Amitsil

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, 0.5 g or 1.0 g.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: porous mass of white or white with a yellowish tint color.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Aminoglycosides. Amikacin.

ATC code J01GB06.

Pharmacological Properties.

Pharmacodynamics.

Amikacin is a semi-synthetic aminoglycoside antibiotic with a broad spectrum of activity. It exhibits bactericidal action. After actively penetrating 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 certain gram-positive bacteria: Staphylococcus spp. (including strains resistant to penicillin, methicillin, and some 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 7.5 mg/kg intravenous infusion over 30 minutes, Cmax is 38 µg/mL. Time to reach peak plasma concentration (Cmax) after intramuscular administration is approximately 1.5 hours.

Distribution.

Distributes uniformly into extracellular fluids (abscess contents, pleural effusion, ascitic, pericardial, synovial, lymphatic, and peritoneal fluids); reaches high concentrations in urine; lower concentrations in bile, breast milk, aqueous humor of the eye, bronchial secretions, sputum, and cerebrospinal fluid. Easily penetrates all body tissues, accumulating intracellularly. High concentrations are found in organs with abundant blood supply: lungs, liver, myocardium, spleen, and especially in the renal cortex; lower concentrations occur in muscle, adipose tissue, and bone.

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 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.

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. Final T½ exceeds 100 hours (due to release from intracellular depots).

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

Pharmacokinetics in Special Clinical Situations.

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

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

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to amikacin, to any other components of the medicinal product, or to any other aminoglycoside antibiotics or 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 forms of interaction.

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

Concomitant use (including local and systemic administration), either simultaneous or sequential, with other neurotoxic, ototoxic, or nephrotoxic agents should be avoided—particularly bacitracin, cisplatin, amphotericin B, cyclosporine, tacrolimus, cephaloridine, paromomycin, viomycin, polymyxin B, colistin, vancomycin, or other aminoglycosides—due to the potential for additive effects. In cases where avoidance is not possible, careful monitoring is required.

Amikacin exhibits synergy when used in combination with carbenicillin, benzylpenicillin, and cephalosporins (in patients with severe chronic renal insufficiency, concomitant use with beta-lactam antibiotics may reduce aminoglycoside efficacy). In vitro mixing of aminoglycosides and beta-lactam antibiotics (penicillins and cephalosporins) may result in significant mutual inactivation. Reduced activity in serum may also occur even if aminoglycoside and penicillin are administered in vivo via separate routes. Inactivation of aminoglycosides is clinically significant only in patients with severe renal impairment. Inactivation may continue in biological fluid samples collected for analysis, leading to erroneous measurements of aminoglycoside levels.

The risk of nephrotoxic effects increases when amikacin is used concomitantly with penicillin, cephalosporins, sulfonamides, vancomycin, methoxyflurane, enflurane, nonsteroidal anti-inflammatory drugs (NSAIDs), radiographic contrast agents, cyclosporine, cisplatin, amphotericine B, cephalothin, polymyxin, and diuretics (especially with furosemide).

Increased nephrotoxicity has been reported after simultaneous parenteral administration of aminoglycoside antibiotics and cephalosporins. Concomitant use of cephalosporins may lead to elevated serum creatinine levels.

The risk of ototoxicity increases when amikacin is used together with potent diuretics (furosemide and ethacrynic acid), particularly when the diuretic is administered intravenously. Diuretics may enhance the toxicity of aminoglycosides by altering antibiotic concentrations in serum and tissue. When used concomitantly with furosemide and ethacrynic acid—both of which have ototoxic effects—there is a risk of irreversible deafness.

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

Indomethacin, phenylbutazone, and other NSAIDs that impair renal blood flow may slow the elimination rate of Amitsil®. When amikacin is administered intravenously together with indomethacin to premature infants, plasma concentrations of the drug increase, raising the risk of toxicity. Parenteral administration of indomethacin increases the risk of aminoglycoside toxicity (prolonged half-life and reduced clearance).

There is an increased risk of hypocalcemia when aminoglycosides are used concomitantly with bisphosphonates.

