Amikacin sulfate

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT amIKACIN SULFATE (Amikacin sulfate)

Composition:

active substance: amikacin;

1 ml of solution contains amikacin sulfate equivalent to 50 mg or 250 mg of amikacin;

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

Pharmaceutical form. Injection solution.

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

Pharmacotherapeutic group. Antimicrobial agents for systemic use.
Aminoglycosides. Amikacin. ATC code J01G B06.

Pharmacological properties.

Pharmacodynamics.

Amikacin is a semi-synthetic aminoglycoside antibiotic with a broad spectrum of activity. Amikacin actively penetrates the bacterial cell membrane. By binding to the 30S ribosomal subunit, it interferes with the formation of the complex between transfer and messenger RNA, blocks protein synthesis, and also disrupts the synthesis of the bacterial cytoplasmic membrane.

Active against aerobic gram-negative microorganisms: Pseudomonas aeruginosa, Escherichia coli, Shigella spp., Salmonella spp., Klebsiella spp., Enterobacter spp., Providencia spp., Proteus spp. (indole-positive and indole-negative strains), Serratia spp., Acinetobacter species, Citrobacter freundii.

Active against certain gram-positive microorganisms: Staphylococcus spp., including penicillin-, methicillin-, and some cephalosporin-resistant strains, as well as some strains of Streptococcus pyogenes, Streptococcus pneumoniae, Enterococcus. Under certain conditions, amikacin may be used as primary therapy for confirmed or suspected infections caused by susceptible staphylococcal strains in patients with allergies to other antibiotics and in mixed staphylococcal-gram-negative infections. Amikacin is inactive against anaerobic pathogens.

Pharmacokinetics.

After intramuscular administration, amikacin is rapidly and completely absorbed. Maximum concentration is reached within 0.5–1.5 hours after intramuscular injection and within 0.5 hours after intravenous administration. Therapeutic concentrations of amikacin are maintained for 10–12 hours.

Distribution. Protein binding to plasma proteins ranges from 4% to 11%. Amikacin distributes well into extracellular fluids (abscess contents, pleural effusion, ascitic, pericardial, synovial, lymphatic, and peritoneal fluids). High concentrations of amikacin are found in urine; lower concentrations are present in bile, breast milk, aqueous humor of the eye, bronchial secretions, sputum, and cerebrospinal fluid. Amikacin penetrates well into all body tissues, where it accumulates intracellularly. High concentrations of amikacin are observed in organs with rich blood supply: lungs, liver, myocardium, spleen, and particularly in the kidneys, where it accumulates in the cortical layer; lower concentrations are found in muscle, adipose tissue, and bone.

In adults receiving average therapeutic doses, amikacin practically does not cross the blood-brain barrier; however, penetration increases sharply during meningeal inflammation. 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.

Elimination. Amikacin is not metabolized and is excreted unchanged by the kidneys via glomerular filtration (65–94%), achieving high concentrations in urine. Renal clearance is 79–100 mL/min. The rate of excretion depends on age, renal function, and concomitant patient pathology.

Excretion is increased in patients with sepsis, and significantly slowed in patients with impaired renal function and in elderly individuals.

The elimination half-life in adults with normal renal function is 2–4 hours, in neonates 5–8 hours, and in older children 2.5–4 hours. In renal failure, the elimination half-life may extend to 70 hours or more; in cystic fibrosis, it is 1–2 hours. The terminal half-life can exceed 100 hours (release from intracellular depots).

During hemodialysis, 50% is removed within 4–6 hours; during peritoneal dialysis, 25% is removed within 48–72 hours.

Clinical characteristics.

Indications.

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

Contraindications.

• Renal insufficiency;
• auditory nerve neuritis;
• hypersensitivity to amikacin or to any other aminoglycoside antibiotic and their derivatives;
• hypersensitivity to any of the excipients contained in the drug;
• myasthenia gravis;
• vestibular apparatus dysfunction;
• azotemia (residual nitrogen above 150 mg%);
• prior treatment with ototoxic or nephrotoxic drugs.

Interaction with other medicinal products and other forms of interactions.

Concomitant administration of Amikacin sulfate with anesthetics and muscle relaxants may cause neuromuscular blockade and paralysis of respiratory muscles.

