Tizanidine

Pharmacological properties

tizanidine is a central skeletal muscle relaxant. the main point of application of its influence is the spinal cord. By stimulating presynaptic α2-adrenergic receptors, it inhibits the release of amino acids that stimulate n-methyl-d-aspartate receptors (nmda receptors). as a result, polysynaptic signal transmission is suppressed at the level of interneuronal connections in the spinal cord, which is responsible for excessive muscle tone, and muscle tone is reduced. Sirdalud is effective both in acute painful muscle spasms and in chronic spasticity of spinal and cerebral origin. it reduces resistance to passive movements and suppresses spasm and clonic convulsions and improves the strength of active muscle contractions.

Pharmacokinetics

Suction and distribution. Tizanidine is rapidly absorbed. C_max in blood plasma is achieved approximately 1 hour after application. The average absolute bioavailability is 34%. The average volume of distribution of a stable state (Vss) after iv administration is 2.6 l / kg of body weight. Binding to plasma proteins - 30%. Relatively low deviation of pharmacokinetic parameters among patients (C_max and AUC) facilitates a reliable preliminary assessment of plasma levels after oral administration.

Metabolism / excretion. The drug undergoes rapid and extensive metabolism in the liver. Tizanidine is metabolized in vitro primarily by CYP 1A2. Metabolites are inactive. They are secreted mainly by the kidneys (70%). The excretion of total radioactivity (i.e., unchanged substance and metabolites) is two-phase, with a fast initial phase (T_½ - 2.5 hours) and a slower elimination phase (T_½ - 22 hours). Only a small amount of the substance in unchanged form (about 2.7%) is excreted by the kidneys. Average T_½ substances in unchanged form is 2–4 hours

Pharmacokinetics in certain groups of patients. In patients with renal failure (creatinine clearance 25 ml / min), the average value of C_max in blood plasma is twice that of healthy volunteers, and the final T_½ increases to approximately 14 hours, as a result of which AUC increased on average 6 times.

No studies have been conducted in patients with impaired liver function.

Tizanidine is metabolized by the CYP 1A2 isoenzyme in the liver. In patients with impaired liver function, higher concentrations of the substance in the blood plasma may occur.

Sirdalud is contraindicated in individuals with severely impaired liver function.

Pharmacokinetic data on elderly patients are limited.

Gender does not affect the pharmacokinetic properties of tizanidine.

The effect of ethnic and racial affiliation on the pharmacokinetics of tizanidine has not been studied.

The effect of food. Simultaneous eating does not affect the pharmacokinetic profile of Sirdalud tablets. Although the value of C_max increases by a third, it is not clinically significant. No significant effect on absorption was noted.

Indications

Painful muscle spasm. spasticity due to multiple sclerosis. spasticity due to spinal cord injuries. spasticity due to brain damage.

Application

Cirdalud has a narrow therapeutic range and high variability in the concentration of tizanidine in plasma in different patients. therefore, it is important to use it in optimal doses according to the needs of the patient. treatment should be started with a low dose of 2 mg, which makes the risk of undesirable effects from taking the drug minimal. if necessary, the dose of the drug can be gradually increased with all the required precautions.

Adults

Relieving painful muscle cramps. Apply 2-4 mg 3 times a day. In severe cases, at bedtime, you can take an additional dose of 2 or 4 mg.

Spasticity in neurological disorders.The dose should be selected individually for each patient.

The initial daily dose should not exceed 6 mg, divided into 3 doses. It can be increased gradually to 2–4 mg 2 times at intervals of 3–7 days. Usually, the optimal therapeutic effect is achieved with a daily dose of 12-24 mg, divided into 3 or 4 doses. Do not exceed the total daily dose of 36 mg.

Special patient populations

Use in children and adolescents. The experience with Sirdalud in children and adolescents is limited, therefore it is not recommended for use in this category of patients.

Use in the elderly. Experience in the use of the drug in elderly patients is limited, therefore caution should be exercised when using the drug Sirdalud in this category of patients. It is recommended to start treatment with a minimum dose and gradually with caution increase it in “small steps” until the optimal ratio of individual tolerance and therapeutic efficacy of the drug is achieved.

Use in patients with impaired renal function. For patients with impaired renal function (creatinine clearance 25 ml / min), the recommended initial single daily therapeutic dose is 2 mg. Increasing the dose occurs gradually and with caution, "in small steps", until the optimal ratio of individual tolerance and therapeutic efficacy of the drug is achieved. In order to increase therapeutic efficacy, you should first increase a single dose before moving on to more frequent use of the drug during the day.

Use in patients with impaired liver function. Treatment of persons with severely impaired liver function is contraindicated. Cirdalud is largely metabolized in the liver. Cirdalud should be used with caution in the treatment of patients with moderate liver dysfunction. Treatment should be started with a minimum dose, a possible dose increase should be carried out with caution and taking into account the individual patient tolerance of the drug Sirdalud.

Interruption of treatment. If it is necessary to interrupt treatment, the dose should be reduced slowly and gradually. This is especially true for patients who have used the drug in high doses for a long time. Thus, the risk of developing a ricocheted increase in blood pressure and tachycardia is reduced.

