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Zanaflex

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Zanaflex

Zanaflex

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypotension

Tizanidine is an α2-adrenergic agonist that can produce hypotension. Syncope has been reported in the post marketing setting. The chance of significant hypotension may possibly be minimized by titration of the dose and by focusing attention on signs and symptoms of hypotension prior to dose advancement. 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 α2- adrenergic agonists. Clinically significant hypotension (decreases in both systolic and diastolic pressure) has been reported with concomitant administration of either fluvoxamine or ciprofloxacin and single doses of 4 mg of Zanaflex. Therefore, concomitant use of Zanaflex with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated [see CONTRAINDICATIONS and DRUG INTERACTIONS].

Risk of Liver Injury

Zanaflex may cause hepatocellular liver injury. Zanaflex should be used with caution in patients with any hepatic impairment.. Monitoring of aminotransferase levels is recommended for baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected. [see DOSAGE AND ADMINISTRATION and Use In Specific Populations]

Sedation

Zanaflex can cause sedation, which may interfere with everyday activity. In the multiple dose studies, 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 Zanaflex with alcohol and other 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. [see DRUG INTERACTIONS]

Hallucinosis/Psychotic-Like Symptoms

Zanaflex use has been associated with hallucinations. Formed, visual hallucinations or delusions have been 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. Consider discontinuing Zanaflex in patients who develop hallucinations.

Interaction with CYP1A2 Inhibitors

Because of potential drug interactions, Zanaflex is contraindicated in patients taking potent CYP1A2 inhibitors, such as fluvoxamine or ciprofloxacin. Adverse reactions such as hypotension, bradycardia, or excessive drowsiness can occur when Zanaflex is taken with other CYP1A2 inhibitors, such as zileuton, fluoroquinolones other than ciprofloxacin (which is contraindicated), antiarrythmics (amiodarone, mexiletine, propafenone), cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine ). Concomitant use should be avoided unless the necessity for Zanaflex therapy is clinically evident. In such a case, use with caution. [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY]

Hypersensitivity Reactions

Zanaflex can cause anaphylaxis. Signs and symptoms including respiratory compromise, urticaria, and angioedema of the throat and tongue have been reported. Patients should be informed of the signs and symptoms of severe allergic reactions and instructed to discontinue Zanaflex and seek immediate medical care should these signs and symptoms occur. [see CONTRAINDICATIONS]

Increased Risk of Adverse Reactions 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. These patients should be monitored closely for the onset or increase in severity of the common adverse events (dry mouth, somnolence, asthenia and dizziness) as indicators of potential overdose. [see DOSAGE AND ADMINISTRATION and Use In Specific Populations]

Withdrawal Adverse Reactions

Withdrawal adverse reactions include rebound hypertension, tachycardia, and hypertonia. To minimize the risk of these reactions, particularly in patients who have been receiving high doses (20 to 28 mg daily) for long periods of time (9 weeks or more) or who may be on concomitant treatment with narcotics, the dose should be decreased slowly (2 to 4 mg per day). [see DOSAGE AND ADMINISTRATION]

Nonclinical Toxicology

Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenesis

Tizanidine was administered to mice for 78 weeks at oral doses up to 16 mg/kg/day, which is 2 times the maximum recommended human dose (MRHD) on a mg/m² basis. Tizanidine was administered to rats for 104 weeks at oral doses up to 9 mg/kg/day, which is 2.5 times the MRHD on a mg/m² basis. There was no increase in tumors in either species.

Mutagenesis

Tizanidine was negative in in vitro (bacterial reverse mutation [Ames] , mammalian gene mutation, and chromosomal aberration test in mammalian cells) and in vivo (bone marrow micronucleus, and cytogenetics) assay.

Impairment of fertility

Oral administration of tizanidine resulted in reduced fertility in male and female rats following doses of 30 and 10 mg/kg/day, respectively. No effect on fertility was observed at doses of 10 (male) and 3 (female) mg/kg/day, which are approximately 8 and 3 times, respectively, the MRHD on a mg/m² basis).

Use In Specific Populations

Pregnancy

Pregnancy Category C

Zanaflex has not been studied in pregnant women. Zanaflex should be given to pregnant women only if the benefit outweighs the risk to the unborn fetus. Reproduction studies performed in rats at a dose of 3 mg/kg, equal to the maximum recommended human dose on a mg/m² basis, and in rabbits at 30 mg/kg, 16 times the maximum recommended human dose on a mg/m² basis, did not show evidence of teratogenicity. Tizanidine at doses that are equal to and up to 8 times the maximum recommended human dose on a mg/m² basis increased gestation duration in rats. Prenatal and postnatal pup loss was increased and developmental retardation occurred. Post-implantation loss was increased in rabbits at doses of 1 mg/kg or greater, equal to or greater than 0.5 times the maximum recommended human dose on a mg/m² basis.

Nursing mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Zanaflex is administered to a nursing woman.

Pediatric use

Safety and effectiveness in pediatric patients have not been established.

Geriatric use

Zanaflex is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Clinical studies of Zanaflex did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Crossstudy comparison of pharmacokinetic data following single dose administration of 6 mg Zanaflex showed that younger subjects cleared the drug four times faster than the elderly subjects. In elderly patients with renal insufficiency (creatinine clearance < 25 mL/min), tizanidine clearance is reduced by more than 50% compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. During titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. Monitor elderly patients because they may have an increased risk for adverse reactions associated with Zanaflex.

Impaired Renal Function

Zanaflex is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. In patients with renal insufficiency (creatinine clearance < 25 mL/min) clearance was 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. These patients should be monitored closely for the onset or increase in severity of the common adverse events (dry mouth, somnolence, asthenia and dizziness) as indicators of potential overdose. [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]

Impaired Hepatic Function

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 DOSING AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 11/22/2013
This monograph has been modified to include the generic and brand name in many instances.

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