Zanaflex Adverse Reactions
- arrhythmia exacerbation
- asthenia
- blurred vision
- cholelithiasis
- constipation
- dizziness
- drowsiness
- dyskinesia
- elevated hepatic enzymes
- excitability
- exfoliative dermatitis
- fatigue
- hallucinations
- hepatic failure
- hepatic necrosis
- hypotension
- infection
- jaundice
- nausea/vomiting
- orthostatic hypotension
- pharyngitis
- psychosis
- rash (unspecified)
- rhinitis
- sinus bradycardia
- syncope
- weakness
- withdrawal
- xerostomia
Zanaflex (Tizanidine) Adverse Reactions
Adverse effects due to tizanidine are common and frequently are dose-related. Adverse events generally correlate with the pharmacological properties of tizanidine, a central-acting alpha2-adrenergic agonist. The adverse events most frequently leading to discontinuation of tizanidine in controlled clinical trials were: asthenia (defined as weakness, fatigue and/or tiredness) (3%), sedation or drowsiness (3%), xerostomia (dry mouth) (3%), increased spasm or tone (2%), and dizziness (2%). Overall, tizanidine or placebo treatments was discontinued due to adverse events in 17% versus 5% of patients, respectively. The most common adverse effects (>10%) which occurred in three controlled clinical trials with tizanidine at a frequency exceeding placebo included: xerostomia (49% vs. 10%), sedation (somnolence or drowsiness) (48% vs. 10%), asthenia (41% vs. 16%), and dizziness (16% vs. 4%). These four adverse event categories were rated by the patients to be mild-moderate (75%) or severe (25%). In 10% of the tizanidine-treated cases, sedation was rated to be severe compared to <1% of the placebo treated patients. In the multiple dose studies, the prevalence of patients with sedation peaked following the first week of titration, and then remained unchanged throughout the study. When comparing the 8 mg and 16 mg tizanidine doses, the following dose-related increase in adverse events were identified: sedation (78% vs. 92%), xerostomia (76% vs. 88%), asthenia (67% vs. 78%), and dizziness (22% vs. 45%). Since long-term clinical study experience with high doses (>= 8 mg) or total daily dosage >= 24 mg/day is limited, only those adverse events with a relatively high incidence are likely to have been identified. Approximately 75 patients have been exposed to individual doses of >= 12 mg for at least one year and approximately 80 patients have been exposed to total daily doses of 30-36 mg/day for at least one year. There is virtually no long-term experience with single, daytime doses of 16 mg. Due to dose-related adverse effects, the dose should be titrated to the lowest tolerated dose which controls spasticity.
Dose-related hypotension occurred relatively frequently in patients treated with single oral doses of 8 mg (16%) or 16 mg (33%) of tizanidine (0% placebo). Hypotension were also more severe in the 16 mg group. 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 sinus bradycardia, orthostatic hypotension, lightheadedness or dizziness and rarely syncope. The hypotensive effect is dose-related. The chance of significant hypotension may possibly be minimized by titration of the dose and by monitoring for signs and symptoms of orthostatic effects or hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy. Bradycardia occurred in 2% and 10% of patients receiving 8 mg or 16 mg, respectively (0% placebo). QT prolongation and bradycardia have been noted in canine chronic toxicity studies at doses equal to the maximum human dose on a mg/m2 basis; however, ECG evaluation has not performed in the controlled clinical studies. Infrequent cardiac reactions included: arrhythmia exacerbation (<=1%) and rare (<=0.1%) cases of angina, coronary artery disorder, heart failure, myocardial infarction, ventricular extrasystoles, ventricular tachycardia.
Other frequent (2-10%) adverse events which occurred more often with tizanidine therapy than placebo (without regard to causality) included: urinary tract infection (10% vs. 7%), infection (6% vs. 5%), constipation (4% vs. 1%), nausea/vomiting (3% vs. 0%), speech disorder (3% vs. 0%), amblyopia (blurred vision) (3% vs. <1%), urinary frequency (3% vs. 2%), flu syndrome (3% vs. 2%), dyskinesia (3% vs. 0%), nervousness (excitability) (3% vs. <1%), pharyngitis (3% vs. 1%), and rhinitis (3% vs. 2%). Less frequent adverse (<= 1%) experiences reported without regard to causality are detailed in the prescribing information for tizanidine.
Tizanidine use has been associated with hallucinations. In two controlled clinical studies, formed/visual hallucinations or delusions have been reported within the first 6 weeks of therapy in 5 of 170 tizanidine-treated patients (3%). These 5 cases occurred within the first 6 weeks. Most of the patients were aware that the events were unreal. One patient developed psychosis in association with hallucinations.
Dermatological adverse events may occur with tizanidine. Rash (unspecified) is reported in <=1% patients. Exfoliative dermatitis has been reported rarely (< 0.1%).
Dose-related retinal degeneration and corneal opacities have been reported in animals at doses similar to the maximum recommended human dose (mg/m2). No cases of corneal opacities or retinal degeneration were observed in clinical trials.
Tizanidine occasionally causes hepatotoxicity, most often hepatocellular in type. In controlled clinical studies, approximately 5% of patients treated with tizanidine had elevated hepatic enzymes (ALT or AST) compared to 0.4% in the control patients. Most cases resolved rapidly upon drug discontinuation with no residual problems. In occasional symptomatic cases, nausea, vomiting, anorexia and jaundice have been reported. Cholelithiasis has also been reported infrequently (<=1%). One case report describes elevated hepatic enzymes during therapy with 36 mg/day tizanidine, which improved upon drug discontinuation and recurred upon drug re-challenge. In post-marketing 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 three times daily. A liver biopsy showed multilobular hepatic necrosis without eosinophilic infiltration. Treatment was discontinued and the patient died in hepatic coma 10 days later; other explanations for hepatotoxicity were ruled out. In the two other cases, patients were taking other drugs with known potential for hepatotoxicity. 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, and 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 only be used with extreme caution in patients with impaired hepatic function.
Tizanidine is closely related to clonidine, which is often abused in combination with opiate agonists and is known to cause symptoms of rebound upon abrupt discontinuation. Three cases of rebound symptoms on sudden discontinuation of tizanidine have been reported. The case reports suggest that these patients were also misusing opiate agonists. Withdrawal symptoms included hypertension, tachycardia, hypertonia, tremor, and anxiety. As with clonidine, withdrawal is expected to be more likely in cases where high doses are used, especially for prolonged periods.
[ Last revised: 4/23/2003 4:58:00 PM ]
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