ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in other sections of the prescribing information: Hypotension [see Warnings and Precautions 5.1 )] Liver Injury [see Warnings and Precautions 5.2 )] Sedation [see Warnings and Precautions 5.3 )] Hallucinosis/Psychotic-Like Symptoms [see Warnings and Precautions 5.4 )] Hypersensitivity Reactions [see Warnings and Precautions 5.6 )] Hypotension [see Warnings and Precautions 5.1 )] Liver Injury [see Warnings and Precautions 5.2 )] Sedation [see Warnings and Precautions 5.3 )] Hallucinosis/Psychotic-Like Symptoms [see Warnings and Precautions 5.4 )] Hypersensitivity Reactions [see Warnings and Precautions 5.6 )] The most common adverse reactions (greater than 2% of 264 patients taking tizanidine and greater than in placebo-treated patients in three multiple dose, placebo-controlled studies) were dry mouth, somnolence, asthenia, dizziness, urinary tract infection, constipation, liver function tests abnormal, vomiting, speech disorder, amblyopia, urinary frequency, flu syndrome, SGPT/ALT increased, dyskinesia, nervousness, pharyngitis, and rhinitis (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA,Inc. at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of 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 13-week active treatment period which included 3-week titration phase to the maximum tolerated dose up to 36 mg/day in three divided doses, 9-week plateau phase where the dose of tizanidine was held constant and 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 lists signs and symptoms that were reported in greater than 2% of patients in three multiple dose, placebo-controlled studies who received tizanidine hydrochloride where the frequency in the tizanidine hydrochloride 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 Tizanidine Hydrochloride Tablets Incidence is Greater than Placebo Event Placebo = 261 Tizanidine ydrochloride Tablet = 264 Dry mouth 10 49 Somnolence 10 48 Asthenia 16 41 Dizziness 16 UTI 10 Infection 6 Constipation 4 Liver test abnormality 6 Vomiting 3 Speech disorder 3 Amblyopia (blurred vision) <1 Urinary frequency 3 Flu syndrome 3 Dyskinesia 3 Nervousness <1 Pharyngitis 3 Rhinitis 3(weakness, fatigue, and/or tiredness)In the single dose, placebo-controlled study involving 142 patients with spasticity due to multiple sclerosis (Study 1) [see Clinical Studies 14 )], 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 rate of 2% or less.Table 2: Single Dose, Placebo-Controlled Study--Common Adverse Reactions Reported Event Placebo = 48 Tizanidine ydrochloride Tablet, 8mg, = 45 Tizanidine ydrochloride Tablet, 16 mg, = 49 Somnolence 31 78 92 Dry mouth 35 76 88 Asthenia 40 67 78 Dizziness 22 45 Hypotension 16 33 Bradycardia 2 10(weakness, fatigue, and/or tiredness). 6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of tizanidine hydrochloride. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 postmarketing 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 tizanidine hydrochloride. Based on the information provided regarding these reactions, causal relationship with tizanidine hydrochloride cannot be entirely excluded. The events are listed in order of decreasing clinical significance; severity in the post marketing setting is not reported.Stevens Johnson Syndrome Anaphylactic Reaction Exfoliative Dermatitis Ventricular Tachycardia Hepatitis Convulsion Depression Arthralgia Paresthesia Rash Tremor. Stevens Johnson Syndrome Anaphylactic Reaction Exfoliative Dermatitis Ventricular Tachycardia Hepatitis Convulsion Depression Arthralgia Paresthesia Rash Tremor.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Tizanidine is central alpha-2-adrenergic receptor agonist and presumably reduces spasticity by increasing presynaptic inhibition of motor neurons. The effects of tizanidine are greatest on polysynaptic pathways. The overall effect of these actions is thought to reduce facilitation of spinal motor neurons. 12.3 Pharmacokinetics. Absorption and DistributionFollowing oral administration, tizanidine is essentially completely absorbed. The absolute oral bioavailability of tizanidine is approximately 40% (CV 24%), due to extensive first-pass hepatic metabolism. Tizanidine is extensively distributed throughout the body with mean steady state volume of distribution of 2.4 L/kg (CV 21%) following intravenous administration in healthy adult volunteers. Tizanidine is approximately 30% bound to plasma proteins.Differences Between Tizanidine Hydrochloride Capsules and Tizanidine Hydrochloride TabletsTizanidine hydrochloride capsules and tizanidine hydrochloride tablets are bioequivalent to each other under fasting conditions, but not under fed conditions. single dose of either two mg tablets or two mg capsules was administered under fed and fasting conditions in an open label, four period, randomized crossover study in 96 human volunteers, of whom 81 were eligible for the statistical analysis. Following oral administration of either the tablet or capsule (in the fasted state), peak plasma concentrations of tizanidine occurred 1.0 hours after dosing with half-life of approximately hours. When two mg tablets were administered with food, the mean maximal plasma concentration was increased by approximately 30%, and the median time to peak plasma concentration was increased by 25 minutes, to hour and 25 minutes. In contrast, when two mg capsules were administered with food, the mean maximal plasma concentration was decreased by 20%, the median time to