Tablet containing 2 mg tizanidine hydrochloride.
Tablet for oral administration. Can be divided in two equal halves.
Active substance: 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole (= tizanidine).
Excipients/Inactive Ingredients: Colloidal anhydrous silica, stearic acid, microcrystalline cellulose, anhydrous lactose.
Pharmacology: Mechanism of action: Tizanidine is a centrally acting skeletal muscle relaxant. Its principal site of action is the spinal cord, where the evidence suggests that, by stimulating presynaptic alpha2-receptors, it inhibits the release of excitatory amino acids that stimulate N-methyl-D-aspartate (NMDA) receptors. Polysynaptic signal transmission at spinal interneuron level, which is responsible for excessive muscle tone, is thus inhibited and muscle tone reduced. In addition to its muscle-relaxant properties, tizanidine also exerts a moderate central analgesic effect.
Pharmacodynamics: Tizanidine (Sirdalud) is effective in both acute painful muscle spasms and chronic spasticity of spinal and cerebral origin. It reduces resistance to passive movements, alleviates spasms and clonus, and may improve voluntary strength.
The antispastic activity (measured by the Ashworth score and pendulum test) and adverse effects (heart rate and blood pressure) of tizanidine (Sirdalud) are related to plasma tizanidine concentrations.
Clinical Studies: No recent clinical data regarding the approved indications for tizanidine (Sirdalud) are available.
Pharmacokinetics: Absorption: Tizanidine is rapidly and almost completely absorbed, reaching peak plasma concentration approximately 1 hour after dosing. Mean absolute bioavailability from the tablet formulation is about 34% (CV 38%) due to extensive first-pass metabolism. The mean maximum plasma concentration (Cmax) of tizanidine is 12.3 ng/mL (CV 10%) and 15.6 ng/mL (CV 13%) after single and repeated administration of 4 mg doses, respectively.
Concomitant food intake has no relevant influence on the pharmacokinetic profile of tizanidine (given as 4 mg tablets or 12 mg MR capsules). Although Cmax is about one-third higher after administration of the tablet under fed conditions, this is not considered to be of any clinical relevance, and absorption (AUC) is not significantly affected.
Distribution: Mean steady-state volume of distribution (VSS) following i.v. administration is 2.6 L/kg (CV 21%). Plasma protein binding is 30%.
Biotransformation/Metabolism: The drug has been shown to be rapidly and extensively (about 95%) metabolized by the liver. Tizanidine is mainly metabolized by cytochrome P450 1A2 in vitro. The metabolites appear to be inactive.
Elimination: Tizanidine is eliminated from the systemic circulation with a mean terminal half-life of 2 to 4 hours. Excretion is primarily via the kidneys (approximately 70% of dose) in the form of metabolites, with unchanged drug accounting for only about 4.5% of urinary recovery.
Linearity: Tizanidine has linear pharmacokinetics over the dose range 1 to 20 mg.
Special populations: Renal impairment (creatinine clearance <25 mL/min): Maximal mean plasma levels were found to be twice as high as in normal volunteers, and the terminal half-life was prolonged to approximately 14 hours, resulting in much higher (approximately 6-fold on average) AUC values (see PRECAUTIONS).
Hepatic impairment: No specific studies were conducted in this population. As tizanidine is extensively metabolized in the liver by CYP1A2 enzyme, hepatic impairment may increase its systemic exposure. Tizanidine (Sirdalud) is contraindicated in patients with severe hepatic impairment (see CONTRAINDICATIONS).
Geriatrics (65 years of age and older): Pharmacokinetic data in this population are limited.
Gender: Gender has no clinically significant effect on the pharmacokinetics of tizanidine.
Ethnic sensitivity: Impact of ethnic sensitivity and race on the pharmacokinetics of tizanidine has not been studied.
Toxicology: Non-clinical safety data: Preclinical data reveal no special hazard for humans at the recommended therapeutic dose based on conventional studies of repeated dose toxicity, mutagenicity and carcinogenic potential.
Acute toxicity: The acute toxicity of tizanidine is of a low order. Signs of overdosage were seen related to the drug's pharmacological action.
Repeat dose toxicity: In a 13-week oral toxicity study in rats given average daily doses of 1.7, 8 and 40 mg/kg, the major findings were related to CNS stimulation (e.g. motor excitation, aggressiveness, tremor, and convulsions), and occurred mainly at the highest dose level.
ECG changes and CNS effects were observed at daily doses of 1 mg/kg and higher in dogs in a 13-week study with dose levels of 0.3, 1 and 3 mg/kg/day given as capsules and a 52-week study with 0.15, 0.45 and 1.5 mg/kg/day. These represent exaggerated pharmacological effects. Transient increases in SGPT seen at daily doses of 1 mg/kg and above were not related to histopathological findings but indicate that the liver is a potential target organ.
