Amikacin Sulfate Injection  Precautions

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, USP 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 aminoglycoside 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 (see DOSAGE AND ADMINISTRATION)  are not exceeded. 

Elderly patients may have reduced renal function which may not be evident in routinescreening 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 beta-lactamase). 

Cross-allergenicity among aminoglycosides has been demonstrated. 

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

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

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 sulfate administered subcutaneously to rats at doses up to 4 times the human daily dose did not impair male or female fertility. 

Pregnancy  

-Category D (See “WARNINGS” section). 

Nursing Mother 

s-It is not known whether amikacin 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.

General

Prescribing amikacin 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. 
Information for Patients 

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

ADVERSE REACTIONS 

All aminoglycosides  have the potential to induce auditory, vestibular, and renal toxicity and neuromuscular blockade (see “WARNINGS” box). They occur more frequently in patients with present  or past history of renal impairment, of treatment with other ototoxic or nephrotoxic drugs, and  in patients treated for longer periods and/or with higher doses than recommended. 

Neurotoxicity-Ototoxicity-Toxic effects on  the eighth cranial nerve can result in hearing loss, loss of balance,  or both. Amikacin primarily affects auditory function. Cochlear damage, includes high frequency deafness and usually occurs before clinical hearing loss can be detected. 

Neurotoxicity-Neuromuscular Blockage-Acute muscular paralysis and apnea can occur following treatment with aminoglycoside drugs. 

Nephrotoxicity-Elevation of serum creatinine, albuminuria, presence of red and white cells, casts, azotemia, and oliguria have been reported. Renal function changes  are usually reversible when the drug is discontinued. As would be expected with any aminoglycoside, reports of toxic nephropathy and acute renal failure have been received during postmarketing surveillance. 

Other-In addition  to those described above, other adverse reactions which have been reported on rare occasions  are skin rash, drug fever, headache, paresthesia, tremor, nausea and vomiting, eosinophilia, arthralgia, anemia, hypotension, and hypomagnesemia. Macular infarction sometimes leading to permanent loss of vision has been reported following intravitreous administration (injection into  the eye) of amikacin. 

OVERDOSAGE

In the event of overdosage or toxic reaction, peritoneal dialysis or hemodialysis will aid in the removal of amikacin from the blood. In the newborn infant, exchange transfusion may also be considered. 

DOSAGE AND ADMINISTRATION 

The patient’s pretreatment body weight should be obtained for calculation of correct dosage. Amikacin Sulfate Injection, USP may be given intramuscularly or intravenously. 

The status of renal function should be estimated by measurement of the serum creatinine concentration or calculation of the endogenous creatinine clearance rate. The blood urea nitrogen (BUN) is much less reliable for this purpose. Reassessment of renal function should be made periodically during therapy. 

Whenever possible, amikacin concentrations in serum should be measured to assure adequate but not excessive levels. It is desirable to measure both peak and trough serum concentrations intermittently during therapy. Peak concentrations (30-90 minutes after injection) above 35 micrograms per mL and trough concentrations (just prior to the next dose) above 10 micrograms per mL should be avoided. Dosage should be adjusted as indicated. 
Intramuscular Administration for Patients with Normal Renal Function-The recommended dosage for adults, children and older infants (see “WARNINGS” box) with normal renal function is 15 mg/kg/day divided into 2 or 3 equal doses administered  at equally-divided intervals, i.e., 7.5 mg/kg q.12h or 5 mg/kg q.8h. Treatment of patients in  the heavier weight classes should not exceed 1.5 gram/day. 

When amikacin is indicated in newborns (see “WARNINGS” box), it is recommended that a loading dose of 10 mg/kg be administered initially to be followed with 7.5 mg/kg every 12 hours. 

