1. Name Of The Medicinal Product
Gentamicin 40 mg/ml Injection
2. Qualitative And Quantitative Composition
1 ml of solution for injection contains 40 mg of gentamicin (as sulphate)
1 vial of 2 ml solution for injection contains 80 mg of gentamicin (as sulphate)
For excipients, see 6.1
3. Pharmaceutical Form
Solution for injection.
Vials containing a clear colourless solution.
4. Clinical Particulars
4.1 Therapeutic Indications
Gentamicin is bactericidal and is active against many strains of Gram-positive and Gram-negative pathogens including species of Escherichia, Enterobacter, Klebsiella, Salmonella, Serratia, Shigella, Staphylococcus aureus, some Proteus and against Pseudomonas aeruginosa. Gentamicin is often effective against strains of these organisms which are resistant to other antibiotics such as streptomycin, kanamycin and neomycin. Gentamicin is effective against penicillin-resistant Staphylococci, but rarely effective against Streptococci.
Gentamicin is indicated in the treatment of the following infections when caused by susceptible organisms.
Severe Gram-Negative Infections:
Upper and lower urinary tract infections
Burn and wound infections
Septicaemia, Bacteraemia
Abscesses
Subacute Bacterial Endocarditis
Respiratory Tract infections (Bronchopneumonia)
Neonatal infections
Gynaecological infections
Gram-Positive Infections:
Bacteraemia
Abscesses
Accidental and operative trauma
Burns and serious skin lesions.
4.2 Posology And Method Of Administration
Gentamicin is normally given by the intramuscular route, but can be given intravenously when intramuscular administration is not feasible.
Gentamicin is normally given by the intramuscular route, but can be given intravenously when intramuscular administration is not feasible, e.g. in shocked or severely burned patients. When given intravenously, the prescribed dose should be administered slowly over 2 to 3 minutes directly into a vein or into the rubber tubing of a giving set. Rapid, direct intravenous administration may give rise, initially, to potentially neurotoxic concentrations and it is essential that the prescribed dose is administered over the recommended period of time. Alternatively the prescribed dose should be dissolved in up to 100 ml of normal saline or 5% glucose in water, but not solutions containing bicarbonate (see Incompatibilities P6B, 7h), and the solution infused over a period of 20 to 30 minutes.
The same dosage schedule is recommended for intramuscular and intravenous dosing. Dosage is related to the severity of infection, the age of the patient and the patient's renal function.
Dosage in Patients with Normal Renal Function:
1.
Adult Dosage:
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2.
Paediatric Dosage:
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3. Doses in Patients with Impaired Renal Function:
Dosage is adjusted for patients with renal impairment to minimise the risk of toxicity. The first dose should be as normal - after this, doses should be given less frequently, the interval being determined by results of renal function tests as below:
Renal Function Tests:
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Serum levels should be monitored daily.
Peak levels in infants and young children: Peak serum levels are reached in 1 hour and dosage should be adjusted to achieve levels of more than 4 micrograms/ml, but not exceed 10 micrograms/ml.
4.3 Contraindications
Patients being treated with gentamicin should be under close clinical observation because of its potential toxicity. There are no absolute contraindications other than a history of hypersensitivity to gentamicin. Gentamicin should be used with caution in premature infants because of their renal immaturity, in elderly people and generally in patients with impaired renal function. Diabetes, auditory vestibular dysfunctions, otitis media, a history of otitis media, previous use of ototoxic drugs and a genetically determined high sensitivity to aminoglycoside induced ototoxicity, are other main factors which may pre-dispose the patient to toxicity.
4.4 Special Warnings And Precautions For Use
As with other aminoglycosides toxicity is related to serum concentration. At serum levels more than 10 micrograms/ml the vestibular mechanism may be affected. Toxicity can be minimised by monitoring serum concentrations and it is advisable to check serum levels to confirm that peak levels (one hour) do not exceed 10 micrograms/ml and that trough levels (one hour before next injection) do not exceed 2 micrograms/ml. Evidence of toxicity requires adjustment of dosage or withdrawal of the drug.
Concurrent use of other neurotoxic and/or nephrotoxic drugs can increase the possibility of gentamicin toxicity. Co-administration with the following agents should be avoided:
Neuromuscular blocking agents such as succinylcholine and tubocurarine.
Other potentially nephrotoxic or ototoxic drugs such as cephalosporins and methicillin.
Potent diuretics such as ethacrynic acid and furosemide.
Other aminoglycosides.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
(i) Antibacterials: increased risk of nephrotoxicity with cephalosporins notably cephalothin .
(ii) Gentamicin has been known to potentiate anticoagulants such as warfarin and phenindione.
(iii) Antifungals: increased risk of nephrotoxicity with amphotericin.
(iv) Cholinergics: antagonism of effect of neostigmine and pyridostigmine.
(v) Cyclosporin: increased risk of nephrotoxicity.
(vi) Cytotoxics: increased risk of nephrotoxicity and possible risk of ototoxicity with cisplatin.
(vii) Diuretics: increased risk of ototoxicity with loop diuretics.
(viii) Muscle relaxants: effect of non-depolarising muscle relaxants such as tubocurarine enhanced.
4.6 Pregnancy And Lactation
Use in Pregnancy:
Although no teratogenic effects have been observed, gentamicin is known to cross the placenta. Ototoxicity in the foetus is also a potential hazard. The benefits should, therefore, be weighed against such hazards to the foetus before using gentamicin during pregnancy.
Use in Lactation:
Small amounts of gentamicin have been reported in breast milk. Because of the potential for serious adverse reactions to an aminoglycoside in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
4.7 Effects On Ability To Drive And Use Machines
Not applicable.
