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Uses

Spasticity

Tizanidine is used alone or in conjunction with other standard therapies (e.g., baclofen) for the management of spasticity associated with cerebral or spinal injury. In these patients, tizanidine decreases the number and severity of spasms, alleviates clonus, and improves mobility to a greater extent than does placebo. Some evidence from comparative studies suggests that tizanidine may produce muscle weakness less frequently than other antispastic agents (e.g., baclofen, diazepam). The manufacturer states that because of its short duration of effect, tizanidine should be reserved for those daily activities and times when relief of spasticity is most important.

Efficacy for the management of spasticity has been demonstrated in 2 placebo-controlled, randomized studies in patients with multiple sclerosis or spinal cord injury. In these studies, patients 18-75 years of age received initial tizanidine hydrochloride dosages of 2 or 4 mg daily, which were titrated according to response and tolerance to a maximum of 36 mg (in up to 3 divided doses) daily over a 3-week period. Following initial dosage titration, tizanidine hydrochloride dosages averaged 30.7-31.1 mg daily. Based on changes in Ashworth scores (a 5-point rating scale for assessing muscle tone, with 0 representing normal muscle tone and 4 representing immobilization of the muscle by spasticity), reductions in muscle tone were greater with tizanidine than with placebo during dosage titration, plateau, and/or study end point assessments. Mean reductions from baseline in Ashworth scores at the end point assessment were 4.41 and 0.44 for the tizanidine and placebo groups, respectively, in one study and 4.4 and 1.2, respectively, in the other study. However, in the larger of these studies, reductions in muscle tone (primary outcome measure) with tizanidine were not associated with comparable improvements in secondary outcome measures such as muscle strength, the frequency of daytime muscle spasms, pain, or deep tendon reflex activity. Improvement in muscle tone with tizanidine therapy was not consistently associated with improvements in quality of life as determined by activities of daily living (ADL) assessment scores.

In comparative studies in patients with spasticity associated with multiple sclerosis or cerebrovascular disorders, principally stroke, tizanidine's ability to improve muscle tone has been shown to be similar to that of baclofen or diazepam. Combined analysis of data from studies of 4-8 weeks' duration indicated improvements in muscle tone, spasms, and clonus in about 50-67% of patients treated with any of these drugs, while improvement in muscle strength was noted in about 33% of such patients. In these studies, patients receiving tizanidine exhibited better retention of muscle strength than those receiving baclofen or diazepam, and the incidence of somnolence was somewhat lower with tizanidine than with diazepam.

Concomitant therapy with tizanidine and another antispastic agent (e.g., baclofen) reportedly may allow control of spasticity with lower dosages of each agent. However, it should be kept in mind that such concomitant therapy may cause additive sedative effects(see Drug Interactions: Alcohol and Other CNS Depressants); some clinicians suggest that tizanidine not be given concomitantly with benzodiazepines (e.g., diazepam).

Dosage and Administration

General

Tizanidine hydrochloride is administered orally. Food has complex effects on the pharmacokinetics of tizanidine, and these effects differ between the commercially available capsule and tablet formulations. Clinically important differences (e.g., increased adverse effects, delayed or more rapid onset of activity) may be apparent when switching administration of capsules or tablets between fed and/or fasting states, switching between capsules and tablets in the fed state, or switching between administration of intact capsules and sprinkling capsule contents on applesauce. Clinicians should be thoroughly familiar with possible pharmacokinetic changes associated with these conditions.(See Description.)

Dosage of tizanidine hydrochloride is expressed in terms of tizanidine.

The dosage of tizanidine should be individualized according to the patient's requirements and response using the lowest dosage that produces optimum response without adverse effects. While single doses of tizanidine smaller than 8 mg have not been shown to be effective in controlled clinical studies, initiation of tizanidine therapy with single doses of 4 mg is recommended to minimize the incidence of common dose-related adverse effects (e.g., orthostatic hypotension). The dose can be repeated every 6-8 hours as needed for a maximum of 3 doses in 24 hours. Dosage of tizanidine may be increased gradually in increments of 2-4 mg daily until optimum therapeutic effects are obtained with tolerable adverse effects; optimum dosage generally can be attained over a period of 2-4 weeks.

