Arduan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ARDUAN® (ARDUAN®)

Composition:

Active substance: pipecuronium bromide;

1 vial contains 4 mg of pipecuronium bromide;

Excipients: mannite (E 421);

1 ml of solvent contains 9 mg of sodium chloride;

Excipients: water for injections.

Pharmaceutical form.

Lyophilisate for solution for injection.

Main physicochemical properties: white or almost white lyophilisate;

solvent: colorless, clear solution, practically free from particles.

Pharmacotherapeutic group. Peripheral-acting muscle relaxants.

ATC code M03AC06.

Pharmacological properties.

Pharmacodynamics.

Pipecuronium bromide is a long-acting non-depolarizing neuromuscular blocker. By competitively binding to nicotinic acetylcholine receptors located at motor end plates of striated muscle fibers, it blocks signal transmission from nerve endings to muscle fibers. Its antidotes are acetylcholinesterase inhibitors (e.g., neostigmine, pyridostigmine, edrophonium). Unlike depolarizing muscle relaxants (e.g., succinylcholine), pipecuronium bromide does not cause muscle fasciculations. Pipecuronium bromide has no hormonal effects.

Even at doses several times higher than its effective dose required for 90% reduction of muscle contractility (ED90), it shows no ganglion-blocking, vagolytic, or sympathomimetic activity.

According to study data, under balanced anesthesia, the ED50 and ED90 doses of pipecuronium bromide are 0.03 and 0.05 mg/kg body weight, respectively.

A dose of 0.05 mg/kg provides 40–50 minutes of muscle relaxation during various surgical procedures.

The maximum effect of pipecuronium bromide is dose-dependent and occurs within 1.5–5 minutes. The effect develops most rapidly at doses of 0.07–0.08 mg/kg body weight. Further dose increases shorten the onset time and significantly prolong the duration of action.

Pharmacokinetics.

After intravenous administration, the initial volume of distribution (Vdc) is 110 mL/kg body weight; the volume of distribution at steady state (Vdss) is 300 ± 78 mL/kg; plasma clearance (Cl) is 2.4 ± 0.5 mL/min/kg; mean elimination half-life (t1/2) is 121 ± 45 minutes; mean residence time (MRT) is 140 minutes.

With repeated administration of maintenance doses, cumulative effects are negligible if doses of 0.01–0.02 mg/kg are administered at the time when 25% of the original contractility is restored.

75% of the drug is excreted unchanged, primarily via the kidneys, with 56% eliminated within the first 24 hours, and the remainder as 3-desacetyl-pipecuronium. Preclinical studies indicate that the liver also participates in the elimination of pipecuronium.

Clinical characteristics.

Indications.

Muscle relaxation under general anesthesia to facilitate endotracheal intubation and to provide conditions for surgical procedures requiring more than 20–30 minutes of muscle relaxation.

Contraindications.

Known hypersensitivity to the active substance of the drug (to pipecuronium or bromide) or to any excipient of the drug. Myasthenia gravis.

Interaction with other medicinal products and other forms of interaction.

The medicinal products listed below may affect the magnitude and/or duration of action of non-depolarizing neuromuscular blockers.

Potentiate or prolong the effect:

• inhalational anesthetics (halothane, methoxyflurane, diethyl ether, enflurane, isoflurane, cyclopropane);
• intravenous anesthetic agents (ketamine, fentanyl, propanidid, barbiturates, etomidate, γ-hydroxybutyric acid), high doses of local anesthetics;
• other non-depolarizing muscle relaxants, prior administration of succinylcholine;
• certain antibiotics and chemotherapeutic agents (aminoglycosides, polypeptides, imidazoles, metronidazole, and others);
• diuretics, α- and β-blockers, thiamine, monoamine oxidase inhibitors, guanidine, protamine, phenytoin, calcium channel antagonists, magnesium salts, most antiarrhythmic drugs, including intravenous quinidine and lidocaine, which enhance the blockade induced by non-depolarizing muscle relaxants.

