Mivacron

Patient Information Leaflet: User Information

Mivacron, 2 mg/ml, Solution for Injection

Mivacurium Chloride

Read the leaflet carefully before using the medicine, as it contains important information for the patient.

• Keep this leaflet, you may need to read it again.
• In case of any doubts, consult a doctor.
• This medicine has been prescribed specifically for you. Do not pass it on to others. The medicine may harm another person, even if their symptoms are the same.
• If the patient experiences any side effects, including any not listed in this leaflet, they should inform their doctor or nurse. See section 4.

Table of Contents of the Leaflet

• 1. What is Mivacron and what is it used for
• 2. Important information before using Mivacron
• 3. How to use Mivacron
• 4. Possible side effects
• 5. How to store Mivacron
• 6. Contents of the pack and other information

1. What is Mivacron and what is it used for

Mivacron belongs to a group of muscle relaxant medicines, it is a highly specific, short-acting compound blocking neuromuscular conduction, causing a non-depolarizing (polarizing, competitive) block, characterized by rapid offset. Mivacurium binds to cholinergic receptors at the motor endplate, antagonizing the action of acetylcholine, resulting in competitive blockade of neuromuscular conduction. This action can be easily reversed by cholinesterase inhibitors, such as neostigmine or edrophonium. Mivacron is used as an adjunct to general anesthesia to provide skeletal muscle relaxation and to facilitate endotracheal intubation and mechanical ventilation in adults, children, and infants over 2 months of age. Mivacron 2 mg/ml solution for injection does not contain antimicrobial preservatives and is intended for single use in individual patients.

2. Important information before using Mivacron

When not to use Mivacron

• If the patient is allergic (hypersensitive) to mivacurium or any of the other ingredients of Mivacron (listed in section 6);
• If the patient or any of their family members have been diagnosed with abnormal plasma cholinesterase activity (patients who are homozygous for the atypical gene encoding plasma cholinesterase).

Warnings and precautions

Like all other neuromuscular blocking agents, Mivacron paralyzes the respiratory muscles as well as other skeletal muscles, without affecting consciousness. Mivacron should only be administered by an experienced anesthesiologist or under their direct supervision in conditions that allow for endotracheal intubation and mechanical ventilation. Before starting treatment with Mivacron, the patient should discuss the following with their doctor:

• if the patient has a history of hypersensitivity to histamine (e.g., patients with asthma);
• if the patient shows hypersensitivity to other neuromuscular blocking agents. There are reports of a high frequency of cross-sensitivity (greater than 50%) between neuromuscular blocking agents;
• if the patient is at risk of decreased blood pressure (e.g., patients with hypovolemia, i.e., too low blood volume);
• if the patient has muscle weakness, fatigue, or difficulty coordinating movements (myasthenia);
• if the patient has a debilitating disease;
• if the patient has severe acid-base or electrolyte imbalance;
• if the patient has had severe burns requiring medical intervention within the last two to three months.

Certain conditions or diseases may reduce plasma cholinesterase activity. The patient should inform their doctor if they have any of the following conditions or diseases:

• pregnancy and postpartum;
• genetically determined abnormalities of plasma cholinesterase activity;
• severe, generalized tetanus, tuberculosis, or other severe or chronic infections;
• chronic, debilitating disease, malignant tumors, chronic anemia, and malnutrition;
• myxedema (associated with hypothyroidism) and collagenosis (connective tissue disease);
• uncontrolled heart disease;
• peptic ulcer;
• burns;
• end-stage liver failure;
• acute, chronic, or end-stage renal failure;
• reduced plasma cholinesterase activity due to therapeutic procedures: after plasma exchange, plasmapheresis (a method of blood purification), after cardiopulmonary bypass, and occurring during treatment with other medicines (see 'Mivacron and other medicines').

Reversal of neuromuscular blockade induced by Mivacron

As with other neuromuscular blocking agents, before administering acetylcholinesterase inhibitors (e.g., neostigmine), the doctor should confirm the signs of spontaneous recovery of neuromuscular conduction. The use of a peripheral nerve stimulator to assess the return of neuromuscular conduction before and during the administration of acetylcholinesterase inhibitors is highly recommended. The usual doses of neostigmine administered at the start of spontaneous recovery of the block resulted in its reversal.

