Tizanidine

1 INDICATIONS AND USAGE Tizanidine Tablets, USP is a central alpha-2-adrenergic agonist indicated for the management of spasticity. Because of the short duration of therapeutic effect, treatment with Tizanidine Tablets, USP should be reserved for those daily activities and times when relief of spasticity is most important [see Dosage and Administration(2.1) ]. Tizanidine Tablets, USP is a central alpha-2-adrenergic agonist indicated for the management of spasticity. Because of the short duration of therapeutic effect, treatment with Tizanidine Tablets, USP should be reserved for those daily activities and times when relief of spasticity is most important [ SEE DOSAGE AND ADMINISTRATION (1) ].

2 DOSAGE AND ADMINISTRATION Recommended starting dose: 2 mg; dose can be repeated at 6 to 8 hour intervals, up to a maximum of 3 doses in 24 hours (2.1) Dosage can be increased by 2 mg to 4 mg per dose, with 1 to 4 days between increases; total daily dose should not exceed 36 mg (2.1) Tizanidine pharmacokinetics differs between tablets and capsules, and when taken with or without food. These differences could result in a change in tolerability and control of symptoms ( 2.1 , 12.3 ) To discontinue Tizanidine Tablets, USP, decrease dose slowly to minimize the risk of withdrawal and rebound hypertension, tachycardia, and hypertonia ( 2.2 ) 2.1 Dosing Information Tizanidine Tablets, USP tablets may be prescribed with or without food. Once the formulation has been selected and the decision to take with or without food has been made, this regimen should not be altered. Food has complex effects on tizanidine pharmacokinetics, which differ with the different formulations. Tizanidine Capsules and Tizanidine Tablets, USP are bioequivalent to each other under fasting conditions (more than 3 hours after a meal), but not under fed conditions (within 30 minutes of a meal). These pharmacokinetic differences may result in clinically significant differences when switching administration of tablet and capsules and when switching administration between the fed or fasted state. These changes may result in increased adverse events, or delayed or more rapid onset of activity, depending upon the nature of the switch. For this reason, the prescriber should be thoroughly familiar with the changes in kinetics associated with these different conditions [ SEE CLINICAL PHARMACOLOGY (12.3) ]. The recommended starting dose is 2 mg. Because the effect of Tizanidine Tablets, USP peaks at approximately 1 to 2 hours post-dose and dissipates between 3 to 6 hours post-dose, treatment can be repeated at 6 to 8 hour intervals, as needed, to a maximum of three doses in 24 hours. Dosage can be gradually increased by 2 mg to 4 mg at each dose, with 1 to 4 days between dosage increases, until a satisfactory reduction of muscle tone is achieved. The total daily dose should not exceed 36 mg. Single doses greater than 16 mg have not been studied. 2.2 Dosing in Patients with Renal Impairment Tizanidine Tablets, USP 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 [ SEE WARNINGS AND PRECAUTIONS (5.7) ]. 2.3 Dosing in Patients with Hepatic Impairment Tizanidine Tablets, USP should be used with caution in patients with any hepatic impairment. 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. Monitoring of aminotransferase levels is recommended for baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected. [ SEE USE IN SPECIFIC POPULATIONS (8.7) ] 2.4 Drug Discontinuation If therapy needs to be discontinued, particularly in patients who have been receiving high doses (20 mg to 36 mg daily) for long periods (9 weeks or more) or who may be on concomitant treatment with narcotics, the dose should be decreased slowly (2 mg to 4 mg per day) to minimize the risk of withdrawal and rebound hypertension, tachycardia, and hypertonia [ SEE DRUG ABUSE AND DEPENDENCE (9.3) ].

5 WARNINGS AND PRECAUTIONS Hypotension: monitor for signs and symptoms of hypotension, in particular in patients receiving concurrent antihypertensives; Tizanidine Tablets, USP should not be used with other α2-adrenergic agonists ( 5.1 , 7.7 ) Risk of liver injury: monitor ALTs; discontinue Tizanidine Tablets, USP if liver injury occurs ( 5.2 ) Sedation: Tizanidine Tablets, USP may interfere with everyday activities; sedative effects of Tizanidine Tablets, USP, alcohol, and other CNS depressants are additive ( 5.3 , 7.5 , 7.6 ) Hallucinations: consider discontinuation of Tizanidine Tablets, USP ( 5.4 ) Less potent inhibitors of CYP1A2: may cause hypotension, bradycardia, or excessive drowsiness, use caution if Tizanidine Tablets, USP 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 Tablets, USP 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 α2-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 Tablets, USP is used in patients receiving concurrent antihypertensive therapy. It is not recommended thatTizanidine Tablets, USP be used with other α2-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 Tablets, USP. Therefore, concomitant use of Tizanidine Tablets, USP with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated [ SEE CONTRAINDICATIONS (4) and DRUG INTERACTIONS (7.1 , 7.2) ]. 5.2 Risk of Liver Injury Tizanidine Tablets, USP may cause hepatocellular liver injury. Tizanidine Tablets, USP 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 Tablets, USP 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 Tablets, USP with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take Tizanidine Tablets, USP with another CNS depressant for symptoms of excess sedation. [ SEE DRUG INTERACTIONS (7.5 , 7.6 ) ] 5.4 Hallucinosis/Psychotic-Like Symptoms Tizanidine Tablets, USP 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. 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. Consider discontinuing Tizanidine Tablets, USP in patients who develop hallucinations. 5.5 Interaction with CYP1A2 Inhibitors Because of potential drug interactions, Tizanidine Tablets, USP is contraindicated in patients taking…

