Midocalm

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MİDOCALM (MYDOCALM)

Composition:

Active substance: tolperisone hydrochloride;

One film-coated tablet contains 50 mg or 150 mg of tolperisone hydrochloride;

Excipients:

Core: citric acid monohydrate (E 330); colloidal anhydrous silicon dioxide (E 551); stearic acid (E 570); talc (E 553b); microcrystalline cellulose (E 460); corn starch; lactose monohydrate;

Coating: colloidal anhydrous silicon dioxide (E 551); titanium dioxide (E 171); lactose monohydrate; macrogol 6000; hypromellose.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Midocalm, film-coated tablets, 50 mg:

white or almost white, biconvex tablets with slightly glossy film coating, engraved with "50" on one side;

Midocalm, film-coated tablets, 150 mg:

white or almost white, round, biconvex tablets with film coating, characteristic odor, engraved with "150" on one side.

Pharmacotherapeutic group. Centrally acting muscle relaxants.

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 inhibition of 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 action, tolperisone may also inhibit neurotransmitter release.

Furthermore, tolperisone has some weakly expressed properties of alpha-adrenergic antagonists and exhibits antimuscarinic activity.

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 as measured by the Ashworth scale, which was the primary endpoint. According to the overall efficacy assessment by investigators and physicians, tolperisone was superior to placebo (p < 0.001). The mean improvement on the Ashworth scale was 32% in the overall treated patient population (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 increased muscle tone in patients with musculoskeletal disorders other than post-stroke muscle spasm are conflicting. Some studies have reported positive results on certain test parameters, while others have found no 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. After oral administration, tolperisone is well absorbed in the small intestine. Maximum plasma concentration is reached within 0.5–1.5 hours after intake. Due to significant first-pass metabolism, the bioavailability of tolperisone is approximately 20%. A fatty meal increases the bioavailability of the drug by approximately 100% and the maximum plasma concentration by approximately 45% compared to administration on an empty stomach. The time to reach maximum concentration is prolonged by approximately 30 minutes under these conditions.

Tolperisone is extensively metabolized in the liver and kidneys.

The drug is almost completely excreted by the kidneys (more than 99%) in the form of metabolites.

The pharmacological activity of metabolites is unknown.

The elimination half-life of tolperisone is approximately 1.5 hours after intravenous administration and approximately 2.5 hours after oral administration.

Preclinical Safety Data

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

Effects observed in preclinical studies occurred only at doses significantly exceeding the maximum recommended human doses, indicating limited relevance for clinical use.

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

Clinical characteristics.

Indications.

Symptomatic treatment of muscle spasm in adults following stroke.

Contraindications.

• Hypersensitivity to the active substance or to eperisone, which is chemically similar, or to any of the excipients.
• Myasthenia gravis.
• Breastfeeding period.

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 concentrations of 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).

A clinically relevant increase in tolperisone exposure is not expected when administered concomitantly with other CYP2D6 substrates and/or other drugs, due to the multiple metabolic pathways of tolperisone.

When tolperisone is administered on an empty stomach, its bioavailability is reduced; therefore, administration with food should be considered.

Although tolperisone is a centrally acting agent, the likelihood of sedative effects is low. However, when used 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 co-administered with tolperisone, the dose of niflumic acid, as well as other NSAIDs, should be reduced.

Special precautions for use.

Hypersensitivity reactions

During the post-marketing period, hypersensitivity reactions have been the most frequently reported adverse effects associated with tolperisone use. The severity of these reactions ranges from mild skin reactions to severe systemic reactions, including anaphylactic shock. Symptoms of hypersensitivity may include erythema, rash, urticaria, pruritus, angioneurotic edema, tachycardia, hypotension, or dyspnea.

Women with a history of hypersensitivity to other drugs or allergic conditions are at higher risk of hypersensitivity reactions when taking tolperisone.

Patients should be advised to monitor their condition carefully for possible signs of allergy. They must be informed that if allergic symptoms occur, tolperisone should be discontinued immediately and medical help should be sought without delay.

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

The product contains lactose monohydrate. Patients with rare hereditary conditions such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medication.

Use during pregnancy or breastfeeding

Animal studies have shown that tolperisone has no teratogenic effects.

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

As it is unknown whether tolperisone passes into breast milk, Midocalm is contraindicated during breastfeeding.

Ability to affect reaction speed when driving or operating machinery

Given the possible occurrence of symptoms such as dizziness, somnolence, attention disturbances, epilepsy, or blurred vision, caution should be exercised when using the drug while driving or operating machinery.

Dosage and Administration.

The drug should be taken after meals, with a glass of water. Insufficient food intake may reduce tolperisone bioavailability.

Adults: depending on individual needs and tolerability – 150–450 mg daily in 3 divided doses.

Patients with renal impairment

Experience with the use of the drug in patients with kidney damage is limited; in such patients, a higher incidence of adverse effects has been observed. 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 in severe kidney impairment.

Patients with hepatic impairment

Experience with the use of the drug in patients with liver damage is limited; in such patients, a higher incidence of adverse reactions has been observed. 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 in severe liver impairment.

Children

The safety and efficacy of tolperisone in children have not been established.

Overdose.

Data regarding tolperisone overdose are insufficient.

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

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

Adverse Reactions

The safety profile of tablets containing tolperisone is based on data from more than 12,000 patients. According to these data, the most commonly occurring adverse reactions were those affecting the skin and subcutaneous tissue, systemic disorders, and disturbances of the nervous and gastrointestinal systems.

Post-marketing surveillance data indicate that approximately 50–60% of adverse reactions associated with tolperisone use are hypersensitivity reactions. Most of these reactions were non-serious and resolved spontaneously. Life-threatening hypersensitivity reactions occurred in isolated cases.

Adverse reactions are listed below by organ system classes according to the Medical Dictionary for Regulatory Activities (MedDRA), using MedDRA frequency categories: uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), and frequency not known (cannot be estimated from the available data).

Expiry date. 3 years.

Storage conditions.

The medicinal product does not require special storage conditions.

Keep the medicine out of reach of children!

Packaging.

10 tablets per blister pack; 3 blister packs in a cardboard package.

Prescription status. Prescription only.

Manufacturer.

JSC "Gedeon Richter".

Manufacturer's address and location of its business activities.

19-21, Demre utca, Budapest, H-1103, Hungary.