Tizanidine 4mg Tablets

Each 4mg tablet contains:

4 mg tizanidine (as 4.576mg tizanidine hydrochloride)

200mg of lactose, anhydrous

For a full list of excipients, see section 6.1.

Tablet.

Tizanidine Tablets are white, round tablets.

Tizanidine 4 mg Tablets are scored and marked 'N 63' on the other side.

The 4mg tablet can be divided into equal halves.

Treatment of spasticity associated with multiple sclerosis or with spinal cord injury or disease.

For oral use.

The effect of tizanidine on spasticity is maximal within 2-3 hours of dosing and it has a relatively short duration of action. The timing and frequency of dosing should therefore be tailored to the individual, and tizanidine should be given in divided doses, up to 3-4 times daily, depending on the patient's needs. There is considerable variation in response between patients so careful titration is necessary. Care should be taken not to exceed the dose producing the desired therapeutic effect.

It is usual to start with a single dose of 2mg increasing by 2mg increments at no less than half-weekly intervals. The optimum therapeutic response is generally achieved with a daily dose of between 12 and 24mg, administered in 3 or 4 equally spaced doses. Single doses should not exceed 12mg. The total daily dose should not exceed 36mg.

Adverse events (see section 4.8) may occur at therapeutic doses but these can be minimised by slow titration so that in the large majority of patients they are not a limiting factor.

Discontinuing therapy

If therapy needs to be discontinued, particularly in patients who have been receiving high doses for long periods, the dose should be decreased slowly (see section 4.4).

Elderly

Experience in the elderly is limited and use of tizanidine is not recommended unless the benefit of treatment clearly outweighs the risk. Pharmacokinetic data suggest that renal clearance in the elderly may in some cases be significantly decreased. Caution is therefore indicated when using tizanidine in elderly patients.

Children and adolescents

Experience with tizanidine in patients under the age of 18 years is limited. Tizanidine is not recommended for use in this population.

Patients with renal impairment

In patients with renal insufficiency (creatinine clearance < 25 ml/min) treatment should be started with 2mg once daily with slow titration to achieve the effective dose. Dosage increases should be in increments of no more than 2mg according to tolerability and effectiveness. If efficacy has to be improved, it is advisable to slowly increase the once-daily dose before increasing the frequency of administration. Renal function should be monitored as appropriate in these patients (see section 4.4).

Patients with hepatic impairment

Tizanidine is contraindicated in patients with significantly impaired hepatic function (see sections 4.3 and 4.4).

The use of tizanidine in patients with significantly impaired hepatic function is contraindicated, because tizanidine is extensively metabolised by the liver.

Concomitant use of tizanidine with strong inhibitors of CYP1A2 such as fluvoxamine or ciprofloxacin is contraindicated (see sections 4.4 and 4.5).

Hypersensitivity to tizanidine or to any of the excipients.

Cytochrome P450 (CYP) inhibitors

Concomitant use of tizanidine with CYP1A2 inhibitors is not recommended (see sections 4.3 and 4.5).

Hypotension

Hypotension may occur during treatment with tizanidine (see section 4.8) and also as a result of interactions with CYP1A2 inhibitors and/or antihypertensive agents (see section 4.5). Severe manifestations of hypotension such as loss of consciousness and circulatory collapse have been observed.

Withdrawal syndrome

Rebound hypertension and tachycardia have been observed after sudden withdrawal of tizanidine, 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 should not be stopped abruptly, but rather gradually (see section 4.5 Interaction with other medicinal products and other forms of interaction and section 4.8 Undesirable effects).

Use in renal impairment

Patients with renal impairment may require lower doses and therefore caution should be exercised when using tizanidine in these patients (see section 4.2).

Cardiovascular, hepatic or renal disorders

Caution is required in patients with cardiovascular disorders, coronary artery disease or renal or hepatic disorders. Regular clinical laboratory and ECG monitoring is recommended during treatment with tizanidine.

Hepatic dysfunction

Hepatic dysfunction has been reported in association with tizanidine but rarely at daily doses up to 12mg. It is recommended in all patients that before beginning therapy, liver function tests should be performed in order to establish a baseline and to exclude pre-existing liver disease or significantly impaired hepatic function. Liver function tests should then be monitored monthly for the first four months of treatment in in patients receiving doses of 12mg and higher and in those patients who develop clinical symptoms suggestive of liver dysfunction such as unexplained nausea, anorexia or tiredness. Treatment with tizanidine should be discontinued if serum levels of SGPT (serum glutamic-pyruvic transaminase) and/or SGOT (serum glutamic-oxaloacetic transaminase) are persistently above three times the upper limit of normal range. Tizanidine should be discontinued in patients with symptoms compatible with hepatitis or where jaundice occurs.

