Tolimid-almi

INSTRUCTIONS for medical use of the medicinal product TOLIMID-AlMi (TOLIMID-AlMi)

Composition:

Active substances: tolperisone hydrochloride, lidocaine hydrochloride;

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, colourless or slightly coloured solution.

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, together with its inhibitory action on descending motor pathways, likely accounts 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.

Tolperisone also exhibits some weak alpha-adrenergic antagonist properties and has antimuscarinic activity.

Clinical Efficacy and Safety

The efficacy of tolperisone in the treatment of muscle spasticity following stroke has been demonstrated.

According to literature data, in a randomized, double-blind, placebo-controlled study involving 120 patients with post-stroke muscle spasticity, 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 treated patient population (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 compared to placebo in functional test assessments, the differences were not statistically significant.

There are also data from a randomized, double-blind comparative study involving 48 patients with brain damage, showing that the efficacy of tolperisone, as measured by the Barthel Index, was comparable to that of baclofen. At the same time, 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 spasticity are conflicting. Some studies have reported positive results in certain functional tests, 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

Tolperisone undergoes extensive metabolism in the liver and kidneys. It is excreted renally, 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

Based on preclinical data from pharmacological safety, repeated-dose toxicity, genotoxicity, and reproductive toxicity studies, no specific risk for 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 in 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 similar to tolperisone, as well as to any of the excipients of the medicinal product and to other amide-type local anesthetics.

Myasthenia gravis.

Breastfeeding period.

Pediatric age.

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 primarily metabolized by cytochrome CYP2D6, including 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).

Concomitant administration with other CYP2D6 substrates and/or other drugs is not expected to 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. However, when co-administered 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 nonsteroidal anti-inflammatory drugs, 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 most frequently reported with tolperisone. The severity of these reactions varies 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 tolperisone.

Patients should be advised to be aware of the possibility of allergic reactions. They must be informed that if symptoms of allergy 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 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 product contains methylparahydroxybenzoate (E 218), which may cause allergic reactions (possibly delayed) and, in rare cases, bronchospasm.

Use during pregnancy or breastfeeding

Animal studies have shown that tolperisone has no teratogenic effects.

Due to the lack of significant clinical data on the use of this medicinal product, it should not be used during pregnancy.

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

Ability to influence reaction rate when driving or operating machinery

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

Administration and Dosage

For parenteral use only.

For adult use 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, 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 control of kidney function. Tolperisone is not recommended 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 events 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 control of liver function. Tolperisone is not recommended in patients with severe liver 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 have been reported.

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

Adverse reactions

Adverse reactions are listed by system organ classes according to the Medical Dictionary for Regulatory Activities (MedDRA) using MedDRA frequency definitions: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

According to post-marketing surveillance data, 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 rare cases.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature of 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 medicinal products in the same syringe. Administer separately from other drugs.

Packaging.

1 ml in vials No. 5 (5×1) in a blister pack in a box.

Prescription status.

Prescription only.

Manufacturer.

Limited Liability Company "Pharmaceutical Company "Zdorov'ya".

Manufacturer's address and location of business activities.

22 Shevchenka Street, Kharkiv, Kharkiv region, 61013, Ukraine.

Marketing Authorization Holder.

Limited Liability Company "PHARMDISTRIBUTION".

Address of the Marketing Authorization Holder and/or its representative.

45V Yurii Lytvynskyi Street, Kyiv, 02099, Ukraine.