Clinical experience is limited with single doses exceeding 8 mg or total daily dosages exceeding 24 mg, and the manufacturer states that there is essentially no experience with repeated single or total daily dosages exceeding 12 or 36 mg, respectively. The dosage of tizanidine in adults should not exceed 36 mg in any 24-hour period.

Special Populations

Initiate with caution in patients with renal impairment (creatinine clearance less than 25 mL/minute). In these patients, the manufacturer recommends using smaller individual doses during dosage titration. If higher doses are needed, the manufacturer recommends increasing the amount of each individual dose rather than increasing the frequency of dosing.

Pharmacokinetics not studied in patients with hepatic impairment; however, tizanidine is known to undergo extensive first-pass hepatic metabolism. Therefore, the manufacturer recommends that the drug be avoided or used only with extreme caution in patients with hepatic impairment.

Although use of tizanidine ordinarily should be avoided in women taking oral contraceptives, if the drug is considered clinically necessary in such women, the initial dosage and rate of titration should be reduced.(See Drug Interactions: Oral Contraceptives.)

Cautions

Contraindications

Concomitant therapy with ciprofloxacin or fluvoxamine.(See Drug Interactions.)

Known hypersensitivity to tizanidine hydrochloride or any ingredient in the formulation.

Warnings/Precautions

Warnings

Limited Experience with Long-term Use of Higher Dosages

Clinical experience with long-term use of tizanidine at single doses of 8-16 mg or total daily dosages of 24-36 mg is limited. Therefore, only adverse effects with a relatively high incidence are likely to have been identified in long-term clinical studies.(See Dosage and Administration.)

Hypotension

Hypotension was reported in two-thirds of patients treated with 8 mg of tizanidine in a single-dose study. Patients in the study had a 20% reduction in either diastolic or systolic blood pressures within 1 hour after dosing; hypotensive effects peaked 2-3 hours after dosing and were occasionally associated with bradycardia, orthostatic effects, dizziness, and, rarely, syncope. Tizanidine's hypotensive effect is dose related. The risk of marked hypotension may therefore be minimized by careful dosage titration; patients should be observed for manifestations of hypotension prior to dosage adjustment.(See Advice to Patients.)

Tizanidine should be used with caution in patients receiving concomitant antihypertensive therapy.(See Drug Interactions: Hypotensive Agents.) Concomitant use of tizanidine and other α₂-adrenergic agonists (e.g., clonidine) is not recommended.

Because clinically important hypotension has been reported with concurrent use of either fluvoxamine or ciprofloxacin, these drugs are contraindicated in patients receiving tizanidine.(See Drug Interactions.)

Risk of Liver Injury

Liver injury (most often hepatocellular in type) has been reported occasionally. Elevations (i.e., exceeding 3 times the upper limit of normal, or 2 times the upper limit of normal if baseline levels were elevated) of ALT or AST have occurred in approximately 5% of patients receiving tizanidine in controlled clinical studies. Nausea, vomiting, anorexia, and jaundice occasionally have been reported in patients with elevated aminotransferase concentrations. Death associated with liver failure has been reported rarely.

Monitoring of serum aminotransferase concentrations should be performed prior to and during the first 6 months of treatment (e.g., at baseline and at 1, 3, and 6 months) and periodically thereafter based on clinical status. Tizanidine should be avoided or used only with extreme caution in patients with impaired hepatic function.(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Sedation

Sedation was reported in 48% of patients receiving any dose of tizanidine in multiple-dose, controlled clinical studies. Sedation was rated as severe by 10% of these tizanidine-treated patients compared with less than 1% of patients receiving placebo. Risk of sedation appears to be dose related. Sedation may interfere with daily activity. During multiple-dose studies, the prevalence of sedation peaked following the first week of dosage titration, then remained stable for the duration of the maintenance treatment phase. In comparative studies with baclofen or diazepam, the incidence of somnolence/drowsiness in patients receiving tizanidine or baclofen (15-67%) was slightly lower than that in patients receiving diazepam (44-82%).

