Amicyl

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMICIL® (AMICIL)

Composition:

Active substance: amikacin;

1 vial contains amikacin sulfate (1 : 1.8), calculated as amikacin – 250 mg;

Excipient: mannite (E 421).

Pharmaceutical form. Lyophilisate for solution for injection.

Main physico-chemical properties: porous mass of white or white with yellowish tint color.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Aminoglycosides.

ATC code J01GB06.

Pharmacological properties.

Pharmacodynamics.

Amikacin is a semisynthetic aminoglycoside antibiotic with a broad spectrum of activity. It exhibits bactericidal action. Penetrating actively through the bacterial cell membrane, it binds irreversibly to the 30S subunit of bacterial ribosomes, thereby inhibiting pathogen protein synthesis.

Highly active against aerobic gram-negative bacteria: Pseudomonas aeruginosa, Escherichia coli, Shigella spp., Salmonella spp., Klebsiella spp., Enterobacter spp., Serratia spp., Providencia stuartii.

Also active against some gram-positive bacteria: Staphylococcus spp. (including strains resistant to penicillin, methicillin, and certain cephalosporins), and some strains of Streptococcus spp.

Inactive against anaerobic bacteria.

Pharmacokinetics.

Absorption.

After intramuscular administration, amikacin is rapidly and completely absorbed. Maximum plasma concentration (Cmax) following a 7.5 mg/kg intramuscular dose is 21 µg/mL; following a 30-minute intravenous infusion of 7.5 mg/kg, Cmax is 38 µg/mL. Time to reach maximum plasma concentration (Cmax) after intramuscular injection is approximately 1.5 hours.

Distribution.

Distributed uniformly in extracellular fluid (abscess contents, pleural effusion, ascites, pericardial, synovial, lymphatic, and peritoneal fluids); found in high concentrations in urine; lower concentrations are found in bile, breast milk, aqueous humor of the eye, bronchial secretions, sputum, and cerebrospinal fluid. It readily penetrates all body tissues, where it accumulates intracellularly. High concentrations are found in organs with intensive blood supply: lungs, liver, myocardium, spleen, and especially in the renal cortex; lower concentrations are found in muscles, adipose tissue, and bones.

In adults, at normal therapeutic doses, amikacin does not cross the blood-brain barrier. In neonates, higher concentrations in cerebrospinal fluid are achieved compared to adults.

Amikacin crosses the placental barrier and is detected in fetal blood and amniotic fluid.

Volume of distribution (Vd) is 0.26 L/kg in adults, 0.2–0.4 L/kg in children, up to 0.68 L/kg in newborns under one week of age with body weight less than 1.5 kg, up to 0.58 L/kg in those with body weight over 1.5 kg, and 0.3–0.39 L/kg in patients with cystic fibrosis.

Therapeutic plasma concentrations are maintained for 10–12 hours after intravenous or intramuscular administration.

Metabolism.

Not metabolized.

Elimination.

Terminal elimination half-life (T½) in adults is 2–4 hours, in infants 5–8 hours, and in children 2.5–4 hours. The terminal T½ value exceeds 100 hours (due to slow release from intracellular depots).

Excreted primarily unchanged by the kidneys via glomerular filtration (65–94%). Renal clearance is 79–100 mL/min.

Pharmacokinetics in special clinical conditions.

In adults with impaired renal function, T½ varies depending on the degree of impairment and may extend up to 100 hours. In patients with cystic fibrosis, T½ is shorter (1–2 hours). In patients with burns and hyperthermia, T½ may be shorter than average due to increased clearance.

Amikacin is removed during hemodialysis (50% removed within 4–6 hours) and peritoneal dialysis (25% removed within 48–72 hours).

Clinical characteristics.

Indications.

Infections caused by amikacin-sensitive strains of microorganisms resistant to other aminoglycosides.

Contraindications.

• Hypersensitivity to amikacin, to other components of the medicinal product, or to other aminoglycoside antibiotics and their derivatives;
• renal failure;
• auditory nerve neuritis;
• myasthenia gravis;
• vestibular apparatus dysfunction;
• azotemia (residual nitrogen above 150 mg%);
• prior treatment with ototoxic or nephrotoxic agents.

Interaction with other medicinal products and other types of interactions.

Pharmaceutically incompatible with penicillins, heparin, cephalosporins, capreomycin, amphotericin B, hydrochlorothiazide, erythromycin, nitrofurantoin, B-complex vitamins and vitamin C, potassium chloride.

Amikacin exhibits synergy in combination with carbenicillin, benzylpenicillin, and cephalosporins (in patients with severe chronic renal insufficiency, concomitant use with beta-lactam antibiotics may reduce the efficacy of aminoglycosides).

Nalidixic acid, polymyxin B, cisplatin, and vancomycin increase the risk of ototoxicity and nephrotoxicity.

