg/kg of body weight, maximum serum concentrations reach about 4 mcg/mL, and measurable concentrations persist for as long as 8 hours. Therapeutic serum concentrations are generally considered to range from 4 to 6 mcg/mL. When tobramycin is administered by intravenous infusion over a 1-hour period, the serum concentrations are similar to those obtained by intramuscular administration. Tobramycin is poorly absorbed from the gastrointestinal tract. Distribution Based on ultrafiltration studies, practically no serum protein binding of tobramycin occurs. Tobramycin can be detected in tissues and body fluids after parenteral administration. Concentrations of tobramycin in bile and stools ordinarily have been low, which suggests minimal biliary excretion. The concentration of tobramycin in cerebrospinal fluid following parenteral administration is low, and concentrations are dependent on dose, rate of penetration, and degree of meningeal inflammation. Tobramycin has also been detected in sputum, peritoneal fluid, synovial fluid, and abscess fluids, and it crosses the placental membranes. Concentrations in the renal cortex are several times higher than serum concentrations. Metabolism Following parenteral administration, minimal, metabolic transformation occurs, and tobramycin is eliminated almost exclusively by glomerular filtration. Excretion Peak urine concentrations ranging from 75 to 100 mcg/mL have been observed following the intramuscular injection of a single dose of 1 mg/kg. After several days of treatment, the amount of tobramycin excreted in the urine approaches the daily dose administered. Renal clearance is similar to that of endogenous creatinine. In patients with normal renal function, up to 84% of the dose is recoverable from the urine in 8 hours and up to 93% in 24 hours. When renal function is impaired, excretion of tobramycin is slowed, and accumulation of the drug may cause toxic blood concentrations. Drug Interactions Probenecid does not affect the renal tubular transport of tobramycin. 12.4 Microbiology Mechanism of Action Tobramycin is an aminoglycoside that inhibits protein synthesis by binding irreversibly to the aminoacyl site (A) of the 16S RNA within the bacterial 30S ribosomal subunit. Tobramycin enters the bacterial cell by an aerobic energy-dependent mechanism to penetrate the bacterial inner cell membrane. The effect of this action is two fold (i) it makes the ribosome unavailable for translation into mRNA and (ii) it causes the production of nonsense proteins because of misreading of the genetic code. Tobramycin is bactericidal to susceptible bacteria. Resistance Resistance to tobramycin can occur by any of the following known mechanisms. The most common mechanism of resistance and the one that generates the greatest level of resistance, results from the structural modification of the antibiotic by specific methyltransferase enzymes expressed in resistant organisms. This modification prevents the antibiotic from binding to its target site on the ribosome. A second mechanism of resistance is associated with drug concentration in the bacterial cell. Tobramycin is a hydrophilic antibiotic and its efficacy is concentration – dependent. The action by some bacteria results in a decrease in permeability of the cell membrane and leads to a decrease in the uptake of the drug by the bacteria. The third known mechanism of resistance is caused by mutations in the 16S rRNA of the 30S subunit of the ribosome which prevents the binding of the antibiotic to the target site and stops the bactericidal activity. The fourth mechanism is efflux of the antibiotic from the bacterial cell. Interaction with Other Antibacterial Drugs In vitro studies have shown that an aminoglycoside combined with an antibacterial that interferes with cell-wall synthesis, such as penicillin, results in a synergistic bactericidal effect in some isolates of Enterococcus faecalis . This combination is not synergistic against other closely related organisms, e.g., Enterococcus faecium. Species-level identification of enterococci alone cannot be used to predict susceptibility. Susceptibility testing and tests for antibacterial synergism must be performed. Cross-resistance between aminoglycosides may occur. Antimicrobial Activity Tobramycin has been shown to be active against most isolates of the following organisms both in vitro and in clinical infections [see Indications and Usage ( 1 )] : Gram-positive bacteria Staphylococcus aureus Gram-negative bacteria Citrobacter species Enterobacter species Escherichia coli Klebsiella species Morganella morganii Pseudomonas aeruginosa Proteus mirabilis Proteus vulgaris Providencia species Serratia species Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