Carcinogenicity and Mutagenicity: No evidence of mutagenic potential was found in in vitro, in vivo, or cytogenetic assays.
No indication of carcinogenic potential was seen in rats or mice given doses of up to 9 mg/kg/day and 16 mg/kg/day, respectively, in the feed.
Reproductive toxicity: Reproduction studies performed in rats at a dose of 3 mg/kg/day and in rabbits at 30 mg/kg/day did not show evidence of teratogenicity. Dose levels of 10 and 30 mg/kg/day increased gestation duration in female rats. Prenatal and postnatal pup loss was increased and development retardation occurred. At these doses, dams showed marked signs of muscle relaxation and sedation. (See USE IN PREGNANCY & LACTATION).
Treatment of painful muscle spasms: associated with static and functional disorders of the spine (cervical and lumbar syndromes); following surgery, e.g. for herniated intervertebral disc or osteoarthritis of the hip.
Treatment of spasticity due to neurological disorders: e.g. multiple sclerosis, chronic myelopathy, degenerative spinal cord diseases, cerebrovascular accidents, and cerebral palsy.
Tizanidine (Sirdalud) has a narrow therapeutic index and a high inter-patient variability in tizanidine plasma concentrations which requires individualized dose adjustment.
A low starting dose of 2 mg three times daily can minimize the risk for adverse effects. The dose should be carefully adjusted upward according to the needs of the individual patient.
Relief of painful muscle spasms: The usual dose is 2 to 4 mg three times daily in tablet form. In severe cases, an extra dose of 2 or 4 mg may be taken, preferably at night to minimize sedation.
Spasticity due to neurological disorders: The initial daily dose should not exceed 6 mg given in 3 divided doses. It may be increased stepwise at half-weekly or weekly intervals by 2 to 4 mg. The optimum therapeutic response is generally achieved with a daily dose of between 12 and 24 mg, administered in 3 or 4 equally spaced doses. The daily dose of 36 mg should not be exceeded.
Special populations: Pediatrics patients: Experience in patients below 18 years of age is limited and the use of tizanidine (Sirdalud) in this population is not recommended.
Geriatrics patients (65 years of age or older): Experience with the use in the elderly is limited. Therefore, it is recommended to start treatment at the lowest dose and increases should be done in small steps according to tolerability and efficacy.
Renal impairment: In patients with renal impairment (creatinine clearance <25 mL/min), it is recommended to start treatment at 2 mg once daily. Increase in dosage should be done in small steps according to tolerability and efficacy. If efficacy has to be improved, it is advisable to first increase the strength of daily dose before increasing the frequency of administration (see PRECAUTIONS).
Hepatic impairment: Use of tizanidine (Sirdalud) in patients with severe hepatic impairment is contraindicated (see CONTRAINDICATIONS).
While the drug is extensively metabolized in the liver limited data are available in this population (see PHARMACOLOGY: PHARMACOKINETICS under ACTIONS). Its use has been associated with reversible abnormality in liver function tests (see PRECAUTIONS and ADVERSE REACTIONS). Tizanidine (Sirdalud) should be used with caution in patients with moderate hepatic impairment and treatment should be started with the lowest dose. Afterwards, increase in dosage should be done carefully and according to patient tolerability.
Discontinuation of treatment: If treatment has to be discontinued, the dosage should be slowly down titrated, particularly in patients who have received high doses for a longer period of time to avoid or minimize the risk of rebound hypertension and tachycardia (see PRECAUTIONS).
In the few reports of drug overdosage received, recovery was uneventful, including by a patient who ingested 400 mg tizanidine (Sirdalud).
Symptoms: Nausea, vomiting, hypotension, QT(c) prolongation, dizziness, somnolence, miosis, restlessness, respiratory distress, coma.
Treatment: It is recommended to eliminate the ingested drug by repeated administration of high doses of activated charcoal. Forced diuresis is expected to accelerate the elimination of the drug. Further treatment should be symptomatic.
Known hypersensitivity to tizanidine or to any of the excipients.
Severely impaired hepatic function (see PHARMACOLOGY: PHARMACOKINETICS under ACTIONS).
Concomitant use of tizanidine with strong inhibitors of CYP1A2 such as fluvoxamine or ciprofloxacin is contraindicated (see INTERACTIONS).
CYP inhibitors: The concomitant use of tizanidine (Sirdalud) with moderate CYP1A2 inhibitors is not recommended (see INTERACTIONS).
Caution should be exercised when given with drugs known to increase the QT interval (see INTERACTIONS).
