Sirdalud®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SIRDALUD® (SIRDALUD®)

Composition:

Active substance: tizanidine;

One tablet contains 2.288 mg or 4.576 mg of tizanidine hydrochloride, corresponding to 2 mg or 4 mg of tizanidine, respectively;

Excipients: anhydrous lactose, microcrystalline cellulose, stearic acid, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical properties:

Sirdalud® 2 mg – white or almost white, round, flat tablets with bevelled edges, marked with a score line and the inscription "OZ" on one side;

Sirdalud® 4 mg – white or almost white, round, flat tablets with bevelled edges, marked with cross-score lines on one side and the inscription "RL" on the other side.

Pharmacotherapeutic group. Centrally acting muscle relaxants. ATC code M03B X02.

Pharmacological properties.

Pharmacodynamics.

Tizanidine is a centrally-acting muscle relaxant/spasmolytic. Its primary site of action is the spinal cord. Evidence suggests that by stimulating presynaptic α-2-adrenergic receptors, it inhibits the release of excitatory amino acids that stimulate N-methyl-D-aspartate (NMDA) receptors. As a result, polysynaptic signal transmission at interneuronal connections in the spinal cord responsible for excessive muscle tone is suppressed, leading to reduced muscle tone. Sirdalud® is effective both in acute painful muscle spasms and in chronic spasticity of spinal and cerebral origin. It reduces resistance to passive movements, suppresses spasms and clonic seizures, and improves the strength of active muscle contractions.

Pharmacokinetics.

Absorption and distribution. Tizanidine is rapidly absorbed. Maximum plasma concentration is reached approximately 1 hour after administration. The mean absolute bioavailability is 34% (CV 38%). The mean volume of distribution at steady state (Vss) after intravenous administration is 160 L. Plasma protein binding is 30%. The relatively low variability in pharmacokinetic parameters (Cmax and AUC) facilitates reliable prediction of plasma levels in patients after oral administration.

Metabolism/elimination. The drug undergoes rapid and extensive (approximately 95%) hepatic metabolism. Tizanidine is metabolized in vitro predominantly by CYP1A2. The metabolites are inactive. They are excreted mainly via the kidneys (70%). Elimination of total radioactivity (i.e., unchanged substance and metabolites) is biphasic, with an initial rapid phase (elimination half-life t1/2 = 2.5 hours) and a slower elimination phase (t1/2 = 22 hours). Only a small amount of unchanged substance (approximately 2.7%) is excreted renally. The mean elimination half-life of unchanged substance is 2–4 hours.

Linearity.

Tizanidine pharmacokinetics are linear within the dose range of 1 to 20 mg.

Pharmacokinetics in specific patient groups. In patients with renal impairment (creatinine clearance less than 25 ml/min), the mean maximum plasma concentration is twice that observed in healthy volunteers, and the terminal elimination half-life is prolonged to approximately 14 hours, resulting in an average 6-fold increase in the area under the concentration-time curve (AUC).

Studies in patients with hepatic impairment have not been conducted.

Tizanidine is extensively metabolized by the CYP1A2 isoenzyme in the liver. In patients with impaired liver function, higher plasma concentrations of the substance may occur.

Sirdalud® is contraindicated in patients with severe hepatic impairment (see section "Contraindications").

Pharmacokinetic data in elderly patients are limited.

Gender has no clinically significant effect on the pharmacokinetic properties of tizanidine.

The effect of ethnicity on tizanidine pharmacokinetics has not been studied.

Effect of food. Concomitant intake of food does not affect the pharmacokinetic profile of Sirdalud® tablets. Although maximum concentration increases by one-third, this is not clinically significant. No substantial effect on absorption has been observed.

Clinical characteristics.

Indications.

• Painful muscle spasm.
• Spasticity due to multiple sclerosis.
• Spasticity due to spinal cord injury.
• Spasticity due to brain injury.

Contraindications.

• Hypersensitivity to tizanidine or to any of the excipients of the medicinal product.
• Severe hepatic impairment.
• Concomitant use of tizanidine with strong CYP1A2 inhibitors, such as fluvoxamine or ciprofloxacin.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of known CYP1A2 inhibitors may increase plasma levels of tizanidine. Elevated plasma levels of tizanidine may lead to symptoms of overdose, such as QT interval prolongation.

Concomitant use of known CYP1A2 inducers may reduce plasma levels of tizanidine. Reduced plasma levels of tizanidine may result in decreased therapeutic effect of Sirdalud®.

