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

Active substanceTizanidineTizanidine

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Dosage form: & nbsptabscesses

Composition:

For a dosage of 2 mg:

Active substance: One tablet contains the active substance tizanidine hydrochloride in an amount of 2.288 mg, calculated as tizanidine 2 mg.

Excipients: cellulose microcrystalline - 50.512 mg, anhydrous - 55 mg, silicon colloidal dioxide - 1,1 mg, magnesium stearate - 1,1 mg.

For a dosage of 4 mg:

Active substance: One tablet contains the active substance tizanidine hydrochloride in an amount of 4.576 mg, calculated on tizanidine 4 mg.

Excipients: cellulose microcrystalline - 101,024 mg, anhydrous lactose - 110 mg, silicon dioxide colloid - 2.2 mg, magnesium stearate - 2.2 mg.

Description:

Tablets are round, biconvex, white or almost white, or white with a yellowish hue.

Pharmacotherapeutic group:central muscle relaxant

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. Stimulates presynaptic alpha₂-adrenoceptors of the spinal cord, suppressing the release of mediator amino acids, which stimulate receptors to N-methyl-D-aspartate (NMDAreceptors), which leads to inhibition of the polysynaptic transmission of excitation in the spinal cord, which regulates the tone of the skeletal muscles. Since this mechanism is responsible for the excess muscle tone, when it is suppressed, the muscle tone decreases.

Reduces the rigidity of muscles with passive movements, resulting in reduced resistance to passive movements and increases the volume of active movements, reduces clonic convulsions and spasms, and increases the strength of contractions of arbitrary nature of skeletal muscles.

Pharmacokinetics:

Suction

Ingestion tizanidine absorbed quickly and almost completely. The maximum concentration in plasma (C_max) is achieved approximately 1 hour after taking the drug.Due to the expressed metabolism, the average bioavailability is about 34%.

FROM_max tizanidine is 12.3 ng / ml and 15.6 ng / ml after a single and repeated administration of tizanidine at a dose of 4 mg, respectively.

Distribution

The average value of the distribution volume is 2.6 l / kg. The binding with plasma proteins is 30%. In the dosage range of 4 to 20 mg, the pharmacokinetics are linear. Given the low interindividual variability of pharmacokinetic parameters (in particular, C_max and the area under the "concentration-time" curve (AUC)), when taking tizanidine inside you can reliably predict the value of its concentration in the blood plasma.

Metabolism

Tizanidine is metabolized rapidly and to a large extent in the liver (about 95%) with the formation of inactive metabolites. In vitro it was shown that tizanidine is mainly metabolized by the isoenzyme 1A2 of the cytochrome P450 system.

Excretion

The mean value of the half-life of tizanidine from the bloodstream system (T_1/2) is 2-4 hours. Tizanidine is excreted mainly by the kidneys (approximately 70% of the dose) in the form of metabolites; the share of unchanged substance accounts for about 4.5%.

Peculiarities of pharmacokinetics of tizanidine the separate patient groups

Patients with impaired renal function

In patients with renal insufficiency (creatinine clearance less than or equal to 25 ml / min), the mean maximum plasma concentration in the plasma (C_max) is 2 times higher than in healthy volunteers, and the final half-life of tizanidine (T_1/2) reaches 14 hours, which leads to an increased (approximately 6-fold) systemic bioavailability of tizanidine (measured by AUC).

Patients with impaired hepatic function

Specific studies in this category of patients was not conducted. As tizanidine intensively metabolized in the liver by isoenzyme CYP1A2, a violation of liver function can lead to an increase in systemic exposure to tizanidine.

Patients over 65 years of age

Data on the pharmacokinetics of tizanidine in this group of patients are limited.

Dependence on sex and race

Sex does not affect the pharmacokinetic parameters of tizanidine.

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

Effect of food

The intake of food does not affect the pharmacokinetics of tizanidine. Although the value of C_max increases by 1/3, it is believed that this is not clinically relevant.A significant effect on absorption (AUC) is not observed.

Indications:

Painful muscle spasms.

Spasticity of skeletal muscles in multiple sclerosis, with diseases and injuries of the spinal cord.

Contraindications:

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

- severe violations of liver function;

- simultaneous use with potent inhibitors of isoenzyme CYP1A2 (fluvoxamine and ciprofloxacin), alpha₂-adrenomimetics;

- pregnancy;

- the period of breastfeeding;

- children under 18 years of age (efficacy and safety not established).

Since the composition of the drug includes lactose, it is not recommended to use the drug in patients with rare hereditary intolerance to galactose, with a deficiency of lactase, glucose-galactose malabsorption.

