Gentamicin-zdorovya

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT GENTAMICIN-ZDOROVYE (GENTAMICIN-ZDOROVYE)

Composition:

active substance: gentamicin;

1 ml of solution contains 40 mg of gentamicin sulfate calculated as gentamicin;

excipients: sodium metabisulfite (E 223), edetate disodium, water for injections.

Pharmaceutical form. Injection solution.

Basic physico-chemical properties: transparent, colorless or slightly greenish-yellow solution.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Aminoglycosides. Gentamicin. ATC code J01GB03.

Pharmacological properties.

Pharmacodynamics. Gentamicin is a broad-spectrum aminoglycoside antibiotic of the second generation.

It exhibits bactericidal activity. By actively penetrating the bacterial cell membrane, it irreversibly binds to the 30S subunit of bacterial ribosomes, thereby interfering with the formation of the complex between transport and messenger RNA, which disrupts pathogen protein synthesis.

Highly effective against various Gram-positive and Gram-negative microorganisms: Escherichia coli, Proteus spp. (both indole-positive and indole-negative), Pseudomonas aeruginosa, Klebsiella spp., Enterobacter spp., Serratia spp., Citrobacter spp., Salmonella spp., Shigella spp., and Staphylococcus spp. (including penicillin- and methicillin-resistant strains).

Resistant to gentamicin are: Streptococcus pneumoniae, most other streptococcal species, enterococci, Treponema pallidum, and anaerobic microorganisms such as Bacteroides spp. or Clostridium spp.

Gentamicin is one of the main agents used in combating severe purulent infections, especially those caused by resistant Gram-negative flora. In certain cases, gentamicin remains effective when other antibiotics show insufficient activity. Compared to streptomycin, it is more nephrotoxic but less ototoxic and vestibulotoxic. Microbial resistance to gentamicin develops slowly; however, strains resistant to neomycin and kanamycin are also resistant to gentamicin (cross-resistance).

Pharmacokinetics. After parenteral administration, gentamicin is readily absorbed, reaching peak plasma concentration (C_max) within 30 minutes after completion of intravenous infusion and within 0.5–2 hours after intramuscular injection.

Therapeutic plasma concentrations (at least 6–10 μg/mL) are maintained for 6–8 hours.

During intravenous infusion, plasma gentamicin concentrations in the first hours exceed those achieved after intramuscular administration of the drug. Protein binding ranges from 20–30%. Volume of distribution is 0.25 L/kg.

Therapeutic concentrations are achieved in kidney tissue, lung tissue, pleural and peritoneal exudates. Normally, gentamicin poorly penetrates the blood-brain barrier; however, during meningitis, its concentration in cerebrospinal fluid increases.

Approximately 70% of gentamicin is excreted unchanged in urine within 24 hours via glomerular filtration. The elimination half-life in plasma is 2–4 hours in adults with normal hepatic function, 2.5–4 hours in children, and 5–8 hours in newborns. In case of impaired renal excretory function, gentamicin plasma concentrations increase significantly, and its elimination half-life is prolonged (up to 70 hours or more).

Clinical characteristics.

Indications. Due to the limited therapeutic index of gentamicin, it should be used only in cases where microorganisms are resistant to safer antibiotics.

Gentamicin is indicated for the treatment of infections caused by susceptible organisms, including:

• sepsis (including neonatal sepsis);
• complicated urinary tract infections;
• lower respiratory tract infections;
• skin, bone, joint, and soft tissue infections; infected burn wounds;
• central nervous system infections (including meningitis) in combination with β-lactam antibiotics;
• intra-abdominal infections (including 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 neuromuscular blockade, leading to further weakening of skeletal muscles), advanced age, prior treatment with ototoxic drugs. Acute renal failure is a restriction for the use of the drug.

Interaction with other medicinal products and other forms of interaction. Concomitant 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.

Enhances (mutually) the effect of carbenicillin, benzylpenicillin, and cephalosporins; increases digoxin toxicity. The risk of hypocalcemia increases when used concomitantly with bisphosphonates.

Loop diuretics (furosemide, ethacrynic acid) enhance ototoxicity and nephrotoxicity; neuromuscular blockers (succinylcholine, tubocurarine, decamethonium) increase the possibility of respiratory dysfunction due to neuromuscular blockade. When used simultaneously with inhalational anesthetics, opioid analgesics, magnesium sulfate, and transfusion of large volumes of citrated blood, the risk of neuromuscular blockade increases, potentially leading to apnea.

The risk of renal impairment increases when gentamicin is used concomitantly with indomethacin, phenylbutazone, and other nonsteroidal anti-inflammatory drugs that impair renal blood flow, as well as with quinidine, cyclophosphamide, cephalosporins (monitoring of renal function is recommended), ganglion blockers, verapamil, and polyglucin.

A reduced elimination half-life has been observed in patients with significant renal impairment when carbenicillin is used in combination with gentamicin.

Botulinum toxin increases the risk of toxicity due to enhanced neuromuscular blockade.

Concomitant use with oral anticoagulants may potentiate the hypoprothrombinemic effect.

An antagonistic effect may occur when gentamicin is administered simultaneously with proserin (neostigmine) or pyridostigmine.

Special precautions for use. Due to its broad spectrum of activity, gentamicin may be prescribed for mixed infections or when the causative agent has not been identified, usually in combination with semisynthetic penicillins (ampicillin, carbenicillin).

Rapid intravenous bolus injection is not recommended.

