Controlflex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CONTROLFLEX

Composition:

Active substance: thiocolchicoside;

1 ml of injection solution contains thiocolchicoside 2 mg;

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear yellow liquid.

Pharmacotherapeutic group.

Muscle relaxants. Muscle relaxants with central mechanism of action. Other centrally-acting agents. Thiocolchicoside. ATC code M03BX05.

Pharmacological Properties

Pharmacodynamics

Thiocolchicoside is a semisynthetic sulfide derivative of colchicoside with pharmacological activity as a muscle relaxant.

In in vitro studies, thiocolchicoside binds exclusively to gamma-aminobutyric acid (GABA) and strychnine-sensitive glycine receptors. In autoradiographic studies, thiocolchicoside displaces [3H]strychnine binding predominantly in the brainstem and spinal cord of rats. In electrophysiological studies on native or recombinant GABA receptors, thiocolchicoside showed no effect but antagonized GABA-induced chloride channels.

Thiocolchicoside did not significantly affect glycine-induced motoneuronal channels in spinal cord slices of young (10-day-old) rats.

It has been demonstrated that in vivo, thiocolchicoside counteracts the strychnine-induced linguomandalibular reflex in anesthetized male rabbits. These findings are consistent with the hypothesis of a glycine-mediated mechanism of action.

In animal models, two intraperitoneal injections of thiocolchicoside reduced the stretch reflex in spastic rats, while injections of 10 mg/kg intraperitoneally, or 1 mg/kg intramuscularly, or 10 mg/kg orally reduced the postsynaptic reflex by 60% in healthy rats. Thiocolchicoside has no sedative effect.

Pharmacokinetics

Absorption

After intramuscular administration of thiocolchicoside, maximum plasma concentration (Cmax) is reached within 30 minutes, with values of 113 ng/mL for the 4 mg dose and 175 ng/mL for the 8 mg dose. The area under the plasma concentration-time curve (AUC) values are 283 ng·h/mL and 417 ng·h/mL, respectively.

The pharmacologically active metabolite SL18.0740 is also detected at a lower Cmax of 11.7 ng/mL, reached 5 hours after dose administration, with an AUC of 83 ng·h/mL. No data are available on the inactive metabolite SL59.0955.

Distribution

The apparent volume of distribution of thiocolchicoside is approximately 42.7 L after intramuscular administration of 8 mg. Data on both metabolites are lacking.

Elimination

After intramuscular administration, the expected elimination half-life (T1/2) of thiocolchicoside is 1.5 hours, and the plasma clearance is 19.2 L/h.

Clinical characteristics.

Indications.

For adjuvant therapy of painful muscular contractures associated with acute spinal disorders in adults and adolescents aged 16 years and older.

Contraindications.

The medicinal product KONTROFLEKS is contraindicated:

• in patients with hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• in cases of flaccid paralysis, muscular hypotonia;
• throughout the entire pregnancy period;
• during breastfeeding;
• in women of childbearing potential who are not using appropriate contraceptive measures during treatment and for one month after discontinuation of KONTROFLEKS;
• in men who are not using appropriate contraceptive measures during treatment with KONTROFLEKS and for three months after treatment discontinuation.

Interaction with other medicinal products and other forms of interaction.

Information on the interaction of thiocolchicoside with other medicinal products is not available.

Special precautions for use

If diarrhoea occurs, treatment with CONTROLFLEX should be discontinued (see section "Side effects").

Thiocolchicoside may cause epileptic seizures in patients suffering from epilepsy or conditions associated with a risk of epileptic seizures (see section "Side effects").

Cases of vasovagal syncope have been reported. Patients should be monitored after intramuscular administration of the medicinal product (see section "Side effects").

