Tobramycin Sulfate

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.

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 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 ).

Nephrotoxicity and ototoxicity: See Boxed Warning ( 5.1 , 5.2 ) Allergic Reactions: anaphylaxis, exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson Syndrome have been reported in patients on Tobramycin for Injection therapy. If an allergic reaction occurs, discontinue the drug and institute appropriate therapy ( 5.4 ) Neuromuscular Blockade: Respiratory paralysis can occur at high doses or with concurrent use of neuromuscular blocking agents. If neuromuscular blockade occurs, consider administration of calcium salts but mechanical assistance may be necessary. ( 5.5 ) Clostridioides difficile -associated diarrhea (CDAD): Evaluate patients if diarrhea occurs. ( 5.6 )

5.1 Nephrotoxicity Systemic exposure to Tobramycin for Injection and other aminoglycosides can cause nephrotoxicity, primarily manifested as acute tubular necrosis. Signs of nephrotoxicity include rising blood urea nitrogen (BUN) and creatinine (Cr), decreased urinary output, and sodium, potassium, bicarbonate, magnesium, phosphate and calcium urinary losses. Aminoglycoside-induced nephrotoxicity may occur during therapy but may not become apparent until the first few days after cessation of therapy and usually is reversible. The risk for nephrotoxicity increases with tobramycin accumulation (indicated by rising trough levels above 2 mcg/mL), excessive peak concentrations (above 12 mcg/mL), total cumulative dose, advanced age, volume depletion, concurrent or sequential use of other nephrotoxic drugs and in patients with diabetes. Monitor serum tobramycin concentrations in all patients and avoid peak levels above 12 mcg/mL and trough levels above 2 mcg/mL [see Dosage and Administration ( 2.9 )] . Monitor renal function, serum electrolytes, potassium, sodium, magnesium, calcium and phosphate, urine output and urinalysis during therapy in all patients. Reduce the dose or discontinue treatment if renal impairment occurs.

5.2 Ototoxicity Ototoxicity with use of Tobramycin for Injection Tobramycin for Injection can cause both auditory and vestibular eighth nerve damage. The auditory changes are irreversible, are usually bilateral, and may be partial or total. Symptoms of ototoxicity can include dizziness, vertigo, tinnitus, roaring in the ears and hearing loss. Ototoxicity symptoms may manifest during therapy or after tobramycin has been discontinued. The risk of ototoxicity increases with higher peak and trough serum tobramycin concentrations, in patients who receive high doses or prolonged or prior treatment with tobramycin or other aminoglycosides, in patients with renal impairment, patients receiving with other nephrotoxic or ototoxic drugs and in the extremes of age. To decrease the risk of ototoxicity, use as short a duration of therapy as clinically appropriate, adequately hydrate patients, limit the use of other ototoxic drugs, and closely monitor tobramycin concentrations during therapy [see Dosage and Administration ( 2.9 )] . Monitor patients for signs and symptoms of auditory or vestibular toxicity and consider serial audiograms in high-risk patients. Discontinue tobramycin in patients with evidence of auditory or vestibular toxicity. 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.

5.3 Embryo-Fetal Toxicity Aminoglycosides, including Tobramycin for Injection, can cause fetal harm when administered to a pregnant woman. Aminoglycosides cross the placenta. Streptomycin, another aminoglycoside, has been associated with several reports of total, irreversible, bilateral congenital deafness in pediatric patients whose mothers received streptomycin during pregnancy. Apprise patients of potential hazard to the fetus if Tobramycin for Injection is used during pregnancy or if the patient becomes pregnant while taking Tobramycin for Injection [see Use in Specific Populations ( 8.1 )] .

5.4 Allergic Reactions Serious and fatal allergic reactions including anaphylaxis and dermatologic reactions including exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson Syndrome have been reported in patients on tobramycin therapy [see Contraindications ( 4 ) and Adverse Reactions ( 6 )]. If an allergic reaction occurs, discontinue Tobramycin for Injection and institute appropriate therapy. A history of hypersensitivity to other aminoglycosides is a contraindication to the use of Tobramycin for Injection, because cross-allergenicity among aminoglycosides has been demonstrated [see Contraindications ( 4 )] .

5.5 Neuromuscular Blockade and Other Neurologic Adverse Reactions Neuromuscular blockade with respiratory paralysis and respiratory failure may occur following administration of aminoglycosides. Neuromuscular blockade, respiratory failure, and prolonged respiratory paralysis may occur more commonly and be more severe in patients with myasthenia gravis or Parkinson's disease and in patients concomitantly receiving neuromuscular blocking agents such as succinylcholine. If neuromuscular blockade occurs following the administration of Tobramycin for Injection, it may be reversed by the administration of calcium salts but mechanical assistance may be necessary. Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching, and convulsions.

5.6 Clostridioides difficile -Associated Diarrhea (CDAD) Clostridioides difficile- associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Tobramycin for Injection, USP, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.7 Risk of Development of Drug-Resistant Bacteria Prescribing Tobramycin for Injection, USP in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

5.8 Macular Necrosis Tobramycin for Injection is not approved for intraocular and/or subconjunctival use. Macular necrosis has been reported following intraocular and/ or subconjunctival administration of aminoglycosides, including tobramycin. […]

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.

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.

8.1 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.

Tobramycin sulfate is an aminoglycoside antibacterial drug [see Microbiology ( 12.4 )].