Gentamicin sulfate

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GENTAMICIN SULPHATE (GENTAMYCIN SULPHATE)

Composition:

Active substance: gentamicin;

1 ml contains gentamicin sulfate (calculated as gentamicin and anhydrous substance) 40 mg;

Excipients: sodium metabisulfite, disodium edetate, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless or slightly tinted liquid.

Pharmacotherapeutic group. Antimicrobials for systemic use. Antibacterial agents for systemic use. Aminoglycosides. Gentamicin.

ATC Code J01G B03.

Pharmacological Properties

Pharmacodynamics

Gentamicin is an antibiotic of the aminoglycoside group with a broad spectrum of activity. Its mechanism of action is associated with inhibition of the 30S ribosomal subunits. In vitro tests confirm its activity against various gram-positive and gram-negative microorganisms: Escherichia coli, Proteus spp. (indole-positive and indole-negative), Pseudomonas aeruginosa, Klebsiella spp., Enterobacter spp., Citrobacter spp., Salmonella spp., Shigella spp., and Staphylococcus spp. (including penicillin- and methicillin-resistant strains). The following microorganisms are generally resistant to gentamicin: Streptococcus pneumoniae, most other streptococcal species, enterococci, Neisseria meningitidis, Treponema pallidum, and anaerobic microorganisms such as Bacteroides spp. or Clostridium spp.

Pharmacokinetics

Gentamicin is readily absorbed, reaching maximum plasma concentration within 30–60 minutes after intramuscular administration.

Therapeutic plasma concentrations are maintained for 6–8 hours.

With intravenous infusion, the antibiotic concentration in plasma during the first hours exceeds that achieved after intramuscular administration. Protein binding ranges from 0–10%.

Therapeutically active concentrations are found in kidney and lung tissues, as well as in pleural and peritoneal exudates. Normally, gentamicin poorly penetrates the blood-brain barrier following parenteral administration; however, in cases of meningitis, concentrations in cerebrospinal fluid increase. The drug penetrates into breast milk.

Approximately 70% of gentamicin is excreted unchanged in urine within 24 hours via glomerular filtration. The elimination half-life from plasma is approximately 2 hours. In cases of impaired renal excretory function, gentamicin concentration is significantly increased and its half-life prolonged.

Clinical characteristics.

Indications.

Due to the narrow therapeutic window of gentamicin, it should be used only in cases where microorganisms are resistant to safer antibiotics. Gentamicin sulfate is indicated for the treatment of infections caused by susceptible organisms, such as:

• sepsis;
• urinary tract infections;
• lower respiratory tract infections;
• skin, bone, soft tissue infections; infected burn wounds;
• central nervous system (CNS) infections (meningitis), in combination with β-lactam antibiotics;
• intra-abdominal infections (peritonitis).

Contraindications.

Hypersensitivity to the components of the drug or to aminoglycoside antibiotics; chronic renal failure with azotemia and uremia; auditory nerve neuritis; myasthenia gravis; Parkinsonism; botulism (gentamicin may cause impairment of neuromuscular transmission, which can lead to further weakening of skeletal muscles); advanced age; prior treatment with ototoxic agents. An additional limitation for the use of the drug is acute renal failure.

Interaction with other medicinal products and other types of interactions.

Concomitant administration with potent diuretics (furosemide, ethacrynic acid) should be avoided, as they may enhance ototoxic and nephrotoxic effects. Respiratory dysfunction due to neuromuscular blockade may occur in patients receiving muscle relaxants (succinylcholine, tubocurarine, decamethonium), anesthetics, or in patients who have received massive blood transfusions with citrate anticoagulant prior to gentamicin administration. Administration of calcium salts and anticholinesterase agents may reverse the effects of neuromuscular blockade.

Concomitant and/or sequential systemic or local use of other neurotoxic and/or nephrotoxic agents such as cisplatin, cephaloridine, aminoglycoside antibiotics, polymyxin B, colistin, and vancomycin should be avoided.

The risk of renal function impairment increases with concomitant use of gentamicin and indomethacin, phenylbutazone, and other nonsteroidal anti-inflammatory drugs, as well as quinidine, cyclophosphamide, cephalosporins (renal function monitoring is recommended), ganglionic blockers, verapamil, and polyglucin. Gentamicin increases digoxin toxicity.

When aminoglycosides and penicillins are administered simultaneously, the elimination half-life is reduced and their serum concentrations decrease.

The elimination half-life is shortened in patients with severe renal impairment when carbenicillin is used concomitantly with gentamicin.

The risk of developing hypocalcemia increases when gentamicin is used concomitantly with bisphosphonates; when used with botulinum toxin, the risk of toxicity increases due to enhanced neuromuscular blockade.

Concomitant use with oral anticoagulants may enhance the hypoprothrombinemic effect.

Antagonism is possible when gentamicin is administered simultaneously with proserine (neostigmine) or pyridostigmine.

Special precautions for use.