Contraindications

Hypersensitivity to tizanidine or any other component of the drug. severe dysfunction of the liver. concomitant use of tizanidine with potent cyp 1a2 inhibitors such as fluvoxamine or ciprofloxacin.

Side effects

Adverse reactions - such as drowsiness, fatigue, dizziness, dry mouth, decreased hell, nausea, digestive tract disorders, and elevated plasma transaminases - are usually mild and transient in patients using the drug at low doses, recommended for stopping painful muscle spasm.

When taken in doses exceeding the recommended, to eliminate spasticity, the above adverse reactions occur more often and are more pronounced, however, they are rarely so serious as to discontinue treatment. Adverse reactions may also occur: arterial hypotension, bradycardia, muscle weakness, sleep disturbance, hallucinations, and hepatitis.

The appearance of such symptoms is registered after the sudden withdrawal of tizanidine, especially after prolonged treatment and / or administration at high daily doses and / or concomitant therapy with antihypertensive drugs. Under such circumstances, patients may experience hypertension and tachycardia. In some cases, such a rebound hypertension can cause a stroke. Therefore, treatment with tizanidine should not be stopped suddenly, but only by gradually reducing the dose.

The following classification was used to assess the incidence of various adverse reactions: very often (≥1 / 10), often (≥1 / 100, 1/10), infrequently (≥1 / 1000, 1/100), rarely (≥1 / 10 000, 1/1000), very rarely (1/10 000), including individual messages.

Mental disorders: often - insomnia, sleep disturbance.

From the side of the central nervous system: very often - drowsiness, dizziness; frequency unknown - confusion, vertigo.

From the side of the heart: infrequently - bradycardia

From the vascular system: often - arterial hypotension; slight decrease in blood pressure.

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

Hepatobiliary disorders: often - elevated plasma transaminases.

From the musculoskeletal system: very often - muscle weakness.

General disorders: very often - increased fatigue.

Post Marketing Research

Additional adverse reactions to the drug have been reported in post-registration studies.

These adverse reactions have been reported from an undetermined number of patients, so it is not possible to reliably estimate their frequency.

On the part of the immune system: hypersensitivity reactions (including anaphylaxis, throat edema, shortness of breath and urticaria).

Mental disorders: hallucinations, confusion.

From the side of the central nervous system: vertigo.

From the cardiovascular system: syncope.

From the side of the organ of vision: blurred vision.

Hepatobiliary disorders: hepatitis, liver failure.

On the part of the skin and subcutaneous tissue: rash, erythema, pruritus, dermatitis.

General disorders: asthenia, withdrawal syndrome.

special instructions

The simultaneous use of cyp 1a2 inhibitors with tizanidine is not recommended.

After a sudden withdrawal of the drug or a rapid dose reduction, patients may experience hypertension and tachycardia. In some cases, such a rebound hypertension can cause a stroke. Treatment with tizanidine should not be stopped suddenly, but only gradually reducing the dose.

For patients with renal failure (creatinine clearance 25 ml / min), the initial dose is 2 mg 1 time per day. The dose should be increased sequentially, in small "steps", taking into account the effectiveness and tolerability. To achieve a more pronounced effect, it is recommended first to increase the dose prescribed once a day, and then increase the frequency of administration.

Hepatic insufficiency associated with the use of tizanidine was reported, but this was rarely observed in patients who received daily doses of up to 12 mg. In this regard, it is recommended to monitor liver function 1 time per month during the first 4 months of therapy in patients using tizanidine at a dose of ≥12 mg, and in patients with clinical symptoms indicating liver failure (e.g. nausea, loss of appetite or increased fatigue of an unknown etiology). The use of the drug Sirdalud should be discontinued if the level of AlAT or AsAT in the blood plasma exceeds the upper limit of the norm by ≥3 times for a long period.

Careful monitoring of patients within 1 or 2 days after taking the first dose of tizanidine is recommended. In the case of anaphylaxis or swelling of the throat with anaphylactic shock or shortness of breath, the use of Sirdalud should be stopped immediately and the necessary treatment should be prescribed to the patient.

Arterial hypotension can occur with the use of tizanidine, as well as the result of drug interactions with CYP 1A2 inhibitors and / or antihypertensive drugs. Severe forms of arterial hypotension have been reported, such as loss of consciousness and circulatory collapse.

Caution should be exercised when using this drug with agents that extend the Q – T interval (for example, cisapride, amitriptyline, azithromycin).

Caution is necessary for patients with coronary artery disease and / or heart failure.ECG monitoring should be carried out at regular intervals at the beginning of the use of Sirdalud in these patients.

Before using this drug, patients with gravis myasthenia gravis need to carefully evaluate the risk / benefit ratio.

The experience of use in children and adolescents is limited, so the use of the drug Sirdalud is not recommended in this category of patients.

Caution should be exercised when using this drug in the elderly.

Sirdalud tablets contain lactose. Sirdalud tablets are not recommended for patients with rare hereditary diseases - galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption syndrome.

