Tokkata

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TOCCATA® (TOCCATA)

Composition:

Active substance: tolperisone hydrochloride;

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

Excipients:

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

Coating: OpaDry 03F180011 white (hypromellose, titanium dioxide (E 171), macrogol).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, round, biconvex film-coated tablets with a characteristic odor.

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, achieving 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, together with its inhibitory action on descending motor pathways, is likely responsible for 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. 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 effect, tolperisone may also inhibit neurotransmitter release.

Furthermore, tolperisone has some weakly expressed alpha-adrenergic antagonist properties 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, highly significant reduction in spasticity according to the Ashworth scale—the primary endpoint—was observed with tolperisone treatment. 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 per 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 damage, the efficacy of tolperisone, as measured by the Barthel Index, was comparable to that of baclofen. However, tolperisone outperformed 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 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

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 increases 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 the 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, and genotoxicity, no specific risk to humans has been identified regarding toxic effects on reproductive function.

Observed effects 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 the drug 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 the active substance or to eperisone, which is chemically similar, or to any of the excipients of the medicinal product.
• 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 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).

Exposure to tolperisone is not expected to increase when administered concomitantly with other CYP2D6 substrates and/or other drugs, due to the diversity of tolperisone's metabolic pathways.

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 drug, the likelihood of developing a sedative effect with its use is low. However, 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 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 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, angioedema, tachycardia, hypotension, or dyspnea.

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

Patients should be advised to monitor their condition carefully for possible signs of allergy. Patients must be informed that if allergic symptoms 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 product contains lactose monohydrate. Patients with rare hereditary disorders 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 tolperidone has no teratogenic effects.

Due to the lack of significant clinical data on the use of this drug, tolperidone should not be used during pregnancy.

Since it is unknown whether tolperidone is excreted in human breast milk, the use of Tokkata® 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 driving or operating machinery while taking this medication.

Dosage and Administration

The medication should be taken after a meal, with a glass of water. Inadequate food intake may reduce tolperisone bioavailability.

Adults: Depending on individual needs and tolerability, 150–450 mg daily in three divided doses.

Patients with renal impairment

Experience with the use of tolperisone in patients with renal impairment 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 renal function. Tolperisone is not recommended for use in patients with severe renal impairment.

Patients with hepatic impairment

Experience with the use of tolperisone in patients with hepatic impairment 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 liver function. Tolperisone is not recommended for use in patients with severe hepatic 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 observed adverse reactions were those affecting the skin and subcutaneous tissue, systemic disorders, and disorders 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 system organ classes according to the Medical Dictionary for Regulatory Activities (MedDRA), using MedDRA frequency definitions: uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated from available data).

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization of a medicinal product is of significant importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare 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. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

The medicinal product does not require special storage conditions. Store in the original packaging. Keep out of reach of children.

Packaging.

10 tablets in a blister. 3 blisters in a carton.

Prescription status. Prescription only.

Manufacturer.

JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.