There is an increased risk of nephrotoxicity and possibly ototoxicity when aminoglycosides are used with platinum-containing compounds.

The risk of respiratory depression increases when amikacin is used concomitantly with ethyl ether and neuromuscular blocking agents.

Amikacin potentiates the muscle relaxant effect of curare-like agents. Amikacin is not recommended in patients receiving anesthetics or muscle relaxants (including halothane, tubocurarine, succinylcholine, decamethonium, atracurium, rocuronium, vecuronium, methoxyflurane, parenterally administered polymyxins, capreomycin, and other agents that block neuromuscular transmission—such as halogenated hydrocarbons used for inhalational anesthesia, opioid analgesics), or during massive blood transfusion with citrate-containing anticoagulants, due to the possibility of neuromuscular blockade and increased risk of respiratory arrest. In the event of neuromuscular blockade, calcium salts may reverse this effect.

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

The antibiotic combinations—amikacin + ceftazidime and amikacin + cefoperazone—demonstrate the greatest additive and synergistic effects against Pseudomonas aeruginosa.

When multiple antibiotics are used, Amitsil® 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, susceptibility of isolated pathogens should be determined.

Amicyl® must not be used in patients with known hypersensitivity to other aminoglycosides due to the risk of cross-allergy.

Caution should be exercised in patients with pre-existing renal impairment or existing hearing or vestibular dysfunction. If audiometric testing results are unsatisfactory, the dose should be reduced or treatment discontinued.

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

Patients receiving aminoglycosides parenterally must be under close clinical monitoring due to the potential ototoxicity and nephrotoxicity associated with their use. The safety of prolonged treatment (more than 14 days) has not been established. Precautions regarding dosage and adequate hydration must be observed.

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

If therapy is expected to last seven days or longer in patients with impaired renal function, or ten days or longer in patients with normal renal function, an audiogram should be performed before treatment initiation and repeated during therapy. Amikacin therapy should be discontinued if patients report tinnitus, subjective sensations of hearing loss, or if subsequent audiograms show significant high-frequency hearing loss.

Ototoxicity

Patients with mitochondrial DNA mutations (particularly the A-to-G substitution at nucleotide 1555 in the 12S rRNA gene) may have an increased risk of ototoxicity, even if serum aminoglycoside levels 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 drug administration.

Neuro/ototoxicity

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.

Neurotoxicity, presenting as vestibular and/or bilateral ototoxicity, may occur in patients receiving aminoglycosides. The risk of ototoxic complications is significantly higher in patients with renal impairment and in those receiving high doses or prolonged therapy lasting 5–7 days. High-frequency hearing loss usually occurs first and may only be detected by audiometric testing. Dizziness may occur, indicating vestibular damage.

Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching, and seizures. The risk of ototoxicity due to aminoglycoside use increases with persistently high peak or elevated serum concentrations. Patients who develop vestibular or cochlear damage may not exhibit any adverse symptoms at the beginning of treatment. They should be warned about the potential for toxic damage to the eighth cranial nerve, including the development of complete or partial irreversible bilateral hearing loss or dizziness, which may occur after completion of therapy. Aminoglycoside-induced ototoxicity is typically irreversible.

The use of amikacin in patients with a history of allergic reactions to aminoglycosides, or in patients with subclinical kidney or eighth cranial nerve damage caused by prior use of nephrotoxic and/or ototoxic agents—such as streptomycin, dihydrostreptomycin, gentamicin, tobramycin, kanamycin, becanamycin, neomycin, polymyxin B, colistin, cephaloridine, or viomycin—should be considered with caution, as toxicity may be additive. In such patients, amikacin should only be used under physician supervision when the expected benefit outweighs potential risks.

Concomitant administration 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 one.

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

Neuromuscular blockade

Neuromuscular blockade and respiratory paralysis have been reported following parenteral administration, local instillation (e.g., 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 whenever aminoglycosides are administered by any route, especially in patients receiving anesthetics, neuromuscular blocking agents, or massive transfusions of citrate-anticoagulated blood. In the event of neuromuscular blockade, calcium salts may reverse this effect, but mechanical ventilation may be required. Neuromuscular blockade and muscle paralysis have been demonstrated in laboratory animals receiving high doses of amikacin. Amikacin must not be used in patients with myasthenia gravis. The drug should be used with caution in patients with myasthenia, Parkinsonism, botulism (aminoglycosides may impair neuromuscular transmission, leading to further skeletal muscle weakness), dehydration, renal impairment, neonates (especially premature infants), and elderly patients.

