Amikacin 250 mg/ml Injection

1 ml of solution for injection contains 250 mg of amikacin (as sulphate).

1 vial of 2 ml of solution for injection contains 500 mg of amikacin (as sulphate).

For excipients, see 6.1.

Solution for Injection.

Vials containing a clear, colourless to pale yellow solution

Amikacin Injection is a semi-synthetic, aminoglycoside antibiotic which is active against a broad spectrum of Gram-negative organisms, including pseudomonas and some Gram-positive organisms.

Sensitive Gram-negative organisms include; Pseudomonas aeruginosa, Escherichia coli., indole-positive and indole-negative Proteus spp., Klebsiella, Enterobacter and Serratia spp., Minea-Herralae, Citrobacter freundii, Salmonella, Shigella, Acinetobacter and Providencia spp.

Many strains of these Gram-negative organisms resistant to gentamicin and tobramycin show sensitivity to amikacin in vitro.

The principal Gram-positive organism sensitive to amikacin is Staphylococcus aureus, including some 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, including Pseudomonas species. Although amikacin is not the drug of choice for infections due to staphylococci, at times it may be indicated for the treatment of known or suspected staphylococcal disease. These situations include: the initiation of therapy for severe infections when the organisms suspected are either Gram-negative or staphylococci, patients allergic to other antibiotics, and mixed staphylococcal/Gram-negative infections.

Therapy with amikacin may be instituted prior to obtaining the results of sensitivity testing. Surgical procedures should be performed where indicated.

Consideration should be given to official guidance on the appropriate use of antibacterial Agents.

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

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.

If required, suitable diluents for intravenous use are: Normal saline, 5% dextrose in water. Once the product has been diluted the solution must be used as soon as possible and NOT STORED.

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 q 12 h. 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 q 12 h. 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 q 12 h (see sections 4.4 and 5.2).

Premature Infants

The recommended dose in prematures is 7.5 mg/kg in every 12 hours (see sections 4.4 and 5.2).

Specific recommendation for intravenous administration

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.

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 never 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 pseudomonas infections)

7.5 mg/kg/day in two equally divided doses (equivalent to 250 mg b.i.d. in adults). As the activity of amikacin is enhanced by increasing the pH, a urinary alkalinising agent may be administered concurrently.

Impaired renal function

In patients with impaired renal function, the daily dose should be reduced and/or the intervals between doses increased to avoid accumulation of the drug. A suggested method for estimating dosage in patients with known or suspected diminished renal function is to multiply the serum creatinine concentration (in mg/100 ml) by 9 and use the resulting figure as the interval in hours between doses.

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

Other routes of administration

Amikacin in concentrations 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.

Aminoglycosides may impair neuromuscular transmission, and should not be given to patients with myasthenia gravis.

Patients should be well hydrated during amikacin therapy. In patients with impaired renal function or diminished glomerular filtration amikacin should be used with caution.

In such patients, 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 ie. 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.

If signs of renal irritation appear (such as albumin, casts, red or white blood cells), hydration should be increased and a reduction in dosage may be desirable. These findings usually disappear when treatment is completed. However, if azotaemia or a progressive decrease in urine output occurs, treatment should be stopped.

As with other aminoglycosides, ototoxicity and/or nephrotoxicity can result from the use of amikacin; precautions on dosage and adequate hydration should be observed.

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, 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.

Large doses of amikacin administered during surgery have been responsible for a transient myasthenic syndrome.

Sulphites can cause allergic-type reactions including anaphylactic symptoms and bronchospasm in susceptible people, especially those with a history of asthma or allergy.

Paediatric 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.

The risk of ototoxicity is increased when amikacin is used in conjunction with rapidly acting diuretic drugs, particularly when the diuretic is administered intravenously. Such agents include furosemide and ethacrynic acid. Irreversible deafness may result.

The intraperitoneal use of amikacin is not recommended in patients under the influence of anaesthetics or muscle-relaxing drugs (including ether, halothane, d-tubocurarine, succinylcholine and decamethonium) as neuromuscular blockade and consequent respiratory depression may occur.

Concurrent use with other potentially nephrotoxic or ototoxic drug substances should be avoided. Where this is not possible, monitor carefully.

