Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 06 November 2017


INDICATIONS AND USAGE Tizanidine tablets USP is a short-acting drug for the management of spasticity. Because of the short duration of effect, treatment with tizanidine tablets USP should be reserved for those daily activities and times when relief of spasticity is most important (see DOSAGE AND ADMINISTRATION ).

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Advisory information

CONTRAINDICATIONS Concomitant use of tizanidine with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated. Significant alterations of pharmacokinetic parameters of tizanidine including increased AUC, t 1/2, C max, increased oral bioavailability and decreased plasma clearance have been observed with concomitant administration of either fluvoxamine or ciprofloxacin. This pharmacokinetic interaction can result in potentially serious adverse events (see WARNINGS and CLINICAL PHARMACOLOGY, Drug Interactions ). Tizanidine is contraindicated in patients with known hypersensitivity to tizanidine or its ingredients.
Special warnings and precautions
PRECAUTIONS Cardiovascular Prolongation of the QT interval and bradycardia were noted in chronic toxicity studies in dogs at doses equal to the maximum human dose on a mg/m 2 basis. ECG evaluation was not performed in the controlled clinical studies. Reduction in pulse rate has been noted in association with decreases in blood pressure in the single dose controlled study (see WARNINGS ). Ophthalmic Dose-related retinal degeneration and corneal opacities have been found in animal studies at doses equivalent to approximately the maximum recommended dose on a mg/m 2 basis. There have been no reports of corneal opacities or retinal degeneration in the clinical studies. Use in Renally Impaired Patients Tizanidine 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. Use in Women Taking Oral Contraceptives Because drug interaction studies of tizanidine with oral contraceptives have shown that concomitant use may reduce the clearance of tizanidine by as much as 50%, concomitant use of tizanidine with oral contraceptives should ordinarily be avoided (see CLINICAL PHARMACOLOGY, Drug Interactions). However, if concomitant use is clinically necessary, the starting dose and subsequent titration rate of tizanidine should be reduced. Discontinuing Therapy If therapy needs to be discontinued, particularly in patients who have been receiving high doses for long periods, the dose should be decreased slowly to minimize the risk of withdrawal and rebound hypertension, tachycardia, and hypertonia. Information for Patients Because of the possibility of tizanidine lowering blood pressure, patients should be warned about the risk of clinically significant orthostatic hypotension (see WARNINGS). Because of the possibility of sedation, patients should be warned about performing activities requiring alertness, such as driving a vehicle or operating machinery (see WARNINGS). Patients should also be instructed that the sedation may be additive when tizanidine is taken in conjunction with drugs (baclofen, benzodiazepines) or substances (e.g., alcohol) that act as CNS depressants. Patients should be advised of the change in the absorption profile of tizanidine if taken with food and the potential changes in efficacy and adverse effect profiles that may result (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Patients should be advised not to stop tizanidine suddenly as rebound hypertension and tachycardia may occur (see PRECAUTIONS, Discontinuing Therapy). Tizanidine should be used with caution where spasticity is utilized to sustain posture and balance in locomotion or whenever spasticity is utilized to obtain increased function. Because of the potential for the increased risk of serious adverse reactions including severe lowering of blood pressure and sedation when tizanidine and either fluvoxamine or ciprofloxacin are used together, tizanidine should not be used with either fluvoxamine or ciprofloxacin. Because of the potential for interaction with other CYP1A2 inhibitors, patients should be instructed to inform their physicians and pharmacists when any medication is added or removed from their regimen. Drug Interactions In vitro studies of cytochrome P450 isoenzymes using human liver microsomes indicate that neither tizanidine nor the major metabolites are likely to affect the metabolism of other drugs metabolized by cytochrome P450 isoenzymes. Fluvoxamine The effect of fluvoxamine on the pharmacokinetics of a single 4 mg dose of tizanidine was studied in 10 healthy subjects. The Cmax, AUC, and half-life of tizanidine increased by 12-fold, 33-fold, and 3-fold, respectively. These changes resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment (see CONTRAINDICATIONS and WARNINGS). Ciprofloxacin The effect of ciprofloxacin on the pharmacokinetics of a single 4 mg dose of tizanidine was studied in 10 healthy subjects. The Cmax and AUC of tizanidine increased by 7-fold and 10-fold, respectively. These changes resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment (see CONTRAINDICATIONS and