Mivacron (Solution) Instructions for Use

Marketing Authorization Holder

GlaxoSmithKline, S.p.A. (Italy)

ATC Code

M03AC10 (Mivacurium chloride)

Active Substance

Mivacurium chloride (Rec.INN registered by WHO)

Dosage Forms

	Mivacron	Solution for intravenous administration 10 mg/5 ml: amp. 5 pcs.
		Solution for intravenous administration 20 mg/10 ml: amp. 5 pcs.

Dosage Form, Packaging, and Composition

Solution for intravenous administration clear, free from inclusions.

Excipients: hydrochloric acid, water for injections; does not contain preservatives.

5 ml – ampoules (5) – carton packs.

Solution for intravenous administration clear, free from inclusions.

Excipients: hydrochloric acid, water for injections; does not contain preservatives.

10 ml – ampoules (5) – carton packs.

Clinical-Pharmacological Group

Peripherally acting non-depolarizing competitive-type muscle relaxant

Pharmacotherapeutic Group

Peripherally acting muscle relaxant

Pharmacological Action

Non-depolarizing peripherally acting competitive-type muscle relaxant. It inhibits neuromuscular transmission by blocking skeletal muscle nicotinic cholinergic receptors and eliminating the depolarizing action of the neurotransmitter acetylcholine.

Mivacurium chloride is a mixture of three stereoisomers. The trans-trans and cis-trans stereoisomers constitute 92-96% of mivacurium chloride and have been shown in experimental studies to differ little from each other and from mivacurium chloride in their ability to cause neuromuscular blockade.

The efficacy of the cis-cis stereoisomer is 10 times less than that of the two stereoisomers mentioned above.

The drug has a short duration of action.

Pharmacokinetics

Mivacurium chloride is metabolized by enzymatic hydrolysis under the action of plasma cholinesterase to form two metabolites – an alcohol (1/4 part) and a monoester (1/4 part). Experimental studies have revealed that the metabolites do not have a significant effect on neuromuscular conduction and the cardiovascular system, and do not possess intrinsic activity at concentrations higher than those used in humans.

Cessation of neuromuscular blockade after drug administration is primarily associated with the hydrolysis of mivacurium chloride by pseudocholinesterase, which is present in high concentrations in human plasma.

Apparently, there are various pathways for the breakdown/elimination of mivacurium chloride (e.g., hydrolysis by liver esterases, biliary excretion, renal excretion).

Indications

• For skeletal muscle relaxation to facilitate tracheal intubation and to maintain myoplegia during artificial ventilation in surgical operations.

ICD codes

Dosage Regimen

Mivacron is intended for intravenous administration only.

When using Mivacron (like other muscle relaxants), it is necessary to regularly monitor neuromuscular conduction to determine the individual patient’s need for the drug.

Adults

Bolus administration. During general anesthesia, the average dose required for 95% suppression of the abductor pollicis muscle response to ulnar nerve stimulation (ED₉₅) is 70 mcg/kg (ranging from 60 mcg/kg to 90 mcg/kg).

Recommended regimens for tracheal intubation

1. Mivacron is administered at a dose of 200 mcg/kg over 30 seconds. Optimal conditions for tracheal intubation occur 2-2.5 minutes after drug administration.
2. According to another regimen, Mivacron is administered at a dose of 250 mcg/kg in divided doses (150 mcg/kg and 100 mcg/kg with a 30-second interval). Optimal conditions for tracheal intubation are noted 1.5-2 minutes after the first dose administration.

For bolus administration of Mivacron, the recommended doses are 70-250 mcg/kg. The duration of neuromuscular blockade depends on the drug dose. When administered at doses of 70 mcg/kg, 150 mcg/kg, 200 mcg/kg, and 250 mcg/kg, the duration of neuromuscular blockade was 13, 16, 20, and 23 minutes, respectively. Mivacron at doses up to 150 mcg/kg can be administered over 5-15 seconds; at higher doses, it should be administered over 30 seconds to avoid the development of cardiovascular system reactions.

Maintenance of myoplegia and extension of the muscle relaxation period can be achieved by administering maintenance doses of Mivacron. Thus, additional administration of the drug during general anesthesia at a dose of 100 mcg/kg increases the duration of neuromuscular blockade by approximately 15 minutes. Additional doses of Mivacron do not enhance its effect.

Isoflurane and enflurane may enhance the effect of mivacurium chloride, and its initial dose should therefore be reduced by 25%.

Halothane slightly potentiates the effect of mivacurium, so when both drugs are used simultaneously, a reduction in the Mivacron dose is not required.

Spontaneous recovery of neuromuscular conduction is completed within 15 minutes and does not depend on the administered dose.

