Tizanidine - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate - 55,000 mg; cellulose microcrystalline - 50.312 mg; povidone K-30 - 1,100 mg; stearic acid 1,100 mg; silicon dioxide colloidal hydrophobic - 0.200 mg.

Dosage 4 mg

active substance: tizanidine hydrochloride 4.576 mg (in terms of tizanidine- 4,0 mg);

Excipients: lactose monohydrate - 110,000 mg; cellulose microcrystalline - 100.624 mg; Povidone K-30 - 2,200 mg; stearic acid 2,200 mg; silicon dioxide colloidal hydrophobic - 0.400 mg.

Description:

Round flat cylindrical tablets white or white with a yellowish tinge color with a bevel (for a dosage of 2 mg) or with a facet and a crosswise risk (for a dosage of 4 mg).

Pharmacotherapeutic group:Miorelaxant of central action

ATX: & nbsp

M.03.B.X Other muscle relaxants of central action

M.03.B.X.02 Tizanidine

Pharmacodynamics:

Tizanidine is a central muscle relaxant. The main point of application of its action is in the spinal cord. Stimulating presynaptic alpha₂-receptors. it inhibits the release of excitatory amino acids that stimulate receptors to N-methyl-Daspartate (NMDA-receptors). As a result, the polysynaptic transmission of excitation is suppressed at the level of the intermediate neurons of the spinal cord. Since this mechanism is responsible for the excess muscle tone, when it is suppressed, the muscle tone decreases. In addition to the muscle relaxant properties, tizanidine renders also moderately central pronounced analgesic effect.

Tizanidine is effective both in acute painful muscular spasm and in chronic spasticity of spinal and cerebral genesis. Reduces spasticity and clonic convulsions, resulting in reduced resistance to passive movements and increases the volume of active movements.

The miorelaxing effect (measurement on the Ashworth scale and with the "pendulum" test) and side effects (decrease in the heart rate (HR) and blood pressure reduction (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 the blood plasma (C_max) is achieved approximately 1 hour after taking the drug. Due to the expressed metabolism at the "first passage" through the liver, the average bioavailability is about 34%. FROM_max tizanidine is 12.3 ng / ml and 15.6 g / ml after a single and repeated administration of tizanidine at a dose of 4 mg, respectively.

Distribution

The average volume of distribution in the equilibrium state with intravenous administration 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.

Excretion

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

Effect of food

Simultaneous food intake does not affect the pharmacokinetics of tizanidine (with the use of 4 mg in the form of tablets or 12 mg in the form of capsules with modified release). Despite the fact that the value of C_max increases by 1/3 when taken after a meal, it is not clinically relevant. There is no significant effect on absorption (AUC-area under the pharmacokinetic curve "concentration-time").

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

Pharmacokinetics in specific patient groups

Patients with impaired renal function

In patients with impaired renal function (creatinine clearance (CK) <25 ml / min) C_maxtizanidine in blood plasma is 2 times higher than in healthy volunteers, the final half-life reaches 14 hours, which leads to an increase (approximately 6-fold) in the systemic bioavailability of tizanidine (measured by AUC).

Patients with impaired hepatic function

Special studies in patients in this category were not conducted. Because the tizanidine mainly metabolized in the liver by the CYP1A2 isoenzyme of the cytochrome system, a violation of the liver function can lead to an increase in the systemic effect of the drug.

Patients over 65 years of age

Data on pharmacokinetics in patients in this group are limited.

Dependence on sex and race

Sex does not affect the pharmacokinetic properties of tizanidine.

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

Indications:

Painful muscular spasm:

- associated with static and functional diseases of the spine (cervical and lumbar syndromes);

- after surgical interventions, for example, about the hernia of the intervertebral disc or osteoarthrosis of the hip joint.

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

Contraindications:

- hypersensitivity to tizanidine or any other component of the drug;

- impaired hepatic function;

- simultaneous application with potent inhibitors of isoenzyme CYP1A2, 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 tizanidine in patients under 18 years of age is limited. Application of the drug Tizanidine in patients of this population is not recommended.

Carefully:

Care should be taken when using the drug in patients older than 65 years, patients with impaired renal function, patients with impaired liver function of moderate severity.

Care must be taken when using the drug simultaneously Tizanidine with drugs that extend the interval QT (e.g., cisapride, amitriptyline, azithromycin).

Pregnancy and lactation:

Pregnancy

Since controlled trials of tizanidine in pregnant women have not been performed, it should not be used during pregnancy, unless the potential benefit exceeds the potential risk.

In studies in animals, teratogenicity was not detected. When applied at doses of 10 and 30 mg / kg / day in animals, an increase in the gestation period was noted, cases of prenatal and postnatal fetal loss as well as delayed fetal development were recorded. When applying the above doses, the females showed marked signs of muscle relaxation and sedation. Based on the surface area of the body, these doses exceeded the maximum recommended dose for a person (0.72 mg / kg per day) in 2.2 and 6.7 times.