Hypotension: Hypotension may occur during treatment (see ADVERSE REACTIONS) and also as a result of drug interactions with CYP1A2 inhibitors and/or antihypertensive drugs (see INTERACTIONS). Severe manifestations of hypotension such as loss of consciousness and circulatory collapse have also been observed.
Withdrawal syndrome: Rebound hypertension and tachycardia have been observed after sudden withdrawal of tizanidine (Sirdalud), when it had been used chronically, and/or in high daily dosages, and/or concomitantly with antihypertensive drugs. In extreme cases, rebound hypertension might lead to cerebrovascular accident. Tizanidine (Sirdalud) should not be stopped abruptly, but rather gradually down titrated (see DOSAGE & ADMINISTRATION and ADVERSE REACTIONS).
Hepatic dysfunction: Since hepatic dysfunction has been reported in association with tizanidine, but rarely at daily doses up to 12 mg, it is recommended that liver function tests should be monitored monthly for the first four months in patients receiving doses of 12 mg and higher and in patients who develop clinical symptoms suggestive of hepatic dysfunction, such as unexplained nausea, anorexia, or tiredness. Treatment should be discontinued if serum levels of SGPT or SGOT are persistently above three times the upper limit of the normal range.
Patients with renal impairment: In patients with renal impairment (creatinine clearance <25 mL/min) systemic exposure to tizanidine may increase up to 6 times compared to patient with normal renal function. Therefore, it is recommended to start treatment at 2 mg once daily (see DOSAGE & ADMINISTRATION and PHARMACOLOGY: PHARMACOKINETICS under ACTIONS).
Hypersensitivity reactions: Hypersensitivity reactions including anaphylaxis, angioedema, dermatitis, rash, urticarial, pruritis and erythema have been reported in association with tizanidine. Careful observation of the patient is recommended for one to two days after the first dose is administered. If anaphylaxis or angioedema with anaphylactic shock or difficulty of breathing is observed treatment with tizanidine (Sirdalud) should be discontinued immediately and appropriate medical treatment should be instituted.
Driving and using machines: Patients experiencing somnolence, dizziness or any signs or symptoms of hypotension should refrain from activities requiring a high degree of alertness, e.g. driving a vehicle or operating machines.
Pregnancy: Risk Summary: As there is limited experience with the use of tizanidine (Sirdalud) in pregnant women, it should not be used during pregnancy unless the benefit clearly outweighs the risk (see PHARMACOLOGY: TOXICOLOGY: NON-CLINICAL SAFETY DATA under ACTIONS).
Animal data: Reproduction studies performed in rats and rabbits did not show evidence of teratogenicity. In rats, dose levels of 10 and 30 mg/kg/day increased gestation duration. Prenatal and postnatal pup loss was increased and development retardation occurred. At these doses, dams showed marked signs of muscle relaxation and sedation. Based on body surface area, these doses were 2.2 and 6.7 times the maximum recommended human dose of 0.72 mg/kg/day.
Lactation: Risk Summary: Small amounts of tizanidine are excreted in rat milk. Since no human data are available tizanidine (Sirdalud) should not be given to women who are breast-feeding.
Females and males of reproductive potential: Pregnancy testing: Sexually-active females of reproductive potential are recommended to have a pregnancy test prior to starting treatment with tizanidine (Sirdalud).
Contraception: Females of reproductive potential should be advised that animal studies have been performed showing tizanidine (Sirdalud) to be harmful to the developing fetus. Sexually-active females of reproductive potential are recommended to use effective contraception (methods that result in less than 1% pregnancy rates) when using tizanidine (Sirdalud) during treatment and for 1 day after stopping treatment with tizanidine (Sirdalud).
Fertility: Animal Data: No impairment of fertility was observed in male rats at a dose of 10 mg/kg/day and in female rats at a dose of 3 mg/kg/day. Fertility was reduced in male rats receiving 30 mg/kg/day and in female rats receiving 10 mg/kg/day. Based on body surface area, these doses were 6.7 and 2.2 times the maximum recommended human dose of 0.72 mg/kg. At these doses, maternal behavioral effects and clinical signs were observed including marked sedation, weight loss, and ataxia (see PHARMACOLOGY: TOXICOLOGY: NON-CLINICAL SAFETY DATA under ACTIONS).
With low doses, such as those recommended for the relief of painful muscle spasms, somnolence, fatigue, dizziness, dry mouth, blood pressure decrease, nausea, gastrointestinal disorder and transaminase increase have been reported, usually as mild and transient adverse reactions.
