Amikacin-vista

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMIKACIN-VISTA (AMIKACIN-VISTA)

Composition:

active substance: amikacin;

1 ml of solution contains amikacin sulfate equivalent to amikacin 250 mg;
excipients: sodium citrate, sodium metabisulfite, water for injections, sulfuric acid (10 N).

Pharmaceutical form.
Injection solution.

Main physico-chemical properties: clear solution ranging from colorless to pale yellow.

Pharmacotherapeutic group.
Antibacterial agents for systemic use. Aminoglycosides.

ATC code J01G B06.

Pharmacological properties.

Pharmacodynamics.

Amikacin is a semi-synthetic aminoglycoside antibiotic with broad-spectrum activity. It exhibits bactericidal action. After actively penetrating the bacterial membrane, it binds irreversibly to the 30S ribosomal subunit, thereby inhibiting protein synthesis in the microorganism. It is highly active against aerobic Gram-negative bacteria: Pseudomonas aeruginosa, Escherichia coli, Shigella spp., Salmonella spp., Klebsiella spp., Enterobacter spp., Serratia spp., Providencia stuartii.

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

It is inactive against anaerobic bacteria.

Pharmacokinetics.

Absorption.

After intramuscular administration, amikacin is rapidly and completely absorbed. Maximum plasma concentration (C_max) following a 7.5 mg/kg intramuscular dose is 21 mg/mL; following a 7.5 mg/kg intravenous infusion over 30 minutes, it is 38 µg/mL. Time to reach C_max in plasma after intramuscular administration is approximately 1.5 hours.

Distribution.

Amikacin distributes uniformly in extracellular fluid (abscess contents, pleural effusion, ascites, pericardial, synovial, lymphatic, and peritoneal fluids); high concentrations are achieved 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 and accumulates intracellularly. High concentrations are observed in organs with rich blood supply: lungs, liver, myocardium, spleen, and especially in the renal cortex; lower concentrations are found in muscle, adipose tissue, and bone.

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

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

Volume of distribution 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 weighing less than 1.5 kg, up to 0.58 L/kg in those weighing more than 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.

Amikacin is not metabolized.

Excretion.

Elimination half-life (T_½) in the terminal (β) phase is 2–4 hours in adults, 5–8 hours in infants, and 2.5–4 hours in children. The final elimination phase T_½ exceeds 100 hours (due to slow release from intracellular depots).

It is excreted by the kidneys via glomerular filtration (65–94%) predominantly in unchanged form. Renal clearance ranges from 79 to 100 mL/min.

Pharmacokinetics in special clinical situations.

In adults with impaired renal function, T_½ varies depending on the degree of impairment and may extend up to 100 hours. In patients with cystic fibrosis, T_½ is shorter (1–2 hours). In burn patients and those with hyperthermia, T_½ may be shorter than average due to increased clearance.

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

Clinical characteristics.

Indications.

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

Contraindications.

• Renal failure;
• Auditory nerve neuritis;
• Hypersensitivity to amikacin or to any other aminoglycoside antibiotic and their derivatives;
• Hypersensitivity to any of the excipients contained in the medicinal product;
• Myasthenia gravis;
• Vestibular apparatus dysfunction;
• Azotemia (residual nitrogen above 150 mg%);
• Prior treatment with ototoxic or nephrotoxic medicinal agents.

Interaction with other medicinal products and other forms of interactions.

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

Amikacin-Vista demonstrates synergy when used in combination with carbenicillin, benzylpenicillin, and cephalosporins (in patients with severe chronic renal failure, concomitant use with β-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 penicillins, cephalosporins, sulfonamides, vancomycin, methoxyflurane, enflurane, nonsteroidal anti-inflammatory drugs (NSAIDs), radiographic contrast agents, cyclosporine, cisplatin, amphotericin B, cephalothin, 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 Amikacin-Vista. If Amikacin-Vista is administered simultaneously with intravenous indomethacin in premature infants, plasma concentrations of the drug increase, increasing the risk of toxicity.

Enhances the myorelaxant effect of curare-like medicinal agents.

Administration of aminoglycosides together with bisphosphonates increases the risk of hypocalcemia.

Administration of aminoglycosides together with platinum compounds increases the risk of nephrotoxicity and possibly ototoxicity.