Concomitant use with penicillin, cephalosporins, sulfonamides, vancomycin, methoxyflurane, enflurane, nonsteroidal anti-inflammatory drugs (NSAIDs), radiographic contrast agents, cyclosporine, cisplatin, amphotericin B, cefalotin, polymyxin, and diuretics (especially furosemide) increases the risk of nephrotoxic effects.

Indomethacin, phenylbutazone, and other NSAIDs that impair renal blood flow may slow down the elimination rate of Amicil®. If amikacin is administered concomitantly with intravenous indomethacin in premature infants, plasma drug concentration increases, increasing the risk of toxicity.

Amikacin enhances the myorelaxant effect of curare-like agents.

Methoxyflurane, parenterally administered polymyxins, capreomycin, and other drugs that block neuromuscular transmission (halogenated hydrocarbons used for inhalational anesthesia, opioid analgesics), as well as massive blood transfusion with citrate-containing anticoagulants, increase the risk of respiratory arrest. Parenteral administration of indomethacin increases the risk of toxic effects of aminoglycosides (prolongation of T½ and reduction of clearance).

Amikacin reduces the efficacy of drugs used in the treatment of myasthenia gravis.

Concomitant use with ethyl ether and neuromuscular blocking agents increases the risk of respiratory depression.

The risk of ototoxicity increases when Amicil® is used concomitantly with furosemide and ethacrynic acid.

The antibiotic combinations amikacin + ceftazidime and amikacin + cefoperazone exhibit the greatest additive and synergistic effect against Pseudomonas aeruginosa.

When multiple antibiotics are used, Amicil® must not be mixed in the same syringe or vial with other antibacterial agents.

Special precautions for use

Prior to administration of the medicinal product, the susceptibility of the isolated pathogens should be determined.

Do not use Amitsyl® in patients with hypersensitivity to other aminoglycosides due to the risk of cross-allergy.

The drug should be used with caution in patients with myasthenia gravis, Parkinsonism, botulism (aminoglycosides may impair neuromuscular transmission, leading to further weakening of skeletal muscles), dehydration, renal impairment, neonates (especially premature infants), and elderly patients.

During treatment, kidney function, auditory nerve function, and vestibular apparatus function should be monitored at least once a week.

The risk of nephrotoxicity is higher in patients with impaired renal function and when the drug is administered at high doses or for prolonged periods (such patients require daily monitoring of renal function).

If audiometric tests yield unsatisfactory results, the dose of the drug should be reduced or treatment discontinued.

Patients with infectious-inflammatory diseases of the urinary tract are advised to consume plenty of fluids.

Ototoxicity

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

Patients with a family history of mitochondrial DNA mutations or aminoglycoside-induced hearing loss should consider alternative treatment options or undergo genetic testing prior to administration of the medicinal product.

The main toxic effect of the drug following parenteral administration is its action on the eighth cranial nerve, initially manifesting as hearing loss in the high-frequency range. The risk of ototoxic complications is significantly higher in patients with impaired renal function. Prior to initiating treatment, fluid and electrolyte balance should be corrected. During treatment with amikacin sulfate, adequate fluid intake is necessary, plasma creatinine concentration should be frequently monitored, and the dosing regimen adjusted as needed.

Dosage of Amitsyl® should be reduced in elderly patients due to decreased renal functional activity and possible reduction in body weight. Renal functional activity should be regularly assessed. Urinalysis is required either before or during treatment. Amitsyl® administration may alter the following laboratory parameters: serum alanine aminotransferase, aspartate aminotransferase, bilirubin, lactate dehydrogenase, alkaline phosphatase, blood urea nitrogen, creatinine, and calcium, magnesium, potassium, and sodium ion concentrations.

In patients with impaired renal function, the daily dose should be reduced and/or the dosing interval extended according to serum creatinine concentration to prevent drug accumulation in blood and minimize the risk of ototoxicity. If signs of renal irritation occur (albuminuria, microhematuria, leukocyturia), hydration should be increased and the dose reduced. These manifestations usually resolve after completion of treatment. If signs of ototoxicity (e.g., dizziness, tinnitus, hearing loss) or nephrotoxicity (e.g., decreased creatinine clearance, oliguria) occur, Amitsyl® should be discontinued or the dose reduced. If azotemia develops or oliguria worsens, treatment should be stopped.

Concomitant use of amikacin sulfate and potent diuretics such as ethacrynic acid derivatives, furosemide, or mannitol (especially if the diuretic is administered intravenously) may lead to irreversible hearing loss.

Two aminoglycosides should not be administered simultaneously, nor should one aminoglycoside be replaced by another if the first has been used for 7–10 days. A repeat course should not be initiated earlier than 4–6 weeks after the previous course.

In the absence of positive clinical response, the possibility of development of resistant microorganisms should be considered. In such cases, treatment should be discontinued and appropriate therapy initiated.

