MIVACRON Liquid for injection Ref.[9356] Active ingredients:

In common with all the other neuromuscular blocking agents, Mivacron paralyses the respiratory muscles as well as the other skeletal muscles but has no effect on consciousness. Mivacron should be administered only by or under close supervision of an experienced anaesthetist with adequate facilities for endotracheal intubation and artificial ventilation.

Prolonged and intensified neuromuscular blockade following mivacurium may occur secondary to reduced plasma cholinesterase activity in the following states or pathological conditions:

• Physiological variation as in pregnancy and the puerperium (see Pregnancy and Lactation).
• Genetically determined abnormalities of plasma cholinesterase (see below and Contraindications).
• Severe generalised tetanus, tuberculosis and other severe or chronic infections.
• Chronic debilitating disease, malignancy, chronic anaemia and malnutrition.
• Myxoedema and collagen diseases.
• Decompensated heart disease.
• Peptic ulcer.
• Burns (see below).
• End-stage hepatic failure, (see Dosage and Administration).
• Acute, chronic or end-stage renal failure (see Dosage and Administration).
• Iatrogenic: following plasma exchange, plasmapheresis, cardiopulmonary bypass, and as a result of concomitant drug therapy (see Interactions).

In common with suxamethonium/succinylcholine, adult and paediatric patients homozygous for the atypical plasma cholinesterase gene (1 in 2500 patients) are extremely sensitive to the neuromuscular blocking effect of Mivacurium. In three such adults patients, a small dose of 0.03 mg/kg (approximately the ED10-20 in genotypically normal patients) produced complete neuromuscular block for 26 to 128 minutes.

In patients heterozygous for the atypical plasma cholinesterase gene, the clinically effective duration of block of mivacurium 0.15 mg/kg is approximately 10 min longer than in control patients.

Once spontaneous recovery had begun, neuromuscular block in these patients was antagonised with conventional doses of neostigmine.

Patients with burns may develop resistance to non-depolarising neuromuscular blocking agents and require increased doses. However such patients may also have reduced plasma cholinesterase activity, requiring dose reduction.

Consequently burn patients should be given a test dose of 0.015-0.020 mg/kg Mivacron followed by appropriate dosing guided by monitoring of block with a nerve stimulator.

Caution should be exercised in administering Mivacron to patients with a history suggestive of an increased sensitivity to the effects of histamine e.g. asthma. If Mivacron is used in this group of patients it should be administered over 60 seconds.

High rates of cross-sensitivity (greater than 50%) between neuromuscular blocking agents have been reported. Therefore, where possible, before administering mivacurium, hypersensitivity to other neuromuscular blocking agents should be excluded. Mivacurium should only be used when absolutely essential in susceptible patients. Patients who experience a hypersensitivity reaction under general anaesthesia should be tested subsequently for hypersensitivity to other neuromuscular blockers.

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

In adults, doses of Mivacron ≥0.2 mg/kg (≥3 x ED95) have been associated with histamine release when administered by rapid bolus injection. However, the slower administration of the 0.2 mg/kg Mivacron dose and the divided administration of the 0.25 mg/kg Mivacron dose minimised the cardiovascular effects of these doses. Cardiovascular safety did not appear to be compromised in children given a rapid bolus dose of 0.2 mg/kg in clinical studies.

The use in neonates and infants <2 months is not recommended due to limited data. (see also section 4.2 and 5.1)

Mivacron does not have significant vagal or ganglion blocking properties in the recommended dosage range. Recommended doses of Mivacron consequently have no clinically significant effects on heart rate and will not counteract the bradycardia produced by many anaesthetic agents or by vagal stimulation during surgery.

In common with other non-depolarising neuromuscular blocking agents, increased sensitivity to mivacurium can be expected in patients with Myasthenia Gravis, other forms of neuromuscular disease and cachectic patients. Severe acid base or electrolyte abnormalities may increase or reduce sensitivity to mivacurium.

Mivacron solution is acidic (approximately pH 4.5) and should not be mixed in the same syringe or administered simultaneously through the same needle as highly alkaline solutions (e.g. barbiturate solutions). It has been shown to be compatible with some commonly used peri-operative drugs supplied as acidic solutions e.g. fentanyl, alfentanil, sufentanil, droperidol and midazolam. Where other anaesthetic agents are administered through the same indwelling needle or cannula as used for Mivacron, and compatibility has not been demonstrated, it is recommended that each drug is flushed through with physiological saline.