Reduce the effect:

prolonged prior use of glucocorticoids, neostigmine, edrophonium, pyridostigmine, norepinephrine, azathioprine, theophylline, potassium chloride, sodium chloride, calcium chloride prior to surgery may reduce the effect of pipecuronium bromide. Small doses of pipecuronium bromide added to succinylcholine to prevent fasciculations may reduce the effect of succinylcholine.

Unpredictable effect:

depolarizing muscle relaxants administered after pipecuronium bromide may either potentiate or reduce the effectiveness of neuromuscular blockade (depending on dose, duration of administration, and individual hypersensitivity).

Others.

Pipecuronium bromide should not be mixed with other solutions or drugs in the same syringe or vial (bag).

Special precautions for use.

• Since pipecuronium bromide causes relaxation of respiratory muscles, artificial ventilation is required for patients who have received this agent until spontaneous respiration is fully restored.

• Arduan® should be administered exclusively in specialized healthcare facilities and only in the presence of a qualified medical team, with equipment available for endotracheal intubation, artificial ventilation, oxygen therapy, and antagonistic agents.

• Anaphylactic and anaphylactoid reactions have been reported with neuromuscular blocking agents. Although such reactions have not been reported with Arduan®, appropriate treatment should be readily available in case such reactions occur.

• Arduan® should be used with particular caution in patients with a history of allergic reactions to other muscle relaxants, as cross-allergic reactions between non-depolarizing neuromuscular blockers have been reported.

• Histamine release and histamine-like reactions: pipecuronium bromide does not cause histamine release.

• Pipecuronium bromide has minimal hemodynamic effects, possibly due to its weak cardiostimulant, vagolytic effect. At doses up to 0.1 mg/kg body weight, no ganglion-blocking or vagolytic activity has been observed. Only mild cardiovascular side effects (e.g., decreased arterial pressure, bradycardia) may occur, particularly when administered concurrently with halothane or fentanyl during anesthesia induction.

• Doses of Arduan® that produce muscle relaxation have no significant cardiovascular effects.

• Given the above, the use and dosage of vagolytic agents for premedication should be carefully evaluated. The vagal-stimulating effects of other concurrently administered drugs and the type of surgery should also be taken into account.

• To prevent relative overdosing and to ensure adequate monitoring of muscle function recovery, peripheral nerve stimulation is recommended.

Factors that may influence the pharmacokinetics and/or neuromuscular blocking effect of Arduan®:

Renal insufficiency: prolongs the duration of action and the so-called "recovery time" of the patient.

Neuromuscular disorders: Arduan® should be administered with caution, as neuromuscular blockade may be either potentiated or reduced in such cases.

In patients with known myasthenia gravis or myasthenic syndrome (Eaton-Lambert), an atypical response may be expected even to small doses of pipecuronium bromide. Therefore, significantly reduced doses of pipecuronium bromide are recommended for these patients. Anticholinesterase agents should be administered 10–15 minutes before the expected reversal effect at the end of surgery. Prolonged postoperative mechanical ventilation should be planned.

Hepatic disease: Arduan® may be used only if the expected benefit outweighs the potential risk.

Malignant hyperthermia: Malignant hyperthermia has not been observed during clinical studies or clinical practice with Arduan®. Since neuromuscular blockers are never used in isolation and because this syndrome may develop even without known triggering factors, physicians should be familiar with its early signs, diagnostic methods, and treatment.

Other: Any existing fluid-electrolyte imbalances and blood pH disturbances should be corrected before initiating anesthesia.

In patients with cardiovascular diseases, edema, and in elderly patients with reduced circulatory rate, the onset of action of the drug may be delayed.

Hypothermia may prolong the duration of action of the drug.

Hypokalemia, digitalization, diuretic use, hypermagnesemia, hypocalcemia (transfusion), dehydration, acidosis, hypercapnia, and cachexia may enhance and prolong the effect of Arduan®.