Breastfeeding period

In studies in animals tizanidine was excreted in small quantities with the milk of lactating females. Do not use the drug during breastfeeding, since there is no evidence of penetration of tizanidine into human milk in human milk.

Pregnancy test

Before starting the preparation Tizanidine in patients with preserved reproductive potential, it is recommended to obtain a pregnancy test result.

Impact on fertility

In studies in animals, there was no adverse effect on fertility of males and females with the use of 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 that received tizanidine in a dose exceeding 30 mg / kg per day, and in females - in a dose exceeding 10 mg / kg per day. Based on the surface area of the body, these doses exceeded the maximum recommended dose for a person (0.72 mg / kg per day) in 2.2 and 6.7 times. When these doses were applied from the mother's side, behavioral effects and clinical signs, including pronounced sedation, weight loss and ataxia, were noted.

Dosing and Administration:

A drug Tizanidine has a narrow therapeutic index and a high variability in the concentration of tizanidine in the blood plasma, so a careful dose selection is necessary.

Dose and dosage regimen should be selected individually, depending on the needs of the patient. The use of the drug in an initial dose of 2 mg 3 times a day reduces the risk of side effects.

The drug is taken orally. A tablet of 4 mg can be divided into two or four equal parts.

With painful muscle spasms a drug Tizanidine used, usually in a dose of 2 mg or 4 mg 3 times a day.

In severe cases, additional use of 2 mg or 4 mg is possible (preferably at bedtime due to possible increased sleepiness).

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

Use in patients over 65 years of age

The experience with tizanidine in patients older than 65 years is limited. It is recommended to start therapy with a minimal dose with a gradual increase to achieve the optimal ratio of tolerability and efficacy of therapy.

Use in patients with impaired renal function

Treatment of patients with renal insufficiency (CC less than 25 ml / min) is recommended to begin with a dose of 2 mg 1 time per day. Increase the dose in small "steps" taking into account portability and effectiveness. If it is necessary to achieve a more pronounced effect, it is recommended first to increase the dose applied once a day, after which increase the frequency of application.

Use in patients with impaired hepatic function

Application of the drug Tizanidine in patients with impaired hepatic function is severely contraindicated.

In patients with impaired liver function of moderate severity, the drug should be used with caution; it is recommended to start therapy with a minimal dose, with a gradual increase to achieve the optimal ratio of tolerability and efficacy of therapy. Recommendations for monitoring liver function indicators are indicated in the section "Special instructions".

Interruption of treatment

When discontinuing drug therapy Tizanidine in order to reduce the risk of developing ricochet hypertension and tachycardia, the dose should be slowly reduced until the drug is completely discontinued, especially in patients receiving high doses of the drug for a long time.

Side effects:

When taking small doses, recommended for arresting a painful muscle spasm, there were drowsiness, increased fatigue, dizziness, dry mouth, decreased blood pressure, nausea, gastrointestinal disorders, increased activity of hepatic transaminases. Typically, the above-described adverse reactions are moderately expressed and transient.

When taking the higher doses recommended for the treatment of spasticity, the above-described undesirable reactions occur more often and more pronounced, but they rarely require discontinuation of the drug due to the severity of unwanted reactions. In addition, the following phenomena can occur: bradycardia, muscle weakness, insomnia, sleep disorders, hallucinations, hepatitis.

Undesirable reactions (HP) are grouped according to the classification of organs and systems of organs of MedDRA, within each group are listed in order of decreasing incidence.

Classification of the incidence of adverse events according to the recommendations of the World Health Organization (WHO):

very often ≥ 1/10;

often from ≥ 1/100 to <1/10;

infrequently from ≥ 1/1000 to <1/100;

rarely from ≥ 1/10000 to <1/1000;

very rarely <1/10000, including individual messages;

the frequency is unknown - it is not possible to establish the frequency of occurrence from the available data.

Impaired nervous system: very often - drowsiness, dizziness.

Disorders of the psyche: often - insomnia, sleep disturbances.

Heart Disease: infrequently bradycardia.

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

Disorders from the digestive system: very often - gastrointestinal disorders, dry mouth; often - nausea.

Disturbances from the musculoskeletal and connective tissue: very often - muscle weakness.

General disorders: very often - increased fatigue.

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

With a sharp cancellation of tizanidine after prolonged treatment and / or high doses (and also after simultaneous application together with antihypertensive drugs), development of tachycardia and increased blood pressure were noted, which in some cases can lead to acute impairment of cerebral circulation, and therefore the dose of the drug Tizanidine should be reduced gradually until the drug is completely discontinued.

Separate reports on HP according to application in clinical practice

Since in the post-marketing period, reports of HP are received voluntarily from a population of undetermined size, it is not possible to reliably estimate the frequency of their occurrence (the frequency is unknown).

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

Disorders of the psyche: hallucinations, confusion.

Disturbances from the nervous system: dizziness.

Disorders from the side of the organ of vision: blurring of vision.

Disturbances from the liver and bile ducts: hepatitis, hepatic insufficiency.

Disturbances from the skin and subcutaneous tissues: skin rash, erythema, itching, dermatitis.

General disorders: asthenia, withdrawal syndrome.

