Tolcimado

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TolkImado (Tolkimado)

Composition:

Active substance: tolperisone hydrochloride;

1 film-coated tablet contains 150 mg of tolperisone hydrochloride;

Excipients: citric acid monohydrate; microcrystalline cellulose; lactose monohydrate; corn starch; colloidal anhydrous silicon dioxide; talc; stearic acid;

Film coating: Opadry® white 03F180011 (hypromellose, titanium dioxide (E 171), macrogol).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, film-coated tablets of white to almost white color, with "T150" engraved on one side.

Pharmacotherapeutic group.

Muscle relaxants with central mechanism of action. ATC code M03BX04.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action.

Tolperisone is a centrally-acting muscle relaxant. Its mechanism of action has not yet been fully elucidated.

Tolperisone 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 combined 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-dependent sodium channels. Consequently, 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 properties, 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 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. Based on 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 compared to 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 in certain test parameters, while others have failed to demonstrate 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.

Absorption.

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 oral bioavailability by approximately 100% and 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.

Metabolism.

Tolperisone is extensively metabolized in the liver and kidneys. It is almost completely excreted by the kidneys (more than 99%) in the form of metabolites. The pharmacological activity of metabolites is unknown.

Elimination.

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 to humans has been identified.

Observed effects in preclinical studies occurred only at doses substantially 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 for humans.

Clinical characteristics.

Indications.

Symptomatic treatment of muscle spasm in adults following stroke.

Contraindications.

• Hypersensitivity to tolperisone, to eperisone (a structurally similar compound), and/or to any of the excipients of the medicinal product.
• 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 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 co-administered with other CYP2D6 substrates and/or other medicinal products, 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 sedative effects 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, the dose of niflumic acid, as well as other NSAIDs, should be reduced.

Special precautions for use.

Risk of hypersensitivity reactions.

During the post-marketing period, hypersensitivity reactions have been the most commonly observed adverse effects associated with tolperisone 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, 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 during treatment. Patients must be informed that if allergic symptoms occur, they should discontinue tolperisone immediately and seek urgent medical attention.

If a hypersensitivity reaction to tolperisone occurs, the drug must not be re-administered.

Precautions regarding excipients.

The medicinal product contains lactose and therefore should not be used in patients with rare hereditary forms of galactose 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 significant clinical data, the medicinal product should not be used during pregnancy.

Since it is unknown whether tolperisone passes into breast milk, the use of the medicinal product during breastfeeding is contraindicated.

Ability to affect reaction rate 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 using the medicinal product while driving or operating machinery.

Dosage and Administration.

The medicinal product is intended for oral administration.

The tablets should be taken after meals with one glass of water. Inadequate food intake may reduce tolperisone bioavailability.

Adults.

The medicinal product should be administered according to individual need and tolerability at a daily dose of 150–450 mg (in 3 divided doses).

Patients with renal impairment.

Experience with tolperisone in patients with kidney damage is limited, and a higher incidence of adverse reactions has been observed in such patients. Therefore, in cases of moderate renal impairment, individual dose titration is recommended with careful monitoring of the patient's condition and control of kidney function. The use of the medicinal product is not recommended in severe renal impairment.

Patients with hepatic impairment.

Experience with tolperisone in patients with liver damage is limited, and a higher incidence of adverse reactions has been observed in such patients. Therefore, in cases of moderate hepatic impairment, individual dose titration is recommended with careful monitoring of the patient's condition and control of liver function. The use of the medicinal product is not recommended in severe hepatic impairment.

Children.

Safety and efficacy of tolperisone in children have not been studied.

Overdose.

Data regarding tolperisone overdose are insufficient.

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

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

Adverse Reactions

The most commonly observed adverse reactions during tolperisone use were disorders of 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 tolperisone administration were 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 definitions: uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), and not known (frequency cannot be estimated from available data).

Blood and lymphatic system disorders:

very rare – anaemia, lymphadenopathy.

Immune system disorders:

rare – hypersensitivity reaction, anaphylactic reaction; very rare – anaphylactic shock.

Metabolism and nutrition disorders:

uncommon – anorexia; very rare – polydipsia.

Psychiatric disorders:

uncommon – insomnia, sleep disorder; rare – decreased activity, depression; very rare – confusion.

Nervous system disorders:

uncommon – headache, dizziness, somnolence; rare – attention disorder, tremor, seizures, hypaesthesia, paraesthesia, lethargy (increased drowsiness).

Eye disorders:

rare – visual disturbance.

Ear and labyrinth disorders:

rare – tinnitus, vertigo.

Cardiac disorders:

rare – angina pectoris, tachycardia, palpitations, decreased blood pressure; very rare – bradycardia.

Vascular disorders:

uncommon – hypotension; rare – skin hyperemia.

Respiratory, thoracic and mediastinal disorders:

rare – dyspnoea, epistaxis, tachypnoea.

Gastrointestinal disorders:

uncommon – abdominal discomfort, diarrhoea, dry mouth, dyspepsia, nausea; rare – epigastric pain, constipation, flatulence, vomiting.

Hepatobiliary disorders:

rare – mild liver injury.

Skin and subcutaneous tissue disorders:

rare – allergic dermatitis, hyperhidrosis, pruritus, urticaria, rash.

Musculoskeletal and connective tissue disorders:

uncommon – muscle weakness, myalgia, limb pain; rare – discomfort in limbs; very rare – osteopenia.

Renal and urinary disorders:

rare – enuresis, proteinuria.

General disorders and administration site conditions:

uncommon – asthenia, discomfort, increased fatigue; rare – feeling drunk, hot flush, irritability, thirst; very rare – chest discomfort.

Investigations:

rare – decreased blood pressure, increased plasma bilirubin concentration, changes in liver enzyme activity, decreased platelet count, leukocytosis; very rare – increased plasma creatinine concentration.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is highly important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

10 tablets in a blister; 3 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

UORLID MEDITSIN ILACH SAN. VE TIDJ. A.S.H./
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine.