Tizanidine Drug Information
Generic name: TIZANIDINE
Uses of Tizanidine
Tizanidine is indicated for the treatment of spasticity in adults. Tizanidine is a central alpha-2-adrenergic agonist indicated for the treatment of spasticity.
Dosage & Administration of Tizanidine
Recommended Evaluation and Testing Before and After Initiating Tizanidine Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved.
Recommended Dosage
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. The maximum total daily dosage is 36 mg. Single doses greater than 16 mg have not been studied.
There are pharmacokinetic differences when administering tizanidine between the fed or fasted state. Tizanidine 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 tizanidine should be reserved for those daily activities and times when relief of spasticity is most important.
Recommended Dosage in Patients with Renal Impairment
I n 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.
Recommended Dosage in Patients with Hepatic Impairment
I n patients with hepatic impairment, use lower individual doses during titration.
Discontinuation of Tizanidine Tablets
When discontinuing tizanidine tablets, 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.
Switching Between With/Without Food and Different Tizanidine Dosage Forms There are pharmacokinetic differences when: 1 switching between administration of tizanidine tablets 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.
Side Effects of Tizanidine
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. The safety of tizanidine has been evaluated in three double-blind, randomized, placebo-controlled clinical studies. 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 tizanidine) 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 1 lists adverse reactions that were reported in greater than 2% of patients in three multiple dose, placebo-controlled studies who received tizanidine where the frequency in the tizanidine group was greater than the placebo group. Table 1: Multiple Dose, Placebo-Controlled Studies—Adverse Reactions Reported in >2% of Patients Treated with Tizanidine Tablets and Incidence Greater than Placebo 2 3 *includes weakness, fatigue, and/or tiredness 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.
Postmarketing Experience
The following adverse reactions have been identified during post approval use of tizanidine. 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, hepatitis Musculoskeletal and Connective Tissue Disorders: arthralgia Nervous System Disorders: Convulsion, paresthesia, tremor, muscle spasms Psychiatric Disorders: Hallucinations, depression Skin and Subcutaneous Tissue Disorders: Stevens Johnson Syndrome, anaphylactic reaction, exfoliative dermatitis, rash
| Adverse Reaction | Placebo N = 261 % | Tizanidine Tablet N = 264 % |
|---|---|---|
| Dry mouth | 10 | 49 |
| Somnolence | 10 | 48 |
| Asthenia | 16 | 41 |
| Dizziness | 4 | 16 |
| UTI | 7 | 10 |
| Infection | 5 | 6 |
| Liver test abnormality | 2 | 6 |
| Constipation | 1 | 4 |
| 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 |
| Adverse Reaction | Placebo N = 48 % | Tizanidine Tablet, 8mg, N = 45 % | Tizanidine Tablet, 16 mg, N = 49 % |
|---|---|---|---|
| Somnolence | 31 | 78 | 92 |
| Dry mouth | 35 | 76 | 88 |
| Asthenia | 40 | 67 | 78 |
| Dizziness | 4 | 22 | 45 |
| Hypotension | 0 | 16 | 33 |
| Bradycardia | 0 | 2 | 10 |
Warnings & Cautions for Tizanidine
Hypotension Tizanidine is an α 2 -adrenergic agonist that can produce hypotension. 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 tizanidine is used in patients receiving concurrent antihypertensive therapy. It is not recommended that tizanidine 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. Therefore, concomitant use of tizanidine with strong CYP1A2 inhibitors is contraindicated.
Liver Injury Tizanidine may cause hepatocellular liver injury. Liver function test abnormality and hepatotoxicity have been observed with tizanidine. Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected.
Sedation Tizanidine can cause sedation, which may interfere with everyday activity. In the multiple dose studies of tizanidine, 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. The CNS depressant effects of tizanidine with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive.
Monitor patients who take tizanidine with another CNS depressant for symptoms of excess sedation.
Hallucinosis / Psychotic-Like Symptoms
Tizanidine 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 tizanidine in patients who develop hallucinations.
Hypersensitivity Reactions Tizanidine can cause anaphylaxis. Signs and symptoms of hypersensitivity, including respiratory compromise, urticaria, and angioedema of the throat and tongue, have been reported. Tizanidine is contraindicated in patients with a history of hypersensitivity reactions to tizanidine.
Withdrawal Adverse Reactions Tizanidine 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 tizanidine (20 to 28 mg daily) for long periods of time (9 weeks or more) or who may be on concomitant treatment with narcotics, the tizanidine dosage should be decreased slowly.
Drug Interactions with Tizanidine
Strong CYP1A2 Inhibitors
Concomitant use of tizanidine with strong cytochrome P450 1A2 (CYP1A2) inhibitors (e.g., fluvoxamine, ciprofloxacin) is contraindicated. Changes in pharmacokinetics of tizanidine when administered with a strong CYP1A2 inhibitor resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment.
Moderate or Weak CYP1A2 Inhibitors
Concomitant use of tizanidine with moderate or weak CYP1A2 inhibitors (e.g., zileuton, antiarrhythmics, cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine) should be avoided. If concomitant use is clinically necessary, and adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce tizanidine dosage or discontinue tizanidine therapy.
Oral Contraceptives
Concomitant use of tizanidine with oral contraceptives is not recommended.
Alcohol and Other CNS Depressants
Alcohol increases the exposure of tizanidine after administration of tizanidine. This was associated with an increase in adverse reactions of tizanidine. Concomitant use of tizanidine with CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may cause additive CNS depressant effects, including sedation.
Monitor patients who take tizanidine with another CNS depressant for symptoms of excess sedation. 7.5 α 2 -Adrenergic Agonists Concomitant use of tizanidine with other α 2 -adrenergic agonists is not recommended because hypotensive effects may be cumulative.
Antihypertensive Medications
Concomitant use of tizanidine tablets with antihypertensive medications may cause additive hypotensive effects. Monitor patients who take tizanidine tablets with antihypertensive medications for hypotension.
Contraindications for Tizanidine
- Tizanidine is contraindicated in patients:
- Taking strong CYP1A2 inhibitors.
- With a history of hypersensitivity to tizanidine or the ingredients in tizanidine tablets. Symptoms have included anaphylaxis and angioedema. Concomitant use with strong CYP1A2 inhibitors Patients with a history of hypersensitivity to tizanidine or the ingredients in tizanidine tablets
Overdosage Information for Tizanidine
A review of the safety surveillance database revealed cases of intentional and accidental tizanidine 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 monitor cardiovascular and respiratory function. Dialysis is not likely to be an efficient method of removing tizanidine from the body. 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.
Clinical Studies of Tizanidine
The efficacy of tizanidine 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, 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 hours after treatment. A statistically significant reduction of the Ashworth score for tizanidine 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 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. 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 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 treated patients on measures of activities of daily living.
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)
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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