Mivacron and other medicines

The patient should inform their doctor about all medicines they are currently taking or have recently taken, as well as any medicines they plan to take. Concomitant use of inhalational anesthetics, such as enflurane, isoflurane, sevoflurane, or halothane, may enhance the neuromuscular blockade induced by mivacurium. The use of Mivacron is safe in patients who have previously received suxamethonium to facilitate endotracheal intubation. Administration of Mivacron should be started after the signs of spontaneous recovery of the block induced by suxamethonium appear. As with other competitive neuromuscular blocking agents, the intensity and/or duration of the non-depolarizing (polarizing, competitive) neuromuscular block may be increased, and the required infusion rate may be lower due to interactions with certain medicines. These include:

• antibiotics: aminoglycosides, polymyxins, spectinomycin, tetracyclines, lincomycin, and clindamycin;
• antiarrhythmic medicines (for heart rhythm disorders): propranolol, calcium channel blockers, lidocaine, procainamide, and quinidine;
• diuretics: furosemide and possibly thiazide diuretics, mannitol, and acetazolamide;
• magnesium salts (used in the treatment of indigestion and heartburn);
• ketamine (an anesthetic agent);
• lithium salts (used in the treatment of mental disorders);
• ganglion blockers, such as trimethaphan and hexamethonium.

Medicines and substances that may reduce plasma cholinesterase activity may also prolong the neuromuscular blocking effect of Mivacron. These include:

• cytotoxic medicines (used in the treatment of cancer);
• monoamine oxidase inhibitors (used in the treatment of depression);
• ecothiopate iodide (used in the treatment of glaucoma);
• pancuronium (a muscle relaxant);
• cholinesterase inhibitors (used in the treatment of myasthenia, Alzheimer's disease, glaucoma, and as an antidote in poisoning with cholinolytic medicines, e.g., atropine);
• certain hormones;
• bambuterol (used in the treatment of asthma);
• selective serotonin reuptake inhibitors (used in the treatment of severe episodes of depression, obsessive-compulsive disorder, anxiety disorders, panic disorder, social phobia, and generalized anxiety disorder);
• organophosphorus compounds (insecticides).

Rarely, some medicines may sometimes exacerbate or reveal latent myasthenia or even induce a myasthenic syndrome, resulting in increased sensitivity to the effect of Mivacron. These medicines include:

• various types of antibiotics;
• beta-adrenergic blockers, such as propranolol, oxprenolol (used in the treatment of hypertension);
• antiarrhythmic medicines (procainamide, quinidine);
• antirheumatic medicines (chloroquine, D-penicillamine);
• trimethaphan (a ganglion blocker);
• chlorpromazine, lithium salts (used in mental disorders);
• corticosteroids;
• phenytoin (an antiepileptic medicine).

Administration of medicines inducing non-depolarizing neuromuscular blockade in combination with Mivacron may result in a higher degree of blockade than would be expected from the administration of an equivalent total dose of Mivacron alone. The synergistic effect (mutually enhancing) may vary depending on the combination of medicines used. Depolarizing muscle relaxants, such as suxamethonium, should not be used to prolong the muscle relaxation induced by non-depolarizing agents, as this may result in an excessively prolonged and complex blockade, the reversal of which by cholinomimetics may be difficult. The solution of Mivacron has an acidic pH (around 4.5) and should not be mixed in the same syringe or administered through the same needle as strongly alkaline solutions, such as barbiturate solutions (see 'Method of administration').

Pregnancy and breastfeeding

If the patient is pregnant or breastfeeding, thinks they may be pregnant, or plans to have a child, they should consult their doctor before using this medicine. Animal studies have shown that mivacurium does not have a negative effect on fetal development. Mivacron may be used during pregnancy only when, in the doctor's opinion, the benefit to the mother outweighs the potential risk to the fetus. It is not known whether mivacurium passes into human milk.

Driving and using machines

This does not apply to the use of Mivacron. Mivacron is always used in conjunction with general anesthetic medicines. The usual precautions related to the effect of general anesthesia on the patient's psychophysical fitness apply.

