ZANAFLEX Tablet Ref.[8261] Active ingredients: Tizanidine

Cytochrome P45 0 (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 a 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 sections 4.2, 4.5 and 4.8).

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. It is recommended in all patients that before beginning therapy, liver function tests should be performed in order to establish a base line 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 all patients and in those who develop 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. 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). Coadministration 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).

Caution should be exercised when tizanidine is prescribed with substances known to increase the QT interval. 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).

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.

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

Pregnancy

Animal studies did not indicate teratogenic effects in animals. 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.

Breast-feeding

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 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 (≥1/10,0 00 to ≤1/1,00 0), very rare, including isolated reports (<1/10,0 00), not known (cannot be estimated from the available data)

Immune system disorders

Not known: hypersensitivity reactions

Psychiatric disorders

Rare: hallucinations^*

Not known: anxiety disorders

Nervous system disorders

Common: drowsiness, fatigue, dizziness^**

Rare: sleep disorders, insomnia

Not known: headache, ataxia, dysarthria

Eye disorders

Not known: accommodation disorder

Cardiac disorders

Common: bradycardia, tachycardia (see sections 4.4 and 4.5)

Not known: QT prolongation has been reported in post-marketing surveillance (see section 4.9)

Vascular disorders

Common: reduction in blood pressure^**, rebound hypertension (see sections 4.4 and 4.5)

Gastrointestinal disorders

Common: dry mouth, nausea, gastrointestinal disturbances^**

Not known: abdominal pain, vomiting

Hepatobiliary disorders

Rare: increases in hepatic serum transaminases

Very rare: hepatitis, hepatic failure

Skin and subcutaneous tissue disorders

Rare: allergic reactions (e.g. pruritus and rash)

Musculoskeletal and connective tissue disorders

Rare: muscle weakness

General disorders and administration site conditions

Not known: absence of appetite

* The hallucinations are self-limiting, without evidence of psychosis, and have invariably occurred inpatients concurrenty taking potentially hallucinogenic substances, e.g. anti-depressants.
** With slow upward titration of the dose of tizanidine these effects are usually not severe enough to require discontinuation of treatment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517; Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

Not applicable.