Carefully:

It is advisable to use caution when using tizanidine in patients with mild liver function abnormalities, with arterial hypotension, bradycardia, congenital lengthening syndrome QT, over the age of 65 years. It is necessary to regularly monitor laboratory parameters of the functional state of the heart and monitor ECG parameters.

Use in patients with renal insufficiency and / or in elderly patients

Patients with renal insufficiency (creatinine clearance less than or equal to 25 ml / min) need a correction of the dosing regimen. The experience with tizanidine in elderly patients is limited. Based on pharmacokinetic data, it can be assumed that in some cases, renal clearance in these patients can be significantly reduced. Caution should be exercised when using tizanidine in patients with renal insufficiency and in elderly patients.

Caution is also necessary when taking tizanidine with oral contraceptives, antiarrhythmics, cimetidine, norfloxacin, rofecoxib, ticlopidine, digoxin, beta-blockers, sedatives, ethanol, diuretics and antihypertensive drugs (see "Interaction with other drugs" ).

Pregnancy and lactation:

Pregnancy

Since controlled trials of tizanidine in pregnant women have not been performed, it should not be used during pregnancy.

Lactation

For the duration of treatment with tizanidine, breast-feeding should be discontinued, since there is no data on the penetration of the drug into breast milk.

Dosing and Administration:

Tizanidine has a narrow therapeutic index and a high variability in plasma concentrations of patients, so a careful dose selection is necessary.

The initial dose of 2 mg 3 times a day can minimize the risk of adverse reactions. The drug is prescribed inside. The dose should be carefully selected according to the individual needs of the patient.

With painful muscle spasms prescribe a dose of 2 mg or 4 mg 3 times a day. In severe cases, 2 mg or 4 mg (preferably at bedtime, because of possible increased sleepiness) may be taken at bedtime.

With spasticity of skeletal muscles due to neurological diseases, The dose should be selected individually.

The initial daily dose should not exceed 6 mg, divided into three doses - 2 mg 3 times a day. The dose can be increased gradually, by 2-4 mg, at intervals of 3-4 to 7 days. Usually, the optimal therapeutic effect is achieved at a daily dose of 12 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 of using the drug in patients aged 65 years and older is limited. It is recommended to start therapy with a minimal dose with a gradual increase until an optimal ratio of tolerability and efficacy is achieved.

Patients with renal insufficiency (the creatinine clearance is less than or equal to 25 ml / min), the recommended initial dose is 2 mg once a day. Increase in the dose is carried out gradually, slowly, taking into account the portability and effectiveness. If it is necessary to obtain a more pronounced effect, it is recommended first to increase the dose prescribed once a day, then increase the multiplicity of the appointment.

Use in patients with impaired hepatic function

The use of the drug in patients with severe impairment of liver function is contraindicated.

Interruption of treatment

When discontinuing therapy with the drug, in order to reduce the risk of developing ricochet arterial pressure 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:

The frequency of side effects listed below,was determined according to the following (classification of the World Health Organization): very often (more than 10%); often (more than 1% and less than 10%); infrequently (more than 0.1% and less than 1%); rarely (more than 0.01% and less than 0.1%); very rarely (less than 0.01%), including individual reports; the frequency is unknown (can not be estimated with the help of available data).

From the nervous system: very often - drowsiness, dizziness.

From the side of the psyche: often - insomnia, hallucinations, sleep disturbances.

From the side of the cardiovascular system: often - lowering blood pressure (in some cases, expressed, up to collapse and loss of consciousness); infrequently bradycardia.

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

Laboratory indicators: often - increased activity of microsomal liver enzymes.

From the musculoskeletal system: very often - muscle weakness.

From the skin and subcutaneous tissues: allergic reactions (eg, rashes).

General disorders: very often - increased fatigue, withdrawal syndrome.

With a sharp abolition of tizanidine after prolonged treatmentand / or taking high doses of the drug (and also after simultaneous application together with antihypertensive drugs), the development of tachycardia and an increase in blood pressure, which in some cases can lead to acute impairment of cerebral circulation, was noted, so the dose should be reduced gradually until the drug is completely discontinued.

Separate reports of adverse events according to application in clinical practice:

Against the background of therapy with tizanidine, the following undesirable phenomena were noted in clinical practice without indication of the cause-and-effect relationship with the use of the drug (the incidence of undesirable events was not established).

From the side of the psyche: the frequency is unknown - hallucinations, anxiety disorders, confusion.

From the nervous system: frequency unknown - vertigo.

