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Tobramycin (Tobramycin Sulfate) - Warnings and Precautions

 
 



BOXED WARNING

Patients treated with tobramycin and other aminoglycosides should be under close clinical observation, because these drugs have an inherent potential for causing ototoxicity and nephrotoxicity.

Neurotoxicity, manifested as both auditory and vestibular ototoxicity, can occur.  The auditory changes are irreversible, are usually bilateral, and may be partial or total.  Eighth-nerve impairment and nephrotoxicity may develop, primarily in patients having pre-existing renal damage and in those with normal renal function to whom aminoglycosides are administered for longer periods or in higher doses than those recommended.  Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching, and convulsions.  The risk of aminoglycoside-induced hearing loss increases with the degree of exposure to either high peak or high trough serum concentrations.  Patients who develop cochlear damage may not have symptoms during therapy to warn them of eighth-nerve toxicity, and partial or total irreversible bilateral deafness may continue to develop after the drug has been discontinued.

Rarely, nephrotoxicity may not become apparent until the first few days after cessation of therapy.  Aminoglycoside-induced nephrotoxicity usually is reversible.

Renal and eighth-nerve function should be closely monitored in patients with known or suspected renal impairment and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy.  Peak and trough serum concentrations of aminoglycosides should be monitored periodically during therapy to assure adequate levels and to avoid potentially toxic levels.  Prolonged serum concentrations above 12 mcg/mL should be avoided.  Rising trough levels (above 2 mcg/mL) may indicate tissue accumulation.  Such accumulation, excessive peak concentrations, advanced age, and cumulative dose may contribute to ototoxicity and nephrotoxicity (see PRECAUTIONS ).  Urine should be examined for decreased specific gravity and increased excretion of protein, cells, and casts.  Blood urea nitrogen, serum creatinine, and creatinine clearance should be measured periodically.  When feasible, it is recommended that serial audiograms be obtained in patients old enough to be tested, particularly high-risk patients.  Evidence of impairment of renal, vestibular, or auditory function requires discontinuation of the drug or dosage adjustment.

Tobramycin should be used with caution in premature and neonatal infants because of their renal immaturity and the resulting prolongation of serum half-life of the drug.

Concurrent and sequential use of other neurotoxic and/or nephrotoxic antibiotics, particularly other aminoglycosides (e.g., amikacin, streptomycin, neomycin, kanamycin, gentamicin, and paromomycin), cephaloridine, viomycin, polymyxin B, colistin, cisplatin, and vancomycin, should be avoided.  Other factors that may increase patient risk are advanced age and dehydration.

Aminoglycosides should not be given concurrently with potent diuretics, such as ethacrynic acid and furosemide.  Some diuretics themselves cause ototoxicity, and intravenously administered diuretics enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.

Aminoglycosides can cause fetal harm when administered to a pregnant woman (see PRECAUTIONS ).

 

WARNINGS

See WARNINGS box above.

Tobramycin injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes, in certain susceptible people.  The overall prevalence of sulfite sensitivity in the general population is unknown and probably low.  Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

Serious allergic reactions including anaphylaxis and dermatologic reactions including exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson Syndrome have been reported rarely in patients on tobramycin therapy.  Although rare, fatalities have been reported (see CONTRAINDICATIONS ).

If an allergic reaction occurs, the drug should be discontinued and appropriate therapy instituted.

PRECAUTIONS

General

Prescribing tobramycin injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Serum and urine specimens for examination should be collected during therapy, as recommended in the WARNINGS box.  Serum calcium, magnesium, and sodium should be monitored.

Peak and trough serum levels should be measured periodically during therapy.  Prolonged concentrations above 12 mcg/mL should be avoided.  Rising trough levels (above 2 mcg/mL) may indicate tissue accumulation.  Such accumulation, advanced age, and cumulative dosage may contribute to ototoxicity and nephrotoxicity.  It is particularly important to monitor serum levels closely in patients with known renal impairment.

A useful guideline would be to perform serum level assays after 2 or 3 doses, so that the dosage could be adjusted if necessary, and at 3- to 4-day intervals during therapy.  In the event of changing renal function, more frequent serum levels should be obtained and the dosage or dosage interval adjusted according to the guidelines provided in DOSAGE AND ADMINISTRATION .

