Tizanidine

TIZANIDINE- tizanidine hydrochloride tablet
RedPharm Drug, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use TIZANIDINE TABLETS safely and effectively. See full prescribing information for TIZANIDINE TABLETS.
TIZANIDINE tablets, for oral use
Initial U.S. Approval: 1996

INDICATIONS AND USAGE

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

DOSAGE AND ADMINISTRATION

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 (2.1)
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 (2.1)
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 tizanidine, decrease dose slowly to minimize the risk of withdrawal and rebound hypertension, tachycardia, and hypertonia (2.2)

DOSAGE FORMS AND STRENGTHS

Tablets 2 mg and 4 mg (3)

CONTRAINDICATIONS

Concomitant use with potent inhibitors of CYP1A2, such as fluvoxamine or ciprofloxacin(4,5.5, 7.1, 7.2)

WARNINGS AND PRECAUTIONS

Hypotension: monitor for signs and symptoms of hypotension, in particular in patients receiving concurrent antihypertensives; tizanidine should not be used with other α2-adrenergic agonists (5.1, 7.7)
Risk of liver injury: monitor ALTs; discontinue tizanidine if liver injury occurs (5.2)
Sedation: Tizanidine may interfere with everyday activities; sedative effects of tizanidine, alcohol, and other CNS depressants are additive (5.3, 7.5, 7.6)
Hallucinations: consider discontinuation of tizanidine (5.4)
Less potent inhibitors of CYP1A2: may cause hypotension, bradycardia, or excessive drowsiness, use caution if tizanidine is used with less potent inhibitors of CYP1A2, e.g., zileuton, other fluoroquinolones, antiarrythmics , cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine (5.5, 7.3, 12.3)
Renal impairment (creatinine clearance < 25 mL/min): use tizanidine with caution, and monitor closely for dry mouth, somnolence, asthenia and dizziness as indicators of potential overdose (5.7)

ADVERSE REACTIONS

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 Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on animal data, may cause fetal harm (8.1)
Geriatric use: tizanidine should be used with caution in elderly patients because clearance is decreased four-fold (8.5)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 10/2015

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Information
2.2 Dosing in Patients with Renal Impairment
2.3 Dosing in Patients with Hepatic Impairment
2.4 Drug Discontinuation
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hypotension
5.2 Risk of Liver Injury
5.3 Sedation
5.4 Hallucinosis/Psychotic-Like Symptoms
5.5 Interaction with CYP1A2 Inhibitors
5.6 Hypersensitivity Reactions
5.7 Increased Risk of Adverse Reactions in Patients with Renal Impairment
5.8 Withdrawal Adverse Reactions
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Post-Marketing Experience
7 DRUG INTERACTIONS
7.1 Fluvoxamine
7.2 Ciprofloxacin
7.3 CYP1A2 Inhibitors other than Fluvoxamine and Ciprofloxacin
7.4 Oral Contraceptives
7.5 Alcohol
7.6 Other CNS Depressants
7.7 α2-adrenergic Agonists
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Impaired Renal Function
8.7 Impaired Hepatic Function
9 DRUG ABUSE AND DEPENDENCE
9.2 Abuse
9.3 Dependence
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.2 Tizanidine Tablets
17 PATIENT COUNSELING INFORMATION

*
Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

Tizanidine is a central alpha-2-adrenergic agonist indicated for the management of spasticity. Because of the short duration of therapeutic effect, treatment with tizanidine 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

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 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 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 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

Tablets
2 mg — white to off-white, round, scored tablets, imprinted “APO” over “TI-2” on one side and plain with a bisect score on the other side.

4 mg- white to off-white, round, scored tablets, imprinted “APO” over “TI-4” on one side and plain with a quadrisect score on the other side.

4 CONTRAINDICATIONS

Tizanidine is contraindicated in patients taking potent inhibitors of CYP1A2, such as fluvoxamine or ciprofloxacin [see DRUG INTERACTIONS (7.1, 7.2)].