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.

Inhaled liposomal amikacin has not been studied in patients with renal impairment.

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.

In clinical trials, exacerbation of underlying pulmonary disease (chronic obstructive pulmonary disease, infective exacerbation of chronic obstructive pulmonary disease, infective exacerbation of bronchiectasis) was reported with a higher frequency in patients treated with inhaled liposomal amikacin compared with patients not receiving inhaled liposomal amikacin. Caution should be exercised when initiating inhaled liposomal amikacin in patients presenting with these underlying conditions. Discontinuation of treatment with inhaled liposomal amikacin should be considered if signs of exacerbation are observed.

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

There are no data from the use of inhaled liposomal amikacin in pregnant women. Systemic exposure to amikacin following inhalation of inhaled liposomal amikacin is expected to be low compared to parenteral administration of amikacin.

There are limited data from the use of aminoglycosides in pregnant women. 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 reactions on the foetus or newborns have not been reported in pregnant women treated with other aminoglycosides, the potential for harm exists. Animal reproductive toxicity studies have not been conducted with inhaled amikacin. In reproductive toxicity studies in mice, rats and rabbits with amikacin administered parenterally, no foetal malformations were reported.

As a precautionary measure, it is preferable to avoid the use of inhaled liposomal amikacin during pregnancy.

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

There is no information regarding the presence of amikacin in human milk. However, systemic exposure to inhaled liposomal amikacin following inhalation is expected to be low compared to parenteral administration of amikacin.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from inhaled liposomal amikacin therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

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

No fertility studies were conducted with inhaled liposomal amikacin.

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.

The administration of inhaled liposomal amikacin can cause dizziness and other vestibular disturbances. Patients should be advised not to drive or operate machinery while using inhaled liposomal amikacin.

IM / IV administration

The list is presented by system organ class, MedDRA preferred term, and frequency using the following frequency categories: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), and not known (cannot be estimated from the available data).

^a Amikacin is not formulated for intavitreal use. Blindness and retinal infarction have been reported following intravitreous administrations (injection into the eye) of amikacin.

All aminoglycosides have the potential to induce ototoxicity, renal toxicity, and neuromuscular blockade. These toxicities occur more frequently in patients with renal impairment, in patients treated with other ototoxic or nephrotoxic drugs, and in patients treated for longer periods and/or with higher doses than recommended.

Renal function changes are usually reversible when the drug is discontinued.

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 by audiometric testing.

Inhaled liposomal amikacin

Summary of the safety profile

The most commonly reported respiratory adverse reactions were dysphonia (42.6%), cough (30.9%), dyspnoea (14.4%), haemoptysis (10.9%), oropharyngeal pain (9.2%), and bronchospasm (2.2%). Other commonly reported non-respiratory adverse reactions included fatigue (7.2%), diarrhoea (6.4%), infective exacerbation of bronchiectasis (6.2%), and nausea (5.9%).

Most common serious adverse reactions included Chronic Obstructive Pulmonary Disease (COPD) (1.5%), haemoptysis (1.2%), and infective exacerbation of bronchiectasis (1.0%).

Tabulated list of adverse reactions

Adverse drug reactions in the table below are listed according to system organ classes in MedDRA based on clinical trials and post marketing data. Within each system organ class, the following definitions apply to the frequency terminology used hereafter: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known: (cannot be estimated from the available data).

Summary of adverse reactions: