Zanaflex Warnings, Precautions, Pregnancy, Nursing, Abuse - Tizanidine

Zanaflex Warnings, Precautions, Pregnancy, Nursing, Abuse - Tizanidine

WARNINGS

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. 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).

Tizanidine is an a2-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.

Clinically significant hypotension (decreases in both systolic and diastolic pressure) has been reported with concomitant administration of fluvoxamine following single doses of 4 mg (see DRUG INTERACTIONS, CONTRAINDICATIONS, ADVERSE REACTIONS).

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 a2-adrenergic agonists.

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 tizanidine. 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 be used only with extreme caution in patients with impaired hepatic function.

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.

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.

Prolongation of the QTinterval 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).

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.

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.

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.

No evidence for carcinogenicity was seen in two dietary studies in rodents. Tizanidine was administered to mice for 78 weeks at doses up to 16 mg/kg, which is equivalent to 2 times the maximum recommended human dose on a mg/m² basis. Tizanidine was also administered to rats for 104 weeks at doses up to 9 mg/kg, which is equivalent to 2.5 times the maximum recommended human dose on a mg/m² basis. There was no statistically significant increase in tumors in either species.

Tizanidine was not mutagenic or clastogenic in the following in vitro assays: the bacterial Ames test and the mammalian gene mutation test and chromosomal aberration test in Chinese hamster cells. It was also negative in the following in vivo assays: the bone marrow micronucleus test in mice, the bone marrow micronucleus and cytogenicity test in Chinese hamsters, the dominant lethal mutagenicity test in mice, and the unscheduled DNAsynthesis (UDS) test in mice.

Tizanidine did not affect fertility in male rats at doses of 10 mg/kg, approximately 2.7 times the maximum recommended human dose on a mg/m² basis, and in females at doses of 3 mg/kg, approximately equal to the maximum recommended human dose on a mg/m² basis; fertility was reduced in males receiving 30 mg/kg (8 times the maximum recommended human dose on a mg/m² basis) and in females receiving 10 mg/kg (2.7 times the maximum recommended human dose on a mg/m² basis). At these doses, maternal behavioral effects and clinical signs were observed including marked sedation, weight loss, and ataxia.

Pregnancy Category C: Reproduction studies performed in rats at a dose of 3 mg/kg, equal to the maximum recommended human dose on a mg/m² basis, and in rabbits at 30 mg/kg, 16 times the maximum recommended human dose on a mg/m² basis, did not show evidence of teratogenicity. Tizanidine at doses that are equal to and up to 8 times the maximum recommended human dose on a mg/m² basis increased gestation duration in rats. -Prenatal and postnatal pup loss was increased and developmental retardation occurred. Postimplantation loss was increased in rabbits at doses of 1 mg/kg or greater, equal to or greater than 0.5 times the maximum recommended human dose on a mg/m² basis. Tizanidine has not been studied in pregnant women. Tizanidine should be given to pregnant women only if clearly needed.

The effect of tizanidine on labor and delivery in humans is unknown.

It is not known whether tizanidine is excreted in human milk, although as a lipid soluble drug, it might be expected to pass into breast milk.

Tizanidine should be used with caution in elderly patients because clearance is decreased four-fold.

There are no adequate and well-controlled studies to document the safety and efficacy of tizanidine in children.