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Information for Health Professionals

GENTAMICIN

Gentamicin 80mg/2mL injection as gentamicin sulphate

Presentation

Gentamicin (as gentamicin sulphate BP) 80mg/2mL is a clear, pale yellow, sterile, aqueous solution packed in a 2mL luer fit polyethylene ampoule, clearly printed with the appropriate artwork.

Uses

Actions

Gentamicin is an aminoglycoside antibiotic that interferes with bacterial protein synthesis by binding primarily to the 30S sub-unit of bacterial ribosomes in susceptible organisms. Cell death results. Other mechanisms of action may contribute to the bactericidal effect of gentamicin.

Gentamicin is active against a wide range of gram-negative organisms including Escherichia coli, Pseudomonas aeruginosa, Proteus species (both indole positive and indole negative), Neisseria species including N. gonnorrhoeae, Klebsiellia, Enterobacter and Serratia species. It is also active against some gram-positive organisms, e.g. Staphylococcus (including methicillin and penicillin resistant strains). Bacterial resistance of aminoglycosides may occur and is usually associated with the plasma-mediated production of inactivating enzymes which are capable of phosphorylation, acetylation, or adenylation.

Resistance may be found in staphylococci, enterococci, Pseudomonas aeruginosa, the Enterobacteriaceae, and other gram-negative organisms.

Pharmacokinetics

Gentamicin is rapidly absorbed after IM injection and peak serum levels are usually achieved within 30 to 90 minutes and are measurable for 6-8 hours. Following parenteral administration, gentamicin can be detected in tissues and body fluids. Penetration occurs into the bile, pleural and pericardial fluids and the perilymph of the inner ear but little, if any, penetrates the blood/brain barrier or diffuses into the eye. Gentamicin crosses the placenta but only small amounts have been reported in breast milk. Binding of gentamicin to plasma proteins is usually low.

Gentamicin does not appear to be metabolised and is excreted virtually unchanged in the urine almost entirely by renal glomerular filtration, hence the half-life of the medicine is prolonged in the presence of renal failure. Adjustments in the frequency of administration of gentamicin are necessary to allow for the degree of renal failure (see Dosage and Administration).

The serum half-life of gentamicin is approximately 2-3 hours in adults with normal renal function. It is prolonged in patients with impaired renal function and in premature or newborn infants. At steady-state at least 70% of a dose may be recovered in the urine within 24 hours. However, gentamicin does accumulate in body tissues to some extent, mainly in the kidney and release from these sites is slow and it may be detected in the urine for up to 20 days or more after administration ceases.

Indications

Gentamicin is clinically effective in infections due to one or more susceptible strains of bacteria, including Pseudomonas aeruginosa, Proteus species (indole positive and indole negative), Neisseria species including N. gonnorrhoeae, Escherichia coli, Klebsiella, Enterobacter, Serratia species and Staphylococcus (including strains resistant to other antibiotics). Gentamicin should be considered for the treatment of the following conditions when caused by susceptible organisms: bacteraemia, respiratory tract infections, urinary tract infections, infected wounds, bone and soft tissue infections, including peritonitis, septic abortion and burns complicated by sepsis, etc.

In suspected or documentated gram-negative sepsis, gentamicin should be considered for initial microbial therapy. If anaerobic organisms are suspected, antimicrobial therapy in addition to the gentamicin regimen should be considered.

Gentamicin shows enhanced activity with penicillin against some enterococci and streptococci.

Dosage and Administration

Gentamicin is normally given by IM injection. Intravenous administration may be used for particular indications when the IM route is not appropriate. The standard dose is 3mg/kg/day in three equal doses in patients with normal renal function.

1. Dosage in Patients with Normal Renal Function

    

   1. Systemic and Urinary Tract Infections: 3mg/kg/day (where bodyweight > 60kg, usual dose is 80mg; where lean bodyweight < 60kg, usual dose is 60mg) given in divided doses every 8 hours. Duration of therapy is 7-10 days.

      Note: Gentamicin activity is increased at pH 7.5. It may therefore be advantageous to alkalinise the patients urine before therapy.

