Tizanidine Hydrochloride

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, 7.7) 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 CNS depressants are additive (5.3, 7.5, 7.6) Hallucinations: consider discontinuation of tizanidine (5.4) Less potent inhibitors of CYP1A2: may cause hypotension, bradycardia, or excessive drowsiness, use caution if tizanidine is used with less potent inhibitors of CYP1A2, e.g., zileuton, other fluoroquinolones, antiarrythmics , cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine (5.5, 7.3, 12.3) Renal impairment (creatinine clearance < 25 mL/min): use tizanidine with caution, and monitor closely for dry mouth, somnolence, asthenia and dizziness as indicators of potential overdose (5.7) 5.1 Hypotension Tizanidine is an α 2 -adrenergic agonist that can produce hypotension. Syncope has been reported in the post marketing setting. 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 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 either fluvoxamine or ciprofloxacin and single doses of 4 mg of tizanidine. Therefore, concomitant use of tizanidine with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated [see Contraindications (4) and Drug Interactions (7.1, (7.2) ]. 5.2 Liver Injury Tizanidine may cause hepatocellular liver injury. Tizanidine should be used with caution in patients with any hepatic impairment. Monitoring of aminotransferase levels is recommended for baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected [see Dosage and Administration (2.3) 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, 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. The CNS depressant effects of tizanidine with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take tizanidine with another CNS depressant for symptoms of excess sedation [see Drug Interactions (7.5, 7.6) ]. 5.4 Hallucinosis/Psychotic-Like Symptoms Tizanidine use has been associated with hallucinations. Formed, visual hallucinations or delusions were reported in 5 of 170 patients (3%) in two North American controlled clinical studies. Most of the patients were aware that the events were unreal. One patient developed psychosis in association with the hallucinations. One patient among these 5 continued to have problems for at least 2 weeks following discontinuation of tizanidine. Hallucinations have also been reported with tizanidine use in the postmarketing setting. Consider discontinuing tizanidine in patients who develop hallucinations. 5.5 Hypersensitivity Reactions Tizanidine can cause anaphylaxis. Signs and symptoms of hypersensitivity, including respiratory compromise, urticaria, and angioedema of the throat and tongue, have been reported. Tizanidine is contraindicated in patients with a history of hypersensitivity reactions to tizanidine [see Contraindications (4)]. 5.6 Withdrawal Adverse Reactions Tizanidine can cause withdrawal adverse reactions, which include rebound hypertension, tachycardia, and hypertonia. To minimize the risk of these reactions, particularly in patients who have been receiving high doses of tizanidine (20 to 28 mg daily) for long periods of time (9 weeks or more) or who may be on concomitant treatment with narcotics, the tizanidine dosage should be decreased slowly [see Dosage and Administration (2.5)].

6 ADVERSE REACTIONS 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)] The most common adverse reactions (greater than 2% of 264 patients taking tizanidine and greater than in placebo-treated patients in three multiple dose, placebo-controlled studies) were dry mouth, somnolence, asthenia, dizziness, urinary tract infection, constipation, liver function tests abnormal, vomiting, speech disorder, amblyopia, urinary frequency, flu syndrome, SGPT/ALT increased, dyskinesia, nervousness, pharyngitis, and rhinitis (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 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 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 greater than the placebo group. Table 1: Multiple Dose, Placebo-Controlled Studies—Frequent (>2%) Adverse Reactions Reported for Which Tizanidine Tablets Incidence is Greater than Placebo Placebo Tizanidine Tablet N = 261 N = 264 Event % % 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 * includes weakness, fatigue, and/or tiredness In the single dose, placebo-controlled study involving 142 patients with spasticity due to multiple sclerosis (Study 1) [see Clinical Studies (14) ], the patients were specifically asked if they had experienced any of the four most common adverse reactions: dry mouth, somnolence (drowsiness), asthenia (weakness, fatigue and/or tiredness) and dizziness. In addition, hypotension and bradycardia were observed. The occurrence of these reactions 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 Reactions Reported Event Placebo N = 48 % Tizanidine Tablet, 8mg, N = 45 % Tizanidine Tablet, 16 mg, N = 49 % Somnolence 31 78 92 Dry mouth 35 76 88 Asthenia* 40 67 78 Dizziness 4 22 45 Hypotension 0 16 33 Bradycardia 0 2 10 * includes weakness, fatigue, and/or tiredness 6.2 Post-Marketing Experience The following adverse reactions have been identified during post approval use of tizanidine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders: Ventricular tachycardia, decreased blood pressure Hepatobiliary Disorders: Hepatotoxicity [see Warnings and Precautions (5.2)], hepatitis Musculoskeletal and Connective Tissue Disorders: arthralgia Nervous System Disorders: Convulsion, paresthesia, tremor, muscle spasms Psychiatric Disorders: Hallucinations [see Warnings and Precautions (5.4)], depression Skin and Subcutaneous Tissue Disorders: Stevens Johnson Syndrome, anaphylactic reaction [see Warnings and Precautions (5.5)], exfoliative dermatitis, rash To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

