Tizanidine

2 DOSAGE AND ADMINISTRATION Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved. 2 ) Tizanidine pharmacokinetics differs between tablets and capsules, and when taken with or without food.

These differences could result in a change in tolerability and control of symptoms. Consistent administration with respect to food is recommended. If substitution between dosage forms is necessary, take into consideration these pharmacokinetic differences.

If higher doses are required, individual doses rather than dosing frequency should be increased. 2 )]. 2 Recommended Dosage The recommended starting dose is 2 mg by mouth every 6 to 8 hours, as needed, to a maximum of three doses in 24 hours.

Dosage can be gradually increased every 1 to 4 days by 2 mg to 4 mg at each dose based on clinical response and tolerability. The maximum total daily dosage is 36 mg. Single doses greater than 16 mg have not been studied. 3 )] . Tizanidine may be taken with or without food; however, consistent administration with respect to food is recommended to reduce variability in tizanidine plasma exposure.

Because of the short duration of therapeutic effect, treatment with tizanidine should be reserved for those daily activities and times when relief of spasticity is most important. 3 Recommended Dosage in Patients with Renal Impairment I n patients with creatinine clearance < 25 mL/min, use lower individual doses during titration.

3 )] . 4 Recommended Dosage in Patients with Hepatic Impairment I n patients with hepatic impairment, use lower individual doses during titration. 3 )]. 3 )]. 6 Switching Between With/Without Food and Different Tizanidine Dosage Forms There are pharmacokinetic differences when: 1) switching between administration of tizanidine tablets with or without food 2) switching between dosage forms if being administered with food.

3 )].

6 )] The most common adverse reactions (greater than 10% of patients taking tizanidine and greater than in patients taking placebo) were dry mouth, somnolence, asthenia, and dizziness. 1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp.

1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

The safety of tizanidine has been evaluated in three double-blind, randomized, placebo-controlled clinical studies [see Clinical Studies ( 14 )] . Two studies were conducted in patients with multiple sclerosis and one in patients with spinal cord injury.

Each study had a 13-week active treatment period which included a 3-week titration phase to the maximum tolerated dose up to 36 mg/day in three divided doses, a 9-week plateau phase where the dose of tizanidine was held constant and a 1-week dose tapering period.

In all, 264 patients received tizanidine and 261 patients received placebo. Across the three studies approximately 51% of patients were women, and the median dose during the plateau phase ranged from 20 to 28 mg/day. The most common adverse reactions (>10% of patients treated with tizanidine) reported in multiple dose, placebo-controlled clinical studies involving 264 patients with spasticity were dry mouth, somnolence/sedation, asthenia (weakness, fatigue and/or tiredness), and dizziness.

Three-quarters of the patients rated the reactions as mild to moderate and one-quarter of the patients rated the reactions as being severe. These adverse reactions appeared to be dose related. Table 1 lists adverse reactions that were reported in greater than 2% of patients in three multiple dose, placebo-controlled studies who received tizanidine where the frequency in the tizanidine group was greater than the placebo group.

5 )] . Syncope has been reported in patients treated with tizanidine in the postmarketing setting. The risk of hypotension may be minimized by dose titration; monitoring for signs and symptoms of hypotension prior to dosage increase may minimize the risks associated with hypotension.

In addition, patients moving from a supine to fixed upright position may be at increased risk for hypotension and orthostatic effects. Monitor for hypotension when tizanidine is used in patients receiving concurrent antihypertensive therapy.

It is not recommended that tizanidine be used with other α 2 -adrenergic agonists. 3 )] . 1 )]. 2 Liver Injury Tizanidine may cause hepatocellular liver injury. 2 )]. 7 )] . 3 Sedation Tizanidine can cause sedation, which may interfere with everyday activity.

1 )]. 4 )] . Monitor patients who take tizanidine with another CNS depressant for symptoms of excess sedation. 4 Hallucinosis / Psychotic-Like Symptoms Tizanidine use has been associated with hallucinations. Formed, visual hallucinations or delusions were reported in 5 of 170 patients (3%) in two North American controlled clinical studies.

Most of the patients were aware that the events were unreal. One patient developed psychosis in association with the hallucinations. One patient among these 5 continued to have problems for at least 2 weeks following discontinuation of tizanidine.

Hallucinations have also been reported with tizanidine use in the postmarketing setting. Consider discontinuing tizanidine in patients who develop hallucinations. 5 Hypersensitivity Reactions Tizanidine can cause anaphylaxis. Signs and symptoms of hypersensitivity, including respiratory compromise, urticaria, and angioedema of the throat and tongue, have been reported.

Tizanidine is contraindicated in patients with a history of hypersensitivity reactions to tizanidine [see Contraindications ( 4 )]. 6 Withdrawal Adverse Reactions Tizanidine can cause withdrawal adverse reactions, which include rebound hypertension, tachycardia, and hypertonia.

1 )]. • with a history of hypersensitivity to tizanidine or the ingredients in tizanidine tablets. 5 )]. 5 )