Tolizor^® (Capsules) Instructions for Use

Marketing Authorization Holder

Atoll LLC (Russia)

Manufactured By

Ozon, LLC (Russia)

Or

Ozon Pharm, LLC (Russia)

Contact Information

OZON LLC (Russia)

ATC Code

M03BX04 (Tolperisone)

Active Substance

Tolperisone (Rec.INN registered by WHO)

Dosage Forms

	Tolizor®	Capsules 50 mg: from 5 to 300 pcs.
		Capsules 150 mg: from 5 to 300 pcs.

Dosage Form, Packaging, and Composition

Capsules hard, gelatin No. 2, light yellow body, light gray cap, opaque; capsule contents – a mixture of powder and granules white or almost white in color, with a characteristic odor; compaction of the capsule contents into lumps shaped like the capsule is allowed.

Excipients : microcrystalline cellulose (MCC-101) – 46.1 mg, lactose monohydrate (milk sugar) – 38.43 mg, corn starch – 7.5 mg, talc – 3 mg, stearic acid – 2 mg, hypromellose – 1.46 mg, colloidal silicon dioxide – 0.77 mg, citric acid monohydrate – 0.74 mg.

Capsule body composition iron oxide yellow dye – 0.0733%, titanium dioxide – 1%, water – 14.5%, gelatin – up to 100%.
Capsule cap composition iron oxide black dye – 0.05%, titanium dioxide – 2%, water – 14.5%, gelatin – up to 100%.

From 5 to 30 pcs. – blister packs (from 1 to 10 pcs.) – cardboard packs.

Capsules hard, gelatin No. 0, light gray body, yellow cap, opaque; capsule contents – a mixture of powder and granules white or almost white in color, with a characteristic odor; compaction of the capsule contents into lumps shaped like the capsule is allowed.

Excipients : microcrystalline cellulose (MCC-101) – 56.69 mg, lactose monohydrate (milk sugar) – 47.24 mg, corn starch – 14.25 mg, talc – 5.7 mg, stearic acid – 6 mg, hypromellose – 1.79 mg, colloidal silicon dioxide – 1.11 mg, citric acid monohydrate – 2.22 mg.

Capsule body composition iron oxide black dye – 0.05%, titanium dioxide – 2%, water – 14.5%, gelatin – up to 100%.
Capsule cap composition quinoline yellow dye – 0.75%, sunset yellow FCF dye – 0.0059%, titanium dioxide – 2%, water – 14.5%, gelatin – up to 100%.

From 5 to 30 pcs. – blister packs (from 1 to 10 pcs.) – cardboard packs.

Clinical-Pharmacological Group

Centrally acting muscle relaxant

Pharmacotherapeutic Group

Centrally acting muscle relaxants; other centrally acting muscle relaxants

Pharmacological Action

Tolperisone is a centrally acting muscle relaxant. The mechanism of action is not fully understood.

Tolperisone has a high affinity for nervous tissue, reaching the highest concentrations in the brainstem, spinal cord, and peripheral nervous system. The main effect of tolperisone is mediated by inhibition of spinal reflex arcs.

This effect, combined with the elimination of facilitation of conduction along descending pathways, probably provides the therapeutic effect of tolperisone. The chemical structure of tolperisone is similar to that of lidocaine.

Like lidocaine, Tolperisone has a membrane-stabilizing effect and reduces the electrical excitability of motor neurons and primary afferent fibers. Tolperisone dose-dependently inhibits the activity of voltage-gated sodium channels. Accordingly, the amplitude and frequency of the action potential decrease. An inhibitory effect on voltage-gated calcium channels has been proven.

It is assumed that in addition to its membrane-stabilizing action, Tolperisone may also inhibit neurotransmitter release. Tolperisone has some weak α-adrenergic antagonist and antimuscarinic properties.

Pharmacokinetics

Absorption

After oral administration, Tolperisone is well absorbed from the small intestine. The maximum plasma concentration (C_max) is noted 0.5-1 h after administration. Due to significant presystemic metabolism, bioavailability is about 20%.

A fat-rich meal increases the bioavailability of orally administered tolperisone to approximately 100% and increases the maximum plasma concentration by approximately 45% compared to taking the drug on an empty stomach, delaying the time to reach C_max by approximately 30 min.

Metabolism

Tolperisone is intensively metabolized in the liver and kidneys. The pharmacological activity of the metabolites is unknown.

Excretion

It is almost completely (more than 99%) excreted by the kidneys in the form of metabolites. T_1/2 after oral administration is about 2.5 h.

Indications

• Symptomatic treatment of spasticity in adults due to stroke;
• Moderate to severe myofascial pain syndrome (including muscle spasm in dorsopathies).

ICD codes

Dosage Regimen

The drug is taken orally, after meals, without chewing, without opening the capsule, with a small amount of water. The bioavailability of tolperisone decreases when taken on an empty stomach.

The dose of the drug is selected based on the individual needs of the patient and drug tolerance.

It is prescribed as 50 mg 3 times/day, gradually increasing the dose to 150 mg 3 times/day. The recommended daily dose is 150-450 mg, divided into three doses.

Experience with the use of tolperisone in patients with renal impairment is limited; adverse reactions occurred more frequently in this category of patients. Therefore, in patients with moderate renal impairment, it is necessary to titrate the dose of tolperisone, with careful monitoring of the patient’s health and renal function. The use of the drug is not recommended in patients with severe renal impairment.

Experience with the use of tolperisone in patients with hepatic impairment is limited; adverse reactions occurred more frequently in this category of patients. Therefore, in patients with moderate hepatic impairment, it is necessary to titrate the dose of tolperisone, with careful monitoring of the patient’s health and hepatic function. The use of the drug is not recommended in patients with severe hepatic impairment.