Like other neuromuscular blocking agents, Arduan® may partially reduce thromboplastin time and prothrombin time.

Only freshly prepared solutions should be used.

Mixing Arduan® with infusion solutions is not recommended.

Use during pregnancy or breastfeeding.

Data sufficient to confirm the safety of Arduan® in pregnant women and the fetus are lacking. Arduan® may be used during pregnancy only if the expected therapeutic benefit justifies the potential risk. It is unknown whether the drug is excreted in breast milk.

Cesarean section.

The use of Arduan® during cesarean section does not affect Apgar scores, muscle tone, or cardiovascular adaptation of the newborn. Only minimal amounts of the active substance cross the placenta and are detectable in umbilical cord blood.

In pregnant women treated with magnesium salts for toxemia, which enhance neuromuscular blockade, pharmacological reversal of the muscle relaxant effect may be insufficient. In such cases, peripheral nerve stimulation must be used.

Ability to affect reaction speed when driving or operating machinery.

For the first 24 hours after termination of the neuromuscular blocking effect of Arduan®, driving vehicles or operating machinery associated with a high risk of injury is not recommended.

Administration and Dosage

As with other neuromuscular blocking agents, the dose of Arduan® should be individually adjusted for each patient, taking into account the type of anesthesia, expected duration of surgery, possible interactions with other medicinal products used before or during anesthesia, concomitant diseases, and the patient's general condition. It is recommended to use peripheral nerve stimulation to monitor neuromuscular blockade.

Arduan® is administered intravenously. Immediately before administration, dissolve 4 mg of the dry substance with the provided solvent—0.9% sodium chloride solution.

Recommended doses for adults:

• Initial dose for intubation and subsequent surgical procedure: 0.06–0.08 mg/kg body weight, providing conditions suitable for intubation within 150–180 seconds, with muscle relaxation lasting 60–90 minutes;
• Initial dose for muscle relaxation during intubation using succinylcholine: 0.05 mg/kg body weight, providing 30–60 minutes of myorelaxation;
• Maintenance dose: 0.01–0.02 mg/kg body weight, providing 30–60 minutes of myorelaxation during surgery;
• Patients with impaired renal function should not receive doses exceeding 0.04 mg/kg body weight.

Use in children

In combined anesthesia, the initial dose of Arduan® for children aged 1 to 14 years is 0.08–0.09 mg/kg body weight.

For neonates and children under 1 year of age, lower doses are recommended—0.04–0.06 mg/kg body weight.

These doses provide muscle relaxation suitable for surgical procedures lasting 25–35 minutes. If prolonged myorelaxation is required for an additional 25–35 minutes, repeat administration of the drug at a dose equal to one-third of the initial dose is recommended.

Possible prolongation of drug effect in the following cases:

• Excess body weight, obesity (dose should be based on ideal body weight);
• Concomitant use of inhalational anesthetics (the dose of Arduan® may be reduced);
• During intubation following succinylcholine (Arduan® is administered after the clinical effects of succinylcholine have subsided. As with other non-depolarizing muscle relaxants, administration of Arduan® after a depolarizing muscle relaxant may shorten the onset time of myorelaxation and increase the duration of maximum effect).

Reversal of effect: When 80–85% blockade is measured using peripheral nerve stimulator, or partial blockade is determined clinically, the muscle relaxant effect of Arduan® can be reversed by administering atropine (0.5–1.25 mg for adults) in combination with neostigmine (1–3 mg for adults) or galantamine (10–30 mg for adults).

Children. The drug is administered to children (see section "Administration and Dosage").

Overdose.

In case of overdose or prolonged neuromuscular blockade, artificial ventilation of the lungs should be continued until spontaneous respiration is restored. At the beginning of recovery of spontaneous respiration, an acetylcholinesterase inhibitor (e.g., neostigmine, pyridostigmine, edrophonium) should be administered as an antidote in an appropriate dose. Respiratory function should be carefully monitored until satisfactory spontaneous respiration is achieved.

