Atracurium kalceks

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ATRACURIUM KALCEKS (ATRACURIUM KALCEKS)

Composition:

Active substance: atracurium besilate;

1 ml of solution contains atracurium besilate 10 mg;

Excipients: benzolsulfonic acid solution, water for injections.

Pharmaceutical form. Injection solution.

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

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

Pharmacological properties.

Pharmacodynamics.

A highly selective non-depolarizing competitive peripheral-acting myorelaxant with intermediate duration of action. 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.

Pediatric patients. Scientific literature provides some data on possible variability in onset and duration of action of atracurium in neonates (infants up to 1 month of age) compared to older children (see section "Children").

Pharmacokinetics.

After intravenous administration, atracurium besilate is spontaneously metabolized via Hofmann elimination (a non-enzymatic process occurring at physiological pH and body temperature) and by 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 besilate is approximately 82%, and the elimination half-life is 20 minutes. Metabolites are excreted in urine and bile.

Metabolite concentrations are higher in blood of intensive care unit patients with impaired renal and/or hepatic function (see section "Special precautions"). These metabolites do not participate in neuromuscular blockade.

Clinical characteristics.

Indications.

For muscle relaxation during surgical interventions and diagnostic procedures (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 interactions.

Neuromuscular blockade induced by the medicinal product Atracurium Calceks 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 the medicinal product Atracurium Calceks, may be increased when administered simultaneously with:

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

Rarely, when used concomitantly 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 drugs, the onset of neuromuscular blockade induced by the medicinal product Atracurium Calceks may be delayed and the duration of blockade may be reduced.

Concomitant use of non-depolarizing muscle relaxants together with atracurium besylate may result in more intense neuromuscular blockade than that which may occur with administration of an equivalent total dose of atracurium besylate. The synergistic effect may vary depending on the combination of these agents.

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

The use of anticholinesterase drugs widely used in the treatment of Alzheimer's disease, such as donepezil, may reduce the duration and intensity 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 medicinal product should be administered only under conditions of adequate general anesthesia and only under the close supervision of an experienced anesthesiologist, with appropriate equipment available for endotracheal intubation and artificial ventilation of the lungs.

Administration of atracurium may cause histamine release. Particular caution should be exercised when treating patients with severe cardiovascular diseases who may be more susceptible to transient hypotension, as well as patients with a history of hypersensitivity to histamine (e.g., severe hypersensitivity reactions to multiple antigens or asthma). In such patients, slow intravenous administration of divided doses is recommended.

Atracurium should be used with caution in patients with known hypersensitivity to other neuromuscular blocking agents, as a high rate (over 50%) of cross-sensitivity between neuromuscular blocking agents has been documented (see section "Contraindications"). Therefore, prior to prescribing atracurium, hypersensitivity to other neuromuscular blocking agents should be excluded whenever possible. If hypersensitivity is suspected, atracurium should be used only under absolute indications. In patients with a history of hypersensitivity reactions during general anesthesia, testing for hypersensitivity to other neuromuscular blocking agents should be performed.

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

When used at recommended doses, atracurium has no significant vagolytic or ganglion-blocking properties. Therefore, atracurium does not significantly affect heart rate when administered at recommended doses and does not prevent bradycardia that may be caused by anesthetic agents or vagus nerve stimulation during surgery. Consequently, bradycardia may occur more frequently during anesthesia with atracurium than with other muscle relaxants.

As with other non-depolarizing muscle relaxants, patients with myasthenia gravis, other neuromuscular disorders, carcinomatosis, or those with severe acid-base and/or electrolyte disturbances may exhibit increased sensitivity to atracurium.

When administering atracurium, as with other non-depolarizing muscle relaxants, hypophosphatemia may persist for a prolonged period. The recovery period may be shortened. Atracurium should be administered over a period of at least 60 seconds in patients who may be unusually sensitive to a decrease in arterial pressure, such as those with hypovolemia.

Atracurium is inactivated at high pH solutions; 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 volume of 0.9% sodium chloride solution should be administered after injection. When used concomitantly with other drugs, the needle or cannula should be flushed each time with 0.9% sodium chloride solution.

Atracurium Calceks is a hypotonic solution and must not be used in the same infusion system with blood products or during blood transfusion. In patients susceptible to malignant hyperthermia, atracurium has been shown not to trigger this syndrome.

When other anesthetic agents are administered through the same needle or cannula as atracurium, it is essential to flush the needle or cannula with an adequate volume of sterile, pyrogen-free water or 0.9% sodium chloride solution after administration of each agent.

As with other non-depolarizing muscle relaxants, resistance to atracurium may develop in patients with burns. 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 studies in animals have shown that laudanosine, a metabolite of atracurium, may cause reversible hypotension when high doses of the drug are administered, and in some individuals, may produce cerebral excitation. Although seizures have been observed in intensive care unit patients receiving Atracurium Calceks, these cases have not been definitively attributed to laudanosine or atracurium, even when atracurium was administered by continuous infusion over prolonged periods (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 besilate does not have a significant effect on fetal development. Like all neuromuscular blocking agents, Atracurium Calceks should be used during pregnancy only if the expected benefit to the mother 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 that could affect the fetus. However, the possibility of respiratory depression in the newborn should always be considered.