Due to its broad spectrum of activity, gentamicin is frequently prescribed for mixed infections and in cases where the causative pathogen has not been identified, usually in combination with semi-synthetic penicillins (ampicillin, carbenicillin).

In patients with kidney disease, it is necessary to regularly monitor serum gentamicin concentrations and renal function, as well as auditory and vestibular functions.

Symptoms of impaired renal function or damage to the auditory or vestibular apparatus require discontinuation of gentamicin therapy or, only in exceptional cases, dose adjustment.

Gentamicin sulfate should be used with caution in patients with dehydration, botulism, Parkinsonism, hypocalcemia, diabetes, obesity, otitis media (including in medical history), as well as in elderly patients and those who have previously received ototoxic drugs. Adequate fluid intake is recommended during treatment.

Rapid intravenous bolus injection of the drug is not recommended.

Patients with kidney disease, hearing loss, dizziness, or tinnitus are particularly sensitive to gentamicin.

Due to limited clinical experience, administration of the total daily dose of gentamicin sulfate is not recommended under the following conditions:

• Burns covering more than 20% of body surface area;
• Cystic fibrosis;
• Ascites;
• Endocarditis;
• Chronic renal failure requiring hemodialysis;
• Sepsis.

During prolonged treatment or administration of high doses, the dosage should ensure that gentamicin blood concentrations do not exceed the maximum allowable levels. Therefore, in high-risk patients, serum gentamicin concentrations should be monitored throughout treatment. Renal function should be monitored regularly (once or twice weekly; in patients receiving higher doses or undergoing treatment for more than 10 days, monitoring should be daily). To prevent hearing impairment, vestibular function should be assessed regularly (once or twice weekly), or high-frequency hearing loss should be evaluated.

In individual cases, hearing disturbances may occur after completion of therapy.

There is an increased risk of ototoxicity in patients with mitochondrial DNA mutations (particularly the 1555 A>G substitution in the 12S rRNA gene), even when aminoglycoside serum levels during treatment remain within the recommended range. Alternative treatment options should be considered for such patients.

For patients with a family history of such mutations in the mother or with aminoglycoside-induced hearing loss, alternative treatment options or genetic testing prior to drug administration should be considered.

Patients should inform their physician immediately if they experience any of the following symptoms during treatment: any sensation of hearing loss, tinnitus, dizziness, impaired coordination, numbness, skin tingling, muscle twitching, or seizures. These may indicate the development of neurological adverse effects.

Cross-sensitivity may occur among aminoglycoside antibiotics.

Microbial resistance may develop during treatment. In such cases, the drug should be discontinued and microbial susceptibility testing performed.

Use during pregnancy or breastfeeding.

Since gentamicin sulfate crosses the placenta and may exert nephrotoxic effects on the fetus, the drug is contraindicated during pregnancy.

The drug is excreted in breast milk; therefore, either breastfeeding should be discontinued or the use of the drug should be avoided.

Ability to affect reaction speed when driving or operating machinery.

There are no data available on the effect of gentamicin on the ability to drive or operate machinery. However, in some patients, high doses of the drug may cause balance disturbances accompanied by nausea and dizziness. Therefore, during therapy, patients should avoid potentially hazardous activities requiring heightened attention and rapid psychomotor responses (including driving vehicles and operating machinery).

Administration and Dosage

The drug is administered intramuscularly and intravenously.

The dosage, route of administration, and intervals between doses depend on the site and severity of infection, patient age, and renal function. The dosing regimen is calculated based on the patient's body weight. The dose should be reduced when the clinical condition improves or if adverse effects develop.

Adults and children aged 14 years and older. The usual daily dose of the drug for patients with moderate to severe infections is 3 mg/kg body weight administered intramuscularly, divided into 2–3 doses. The maximum daily dose for adults is 5 mg/kg, divided into 3–4 doses. The usual duration of treatment for all patients is 7–10 days.

In severe and complicated infections, the treatment course may be extended if necessary. In such cases, monitoring of kidney function, hearing organs, and vestibular apparatus is recommended, since the drug's toxicity may manifest after administration for more than 10 days.

Dose calculation based on body weight. The dose is calculated using actual body weight (ABW) if the patient does not have excess weight (i.e., no more than 20% above ideal body weight (IBW)). Since gentamicin is poorly distributed in adipose tissue, if the patient has excess body weight, the dose should be calculated using the following formula: IBW + 0.4 (ABW – IBW).

In case of impaired renal function, the dosing regimen must be adjusted to ensure therapeutic adequacy of treatment. Whenever possible, serum gentamicin concentrations should be monitored; these should be 5–10 mcg/mL 30–60 minutes after intramuscular administration.

Before prescribing gentamicin, creatinine clearance must be determined. The initial single dose for patients with stable chronic renal insufficiency is 1–1.5 mg/kg; subsequent doses and dosing intervals should be determined according to creatinine clearance.

Adult patients with bacterial infection undergoing dialysis should be administered 1–1.5 mg/kg after completion of each dialysis session. For peritoneal dialysis, 1 mg of gentamicin is added to 2 L of dialysis solution.