Use during pregnancy and lactation

Women of childbearing age. Women of childbearing age who live sexually should have a pregnancy test before starting treatment with Sirdalud. Women of childbearing age should be informed that the results of animal studies indicate that Cirdalud negatively affects the fetus. Women of childbearing age who live sexually should use effective methods of contraception (methods that allow pregnancy in less than 1% of cases) throughout the entire period of treatment with Sirdalud and within 1 day after stopping treatment with the drug.

Pregnancy. Data on the use of Sirdalud in pregnant women are limited, therefore, should not be prescribed during pregnancy, unless the potential benefit to the mother outweighs the potential risk to the fetus.

Lactation. When tizanidine was used in rats and rabbits, no teratogenic effects were observed. Animal experiments have shown that tizanidine passes into breast milk in an insignificant amount. Therefore, women who are breastfeeding should not be prescribed the drug.

Fertility. There was no impaired fertility in male rats receiving the drug at a dose of 10 mg / kg / day and in female rats receiving the drug at a dose of 3 mg / kg / day. A decrease in fertility was detected in male rats receiving the drug at a dose of 30 mg / kg / day, and in female rats receiving the drug at a dose of 10 mg / kg / day. When using the drug in these doses, sedation, weight loss and ataxia are also noted.

Children. The experience of using the drug in pediatrics is limited. Prescribing Sirdalud to children is not recommended.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Tizanidine can cause drowsiness, dizziness, and / or arterial hypotension, thereby impairing the patient’s ability to drive vehicles or operate machinery. Risks increase with the simultaneous use of alcohol.

Therefore, one should refrain from activities requiring a high concentration of attention and quick reaction, for example, from driving vehicles or working with machines and mechanisms.

Interactions

The simultaneous use of known cyp 1a2 inhibitors can increase the level of tizanidine in blood plasma. increased levels of tizanidine in blood plasma can lead to overdose symptoms, such as lengthening the q – t interval.

The simultaneous use of known inducers of CYP 1A2 can reduce the level of tizanidine in blood plasma. A decrease in the level of tizanidine in blood plasma can lead to a decrease in the therapeutic effect of Sirdalud.

The simultaneous use of potent CYP 1A2 inhibitors, such as fluvoxamine or ciprofloxacin, with tizanidine is contraindicated. The simultaneous use of tizanidine with fluvoxamine increases the AUC of tizanidine by 33 times, while the simultaneous use of tizanidine with ciprofloxacin increases the AUC of tizanidine by 10 times.This can lead to a clinically significant and long-term decrease in blood pressure, accompanied by drowsiness, dizziness, and decreased psychomotor performance.

The simultaneous use of tizanidine with other CYP 1A2 inhibitors, such as antiarrhythmic drugs (amiodarone, mexiletine, propafenone), cimetidine, some fluoroquinolones (enoxacin, pefloxacin, norfloxacin), rofecoxib, oral contraceptives and ticlopidine are not recommended.

An increase in plasma tizanidine levels can cause symptoms of overdose, including prolongation of the Q – T interval.

The simultaneous use of the drug Sirdalud with antihypertensive drugs, including diuretics, can sometimes cause arterial hypotension and bradycardia. In some patients who used simultaneous treatment with antihypertensive drugs, rebound hypertension and rebound tachycardia were noted with abrupt cancellation of tizanidine. In some cases, rebound hypertension can cause a stroke.

The combined use of Sirdalud with rifampicin can lead to a 50% decrease in the concentration of tizanidine. Thus, the therapeutic effect can be reduced when rifampicin is used during therapy with Sirdalud, which may be clinically significant for some patients. Long-term simultaneous use should be avoided, and if necessary, it is necessary to very carefully adjust the dose.

The use of Sirdalud leads to a 30% decrease in the systemic effect of tizanidine in smokers (more than 10 cigarettes per day). Long-term use of the drug in patients who smoke a lot requires the use of the drug in higher doses.

The simultaneous use of Sirdalud and other centrally acting drugs (for example, sedatives and hypnotics (benzodiazepine or baclofen), some antihistamines and analgesics, psychotropic drugs, narcotic drugs) can increase the severity of the effects of each drug and enhance the hypnotic effect of Sirdalud. This applies, in particular, to the simultaneous use of alcohol, which can unpredictably change or enhance the effect of Sirdalud and increase the risk of adverse reactions, so you should refrain from drinking alcohol.

The use of the drug Sirdalud simultaneously with α₂β-adrenergic agonists (e.g., with clonidine) should be avoided due to their potential additive hypotensive effect.

Overdose

Very few reports have been received regarding an overdose of Sirdalud. in all patients in whom isolated cases of an overdose of this drug were recorded, including 1 patient who took 400 mg of the drug sirdalud, the recovery went without complications.

Symptoms: nausea, vomiting, arterial hypotension, bradycardia, prolongation of the Q – T interval, dizziness, miosis, respiratory distress, coma, anxiety, drowsiness.

Treatment. For the removal of the drug from the body, repeated use of activated carbon in high doses is recommended. Forced diuresis may accelerate the elimination of the drug. In the future, symptomatic treatment should be carried out.

Storage conditions

At a temperature not exceeding 25 ° c.

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