Tizanidine

Description

11 DESCRIPTION Tizanidine hydrochloride USP, is a central α 2 -adrenergic agonist. Tizanidine hydrochloride USP is almost white to slightly yellow crystalline powder, which is slightly soluble in water and methanol. Its chemical name is 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiodiazole 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: Tizanidine tablets USP, are supplied as 2 mg and 4 mg tablets for oral administration. Tizanidine tablets USP, contain the active ingredient, tizanidine hydrochloride USP (2.288 mg equivalent to 2 mg tizanidine base and 4.576 mg equivalent to 4 mg tizanidine base), and the inactive ingredients, anhydrous lactose, microcrystalline cellulose, colloidal silicon dioxide and stearic acid. structure

What Is Tizanidine Used For?

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

Dosage and Administration

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...

Side Effects (Adverse Reactions)

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 Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 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 to 69 years and 51.4 percent were women. The median dose during the plateau phase ranged from 20 to 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 hydrochloride where the frequency in the tizanidine hydrochloride 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 Incidence is Greater than Placebo Event Placebo N = 261 % Tizanidine Tablet 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 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 *(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,...

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 ) ]

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 )

Pregnancy and Breastfeeding

8.1 Pregnancy Pregnancy Category C Tizanidine hydrochloride has not been studied in pregnant women. Tizanidine hydrochloride 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 hydrochloride is administered to a nursing woman.

Overdosage

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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Tizanidine Tablets USP, 4 mg are white to off white, oval, flat, beveled edged tablets debossed with “R180” on one side and “quadrisecting score” on other side. NDC 85509-1180-6 : 60 tablets in a BOTTLE NDC 85509-1180-9 : 90 tablets in a BOTTLE NDC 85509-1180-2 : 28 tablets in a BOTTLE NDC 85509-1180-3 : 30 tablets in a BOTTLE NDC 85509-1180-1 : 120 tablets in a BOTTLE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in containers with child resistant closure. Repackaged/Relabeled by: PHOENIX RX LLC Hatboro, PA 19040