Concomitant use of tizanidine with strong CYP1A2 inhibitors, such as fluvoxamine or ciprofloxacin, is contraindicated (see section "Contraindications"). Concomitant administration of tizanidine with fluvoxamine increases the AUC of tizanidine by 33 times, whereas concomitant administration with ciprofloxacin increases the AUC of tizanidine by 10 times. This may lead to clinically significant and prolonged reduction in blood pressure, accompanied by somnolence, dizziness, and reduced psychomotor performance (see section "Special precautions for use").

Concomitant use of tizanidine with other CYP1A2 inhibitors, such as antiarrhythmic agents (amiodarone, mexiletine, propafenone), cimetidine, certain fluoroquinolones (enoxacin, pefloxacin, norfloxacin), rofecoxib, oral contraceptives, and ticlopidine, is not recommended.

Increased plasma levels of tizanidine may manifest as symptoms of overdose, including QT interval prolongation (see section "Overdose").

Concomitant use of Sirdalud® with antihypertensive agents, including diuretics, may occasionally cause arterial hypotension and bradycardia. In some patients receiving concomitant antihypertensive therapy, rebound arterial hypertension and rebound tachycardia have been observed upon abrupt discontinuation of tizanidine. In individual cases, rebound arterial hypertension may lead to stroke (see sections "Special precautions for use" and "Adverse reactions").

Caution should be exercised when using Sirdalud® concomitantly with medicinal products that prolong the QT interval.

Concomitant use of Sirdalud® with rifampicin may result in a 50% reduction in tizanidine concentration. Thus, the therapeutic effect may be diminished during rifampicin treatment while on Sirdalud®, which may be clinically significant for some patients. Prolonged concomitant use should be avoided, and if necessary, dose adjustment should be performed with extreme caution. Careful dose titration (dose increase) is required in case of planned long-term combination therapy.

Administration of Sirdalud® results in a 30% reduction in systemic exposure to tizanidine in men who smoke (more than 10 cigarettes per day). Long-term use in men who smoke heavily may require higher doses of the drug.

Concomitant use of Sirdalud® with other centrally acting medicinal products (e.g., sedatives and hypnotics (benzodiazepines or baclofen), certain antihistamines, general anesthetics and analgesics, psychotropic agents, narcotics) may enhance the effects of each agent and increase the sedative effect of Sirdalud®. This particularly applies to concomitant alcohol intake, which may unpredictably alter or enhance the effect of Sirdalud® and increase the risk of adverse reactions; therefore, alcohol consumption should be avoided. The CNS depressant effect of alcohol may be potentiated by Sirdalud®.

Concomitant use of Sirdalud® with α-2-adrenergic agonists (e.g., clonidine) should be avoided due to their potential additive hypotensive effect.

Special precautions for use.

Concomitant use of moderate CYP1A2 inhibitors with tizanidine is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Contraindications").

After abrupt discontinuation of the drug, especially following prolonged use, rapid dose reduction and/or use of high daily doses, and/or concomitant use of antihypertensive medicinal products, patients may experience a rebound phenomenon. Under such circumstances, patients may develop arterial hypertension and tachycardia. In individual cases, such rebound arterial hypertension may lead to stroke. Tizanidine treatment should not be stopped abruptly, but only gradually tapered (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects").

In patients with renal impairment (creatinine clearance < 25 mL/min), systemic exposure to tizanidine may be up to six times higher; therefore, the recommended initial dose is 2 mg once daily (see section "Dosage and administration"). The dose should be increased sequentially in small increments, taking into account efficacy and tolerability. To achieve a more pronounced effect, it is recommended to first increase the dose administered once daily, followed by increasing the frequency of administration.

Hepatic failure associated with tizanidine use has been reported; however, it is rare in patients receiving daily doses up to 12 mg. Therefore, liver function should be monitored monthly during the first four months of therapy in patients receiving tizanidine at doses of 12 mg or higher, and in patients presenting clinical symptoms suggestive of hepatic impairment (such as nausea, loss of appetite, or unexplained fatigue). Sirdalud® should be discontinued if serum ALT or AST levels exceed three times or more the upper limit of normal for a prolonged period.

Hypersensitivity reactions, including anaphylaxis, angioedema, dyspnea, dermatitis, rash, urticaria, pruritus, and erythema, have been reported during tizanidine use. Close monitoring of patients is recommended for one or two days after administration of the first dose of tizanidine. If anaphylaxis or angioedema with anaphylactic shock or dyspnea occurs, Sirdalud® should be discontinued immediately and appropriate treatment initiated.

