What is Zanaflex (tizanidine)?

Zanaflex (tizanidine) is a skeletal muscle relaxant used to treat and manage skeletal muscle spasticity. Spasticity may be due to multiple sclerosis or spinal cord injury. Zanaflex works on alpha 2 receptors in the central nervous system (brain and spinal cord) and blocks nerve impulses from reaching muscles which produces muscle relaxation. 

Common side effects of Zanaflex include:

Serious side effects of Zanaflex include:

Drug interactions of Zanaflex include ciprofloxacin, amiodarone, cimetidine, oral contraceptives, acyclovir, and fluvoxamine, which can slow the breakdown of Zanaflex and lead to increased sedation, drowsiness, and slowed reflexes. 

Zanaflex should be used with caution with medications like alprazolam, clonazepam, diazepam, zolpidem, oxycodone, hydromorphone, amitriptyline, nortriptyline, and alcohol, because they can further increase the side effects of Zanaflex. 

There are no adequate studies done on Zanaflex to determine safe and effective use in pregnant women. 

It is unknown if Zanaflex enters human milk. Because it is soluble in lipids, it might pass into breast milk. Consult your doctor before breastfeeding

What are the important side effects of Zanaflex (tizanidine)?

Common side effects of tizanidine include:

Zanaflex (tizanidine) side effects list for healthcare professionals

The following adverse reactions are described elsewhere in other sections of the prescribing information:

  • Hypotension
  • Liver Injury
  • Sedation
  • Hallucinosis/Psychotic-Like Symptoms
  • Hypersensitivity Reactions

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

EventPlacebo
N = 261
%
Zanaflex Tablet
N = 264
%
Dry mouth1049
Somnolence1048
Asthenia*1641
Dizziness416
UTI710
Infection56
Constipation14
Liver test abnormality26
Vomiting03
Speech disorder03
Amblyopia (blurred vision)< 13
Urinary frequency23
Flu syndrome23
Dyskinesia03
Nervousness< 13
Pharyngitis13
Rhinitis23
*(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.

Table 2: Single Dose, Placebo-Controlled Study—Common Adverse Reactions Reported

EventPlacebo
N = 48
%
Zanaflex Tablet, 8mg,
N = 45
%
Zanaflex Tablet, 16 mg,
N = 49
%
Somnolence317892
Dry mouth357688
Asthenia*406778
Dizziness42245
Hypotension01633
Bradycardia0210
*(weakness, fatigue, and/or tiredness)

Post-Marketing 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.

What drugs interact with Zanaflex (tizanidine)?

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 ciprofoxacin 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), antiarrythmics (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.

α2-adrenergic agonists

Because hypotensive effects may be cumulative, it is not recommended that Zanaflex be used with other a2-adrenergic agonists.

Drug Abuse And Dependence

Abuse

Abuse potential was not evaluated in human studies. Rats were able to distinguish tizanidine from saline in a standard discrimination paradigm, after training, but failed to generalize the effects of morphine, cocaine, diazepam, or phenobarbital to tizanidine.

Dependence

Tizanidine is closely related to clonidine, which is often abused in combination with narcotics and is known to cause symptoms of rebound upon abrupt withdrawal. Three cases of rebound symptoms on sudden withdrawal of tizanidine have been reported. The case reports suggest that these patients were also misusing narcotics.

Withdrawal symptoms included hypertension, tachycardia, hypertonia, tremor, and anxiety. Withdrawal symptoms are more likely to occur in cases where high doses are used, especially for prolonged periods, or with concomitant use of narcotics. If therapy needs to be discontinued, the dose should be decreased slowly to minimize the risk of withdrawal symptoms.

Monkeys were shown to self-administer tizanidine in a dose-dependent manner, and abrupt cessation of tizanidine produced transient signs of withdrawal at doses > 35 times the maximum recommended human dose on a mg/m² basis. These transient withdrawal signs (increased locomotion, body twitching, and aversive behavior toward the observer) were not reversed by naloxone administration.

Summary

Zanaflex (tizanidine) is a skeletal muscle relaxant used to treat and manage skeletal muscle spasticity. Spasticity may be due to multiple sclerosis or spinal cord injury. Common side effects of Zanaflex include low blood pressure (hypotension), dry mouth, dizziness, sleepiness, weakness, fatigue, blurred vision, and constipation. There are no adequate studies done on Zanaflex to determine safe and effective use in pregnant women. It is unknown if Zanaflex enters human milk. Because it is soluble in lipids, it might pass into breast milk. Consult your doctor before breastfeeding.

Treatment & Diagnosis

Medications & Supplements

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Medically Reviewed on 5/13/2020
References
FDA Prescribing Information

Professional side effects and drug interactions sections courtesy of the U.S. Food and Drug Administration.
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