Gentamycinsulfate-darnitsa

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

Composition:

Active substance: gentamicin;

1 ml of solution contains 40 mg of gentamicin sulfate;

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

Pharmaceutical form. Solution for injection.

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

Pharmacotherapeutic group. 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 30S ribosomal subunits. In vitro tests confirm its activity against various species of gram-positive and gram-negative microorganisms: Escherichia coli, Proteus sp. (indole-positive and indole-negative), Pseudomonas aeruginosa, Klebsiella sp., Enterobacter sp., Serratia sp., Citrobacter sp., Salmonella sp., Shigella sp., and Staphylococcus sp. (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 sp. or Clostridium sp.

Pharmacokinetics

Maximum plasma concentration is reached within 0.5–2 hours after intramuscular administration of 80 mg gentamicin and ranges from 4–12 μg/mL. Similar concentrations are achieved after intravenous administration. The elimination half-life is 2.5 hours and increases in case of impaired renal excretory function. Plasma protein binding is 20–30%. The volume of distribution is 0.25 L/kg. Normally, gentamicin poorly penetrates the blood-brain barrier; however, during meningitis, concentrations in cerebrospinal fluid increase.

Gentamicin crosses the placenta. Fetal blood concentrations are approximately 40% of those observed in the mother.

Gentamicin is not metabolized in the body. It is excreted unchanged in urine, primarily via glomerular filtration and partially through tubular secretion.

Clinical characteristics.

Indications.

Due to the limited therapeutic window of Gentamicin-Darnytsia, it should be used only in cases where microorganisms are resistant to safer antibiotics.

Bacterial infections caused by microflora sensitive to gentamicin, particularly: lower respiratory tract infections, complicated urinary tract and genital infections, bone and joint infections including osteomyelitis, skin and soft tissue infections, infected burn wounds, abdominal infections (peritonitis), central nervous system infections, particularly meningitis in combination with β-lactam antibiotics, septicemia.

Contraindications.

Hypersensitivity to the active substance or to other components of the medicinal product; auditory nerve neuritis; chronic renal failure with azotemia and uremia; myasthenia; Parkinsonism; botulism (gentamicin may cause impairment of neuromuscular transmission which can lead to further weakening of skeletal muscles); advanced age; prior treatment with ototoxic medicinal agents. Acute renal failure is a restriction for the use of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of the medicinal product with other drugs may result in:

with ototoxic agents (e.g., capreomycin, cisplatin, teicoplanin, vancomycin, potent diuretics: furosemide, ethacrynic acid) – enhanced ototoxic effect; such combination is not recommended;

with neurotoxic or nephrotoxic agents (e.g., streptomycin, neomycin, kanamycin, capreomycin, tobramycin, cephaloridine, paromomycin, biomycin, polymyxin B, colistin, amikacin, vancomycin, teicoplanin, tacrolimus, amphotericin B, cyclosporine, clindamycin, piperacillin, methoxyflurane, foscarnet, intravenous radiographic contrast agents, cisplatin) – enhanced neurotoxic or nephrotoxic effect; such combination is not recommended;

with non-depolarizing muscle relaxants – enhanced muscle relaxant effect of curare-like medicinal products;

with methoxyflurane, parenterally administered polymyxins, medicinal products that block neuromuscular transmission (inhalational agents for general anesthesia, narcotic analgesics, transfusion of large volumes of citrated blood) – increased risk of respiratory arrest due to enhanced neuromuscular blockade;

with botulinum toxin – increased risk of toxicity due to enhanced neuromuscular blockade;

with medicinal products that increase muscle tone – reduced efficacy of the latter;

with cephalosporins – enhanced nephrotoxic effect; monitoring of kidney function is recommended during therapy;

with penicillins – enhanced bactericidal effect;

with bisphosphonates – increased risk of hypocalcemia development;

with indomethacin (parenteral administration) – increased risk of gentamicin toxicity due to prolonged elimination half-life and reduced clearance.

