Zanaflex is indicated for the treatment of spasticity in adults.

Zanaflex is a central alpha-2-adrenergic agonist indicated for the treatment of spasticity. ( 1)

• Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved. ( 2.1)
• Recommended starting dose: 2 mg by mouth every 6 to 8 hours, as needed, up to a maximum of 3 doses in 24 hours ( 2.2)
• Dosage can be increased by 2 mg to 4 mg per dose every 1 to 4 days; maximum total daily dosage is 36 mg ( 2.2)
• 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. Consistent administration with respect to food is recommended. If substitution between dosage forms is necessary, take into consideration these pharmacokinetic differences. ( 2.2, 2.6, 12.3)
• Patients with renal impairment (creatinine clearance <25 mL/min) or hepatic impairment: use lower individual doses during titration. If higher doses are required, individual doses rather than dosing frequency should be increased. ( 2.3, 2.4)
• To discontinue Zanaflex, decrease dose slowly to minimize the risk of withdrawal adverse reactions ( 2.5)

Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved [see Warnings and Precautions ( 5.2)] .

The recommended starting dose is 2 mg by mouth every 6 to 8 hours, as needed, to a maximum of three doses in 24 hours.

Dosage can be gradually increased every 1 to 4 days by 2 mg to 4 mg at each dose based on clinical response and tolerability. The maximum total daily dosage is 36 mg. Single doses greater than 16 mg have not been studied.

There are pharmacokinetic differences when administering Zanaflex between the fed or fasted state [see Clinical Pharmacology ( 12.3)] . Zanaflex may be taken with or without food; however, consistent administration with respect to food is recommended to reduce variability in tizanidine plasma exposure.

Because of the short duration of therapeutic effect, treatment with Zanaflex should be reserved for those daily activities and times when relief of spasticity is most important.

In patients with creatinine clearance < 25 mL/min, use lower individual doses during titration. If higher doses are required, the individual doses rather than dosing frequency should be increased [see Use in Specific Populations ( 8.6) and Clinical Pharmacology ( 12.3)] .

In patients with hepatic impairment, use lower individual doses during titration. If higher doses are required, individual doses rather than dosing frequency should be increased [see Use in Specific Populations ( 8.7) and Clinical Pharmacology ( 12.3)] .

When discontinuing Zanaflex, particularly in patients who have been receiving high doses for long periods or who may be on concomitant treatment with narcotics, decrease the dosage by 2 mg to 4 mg per day to minimize the risk of withdrawal adverse reactions [see Drug Abuse and Dependence ( 9.3)] .

There are pharmacokinetic differences when:

1. switching between administration of Zanaflex with or without food
2. switching between dosage forms if being administered with food.

If these situations occur, monitor patients for therapeutic effect or adverse reactions [see Dosage and Administration ( 2.2) and Clinical Pharmacology ( 12.3)] .

Zanaflex is contraindicated in patients

• taking strong CYP1A2 inhibitors [see Drug Interactions ( 7.1)] .
• with a history of hypersensitivity to tizanidine or the ingredients in Zanaflex. Symptoms have included anaphylaxis and angioedema [see Warnings and Precautions ( 5.5)]

• Concomitant use with strong CYP1A2 inhibitors ( 4, 7.1)
• Patients with a history of hypersensitivity to tizanidine or the ingredients in Zanaflex. ( 4, 5.5)

• Hypotension: monitor for signs and symptoms of hypotension, in particular in patients receiving concurrent antihypertensives; Zanaflex should not be used with other α ₂-adrenergic agonists ( 5.1, 7.7)
• Risk of liver injury: monitor ALTs; discontinue Zanaflex if liver injury occurs ( 5.2)
• Sedation: Zanaflex may interfere with everyday activities; sedative effects of Zanaflex, alcohol, and other central nervous system (CNS) depressants are additive ( 5.3, 7.4)
• Hallucinations: consider discontinuation of Zanaflex ( 5.4)

Zanaflex is an α ₂-adrenergic agonist that can produce hypotension [see Adverse Reactions ( 6.1) and Drug Interactions ( 7.5)] . Syncope has been reported in patients treated with tizanidine in the postmarketing setting. The risk of hypotension may be minimized by dose titration; monitoring for signs and symptoms of hypotension prior to dosage increase may minimize the risks associated with hypotension. In addition, patients moving from a supine to fixed upright position may be at increased risk for hypotension and orthostatic effects.