peak plasma concentration was increased to hours. Consequently, the mean Cmax for the capsule when administered with food is approximately 66% the Cmax for the tablet when administered with food.Food also increased the extent of absorption for both the tablets and capsules. The increase with the tablet (~30%) was significantly greater than with the capsule (~10%). Consequently, when each was administered with food, the amount absorbed from the capsule was about 80% of the amount absorbed from the tablet. Administration of the capsule contents sprinkled on applesauce was not bioequivalent to administration of an intact capsule under fasting conditions. Administration of the capsule contents on applesauce resulted in 15%-20% increase in Cmax and AUC of tizanidine and 15 minute decrease in the median lag time and time to peak concentration compared to administration of an intact capsule while fasting.Figure 1: Mean Tizanidine Concentration vs. Time Profiles For Tizanidine Hydrochloride Tablets and Capsules (2 4 mg) Under Fasted and Fed ConditionsMetabolism and ExcretionTizanidine has linear pharmacokinetics over the doses studied in clinical development (1-20 mg). Tizanidine has half-life of approximately 2.5 hours (CV=33%). Approximately 95% of an administered dose is metabolized. The primary cytochrome P450 isoenzyme involved in tizanidine metabolism is CYP1A2. Tizanidine metabolites are not known to be active; their half-lives range from 20 to 40 hours.Following single and multiple oral dosing of 14C-tizanidine, an average of 60% and 20% of total radioactivity was recovered in the urine and feces, respectively.Specific PopulationsAge EffectsNo specific pharmacokinetic study was conducted to investigate age effects. Cross study comparison of pharmacokinetic data following single dose administration of mg tizanidine hydrochloride showed that younger subjects cleared the drug four times faster than the elderly subjects. Tizanidine hydrochloride has not been evaluated in children [see Use in Specific Populations (8.4, 8.5)].Hepatic ImpairmentThe 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. Tizanidine hydrochloride is not recommended in this patient population [see Use in Specific Populations 8.7 )]. Renal ImpairmentTizanidine clearance is reduced by more than 50% in elderly patients with renal insufficiency (creatinine clearance 25 mL/min) compared to healthy elderly subjects; this would be expected to lead to longer duration of clinical effect. Tizanidine hydrochloride should be used with caution in renally impaired patients [see Warnings and Precautions 5.7 and Use in Specific Populations 8.6 )]. Gender EffectsNo specific pharmacokinetic study was conducted to investigate gender effects. Retrospective analysis of pharmacokinetic data, however, following single and multiple dose administration of mg tizanidine hydrochloride showed that gender had no effect on the pharmacokinetics of tizanidine.Race EffectsPharmacokinetic differences due to race have not been studied.Drug InteractionsCYP1A2 InhibitorsThe interaction between tizanidine hydrochloride and either fluvoxamine or ciprofloxacin is most likely due to inhibition of CYP1A2 by fluvoxamine or ciprofloxacin. The effect of fluvoxamine on the pharmacokinetics of single mg dose of tizanidine hydrochloride was studied in 10 healthy subjects. The Cmax, AUC, and half-life of tizanidine increased by 12-fold, 33-fold, and 3-fold, respectively. The effect of ciprofloxacin on the pharmacokinetics of single mg dose of tizanidine hydrochloride was studied in 10 healthy subjects. The Cmax and AUC of tizanidine increased by 7-fold and 10-fold, respectively s ee Contraindications 4 )]. Although there have been no clinical studies evaluating the effects of other CYP1A2 inhibitors on tizanidine, other CYP1A2 inhibitors, such as zileuton, other fluoroquinolones, antiarrhythmics (amiodarone, mexiletine, propafenone and verapamil), cimetidine, famotidine, oral contraceptives, acyclovir and ticlopidine, may also lead to substantial increases in tizanidine blood concentrations [see Warnings and Precautions 5.5 )].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.Oral ContraceptivesNo specific pharmacokinetic study was conducted to investigate interaction between oral contraceptives and tizanidine hydrochloride. Retrospective analysis of population pharmacokinetic data following single and multiple dose administration of mg tizanidine hydrochloride, however, showed that women concurrently taking oral contraceptives had 50% lower clearance of tizanidine compared to women not on oral contraceptives [see Warnings and Precautions (5.5)].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.. Figure 1.