Special precautions for use.

Gentamicin is one of the main agents for the treatment of severe purulent infections caused by resistant Gram-negative flora. Due to its broad spectrum of activity, gentamicin may be prescribed for mixed infections and also when the causative agent has not been identified, usually in combination with semi-synthetic penicillins: ampicillin, carbenicillin.

Treatment with the drug should be carried out only under a physician's prescription and under careful clinical monitoring due to the potential toxicity of gentamicin.

During treatment with gentamicin, regular blood tests should be performed to determine plasma concentrations of the drug in order to ensure adequate levels and to avoid potentially toxic drug concentrations in the blood.

Adequate fluid intake should be maintained during treatment.

Like other aminoglycosides, gentamicin is potentially nephro- and neurotoxic. The risk of developing these adverse effects is higher in patients with impaired renal function, as well as when the drug is administered in high doses or for prolonged periods. Therefore, renal function should be monitored regularly (once or twice weekly, and daily in patients receiving higher doses or those undergoing treatment for more than 10 days). To prevent hearing impairment, regular testing of vestibular function or detection of high-frequency hearing loss (once or twice weekly) is recommended.

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

Patients should inform their physician about the presence of the following symptoms at any time during treatment: any sensation of hearing loss, tinnitus (ringing or buzzing in the ears), dizziness, impaired coordination, numbness, skin tingling, muscle twitching, or seizures. These may indicate the development of neurological adverse effects.

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

In patients with a personal or maternal family history of such mutations or aminoglycoside-induced hearing loss, consideration should be given to using alternative treatment approaches or performing genetic testing prior to drug administration.

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

The drug should be used with caution in patients with dehydration, hypocalcemia, impaired renal function, or obesity.

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

Rapid intravenous injection of the drug may lead to potentially neurotoxic concentrations of gentamicin at the initial stage; therefore, it is essential to administer the dose at the recommended time intervals.

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 to antibiotics should be performed.

Use during pregnancy or breastfeeding.

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

The drug passes into breast milk; therefore, if gentamicin must be administered to a nursing mother, either breastfeeding should be discontinued or use of the drug should be avoided.

Ability to affect reaction speed when driving or operating machinery.

The drug affects neuromuscular conduction speed; therefore, patients should refrain from driving vehicles or operating machinery requiring high attention during treatment with this drug.

Administration and Dosage

Gentamicin should be administered intramuscularly or intravenously. The dosage, route of administration, and dosing intervals depend on the severity of the infection and the patient's condition. The dosing regimen should be calculated based on the patient's body weight.

Adults and children aged 14 years and older.

The usual daily dose of gentamicin for patients with moderate to severe infections is 3 mg/kg of body weight administered intramuscularly, divided into 2–3 doses. The maximum daily dose for adults is 5 mg/kg of body weight, divided into 3–4 doses. The usual duration of treatment for all patients is 7–10 days.

In cases of severe or complicated infections, the treatment course may be extended if necessary. In such cases, monitoring of renal function, hearing, and vestibular function is recommended, as the drug's toxicity may manifest after administration exceeding 10 days.

Body weight calculation for gentamicin dosing.

Calculate the dose based on actual body weight (ABW) if the patient does not have excess body weight (i.e., body weight not exceeding 20% above ideal body weight (IBW)). If the patient has excess body weight, the dose should be calculated based on adjusted body weight (ADJ BW) using the following formula:

ADJ BW = IBW + 0.4 × (ABW – IBW).

In renal impairment, the dosing regimen should be adjusted to ensure therapeutic adequacy. Whenever possible, serum concentrations of gentamicin should be monitored. Serum concentrations measured 30–60 minutes after intramuscular administration should be in the range of 5–10 mcg/mL.

The initial dose for patients with stable chronic kidney disease (CKD) is 1–1.5 mg/kg of body weight. Subsequent doses and dosing intervals should be adjusted according to creatinine clearance.

