TIZANIDINE HYDROCHLORIDE

WARNINGS SECTION LIMITED DATA BASE FOR CHRONIC USE OF SINGLE DOSES ABOVE 8 MG AND MULTIPLE DOSES ABOVE 24 MG PER DAY Clinical experience with long-term use of tizanidine at doses of 8 to 16 mg single doses or total daily doses of 24 to 36 mg (see Dosage and Administration) is limited. In safety studies, approximately 75 patients have been exposed to individual doses of 12 mg or more for at least one year or more and approximately 80 patients have been exposed to total daily doses of 30 to 36 mg/day for at least one year or more. There is essentially no long-term experience with single, daytime doses of 16 mg. Because long-term clinical study experience at high doses is limited, only those adverse events with a relatively high incidence are likely to have been identified (see WARNINGS, PRECAUTIONS and ADVERSE REACTIONS). HYPOTENSION Tizanidine is a α2-adrenergic agonist (like clonidine) and can produce hypotension. In a single dose study where blood pressure was monitored closely after dosing, two-thirds of patients treated with 8 mg of tizanidine had a 20% reduction in either the diastolic or systolic BP. The reduction was seen within 1 hour after dosing, peaked 2 to 3 hours after dosing and was associated, at times, with bradycardia, orthostatic hypotension, lightheadedness/dizziness and rarely syncope. The hypotensive effect is dose related and has been measured following single doses of ≥ 2 mg. The chance of significant hypotension may possibly be minimized by titration of the dose and by focusing attention on signs and symptoms of hypotension prior to dose advancement. In addition, patients moving from a supine to a fixed upright position may be at increased risk for hypotension and orthostatic effects. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy and should not be used with other α2-adrenergic agonists. Clinically significant hypotension (decreases in both systolic and diastolic pressure) has been reported with concomitant administration of either fluvoxamine or ciprofloxacin and single doses of 4 mg of tizanidine. Therefore, concomitant use of tizanidine with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated (see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interactions). RISK OF LIVER INJURY Tizanidine occasionally causes liver injury, most often hepatocellular in type. In controlled clinical studies, approximately 5% of patients treated with tizanidine had elevations of liver function tests (ALT/SGPT, AST/SGOT) to greater than 3 times the upper limit of normal (or 2 times if baseline levels were elevated) compared to 0.4% in the control patients. Most cases resolved rapidly upon drug withdrawal with no reported residual problems. In occasional symptomatic cases, nausea, vomiting, anorexia and jaundice have been reported. Based upon postmarketing experience, death associated with liver failure has been a rare occurrence reported in patients treated with tizanidine. Monitoring of aminotransferase levels is recommended during the first 6 months of treatment (e.g., baseline, 1, 3 and 6 months) and periodically thereafter, based on clinical status. Because of the potential toxic hepatic effect of tizanidine, the drug should ordinarily be avoided or used with extreme caution in patients with impaired hepatic function. SEDATION In the multiple doses, controlled clinical studies, 48% of patients receiving any dose of tizanidine reported sedation as an adverse event. In 10% of these cases, the sedation was rated as severe compared to < 1% in the placebo treated patients. Sedation may interfere with everyday activity. The effect appears to be dose related. In a single dose study, 92% of the patients receiving 16 mg, when asked, reported that they were drowsy during the 6 hour study. This compares to 76% of the patients on 8 mg and 35% of the patients on placebo. Patients began noting this effect 30 minutes following dosing. The effect peaked 1.5 hours following dosing. Of the patients who received a single dose of 16 mg, 51% continued to report drowsiness 6 hours following dosing compared to 13% in the patients receiving placebo or 8 mg of tizanidine. In the multiple dose studies, the prevalence of patients with sedation peaked following the first week of titration and then remained stable for the duration of the maintenance phase of the study. HALLUCINOSIS/PSYCHOTIC-LIKE SYMPTOMS Tizanidine use has been associated with hallucinations. Formed, visual hallucinations or delusions have been reported in 5 of 170 patients (3%) in two North American controlled clinical studies. These 5 cases occurred within the first 6 weeks. Most of the patients were aware that the events were unreal. One patient developed psychoses in association with the hallucinations. One patient among these 5 continued to have problems for at least 2 weeks following discontinuation of tizanidine. USE IN PATIENTS WITH HEPATIC IMPAIRMENT The influence of hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. Because tizanidine is extensively metabolized in the liver, hepatic impairment would be expected to have significant effects on the pharmacokinetics of tizanidine. Tizanidine should ordinarily be avoided or used with extreme caution in patients with hepatic impairment (See also RISK OF LIVER INJURY). POTENTIAL INTERACTION WITH FLUVOXAMINE OR CIPROFLOXACIN In a pharmacokinetic study, tizanidine serum concentration was significantly increased (Cmax 12-fold, AUC 33-fold) when the drug was given concomitantly with fluvoxamine. Potentiated hypotensive and sedative effects were observed. Fluvoxamine and tizanidine should not be used together. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interactions). In a pharmacokinetic study, tizanidine serum concentration was significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with ciprofloxacin. Potentiated hypotensive and sedative effects were observed. Ciprofloxacin and tizanidine should not be used together (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interactions). POSSIBLE INTERACTION WITH OTHER CYP1A2 INHIBITORS Because of potential drug interactions, concomitant use of tizanidine with other CYP1A2 inhibitors, such as zileuton, other fluoroquinolones, antiarrythmics (amiodarone, mexiletine, propafenone, and verapamil), cimetidine, famotidine, oral contraceptives, acyclovir and ticlopidine (see CLINICAL PHARMACOLOGY: Drug Interactions) should ordinarily be avoided. If their use is clinically necessary, they should be used with caution.