Tizanidin-Teva, tablets 4 mg 30 pcs

Pharmacotherapeutic group: myorelaxant of central action

ATX code: M03BX02

Pharmacological properties

Pharmacodynamics

Tizanidine is a centrally acting muscle relaxant. Its main point of action is in the spinal cord. By stimulating presynaptic alpha₂ receptors it inhibits release of excitatory amino acids which stimulate receptors for N-methyl-D-aspartate (NMDA-receptors). As a consequence, polysynaptic excitation transmission is inhibited at the level of intermediate spinal cord neurons. Since it is this mechanism that is responsible for excess muscle tone, when it is suppressed, muscle tone decreases. In addition to its myorelaxant properties, tizanidine also has a central moderately pronounced analgesic effect.

The drug Tizanidine-Teva is effective both in acute painful muscle spasm and in chronic spasticity of spinal and cerebral genesis. It reduces spasticity and clonic convulsions, as a result of which resistance to passive movements decreases and the volume of active movements increases.

The myorelaxant effect (as measured with the Ashworth scale and the pendulum test) and side effects (decrease in heart rate (HR) and blood pressure (BP)) of the drug depend on the concentration of tizanidine in plasma.

Pharmacokinetics

Intake

Tizanidine is absorbed rapidly and almost completely. The maximum plasma concentration (C_max) is reached approximately 1 hour after drug administration. Due to the pronounced metabolism during the “first passage” through the liver, the average bioavailability is about 34%. C_max of tizanidine is 12.3 ng/ml and 15.6 ng/ml after single and multiple doses of tizanidine at a dose of 4 mg, respectively.

Distribution

The average volume of distribution in equilibrium when administered intravenously is 2.6 L/kg. Binding to plasma proteins is 30%.

Metabolism

Tizanidine is rapidly and largely (about 95%) metabolized in the liver. In vitro tizanidine is metabolized mainly by the CYP1A2 isoenzyme of the cytochrome P450 system. Metabolites are inactive.

The average elimination half-life of tizanidine from systemic bloodstream is 2-4 hours; excretion is mainly by kidneys (about 70% of dose) as metabolites; the share of unchanged substance is about 4.5%.

Effects of food

Contemporaneous intake of food has no effect on pharmacokinetics of tizanidine (when used as 4 mg tablets or 12 mg capsules with modified release).

While the C_max value increases by 1/3 when taken after meals, this is not clinically significant. No significant effect on absorption (AUC, area under the pharmacokinetic curve “concentration-time”) is observed.

Tizanidine in the dose range from 1 mg to 20 mg has linear pharmacokinetics.

Peculiarities of pharmacokinetics in selected patient groups

Patients with impaired renal functionPatients with impaired renal function

In patients with impaired renal function (creatinine clearance (CK) ≤ 25 mL/min), C_max of tizanidine in plasma is 2 times higher than in healthy volunteers, the terminal elimination half-life reaches 14 hours, resulting in an increased (approximately 6-fold) systemic bioavailability of tizanidine (measured by AUC).

Patients with impaired hepatic function

There have been no special studies in patients in this category. Since tizanidine is primarily metabolized in the liver by the cytochrome system CYP1A2 isoenzyme, impairment of liver function may increase the systemic exposure to the drug.

Patients older than 65 years

There are limited data on pharmacokinetics in patients in this group.

Dependence on gender and race

Gender has no effect on the pharmacokinetic properties of tizanidine.

The effect of ethnicity and race on the pharmacokinetics of tizanidine has not been studied.

Indications

Painful muscle spasm:

associated with static and functional diseases of the spine (cervical and lumbar syndromes);
after surgery, for example, for a herniated disc or osteoarthritis of the hip joint.

Spasticity of skeletal muscles in neurological diseases, for example, multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, consequences of cerebrovascular accidents and cerebral palsy (patients over 18 years of age).

Pharmacological effect

Pharmacotherapeutic group: centrally acting muscle relaxant

ATX code: М03ВХ02

Pharmacological properties

Pharmacodynamics

Tizanidine is a centrally acting muscle relaxant. The main point of application of its action is in the spinal cord. By stimulating presynaptic alpha2 receptors, it inhibits the release of excitatory amino acids that stimulate N-methyl-D-aspartate receptors (NMDA receptors). As a result, polysynaptic transmission of excitation is suppressed at the level of interneurons of the spinal cord. Since it is this mechanism that is responsible for excess muscle tone, when it is suppressed, muscle tone decreases. In addition to muscle relaxant properties, tizanidine also has a moderate central analgesic effect.