12.1 Mechanism of Action Tobramycin sulfate is an aminoglycoside antibacterial drug [see Microbiology ( 12.4 )].

12.3 Pharmacokinetics In patients with normal renal function, except neonates, tobramycin administered every 8 hours does not accumulate in serum. The serum elimination half-life in patients with normal renal function is 2 hours. However, in patients with renal impairment and in neonates, serum concentrations of the antibacterial are usually higher and can be measured for longer periods of time than in adults with normal renal function. Thus, the dosage of tobramycin for patients with renal impairment and neonates must be adjusted accordingly [see Dosage and Administration ( 2.3 , 2.6 )]. Absorption Following intramuscular administration, peak serum concentrations of tobramycin occur between 30 and 90 minutes. Following an intramuscular dose of 1 mg/kg of body weight, maximum serum concentrations reach about 4 mcg/mL, and measurable concentrations persist for as long as 8 hours. Therapeutic serum concentrations are generally considered to range from 4 to 6 mcg/mL. When tobramycin is administered by intravenous infusion over a 1-hour period, the serum concentrations are similar to those obtained by intramuscular administration. Tobramycin is poorly absorbed from the gastrointestinal tract. Distribution Based on ultrafiltration studies, practically no serum protein binding of tobramycin occurs. Tobramycin can be detected in tissues and body fluids after parenteral administration. Concentrations of tobramycin in bile and stools ordinarily have been low, which suggests minimal biliary excretion. The concentration of tobramycin in cerebrospinal fluid following parenteral administration is low, and concentrations are dependent on dose, rate of penetration, and degree of meningeal inflammation. Tobramycin has also been detected in sputum, peritoneal fluid, synovial fluid, and abscess fluids, and it crosses the placental membranes. Concentrations in the renal cortex are several times higher than serum concentrations. Metabolism Following parenteral administration, minimal, metabolic transformation occurs, and tobramycin is eliminated almost exclusively by glomerular filtration. Excretion Peak urine concentrations ranging from 75 to 100 mcg/mL have been observed following the intramuscular injection of a single dose of 1 mg/kg. After several days of treatment, the amount of tobramycin excreted in the urine approaches the daily dose administered. Renal clearance is similar to that of endogenous creatinine. In patients with normal renal function, up to 84% of the dose is recoverable from the urine in 8 hours and up to 93% in 24 hours. When renal function is impaired, excretion of tobramycin is slowed, and accumulation of the drug may cause toxic blood concentrations. Drug Interactions Probenecid does not affect the renal tubular transport of tobramycin.

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3 DOSAGE FORMS AND STRENGTHS Tobramycin for Injection, USP is supplied as a sterile dry powder in a pharmacy bulk package vial containing tobramycin sulfate equivalent to 1.2 g of tobramycin. The contents of the vial should be diluted with 30 mL of Sterile Water for Injection, USP, to provide a solution containing 40 mg of tobramycin per mL. Tobramycin for Injection, USP is supplied as a dry powder in a bulk package vial. Reconstitute the contents of the vial with 30 mL of Sterile Water for Injection, USP, to provide a solution containing 40 mg of tobramycin per mL ( 3 ).

Tobramycin TOBRAMYCIN SULFATE TOBRAMYCIN SULFATE TOBRAMYCIN

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Subcutaneous administration of up to 100 mg/kg of tobramycin (3.2x an adult human dose of 5 mg/kg/day based on body surface area) did not affect mating behavior or cause impairment of fertility in male or female rats.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Subcutaneous administration of up to 100 mg/kg of tobramycin (3.2x an adult human dose of 5 mg/kg/day based on body surface area) did not affect mating behavior or cause impairment of fertility in male or female rats.