If any of the side effects listed in the instruction are aggravated, or you notice any other side effects not listed in the instructions, inform the doctor about it.

Overdose:

To date, several reports of an overdose of tizanidine have been received, including the case when the dose taken was 400 mg. In all cases, the recovery was without any special features.

Symptoms

Nausea, vomiting, decreased blood pressure, lengthening of the interval QT(c), dizziness, drowsiness, miosis, anxiety, respiratory depression, coma.

Treatment

To remove the drug from the body is recommended multiple use of activated carbon.Forced diuresis may also accelerate the excretion of tizanidine. In the future, symptomatic treatment is carried out.

Interaction:

When using the drug Tizanidine with inhibitors of the isoenzyme CYP1A2, 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 the prolongation of the QT interval (c).

Simultaneous use of the drug Tizanidine with inducers of the isoenzyme CYP1A2 can 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

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

When tizanidine is used with fluvoxamine or ciprofloxacin, a 33-fold and 10-fold increase in the aUC of tizanidine is observed, respectively. The result of simultaneous application may be significant and prolonged hypotension, accompanied by drowsiness, dizziness, decreased speed of psychomotor reactions (in some cases up tocirculatory collapse and loss of consciousness).

Unrecommended combinations with tizanidine

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

Combinations with tizanidine, requiring caution

Care must be taken when using the drug simultaneously Tizanidine with drugs that extend the QT interval (eg, cisapride, amitriptyline, azithromycin).

Hypotensive drugs

Simultaneous use of the drug Tizanidine with antihypertensive drugs, including diuretics, can sometimes cause a marked decrease in blood pressure (in some cases, up to circulatory collapse and loss of consciousness) and bradycardia.

With a sharp cancellation of tizanidine after simultaneous use with antihypertensive drugs, there was a development of tachycardia and an increase in blood pressure, which in some cases can lead to acute impairment of cerebral circulation.

Rifampicin

Simultaneous administration of tizanidine and rifampicin results in a 50% decrease in tizanidine concentration in the blood plasma. As a consequence, the therapeutic effect of the drug may decrease, which may be of clinical significance for some patients. Avoid prolonged simultaneous use of rifampicin and tizanidine, failing recommended careful dose selection tizanidine (increase).

Smoking of tobacco

Systemic bioavailability of tizanidine in smoking patients (more than 10 cigarettes a 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 therapy with the drug, alcohol intake should be avoided, as it may increase the likelihood of adverse events (eg, LD reduction and retardation). Tizanidine can enhance the depressant effect of alcohol on the central nervous system.

Other medicines

Sedative, hypnotics (benzodiazepine, baclofen) and other drugs, such as antihistamines, can also enhance the sedative effect of tizanidine.Avoid taking the drug with other α2-adrenoreceptor agonists (eg clonidine) due to the potential increase in the hypotensive effect.

Special instructions:

Hypotension may occur when the drug is used Tizanidine, as well as as a result of drug interaction with inhibitors of the isoenzyme CYP1A2 and / or hypotensive drugs. A pronounced decrease in blood pressure can lead to loss of consciousness and circulatory collapse.

Reported cases of violations of liver function associated with tizanidine, but with a daily dose of up to 12 mg, these cases were rare. In this regard, it is recommended to monitor functional "liver tests" once a month in the first 4 months of treatment in patients who receive tizanidine in a daily dose of 12 mg and above, as well as in those cases when there are clinical signs suggesting a violation of liver function - such as unexplained nausea, anorexia, a feeling of fatigue. In the case where the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (ACT) in blood plasma persistently exceed the upper limit of the norm by 3 times or more, the use of the drug Tizanidine should be discontinued.

Contraception

It is necessary to inform patients with the preserved reproductive potential of the adverse effect of tizanidine on the developing fetus found in studies in animals. During the use of the drug, as well as within 1 day after discontinuation of the drug, patients with preserved reproductive potential should use reliable contraceptive methods (with a correct and prolonged use of which the pregnancy rate is <1%).

Effect on the ability to drive transp. cf. and fur:

Patients who have drowsiness, dizziness, or any signs of arterial hypotension should be recommended to abstain from activities requiring high concentration of attention and quick reaction, for example, driving vehicles and mechanisms.

Form release / dosage:

Tablets 2 mg and 4 mg.

Packaging:

10, 15, 20 or 30 tablets in a planar cell pack of film polyvinylchloride and aluminum foil.

30 or 60 tablets in a can of high-density polyethylene.

3 or 6 contour cell packs of 10 tablets, 2 or 4 contour packs of 15 tablets each, 3 contour packs of 20 tablets, 1 or 2 contourcell packs of 30 tablets or one pot together with instructions for use in a pack of cardboard.

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004171

Date of registration:03.03.2017

Expiration Date:03.03.2022

The owner of the registration certificate:VERTEKS, AO VERTEKS, AO Russia

Manufacturer: & nbsp

VERTEKS, AO Russia

Information update date: & nbsp29.03.2017

Illustrated instructions

Instructions

Tizanidine (Tizanidine)