Studies in malignant hyperthermia-susceptible pigs, indicated that Mivacron does not trigger this syndrome. Mivacron has not been studied in malignant hyperthermia-susceptible patients.

No data are available on the long-term use of Mivacron in patients undergoing mechanical ventilation in the intensive care unit.

Reversal of Neuromuscular Block: as with other neuromuscular blocking agents, evidence of spontaneous recovery should be observed prior to administration of reversal agent (e.g. neostigmine). The use of a peripheral nerve stimulator to evaluate recovery prior to and following reversal of neuromuscular block is strongly recommended.

Pharmaceutical Precautions – see section 6.2 Incompatibilities and section 6.4 Special precautions for disposal and other handling.

The neuromuscular block produced by Mivacron may be increased by the concomitant use of inhalational anaesthetics such as enflurane, isoflurane, sevoflurane and halothane.

Mivacron has been safely administered following succinylcholine facilitated intubation. Evidence of spontaneous recovery from succinylcholine should be observed prior to administration of Mivacron.

In common with all non-depolarising neuromuscular blocking agents, the magnitude and/or duration of non-depolarising neuromuscular block may be increased and infusion requirements may be reduced as a result of interaction with;

• antibiotics, including the aminoglycosides, polymyxins, spectinomycin, tetracyclines, lincomycin and clindamycin
• anti-arrhythmic drugs: propranolol, calcium channel blockers, lidocaine procainamide and quinidine
• diuretics: furosemide and possibly thiazides, mannitol and acetazolamide
• magnesium salts
• ketamine
• lithium salts
• ganglion blocking drugs: trimetaphan, hexamethonium

Drugs that may reduce plasma cholinesterase activity may also prolong the neuromuscular blocking action of Mivacron. These include anti-mitotic drugs, monoamine oxidase inhibitors, ecothiophate iodine, pancuronium, organophosphates, anticholinesterases, certain hormones, bambuterol and selective serotonin reuptake inhibitors.

Rarely, certain drugs may aggravate or unmask latent Myasthenia Gravis or actually induce a Myasthenic syndrome: increased sensitivity to Mivacron would be consequent on such a development. Such drugs include various antibiotics, beta-blockers (propranolol, oxprenolol), antiarrhythmic drugs (procainamide, quinidine), antirheumatic drugs (chloroquine, D-pencillamine), trimetaphan, chlorpromazine, steroids, phenytoin and lithium.

The administration of combinations of non-depolarising neuromuscular blocking agents in conjunction with Mivacron may produce a degree of neuromuscular blockade in excess of that which might be expected from an equipotent total dose of Mivacron. 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 agents, as this may result in a prolonged and complex block which can be difficult to reverse with anticholinesterase drugs.

Fertility studies have not been performed.

Animal studies have indicated that mivacurium has no adverse effect on foetal development. Mivacurium should not be used during pregnancy unless the expected clinical benefit to the mother outweighs any potential risk to the foetus.

Plasma cholinesterase levels decrease during pregnancy. Mivacurium has been used to maintain neuromuscular block during Caesarean section, but due to the reduced levels of plasma cholinesterase, dosage adjustments to the infusion rate were necessary. A further reduction in the infusion rate may also be required during Caesarean section in patients pre-treated with magnesium sulfate, due to the potentiating effects of magnesium.

It is not known whether mivacurium is excreted in human milk.

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

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000) and very rare (<1/10,000) including isolated reports.

Immune disorders

Very rare: Severe anaphylactic or anaphylactoid reaction. Severe anaphylactic or anaphylactoid reactions have been reported in patients receiving mivacurium chloride in conjunction with one or more anaesthetic agents.

Cardiac disorders

Uncommon: Transient tachycardia*

Vascular disorders

Very common: Flushing*

Uncommon: Hypotension*

Respiratory, thoracic and mediastinal disorders

Uncommon: Bronchospasm*

Skin and subcutaneous tissue disorders

Uncommon: Erythema*, urticaria*

* Associated with the use of Mivacron there have been reports of skin flushing, erythema, urticaria, hypotension, transient tachycardia or bronchospasm which have been attributed to histamine release. These effects are dose related and more common following initial doses of ≥0.2 mg/kg or more when given rapidly and are reduced if Mivacron is injected over 30 to 60 seconds or in divided doses over 30 seconds.

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.

Mivacurium is acidic (approximately pH 4.5) and should not be mixed with highly alkaline solutions, e.g. barbiturates.