Muscamed

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

Composition:

Active ingredient: thiocolchicoside;

1 hard capsule contains 4 mg or 8 mg of thiocolchicoside;

Excipients: lactose monohydrate; maize starch; magnesium stearate;

capsule shell composition: titanium dioxide (E 171), gelatin.

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

4 mg capsules – hard gelatin capsules, size №3, with a cap and body of matt white color, containing a yellow powder;

8 mg capsules – hard gelatin capsules, size №2, with a cap and body of matt white color, containing a yellow powder.

Pharmacotherapeutic group.

Muscle relaxants with central mechanism of action. ATC code M03BX05.

Pharmacological properties.

Pharmacodynamics.

Thiocolchicoside is a semi-synthetic sulfide derivative of colchicoside with myorelaxant activity.

In vitro studies show that thiocolchicoside binds exclusively to GABA and strychnine-sensitive glycine receptors. Thiocolchicoside exhibits selective affinity for GABA receptors and produces an effective myorelaxant effect through regulatory complex mechanisms at various levels of the nervous system, both in locally induced spasms and in spasms of central origin; however, its glycine-mediated mechanism of action cannot be ruled out.

The characteristics of thiocolchicoside’s interaction with GABA receptors are the same as those of its glucuronide derivative, which is the main metabolite (see below).

In vivo studies have demonstrated the myorelaxant properties of thiocolchicoside and its main metabolite in various experimental models.

Electroencephalographic studies have also shown that thiocolchicoside and its major metabolite do not produce a sedative effect.

Muscemed does not exhibit curare-like effects, does not cause paralysis, and does not affect the cardiovascular or respiratory systems.

Pharmacokinetics.

Absorption.

After oral administration of thiocolchicoside, only two metabolites are detected in blood plasma: the pharmacologically active metabolite SL18.0740 and the inactive metabolite SL59.0955. Maximum plasma concentration (Cmax) of both metabolites is reached approximately 60 minutes after administration. After a single 8 mg oral dose, Cmax and AUC (area under the concentration-time curve) values for metabolite SL18.0740 are approximately 60 ng/mL and 130 ng·hour/mL, respectively. For metabolite SL59.0955, these values are considerably lower: Cmax is about 13 ng/mL, and AUC ranges from 15.5 ng·hour/mL (up to 3 hours) to 39.7 ng·hour/mL (up to 24 hours).

Metabolism.

After oral administration, thiocolchicoside is rapidly metabolized into aglycone-3-dimethylthiocolchicoside (SL59.0955). This occurs primarily via intestinal metabolism, explaining the absence of unchanged thiocolchicoside after oral administration. Metabolite SL59.0955 is glucuronidated to form SL18.0740, which has pharmacological activity equivalent to that of thiocolchicoside and thus accounts for the pharmacological activity observed after oral administration of thiocolchicoside. SL59.0955 is also demethylated to form dimethylthiocolchicine.

Elimination.

After oral administration of 14C-thiocolchicoside, the compound is excreted mainly in feces (79%) and to a lesser extent in urine (20%). Unchanged thiocolchicoside is not excreted in urine or feces. Metabolites SL18.0740 and SL59.0955 are found in both urine and feces, whereas didemethylthiocolchicine is excreted exclusively in feces.

The elimination half-life of metabolite SL18.0740 is 3.2–7 hours, and that of metabolite SL59.0955 is on average 0.8 hours.

Clinical characteristics.

Indications.

Adjunctive therapy for painful muscle spasms associated with acute spinal disorders in adults and adolescents aged 16 years and older.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• Flaccid paralysis, muscle hypotonia;
• Pregnancy;
• Breastfeeding;
• Use in women of childbearing potential who are not using adequate contraceptive measures during treatment and for one month after completion of treatment;
• Use in men who are not using adequate contraceptive measures during treatment and for three months after completion of treatment.

Interaction with other medicinal products and other forms of interaction.

Information on interactions is not available.

Special precautions for use

If diarrhoea develops during treatment, the dose of the medicinal product should be reduced.

