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 ampoule of 1 ml solution for injection contains 40 mg of gentamicin (as sulphate). 1 ampoule of 2 ml solution for injection contains 80 mg of gentamicin (as sulphate). 1 vial of 6 ml solution for injection contains 240 mg of gentamicin (as sulphate).
For excipients, see 6.1
3. Pharmaceutical Form
Solution for Injection
A clear colourless solution
4. Clinical Particulars
4.1 Therapeutic Indications
Gentamicin is indicated for the treatment of systemic infections due to susceptible bacteria such as bacteraemia, septicaemia, urinary-tract infections and severe chest infections.
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, 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 be 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, and the solution infused over a period of 20 to 30 minutes. Doses in excess of 4 mg/kg must be administered over one hour.
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.
Single-daily dosing: When administered as a single daily dose, gentamicin should be infused intravenously over 30-60 minutes.
Dosage in Patients with Normal Renal Function:
1.
Adult Dosage:
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Single-daily dosing: A dose of 3-5 mg/kg may be administered as a single daily dose.
Whenever possible the duration of therapy with gentamicin should not exceed 7 days.
2. Paediatric Dosage:
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Single-daily dosing: A dose of 4-5 mg/kg (for neonates) or 4.5-6 mg/kg (for older children) may be administered as a single daily dose.
Dosage 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.
Dose adjustment recommendations for divided dosing regimen:
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Dose adjustment recommendations for single-daily dosing regimen:
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Dosage in Obese Patients
Dosage reduction may be required when calculating doses for obese patients.
Serum levels should be monitored regularly
Peak levels in infants, children and adults: Peak Serum levels after intramuscular dosing 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. Peak serum levels more than 10 micrograms/ml may be associated with toxicity.
Single daily dosing may produce peak levels higher than that experienced with 6-8 hourly dosing, and peak levels of 10-15 micrograms/ml have been reported with minimal toxicity.
Trough levels should not exceed 2 micrograms/ml.
Dosage adjustment depends upon plasma levels. Dosage selection and adjustment should be performed in consultation with your microbiology department.
4.3 Contraindications
Hypersensitivity to gentamicin, any other ingredient or to other aminoglycosides.
Myasthenia gravis
4.4 Special Warnings And 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. With 6-8 hourly dosing, serum levels more than 10 micrograms/ml may be associated with effects on the vestibular mechanism. 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. Single daily dosing may produce peak levels higher than that experienced with 6-8 hourly dosing, and peak levels of 10-15 micrograms/ml have been reported with minimal toxicity. However, renal and vestibular function and serum electrolytes should be monitored for evidence of toxicity. Evidence of toxicity requires adjustment of dosage or withdrawal of the drug.
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 and 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.
There is insufficient information to support the use of single daily dosing of gentamicin in patients with severe burns, pregnant patients, and patients with endocarditis, since the pharmacokinetics and/or pharmacodynamics of gentamicin differ in these patient groups. Additionally, once-daily dosing should be avoided in patients with serious infections, impaired host defences or clinical conditions associated with rapid clearance or unpredictable pharmacokinetics of gentamicin (Cystic Fibrosis patients, ascites).
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.
Caution should be used with single daily dosing in the treatment of neutropenic patients since single-daily dosing regimens could allow prolonged intervals of undetectable gentamicin concentrations that could outlast the post-antibiotic effect.
Concurrent use of other neurotoxic and/or nephrotoxic drugs can increase the possibility of gentamicin toxicity, see section 4.5 (Interaction with other medicincal products and other forms of interaction).
Sulphites can cause allergic-type reactions including anaphylactic symptoms and bronchospasm in susceptible people, especially those with a history of asthma or allergy.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
• Antibacterials: increased risk of nephrotoxicity with cephalosporins notably cephalothin.
• 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 and patients with poor renal function should be monitored for effectiveness of the gentamicin. Cross-sensitivity with aminoglycosides may occur.
• Gentamicin has been known to potentiate anticoagulants such as warfarin and phenindione.
• Antifungals: increased risk of nephrotoxicity with amphotericin.
• Cholinergics: antagonism of effect of neostigmine and pyridostigmine.
• Cyclosporin: increased risk of nephrotoxicity.
• Cytotoxics: increased risk of nephrotoxicity and possible risk of ototoxicity with cisplatin.
• Diuretics: increased risk of ototoxicity with loop diuretics.
• Furosemide and piretanide may potentiate the ototoxicity of gentamicin, and ethacrynic acid, which is ototoxic in its own right, should be avoided with gentamicin.
• Muscle relaxants: effect of non-depolarising muscle relaxants such as tubocurarine enhanced.
• 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.
4.6 Pregnancy And Lactation
Use in Pregnancy:
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. Some animal studies have shown a teratogenic effect. There is insufficient evidence available to support single daily dosing of gentamicin in pregnant patients.
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. In addition, there have been rare reports of changes in electrolyte balance including hypomagnesaemia, hypocalcaemia and hypokalaemia caused by renal tubular dysfunction.
Other adverse reactions associated with gentamicin therapy include nausea, vomiting, urticaria, reversible granulocytopenia, allergic contact sensitization and neuromuscular blockade.
There is a possibility of endotoxin-like reactions following higher doses of gentamicin therapy.
Gentamicin has rarely been associated with pseudomembranous colitis and usually in these cases other antibiotics are also involved. Hypersensitivity reactions have occurred.
4.9 Overdose
As in the case of other aminoglycosides, toxicity is associated with serum levels above a critical value.
Symptoms include dizziness, vertigo and hearing loss if overdose accidentally given parenterally.
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 adenylation 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 bodyweight 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 in 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 preclinical 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
Water for Injections
Sulphuric Acid (2.5N)
Sodium Hydroxide (2.5N)
6.2 Incompatibilities
Gentamicin 40 mg/ml 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
Prior to first use: 36 months.
In use: Following dilution in either normal saline or 5% dextrose in PVC infusion bags, chemical and physical in-use stability has been demonstrated for 7 days at 2-8ºC.
However, 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 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.
6.4 Special Precautions For Storage
Prior to first use: Do not store above 25°C.
In use: see 6.3
6.5 Nature And Contents Of Container
Gentamicin is available as 40 mg in 1 ml and 80 mg in 2 ml in clear type I glass ampoules in packs of 5.
Gentamicin 240 mg in 6 ml is available in 10 ml clear type I glass vials in single packs and packs of 5.
6.6 Special Precautions For Disposal And Other Handling
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 04515/0028
9. Date Of First Authorisation/Renewal Of The Authorisation
24 September 1997
10. Date Of Revision Of The Text
3rd April, 2003
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