3. How to use Mivacron

Mivacron can only be administered by an experienced anesthesiologist or under their direct supervision in conditions that allow for endotracheal intubation and mechanical ventilation. Mivacron can be administered by injection or infusion. The method of administration and dose will be decided by the doctor.

4. Possible side effects

Like all medicines, Mivacron can cause side effects, although not everybody gets them. Side effects have been grouped by frequency of occurrence.

Very common side effects(may affect more than 1 in 10 people taking Mivacron):

• redness of the skin*

Uncommon side effects(may affect up to 1 in 100 people taking Mivacron):

• transient tachycardia (abnormal rapid heart rate)*
• decreased blood pressure*
• bronchospasm*
• flushing*, urticaria*

Rare side effects(may affect up to 1 in 10,000 people taking Mivacron):

• severe anaphylactic reactions (immediate allergic reaction) or anaphylactoid reactions (reactions similar to allergic reactions). Severe anaphylactic reactions or anaphylactoid reactions have been reported in patients receiving mivacurium in combination with at least one anesthetic medicine.

*The use of mivacurium is associated with the occurrence of skin redness, flushing, urticaria, decreased blood pressure, transient tachycardia, bronchospasm, which are attributed to the release of histamine. These symptoms are dose-dependent and their frequency increases after administration of a rapid initial dose of 0.2 mg/kg body weight or more. The symptoms are less severe if mivacurium is administered by injection lasting 30 to 60 seconds or in divided doses injected at 30-second intervals. The safety profile of Mivacron in children is similar to that in adults.

Reporting side effects

If side effects occur, including any not listed in this leaflet, the patient should inform their doctor, pharmacist, or nurse. Side effects can be reported directly to the Department of Adverse Reaction Monitoring of Medicinal Products, Medical Devices, and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw, tel.: +48 22 49-21-301, fax: +48 22 49-21-309, e-mail: [email protected]. Side effects can also be reported to the marketing authorization holder or its representative. Reporting side effects will help to gather more information on the safety of the medicine.

5. How to store Mivacron

Do not store above 25°C. Protect from light. Do not freeze. Store the medicine in a place out of sight and reach of children. Do not use Mivacron after the expiry date stated on the packaging. The expiry date 'EXP' means the last day of the month stated. The abbreviation 'Lot' means batch number.

6. Contents of the pack and other information

What Mivacron contains

The active substance of Mivacron is mivacurium (1 ml of solution contains 2 mg of mivacurium as mivacurium chloride). The other ingredients are hydrochloric acid 0.1 M and water for injections.

What Mivacron looks like and contents of the pack

A clear, sterile aqueous solution, yellow in color. The pack contains: 5 ampoules containing 5 ml of solution or 5 ampoules containing 10 ml of solution. Ampoules made of colorless glass in a cardboard box. One 5 ml ampoule contains 10 mg of mivacurium (as mivacurium chloride). One 10 ml ampoule contains 20 mg of mivacurium (as mivacurium chloride). Mivacron does not contain antimicrobial preservatives.

Marketing Authorization Holder:

Aspen Pharma Trading Limited, 3016 Lake Drive, Citywest Business Campus, Dublin 24, Ireland, Tel: 0048 221253376

Manufacturer:

Aspen Pharma Ireland Limited, One George’s Quay Plaza, Dublin 2, Ireland, GlaxoSmithKline Manufacturing S.p.A., Strada Provinciale Asolana, 90, 43056 San Polo di Torrile, Parma, Italy

Importer:

Aspen Bad Oldesloe GmbH, 32-36 Industriestrasse, 23843 Bad Oldesloe, Germany

Date of last revision of the leaflet:

Information intended for healthcare professionals only

Dosage

Dosage in adults - intravenous injections

Mivacron is administered by intravenous injection. The average dose required to achieve 95% inhibition of the twitch response of the adductor pollicis muscle to stimulation of the ulnar nerve (ED95) is 0.07 mg/kg body weight (range 0.06 - 0.09 mg/kg body weight) in adults anesthetized with narcotic analgesics. To facilitate endotracheal intubation, the following dosing regimens are recommended:

• A dose of 0.2 mg/kg body weight, administered over 30 seconds, provides good or excellent intubating conditions within 2.0 - 2.5 minutes.
• A dose of 0.25 mg/kg body weight, administered in two divided doses (0.15 mg/kg body weight and, after 30 seconds, 0.1 mg/kg body weight), provides good or excellent intubating conditions within 1.5 - 2.0 minutes from the end of the first injection.

