Tolperil-zdorovya

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TOLOPERIL-ZDOROVYE (TOLPERIL-ZDOROVYE)

Composition:

Active substances: tolperisone, lidocaine;

1 ml of the preparation contains tolperisone hydrochloride 100 mg, lidocaine hydrochloride 2.5 mg;

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or slightly colored solution.

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 a 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, 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 action, tolperisone may also inhibit neurotransmitter release.

Furthermore, tolperisone has 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.

According to scientific literature, 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 physicians and investigators, 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. 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 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 based on 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 data from 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 (T½) is approximately 1.5 hours.

Preclinical Safety Data

According to preclinical pharmacological safety studies, repeated-dose toxicity, genotoxicity, and toxic effects on reproductive function, no specific risk to humans has been identified.

Effects observed in preclinical studies occurred only at doses significantly exceeding the maximum recommended human doses and are therefore of 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 related to tolperisone, as well as to any of the excipients and to other amide-type local anesthetics.

Myasthenia gravis.

Breastfeeding period.

Children.

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).

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

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 non-steroidal anti-inflammatory drugs (NSAIDs), should be reduced.

Special precautions for use.

Do not prescribe the injectable form of the medicinal product to children.

Hypersensitivity reactions. During post-marketing surveillance, hypersensitivity reactions have been the most frequently reported events associated with tolperidone use. These reactions may vary in severity from mild skin reactions to severe systemic reactions, including anaphylactic shock. Symptoms of hypersensitivity reactions 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 a higher risk of hypersensitivity reactions when using tolperidone.

Patients should be advised to remain alert for possible allergic reactions. Patients must be informed that if symptoms of allergy occur, they should discontinue tolperidone immediately and seek urgent medical attention.

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

The medicinal product contains lidocaine; therefore, it should not be used in patients with known hypersensitivity to lidocaine or to other amide-type local anesthetics due to the possibility of cross-allergic reactions.

The medicinal product contains methylparaben (E 218), which may cause allergic reactions (possibly delayed) and, in rare cases, bronchospasm.

Use during pregnancy or breast-feeding.

Animal studies indicate that tolperidone has no teratogenic effects.

Due to the lack of adequate clinical data, the medicinal product should not be used during pregnancy.

As it is unknown whether tolperidone passes into breast milk, the use of the medicinal product during lactation is contraindicated.

Effects on ability to drive vehicles or operate machinery.

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

Dosage and Administration.

For parenteral use only.

For use in adults only. Administer the medicinal product intramuscularly at a dose of 100 mg tolperisone twice daily or as a slow intravenous injection of 100 mg tolperisone once 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: a higher frequency of adverse effects 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 in severe renal impairment.

Patients with hepatic impairment.

Experience with the use of the drug in patients with liver damage is limited: a higher frequency 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 in severe hepatic impairment.

Children.

The medicinal product must not be used in children.

Overdose.

Data regarding overdose are insufficient.

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

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

Adverse reactions.

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

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

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature from 2 °C to 8 °C.

Keep out of reach of children.

Incompatibility. No data available; therefore, the medicinal product should not be mixed with other drugs in the same syringe. Administer separately from other drugs.

Packaging.

1 ml in ampoules, pack of 5 in a box; pack of 5 (5×1) in a blister pack in a box.

Prescription status.

Prescription only.

Manufacturer.

LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's address and place of business activity.