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Tizanidines capacity to reduce increased muscle tone associated with spasticity was demonstrated in two adequate and well controlled studies in patients with multiple sclerosis or spinal cord injury (Studies and 2).Single-Dose Study in Patients with Multiple Sclerosis with Spasticity In Study 1, patients with multiple sclerosis were randomized to receive single oral doses of drug or placebo. Patients and assessors were blind to treatment assignment and efforts were made to reduce the likelihood that assessors would become aware indirectly of treatment assignment (e.g., they did not provide direct care to patients and were prohibited from asking questions about side effects). In all, 140 patients received placebo, mg or 16 mg of tizanidine hydrochloride. Response was assessed by physical examination; muscle tone was rated on 5 point scale (Ashworth score), with score of used to describe normal muscle tone. score of indicated slight spastic catch while score of indicated more marked muscle resistance. score of was used to describe considerable increase in tone, making passive movement difficult. muscle immobilized by spasticity was given score of 4. Spasm counts were also collected. Assessments were made at 1, 2, and hours after treatment. statistically significant reduction of the Ashworth score for tizanidine hydrochloride compared to placebo was detected at 1, and hours after treatment. Figure below shows comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale. The greatest reduction in muscle tone was to hours after treatment. By hours after treatment, muscle tone in the and 16 mg tizanidine hydrochloride groups was indistinguishable from muscle tone in placebo treated patients. Within given patient, improvement in muscle tone was correlated with plasma concentration. Plasma concentrations were variable from patient to patient at given dose. Although 16 mg produced larger effect, adverse events including hypotension were more common and more severe than in the mg group. There were no differences in the number of spasms occurring in each group.Figure 2: Single Dose Study--Mean Change in Muscle Tone from Baseline as Measured by the Ashworth Scale +- 95% Confidence Interval (A Negative Ashworth Score Signifies an Improvement in Muscle Tone from Baseline)Seven-Week Study in Patients with Spinal Cord Injury with Spasticity In 7-week study (Study 2), 118 patients with spasticity secondary to spinal cord injury were randomized to either placebo or tizanidine hydrochloride. Steps similar to those taken in the first study were employed to ensure the integrity of blinding.Patients were titrated over weeks up to maximum tolerated dose or 36 mg daily given in three unequal doses (e.g., 10 mg given in the morning and afternoon and 16 mg given at night). Patients were then maintained on their maximally tolerated dose for additional weeks (i.e., maintenance phase). Throughout the maintenance phase, muscle tone was assessed on the Ashworth scale within period of 2.5 hours following either the morning or afternoon dose. The number of daytime spasms was recorded daily by patients.At endpoint (the protocol-specified time of outcome assessment), there was statistically significant reduction in muscle tone and frequency of spasms in the tizanidine hydrochloride treated group compared to placebo. The reduction in muscle tone was not associated with reduction in muscle strength (a desirable outcome) but also did not lead to any consistent advantage of tizanidine hydrochloride treated patients on measures of activities of daily living. Figure below shows comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale.Figure 3: Seven Week Study--Mean Change in Muscle Tone 0.5-2.5 Hours After Dosing as Measured by the Ashworth Scale +- 95% Confidence Interval (A Negative Ashworth Score Signifies an Improvement in MuscleTone from Baseline). Figure 2. Figure 3.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended starting dose: mg; dose can be repeated at to hour intervals, up to maximum of doses in 24 hours (2.1) Dosage can be increased by mg to mg per dose, with to days between increases; total daily dose should not exceed 36 mg (2.1) Tizanidine pharmacokinetics differs between tablets and capsules, and when taken with or without food. These differences could result in change in tolerability and control of symptoms (2.1, 12.3) To discontinue tizanidine hydrochloride, decrease dose slowly to minimize the risk of withdrawal and rebound hypertension, tachycardia, and hypertonia (2.2) Recommended starting dose: mg; dose can be repeated at to hour intervals, up to maximum of doses in 24 hours (2.1) Dosage can be increased by mg to mg per dose, with to days between increases; total daily dose should not exceed 36 mg (2.1) Tizanidine pharmacokinetics differs between tablets and capsules, and when taken with or without food. These differences could result in change in tolerability and control of symptoms (2.1, 12.3) To discontinue tizanidine hydrochloride, decrease dose slowly to minimize the risk of withdrawal and rebound hypertension, tachycardia, and hypertonia (2.2) 2.1 Dosing Information. Tizanidine hydrochloride capsules 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 hydrochloride capsules and tizanidine hydrochloride tablets are bioequivalent to each other under fasting conditions (more than hours after meal), but not under fed conditions (within 30 minutes of 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 mg. Because the effect of tizanidine hydrochloride peaks at approximately to hours post-dose and dissipates between to hours post-dose, treatment can be repeated at to hour intervals, as needed, to maximum of three doses in 24 hours. Dosage can be gradually increased by mg to mg at each dose, with to days between dosage increases, until 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 hydrochloride 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 5.7 )].. 2.3 Dosing in Patients with Hepatic Impairment. Tizanidine hydrochloride 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 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 mg per day) to minimize the risk of withdrawal and rebound hypertension, tachycardia, and hypertonia [see Drug Abuse and Dependence 9.3 )].