Simultaneously administered thiamine (vitamin B1) may be degraded due to the reactive component bisulfite sodium in amikacin sulfate formulation.

Methoxyflurane, parenteral polymyxin, capreomycin, and other medicinal agents that block neuromuscular transmission (halogenated hydrocarbon agents used for inhalational anesthesia, opioid analgesics), as well as transfusion of large volumes of blood preserved with citrate anticoagulants, increase the risk of respiratory arrest. Parenteral administration of indomethacin increases the risk of toxic effects of aminoglycosides (increased T½ and reduced clearance).

Amikacin reduces the efficacy of medicinal agents 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 ototoxic effects increases when Amikacin-Vista is used concomitantly with furosemide and ethacrynic acid.

Combinations of antibiotics—amikacin + ceftazidime and amikacin + cefotaxime—demonstrate the greatest additive and synergistic effect against Pseudomonas aeruginosa.

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

Special precautions for use.

Do not use Amikacin-Vista in patients with increased sensitivity to other aminoglycosides due to the risk of cross-allergy. Because of the potential ototoxicity and nephrotoxicity of aminoglycosides, patients must be under close medical supervision.

The medicinal product should be used with caution in patients with Parkinsonism, botulism (aminoglycosides may impair neuromuscular transmission, leading to further weakening of skeletal muscles), dehydration, infants (especially premature infants), elderly patients, and patients with impaired neuromuscular conduction, due to the possibility of developing a curare-like effect. During treatment, renal function, auditory nerve function, and vestibular apparatus function should be monitored at least once a week.

The likelihood of nephrotoxic effects is increased in patients with impaired renal function, as well as when the medicinal product is used in high doses or for prolonged periods (such patients require daily monitoring of renal function).

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

In cases of difficult-to-treat infections or complicated infections, the treatment with the drug should be evaluated after 10 days, and before initiating the next course, renal function, hearing, vestibular function, and drug concentration in blood serum should be checked. If no expected clinical effect is observed within 3–5 days, treatment should be discontinued and microbial susceptibility to antibiotics should be determined. Patients with infectious-inflammatory diseases of the urinary tract are advised to drink plenty of fluids.

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 aminoglycoside-induced ototoxicity is higher in patients with impaired renal function, those receiving high doses, or those undergoing therapy for 5–7 days or longer.

Before starting treatment, fluid and electrolyte balance should be corrected in the patient. During treatment with amikacin sulfate, adequate fluid intake is necessary, plasma creatinine concentration should be frequently determined, and the dosing regimen should be adjusted if needed. The dose of Amikacin-Vista 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 before or during treatment. Periodic examination and recording of audiograms and assessment of vestibular function are necessary. If renal, vestibular, or hearing impairment occurs, the dose should be reduced or amikacin sulfate discontinued. The use of Amikacin-Vista 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 ions. For 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 the blood and minimize the risk of ototoxicity. If signs of renal irritation occur (e.g., albuminuria, microhematuria, leukocyturia), hydration should be increased and the dose reduced. These symptoms usually resolve after treatment ends. If signs of ototoxicity (e.g., dizziness, tinnitus, hearing loss) or nephrotoxicity (e.g., decreased creatinine clearance, oliguria) appear, Amikacin-Vista should be discontinued or the dose reduced. If azotemia or worsening oliguria develops, treatment must be stopped.

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

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

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

Neuromuscular blockade and respiratory paralysis have been reported following parenteral administration, local instillation (during orthopedic or abdominal irrigation or local treatment of empyema), and even after oral administration of aminoglycosides. The possibility of respiratory paralysis should be considered when aminoglycosides are administered by any route, especially in patients receiving anesthetics or neuromuscular blocking agents such as tubocurarine, succinylcholine, decamethonium, atracurium, rocuronium, or vecuronium, as well as in patients undergoing massive transfusion of citrate-anticoagulated blood. If neuromuscular blockade occurs, calcium salts may precipitate respiratory paralysis—mechanical respiratory support may be required.

Neuromuscular blockade and muscle paralysis have been demonstrated in laboratory animals receiving high doses of amikacin.

Amikacin-Vista should not be used in patients with myasthenia gravis (see section "Contraindications").