Adverse Reactions

The safety profile of tolperisone is confirmed by data from use in more than 12,000 patients. According to this data, the most frequent were disorders of the skin and subcutaneous tissues, general disorders, disorders of the nervous system and gastrointestinal tract.

In the post-registration period, hypersensitivity reactions accounted for about 50-60% of all adverse reactions. Most adverse reactions were not serious and resolved on their own. Life-threatening hypersensitivity reactions were reported very rarely.

Adverse reactions are listed below according to the MedDRA classification and frequency: infrequent (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

Blood and lymphatic system disorders very rare – anemia, lymphadenopathy.

Immune system disorders rare – hypersensitivity reactions, anaphylactic reactions; very rare – anaphylactic shock.

Metabolism and nutrition disorders infrequent – anorexia; very rare – polydipsia.

Psychiatric disorders infrequent – sleep disorder, insomnia; rare – asthenia, depression; very rare – confusion.

Nervous system disorders infrequent – headache, dizziness, drowsiness; rare – attention deficit disorder, tremor, convulsions, malaise, paresthesia, lethargy.

Eye disorders rare – decreased visual acuity.

Ear and labyrinth disorders rare – tinnitus, vertigo.

Cardiac disorders infrequent – arterial hypotension; rare – angina pectoris, tachycardia, palpitations, flushing; very rare – bradycardia.

Respiratory, thoracic and mediastinal disorders rare – dyspnea, epistaxis, tachypnea.

Gastrointestinal disorders infrequent – abdominal discomfort, dyspepsia, diarrhea, dry mouth, nausea; rare – epigastric pain, constipation, flatulence, vomiting.

Hepatobiliary disorders rare – moderate hepatic failure.

Skin and subcutaneous tissue disorders rare – allergic dermatitis, hyperhidrosis, skin itching, skin rash, urticaria.

Musculoskeletal and connective tissue disorders infrequent – muscle weakness, myalgia, limb pain; rare – limb discomfort; very rare – osteopenia.

Renal and urinary disorders rare – enuresis, proteinuria.

General disorders and administration site conditions infrequent – asthenia, discomfort, feeling of tiredness; rare – feeling of drunkenness, feeling hot, irritability, thirst; very rare – chest discomfort.

Investigations rare – hyperbilirubinemia, change in liver enzyme activity, thrombocytopenia, leukocytosis; very rare – hypercreatininemia.

*Within the framework of post-registration monitoring, angioedema, including swelling of the face and lips, has been reported (frequency unknown).

If any of the reactions listed in the instructions worsen or any other adverse reactions not listed in the instructions are noted, the patient must inform the doctor.

Contraindications

• Hypersensitivity to any component of the drug;
• Myasthenia gravis;
• Age under 18 years;
• Breastfeeding;
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

Use in Pregnancy and Lactation

Pregnancy

Experimental studies in animals have not revealed a teratogenic effect of tolperisone. Due to the lack of significant clinical data, Tolperisone should not be used during pregnancy (especially in the first trimester), except in cases where the expected benefit definitely justifies the potential risk to the fetus.

Breastfeeding period

Since data on the excretion of tolperisone in breast milk are lacking, the use of the drug during breastfeeding is contraindicated.

Use in Hepatic Impairment

The drug should be prescribed with caution to patients with hepatic impairment.

Use in Renal Impairment

The drug should be prescribed with caution to patients with renal impairment.

Pediatric Use

The use of the drug is contraindicated under the age of 18 years.

Special Precautions

The most frequent adverse reactions are hypersensitivity reactions.

Allergic reactions range from mild skin reactions to severe systemic reactions, including anaphylactic shock. Symptoms of an allergic reaction: redness, rash, urticaria, itching, angioedema, tachycardia, arterial hypotension and dyspnea.

Female patients with a history of hypersensitivity reactions to other drugs or allergic reactions are at higher risk.

In case of known hypersensitivity to lidocaine, increased caution should be exercised when using tolperisone due to possible cross-reactions.

Patients should be attentive to any symptoms of hypersensitivity. If symptoms occur, tolperisone should be discontinued immediately and a doctor should be consulted immediately. Tolperisone should not be re-administered after an episode of hypersensitivity to the drug containing it.

Effect on ability to drive vehicles and machinery

Tolizor^® does not affect the ability to drive vehicles and machinery. Patients who experienced dizziness, drowsiness, attention impairment, convulsions, visual impairment, or muscle weakness while taking the drug should consult a doctor.

Overdose

Data on tolperisone overdose are limited. In preclinical studies of acute toxicity, high doses of tolperisone caused ataxia, tonic-clonic convulsions, dyspnea, and respiratory paralysis. Tolperisone does not have a specific antidote. In case of overdose, symptomatic and supportive treatment is recommended.

Drug Interactions

Studies of pharmacokinetic drug interaction with the CYP2D6 isoenzyme marker substrate dextromethorphan have shown that simultaneous use of tolperisone may increase the blood levels of drugs that are metabolized primarily by the CYP2D6 isoenzyme (thioridazine, tolterodine, venlafaxine, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine).

In laboratory experiments on human liver microsomes and human hepatocytes, no significant inhibition or induction of other CYP isoenzymes (CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP1A2, CYP3A4) was detected.

Due to the diversity of tolperisone’s metabolic pathways, an increase in tolperisone exposure during simultaneous use with CYP2D6 isoenzyme substrates and/or other drugs is not expected.

The bioavailability of tolperisone decreases when taken on an empty stomach.

Although Tolperisone is a centrally acting drug, its sedative effect is very low. When used simultaneously with other centrally acting muscle relaxants, the dose of tolperisone should be reduced.

Tolperisone enhances the effect of niflumic acid, so when used simultaneously, a reduction in the dose of niflumic acid or other NSAIDs should be considered.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.