DRUG ABUSE AND DEPENDENCE SECTION.

9 DRUG ABUSE AND DEPENDENCE. 9.2 Abuse. Abuse potential was not evaluated in human studies. Rats were able to distinguish tizanidine from saline in standard discrimination paradigm, after training, but failed to generalize the effects of morphine, cocaine, diazepam, or phenobarbital to tizanidine. 9.3 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 [see Dosage and Administration 2.2 )]. Monkeys were shown to self-administer tizanidine in dose-dependent manner, and abrupt cessation of tizanidine produced transient signs of withdrawal at doses 35 times the maximum recommended human dose on mg/m2 basis. These transient withdrawal signs (increased locomotion, body twitching, and aversive behavior toward the observer) were not reversed by naloxone administration.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1 Fluvoxamine. Concomitant use of fluvoxamine and tizanidine hydrochloride is contraindicated. Changes in pharmacokinetics of tizanidine when administered with fluvoxamine resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment s ee Contraindications 4 and Clinical Pharmacology 12.3 )]. 7.2 Ciprofloxacin. Concomitant use of ciprofoxacin and tizanidine hydrochloride is contraindicated. Changes in pharmacokinetics of tizanidine when administered with ciprofloxacin resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment [s ee 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 hydrochloride with other CYP1A2 inhibitors, such as zileuton, fluoroquinolones other than strong CYP1A2 inhibitors (which are contraindicated), antiarrhythmics (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 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 therapy s ee Warnings and Precautions 5.5 and Clinical Pharmacology 12.3 )]. 7.4 Oral Contraceptives Concomitant use of tizanidine hydrochloride with oral contraceptives is not recommended. However, if concomitant use is clinically necessary, initiate tizanidine hydrochloride with single 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 therapy s ee Clinical Pharmacology 12.3 )]. 7.5 Alcohol. Alcohol increases the overall amount of drug in the bloodstream after dose of tizanidine hydrochloride. This was associated with an increase in adverse reactions of tizanidine hydrochloride. The CNS depressant effects of tizanidine hydrochloride and alcohol are additive s ee Clinical Pharmacology 12.3 )]. 7.6 Other CNS Depressants. The sedative effects of tizanidine hydrochloride with CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take tizanidine hydrochloride with another CNS depressant for symptoms of excess sedation s ee Clinical Pharmacology 12.3 )]. 7.7 2-Adrenergic Agonists. Because hypotensive effects may be cumulative, it is not recommended that tizanidine hydrochloride be used with other 2-adrenergic agonists s ee Warnings and Precautions 5.1 )].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Serious Drug InteractionsAdvise patients they should not take tizanidine hydrochloride if they are taking fluvoxamine or ciprofloxacin because of the increased risk of serious adverse reactions including severe lowering of blood pressure and sedation. Instruct patients to inform their physicians or pharmacists when they start or stop taking any medication because of the risks associated with interaction between tizanidine hydrochloride and other medicines.Tizanidine Hydrochloride DosingTell patients to take tizanidine hydrochloride capsules exactly as prescribed (consistently either with or without food) and not to switch between tablets and capsules. Inform patients that they should not take more tizanidine hydrochloride than prescribed because of the risk of adverse events at single doses greater than mg or total daily doses greater than 36 mg. Tell patients that they should not suddenly discontinue tizanidine hydrochloride, because rebound hypertension and tachycardia may occur.Effects of Tizanidine HydrochlorideWarn patients that they may experience hypotension and to be careful when changing from lying or sitting to standing position. Tell patients that tizanidine hydrochloride may cause them to become sedated or somnolent and they should be careful when performing activities that require alertness, such as driving vehicle or operating machinery. Tell patients that the sedation may be additive when tizanidine hydrochloride 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 tizanidine hydrochloride decreases spasticity and caution should be used.Manufactured for:Teva Pharmaceuticals USA, Inc.Parsippany, NJ 07054Revised: February 2021.