Atracurium-novo

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ATRACURIUM-NOVO (ATRACURIUM-NOVO)

Composition:

Active substance: atracurium besilate;

1 ml of solution contains atracurium besilate (calculated as 100% substance) 10 mg;

Excipients: benzene sulfonic acid solution, water for injections.

Pharmaceutical form. Injection solution.

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

Pharmacotherapeutic group. Peripheral-acting muscle relaxants. Other quaternary ammonium compounds. ATC code M03A C04.

Pharmacological properties.

Pharmacodynamics.

A highly selective nondepolarizing competitive peripheral-acting myorelaxant with intermediate duration of action. It blocks nicotinic cholinoreceptors of the motor end plates of skeletal muscle fibers and prevents the depolarizing effect of acetylcholine, resulting in inhibition of neuromuscular transmission at the level of the postsynaptic membrane.

Children.

Limited data are available in the literature regarding possible variability in the onset and duration of action of atracurium in neonates (children under 1 month of age) compared to children of other ages (see section "Children").

Pharmacokinetics.

After intravenous administration, atracurium besylate undergoes spontaneous metabolism via Hofmann elimination (a non-enzymatic process occurring at physiological pH and body temperature) and ester hydrolysis mediated by nonspecific plasma esterases. Elimination of atracurium is independent of renal or hepatic function. The degradation products of atracurium are laudanosine and other metabolites. The metabolites lack myorelaxant activity. Plasma protein binding of atracurium besylate is approximately 82%. The elimination half-life is 20 minutes. Metabolites are excreted in urine and bile.

Higher concentrations of metabolites are observed in the blood of intensive care unit patients with impaired renal and/or hepatic function (see section "Special precautions for use"). These metabolites do not contribute to neuromuscular blockade.

Clinical characteristics.

Indications.

For muscle relaxation during surgical procedures and diagnostic interventions (provided that equipment for endotracheal intubation and artificial ventilation of the lungs is available).

Contraindications.

Hypersensitivity to atracurium, cisatracurium, or benzenesulfonic acid.

Interaction with other medicinal products and other forms of interaction.

Neuromuscular blockade caused by atracurium besylate may be enhanced when used concomitantly with inhalational anesthetics such as halothane, isoflurane, and enflurane.

The intensity and duration of neuromuscular blockade caused by non-depolarizing muscle relaxants, including atracurium besylate, may be increased when administered simultaneously with:

• antibiotics, including aminoglycosides, polymyxins, spectinomycin, tetracyclines, lincomycin, and clindamycin;
• antiarrhythmic agents: propranolol, calcium channel blockers, lidocaine, procainamide, quinidine;
• diuretics: furosemide and possibly mannitol, thiazide diuretics, acetazolamide;
• magnesium sulfate;
• ketamine;
• lithium salts;
• ganglion blockers (trimethaphan, hexamethonium).

Rarely, when co-administered with certain drugs that may enhance symptoms of myasthenia (including latent forms) and provoke the development of a myasthenic syndrome, increased sensitivity to atracurium besylate may occur. Such drugs include antibiotics, beta-blockers (propranolol, oxprenolol), antiarrhythmic agents (procainamide, quinidine), antirheumatic agents (chloroquine, D-penicillamine), trimethaphan, chlorpromazine, steroids, phenytoin, and lithium.

During prolonged treatment with anticonvulsant medications, the onset of neuromuscular blockade caused by atracurium besylate may be delayed and its duration reduced.

Concomitant use of other non-depolarizing muscle relaxants with atracurium besylate may result in more intense neuromuscular blockade than would be expected from an equivalent total dose of atracurium besylate alone. The synergistic effect may vary depending on the combination of agents used.

Depolarizing muscle relaxants (e.g., succinylcholine chloride) should not be used to prolong neuromuscular blockade induced by non-depolarizing muscle relaxants, including atracurium besylate, as prolonged and complex deep blockade may develop, which is difficult to reverse with anticholinesterase agents.

Concomitant use of anticholinesterase drugs, commonly used in the treatment of Alzheimer's disease (e.g., donepezil), may reduce the duration and intensity of neuromuscular blockade induced by atracurium.

Special precautions for use.

Like all other neuromuscular blocking agents, atracurium causes paralysis of respiratory muscles as well as other skeletal muscles, but does not affect consciousness. Therefore, the drug should be administered only under adequate general anesthesia and strictly under the supervision of an experienced anesthesiologist, with appropriate equipment available for endotracheal intubation and artificial ventilation of the lungs.

In sensitized patients, there is a potential risk of histamine release during administration of atracurium; therefore, the drug should be used with caution in patients with increased sensitivity to histamine. In particular, bronchospasm may occur in patients with a history of allergy or asthma.

