TIZANIDINE HYDROCHLORIDE (Page 2 of 4)

INDICATIONS AND USAGE

Tizanidine is a short-acting drug for the management of spasticity. Because of the short duration of effect, treatment with tizanidine should be reserved for those daily activities and times when relief of spasticity is most important (see DOSAGE AND ADMINISTRATION).

CONTRAINDICATIONS

Tizanidine is contraindicated in patients with known hypersensitivity to tizanidine hydrochloride or its ingredients.

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 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.

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. In postmarketing experience, three deaths associated with liver failure have been reported in patients treated with tizandine.In one case, a 49 year-old male developed jaundice and liver enlargement following 2 months of tizanidine treatment, primarily at 6 mg tid. A liver biopsy showed multilobular necrosis without eosinophilic infiltration. Treatment was discontinued and the patient died in hepatic coma 10 days later. There was no evidence of hepatitis B and C in this patient and other therapy included only oxazepam and ranitidine. There was thus no explanation, other than a reaction to tizanidine, to explain the liver injury. In the two other cases, patients were taking other drugs with known potential for liver toxicity. One patient, treated with tizanidine at a dose of 4 mg/day, was also on carbamazepine when he developed cholestatic jaundice after 2 months of treatment; this patient died with pneumonia about 20 days later. Another patient, treated with tizanidine for 11 days, was also treated with dantrolene for about 2 weeks prior to developing fatal fulminant hepatic failure.

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 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 <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.

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/m2 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/m2 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 < 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
Tizanidine should be used with caution in women taking oral contraceptives, as clearance of tizanidine is reduced by approximately 50% in such patients. In these patients, during titration, the individual doses should be reduced.

Information for Patients
Patients should be advised of the limited clinical experience with tizanidine both in regard to duration of use and the higher doses required to reduce muscle tone (see WARNINGS).

Because of the possibility of tizanidine lowering blood pressure, patients should be warned about the risk of clinically significant orthostatic hypotension (see WARNINGS).

Because of the possibility of sedation, patients should be warned about performing activities requiring alertness, such as driving a vehicle or operating machinery (see WARNINGS). Patients should also be instructed that the sedation may be additive when tizanidine is taken in conjunction with drugs (baclofen, benzodiazepines) or substances (e.g., alcohol) that act as CNS depressants.

Tizanidine should be used with caution where spasticity is utilized to sustain posture and balance in locomotion or whenever spasticity is utilized to obtain increased function.

Drug Interactions
In vitro studies of cytochrome P450 isoenzymes using human liver microsomes indicate that neither tizanidine nor the major metabolites are likely to affect the metabolism of other drugs metabolized by cytochrome P450 isoenzymes.

Acetaminophen
Tizanidine delayed the Tmax of acetaminophen by 16 minutes. Acetaminophen did not affect the pharmacokinetics of tizanidine.

Alcohol
Alcohol increased the AUC of tizanidine by approximately 20% while also increasing its Cmax by approximately 15%. This was associated with an increase in side effects of tizanidine. The CNS depressant effects of tizanidine and alcohol are additive.

Oral Contraceptives
No specific pharmacokinetic study was conducted to investigate interaction between oral contraceptives and tizanidine, but retrospective analysis of population pharmacokinetic data following single and multiple dose administration of 4 mg tizanidine showed that women concurrently taking oral contraceptives had 50% lower clearance of tizanidine than women not on oral contraceptives.

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