Tizanidine HCL

1. Indications and Usage Section 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)].

2. Dosage and Administration Section 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)].

3. Dosage Forms and Strengths Tizanidine Tablets, USP 2 mg are white to off-white, round, flat beveled, uncoated tablets debossed with product code “502” on one side, and bisecting score on the other. Tizanidine Tablets, USP 4 mg are white to off-white, round, flat beveled, uncoated tablets debossed with product code “503” on one side, and quadrisecting score on the other.

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)].

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)] 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* 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, Placebo-Controlled Study—Common Adverse Reactions Reported Event Placebo N = 48 % Tizanidine Tablets, USP, 8 mg, N = 45 % Tizanidine Tablets, USP, 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 * (weakness, fatigue, and/or tiredness) 6.2 Post-Marketing Experience The following adverse reactions have been identified during post approval use of Tizanidine Tablets, USP. 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 …

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 α2-adrenergic agonists Because hypotensive effects may be cumulative, it is not recommended that tizanidine hydrochloride be used with other α2-adrenergic agonists. [see Warnings and Precautions (5.1)]

8. Use in Specific Populations 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/m2 basis, and in rabbits at 30 mg/kg, 16 times the maximum recommended human dose on a mg/m2 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/m2 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/m2 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. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Tizanidine hydrochloride is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Clinical studies of tizanidine hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Cross-study comparison of pharmacokinetic data following single dose administration of 6 mg tizanidine hydrochloride showed that younger subjects cleared the drug four times faster than the elderly subjects. In elderly patients with renal insufficiency (creatinine clearance <25 mL/min), tizanidine clearance is reduced by more than 50% compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. During titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. Monitor elderly patients because they may have an increased risk for adverse reactions associated with tizanidine hydrochloride. 8.6 Impaired Renal Function Tizanidine hydrochloride is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. In patients with renal insufficiency (creatinine clearance < 25 mL/min) clearance was 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. [see Dosage and Administration (2.2), Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)] 8.7 Impaired Hepatic Function The influence of hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. Because tizanidine is extensively metabolized in the liver, hepatic impairment would be expected to have significant effects on pharmacokinetics of tizanidine. [see Dosing and Administration (2.3), Warnings and Precautions (5.2), and Clinical Pharmacology (12.3)].

11. Description Tizanidine Tablets, USP (tizanidine hydrochloride) is a central alpha2-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 C9H8ClN5S-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 (2.288 mg equivalent to 2 mg tizanidine base and 4.576 mg equivalent to 4 mg tizanidine base), and the inactive ingredients, colloidal silicon dioxide, stearic acid, microcrystalline cellulose, lactose monohydrate and anhydrous lactose. Structure

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.

16. How Supplied/Storage and Handling 16.2 Tizanidine Tablets Tizanidine Tablets USP, 2 mg are white to off white, oval, flat, beveled edged tablets debossed with “R179” on one side and “bisecting score” on other side. The tablets are available in bottles of: Bottles of 30 Tablets NDC: 80425-0425-01 Bottles of 60 Tablets NDC: 80425-0425-02 Bottles of 90 Tablets NDC: 80425-0425-03 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. The tablets are available in bottles of: Bottles of 60 Tablets NDC: 80425-0023-01 Bottles of 90 Tablets NDC: 80425-0023-02 Bottles of 30 Tablets NDC: 80425-0023-03 Bottles of 120 Tablets NDC: 80425-0023-04 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.