Zanaflex ® (tizanidine hydrochloride) is a central alpha 2 -adrenergic agonist. Tizanidine HCl is a white to off-white, fine crystalline powder, which is odorless or with a faint characteristic odor. Tizanidine is slightly soluble in water and methanol; solubility in water decreases as the pH increases. Its chemical name is 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole monohydrochloride. Tizanidine’s molecular formula is C 9 H 8 ClN 5 S-HCl, its molecular weight is 290.2 and its structural formula is: Zanaflex Capsules ® are supplied as 2, 4, and 6 mg capsules for oral administration. Zanaflex Capsules ® contain the active ingredient, tizanidine hydrochloride (2.29 mg equivalent to 2 mg tizanidine base, 4.58 mg equivalent to 4 mg tizanidine base, and 6.87 mg equivalent to 6 mg tizanidine base), and the inactive ingredients, hypromellose, silicon dioxide, sugar spheres, titanium dioxide, gelatin, and colorants. Zanaflex ® tablets are supplied as 4 mg tablets for oral administration. Zanaflex ® tablets contain the active ingredient, tizanidine hydrochloride (4.58 mg equivalent to 4 mg tizanidine base), and the inactive ingredients, colloidal silicon dioxide, stearic acid, microcrystalline cellulose and anhydrous lactose. Structural Formula

Zanaflex is indicated for the management of spasticity. Because of the short duration of therapeutic effect, treatment with Zanaflex should be reserved for those daily activities and times when relief of spasticity is most important . Zanaflex is a central alpha-2-adrenergic agonist indicated for the management of spasticity. Because of the short duration of therapeutic effect, treatment with Zanaflex should be reserved for those daily activities and times when relief of spasticity is most important.

Capsules 2 mg: Light blue opaque body with a light blue opaque cap with “2 MG” printed on the cap 4 mg: White opaque body with a blue opaque cap with “4 MG” printed on the cap 6 mg: Blue opaque body with a white stripe and blue opaque cap with “6 MG” printed on the cap Tablets 4 mg white, uncoated tablets with a quadrisecting score on one side and debossed with “A594” on the other side Capsules: 2 mg, 4 mg or 6 mg Tablets 4 mg

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 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 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 Zanaflex, decrease dose slowly to minimize the risk of withdrawal and rebound hypertension, tachycardia, and hypertonia 2.1 Dosing Information Zanaflex Capsules ® or Zanaflex ® 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. Zanaflex Capsules and Zanaflex tablets 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 . The recommended starting dose is 2 mg. Because the effect of Zanaflex 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

Dosing in Patients with Renal Impairment Zanaflex 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

Dosing in Patients with Hepatic Impairment Zanaflex 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

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 .

Hypotension: monitor for signs and symptoms of hypotension, in particular in patients receiving concurrent antihypertensives; Zanaflex should not be used with other α 2 -adrenergic agonists Risk of liver injury: monitor ALTs; discontinue Zanaflex if liver injury occurs Sedation: Zanaflex may interfere with everyday activities; sedative effects of Zanaflex, alcohol, and other CNS depressants are additive ( 5.3 , 7.5 , 7.6 ) Hallucinations: consider discontinuation of Zanaflex Less potent inhibitors of CYP1A2: may cause hypotension, bradycardia, or excessive drowsiness, use caution if Zanaflex is used with less potent inhibitors of CYP1A2, e.g., zileuton, other fluoroquinolones, antiarrhythmics, cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine ( 5.5 , 7.3 , 12.3 ) Renal impairment (creatinine clearance < 25 mL/min): use Zanaflex with caution, and monitor closely for dry mouth, somnolence, asthenia and dizziness as indicators of potential overdose 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 Zanaflex is used in patients receiving concurrent antihypertensive therapy. It is not recommended that Zanaflex 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 Zanaflex. Therefore, concomitant use of Zanaflex with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated

Risk of Liver Injury Zanaflex may cause hepatocellular liver injury. Zanaflex 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

Sedation Zanaflex 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 Zanaflex with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take Zanaflex with another CNS depressant for symptoms of excess sedation

Hallucinosis/Psychotic-Like Symptoms Zanaflex 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 Zanaflex in patients who develop hallucinations

Interaction with CYP1A2 Inhibitors Because of potential drug interactions, Zanaflex is contraindicated in patients taking potent CYP1A2 inhibitors, such as fluvoxamine or ciprofloxacin. Adverse reactions such as hypotension, bradycardia, or excessive drowsiness can occur when Zanaflex is taken with other CYP1A2 inhibitors, such as zileuton, fluoroquinolones other than ciprofloxacin (which is contraindicated), antiarrhythmics (amiodarone, mexiletine, propafenone), cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine). Concomitant use should be avoided unless the necessity for Zanaflex therapy is clinically evident. In such a case, use with caution

Hypersensitivity Reactions Zanaflex can cause anaphylaxis. Signs and symptoms including respiratory compromise, urticaria, and angioedema of the throat and tongue have been reported. Patients should be informed of the signs and symptoms of severe allergic reactions and instructed to discontinue Zanaflex and seek immediate medical care should these signs and symptoms occur

Increased Risk of Adverse Reactions in Patients with Renal Impairment Zanaflex 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. These patients should be monitored closely for the onset or increase in severity of the common adverse events (dry mouth, somnolence, asthenia and dizziness) as indicators of potential overdose

Withdrawal Adverse Reactions Withdrawal adverse reactions include rebound hypertension, tachycardia, and hypertonia. To minimize the risk of these reactions, particularly in patients who have been receiving high doses (20 to 28 mg daily) for long periods of time (9 weeks or more) or who may be on concomitant treatment with narcotics, the dose should be decreased slowly (2 to 4 mg per day) .

7.1 Fluvoxamine Concomitant use of fluvoxamine and Zanaflex is contraindicated. Changes in pharmacokinetics of tizanidine when administered with fluvoxamine resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment

Ciprofloxacin Concomitant use of ciprofloxacin and Zanaflex is contraindicated. Changes in pharmacokinetics of tizanidine when administered with ciprofloxacin resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment

CYP1A2 Inhibitors other than Fluvoxamine and Ciprofloxacin Because of potential drug interactions, concomitant use of Zanaflex with other CYP1A2 inhibitors, such as zileuton, fluoroquinolones other than strong CYP1A2 inhibitors (which are contraindicated), antiarrhythmics (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 Zanaflex therapy

Oral Contraceptives Concomitant use of Zanaflex with oral contraceptives is not recommended. However, if concomitant use is clinically necessary, initiate Zanaflex 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 Zanaflex therapy

Alcohol Alcohol increases the overall amount of drug in the bloodstream after a dose of Zanaflex. This was associated with an increase in adverse reactions of Zanaflex. The CNS depressant effects of Zanaflex and alcohol are additive

Other CNS Depressants The sedative effects of Zanaflex with CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take Zanaflex with another CNS depressant for symptoms of excess sedation

α 2 -Adrenergic Agonists Because hypotensive effects may be cumulative, it is not recommended that Zanaflex be used with other α 2 -adrenergic agonists .