MIDOCALM

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MIDOCALM (MYDOCALM)

Composition:

Active substances: tolperisone hydrochloride, lidocaine hydrochloride;

1 ml of solution contains 100 mg of tolperisone hydrochloride and 2.5 mg of lidocaine hydrochloride;

Excipients: methylparahydroxybenzoate (E 218), diethylene glycol monoethyl ether, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: colorless or slightly greenish transparent solution, practically free from particles.

Pharmacotherapeutic group. Muscle relaxants with central mechanism of action.

ATC code M03BX04.

Pharmacological properties.

Pharmacodynamics.

Tolperisone is a centrally-acting muscle relaxant. The mechanism of action of tolperisone is not fully understood.

It has high affinity for nervous tissue, reaching the highest concentrations in the brainstem, spinal cord, and peripheral nervous system.

The most significant effect of tolperisone is its inhibitory action on the spinal reflex pathway. This effect, likely in combination with its inhibitory action on descending motor pathways, underlies the therapeutic benefit of tolperisone.

The chemical structure of tolperisone is similar to that of lidocaine. Like lidocaine, it exerts a membrane-stabilizing effect and reduces the electrical excitability of motor neurons and primary afferent fibers. Tolperisone dose-dependently inhibits the activity of voltage-dependent sodium channels. As a result, the amplitude and frequency of action potentials are reduced.

An inhibitory effect on voltage-dependent calcium channels has also been demonstrated. In addition to its membrane-stabilizing effect, tolperisone is presumed to inhibit neurotransmitter release.

Furthermore, tolperisone exhibits some weakly expressed alpha-adrenergic antagonist properties and exerts an antimuscarinic effect.

Clinical efficacy and safety

The efficacy of tolperisone in the treatment of muscle spasm following stroke has been demonstrated.

In a randomized, double-blind, placebo-controlled study involving 120 patients with post-stroke muscle spasm, treatment with tolperisone resulted in a highly significant reduction in spasticity according to the Ashworth scale, which was the primary endpoint. According to the overall assessment of efficacy by investigators and physicians, tolperisone was superior to placebo (p <0.001). The mean improvement on the Ashworth scale was 32% in the overall patient population treated (intention-to-treat, ITT) and 42% in the subgroup of patients receiving tolperisone at a dose of 300–450 mg/day. Although tolperisone showed higher efficacy than placebo in functional test assessments, the differences were not statistically significant.

In a randomized, double-blind, comparative study involving 48 patients with brain injury, the efficacy of tolperisone, as measured by the Barthel Index, was comparable to that of baclofen. However, tolperisone was superior to baclofen in improving scores on the Rivermead Motor Assessment Scale (RMAS).

Data on the efficacy of tolperisone in patients with increased muscle tone due to musculoskeletal disorders other than post-stroke muscle spasm are conflicting. Some studies have reported positive results in certain functional tests, while others have not demonstrated any advantage of tolperisone in such conditions.

The safety profile of tolperisone is based on data from clinical trials involving patients with increased muscle tone of various etiologies, as well as on spontaneous reports of adverse reactions.

Pharmacokinetics.

Tolperisone undergoes extensive metabolism in the liver and kidneys. It is excreted by the kidneys, with more than 99% eliminated as metabolites. The pharmacological activity of metabolites is unknown. After intravenous administration, the elimination half-life is approximately 1.5 hours.

Preclinical safety data

Based on preclinical studies of pharmacological safety, repeated-dose toxicity, genotoxicity, and reproductive toxicity, no specific risk to humans has been identified.

Observed effects in preclinical studies occurred only at doses substantially exceeding the maximum recommended human doses, indicating limited relevance to clinical use.

Embryotoxic effects were observed in rats and rabbits following oral administration of the drug at doses of 500 mg/kg body weight and 250 mg/kg body weight, respectively. However, these doses are many times higher than the recommended therapeutic doses for humans.

Clinical characteristics.

Indications.

Muscle spasticity, including post-stroke spasticity, in cases where the injectable form is the treatment of choice.

Contraindications.

Hypersensitivity to the active substances or to eperisone, which is chemically similar to tolperisone, as well as to any of the excipients or to other amide-type local anesthetics.

Myasthenia gravis.

Breastfeeding period.

Pediatric age.

Interaction with other medicinal products and other forms of interaction.

Pharmacokinetic studies of drug interactions with dextromethorphan, a CYP2D6 substrate, have demonstrated that concomitant administration of tolperisone increases plasma concentrations of drugs primarily metabolized by cytochrome CYP2D6, particularly thioridazine, tolterodine, venlafaxine, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, and perphenazine.

In vitro studies in human liver microsomes and hepatocytes showed no significant inhibition or induction of other CYP isoenzymes (CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP1A2, CYP3A4).