4 CONTRAINDICATIONS Tizanidine Tablets, USP is contraindicated in patientstaking potent inhibitors of CYP1A2, such as fluvoxamine or ciprofloxacin [ SEE DRUG INTERACTIONS (7.1 , 7.2 ) ]. Concomitant use with potent inhibitors of CYP1A2, such as fluvoxamine or ciprofloxacin ( 4 , 5.5 , 7.1 , 7.2 )

7 DRUG INTERACTIONS 7.1 Fluvoxamine Concomitant use of fluvoxamine and Tizanidine Tablets, USP is contraindicated. Changes in pharmacokinetics of tizanidine when administered with fluvoxamine resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment. [ SEE CONTRAINDICATIONS (4) and CLINICAL PHARMACOLOGY (12.3) ] 7.2 Ciprofloxacin Concomitant use of ciprofoxacin and Tizanidine Tablets, USP is contraindicated. Changes in pharmacokinetics of tizanidine when administered with ciprofloxacin resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment. [ SEE CONTRAINDICATIONS (4) and CLINICAL PHARMACOLOGY (12.3) ] 7.3 CYP1A2 Inhibitors other than Fluvoxamine and Ciprofloxacin Because of potential drug interactions, concomitant use of Tizanidine Tablets, USP with other CYP1A2 inhibitors, such as zileuton, fluoroquinolones other than strong CYP1A2 inhibitors (which are contraindicated), antiarrythmics (amiodarone, mexiletine, propafenone, and verapamil), cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine) should be avoided. If their use is clinically necessary, therapy should be initiated with 2 mg dose and increased in 2–4 mg steps daily based on patient response to therapy. If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue Tizanidine Tablets, USP therapy. [ SEE WARNINGS AND PRECAUTIONS (5.5) and CLINICAL PHARMACOLOGY (12.3) ] 7.4 Oral Contraceptives Concomitant use of Tizanidine Tablets, USP with oral contraceptives is not recommended. However, if concomitant use is clinically necessary, initiate Tizanidine Tablets, USP with a single 2 mg dose and increase in 2–4 mg steps daily based on patient response to therapy. If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue Tizanidine Tablets, USP therapy. [ SEE CLINICAL PHARMACOLOGY (12.3) ] 7.5 Alcohol Alcohol increases the overall amount of drug in the bloodstream after a dose of Tizanidine Tablets, USP. This was associated with an increase in adverse reactions of Tizanidine Tablets, USP. The CNS depressant effects of Tizanidine Tablets, USP and alcohol are additive. [ SEE CLINICAL PHARMACOLOGY (12.3) ] 7.6 Other CNS Depressants The sedative effects of Tizanidine Tablets, USP with CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take Tizanidine Tablets, USP with another CNS depressant for symptoms of excess sedation. [ SEE CLINICAL PHARMACOLOGY (12.3) ] 7.7 α2-adrenergic agonists Because hypotensive effects may be cumulative, it is not recommended that Tizanidine Tablets, USP be used with other α2-adrenergic agonists. [ SEE WARNINGS AND PRECAUTIONS (5.1) ]

8.1 Pregnancy Pregnancy Category C Tizanidine Tablets, USP has not been studied in pregnant women. Tizanidine Tablets, USP should be given to pregnant women only if the benefit outweighs the risk to the unborn fetus. Reproduction studies performed in rats at a dose of 3 mg/kg, equal to the maximum recommended human dose on a mg/m 2 basis, and in rabbits at 30 mg/kg, 16 times the maximum recommended human dose on a mg/m 2 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/m 2 basis increased gestation duration in rats. Prenatal and postnatal pup loss was increased and developmental retardation occurred. Post-implantation 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/m 2 basis.

8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Tizanidine Tablets, USP is administered to a nursing woman.

6 ADVERSE REACTIONS The following 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 (5.6) ] 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 Medcore LLC at 1-908-280-2269 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. Three double-blind, randomized, placebo controlled -clinical studies were conducted to evaluate the effect of tizanidine on spasticity control. 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. In all, 264 patients received tizanidine and 261 patients received placebo. Across the three studies patient ages ranged from 15–69 years and 51.4 percent were women. The median dose during the plateau phase ranged from 20–28 mg/day. The most frequent adverse reactions 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 events as mild to moderate and one-quarter of the patients rated the events as being severe. These events appeared to be dose related. Table 1 lists signs and symptoms that were reported in greater than 2% of patients in three multiple dose, placebo-controlled studies who received Tizanidine Tablets, USP where the frequency in the Tizanidine Tablets, USP group was greater than the placebo group. 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 Reactions Reported for Which Tizanidine Tablets, USP Incidence is Greater than Placebo Event Placebo N = 261 % Tizanidine Tablets, USP N = 264 % Dry mouth 10 49 Somnolence 10 48 Asthenia (weakness, fatigue, and/or tiredness) 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 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—Commo…