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

Stroke sequelae, Pain, Neck pain, Back pain, Cramps

Painful muscle spasm:

• related to static and functional diseases of the spine (cervical and lumbar syndromes);
• after surgical interventions, such as for herniated disc or osteoarthritis of the hip joint.

Spasticity of the skeletal muscles in neurological diseases, such as multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, the effects of cerebral circulatory disorders and infantile cerebral palsy (patients over 18 years).

Active ingredient

Tizanidine

Composition

1 tablet contains: active substance 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 silica 2%) 22.575 mg/45.15 mg; proSolv SMCC 901 (microcrystalline cellulose 98%, colloidal silica 2%) 22.575 mg/45.15 mg; stearic acid 2.150 mg/4.30 mg.

How to take, the dosage

The drug Tizanidine-Teva has a narrow therapeutic index and high variability of tizanidine plasma concentrations; therefore, careful dosage selection is necessary.

The dose and dosing regimen should be adjusted individually according to the patient’s needs. The use of the drug in the initial dose of 2 mg 3 times a day reduces the risk of side effects.

The drug is taken orally. The 2 mg and 4 mg tablets can be divided at risk for easy swallowing.

In painful muscle spasm Tizanidine-Teva is usually used in a dose of 2 mg or 4 mg 3 times daily.

In severe cases, additional 2 mg or 4 mg may be used (preferably before bedtime because of possible increased sleepiness).

In skeletal muscle spasticity due to neurological diseases, the initial daily dose should not exceed 6 mg divided into 3 doses. The dose may be increased gradually, by 2-4 mg, at intervals of 3 to 4 to 7 days. Typically, optimal therapeutic effect is achieved with a daily dose of 12 to 24 mg divided into 3 or 4 doses at regular intervals. A dose of 36 mg per day should not be exceeded.

Application in patients over 65 years

The experience with Tizanidine-Teva in patients over 65 years of age is limited. It is recommended to start therapy with the lowest dose with gradual increase until an optimal balance between tolerability and efficacy of therapy is achieved.

Application in patients with impaired renal function

The treatment of patients with renal impairment (CKR less than 25 ml/min) is recommended to start with a dose of 2 mg once daily. The dose is increased in small “steps” with regard to tolerability and efficacy. If a more pronounced effect is needed, it is recommended to first increase the dose administered once daily, followed by increasing the frequency of administration.

Application in patients with hepatic impairment

The use of Tizanidine-Teva in patients with severe hepatic impairment is contraindicated.

In patients with moderate hepatic impairment the drug should be used with caution; it is recommended to start therapy at the lowest dose with gradual increase until an optimal balance of tolerability and efficacy is achieved. For recommendations to monitor liver function parameters, see section “Cautions”.

Cessation of treatment

. If therapy with Tizanidine-Teva is discontinued to decrease the risk of ricochet hypertension and tachycardia, the dose should be slowly reduced until the drug is completely withdrawn, especially in patients who have been receiving high doses of the drug for a long time.

Interaction

When using Tizanidine-Teva with CYP1A2 isoenzyme inhibitors, plasma concentrations of Tizanidine may be increased. In turn, increased plasma concentration of tizanidine may lead to symptoms of drug overdose, including prolongation of the QT(c) interval.

The concomitant use of Tizanidine-Teva with CYP1A2 isoenzyme inducers may decrease tizanidine plasma concentrations, which may decrease the therapeutic effect of the drug.

Controlled combinations with tizanidine

The simultaneous use of tizanidine with fluvoxamine or ciprofloxacin, CYP1A2 isoenzyme inhibitors is contraindicated.

When using tizanidine with fluvoxamine or ciprofloxacin a 33-fold and 10-fold increase in AUC of tizanidine is noted, respectively. Concomitant use may result in significant and prolonged hypotension accompanied by drowsiness, dizziness, decreased rate of psychomotor reactions (in some cases up to circulatory collapse and loss of consciousness).

Unrecommended combinations with tizanidine

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

Combinations with tizanidine requiring caution

Cautious use of Tizanidine-Teva with drugs that prolong the QT interval (e.g., cisapride, amitriptyline, azithromycin) should be used simultaneously.

Hypotensive drugs

The concomitant use of the drug Tizanidine-Teva with hypotensive drugs, including diuretics, can sometimes cause significant BP decrease (in some cases up to and including circulatory collapse and loss of consciousness) and bradycardia.

In abrupt withdrawal of the drug Tizanidine-Teva after concomitant use with hypotensive drugs, tachycardia and increased BP have been noted, which in some cases can lead to acute cerebral circulation disorder.

Rifampicin

The simultaneous use of tizanidine and rifampicin leads to 50% decrease of tizanidine concentration in plasma. As a consequence, the therapeutic effect of the drug may decrease, which may be of clinical significance in some patients. Prolonged concomitant use of rifampicin and tizanidin should be avoided; if this is not possible, careful selection of the tizanidine dose (increase) is recommended.

Smoking tobacco

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

Alcohol

Alcohol should be avoided during therapy with the drug because it may increase the likelihood of adverse events (e.g., decreased BP and lethargy). Tizanidine may increase the depressant effect of alcohol on the central nervous system.

Other drugs

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

The drug should be avoided with other alpha₂ adrenoreceptor agonists (e.g., clonidine) because of the potential for increased hypotensive effects.

Special Instructions

Hypotension may occur during the use of the drug Tizanidine-Teva, as well as a result of drug interaction with CYP1A2 isoenzyme inhibitors and/or hypotensive drugs. Significant decrease in BP may lead to loss of consciousness and circulatory collapse.

