Tizanidine Other names: Tizanidine hydrochloride

Caution should be exercised when tizanidine is prescribed with substances known to increase the QT interval. Electrocardiographic monitoring may be advisable.

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

Concomitant administration of agents known to inhibit the activity of CYP1A2 may increase the plasma levels of tizanidine.

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.

In patients with renal insufficiency (creatinine clearance <25 ml/min) treatment should be started with2 m g 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.

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.

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.

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.

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.

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

Not known: QT prolongation has been reported in post-marketing surveillance

Vascular disorders

Common: reduction in blood pressure^**, rebound hypertension

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.