NIMBEX Solution for injection / infusion Ref.[2659] Active ingredients: Cisatracurium

Product specific topics

Cisatracurium paralyses the respiratory muscles as well as other skeletal muscles but has no known effect on consciousness or pain threshold. Nimbex 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.

Caution should be exercised when administering Nimbex to patients who have shown hypersensitivity to other neuromuscular blocking agents since a high rate of cross-sensitivity (greater than 50%) between neuromuscular blocking agents has been reported (see section 4.3).

Cisatracurium does not have significant vagolytic or ganglion-blocking properties. Consequently, Nimbex has 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 Nimbex 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 Nimbex 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 Nimbex injection is administered to these patients.

Nimbex 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 (eg. 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, lidocaine, procainamide and quinidine), diuretics, (including furosemide and possibly thiazides, mannitol and acetazolamide), magnesium and lithium salts and ganglion blocking drugs (trimetaphan, hexamethonium).

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.

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.

Decreased effect:

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

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.

No effect:

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

Pregnancy

There are no adequate data from the use of Nimbex 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.

Nimbex should not be used during pregnancy.

Breastfeeding

It is not known whether cisatracurium or its metabolites are excreted in human milk.

A risk to the breastfed infant cannot be excluded. However, due to the short half-life, an influence on the breastfed infant 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 for at least five elimination half-lives of cisatracurium, i.e. for about 3 hours after the last dose or the end of infusion of cisatracurium.

Fertility

Fertility studies have not been performed.

This precaution is not relevant to the use of Nimbex. Nimbex 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.

The following convention has been used for the classification of frequency:- 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).

Clinical Trial Data:

Cardiac disorders

Common: Bradycardia

Vascular disorders

Common: Hypotension

Uncommon: Cutaneous flushing

Respiratory, thoracic and mediastinal disorders

Uncommon: Bronchospasm

Skin and subcutaneous tissue disorders

Uncommon: Rash

Postmarketing Data

Immune system disorders

Very rare: Anaphylactic reaction, Anaphylactic shock

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

Musculoskeletal and connective tissue disorders

Very rare: Myopathy, muscle weakness

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 Nimbex 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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Degradation of cisatracurium besilate has been demonstrated to occur more rapidly in lactated Ringer’s Injection and 5% Dextrose and lactated Ringer’s Injection than in the infusion fluids listed under Section 6.6.

Therefore it is recommended that lactated Ringer’s Injection and 5% Dectrose and lactated Ringer’s Injection are not used as the diluent in preparing solutions of Nimbex for infusion.

Since Nimbex 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.