SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Zanaflex 4mg tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Zanaflex tablets containing 4 mg of tizanidine as the hydrochloride.

Excipient(s) with known effect:

Zanaflex 4 mg tablets contain 110 mg of Lactose per tablet For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Tablet

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

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

4.2    Posology and method of administration

Posology

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 halfweekly 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) 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.

Renal impairment

In patients with renal insufficiency 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.

Hepatic impairment

Zanaflex is contraindicated in patients with significantly impaired hepatic function. Zanaflex should not be used in patients with moderate hepatic impairment unless the potential benefit outweighs the potential risk to the patient. Any treatment should start with the lowest dose and afterwards, dosage increases should be done carefully and according to patient tolerability.

4.3 Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

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).

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

4.4 Special warnings and precautions for use

CYP inhibitors

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

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.

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 (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 (see section 4.5 and section 4.8).

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).

Hepatic 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 sight and reach of children.

4.5 Interaction with other medicinal products and other forms of interaction

Tizanidine is almost exclusively metabolised by the cytochrome p450 isoenzyme CYP1A2. Concomitant administration of drugs known to inhibit or induce the activity of CYP1A2 may affect the plasma levels of tizanidine.

Observed interactions resulting in a contraindication

Concomitant use of tizanidine with fluvoxamine or ciprofloxacin, both potent 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 (see section 4.3). Clinically significant and prolonged hypotension may result along with somnolence, dizziness and decreased psychomotor performance (see section 4.4).

Observed interactions resulting in a concomitant use not recommended

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).

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 (e.g. amitryptaline and azithromycin) is not recommended.

Due to their potential additive hypotensive effects , concomitant use of Zanaflex with other alpha-2 adrenergic agonists (such as clonidine) is not recommended.

Oral contraceptives

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.

Interactions to be considered

Rifampicin

Concomitant administration of Zanaflex with rifampicin results in an approximate 50% decrease in tizanidine concentrations (AUC and peak plasma concentration). Therefore, the therapeutic effects of Zanaflex 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

Exposure to the polycyclic aromatic hydrocarbons of cigarette smoke leads to induction of CYP1A2. In a study of young male smokers, administration of Zanaflex (>10 cigarettes per day) results in about 30% decrease in tizanidine systemic exposure. Long-term therapy with Zanaflex in heavy smokers may require higher doses than the average doses.

Antihypertensives

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

Alcohol

While on Zanaflex 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 Zanaflex.

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

Caution should be exercised if concomitant use of Zanaflex with sedative drugs including hypnotics (e.g. benzodiazepines), antihistamines (e.g. chlorphenamine) and baclofen is considered as this may enhance the sedative action of Zanaflex.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of tizanidine in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

Zanaflex is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

Small amounts of tizanidine are excreted in rat milk (see section 5.3). A risk to the breast-fed child cannot be excluded. Zanaflex should not be used during breastfeeding.

Fertility

Animal studies have shown no effect on fertility at 10mg/kg/day and 3mg/kg/day in male and female rats, respectively (see section 5.3).

4.7 Effects on ability to drive and use machines

Patients experiencing blurred vision, somnolence, 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.

4.8 Undesirable effects

Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: 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), including isolated reports, not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

Table 1

Immune system disorders
Not known	Hypersensitivity reactions including pruritis and rash
Psychiatric disorders

4.9 Overdose

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.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

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

Tizanidine is an a₂-adrenergic 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.

5.2 Pharmacokinetic properties

Absorption and distribution

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. Mean steady-state volume of distribution (VSS) following i.v. administration is 2.6 L/kg (CV 21%). Although tizanidine is well absorbed, first pass metabolism limits plasma availability to 34% of that of an intravenous dose. The mean maximum plasma concentration (Cmax) of tizanidine is 12.3 ng/mL (coefficient of variation (CV) 56%) and 15.6 ng/mL (CV 60%) after single and repeated administration of 4 mg doses, respectively.

Concomitant food intake has no influence on the pharmacokinetic profile of tizanidine tablets (given as 4 mg tablets). Although Cmax is about one-third higher after administration of the tablet under fed conditions, this is not thought to be of any clinical relevance, and absorption (AUC) is not significantly affected.

Metabolism and elimination

Tizanidine undergoes rapid and extensive (about 95%) metabolism in the liver and the pattern of biotransformation in animals and humans is qualitatively similar. Tizanidine is mainly metabolized by cytochrome p450 1A2 in vitro. The metabolites are primarily excreted via the renal route (approximately 70% of the administered dose) and appear to be inactive. Renal excretion (determined by percentage recovery in the urine of the total amount of administered radioactivity) 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 1 to 20 mg Special populations Renal impairment

In patients with severe renal impairment (creatinine clearance <25 mL/min) the maximal mean plasma levels were found to be twice as high as in normal volunteers. The AUC was also increased (approximately 6-fold on average) resulting in the prolongation of the terminal half-life to approximately 14 hours (see section 4.2).

Hepatic impairment

No specific studies were conducted in patients with hepatic impairment. As tizanidine is extensively metabolized in the liver by CYP1A2 enzyme, hepatic impairment may increase its systemic exposure. Zanaflex is contraindicated in patients with significant hepatic impairment (see section 4.3).

Elderly

Pharmacokinetic data in the elderly population are limited.

Effect of gender and ethnicity

Gender has no clinically significant effect on the pharmacokinetics of tizanidine and the impact of ethnic sensitivity and race on the pharmacokinetics of tizanidine has not been studied.

5.3 Preclinical safety data

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 ^-agonist 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 52-week 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 preneoplastic pathology, attributable to treatment, was observed.

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 and dystocia in female rats. Prenatal and postnatal pup loss was increased and developmental retardation (as seen by lower foetal body weights and retarded skeletal ossification) occurred. At these doses, dams showed marked signs of muscle relaxation and sedation.

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 (fully reversible after a 2-week recovery period) and in female rats receiving 10 mg/kg/day. At these doses, maternal behavioural effects and clinical signs were observed including marked sedation, weight loss, and ataxia.

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

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

silica, colloidal anhydrous stearic acid

cellulose, microcrystalline lactose, anhydrous.

10 DATE OF REVISION OF THE TEXT

06/06/2016