MYOREL

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MIOREL (MIOREL)

Composition:

Active substance: thiocolchicoside;

1 ampoule (2 ml) contains thiocolchicoside 4 mg;

Excipients: sodium chloride, water for injections;

Pharmaceutical form. Solution for injection.

Main physico-chemical properties: Clear yellow solution.

Pharmacotherapeutic group. Centrally acting muscle relaxants. Thiocolchicoside. ATC code M03BX05.

Pharmacological Properties

Pharmacodynamics

Tiocolchicoside is a semi-synthetic sulfur derivative of colchicoside with muscle relaxant properties.

In vitro, tiocolchicoside binds only to strychnine-sensitive GABAergic and glycinergic receptors. Since tiocolchicoside acts as a GABAergic receptor antagonist, its muscle relaxant effect may be mediated at the supraspinal level via a complex regulatory mechanism, although a glycinergic mechanism of action cannot be excluded. The qualitative and quantitative characteristics of interaction with GABAergic receptors are similar between tiocolchicoside and its main circulating metabolite, which is a glucuronidated derivative (see section "Pharmacokinetics").

In vivo studies have demonstrated the muscle relaxant properties of tiocolchicoside and its main metabolite in various experimental models in rats and rabbits. The absence of a muscle relaxant effect of tiocolchicoside in rats with transected spinal cord indicates predominantly supraspinal activity. Furthermore, electroencephalographic studies have shown that tiocolchicoside and its main metabolite do not have sedative effects.

Pharmacokinetics

Absorption

After intramuscular administration, maximum plasma concentration (C_max) of tiocolchicoside is observed within 30 minutes. Plasma levels of 113 ng/mL are achieved after a 4 mg dose, and 175 ng/mL after an 8 mg dose. Corresponding values for the area under the plasma concentration–time curve (AUC) are 283 ng·h/mL and 417 ng·h/mL, respectively.

The pharmacologically active metabolite SL18.0740 is also detected at lower concentrations, with a C_max of 11.7 ng/mL reached 5 hours after administration of the dose, and an AUC of 83 ng·h/mL.

Data on the inactive metabolite SL59.0955 are not available.

Distribution

The apparent volume of distribution of tiocolchicoside is estimated at 42.7 L following intramuscular administration of 8 mg. Data on both metabolites are not available.

Elimination

After intramuscular administration, the expected elimination half-life of tiocolchicoside is 1.5 hours, and plasma clearance is 19.2 L/h.

Clinical characteristics

Indications. Use as an additional therapy for painful muscular contractures in acute spinal disorders in adults and adolescents aged 16 years and older.

Contraindications. Thiocolchicoside should not be used:

• in patients with hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• in patients with hypersensitivity to colchicine;
• during the entire pregnancy period;
• during breastfeeding;
• in women of childbearing potential who are not using effective contraceptive methods during treatment and for one month after discontinuation of treatment (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding");
• in patients with flaccid paralysis or muscular hypotonia;
• in men who are not using effective contraceptive methods during treatment and for three months after discontinuation of treatment;
• in patients with coagulation disorders or those undergoing long-term anticoagulant therapy.

Interaction with other medicinal products and other forms of interaction. Information on interactions is not available.

Special precautions for use

In case of diarrhea, the dosage should be reduced accordingly.

After intramuscular administration, episodes of vasovagal syncope have been observed; therefore, patients should be monitored following injection (see section "Adverse reactions").

During the post-marketing period, cases of liver injury (e.g., cytolytic or cholestatic hepatitis) have been reported with the use of thiocolchicoside. Severe cases (fulminant hepatitis) have been reported in patients concurrently using non-steroidal anti-inflammatory drugs (NSAIDs) or paracetamol. Patients should discontinue treatment and consult a physician immediately upon the appearance of signs and symptoms of liver injury (see section "Adverse reactions").

In patients with epilepsy or conditions associated with a risk of seizures, thiocolchicoside may provoke seizures. Therefore, a risk-benefit assessment should be performed before initiating treatment, and clinical monitoring should be intensified. Treatment must be discontinued if seizures occur.

The maximum recommended daily dose of thiocolchicoside—8 mg—must not be exceeded. This dose should be divided into two administrations with a 12-hour interval. If a dose is missed, the next dose should be administered at the usual time.