The risk of nephrotoxic effects increases when used concomitantly with amphotericin B, cephalothin, polymyxin, and furosemide. The risk of ototoxic effects increases when the drug is used concomitantly with furosemide, ethacrynic acid, or cisplatin.

Amikacin sulfate is incompatible in solution with penicillins, cephalosporins, amphotericin, hydrochlorothiazide, erythromycin, heparin, nitrofurantoin, thiopental, warfarin, tetracyclines, vitamin B complex, vitamin C, and potassium chloride.

Indomethacin, phenylbutazone, and other NSAIDs that impair renal blood flow may slow the elimination rate of amikacin sulfate. When amikacin sulfate is administered concomitantly with intravenous indomethacin in premature infants, increased plasma concentrations of the drug occur, increasing the risk of toxicity.

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

Special precautions for use

Due to the potential ototoxicity and nephrotoxicity of aminoglycosides, patients must be under close medical supervision.

Amikacin sulfate is not recommended for patients with hypersensitivity to other aminoglycosides because of the risk of cross-allergy.

Caution is advised in patients with myasthenia gravis and Parkinsonism, as well as elderly patients and those with impaired neuromuscular conduction, due to the possibility of curare-like effects.

In cases of difficult-to-treat or complicated infections, the treatment with the drug should be evaluated after 10 days. Before initiating the next course, renal function, hearing, vestibular function, and serum drug concentration should be assessed. If no expected clinical effect is observed within 3–5 days, treatment should be discontinued and microbial susceptibility to antibiotics should be determined.

Dosage regimen adjustments are required in patients with impaired renal function based on creatinine clearance. The risk of ototoxic and nephrotoxic effects increases with high doses of the drug. To prevent oto- and nephrotoxic complications and reduce their incidence during treatment, monitoring of renal function, hearing, and vestibular function is recommended at least once a week.

The main toxic effect of the drug after parenteral administration is its action on the VIII 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 therapy, 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 dosage regimen adjusted if needed.

Elderly patients require reduced doses of amikacin sulfate due to decreased renal functional activity and possible reduction in body weight. Renal functional activity should be regularly assessed. Urinalysis should be performed before or during treatment. Periodic examinations and recording of audiograms, as well as assessment of vestibular function, are necessary. If renal, vestibular, or hearing impairment occurs, the dose of amikacin sulfate should be reduced or discontinued.

In patients with impaired renal function, the daily dose should be reduced and/or the dosing interval prolonged according to serum creatinine concentration to prevent drug accumulation in blood and minimize the risk of ototoxicity. If signs of renal damage appear (e.g., albuminuria, microhematuria, leukocyturia), hydration should be increased and dosage reduced. These manifestations usually resolve after completion of treatment. If signs of ototoxicity (e.g., dizziness, tinnitus, hearing loss) or nephrotoxicity (e.g., reduced creatinine clearance, oliguria) occur, amikacin sulfate should be discontinued or the dose reduced. However, if symptoms of azotemia or worsening oliguria develop, treatment must be stopped.

Ototoxicity caused by aminoglycoside antibiotics may develop even after discontinuation of the drug and is usually irreversible. The risk of ototoxicity is increased in patients with impaired renal function, as well as with high-dose or prolonged treatment.

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

Prior to prescribing the drug, alternative treatment options or genetic testing should be considered for patients with a family history of mitochondrial DNA mutations or those with aminoglycoside-induced hearing loss.

The risk of toxicity is increased in dehydrated patients due to elevated drug concentrations in serum.

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

Simultaneous administration of two aminoglycosides is not recommended, nor should one aminoglycoside be substituted for another if the first has been used for 7–10 days. Repeated courses should not be initiated earlier than 6 weeks after the previous course.

The drug contains sodium metabisulfite, which may cause allergic-type reactions, including anaphylactic symptoms and asthma attacks of varying severity, particularly in patients with bronchial asthma.

When used concomitantly with cephalosporins, administration at different sites (for intramuscular injection) with an interval of at least 1 hour is recommended.

Amikacin sulfate 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.

Use during pregnancy or breastfeeding

The drug is contraindicated during pregnancy and breastfeeding.