Potential genotoxicity

Preclinical studies have shown that one of the metabolites of thiocolchicoside (SL59.0955) induces aneuploidy (a change in the number of chromosomes during cell division) at concentrations close to those achieved with an oral dose of 8 mg twice daily, which similarly affects humans. Aneuploidy is considered a risk factor for teratogenicity, embryotoxicity/foetotoxicity, miscarriage, impairment of fertility in males, and a potential risk factor for carcinogenesis. To prevent such risks, exceeding the recommended dose or prolonged use of the medicinal product should be avoided (see section "Posology and method of administration").

Patients (both women and men) should be informed about the potential risk when using the drug during pregnancy and the necessity of using effective contraceptive methods (see section "Contraindications" and "Pregnancy and breastfeeding").

Post-marketing reports have indicated hepatic function disorders associated with the use of thiocolchicoside. Serious cases of liver dysfunction (e.g., fulminant hepatitis) have been observed in patients who concurrently used non-steroidal anti-inflammatory drugs (NSAIDs) or paracetamol. Patients should be advised to discontinue treatment and consult a physician if signs of liver dysfunction occur (see section "Side effects").

Injection site reactions

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

Excipients

This 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, and must also refrain from fathering a child (see section "Contraindications").

Pregnancy

Information on the use of thiocolchicoside in pregnant women is limited. Animal studies have shown teratogenic effects of thiocolchicoside. The medicinal product CONTROLFLEX is contraindicated during pregnancy (see section "Contraindications").

Breastfeeding

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

Fertility

Thiocolchicoside and its metabolites exhibit aneugenic activity at various concentration levels, which represents a risk factor for impaired fertility in humans.

Effects on ability to drive and use machines

There are no data on the effect of thiocolchicoside on driving or operating machinery.

Clinical studies have shown that thiocolchicoside does not affect psychomotor skills. However, somnolence may occur, which should be taken into account when driving or operating complex machinery.

Dosage and Administration.

The medicinal product CONTROFLEX is administered by intramuscular injection.

The recommended maximum daily dose is 4 mg every 12 hours (i.e. 8 mg per day). Treatment should not exceed 5 consecutive days.

The recommended dose or duration of use should not be exceeded (see section "Special Warnings and Precautions for Use").

Children.

The medicinal product is not recommended for use in children and adolescents under 16 years of age.

Overdose.

Cases of overdose have not been observed in patients using thiocolchicoside.

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

Adverse Reactions

The frequency of adverse reactions is defined as follows: very common (> 1/10), common (from > 1/100 to < 1/10), uncommon (from > 1/1000 to < 1/100), rare (from > 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Immune system disorders:
Uncommon – urticaria;
Rare – angioneurotic edema and anaphylactic shock after intramuscular injection;
Very rare – hypotension;
Frequency not known – anaphylactic reactions.

Skin and subcutaneous tissue disorders:
Uncommon – erythema after intramuscular injection.

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 embolism" and "livedoid dermatitis") following intramuscular injection.

Nervous system disorders:
Common – drowsiness;
Rare – excitement or brief confusion;
Frequency not known – vasovagal syncope occurring within the first few minutes after intramuscular injection, seizures (see section "Special Warnings and Precautions for Use").

Gastrointestinal disorders:
Common – diarrhea (see section "Special Warnings and Precautions for Use"), abdominal pain;
Uncommon – nausea, vomiting;
Rare – heartburn.

Hepatobiliary and biliary system disorders:
Frequency not known – liver function abnormalities (see section "Special Warnings and Precautions for Use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

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

2 ml in ampoules, 5 ampoules in a blister, 1 or 2 blisters in a cardboard box.

Prescription status

Prescription only.

Manufacturer

MICROCHEM LLC (responsible for batch release, excluding batch control/testing)

Halychpharm JSC (responsible for manufacturing and batch control/testing, excluding batch release)

Manufacturer's address and place of business

Ukraine, 01013, Kyiv, Budynsturiyi St., 5 (MICROCHEM LLC).

Ukraine, 79024, Lviv region, Lviv city, Opryshkovska St., 6/8 (Halychpharm JSC).

Marketing Authorization Holder

MICROCHEM LLC.

Address of the Marketing Authorization Holder

Ukraine, 01013, Kyiv, Budynsturiyi St., 5.

