SELEMYCIN Solution for injection/infusion Ref.[28294] Active ingredients: Amikacin

Caution should be applied to patients with pre-existing renal insufficiency, or pre-existing hearing or vestibular damage. 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. Precautions on dosage and adequate hydration should be observed.

In patients with impaired renal function or diminished glomerular filtration, renal function should be assessed by the usual methods prior to therapy and periodically during therapy. Daily doses should be reduced and/or the interval between doses lengthened in accordance with serum creatinine concentrations to avoid accumulation of abnormally high blood levels and to minimise the risk of ototoxicity. Regular monitoring of serum drug concentration and of renal function is particularly important in elderly patients, who may have reduced renal function that may not be evident in the results of routine screening tests i.e. blood urea and serum creatinine.

If therapy is expected to last seven days or more in patients with renal impairment, or 10 days in other patients, a pre-treatment audiogram should be obtained and repeated during therapy. Amikacin therapy should be stopped if tinnitus or subjective hearing loss develops, or if follow-up audiograms show significant loss of high frequency response.

Neurotoxicity /Ototoxicity

Neurotoxicity, manifested as vestibular and/or bilateral auditory ototoxicity, can occur in patients treated with aminoglycosides. The risk of aminoglycoside-induced ototoxicity is greater in patients with impaired renal function, and in those who receive high doses, or in those whose therapy is prolonged over 5-7 days. 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 ototoxicity due to aminoglycosides increases with the degree of exposure to either persistently high peak or high trough serum concentrations. Patients developing cochlear or vestibular damage may not have symptoms during therapy to warn them of developing eighth nerve toxicity, and total or partial irreversible bilateral deafness or disabling vertigo may occur after the drug has been discontinued. Aminoglycoside-induced ototoxicity is usually irreversible.

The use of amikacin in patients with a history of allergy to aminoglycosides or in patients who may have subclinical renal or eighth nerve damage induced by prior administration of nephrotoxic and/or ototoxic agents such as streptomycin, dihydrostreptomycin, gentamicin, tobramycin, kanamycin, bekanamycin, neomycin, polymyxin B, colistin, cephaloridine, or viomycin should be considered with caution, as toxicity may be additive.

In these patients amikacin should be used only if, in the opinion of the physician, therapeutic advantages outweigh the potential risks.

Neuromuscular toxicity

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 respiratory paralysis should be considered if aminoglycosides are administered by any route, especially in patients receiving anesthetics, neuromuscular blocking agents (see section 4.5), or in patients receiving massive transfusions of citrate-anticoagulated blood. If neuromuscular blockade occurs, calcium salts may reverse respiratory paralysis, but mechanical respiratory assistance may be necessary. Neuromuscular blockade and muscular paralysis have been demonstrated in laboratory animals given high doses of amikacin.

Amikacin must not be used in patients with Myasthenia Gravis. Aminoglycosides should be used with caution in patients with muscular disorders such as parkinsonism, since these drugs may aggravate muscle weakness because of their potential curare-like effect on the neuromuscular junction.

Renal toxicity

Aminoglycosides are potentially nephrotoxic. Renal toxicity is independent of plasma obtained at the peak (Cmax). The risk of nephrotoxicity is greater in patients with impaired renal function, and in those who receive high doses, or in those whose therapy is prolonged. Patients should be well hydrated during treatment and renal function should be assessed by the usual methods prior to starting therapy and daily during the course of treatment. A reduction of dosage is required if evidence of renal dysfunction occurs, such as presence of urinary casts, white or red cells, albuminuria, decreased creatinine clearance, decreased urine specific gravity, increased BUN, serum creatinine, or oliguria. If azotemia increases, or if a progressive decrease in urinary output occurs, treatment should be stopped.

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 in elderly patients during treatment with aminoglycosides is particularly important.

Renal and eighth-cranial 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. 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.

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).

Allergic reactions

Amikacin sulphate injection in vials contains sodium metabisulphite (E223), a sulphite 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 sulphite sensitivity in the general population is uncommon and probably low. Sulphite sensitivity is seen more frequently in asthmatic than in non-asthmatic subjects.

Other

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.

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 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.

Macular infarction sometimes leading to permanent loss of vision has been reported following intravitreous administration (injection into the eye) of amikacin.

Paediatric population

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.

The intraperitoneal use of amikacin is not recommended in young children.

Selemycin 100mg/2ml solution for injection/infusion contains 0.13 mmol sodium per 2 ml. This medicinal product contains less than 1 mmol sodium (23 mg) per ml, i.e. essentially ‘sodium-free’.

Selemycin 250mg/2ml solution for injection/infusion contains 0.33 mmol sodium per 2 ml. This medicinal product contains less than 1 mmol sodium (23 mg) per ml, i.e. essentially ‘sodium-free’.

Selemycin 500mg/2ml solution for injection/infusion contains 0.65 mmol sodium per 2 ml. This medicinal product contains less than 1 mmol sodium (23 mg) per ml, i.e. essentially ‘sodium-free’.

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. 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.

The use of amikacin is not recommended in patients under the influence of anaesthetics or muscle-relaxing drugs (including ether, halothane, d-tubocurarine, succinylcholine decamethonium, atracurium, rocuronium, vecuronium or in patients receiving massive transfusions of citrate-anticoagulated blood) as neuromuscular blockade and consequent respiratory depression may occur. If blockade occurs, calcium salts may reverse this phenomenon.

Indomethacin may increase the plasma concentration of amikacin in neonates.

In patients with severely impaired renal function, a reduction in activity of aminoglycosides may occur with concomitant use of penicillin-type drugs.

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 betalactamase).

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

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

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

Pregnancy

Amikacin should be administered to pregnant women and neonatal infants only when clearly needed and under medical supervision (see section 4.4).

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 new-borns 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.

Breast-feeding

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.

Fertility

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

No studies on the effects on the ability to drive and use machines have been performed. Due to the occurrence of some adverse reactions (see section 4.8) the ability to drive and use machinery may be impaired.

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 See section 4.4.
^b 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 (see section 4.4).

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 (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Fax: +357 22608649..

Selemycin is incompatible with some penicillins and cephalosporins, amphotericin chlorothiazide sodium, erythromycin gluceptate, heparin, nitrofurantoin sodium, phenytoin sodium, thiopentone sodium and warfarin sodium, and depending on the composition and strength of the vehicle, tetracyclines, vitamins of the B group with vitamin C, and potassium chloride.

At times, Selemycin may be indicated as concurrent therapy with other antibacterial agents in mixed or superinfections. In such instances, Selemycin should not be physically mixed with other antibacterial agents in syringes, infusion bottles or any other equipment. Each agent should be administered separately.