NDA050789

Tobramycin

TOBRAMYCIN SULFATE

63323-303

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

12.4 Microbiology Mechanism of Action Tobramycin is an aminoglycoside that inhibits protein synthesis by binding irreversibly to the aminoacyl site (A) of the 16S RNA within the bacterial 30S ribosomal subunit. Tobramycin enters the bacterial cell by an aerobic energy-dependent mechanism to penetrate the bacterial inner cell membrane. The effect of this action is two fold (i) it makes the ribosome unavailable for translation into mRNA and (ii) it causes the production of nonsense proteins because of misreading of the genetic code. Tobramycin is bactericidal to susceptible bacteria. Resistance Resistance to tobramycin can occur by any of the following known mechanisms. The most common mechanism of resistance and the one that generates the greatest level of resistance, results from the structural modification of the antibiotic by specific methyltransferase enzymes expressed in resistant organisms. This modification prevents the antibiotic from binding to its target site on the ribosome. A second mechanism of resistance is associated with drug concentration in the bacterial cell. Tobramycin is a hydrophilic antibiotic and its efficacy is concentration – dependent. The action by some bacteria results in a decrease in permeability of the cell membrane and leads to a decrease in the uptake of the drug by the bacteria. The third known mechanism of resistance is caused by mutations in the 16S rRNA of the 30S subunit of the ribosome which prevents the binding of the antibiotic to the target site and stops the bactericidal activity. The fourth mechanism is efflux of the antibiotic from the bacterial cell. Interaction with Other Antibacterial Drugs In vitro studies have shown that an aminoglycoside combined with an antibacterial that interferes with cell-wall synthesis, such as penicillin, results in a synergistic bactericidal effect in some isolates of Enterococcus faecalis . This combination is not synergistic against other closely related organisms, e.g., Enterococcus faecium. Species-level identification of enterococci alone cannot be used to predict susceptibility. Susceptibility testing and tests for antibacterial synergism must be performed. Cross-resistance between aminoglycosides may occur. Antimicrobial Activity Tobramycin has been shown to be active against most isolates of the following organisms both in vitro and in clinical infections [see Indications and Usage ( 1 )] : Gram-positive bacteria Staphylococcus aureus Gram-negative bacteria Citrobacter species Enterobacter species Escherichia coli Klebsiella species Morganella morganii Pseudomonas aeruginosa Proteus mirabilis Proteus vulgaris Providencia species Serratia species Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

PACKAGE LABEL - PRINCIPAL DISPLAY - Tobramycin 1.2 g Vial Label NDC 63323-303-01 300351 TOBRAMYCIN FOR INJECTION, USP PHARMACY BULK PACKAGE - NOT FOR DIRECT INFUSION equivalent to 1.2 g Tobramycin Rx only PACKAGE LABEL - PRINCIPAL DISPLAY - Tobramycin 1.2 g Tray Label NDC 63323-303-51 300351 TOBRAMYCIN FOR INJECTION, USP PHARMACY BULK PACKAGE - NOT FOR DIRECT INFUSION equivalent to 1.2 g Tobramycin Rx only 6 x 50 mL pharmacy bulk package vials vial tray

17 PATIENT COUNSELING INFORMATION Serious Allergic Reactions Advise patients that serious allergic reactions could occur. Advise patients to report fever, swelling, difficulty breathing, wheezing, decrease blood pressure or dizziness, or skin rash. If an allergic reaction occurs, discontinue the drug and institute appropriate therapy immediately. Impairment of Kidney Function Advise patients that tobramycin may cause impairment in kidney function and that periodic blood draws are required to monitor kidney function and tobramycin drug levels. Hearing Loss and Impaired Balance Advise patients that tobramycin may cause serious and irreversible hearing loss and impaired balance. Advise patients to report hearing loss, ringing or roaring in the ears, dizziness or imbalance. Antibacterial Resistance Counsel patients that antibacterial drugs, including Tobramycin for Injection, USP should be used to treat bacterial infections only. They do not treat viral infections (e.g., the common cold). When Tobramycin for Injection, USP is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be administered exactly as directed. Skipping doses or not completing the full course of therapy may ( 1 ) decrease the effectiveness of the immediate treatment and ( 2 ) increase the likelihood that bacteria will develop resistance and will not be treatable by Tobramycin for Injection, USP or other antibacterial drugs in the future. Diarrhea Counsel patients that diarrhea is a common problem caused by antibacterials, and it usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken their last dose of the antibacterial. If this occurs, patients should contact their physician as soon as possible. 45932E logo

