Atracurium-novopharm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ATRACURIUM-NOVOFARM (ATRACURIUM-NOVOFARM)

Composition:

Active substance: atracurium besilate;

1 ml of solution contains 10 mg of atracurium besilate;

Excipients: benzenesulfonic acid, water for injections.

Pharmaceutical form. Solution for injection/infusion.

Main physicochemical properties: clear colorless or slightly yellow liquid.

Pharmacotherapeutic group. Peripheral-acting muscle relaxants. Other quaternary ammonium compounds. ATC code M03AC04.

Pharmacological Properties

Pharmacodynamics

Atracurium besylate is a highly selective, non-depolarizing, competitive peripheral-acting myorelaxant with an intermediate duration of action. It blocks nicotinic cholinoreceptors at 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.

Pharmacodynamic effects

Atracurium besylate has no direct effect on intraocular pressure and is therefore suitable for use in ophthalmic surgery.

Spontaneous recovery following complete blockade occurs in approximately 35 minutes, measured as the return of the twitch response to 95% of normal neuromuscular function.

Neuromuscular blockade induced by atracurium can be rapidly reversed by standard doses of anticholinesterase agents such as neostigmine and edrophonium, in combination with an anticholinergic agent (e.g., atropine), without signs of recurarization.

The time to complete recovery is approximately 40 minutes under halothane, isoflurane, or enflurane anesthesia.

There is a dose-dependent relationship between increasing doses of atracurium besylate and the amount of histamine released.

Children

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

Pharmacokinetics

Following 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 non-specific plasma esterases. Elimination of atracurium is independent of hepatic or renal function. The breakdown products of atracurium include laudanosine and other metabolites. The metabolites lack myorelaxant activity. Plasma protein binding of atracurium besylate is approximately 82%, elimination half-life is 20 minutes, and volume of distribution is 0.16 L/kg.

Metabolites are excreted in urine and bile.

Haemofiltration and haemodiafiltration have only a minimal effect on plasma levels of atracurium and its metabolites, including laudanosine. The effect of haemodialysis and haemoperfusion on plasma levels of atracurium and its metabolites is unknown.

Metabolite concentrations are higher in blood in intensive care 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

Used as an adjunct to general anesthesia to facilitate tracheal intubation and to provide skeletal muscle relaxation during surgical procedures or controlled mechanical ventilation. The medicinal product is also indicated to facilitate mechanical ventilation in intensive care units (ICU).

Contraindications

Hypersensitivity to atracurium, cisatracurium, or benzenesulfonic acid.

Interaction with other medicinal products and other forms of interaction

Neuromuscular blockade caused by atracurium may be potentiated by concomitant administration of 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 concurrently with:

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

Rarely, when used concomitantly with certain medicinal products that may enhance manifestations of myasthenia (including latent forms) and provoke the development of a myasthenic syndrome, increased sensitivity to atracurium besylate may occur. These include antibiotics, beta-blockers (propranolol, oxprenolol), antiarrhythmic agents (procainamide, quinidine), antirheumatic agents (chloroquine, d-penicillamine), trimethaphan, chlorpromazine, steroids, phenytoin, and lithium.

In patients receiving long-term anticonvulsant therapy (e.g., carbamazepine, phenytoin), the onset of neuromuscular blockade may be prolonged, while the duration of blockade may be shortened.

Concomitant use of non-depolarizing muscle relaxants with atracurium besylate may result in more intense neuromuscular blockade than that produced by an equivalent total dose of atracurium besylate alone. The synergistic effect may vary depending on the combination of these medicinal products.

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 this may result in prolonged and complex blockade that is difficult to reverse with anticholinesterase agents.

The use of anticholinesterase medicinal products commonly used in the treatment of Alzheimer's disease, such as donepezil, may shorten the duration and reduce the degree of neuromuscular blockade caused 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, under close supervision of an experienced anesthesiologist, and with availability of appropriate equipment for endotracheal intubation and artificial ventilation of the lungs.

Atracurium may cause histamine release. Particular caution should be exercised when treating patients with a history of hypersensitivity to histamine. In particular, bronchospasm may occur in patients with a history of allergies or asthma.

Atracurium should be used with caution in patients with known hypersensitivity to other neuromuscular blocking agents, as there have been reports of a high rate (over 50%) of cross-sensitivity between neuromuscular blocking agents (see section "Contraindications").

When used in recommended doses, atracurium has no significant vagolytic or ganglion-blocking properties. Therefore, atracurium does not significantly affect heart rate at recommended doses 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 besylate can be expected in patients with myasthenia gravis or other neuromuscular disorders, and in those with severe electrolyte imbalances.

In patients who may be unusually sensitive to a drop in blood pressure, such as those with hypovolemia, atracurium should be administered over a period of 60 seconds.

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

If the drug is administered by puncture of a small vein, a sufficient volume of 0.9% sodium chloride solution should be administered after injection. When other drugs are administered through the same needle or cannula as atracurium, it is important to flush the needle or cannula with an adequate volume of 0.9% sodium chloride solution after each drug administration.

The drug is a hypotonic solution and therefore must not be administered in the same infusion system with blood products or during blood transfusion.

Studies on malignant hyperthermia in susceptible animals (pigs) and clinical studies in patients susceptible to malignant hyperthermia indicate that atracurium does not trigger this syndrome.

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

Patients with malignancies, particularly those associated with bronchial carcinoma, may exhibit marked sensitivity to atracurium, and neuromuscular blockade induced by atracurium may respond poorly to neostigmine.

Neuromuscular blockade caused by atracurium can be rapidly reversed by administration of standard doses of anticholinesterase agents (e.g., neostigmine) in combination with an anticholinergic agent (e.g., atropine).