Nephrotoxicity

Aminoglycosides are potentially nephrotoxic. Renal impairment is not dependent on peak plasma concentrations (Cmax). The risk of ototoxic complications is significantly higher in patients with impaired renal function. The likelihood of nephrotoxicity is greater in patients with renal dysfunction and when the drug is administered at high doses or for prolonged periods (such patients require daily monitoring of kidney function).

Prior to initiating treatment, the patient's fluid and electrolyte balance should be corrected. During treatment with amikacin sulfate, the patient must consume adequate fluids. Serum creatinine concentration should be frequently monitored, and dosage regimens adjusted as necessary. In patients with impaired renal function, the daily dose should be reduced and/or the dosing interval extended according to serum creatinine levels to prevent drug accumulation and minimize the risk of ototoxicity. Renal functional activity should be regularly assessed. Urinalysis is required before or during treatment. The use of Amicyl® 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.

If signs of renal irritation appear (presence of urinary casts, albuminuria, microhematuria, leukocyturia, decreased creatinine clearance, reduced urine specific gravity, increased blood urea nitrogen, elevated serum creatinine, or oliguria), hydration should be increased and the dose reduced. These manifestations usually resolve after treatment completion. Monitoring of kidney function is particularly important in elderly patients during aminoglycoside therapy. Elderly patients should receive reduced doses of Amicyl® due to decreased renal functional activity and possible reduction in body mass that may not be detected by routine screening tests such as blood urea nitrogen or serum creatinine. Measurement of creatinine clearance is more informative. Renal function and the function of the eighth cranial nerve must be carefully monitored, especially in patients with known or suspected renal impairment at the start of therapy, as well as in those whose renal function was initially normal but who develop signs of renal dysfunction during treatment. Serum amikacin concentrations should be monitored whenever possible to ensure adequate levels and avoid potentially toxic concentrations. Urine should be examined for reduced specific gravity, increased protein excretion, and presence of cells or casts. Blood urea nitrogen, serum creatinine, or creatinine clearance should be measured periodically. Serial audiograms should be obtained whenever possible in elderly patients, particularly those at high risk. If signs of ototoxicity (e.g., dizziness, tinnitus, or hearing loss) or nephrotoxicity (e.g., decreased creatinine clearance, oliguria) appear, Amicyl® should be discontinued or the dose reduced. If azotemia develops or oliguria worsens, treatment should be stopped.

Concomitant and/or sequential systemic, oral, or topical use of other neurotoxic or nephrotoxic agents—such as bacitracin, cisplatin, amphotericin B, cephaloridine, paromomycin, viomycin, polymyxin B, colistin, vancomycin, or other aminoglycosides—should be avoided. Other factors that may increase the risk of toxicity include advanced age and dehydration.

Inactivation of aminoglycosides is clinically significant only in patients with severe renal impairment. Inactivation may continue in biological fluid samples collected for analysis, leading to falsely low aminoglycoside level readings.

Other

Aminoglycosides are rapidly and almost completely absorbed following local application, except in the urinary bladder, due to surgical procedures. Cases of irreversible hearing loss, renal failure, and death due to neuromuscular blockade have been reported after application of aminoglycoside preparations to both small and large surgical areas. As with other antibiotics, amikacin use may lead to overgrowth of non-susceptible microorganisms. If this occurs, appropriate therapy should be initiated. Aminoglycosides should be used with caution in premature and full-term neonates due to the renal immaturity of these patients and the resulting prolonged elimination half-life of these drugs from serum.

Cases of macular infarction, potentially leading to complete vision loss, have been reported following intravitreal injection (injection into the eye) of amikacin.

Use during pregnancy or breastfeeding.