8.5 Geriatric Use Elderly patients may be at a higher risk of developing nephrotoxicity and ototoxicity while receiving tobramycin [see Warnings and Precautions ( 5.1 )]. Tobramycin is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function and serum tobramycin levels [see Dosage and Administration ( 2.6 ) and Warnings and Precautions ( 5.1 )].

8.3 Nursing Mothers It is not known whether tobramycin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions such as nephrotoxicity and neurotoxicity, in nursing infants from tobramycin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use Use Tobramycin for Injection with caution in premature infants and neonates because of their renal immaturity and the resulting prolongation of serum half-life. For pediatric dosing information [see Dosage and Administration ( 2.3 )]. Similar to adults, monitor renal function and serum tobramycin concentrations in pediatric patients receiving Tobramycin for Injection.

8.1 Pregnancy Pregnancy Category D. [See Warnings and Precautions ( 5.3 )] Aminoglycosides can cause fetal harm when administered to a pregnant woman. Aminoglycosides cross the placenta, and there have been reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. If tobramycin is used during pregnancy or if the patient becomes pregnant while taking tobramycin, she should be apprised of the potential hazard to the fetus.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D. [See Warnings and Precautions ( 5.3 )] Aminoglycosides can cause fetal harm when administered to a pregnant woman. Aminoglycosides cross the placenta, and there have been reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. If tobramycin is used during pregnancy or if the patient becomes pregnant while taking tobramycin, she should be apprised of the potential hazard to the fetus. 8.3 Nursing Mothers It is not known whether tobramycin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions such as nephrotoxicity and neurotoxicity, in nursing infants from tobramycin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Use Tobramycin for Injection with caution in premature infants and neonates because of their renal immaturity and the resulting prolongation of serum half-life. For pediatric dosing information [see Dosage and Administration ( 2.3 )]. Similar to adults, monitor renal function and serum tobramycin concentrations in pediatric patients receiving Tobramycin for Injection. 8.5 Geriatric Use Elderly patients may be at a higher risk of developing nephrotoxicity and ototoxicity while receiving tobramycin [see Warnings and Precautions ( 5.1 )]. Tobramycin is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function and serum tobramycin levels [see Dosage and Administration ( 2.6 ) and Warnings and Precautions ( 5.1 )]. 8.6 Patients with Renal Impairment The dosage schedule should be adjusted according to the degree of renal impairment and serum concentration [see Dosage and Administration ( 2.6 )]. In patients undergoing hemodialysis, 25% to 70% of the administered dose may be removed, depending on the duration and type of dialysis.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Tobramycin for Injection, USP is supplied as a sterile dry powder containing tobramycin sulfate equivalent to 1.2 g tobramycin in a 50 mL Pharmacy Bulk Package Vial packaged in trays of 6. Product Code Unit of Sale Strength Each 300351 NDC 63323-303-51 Unit of 6 1.2 g in 50 mL NDC 63323-303-01 50 mL Pharmacy Bulk Package Vials Vial stoppers do not contain natural rubber latex. 16.2 Storage and Handling Prior to reconstitution, the vial should be stored at 20°C to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. After reconstitution, the solution should be kept in a refrigerator and used within 96 hours. If kept at room temperature, the solution must be used within 24 hours [see Dosage and Administration ( 2.1 , 2.8 )] .

16.2 Storage and Handling Prior to reconstitution, the vial should be stored at 20°C to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. After reconstitution, the solution should be kept in a refrigerator and used within 96 hours. If kept at room temperature, the solution must be used within 24 hours [see Dosage and Administration ( 2.1 , 2.8 )] .

