Thiocolchicoside

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT THIOCOLCHICOSIDE

Composition:

Active substance: thicolchicoside;

1 ampoule (2 ml) contains thicolchicoside 4 mg;

Excipients: sodium chloride, hydrochloric acid concentrated, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear yellow solution, practically free from particles.

Pharmacotherapeutic group. Muscle relaxants. Muscle relaxants with central mechanism of action. Other centrally acting agents. Thicolchicoside.

ATC code M03BX05.

Pharmacological Properties

Pharmacodynamics

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

In vitro studies have shown that thiocolchicoside binds only 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 different levels of the nervous system; however, its glycine-mediated mechanism of action cannot be excluded.

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.

Additionally, electroencephalographic studies have shown that thiocolchicoside and its major metabolite do not produce a sedative effect.

Pharmacokinetics

Absorption

After intramuscular administration, maximum plasma concentration (C_max) of thiocolchicoside is reached 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 area under the pharmacokinetic curve (AUC) are 283 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 AUC of 83 ng·h/mL.

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

Distribution

The apparent volume of distribution of thiocolchicoside is approximately 42.7 L after intramuscular administration of 8 mg. Data on both metabolites are not available.

Elimination

The elimination half-life of thiocolchicoside is 1.5 hours, and plasma clearance is 19.2 L/h.

Clinical characteristics

Indications

Adjunctive therapy for painful muscular contractures in acute spinal disorders in adults and children aged 16 years and older.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• flaccid paralysis, muscular hypotonia;
• pregnancy;
• breastfeeding period;
• women of childbearing potential who are not using appropriate contraceptive methods during treatment with Thiocolchicoside and for one month after discontinuation of treatment (see sections "Special warnings and precautions for use" and "Use in pregnancy or lactation");
• men who are not using appropriate contraceptive methods during treatment with Thiocolchicoside and for three months after discontinuation of treatment (see sections "Special warnings and precautions for use" and "Use in pregnancy or lactation").

Interaction with other medicinal products and other forms of interaction

Information regarding interaction is lacking.

Special precautions for use

Vasovagal syncope has been reported after intramuscular injection of thiocolchicoside; therefore, patients should be monitored after administration of the medicinal product (see section "Adverse reactions").

Hepatic injury associated with the use of thiocolchicoside has been reported in the post-marketing period. 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").

Seizures may occur in patients with epilepsy or conditions associated with a risk of seizures during treatment with thiocolchicoside (see section "Adverse reactions").

The maximum recommended dose of thiocolchicoside, 8 mg per day, 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 preclinical data, one of the metabolites of thiocolchicoside, SL59.0955, causes aneuploidy (alteration in the number of chromosomes in dividing cells) at concentrations close to those achieved in humans at an oral dose of 8 mg twice daily.

Aneuploidy is considered a risk factor for teratogenicity, embryotoxicity/fetotoxicity, spontaneous abortion, changes in male fertility, and potential carcinogenic risk. As a precaution, exceeding the recommended dose or prolonged use of the medicinal product should be avoided (see section "Method of administration and dosage").

Patients should be adequately informed about the potential risks for possible pregnancy and the need to use effective contraceptive methods.

Reactions at the injection site

Reactions at the injection site have been reported after intramuscular administration of thiocolchicoside, including necrosis at the injection site and cutaneous drug embolism, also known as Nicolau syndrome and livedoid dermatitis (see section "Adverse reactions"). Proper injection technique must be followed when administering thiocolchicoside intramuscularly.

Genotoxic potential

Preclinical studies have shown that one of the metabolites of thiocolchicoside (SL59.0955), at concentrations close to human exposure levels, causes aneuploidy (i.e., an abnormal number of chromosomes in dividing cells) at oral doses of 8 mg twice daily. Aneuploidy is considered a risk factor for teratogenicity, embryotoxicity/fetotoxicity, spontaneous abortion, reduced male fertility, and potential tumour development.

As a precautionary measure, the use of the medicinal product at doses higher than recommended or for prolonged periods should be avoided (see section "Method of administration and dosage").

Patients (both men and women) should be thoroughly informed about the potential risks in case of pregnancy and the effective contraceptive measures to be followed (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Important information on excipients

The medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Contraception in women and men

Thiocolchicoside is contraindicated in women of childbearing potential and in men who do not use 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 fetus is unknown. Animal studies have shown teratogenic effects of thiocolchicoside. The medicinal product is contraindicated during pregnancy (see section "Contraindications").

Breastfeeding

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 concentration levels, which represents a risk factor for impaired human fertility.

Ability to influence the speed of reactions while driving or operating machinery

No studies on the effect of thiocolchicoside on the ability to drive or operate machinery have been conducted.

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

Dosage and Administration

The medicinal product is intended for intramuscular injection.

The recommended maximum daily dose is 4 mg every 12 hours (8 mg per day).

Treatment should not exceed 5 consecutive days.

Exceeding the recommended dose or duration of use should be avoided (see section "Special Warnings and Precautions for Use").

Children

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

Overdose

There are no data regarding cases of overdose. In the event 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 based on 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, with or without vasovagal syncope within the first few minutes after intramuscular injection; seizures (see section "Dosage and Administration").

Gastrointestinal disorders:

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

Hepatobiliary disorders:

Frequency not known – liver injury (see section "Dosage and Administration").

Skin and subcutaneous tissue disorders:

Uncommon – allergic skin reactions.

General disorders and administration site conditions:

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

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after medicinal product registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life

2.5 years.

Do not use after the expiry date stated on the packaging.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging

2 ml in an ampoule; 5 ampoules in a blister pack made of film, 1 or 2 blisters per cardboard box.

Prescription status

Prescription only.

Manufacturer

JSC "Lubnipharm".

Manufacturer's address and location of its business activity

16, Barvinkova St., Lubny, Poltava Oblast, 37500, Ukraine.