Use during pregnancy or breastfeeding

Since amikacin crosses the placenta and may exert ototoxic and nephrotoxic effects on the fetus, the medicinal product is contraindicated during pregnancy.

As amikacin passes into breast milk in low concentrations and may affect the intestinal microflora of a breastfed infant, breastfeeding should be discontinued during treatment with Amitsyl®.

Ability to influence reaction speed when operating vehicles or machinery

The drug generally does not affect reaction speed; however, the possibility of central nervous system adverse effects such as drowsiness and impaired neuromuscular transmission should be taken into account.

Dosage and Administration

Administer Amitsil® intramuscularly or intravenously.

The usual dose for children aged 12 years and older, and adults, is 5 mg/kg every 8 hours or 7.5 mg/kg body weight every 12 hours. The maximum daily dose for adults is 15 mg/kg/day. In severe cases and in infections caused by Pseudomonas, divide the daily dose into 3 administrations. The maximum daily dose is 1.5 g. The total course dose should not exceed 15 g.

Duration of treatment: up to 7 days for intravenous administration; 7–10 days for intramuscular administration.

For premature newborns, administer an initial loading dose of 10 mg/kg body weight, followed by 7.5 mg/kg body weight every 18–24 hours for 7–10 days.

For full-term newborns and children under 12 years of age, initially administer 10 mg/kg body weight, followed by 7.5 mg/kg body weight every 12 hours for 7–10 days.

Dosage adjustment is required for patients with renal insufficiency: either reduce the dose or extend the dosing intervals without changing the single dose. Adjust the dose according to plasma creatinine levels and patient body weight. The dosing interval can be calculated by multiplying the plasma creatinine level by 9; for example, if the creatinine level is 2 mg, administer the drug every 18 hours.

Prepare the Amitsil® solution immediately before use.

Administer Amitsil® by intravenous infusion to adults and children using a sufficient volume of fluid for slow drip infusion over 60–90 minutes (at a rate of 50 drops per minute). For newborns, administer over 1–2 hours.

For intravenous infusions, reconstitute the contents of the vial in 100–200 mL of 0.9% sodium chloride solution or 5% glucose solution.

The concentration of amikacin solution for intravenous administration should not exceed 5 mg/mL. Intravenous bolus injection of Amitsil® must be performed very slowly (over approximately 7 minutes).

For intramuscular injections, reconstitute the vial contents in 2–3 mL of water for injections and inject deeply into the upper outer quadrant of the buttock.

Children.

Use Amitsil® with caution in the treatment of premature and full-term infants due to immature excretory systems, which may prolong aminoglycoside elimination and lead to toxic effects.

Overdose.

Symptoms of ototoxicity and nephrotoxicity, as well as signs of neuromuscular blockade, may occur: tinnitus, hearing disturbances, skin rashes, headache, dizziness, malaise, paresthesia, decreased renal function (up to renal failure), respiratory depression or paralysis, and toxic reactions (ataxia, urinary disorders, thirst, loss of appetite, nausea, vomiting).

Treatment: hemodialysis or peritoneal dialysis to relieve neuromuscular blockade and its consequences; anticholinesterase agents, calcium salts, artificial ventilation of the lungs, and other symptomatic and supportive therapy.

Side effects.

Gastrointestinal system: nausea, vomiting, liver function disorders (elevated liver transaminase activity, hyperbilirubinemia).

Hematopoietic system: anemia, leukopenia, granulocytopenia, thrombocytopenia.

Cardiovascular system: vasculitis, arterial hypotension.

Central and peripheral nervous system: headache, drowsiness, neurotoxic effects (muscle twitching, numbness, tingling, epileptic seizures), neuromuscular transmission disorders (respiratory arrest).

Sensory organs: ototoxicity (hearing loss, tinnitus, vestibular and labyrinthine disorders, reversible deafness), toxic effects on the vestibular apparatus (motor incoordination, dizziness, nausea, vomiting).

Urinary system: nephrotoxicity – kidney function impairment (oliguria, proteinuria, hematuria, albuminuria, cylindruria, hyperazotemia), renal failure.

Allergic reactions: skin rashes, itching, skin hyperemia, fever, angioedema (Quincke's edema).

Other: reactions at injection site, pain at injection site, paresthesia, tremor.

Shelf life: 2 years.

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

Keep out of reach of children.

Incompatibility.

Amikacin sulfate solution should not be directly mixed with other aminoglycosides, penicillins, heparin, cephalosporins, capreomycin, amphotericin B, thiopental, hydrochlorothiazide, erythromycin, nitrofurantoin, vitamin B complex, vitamin C, or potassium chloride. If administration of two drugs is necessary, they should be given separately and sequentially.

Packaging. 250 mg of amikacin in vials.

Prescription category. Prescription only.

Manufacturer. JSC "Kievmedpreparat".

Manufacturer's address and location of business activity.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.