WARNING: NEPHROTOXICITY, OTOTOXICITY, NEUROMUSCULAR BLOCKADE AND EMBRYO-FETAL TOXICITY WARNING: NEPHROTOXICITY, OTOTOXICITY, NEUROMUSCULAR BLOCKADE AND EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Nephrotoxicity Tobramycin for Injection can result in acute kidney injury, including acute renal failure. Risk factors that may contribute to nephrotoxicity include tobramycin accumulation (increasing serum trough levels), high peak concentrations (above 12 mcg mL), total cumulative dose, advanced age, volume depletion and concurrent or sequential use of other nephrotoxic drugs. Avoid concurrent or sequential use of other potentially nephrotoxic drugs. Monitor serum tobramycin levels and renal function in all patients during drug treatment. Reduce the dose or discontinue the drug if renal impairment occurs [see Warnings and Precautions ( 5.1 )]. Ototoxicity Tobramycin for Injection can cause irreversible auditory and vestibular toxicity that may continue to develop after the drug has been discontinued. Risk factors include high serum concentrations, prolonged therapy, renal impairment, concurrent and sequential use of other nephrotoxic or ototoxic drugs (e.g. aminoglycosides), and extremes of age. Avoid concurrent or sequential use with other potentially ototoxic drugs. Monitor for signs and symptoms of auditory and vestibular toxicity. Reduce the dose or discontinue the drug if renal impairment occurs. Discontinue the drug if ototoxicity occurs, [see Warnings and Precautions ( 5.2 )] . Neuromuscular Blockade Aminoglycosides have been associated with neuromuscular blockade. During therapy with tobramycin, monitor for adverse reactions associated with neuromuscular blockade, particularly in high-risk patients, such as patients with underlying neuromuscular disorders (including myasthenia gravis) or in patients concomitantly receiving neuromuscular blocking agents [see Warnings and Precautions ( 5.5 )]. Embryo-Fetal Toxicity Tobramycin and other aminoglycosides can cause fetal harm when administered to a pregnant woman. If tobramycin is used during pregnancy or if the patient becomes pregnant while taking tobramycin, apprise the patient of the potential hazard to the fetus [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.1 )]. Nephrotoxicity Tobramycin for Injection can result in acute kidney injury, including acute renal failure. Risk factors that may contribute to nephrotoxicity include tobramycin accumulation (increasing serum trough levels), high peak concentrations (above 12 mcg/mL), total cumulative dose, advanced age, volume depletion and concurrent or sequential use of other nephrotoxic drugs. Avoid concurrent or sequential use of other potentially nephrotoxic drugs. Monitor serum tobramycin levels and renal function in all patients during drug treatment. Reduce the dose or discontinue the drug if renal impairment occurs [see Warnings and Precautions ( 5.1)] . Ototoxicity Tobramycin for Injection can cause irreversible auditory and vestibular toxicity that may continue to develop after the drug has been discontinued. Risk factors include high serum concentrations, prolonged therapy, renal impairment, concurrent and sequential use of other nephrotoxic or ototoxic drugs (e.g. aminoglycosides), and extremes of age. Avoid concurrent or sequential use with other potentially ototoxic drugs. Monitor for signs and symptoms of auditory and vestibular toxicity. Reduce the dose or discontinue the drug if renal impairment occurs. Discontinue the drug if ototoxicity occurs. [see Warnings and Precautions ( 5.2 )]. Neuromuscular Blockade Aminoglycosides have been associated with neuromuscular blockade. During therapy with tobramycin, monitor for adverse reactions associated with neuromuscular blockade, particularly in high-risk patients, such as patients with underlying neuromuscular disorders (including myasthenia gravis) or in patients concomitantly receiving neuromuscular blocking agents [see Warnings and Precautions ( 5.5 )]. Embryo-Fetal Toxicity Tobramycin and other aminoglycosides can cause fetal harm when administered to a pregnant woman. If tobramycin is used during pregnancy or if the patient becomes pregnant while taking tobramycin, apprise the patient of the potential hazard to the fetus [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.1 )].