   2. Life Threatening and Respiratory Tract Infections and Infections with Relatively Resistant Organisms, i.e. Pseudomonas: 5mg/kg/day initially, then 3mg/kg/day as soon as improvement is indicated, given in divided doses every 6-8 hours. Duration of therapy is usually 7-10 days. Longer therapy may be required. If so, auditory, renal and vestibular functions should be monitored.
2. Dosage in Patients with Impaired Renal Function

   Dosage should be adjusted to minimise the risk of toxicity. The first dose should be as normal, e.g. 80mg (bodyweight > 60kg) and subsequent doses should be given less frequently, depending on the degree of renal impairment. See Table 1.

Table 1: Approximate Dosage Guidelines in Adult Patients Based on Renal Function

When only a blood urea nitrogen concentration is available, this value may be utilised initially, however, it should be supplemented with a serum creatinine level or creatinine clearance rate whenever possible.

N.B. The standard dose of 80mg three times daily may be inappropriate and a more appropriate dose can be calculated using a nomogram which takes into account the patients serum creatinine levels, body weight and age. This dose can be adjusted, if necessary, following determination of serum creatinine levels. Desirable serum levels of gentamicin are 5-8mcg/mL as a peak and a 1-2mcg/mL as a trough.

Contraindications

Gentamicin is contraindicated in patients with a history of hypersensitivity to gentamicin or who have experienced previous toxic reactions (ototoxicity, nephrotoxicity) resulting from aminoglycoside therapy.

Warnings and Precautions

• Nephrotoxicity and ototoxicity: As for other aminoglycosides, patients being treated with gentamicin should be under close clinical observation during treatment because of the potential toxicity associated with their use. Gentamicin, as with other aminoglycosides, is potentially nephrotoxic and ototoxic and the risk of this toxicity is higher in patients receiving high doses, prolonged treatment, or with impaired renal function. Gentamicin should therefore be used with caution in patients with impaired renal function. In such patients the frequency of administration should be reduced and renal function should be monitored. Prolonged concentrations above 10 microgram/mL should be avoided and trough concentrations should not exceed 2 microgram/mL. In neonates, infants and children, dosage reductions may also be necessary to avoid toxicity. Peak and trough blood levels should be constantly monitored as should renal and eighth cranial nerve function. Treatment period should not normally exceed 10-14 days.
• Allergic reactions: May occur after administration of gentamicin. Cross allergenicity among aminoglycosides has also been known to occur.
• Use during anaesthesia: The possibility of prolonged or secondary apnoea should be considered if the drug is administered to anaesthetised patients who are concurrently receiving neuromuscular blocking agents such as succinylcholine, tubocurarine or decamethonium. This also applies to patients who are receiving massive transfusions of citrated blood. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts.
• Recent evidence suggests that neurotoxic and nephrotoxic antibiotics may be absorbed in significant quantities from body surfaces after local irrigation or application. The potential toxic effect of antibiotics administered in this fashion should be considered and inadvertent contact with the skin should be removed with water.
• Aminoglycosides should be used cautiously in patients with neuromuscular disorders such as myasthenia gravis or parkinsonism. In such cases, gentamicin may aggravate muscle weakness because of its curare-like effect on neuro-muscular function.

Use in pregnancy: Category D. Gentamicin crosses the placenta. Safety for use in pregnancy in regard to potential for ototoxicity or nephrotoxicity has not been established. All aminoglycosides should be considered potentially nephrotoxic and ototoxic to the foetus. Therapeutic blood levels in the mother do not necessarily equate to safety for the foetus. It is therefore advisable not to use gentamicin during pregnancy unless deemed essential by the physician and the expected benefits of therapy outweigh any potential risk.

Use in lactation: Small amounts of gentamicin have been detected in breast milk. Because of the potential risk to the newborn, it is recommended that breastfeeding be discontinued during therapy unless the expected benefits outweigh any potential risk.

Carcinogenicity and Mutagenicity: No data is available on this at present.

Adverse Effects

If serum levels of gentamicin are maintained within the therapeutic range, adverse reactions are not common. However, as with other aminoglycosides, ototoxicity and nephrotoxicity can occur; the incidence of either being approximately less than 2%.

Gentamicin nephrotoxicity is usually mild and reversible. However, severe renal impairment may occur and dialysis may be necessary. Nephrotoxicity may be increased by the concurrent administration of other medicines (see Interactions).