With the higher doses recommended for the treatment of spasticity, the adverse reactions reported with low doses are more frequent and more pronounced, but seldom severe enough to require discontinuation of treatment. In addition, the following adverse reactions may occur: hypotension, bradycardia, muscular weakness, insomnia, sleep disorder, hallucination, hepatitis.
Adverse drug reactions from clinical trials (Table 1) are listed according to the system organ class in MedDRA. Within each system organ class, the adverse drug reactions are ranked by frequency, the most frequent first. Within each frequency grouping, adverse drug reactions are presented in the order of decreasing seriousness. In addition the corresponding frequency using the following convention (CIOMS III) is also provided for each adverse drug reaction: 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). (See Table 1.)
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Adverse drug reactions from spontaneous reports and literature cases (frequency not known):
The following adverse drug reactions have been reported during post approval use of tizanidine (Sirdalud) via spontaneous reports and literature cases. Since these reactions are reported voluntarily from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency (which is therefore quoted as not known). Adverse drug reactions are listed according to system organ classes in MedDRA. (See Table 2.)
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Rebound hypertension and tachycardia have been observed after sudden withdrawal of the drug. In extreme cases, rebound hypertension might lead to cerebrovascular accident (see PRECAUTIONS and INTERACTIONS).
Concomitant administration of drugs known to inhibit the activity of CYP1A2 may increase the plasma levels of tizanidine (see PHARMACOLOGY: PHARMACOKINETICS under ACTIONS). The increased plasma levels of tizanidine may result in overdose symptoms such as QT(c) prolongation (see also OVERDOSAGE).
Concomitant administration of drugs known to induce the activity of CYP1A2 may decrease the plasma levels of tizanidine (see PHARMACOLOGY: PHARMACOKINETICS under ACTIONS). The decreased plasma levels of tizanidine may reduce the therapeutic effect of tizanidine (Sirdalud).
Observed interactions resulting in a contraindication: Concomitant use of tizanidine (Sirdalud) with fluvoxamine or ciprofloxacin, both CYP1A2 inhibitors is contraindicated. Concomitant use with fluvoxamine or ciprofloxacin resulted in a 33-fold and 10-fold increase in tizanidine AUC, respectively (see CONTRAINDICATIONS). Clinically significant and prolonged hypotension may result along with somnolence, dizziness and decreased psychomotor performance (see PRECAUTIONS). The increased plasma levels of tizanidine may result in overdose symptoms such as QT(c) prolongation (see also OVERDOSAGE).
Observed interactions resulting in a concomitant use not recommended: Co-administration of with other inhibitors of CYP1A2 such as antiarrhythmics (amiodarone, mexiletine, propafenone), cimetidine, fluoroquinolones (enoxacin, pefloxacin, norfloxacin), rofecoxib, oral contraceptives, and ticlopidine is not recommended (see PRECAUTIONS).
Observed interactions to be considered: Caution should be exercised when given with drugs known to prolong the QT interval (including but not limited to cisapride, amytriptyline and azithromycin) (see PRECAUTIONS).
Antihypertensives: Concomitant use with antihypertensives, including diuretics, may occasionally cause hypotension (see PRECAUTIONS) and bradycardia. In some patients rebound hypertension and tachycardia have been observed upon abrupt discontinuation of tizanidine (Sirdalud) when concomitantly used with antihypertensive drugs. In extreme cases, rebound hypertension might lead to cerebrovascular accident (see PRECAUTIONS and ADVERSE REACTIONS).
Rifampicin: Concomitant administration with rifampicin results in 50% decrease in tizanidine concentrations. Therefore, the therapeutic effects of tizanidine (Sirdalud) may be reduced during treatment with rifampicin, which may be of clinical significance in some patients. Long term co-administration should be avoided and if co-administration is considered a careful dose adjustment (increase) may be required.
Cigarette smoke: Administration of tizanidine (Sirdalud) in smokers (>10 cigarettes per day) results in about 30% decrease in tizanidine systemic exposure. Long-term therapy in heavy smokers may require higher doses than the average doses.
Alcohol: While on tizanidine (Sirdalud) therapy, alcohol consumption should be minimized or avoided as it may increase the potential for adverse events (e.g. sedation and hypotension). The central nervous system depressant effects of alcohol may be enhanced by the drug.
Anticipated interactions to be considered: Sedatives, hypnotics (e.g. benzodiazepine or baclofen), and other drug such as antihistamines may enhance the sedative action of tizanidine.
Tizanidine (Sirdalud) should be avoided when using with other alpha-2 adrenergic agonists (such as clonidine) because of their potential additive hypotensive effect.
Incompatibilities: None known.
Store at temperatures not exceeding 30°C.
M03BX02 - tizanidine ; Belongs to the class of other centrally-acting muscle relaxants.