Maxigen

Gentamicin sulfate.

Each mL contains: Gentamicin (as sulfate) 10 mg and 40 mg, respectively.

Pharmacology: Gentamicin is an aminoglycoside antibiotic and has a bactericidal action against many Gram-negative aerobes and against some strains of staphylococci.
Mechanism of Action: Aminoglycosides are taken up into sensitive bacterial cells by an active transport process which is inhibited in anaerobic, acidic or hyperosmolar environments. Within the cell they bind to the 30S, and to some extent, to the 50S subunits of the bacterial ribosome, inhibiting protein synthesis and generating errors in the transcription of the genetic code. The manner in which cell death is brought about is imperfectly understood, and other mechanisms may contribute, including effects on membrane permeability.
Pharmacokinetics: Gentamicin and other aminoglycosides are poorly absorbed from the gastrointestinal tract but are rapidly absorbed after intramuscular injection. Average peak plasma concentrations of about 4 micrograms/mL have been attained in patients with normal renal function 30 to 60 minutes after an intramuscular dose equivalent to gentamicin 1 mg/kg, which is similar to concentrations achieved after intravenous infusion. There may be considerable individual variation. Several doses are required before plasma equilibrium concentrations occur 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.
On parenteral use, gentamicin and other aminoglycosides diffuse mainly into extracellular fluids. However, there is little diffusion into the CSF 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. They cross 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 on instillation into, and irrigation of, wounds, body cavities (except the urinary bladder), 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 micrograms/mL may be achieved. 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 small amounts of aminoglycosides may be detected in the urine for up to 20 days or more after treatment stops. Small amounts of gentamicin appear in the bile.
The pharmacokinetics of the aminoglycosides are affected by many factors, which may become significant because of the relatively small difference between therapeutic and toxic concentrations, reinforcing the need for monitoring.
Absorption from intramuscular sites may be reduced in critically ill patients, especially in conditions that reduce perfusion such as shock, resulting in reduced plasma concentrations. Plasma concentrations may also be reduced in patients with conditions which expand extracellular fluid volume or increase renal clearance including ascites, cirrhosis, heart failure, malnutrition, spinal cord injury, burns, cystic fibrosis, and possibly leukaemia. Clearance is also reportedly increased in intravenous drug abusers, and in patients who are febrile.
In contrast, renal impairment or reduced renal clearance for any reason (for example in neonates with immature renal function, or in the elderly in whom glomerular function tends to decline with age) can result in markedly increased plasma concentrations and/or prolonged half-lives. However, in neonates initial plasma concentrations may actually be reduced, due to a larger volume of distribution. Plasma concentrations may also be higher than expected for a given dose in obese patients (in whom extracellular volume is low relative to weight), and in patients with anaemia.
Renal clearance, and hence plasma concentrations, of aminoglycosides may vary according to a circadian cycle, and it has been suggested that this should be taken into account when determining and comparing plasma aminoglycoside concentrations.

For the treatment of severe systemic infections due to sensitive Gram-negative and other organisms, such infections include biliary tract infections (acute cholecystitis or cholangitis), brucellosis, cat scratch disease, cystic fibrosis, endocarditis (in the treatment and prophylaxis of endocarditis due to streptococci, enterococci, or staphylococci), endometritis, gastroenteritis, granuloma inguinale, listeriosis, meningitis, otitis externa, otitis media, pelvic inflammatory disease, peritonitis, plague, pneumonia, septicaemia, skin infections such as in burns or ulcers (given systemically for pseudomonal and other Gram-negative infections), tularaemia, and urinary-tract infections (acute pyelonephritis), as well as in the prophylaxis of surgical infection and the treatment of immunocompromised patients and those in the intensive care.

In the management of many of the infections it is commonly given intramuscularly every 8 hours to provide a total daily dose of 3 to 5 mg of gentamicin per kg body-weight. Slightly lower doses have been suggested in the prophylaxis and treatment of streptococcal and enterococcal endocarditis: a dose of 80 mg of gentamicin, given twice daily has been suggested for treatment, and 120 mg before induction of anaesthesia. For urinary-tract infections, if renal function is not impaired, 160 mg once daily may be used.
Gentamicin sulfate may also be given intravenously in similar doses to those used intramuscularly. The course of treatment should generally be limited to 7 to 10 days. As gentamicin is poorly distributed into fatty tissue some authorities suggest that dosage calculations should be based on an estimate of lean body-weight.
Doses in infants and children are usually somewhat higher than those in adults but exact dosage recommendations vary. One regimen is gentamicin 3 mg/kg every 12 hours in premature infants and those up to 2 weeks of age, with older neonates and children receiving 2 mg/kg every 8 hours. Alternatively, 2.5 mg/kg every 12 hours in the first week of life, 2.5 mg/kg every 8 hours or 3 mg/kg every 12 hours in infants and neonates, and 1.5 to 2 mg/kg every 8 hours in children has been given. Or as prescribed by the physician.
Single Dose. Discard any remaining portion.

Aminoglycosides possesses a neuromuscular-blocking action and respiratory depression and muscular paralysis has been reported, notably after absorption from serous surfaces.
Treatment: Aminoglycosides may be removed by haemodialysis or to a much lesser extent by peritoneal dialysis. Calcium salts given intravenously have been used to counter neuromuscular blockade; the effectiveness of neostigmine has been variable.

Gentamicin sulfate is contraindicated in patients with a known history of allergy to gentamicin and other aminoglycosides.

