Tobramycin

Warnings and Precautions, Ototoxicity ( 5.2 ) 2/2023

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 ( 1.1 ): 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.

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 Usual Dose for Serious Infections 1 mg/kg Every 8 hours (h) kg lb (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 Maximum Dose for Life- Threatening Infections (Reduce as soon as possible) 1.66 mg/kg Every 8 hours kg lb (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 to 10 days. A longer course …

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 ).

CONTRAINDICATIONS A hypersensitivity to any aminoglycoside is a contraindication to the use of tobramycin. A history of hypersensitivity or serious toxic reactions to aminoglycosides may also contraindicate the use of any other aminoglycoside because of the known cross-sensitivity of patients to drugs in this class.

ADVERSE REACTIONS Neurotoxicity Adverse effects on both the vestibular and auditory branches of the eighth nerve have been noted, especially in patients receiving high doses or prolonged therapy, in those given previous courses of therapy with an ototoxin, and in cases of dehydration. Symptoms include dizziness, vertigo, tinnitus, roaring in the ears, and hearing loss. Hearing loss is usually irreversible and is manifested initially by diminution of high-tone acuity. Tobramycin and gentamicin sulfates closely parallel each other in regard to ototoxic potential. Nephrotoxicity Renal function changes, as shown by rising BUN, NPN, and serum creatinine and by oliguria, cylindruria, and increased proteinuria, have been reported, especially in patients with a history of renal impairment who are treated for longer periods or with higher doses than those recommended. Adverse renal effects can occur in patients with initially normal renal function. Clinical studies and studies in experimental animals have been conducted to compare the nephrotoxic potential of tobramycin and gentamicin. In some of the clinical studies and in the animal studies, tobramycin caused nephrotoxicity significantly less frequently than gentamicin. In some other clinical studies, no significant difference in the incidence of nephrotoxicity between tobramycin and gentamicin was found. Other reported adverse reactions possibly related to tobramycin sulfate include anemia, granulocytopenia, and thrombocytopenia; and fever, rash, exfoliative dermatitis, itching, urticaria, nausea, vomiting, diarrhea, headache, lethargy, pain at the injection site, mental confusion, and disorientation. Laboratory abnormalities possibly related to tobramycin include increased serum transaminases (SGOT, SGPT); increased serum LDH and bilirubin; decreased serum calcium, magnesium, sodium, and potassium; and leukopenia, leukocytosis, and eosinophilia.

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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Aminoglycosides, including Tobramycin for Injection, can cause fetal harm when administered to a pregnant woman. Published literature reports that use of streptomycin, an aminoglycoside, can cause total, irreversible, bilateral congenital deafness when administered to a pregnant woman [see Warnings and Precautions ( 5.3 )]. In animal reproduction studies with subcutaneous administration of tobramycin in pregnant rats and rabbits during organogenesis, there were no adverse developmental outcomes at doses up to 3.2 times and 1.3 times the maximum recommended clinical dose based on body surface area; however, ototoxicity was not evaluated in the offspring from these studies (see Data ). Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20% respectively. Data Animal Data Subcutaneous administration of tobramycin at doses of up to 100 mg/kg/day (rat) or 20 mg/kg/day (rabbit) during organogenesis was not associated with adverse developmental outcomes. These doses are 3.2 and 1.3 times the maximum recommended clinical daily dose of 5 mg/kg based on body surface area. Doses of tobramycin ≥40 mg/kg/day were maternally toxic to rabbits and precluded the evaluation of adverse developmental outcomes. Ototoxicity was not evaluated in offspring during nonclinical reproductive toxicity studies with tobramycin. 8.2 Lactation Risk Summary Limited published data with Tobramycin for Injection in lactating women indicate that tobramycin is present in human milk. There are no data on the effects of Tobramycin for Injection on milk production. Tobramycin may cause alteration in the intestinal flora of the breastfeeding infant. Advise a woman to monitor the breastfed infant for loose or bloody stools and candidiasis (thrush, diaper rash). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Tobramycin for Injection and any potential adverse effects on the breastfed infant from Tobramycin for Injection or from the underlying maternal condition. 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 for Injection [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 of Tobramycin for Injection 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.