INSTRUCTION

for medical use of the medicinal product

CONTROLFLEX

(CONTROLFLEX)

Composition:

Active substance: thiocolchicoside;

1 ml of injectable solution contains thiocolchicoside 2 mg;

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

Pharmaceutical form. Injectable solution.

Main physicochemical properties: clear yellow liquid.

Pharmacotherapeutic group.

Muscle relaxants. Muscle relaxants with central mechanism of action. Other centrally acting agents. Thiocolchicoside. ATC code M03BX05.

Pharmacological Properties.

Pharmacodynamics.

Thiocolchicoside is a semi-synthetic sulfide derivative of colchicoside with pharmacological activity as a muscle relaxant.

In in vitro studies, thiocolchicoside binds only to gamma-aminobutyric acid (GABA) and strychnine-sensitive glycine receptors. In autoradiographic studies, thiocolchicoside displaces [3H]strychnine binding predominantly in the brainstem and spinal cord of rats. In electrophysiological studies on native or recombinant GABA receptors, thiocolchicoside showed no effect but antagonized GABA-induced chloride channels.

Thiocolchicoside did not significantly affect glycine-induced motor neuron channels in spinal cord slices of young (10-day-old) rats.

It has been shown that in vivo, thiocolchicoside counteracts the strychnine-induced linguomandalibular reflex in anesthetized male rabbits. These results are consistent with the hypothesis of a glycinergic mechanism of action.

In animal models, two intraperitoneal injections of thiocolchicoside reduced the stretch reflex in spastic rats, and injections of 10 mg/kg intraperitoneally, or 1 mg/kg intramuscularly, or 10 mg/kg orally reduced the postsynaptic reflex by 60% in healthy rats. Thiocolchicoside has no sedative effect.

Pharmacokinetics.

Absorption

After intramuscular administration of thiocolchicoside, maximum concentration (Cmax) is reached within 30 minutes and amounts to 113 ng/mL for a 4 mg dose and 175 ng/mL for an 8 mg dose. The area under the plasma concentration-time curve (AUC) values are 283 ng·h/mL and 417 ng·h/mL, respectively.

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·h/mL. No data are available on the inactive metabolite SL59.0955.

Distribution

The apparent volume of distribution of thiocolchicoside is approximately 42.7 L after intramuscular administration of 8 mg. Data on both metabolites are lacking.

Elimination

After intramuscular administration, the expected elimination half-life (T1/2) of thiocolchicoside is 1.5 hours, and plasma clearance is 19.2 L/h.

Clinical characteristics.

Indications.

For adjuvant therapy of painful muscular contractures associated with acute spinal disorders in adults and adolescents aged 16 years and older.

Contraindications.

The medicinal product KONTROLFLEKS is contraindicated:

• in patients with hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• in cases of flaccid paralysis, muscular hypotonia;
• throughout the entire pregnancy period;
• during breastfeeding;
• in women of reproductive age who are not using appropriate contraceptive methods during treatment and for one month after discontinuation of treatment with KONTROLFLEKS;
• in men who are not using appropriate contraceptive methods during treatment with KONTROLFLEKS and for three months after discontinuation of treatment.

Interaction with other medicinal products and other forms of interaction.

Information on the interaction of thiocolchicoside with other medicinal products is not available.

Special precautions for use

If diarrhoea occurs, treatment with the medicinal product CONTROLFLEX must be discontinued (see section "Side effects").

Thiocolchicoside may trigger epileptic seizures in patients suffering from epilepsy or from diseases associated with a risk of epileptic seizures (see section "Side effects").

Cases of vasovagal syncope have been reported. Patients should be monitored after intramuscular administration of the medicinal product (see section "Side effects").