In the initial phase of the action of Mivacron, no significant decrease in twitch response is observed, measured by the train-of-four method. Often, endotracheal intubation can be performed before complete abolition of the twitch response of the adductor pollicis muscle to stimulation by the train-of-four method. In healthy adult subjects, the recommended dose of Mivacron administered by rapid intravenous injection ranges from 0.07 to 0.25 mg/kg body weight. The duration of neuromuscular blockade depends on the dose administered. Doses of 0.07; 0.15; 0.20, and 0.25 mg/kg body weight produce clinically effective blockade lasting approximately 13, 16, 20, and 23 minutes, respectively. Doses up to 0.15 mg/kg body weight can be administered by injection lasting 5 to 15 seconds. Larger doses should be administered over 30 seconds to minimize the risk of hemodynamic disturbances. Complete blockade can be prolonged by administering maintenance doses of Mivacron. Each dose of 0.1 mg/kg body weight, administered during anesthesia induced by narcotic analgesics, prolongs the clinically effective blockade by approximately 15 minutes. Subsequent maintenance doses do not result in accumulation of the blocking effect. The neuromuscular blocking effect of Mivacron is potentiated if isoflurane or enflurane is used for anesthesia. In stable anesthesia induced by isoflurane or enflurane, the recommended initial dose of Mivacron should be reduced by up to 25%. It appears that halothane only slightly potentiates the effect of mivacurium, and reduction of the dose of Mivacron is probably not necessary. From the start of spontaneous recovery of the block to its complete resolution, approximately 15 minutes elapse, regardless of the dose administered. The neuromuscular blockade induced by Mivacron can be reversed by administering standard doses of cholinesterase inhibitors. However, since spontaneous recovery of neuromuscular conduction after administration of Mivacron is rapid, reversal of the block may not be necessary in routine practice, as it shortens the time to recovery by only 5 - 6 minutes.

Dosage in adults - continuous infusion

To maintain neuromuscular blockade, Mivacron can be administered by continuous infusion. After the onset of early signs of spontaneous recovery of the block after administration of the initial dose of Mivacron, it is recommended to administer 8 to 10 µg/kg body weight/min (0.5 to 0.6 mg/kg body weight/hour) by infusion. The initial infusion rate should be determined based on the patient's response to peripheral nerve stimulation and clinical criteria. The infusion rate should be adjusted by gradually changing the administered dose by approximately 1 µg/kg body weight/min (0.06 mg/kg body weight/hour). In general, it is recommended to maintain the given infusion rate for at least 3 minutes before making any changes. In adults anesthetized with narcotic analgesics, the average infusion rate in the range of 6 to 7 µg/kg body weight/min allows for long-term maintenance of 89 to 99% neuromuscular blockade. In stable anesthesia induced by isoflurane or enflurane, the recommended infusion rate of Mivacron should be reduced by up to 40%. Clinical studies have shown that during sevoflurane anesthesia, the infusion rate of mivacurium may be reduced by 50%. During halothane anesthesia, the need to reduce the infusion rate may be less. Spontaneous recovery of neuromuscular conduction after administration of Mivacron by infusion does not depend on the duration of infusion and is comparable to recovery after administration of single doses. Administration of Mivacron by continuous infusion was not associated with the development of tachyphylaxis or accumulation of the blocking effect. Mivacron (2 mg/ml) administered by infusion does not need to be diluted. Mivacron can be diluted with the following infusion solutions:

• 0.9% sodium chloride infusion solution;
• 5% glucose infusion solution;
• 0.18% sodium chloride with 4% glucose infusion solution;
• Ringer's solution buffered with lactate (USP).

It has been shown that Mivacron, after dilution with one of the above solutions in a ratio of 1:3 (i.e., at a concentration of 0.5 mg/ml), maintains its physical and chemical properties for at least 48 hours at 30°C. However, since the medicine does not contain antimicrobial preservatives, dilutions should be made immediately before use, and infusion should be started as soon as possible, and any unused portion of the solution should be discarded.