The drug Tizanidin-Teva is effective both in acute painful muscle spasms and in chronic spasticity of spinal and cerebral origin. Reduces spasticity and clonic convulsions, as a result of which resistance to passive movements decreases and the range of active movements increases.

The muscle relaxant effect (measured using the Ashworth scale and the pendulum test) and side effects (decrease in heart rate (HR) and decrease in blood pressure (BP)) of the drug depend on the concentration of tizanidine in the blood plasma.

Pharmacokinetics

Suction

Tizanidine is absorbed quickly and almost completely. The maximum concentration in blood plasma (Cmax) is achieved approximately 1 hour after taking the drug. Due to the pronounced first-pass metabolism through the liver, the average bioavailability is about 34%. Cmax of tizanidine is 12.3 ng/ml and 15.6 ng/ml after single and multiple doses of tizanidine 4 mg, respectively.

Distribution

The average volume of distribution at steady state after intravenous administration is 2.6 l/kg. Plasma protein binding is 30%.

Metabolism

Tizanidine is rapidly and extensively (about 95%) metabolized in the liver. In vitro, tizanidine is metabolized mainly by the CYP1A2 isoenzyme of the cytochrome P450 system. Metabolites are inactive.

Removal

The average half-life of tizanidine from the systemic circulation is 2-4 hours, excretion is carried out primarily by the kidneys (approximately 70% of the dose) in the form of metabolites; the share of unchanged substance accounts for about 4.5%.

Food influence

Concomitant food intake does not affect the pharmacokinetics of tizanidine (when administered as 4 mg tablets or 12 mg modified-release capsules).

Although the Cmax value increases by 1/3 when taken after meals, this is not clinically significant. There is no significant effect on absorption (AUC, area under the concentration-time pharmacokinetic curve).

Tizanidine in the dose range from 1 mg to 20 mg has linear pharmacokinetics.

Features of pharmacokinetics in certain groups of patients

Patients with impaired renal function

In patients with impaired renal function (creatinine clearance (CC) ≤ 25 ml/min), tizanidine plasma Cmax is 2 times higher than in healthy volunteers, the terminal half-life reaches 14 hours, which leads to increased (approximately 6-fold) systemic bioavailability of tizanidine (measured by AUC).

Patients with liver dysfunction

No special studies have been conducted in patients in this category. Since tizanidine is predominantly metabolized in the liver by the CYP1A2 isoenzyme of the cytochrome system, impaired liver function may lead to increased systemic exposure of the drug.

Patients over 65 years of age

Data on pharmacokinetics in patients in this group are limited.

Dependence on gender and race

Gender does not affect the pharmacokinetic properties of tizanidine.

The influence of ethnicity and race on the pharmacokinetics of tizanidine has not been studied.

Special instructions

Hypotension may occur during the use of the drug Tizanidine-Teva, as well as as a result of drug interactions with inhibitors of the CYP1A2 isoenzyme and/or antihypertensive drugs. A pronounced decrease in blood pressure can lead to loss of consciousness and circulatory collapse.

Cases of liver dysfunction associated with tizanidine have been reported, but these cases are rare at daily doses up to 12 mg. In this regard, it is recommended to monitor liver function tests once a month in the first 4 months of treatment in patients receiving tizanidine at a daily dose of 12 mg or higher, as well as in cases where clinical signs suggestive of impaired liver function are observed, such as unexplained nausea, anorexia, and fatigue. If the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum persistently exceeds the upper limit of normal by 3 times or more, the use of Tizanidin-Teva should be discontinued.

Contraception

Patients with preserved reproductive potential should be informed about the adverse effects of the drug on the developing fetus identified in animal studies. While using the drug, as well as for 1 day after stopping the drug, patients with preserved reproductive potential should use reliable methods of contraception (with correct and long-term use of which the pregnancy rate is <1%).

Influence on the ability to drive vehicles and work with equipment

Patients who experience drowsiness, dizziness, or any signs of arterial hypotension while using the drug should be advised to refrain from activities that require high concentration and quick reaction, for example, driving vehicles and machinery.

Active ingredient

Tizanidine

Composition

1 tablet contains: active ingredient tizanidine hydrochloride (in terms of tizanidine) 2.29 mg (2.00 mg)/4.58 mg (4.00 mg); excipients: lactose (lactose anhydrous) 57.91 mg/115.82 mg; proSolv SMCC 501 (microcrystalline cellulose 98%, colloidal silicon dioxide 2%) 22.575 mg/45.15 mg; proSolv SMCC 901 (microcrystalline cellulose 98%, colloidal silicon dioxide 2%) 22.575 mg/45.15 mg; stearic acid 2.150 mg/4.30 mg.