The usual duration of treatment is 7 to 10 days.  It is desirable to limit the duration of treatment to short term whenever feasible. The total daily dose by all routes of administration should not exceed 15 mg/kg/day. In difficult and complicated infections where treatment beyond 10 days is considered, the use of amikacin  should be re-evaluated. If continued, amikacin serum levels  and renal, auditory, and vestibular functions should be monitored. At the recommended dosage level, uncomplicated infections due to amikacin-sensitive organisms should respond in 24 to 48 hours. If definite clinical response does not occur within 3 to 5 days, therapy should be stopped and the antibiotic susceptibility pattern  of the invading organism should be rechecked. Failure of  the infection  to respond may be due to resistance of the organism or to the presence of septic foci requiring surgical drainage. 

When amikacin is indicated in uncomplicated urinary tract infections, a dose of 250 mg twice daily may be used. 

Intramuscular Administration for Patients with Impaired Renal Function-Whenever possible, serum amikacin concentrations should be monitored by appropriate assay procedures. Doses may be adjusted in patients with impaired renal function either by administering normal doses at prolonged intervals or by administering reduced doses at a fixed interval. 

Both methods  are based on the patient’s creatinine clearance or serum creatinine values since these have been found to correlate with aminoglycoside half-lives in patients with diminished renal function. These dosage schedules must 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. 

Normal Dosage at Prolonged Intervals-If the creatinine clearance rate is  not available and  the patient’s condition  is stable, a dosage interval in hours for the normal dose can be calculated by multiplying the patient’s serum creatinine by 9, e.g.,  if the serum creatinine concentration is 2 mg/100 mL, the recommended single dose (7.5 mg/kg) should be administered every 18 hours. 

Reduced Dosage at Fixed Time Intervals-When renal function is impaired and  it is desirable to administer amikacin at a fixed time interval, dosage must be reduced. In these patients serum amikacin concentrations should be measured to assure accurate administration of amikacin and to avoid concentrations above 35 mcg/mL. If serum assay determinations are not available and  the patient’s condition is stable, serum creatinine and creatinine clearance values are the most readily available indicators of the degree of renal impairment to use as  a guide for dosage. 

First, initiate therapy by administering a normal dose, 7.5 mg/kg, as a loading dose. This loading dose is  the same as the normally recommended dose which would be calculated for a patient with a normal renal function as described above. 

To determine the size of maintenance doses administered every 12 hours, the loading dose should be reduced in proportion  to the reduction in the patient’s creatinine clearance rate: 

An alternate rough guide for determining reduced dosage at 12 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. 
The above dosage schedules are not intended to be rigid recommendations but are provided as guides to dosage when the measurement of amikacin serum levels  is not feasible. 

Intravenous Administration-The individual dose, the total daily dose, and the total cumulative dose of amikacin sulfate are identical to the dose recommended for intramuscular administration. The solution for intravenous  use is prepared by adding the contents of a 500 mg vial to 100-200 mL of sterile diluent such  as 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP or any of the compatible solutions listed below. 

The solution is administered to adults over a 30 to 60 minute period. The total daily dose should  not exceed 15 mg/kg/day and may be divided into either 2 or 3 equally-divided doses at equally-divided intervals. 
In pediatric patients the amount of fluid used will depend  on the amount ordered  for the patient. It should be a sufficient amount to infuse the amikacin over a 30 to 60 minute period. Infants should receive a 1 to 2 hour infusion. 

Stability in I.V. Fluids-Amikacin sulfate is stable for 24 hours at room temperature at concentrations of 0.25  and 5.0 mg/mL  in the following solutions: 

• 5% Dextrose Injection, USP 
• 5% Dextrose and 0.2% Sodium Chloride Injection, USP 
• 5% Dextrose and 0.45% Sodium Chloride Injection, USP 
• 0.9% Sodium Chloride Injection, USP 
• Lactated Ringer’s Injection, USP 
• Normosol®-M in 5% Dextrose Injection 
• Normosol®-R in 5% Dextrose Injection 

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. 

Aminoglycosides administered by any of the above routes should  not be physically premixed with other drugs but should be administered separately. 

Because of the potential toxicity of aminoglycosides, “fixed dosage”recommendations which are not based upon body weight are not advised. Rather, it is essential  to calculate the dosage  to fit  the needs of each patient. 
To prevent needle-stick injuries, needles should not be recapped, purposely bent,  or broken by hand.