Amdipharm Limited

Genticin^® 80mg/2ml Solution for Injection.

Gentamicin sulphate equivalent to 4.0% w/v (80mg) gentamicin base.

For excipients, see section 6.1.

Solution for injection.

Each ampoule contains a sterile, clear, colourless to pale yellow liquid. The solution is preservative free.

Genticin Injectable ampoules are indicated for the treatment of systemic infections due to susceptible bacteria such as, bacteraemia, septicaemia, urinary-tract infections and severe chest infections.

Genticin is normally administered intramuscularly but may be given intravenously as a slow intravenous injection over at least 3 minutes or short infusion if required. Genticin should not be given as a slow infusion or mixed with other drugs before use (see Incompatibilities).

With either intramuscular or intravenous administration the following dosage applies for patients with normal renal function:

Adults

3 - 4mg/kg body weight daily in divided doses. Typical doses are 80 mg 8-hourly for patients over 60 kg and 60 mg 8-hourly for patients less than 60 kg.

In cases of impaired renal function a reduction in dosage frequency is recommended. The following table is a guide to recommended dosage schedules:

In life-threatening infections the frequency of dosage may need to be increased to 6-hourly and the quantity of each dose may also be increased at the discretion of the clinician up to a total dosage of 5mg/kg in 24 hours. In such cases it is advisable to monitor gentamicin serum levels.

If renal function is not impaired, 160mg once daily may be used in some cases.

Elderly

Adjust dosage according to weight and renal function. Periodic serum monitoring is desirable.

Children

In children and in neonates, it can be expected that serum levels will be lower than those found in adults at equivalent dosage per kg body weight.

The recommended paediatric dosage is therefore as follows:

Up to 12 years:

6mg/kg in 24 hours in three equally divided doses (i.e. 2mg/kg 8-hourly).

In infants up to 2 weeks this dosage should be given in two equally divided doses (i.e. 3mg/kg 12-hourly).

Serum peak and trough levels should be monitored regularly. Peak levels should be measured about 1 hour after intramuscular or intravenous injection and should reach 4 micrograms/ml, but not exceed 10 micrograms/ml. Trough levels should be measured just prior to a dose and should be below 2 micrograms/ml.

Prolonged use should be avoided and whenever possible the treatment should not exceed 7 days.

Caution is advised in significant obesity as gentamicin is poorly distributed into fatty tissue. The dosage calculation should be based on an estimate of lean body weight. Serum levels should be monitored closely and the dose possibly adjusted (see 4.4).

Hypersensitivity to gentamicin, any other ingredient or to other aminoglycosides.

Myasthenia gravis.

Where renal function is impaired through disease or old age the frequency, but not the amount, of each dose should be reduced according to the degree of impairment. Gentamicin is excreted by simple glomerular filtration, and dosage frequency may be predicted by assessing creatinine clearance rates or blood urea and reducing the frequency accordingly.

It is also advisable to check serum levels to confirm that peak (1 hour) levels do not exceed 10 micrograms/ml and that trough levels (before next injection) do not exceed 2 micrograms/ml.

Caution is required in Parkinsonism and other conditions characterised by muscular weakness.

Regular assessment of auditory, vestibular and renal function is particularly necessary in patients with additional risk factors. Impaired hepatic function or auditory function, bacteraemia and fever have been reported to increase the risk of ototoxicity. Volume depletion or hypotension and liver disease have been reported as additional risk factors for nephrotoxicity.

Caution is advised in significant obesity (see 4.2).

Gentamicin should not be used concurrently with other potentially nephrotoxic or ototoxic drug substances unless considered essential by the physician. The potential nephrotoxicity of other aminoglycosides, vancomycin and some cephalosporins (when used in conjunction with gentamicin and reported renal failure), ciclosporin, cisplatin, fludarabine and amphotericin may be increased in the presence of gentamicin and monitoring of renal function is therefore recommended.

Furosemide (frusemide) and piretanide may potentiate the ototoxicity of gentamicin, and etacrynic acid, which is ototoxic in its own right, should be avoided with gentamicin.

Aminoglycosides, including gentamicin, may induce neuromuscular blockade and respiratory paralysis and should therefore only be used with great caution in patients receiving curare-type muscle relaxants.

Aminoglycosides antagonise the effects of cholinergic agents such as neostigmine and pyridostigmine.

Indometacin has been reported to increase the plasma concentrations of aminoglycosides when given concomitantly.

Bacteriostatic antibiotics may give an antagonistic interaction, but in some cases (e.g. with clindamycin and lincomycin) the disadvantage of antagonism may be outweighed by the addition of activity against anaerobic organisms. Synergistic action has been demonstrated with penicillin. However, if penicillins (such as ticarcillin) are used with gentamicin the drugs should not be physically mixed. In cases where both drugs need to be administered intravenously, patients with poor renal function should be monitored for effectiveness of the gentamicin. There should also be an intervenining flush of suitable fluid between both medicinal products, or they should be given at separate sites (see also 6.2 Incompatibilities). Cross-sensitivity with aminoglycosides may occur.

