Tobramycin (Page 3 of 4)

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 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 (AST, ALT); increased serum LDH and bilirubin; decreased serum calcium, magnesium, sodium, and potassium; and leukopenia, leukocytosis, and eosinophilia.

To report SUSPECTED ADVERSE EVENTS, contact FDA at 1-800-FDA-1088 or www.fda.gov.

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, in pediatric patients given more than 7.5 mg/kg/day, or in patients with reduced renal function where 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 toxicities have 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 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 succinyl choline. 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 who 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.

DOSAGE & ADMINISTRATION

This insert is for a Pharmacy Bulk Package and is intended for preparing intravenous admixtures only.

Tobramycin for Injection may be given intravenously. 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 1).

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 blood levels, dosage should not exceed 5 mg/kg/day unless serum levels are monitored (see Warnings box and Precautions).

Table 1: DOSAGE SCHEDULE GUIDE FOR ADULTS WITH NORMAL RENAL FUNCTION (Dosage at 8-Hour Intervals)
For Weighing Kg lb Usual Dose for Serious Infections 1 mg/kg q8h (Total, 3 mg/kg/day) Maximum Dose for Life- Threatening Infections (Reduce as soon as possible) 1.66 mg/kg q8h (Total, 5 mg/kg/day)
mg/dosemL/dosemg/dosemL/dose
q8hq8h
120264120 mg3 mL200 mg5 mL
115253115 mg2.9 mL191 mg4.75 mL
110242110 mg2.75 mL183 mg4.5 mL
105231105 mg2.6 mL175 mg4.4 mL
100220100 mg2.5 mL166 mg4.2 mL
9520995 mg2.4 mL158 mg4 mL
9019890 mg2.25 mL150 mg3.75 mL
8518785 mg2.1 mL141 mg3.5 mL
8017680 mg2 mL133 mg3.3 mL
7516575 mg1.9 mL125 mg3.1 mL
7015470 mg1.75 mL116 mg2.9 mL
6514365 mg1.6 mL108 mg2.7 mL
6013260 mg1.5 mL100 mg2.5 mL
5512155 mg1.4 mL91 mg2.25 mL
5011050 mg1.25 mL83 mg2.1 mL
459945 mg1.1 mL75 mg1.9 mL
408840 mg1 mL66 mg1.6 mL

Pediatric patients: 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 dosage 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 level or the serum creatinine level 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 1 by the percent of normal dose from the accompanying nomogram.

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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 1 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.
Intramuscular Administration – Tobramycin for injection may be administered by withdrawing the appropriate dose directly from a vial or by using a prefilled syringe. The Pharmacy Bulk Package is not intended for Intramuscular administration.

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.

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 allows 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 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, 20º to 25ºC (68º to 77ºF). 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.

Prior to administration, parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit.

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