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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hypotension: monitor for signs and symptoms of hypotension, in particular in patients receiving concurrent antihypertensives;tizanidine should not be used with other α 2 -adrenergic agonists ( 5.1 , 7.5 ) Risk of liver injury: monitor ALTs; discontinue tizanidine if liver injury occurs ( 5.2 ) Sedation: Tizanidine may interfere with everyday activities; sedative effects of tizanidine, alcohol, and other central nervous system (CNS) depressants are additive ( 5.3 , 7.4 ) Hallucinations: consider discontinuation of tizanidine ( 5.4 ) 5.1 Hypotension Tizanidine is an α 2 -adrenergic agonist that can produce hypotension [see Adverse Reactions (6.1) and Drug Interactions (7.5) ] . Syncope has been reported in patients treated with tizanidine in the postmarketing setting. The risk of hypotension may be minimized by dose titration; monitoring for signs and symptoms of hypotension prior to dosage increase may minimize the risks associated with hypotension. In addition, patients moving from a supine to fixed upright position may be at increased risk for hypotension and orthostatic effects. Monitor for hypotension when tizanidine is used in patients receiving concurrent antihypertensive therapy. It is not recommended that tizanidine be used with other α 2 -adrenergic agonists. Clinically significant hypotension (decreases in both systolic and diastolic pressure) has been reported with concomitant administration of tizanidine and strong CYP1A2 inhibitors [see Clinical Pharmacology (12.3) ]. Therefore, concomitant use of tizanidine with strong CYP1A2 inhibitors is contraindicated [see Contraindications (4) and Drug Interactions (7.1) ] . 5.2 Liver Injury Tizanidine may cause hepatocellular liver injury. Liver function test abnormality and hepatotoxicity have been observed with tizanidine [see Adverse Reactions ( 6.1 , 6.2 )]. Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected [see Dosage and Administration (2.1) and Use in Specific Populations (8.7) ] . 5.3 Sedation Tizanidine can cause sedation, which may interfere with everyday activity. In the multiple dose studies of tizanidine, 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 [see...
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adverse reactions
6 ADVERSE REACTIONS The most common adverse reactions (greater than 10% of patients taking tizanidine and greater than in patients taking placebo) were dry mouth, somnolence, asthenia, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Viona Pharmaceuticals Inc. at 1-888-304-5011 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following clinically significant adverse reactions are described elsewhere in other sections of the prescribing information: Hypotension [ see Warnings and Precautions (5.1) ] Liver Injury [ see Warnings and Precautions (5.2) ] Sedation [ see Warnings and Precautions (5.3) ] Hallucinosis/Psychotic-Like Symptoms [ see Warnings and Precautions (5.4) ] Hypersensitivity Reactions [see Warnings and Precautions (5.5) ] Withdrawal Adverse Reactions [see Warnings and Precautions (5.6 )] 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. The safety of tizanidine has been evaluated in three double-blind, randomized, placebo-controlled clinical studies [see Clinical Studies (14) ] . Two studies were conducted in patients with multiple sclerosis and one in patients with spinal cord injury. Each study had a 13-week active treatment period which included a 3-week titration phase to the maximum tolerated dose up to 36 mg/day in three divided doses, a 9-week plateau phase where the dose of tizanidine was held constant and a 1-week dose tapering period. In all, 264 patients received tizanidine and 261 patients received placebo. Across the three studies approximately 51% of patients were women, and the median dose during the plateau phase ranged from 20 mg/day to 28 mg/day. The most common adverse reactions (>10% of patients treated with tizanidine) reported in multiple dose, placebo-controlled clinical studies involving 264 patients with spasticity were dry mouth, somnolence/sedation, asthenia (weakness, fatigue and/or tiredness), and dizziness. Three-quarters of the patients rated the reactions as mild to moderate and one-quarter of the patients rated the reactions as being severe. These adverse reactions appeared to be dose related. Table 1 lists adverse reactions that we...
adverse reactions table
Table 1: Multiple Dose, Placebo-Controlled Studies—Adverse Reactions Reported in >2% of Patients Treated with Tizanidine Tablets and Incidence Greater than Placebo Adverse Reaction Placebo N = 261 % Tizanidine Tablet N = 264 % Dry mouth 10 49 Somnolence 10 48 Asthenia* 16 41 Dizziness 4 16 UTI 7 10 Infection 5 6 Constipation 1 4 Liver test abnormality 2 6 Vomiting 0 3 Speech disorder 0 3 Amblyopia (blurred vision) <1 3 Urinary frequency 2 3 Flu syndrome 2 3 Dyskinesia 0 3 Nervousness <1 3 Pharyngitis 1 3 Rhinitis 2 3 *includesweakness, fatigue, and/or tiredness