Amikacin warnings and precautions

Amikacin
AMIKACIN SULFATE® FDA Package Insert
Description
Clinical Pharmacology
Microbiology
Indications and Usage
Contraindications
Warnings and Precautions
Adverse Reactions
Overdosage
Dosage and Administration
How Supplied
Labels and Packages

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Warnings

WARNING Patients treated with parenteral aminoglycosides should be under close clinical observation because of the potential ototoxicity and nephrotoxicity associated with their use. Safety for treatment periods which are longer than 14 days has not been established. Neurotoxicity, manifested as vestibular and permanent bilateral auditory ototoxicity, can occur in patients with preexisting renal damage and in patients with normal renal function treated at higher doses and/or for periods longer than those recommended. The risk of aminoglycoside-induced ototoxicity is greater in patients with renal damage. High frequency deafness usually occurs first and can be detected only by audiometric testing. Vertigo may occur and may be evidence of vestibular injury. Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching and convulsions. The risk of hearing loss due to aminoglycosides increases with the degree of exposure to either high peak or high trough serum concentrations. Patients developing cochlear damage may not have symptoms during therapy to warn them of developing eighth-nerve toxicity, and total or partial irreversible bilateral deafness may occur after the drug has been discontinued. Aminoglycoside-induced ototoxicity is usually irreversible. Aminoglycosides are potentially nephrotoxic. The risk of nephrotoxicity is greater in patients with impaired renal function and in those who receive high doses or prolonged therapy. Neuromuscular blockade and respiratory paralysis have been reported following parenteral injection, topical instillation (as in orthopedic and abdominal irrigation or in local treatment of empyema), and following oral use of aminoglycosides. The possibility of these phenomena should be considered if aminoglycosides are administered by any route, especially in patients receiving anesthetics; neuromuscular blocking agents such as tubocurarine, succinylcholine, decamethonium; or in patients receiving massive transfusions of citrate-anticoagulated blood. If blockage occurs, calcium salts may reverse these phenomena, but mechanical respiratory assistance may be necessary. Renal and eighth-nerve function should be closely monitored especially in patients with known or suspected renal impairment at the onset of therapy and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy. Serum concentrations of amikacin should be monitored when feasible to assure adequate levels and to avoid potentially toxic levels and prolonged peak concentrations above 35 micrograms per mL. Urine should be examined for decreased specific gravity, increased excretion of proteins and the presence of cells or casts. Blood urea nitrogen, serum creatinine or creatinine clearance should be measured periodically. Serial audiograms should be obtained where feasible in patients old enough to be tested, particularly high risk patients. Evidence of ototoxicity (dizziness, vertigo, tinnitus, roaring in the ears and hearing loss) or nephrotoxicity requires discontinuation of the drug or dosage adjustment. Concurrent and/or sequential systemic, oral or topical use of other neurotoxic or nephrotoxic products, particularly bacitracin, cisplatin, amphotericin B, cephaloridine, paromomycin, viomycin, polymyxin B, colistin, vancomycin or other aminoglycosides should be avoided. Other factors that may increase risk of toxicity are advanced age and dehydration. The concurrent use of amikacin with potent diuretics (ethacrynic acid or furosemide) should be avoided since diuretics by themselves may cause ototoxicity. In addition, when administered intravenously, diuretics may enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.

Aminoglycosides can cause fetal harm when administered to a pregnant woman. Aminoglycosides cross the placenta and there have been several reports of total irreversible, bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Although serious side effects to the fetus or newborns have not been reported in the treatment of pregnant women with other aminoglycosides, the potential for harm exists. Reproduction studies of amikacin have been performed in rats and mice and revealed no evidence of impaired fertility or harm to the fetus due to amikacin. There are no well-controlled studies in pregnant women, but investigational experience does not include any positive evidence of adverse effects to the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

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 non-asthmatic people.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amikacin, 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 antimicrobial 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 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Precautions

General

Prescribing amikacin sulfate 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.

Aminoglycosides are quickly and almost totally absorbed when they are applied topically, except to the urinary bladder, in association with surgical procedures. Irreversible deafness, renal failure and death due to neuromuscular blockade have been reported following irrigation of both small and large surgical fields with an aminoglycoside preparation.

Amikacin sulfate injection is potentially nephrotoxic, ototoxic and neurotoxic. The concurrent or serial use of other ototoxic or nephrotoxic agents should be avoided either systemically or topically because of the potential for additive effects. Increased nephrotoxicity has been reported following concomitant parenteral administration of aminoglycosides, antibiotics and cephalosporins. Concomitant cephalosporins may spuriously elevate creatinine determinations.

Since amikacin is present in high concentrations in the renal excretory system, patients should be well-hydrated to minimize chemical irritation of the renal tubules. Kidney function should be assessed by the usual methods prior to starting therapy and daily during the course of treatment.

If signs of renal irritation appear (casts, white or red cells or albumin), hydration should be increased. A reduction in dosage (see DOSAGE AND ADMINISTRATION) may be desirable if other evidence of renal dysfunction occurs such as decreased creatinine clearance; decreased urine specific gravity; increased BUN, creatinine or oliguria. If azotemia increases or if a progressive decrease in urinary output occurs, treatment should be stopped.

Note: When patients are well hydrated and kidney function is normal, the risk of nephrotoxic reactions with amikacin is low if the dosage recommendations (seeDOSAGE AND ADMINISTRATION) are not exceeded.

Elderly patients may have reduced renal function which may not be evident in 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.

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 the neuromuscular junction.

In vitro mixing of aminoglycosides with beta-lactam antibiotics (penicillin or cephalosporins) may result in a significant mutual inactivation. A reduction in serum half-life or serum level may occur when an aminoglycoside or penicillin-type drug is administered by separate routes. Inactivation of the aminoglycoside is clinically significant only in patients with severely impaired renal function. Inactivation may continue in specimens of body fluids collected for assay, resulting in inaccurate aminoglycoside readings.

Such specimens should be properly handled (assayed promptly, frozen or treated with betalactamase).

Cross-allergenicity among aminoglycosides has been demonstrated.

As with other antibiotics, the use of amikacin may result in overgrowth of non-susceptible organisms. If this occurs, appropriate therapy should be instituted.

Aminoglycosides should not be given concurrently with potent diuretics (see WARNINGS box).

Information for Patients

Patients should be counseled that antibacterial drugs including amikacin sulfate injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When amikacin sulfate 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 amikacin sulfate injection or other antibacterial drugs in the future.

Patients should be counseled that diarrhea is a common problem caused by antibiotics, and it usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken their last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term studies in animals to evaluate carcinogenic potential have not been performed, and mutagenicity has not been studied. Amikacin administered subcutaneously to rats at doses up to 4 times the human daily dose did not impair male or female fertility.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from amikacin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Aminoglycosides should be used with caution in premature and neonatal infants because of the renal immaturity of these patients and the resulting prolongation of serum half-life of these drugs.

References

Adapted from the FDA Package Insert.