Concomitant use with other CYP2D6 substrates and/or other drugs is not expected to increase tolperisone exposure due to the diverse metabolic pathways of tolperisone.

Although tolperisone is a centrally-acting agent, the likelihood of developing a sedative effect with its use is low. When administered concomitantly with other centrally-acting muscle relaxants, consideration should be given to reducing the dose of tolperisone.

Tolperisone potentiates the effects of niflumic acid; therefore, when used concomitantly with tolperisone, the dose of niflumic acid, as well as other NSAIDs, should be reduced.

Special precautions for use.

Do not prescribe the injectable form of the medication to children.

Hypersensitivity reactions

During post-marketing surveillance, hypersensitivity reactions have been the most frequently reported adverse events associated with tolperidone use. These reactions vary in severity from mild skin reactions to severe systemic reactions, including anaphylactic shock. Symptoms of hypersensitivity may include erythema, rash, urticaria, pruritus, angioneurotic edema, tachycardia, arterial hypotension, or dyspnea.

Women with a history of hypersensitivity to other drugs or allergic conditions have an increased risk of hypersensitivity reactions when taking tolperidone.

Patients should be advised to remain alert for possible allergic reactions. They must be informed that if symptoms of allergy occur, tolperidone should be discontinued immediately and medical help should be sought without delay.

After an episode of hypersensitivity to tolperidone, the drug must not be re-administered.

The medication contains lidocaine; therefore, Midocalm for injection should not be used in patients with known hypersensitivity to lidocaine or to other amide-type local anesthetics due to the risk of cross-allergic reactions.

Excipients

Midocalm injection solution contains methylparahydroxybenzoate (E 218), which may cause allergic reactions (possibly delayed) and, in individual cases, bronchospasm.

Use during pregnancy or breastfeeding

Animal studies have shown that tolperidone has no teratogenic effects.

Due to the lack of substantial clinical data on the use of this medication, Midocalm should not be used during pregnancy.

Since it is unknown whether tolperidone is excreted in breast milk, the use of Midocalm during breastfeeding is contraindicated.

Ability to affect reaction speed when driving or operating machinery

Given the possible occurrence of symptoms such as dizziness, somnolence, impaired attention, epilepsy, or blurred vision, caution should be exercised when driving or operating machinery while taking this medication.

Dosage and method of administration

For intramuscular use only.

Use only in adults. Administer 100 mg of the drug intramuscularly twice daily.

The injection solution must not be used in children.

The duration of treatment is determined by the physician, depending on the nature of the disease course and treatment efficacy.

Patients with renal impairment

Experience with the use of the drug in patients with kidney damage is limited, and a higher frequency of adverse effects has been observed in such patients. Therefore, in cases of moderate kidney impairment, individual dose titration is recommended with careful monitoring of the patient's condition and kidney function. Tolperisone is not recommended for use in patients with severe kidney damage.

Patients with hepatic impairment

Experience with the use of the drug in patients with liver damage is limited, and a higher frequency of adverse events has been observed in such patients. Therefore, in cases of moderate liver impairment, individual dose titration is recommended with careful monitoring of the patient's condition and liver function. Tolperisone is not recommended for use in patients with severe liver damage.

Children

Midocalm injection solution must not be used in children.

Overdose

Data regarding tolperisone overdose are insufficient.

Symptoms of overdose may mainly include drowsiness, gastrointestinal manifestations (nausea, vomiting, epigastric pain), tachycardia, arterial hypertension, bradykinesia, and vertigo. In severe cases, seizures and coma have been reported.

There is no specific antidote for tolperisone. In case of overdose, symptomatic treatment is recommended.

Adverse reactions

Adverse reactions are listed by system organ classes according to the Medical Dictionary for Regulatory Activities (MedDRA), using MedDRA frequency definitions: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), and frequency not known (cannot be estimated from the available data).

According to post-marketing surveillance data, approximately 50–60% of adverse reactions associated with tolperisone use are hypersensitivity reactions. Most of these reactions were mild and resolved spontaneously. Life-threatening hypersensitivity reactions occurred in rare cases.

Reporting of adverse reactions after marketing authorization of the medicinal product is important. This enables ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at 8–15 °C in the original packaging to protect from light.

Keep the medicinal product out of the reach of children!

Incompatibility.

Data on compatibility studies are not available; therefore, Midocalm should not be mixed with other medicinal products in the same syringe. Administer separately from other drugs.

Packaging.

1 ml in a vial made of brown glass, 5 vials per cardboard package.

Prescription status. Prescription only.

Manufacturer.

JSC "Gedeon Richter".

Manufacturer's address and place of business.

H-1103 Budapest, 19-21 Deményi Street, Hungary