Dosage in children aged 7 months to 12 years

In children aged 7 months to 12 years, compared to adults, the ED95 dose of Mivacron is higher (approximately 0.1 mg/kg body weight), the onset of action is faster, the duration of clinically effective blockade is shorter, and spontaneous recovery is faster. For children aged 7 months to 12 years, the recommended dose range, administered by intravenous injection lasting 5 to 15 seconds, is 0.1 to 0.2 mg/kg body weight. A dose of 0.2 mg/kg body weight, administered during stable anesthesia induced by narcotic analgesics or halothane, produces clinically effective neuromuscular blockade for approximately 9 minutes. To facilitate endotracheal intubation in children aged 7 months to 12 years, a dose of 0.2 mg/kg body weight of Mivacron is recommended. Maximum neuromuscular blockade occurs usually within 2 minutes after administration of this dose, and intubation should be possible at this time. In infants and children, maintenance doses are usually administered more frequently than in adults. Available data indicate that a maintenance dose of 0.1 mg/kg body weight prolongs the clinically effective blockade by approximately 6 to 9 minutes during anesthesia induced by narcotic analgesics or halothane. Infants and children usually require faster infusion rates than adults. The average infusion rate required to maintain 89 to 99% neuromuscular blockade in children aged 7 to 23 months anesthetized with halothane is approximately 11 µg/kg body weight/min (approximately 0.7 mg/kg body weight/hour). The range is 3 to 26 µg/kg body weight/min (approximately 0.2 to 1.6 mg/kg body weight/hour). In children aged 2 to 12 years, the average infusion rate during halothane or narcotic analgesic anesthesia, required to achieve such a blockade, is approximately 13 to 14 µg/kg body weight/min (approximately 0.8 mg/kg body weight/hour). The range is 5 to 31 µg/kg body weight/min (approximately 0.3 to 1.9 mg/kg body weight/hour). Neuromuscular blockade induced by mivacurium is potentiated by concomitant administration of inhalational anesthetic agents. Clinical studies have shown that in children aged 2 to 12 years, during sevoflurane anesthesia, the infusion rate of mivacurium may be reduced by 70%. From the start of spontaneous recovery of the block to its complete resolution, approximately 10 minutes elapse.

Dosage in infants aged 2 to 6 months

In infants aged 2 to 6 months, compared to adults, the ED95 dose of Mivacron is similar (0.07 mg/kg body weight), but the onset of action is faster, the duration of clinically effective blockade is shorter, and spontaneous recovery is faster. For infants aged 2 to 6 months, the recommended dose range, administered by intravenous injection lasting 5 to 15 seconds, is 0.1 to 0.15 mg/kg body weight. A dose of 0.15 mg/kg body weight, administered during stable anesthesia induced by halothane, produces clinically effective neuromuscular blockade lasting approximately 9 minutes. To facilitate endotracheal intubation in infants aged 2 to 6 months, a dose of 0.15 mg/kg body weight of Mivacron is recommended. Maximum neuromuscular blockade occurs usually within 1.4 minutes after administration of this dose, and intubation should be possible at this time. In infants aged 2 to 6 months, maintenance doses are usually administered more frequently than in adults. Available data indicate that a maintenance dose of 0.1 mg/kg body weight prolongs the clinically effective blockade by approximately 7 minutes during halothane anesthesia. Infants aged 2 to 6 months usually require faster infusion rates than adults. The average infusion rate required to maintain 89 to 99% neuromuscular blockade during halothane anesthesia is approximately 11 µg/kg body weight/min (approximately 0.7 mg/kg body weight/hour). The range is 4 to 24 µg/kg body weight/min (approximately 0.2 to 1.5 mg/kg body weight/hour). From the start of spontaneous recovery of the block to its complete resolution, approximately 10 minutes elapse.

Dosage in newborns and infants under 2 months of age

The safety and efficacy of mivacurium chloride in newborns and infants under 2 months of age have not been established. No dosage recommendations can be made.

Dosage in elderly patients

In elderly patients receiving a single dose of Mivacron by rapid intravenous injection, the time from administration to onset of action and the duration and rate of recovery of the block may be prolonged by 20 to 30% compared to younger subjects. Elderly patients may require slower infusion rates or less frequent administration of maintenance doses.

