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Pharmacotherapeutic group: Antiinfectives for systemic use, Aminoglycoside antibacterials; Other aminoglycosides, ATC code: J01G B06 Amikacin sulphate is an aminoglycoside antibiotic which is active against a broad spectrum of Gramnegative organisms, including Pseudomonas spp, Escherichia coli, indole-positive and indolenegative Proteus spp, Klebsiella-Enterobacter-Serratia spp, Salmonella, Shigella, Minea-Herellae, Citrobacter Freundii and Providencia spp. Many strains of these Gram-negative organisms resistant to gentamicin and tobramycin may show sensitivity to amikacin in vitro. The principal Gram-positive organism sensitive to amikacin is Staphylococcus aureus, including methicillin-resistant strains. Amikacin has some activity against other Gram-positive organisms including certain strains of Streptococcus pyogenes, Enterococci and Diplococcus pneumoniae.

Each ampoule contains amikacin 500 mg as amikacin sulfate. Excipients with known effect: sodium metabisulphite and sodium.

Amikacin sulphate is an aminoglycoside antibiotic which is active against a broad spectrum of Gramnegative organisms, including Pseudomonas spp., Escherichia coli, indole-positive and indolenegative Proteus spp., Klebsiella-Enterobacter-Serratia spp, Salmonella, Shigella, Minea-Herellae, Citrobacter freundii and Providencia spp. Many strains of these gram-negative organisms resistant to gentamicin and tobramycin may show sensitivity to amikacin in vitro. The principal Gram-positive organism sensitive to amikacin is Staphylococcus aureus, including methicillin-resistant strains. Amikacin has some activity against other Gram-positive organisms including certain strains of Streptococcus pyogenes, Enterococci and Diplococcus pneumoniae. Amikacin is indicated in the short-term treatment of serious infections due to susceptible strains of Gram-negative bacteria. It may also be indicated for the treatment of known or suspected staphylococcal disease. Consideration should be given to official guidance on the appropriate use of antibacterial agents.

A history of hypersensitivity or serious toxic reactions to aminoglycosides may contraindicate the use of any aminoglycoside because of the known cross sensitivities of patients to drugs in this class. Myasthenia gravis.

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). 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. 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 via the national reporting system

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 musclerelaxing drugs (including ether, halothane, d-tubocurarine, succinylcholine decamethonium, atracurium, rocuronium, vecuronium or in patients receiving massive transfusions of citrateanticoagulated 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.

In case of overdosage there is a general risk for nephro-, oto- and neurotoxic (neuromuscular blockage) reactions. Neuromuscular blockage with respiratory arrest needs appropriate treatment including application of ionic calcium (e.g. as gluconate or lactobionat in 10-20% solution). In the event of overdosage or toxic reaction, peritoneal dialysis or haemodialysis will aid in the removal of amikacin from the blood. Amikacin levels are also reduced during continuous arteriovenous hemofiltration. In the new-born infant, exchange transfusion may also be considered.

Posology For most infections the intramuscular route is preferred, but in life-threatening infections, or in patients in whom intramuscular injection is not feasible the intravenous route, either slow bolus (2 to 3 minutes) or infusion (0.25% over 30 minutes) may be used. Intramuscular and intravenous administration Amikacin sulphate injection may be given intramuscularly or intravenously. At the recommended dosage level, uncomplicated infections due to sensitive organisms should respond to therapy within 24 to 48 hours. If clinical response does not occur within three to five days consideration should be given to alternative therapy. The patient’s pre-treatment body weight should be obtained for calculation of correct dosage. 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 mcg/mL and trough concentrations (just prior to the next dose) above 10 mcg/mL should be avoided. Dosage should be adjusted as indicated. In patients with normal renal function, once daily dosing may be used; peak concentrations in these cases may exceed 35 mcg/mL. The usual duration of treatment is 7 to 10 days. The total daily dose by all routes of administration should not exceed 15-20 mg/kg/day. In difficult and complicated infections where treatment beyond 10 days is considered, the use of amikacin sulphate injection should be re-evaluated and if continued, renal, auditory, vestibular function should be monitored, as well as serum amikacin levels. 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. Adults and children over 12 years: The recommended intramuscular or intravenous dosage for adults and adolescents with normal renal function (creatinine clearance ≥50 mL/min) is 15 mg/kg/day which may be administered as a single daily dose or divided into 2 equal doses i.e. 7.5 mg/kg every 12 hours. The total daily dose should not exceed 1.5 g. In endocarditis and in febrile neutropenic patients dosing should be twice daily, as there is not enough data to support once daily dosing. Children 4 weeks to 12 years: The recommended intramuscular or intravenous (slow intravenous infusion) dose in children with normal renal function is 15-20 mg/kg/day which may be administered as 15-20 mg/kg, once a day; or as 7.5 mg/kg every 12 hours. In endocarditis and in febrile neutropenic patients dosing should be twice daily, as there is not enough data to support once daily dosing. Neonates: An initial loading dose of 10 mg/kg followed by 7.5 mg/kg every 12 hours Premature infants: The recommended dose in prematures is 7.5 mg/kg in every 12 hours. Specific recommendation for intravenous administration The solution for intravenous use is prepared by adding the desired dose to 100mL or 200mL of sterile diluent such as normal saline or 5% dextrose in water or any other compatible solution. The solution is administered to adults over a 30 to 60 minute period. In paediatric patients the amount of diluents used will depend on the amount of amikacin tolerated by the patient. The solution should normally be infused over a 30 to 60 minute period. Infants should receive a 1 to 2 hour infusion. Amikacin should not be physically premixed with other drugs, but should be administered separately according to the recommended dose and route. Elderly Amikacin is excreted by the renal route. Renal function should be assessed whenever possible and dosage adjusted as described under impaired renal function. Life-threatening infections and/or those caused by Pseudomonas The adult dose may be increased to 500 mg every eight hours but should neither exceed 1.5 g/day nor be administered for a period longer than 10 days. A maximum total adult dose of 15 g should not be exceeded. Urinary tract infections (other than pseudomonal infections): 7.5 mg/kg/day in two equally divided doses (equivalent to 250 mg twice daily in adults). As the activity of amikacin is enhanced by increasing the pH, a urinary alkalising agent may be administered concurrently. Impaired renal function 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 CrCl 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. Intraperitoneal use Following exploration for established peritonitis, or after peritoneal contamination due to faecal spill during surgery, amikacin may be used as an irrigant after recovery from anaesthesia in concentrations of 0.25% (2.5 mg/mL). If instillation is desired in adults, a single dose of 500 mg is diluted in 20 mL of sterile distilled water and may be instilled through a polyethylene catheter sutured into the wound at closure. If possible, instillation should be postponed until the patient has fully recovered from the effects of anaesthesia and muscle-relaxing drugs. Other routes of administration Amikacin in concentrations of 0.25% (2.5 mg/mL) may be used satisfactorily as an irrigating solution in abscess cavities, the pleural space, the peritoneum and the cerebral ventricles.

Prior to first use: Store below 30oC, in the original package. Do not refrigerate or freeze. Following dilution: in 0.9% sodium chloride and 5% glucose solutions chemical and physical in-use stability has been demonstrated for 24 hours at temperature not above 25°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.