Breastfeeding period.

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

Ability to affect reaction speed when driving or operating machinery.

Warnings regarding the effect on reaction speed when driving or operating machinery are not applicable to the indications for the use of atracurium. Since atracurium is always administered in combination with agents used for general anesthesia, 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.

Atracurium Calceks should be administered slowly in order to avoid transient hypotension, which may occasionally occur after rapid administration.

Adults.

Administration by injection.

Atracurium Calceks is administered by intravenous bolus 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 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 prolonged blockade is required, additional doses of 0.1–0.2 mg/kg body weight should be administered. Proper supplemental dosing does not increase the cumulative effect of neuromuscular blockade.

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

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

Administration by infusion.

Following the initial bolus dose 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 0.005–0.01 mg/kg/min.

The drug may be administered by intravenous infusion during coronary artery bypass grafting at the above-mentioned infusion rate. 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 drug stability period:

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 at temperatures not exceeding 30°C.

Elderly patients.

Use the standard dosage regimen; however, it is recommended to administer the lowest initial dose and to inject the drug more slowly.

Patients with renal or hepatic impairment.

The drug may be administered at 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 slowly over a period of at least 60 seconds.

Patients in intensive care units.

Following an initial bolus dose 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 dosage requirements, which may also change over time. Some patients may require a lower infusion rate of 4.5 mcg/kg/min (0.27 mg/kg/h), while others may require a higher rate of up to 29.5 mcg/kg/min (1.77 mg/kg/h). Available data indicate that dosage escalation of atracurium besylate may be required during prolonged use in intensive care patients, particularly in those with peripheral edema.

The rate of recovery of neuromuscular transmission is independent of the duration of drug administration. According to clinical studies, spontaneous recovery occurs approximately 60 minutes after discontinuation (range: 32 to 108 minutes).

Monitoring.

To individualize the dosing regimen, monitoring of neuromuscular transmission is recommended, as with other neuromuscular blocking agents.

Children.

The drug may be used in children aged 1 month and older at the same dosage as in adults, with the dose calculated according to body weight. Use in children under 1 month of age is not recommended due to limited data (see section "Pharmacokinetics").

How to open the ampoule:

1. Turn the ampoule so that the colored dot faces you. Gently tap the top of the ampoule with your finger to allow the solution to flow down to the lower part of the ampoule (Fig. 1).
2. Use both hands to open the ampoule: hold the lower part of the ampoule in one hand and press the top part away from the colored dot with the other hand (Fig. 2).

Fig. 1 Fig. 2

Overdose.

Symptoms.

Prolonged skeletal muscle paralysis and its consequences are the primary manifestations of overdose.

Treatment.

Maintain an unobstructed airway and provide artificial ventilation until adequate spontaneous respiration returns.

Since patient consciousness remains intact, full sedation may be necessary.

Anticholinesterase agents should be used together with atropine or glycopyrrolate 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. Severe anaphylactoid or anaphylactic reactions have been very rarely reported in patients receiving atracurium simultaneously with one or more anesthetic agents.

The adverse effects listed below are classified by organ systems and frequency of occurrence. The frequency of adverse effects is defined according to the following categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data). Data on adverse reactions occurring "very commonly," "commonly," and "uncommonly" were obtained from clinical trials. Data on "rare" and "very rare" adverse reactions were generally obtained from spontaneous reports. The term "frequency not known" refers to adverse effects 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*, flushing.

Respiratory, thoracic and mediastinal disorders

Uncommon: bronchospasm*.

Data obtained from post-marketing use.

Immune system disorders

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

Isolated cases of severe anaphylactoid or anaphylactic reactions have occurred when Atracurium Calceks was administered with other anesthetic agents (in all reported cases, prompt resuscitation measures resulted in a positive outcome).

Nervous system disorders

Frequency not known: seizures.

There have been isolated reports of seizures in critically ill patients receiving intensive care treatment and concomitant administration of atracurium besylate 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 trial data 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

Frequency not known: myopathy, muscle weakness.

Cases of muscle weakness and/or myopathy have been observed during 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 cases were infrequent, and a causal relationship with atracurium besylate administration has not been established.

Reporting of suspected adverse reactions after drug authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store in a refrigerator at a temperature of 2 °C to 8 °C. Do not freeze.

Keep in the original packaging to protect from light.

Keep out of reach of children.

Incompatibilities.

Atracurium Calceks is a hypotonic solution and must not be administered in the same infusion system with blood products or during blood transfusion. Atracurium should not be mixed with thiopental or any alkaline solution, as it is inactivated at high pH.

Packaging.

2.5 ml or 5 ml in a vial made of colorless glass of hydrolytic class I, with marking rings and a break point.

5 vials in a blister pack (cavity tray) made of polyvinyl chloride film; 1 blister pack (cavity tray) in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Manufacturer responsible for batch release:

JSC "Calceks".

Manufacturer’s address and place of business.

71E Krustpils Street, Riga, LV-1057, Latvia.

Marketing Authorization Holder.

JSC "Calceks".

Address of the Marketing Authorization Holder.

71E Krustpils Street, Riga, LV-1057, Latvia.