Amikacin

In patients with renal impairment reflected by creatinine clearance less than 50 mL/min, administration of the recommended total daily dose of amikacin in single daily doses is not desirable since these patients will have protracted exposure to high trough concentrations. See below for dosage adjustments in patients with impaired renal function.

For patients with impaired renal function receiving usual twice or three times daily dosing, whenever possible, serum amikacin concentrations should be monitored by appropriate assay procedures. Doses should be adjusted in patients with impaired renal function either by administering normal doses at prolonged intervals or by administering reduced doses at fixed intervals.

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, including modification when dialysis is being performed.

Normal Dose at Prolonged Intervals Between Dosing: If the creatinine clearance rate is not available and the patient’s condition is stable, a dosage interval in hours for the normal single dose (i.e., that which would be given to patients with normal renal function on a twice daily schedule, 7.5 mg/kg) can be calculated by multiplying the patient’s serum creatinine concentration (in mg/100mL) by nine; 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 Dose at Fixed Time Intervals Between Dosing: When renal function is impaired and it is desirable to administer amikacin sulfate injection at a fixed time interval, dose must be reduced. In these patients, serum amikacin concentrations should be measured to assure accurate administration and to avoid excessive serum concentrations. 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 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:

Maintenance dose every 12 hours = observed CrCl in mL/min x calculated loading dose in mg / normal Cr/Cl in mL/min

(CrCl = creatinine clearance rate)

An alternate rough guide for determining reduced dosage at twelve-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.

As renal function may alter appreciably during therapy, the serum creatinine should be checked frequently and the dosage regimen modified as necessary.

Injection of calcium salts may reverse the neuromuscular blockade due to aminoglycosides.

The risk of ototoxicity is increased when amikacin is used in conjunction with rapidly acting diuretic drugs, particularly when the diuretic is administered intravenously. Diuretics may enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. Such agents include furosemide and ethacrynic acid which is itself an ototoxic agent. Irreversible deafness may result.

In vitro admixture of aminoglycosides with beta-lactam antibiotics (penicillins or cephalosporins) may result in significant mutual inactivation. A reduction in serum activity may also occur when an aminoglycoside or penicillin-type drug is administered in vivo 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).

There is an increased risk of nephrotoxicity and possibly of ototoxicity when aminoglycosides are administered with platinum compounds.

There is an increased risk of hypocalcaemia when aminoglycosides are administered with bisphosphonates.

Concurrent or serial use with other neurotoxic, ototoxic or nephrotoxic agents, particularly bacitracin, cisplatin, amphotericin B, cyclosporine, tacrolimus, cephaloridine, paromomycin, viomycin, polymyxin B, colistin, vancomycin, or other aminoglycosides 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 cephalosporin use may spuriously elevate creatinine serum level determinations. Where this is not possible, monitor carefully.

Aminoglycosides may increase the detrimental effect of methoxyflurane on the kidneys. When used at the same time, extremely severe neuropathies are likely to occur.

Concomitantly administered thiamine (vitamin B₁) may be destroyed by the reactive sodium metabisulfite component of the amikacin sulfate formulation.

Indomethacin may increase the plasma concentration of amikacin in neonates.

IM / IV administration

Amikacin should be administered to pregnant women and neonatal infants only when clearly needed and under medical supervision.

There are limited data on use of aminoglycosides in pregnancy. Aminoglycosides can cause foetal harm. Aminoglycosides cross the placenta and there have been reports of total, irreversible, bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Although adverse effects on the foetus or newborns have not been reported in pregnant women treated with other aminoglycosides, the potential for harm exists. If amikacin 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 foetus.

Respiratory administration

Risk Summary

There are no data on amikacin use in pregnant women to evaluate for any drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Although systemic absorption of amikacin following oral inhalation is expected to be low, systemic exposure to aminoglycoside antibacterial drugs, including amikacin, may be associated with total, irreversible, bilateral congenital deafness when administered to pregnant women. Advise pregnant women of the potential risk to a fetus.

Animal reproductive toxicology studies have not been conducted with inhaled amikacin. Subcutaneous administration of amikacin to pregnant rats (up to 100 mg/kg/day) and mice (up to 400 mg/kg/day) during organogenesis was not associated with fetal malformations. Ototoxicity was not adequately evaluated in offspring in animal studies.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

No animal reproductive toxicology studies have been conducted with amikacin or non-liposomal amikacin administered by inhalation.

Amikacin was subcutaneously administered to pregnant rats (Gestation Days 8-14) and mice (Gestation Days 7-13) at doses of 25, 100, or 400 mg/kg to assess developmental toxicity. These doses did not cause fetal visceral or skeletal malformations in mice. The high dose was excessively maternally toxic in rats (nephrotoxicity and mortality were observed), precluding the evaluation of offspring at this dose. Fetal malformations were not observed at the low or mid dose in rats. Postnatal development of the rats and mice exposed to these doses of amikacin in utero did not differ significantly from control.

Ototoxicity was not adequately evaluated in offspring in animal developmental toxicology studies.

IM / IV administration

It is not known whether amikacin is excreted in human milk. A decision should be made whether to discontinue breast-feeding or to discontinue therapy.

Respiratory administration

Risk Summary

There is no information regarding the presence of amikacin in human milk, the effects on the breastfed infant, or the effects on milk production after administration of amikacin by inhalation. Although limited published data on other routes of administration of amikacin indicate that amikacin is present in human milk, systemic absorption of amikacin following inhaled administration is expected to be low. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for amikacin and any potential adverse effects on the breastfed child from amikacin or from the underlying maternal condition.

IM / IV administration

In reproduction toxicity studies in mice and rats, no effects on fertility or foetal toxicity were reported.

Respiratory administration

In a 2-year inhalation carcinogenicity study, rats were exposed to amikacin for 15-25, 50-70, or 155-170 minutes per day for 96-104 weeks. These provided approximate inhaled doses of 5, 15, and 45 mg/kg/day. Squamous cell carcinoma was observed in the lungs of 2 of 120 rats administered the highest dose tested. Maximum serum AUC levels of amikacin in the rats at steady state were approximately 1.3, 2.8, and 7.6 mcg∙hr/mL at the low, mid, and high doses, respectively, compared with 23.5 mcg∙hr/mL (8.0 to 46.5 mcg∙hr/mL) measured in humans. The squamous cell carcinomas may be the result of a high lung burden of particulates from amikacin in the rat lung. The relevance of the lung tumor findings with regards to humans receiving amikacin is unknown.

No evidence of mutagenicity or genotoxicity was observed in a battery of in vitro and in vivo genotoxicity studies with a liposome-encapsulated amikacin formulation similar to amikacin (in vitro microbial mutagenesis test, in vitro mouse lymphoma mutation assay, in vitro chromosomal aberration study, and an in vivo micronucleus study in rats).

Intraperitoneal administration of amikacin to male and female rats at doses up to 200 mg/kg/day prior to mating through Day 7 of gestation were not associated with impairment of fertility or adverse effects on early embryonic development.

No studies on the effects on the ability to drive and use machines have been performed. Due to the occurrence of some adverse reactions the ability to drive and use machinery may be impaired.