Tizanidine for Pain

INDICATIONS AND USAGE Tizanidine Tablets, USP is a central alpha-2-adrenergic agonist indicated for the management of spasticity. Because of the short duration of therapeutic 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(2.1) ]. Tizanidine Tablets, USP is a central alpha-2-adrenergic agonist indicated for the management of spasticity. Because of the short duration of therapeutic 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 (1) ].

DOSAGE & ADMINISTRATION 2.1 Dosing Information Tizanidine Tablets, USP tablets may be prescribed with or without food. Once the formulation has been selected and the decision to take with or without food has been made, this regimen should not be altered. Food has complex effects on tizanidine pharmacokinetics, which differ with the different formulations. Tizanidine Capsules and Tizanidine Tablets, USP are bioequivalent to each other under fasting conditions (more than 3 hours after a meal), but not under fed conditions (within 30 minutes of a meal). These pharmacokinetic differences may result in clinically significant differences when switching administration of tablet and capsules and when switching administration between the fed or fasted state. These changes may result in increased adverse events, or delayed or 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 ( 12.3 ) ]. The recommended starting dose is 2 mg. Because the effect of Tizanidine Tablets, USP peaks at approximately 1 to 2 hours post-dose and dissipates between 3 to 6 hours post-dose, treatment can be repeated at 6 to 8 hour intervals, as needed, to a maximum of three doses in 24 hours. Dosage can be gradually increased by 2 mg to 4 mg at each dose, with 1 to 4 days between dosage increases, until a satisfactory reduction of muscle tone is achieved. The total daily dose should not exceed 36 mg. Single doses greater than 16 mg have not been studied. 2.2 Dosing in Patients with Renal Impairment Tizanidine Tablets, USP 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 [ see Warnings and Precautions ( Error! Hyperlink reference not valid. ) ]. 2.3 Dosing in Patients with Hepatic Impairment Tizanidine Tablets, USP should be used with caution in patients with any hepatic impairment. 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. Monitoring of aminotransferase levels is recommended for baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected. [ see Use in Specific Populations ( 8.7 ) ] 2.4 Drug Discontinuation If therapy needs to be discontinued, particularly in patients who have been receiving high doses (20 mg to 36 mg daily) for long periods (9 weeks or more) or who may be on concomitant treatment with narcotics, the dose should be decreased slowly (2 mg to 4 mg per day) to minimize the risk of withdrawal and rebound hypertension, tachycardia, and hypertonia [ see Drug Abuse and Dependence ( 9.3 )]. • Recommended starting dose: 2 mg; dose can be repeated at 6 to 8 hour intervals, up to a maximum of 3 doses in 24 hours ( Error! Hyperlink reference not valid. ) • Dosage can be increased by 2 mg to 4 mg per dose, with 1 to 4 days between increases; total daily dose should not exceed 36 mg ( Error! Hyperlink reference not valid. ) • Tizanidine pharmacokinetics differs between tablets and capsules, and when taken with or without food. These differences could result in a change in tolerability and control of symptoms ( Error! Hyperlink reference not valid. , 12.3 ) • To discontinue Tizanidine Tablets, USP, decrease dose slowly to minimize the risk of withdrawal and rebound hypertension, tachycardia, and hypertonia ( Error! Hyperlink reference not valid. )

