Calmirex^® (Solution) Instructions for Use

Marketing Authorization Holder

Pharmfirma Sotex, CJSC (Russia)

Contact Information

PharmFirma Sotex CJSC (Russia)

ATC Code

M03BX04 (Tolperisone)

Active Substances

Lidocaine (Rec.INN registered by WHO)

Tolperisone (Rec.INN registered by WHO)

Dosage Form

Calmirex®

Solution for intravenous and intramuscular administration 100 mg+2.5 mg/1 ml: amp. 5 or 10 pcs.

Dosage Form, Packaging, and Composition

Solution for intravenous and intramuscular administration transparent, colorless or slightly greenish, with a specific odor.

Excipients : methylparahydroxybenzoate – 0.6 mg, diethylene glycol monoethyl ether – 0.3 ml, concentrated hydrochloric acid – to pH 3.0-4.5, water for injection – to 1 ml.

1 ml – ampoules of light-protective glass type I with a colored break ring or with a colored dot and a notch (5) – contour cell packs (1) – cardboard boxes.
1 ml – ampoules of light-protective glass type I with a colored break ring or with a colored dot and a notch (5) – contour cell packs (2) – cardboard boxes.

Clinical-Pharmacological Group

Centrally acting muscle relaxant

Pharmacotherapeutic Group

Centrally-acting muscle relaxant

Pharmacological Action

Tolperisone hydrochloride – a centrally acting muscle relaxant. It has a membrane-stabilizing, local anesthetic effect, inhibits the conduction of nerve impulses in primary afferent fibers and motor neurons, which leads to the blocking of spinal mono- and polysynaptic reflexes. Presumably, tolperisone mediates the blocking of neurotransmitter release by inhibiting the influx of calcium ions into synapses. It inhibits the conduction of excitation along the reticulospinal pathway in the brainstem. Independently of its effect on the CNS, it enhances peripheral blood flow. This effect is not associated with the drug’s effect on the CNS and may be due to the weak antispasmodic and antiadrenergic action of tolperisone.

Lidocaine hydrochloride has a local anesthetic effect and, when dosed according to the instructions, does not have a systemic effect.

Pharmacokinetics

Tolperisone hydrochloride

Tolperisone undergoes intensive metabolism in the liver and kidneys. It is excreted in the urine almost exclusively (more than 99%) as metabolites, the pharmacological activity of which is unknown. T_1/2 after intravenous administration is about 1.5 hours.

Lidocaine hydrochloride

Absorption is complete (the rate of absorption depends on the site of administration and the dose). Time to reach C_max in plasma after intramuscular administration is 30-45 minutes. Plasma protein binding is 50-80%.

It is rapidly distributed in tissues and organs. It penetrates the blood-brain barrier and the placental barrier, and is secreted into breast milk (40% of the concentration in maternal plasma). It is metabolized in the liver (90-95%) with the participation of microsomal enzymes by dealkylation of the amino group and cleavage of the amide bond with the formation of active metabolites. It is excreted in the bile (part of the dose undergoes reabsorption in the gastrointestinal tract) and by the kidneys (up to 10% unchanged).

Indications

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

ICD codes

Dosage Regimen

Adults – daily 1 ml (100 mg tolperisone) 2 times intramuscularly or 1 ml (100 mg tolperisone) 1 time/day intravenously, slowly.

Patients with renal impairment

Experience with tolperisone in patients with renal impairment is limited, and adverse reactions occurred more frequently in this category of patients. Therefore, in patients with moderate renal impairment, dose titration should be performed with careful monitoring of the patient’s health and renal function. In severe renal impairment, the use of tolperisone is not recommended.

Patients with hepatic impairment

Experience with tolperisone in patients with hepatic impairment is limited, and adverse reactions occurred more frequently in this category of patients. Therefore, in patients with moderate hepatic impairment, dose titration of tolperisone should be performed with careful monitoring of the patient’s health and hepatic function. In severe hepatic impairment, the use of tolperisone is not recommended.

Children

The drug is not intended for use in children and adolescents under 18 years of age.

Adverse Reactions

The safety profile of tolperisone was assessed based on post-marketing use data from 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 post-marketing use, hypersensitivity reactions accounted for 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: uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <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; frequency unknown – angioneurotic edema, including facial edema, lip edema.

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

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

Nervous system disorders uncommon – headache, dizziness, drowsiness; rare – attention disturbance, tremor, epilepsy, hypesthesia, paresthesia, lethargy.

Eye disorders rare – blurred vision.

Ear and labyrinth disorders rare – tinnitus, vertigo.

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

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

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

Hepatobiliary disorders rare – mild hepatic failure.

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

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

Renal and urinary disorders rare – enuresis, proteinuria.

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

Investigations rare – decreased blood pressure, hyperbilirubinemia, change in liver enzyme activity, thrombocytopenia, leukocytosis; very rare – increased plasma creatinine concentration.

Contraindications

• Hypersensitivity to tolperisone or the chemically similar eperisone or to any of the components of the drug (including lidocaine);
• Myasthenia gravis;
• Pregnancy;
• Lactation period;
• Children and adolescents under 18 years of age.

With caution the drug should be used in women, patients with hypersensitivity to other drugs or with a history of allergy (see section “Special Precautions”), in patients with renal and hepatic impairment (see section “Dosage Regimen”).

Use in Pregnancy and Lactation

Pregnancy

Experimental animal studies have not revealed a teratogenic effect of tolperisone. Due to the lack of significant clinical data, tolperisone should not be used during pregnancy, 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 not available, the use of the drug during breastfeeding is contraindicated.

Use in Hepatic Impairment

The drug should be used with caution in hepatic impairment.

Use in Renal Impairment

The drug should be used with caution in renal impairment.

Pediatric Use

The use of the drug in children and adolescents under 18 years of age is contraindicated.

Special Precautions

The most frequent adverse reactions during the post-registration use of tolperisone were hypersensitivity reactions. Their severity varies from mild skin reactions to severe systemic reactions, including anaphylactic shock. Symptoms of hypersensitivity reactions may include erythema, rash, urticaria, pruritus, angioedema, tachycardia, arterial hypotension, or dyspnea.

Women and patients with hypersensitivity to other drugs or with a history of allergy may be at a higher risk of hypersensitivity to tolperisone.

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, the drug should be discontinued immediately and a doctor should be consulted promptly. Tolperisone should not be re-administered after an episode of hypersensitivity to the drug containing it.

Excipients

The drug contains methylparahydroxybenzoate, which may cause allergic reactions (possibly delayed) and, in exceptional cases, bronchospasm.

Effect on ability to drive vehicles and operate machinery

Tolperisone does not affect the ability to drive vehicles and operate machinery. Patients who experience dizziness, drowsiness, attention disturbance, epilepsy, blurred vision, or muscle weakness while taking tolperisone should consult a doctor.

Overdose

Symptoms drowsiness, gastrointestinal disorders (nausea, vomiting, epigastric pain), tachycardia, increased blood pressure, bradykinesia and vertigo. In severe cases – ataxia, tonic-clonic convulsions, shortness of breath and respiratory paralysis.

Treatment symptomatic therapy is recommended. There is no specific antidote.

Drug Interactions

Pharmacokinetic drug interaction studies 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 and 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 of CYP2D6 isoenzyme substrates and/or other drugs is not expected.

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 dose reduction 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 from 8°C (46.4°F) to 15°C (59°F).

Shelf Life

Shelf life – 2 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.