Tizanidine

Brand names: Comfort Pac with Tizanidine, TIZANDINE, TIZANIDINE HYDROCHLORIDE, Tizanidine HCl, Tizanidine Hydrochloride, Tizanidine hydrochloride, Tizanidne hydrochloride, ZANAFLEX, Zanaflex, tizanidine hydrochloride, Tizanidine, tizanidine, TIZANIDINE

Warnings

No boxed warning. Key warnings include hypotension/bradycardia (blood pressure drops of ≥20% occurred in about two-thirds of patients, with risk of syncope), hepatotoxicity (roughly 5% of patients had liver enzyme elevations, with rare reports of fatal hepatic failure, requiring baseline and periodic LFT monitoring), marked sedation (reported by 48% of patients overall, and 92% at a single 16 mg dose), and hallucinations/psychotic-like symptoms (about 3% of patients). Contraindicated with concomitant fluvoxamine or ciprofloxacin (potent CYP1A2 inhibitors), which markedly increase tizanidine blood levels.

Contraindications

4 CONTRAINDICATIONS Tizanidine hydrochloride is contraindicated in patients taking 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 )

Overdose

10 OVERDOSAGE A review of the safety surveillance database revealed cases of intentional and accidental tizanidine hydrochloride overdose. Some of the cases resulted in fatality and many of the intentional overdoses were with multiple drugs including CNS depressants. The clinical manifestations of tizanidine overdose were consistent with its known pharmacology. In the majority of cases a decrease in sensorium was observed including lethargy, somnolence, confusion and coma. Depressed cardiac function is also observed including most often bradycardia and hypotension. Respiratory depression is another common feature of tizanidine overdose. Should overdose occur, basic steps to ensure the adequacy of an airway and the monitoring of cardiovascular and respiratory systems should be undertaken. Tizanidine is a lipid-soluble drug, which is only slightly soluble in water and methanol. Therefore, dialysis is not likely to be an efficient method of removing drug from the body. In general, symptoms resolve within one to three days following discontinuation of tizanidine and administration of appropriate therapy. Due to the similar mechanism of action, symptoms and management of tizanidine overdose are similar to that following clonidine overdose. For the most recent information concerning the management of overdose, contact a poison control center.

Drug interactions

7 DRUG INTERACTIONS 7.1 Fluvoxamine Concomitant use of fluvoxamine and tizanidine hydrochloride 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 hydrochloride 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 hydrochloride 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 to 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 hydrochloride therapy. [see Warnings and Precautions ( 5.5 ) and Clinical Pharmacology ( 12.3 ) ] 7.4 Oral Contraceptives Concomitant use of tizanidine hydrochloride with oral contraceptives is not recommended. However, if concomitant use is clinically necessary, initiate tizanidine hydrochloride with a single 2 mg dose and increase in 2 to 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 hydrochloride therapy. [see Clinical Pharmacology ( 12.3 ) ] 7.5 Alcohol Alcohol increases the overall amount of drug in the bloodstream after a dose of tizanidine hydrochloride. This was associated with an increase in adverse reactions of tizanidine hydrochloride. The CNS depressant effects of tizanidine hydrochloride and alcohol are additive. [see Clinical Pharmacology ( 12.3 ) ] 7.6 Other CNS Depressants The sedative effects of tizanidine hydrochloride with CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take tizanidine hydrochloride with another CNS depressant for symptoms of excess sedation. [see Clinical Pharmacology ( 12.3 ) ] 7.7 α 2 -adrenergic agonists Because hypotensive effects may be cumulative, it is not recommended that tizanidine hydrochloride be used with other α 2 -adrenergic agonists. [see Warnings and Precautions ( 5.1 ) ]

Uses

Tizanidine is indicated for "the management of spasticity." The label notes it is short-acting and should be reserved for the daily activities and times when relief of spasticity is most important, as its benefit is limited to the duration of drug action and not all patients respond.

Dosage forms & strengths

Capsule Capsule, Gelatin Coated Tablet TABLET CAPSULE

TIZANIDINE 4 mg TIZANIDINE HYDROCHLORIDE 2 mg TIZANIDINE HYDROCHLORIDE 4 mg TIZANIDINE HYDROCHLORIDE 6 mg Tizanidine 2 mg Tizanidine 4 mg Tizanidine 6 mg Tizanidine Hydrochloride 2 mg Tizanidine Hydrochloride 4 mg tizanidine hydrochloride 2 mg tizanidine hydrochloride 4 mg tizanidine hydrochloride 6 mg TIZANIDINE HYDROCHLORIDE 2 mg/1 TIZANIDINE HYDROCHLORIDE 4 mg/1 TIZANIDINE HYDROCHLORIDE 6 mg/1

2 DOSAGE AND ADMINISTRATION Recommended starting dose: 2 mg; dose can be repeated at 6 to 8 hourintervals, 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 daysbetween increases; total daily dose should not exceed 36 mg (2.1) Tizanidine pharmacokinetics differs between tablets and capsules, andwhen taken with or without food. These differences could result in achange in tolerability and control of symptoms ( 2.1 , 12.3 ) To discontinue tizanidine tablet, decrease dose slowly to minimize the risk of withdrawal and rebound hypertension, tachycardia, and hypertonia ( 2.2 ) 2.1 Dosing Information Tizanidine 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 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 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 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 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 ) ].