Thionex

INSTRUCTIONS for medical use of the medicinal product THIONEX (THIONEX)

Composition:

Active substance: thiocolchicoside;

1 tablet contains 8 mg of thiocolchicoside;

Excipients: lactose monohydrate; microcrystalline cellulose (type 101); microcrystalline cellulose (type 102); povidone (type K30); colloidal anhydrous silicon dioxide; crospovidone (type A); magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: yellow, round, biconvex tablets.

Pharmacotherapeutic group. Muscle relaxants with central mechanism of action. Thiocolchicoside. ATC code M03BX05.

Pharmacological Properties

Pharmacodynamics

Thiocolchicoside is a semi-synthetic sulfide analogue of the natural glycoside colchicine. It acts as a centrally-acting muscle relaxant and does not exhibit curare-like effects, as its action is mediated through the central nervous system (CNS) rather than at the neuromuscular junction. It reduces or markedly suppresses contractile activity of spasmed muscles, decreases passive muscle resistance to stretching, and reduces or eliminates residual spasticity. According to studies conducted in 2003 and 2007, the mechanism of action of thiocolchicoside is associated with selective agonistic effects on glycine receptors in the brainstem and spinal cord. Thiocolchicoside does not affect voluntary movements and does not cause paralysis, thereby eliminating the risk of respiratory depression. It acts as a GABA receptor antagonist in the cerebral cortex, which is associated with the risk of seizures and increased seizure susceptibility. Thiocolchicoside has no effect on the cardiovascular system.

Pharmacokinetics

Absorption

After oral administration of thiocolchicoside, two of its metabolites are detected in blood plasma: the pharmacologically active metabolite SL18.0740, which has efficacy comparable to unchanged thiocolchicoside, and the inactive metabolite SL59.0955. Maximum plasma concentrations (Cmax) of these metabolites are observed within 1 hour after administration of thiocolchicoside. Following a single 8 mg oral dose of thiocolchicoside, Cmax and area under the pharmacokinetic curve (AUC) values for SL18.0740 are 60 ng/mL and 130 ng·h/mL, respectively. For SL59.0955, these values are considerably lower: Cmax is approximately 13 ng/mL, and AUC ranges from 15.5 ng·h/mL (up to 3 hours) to 39.7 ng·h/mL (up to 24 hours).

Distribution

Data on the distribution of both metabolites are not available.

Metabolism

After oral administration, thiocolchicoside is initially metabolized to the aglycone 3-demethylthiocolchicine, also known as SL59.0955, primarily in the intestinal wall. This explains the absence of unchanged thiocolchicoside in blood plasma following oral administration. The metabolite SL59.0955 is glucuronidated to form SL18.0740, which retains the pharmacological activity of the parent compound, thereby ensuring the pharmacological activity of orally administered thiocolchicoside. SL59.0955 is also demethylated to didemethylthiocolchicine.

Elimination

Following oral administration, elimination of metabolites occurs predominantly via feces (79%) and urine (20%). Unchanged thiocolchicoside is not excreted in urine or feces. Metabolites SL18.0740 and SL59.0955 are detected in both urine and feces, whereas didemethylthiocolchicine is excreted only in feces.

After oral administration of thiocolchicoside, the elimination half-life of metabolite SL18.0740 ranges from 3.2 to 7 hours, while that of metabolite SL59.0955 is on average 0.8 hours.

Preclinical Safety Data

The aglycone metabolite (3-demethylthiocolchicine-SL59.0955), formed predominantly after oral administration, induces chromosomal damage in vitro (micronucleus test in human lymphocytes) and in vivo (micronucleus test in rat bone marrow after oral administration). Micronuclei arise primarily due to chromosomal loss (centromere-positive micronuclei after FISH or CREST centromere staining), indicating aneugenic properties. The aneugenic effect of SL59.0955 was observed at in vitro concentrations and in vivo exposure levels close to those found in human plasma at therapeutic doses of 8 mg twice daily orally. Aneugenic effects in dividing cells may lead to cellular aneuploidy. Aneuploidy—defined as a change in chromosome number and loss of heterozygosity—is recognized as a risk factor for teratogenicity, embryotoxicity/spontaneous abortions, impaired male fertility (when germ cells are affected), and as a potential risk factor for carcinogenesis (when somatic cells are affected). The presence of the aglycone metabolite (3-demethylthiocolchicine-SL59.0955) after intramuscular administration has not been studied; therefore, its formation following this route of administration cannot be excluded. Thiocolchicoside and its metabolites exhibit aneugenic activity at various concentration levels, which is considered a risk factor for altered human fertility.

Carcinogenic potential has not been evaluated.

Clinical characteristics.

Indications.

