Tiorelax Tablet 8 Mg

Description

Qualitative and Quantitative Composition

Each Tiorelax tablet contains 8 mg thiocolchicoside as the active substance; excipients vary by manufacturer and market and typically include standard tablet bases such as lactose or starches. Thiocolchicoside belongs to the pharmacotherapeutic group of centrally acting muscle relaxants (ATC code M03BX05).

Mechanism of Action and Pharmacodynamics

Thiocolchicoside exerts a myorelaxant action in humans and animals, particularly on painful muscle contractures associated with spinal and peripheral musculoskeletal pathology. Experimental data suggest that its muscle‑relaxant effect results mainly from agonism at inhibitory glycine receptors in the brainstem and spinal cord, which suppresses or markedly reduces induced central muscle contraction without causing paralysis or respiratory depression. In parallel, thiocolchicoside displays antagonist activity at gamma‑aminobutyric acid (GABA) receptors in the brainstem, a property believed to underlie its pro‑convulsant potential.

Pharmacokinetic Properties

Absorption

After intramuscular administration of thiocolchicoside, peak plasma concentrations (Cmax) are reached within approximately 30 minutes, with mean Cmax values around 113 ng/mL and 175 ng/mL after 4 mg and 8 mg doses, respectively. The corresponding exposure (AUC) values are about 283 and 417 ng·h/mL. Following oral administration of thiocolchicoside 8 mg, unchanged parent compound is essentially not detectable systemically, because it undergoes extensive intestinal metabolism, and pharmacological activity is mediated by circulating metabolites.

Distribution

The apparent volume of distribution of thiocolchicoside after an 8 mg intramuscular dose is approximately 42.7 L, consistent with moderate distribution into tissues beyond the vascular compartment. Plasma protein binding of thiocolchicoside and its metabolites is not fully characterized in publicly accessible summaries.

Metabolism

Following oral administration, thiocolchicoside is first metabolized in the intestine to the aglycone 3‑demethylthiocolchicine (also named SL59.0955, sometimes referred to as “M2”), which is then glucuronidated to form SL18.0740, the main circulating active metabolite. SL18.0740 exhibits pharmacological activity comparable to thiocolchicoside and is responsible for the systemic muscle‑relaxant effect after oral dosing, while SL59.0955 is the metabolite implicated in aneugenic (aneuploidy‑inducing) effects in preclinical testing. Additional downstream metabolites such as didemethyl‑thiocolchicine are also formed but appear at lower concentrations.

Elimination

After an 8 mg intramuscular dose, the apparent elimination half‑life (t½) of thiocolchicoside is around 1.5 hours. For the main active metabolite SL18.0740, a single oral 8 mg dose yields a Cmax of about 60 ng/mL and an AUC of approximately 130 ng·h/mL, with maximum levels reached around 1 hour post‑dose. For SL59.0955, Cmax values are near 13 ng/mL and AUC values range from about 15.5 ng·h/mL (0–3 h) to 39.7 ng·h/mL (0–24 h), confirming systemic exposure at levels relevant to the aneugenicity signal. Thiocolchicoside and its metabolites are eliminated via renal and biliary routes, though detailed human mass balance data are limited in public documents.

Indications and Therapeutic Uses

Systemic thiocolchicoside 8 mg (e.g., tablets or capsules such as Tiorelax) is indicated as an adjuvant therapy for painful muscle contractures linked to acute spinal pathology, such as acute low back pain, cervicalgia, and other acute vertebral syndromes. In various product monographs, it is also described as useful for painful muscle spasms associated with degenerative vertebral disorders, vertebral static problems, torticollis, dorsal pain, and certain traumatic or neurologic disorders, always as part of a broader pharmacological and non‑pharmacological treatment strategy.

Posology and Method of Administration

The recommended adult and adolescent (≥16 years) oral dose of thiocolchicoside 8 mg is 8 mg every 12 hours, corresponding to a maximum total daily dose of 16 mg. Treatment duration should be as short as possible, with many regulators recommending not more than 7 consecutive days at the oral dose in order to minimize exposure to aneugenic metabolites. For intramuscular administration of thiocolchicoside (other presentations), the maximum duration is even shorter (often ≤5 days), but Tiorelax 8 mg is an oral tablet and is not intended for parenteral use.

In patients who develop diarrhoea, dose reduction may be considered. Concomitant use with antacids is possible if needed for gastrointestinal tolerability.​

Contraindications

Thiocolchicoside 8 mg tablets are contraindicated in the following situations:

• Hypersensitivity to thiocolchicoside or any excipient.

• Pregnancy at any stage and lactation, due to the aneugenic potential of metabolites and potential harm to the embryo or infant.

• Women of child‑bearing potential who are not using effective contraception, because exposure to the aneugenic metabolite could impair fertility or cause embryotoxicity.

• Patients with a history of epilepsy or at increased risk of seizures should not receive thiocolchicoside or should be treated only after careful risk assessment, given its GABA‑antagonist and seizure‑promoting properties.

Several regulatory authorities also advise against use in children and adolescents under 16 years of age, due to limited safety and efficacy data and concerns about genotoxic risk.