Ability to affect reaction speed when driving or operating machinery

Clinical experience indicates that the drug does not affect the ability to drive or operate machinery. However, possible central nervous system side effects such as drowsiness and impaired neuromuscular transmission should be taken into account.

Administration and Dosage.

The drug is administered intramuscularly or intravenously (either as a bolus or by infusion). The dosage and route of administration are determined individually for each patient depending on the severity of the disease, pathogen sensitivity, renal function, and patient's body weight. For adults and children aged 12 years and older, the dose is 10–15 mg/kg per day. The daily dose is divided into 2 administrations. The maximum daily dose for adults is 1.5 g. The duration of treatment is 3–7 days with intravenous administration and 7–10 days with intramuscular administration.

For uncomplicated urinary tract infections (except those caused by Pseudomonas aeruginosa), the drug is administered intramuscularly at 250 mg twice daily for 5–7 days.

For infections caused by Pseudomonas aeruginosa and for life-threatening infections, the drug is administered at a dose of 15 mg/kg per day, divided into 3 doses.

For newborns and premature infants, the initial loading dose is 10 mg/kg per day, followed by a daily maintenance dose of 15 mg/kg divided into 2 doses, administered over 7–10 days.

In patients with impaired renal function, the daily dose should be reduced or the dosing interval extended to prevent antibiotic accumulation. Dosage regimen adjustments must be based on creatinine clearance.

For preparing the infusion solution, use isotonic sodium chloride solution, 5% glucose solution, or Ringer's solution. The concentration of amikacin solution for intravenous administration should not exceed 5 mg/mL. The duration of infusion is 30–90 minutes. Intravenous injection should be performed slowly over 7 minutes.

Children. The drug is used in pediatric practice.

Amikacin sulfate should be administered with caution for treatment of premature and full-term infants due to possible prolonged elimination of aminoglycosides caused by immature excretory systems, which may lead to toxic effects.

Overdose.

Possible manifestations of ototoxic and nephrotoxic effects of the drug and signs of neuromuscular blockade: tinnitus, hearing disturbances, skin rashes, headache, dizziness, chills, paresthesia, decreased renal function (up to renal failure), respiratory depression or paralysis.

If necessary, the drug can be removed from the body by parenteral dialysis or hemodialysis. The drug level can be reduced by continuous arteriovenous hemofiltration. Exchange transfusion may also be used to eliminate the drug from the body in newborns.

At the first signs of neuromuscular blockade, administration of amikacin sulfate must be discontinued immediately, and calcium chloride solution should be administered intravenously or proserin and atropine solutions subcutaneously. If necessary, the patient should be switched to mechanical ventilation.

Adverse reactions.

Gastrointestinal disorders: nausea, vomiting, diarrhea.

Auditory system disorders: partial reversible or irreversible hearing loss, tinnitus.

CNS disorders: headache, drowsiness, possible hearing impairment, vestibular disorders, dizziness, paresthesia, tremor, seizures, encephalopathy; in isolated cases – neuromuscular conduction disturbances, possible development of neuromuscular blockade (muscle paralysis, respiratory depression).

Hematological disorders: anemia, leukopenia, granulocytopenia, hematuria, thrombocytopenia, eosinophilia.

Urinary system disorders: nephrotoxicity – impaired kidney function (oliguria, albuminuria, cylindruria, hyperazotemia, proteinuria, microhematuria, hematuria, elevated creatinine levels); rarely – acute necrosis, interstitial nephritis, acute renal failure.

Cardiovascular disorders: vasculitis, arterial hypotension.

Endocrine system and metabolism disorders: hypomagnesemia.

Musculoskeletal system disorders: arthralgia.

Allergic reactions: skin rashes, pruritus, urticaria; in isolated cases – Quincke's edema (angioedema).

Other: pain at injection site, hyperemia, swelling, hyperthermia, hyperbilirubinemia, increased blood transaminase levels.

Shelf life. 2 years.

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

Keep out of reach of children.

Packaging. Injection solution 50 mg/mL – 2 mL in ampoules.

Injection solution 250 mg/mL – 2 mL or 4 mL in ampoules.

1 ampoule per pack. 5 ampoules in a blister, 1 or 2 blisters per pack.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Lekhim-Kharkiv".

Manufacturer’s address and place of business.

36 Severyna Pototskoho Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.