WARNINGS). CYP1A2 inhibitors The interaction between tizanidine and either fluvoxamine or ciprofloxacin is most likely due to inhibition of CYP1A2 by fluvoxamine or ciprofloxacin. Although there have been no clinical studies evaluating the effects of other CYP1A2 inhibitors on tizanidine, other CYP1A2 inhibitors, including zileuton, other fluroquinolones, antiarrythmics (amiodarone, mexiletine, propafenone, and verapamil), cimetidine and famotidine, oral contraceptives, acyclovir, and ticlopidine may also lead to substantial increases in tizanidine blood concentrations. Concomitant use of tizanidine with CYP1A2 inhibitors should ordinarily be avoided. If their use is clinically necessary, they should be used with caution (see WARNINGS). Acetaminophen Tizanidine delayed the Tmax of acetaminophen by 16 minutes. Acetaminophen did not affect the pharmacokinetics of tizanidine. Alcohol Alcohol increased the AUC of tizanidine by approximately 20%, while also increasing its Cmax by approximately 15%. This was associated with an increase in side effects of tizanidine. The CNS depressant effects of tizanidine and alcohol are additive. Oral Contraceptives No specific pharmacokinetic study was conducted to investigate interaction between oral contraceptives and tizanidine, but retrospective analysis of population pharmacokinetic data following single and multiple dose administration of 4 mg tizanidine showed that women concurrently taking oral contraceptives had 50% lower clearance of tizanidine than women not on oral contraceptives. Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence for carcinogenicity was seen in two dietary studies in rodents. Tizanidine was administered to mice for 78 weeks at doses up to 16 mg/kg, which is equivalent to 2 times the maximum recommended human dose on a mg/m 2 basis. Tizanidine was also administered to rats for 104 weeks at doses up to 9 mg/kg, which is equivalent to 2.5 times the maximum recommended human dose on a mg/m 2 basis. There was no statistically significant increase in tumors in either species. Tizanidine was not mutagenic or clastogenic in the following in vitro assays: the bacterial Ames test and the mammalian gene mutation test and chromosomal aberration test in Chinese hamster cells. It was also negative in the following in vivo assays: the bone marrow micronucleus test in mice, the bone marrow micronucleus and cytogenicity test in Chinese hamsters, the dominant lethal mutagenicity test in mice, and the unscheduled DNA synthesis (UDS) test in mice. Tizanidine did not affect fertility in male rats at doses of 10 mg/kg, approximately 2.7 times the maximum recommended human dose on a mg/m 2 basis, and in females at doses of 3 mg/kg, approximately equal to the maximum recommended human dose on a mg/m 2 basis; fertility was reduced in males receiving 30 mg/kg (8 times the maximum recommended human dose on a mg/m 2 basis) and in females receiving 10 mg/kg (2.7 times the maximum recommended human dose on a mg/m 2 basis). At these doses, maternal behavioral effects and clinical signs were observed including marked sedation, weight loss, and ataxia. Pregnancy Pregnancy Category C Reproduction studies performed in rats at a dose of 3 mg/kg, equal to the maximum recommended human dose on a mg/m 2 basis, and in rabbits at 30 mg/kg, 16 times the maximum recommended human dose on a mg/m 2 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/m 2 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/m 2 basis. Tizanidine has not been studied in pregnant women. Tizanidine should be given to pregnant women only if clearly needed. Labor and Delivery The effect of tizanidine on labor and delivery in humans is unknown. Nursing Mothers It is not known whether tizanidine is excreted in human milk, although as a lipid soluble drug, it might be expected to pass into breast milk. Geriatric Use Tizanidine should be used with caution in elderly patients because clearance is decreased four-fold. Pediatric Use There are no adequate and well-controlled studies to document the safety and efficacy of tizanidine in children.
Adverse reactions
ADVERSE REACTIONS In multiple dose, placebo-controlled clinical studies, 264 patients were treated with tizanidine and 261 with placebo. Adverse events, including severe adverse events, were more frequently reported with tizanidine than with placebo. Common Adverse Events Leading to Discontinuation Forty-five of 264 (17%) patients receiving tizanidine and 13 of 261 (5%) of patients receiving placebo in three multiple dose, placebo-controlled clinical studies, discontinued treatment for adverse events. When patients withdrew from the study, they frequently had more than one reason for discontinuing. The adverse events most frequently leading to withdrawal of tizanidine treated patients in the controlled clinical studies were asthenia (weakness, fatigue and/or tiredness) (3%), somnolence (3%), dry mouth (3%), increased spasm or tone (2%), and dizziness (2%). Most Frequent Adverse Clinical Events Seen in Association with the Use of Tizanidine In multiple dose, placebo-controlled clinical studies involving 264 patients with spasticity, the most frequent adverse events 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. Adverse Events Reported in Controlled Studies The events cited reflect experience gained under closely monitored conditions of clinical studies in a highly selected patient population. In actual clinical practice or in other clinical studies, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Table 1 lists treatment emergent signs and symptoms 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 at least as common as in the placebo group. These events are not necessarily related to tizanidine treatment. 