Aminoglycosides should be used with caution in patients with neuromuscular disorders such as Parkinsonism, as these drugs may exacerbate muscle weakness due to their potential curare-like effect on neuromuscular conduction. When used concomitantly with cephalosporins, they should be administered at different sites (in case of intramuscular injection) with an interval of at least 1 hour.

The use of 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 ions.

Pediatric population.

Aminoglycosides should be used with caution in premature and newborn infants due to immature renal function in these patients and prolonged elimination half-life of these drugs from blood serum.

Other.

Aminoglycosides are rapidly and almost completely absorbed after local application, except into the urinary bladder, especially when combined with surgical procedures. Cases of irreversible deafness, renal failure, and death due to neuromuscular blockade have been reported after irrigation of small and large surgical fields with aminoglycoside-containing preparations. The use of amikacin, as with other antibiotics, may lead to overgrowth of resistant organisms. If this occurs, appropriate therapy should be initiated. Cases of macular infarction, sometimes leading to permanent vision loss, have been reported after intravitreal injection (injection into the eye) of amikacin.

Important information about excipients.

The medicinal product contains sodium metabisulfite, which may cause allergic-type reactions (possibly delayed), including anaphylactic symptoms and asthma attacks of varying severity, particularly in patients with bronchial asthma.

Use during pregnancy or breastfeeding.

Pregnancy.

The safety of amikacin use during pregnancy has not been established. Amikacin should be administered to pregnant women and newborns only if clearly needed and under strict medical supervision (see section "Special precautions for use").

Data on the use of aminoglycosides during pregnancy are limited. Aminoglycosides may harm the fetus and cross the placenta. Cases of complete, irreversible, bilateral congenital deafness in children whose mothers received streptomycin during pregnancy have been reported. Adverse effects on the fetus or newborns have been reported in pregnant women who received other aminoglycosides. If amikacin is used during pregnancy or if a patient becomes pregnant while taking amikacin, she should be informed of the potential risk to the fetus.

Breastfeeding.

Amikacin is excreted in breast milk. A decision should be made whether to discontinue breastfeeding or to discontinue the medicinal product.

Fertility.

Reproductive toxicity studies in mice and rats did not report any effects on fertility or fetal toxicity.

Ability to affect reaction speed when driving or operating machinery.

Experience with amikacin use indicates that it does not affect the ability to drive a vehicle or operate machinery; however, the possibility of such central nervous system side effects as drowsiness and impaired neuromuscular transmission should be considered.

Administration and Dosage.

Administer Amikacin-Vist intramuscularly or intravenously. The usual doses for children aged 12 years and older, as well as adults, are 5 mg/kg body weight every 8 hours or 7.5 mg/kg body weight every 12 hours. The maximum daily dose for adults is 15 mg/kg body weight. In severe cases and for infections caused by Pseudomonas, divide the daily dose into three administrations. The maximum single daily dose is 1.5 g. The total cumulative dose should not exceed 15 g. The usual duration of treatment is 3–7 days with intravenous administration and 7–10 days with intramuscular administration. For premature newborns, administer an initial 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.

In patients with impaired renal function, the daily dose should be reduced and/or the dosing intervals extended. Adjust the dose based on serum 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/dL, administer the drug every 18 hours. Amikacin-Vist should be administered to adults and children by intravenous infusion using a volume of fluid sufficient for 60–90 minutes of drip infusion (at a rate of 50 drops per minute). For newborns, the infusion should last 1–2 hours. The concentration of the Amikacin-Vist solution for intravenous administration must not exceed 5 mg/mL. Intravenous injection of Amikacin-Vist should be performed very slowly, over 2–7 minutes. The solution for parenteral administration should be prepared immediately before use and used promptly after preparation. The following diluents may be used for intravenous administration: 0.9% sodium chloride solution, 5% glucose solution, Ringer's lactate solution containing glucose (5%).

Children.

The drug is used in pediatric practice.

Amikacin-Vist should be used 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: Possible manifestations of ototoxicity and nephrotoxicity, as well as signs of neuromuscular blockade, including tinnitus, hearing disturbances, skin rashes, headache, dizziness, fever, 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: If necessary, remove the drug from the body via peritoneal dialysis or hemodialysis. The drug concentration can be reduced by continuous arteriovenous hemofiltration. Exchange transfusion may also be used to eliminate the drug in newborns. At the first signs of neuromuscular blockade, administration of amikacin sulfate must be discontinued immediately, and intravenous calcium chloride solution or subcutaneous proserine and atropine solutions should be administered promptly. If necessary, the patient should be placed on mechanical ventilation.