Mechanism of Action Tobramycin acts by inhibiting synthesis of protein in bacterial cells. In vitro tests demonstrate that tobramycin is bactericidal.

DESCRIPTION Tobramycin sulfate, a water-soluble antibiotic of the aminoglycoside group, is derived from the actinomycete Streptomyces tenebrarius . Tobramycin for Injection, USP is a white or off-white lyophilized porous cake for parenteral administration. Each vial contains tobramycin sulfate equivalent to 1200 mg of tobramycin; After reconstitution, each mL contains 40 mg of tobramycin, contains sulfuric acid and may contain sodium hydroxide for pH adjustment. 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, (2:5)(salt) and has the chemical formula (C 18 H 37 N 5 O 9 ) 2 •5H 2 SO 4 . The molecular weight is 1,425.39. The structural formula for tobramycin is as follows: A pharmacy bulk package is a container of a sterile preparation for parenteral use that contains many single doses. The contents are intended for use in a pharmacy admixture service and are restricted to the preparation of admixtures for intravenous infusion (see DOSAGE AND ADMINISTRATION : Directions for proper use of Pharmacy Bulk Package ). structural-formula

OVERDOSAGE Signs and Symptoms 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, and age and whether or not other medications with similar toxicities are being administered concurrently. Toxicity may occur in patients treated more than 10 days, in adults given more than 5 mg/kg/day, children given more than 7.5 mg/kg/day, or patients with reduced renal function whose dose has not been appropriately adjusted. Nephrotoxicity following the parenteral administration of an aminoglycoside is most closely related to the area under the curve of the serum concentration versus time graph. Nephrotoxicity is more likely if trough blood concentrations fail to fall below 2 mcg/mL and is also proportional to the average blood concentration. Patients who are elderly, have abnormal renal function, are receiving other nephrotoxic drugs, or are volume depleted are at greater risk for developing acute tubular necrosis. Auditory and vestibular toxicity has been associated with aminoglycoside overdose; these toxicities occur in patients treated longer than 10 days, in patients with abnormal renal function, in dehydrated patients, or in patients receiving medications with additive auditory toxicities. These patients may not have signs or symptoms or may experience dizziness, tinnitus, vertigo, and a loss of high-tone acuity as ototoxicity progresses. Ototoxicity signs and symptoms may not begin to occur until long after the drug has been discontinued. Neuromuscular blockade or respiratory paralysis may occur following administration of many aminoglycosides. Neuromuscular blockade, respiratory failure, and prolonged respiratory paralysis may occur more commonly in patients with myasthenia gravis or Parkinson’s disease. Prolonged respiratory paralysis may also occur in patients receiving decamethonium, tubocurarine, or succinylcholine. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts but mechanical assistance may be necessary. If tobramycin were ingested, toxicity would be less likely because aminoglycosides are poorly absorbed from an intact gastrointestinal tract. Treatment In all cases of suspected overdosage, call your Regional Poison Control Center 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 overdose may change more rapidly than the package insert. In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. The initial intervention in a tobramycin overdose is to establish an airway and ensure oxygenation and ventilation. Resuscitative measures should be initiated promptly if respiratory paralysis occurs. Patients that have received an overdose of tobramycin and who have normal renal function should be adequately hydrated to maintain a urine output of 3 to 5 mL/kg/hr. Fluid balance, creatinine clearance, and tobramycin plasma levels should be carefully monitored until the serum tobramycin level falls below 2 mcg/mL. Patients in whom the elimination half-life is greater than 2 hours or whose renal function is abnormal may require more aggressive therapy. In such patients, hemodialysis may be beneficial.

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 NP300351 NDC 63323-303-55 Unit of 6 1.2 g in 50 mL NDC 63323-303-21 50 mL Pharmacy Bulk Package Vial 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°F 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 )] .

16.1 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 NP300351 NDC 63323-303-55 Unit of 6 1.2 g in 50 mL NDC 63323-303-21 50 mL Pharmacy Bulk Package Vial Vial stoppers do not contain natural rubber latex.