| 4.2. Posology and method of administration
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3. Doses in Patients with Impaired Renal Function:
Monitoring advice:
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Serum concentration monitoring of gentamicin is recommended, especially in elderly, in newborns and in patients with impaired renal function. Samples are taken at the end of a dosing interval (trough level). Trough levels should not exceed 2 µg/ml administering gentamicin twice daily and 1 µg/ml for a once daily dose. Please refer to section 4.4.
4.3. Contraindications
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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
Hypersensitivity to gentamicin. , any other ingredient or other aminoglycosides.
Myasthenia gravis.
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.
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4.4. Special warnings and special precautions for use
Patients being treated with gentamicin should be under close clinical observation because of its potential toxicity.
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. when administering Gentamicin twice daily and 1µg/ml for a once daily dose. 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.
To avoid adverse events, continuous monitoring (before, during and after) of renal function (serum creatinin, creatinin clearance), control of function of vestibule and cochlea as well as hepatic and laboratory parameters is recommended.
Sulphites can cause allergic-type reactions including anaphylactic symptoms and bronchospasm in susceptible people, especially those with a history of asthma or allergy.
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4.6. Pregnancy and Lactationlactation
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.
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4.8. Undesirable effects
Ototoxicity and nephrotoxicity are the most common side effects associated with gentamicinGentamicin therapy. Both effects are related to renal impairment and hence the dosage in such patients should be altered as suggested. In addition, there have been rare reports of changes in electrolyte balance including hypocalcaemia and hypokalaemia caused by renal tubular dysfunction.
Vestibular damage and ototoxicity may occur. This is usually reversible if observed promptly and the dose adjusted.
Other adverse reactions associated with gentamicinGentamicin therapy include nausea, vomiting, urticaria, reversible granulocytopenia, allergic contact sensitizationsensitisation and neuromuscular blockade. There have been a few reports of anaphylactic reactions associated with gentamicin containing therapy.
Combinations of antibiotics containing gentamicin have been associated with rare reports of Clostridium difficile diarrhoea.
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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 adenylylationadenylation 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.
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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.
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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.
6.6. Instructions for use and handling, (and disposal)
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For single use only. Discard any unused contents.
Not applicable.
10. Date of Revision of the Text
DATE CHANGE TO 19.07.2011
14 September 2010 19th July 2011
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