Mivacron-induced myoplegia can be reversed by administering anticholinesterase drugs in standard doses. Since the period of spontaneous recovery of neuromuscular conduction after Mivacron administration is short, there is probably no need for routine administration of anticholinesterase agents, as they reduce recovery time by only 5-6 minutes.

In elderly patients, with a single bolus administration of Mivacron, the onset, duration of drug action, and rate of spontaneous recovery may increase by 20-30% compared to younger patients. Elderly patients may require a dose reduction, decreased frequency of administration, and reduced infusion rate of the drug.

Infusion administration. For maintenance of neuromuscular blockade, Mivacron can be administered by continuous infusion. Upon the appearance of early signs of spontaneous recovery of neuromuscular conduction after the initial dose of Mivacron, an infusion rate of 8-10 mcg/kg/min (500-600 mcg/kg/h) is recommended. The initial infusion rate is determined by the patient’s response to peripheral nerve stimulation and clinical criteria.

The infusion rate can be increased by 1 mcg/kg/min (60 mcg/kg/h), but it should be maintained at the previous level for at least 3 minutes before the next change.

On average, infusion of Mivacron at a rate of 6-7 mcg/kg/min maintains neuromuscular blockade at 89-99% for a long time. During the stable phase of general anesthesia using isoflurane or enflurane after reaching steady-state parameters, the dose of mivacurium chloride is reduced by 40%, and when using sevoflurane – by 50%. With halothane anesthesia, a smaller reduction in the infusion rate of mivacurium chloride may be required. The time to onset of spontaneous recovery of neuromuscular conduction does not depend on the duration of Mivacron infusion and is comparable to that with bolus administration of the drug.

Continuous infusion was not accompanied by the development of tachyphylaxis or cumulative drug effects.

Children aged 7 months to 12 years

Compared to adults, children aged 7 months to 12 years have a higher ED₉₅ of Mivacron (approximately 100 mcg/kg), the drug’s effect develops faster, its duration of action is less prolonged, and the time for spontaneous recovery of neuromuscular conduction is shorter.

Bolus administration. The recommended dose is 100-200 mcg/kg; the drug is administered over 5-15 seconds. In the stable phase of general anesthesia using narcotic drugs or halothane, administration of Mivacron at a dose of 200 mcg/kg (after reaching steady-state parameters) provides effective muscle relaxation for an average of 9 minutes, and a maintenance dose of 100 mcg/kg increases its duration by 6-9 minutes. Maximum neuromuscular blockade and optimal conditions for tracheal intubation are achieved within 2 minutes after administration of Mivacron at this dose. Maintenance doses should be administered more frequently to children than to adult patients.

Infusion administration. Children usually require a higher administration rate of Mivacron than adult patients.

During general anesthesia with halothane, the average infusion rate of Mivacron required to maintain neuromuscular blockade at 89-99% is

Spontaneous recovery of neuromuscular conduction is completed in approximately 10 minutes.

Inhalation anesthetics enhance the effect of mivacurium chloride.

In children aged 2-12 years during general anesthesia with sevoflurane, a 70% reduction in the dose of mivacurium chloride is recommended.

Children aged 2 to 6 months

Children aged 2 to 6 months have the same ED₉₅ as adults (70 mcg/kg), but the drug’s effect develops faster, its duration of action is less prolonged, and the time for spontaneous recovery of neuromuscular conduction is shorter.

Bolus administration. The recommended dose is 100-150 mcg/kg; the drug is administered over 5-15 seconds. During general anesthesia with halothane, administration of Mivacron at a dose of 150 mcg/kg provides effective muscle relaxation for an average of 9 minutes. Maximum neuromuscular blockade and optimal conditions for tracheal intubation are noted approximately 1.4 minutes after administration of Mivacron at this dose.

Maintenance doses should be administered more frequently to children than to adult patients. During general anesthesia with halothane, administration of a maintenance dose of Mivacron 100 mcg/kg prolongs effective neuromuscular blockade by approximately 7 minutes.

Infusion administration. Children aged 2 to 6 months usually require a higher administration rate of Mivacron than adult patients.

During general anesthesia with halothane in children aged 2 to 6 months, the average infusion rate of Mivacron required to maintain neuromuscular blockade at 89-99% is about 11 mcg/kg/min or 700 mcg/kg/h (4-24 mcg/kg/min, or 0.2-1.5 mg/kg/h).

Spontaneous recovery of neuromuscular conduction is completed in approximately 10 minutes.

Newborns and children under 2 months of age

Available data are insufficient to formulate recommendations for the use of the drug in patients of this age group.

In patients with severe cardiovascular disease, the initial dose of Mivacron must be administered slowly, over 60 seconds, as in this case the drug has minimal impact on hemodynamic parameters during cardiac surgery.

In end-stage renal failure, the duration of neuromuscular blockade with Mivacron administration at a dose of 150 mcg/kg increases by 1.5 times compared to that with preserved renal function. The dose should be adjusted according to the individual patient’s response.