Adverse Reactions

The most common adverse effect of non-depolarizing neuromuscular blockers as a class is prolonged pharmacological action beyond the duration required for surgical intervention and anesthesia. Clinical manifestations may range from skeletal muscle weakness to profound and prolonged skeletal muscle paralysis, which may lead to respiratory insufficiency or apnea.

Adverse reactions are listed by frequency: very common (≥ 1/10); common (≥ 1/100 – < 1/10); uncommon (≥ 1/1000 – < 1/100); rare (≥ 1/10,000 – < 1/1000); very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Immune system

Rare: anaphylactic and anaphylactoid reactions*.

Metabolism and nutrition disorders

Uncommon: increased creatinine levels, hypoglycemia, hyperkalemia;
Rare: tetany.

Psychiatric disorders

Rare: somnolence.

Central nervous system disorders

Uncommon: hypoesthesia, central nervous system depression;
Rare: paralysis.

Eye disorders

Rare: blepharitis, ptosis.

Cardiovascular system disorders**

Uncommon: stroke, thrombosis, myocardial ischemia, atrial fibrillation, ventricular extrasystoles;
Rare: arrhythmia, bradycardia, cardiac depression, tachycardia and ventricular fibrillation**, arterial hypertension, hypotension, vasodilation.

Respiratory system disorders

Uncommon: respiratory depression, laryngospasm, atelectasis;
Rare: apnea, dyspnea, pulmonary hypoventilation, bronchospasm, cough.

Musculoskeletal system disorders

Uncommon: muscle atrophy, difficult intubation;
Rare: muscle weakness.

Skin disorders

Uncommon: rash, urticaria.

Renal and urinary disorders

Uncommon: anuria.

Laboratory findings

Rare: slight decrease in plasma potassium, magnesium, and calcium levels; increased glucose levels; increased blood urea concentration; decreased heart rate.

*Anaphylactic and anaphylactoid reactions may occasionally occur with the use of non-depolarizing muscle relaxants. Although only one case (not proven) of anaphylactic reaction (cough, bronchospasm, facial swelling, redness and swelling of eyes) has been reported during administration of Arduan® injection, medications and equipment for managing anaphylactic reactions should be readily available. The drug must be used with special caution in patients with a history of allergic reaction to other muscle relaxants, as cross-allergies may develop among non-depolarizing muscle relaxants.

Histamine release and histamine-like reactions: Arduan® does not cause histamine release.

**Arduan® has a mild hemodynamic effect, possibly due to the weak cardioselective vagolytic effect of pipecuronium bromide. At doses up to 0.1 mg/kg body weight, no ganglion-blocking or vagolytic effects were observed—only mild cardiovascular adverse effects (decreased arterial pressure, bradycardia), particularly when administered concomitantly with halothane or fentanyl during anesthesia induction.

Shelf life. Lyophilisate – 3 years; solvent – 5 years.

Storage conditions. Store at 2–8 °C, in the original packaging to protect from light. Keep out of reach of children.

Incompatibilities.

Arduan® must not be mixed with other infusion solutions.

Packaging. 4 mg lyophilisate in a vial made of colorless glass. 2 ml solvent in an ampoule made of colorless glass with a break point. 5 vials of lyophilisate and 5 ampoules of solvent in a cardboard tray; 5 cardboard trays per cardboard box.

Prescription status. Prescription only. The drug must be used exclusively on a physician's prescription and under hospital conditions.

Manufacturer. JSC "Gedeon Richter".

Manufacturer's address.
H-1103 Budapest, Demrédi str. 19–21, Hungary.

Marketing authorization holder. JSC "Gedeon Richter".

Address of the marketing authorization holder.
H-1103 Budapest, Demrédi str. 19–21, Hungary.