Special Warnings and Precautions for Use

Aneuploidy and Genotoxic Risk

Preclinical in vitro studies have demonstrated that the metabolite SL59.0955 (M2) induces aneuploidy, defined as an abnormal number of chromosomes in dividing cells, at concentrations close to those observed in humans at the standard oral dose of 8 mg twice daily. Aneuploidy is a recognized risk factor for teratogenic effects, embryo‑foetal toxicity, spontaneous abortion, and impaired male fertility, and long‑term aneugenic exposure may theoretically increase the risk of tumor development.

In response to these data, the European Medicines Agency (EMA) and multiple national agencies have restricted thiocolchicoside use and emphasized:

• Use the lowest effective dose.

• Limit duration to a few days (≤7 days orally).

• Avoid in pregnancy, lactation, and in women of childbearing potential not on reliable contraception.

• Avoid use in chronic conditions or for long‑term continuous therapy.

Seizure Risk

Because thiocolchicoside acts as a GABA receptor antagonist in the brainstem, it can lower seizure threshold. Caution is required in patients with epilepsy or conditions predisposing to seizures, and therapy should be discontinued if seizures occur.

Gastrointestinal Effects

Thiocolchicoside can cause diarrhoea, and dose reduction may be appropriate in patients who develop significant gastrointestinal symptoms. In high‑risk patients, dehydration must be prevented and alternative therapies considered if diarrhoea persists.

Adverse Reactions

Adverse effects associated with thiocolchicoside are mostly mild to moderate and often reversible after discontinuation. However, the genotoxic signal has led to strict risk‑minimisation measures.

Commonly Reported Adverse Reactions

• Gastrointestinal: diarrhoea, abdominal pain, nausea.

• Nervous system: somnolence, dizziness, headache; seizures have been reported, particularly at higher doses or in predisposed individuals.

• Hypersensitivity: rash or other allergic reactions, rarely severe.

Serious Safety Concerns

• Seizures and convulsions, including in individuals without prior epilepsy, particularly with overdosing or improper use.

• Potential effects on male fertility and potential embryotoxicity due to aneugenic metabolites, which have prompted warnings and contraindications around reproductive health.

Table: Key Clinical Pharmacology and Safety Parameters of Thiocolchicoside 8 mg

Reproductive Toxicology and Fertility Considerations

In animal fertility studies in rats, thiocolchicoside did not impair fertility at doses up to 12 mg/kg that produced no overt clinical effects, but these studies predated the mechanistic understanding of aneugenicity. Subsequent in vitro evaluations identified the metabolite SL59.0955 as aneugenic at exposure levels similar to those reached in humans at recommended oral doses, suggesting a potential risk of impaired human fertility and embryotoxicity.

Regulatory safety communications describe aneuploidy as a risk factor for teratogenicity, embryo‑foetal toxicity, spontaneous abortion, and reduced male fertility, and a potential contributor to tumorigenesis with long‑term exposure. A human observational study of pregnancies with first‑trimester exposure to thiocolchicoside reported live births, miscarriages, and elective terminations; while not demonstrating a clear teratogenic pattern, the data set is limited and does not negate preclinical aneugenicity concerns. Consequently, thiocolchicoside is contraindicated in pregnancy and lactation and should not be used in women of child‑bearing potential without effective contraception, and men are also warned about potential effects on sperm due to chromosomal abnormalities.

Regulatory Safety Actions and Label Restrictions

The EMA’s Committee for Medicinal Products for Human Use (CHMP) conducted a safety review and concluded that thiocolchicoside’s benefit–risk balance remains positive only when used in restricted doses and for short durations in limited indications. The committee recommended and many authorities implemented:

• Limiting systemic thiocolchicoside to short‑term treatment of acute muscle contractures associated with spinal conditions in adults and adolescents ≥16 years.

• Setting maximum oral dose at 8 mg twice daily and limiting the duration of oral therapy to 7 days or less.

• Introducing explicit contraindications for pregnancy, lactation, and women of childbearing potential not using effective contraception, and strengthening fertility and genotoxicity warnings.

• Emphasizing seizure risk and advising withdrawal in the event of convulsive episodes.

Recent national safety alerts (e.g., from Egyptian and other regulators) continue to reiterate these limits and discourage high doses, long‑term use, and off‑label indications.

Clinical Use Considerations and Place in Therapy

Within the therapeutic armamentarium for acute painful muscle contractures, thiocolchicoside 8 mg tablets such as Tiorelax may be considered as add‑on pharmacotherapy to non‑steroidal anti‑inflammatory drugs, simple analgesics, and physical modalities like rest and physiotherapy. However, given the aneugenic and seizure‑related safety profile, clinicians should weigh the short‑term symptomatic benefits against potential reproductive and theoretical long‑term carcinogenic risks, especially in younger patients and those of reproductive age.

Appropriate patient selection, strict adherence to recommended dose and duration, and careful counselling on contraception and potential adverse effects are essential for safe use. In patients with comorbid epilepsy, pregnancy, or plans for conception, or in settings where prolonged therapy would be anticipated, alternative muscle relaxants or non‑pharmacological interventions are generally preferred.