Tobramycin

INDICATIONS AND USAGE: Tobramycin is indicated for the treatment of serious bacterial infections caused by susceptible strains of the designated microorganisms in the diseases listed below: Septicemia in the neonate, child, and adult caused by P. aeruginosa , E. coli , and Klebsiella sp. Lower respiratory tract infections caused by P. aeruginos a, Klebsiella sp, Enterobacter sp, Serratia sp, E. coli , and S. aureus (penicillinase- and non-penicillinase-producing strains). Serious central-nervous-system infections (meningitis) caused by susceptible organisms. Intra-abdominal infections, including peritonitis, caused by E. coli , Klebsiella sp, and Enterobacter sp. Skin, bone, and skin-structure infections caused by P. aeruginosa , Proteus sp, E. coli , Klebsiella sp, Enterobacter sp, and S. aureus. Complicated and recurrent urinary tract infections caused by P. aeruginosa , Proteus sp (indole-positive and indole-negative), E. coli , Klebsiella sp, Enterobacter sp, Serratia sp, S. aureus , Providencia sp, and Citrobacter sp. Aminoglycosides, including tobramycin sulfate, are not indicated in uncomplicated initial episodes of urinary tract infections unless the causative organisms are not susceptible to antibiotics having less potential toxicity. Tobramycin may be considered in serious staphylococcal infections when penicillin or other potentially less toxic drugs are contraindicated and when bacterial susceptibility testing and clinical judgment indicate its use. Bacterial cultures should be obtained prior to and during treatment to isolate and identify etiologic organisms and to test their susceptibility to tobramycin. If susceptibility tests show that the causative organisms are resistant to tobramycin, other appropriate therapy should be instituted. In patients in whom a serious life-threatening gram-negative infection is suspected, including those in whom concurrent therapy with a penicillin or cephalosporin and an aminoglycoside may be indicated, treatment with tobramycin sulfate may be initiated before the results of susceptibility studies are obtained. The decision to continue therapy with tobramycin should be based on the results of susceptibility studies, the severity of the infection, and the important additional concepts discussed in the WARNINGS box above. To reduce the development of drug-resistant bacteria and maintain the effectiveness of tobramycin and other antibacterial drugs, tobramycin 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 antimicrobial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

DOSAGE AND ADMINISTRATION: Tobramycin Injection, USP may be given intramuscularly or intravenously. Recommended dosages are the same for both routes. The patient's pretreatment body weight should be obtained for calculation of correct dosage. It is desirable to measure both peak and trough serum concentrations (see WARNINGS box and PRECAUTIONS ). Administration for Patients with Normal Renal Function Adults with Serious Infections: 3 mg/kg/day in 3 equal doses every 8 hours (see Table 3 ). Adults with Life-Threatening Infections: Up to 5 mg/kg/day may be administered in 3 or 4 equal doses (see Table 3 ). The dosage should be reduced to 3 mg/kg/day as soon as clinically indicated. To prevent increased toxicity due to excessive blood levels, dosage should not exceed 5 mg/kg/day unless serum levels are monitored (see WARNINGS box and PRECAUTIONS ). Table 3. DOSAGE SCHEDULE GUIDE FOR TOBRAMYCIN INJECTION, USP IN ADULTS WITH NORMAL RENAL FUNCTION (Dosage at 8-Hour Intervals) *Applicable to all product forms except Tobramycin Injection, USP, 10 mg/mL(Pediatric). For Patient Weighing Usual Dose for Serious Infections 1 mg/kg q8h (Total, 3 mg/kg/day) kg lb 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 For Patient Weighing Maximum Dose for Life- Threatening Infections (Reduce as soon as possible) 1.66 mg/kg q8h (Total, 5 mg/kg/day) kg lb mg/dose mL/dose* q8h 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 Pediatric Patients (Greater Than 1 Week of Age): 6 to 7.5 mg/kg/day in 3 or 4 equally divided doses (2 to 2.5 mg/kg every 8 hours or 1.5 to 1.89 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. It is desirable to limit treatment to a short term. The usual duration of treatment is 7 to 10 days. A longer course of therapy may be necessary in difficult and 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. Dosage in Patients with Cystic Fibrosis In patients with cystic fibrosis, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides. Measurement of tobramycin serum concentration during treatment is especially important as a basis for determining appropriate dose. In patients with severe cystic fibrosis, an initial dosing regimen of 10 mg/kg/day in 4 equally divided doses is recommended. This dosing regimen is suggested only as a guide. The serum levels of tobramycin should be measured directly during treatment due to wide interpatient variability. Administration for Patients with Impaired Renal Function Whenever possible, serum tobramycin concentrations should be monitored during therapy. 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 to be used when serum levels of tobramycin cannot be measured directly. They are based on either the creatinine clearance or the serum creatinine of the patient, because these values correlate with the half-life of tobramycin. The dosage schedules derived from either method should be used in conjunction with careful cli …

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: 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. 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.

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 Injection, USP is a clear and colorless sterile aqueous solution for parenteral administration. Each mL contains tobramycin sulfate equivalent to 10 mg (pediatric) or 40 mg tobramycin; phenol added as preservative, 5 mg; sodium metabisulfite added as an antioxidant, 3.2 mg; and edetate sodium added as a stabilizer, 0.1 mg. Contains sulfuric acid and may contain sodium hydroxide for pH adjustment (3.0 to 6.5). Each mL of tobramycin (10 mg/mL or 40 mg/mL) contains 0.78 mg (0.034 mEq) of sodium. 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 1,425.42. The structural formula for tobramycin is as follows: Structural Formula for Tobramycin

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, pediatric patients 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 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.

HOW SUPPLIED: Tobramycin Injection, USP, in multiple dose vials, is supplied as follows: Product Code Unit of Sale Strength Each 300502 NDC 63323-305-02 Unit of 25 20 mg per 2 mL (10 mg per mL) 2 mL fill, in a 2 mL vial. NDC 63323-305-01 2 mL Multiple Dose Vial 300602 NDC 63323-306-02 Unit of 25 80 mg per 2 mL (40 mg per mL) 2 mL fill, in a 2 mL vial. NDC 63323-306-01 2 mL Multiple Dose Vial 300630 NDC 63323-306-30 Unit of 10 1,200 mg per 30 mL (40 mg per mL) 30 mL fill, in a 30 mL vial. NDC 63323-306-05 30 mL Multiple Dose Vial Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. The container closure is not made with natural rubber latex. Lake Zurich, IL 60047 www.fresenius-kabi.com/us 45963K Revised: December 2023 Fresenius Kabi Logo