4.8 Undesirable Effects
Ototoxicity and nephrotoxicity are the most common side effects associated with gentamicin therapy. Both effects are related to renal impairment and hence the dosage in such patients should be altered as suggested.
Other adverse reactions associated with gentamicin therapy include nausea, vomiting, urticaria, reversible granulocytopenia, allergic contact sensitization and neuromuscular blockade.
4.9 Overdose
As in the case of other aminoglycosides, toxicity is associated with serum levels above a critical value. In patients with normal renal function it is unlikely that toxic serum levels (in excess of 10 micrograms/ml) will be reached after administration of recommended doses. Where higher levels occur because of renal impairment, dosage should be reduced. In the event of an overdose or toxic reaction, peritoneal dialysis or haemodialysis will lower serum gentamicin levels.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Gentamicin is usually bactericidal in action. Although the exact mechanism of action has not been fully elucidated, the drug appears to inhibit protein synthesis in susceptible bacteria by irreversibly binding to 30S ribosomal subunits.
In general, gentamicin is active against many aerobic gram-negative bacteria and some aerobic gram-positive bacteria. Gentamicin is inactive against fungi, viruses, and most anaerobic bacteria.
In vitro, gentamicin concentrations of 1-8 µg/ml inhibit most susceptible strains of Escherichia coli, Haemophilus influenzae, Moraxella lacunata, Neisseria, indole positive and indole negative Proteus, Pseudomonas (including most strains of Ps. aeruginosa), Staphylococcus aureus, S. epidermidis, and Serratia. However, different species and different strains of the same species may exhibit wide variations in susceptibility in vitro. In addition, in vitro susceptibility does not always correlate with in vivo activity. Gentamicin is only minimally active against Streptococci.
Natural and acquired resistance to gentamicin has been demonstrated in both gram-negative and gram-positive bacteria. Gentamicin resistance may be due to decreased permeability of the bacterial cell wall, alteration in the ribosomal binding site, or the presence of a plasmid-mediated resistance factor which is acquired by conjugation. Plasmid-mediated resistance enables the resistant bacteria to enzymatically modify the drug by acetylation, phosphorylation, or adenylylation and can be transferred between organisms of the same or different species. Resistance to other aminoglycosides and several other anti-infectives (e.g. chloramphenicol, sulphonamides, tetracycline) may be transferred on the same plasmid.
There is partial cross-resistance between gentamicin and other aminoglycosides.
5.2 Pharmacokinetic Properties
Gentamicin and other aminoglycosides are poorly absorbed from the gastro-intestinal tract but are rapidly absorbed after intramuscular injection. Average peak plasma concentrations of about 4 µg per ml have been obtained 30 to 60 minutes after intramuscular administration of a dose equivalent to 1 mg of gentamicin per kg body-weight although there may be considerable individual variation and higher concentrations in patients with renal failure. Similar concentrations are obtained after intravenous administration. Several doses are required before equilibrium concentrations are obtained in the plasma and this may represent the saturation of binding sites in body tissues such as the kidney. Binding of gentamicin to plasma proteins is usually low.
Following parenteral administration gentamicin and other aminoglycosides diffuse mainly into extracellular fluids and factors which affect the volume of distribution will also affect plasma concentrations. However, there is little diffusion into the cerebrospinal fluid and even when the meninges are inflamed effective concentrations may not be achieved; diffusion into the eye is also poor. Aminoglycosides diffuse readily into the perilymph of the inner ear. Gentamicin crosses the placenta but only small amounts have been reported in breast milk.
Systemic absorption of gentamicin and other aminoglycosides has been reported after topical use on denuded skin and burns and following instillation into and irrigation of wounds, body-cavities, and joints.
The plasma elimination half-life for gentamicin has been reported to be 2 to 3 hours though it may be considerably longer in neonates and patients with renal impairment. Gentamicin and other aminoglycosides do not appear to be metabolised and are excreted virtually unchanged in the urine by glomerular filtration. At steady-state at least 70% of a dose may be recovered in the urine 24 hours and urine concentrations in excess of 100 µg per ml may be obtained. However, gentamicin and the other aminoglycosides appear to accumulate in body tissues to some extent, mainly in the kidney, although the relative degree to which this occurs may vary with different aminoglycosides. Release from these sites is slow and aminoglycosides may be detected in the urine for up to 20 days or more after administration ceases. Small amounts of gentamicin appear in the bile.
5.3 Preclinical Safety Data
There is no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium metabisulphite
Disodium edetate
Methyl hydroxybenzoate
Propyl hydroxybenzoate
Water for Injections
Sulphuric acid (2.5N)
Sodium hydroxide (2.5N)
6.2 Incompatibilities
Gentamicin Injection should not be mixed with other drugs before injection and where co-administration of penicillins, cephalosporins, erythromycin, lipiphysan, sulphadiazine, furosemide and betalactam antibiotics and heparin is necessary, the drugs should be administered separately, either as bolus injections into the tubing of the giving set or at separate sites. Addition of gentamicin to solutions containing bicarbonate may lead to the release of carbon dioxide.
6.3 Shelf Life
36 months.
6.4 Special Precautions For Storage
Do not store above 25°C.
Unused portions of opened vials must not be stored and should be discarded immediately.
6.5 Nature And Contents Of Container
80 mg/2 ml - Clear, Type I glass vials in packs of 5 vials.
6.6 Special Precautions For Disposal And Other Handling
For single use only. Discard any unused contents.
7. Marketing Authorisation Holder
Mayne Pharma Plc
Queensway
Royal Leamington Spa
Warwickshire CV31 3RW
United Kingdom
8. Marketing Authorisation Number(S)
PL 04515/0037
9. Date Of First Authorisation/Renewal Of The Authorisation
5th February 1998
10. Date Of Revision Of The Text
2nd April, 2003
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