Patients with severe cardiovascular disease may be more sensitive to the effects of transient hypotension. In such patients, the drug should be administered slowly by intravenous injection.

Special attention should be paid to ensuring adequate respiratory function before the patient is discharged from anesthesiologist supervision.

Under no circumstances should atracurium be mixed with any other intravenous drug (except those specified in the section "Administration and dosage"). Such drugs should be properly administered to the patient before atracurium is given.

Intensive care unit (ICU) patients: Administration of high doses of laudanosine (a metabolite of atracurium besylate) to laboratory animals has been associated with transient hypotension and, in some species, with excitatory central nervous system effects. Although seizures have been observed in ICU patients receiving atracurium, a causal relationship with laudanosine has not been established (see section "Adverse reactions").

Use during pregnancy or breastfeeding

Fertility

No fertility studies have been conducted to date.

Pregnancy

Animal studies have shown that atracurium has no significant effect on fetal development. Like all neuromuscular blocking agents, atracurium should be used during pregnancy only when the expected benefit to the pregnant woman outweighs the potential risk to the fetus.

The drug may be used during surgical procedures (e.g., cesarean section), as atracurium does not cross the placental barrier in clinically significant amounts.

Breastfeeding

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

Effect on ability to drive or operate machinery

Warnings regarding effects on reaction speed when driving or operating machinery do not apply to the indications for use of atracurium. Since atracurium is always administered in combination with drugs used for general anesthesia, the effects of general anesthetics on attention and reaction speed should be taken into account.

Administration and Dosage

Intravenous injection

The medicinal product is administered by intravenous injection. The adult dose ranges from 0.3 to 0.6 mg/kg body weight, depending on the required duration of complete neuromuscular blockade, providing adequate relaxation for 15–35 minutes.

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

Complete blockade may be prolonged by additional doses of 0.1–0.2 mg/kg as needed. Repeated supplemental doses do not lead to accumulation of neuromuscular blocking effect.

Caesarean section

Atracurium is suitable for maintaining muscle relaxation during caesarean section, as it does not cross the placenta in clinically significant amounts following administration of recommended doses (0.3–0.6 mg/kg).

Spontaneous recovery after termination of complete blockade occurs approximately 35 minutes after administration, as determined by the return of tetanic response to 95% of normal neuromuscular function.

Neuromuscular blockade caused by atracurium can be rapidly reversed by administration of standard doses of anticholinesterase agents (e.g., neostigmine) in combination with an anticholinergic agent (e.g., atropine).

Continuous infusion

After initial bolus administration of 0.3–0.6 mg/kg body weight, maintenance of neuromuscular blockade during prolonged surgical procedures is achieved by continuous intravenous infusion at a rate of 0.3–0.6 mg/kg/hour.

Atracurium besilate may be administered by intravenous infusion during coronary artery bypass grafting at the infusion rate stated above. If hypothermia to a body temperature of 25–26 °C is required, the inactivation rate of atracurium besilate is reduced; therefore, complete neuromuscular blockade can be maintained at approximately half the initial infusion rate under these low body temperatures.

Compatibility with other infusion/injection solutions and the stability period of the medicinal product are provided below:

When diluted in the solutions mentioned 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 up to 25°C.

From a microbiological standpoint, the diluted medicinal product should be used immediately. If the diluted medicinal product is not used immediately, the responsibility for the duration and storage conditions during its use lies with the user.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Elderly patients

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

Patients with renal or hepatic impairment

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

Patients with cardiovascular disorders

In patients with clinically significant cardiovascular disorders, the initial dose of atracurium besylate should be administered slowly over a period of not less than 60 seconds.

Monitoring: As with all neuromuscular blocking agents, monitoring of neuromuscular function is recommended during the use of atracurium besylate to allow individual dose adjustment.

Children

Administer to children aged 1 month and older at the same dosage as for adults, with the dose calculated according to 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

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

Since consciousness in patients is not impaired, full sedation may be necessary.

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

Adverse Reactions

The most commonly reported adverse reactions were arterial 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 are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); and not known (cannot be estimated based on available data). The data for "very common," "common," and "uncommon" were derived from clinical trials. The data for "rare" and "very rare" were generally obtained from spontaneous reports. Adverse reactions due to histamine release are marked with an asterisk*.

Data from clinical trials

Vascular system

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

Respiratory, thoracic and mediastinal disorders

Uncommon: bronchospasm*.

Data from post-marketing experience

Immune system disorders

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

There have been isolated reports of severe anaphylactoid or anaphylactic reactions when atracurium was used in combination with other anesthetic agents. In all documented cases, prompt resuscitation measures resulted in a positive outcome.

Nervous system disorders

Not known: seizures.

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

Skin and subcutaneous tissue disorders

Rare: urticaria.

Musculoskeletal and connective tissue disorders

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 also receiving concomitant corticosteroid therapy. These reports were infrequent, and a causal relationship with atracurium use has not been established.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions

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

Incompatibilities

The medicinal product Atracurium-Novopharm is a hypotonic solution and must not be administered through the same infusion system as blood products or during blood transfusion.

Atracurium must not be mixed with thiopental or any other alkaline solution, as it is inactivated at high pH.

This medicinal product must not be mixed with other medicinal products except those specified in the section “Dosage and administration.”

Packaging

2.5 ml or 5 ml in a vial; 5 vials in a blister pack; 1 blister pack in a carton.

Prescription status

Prescription only.

Manufacturer

Limited liability company “Novopharm-Biosyntez”.

Manufacturer’s address and location of operations

38 Zhutomyrska Street, city of Zviahel, Zviahel district, Zhytomyr region, 11700, Ukraine.