Due to the fact that amikacin crosses the placenta and may exert ototoxic and nephrotoxic effects on the fetus, the drug is contraindicated during pregnancy.

Since 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 Amicyl®.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product generally does not affect reaction speed; however, the possibility of adverse effects on the central nervous system, such as drowsiness and impaired neuromuscular transmission, should be considered.

Dosage and Administration

Administer Amitsil® intramuscularly or intravenously.

The usual dose for children aged 12 years 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 infections caused by Pseudomonas, divide the daily dose into 3 administrations. The maximum single dose is 1.5 g. The maximum cumulative 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: reduce the dose or increase the dosing intervals without changing the single dose. Adjust the dose based on plasma creatinine levels and patient body weight. Calculate the dosing interval by multiplying the plasma creatinine level by 9; for example, if 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 infusion over 60–90 minutes (at a rate of 50 drops per minute), and to newborns over 1–2 hours.

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

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

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

Children.

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

Overdose.

Possible manifestations of ototoxicity and nephrotoxicity, 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, and toxic reactions (ataxia, urinary disorders, thirst, loss of appetite, nausea, vomiting).

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

Adverse Reactions

The list of adverse reactions is presented by system organ classes, using MedDRA preferred terms and frequency categories as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data).

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

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

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

Metabolism and nutrition disorders: rare: hypomagnesemia.

Skin and subcutaneous tissue disorders: uncommon: skin rashes; rare: pruritus, urticaria, skin hyperemia, fever, angioedema (Quincke's edema).

Immune system disorders: frequency not known: anaphylactic shock, hypersensitivity reactions, anaphylactoid reactions, anaphylactic reactions.

Cardiac disorders: rare: vasculitis, arterial hypotension.

Nervous system disorders: rare: headache, tremor, paresthesia, coordination disturbances, somnolence, neurotoxic effects (muscle twitching, numbness, tingling, seizures), neuromuscular transmission disorders (respiratory arrest); frequency not known: paralysis.

Ear and labyrinth disorders: rare: ototoxicity (hearing loss, tinnitus, vestibular and labyrinthine disorders, reversible deafness); frequency not known: deafness, sensorineural deafness, toxic effects on the vestibular apparatus (discoordination, dizziness, nausea, vomiting).

Eye disorders: rare: blindness, retinal infarction*.

Respiratory, thoracic and mediastinal disorders: frequency not known: apnea, bronchospasm.

Musculoskeletal and connective tissue disorders: rare: arthralgia, muscle tremors.

Renal and urinary disorders: rare: nephrotoxicity – kidney function impairment (oliguria, proteinuria, hematuria, albuminuria, hyperazotemia, elevated blood creatinine levels, leukocyturia); frequency not known: acute renal failure, toxic nephropathy, cylinduria.

Other: injection site reactions, pain at injection site; rare: hyperthermia.

*Amikacin is not indicated for intravitreal use. Cases of blindness and retinal infarction have been reported following intravitreal administration (injection into the eye) of amikacin.

All aminoglycosides are potentially ototoxic, nephrotoxic, and may cause neuromuscular blockade. These effects occur more frequently in patients with renal impairment, those receiving other ototoxic or nephrotoxic drugs, and those undergoing prolonged therapy and/or receiving higher doses than recommended (see section "Special Warnings and Precautions for Use").

Renal function impairment is usually reversible upon discontinuation of the drug.

Toxic effects on the VIII cranial nerve may lead to hearing loss and coordination disturbances. Amikacin primarily affects auditory function. Cochlear damage includes high-frequency hearing loss, which may be detected by audiometric testing and precedes clinical manifestations of hearing loss (see section "Special Warnings and Precautions for Use").

Shelf life: 2 years.

Storage conditions: Store in the original packaging, out of reach of children, at a temperature not exceeding 25°C.

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 co-administration is necessary, the two drugs should be administered separately, sequentially.

Packaging: 0.5 g or 1.0 g of amikacin in vials.

Prescription status: Prescription only.

Manufacturer: JSC "Kyivmedpreparat".

Manufacturer's address and location of business activity:
139 Saksaganskogo Street, Kyiv, 01032, Ukraine.