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

Composition:1 tablet contains: active substance: tizanidine hydrochloride (based on base) - 2.288 mg (2,000 mg) / 4.576 mg (4,000 mg); Excipients: silicon colloidal dioxide - 0,300 mg / 0,400 mg, stearic acid - 3,000 mg / 4,000 mg, microcrystalline cellulose - 74,412 mg / 101,024 mg, lactose - 80,000 mg / 110,000 mg.

Description:

Tablets 2 mg: from white to almost white, round, flat tablets with bevelled edges, on one side of the risk and code OZ.

Tablets 4 mg: from white to almost white, round, flat pills with beveled edges, on one side crossed risks, on the other - code RL.

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.The main point of application of its action is in the spinal cord. By stimulating presynaptic alpha 2 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 also has a central moderately pronounced analgesic effect.

The drug Sirdalud® 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 equal to 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 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 blood flow is 2-4 hours, excretion is performed 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.

Peculiarities of pharmacokinetics in individual 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 increased (about 6-fold) 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.

Dysfunction of the liver of a severe degree.

Simultaneous application with potent inhibitors of isoenzyme CYP1A2, such as fluvoxamine or ciprofloxacin.

It is not recommended for patients with rare hereditary diseases, such as lactase deficiency, lactose intolerance, glucose-galactose malabsorption, since the dosage form contains lactose.

The experience of using the drug in patients younger than 18 years is limited.The use of Sirdalud® in patients in 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 should be taken when using the drug Sirdalud® with drugs that extend the interval QT (e.g., cisapride, amitriptyline, azithromycin).

Pregnancy and lactation:

Pregnancy

Since controlled studies of the use of tizanidine in pregnant women have not been performed, it should not be used during pregnancy, except when the potential benefit exceeds the possible risk. In studies in animals, no teratogenicity has been identified. 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 / day) in 2.2 and 6.7 times.

Breast-feeding

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 use of Sirdalud® in patients with preserved reproductive potential, it is recommended to obtain the result of a pregnancy test.

Impact on fertility

In studies in animals, there was no adverse effect on the fertility of males and females when tizanidine was administered at a dose of 10 mg / kg per day and 3 mg / kg / 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 day. Based on the surface area of the body, these doses exceeded the maximum recommended dose for humans (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:

The drug Sirdalud® 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. Tablets of 2 mg and 4 mg can be divided into two equal parts.

In a painful muscle spasm, the drug Sirdalud® is usually used 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).

When 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 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 Sirdalud® in patients older than 65 years and older 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 start 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

The use of Sirdalud® in patients with severe liver failure is 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 listed in the section "Special instructions".

Interruption of treatment

When discontinuing Sirdalud® therapy 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 HP appear more often and more pronounced, however, they rarely require discontinuation of the drug due to the severity HP. In addition, the following phenomena can occur: bradycardia, muscle weakness, insomnia, sleep disorders, hallucinations, hepatitis.

Undesirable reactions (HP) grouped in accordance with the classification of organs and systems of organs MedDRA, within each group are listed in order of decreasing frequency of occurrence. To assess the frequency of development HP the following criteria were used: very often (≥ 1/10); often (from ≥ 1/100, <1/10); infrequently (≥ 1/1000, <1/100); rarely (≥ 1/10000, <1/1000); very rarely (<1/10000), including individual messages.

Disturbances from the 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, until the 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 and disorders at the site of administration: very often - increased fatigue.

Laboratory and instrumental data: often - increased activity of liver transaminases. With a sharp withdrawal of the drug Sirdalud® after prolonged treatment and / or taking high doses of the drug(and also after simultaneous application together with antihypertensive drugs), development of tachycardia and increased blood pressure was noted, which in some cases can lead to acute impairment of cerebral circulation, and therefore the dose of Sirdalud® should be reduced gradually until the drug is completely discontinued.

Separate reports about HP according to application in clinical practice

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

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

Disorders of the psyche: hallucinations, confusion.

Impaired nervous system: dizziness.

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

Disorders from the liver and bile ducts: hepatitis, hepatic failure.

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

General disorders and disorders at the site of administration: 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, report it the doctor.

Overdose:

To date, several reports of an overdose of Sirdalud® 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 Sirdalud® with isoenzyme inhibitors CYP1A2 it is possible to increase the concentration of tizanidine in blood plasma. In turn, an increase in the concentration of tizanidine in the blood plasma can lead to symptoms of drug overdose, including the lengthening of the interval QT(c).

Simultaneous use of Sirdalud® with isoenzyme inducers CYP1A2 can lead to a decrease in the concentration of tizanidine in the blood plasma, which can lead to a decrease in the therapeutic effect of the drug.

Contraindicated combinations with tizanidine

Simultaneous use of tizanidine with fluvoxamine or ciprofloxacin, inhibitors of isoenzyme CYP1A2, it is contraindicated.

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

Not recommended combinations with tizanidine

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

Combinations with tizanidine, requiring caution

Care should be taken when using the Sirdalud® with time-lengthening drugs QT (e.g., cisapride, amitriptyline, azithromycin).

Hypotensive drugs

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

With the sharp cancellation of Sirdalud® after simultaneous use with antihypertensive drugs, development of tachycardia and an increase in blood pressure were noted, 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 developing adverse events (eg, lowering blood pressure and inhibition). 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 alpha agonists₂-adrenoreceptors (eg, clonidine) due to the potential increase in the hypotensive effect.

Special instructions:

Hypotension may occur with the use of the drug Sirdalud®, 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 activity of alanine aminotransferase (ALT) and aspartate aminotransferase (ACT) in the serum stably exceed the upper limit of the norm 3 times or more, the use of the drug Sirdalud® should be discontinued.

Contraception

It is necessary to inform patients with the preserved reproductive potential of the unfavorable effect of the drug on the developing fetus, revealed 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, 4 mg.

Packaging:

10 tablets in a blister of PVC / PE / PVDC / aluminum foil. For 3 blisters (30 tablets) in a cardboard box together with instructions for use.

Storage conditions:

At a temperature of no higher than 25 ° C.

The drug should be stored out of the reach of children.

Shelf life:

5 years.

The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N012947 / 01

Date of registration:03.08.2010 / 18.07.2014

Expiration Date:Unlimited

The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland

Manufacturer: & nbsp

NOVARTIS Saglik Gida ve Tarim Urunlery Sanayi ve Ticaret, A.S. Turkey

Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC

Information update date: & nbsp24.11.2016

Illustrated instructions

Instructions

Sirdalud® (Sirdalud®)