Genotoxicity

Preclinical studies have shown that one of the metabolites of thiocolchicoside (SL59.0955), at concentrations close to those observed in humans following oral administration of 8 mg twice daily, induces aneuploidy (i.e., an unequal number of chromosomes in dividing cells). Aneuploidy is considered a risk factor for teratogenicity, embryotoxicity/fetotoxicity, pregnancy loss, reduced male fertility, and as a potential risk factor for cancer.

As a precautionary measure, doses higher than recommended or prolonged use should be avoided (see section "Dosage and administration").

Patients (both sexes) should be provided with detailed information about the potential risks in case of pregnancy and the importance of using effective contraception during treatment with thiocolchicoside and after discontinuation of treatment: for one month in women and for three months in men (see sections "Contraindications" and "Use in pregnancy and lactation").

Injection site reactions

Following intramuscular administration of thiocolchicoside, injection site reactions have been reported, including necrosis, cutaneous medication embolism (also known as Nicolau syndrome), and livedoid dermatitis.

Appropriate injection technique should be followed when administering thiocolchicoside intramuscularly.

Sodium content

The medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding

Contraception in women and men

MIOREL is contraindicated in women of childbearing potential and in men if they are not using effective contraception.

Due to the aneugenic potential of thiocolchicoside and its metabolites, women of childbearing potential must use effective contraception during treatment with thiocolchicoside and for one month after discontinuation of treatment.

Men must use effective contraception during treatment with thiocolchicoside and for three months after discontinuation of treatment (see sections "Contraindications" and "Special precautions for use").

Pregnancy

Data on the use of thiocolchicoside in pregnant women are limited. Therefore, the potential risks to the embryo and fetus are unknown. Animal studies have demonstrated teratogenic effects. MIOREL is contraindicated during pregnancy (see section "Contraindications").

Lactation

Since thiocolchicoside passes into breast milk, the medicinal product is contraindicated during breastfeeding (see section "Contraindications").

Fertility

Thiocolchicoside and its metabolites have an aneugenic effect at various concentrations, which poses a risk to human fertility.

Effect on ability to drive and use machines

Clinical studies have not revealed any psychomotor changes associated with the use of thiocolchicoside.

However, somnolence may occur frequently, which should be taken into account by drivers and machine operators.

Method of Administration and Dosage

The medicinal product MIOREL should be administered intramuscularly.

The recommended maximum daily dose is 4 mg every 12 hours (8 mg per day). Treatment should not last longer than 5 consecutive days.

The recommended dose or duration of use should not be exceeded (see section "Special Warnings and Precautions for Use").

Children. The medicinal product MIOREL should not be used in children under 16 years of age.

Overdose

There are no data regarding cases of overdose.

In case of overdose, careful medical monitoring of the patient and symptomatic therapy are recommended.

Adverse Reactions

The frequency of adverse reactions is defined according to the following categories: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

Immune system disorders:

Uncommon: pruritus.

Rare: hypersensitivity reactions such as urticaria.

Very rare: arterial hypotension.

Frequency not known: angioedema and anaphylactic reactions, including anaphylactic shock.

Nervous system disorders:

Common: drowsiness.

Rare: transient excitement or confusion.

Frequency not known: malaise, with or without vasovagal syncope within the first few minutes after intramuscular injection; seizures (see section "Special precautions").

Gastrointestinal disorders:

Common: diarrhea (see section "Special precautions"), gastralgia.

Uncommon: nausea, vomiting.

Rare: heartburn.

Hepatobiliary disorders:

Frequency not known: hepatic injury (e.g., cytolytic or cholestatic hepatitis) (see section "Special precautions").

Skin and subcutaneous tissue disorders:

Uncommon: skin allergic reactions such as pruritus, erythema, maculopapular rash, vesiculobullous rash.

General disorders and administration site conditions:

Frequency not known: injection site reactions, including swelling, erythema, pruritus, pain around the injection site, and Nicolau syndrome (cutaneous embolization or livedoid dermatitis) following intramuscular injection.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions

Store at a temperature not exceeding 25 °C.

Keep out of the reach and sight of children.

Incompatibilities

No data available.

Packaging. 2 ml in a vial, 5 vials in a blister pack and cardboard box.

Prescription status. Prescription only.

Manufacturer. Esseti Farmaceutici S.r.l.

Manufacturer's address

Via Campobello 15, Pomezia, 00071, Italy

Marketing Authorization Holder. FORS-PHARMA DISTRIBUTION LLC.

Address of the Marketing Authorization Holder

132 Holosiivskyi Avenue, Kyiv, 03127, Ukraine