Description:
Gentamicin sulfate, a water-soluble antibiotic of the aminoglycoside group, is derived from Micromonospora purpurea, an actinomycete. Gentamicin Injection is a sterile, nonpyrogenic, aqueous solution for parenteral administration and is available both with and without  preservatives. The molecular formula of gentamicin sulfate is C₁₉H₄₀N₄O₁₀S and molecular weight is 516.6.

Composition:
Gentic 10mg/ml injection: Each ampoule contains
Gentamicin…. 10mg as Gentamicin Sulfate U.S.P.
(Product Specs.: U.S.P.)

Gentic 20mg/2ml injection: Each ampoule contains
Gentamicin…. 20mg as Gentamicin Sulfate U.S.P.
(Product Specs.: U.S.P.)

Gentic 40mg/2ml injection: Each ampoule contains
Gentamicin…. 40mg as Gentamicin Sulfate U.S.P.
(Product Specs.: U.S.P.)

Gentic 80mg/2ml injection: Each ampoule contains
Gentamicin…. 80mg as Gentamicin Sulfate U.S.P.
(Product Specs.: U.S.P.)

Gentic 160mg/2ml injection: Each ampoule contains
Gentamicin…. 160mg as Gentamicin Sulfate U.S.P.
(Product Specs.: U.S.P.)

Clinical Pharmacology:

Pharmacodynamic Properties:
Pharmacotherapeutic group: Antibacterial for systemic use
ATC code: J01GB03

Mechanism Of Action:
Gentamicin has bactericidal efficacy both in the proliferation and in the resting stage of bacteria. It forms a bond with the proteins of the 30S subunits of the bacterial ribosomes, which causes “misreading” of the mRNA.

Microbiology:

Gram-Positive Bacteria:

• Listeria monocytogenes
• Staphylococcus aureus
• Staphylococcus epidermidis
• Staphylococcus haemolyticus
• Staphylococcus hominis
• Enterococcus faecalis
• Enterococcus faecium
• Streptococcus spp.

Gram-Negative Bacteria:

• Campylobacter coli
• Campylobacter jejuni
• Citrobacter koseri
• Enterobacter aerogenes
• Enterobacter cloacae
• Escherichia coli
• Francisella tularensis
• Klebsiella oxytoca
• Klebsiella pneumoniae
• Proteus vulgaris
• Salmonella enterica subsp. enterica
• Serratia marcescens
• Yersinia enterolitica
• Yersinia pseudotuberculosis
• Acinetobacter spp.
• Citrobacter freundii
• Morganella morganii
• Proteus mirabilis
• Pseudomonas aeruginosa
• Burkholderia cepacia
• Legionella pneumophila
• Stenotrophomonas maltophilia

Anaerobic Bacteria:

• Bacteroides spp.
• Clostridium difficile

Other:

• Chlamydia spp.
• Chlamydophila spp.
• Mycoplasma spp.
• Ureaplasma urealyticum

Pharmacokinetic Properties

Absorption:
Gentamicin is barely absorbed by healthy intestinal mucosa after oral administration. Therefore therapeutic application is parenteral. When gentamicin is administered by intravenous short infusion of 30 minutes at 4 mg/kg body weight per day in three divided doses, peak and trough gentamicin concentrations measured in adult patients were 4.7 μg/ml and 1.0 μg/ml, respectively. Therapeutic serum concentrations generally lie between 2 and 8 μg/ml. Therapeutic peak serum concentrations are in the range of 5 – 10 μg/ml for multiple daily dosing and 20 – 30 μg/ml for once daily dosing. Maximum serum concentrations of 10 – 12 μg/ml should not be exceeded when administered conventionally.

Distribution:
The distribution volume of gentamicin is about equivalent to the volume of extracellular water. In the newborn water makes up 70 to 75% of bodyweight, compared with 50 to 55% in adults. The extracellular water compartment is larger. The volume of distribution of gentamicin per kg bodyweight is affected and decreases with increasing age from 0.5 to 0.7 L/kg for a premature newborn to 0.25 L/kg for an

adolescent. The distribution of gentamicin to the individual organs results in varying tissue concentrations, the highest concentrations appear in the renal tissue. Smaller concentrations are found in the liver and gall bladder, the lung and spleen. Gentamicin crosses the placenta; the foetal concentrations can be 30% of the maternal plasma concentrations. After repeated injection approximately 50% of the concentrations reached in plasma is measured in the synovial, pleural, pericardial and peritoneal fluid. The penetration of gentamicin into the cerebrospinal fluid is poor in un-inflamed meninges. In inflamed meninges, concentrations reach up to 30% of the concentrations measured in plasma. Plasma protein binding is less than 10%.

Metabolism:
Gentamicin is not metabolised in the organism but is excreted unchanged in microbiologically active form.

Elimination:
Gentamicin is eliminated unchanged in microbiologically active form principally in the urine by glomerular filtration. The dominant elimination half-life in patients with normal renal function is around 2 – 3 hours.