Hallucinations/Psychotic-like Symptoms

Hallucinations (formed, visual) or delusions were reported in 5 of 170 patients (3%) receiving tizanidine in 2 North American controlled studies. All of these cases occurred within the first 6 weeks of therapy. Psychoses associated with hallucinations have been reported in at least one patient.

Potential Interaction with Fluvoxamine or Ciprofloxacin

In pharmacokinetic studies, substantial increases in serum tizanidine concentrations were observed during concurrent administration of fluvoxamine or ciprofloxacin; potentiated hypotensive and sedative effects also were observed. Concurrent administration of tizanidine with either fluvoxamine or ciprofloxacin is contraindicated.(See Drug Interactions.)

Potential Interaction with Other CYP1A2 Inhibitors

Because of potential drug interactions, concurrent administration of tizanidine with other cytochrome P-450 (CYP) isoenzyme 1A2 (CYP1A2) inhibitors should ordinarily be avoided. However, if their concomitant use is considered clinically necessary, the drugs should be used with caution.(See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

General Precautions

Cardiovascular Effects

Prolongation of the QT interval and bradycardia were reported in chronic toxicity studies in animals at dosages equal to the maximum recommended human daily dosage on a mg/m basis. ECG evaluation was not included in controlled clinical studies, but pulse rate reduction in association with decreases in blood pressure has been reported in patients receiving single doses of tizanidine.

Ocular Effects

Evidence of dose-related retinal degeneration and corneal opacities has been reported in animal studies at tizanidine dosages equivalent to approximately the maximum recommended human daily dosage on a mg/m basis. Retinal degeneration and corneal opacities have not been reported to date in clinical studies.

Use in Women Taking Oral Contraceptives

Because drug interaction studies have demonstrated that concurrent use of tizanidine and oral contraceptives may substantially reduce the clearance of tizanidine, concomitant use should ordinarily be avoided. However, if the drug is considered clinically necessary, tizanidine dosage adjustment is recommended.(See Dosage and Administration: Special Populations and also see Drug Interactions: Oral Contraceptives.)

Discontinuance of Therapy

Tizanidine is pharmacologically related to clonidine, and rebound manifestations similar to those reported with abrupt withdrawal of clonidine therapy, including hypertension, tachycardia, hypertonia, tremor, and anxiety, have been reported upon sudden withdrawal of tizanidine therapy.

If tizanidine therapy is to be discontinued, dosage of the drug should be decreased gradually, particularly in patients who have been receiving high dosages for prolonged periods, to minimize the risk of withdrawal and rebound symptoms.

Specific Populations

Pregnancy

Category C.

Lactation

It is not known whether tizanidine is distributed into milk in humans. However, because it is lipid-soluble, tizanidine might be expected to pass into milk in humans. Tizanidine should be used with caution in nursing women.

Pediatric Use

Safety and efficacy not established in children.

Geriatric Use

The manufacturer states that clearance is decreased fourfold in this patient population. Tizanidine should be used with caution in geriatric patients.

Hepatic Impairment

Although the pharmacokinetics of tizanidine have not been evaluated in patients with hepatic impairment, the drug undergoes extensive first-pass metabolism in the liver. Therefore, hepatic impairment would be expected to have substantial effects on tizanidine pharmacokinetics. The manufacturer states that tizanidine ordinarily should be avoided or used only with extreme caution in patients with impaired hepatic function.(See Risk of Liver Injury under Warnings/Precautions: Warnings, in Cautions.)

Renal Impairment

Clearance of tizanidine reportedly is reduced by greater than 50% in patients with a creatinine clearance less than 25 mL/minute. Tizanidine should be used with caution in patients with renal impairment. Patients should be monitored closely for onset or increased severity of common adverse effects (e.g., dry mouth, somnolence, asthenia, dizziness) that may indicate potential overdosage.(See Special Populations under Dosage and Administration.)

