Zanaflex 2 mg tablets

Zanaflex 4 mg tablets

Zanaflex tablets containing 2 mg of tizanidine as the hydrochloride.

Zanaflex tablets containing 4 mg of tizanidine as the hydrochloride.

For a full list of excipients, see section 6.1

Tablet

White to off-white, circular flat bevelled edge tablet of 8mm. Scored on one side, with 'A' and 592 on the other side.

White to off-white, circular flat bevelled edge tablet of 9mm. Cross scored on one side, with 'A' and 594 on the other side.

Zanaflex is indicated in adults for the treatment of spasticity associated with multiple sclerosis or with spinal cord injury or disease.

For oral administration

The effect of Zanaflex 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 Zanaflex 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 2 mg increasing by 2 mg increments at no less than half-weekly intervals.

The total daily dose should not exceed 36 mg, although it is usually not necessary to exceed 24 mg daily. Secondary pharmacological effects (see section 4.8 Undesirable Effects) 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.

Elderly

Experience in the elderly is limited and use of Zanaflex is not recommended unless the benefit of treatment clearly outweighs the risk. Pharmacokinetic data suggest that renal clearance in the elderly may be decreased by up to three fold.

Children

Experience with Zanaflex in patients under the age of 18 years is limited. Zanaflex is not recommended for use in children.

Patients with Renal impairment

In patients with renal insufficiency (creatinine clearance < 25mL/min) treatment should be started with 2 mg once daily with slow titration to achieve the effective dose. Dosage increases should be in increments of no more than 2 mg according to tolerability and effectiveness. 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.

Patients with Hepatic Impairment

Zanaflex is contraindicated in patients with significantly impaired hepatic function.

Hypersensitivity to tizanidine or any other component of the product (see section 6.1 List of excipients).

The use of Zanaflex in patients with significantly impaired hepatic function is contraindicated, because tizanidine is extensively metabolised by the liver (see section 5.2 Pharmacodynamic properties).

Concomitant use of tizanidine with fluvoxamine or ciprofloxacin is contra-indicated (see section 4.5 Interaction with other medicinal products and other forms of interaction and section 4.4 Special warnings and special precautions for use).

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Concomitant use of tizanidine with CYP1A2 inhibitors is not recommended (see section 4.3 Contraindications and section 4.5 Interaction with other medicaments and other forms of interaction).

Hypotension may occur during treatment with tizanidine (see section 4.8 Undesirable effects) and also as a result of drug interactions with CYP1A2 inhibitors and/or antihypertensive drugs (see section 4.5 Interaction with other medicinal products and other forms of interaction). Severe manifestations of hypotension such as loss of consciousness and circulatory collapse have also been observed.

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 (see also section 4.5 Interaction with other medicinal products and other forms of interaction). In extreme cases, rebound hypertension might lead to cerebrovascular accident. Tizanidine should not be stopped abruptly, but rather gradually, and blood pressure should be monitored regularly on withdrawal.

Use in Renal Impairment

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

Liver Function

Hepatic dysfunction has been reported in association with Zanaflex. It is recommended that liver function tests should be monitored monthly for the first four months in all patients and in those who develop symptoms suggestive of liver dysfunction such as unexplained nausea, anorexia or tiredness. Treatment with Zanaflex should be discontinued if serum levels of SGPT and/or SGOT are persistently above three times the upper limit of normal range.

Zanaflex tablets contain lactose. This medicine is not recommended in patients with the rare hereditary problem of galactose intolerance, of severe lactase deficiency or of glucose-galactose malabsorption.

Zanaflex should be kept out of the reach and sight of children.

Concomitant use of tizanidine with fluvoxamine or ciprofloxacin, both CYP450 1A2 inhibitors in man, is contraindicated. Concomitant use of tizanidine with fluvoxamine or ciprofloxacin 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 4.3 Contraindications and section 4.4 Special warnings and precautions for use). Co-administration of tizanidine with other inhibitors of CYP1A2 such as some antiarrhythmics (amiodarone, mexiletine, propafenone), cimetidine, some fluoroquinolones (enoxacin, norfloxacin) and ticlopidine is not recommended (see section 4.4 Special warnings and special precautions for use).

The increased plasma levels of tizanidine may result in overdose symptoms such as QT(c) prolongation (see also section 4.9 Overdose).

As Zanaflex may induce hypotension (see 4.4 Special warnings and precautions for use) it may potentiate the effect of antihypertensive drugs, including diuretics, and caution should therefore be exercised in patients receiving blood pressure lowering drugs.

Caution should also be exercised when Zanaflex is used concurrently with βadrenoceptor blocking drugs or digoxin as the combination may potentiate hypotension or bradycardia.

