Recalmin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT REKALMIN (REKALMIN)

Composition:

Active substance: tolperisone hydrochloride;

1 tablet contains tolperisone hydrochloride 50 mg or 150 mg;

Excipients: citric acid monohydrate; silicon dioxide colloidal anhydrous; stearic acid; talc; microcrystalline cellulose; corn starch; lactose monohydrate; hypromellose; macrogol 6000; titanium dioxide (E 171).

Pharmaceutical form. Coated tablets.

Main physicochemical characteristics: white or almost white, round, coated tablets with convex upper and lower surfaces. When broken and examined under a magnifying lens, the core surrounded by a single continuous layer is visible.

Pharmacotherapeutic group. Drugs affecting the musculoskeletal system. Muscle relaxants. Centrally acting muscle relaxants. Other centrally acting muscle relaxants. Tolperisone. 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 together 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 voltage-gated sodium channels. Consequently, the amplitude and frequency of action potentials are reduced.

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

Furthermore, tolperisone exhibits some weak alpha-adrenergic antagonist properties and has antimuscarinic activity.

Clinical Efficacy and Safety

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

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 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 doses of 300–450 mg/day. While functional test parameters also indicated higher efficacy with tolperisone compared to placebo, the differences were not statistically significant.

In a randomized, double-blind comparative study involving 48 patients with brain damage, 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 in 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 pronounced 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 (over 99%) in the form of metabolites.

The pharmacological activity of the metabolites is unknown.

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

Preclinical Safety Data

Based on preclinical studies of 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 tolperisone at doses of 500 mg/kg and 250 mg/kg body weight, respectively. However, these doses are many times higher than the recommended therapeutic doses in 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 interactions.

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

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

It is expected that co-administration with other CYP2D6 substrates and/or other drugs will not increase tolperisone exposure, due to the multiple metabolic pathways of tolperisone.

When tolperisone is administered on an empty stomach, its bioavailability decreases; therefore, administration of the drug should take into account its relationship with food intake.

Although tolperisone is a centrally-acting agent, the likelihood of developing a sedative effect with its use 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 used concomitantly 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 manifestations 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 developing hypersensitivity reactions during tolperisone treatment.

The chemical structure of tolperisone is similar to that of lidocaine; therefore, in patients with a history of allergic reaction to lidocaine, cross-reactivity and an allergic reaction to tolperisone are possible. Patients should inform their physician about any known hypersensitivity to lidocaine before starting tolperisone therapy.

Patients should be advised to remain vigilant for possible symptoms 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. This medicinal product should not be used in patients with lactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding

Animal studies have shown that tolperisone has no teratogenic effects.

Due to the lack of sufficient clinical data on use during pregnancy, tolperisone should not be used during pregnancy.

As it is unknown whether tolperisone is excreted in human breast milk, the use of this medicinal product during breastfeeding is contraindicated.

Ability to influence reaction rate while driving or operating machinery

Given the possibility of developing symptoms such as dizziness, somnolence, attention disturbances, epilepsy, or blurred vision, caution should be exercised when driving vehicles or operating machinery during treatment with this medicinal product.

Method of Administration and Dosage

The drug should be taken after a meal, swallowed with one glass of water. Inadequate 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, 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 assessment of renal function. Tolperisone is not recommended for use in patients with severe kidney impairment.

Patients with Hepatic Impairment

Experience with the use of the drug in patients with liver damage is limited, and a higher frequency of adverse reactions 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 assessment of liver function. Tolperisone is not recommended for use in patients with 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 tolperidone 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 disorders of the nervous and gastrointestinal systems.

According to post-marketing surveillance data, approximately 50–60% of adverse reactions associated with tolperidone administration 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 by system organ classes according to the Medical Dictionary for Regulatory Activities (MedDRA), using MedDRA frequency definitions: 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).

Reporting of adverse reactions following the registration of the medicinal product is of significant importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30°C.

Keep out of reach and sight of children.

Packaging.

10 tablets per blister. 3 blisters per carton.

Prescription status.

Prescription-only medicine.

Manufacturer.

PJSC "Tekhnolohiya".

Manufacturer's address and location of its business activity.

8 Stara Prorizna Street, Uman, Cherkasy Oblast, 20300, Ukraine.