Tizanidine Hydrochloride 4 mg Tablet, 90-count — NDC 49999-347-90 (Billing 49999-0347-90)

WARNINGS 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 an α 2 -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 ³ 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 a 2 -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 be used only with extreme caution in patients with impaired hepatic function.

Sedation In the multiple dose, 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 greater than 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 receiving16 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 pe… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS In multiple dose, placebo-controlled clinical studies, 264 patients were treated with tizanidine and 261 with placebo. Adverse events, including severe adverse events, were more frequently reported with tizanidine than with placebo. Common Adverse Events Leading To Discontinuation Forty-five of 264 (17%) patients receiving tizanidine and 13 of 261 (5%) patients receiving placebo in three multiple dose, placebo-controlled clinical studies discontinued treatment for adverse events.

When patients withdrew from the study, they frequently had more than one reason for discontinuing. The adverse events most fr equently leading to withdrawal of tizanidine treated patients in the controlled clinical studies were asthenia (weakness, fatigue and/or tiredness) (3%), somnolence (3%), dry mouth (3%), increased spasm or tone (2%) and dizziness (2%). Most Frequent Adverse Clinical Events Seen In Association With The Use Of Tizanidine In multiple dose, placebo-controlled clinical studies involving 264 patients with spasticity, the most frequent adverse effects were dry mouth, somnolence/sedation, asthenia (weakness, fatigue and/or tiredness) and dizziness.

Three-quarters of the patients rated the events as mild to moderate and one-quarter of the patients rated the events as being severe. These events appeared to be dose related. Adverse Events Reported In Controlled Studies The events cited reflect experience gained under closely monitored conditions of clinical studies in a highly selected patient population.

In actual clinical practice or in other clinical studies, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Table 1 lists treatment emergent signs and symptoms 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 at least as common as in the placebo group. These events are not necessarily related to tizanidine treatment.

For comparison purposes, the corresponding frequency of the event (per 100 patients) among placebo treated patients is also provided. TABLE 1: Multiple Dose, Placebo-Controlled Studies –Frequent (less than 2%) Adverse Events Reports for which Tizanidine Tablets Incidence is Greater than Placebo In the single dose, placebo-controlled study involving 142 patients with spasticity, the patients were specifically asked if they had experienced any of the four most common adverse events: dry mouth, somnolence (drowsiness), asthenia (weakness, fatigue and/or tiredness) and dizziness.

In addition, hypotension and bradycardia were observed. The occurrence of these adverse effects are summarized in Table 2. Other events were, in general, reported at a rate of 2% or less.

Table 2: Single Dose, Placebo-Controlled Study—Common Adverse Events Reported Other Adverse Events Observed During The Evaluation Of Tizanidine Tizanidine was administered to 1385 patients in additional clinical studies where adverse event information was available. The conditions and duration of exposure varied greatly, and included (in overlapping categories) double-blind and open-label studies, uncontrolled and controlled studies, inpatient and outpatient studies, and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing.

Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based dictionary terminology. The frequencies presented, therefore, represent the proportion of the 1385 patients exposed to tizanidine who experienced an event of the type cited on at least one occasion whil… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS Cardiovascular Prolongation of the QT interval and bradycardia were noted in chronic toxicity studies in dogs at doses equal to the maximum human dose on a mg/m 2 basis. ECG evaluation was not performed in the controlled clinical studies. Reduction in pulse rate has been noted in association with decreases in blood pressure in the single dose controlled study (see WARNINGS ).

Ophthalmic Dose-related retinal degeneration and corneal opacities have been found in animal studies at doses equivalent to approximately the maximum recommended dose on a mg/m 2 basis. There have been no reports of corneal opacities or retinal degeneration in the clinical studies. Use in Renally Impaired Patients Tizanidine should be used with caution in patients with renal insufficiency (creatinine clearance greater than 25 mL/min), as clearance is reduced by more than 50%.

In these patients, during titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. These patients should be monitored closely for the onset or increase in severity of the common adverse events (dry mouth, somnolence, asthenia and dizziness) as indicators of potential overdose.

Use in Women Taking Oral Contraceptives Because drug interaction studies of tizanidine with oral contraceptives have shown that concomitant use may reduce the clearance of tizanidine by as much as 50%, concomitant use of tizanidine with oral contraceptives should ordinarily be avoided (see CLINICAL PHARMACOLOGY: Drug Interactions ). However, if concomitant use is clinically necessary, the starting dose and subsequent titration rate of tizanidine should be reduced. Discontinuing Therapy If therapy needs to be discontinued, particularly in patients who have been receiving high doses for long periods, the dose should be decreased slowly to minimize the risk of withdrawal and rebound hypertension, tachycardia, and hypertonia.