Tobramycin

WARNING: NEPHROTOXICITY, OTOTOXICITY AND EMBRYO-FETAL TOXICITY WARNING: NEPHROTOXICITY, OTOTOXICITY, NEURO MUSCULAR BLOCKADE AND FETAL HARM See full prescribing information for complete boxed warning. Nephrotoxicity Tobramycin for Injection may cause acute kidney injury. Monitor renal function and serum tobramycin concentrations in all patients. Reduce the dose or discontinue the Tobramycin for Injection if renal impairment occurs. ( 5.1 ) Ototoxicity Tobramycin for Injection may cause irreversible auditory and vestibular toxicity. Monitor for symptoms of ototoxicity, and for renal function and serum tobramycin levels in all patients. Reduce the dose or discontinue the Tobramycin for Injection if impairment of renal function occurs. Discontinue Tobramycin for Injection if ototoxicity occurs. ( 5.2 ) Neuromuscular Blockade Aminoglycosides have been associated with neuromuscular blockade. During therapy with Tobramycin for Injection, monitor for adverse reactions associated with neuromuscular blockade, particularly in high-risk patients ( 5.5 ) Embryo-Fetal Toxicity Tobramycin for Injection and other aminoglycosides can cause fetal harm when administered to a pregnant woman. Apprise pregnant women of the potential hazard to the fetus. ( 5.3 , 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 Tobramycin for Injection 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 Tobramycin for Injection if renal impairment occurs. Discontinue the Tobramycin for Injection if ototoxicity occurs. [see Warnings and Precautions ( 5.2 )]. Neuromuscular Blockade Aminoglycosides have been associated with neuromuscular blockade. During therapy with Tobramycin for Injection, 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 for Injection 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 )].

5 WARNINGS AND PRECAUTIONS 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. 5.9 Inactivation by Beta-Lactam Antibacterials The inactivation of tobramycin and other aminoglycosides by ß-lactam-type antibacterials (penicillins, cephalosporins) has been demonstrated in vitro and in patients with severe renal impairment. Such inactivation has not been found in patients with normal renal function who have been given the drugs by separate routes of administration.

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.