Safety for use in pregnancy and lactation has not been established. Gentamicin crosses the placenta and there is a risk of ototoxicity (auditory or vestibular nerve damage) in the foetus. Gentamicin should only be used where the seriousness of the mother's condition justifies the risk and use is considered essential by the physician. In such cases, serum gentamicin concentration monitoring is essential. Some animal studies have shown a teratogenic effect.

Gentamicin is excreted in breast milk, but is unlikely to be a hazard to the infant except in the presence of maternal renal insufficiency when breast-feeding should be avoided, as the levels in breast milk then rise appreciably.

None.

As with all aminoglycosides, at critical levels gentamicin exhibits toxicity.

Blood and lymphatic system disorders

Blood dyscrasias, including pancytopenia and neutropenia, have been reported infrequently.

Electrolyte disturbances (e.g. hypomagnesaemia) have occurred rarely.

Immune system disorders

Hypersensitivity reactions and allergic rashes have occurred. Very rarely, anaphylactic reactions to gentamicin have occurred.

Nervous system disorders

Vestibular damage or hearing loss may occur, particularly after exposure to ototoxic drugs or in the presence of renal dysfunction. With gentamicin the vestibular mechanism may be affected when peak serum levels of 10 micrograms/ml or trough levels of 2 micrograms/ml are exceeded. This is usually reversible if observed promptly and the dose adjusted. In patients with normal renal function these levels are unlikely at standard dosage.

Gentamicin can cause neuromuscular blockade which may unmask or aggravate myasthenia gravis and cause postoperative respiratory distress.

Central neurotoxicity, including encephalopathy, convulsions, confusion, hallucinations and mental depression has been reported with gentamicin therapy, but this is extremely rare.

Gastrointestinal disorders

Infrequent effects reported include nausea, vomiting and stomatitis.

Gentamicin has rarely been associated with pseudomembranous colitis and usually in these cases other antibiotics are also involved.

Hepato-biliary disorders

Signs of liver dysfunction such as transient elevation of serum aminotransferase values and increased serum bilirubin concentration have been reported infrequently.

Renal and urinary disorders

Nephrotoxicity may occur, resulting in a gradual reduction in creatinine clearance after several days of treatment. This is usually reversible if the drug is withdrawn. Nephrotoxicity is more common if trough serum concentrations exceed 2 micrograms/ml and where there is pre-existing renal disease or concomitant treatment with other nephrotoxic agents. Renal failure, tubular necrosis and interstitial nephritis have been reported.

Skin and subcutaneous Tisse Disorders

Rash, pruritus and urticaria have been reported.

Symptoms include dizziness, vertigo and hearing loss if overdose accidentally given parenterally.

If the reaction is severe consider haemodialysis as treatment.

Gentamicin may be removed from the body by haemodialysis or peritoneal dialysis. Calcium salts given intravenously have been used to counter the neuromuscular blockade caused by gentamicin.

Gentamicin is a bactericidal aminoglycoside antibiotic which acts by inhibiting protein synthesis.

Gentamicin is rapidly absorbed following intramuscular injection, giving peak plasma concentrations after 30 minutes - 1 hour. Effective concentrations are still present 4 hours after injection. An injection of 1mg/kg body weight results in a peak plasma concentration of approximately 4 micrograms/ml.

> 90% gentamicin is excreted in the urine by glomerular filtration.

< 10% is bound to plasma protein.

T_½ = 2 - 3 hours in individuals with normal kidney function, but can be increased in individuals with renal insufficiency.

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

Water for Injections

Sulphuric acid.

In general, mixing Genticin with other drugs prior to administration is not advised. In particular the following are incompatible in mixed solution: penicillins, cephalosporins, erythromycin, lipiphysan, heparins and sodium bicarbonate. In the latter case carbon dioxide may be liberated on addition of the two solutions. Normally this will dissolve in the solution, but under some circumstances small bubbles may form.

Dilution in the body will obviate the danger of physical and chemical incompatibility and enable Genticin Injectable to be given concurrently with the drugs listed above either as a bolus injection into the drip tubing with adequate flushing, or at separate sites. However, in the case of carbenicillin and gentamicin they should only be given at separate sites.

4 years.

Do not store above 25°C. Do not freeze.

Genticin is available in colourless, Type I glass ampoules containing 2ml, in boxes of 10 ampoules.

Discard any portion of the contents remaining after use.

Amdipharm Limited

Temple Chambers

3 Burlington Road

Dublin 4

Ireland

PA 1142/13/1

20^th April 1995/ 20^th April 2005

May 2008

Genticin is a registered trade mark