Monitor for hypotension when Zanaflex is used in patients receiving concurrent antihypertensive therapy. It is not recommended that Zanaflex be used with other α ₂-adrenergic agonists. Clinically significant hypotension (decreases in both systolic and diastolic pressure) has been reported with concomitant administration of tizanidine and strong CYP1A2 inhibitors [see Clinical Pharmacology ( 12.3)] . Therefore, concomitant use of Zanaflex with strong CYP1A2 inhibitors is contraindicated [see Contraindications ( 4) and Drug Interactions ( 7.1)] .

Zanaflex may cause hepatocellular liver injury. Liver function test abnormality and hepatotoxicity have been observed with Zanaflex [see Adverse Reactions ( 6.1, 6.2)] . Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected [see Dosage and Administration ( 2.1) and Use in Specific Populations ( 8.7)] .

Zanaflex can cause sedation, which may interfere with everyday activity. In the multiple dose studies of Zanaflex, the prevalence of patients with sedation peaked following the first week of titration and then remained stable for the duration of the maintenance phase of the study [see Adverse Reactions ( 6.1)] . The CNS depressant effects of Zanaflex with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive [see Drug Interactions ( 7.4)] . Monitor patients who take Zanaflex with another CNS depressant for symptoms of excess sedation.

Zanaflex use has been associated with hallucinations. Formed, visual hallucinations or delusions were reported in 5 of 170 patients (3%) in two North American controlled clinical studies. Most of the patients were aware that the events were unreal. One patient developed psychosis in association with the hallucinations. One patient among these 5 continued to have problems for at least 2 weeks following discontinuation of tizanidine. Hallucinations have also been reported with tizanidine use in the postmarketing setting. Consider discontinuing Zanaflex in patients who develop hallucinations.

Zanaflex can cause anaphylaxis. Signs and symptoms of hypersensitivity, including respiratory compromise, urticaria, and angioedema of the throat and tongue, have been reported. Zanaflex is contraindicated in patients with a history of hypersensitivity reactions to tizanidine [see Contraindications ( 4)] .

Zanaflex can cause withdrawal adverse reactions, which include rebound hypertension, tachycardia, and hypertonia. To minimize the risk of these reactions, particularly in patients who have been receiving high doses of Zanaflex (20 to 28 mg daily) for long periods of time (9 weeks or more) or who may be on concomitant treatment with narcotics, the Zanaflex dosage should be decreased slowly [see Dosage and Administration ( 2.5)] .

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)]

The most common adverse reactions (greater than 10% of patients taking tizanidine and greater than in patients taking placebo) were dry mouth, somnolence, asthenia, and dizziness. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Legacy Pharma Inc. at 1-8007277151 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.

The safety of Zanaflex has been evaluated in three double-blind, randomized, placebo-controlled clinical studies [see Clinical Studies ( 14)] . 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 period. In all, 264 patients received tizanidine and 261 patients received placebo. Across the three studies approximately 51% of patients were women, and the median dose during the plateau phase ranged from 20 to 28 mg/day.

The most common adverse reactions (>10% of patients treated with Zanaflex) 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 reactions as mild to moderate and one-quarter of the patients rated the reactions as being severe. These adverse reactions appeared to be dose related.

Table 1lists adverse reactions that were reported in greater than 2% of patients in three multiple dose, placebo-controlled studies who received Zanaflex where the frequency in the Zanaflex group was greater than the placebo group.

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.

The following adverse reactions have been identified during post approval use of Zanaflex. 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 causal relationship to drug exposure.

Cardiac Disorders: Ventricular tachycardia, decreased blood pressure

Hepatobiliary Disorders: Hepatotoxicity [see Warnings and Precautions ( 5.2)] , hepatitis

Musculoskeletal and Connective Tissue Disorders: arthralgia

Nervous System Disorders: Convulsion, paresthesia, tremor, muscle spasms

Psychiatric Disorders: Hallucinations [see Warnings and Precautions ( 5.4)] , depression

Skin and Subcutaneous Tissue Disorders: Stevens Johnson Syndrome, anaphylactic reaction [see Warnings and Precautions ( 5.5)] , exfoliative dermatitis, rash