This product contains Sodium Metabisulfite that may cause allergic type of reaction including anaphylactic symptoms and life threatening or less severe asthmatic episodes in certain susceptible persons.

Gentamicin is contra-indicated in patients with a known history of hypersensitivity to it, and probably in those hypersensitive to other aminoglycosides. It should be avoided in patients with myasthenia gravis, and great care is required in patients with parkinsonism and other conditions characterised by muscular weakness.
The risk of ototoxicity and nephrotoxicity from aminoglycosides is increased at high plasma concentrations and it is therefore generally desirable to determine dosage requirements by individual monitoring. In patients receiving standard multiple-dose regimens of gentamicin, dosage should be adjusted to avoid peak plasma concentrations above 10 micrograms/mL, or trough concentrations (immediately before next dose) exceeding 2 micrograms/mL. Local guidelines on serum concentration should be consulted where once daily dosage regimens are used. Monitoring is particularly important in patients receiving high doses or prolonged courses, in infants and the elderly, and in patients with renal impairment, who generally require reduced doses. The BNF also considers monitoring to be important in patients with cystic fibrosis or significant obesity; again, altered doses may be required. Impaired hepatic function or auditory function, bacteraemia, fever, and perhaps exposure to loud noises have also been reported to increase the risk of ototoxicity, while volume depletion or hypotension, liver disease, or female sex have been reported as additional risk factors for nephrotoxicity. Regular assessment of auditory and renal function is particularly necessary in patients with additional risk factors.

The aminoglycosides can produce irreversible, cumulative ototoxicity. This affects both the cochlea (manifest as hearing loss, initially of higher tones, and which, because speech recognition relies greatly on lower frequencies, may not be at first apparent) and the vestibular system (manifest as dizziness or vertigo). The incidence and relative toxicity with different aminoglycosides is a matter of some dispute, but netilmicin is probably less cochleotoxic than gentamicin or tobramycin, and amikacin more so. Netilmicin also exhibits less vestibular toxicity than gentamicin, tobramycin, or amikacin, while streptomycin produces a high incidence of vestibular damage. Vestibular damage is more common than hearing loss in patients receiving gentamicin.
Reversible nephrotoxicity may occur and acute renal failure has been reported, often in association with the use of other nephrotoxic drugs. Renal impairment is usually mild, although acute tubular necrosis and interstitial nephritis have occurred. Decreased glomerular filtration rate is usually seen only after several days, and may even occur after therapy has stopped. Electrolyte disturbances (notably hypomagnesaemia, but also hypocalcaemia and hypokalaemia) have occurred. The nephrotoxicity of gentamicin is reported to be largely due to gentamicin C2 component.
Although particularly associated with high plasma concentrations, many risk factors have been suggested for ototoxicity and nephrotoxicity in patients receiving aminoglycosides.
Aminoglycosides possesses a neuromuscular-blocking action and respiratory depression and muscular paralysis have been reported, notably after absorption from serous surfaces. Neomycin has the most potent action and several deaths have been associated with its use.
Hypersensitivity reactions have occurred, especially after local use, and cross-sensitivity between aminoglycosides may occur. Very rarely, anaphylactic reactions to gentamicin have occurred. Some hypersensitivity reactions have been attributed to the presence of sulfites in parenteral formulations, and endotoxic shock has also been reported.
Infrequent effects reported for gentamicin include blood dyscrasias, purpura, nausea and vomiting, stomatitis, and signs of liver dysfunction such as increased serum-aminotransferase values and increased serum-bilirubin concentrations. Neurotoxicity has occurred, with both peripheral neuropathies and central symptoms being reported including encephalopathy, confusion, lethargy, hallucinations, convulsions, and mental depression.
Atrophy or fat necrosis has been reported at injection sites. There have been isolated reports of meningeal irritation, arachnoiditis, polyradiculitis and ventriculitis after intrathecal, intracisternal, or intraventricular use of aminoglycosides. Subconjunctival injection of gentamicin may lead to pain, hyperaemia, and conjuctival oedema, while severe retinal ischaemia has followed intra-ocular injection.

Concurrent use of other nephrotoxic drugs, including other aminoglycosides, vancomycin, some of the cephalosporins, ciclosporin, cisplatin, and fludarabine, or potentially ototoxic drugs such as etacrynic acid and perhaps furosemide, may increase the risk of aminoglycoside toxicity. It has been suggested that concurrent use of an antiemetic such as dimenhydrinate may mask the early symptoms of vestibular toxicity. Care is also required if other drugs with a neuromuscular-blocking action are given concomitantly. The neuromuscular-blocking properties of aminoglycosides may be sufficient to provoke severe respiratory depression in patients receiving general anaesthetics or opioids. There is a theoretical possibility that the antibacterial effects of aminoglycosides could be reduced by use with a bacteriostatic antibacterial, but such combinations have been used successfully in practice. Since aminoglycosides have been shown to be incompatible with some beta-lactams in vitro, these antibacterials should be administered separately if both are required; antagonism in vivo has been reported only in a few patients with severe renal impairment, in whom aminoglycoside activity was diminished. Aminoglycosides exhibit synergistic activity with a number of beta-lactams in vivo. Renal excretion of zalcitabine may be reduced by concurrent administration of aminoglycosides. Gentamicin may inhibit α-galactoridase activity and should not be used with agalridase alpha or beta.

Store at temperatures not exceeding 30°C.

Aminoglycosides

J01GB03 - gentamicin ; Belongs to the class of other aminoglycosides. Used in the systemic treatment of infections.

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