Tracrium™

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRACRIUM™ (TRACRIUM™)

Composition:

Active substance: atracurium besylate;

1 ml of solution contains 10 mg of atracurium besylate;

Excipients: benzolsulfonic acid solution, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, slightly yellowish solution, practically free from mechanical inclusions.

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

Pharmacological properties.

Pharmacodynamics.

A highly selective non-depolarizing competitive peripheral-acting muscle relaxant 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.

Children.

Limited data have been published regarding possible variability in the 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.

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 non-specific 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 muscle relaxant activity. Plasma protein binding of atracurium besilate is approximately 82%, 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 for use"). 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 benzene sulfonic acid.

Interaction with other medicinal products and other forms of interaction.

Neuromuscular blockade caused by Tracrium™ 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 Tracrium™, may be increased when administered simultaneously with:

• antibiotics, including aminoglycosides, polymyxins, spectinomycin, tetracyclines, 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;
• ganglion blockers (trimethaphan, hexamethonium).

Rarely – when administered concurrently with certain drugs that may enhance manifestations of myasthenia (including latent forms) and provoke the development of a myasthenic syndrome; as a result, increased sensitivity to atracurium besylate may occur. Such drugs include various 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 caused by Tracrium™ may be delayed and its duration reduced.

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

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

Concomitant 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 drug should be administered only under adequate general anesthesia, strictly under the supervision of an experienced anesthesiologist, and only when appropriate equipment for endotracheal intubation and artificial ventilation of the lungs is available.

Atracurium administration may cause histamine release. Particular caution should be exercised when treating patients with severe cardiovascular diseases, who may be more susceptible to transient hypotension, and patients with a history of histamine hypersensitivity (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 reports indicate a high level (over 50%) of cross-sensitivity between neuromuscular blocking agents (see section "Contraindications"). Therefore, whenever possible, hypersensitivity to other neuromuscular blocking agents should be ruled out before prescribing atracurium. Atracurium should be used in patients suspected of hypersensitivity only under absolute indications. Patients with a history of hypersensitivity reactions during general anesthesia should be tested for hypersensitivity to other neuromuscular blocking agents.

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 does not exhibit 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. Consequently, bradycardia may occur more frequently during anesthesia with atracurium than with other muscle relaxants.

As with other non-depolarizing muscle relaxants, increased sensitivity to atracurium may occur in patients with myasthenia gravis, other neuromuscular disorders, carcinomatosis, 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 should be administered over at least 60 seconds in patients who may be unusually sensitive to a decrease in arterial pressure, e.g., 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 via puncture of 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 each time with 0.9% sodium chloride solution.

Tracrium™ is a hypotonic solution and must not be used in the same infusion system with blood products or during blood transfusion. In patients predisposed 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 a sufficient volume of sterile, pyrogen-free water or 0.9% sodium chloride solution after each drug administration.

As with other non-depolarizing muscle relaxants, resistance to atracurium may develop in burn 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 have shown that laudanosine, a metabolite of atracurium, may cause reversible hypotension and, in some individuals, cerebral excitatory effects when high doses of the drug are administered. Although seizures have been observed in intensive care unit patients treated with Tracrium™, 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 Tracrium™ has no significant effect on fetal development. Like all neuromuscular blocking agents, Tracrium™ should be used during pregnancy only if the expected benefit to the pregnant woman 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 clinically significant amounts. However, the possibility of respiratory depression in the newborn should always be considered.

Breastfeeding.

It is unknown whether atracurium besilate and its metabolites are excreted in 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 atracurium use. 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.

Tracrium™ should be administered slowly to avoid transient hypotension, which may occasionally occur after rapid injection.

Adults

Administration by injection

Tracrium™ is administered by intravenous injection. The recommended dose for adults is 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 Tracrium™ 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 initial administration of an intravenous loading dose of 0.3–0.6 mg/kg body weight, maintenance of neuromuscular blockade during prolonged surgical procedures can be 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 infusion rate stated above. If hypothermia to a body temperature of 25–26 °C is required, the rate of inactivation of atracurium is reduced; therefore, the infusion rate needed to maintain complete neuromuscular blockade may be halved.

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

When diluted in the solvents indicated above to achieve a concentration of atracurium besilate of 0.5−0.9 mg/mL or higher, the resulting solution remains stable under daylight conditions for the specified period of time at temperatures not exceeding 30°C.

Tracrium™ may also be diluted with water for injections to a concentration of 0.5–0.9 g/mL; however, such dilution is not recommended for infusion administration. When diluted this way, the solution remains stable for 8 hours at temperatures not exceeding 30°C.

Elderly patients.

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

Patients with renal or 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 disorders, the initial dose should be administered slowly over a period of at least 60 seconds.

Patients in intensive care units.

After administration of the required initial 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/hour). However, there is wide individual variability in dosage 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/hour), while others may require a higher rate, such as 29.5 mcg/kg/min (1.77 mg/kg/hour). Available data indicate that increased dosage requirements for Tracrium™ may occur during prolonged use in intensive care patients, particularly in those with peripheral edema.

The rate of recovery of neuromuscular transmission in patients does not depend on the duration of drug administration. According to clinical studies, spontaneous recovery occurs approximately 60 minutes after discontinuation of infusion, with a range of 32 to 108 minutes.

Monitoring.

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

Children.

Use in children aged 1 month and older at the same dosage regimens as in adults, with dose calculated according to 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 a patent airway and provide artificial ventilation of the lungs until spontaneous adequate respiration returns.

Since consciousness is preserved in patients, full sedation may be necessary.

Anticholinesterase agents, together with atropine or glycopyrrolate, are indicated as soon as signs of spontaneous recovery appear.

Adverse Reactions

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

The adverse reactions listed below are classified by organ system 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 (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000). The data categorized as "very common", "common", and "uncommon" were obtained from clinical trials. The data categorized as "rare" and "very rare" are generally derived from spontaneous reports. The term "not known" refers to adverse reactions for which the frequency cannot be estimated from the available data. Adverse reactions due to histamine release are marked with an asterisk*.

Data from clinical trials.

Vascular system

Common: hypotension (mild, transient)*, flushing.

Respiratory system, thoracic organs

Uncommon: bronchospasm*.

Data from post-marketing experience.

Immune system

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 Tracrium™ was used concomitantly with other anesthetic agents. In all reported cases, prompt resuscitation measures resulted in a positive outcome.

Nervous system

Not known: seizures.

There are isolated reports of seizures in critically ill patients receiving intensive care treatment when Tracrium™ was administered 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 shown a correlation between plasma laudanosine levels and the occurrence of seizures.

Skin and subcutaneous tissue

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 receiving concomitant corticosteroid therapy. Such reports were infrequent, and a causal relationship with Tracrium™ administration has not been established.

Shelf life. 18 months.

Storage conditions.

Store ampoules in the outer carton at a temperature between 2 °C and 8 °C. Do not freeze. Keep out of reach of children.

Incompatibilities. Tracrium™ is a hypotonic solution and must not be used in the same infusion system as 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 of solution in a glass ampoule. 5 ampoules in a blister pack, contained in a cardboard box.

Prescription status. Prescription only.

Manufacturer. GlaxoSmithKline Manufacturing S.p.A.

Manufacturer's address and place of business.

Strada Provinciale Asolana No. 90 (loc. SAN POLO), 43056 Torri le (PR), Italy.