ATRACURIUM BESYLATE Solution for injection Ref.[6334] Active ingredients: Atracurium besilate

Atracurium Besilate Injection should be used only by those skilled in the management of artificial respiration and only when facilities are immediately available for endotracheal intubation and for providing adequate ventilation support, including the administration of oxygen under positive pressure and the elimination of carbon dioxide. The clinician must be prepared to assist or control ventilation, and anticholinesterase agents should be immediately available for reversal of neuromuscular blockade.

Atracurium has no known effect on consciousness, pain threshold, or cerebration. In surgery, it should be used only with adequate general anaesthesia.

In common with other neuromuscular blocking agents, the potential for histamine release exists in susceptible patients during administration of atracurium besilate. Caution should be exercised in patients with a history suggestive of an increased sensitivity to the effects of histamine.

Do not give Atracurium Besilate Injection by intramuscular administration.

Atracurium Besilate Injection has an acid pH and therefore should not be mixed with alkaline solutions (e.g. barbiturate solutions) in the same syringe or administered simultaneously during intravenous infusion through the same needle. Depending on the resultant pH of such mixtures, Atracurium Besilate Injection may be inactivated and a free acid may be precipitated.

When a small vein is selected as the injection site, Atracurium Besilate Injection should be flushed through the vein with physiological saline after injection. When other anaesthetic drugs are administered through the same indwelling needle or cannula as Atracurium Besilate Injection, it is important that each drug is flushed through with an adequate volume of physiological saline.

Atracurium may have profound effects in patients with myasthenia gravis, Eaton-Lambert syndrome, or other neuromuscular diseases in which potentiation of non-depolarising agents has been noted. A reduced dosage of atracurium and the use of a peripheral nerve stimulator for assessing neuromuscular blockade is especially important in these patients. Similar precautions should be taken in patients with severe electrolyte disorders.

Atracurium does not have significant vagal or ganglion blocking properties in the recommended dosage range. Consequently, atracurium will not counteract the bradycardia produced by many anaesthetic agents or by vagal stimulation during surgery. Therefore, bradycardia during anaesthesia may be more common with atracurium than with other muscle relaxants.

As with other non-depolarising neuromuscular blocking agents, resistance to atracurium may develop in patients suffering from burns. Such patients may require increased doses of atracurium depending on the time elapsed since the burn injury and the extent of the burn.

Atracurium Besilate Injection should be administered over a period of at least 60 seconds to patients who may be unusually sensitive to falls in arterial blood pressure, for example those who are hypovolaemic.

Atracurium Besilate Injection is hypotonic and must not be applied into the infusion line of a blood transfusion.

Monitoring of serial creatine phosphokinase (CPK) values should be considered in asthmatic patients receiving high dose corticosteroids and neuromuscular blocking agents in intensive care units.

Special precautions should be taken in patients with known anaphylactic reactions to curares, as cross-reactivity may be possible with this product.

As with other non-depolarising neuromuscular blocking agents, the magnitude and/or duration of atracurium’s effects may be increased as a result of an interaction with the following agents.

Inhalation anaesthetics: atracurium is potentiated by isoflurane, desflurane, sevoflurane and enflurane anaesthesia, and only marginally potentiated by halothane anaesthesia.

Antibiotics: including the aminoglycosides, polymyxins, spectinomycin, tetracyclines, lincomycin, clindamycin and vancomycin.

Anticonvulsants (acute administration only): phenytoin, carbamazepine.

Antiarrhythmic drugs: local anaesthetics such as lidocaine, procainamide, quinidine.

Beta-blockers: propranolol, oxprenolol

Antirheumatic drugs: chloroquine, d-penicillamine

Calcium channel blockers: diltiazem, nicardipine, nifedipine, verapamil.

Diuretics: frusemide, thiazides, acetazolamide and possibly mannitol.

Ganglion blocking agents: trimetaphan, hexamethonium.

Others: dantrolene, parenteral magnesium sulphate, chlorpromazine, steroids, ketamine, lithium salts and quinine.

Rarely, some of the above drugs may aggravate or unmask latent myasthenia gravis or actually induce a myasthenic syndrome. In these situations a consequent increased sensitivity to atracurium would be expected.

The administration of combinations of non-depolarising neuromuscular blocking agents in conjunction with atracurium may produce a degree of neuromuscular blockade in excess of that which might be expected were an equipotent total dose of atracurium administered. Any synergistic effect may vary between different drug combinations.

A depolarising muscle relaxant such as suxamethonium chloride should not be administered to prolong the neuromuscular blocking effects of non-depolarising blocking agents such as atracurium, as this may result in a prolonged and complex block which can be difficult to reverse with anticholinesterase drugs.

The prior use of suxamethonium reduces the onset (to maximum blockade) by approximately 2 to 3 minutes and may increase the depth of neuromuscular blockade induced by atracurium. Therefore, the initial atracurium dose should be reduced and the reduced dose should not be administered until the patient has recovered from the neuromuscular blocking effects of suxamethonium.