<table><tbody><tr><td colspan="3"><content styleCode="bold">Table 1: Multiple Dose, Placebo-Controlled Studies&#x2014;Frequent (&gt;2%) Adverse Reactions Reported for Which Tizanidine Tablets Incidence is Greater than Placebo </content></td></tr><tr><td/><td><content styleCode="bold">Placebo</content></td><td><content styleCode="bold">Tizanidine Tablet</content></td></tr><tr><td/><td><content styleCode="bold">N = 261</content></td><td><content styleCode="bold">N = 264</content></td></tr><tr><td><content styleCode="bold">Event</content></td><td><content styleCode="bold">%</content></td><td><content styleCode="bold">%</content></td></tr><tr><td>Dry mouth</td><td>10</td><td>49</td></tr><tr><td>Somnolence</td><td>10</td><td>48</td></tr><tr><td>Asthenia*</td><td>16</td><td>41</td></tr><tr><td>Dizziness</td><td>4</td><td>16</td></tr><tr><td>UTI</td><td>7</td><td>10</td></tr><tr><td>Infection</td><td>5</td><td>6</td></tr><tr><td>Constipation</td><td>1</td><td>4</td></tr><tr><td>Liver test abnormality</td><td>2</td><td>6</td></tr><tr><td>Vomiting</td><td>0</td><td>3</td></tr><tr><td>Speech disorder</td><td>0</td><td>3</td></tr><tr><td>Amblyopia (blurred vision)</td><td>&lt;1</td><td>3</td></tr><tr><td>Urinary frequency</td><td>2</td><td>3</td></tr><tr><td>Flu syndrome</td><td>2</td><td>3</td></tr><tr><td>Dyskinesia</td><td>0</td><td>3</td></tr><tr><td>Nervousness</td><td>&lt;1</td><td>3</td></tr><tr><td>Pharyngitis</td><td>1</td><td>3</td></tr><tr><td>Rhinitis</td><td>2</td><td>3</td></tr></tbody></table>

<table><tbody><tr><td colspan="4"><content styleCode="bold">Table 2: Single Dose, Placebo-Controlled Study&#x2014;Common Adverse Reactions Reported</content></td></tr><tr><td><content styleCode="bold">Event</content></td><td><content styleCode="bold">Placebo</content><content styleCode="bold"> N = 48</content><content styleCode="bold">%</content></td><td><content styleCode="bold">Tizanidine Tablet,</content><content styleCode="bold">8mg, N = 45</content><content styleCode="bold">%</content></td><td><content styleCode="bold">Tizanidine Tablet, </content><content styleCode="bold"> 16 mg, N = 49</content><content styleCode="bold">%</content></td></tr><tr><td>Somnolence</td><td>31</td><td>78</td><td>92</td></tr><tr><td>Dry mouth</td><td>35</td><td>76</td><td>88</td></tr><tr><td>Asthenia*</td><td>40</td><td>67</td><td>78</td></tr><tr><td>Dizziness</td><td>4</td><td>22</td><td>45</td></tr><tr><td>Hypotension</td><td>0</td><td>16</td><td>33</td></tr><tr><td>Bradycardia</td><td>0</td><td>2</td><td>10</td></tr></tbody></table>