Pregnancy

Pregnancy

Since there are no controlled studies of tizanidine in pregnant women, it should not be used during pregnancy unless the potential benefit outweighs the potential risk.

Animal studies have not revealed teratogenicity. When used in doses of 10 and 30 mg/kg per day, an increase in gestational age was observed in animals, cases of prenatal and postnatal fetal loss, as well as delayed fetal development, were recorded. When using the above doses, females showed pronounced signs of muscle relaxation and sedation. Based on body surface area, these doses exceeded the maximum recommended dose for humans (0.72 mg/kg per day) by 2.2 and 6.7 times.

Breast-feeding

In animal studies, tizanidine was excreted in small amounts in the milk of lactating females. The drug should not be used during breastfeeding, since there is no data on the penetration of tizanidine into breast milk in humans.

Pregnancy test

Before starting the use of Tizanidin-Teva in patients with preserved reproductive potential, it is recommended to obtain the result of a pregnancy test.

Effect on fertility

In animal studies, there was no adverse effect on fertility in males or females when using tizanidine at a dose of 10 mg/kg per day and
3 mg/kg per day, respectively. There was a decrease in fertility in males receiving tizanidine at a dose exceeding 30 mg/kg per day, and in females at a dose exceeding 10 mg/kg per day. Based on body surface area, these doses exceeded the maximum recommended dose for humans (0.72 mg/kg per day) by 2.2 and 6.7 times. Behavioral effects and clinical signs, including severe sedation, weight loss, and ataxia, were observed in the mother at these doses.

Contraindications

Hypersensitivity to tizanidine or any other component of the drug.
Severe liver dysfunction.
Concomitant use with potent inhibitors of the CYP1A2 isoenzyme, such as fluvoxamine or ciprofloxacin.
Not recommended for patients with rare hereditary diseases, such as lactase deficiency, lactose intolerance, glucose-galactose malabsorption, since the dosage form contains lactose.
Experience with the drug in patients under 18 years of age is limited. The use of Tizanidine-Teva in patients in this population is not recommended.

With caution

It is recommended to exercise caution when using the drug in patients over 65 years of age, patients with impaired renal function, and patients with moderate liver dysfunction.

Caution must be exercised when simultaneous use of Tizanidine-Teva with drugs that prolong the QT interval (for example, cisapride, amitriptyline, azithromycin).

Side Effects

When taking small doses recommended for relieving painful muscle spasms, drowsiness, increased fatigue, dizziness, dry mouth, decreased blood pressure, nausea, gastrointestinal disorders, and increased activity of liver transaminases were observed. Typically, the above-described adverse reactions are moderate and transient.

When taking higher doses, the above-mentioned adverse reactions (ARs) occur more often and are more pronounced, but they rarely require discontinuation of the drug due to the severity of the adverse events.

ADRs are grouped in accordance with the MedDRA classification of organs and organ systems; within each group they are listed in order of decreasing frequency of occurrence. To assess the frequency of development of HP, the following criteria were used: very often (≥ 1/10); often (≥ 1/100, < 1/10); uncommon (≥ 1/1000,
< 1/100); rare (≥ 1/1000, < 1/1000); very rare (< 1/10000), including isolated reports.

Nervous system disorders: very often – drowsiness, dizziness; frequency unknown – headache, ataxia, dysarthria.

Mental disorders: often – insomnia, sleep disorders; rarely – hallucinations*; frequency unknown – confusion.

Cardiac disorders: often – bradycardia.

Vascular disorders: often – a decrease in blood pressure (in some cases pronounced, up to circulatory collapse and loss of consciousness).

Disorders of the digestive system: very often – gastrointestinal disorders, dry mouth; often – nausea; frequency unknown – abdominal pain, vomiting.

Musculoskeletal and connective tissue disorders: very often – muscle weakness.

Immune system disorders: frequency unknown – hypersensitivity reactions, including anaphylactic reactions, angioedema and urticaria.

Visual disturbances: frequency unknown – blurred vision.

Disorders of the skin and subcutaneous tissues: rarely – skin rash; frequency unknown – erythema, itching, dermatitis.

Disorders of the liver and biliary tract: very rarely – hepatitis, liver failure.

General disorders and disorders at the injection site: very often – increased fatigue; often – “withdrawal” syndrome**; frequency unknown – asthenia, loss of appetite.