Caution should be exercised when Zanaflex is prescribed with drugs known to increase the QT interval.

Pharmacokinetic data following single and multiple doses of Zanaflex suggested that clearance of Zanaflex 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 Zanaflex, the possibility of a clinical response and/or adverse effects occurring at lower doses of Zanaflex should be borne in mind when prescribing Zanaflex to a patient taking the contraceptive pill. Clinically significant drug-drug interactions have not been reported in clinical trials.

Alcohol or sedatives may enhance the sedative action of Zanaflex.

Reproductive studies in rats and rabbits indicate that Zanaflex does not have embryotoxic or teratogenic potential but at maternally toxic doses of 10-100 mg/kg per day Zanaflex can retard foetal development due to its pharmacodynamic effects. Zanaflex and/or its metabolites have been found in the milk of rodents (see section 5.3 preclinical safety data). The safety of Zanaflex in pregnancy has not been established and its safety in breast-fed infants of mothers receiving Zanaflex is not known. Therefore Zanaflex should not be used in pregnant or nursing mothers unless the likely benefit clearly outweighs the risk.

Patients experiencing drowsiness, dizziness or any signs or symptoms of hypotension should be advised against activities requiring a high degree of alertness, e.g. driving a vehicle or operating machinery.

The most frequently reported adverse events occurring in association with Zanaflex include drowsiness, fatigue, dizziness, dry mouth, nausea, gastrointestinal disturbances, and a reduction in blood pressure. With slow upward titration of the dose of Zanaflex these effects are usually not severe enough to require discontinuation of treatment. Insomnia, bradycardia and hallucinations have also been reported. The hallucinations are self-limiting, without evidence of psychosis, and have invariably occurred in patients concurrently taking potentially hallucinogenic drugs, e.g. anti-depressants. Increases in hepatic serum transaminases, which are reversible on stopping treatment, have occurred. Infrequent cases of acute hepatitis and hepatic failure have been reported. Muscle weakness has been reported infrequently, although in controlled clinical trials it was clearly demonstrated that Zanaflex does not adversely affect muscle strength. Allergic reactions (e.g. pruritus and rash) have rarely been reported.

Rebound hypertension on withdrawal may lead in severe cases to a cerebrovascular event.

Clinical experience is limited. In one adult case, who ingested 400mg Zanaflex, recovery was uneventful. This patient received mannitol and frusemide.

Symptoms: Nausea, vomiting, hypotension, QT(c) prolongation, dizziness, miosis, respiratory distress, coma, restlessness, somnolence.

Treatment: General supportive measures are indicated and an attempt should be made to remove uningested drug from the gastro-intestinal tract using gastric lavage or activated charcoal. Forced diuresis is expected to accelerate the elimination of Zanaflex. Further treatment should be symptomatic. The patient should be well hydrated.

Pharmacotherapeutic group: Muscle relaxants, other centrally acting agents, ATC code: M03B X02.

Tizanidine is an α₂adrenergic receptor agonist within the central nervous system at supra-spinal and spinal levels. This effect results in inhibition of spinal polysynaptic reflex activity. Tizanidine has no direct effect on skeletal muscle, the neuromuscular junction or on monosynaptic spinal reflexes.

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

Tizanidine is rapidly absorbed, reaching peak plasma concentration in approximately 1 hour. Tizanidine is only about 30% bound to plasma proteins and, in animal studies, was found to readily cross the blood-brain barrier. 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 and the pattern of biotransformation in animals and humans is qualitatively similar. 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.

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

Acute toxicity

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

Repeat dose toxicity

The toxic effects of tizanidine are mainly related to its pharmacological action. At doses of 24 and 40 mg/kg per day in subchronic and chronic rodent studies, the α₂agonist effects resulted in CNS 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 drug, were noted at 1 to 4 mg/kg per day in a 13 week dog study, and at 1.5 mg/kg per day in a 52week dog study.

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

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 9 mg/kg per day in rats and up to 16 mg/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 30 mg/kg per day of tizanidine. However, doses of 10-100 mg/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 30 mg/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.

silica, colloidal anhydrous

stearic acid

cellulose, microcrystalline

lactose, anhydrous.

None known.

5 years in both temperate and hot climates, and 5 years in tropical climate.

No special precautions for storage

PVC/PVDC/Al foil blisters. Carton containing 6 blister strips of 20 tablets to give pack size of 120.

Not applicable.

Cephalon UK Limited

1 Albany Place

Hyde Way

Welwyn Garden City

Hertfordshire

AL7 3BT

Zanaflex 2 mg – PL 16260/0029

Zanaflex 4 mg – PL 16260/0030

Zanaflex 2 mg – 26^th March 2010

Zanaflex 4 mg – 22^nd March 2010

09 April 2010

POM