WARNINGS AND PRECAUTIONS 5.1 Hypotension Tizanidine is an α 2 -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 Tizanidine Tablets, USP is used in patients receiving concurrent antihypertensive therapy. It is not recommended that Tizanidine Tablets, USP 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 either fluvoxamine or ciprofloxacin and single doses of 4 mg of Tizanidine Tablets, USP. Therefore, concomitant use of Tizanidine Tablets, USP with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated [ see Contraindications (4) andDrug Interactions ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ) ]. 5.2 Risk of Liver Injury Tizanidine Tablets, USP may cause hepatocellular liver injury. Tizanidine Tablets, USP 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 ( Error! Hyperlink reference not valid. ) and Use in Specific Populations ( 8.7 ) ] 5.3 Sedation Tizanidine Tablets, USP 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 Tizanidine Tablets, USP with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take Tizanidine Tablets, USP with another CNS depressant for symptoms of excess sedation. [ see Drug Interactions ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ) ] 5.4 Hallucinosis/Psychotic-Like Symptoms Tizanidine Tablets, USP 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 Tizanidine Tablets, USP in patients who develop hallucinations. 5.5 Interaction with CYP1A2 Inhibitors Because of potential drug interactions, Tizanidine Tablets, USP 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 Tizanidine Tablets, USP 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 Tizanidine Tablets, USP therapy is clinically evident. In such a case, use with caution. [ see Drug Interactions ( Error! Hyperlink reference not valid. ) and Clinical Pharmacology ( 12.3 ) ] 5.6 Hypersensitivity Reactions Tizanidine Tablets, USP 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 Tizanidine Tablets, USP and seek immediate medical care should these signs and symptoms occur. [ see Contraindications (4) ] 5.7 Increased Risk of Adverse Reactions in Patients with Renal Impairment Tizanidine Tablets, USP 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 ( Error! Hyperlink reference not valid. ) and Use in Specific Populations ( 8.6 ) ] 5.8 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 ( Error! Hyperlink reference not valid. )] • Hypotension: monitor for signs and symptoms of hypotension, in particular in patients receiving concurrent antihypertensives; Tizanidine Tablets, USP should not be used with other α 2 -adrenergic agonists ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ) • Risk of liver injury: monitor ALTs; discontinue Tizanidine Tablets, USP if liver injury occurs ( Error! Hyperlink reference not valid. ) • Sedation: Tizanidine Tablets, USP may interfere with everyday activities; sedative effects of Tizanidine Tablets, USP, alcohol, and other CNS depressants are additive ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ) • Hallucinations: consider discontinuation of Tizanidine Tablets, USP ( Error! Hyperlink reference not valid. ) • Less potent inhibitors of CYP1A2: may cause hypotension, bradycardia, or excessive drowsiness, use caution if Tizanidine Tablets, USP is used with less potent inhibitors of CYP1A2, e.g., zileuton, other fluoroquinolones, antiarrythmics, cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. , 12.3 ) • Renal impairment (creatinine clearance < 25 mL/min): use Tizanidine Tablets, USP with caution, and monitor closely for dry mouth, somnolence, asthenia and dizziness as indicators of potential overdose ( Error! Hyperlink reference not valid. )

DRUG INTERACTIONS 7.1 Fluvoxamine Concomitant use of fluvoxamine and Tizanidine Tablets, USP is contraindicated. Changes in pharmacokinetics of tizanidine when administered with fluvoxamine resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment. [ see Contraindications (4) and Clinical Pharmacology ( 12.3 ) ] 7.2 Ciprofloxacin Concomitant use of ciprofoxacin and Tizanidine Tablets, USP is contraindicated. Changes in pharmacokinetics of tizanidine when administered with ciprofloxacin resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment. [ see Contraindications (4) and Clinical Pharmacology ( 12.3 ) ] 7.3 CYP1A2 Inhibitors other than Fluvoxamine and Ciprofloxacin Because of potential drug interactions, concomitant use of Tizanidine Tablets, USP 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 Tizanidine Tablets, USP therapy. [ see Warnings and Precautions ( Error! Hyperlink reference not valid. ) and Clinical Pharmacology ( 12.3 ) ] 7.4 Oral Contraceptives Concomitant use of Tizanidine Tablets, USP with oral contraceptives is not recommended. However, if concomitant use is clinically necessary, initiate Tizanidine Tablets, USP 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 Tizanidine Tablets, USP therapy. [ see Clinical Pharmacology ( 12.3 ) ] 7.5 Alcohol Alcohol increases the overall amount of drug in the bloodstream after a dose of Tizanidine Tablets, USP. This was associated with an increase in adverse reactions of Tizanidine Tablets, USP. The CNS depressant effects of Tizanidine Tablets, USP and alcohol are additive. [ see Clinical Pharmacology ( 12.3 ) ] 7.6 Other CNS Depressants The sedative effects of Tizanidine Tablets, USP with CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take Tizanidine Tablets, USP with another CNS depressant for symptoms of excess sedation. [ see Clinical Pharmacology ( 12.3 ) ] 7.7 α 2 -adrenergic agonists Because hypotensive effects may be cumulative, it is not recommended that Tizanidine Tablets, USP be used with other α 2 -adrenergic agonists. [ see Warnings and Precautions ( Error! Hyperlink reference not valid. ) ]

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%) 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 fr equently 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 effects 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 (less than 2%) Adverse Events Reports for which Tizanidine Tablets Incidence is Greater than Placebo 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 effects are 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 Other Adverse Events Observed During The Evaluation Of Tizanidine Tizanidine was administered to 1385 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 1385 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 with 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 1/1000 patients, rare adverse events are those occurring in fewer than 1/1000 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