From the side of the organ of vision: frequency unknown - blurred vision.

From the liver and biliary tract: frequency unknown - acute hepatitis, hepatic insufficiency.

General disorders: frequency unknown - asthenia, withdrawal syndrome.

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

Overdose:

To date, there have been cases of an overdose of tizanidine, including the case when the dose taken was 400 mg. In all cases, the restoration took place without any special features.

Symptoms:

Nausea, vomiting, marked decrease in blood pressure, lengthening of the interval QT(c), dizziness, drowsiness, miosis, anxiety, respiratory failure, coma.

Treatment:

To remove tizanidine from the body, it is recommended to wash the stomach, multiple assignment of activated charcoal, reception of a large amount of liquid. Conduction of forced diuresis, possibly, will also accelerate the excretion of tizanidine. In the future, symptomatic treatment is carried out.

Interaction:

With the simultaneous use of tizanidine and:

- inhibitors of 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 plasma can lead to symptoms of drug overdose, incl. lengthening the interval QT(c).

- inducers of isoenzyme CYP1A2 can lead to a decrease in the level of tizanidine in plasma. A reduced level of tizanidine in plasma may lead to a decrease in the therapeutic effect of the drug.

Contraindicated combinations of tizanidine

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

When tizanidine is used with fluvoxamine or ciprofloxacin, a 33-fold and 10-fold increase is noted AUC tizanidine, respectively. The result of a combined application may be a clinically significant and prolonged decrease in blood pressure, accompanied by drowsiness, dizziness, decreased speed of psychomotor reactions (in some cases, up to collapse and loss of consciousness).

Unrecommended combinations of tizanidine

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

Combinations of the drug tizanidine, requiring caution

Caution should be exercised when tizanidine is used together with drugs that extend the interval QT (e.g., cisapride, amitriptyline, azithromycin).

Hypotensive drugs

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

With a sharp cancellation of tizanidine after use together with antihypertensive drugs, development of tachycardia and an increase in arterial pressure were noted, which in some cases could lead to acute impairment of cerebral circulation.

Rifampicin

Simultaneous administration of tizanidine and rifampicin resulted in a 50% decrease in tizanidine concentration in the blood plasma. As a result, the therapeutic effect of tizanidine may decrease, which may be of clinical significance for some patients. Long-term combined use of rifampicin and tizanidine should be avoided, and careful selection of a dose of tizanidine (increase) is recommended if it is not possible.

Smoking

Systemic bioavailability of tizanidine in men smokers (more than 10 cigarettes a day) is reduced by approximately 30%. Long-term therapy with tizanidine smoking men may require higher doses than the average therapeutic.

Ethanol

During therapy with tizanidine, alcohol should be avoided, since it can increase the likelihood of developing adverse events (eg, lowering blood pressure and inhibition). Tizanidine can enhance the inhibitory effect of ethanol 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. Tizanidine should be avoided with other alpha2-adrenomimetics (eg clonidine) due to the potential increase in the hypotensive effect.

Interaction with food products: see the section "Pharmacokinetics".

Special instructions:

Hypotension can occur against the background of tizanidine, as well as as a result of drug interaction with inhibitors of isoenzyme CYP1A2 and / or antihypertensive drugs. A marked decrease in blood pressure can lead to loss of consciousness and 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 function tests once a month in the first 4 months of treatment in those patients who are assigned 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, fatigue. In the case where ALT levels and ACT in the serum consistently exceed the upper limit of the norm by 3 times or more, the drug should be discontinued.

During treatment should refrain from drinking alcohol.

Due to the threat of the "withdrawal" syndrome, the dose of the drug is reduced gradually.

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

In connection with the profile of adverse reactions, it is recommended to refrain from activities requiring high concentration of attention and quick reaction, for example, driving vehicles or working with machines and mechanisms.

Form release / dosage:Tablets, 2 mg and 4 mg.

Packaging:

10 tablets per contour cell package; 3 contour packs with a medical instruction are placed in a pack of cardboard.

For 30 or 100 tablets in a can of polymer with a lid.Each bank along with instructions for medical use is placed in a pack of cardboard.

Storage conditions:

In a dry, the 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 the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002619

Date of registration:11.09.2014

Expiration Date:11.09.2019

The owner of the registration certificate:Berezovsky Pharmaceutical Plant, ZAO Berezovsky Pharmaceutical Plant, ZAO Russia

Manufacturer: & nbsp

Berezovsky Pharmaceutical Plant, ZAO Russia

Information update date: & nbsp29.12.2016

Illustrated instructions

Instructions

Tizanidine (Tizanidine)