TOBRAMYCIN

Tobramycin sulfate, a water-soluble antibiotic of the aminoglycoside group, is derived from the actinomycete Streptomyces tenebrarius . Sterile tobramycin sulfate is supplied as a sterile dry powder and is intended for reconstitution with 30 mL of Sterile Water for Injection, USP. Sulfuric acid and/or sodium hydroxide may have been added during manufacture to adjust the pH. Each vial contains tobramycin sulfate equivalent to 1200 mg 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 (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 ). Tobramycin-Structure

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. aeruginosa , 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 sulphate, 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 sulphate 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.

Tobramycin for injection, USP may be given intramuscularly or intravenously. Recommended dosages are the same for both routes. This insert is for a Pharmacy Bulk Package and is intended for preparing I.V. admixtures only. Dosage recommendations for intramuscular use are for informational purposes only. 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 FOR INJECTION, USP IN ADULTS WITH NORMAL RENAL FUNCTION (Dosage at 8-Hour Intervals) For Patient Weighing Usual Dose for Serious Infections 1 mg/kg q8h (Total, 3mg/kg/day) 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* m g/dose mL/dose q8h q8h 120 264 120 mg 3 mL 200 mg 5 mL 115 253 115 mg 2.9 mL 191 mg 4.75 mL 110 242 110 mg 2.75 mL 183 mg 4.5 mL 105 231 105 mg 2.6 mL 175 mg 4.4 mL 100 220 100 mg 2.5 mL 166 mg 4.2 mL 95 209 95 mg 2.4 mL 158 mg 4 mL 90 198 90 mg 2.25 mL 150 mg 3.75 mL 85 187 85 mg 2.1 mL 141 mg 3.5 mL 80 176 80 mg 2 mL 133 mg 3.3 mL 75 165 75 mg 1.9 mL 125 mg 3.1 mL 70 154 70 mg 1.75 mL 116 mg 2.9 mL 65 143 65 mg 1.6 mL 108 mg 2.7 mL 60 132 60 mg 1.5 mL 100 mg 2.5 mL 55 121 55 mg 1.4 mL 91 mg 2.25 mL 50 110 50 mg 1.25 mL 83 mg 2.1 mL 45 99 45 mg 1.1 mL 75 mg 1.9 mL 40 88 40 mg 1 mL 66 mg 1.6 mL *Applicable to all product forms except Tobramycin Injection, USP, 10 mg /mL (Pediatric). 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 schedule derived from either method should be used in conjunction with careful clinical and laboratory observations of the patient 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 70 mL or less per minute or when the serum creatinine value is known, the amount of the reduced dose can be determined by multiplying the normal dose from Table 3 by the percent of normal dose from the accompanying nomogram. An alternate rough guide for determining reduced dosage at 8-hour intervals (for patients whose steady-state serum creatinine values are known) is to divide the normally recommended dose by the patient's serum creatinine. 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 dosage given in Table 3 can be determined by multiplying the patient's serum creatinine by 6. 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 basic weight on which to figure mg/kg. Intravenous Administration — For intravenous administration, the usual volume of diluent (0.9% Sodium Chloride Injection or 5% Dextrose Injection) is 50 to 100 mL for adult doses. For pediatric patients, the volume of diluent should be proportionately less than that for adults. The diluted solution usually should be infused over a period of 20 to 60 minutes. Infusion periods of less than 20 minutes are not recommended because peak serum levels may exceed 12 mcg/mL (see WARNINGS box). Tobramycin for injection, USP should not be physically premixed with other drugs but should be administered separately according to the recommended dose and route. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Preparation and Storage- Directions for Proper Use of Pharmacy Bulk Package - Not for Direct Infusion. The pharmacy bulk package is for use in the Hospital Pharmacy Admixture Service and only in a suitable work area, such as a laminar flow hood. Using aseptic technique, the closure may be penetrated only 1 time after reconstitution using a suitable sterile transfer device or dispensing set, which allow measured dispensing of the contents. Use of a syringe and needle is not recommended as it may cause leakage. After entry, entire contents of Pharmacy Bulk Package bottle should be dispensed within 24 hours. Tobramycin for injection USP is supplied as a dry powder. The contents of the Pharmacy Bulk Package bottle should be diluted with 30 mL of Sterile Water for Injection, USP to provide a solution containing 40 mg of tobramycin per mL. Prior to reconstitution, the Pharmacy Bulk Package bottle should be stored at controlled room temperature, 20 º to 25º C (6 8 º to 77º F). After reconstitution, the solution should be kept in a refrigerator and used within 96 hour. If kept at room temperature, the solution must be used within 24 hours. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Tobramycin-Nomogram

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.

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. To report SUSPECTED ADVERSE REACTIONS, contact Fosun Pharma USA Inc. at 1-866-611-3762 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.