ALTIOZA

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

Composition:

Active substance: thiocolchicoside;

1 ml of injection solution contains thiocolchicoside 2.0 mg;

1 vial (2 ml injection solution) contains thiocolchicoside 4.0 mg;

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

Pharmaceutical form. Injection solution.

Main physico-chemical properties: clear yellow-colored solution.

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

Pharmacological Properties

Pharmacodynamics

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

In vitro, thiocolchicoside binds only to strychnine-sensitive GABAergic and glycinergic receptors. Since thiocolchicoside acts as a GABAergic receptor antagonist, its myorelaxant effect may manifest at the supraspinal level through a complex regulatory mechanism, although a glycinergic mechanism of action cannot be ruled out. The characteristics of interaction with GABAergic receptors are qualitatively and quantitatively similar for both thiocolchicoside and its main circulating metabolite—glucuronidated derivative (see section "Pharmacokinetics").

In vivo, the myorelaxant properties of thiocolchicoside and its main metabolite have been demonstrated in various experimental models in rats and rabbits. The absence of a myorelaxant effect of thiocolchicoside in rats with transected spinal cord indicates predominant supraspinal activity. Furthermore, electroencephalographic studies have shown that thiocolchicoside and its main metabolite do not possess sedative effects.

Pharmacokinetics

Absorption

After intramuscular administration, the Cmax of thiocolchicoside is reached within 30 minutes and attains values of 113 ng/mL following a 4 mg dose and 175 ng/mL following an 8 mg dose. Corresponding AUC values are 283 and 417 ng×h/mL, respectively.

The pharmacologically active metabolite SL18.0740 is also detected, but at lower concentrations: Cmax is 11.7 ng/mL, reached 5 hours after administration, with an AUC of 83 ng×h/mL.

Data regarding the inactive metabolite SL59.0955.22 are not available.

Distribution

The apparent volume of distribution of thiocolchicoside is approximately 42.7 L after intramuscular administration of 8 mg. There are no data available regarding metabolites.

Elimination

After intramuscular administration, the apparent half-life (T½) of thiocolchicoside is 1.5 hours, and plasma clearance is 19.2 L/h.

Clinical Characteristics

Indications. Adjunctive therapy for painful muscular contractures in cases of acute spinal disorders in adults and children 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 or muscle hypotonia;
• during the entire pregnancy period;
• during breastfeeding;
• in women of childbearing potential who are not using appropriate contraceptive methods during treatment and for 1 month after discontinuation of thiocolchicoside;
• in men who are not using contraceptive methods during treatment and for 3 months after discontinuation of thiocolchicoside.

Interaction with other medicinal products and other forms of interaction. Information regarding interactions is lacking.

Special precautions for use

After intramuscular administration of thiocolchicoside, episodes of vasovagal syncope have been observed; therefore, patients should be monitored following injection (see section "Adverse reactions").

During the post-marketing period, cases of liver injury (cytolytic and cholestatic hepatitis) have been reported with the use of thiocolchicoside. Severe cases of liver injury (e.g., fulminant hepatitis) have been recorded in patients who were concomitantly taking non-steroidal anti-inflammatory drugs (NSAIDs) or paracetamol. If signs of liver injury develop during treatment with the medicinal product—information that patients should be provided with—treatment should be discontinued and medical advice sought (see section "Adverse reactions").

Thiocolchicoside may induce seizures in patients with epilepsy or conditions associated with a risk of seizures (see section "Adverse reactions").

The maximum recommended daily dose of thiocolchicoside (8 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.

Genotoxicity

Preclinical studies have shown that one of the metabolites of thiocolchicoside (SL59.0955) causes aneuploidy (alteration in chromosome number in dividing cells) at concentrations close to the exposure level observed in humans following oral administration of 8 mg twice daily.

Aneuploidy is considered a risk factor for teratogenicity, embryotoxicity/fetotoxicity, miscarriage, impairment of male fertility, and as a potential risk factor for carcinogenesis. To minimize risk, exceeding the recommended dose or prolonged use of the drug should be avoided (see section "Posology and method of administration").

Patients of both sexes should be given detailed information about the potential risks in the event of pregnancy and the importance of using effective contraceptive methods during treatment with thiocolchicoside and after discontinuation of treatment: for one month in women and for three months in men (see sections "Contraindications" and "Use in pregnancy and lactation").

Injection site reactions

Following intramuscular administration of thiocolchicoside, injection site reactions have been reported, including necrosis, cutaneous medication embolism (also known as Nicolau syndrome), and livedoid dermatitis.

Appropriate injection technique should be followed when administering thiocolchicoside intramuscularly.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, 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 unless effective contraception is used.

Due to the aneugenic potential of thiocolchicoside and its metabolites, women of childbearing potential must use effective contraceptive measures during treatment with thiocolchicoside and for one month after discontinuation of treatment.

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

Pregnancy

Information on the use of thiocolchicoside in pregnant women is limited, and 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").

Lactation

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

Fertility

Thiocolchicoside and its metabolites have shown aneugenic effects at various concentration levels, representing a risk factor for impaired human fertility.

Effects on ability to drive and use machines

No studies on the effects 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 administration.

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 prolonged 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 is no data available on 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 classified according to MedDRA system organ 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 – pruritus; rare – urticaria; very rare – hypotension; frequency not known – angioedema and anaphylactic reactions, including anaphylactic shock.

Nervous system disorders: common – somnolence; rare – excitement or brief confusion; frequency not known – vasovagal syncope occurring within the first few minutes after intramuscular injection, seizures (see section "Special precautions").

Gastrointestinal disorders: common – diarrhea, abdominal pain; uncommon – nausea, vomiting; rare – heartburn.

Hepatobiliary and biliary tract disorders: frequency not known – liver injury, hepatic function abnormalities (see section "Special precautions").

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, Nicolau syndrome (cutaneous drug embolism), and livedoid dermatitis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, and 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

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

Keep out of reach and sight of children.

Incompatibilities. Data not available.

Packaging. 2 mL in a vial; 5 vials in a blister pack; 1 or 2 blister packs in a carton.

Prescription category. Prescription only.

Manufacturer. Limited liability company "Novopharm-Biosynthesis".

Manufacturer's address and place of business. Ukraine, 11700, Zhytomyr Oblast, Zviahel Raion, city of Zviahel, 38 Zhytomyrska Street.