During the post-marketing period, cases of liver injury associated with the use of thiocolchicoside have been reported. Severe cases (e.g., fulminant hepatitis) of liver injury have been observed in patients who concurrently used non-steroidal anti-inflammatory drugs or paracetamol. If signs of liver injury occur during treatment with the medicinal product, therapy should be discontinued and medical advice sought (see section "Adverse reactions").

Epileptic seizures may occur during the use of thiocolchicoside in patients suffering from epilepsy or from diseases associated with a risk of seizures (see section "Adverse reactions").

The maximum recommended daily dose of thiocolchicoside, 16 mg, should 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.

According to data from preclinical studies, one of the metabolites of thiocolchicoside, SL59.0955, causes aneuploidy (a change in the number of chromosomes in dividing cells) at concentrations close to those achieved with 8 mg twice daily following oral administration, which may similarly affect humans.

Aneuploidy is considered a risk factor for teratogenicity, embryotoxicity/foetotoxicity, miscarriage, changes in male fertility, and a potential risk factor for carcinogenesis. As a preventive measure, exceeding the recommended dose or prolonged use of the medicinal product should be avoided (see section "Dosage and administration").

Patients should be adequately informed about the potential risks for possible pregnancy and about the effective contraceptive methods that should be used.

The medicinal product contains lactose and therefore should not be used in patients with rare hereditary forms of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Contraception in women and men.

The medicinal product is contraindicated in women of childbearing potential and in men who are not using effective contraception (see section "Contraindications").

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 the end of treatment.

Men must use effective contraception during treatment with thiocolchicoside and for three months after the end of treatment (see section "Contraindications").

Pregnancy.

Information on the use of thiocolchicoside in pregnant women is limited, therefore the potential risk to the embryo and foetus is unknown. Animal studies have shown teratogenic effects of thiocolchicoside. The medicinal product is contraindicated during pregnancy and in women of childbearing potential who are not using appropriate contraceptive measures (see section "Contraindications").

Breastfeeding period.

Thiocolchicoside passes into breast milk. The medicinal product is contraindicated during breastfeeding (see section "Contraindications").

Fertility.

Fertility studies conducted in animals did not show effects on fertility at doses up to 12 mg/kg, i.e., at dose levels that did not cause clinical effects. Thiocolchicoside and its metabolites have an aneugenic effect at various concentration levels, which represents a potential risk factor for human fertility.

Ability to affect reaction speed when driving vehicles or operating machinery.

Studies on the influence of thiocolchicoside on the ability to drive vehicles or operate machinery have not been conducted.

Somnolence may occur during treatment with thiocolchicoside, which should be taken into account when driving vehicles or operating machinery.

Method of Administration and Dosage

The medicinal product is intended for oral administration.

The recommended and maximum daily dose is 8 mg every 12 hours (16 mg per day).

Treatment should not exceed 7 consecutive days.

Exceeding the recommended dose or duration of use should be avoided (see section "Special Instructions").

Children.

The medicinal product is contraindicated in children under 16 years of age.

Overdose.

There is no data regarding cases of overdose. In case of overdose, careful medical monitoring of the patient and symptomatic therapy are recommended.

Adverse Reactions

The adverse reactions listed below are systematized according to MedDRA organ system classes and frequency: 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), and not known (frequency cannot be estimated from available data).

Immune system disorders:

Uncommon – pruritus; rare – urticaria; very rare – hypotension; not known – angioneurotic edema and anaphylactic reactions, including anaphylactic shock.

Nervous system disorders:

Common – somnolence; rare – excitement or brief confusion; not known – malaise, convulsions (see section "Special precautions for use").

Gastrointestinal disorders:

Common – diarrhea, stomach pain; uncommon – nausea, vomiting; rare – heartburn.

Hepatobiliary disorders:

Frequency not known – liver injury (see section "Special precautions for use").

Skin and subcutaneous tissue disorders:

Uncommon – allergic skin reactions.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life.

5 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Packaging.

10 capsules in a blister, 1 or 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

UORLД MEDICINE ILAC SAN. VE TIDJ. A.S., Turkey /
WORLD MEDICINE ILLAC SAN. VE TIC. A.S., Turkey.

Manufacturer's address and place of business.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey /
15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing Authorization Holder.

LLC "WORLD MEDICINE", Ukraine /
WORLD MEDICINE, LLC, Ukraine.