Adverse Reactions

Infections and infestations: superinfection or colonization by resistant bacteria or yeast fungi.

Immune system disorders: anaphylactic reactions, including anaphylactic shock, anaphylactoid reactions, hypersensitivity reactions.

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

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

Eye disorders: blindness, retinal infarction.

Cardiovascular system disorders: vasculitis, arterial hypotension.

Nervous system disorders: headache, drowsiness, neurotoxic effects (muscle twitching, numbness, tingling, epileptic seizures), possible hearing loss, vestibular disorders, dizziness, paresthesia, tremor, convulsions, encephalopathy; in isolated cases — impaired neuromuscular conduction, potentially leading to neuromuscular blockade (muscle paralysis, respiratory depression).

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

Renal and urinary system disorders: nephrotoxicity — impaired kidney function (oliguria, proteinuria, microhematuria, albuminuria, cylinduria, hyperazotemia, hematuria, elevated creatinine levels); rarely — acute necrosis, interstitial nephritis, acute renal failure, toxic nephropathy, azotemia, presence of altered erythrocytes in urine, leukocytes in urine.

Endocrine and metabolic disorders: hypomagnesemia.

Musculoskeletal and connective tissue disorders: arthralgia, muscle cramps.

Respiratory system disorders: apnea, bronchospasm.

Skin and subcutaneous tissue disorders: skin rashes, pruritus, urticaria, skin hyperemia, fever, Quincke's edema.

Other: injection site reactions, pain at injection site, paresthesia, tremor, hyperemia, swelling, hyperthermia, hyperbilirubinemia, elevated blood transaminase levels. Sodium metabisulfite, an ingredient of the medicinal product, may cause severe hypersensitivity reactions and bronchospasm.

Amikacin is not intended for intravitreal use. Cases of blindness and retinal infarction have been reported following intravitreal administration (injection into the eye) of amikacin. All aminoglycosides can cause ototoxicity, nephrotoxicity, and neuromuscular blockade. These toxic effects are more frequent in patients with renal impairment, in patients receiving other ototoxic or nephrotoxic medicinal products, and in patients receiving treatment for longer durations and/or at higher doses than recommended.

Renal function changes are usually reversible upon discontinuation of the drug. Toxic effects on the eighth cranial nerve may lead to hearing loss and loss of balance. Amikacin primarily affects auditory function. Cochlear damage, which results in high-frequency irreversible deafness, often occurs before hearing impairment can be clinically detected. Cases of macular infarction have been reported, sometimes leading to permanent vision loss following intravenous administration (injection into the eye) of amikacin.

When recommended precautions and dosing regimens are followed, the incidence of toxic reactions such as tinnitus, dizziness, and partial reversible deafness, skin rashes, drug fever, headache, paresthesia, nausea, and vomiting is low.

Adverse reactions affecting the urinary system (kidney function disorders such as albuminuria, cylinduria, azotemia, and oliguria) have been reported very rarely.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national pharmacovigilance system.

Incompatibilities.

Amikacin sulfate solution should not be directly mixed with other aminoglycosides, penicillins, heparin, cephalosporins, capreomycin, amphotericin B, thiopental, hydrochlorothiazide, erythromycin, nitrofurantoin, vitamin B and C complexes, or potassium chloride. If co-administration is necessary, the two medicinal products should be administered separately, sequentially.

Shelf life. 2 years.

For the 500 mg/2 mL pack — 2 years.

For the 1000 mg/4 mL pack — 18 months.

Storage conditions.

No special storage conditions are required for this medicinal product. Store in a place inaccessible to children.

Packaging.

2 mL (500 mg) or 4 mL (1000 mg) in a vial, 1 vial per carton.

Prescription status.

Prescription only.

Manufacturer.

ANFARM HELLAS S.A. / ANFARM HELLAS S.A.

Manufacturer's address and place of business.

61st km Nat. Rd. Athens-Lamia, Schimatari Viotias 32009, Greece