This medicinal product contains lactose anhydrous. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

CYP inhibitors

Concomitant administration of agents known to inhibit the activity of CYP1A2 may increase the plasma levels of tizanidine (see section 5.2). Concomitant use of tizanidine with fluvoxamine or ciprofloxacin, both CYP1A2 inhibitors in man, is contraindicated (see section 4.3), as it resulted in a 33-fold and 10-fold increase in tizanidine AUC, respectively. Clinically significant and prolonged hypotension may result along with somnolence, dizziness and decreased psychomotor performance (see section 4.4). Co-administration of tizanidine with other inhibitors of CYP1A2 such as some antiarrhythmics (amiodarone, mexiletine, propafenone), cimetidine, some fluoroquinolones (enoxacin, pefloxacin, norfloxacin), rofecoxib, oral contraceptives, and ticlopidine is not recommended (see section 4.4).

The increased plasma levels of tizanidine may result in overdose symptoms such as QT(c) prolongation (see also section 4.9). Concomitant use of tizanidine (in high doses) with other products that could cause QT (c) prolongation is not recommended. Electrocardiographic monitoring may be advisable.

Antihypertensives

As tizanidine may induce hypotension it may potentiate the effect of antihypertensive products, including diuretics, and caution should therefore be exercised in patients receiving blood pressure lowering products. Caution should also be exercised when tizanidine is used concurrently with β-adrenoceptor blocking substances or digoxin as the combination may potentiate hypotension or bradycardia. In some patients rebound hypertension and tachycardia have been observed upon abrupt discontinuation of tizanidine when concomitantly used with antihypertensive drugs. In extreme cases, rebound hypertension might lead to cerebrovascular accident (see sections 4.4 and 4.8).

Oral contraceptives

Pharmacokinetic data following single and multiple doses of tizanidine suggested that clearance of tizanidine was reduced by approximately 50% in women who were concurrently taking oral contraceptives. Although no specific pharmacokinetic study has been conducted to investigate a potential interaction between oral contraceptives and tizanidine, the possibility of a clinical response and/or adverse effects occurring at lower doses of tizanidine should be borne in mind when prescribing tizanidine to a patient taking the contraceptive pill. Clinically significant interactions have not been reported in clinical trials.

Other

Alcohol or centrally-acting agents may enhance the sedative action of tizanidine.

Pregnancy

Animal studies indicate increased pre- and perinatal mortality at maternally toxic doses.

As there have been no controlled studies in pregnant women, however, it should not be used during pregnancy unless the benefit clearly outweighs the risk.

Lactation

Although only small amounts of tizanidine are excreted in animal milk, tizanidine should not be taken by women who are breast-feeding.

Tizanidine has minor or moderate influence on the ability to drive and use machines: patients experiencing drowsiness or dizziness or any signs or symptoms of hypotension should be advised against activities requiring a high degree of alertness.

The adverse effects are classified below by system organ class according to the following convention:

Very common (1/10)

Common (1/100 to <1/10)

Uncommon (1/1,000 to 1/100)

Rare (1/10,000 to 1/1,000)

Very rare, including isolated reports (<1/10,000)

Not known (cannot be estimated from the available data)

With low doses of tizanidine, such as those recommended for the relief of painful muscle spasms, somlonence, fatigue, dizziness, dry mouth, blood pressure decrease, nausea, gastrointestinal disorder and transaminase increase have been reported, but usually as mild and transient.

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.

Withdrawal syndrome

Rebound hypertension and tachycardia have been observed after sudden withdrawal of tizanidine, 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 (see section 4.4 Special warnings and precautions for use and section 4.5 Interaction with other medicinal products and other forms of interaction).

Clinical experience is limited. In one case, where an adult patient ingested 400mg tizanidine, recovery was uneventful. This patient received mannitol and furosemide.

Symptoms

Nausea, vomiting, hypotension, bradycardia, QT prolongation, dizziness, miosis, respiratory distress, coma, restlessness, somnolence.

Treatment

General supportive measures are indicated and an attempt should be made to remove ingested substance from the gastro-intestinal tract using gastric lavage or by repeated administration of high doses of activated charcoal. The patient should be well hydrated as forced diuresis is expected to accelerate the elimination of tizanidine. Further treatment should be symptomatic.

Pharmacotherapeutic group: Musculo-skeletal system; muscle relaxants; centrally acting agents; other centrally acting agents

ATC code: M03B X02

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 aminoacids 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. Tizanidine has no direct effect on skeletal muscle, the neuromuscular junction or on monosynaptic spinal reflexes. In addition to its muscle-relaxant properties, tizanidine also exerts a moderate central analgesic effect.