Common Adverse Effects

Adverse effects reported in greater than 2% of patients receiving tizanidine in multiple-dose, controlled clinical studies include dry mouth, somnolence, asthenia (weakness, fatigue, and/or tiredness), dizziness, urinary tract infection, infection, constipation, abnormal liver function test results (e.g., elevated ALT), vomiting, speech disorder, amblyopia (blurred vision), urinary frequency, flu symptoms, dyskinesia, nervousness, pharyngitis, and rhinitis. In addition, hypotension and bradycardia also have been reported in single-dose, placebo-controlled studies.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction; decreased plasma clearance of tizanidine may occur when tizanidine is given concurrently with other inhibitors of cytochrome P-450 (CYP) isoenzyme 1A2, including acyclovir, antiarrhythmics (e.g., amiodarone, mexiletine, propafenone, verapamil), cimetidine, famotidine, fluvoxamine (see Drug Interactions: Fluvoxamine), fluoroquinolones (e.g., ciprofloxacin [see Drug Interactions: Ciprofloxacin]), oral contraceptives (see Drug Interactions: Oral Contraceptives), ticlopidine, and zileuton. Concomitant use ordinarily should be avoided; if considered clinically necessary, the drugs should be used with caution.

Tizanidine and its major metabolites are not likely to affect the metabolism of other drugs metabolized by CYP isoenzymes.

Hypotensive Agents

Potential pharmacologic interaction (additive hypotensive effects) when used concomitantly with antihypertensive agents; should not be used with other α₂-adrenergic agonists (e.g., clonidine).

Acetaminophen

Potential pharmacokinetic interaction (delayed time to peak plasma concentration of acetaminophen). Acetaminophen does not affect pharmacokinetics of tizanidine.

Alcohol and Other CNS Depressants

Alcohol increased the areas under the plasma concentration-time curve (AUCs) and peak concentrations of tizanidine by approximately 20 and 15%, respectively; these changes were associated with an increase in adverse effects of tizanidine.

Potential pharmacologic interaction (additive CNS depression) with alcohol or other CNS depressants (e.g., baclofen, dantrolene, diazepam).

Ciprofloxacin

Potential pharmacokinetic interaction; significantly increased plasma concentrations and AUCs of tizanidine have been observed with concomitant administration, resulting in increased risk of adverse cardiovascular (including substantial hypotension) and CNS (e.g., drowsiness, psychomotor impairment) effects associated with tizanidine use. Concomitant use of tizanidine and ciprofloxacin is contraindicated.

Fluvoxamine

Potential pharmacokinetic interaction; significantly increased plasma concentrations, elimination half-life, and AUCs of tizanidine have been observed with concomitant administration, resulting in increased risk of adverse cardiovascular (including substantial hypotension) and CNS (e.g., drowsiness, psychomotor impairment) effects associated with tizanidine use. Concomitant use of tizanidine and fluvoxamine is contraindicated.

Oral Contraceptives

Potential pharmacokinetic interaction; decreased plasma clearance (by up to 50%) of tizanidine reported with concomitant use. Although use of tizanidine ordinarily should be avoided in women taking oral contraceptives, if the drug is considered clinically necessary in such women, tizanidine dosage adjustment is recommended.(See Dosage and Administration: Special Populations.)

Pharmacokinetics

Absorption

Bioavailability

Essentially completely absorbed following oral administration of capsules and tablets; peak plasma concentrations attained in about 1 hour.

Commercially available capsules and tablets are bioequivalent under fasting conditions, but not under nonfasting conditions.

Food

Tablets: Food increases the mean peak plasma concentration by about 30%, increases the median time to peak plasma concentration from about 60 minutes to about 85 minutes, and increases the extent of absorption by about 30%.

Capsules: Food decreases the mean peak plasma concentration by 20% and increases the median time to peak plasma concentration from about 1 hour to 3 hours, and increases the extent of absorption by about 10%. When given with food, the amount of tizanidine absorbed from the capsule is about 80% of the amount absorbed from the tablet.

Administration of the capsule contents sprinkled on applesauce is not bioequivalent to intact capsule under fasting conditions and results in a 15-20% increase in peak plasma concentration and AUC and a 15-minute decrease in median lag time and time to achieve peak plasma concentration compared with administration of intact capsule while fasting.

Distribution

Plasma Protein Binding

About 30%.

Elimination

Metabolism

Undergoes extensive first-pass hepatic metabolism. Metabolized mainly by CYP1A2.

Elimination Route

Recovered in urine (60%) and feces (20%) following administration of single or multiple radiolabeled doses.

Half-life

About 2.5 hours.