Indomethacin may increase the plasma concentration of amikacin in neonates.

There are limited data on use of aminoglycosides in pregnancy. Amnioglycosides 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. In reproduction toxicity studies in mice and rats no effects on fertility or foetal toxicity were reported. 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.

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.

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

The safety of amikacin in pregnancy has not yet been established.

Amikacin rapidly crosses the placenta into the foetal circulation and amniotic fluid, and there is a potential risk of ototoxicity in the foetus.

Not applicable.

When the recommended precautions and dosages are followed the incidence of toxic reactions, such as tinnitis, vertigo, and partial reversible deafness, skin rash, drug fever, headache, paraesthesia, nausea and vomiting is low. Urinary signs of renal irritation (albumin, casts, and red or white cells), azotaemia and oliguria have been reported.

There have been reports of retinal toxicity following intravitreal injection of amikacin.

In the event of overdosage or toxic reaction, peritoneal dialysis or haemodialysis will aid in the removal of amikacin from the blood.

ATC code: J01G B06

Amikacin is a semi-synthetic aminoglycoside antibiotic derived from Kanamycin A. It is active against a broad spectrum of Gram-negative organisms, including pseudomonas, Escherichia coli and some Gram-positive organisms, e.g. Staphylococcus aureus.

Aminoglycoside antibiotics are bactericidal in action. Although the exact mechanism of action has not been fully elucidated, the drugs appear to inhibit protein synthesis in susceptible bacteria by irreversibly binding to 30S ribosomal subunits.

Amikacin is rapidly absorbed after intramuscular injection. Peak plasma concentrations equivalent to about 20 mg/ml are achieved one hour after IM doses of 500 mg, reducing to about 2 µg/ml 10 hours after injections.

Twenty per cent or less is bound to serum protein and serum concentrations remain in the bactericidal range for sensitive organisms for 10 to 12 hours.

Single doses of 500 mg administered as an intravenous infusion over a period of 30 minutes produce a mean peak serum concentration of 38 µg/ml. Repeated infusions do not produce drug accumulation in adults with normal renal function. However, decreased renal function will lead to accumulation.

In adults with normal renal function the plasma elimination half-life of amikacin is usually 2-3 hours. 94 - 98% of a single IM or IV dose of amikacin is excreted unchanged by glomerular filtration within 24 hours. Urine concentrations of amikacin average 563 µg/ml in the first 6 hours following a single 250 mg IM dose and 163 µg/ml over 6-12 hours. Following a single 500 mg IM dose urine concentrations average 832 µg/ml in adults with normal renal function.

Amikacin diffuses readily through extracellular fluids and is excreted in the urine unchanged, primarily by glomerular filtration. It has been found in pleural fluid, amniotic fluid and in the peritoneal cavity following parenteral administration.

Data from multiple daily dose trials show that spinal fluid levels in normal infants are approximately 10 to 20% of the serum concntrations and may reach 50% in meningitis.

Intamuscular and intravenous administration

In neonates and particularly in premature babies, the renal elimination of amikacin is reduced.

In a single study in newborns (1-6 days of post natal age) grouped according to birth weights (<2000, 2000-3000 and >3000g). Amikacin was administered intramuscularly and/or intravenously at a dose of 7.5 mg/kg. Clearance in neonates >3000 g was 0.84 ml/min/kg and terminal half-life was about 7 hours. In this group, the initial volume of distribution and volume of distribution at steady state was 0.3 ml/kg and 0.5 mg/kg, respectively. In the groups with lower birth weight clearance/kg was lower and half-life longer. Repeated dosing every 12 hours in all the above groups did not demonstrate accumulation after 5 days.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Sodium citrate

Sodium metabisulphite

Water for Injections

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

Prior to first use: 36 months.

In use: 24 hours

Prior to first use: Do not store above 25°C.

In use: 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.

500 mg/2 ml – clear Type I glass vial with rubber closure in packs of 5 vials.

Single use only. Discard any unused contents.

The solution may darken from colourless to a pale yellow but this does not indicate a loss of potency.

Hospira UK Limited

Queensway

Royal Leamington Spa

Warwickshire, CV31 3RW

United Kingdom.

PL 04515/0075

24^th January 1996/23^rd May 2001

16^th September 2010