In end-stage hepatic failure, the duration of neuromuscular blockade with Mivacron administration at a dose of 150 mcg/kg increases approximately 3 times compared to that with normal liver function, which is due to a significant decrease in plasma cholinesterase activity in this pathology. The dose should be adjusted according to the individual patient’s response.

With reduced plasma cholinesterase activity, the duration of Mivacron-induced neuromuscular blockade may increase. A slight decrease in plasma cholinesterase activity (within 20% of the lower limit of normal) does not lead to a clinically significant change in the duration of neuromuscular blockade. In patients heterozygous for the atypical cholinesterase gene, the duration of effective blockade after Mivacron administration at a dose of 150 mcg/kg is 10 minutes longer than in the control group.

In obesity (exceeding ideal body weight for a given height by 30% or more), the initial dose of Mivacron should be calculated based on ideal, not actual, body weight.

Rules for preparation of injection solution

Mivacron solution for intravenous administration can be used for infusions undiluted or after dilution with the following infusion solutions: sodium chloride solution for intravenous infusion 0.9%, glucose solution for intravenous infusion 5%, sodium chloride 0.18% and glucose 4% solution for intravenous infusion, Ringer’s lactate solution for injection. If the Mivacron solution for intravenous administration is diluted with one of the listed solutions in a ratio of 1:3 (to obtain a Mivacron concentration of 500 mcg/ml), the prepared solution remains stable for at least 48 hours at a temperature of 30°C (86°F).

The Mivacron solution does not contain preservatives, so the drug should be diluted immediately before administration, administered under aseptic conditions, and the unused solution in an opened ampoule should be discarded.

Adverse Reactions

Allergic reactions ≥0.1% and <1% – erythema, urticaria; <0.01% – severe anaphylactic and anaphylactoid reactions (when Mivacron is used in combination with other anesthetic drugs).

Cardiovascular system ≥10% – flushing; ≥0.1% and <1% – transient tachycardia, arterial hypotension.

Respiratory system ≥0.1% and <1% – bronchospasm.

Adverse effects are mainly associated with histamine release, are dose-dependent, usually observed after rapid administration of the drug at an initial dose of 200 mcg/kg or more; these effects are reduced if the Mivacron injection is administered over 30-60 seconds or more than 30 seconds when the drug is administered in divided doses.

Contraindications

• Homozygosity for the atypical cholinesterase gene;
• Hypersensitivity to the drug.

Use in Pregnancy and Lactation

Mivacron should not be used during pregnancy, except in cases where the expected benefit of the drug for the mother outweighs the potential risk to the fetus.

Plasma cholinesterase levels decrease during pregnancy, so dose adjustment and infusion rate of Mivacron may be required to maintain neuromuscular blockade during cesarean section. A reduction in the infusion rate of Mivacron is also necessary in cases where magnesium sulfate was prescribed before cesarean section, as magnesium ions potentiate the effect of Mivacron.

It is currently unknown whether mivacurium is excreted in breast milk.

Geriatric Use

In elderly patients, with a single bolus administration of Mivacron, the onset, duration of drug action, and rate of spontaneous recovery may increase by 20-30% compared to younger patients. Elderly patients may require a dose reduction, decreased frequency of administration, and reduced infusion rate of the drug.