For adult patients with bacterial infection undergoing dialysis, the drug should be administered at a dose of 1–1.5 mg/kg body weight at the end of each dialysis session.

For peritoneal dialysis in adults, add 1 mg of gentamicin to 2 liters of dialysis solution.

For intravenous administration, dilute the drug dose with a suitable solvent. The usual volume of diluent (sterile physiological saline or 5% glucose solution) for adults is 50–300 mL; for children, the volume of diluent should be proportionally reduced. The duration of intravenous infusion is 1–2 hours.

The concentration of gentamicin in the solution should not exceed 1 mg/mL (0.1%).

Children.

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

The usual daily dose of gentamicin is: for newborns and children under 1 year of age – 2–5 mg/kg body weight; for children aged 1 to 5 years – 1.5–3 mg/kg body weight; for children aged 6–14 years – 3 mg/kg body weight. The maximum daily dose for children of all age groups is 5 mg/kg body weight, divided into 2–3 doses. The average duration of treatment is 7–10 days.

Children.

The drug may be used in children. Gentamicin may be administered to children under 3 years of age only under life-threatening indications.

Overdose.

Symptoms: dizziness, nausea, vomiting, nephrotoxic and ototoxic effects, neuromuscular blockade (respiratory arrest).

Treatment: in adults, administer intravenously proserin (neostigmine), as well as 10% calcium chloride solution or 5% calcium gluconate solution. Prior to proserin administration, atropine should be given intravenously at a dose of 0.5–0.7 mg; wait for an increase in heart rate, and after 1.5–2 minutes, administer intravenously 1.5 mg (3 mL of 0.05% solution) of proserin. 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.

Auditory and vestibular system disorders: ototoxicity (damage to the VIII cranial nerve, especially if treatment duration exceeds 2–3 months) – tinnitus, hearing loss, vestibular and labyrinthine dysfunction, irreversible deafness.

Respiratory, thoracic and mediastinal disorders: sore throat, dyspnea.

Gastrointestinal disorders: nausea, vomiting, increased thirst, loss of appetite, stomatitis, in individual cases – pseudomembranous colitis.

Hepatobiliary disorders: increased liver transaminase activity, hyperbilirubinemia.

Renal and urinary disorders: nephrotoxicity (kidney function impairment) – oliguria, azotemia, proteinuria, microhematuria, interstitial nephritis, renal failure, in individual cases – renal tubular necrosis.

Metabolism and nutrition disorders: hypomagnesemia, hypocalcemia, hypokalemia, hyponatremia.

Nervous system disorders: headache, drowsiness, confusion, muscle twitching, paresthesia, numbness, seizures, epileptic seizures, peripheral neuropathy, encephalopathy, neuromuscular transmission disorders.

Psychiatric disorders: depression, hallucinations, in children – psychosis.

Cardiovascular disorders: decreased arterial blood pressure.

Blood and lymphatic system disorders: anemia, leukopenia, granulocytopenia, thrombocytopenia, eosinophilia, purpura.

Immune system disorders: hypersensitivity reactions, including rash, pruritus, hyperemia, urticaria, angioedema (Quincke's edema), anaphylactic shock, development of superinfections.

General disorders and administration site conditions: general weakness, muscle pain, edema, fever, chills, increased salivation, injection site reactions (including hyperemia, skin induration, subcutaneous tissue atrophy or necrosis; with intravenous administration – development of phlebitis and periphlebitis).

Shelf life. 3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze. Keep out of reach of children.

Incompatibility.

The medicinal product should not be mixed with other medicinal products. It is pharmaceutically incompatible with other aminoglycosides, amphotericin B, heparin, ampicillin, benzylpenicillin, cloxacillin, carbenicillin, and capreomycin.

Packaging.

2 ml in a vial; 5 vials in a blister pack; 2 blister packs in a carton.

Prescription status. Prescription only.

Manufacturer/Marketing Authorization Holder.

JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and place of business.

13, Boryspilska Street, Kyiv, 02093, Ukraine.