Children. Gentamicin sulfate should be administered to children under 3 years of age only under life-threatening indications.

Daily doses are as follows: 2–5 mg/kg for newborns and children under 1 year of age; 1.5–3 mg/kg for children aged 1 to 5 years; 3 mg/kg for children aged 6–14 years. The maximum daily dose for children of all age groups is 5 mg/kg. The drug should be administered 2–3 times daily for 7–10 days.

For intravenous administration, the single dose should be diluted with a solvent. The usual volume of diluent (sterile 0.9 % sodium chloride solution or 5 % glucose solution) for adults is 50–300 mL; for children, the volume of diluent should be proportionally reduced. The concentration of gentamicin in the solution should not exceed 1 mg/mL (0.1 %). The duration of intravenous infusion is 1–2 hours; the infusion rate should be 60–80 drops/min. Intravenous infusions should be administered for 2–3 days, after which treatment should be switched to intramuscular administration.

Children. Gentamicin sulfate should be administered to children under 3 years of age only under life-threatening indications.

Overdose.

Symptoms: dizziness, nausea, vomiting, nephrotoxicity, ototoxicity, neuromuscular blockade leading to respiratory depression.

Treatment: intravenous administration of proserin (neostigmine), as well as 10 % calcium chloride solution or 5 % calcium gluconate solution. Prior to intravenous administration of proserin, atropine should be administered intravenously at a dose of 0.5–0.7 mg; wait for pulse acceleration and then administer 1.5 mg of proserin intravenously after 1.5–2 minutes. If the effect of this dose is insufficient, repeat the same dose of proserin (in case of bradycardia, administer an additional injection of atropine). In severe cases of respiratory depression, artificial ventilation of the lungs is required. The drug may be removed by hemodialysis (more effective) and peritoneal dialysis.

Adverse Reactions.

Ototoxicity (damage to the eighth cranial nerve): possible reduction in hearing acuity, initially affecting high-frequency sounds (therefore, speech recognition impairment, which involves low-frequency sounds, is not among the first signs of ototoxicity), and vestibular apparatus damage (in case of bilateral vestibular damage, these disorders may even go unnoticed in the early stages). Manifested by dizziness or vertigo, tinnitus, and hearing loss. A particular risk may arise from prolonged gentamicin treatment courses of 2–3 weeks. Frequency unknown – irreversible hearing loss, deafness.

Nephrotoxicity: the frequency and severity of kidney damage depend on the single dose, duration of treatment, individual patient characteristics, quality of therapy monitoring, and concomitant use of other nephrotoxic drugs. Kidney damage manifests as renal insufficiency usually of mild degree, acute tubular necrosis, interstitial nephritis, decreased glomerular filtration rate (observed after several days of treatment or after discontinuation of therapy), proteinuria, azotemia, and less frequently oliguria; it is generally reversible.

In addition to high plasma drug concentration, which particularly increases the risk of ototoxicity and nephrotoxicity, many other risk factors exist (see section "Special Warnings and Precautions for Use"). Very rare: acute renal failure; elevated levels of phosphates and amino acids in urine (so-called Fanconi syndrome associated with long-term use of high doses).

Electrolyte disturbances: hypomagnesemia, hypocalcemia, and hypokalemia.

Gastrointestinal disorders: stomatitis, nausea, vomiting, increased salivation, loss of appetite, weight loss, pseudomembranous colitis.

Immune system disorders: allergic reactions including skin rashes, urticaria, pruritus, fever, purpura. Anaphylactic reactions and endotoxic shock. Dyspnea, Quincke's edema.

The product contains sodium metabisulfite (E 223), which rarely may cause hypersensitivity reactions and bronchospasm.

Blood disorders: thrombocytopenia, granulocytopenia, anemia, leukopenia.

Laboratory test abnormalities: increased serum transaminase levels (ALT, AST), bilirubin, and reticulocytes.

Central nervous system (CNS) disorders: headache, drowsiness, neurotoxicity (encephalopathy, confusion, lethargy, hallucinations, seizures, and depression), peripheral neuropathy.

Cardiovascular system disorders: hypotension.

Other: neuromuscular blockade and respiratory depression, joint pain, muscle pain, general weakness.

Local site reactions: at the injection site – hyperemia, pain, induration, subcutaneous tissue atrophy or necrosis; following intravenous administration – development of phlebitis and periphlebitis.

Reporting of adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of this medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibility.

Pharmaceutically incompatible in the same syringe or infusion system with other medicinal products (especially with β-lactam antibiotics, heparin, amphotericin).

Packaging.

2 ml in an ampoule; 10 ampoules in a blister pack; 1 blister pack in a carton; 2 ml in an ampoule; 10 ampoules in a paper-sealed blister pack.

Prescription status. Prescription only.

Manufacturer.

JSC "Halychpharm".

Manufacturer's location and address of its place of business.

6/8 Opryshkivska Street, Lviv, 79024, Ukraine.