During treatment, especially with high doses or prolonged therapy, to avoid toxicity and ensure clinical efficacy (particularly in patients with impaired renal function), regular blood tests should be performed, and glomerular filtration rate should be monitored every 3 days (if this parameter decreases by 50%, the drug should be discontinued). Renal function should be monitored regularly (1–2 times per week, or daily in patients receiving higher doses or those treated for more than 10 days). Vestibular function or high-frequency hearing loss should be assessed 1–2 times per week. Symptoms of renal dysfunction or damage to the auditory or vestibular apparatus require discontinuation of gentamicin therapy or, in exceptional cases, dose adjustment. In some cases, hearing disturbances may occur after completion of treatment.

Gentamicin sulfate should be used with caution in patients with dehydration, botulism, Parkinsonism, diabetes, otitis media (including in medical history), hypocalcemia, obesity, as well as in elderly patients and those previously treated with ototoxic drugs.

Adequate fluid intake is recommended during treatment.

Patients should be advised to inform their physician immediately if they experience any hearing loss, tinnitus, dizziness, loss of coordination, numbness, skin tingling, muscle twitching, or seizures during treatment, as these may indicate neurological adverse effects.

Due to limited clinical experience, administration of the total daily dose of gentamicin is not recommended in the following conditions: burns affecting more than 20% of body surface area, cystic fibrosis, ascites, endocarditis, chronic renal failure requiring hemodialysis, and sepsis.

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

In patients with a family history of maternal mutations or aminoglycoside-induced deafness, alternative treatments or genetic testing should be considered before initiating therapy.

Cross-sensitivity may occur among aminoglycoside antibiotics.

Microbial resistance may develop during treatment. In such cases, the drug should be discontinued, and microbial susceptibility to other antibiotics should be tested.

Sodium metabisulfite (E 223) may rarely cause hypersensitivity reactions and bronchospasm.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding. The drug is contraindicated during pregnancy. If use of the drug is necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery. Data on the effect of gentamicin on the ability to drive or operate machinery are lacking. 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 high concentration and rapid psychomotor responses (including driving vehicles and operating machinery).

Method of administration and dosage. The drug is administered intramuscularly or intravenously.

The dose, 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 if the clinical condition improves or if adverse effects develop.

Adults and children aged 14 years and older. The usual daily dose for patients with moderate to severe infection 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 or complicated infections, therapy may be extended if necessary. In such cases, monitoring of renal function, hearing, and vestibular function is recommended, as drug toxicity typically manifests after more than 10 days of treatment.

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

In case of impaired renal function, the dosing regimen should be adjusted to ensure therapeutic adequacy. Whenever possible, serum gentamicin concentrations should be monitored; the level measured 30–60 minutes after intramuscular injection should be 5–10 µg/mL.

Before prescribing gentamicin, creatinine clearance must be determined. The initial dose for patients with stable chronic renal failure is 1–1.5 mg/kg. Subsequent doses and dosing intervals should be determined based on 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, add 1 mg of gentamicin to 2 liters 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: for newborns and children under 1 year of age – 2-5 mg/kg; for children aged 1 to 5 years – 1.5-3 mg/kg; for children aged 6-14 years – 3 mg/kg. The maximum daily dose for children of all age groups is 5 mg/kg. The drug is administered 2-3 times daily for 7-10 days.

For intravenous administration, dilute the single dose of the drug with a solvent. The usual volume of solvent (sterile isotonic sodium chloride solution or 5% glucose solution) for adults is 50-300 ml; for children, the solvent volume 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; administer at a rate of 60-80 drops/min. Perform intravenous infusions for 2-3 days, then switch to intramuscular administration.

Children. The drug 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. Before administering proserin intravenously, administer atropine intravenously at a dose of 0.5-0.7 mg, wait for an increase in pulse rate, 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 via hemodialysis (more effective) and peritoneal dialysis.

Side effects.

Ototoxicity (damage to the eighth cranial nerve): may lead to decreased hearing/acoustic acuity or hearing loss and damage to the vestibular apparatus. Manifested by dizziness or vertigo. Tinnitus, irreversible hearing loss, deafness. A particular risk may be caused by prolonged gentamicin therapy – 2–3 weeks.

Nephrotoxicity: the frequency and severity of kidney damage depend on the dose, duration of treatment, individual patient characteristics, quality of therapy monitoring, and concomitant use of other nephrotoxic drugs. Kidney damage manifests as proteinuria, azotemia, oliguria, and is usually reversible. Interstitial nephritis, renal failure (including acute), renal tubular necrosis, and Fanconi-like syndrome may also occur in patients receiving prolonged high-dose therapy.

Central nervous system effects: headache, confusion, drowsiness, peripheral neuropathy, muscle pain, joint pain, neuromuscular blockade, general weakness, seizures, encephalopathy, depression, hallucinations, lethargy.

Gastrointestinal effects: vomiting, elevated liver transaminases (ALT, AST), hyperbilirubinemia, nausea, increased salivation, loss of appetite/body weight, stomatitis, pseudomembranous colitis.

Hematological effects: thrombocytopenia, granulocytopenia, anemia, leukopenia, purpura.

Metabolic effects: hypomagnesemia, hypokalemia, hypocalcemia.

Immune system effects: hypersensitivity reactions, including skin itching/rash, urticaria, urticaria, anaphylactic reactions (including decreased blood pressure, dyspnea), Quincke's edema.

At the site of intramuscular injection, pain, atrophy, or necrosis of subcutaneous tissue may occur; with intravenous administration, phlebitis and periphlebitis may develop.

Shelf life. 5 years.

Storage conditions. Store in the 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. 1 ml in ampoules, №10 in a box; №5x2 in blisters in a box; 2 ml in ampoules, №10 in a box; №5x2, №10 in blister in a box.

Prescription status. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's address and place of business. Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenko Street, 22.