Arterial hypotension may occur during tizanidine use, as well as as a result of drug interactions with CYP1A2 inhibitors and/or antihypertensive agents (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects"). Severe manifestations of arterial hypotension, such as loss of consciousness and circulatory collapse, have been reported.

Caution is advised when co-administering this medicinal product with agents that prolong the QT interval (such as cisapride, amitriptyline, azithromycin) (see section "Interaction with other medicinal products and other forms of interaction").

Caution is necessary in patients with ischemic heart disease and/or heart failure. Regular ECG monitoring should be performed at the beginning of Sirdalud® treatment in such patients.

The benefit-risk ratio should be carefully evaluated before administering this medicinal product to patients with myasthenia gravis.

Experience with use in children and adolescents is limited; therefore, the use of Sirdalud® is not recommended in this patient population.

Caution should be exercised when administering this medicinal product to elderly patients.

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

Use during pregnancy or breastfeeding.

Women of reproductive age.

Women of reproductive age who are sexually active should undergo a pregnancy test before initiating treatment with Sirdalud®.

Women of reproductive age should be informed that animal studies indicate that Sirdalud® may be harmful to the fetus. Sexually active women of reproductive age should use effective contraceptive methods (methods allowing pregnancy in less than 1% of cases) throughout the entire treatment period with Sirdalud® and for one day after discontinuation of Sirdalud®.

Pregnancy.

Data on the use of Sirdalud® in pregnant women are limited; therefore, it should not be prescribed during pregnancy except when the potential benefit to the mother outweighs the possible risk to the fetus. Sirdalud® has no teratogenic effect in rats and rabbits, but it causes difficult labor, increased prenatal and postnatal mortality, and delayed fetal development in rats.

Breastfeeding.

Teratogenic effects were not observed in rats and rabbits treated with tizanidine. The risk to the breastfed infant should be considered. Animal studies have shown that tizanidine passes into breast milk in small amounts. Therefore, Sirdalud® should not be administered to breastfeeding women.

Fertility.

No impairment of fertility was observed in male rats treated with the drug at a dose of 10 mg/kg/day and in female rats treated at 3 mg/kg/day. Decreased fertility was observed in male rats receiving the drug at 30 mg/kg/day and in female rats receiving the drug at 10 mg/kg/day. Sedation, weight loss, and ataxia were also observed at these doses.

Ability to affect reaction speed when driving or operating machinery.

Even when used as recommended, tizanidine may cause somnolence, dizziness, and/or arterial hypotension, thereby impairing the patient's ability to drive a car or operate machinery. Risks increase with concomitant alcohol consumption.

Therefore, patients should refrain from activities requiring high concentration and rapid reaction, such as driving vehicles or operating machines.

Method of Administration and Dosage

Sirdalud® has a narrow therapeutic range and high variability in plasma concentrations of tizanidine among different patients. Therefore, it is important to use optimal doses according to individual patient needs. Treatment should be initiated with a low dose of 2 mg to minimize the risk of adverse effects. If necessary, the dose may be gradually increased, observing all necessary precautions.

Adults

Relief of Painful Muscular Spasms

Administer 2–4 mg three times daily. In severe cases, an additional dose of 2 or 4 mg may be taken before bedtime.

Spasticity in Neurological Disorders

The dose should be individually titrated for each patient.

Initial daily dose should not exceed 6 mg in three divided doses. The daily dose may be gradually increased by 2–4 mg at intervals of 3–7 days. The optimal therapeutic effect is usually achieved at a daily dose of 12–24 mg, divided into 3 or 4 doses. The total daily dose should not exceed 36 mg.

Special Patient Populations

Use in Children and Adolescents

Experience with the use of Sirdalud® in children and adolescents is limited; therefore, the drug is not recommended for use in this population.

Use in Elderly Patients

Experience with the use of Sirdalud® in elderly patients is limited; therefore, caution should be exercised when administering the drug to this patient group. It is recommended to initiate treatment with the lowest dose and gradually increase it cautiously in small increments until the optimal balance between individual tolerability and therapeutic efficacy is achieved.

Use in Patients with Renal Impairment

For patients with renal impairment (creatinine clearance < 25 mL/min), the recommended initial single daily therapeutic dose is 2 mg. Dose escalation should be gradual and cautious, in small increments, until the optimal balance between individual tolerability and therapeutic efficacy is achieved. To enhance therapeutic efficacy, the single dose should first be increased before considering more frequent daily dosing (see section "Special Instructions").