There have been reports of a high incidence (over 50%) of cross-sensitivity between neuromuscular blocking agents. Therefore, prior to administration of atracurium, and whenever possible, hypersensitivity to other neuromuscular blocking agents should be excluded. Atracurium should be used in patients suspected of hypersensitivity only under absolute indications. Patients with a history of hypersensitivity reactions during general anesthesia should undergo testing for hypersensitivity to other neuromuscular blocking agents.

In asthmatic patients receiving high doses of corticosteroids and neuromuscular blocking agents in intensive care units, monitoring of serial creatine phosphokinase levels is advisable.

When used at recommended doses, atracurium has no significant vagolytic or ganglion-blocking properties. Therefore, at recommended doses, atracurium does not significantly affect heart rate and does not prevent bradycardia that may be caused by anesthetic agents or vagus nerve stimulation during surgery.

As with other non-depolarizing muscle relaxants, increased sensitivity to atracurium may occur in patients with myasthenia gravis, other neuromuscular disorders, or severe acid-base and/or electrolyte imbalances.

As with other non-depolarizing muscle relaxants, hypophosphatemia may prolong recovery time. Recovery time may be shortened. Atracurium besylate should be administered over at least 60 seconds in patients who may be unusually sensitive to decreases in arterial blood pressure, such as those with hypovolemia.

Atracurium besylate is inactivated at high pH of the solution; therefore, it must not be mixed in the same syringe with thiopental or any other alkaline solution.

If the drug is administered by injection into a small vein, a sufficient amount of 0.9% sodium chloride solution should be administered after injection. When co-administered with other drugs, the needle or cannula should be flushed with 0.9% sodium chloride solution each time.

The medicinal product is a hypotonic solution and must not be administered in the same infusion system with blood products or during blood transfusion. In patients predisposed to malignant hyperthermia, atracurium besylate has been shown not to trigger this syndrome.

As with other non-depolarizing muscle relaxants, resistance to atracurium besylate may develop in burn patients. In such patients, higher doses of the drug may be required depending on the time elapsed since the injury and the extent of the burns.

Intensive care unit patients: Clinical animal studies indicate that laudanosine, a metabolite of atracurium besylate, may cause reversible hypotension and, in some individuals, cerebral excitation when high doses of the drug are administered. Although seizures have also been observed in intensive care unit patients receiving atracurium besylate, a definitive causal relationship with laudanosine has not been established (see section "Adverse reactions").

Use during pregnancy or breastfeeding.

Fertility.

Studies on fertility have not been conducted to date.

Pregnancy.

Animal studies have shown that atracurium besylate does not have a significant effect on fetal development. Like all neuromuscular blocking agents, atracurium should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

The drug can be used during surgical procedures (e.g., cesarean section), as it does not cross the placental barrier in quantities sufficient to affect the fetus.

Breastfeeding.

It is unknown whether atracurium besylate and its metabolites are excreted in human breast milk.

Ability to affect reaction speed when driving or operating machinery.

This warning is not applicable to the indications for use of atracurium besylate. Since atracurium is always administered in combination with general anesthetic agents, the effects of general anesthetics on attention and reaction speed should be taken into account.

Administration and Dosage.

Route of administration.

Intravenous injection or prolonged infusion.

Adults.

Administration by injection.

The medicinal product should be administered by intravenous bolus injection. The dosage regimen for adults ranges from 0.3 to 0.6 mg/kg body weight, depending on the required duration of complete neuromuscular blockade, providing adequate muscle relaxation for 15–35 minutes.

Endotracheal intubation can be performed within the first 90 seconds after intravenous administration of the drug at doses of 0.5–0.6 mg/kg body weight.

If prolongation of the blocking effect is required, additional doses of the drug should be administered at 0.1–0.2 mg/kg body weight. Proper additional dosing does not increase the cumulative effect of neuromuscular blockade.

Recovery of normal neuromuscular transmission occurs within 35 minutes, with recovery of tetanic response to 95% of normal neuromuscular function.

Neuromuscular blockade induced by atracurium besilate can be rapidly reversed by administering standard doses of anticholinesterase agents.

Administration by infusion.

Following the initial bolus dose of 0.3–0.6 mg/kg body weight, further maintenance of neuromuscular blockade during prolonged surgical procedures is achieved by continuous intravenous infusion of the drug at a rate of 0.3–0.6 mg/kg body weight per hour.

The drug may be used via intravenous infusion during aortocoronary bypass surgery. If hypothermia to a body temperature of 25–26 °C is required, the rate of atracurium inactivation is reduced; therefore, in such cases, the infusion rate may be halved to maintain complete neuromuscular blockade.