The use of intravenous corticosteroids with neuromuscular blocking agents has been reported to antagonise neuromuscular blockades. In addition, prolonged co-administration of these agents may increase the risk and/or severity of myopathy resulting in prolonged flaccid paralysis following discontinuation of the neuromuscular blocking agent. The myopathy is usually reversible with recovery in several months.

The onset of neuromuscular blockade is likely to be lengthened and the duration of blockade shortened in patients receiving chronic anticonvulsant therapy (e.g. carbamazepine, phenytoin). However, if the anticonvulsants are given acutely, the neuromuscular blocking effects may be increased.

In principle, maintaining neuromuscular monitoring until complete reversal of neuromuscular blockade should permit detection of most interactions. Nevertheless, recurrence of neuromuscular blockade may occur, for example, upon treatment with post surgical antibiotics.

Fertility

No fertility data are available.

Pregnancy

Atracurium crosses the placenta but there have been no demonstrated adverse effects in the foetus or newborn infant. Animal studies have indicated that atracurium has no adverse effects on foetal development. As with all neuromuscular blocking agents, the use of atracurium in the first three months of pregnancy should be avoided and it should not be used during the second and third trimesters unless clearly necessary.

Atracurium is suitable for maintenance of muscle relaxation during caesarean section as it does not cross the placenta in clinically significant amounts following recommended doses. In an open study, atracurium besilate (0.3 mg/kg) was administered to 26 pregnant women during delivery by caesarean section. No harmful effects were attributable to atracurium in any of the newborn infants, although small amounts of atracurium were shown to cross the placental barrier. The possibility of respiratory depression in the newborn infant should always be considered following caesarean section during which a neuromuscular blocking agent has been administered.

Anaesthesia during the third trimester of pregnancy exposes the mother to Mendelson syndrome (acid pneumopathy due to gastric acid aspiration). If a muscle relaxant is used at induction of anaesthesia, one should be chosen with a short onset and duration of action and low placental transfer and used in the lowest dose required to induce adequate neuromuscular relaxation. In patients receiving magnesium sulphate, the reversal of neuromuscular blockade may be unsatisfactory and the atracurium dose should be lowered as indicated.

Breastfeeding

Atracurium has a relatively high molecular weight and is highly ionized at physiologic pH, both factors that markedly reduce transfer into milk. In addition, even though milk is slightly more acidic than plasma, any atracurium transferred into milk would be rapidly degraded. Nevertheless, in view of the potential respiratory depressant effect on the neonate, especially if premature, it is recommended that if breastfeeding is started within 24 hours after administration of atracurium, the neonate is closely monitored.

It is not recommended to use potentially dangerous machinery or drive a car within 24 hours after full recovery from the neuromuscular blocking action of atracurium.

The adverse effects are reported in decreasing order of frequency within each system order class (SOC).

As with most neuromuscular blocking agents, the potential exists for undesirable effects suggestive of histamine release in susceptible patients. In clinical trials (875 patients) reports of skin flushing ranged from 1% at doses up to 0.3 mg/kg, to 29% at doses of 0.6 mg/kg or greater. The incidence of transient hypotension ranged from 1 to 14% respectively for the corresponding dosages.

Table for frequency of adverse reactions for Atracurium Besilate 10 mg/ml Solution for injection:

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), Not known (cannot be estimated from the available data).

Cardiac disorders

Common: Tachycardia, bradycardia (observed in 1% of patients)

Rare: Severe allergic reactions (e.g. shock, cardiac failure, cardiac arrest)

General disorders and administration site condition

Common: Reaction at injection site

Immune system disorders

Very rare: Allergic reactions (i.e. anaphylactic or anaphylactoid responses) Anaphylactoid reactions

Injury, poisoning and procedural complications

Not known: Prolonged block

Respiratory, thoracic and mediastinal disorders

Common: Wheezing

Uncommon: Broncospasm (0.2% of patients)

Rare: Dysponea, laryngospasm

Very rare: Hypoxemia

Not known: Bronchial secretions

Skin and subcutaneous tissue disorders

Common: Localized skin reactions, rash, itching

Uncommon: Generalized Erythema, Hives

Rare: Angioneurotic oedema, utricaria

Nervous system disorders

Not known: Inadequate block

Vascular disorders

Common: Hypertension (observed in approximately 1% of patients), Hypotension, vasodilatation (flushing)-each occurred in approximately 2-3% of patients)

After prolonged administration of atracurium besilate in severely ill patients under intensive care, some incidences of muscle weakness and/or myopathy occurred. Most patients were concomitantly treated with corticosteroids. A causal relationship with atracurium therapy has not been established.

There have been rare reports of seizures in ICU patients who have been receiving atracurium concurrently with several other agents. These patients usually had one or more medical conditions predisposing to seizures (e.g. cranial trauma, cerebral oedema, viral encephalitis, hypoxic encephalopathy, uraemia). In clinical trials, there appears to be no correlation between plasma laudanosine concentration and the occurrence of seizures.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Malta, ADR Reporting, Website: www.medicinesauthority.gov.mt/adrportal, UK, Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.

Atracurium Besilate Solution for Injection has an acid pH and therefore should not be mixed with alkaline solutions (e.g. barbiturate solutions) in the same syringe or administered simultaneously during intravenous infusion through the same needle.