Special Precautions

Like other muscle relaxants, Mivacron causes paralysis of skeletal muscles, including respiratory muscles, but does not affect consciousness. Mivacron should be used by a qualified anesthesiologist and only in departments equipped with equipment for tracheal intubation and artificial ventilation.
Reduced plasma cholinesterase activity may be due to genetic abnormalities of this enzyme (e.g., in patients homozygous or heterozygous for the atypical plasma cholinesterase gene), various pathological conditions, and the use of certain drugs.
As with the use of suxamethonium/succinylcholine, patients homozygous for the atypical plasma cholinesterase gene are extremely sensitive to the action of mivacurium: in three adult patients, a small dose of Mivacron 30 mcg/kg (approximately equal to ED_10-20 in genotypically healthy patients) caused complete neuromuscular blockade for 26-128 minutes.
When signs of spontaneous recovery of neuromuscular conduction appeared, administration of a standard dose of neostigmine completely reversed the blockade.
Mivacron should be used with caution in patients with increased sensitivity to histamine (e.g., with bronchial asthma). In such cases, Mivacron should be administered over a period of more than 60 seconds. Patients prone to arterial hypotension, for example, with hypovolemia, are also recommended to receive Mivacron over more than 60 seconds. In adults, with rapid bolus administration of Mivacron at a dose of 200 mcg/kg (greater than or equal to 3 x ED₉₅), symptoms associated with histamine release were observed. However, with slow administration of Mivacron at the same dose or divided administration at a dose of 250 mcg/kg, adverse cardiovascular reactions are significantly reduced. During clinical trials in children, Mivacron at a dose of 200 mcg/kg with rapid bolus administration did not affect the cardiovascular system.
When prescribed in the recommended dose range, Mivacron does not block the vagus nerve and nerve ganglia, does not significantly affect heart rate, and does not prevent bradycardia caused by anesthetics or vagus nerve stimulation during surgery.
Mivacron solution has an acidic reaction (pH about 4.5), and it should not be mixed in the same syringe or administered simultaneously through the same needle with highly alkaline solutions (e.g., barbiturate solutions). It is compatible with many acidic solutions commonly used during surgery, such as fentanyl, alfentanil, sufentanil, droperidol, and midazolam. If Mivacron and other anesthetics incompatible with it are administered through the same needle or cannula, it is recommended to flush the needle or cannula with saline after each drug.
In patients with myasthenia gravis or other neuromuscular diseases, as well as with cachexia, as with the use of other non-depolarizing muscle relaxants, increased sensitivity to mivacurium may be observed.
In burn patients, resistance to non-depolarizing muscle relaxants may develop, and therefore increased doses of these drugs may be required. On the other hand, patients in this group may also have reduced plasma cholinesterase activity, which in turn will require a reduction in the dose of non-depolarizing muscle relaxants. Therefore, burn patients are first prescribed a test dose of Mivacron 15-20 mcg/kg, then the required dose is administered under the control of peripheral nerve stimulation.
There are no data on the use of Mivacron in patients on long-term artificial ventilation in intensive care units.
Reversibility of neuromuscular blockade. Signs of spontaneous recovery of neuromuscular conduction after Mivacron administration should be observed before administering drugs that restore it (e.g., neostigmine).
The use of peripheral nerve stimulators is strongly recommended to assess the degree of conduction recovery before and after the administration of such drugs.

Overdose

Symptoms prolonged muscle paralysis and its consequences, increased risk of hemodynamic disturbances, especially arterial hypotension.

Treatment immediate securing of the airway and application of artificial ventilation until spontaneous breathing is restored.

Sedative drugs are necessary since patients’ consciousness is not impaired.

If spontaneous recovery of neuromuscular conduction has begun, it can be accelerated with anticholinesterase drugs in combination with atropine or glycopyrrolate. Maintaining cardiovascular function can be achieved by a specific patient position, or, if necessary, by administration of solutions or vasopressor drugs.

Drug Interactions

When Mivacron is used concomitantly with inhalation anesthesia agents (including enflurane, isoflurane, sevoflurane, and halothane), an enhancement of the neuromuscular blockade is observed.

No complications were observed when Mivacron was administered after succinylcholine, which was prescribed to facilitate tracheal intubation. It should be borne in mind that signs of spontaneous recovery of neuromuscular conduction blocked by the action of succinylcholine must appear before the administration of Mivacron.

The degree and/or duration of neuromuscular conduction blockade caused by non-depolarizing muscle relaxants (including Mivacron) may increase when they interact with the following drugs: antibiotics (aminoglycosides, polymyxins, spectinomycins, tetracyclines, lincomycin, and clindamycin); antiarrhythmics (propranolol, calcium channel blockers, lidocaine, procainamide, and quinidine); diuretics (furosemide and, possibly, thiazide diuretics, mannitol, acetazolamide); magnesium salts; ketamine; lithium salts; ganglion blockers (trimethaphan, hexamethonium).

Agents that cause a decrease in plasma cholinesterase activity may increase the duration of the neuromuscular blockade induced by Mivacron. These include antifungal agents, anticholinesterase drugs, MAO inhibitors, ecothiopate iodide, pancuronium, organic phosphates, certain hormones, bambuterol.

In rare cases, the following drugs cause exacerbation of myasthenia, development of myasthenic syndrome, and manifestation of latent myasthenia, which is accompanied by increased sensitivity to Mivacron: some antibiotics; beta-blockers (propranolol, oxprenolol); antiarrhythmics (procainamide, quinidine); antirheumatic agents (chloroquine, D-penicillamine); trimethaphan; chlorpromazine; steroids; phenytoin; lithium preparations.

Concomitant use of non-depolarizing muscle relaxants and Mivacron may cause a more profound neuromuscular blockade than expected from the administration of Mivacron alone in an equivalent total dose. The degree of synergism varies depending on the drug combination.

The depolarizing muscle relaxant succinylcholine chloride should not be prescribed to prolong the duration of action of non-depolarizing muscle relaxants, as this may cause a prolonged blockade that is difficult to reverse with anticholinesterase drugs.

Storage Conditions

The drug should be stored in a light-protected place, out of the reach of children, at a temperature below 25°C (77°F); do not freeze.

Shelf Life

Shelf life – 1.5 years.

Dispensing Conditions

The drug is dispensed by prescription.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.