Elderly patients eliminate gentamicin more slowly than younger adults.

Therapeutic Indications:

Gentamicin is indicated in:

• Bacteraemia
• Urinary tract infections
• Chest infections
• Severe neonatal infections
• Other serious systemic infections due to susceptible organisms, in adults and children including neonates.

Dosage And Administration:

Adults:
Systemic infections: if renal function is not impaired, 3-5 mg/kg/day in divided doses according to severity of infection, adjusting according to clinical response and body weight. Serious infections: if renal function is not impaired, 5mg/kg daily in divided doses at six or eight hourly intervals. The total daily dose may be subsequently increased or decreased as clinically indicated. Urinary tract infections: as ‘systemic infections’. Or, if renal function is not impaired, 160mg once daily may be used.

Paediatric Patients:
The daily dose recommended in children (aged 1 year and above) and adolescents with normal renal function, is 3-6 mg/kg body weight per day as 1 single dose (preferred) or up to 2 single doses. The  daily dose in infants after the first month of life is 4.5-7.5 mg/kg body weight per day as 1 single dose

(preferred) or up to 2 single doses. The daily dose in neonates is 4-7 mg/kg body weight per day. Due to the longer half-life, neonates are given the required daily dose in 1 single dose.

Elderly:
Elderly patients may be more susceptible to aminoglycoside toxicity whether secondary to previous eighth nerve impairment or borderline renal dysfunction. Once daily dosing of gentamicin in elderly patients, which may not be suitable and therefore therapy should be closely monitored by frequent determination of gentamicin serum levels, assessment of renal function and signs of toxicity.

Patients With Renal Impairment:
Gentamicin is excreted by simple glomerular filtration. In impaired renal function, the recommended daily dose has to be decreased and adjusted to the renal function.

Method Of Administration:
The recommended dose and precautions for intramuscular and intravenous administration are identical. Gentamicin when given intravenously should be injected directly into a vein or into the drip set tubing over no less than three minutes. If administered by infusion, this should be over no longer than 20 minutes and in no greater volume of fluid than 100ml. Trough levels should not exceed 2 μg/ml administering gentamicin twice daily and 1 μg/ml for a once daily dose. Gentamicin can be diluted with 0.9% sodium chloride or 5% glucose solution. For single use only.

Contraindications:
Hypersensitivity to the active substance or to any of the excipients and myasthenia gravis.

Warnings And Precautions:

Renal impairment
Renal impairment such as restriction of glomerular filtration is observed in approximately 10% of patients treated with gentamicin and is usually reversible. The most important risk factors are high total dose, long duration of therapy, raised serum level, age, hypovolaemia and shock. The frequency or dose of administration should be reduced in patients with impaired renal function. Ensure adequate hydration and urine production.

Neuromuscular disorders
Gentamicin has neuromuscular blocking properties, particular caution should be exercised in patients with pre- existing neuromuscular diseases. Neuromuscular blockade and respiratory paralysis have been reported from administration of aminoglycosides to patients who have received curare-type muscle relaxants during anaesthesia. Careful monitoring is mandatory.

Effect on vestibulocochlear nerve
Damage to the vestibulocochlear nerve, whereby both balance and hearing may be affected, is possible. Vestibular damage is the most common ototoxic reaction. Hearing loss is manifested initially by diminution of high-tone acuity and is usually irreversible. Important risk factors are pre-existing renal impairment or a history of damage to the eighth cranial nerve. Symptoms of ototoxic effects are: dizziness, ringing in the ears (tinnitus), vertigo and less common hearing loss. With gentamicin the vestibular mechanism may be affected if trough levels of 2 μg/ml are exceeded. This is usually reversible if observed promptly and the dose adjusted.

Antibiotic-associated diarrhoea
Diarrhoea and pseudomembranous colitis have been observed when gentamicin is combined with other antibiotics. Gentamicin should be discontinued if the patients suffers severe diarrhoea and/or bloody diarrhoea during treatment. Drugs that inhibit peristalsis should not be administered. Treatment with gentamicin may produce an excessive growth of drug-resistant microorganisms. If this happens, an appropriate treatment should be initiated.

Drug Interactions:

Muscle relaxants and ether
The neuromuscular blocking activity of aminoglycosides is enhanced by ether and muscle relaxants. If gentamicin is administered during or immediately after surgery, the neuromuscular blockade may be enhanced and prolonged if non-depolarising muscle relaxants are used. Injection with calcium chloride may reverse the neuromuscular blockade due to aminoglycosides but should be undertaken with caution.

Methoxyflurane anaesthesia
Aminoglycosides may increase the kidney damaging effect of methoxyflurane. When used concurrently, extremely severe nephropathies are possible. The anaesthetist should be made aware of the use of aminoglycosides before a surgical procedure.

