CISATRACURIUM Solution for injection/infusion Ref.[6709] Active ingredients: Cisatracurium

Cisatracurium paralyses the respiratory muscles as well as other skeletal muscles but has no known effect on consciousness or pain threshold. Cisatracurium should be only administered by or under the supervision of anaesthetists or other clinicians who are familiar with the use and action of neuromuscular blocking agents. Facilities for tracheal intubation and maintenance of pulmonary ventilation and adequate arterial oxygenation have to be available.

Severe anaphylactic reactions to neuromuscular blocking agents have been reported. These reactions have, in some cases, been life threatening and fatal. Due to the potential severity of these reactions, the necessary precautions, such as the immediate availability of appropriate emergency treatment, should be taken. Precautions should also be taken in those patients who have had previous anaphylactic reactions to other neuromuscular blocking agents, since cross- reactivity between neuromuscular blocking agents, both depolarizing and non-depolarizing, has been reported (see section 4.3).

Cisatracurium does not have significant vagolytic or ganglion- blocking properties. Consequently, there is no clinically significant effect on heart rate and will not counteract the bradycardia produced by many anaesthetic agents or by vagal stimulation during surgery.

Patients with myasthenia gravis and other forms of neuromuscular disease have shown greatly increased sensitivity to non-depolarising blocking agents. An initial dose of not more than 0.02 mg/kg is recommended in these patients.

Severe acid-base and/or serum electrolyte abnormalities may increase or decrease the sensitivity of patients to neuromuscular blocking agents.

There is no information on the use of this medicinal product in neonates aged less than one month since it has not been studied in this patient population.

Cisatracurium has not been studied in patients with a history of malignant hyperthermia. Studies in malignant hyperthermia- susceptible pigs indicated that cisatracurium does not trigger this syndrome.

There have been no studies of cisatracurium in patients undergoing surgery with induced hypothermia (25 to 28°C). As with other neuromuscular blocking agents the rate of infusion required to maintain adequate surgical relaxation under these conditions may be expected to be significantly reduced.

Cisatracurium has not been studied in patients with burns; however, as with other non-depolarising neuromuscular blocking agents, the possibility of increased dosing requirements and shortened duration of action must be considered if cisatracurium injection is administered to these patients.

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

Intensive Care Unit (ICU) Patients

When administered to laboratory animals in high doses, laudanosine, a metabolite of cisatracurium and atracurium, has been associated with transient hypotension and in some species, cerebral excitatory effects. In the most sensitive animal species, these effects occurred at laudanosine plasma concentrations similar to those that have been observed in some ICU patients following prolonged infusion of atracurium.

Consistent with the decreased infusion rate requirements of cisatracurium, plasma laudanosine concentrations are approximately one third those following atracurium infusion.

There have been rare reports of seizures in ICU patients who have received atracurium and other agents. These patients usually had one or more medical conditions predisposing to seizures (e.g. cranial trauma, hypoxic encephalopathy, cerebral oedema, viral encephalitis, uraemia). A causal relationship to laudanosine has not been established.

Many drugs have been shown to influence the magnitude and/or duration of action of non-depolarising neuromuscular blocking agents, including the following:

Increased Effect

By anaesthetic agents such as enflurane, isoflurane, halothane (see section 4.2) and ketamine, by other non- depolarising neuromuscular blocking agents or by other drugs such as antibiotics (including the aminoglycosides, polymyxins, spectinomycin, tetracyclines, lincomycin and clindamycin), anti- arrhythmic drugs (including propranolol, calcium channel blockers, lignocaine, procainamide and quinidine), diuretics, (including frusemide and possibly thiazides, mannitol and acetazolamide), magnesium and lithium salts and ganglion blocking drugs (trimetaphan, hexamethonium).

A decreased effect is seen after prior chronic administration of phenytoin or carbamazepine.

Prior administration of suxamethonium has no effect on the duration of neuromuscular block following bolus doses of cisatracurium or on infusion rate requirements.

Administration of suxamethonium to prolong the effects of non- depolarising neuromuscular blocking agents may result in a prolonged and complex block which can be difficult to reverse with anticholinesterases.

Rarely, certain drugs may aggravate or unmask latent myasthenia gravis or actually induce a myasthenic syndrome; increased sensitivity to non-depolarising neuromuscular blocking agents might result. Such drugs include various antibiotics, b-blockers (propranolol, oxprenolol), anti-arrhythmic drugs (procainamide, quinidine), anti-rheumatic drugs (chloroquine, D-penicillamine), trimetaphan, chlorpromazine, steroids, phenytoin and lithium.

Treatment with anticholinesterases, commonly used in the treatment of Alzheimer’s disease e.g. donepezil, may shorten the duration and diminish the magnitude of neuromuscular blockade with cisatracurium.

Pregnancy

There is insufficient data on the use of cisatracurium in pregnant women. Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition and postnatal development (see section 5.3). The potential risk for humans is unknown.

Cisatracurium should not be used during pregnancy.

Breast-feeding

It is not known whether cisatracurium or its metabolites are excreted in human milk. A risk to the breast-feeding child cannot be excluded. Due to the short half-life, an influence on the breast-feeding child is not to be expected if the mother restarts breast-feeding after the effects of the substance have worn off. As a precaution breast-feeding should be discontinued during treatment and for at least 12 hours after administration of this medicinal product.

Fertility

Fertility data are not available

This precaution is not relevant to the use of cisatracurium. This medicinal product will always be used in combination with a general anaesthetic and therefore the usual precautions relating to performance of tasks following general anaesthesia apply.

Data from pooled internal clinical trials were used to determine the frequency of very common to uncommon adverse reactions.

Within each system organ class, the adverse drug reactions are ranked under the headings of reporting frequency, using the following convention:

Very common (1/10)
Common (1/100 to <1/10)
Uncommon (1/1,000 to <1/100)
Rare (1/10,000 to <1/1,000) Very rare (<1/10,000)
Not known (cannot be estimated from the available data)

Cardiac disorders

Common: Bradycardia

Immune system disorders

Very rare: Anaphylactic reaction

Musculoskeletal and connective tissue disorders

Very rare: Myopathy, Muscle weakness

Respiratory, thoracic and mediastinal disorders

Uncommon: Bronchospasm

Skin and subcutaneous disorders

Uncommon: Rash

Vascular disorders

Common: Hypotension

Uncommon: Cutaneous flushing

Anaphylactic reactions of varying degrees of severity have been observed after the administration of neuromuscular blocking agents. Very rarely, severe anaphylactic reactions have been reported in patients receiving cisatracurium in conjunction with one or more anaesthetic agents.

There have been some reports of muscle/weakness and/or myopathy following prolonged use of muscle relaxants in severely ill patients in the ICU. Most patients were receiving concomitant corticosteroids. These events have been reported infrequently in association with cisatracurium and a causal relationship has not been established.

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: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Since cisatracurium is stable only in acidic solutions it should not be mixed in the same syringe or administered simultaneously through the same needle with alkaline solutions, e.g. sodium thiopentone. It is not compatible with ketorolac, trometamol or propofol injectable emulsion.