U.S. flag An official website of the United States government
  1. Home
  2. Drug Databases
  3. Drug Safety-related Labeling Changes

Drug Safety-related Labeling Changes (SrLC)

Get Email Alerts | Guide

ZANAFLEX (NDA-021447)

(TIZANIDINE HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

Download Data

Expand all

11/22/2024 (SUPPL-17)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

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)].

5 Warnings and Precautions

5.1 Hypotension

Additions and/or revisions underlined:

Zanaflex is an ?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 ?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)].

5.2 Liver Injury

Subsection title revised

Additions and/or revisions underlined:

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)].

5.3 Sedation

Additions and/or revisions underlined:

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.

5.4 Hallucinosis/Psychotic-Like Symptoms

Additions and/or revisions underlined:

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.

5.5 Hypersensitivity Reactions

Additions and/or revisions underlined:

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)].

5.6 Withdrawal Adverse Reactions

Additions and/or revisions underlined:

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)].

6 Adverse Reactions

Addition of the following to the bulleted line listing:

  • Withdrawal Adverse Reactions [see Warnings and Precautions (5.6)]

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

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 1 lists 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.

6.2 Postmarketing Experience

Additions and/or revisions underlined:

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

7 Drug Interactions

7.1 Strong CYP1A2 Inhibitors

Subsection title revised

Additions and/or revisions underlined:

Concomitant use of Zanaflex 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 [see Contraindications (4) and Clinical Pharmacology (12.3)].

7.2 Moderate or Weak CYP1A2 Inhibitors

Subsection title revised

Additions and/or revisions underlined:

Concomitant use of Zanaflex with moderate or weak CYP1A2 inhibitors (e.g., zileuton, antiarrhythmics [amiodarone, mexiletine, propafenone, and verapamil], 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 Zanaflex dosage or discontinue Zanaflex therapy [see Clinical Pharmacology (12.3)].

7.3 Oral Contraceptives

Additions and/or revisions underlined:

Concomitant use of Zanaflex with oral contraceptives is not recommended. However, if concomitant use is clinically necessary and adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue Zanaflex therapy [see Clinical Pharmacology (12.3)].

7.4 Alcohol and Other CNS Depressants

Subsection title revised

Additions and/or revisions underlined:

Alcohol increases the exposure of tizanidine after administration of Zanaflex. This was associated with an increase in adverse reactions of Zanaflex. Concomitant use of Zanaflex with CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may cause additive CNS depressant effects, including sedation. Monitor patients who take Zanaflex with another CNS depressant for symptoms of excess sedation [see Clinical Pharmacology (12.3)].

7.6 Antihypertensive Medications

Newly added subsection:

Concomitant use of Zanaflex with antihypertensive medications may cause additive hypotensive effects [see Warnings and Precautions (5.1)]. Monitor patients who take Zanaflex with antihypertensive medications for hypotension.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

Safety and effectiveness in pediatric patients have not been established.

Juvenile Animal Toxicity Data

Oral administration of tizanidine (0, 1, 3, and 10 mg/kg/day) to juvenile rats from postnatal day (PND) 7 through PND 70 resulted in delayed sexual maturation in males at all doses, reduced body weight gain, delayed sexual maturation in females, and bilateral corneal crystals at the mid and high doses. Corneal crystals were still observed at the mid and high doses after a three-week recovery period. Neurobehavioral deficits were observed on a learning and memory task at the high dose. A no-effect dose for adverse effects on postnatal development not identified.

8.6 Renal Impairment

Subsection title revised

Additions and/or revisions underlined:

In patients with renal insufficiency (creatinine clearance < 25 mL/min), clearance of tizanidine was reduced [see Clinical Pharmacology (12.3)]. In these patients, dosage reduction
is recommended [see Dosage and Administration (2.3)]. Because the risk of adverse reactions to Zanaflex may be greater in patients with impaired renal function, monitor these patients closely for the onset or increase in severity of common adverse reactions [see Adverse Reactions (6.1)].

8.7 Hepatic Impairment

Subsection title revised

Additions and/or revisions underlined:

Zanaflex should be used with caution in patients with hepatic impairment. The influence of hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. Because tizanidine is extensively metabolized in the liver, hepatic impairment would be expected to have significant effects on pharmacokinetics of tizanidine [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. In patients with hepatic impairment, dosage reduction is recommended [see Dosage and Administration (2.4)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Hypotension

Warn patients that they may experience hypotension and to be careful when changing from a lying or sitting to a standing position [see Warnings and Precautions (5.1)].

Sedation

Tell patients that Zanaflex may cause them to become sedated or somnolent and they should be careful when performing activities that require alertness, such as driving a vehicle or operating machinery [see Warnings and Precautions (5.3)]. Tell patients that the sedation may be additive when Zanaflex is taken in conjunction with drugs (baclofen, benzodiazepines) or substances (e.g., alcohol) that act as CNS depressants.

Remind patients that if they depend on their spasticity to sustain posture and balance in locomotion, or whenever spasticity is utilized to obtain increased function, that Zanaflex decreases spasticity and caution should be used.

Hypersensitivity Reactions

Inform patients of the signs and symptoms of severe allergic reactions and instruct them to discontinue Zanaflex and seek immediate medical care should these signs and symptoms occur [see Warnings and Precautions (5.5)].

12/18/2020 (SUPPL-15)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

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/m2) 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/m2 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/m2 basis, respectively.

8.2 Lactation

(PLLR conversion)

Risk Summary

There are no data on the presence of tizanidine in human milk, the effects on the breastfed infant, or the effects on human milk production. Animal studies have reported the presence of tizanidine in the milk of lactating animals.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Zanaflex and any potential adverse effects on the breastfed infant from Zanaflex or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

(PLLR conversion)

There are no adequate and well-controlled studies in humans on the effect of Zanaflex on female or male reproductive potential. Oral administration of tizanidine to male and female rats resulted in adverse effects on fertility [see Nonclinical Toxicology (13.1)].