There have been reported cases of liver function abnormalities associated with Tizanidine, but these cases were rarely reported with daily doses up to 12 mg. In this regard, it is recommended to monitor functional “liver function tests” once a month during the first 4 months of treatment in patients who receive 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 serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity persistently exceeds the upper limit of normal by 3 times or more, the use of Tizanidine-Teva should be stopped.

Contraception

Patients with preserved reproductive potential should be advised of the adverse effects of the drug on the developing fetus that have been identified in animal studies. During the use of the drug as well as for 1 day after discontinuation of the drug, patients of preserved reproductive potential should use reliable contraceptive methods (with correct and continuous use of which the rate of pregnancy is < 1%).

Influence on driving and operating machinery

Patients who experience drowsiness, dizziness or any signs of arterial hypotension while taking the drug should be advised to refrain from activities requiring high concentration and rapid reaction, such as driving vehicles and operating machinery.

Contraindications

• High sensitivity to tizanidine or any other component of the drug.
• Severe hepatic impairment.
• Simultaneous use with potent CYP1A2 isoenzyme inhibitors such as fluvoxamine or ciprofloxacin.
• It is not recommended for patients with rare hereditary diseases such as lactase deficiency, lactose intolerance, glucose-galactose malabsorption because the dosage form contains lactose.
• The experience of using the drug in patients under 18 years old is limited. It is not recommended to use Tizanidine-Teva in patients in this population.

Cautions

Patients over 65 years of age, patients with renal dysfunction, patients with moderate liver function abnormality should be cautioned when using the drug.

Perhaps caution is advised when using Tizanidine-Teva concomitantly with drugs that prolong the QT interval (e.g., cisapride, amitriptyline, azithromycin).

Side effects

Drowsiness, increased fatigue, dizziness, dry mouth, decreased blood pressure, nausea, gastrointestinal disturbances, and increased liver transaminase activity have been reported with low doses recommended to relieve painful muscle spasm. Usually the adverse reactions described above are moderate and transient.

The above adverse reactions (ARs) are more frequent and more severe when taking higher doses, but they rarely require discontinuation due to severity of ARs.

HDs are grouped according to the MedDRA organ and organ system classification, listed within each group in decreasing order of frequency of occurrence. The following criteria were used to assess the incidence of HPs: very common (≥1/10); frequent (≥1/100, < 1/10); infrequent (≥1/1000,
< 1/100); rare (≥1/1000, < 1/1000); very rare (< 1/10000), including individual reports.

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

Psychiatric disorders: frequent – insomnia, sleep disturbances; rare – hallucinations*; frequency unknown – confusion.

Cardiac disorders: frequent – bradycardia.

vascular disorders: frequent – decreased blood pressure (in some cases severe, up to and including circulatory collapse and loss of consciousness).

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

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

Disorders of the immune system: frequency unknown – hypersensitivity reactions, including anaphylactic reactions, angioedema and urticaria.

Visual disorders:frequency unknown – blurred vision.

Skin and subcutaneous tissue disorders: frequently – skin rash; frequency unknown – erythema, skin itching, dermatitis.

Liver and biliary tract disorders: very rare – hepatitis, liver failure.

General disorders and disorders at the place of administration: very often – fatigue; often – syndrome “withdrawal “**; frequency unknown – asthenia, loss of appetite.

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

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

** Abrupt withdrawal of Tizanidine-Teva after prolonged treatment and/or high doses of the drug (as well as after use with hypotensive drugs) increases the risk of tachycardia, high BP, and in some cases, acute cerebral circulation disorders, therefore, the dose of Tizanidine-Teva should be reduced gradually until complete withdrawal of the drug.

If any of the side effects mentioned in the instructions worsen, or if you notice any other side effects not mentioned in the instructions, tell your doctor.

Overdose

There have been several reports of tizanidine overdose to date, including a case in which the dose taken was 400 mg. In all cases, recovery has been uneventful.

Symptoms: Nausea, vomiting, decreased BP, prolonged QT interval (c), dizziness, somnolence, miosis, restlessness, respiratory depression, coma.

Treatment

Multiple administration of activated charcoal is recommended to eliminate the drug from the body. Forced diuresis may also accelerate excretion of tizanidine. Thereafter, symptomatic treatment is carried out.

Pregnancy use

Pregnancy

As controlled studies of tizanidine use in pregnant women have not been conducted, it should not be used during pregnancy unless the potential benefit exceeds the possible risk.

There have been no studies in animals showing teratogenicity. When administered in doses of 10 and 30 mg/kg per day in animals, an increase in gestational age and cases of prenatal and postnatal fetal loss as well as fetal retardation have been reported. When the above doses were used in females, pronounced signs of myorelaxation and sedation were observed. Based on body surface area, the indicated doses exceeded the maximum recommended dose for humans (0.72 mg/kg per day) by a factor of 2.2 and 6.7.

Breastfeeding

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

Pregnancy test

Pregnancy test results are recommended before starting Tizanidine-Teva in patients with preserved reproductive potential.

Influence on fertility

In animal studies, there were no adverse effects on fertility in male and female animals when tizanidine was used 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 greater than 30 mg/kg per day, and in females at a dose greater than 10 mg/kg per day. Based on body surface area, the indicated doses were 2.2 and 6.7 times higher than the maximum recommended dose for humans (0.72 mg/kg/day). Behavioral effects and clinical signs including marked sedation, weight loss, and ataxia were noted on the maternal side when the indicated doses were administered.

Similarities

Sirdalud, Tizalud, Tizanil, Tizanidin-Teva, Tizanidin, Sirdalud MR