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%) of 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 frequently 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 events 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 (> 2%) Adverse Events Reported for Which Tizanidine Incidence is Greater Than Placebo Event Placebo N=261 % Tizanidine 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 function tests abnormal <1 3 Vomiting 0 3 Speech disorder 0 3 Amblyopia (blurred vision) <1 3 Urinary frequency 2 3 Flu symptom 2 3 SGPT/ALT increased <1 3 Dyskinesia 0 3 Nervousness <1 3 Pharyngitis 1 3 Rhinitis 2 3 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 events is 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 Event Placebo N=48 % Tizanidine , 8 mg N=45 % Tizanidine , 16 mg N=49 % Somnolence Dry mouth Asthenia Dizziness Hypotension Bradycardia 31 35 40 4 0 0 78 76 67 22 16 2 92 88 78 45 33 10 Other Adverse Events Observed During the Evaluation of Tizanidine Tizanidine was administered to 1,385 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 1,385 patients exposed to tizanidine who experienced an event of the type cited on at least one occasion while receiving tizanidine. All reported events are included except those already listed in Table 1. If the COSTART term for an event was so general as to be uninformative, it was replaced by a more informative term. It is important to emphasize that, although the events reported occurred during treatment with tizanidine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled studies appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare adverse events are those occurring in fewer than 1/1,000 patients. Body as a Whole: Frequent : fever; Infrequent: allergic reaction, moniliasis, malaise, abscess, neck pain, sepsis, cellulitis, death, overdose; Rare: carcinoma, congenital anomaly, suicide attempt. Cardiovascular System: Infrequent : vasodilatation, postural hypotension, syncope, migraine, arrhythmia; Rare: angina pectoris, coronary artery disorder, heart failure, myocardial infarct, phlebitis, pulmonary embolus, ventricular extrasystoles, ventricular tachycardia. Digestive System: Frequent : abdomen pain, diarrhea, dyspepsia; Infrequent: dysphagia, cholelithiasis, fecal impaction, flatulence, gastrointestinal hemorrhage, hepatitis, melena; Rare: gastroenteritis, hematemesis, hepatoma, intestinal obstruction, liver damage. Hemic and Lymphatic System: Infrequent : ecchymosis, hypercholesteremia, anemia, hyperlipemia, leukopenia, leukocytosis, sepsis; Rare: petechia, purpura, thrombocythemia, thrombocytopenia. Metabolic and Nutritional System: Infrequent : edema, hypothyroidism, weight loss; Rare: adrenal cortex insufficiency, hyperglycemia, hypokalemia, hyponatremia, hypoproteinemia, respiratory acidosis. Musculoskeletal System: Frequent: myasthenia, back pain; Infrequent: pathological fracture, arthralgia, arthritis, bursitis. Nervous System: Frequent : depression, anxiety, paresthesia; Infrequent: tremor, emotional lability, convulsion, paralysis, thinking abnormal, vertigo, abnormal dreams, agitation, depersonalization, euphoria, migraine, stupor, dysautonomia, neuralgia; Rare: dementia, hemiplegia, neuropathy. Respiratory System: Infrequent : sinusitis, pneumonia, bronchitis; Rare: asthma. Skin and Appendages: Frequent : rash, sweating, skin ulcer; Infrequent: pruritus, dry skin, acne, alopecia, urticaria; Rare: exfoliative dermatitis, herpes simplex, herpes zoster, skin carcinoma. Special Senses: Infrequent : ear pain, tinnitus, deafness, glaucoma, conjunctivitis, eye pain, optic neuritis, otitis media, retinal hemorrhage, visual field defect; Rare: iritis, keratitis, optic atrophy. Urogenital System: Infrequent: urinary urgency, cystitis, menorrhagia, pyelonephritis, urinary retention, kidney calculus, uterine fibroids enlarged, vaginal moniliasis, vaginitis; Rare: albuminuria, glycosuria, hematuria, metrorrhagia.