Adjuvant therapy for painful muscular contractures in cases of 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 suffering from flaccid paralysis, muscle hypotonia;
• during pregnancy;
• during breastfeeding;
• in women of childbearing potential who do not use adequate contraceptive measures during treatment with the medicinal product Thionex and for one month after discontinuation of treatment (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding");
• in men who do not use adequate contraceptive measures during treatment with the medicinal product Thionex and for three months after discontinuation of treatment (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Information regarding interactions is lacking.

Special precautions for use.

In case of diarrhea following oral administration, the dose should be appropriately reduced.

Cases of liver injury have been reported after administration of thiocolchicoside. Severe cases (e.g., fulminant hepatitis) have been observed in patients who were concurrently taking non-steroidal anti-inflammatory drugs or paracetamol together with thiocolchicoside. Patients should discontinue treatment and consult a physician if signs or symptoms of liver injury occur (see section "Adverse reactions").

Thiocolchicoside may provoke convulsions, especially in patients with epilepsy or in patients at risk of developing seizures. The occurrence of convulsions requires discontinuation of treatment (see section "Adverse reactions").

The maximum daily dose must not exceed 16 mg and should be divided into two doses administered 12 hours apart.

If a dose is missed, the patient should proceed with the next scheduled dose, avoiding too short an interval between doses.

Genotoxic potential

According to preclinical data, a metabolite of thiocolchicoside (SL59.0955) causes aneuploidy (alteration in chromosome number in dividing cells) at concentrations close to the exposure level observed in humans receiving 8 mg twice daily orally (see section "Pharmacological properties"). Aneuploidy is considered a risk factor for teratogenicity, embryotoxicity/fetotoxicity, miscarriage, impairment of male fertility, and a potential risk factor for carcinogenesis. As a precaution, exceeding the recommended dose or prolonged use of the medicinal product should be avoided (see section "Posology and method of administration").

Patients should be adequately informed about the potential risks for possible pregnancy and the effective contraceptive methods that should be used (see sections "Contraindications" and "Use in pregnancy and lactation").

The medicinal product contains lactose; therefore, it should not be administered to patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Contraception in women and men

Thionex 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 1 month after completion of treatment (see section "Pharmacological properties").

Men must use effective contraception during treatment with thiocolchicoside and for 3 months after completion of treatment (see section "Contraindications").

Pregnancy

Information regarding the use of thiocolchicoside in pregnant women is limited.

Animal studies have shown teratogenic effects of this drug (see section "Pharmacological properties").

Thionex is contraindicated during pregnancy (see section "Contraindications").

Lactation period

Administration of thiocolchicoside is contraindicated during breastfeeding, as it passes into breast milk (see section "Contraindications").

Fertility

Thiocolchicoside and its metabolites exert an aneugenic effect at various concentration levels, which represents a risk factor for impaired fertility in humans (see section "Pharmacological properties").

Ability to influence reaction speed when driving or operating machinery.

There are no clinical data indicating that thiocolchicoside affects the ability to drive or operate machinery.

However, since somnolence is a common adverse reaction, this should be taken into account when driving vehicles or operating machinery.

Dosage and Administration.

Administration

Take orally, swallowing with a glass of water.

Dosage

The recommended dose is 8 mg every 12 hours (the dose of 16 mg of thiocolchicoside is also the maximum daily dose). The duration of treatment should not exceed 7 consecutive days. Exceeding the recommended dose or prolonged use should be avoided (see section "Special Warnings and Precautions for Use").

Children

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

Overdose .

Symptoms

Gastrointestinal manifestations such as diarrhea or vomiting may occur.

Treatment

In case of overdose, careful medical supervision and symptomatic treatment are recommended.

Side effects

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 (≥ 1/1,000 – < 1/100), rare (≥ 1/10,000 – < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Immune system disorders

Uncommon: itching.

Rare: urticaria.

Very rare: decrease in blood pressure.

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

Nervous system disorders

Common: drowsiness.

Rare: excitement or brief confusion.

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

Gastrointestinal disorders

Common: diarrhea, gastralgia (stomach pain).

Uncommon: nausea, vomiting.

Rare: heartburn.

Hepatobiliary disorders

Frequency not known: drug-induced liver injury (see section "Special warnings and precautions for use").

Skin and subcutaneous tissue disorders

Uncommon: allergic skin reactions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

2 years.

Storage conditions

The medicinal product does not require special storage conditions. Keep out of reach and sight of children.

Packaging

14 tablets in a blister; 1 blister per cardboard box.

Prescription status

Prescription-only.

Manufacturer

Biofarm Ltd / Biofarm Sp. z o.o.

Manufacturer's address and location of operations

Walbrzyska str. 13, 60-198 Poznan, Poland / Walbrzyska str. 13, 60-198 Poznan, Poland.