In order to measure the peak level, a serum sample should be drawn about 30 minutes following intravenous infusion or 1 hour after an intramuscular injection.  Trough levels are measured by obtaining serum samples at 8 hours or just prior to the next dose of tobramycin.  These suggested time intervals are intended only as guidelines and may vary according to institutional practices.  It is important, however, that there be consistency within the individual patient program unless computerized pharmacokinetic dosing programs are available in the institution.  These serum-level assays may be especially useful for monitoring the treatment of severely ill patients with changing renal function or of those infected with less susceptible organisms or those receiving maximum dosage.

Neuromuscular blockade and respiratory paralysis have been reported in cats receiving very high doses of tobramycin (40 mg/kg).  The possibility of prolonged or secondary apnea should be considered if tobramycin is administered to anesthetized patients who are also receiving neuromuscular blocking agents, such as succinylcholine, tubocurarine, or decamethonium, or to patients receiving massive transfusions of citrated blood.  If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts.

Cross-allergenicity among aminoglycosides has been demonstrated.

In patients with extensive burns or cystic fibrosis, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides.  In such patients treated with tobramycin, measurement of serum concentration is especially important as a basis for determination of appropriate dosage.

Elderly patients may have reduced renal function that may not be evident in the results of routine screening tests, such as BUN or serum creatinine.  A creatinine clearance determination may be more useful.  Monitoring of renal function during treatment with aminoglycosides is particularly important in such patients.

An increased incidence of nephrotoxicity has been reported following concomitant administration of aminoglycoside antibiotics and cephalosporins.

Aminoglycosides should be used with caution in patients with muscular disorders, such as myasthenia gravis or parkinsonism, since these drugs may aggravate muscle weakness because of their potential curare-like effect on neuromuscular function.

Aminoglycosides may be absorbed in significant quantities from body surfaces after local irrigation or application and may cause neurotoxicity and nephrotoxicity.

Aminoglycosides have not been approved for intraocular and/or subconjunctival use.  Physicians are advised that macular necrosis has been reported following administration of aminoglycosides, including tobramycin, by these routes.

See WARNINGS   box regarding concurrent use of potent diuretics and concurrent and sequential use of other neurotoxic or nephrotoxic drugs.

The inactivation of tobramycin and other aminoglycosides by ß-lactam-type antibiotics (penicillins or 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.

Therapy with tobramycin may result in overgrowth of nonsusceptible organisms.  If overgrowth of nonsusceptible organisms occurs, appropriate therapy should be initiated.

Information for Patients

Patients should be counseled that antibacterial drugs including tobramycin injection should only be used to treat bacterial infections.  They do not treat viral infections (e.g., the common cold).  When tobramycin injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.  Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by tobramycin injection or other antibacterial drugs in the future.

Pregnancy Category D

Aminoglycosides can cause fetal harm when administered to a pregnant woman.  Aminoglycoside antibiotics cross the placenta, and there have been several reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy.  Serious side effects to mother, fetus, or newborn have not been reported in the treatment of pregnant women with other aminoglycosides.  If tobramycin is used during pregnancy or if the patient becomes pregnant while taking tobramycin, she should be apprised of the potential hazard to the fetus.

Pediatric Use

See INDICATIONS AND USAGE   and DOSAGE AND ADMINISTRATION .

Geriatric Use

Elderly patients may be at a higher risk of developing nephrotoxicity and ototoxicity while receiving tobramycin (see WARNINGS , PRECAUTIONS , and OVERDOSAGE ).  Other factors that may contribute to nephrotoxicity and ototoxicity are rising trough levels, excessive peak concentrations, dehydration, concomitant use of other neurotoxic or nephrotoxic drugs, and cumulative dose.  Peak and trough serum levels should be measured periodically during therapy to assure adequate levels and to avoid potentially toxic levels (see WARNINGS and PRECAUTIONS ).  Tobramycin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.  Dose reduction is required for patients with impaired renal function (see DOSAGE AND ADMINISTRATION ).  Elderly patients may have reduced renal function that may not be evident in the results of routine screening tests, such as BUN or serum creatinine.  A creatinine clearance determination may be more useful.  Monitoring of renal function during treatment with aminoglycosides is particularly important in the elderly (see PRECAUTIONS ).

Tobraymcin 20 mg/2 mL vial contains 1.56 mg (0.068 mEq) of sodium.

Page last updated: 2012-09-05

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