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 Events Reported for Which Tizanidine Incidence is Greater Than Placebo Event Placebo N=261 % Tizanidine N=264 % Dry Mouth 10 49 Somnolence 10 48 Asthenia 16 41 Dizziness 4 16 UTI 7 10 Infection 5 6 Constipation 1 4 Liver function tests abnormal <1 3 Vomiting 0 3 Speech disorder 0 3 Amblyopia (blurred vision) <1 3 Urinary frequency 2 3 Flu symptom 2 3 SGPT/ALT increased <1 3 Dyskinesia 0 3 Nervousness <1 3 Pharyngitis 1 3 Rhinitis 2 3 In the single dose, placebo-controlled study involving 142 patients with spasticity, the patients were specifically asked if they had experienced any of the four most common adverse events: dry mouth, somnolence (drowsiness), asthenia (weakness, fatigue and/or tiredness) and dizziness. In addition, hypotension and bradycardia were observed. The occurrence of these adverse events 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 Events Reported Event Placebo N=48 % Tizanidine , 8 mg N=45 % Tizanidine , 16 mg N=49 % Somnolence Dry mouth Asthenia Dizziness Hypotension Bradycardia 31 35 40 4 0 0 78 76 67 22 16 2 92 88 78 45 33 10 Other Adverse Events Observed During the Evaluation of Tizanidine Tizanidine was administered to 1,385 patients in additional clinical studies where adverse event information was available. The conditions and duration of exposure varied greatly, and included (in overlapping categories) double-blind and open-label studies, uncontrolled and controlled studies, inpatient and outpatient studies, and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based dictionary terminology. The frequencies presented, therefore, represent the proportion of the 1,385 patients exposed to tizanidine who experienced an event of the type cited on at least one occasion while receiving tizanidine. All reported events are included except those already listed in Table 1. If the COSTART term for an event was so general as to be uninformative, it was replaced by a more informative term. It is important to emphasize that, although the events reported occurred during treatment with tizanidine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled studies appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare adverse events are those occurring in fewer than 1/1,000 patients. Body as a Whole: Frequent : fever; Infrequent: allergic reaction, moniliasis, malaise, abscess, neck pain, sepsis, cellulitis, death, overdose; Rare: carcinoma, congenital anomaly, suicide attempt. Cardiovascular System: Infrequent : vasodilatation, postural hypotension, syncope, migraine, arrhythmia; Rare: angina pectoris, coronary artery disorder, heart failure, myocardial infarct, phlebitis, pulmonary embolus, ventricular extrasystoles, ventricular tachycardia. Digestive System: Frequent : abdomen pain, diarrhea, dyspepsia; Infrequent: dysphagia, cholelithiasis, fecal impaction, flatulence, gastrointestinal hemorrhage, hepatitis, melena; Rare: gastroenteritis, hematemesis, hepatoma, intestinal obstruction, liver damage. Hemic and Lymphatic System: Infrequent : ecchymosis, hypercholesteremia, anemia, hyperlipemia, leukopenia, leukocytosis, sepsis; Rare: petechia, purpura, thrombocythemia, thrombocytopenia. Metabolic and Nutritional System: Infrequent : edema, hypothyroidism, weight loss; Rare: adrenal cortex insufficiency, hyperglycemia, hypokalemia, hyponatremia, hypoproteinemia, respiratory acidosis. Musculoskeletal System: Frequent: myasthenia, back pain; Infrequent: pathological fracture, arthralgia, arthritis, bursitis. Nervous System: Frequent : depression, anxiety, paresthesia; Infrequent: tremor, emotional lability, convulsion, paralysis, thinking abnormal, vertigo, abnormal dreams, agitation, depersonalization, euphoria, migraine, stupor, dysautonomia, neuralgia; Rare: dementia, hemiplegia, neuropathy. Respiratory System: Infrequent : sinusitis, pneumonia, bronchitis; Rare: asthma. Skin and Appendages: Frequent : rash, sweating, skin ulcer; Infrequent: pruritus, dry skin, acne, alopecia, urticaria; Rare: exfoliative dermatitis, herpes simplex, herpes zoster, skin carcinoma. Special Senses: Infrequent : ear pain, tinnitus, deafness, glaucoma, conjunctivitis, eye pain, optic neuritis, otitis media, retinal hemorrhage, visual field defect; Rare: iritis, keratitis, optic atrophy. Urogenital System: Infrequent: urinary urgency, cystitis, menorrhagia, pyelonephritis, urinary retention, kidney calculus, uterine fibroids enlarged, vaginal moniliasis, vaginitis; Rare: albuminuria, glycosuria, hematuria, metrorrhagia.