In humans, tizanidine reduces pathologically increased muscle tone, including resistance to passive movements and alleviates painful spasms and clonus.

Absorption

Tizanidine is rapidly absorbed, reaching peak plasma concentration in approximately 1 hour after dosing.

Distribution

Tizanidine is only about 30% bound to plasma proteins and, in animal studies, was found to readily cross the bloodbrain barrier. Mean steady-state volume of distribution (VSS) following i.v. administration is 2.6 L/kg.

Metabolism

Although tizanidine is well absorbed, first pass metabolism limits plasma availability to 34% of that of an intravenous dose. Tizanidine undergoes rapid and extensive metabolism in the liver. Tizanidine is mainly metabolized by cytochrome P450 1A2 in vitro.

Elimination

The metabolites are primarily excreted via the renal route (approximately 70% of the administered dose) and appear to be inactive. Renal excretion of the parent compound is approximately 53% after a single 5 mg dose and 66% after dosing with 4 mg three times daily. The elimination half-life of tizanidine from plasma is 2-4 hours in patients.

Linearity

Tizanidine has linear pharmacokinetics over the dose range 4 to 20 mg. The low intraindividual variation in pharmacokinetic parameters (Cmax and AUC) enables reliable prediction of plasma levels following oral administration.

Characteristics in special patient populations

The pharmacokinetic parameters of tizanidine are not affected by gender.

In patients with renal insufficiency (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 section 4.4).

Effect of food

Concomitant food intake has no clinically significant influence on the pharmacokinetic profile of tizanidine tablets.

Acute toxicity

Tizanidine possesses a low order of acute toxicity. Signs of overdose were seen after single doses > 40mg/kg in animals and are related to the pharmacological action of the substance.

Repeat dose toxicity

The toxic effects of tizanidine are mainly related to its pharmacological action. At doses of 24 and 40mg/kg per day in subchronic and chronic rodent studies, the α₂-agonist effects resulted in central nervous system stimulation, e.g. motor excitation, aggressiveness, tremor and convulsions.

Signs related to centrally mediated muscle relaxation, e.g. sedation and ataxia, were frequently observed at lower dose levels in subchronic and chronic oral studies with dogs. Such signs, related to the myotonolytic activity of the substance, were noted at 1 to 4mg/kg per day in a 13 week dog study, and at 1.5mg/kg per day in a 52-week dog study.

Prolongation of the QT interval and bradycardia were noted in chronic toxicity studies in dogs at doses of 1.0mg/kg per day and above.

Retinal atrophy and corneal opacity have been observed in chronic toxicity studies in the rat. The no observed adverse effect load in the rat was below 1mg/kg/day.

Slight increases in hepatic serum transaminases were observed in a number of toxicity studies at higher dose levels. They were not consistently associated with histopathological changes in the liver.

Mutagenicity

Various in vitro assays as well as in vivo assays produced no evidence of mutagenic potential of tizanidine.

Carcinogenicity

No evidence for carcinogenicity was demonstrated in two long-term dietary studies in mice (78 weeks) and rats (104 weeks), at dose levels up to 9mg/kg per day in rats and up to 16mg/kg per day in mice. At these dose levels, corresponding to the maximum tolerated dose, based on reductions in growth rate, no neoplastic or pre-neoplastic pathology, attributable to treatment, was observed.

Reproductive toxicity

No embryotoxicity or teratogenicity occurred in pregnant rats and rabbits at dose levels up to 30mg/kg per day of tizanidine. However, doses of 10-100mg/kg per day in rats were maternally toxic and resulted in developmental retardation of foetuses as seen by lower foetal body weights and retarded skeletal ossification.

In female rats, treated prior to mating through lactation or during late pregnancy until weaning of the young, a dose-dependent (10 and 30mg/kg per day) prolongation of gestation time and dystocia occurred, resulting in an increased foetal mortality and delayed development. These effects were attributed to the pharmacological effect of tizanidine. No developmental effects occurred at 3mg/kg per day although sedation was induced in the treated dams.

Passage of tizanidine and/or its metabolites into milk of rodents is known to occur.

Colloidal anhydrous silica

Stearic acid

Microcrystalline cellulose

Anhydrous lactose.

Not applicable.

3 years.

None.

White PVC/PVdC-aluminium blisters containing 10, 28, 30, 34, 60, 84, 90, 91, 98, 100, 105 or 120 tablets.

Not all pack sizes may be marketed.

No special requirements.

Actavis Group PTC

Reykjavikurvegur 76-78,

220 Hafnarfjordur

Iceland

PL 30306/0237

07/05/2009

25/08/2011

(IF APPLICABLE)

(IF APPLICABLE)