Compatibility with other infusion/injection solutions and the drug's stability period are provided below:

When diluted in the solvents indicated above and achieving a concentration of atracurium besylate of 0.5 mg/mL or higher, the resulting solution will remain stable under daylight conditions for the specified period of time at temperatures not exceeding 30°C.

Elderly patients.

Administer in standard dosage; however, it is recommended to use the lowest initial dose and administer the drug more slowly.

Patients with renal and hepatic impairment.

The drug should be administered in standard doses regardless of the degree of renal or hepatic impairment, including end-stage disease.

Patients with cardiovascular diseases.

In patients with clinically significant cardiovascular disease, the initial dose should be administered over a period of at least 60 seconds.

Patients in intensive care units.

After administration of the required initial bolus dose of atracurium in the range of 0.3 to 0.6 mg/kg body weight, maintenance of neuromuscular blockade is achieved by continuous intravenous infusion of the drug at a rate of 11 to 13 mcg/kg/min (0.65–0.78 mg/kg/h). However, there is wide individual variability in dosing requirements, which may also change over time. Some patients may require a lower infusion rate, such as 4.5 mcg/kg/min (0.27 mg/kg/h), while others may require a higher rate, such as 29.5 mcg/kg/min (1.77 mg/kg/h).

The rate of recovery of neuromuscular transmission in patients does not depend on the duration of drug administration and, according to clinical studies, ranges from 32 to 108 minutes.

Monitoring.

To individualize the dosing regimen, monitoring of neuromuscular transmission function is recommended, as with other drugs that block neuromuscular transmission.

Children.

Administer for treatment of children aged 1 month and older using the same dosing regimens as in adults, with dose calculated based on the child's body weight. Use in children under 1 month of age is not recommended due to limited data (see section "Pharmacokinetics").

Overdose.

Symptoms.

Prolonged skeletal muscle paralysis and its consequences are the main signs of overdose.

Treatment.

Ensure unobstructed airway access and provide artificial ventilation of the lungs until spontaneous adequate respiration returns.

Since patients remain conscious, full sedation may be necessary.

Appropriate use of anticholinesterase agents together with atropine or glycopyrrolate is recommended as soon as signs of spontaneous recovery appear.

Adverse Reactions

The most commonly reported adverse reactions were hypotension (mild, transient) and skin hyperemia; these reactions are associated with histamine release. Very rarely, severe anaphylactoid or anaphylactic reactions have been reported in patients receiving atracurium in combination with one or more anesthetic agents.

The adverse reactions listed below are classified by organ systems and frequency of occurrence. Frequency categories: very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon ≥ 1/1,000 to < 1/100; rare ≥ 1/10,000 to < 1/1,000; very rare < 1/10,000. The data for "very common", "common", and "uncommon" were obtained from clinical trials. The data for "rare" and "very rare" are generally derived from spontaneous reports. The term "not known" refers to adverse reactions for which frequency cannot be determined from available sources. Adverse reactions caused by histamine release are marked with an asterisk*.

Data obtained from clinical trials.

Vascular system.

Common: hypotension (mild, transient)*, skin hyperemia*.

Respiratory system and thoracic organs.

Uncommon: bronchospasm*.

Data obtained from post-marketing experience.

Immune system.

Very rare: anaphylactic reaction, anaphylactoid reaction, including shock, circulatory failure, and cardiac arrest.

There have been isolated reports of severe anaphylactoid or anaphylactic reactions when atracurium was administered with other anesthetic agents.

Nervous system.

Not known: seizures.

There have been individual reports of seizures in critically ill patients receiving intensive care treatment with atracurium in combination with other drugs. These patients usually had one or more predisposing factors for seizures (head trauma, cerebral edema, viral encephalitis, hypoxic encephalopathy, uremia). A causal relationship with laudanosine has not been established. Clinical studies have not demonstrated a correlation between plasma laudanosine levels and the occurrence of seizures.

Skin and subcutaneous tissue.

Rare: urticaria.

Musculoskeletal and connective tissue system.

Not known: myopathy, muscle weakness.

Cases of muscle weakness and/or myopathy have been reported following prolonged use of neuromuscular blocking agents in critically ill patients treated in intensive care units. Most of these patients were receiving concomitant corticosteroid therapy. These reports were infrequent, and a causal relationship with atracurium besylate administration has not been established.

Incompatibility. Atracurium-Novo is a hypotonic solution and must not be administered in the same infusion system as blood products or during blood transfusion.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at 2–8 °C. Keep out of reach of children. Do not freeze.

Packaging.

2.5 ml or 5 ml in a vial; 5 vials in a blister pack, contained in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Limited liability company "Novopharm-Biosyntez".

Manufacturer's address and location of business activity.

38, Zhytomyrska St., Novohrad-Volynskyi, Zhytomyr Oblast, 11700, Ukraine.