Usage information

Dosing and administration
DOSAGE AND ADMINISTRATION A single dose of 8 mg of tizanidine reduces muscle tone in patients with spasticity for a period of several hours. The effect peaks at approximately 1 to 2 hours and dissipates between 3 to 6 hours. Effects are dose-related. Although single doses of less than 8 mg have not been demonstrated to be effective in controlled clinical studies, the dose-related nature of tizanidine’s common adverse events make it prudent to begin treatment with single oral doses of 4 mg. Increase the dose gradually (2 mg to 4 mg steps) to optimum effect (satisfactory reduction of muscle tone at a tolerated dose). The dose can be repeated at 6 to 8 hour intervals, as needed, to a maximum of three doses in 24 hours. The total daily dose should not exceed 36 mg. Experience with single doses exceeding 8 mg and daily doses exceeding 24 mg is limited. There is essentially no experience with repeated, single, daytime doses greater than 12 mg or total daily doses greater than 36 mg (see WARNINGS ). Food has complex effects on tizanidine pharmacokinetics, which differ with the different formulations. These pharmacokinetic differences may result in clinically significant differences when [1] switching administration of the tablet between the fed or fasted state, [2] switching administration of the capsule between the fed or fasted state, [3] switching between the tablet and capsule in the fed state, or [4] switching between the intact capsule and sprinkling the contents of the capsule on applesauce. These changes may result in increased adverse events or delayed/more rapid onset of activity, depending upon the nature of the switch. For this reason, the prescriber should be thoroughly familiar with the changes in kinetics associated with these different conditions (see CLINICAL PHARMACOLOGY, Pharmacokinetics ).

More information

Category Value
Authorisation number ANDA076280
Orphan designation No
Product NDC 43063-237
Date Last Revised 26-10-2017
RXCUI 313413
Marketing authorisation holder PD-Rx Pharmaceuticals, Inc.