Use in Patients with Hepatic Impairment

Treatment of patients with severe hepatic dysfunction is contraindicated (see section "Contraindications"). Sirdalud® is extensively metabolized in the liver. Data on the use of Sirdalud® in patients with hepatic impairment are limited (see section "Pharmacokinetics"). Use of Sirdalud® has been associated with reversible abnormalities in liver function tests (see sections "Special Instructions" and "Adverse Reactions"). Sirdalud® should be used with caution in patients with moderate hepatic impairment. Treatment should be initiated with the lowest available dose; any dose increase should be performed cautiously and based on the individual patient's tolerability of Sirdalud®.

Discontinuation of Treatment

If discontinuation of treatment is necessary, the dose should be tapered slowly and gradually. This is particularly important for patients who have been receiving high doses over a prolonged period. Gradual tapering reduces the risk of rebound hypertension and tachycardia (see section "Special Instructions").

Children

Experience with the use of the drug in pediatric populations is limited. Sirdalud® is not recommended for use in children.

Overdose

Very few cases of overdose with Sirdalud® have been reported. In all patients with documented single cases of overdose, including one patient who ingested 400 mg of Sirdalud®, recovery occurred without complications.

Symptoms: nausea, vomiting, arterial hypotension, bradycardia, QT interval prolongation, dizziness, miosis, respiratory distress, coma, restlessness, somnolence.

Treatment: to enhance drug elimination, repeated administration of high doses of activated charcoal is recommended. Forced diuresis may accelerate drug elimination. Subsequently, symptomatic treatment should be provided.

Side effects.

Side effects – such as somnolence, increased fatigue, dizziness, dry mouth, decreased blood pressure, nausea, gastrointestinal disturbances, and elevated serum transaminase levels – are usually mild and transient in patients receiving the low doses recommended for the relief of painful muscular spasm.

When doses higher than those recommended for the treatment of spasticity are used, the aforementioned side effects occur more frequently and are more pronounced; however, they are rarely so severe as to necessitate discontinuation of treatment. Other possible side effects include arterial hypotension, bradycardia, muscle weakness, sleep disturbances, hallucinations, and hepatitis.

The occurrence of such symptoms has been reported after abrupt withdrawal of tizanidine, particularly following long-term treatment and/or high daily doses and/or concomitant therapy with antihypertensive agents. Under these circumstances, patients may develop arterial hypertension and tachycardia. In isolated cases, such rebound arterial hypertension may lead to stroke. Therefore, tizanidine treatment should not be abruptly discontinued, but rather tapered gradually (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

The following classification has been used to assess the frequency of various adverse reactions: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000).

Psychiatric disorders: common – insomnia, sleep disturbances.

Central nervous system: very common – somnolence, weakness, dizziness.

Cardiac disorders: uncommon – bradycardia.

Vascular disorders: common – hypertension, slight decrease in blood pressure.

Gastrointestinal disorders: very common – gastrointestinal disturbances, dry mouth; common – nausea.

Hepatobiliary disorders: common – elevated serum transaminase levels.

Skeletal muscle disorders: very common – muscle weakness.

General disorders: very common – increased fatigue.

Post-marketing surveillance

Additional adverse reactions have been reported in post-marketing experience. Reports on these adverse reactions came from an undefined number of patients, therefore it is not possible to reliably estimate their frequency.

Immune system disorders: hypersensitivity reactions (including anaphylaxis, angioedema, dyspnea, and urticaria).

Psychiatric disorders: hallucinations, confusion.

Nervous system disorders: vertigo.

Cardiovascular disorders: syncope.

Eye disorders: blurred vision.

Hepatobiliary disorders: hepatitis, hepatic failure.

Skin and subcutaneous tissue disorders: rash, erythema, pruritus, dermatitis.

General disorders: asthenia, withdrawal syndrome.

Shelf life. 5 years.

Storage conditions. Store at temperatures not exceeding 25 °C, in a place inaccessible to children.

Packaging. 10 tablets per blister; 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturers.

1. Novartis Saglik, Gida Ve Tarim Urunleri San. Ve Tic. A.S. / Novartis Saglik, Gida Ve Tarim Urunleri San. Ve Tic. A.S.
2. Novartis Pharma GmbH / Novartis Pharma GmbH.

Manufacturers' addresses.

1. Yenisehir Mahallesi, Ihlara Vadisi Sokak No. 2, Pendik, Istanbul, TR 34912, Turkey / Yenisehir Mahallesi, Ihlara Vadisi Sokak No. 2, Pendik, Istanbul, TR 34912, Turkey.
2. Roonstrasse 25 and Obere Turnstrasse 8, 90429, Nuernberg, Germany / Roonstrasse 25 und Obere Turnstrasse 8, 90429, Nuernberg, Germany.