Potentially nephrotoxic or ototoxic drugs
Concurrent administration of gentamicin and other potentially ototoxic or nephrotoxic drugs should be avoided whenever possible because of the increased risk of undesired effects, careful monitoring is required of patients being treated concurrently or sequentially with potentially nephrotoxic or ototoxic drugs such as:

• Antibacterials: some cephalosporins notably cephalotin and cephaloridine, colistin, vancomycin, viomycin, other aminoglycosides such as streptomycin
• Antifungals: amphotericin B
• Loop diuretics: such as ethacrynic acid and furosemide
• Cytotoxics: cisplatin. It must be noted that the nephrotoxicity of gentamicin can be increased even 3 to 4 weeks after these substances are administered.
• Anti suppressant: ciclosporin

Other antibiotics
A reduction in gentamicin serum half-life has been reported in patients with severe renal impairment receiving carbenicillin concomitantly with gentamicin.

Indometacin
Indometacin possibly increases plasma concentrations of gentamicin in neonates.

Oral anticoagulants
Concurrent use with oral anticoagulants may increase the hypothrombinanaemic effect.

Bisphosphonates
Concurrent use of bisphosphonates may increase the risk of hypocalcaemia.

Cholinergics
Antagonism of effect may occur with concomitant administration of gentamicin with either neostigmine or pyridostigmine.
Concurrent use of botulinum toxin and gentamicin may increase the risk of toxicity due to enhanced neuromuscular block.

Adverse Effects:
Common: Renal function impairment.

Uncommon: Dyscrasia, Allergic skin exanthema.

Rare: Hypokalaemia, hypocalcaemia, hypomagnesaemia, pseudo-Bartter syndrome in patients treated with high doses over a long period (more than 4 weeks), loss of appetite, weight loss, Polyneuropathies, peripheral paraesthesias, Vomiting, nausea, salivation increased, stomatitis, Aspartate aminotransferase (AST) increased, Alanine aminotransferase (ALT) increased, alkaline phosphatase (ALP) increased, reversible increase of serum bilirubin, Skin reddening, Muscle pain (myalgia), Blood urea nitrogen increased, Increased body temperature.

Very Rare: Superinfection, pseudomembranous colitis, Thrombocytopaenia, reticulocytopaenia, leukopaenia, eosinophilia, granulocytopaenia, anaemia, Hypersensitivity reactions of varying severity, ranging from rash and itching, drug fever to severe acute hypersensitivity reactions (anaphylaxis), Hypophosphataemia, Confusion, hallucinations, mental depression, Encephalopathy, convulsions, neuromuscular blockage, dizziness, balance disorder, headache, Visual disorders, Vestibular damage, hearing loss, Meniére`s disease, tinnitus vertigo, Hypotension, hypertension, Toxic epidermal necrolysis, Stevens- Johnson syndrome, Erythema multiforme, Alopecia, Amyostasia, Acute renal failure, hyperphosphaturia, aminoaciduria, Fanconi- like syndrome in patients treated with a prolonged course of high-dose, Pain at injection site.

Not Known: Irreversible hearing loss, deafness.

Use In Pregnancy And Lactation:

Pregnancy:
There are no adequate data from the use of gentamicin in pregnant women. Gentamicin crosses the placenta. Because of the potential risk of inner ear and renal damage to the fetus, gentamicin should not be used in pregnancy unless in case of a life-threatening indication and if the benefit outweighs the risk.

Lactation:
Gentamicin is excreted in human breast milk and was detected in low concentrations in serum of breastfed children. A decision must be made whether to discontinue breast-feeding or to discontinue/ abstain from gentamicin therapy.

Overdose:
Haemodialysis and peritoneal dialysis will aid removal from the blood but the former is probably more efficient. Calcium salts given intravenously have been used to counter the neuromuscular blockade caused by gentamicin.

Incompatibilities:
Following are incompatible in mixed solution with gentamicin injection: beta-lactam antibiotics, erythromycin, or lipiphysan, diazepam, furosemide, flecainide acetate or heparin sodium. In the case of carbenicillin, administration should only be at a separate site. Gentamicin is incompatible with amphotericin B, cephalothin sodium, nitrofurantoin sodium, sulfadiazine sodium and tetracyclines. Addition of gentamicin to solutions containing bicarbonate may lead to the release of carbon dioxide.

Storage & Instructions:

• As directed by the physician.
• Protect from heat & sunlight, store below 25°C. Avoid freezing
• The expiration date refer to the product correctly stored at the required condition.
• Keep out of the reach of children.
• Do not use if injection is leaking, solution is cloudy or contains un-dissolved particles.
• Patients and healthcare professionals can also report suspected adverse drug reaction at ade@bosch-pharma.com.
• To be sold on prescription of a registered medical practitioner only.

Presentation:

GENTIC Injection 10mg/ml Pack of 1×5’s Ampoules.

GENTIC Injection 20mg/2ml Pack of 1×5’s Ampoules.

GENTIC Injection 40mg/ml Pack of 1×5’s Ampoules.

GENTIC Injection 80mg/2ml Pack of 1×5’s Ampoules.

GENTIC Injection 160mg/2ml Pack of 1×5’s Ampoules.