Tizanidine - St. Mary's Medical Park Pharmacy

RECENT MAJOR CHANGES SECTION

RECENT MAJOR CHANGES SECTION

1 INDICATIONS AND USAGE

INDICATIONS & USAGE SECTION

Tizanidine tablets are indicated for the treatment of spasticity in adults.

2 DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION

3 DOSAGE FORMS AND STRENGTHS

DOSAGE FORMS & STRENGTHS SECTION

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. 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.

4 CONTRAINDICATIONS

CONTRAINDICATIONS SECTION

Tizanidine hydrochloride is contraindicated in patients: taking strong CYP1A2 inhibitors [see Drug Interactions (7.1) ]. with a history of hypersensitivity to tizanidine or the ingredients in tizanidine tablets. Symptoms have included anaphylaxis and angioedema [see Warnings and Precautions (5.5) ].

5 WARNINGS AND PRECAUTIONS

WARNINGS AND PRECAUTIONS SECTION

6 ADVERSE REACTIONS

ADVERSE REACTIONS SECTION

The following clinically significant 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 ( 5.5 )] Withdrawal Adverse Reactions [see Warnings and Precautions ( 5.6 )]

7 DRUG INTERACTIONS

DRUG INTERACTIONS SECTION

8 USE IN SPECIFIC POPULATIONS

USE IN SPECIFIC POPULATIONS SECTION

9 DRUG ABUSE AND DEPENDENCE

DRUG ABUSE AND DEPENDENCE SECTION

10 OVERDOSAGE

OVERDOSAGE SECTION

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 ensure the adequacy of an airway and monitorcardiovascular and respiratory function. Dialysis is not likely to be an efficient method of removing tizanidine from the body [see Description (11) ] . In general, symptoms resolve within one to three days following discontinuation of tizanidine and administration of appropriate therapy. Because of 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.

11 DESCRIPTION

DESCRIPTION SECTION

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.

12 CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

NONCLINICAL TOXICOLOGY SECTION

14 CLINICAL STUDIES

CLINICAL STUDIES SECTION

The efficacy of tizanidine hydrochloride for the treatment of spasticity was demonstrated in two adequate and well-controlled studies in patients with multiple sclerosis or spinal cord injury (Studies 1 and 2). Single-Dose Study in Patients with Multiple Sclerosis with Spasticity In Study 1, 140 patients with spasticity caused by multiple sclerosis were randomized to receive single oral doses of 8 mg or 16 mg of tizanidine hydrochloride, or placebo. Patients and assessors were blinded to treatment assignment and efforts were made to reduce the likelihood that assessors would become aware indirectly of treatment assignment (e.g., they did not provide direct care to patients and were prohibited from asking questions about side effects). Response was assessed by physical examination; muscle tone was rated on a 5 point scale (Ashworth score) as follows: 0 = normal muscle tone 1 = slight spastic catch 2 = more marked muscle resistance 3 = considerable increase in tone, making passive movement difficult 4 = a muscle immobilized by spasticity Spasm counts were also collected. Assessments were made at 1, 2, 3 and 6 hours after treatment. A statistically significant reduction of the Ashworth score for tizanidine hydrochloride compared to placebo was detected at 1, 2 and 3 hours after treatment. Figure 2 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale. The greatest reduction in muscle tone was 1 to 2 hours after treatment. By 6 hours after treatment, muscle tone in the 8 mg and 16 mg tizanidine hydrochloride groups was indistinguishable from muscle tone in patients who received placebo. Within a given patient, improvement in muscle tone was correlated with plasma concentration. Plasma concentrations were variable from patient to patient at a given dose. Although 16 mg produced a larger effect, adverse reactions including hypotension were more common and more severe than in the 8 mg group. There were no differences in the number of spasms occurring in each group. Figure 2: Single Dose Study—Mean Change in Muscle Tone from Baseline as Measured by the Ashworth Scale ± 95% Confidence Interval (A Negative Ashworth Score Signifies an Improvement in Muscle Tone from Baseline) Seven-Week Study in Patients with Spinal Cord Injury with Spasticity In a 7-week study (Study 2), 118 patients with spasticity secondary to spinal cord injury were randomized to either placebo or tizanidine hydrochloride. Steps similar to those taken in the first study were employed to ensure the integrity of blinding. Patients were titrated over 3 weeks up to a maximum tolerated dose or 36 mg daily given in three unequal doses (e.g., 10 mg given in the morning and afternoon and 16 mg given at night). Patients were then maintained on their maximally tolerated dose for 4 additional weeks (i.e., maintenance phase). Throughout the maintenance phase, muscle tone was assessed on the Ashworth scale within a period of 2.5 hours following either the morning or afternoon dose. The number of daytime spasms was recorded daily by patients. At endpoint (the protocol-specified time of outcome assessment), there was a statistically significant reduction in muscle tone and frequency of spasms in the tizanidine hydrochloride treated group compared to placebo. The reduction in muscle tone was not associated with a reduction in muscle strength (a desirable outcome) but also did not lead to any consistent advantage of tizanidine hydrochloride treated patients on measures of activities of daily living. Figure 3 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale. Figure 3: Seven Week Study—Mean Change in Muscle Tone 0.5 to 2.5 Hours After Dosing as Measured by the Ashworth Scale ± 95% Confidence Interval (A Negative Ashworth Score Signifies an Improvement in Muscle Tone from Baseline)

16 HOW SUPPLIED/STORAGE AND HANDLING

HOW SUPPLIED SECTION

17 PATIENT COUNSELING INFORMATION

INFORMATION FOR PATIENTS SECTION

Serious Drug Interactions Advise patients they should not take tizanidine hydrochloride if they are taking fluvoxamine or ciprofloxacin because of the increased risk of serious adverse reactions including severe lowering of blood pressure and sedation. Instruct patients to inform their healthcare providers when they start or stop taking any medication because of the risks associated with interaction between tizanidine hydrochloride and other medicines [see Contraindications ( 4 ) and Drug Interactions ( 7 )]. Tizanidine hydrochloride Dosing and Administration Tell patients to take tizanidine hydrochloride exactly as prescribed (consistently either with or without food) and not to switch between tablets and capsules [see Dosage and Administration ( 2) ]. Inform patients that they should not take more tizanidine hydrochloride than prescribed because of the risk of adverse events at single doses greater than 8 mg or total daily doses greater than 36 mg. Tell patients that they should not suddenly discontinue tizanidine hydrochloride, because rebound hypertension and tachycardia may occur [see Warnings and Precautions ( 5.6 )]. Hypotension Warn patients that they may experience hypotension and to be careful when changing from a lying or sitting to a standing position. [see Warnings and Precautions (5.1) ] . Sedation Tell patients that tizanidine hydrochloride may cause them to become sedated or somnolent and they should be careful when performing activities that require alertness, such as driving a vehicle or operating machinery [see Warnings and Precautions ( 5.3 )] . Tell patients that the sedation may be additive when tizanidine hydrochloride is taken in conjunction with drugs (baclofen, benzodiazepines) or substances (e.g., alcohol) that act as CNS depressants. Remind patients that if they depend on their spasticity to sustain posture and balance in locomotion, or whenever spasticity is utilized to obtain increased function, that Tizanidine hydrochloride decreases spasticity and caution should be used. Hypersensitivity Reactions Inform patients of the signs and symptoms of severe allergic reactions and instruct them to discontinue Tizanidine and seek immediate medical care should these signs and symptoms occur [see Warnings and Precautions (5.5) ]. Rx Only Distributor: Dr. Reddy's Laboratories, Inc., Princeton, NJ 08540. Made in India Revised: 12/24