Zanaflex Drug Information

Zanaflex is indicated for the management of spasticity. 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 . Zanaflex is a central alpha-2-adrenergic agonist indicated for the management of spasticity. 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.

Dosing Information Zanaflex Capsules ® or Zanaflex ® 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.

Zanaflex Capsules and Zanaflex 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 . The recommended starting dose is 2 mg.

Because the effect of Zanaflex 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.

Dosing in Patients with Renal Impairment Zanaflex 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 .

Dosing in Patients with Hepatic Impairment Zanaflex 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 .

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 .

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 Zanaflex where the frequency in the Zanaflex 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 Zanaflex Tablets Incidence is Greater than Placebo Event Placebo N = 261 % Zanaflex Tablet N = 264 % Dry mouth 10 49 Somnolence 10 48 Asthenia (weakness, fatigue, and/or tiredness) 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 In the single dose, placebo-controlled study involving 142 patients with spasticity due to multiple sclerosis (Study 1) , 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 % Zanaflex Tablet, 8mg, N = 45 % Zanaflex Tablet, 16 mg, N = 49 % Somnolence 31 78 92 Dry mouth 35 76 88 Asthenia (weakness, fatigue, and/or tiredness) 40 67 78 Dizziness 4 22 45 Hypotension 0 16 33 Bradycardia 0 2 10

Postmarketing Experience

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. Certain events, such as somnolence, dry mouth, hypotension, decreased blood pressure, bradycardia, dizziness, weakness or asthenia, muscle spasms, hallucinations, fatigue, liver function test abnormality and hepatotoxicity, have been observed in post marketing and clinical trials and are discussed in previous sections of this document.

The following adverse reactions have been identified as occurring in the post marketing experience of Zanaflex. Based on the information provided regarding these reactions, a causal relationship with Zanaflex cannot be entirely excluded. The events are listed in order of decreasing clinical significance; severity in the post marketing setting is not reported.

Stevens Johnson Syndrome Anaphylactic Reaction Exfoliative Dermatitis Ventricular Tachycardia Hepatitis Convulsion Depression Arthralgia Paresthesia Rash Tremor

Fluvoxamine

Concomitant use of fluvoxamine and Zanaflex is contraindicated. Changes in pharmacokinetics of tizanidine when administered with fluvoxamine resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment .

Ciprofloxacin

Concomitant use of ciprofloxacin and Zanaflex is contraindicated. Changes in pharmacokinetics of tizanidine when administered with ciprofloxacin resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment .

CYP1A2 Inhibitors other than Fluvoxamine and Ciprofloxacin

Because of potential drug interactions, concomitant use of Zanaflex with other CYP1A2 inhibitors, such as zileuton, fluoroquinolones other than strong CYP1A2 inhibitors (which are contraindicated), antiarrhythmics (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 2–4 mg steps daily based on patient response to therapy. If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue Zanaflex therapy .

Oral Contraceptives

Concomitant use of Zanaflex with oral contraceptives is not recommended. However, if concomitant use is clinically necessary, initiate Zanaflex with a single 2 mg dose and increase in 2–4 mg steps daily based on patient response to therapy. If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue Zanaflex therapy .

Alcohol Alcohol increases the overall amount of drug in the bloodstream after

a dose of Zanaflex. This was associated with an increase in adverse reactions of Zanaflex. The CNS depressant effects of Zanaflex and alcohol are additive .

Other

CNS Depressants The sedative effects of Zanaflex with CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take Zanaflex with another CNS depressant for symptoms of excess sedation . 7.7 α 2 -Adrenergic Agonists Because hypotensive effects may be cumulative, it is not recommended that Zanaflex be used with other α 2 -adrenergic agonists .

Pregnancy Risk Summary There are no adequate data on the developmental risk associated with use of Zanaflex in pregnant women. In animal studies, administration of tizanidine during pregnancy resulted in developmental toxicity (embryofetal and postnatal offspring mortality and growth deficits) at doses less than those used clinically, which were not associated with maternal toxicity (see Animal Data ). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% - 4% and 15% - 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data Animal Data Oral administration of tizanidine (0.3 to 100 mg/kg/day) to pregnant rats during the period of organogenesis resulted in embryofetal and postnatal offspring mortality and reductions in body weight at doses of 30 mg/kg/day and above. Maternal toxicity was observed at the highest dose tested. The no-effect dose for embryofetal developmental toxicity in rats (3 mg/kg/day) is similar to the maximum recommended human dose (MRHD) of 36 mg/day on a body surface area (mg/m 2 ) basis.

Oral administration of tizanidine (1 to 100 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in embryofetal and postnatal offspring mortality at all doses. Maternal toxicity was observed at the highest dose tested. Oral administration of tizanidine (10 and 30 mg/kg/day) during the perinatal period of pregnancy (2-6 days prior to delivery) resulted in increased postnatal offspring mortality at both doses.

A no-effect dose for embryofetal developmental toxicity in rabbit was not identified. The lowest dose tested (1 mg/kg/day) is less than the MRHD on a mg/m 2 basis. In a pre- and postnatal development study in rats, oral administration of tizanidine (3 to 30 mg/kg/day) resulted in increased postnatal offspring mortality.

A no-effect dose for pre- and postnatal developmental toxicity was not identified. The lowest dose tested (3 mg/kg/day) is similar to the MRHD on a mg/m 2 basis, respectively.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

Zanaflex is contraindicated in patients taking potent inhibitors of CYP1A2, such as fluvoxamine or ciprofloxacin . Concomitant use with potent inhibitors of CYP1A2, such as fluvoxamine or ciprofloxacin

A review of the safety surveillance database revealed cases of intentional and accidental Zanaflex 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.