Thiozid

INSTRUCTION for medical use of the medicinal product TIYOZID (TIYOZID)

Composition:

Active substance: thiocolchicoside;

1 tablet contains 8 mg of thiocolchicoside;

Excipients: copovidone, monohydrate lactose, pregelatinized starch, microcrystalline cellulose, colloidal anhydrous silicon dioxide, sodium stearyl fumarate.

Pharmaceutical form. Tablets.

Basic physical and chemical properties: round, biconvex, yellow tablets with a break line on one side and an engraving "8" on the other side.

Pharmacotherapeutic group

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

Pharmacological Properties

Pharmacodynamics

Tiocolchicoside is a semi-synthetic muscle relaxant derived from the glycoside colchicoside. It demonstrates selective affinity for gamma-aminobutyric acid (GABA) and glycine receptors.

The muscle relaxant effect is primarily manifested at the supraspinal level through complex regulatory mechanisms; a glycinergic mechanism of action is also not excluded.

The binding of tiocolchicoside to GABA is qualitatively and quantitatively distinct from that of its active metabolite—glucuronidated derivative.

Tiocolchicoside and its derivatives do not have a sedative effect. Tiocolchicoside does not exert curare-like action, does not cause paralysis, and does not affect the cardiovascular or respiratory systems.

Pharmacokinetics

Absorption

After intramuscular administration of an 8 mg dose of tiocolchicoside, maximum concentration (Cmax) is reached within 30 minutes and reaches a value of 175 ng/mL. The area under the concentration-time curve (AUC) is 417 ng·hour/mL.

The pharmacologically active metabolite SL18.0740 is also detected at lower concentrations, with a Cmax of 11.7 ng/mL reached 5 hours after dosing, and an AUC of 83 ng·hour/mL. No data are available on the inactive metabolite SL59.0955. After oral administration of tiocolchicoside, only two metabolites are detected in blood plasma: the pharmacologically active metabolite SL18.0740 and the inactive metabolite SL59.0955. Maximum plasma concentrations of both tiocolchicoside metabolites are reached approximately 60 minutes after administration. After a single oral dose of 8 mg, Cmax and AUC values for metabolite SL18.0740 are approximately 60 ng/mL and 130 ng·hour/mL, respectively. For metabolite SL59.0955, these values are much 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).

Distribution

The volume of distribution of tiocolchicoside is approximately 42.7 L after administration of 8 mg. Data on the volume of distribution of metabolites are not available.

Metabolism

After oral administration, tiocolchicoside is rapidly metabolized to aglycone-3-dimethyltiocolchicoside or SL59.0955. This occurs primarily via intestinal metabolism, which explains the absence of unchanged tiocolchicoside after oral administration. Metabolite SL59.0955 is glucuronidated to form SL18.0740, which has equivalent pharmacological activity to tiocolchicoside and thus provides pharmacological activity after oral administration of tiocolchicoside. SL59.0955 is also demethylated to form dimethylthiocolchicine.

Elimination

After oral administration of 14C-tiocolchicoside, the compound is excreted mainly in feces (79%), and only 20% in urine. Unchanged tiocolchicoside is 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 tiocolchicoside, 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 muscular contractures in 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;
• Hypersensitivity to colchicine;
• Pregnancy or breastfeeding period (see section "Use during pregnancy or breastfeeding");
• Use in women of childbearing potential who are not using contraception (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction

There are no data regarding drug interactions.

Special Warnings and Precautions for Use

Special Warnings

Thiocolchicoside may cause seizures in patients with a predisposition to seizures or epilepsy; therefore, it is recommended to assess the benefit-risk ratio of thiocolchicoside and intensify clinical monitoring. If seizures occur, treatment must be discontinued.

Cases of liver injury (e.g., cytolytic or cholestatic hepatitis) have been reported with the use of thiocolchicoside. Severe cases of liver injury (e.g., fulminant hepatitis) have been observed in patients who concomitantly used nonsteroidal anti-inflammatory drugs or paracetamol. If signs of liver injury develop during treatment, the drug should be discontinued and medical advice sought (see section "Adverse Reactions").

Precautions for Use

In case of diarrhea, the dose should be reduced.

If nausea occurs, the dose should be reduced.

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

One of the metabolites of thiocolchicoside (SL59.0955) is known to induce aneuploidy (i.e., an unequal number of chromosomes in dividing cells) at concentrations close to those observed in human plasma following an oral dose of 8 mg twice daily. Aneuploidy is a risk factor for teratogenicity, embryo-/fetotoxicity, spontaneous abortion, male fertility impairment, and cancer development. Therefore, use of the drug at doses exceeding the recommended ones and for prolonged periods should be avoided (see section "Dosage and Administration").

Women of childbearing potential should be informed about the potential risk during pregnancy and the necessity of using effective contraception.

Use during Pregnancy or Breastfeeding

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.

The medicinal product is contraindicated during pregnancy and in women of reproductive potential who are not using appropriate contraceptive measures (see section "Contraindications").

Breastfeeding

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

Fertility

Fertility studies conducted in rats did not show effects on fertility at doses up to 12 mg/kg, i.e., at dose levels not causing clinical effects. However, thiocolchicoside and its metabolites have aneugenic activity at various concentration levels, which represents a risk factor for human fertility.

Ability to Influence the Reaction Speed While Driving or Operating Machinery

During treatment, caution should be exercised when driving or engaging in other potentially hazardous activities requiring increased attention and rapid psychomotor reaction times, due to the possibility of somnolence.

Administration and Dosage

For oral use.

Tablets should be swallowed whole with a glass of water.

The recommended dose is 8 mg every 12 hours (daily dose 16 mg). The duration of therapy 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 drug should not be used in children under 16 years of age.

Overdose

Gastrointestinal reactions may occur, such as diarrhea or vomiting.

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

Side effects

The following adverse reactions are systematized according to system organ classes and frequency: common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency not known (frequency cannot be estimated from the available data).

Immune system:

rare – hypersensitivity reactions such as urticaria;

frequency not known – hypersensitivity reactions such as angioedema and anaphylactic shock, anaphylactic reactions.

Skin and subcutaneous tissue:

uncommon – skin allergic reactions such as pruritus, erythema, maculopapular and vesiculobullous rashes.

Gastrointestinal disorders:

common – diarrhea (see section "Special precautions for use"), stomach pain;

uncommon – vomiting, nausea.

Hepatobiliary disorders:

frequency not known – liver injury (e.g., cytolytic or cholestatic hepatitis) (see section "Special precautions for use").

Nervous system disorders:

common – drowsiness;

frequency not known – seizures or seizure recurrence in patients with epilepsy (see section "Special precautions for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after registration 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

2 years.

Storage conditions

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

Keep out of reach and sight of children.

Packaging

10 tablets per blister pack, 1 or 2 blisters per cardboard box.

Prescription status

Prescription only.

Manufacturer

Nobel Ilac Sanai ve Ticaret A.S.

Manufacturer's address and location of its business activity

Sankaklar District, Eskikarakoca Avenue, No. 299, 81100 Duzce, Turkey.