Dosage in patients with cardiovascular disease

Patients with clinically significant cardiovascular disease should receive the initial dose of Mivacron over at least 60 seconds. Mivacron administered in this way caused minimal hemodynamic changes in patients undergoing cardiac surgery.

Dosage in patients with renal failure

In patients with severe renal failure, the clinically effective blockade induced by administration of 0.15 mg/kg body weight of Mivacron lasts approximately 1.5 times longer than in patients with normal renal function. Therefore, the dose of the medicine should be adjusted according to the individual clinical response of the patients. Prolonged and intensified neuromuscular blockade may also occur in patients with acute or chronic renal failure due to reduced plasma cholinesterase activity.

Dosage in patients with liver failure

In patients with severe liver failure, the clinically effective blockade induced by administration of 0.15 mg/kg body weight of Mivacron lasts approximately 3 times longer than in patients with normal liver function. The prolongation of the duration of action is associated with significantly reduced plasma cholinesterase activity in these patients. Therefore, the dose should be adjusted according to the individual clinical response of the patient.

Dosage in patients with reduced plasma cholinesterase activity

Mivacurium is metabolized by plasma cholinesterase. Plasma cholinesterase activity may be reduced in cases of genetic abnormalities of plasma cholinesterase (e.g., in patients who are heterozygous or homozygous for the atypical gene encoding plasma cholinesterase) and in various pathological conditions (see 'Dosage in patients with liver failure') or after administration of certain medicines (see 'Mivacron and other medicines'). In patients with reduced plasma cholinesterase activity, the duration of neuromuscular blockade after administration of Mivacron may be prolonged. A slight reduction in the activity of this enzyme (i.e., to 20% of the lower limit of normal values) does not have a clinically significant effect on the duration of the block. In patients who are heterozygous for the atypical gene encoding plasma cholinesterase, the duration of clinically effective neuromuscular blockade after administration of 0.15 mg/kg body weight of Mivacron is prolonged by approximately 10 minutes compared to the control group.

Dosage in obese patients

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

Monitoring of patients

To individually adjust the appropriate dose during administration of Mivacron, it is recommended to monitor neuromuscular conduction, as is done with all other neuromuscular blocking agents.

Overdose

Symptoms

Prolonged muscle paralysis and its consequences are the main symptoms of overdose of neuromuscular blocking agents. However, there is an increased risk of hemodynamic disturbances, especially decreased blood pressure.

Treatment

Until spontaneous recovery of adequate respiratory function, it is necessary to maintain patent airways and apply positive-pressure ventilation. The use of medicines inducing full loss of consciousness is recommended, as Mivacron does not affect consciousness. Administration of acetylcholinesterase inhibitors, along with atropine or glycopyrrolate, when signs of spontaneous recovery of neuromuscular conduction appear, may accelerate this recovery. Appropriate positioning of the patient and administration of fluids or medicines inducing vasoconstriction, as needed, may support cardiovascular function.

Method of administration

Mivacron (2 mg/ml) administered by infusion does not need to be diluted. Mivacron can be diluted with the following infusion solutions:

• 0.9% sodium chloride infusion solution;
• 5% glucose infusion solution;
• 0.18% sodium chloride with 4% glucose infusion solution;
• Ringer's solution buffered with lactate (USP).

It has been shown that Mivacron, after dilution with one of the above solutions in a ratio of 1:3 (i.e., at a concentration of 0.5 mg/ml), maintains its physical and chemical properties for at least 48 hours at 30°C. However, since the medicine does not contain antimicrobial preservatives, dilutions should be made immediately before use, and infusion should be started as soon as possible, and any unused portion of the solution should be discarded. The solution of Mivacron has an acidic pH (around 4.5) and should not be mixed in the same syringe or administered through the same needle as strongly alkaline solutions, such as barbiturate solutions. It has been shown that Mivacron can be combined with certain medicines commonly used in the perioperative period, which are available in acidic solutions, such as fentanyl, alfentanil, sufentanil, droperidol, and midazolam. When Mivacron and other anesthetic medicines are administered through the same intravenous line or needle, and their compatibility has not been demonstrated, the line or needle should be flushed with isotonic sodium chloride solution after administration of each medicine.