Laboratory and instrumental data: often – increased activity of liver transaminases.

* Hallucinations are usually possible in patients using potentially hallucinogenic drugs, such as antidepressants.

** If Tizanidin-Teva is abruptly discontinued after prolonged treatment and/or taking high doses of the drug (as well as after use together with antihypertensive drugs), the risk of developing tachycardia, increased blood pressure, and in some cases – acute cerebrovascular accident increases, and therefore the dose of Tizanidin-Teva should be reduced gradually until the drug is completely discontinued.

If any of the side effects indicated in the instructions get worse, or you notice any other side effects not listed in the instructions, tell your doctor.

Interaction

When using the drug Tizanidine-Teva with inhibitors of the CYP1A2 isoenzyme, an increase in the concentration of tizanidine in the blood plasma is possible. In turn, an increase in the concentration of tizanidine in the blood plasma can lead to symptoms of drug overdose, including prolongation of the QT(c) interval.

The simultaneous use of Tizanidine-Teva with inducers of the CYP1A2 isoenzyme may lead to a decrease in the concentration of tizanidine in the blood plasma, which may lead to a decrease in the therapeutic effect of the drug.

Contraindicated combinations with tizanidine

Concomitant use of tizanidine with fluvoxamine or ciprofloxacin, inhibitors of the CYP1A2 isoenzyme, is contraindicated.

When tizanidine was used with fluvoxamine or ciprofloxacin, there was a 33-fold and 10-fold increase in tizanidine AUC, respectively. The result of simultaneous use may be significant and prolonged hypotension, accompanied by drowsiness, dizziness, and a decrease in the speed of psychomotor reactions (in some cases, up to circulatory collapse and loss of consciousness).

Combinations not recommended with tizanidine

It is not recommended to use tizanidine simultaneously with other inhibitors of the CYP1A2 isoenzyme – antiarrhythmic drugs (amiodarone, mexiletine, propafenone), cimetidine, some fluoroquinolones (enoxacin, pefloxacin, norfloxacin), rofecoxib, oral contraceptives, ticlopidine.

Combinations with tizanidine requiring caution

Caution must be exercised when simultaneous use of Tizanidine-Teva with drugs that prolong the QT interval (for example, cisapride, amitriptyline, azithromycin).

Antihypertensive drugs

The simultaneous use of Tizanidine-Teva with antihypertensive drugs, including diuretics, can sometimes cause a pronounced decrease in blood pressure (in some cases, up to circulatory collapse and loss of consciousness) and bradycardia.

When the drug Tizanidin-Teva was abruptly discontinued after simultaneous use with antihypertensive drugs, the development of tachycardia and an increase in blood pressure was observed, which in some cases can lead to acute cerebrovascular accident.

Rifampicin

Simultaneous administration of tizanidine and rifampicin leads to a 50% decrease in the concentration of tizanidine in the blood plasma. As a result, the therapeutic effect of the drug may be reduced, which may be clinically significant for some patients. Long-term simultaneous use of rifampicin and tizanidine should be avoided; if impossible, careful selection of the dose of tizanidine (increase) is recommended.

Smoking tobacco

The systemic bioavailability of tizanidine in smoking patients (more than 10 cigarettes per day) is reduced by approximately 30%. Long-term drug therapy in patients in this category may require higher doses of tizanidine than the average therapeutic dose.

Alcohol

During drug therapy, alcohol intake should be avoided, as it may increase the likelihood of adverse events (for example, decreased blood pressure and lethargy). Tizanidine may enhance the depressant effect of alcohol on the central nervous system.

Other medicines

Sedatives, hypnotics (benzodiazepine, baclofen) and other drugs such as antihistamines may also increase the sedative effect of tizanidine.

Avoid taking the drug with other alpha2-adrenergic agonists (eg, clonidine) due to the potential for increased hypotensive effects.

Overdose

To date, there have been several reports of tizanidine overdose, including a case where the dose taken was 400 mg. In all cases, recovery was uneventful.

Symptoms: nausea, vomiting, decreased blood pressure, prolongation of the QT interval (c), dizziness, drowsiness, miosis, anxiety, respiratory depression, coma.

Treatment

To remove the drug from the body, repeated use of activated carbon is recommended. Forced diuresis may also speed up the elimination of tizanidine. Subsequently, symptomatic treatment is carried out.

Storage conditions

In a dry place, protected from light, at a temperature not exceeding 30 °C

Shelf life

3 years

Manufacturer

Teva Pharmaceutical Works Private Limited Company, Hungary