Potential genotoxicity

Preclinical studies have shown that one of the metabolites of thiocolchicoside (SL59.0955) causes aneuploidy (a change in chromosome number during cell division) at concentrations close to those achieved with an oral dose of 8 mg twice daily, which similarly affects humans. Aneuploidy is considered a risk factor for teratogenicity, embryotoxicity/foetotoxicity, miscarriage, impairment of fertility in men, and a potential risk factor for carcinogenesis. To prevent these risks, exceeding the recommended dose or prolonged use of the medicinal product should be avoided (see section "Dosage and administration").

Patients (both women and men) should be informed about the potential risks associated with use during pregnancy and the necessity of using effective contraceptive methods (see section "Contraindications" and "Use during pregnancy or breastfeeding").

Post-marketing reports have described cases of hepatic dysfunction associated with the use of thiocolchicoside. Severe cases of liver dysfunction (e.g. fulminant hepatitis) have been reported in patients who were concomitantly using non-steroidal anti-inflammatory drugs (NSAIDs) or paracetamol. Patients should be advised to discontinue treatment and consult a physician if signs of liver dysfunction occur (see section "Side effects").

Injection site reactions

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

Excipients

This 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 contraceptive methods (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 completion of treatment.

Men must use effective contraception during treatment with thiocolchicoside and for three months after completion of treatment, and must refrain from fathering a child (see section "Contraindications").

Pregnancy

Information on the use of thiocolchicoside in pregnant women is limited. Animal studies have shown teratogenic effects of thiocolchicoside. The medicinal product CONTROLFLEX is contraindicated during pregnancy (see section "Contraindications").

Breastfeeding

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

Fertility

Thiocolchicoside and its metabolites exhibit aneugenic activity at various concentration levels, which represents a risk factor for impaired fertility in humans.

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

There are no data available on the effect of thiocolchicoside on the ability to drive or operate machinery.

Clinical studies have shown that thiocolchicoside does not affect psychomotor performance. However, somnolence may occur, which should be taken into account when driving or operating complex machinery.

Method of administration and dosage.

The medicinal product CONTROFLEX is administered intramuscularly.

The recommended maximum daily dose is 4 mg every 12 hours (i.e., 8 mg per day). Treatment should not exceed 5 consecutive days.

The recommended dose or duration of use should not be exceeded (see section "Special precautions for use").

Children.

The medicinal product is not recommended for children and adolescents under 16 years of age.

Overdose.

Cases of overdose have not been observed in patients using thiocolchicoside.

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

Adverse reactions.

The frequency of adverse reactions is defined as follows: very common (> 1/10), common (from > 1/100 to < 1/10), uncommon (from > 1/1000 to < 1/100), rare (from > 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from available data).

Immune system disorders:
Uncommon – urticaria; rare – angioedema and anaphylactic shock after intramuscular administration; very rare – hypotension; frequency not known – anaphylactic reactions.

Skin and subcutaneous tissue disorders:
Uncommon – erythema after intramuscular administration.

General disorders and administration site conditions:
Frequency not known – injection site reactions, including swelling, erythema, pruritus, pain around the injection site, and Nicolau syndrome (‘pharmacological embolism of the skin’ and ‘livedoid dermatitis’) following intramuscular injection.

Nervous system disorders:
Common – drowsiness; rare – excitement or brief confusion; frequency not known – vasovagal syncope occurring within the first few minutes after intramuscular administration, seizures (see section “Special precautions for use”).

Gastrointestinal disorders:
Common – diarrhoea (see section “Special precautions for use”), stomach pain; uncommon – nausea, vomiting; rare – heartburn.

Hepatobiliary and biliary disorders:
Frequency not known – liver function abnormalities (see section “Special precautions for use”).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is vital. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

2 ml in ampoules, 5 ampoules in a blister pack, 1 or 2 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

MICROCHEM PHARMACEUTICAL COMPANY LTD.

Manufacturer's address and place of business.

24-V Promyslova Street, Severodonetsk, Luhansk region, 93400, Ukraine

Marketing authorization holder.

MICROCHEM PHARMACEUTICAL COMPANY LTD.

Address of the marketing authorization holder.

5 Budyndustrіi Street, Kyiv, 01013, Ukraine