Signs of nephrotoxicity include an increase in excretion of renal tubular enzymes in the urine, proteinurea, the appearance of urinary casts, a decrease in glomerular filtration rate and associated electrolyte disturbances may occur (see Warnings and Precautions).

Ototoxicity is often irreversible (as destroyed or damaged cochlear hair cells are unable to regenerate) and cumulative in nature. Vestibular damage is more common with gentamicin than hearing loss which, when it occurs, is greatest in the high-tone range (see Warnings and Precautions).

Electrolyte disturbances such as hypomagnesaemia, hypokalaemia and hypo-calcaemia have occurred when aminoglycosides have been given for long periods, especially in association with anti-neoplastic agents.

Aminoglycosides may also produce a curare-like neuromuscular blockade leading to muscular paralysis and respiratory depression. Most incidents occurred when aminoglycosides were used in conjunction with general anaesthesia or other neuromuscular blocking agents.

Infrequent adverse reactions reported include purpura, convulsions, visual disturbances, leg cramps, increased serum transaminases, increased serum bilirubin, hypersensitivity reactions (rash, urticaria), nausea, vomiting, headache, leucopenia, granulocytopenia, transient agranulocytosis, increased and decreased reticulocyte counts and thrombocytopenia.

Interactions

Penicillins and Clavulanic Acid (agents with a betalactam structure): Gentamicin is inactivated by solutions containing penicillins and clavulanic acid. Gentamicin and penicillins and/or clavulanic acid should not be administered simultaneously nor should they be combined in the intravenous fluid. When the agents are used in combination, the administration times should be staggered so that several hours separate each infusion or administered at different sites.

Other Antibiotics: Other antimicrobial agents reported to be incompatible in-vitro with gentamicin include erythromycin and chlorampenicol.

Indomethacin: May increase both peak and trough serum concentrations of gentamicin when administered concurrently.

Amphotericin: Concurrent administration increases the serum half-life of gentamicin.

Heparin, Sodium Bicarbonate, Frusemide: Gentamicin is incompatible with heparin and sodium bicarbonate and there have been reports of incompatibility with frusemide.

Diuretics: Potent diuretics such as ethacrynic acid or frusemide may potentiate the ototoxic effects of gentamicin.

Neuromuscular Blocking Agents: Respiratory paralysis and prolongation of neuromuscular blockade may occur if a neuromuscular blocking agent such as succinylcholine or tubocurarine is administered to a patient receiving gentamicin.

Cephalosporins: Increased nephrotoxicity of gentamicin has been observed during concurrent administration of cephalosporins.

Vitamin K: Gentamicin may prevent the action of intravenous vitamin K upon the synthesis of clotting factors.

Other Drugs: Since ototoxic or nephrotoxic effects may be additive, the concurrent or sequential use of gentamicin and other agents with similar toxic potentials should be avoided, if possible.

Potential Interactions: In-vitro synergism and antagonism has been found between various antineoplastic agents and aminoglycosides.

Overdosage

As gentamicin is almost entirely eliminated by the kidneys, fluid loading may hasten its elimination and to a lesser extent peritoneal dialysis will also aid in the removal of gentamicin calcium salts given intravenously have been used to counter neuro-muscular blockade. The effectiveness of neostigmine has been variable.

Pharmaceutical Precautions

Store below 25° C. Protect from light. Keep out of reach of children.

Medicine Classification

Prescription Medicine.

Package Quantities

80mg/mL: 10's and 50's.

Further Information

Gentamicin sulphate is a complex mixture of the sulphates of gentamicin C₁, gentamicin C_1A, and gentamicin C₂ produced by micromonospora purpurea. It is a polycationic compound which contains 2-deoxystreptamine with cyclic amino sugars attached to glycoside linkages.

The potency of gentamicin sulphate is not less than 590 units per mg.

80,000 units of gentamicin is approximately equivalent to 80mg of gentamicin.

Name and Address

Pharmacia
PO Box 11-282
Ellerslie
Auckland
New Zealand

Phone: (09) 580 4300

Date of Preparation

13 November 2000

(Ref: AustPI 09/02/99)