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption and DistributionFollowing oral administration, tizanidine is essentially completely absorbed. The absolute oral bioavailability of tizanidine is approximately 40% (CV 24%), due to extensive first-pass hepatic metabolism. Tizanidine is extensively distributed throughout the body with mean steady state volume of distribution of 2.4 L/kg (CV 21%) following intravenous administration in healthy adult volunteers. Tizanidine is approximately 30% bound to plasma proteins.Differences Between Tizanidine Hydrochloride Capsules and Tizanidine Hydrochloride TabletsTizanidine hydrochloride capsules and tizanidine hydrochloride tablets are bioequivalent to each other under fasting conditions, but not under fed conditions. single dose of either two mg tablets or two mg capsules was administered under fed and fasting conditions in an open label, four period, randomized crossover study in 96 human volunteers, of whom 81 were eligible for the statistical analysis. Following oral administration of either the tablet or capsule (in the fasted state), peak plasma concentrations of tizanidine occurred 1.0 hours after dosing with half-life of approximately hours. When two mg tablets were administered with food, the mean maximal plasma concentration was increased by approximately 30%, and the median time to peak plasma concentration was increased by 25 minutes, to hour and 25 minutes. In contrast, when two mg capsules were administered with food, the mean maximal plasma concentration was decreased by 20%, the median time to peak plasma concentration was increased to hours. Consequently, the mean Cmax for the capsule when administered with food is approximately 66% the Cmax for the tablet when administered with food.Food also increased the extent of absorption for both the tablets and capsules. The increase with the tablet (~30%) was significantly greater than with the capsule (~10%). Consequently, when each was administered with food, the amount absorbed from the capsule was about 80% of the amount absorbed from the tablet. Administration of the capsule contents sprinkled on applesauce was not bioequivalent to administration of an intact capsule under fasting conditions. Administration of the capsule contents on applesauce resulted in 15%-20% increase in Cmax and AUC of tizanidine and 15 minute decrease in the median lag time and time to peak concentration compared to administration of an intact capsule while fasting.Figure 1: Mean Tizanidine Concentration vs. Time Profiles For Tizanidine Hydrochloride Tablets and Capsules (2 4 mg) Under Fasted and Fed ConditionsMetabolism and ExcretionTizanidine has linear pharmacokinetics over the doses studied in clinical development (1-20 mg). Tizanidine has half-life of approximately 2.5 hours (CV=33%). Approximately 95% of an administered dose is metabolized. The primary cytochrome P450 isoenzyme involved in tizanidine metabolism is CYP1A2. Tizanidine metabolites are not known to be active; their half-lives range from 20 to 40 hours.Following single and multiple oral dosing of 14C-tizanidine, an average of 60% and 20% of total radioactivity was recovered in the urine and feces, respectively.Specific PopulationsAge EffectsNo specific pharmacokinetic study was conducted to investigate age effects. Cross study comparison of pharmacokinetic data following single dose administration of mg tizanidine hydrochloride showed that younger subjects cleared the drug four times faster than the elderly subjects. Tizanidine hydrochloride has not been evaluated in children [see Use in Specific Populations (8.4, 8.5)].Hepatic ImpairmentThe 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. Tizanidine hydrochloride is not recommended in this patient population [see Use in Specific Populations 8.7 )]. Renal ImpairmentTizanidine clearance is reduced by more than 50% in elderly patients with renal insufficiency (creatinine clearance 25 mL/min) compared to healthy elderly subjects; this would be expected to lead to longer duration of clinical effect. Tizanidine hydrochloride should be used with caution in renally impaired patients [see Warnings and Precautions 5.7 and Use in Specific Populations 8.6 )]. Gender EffectsNo specific pharmacokinetic study was conducted to investigate gender effects. Retrospective analysis of pharmacokinetic data, however, following single and multiple dose administration of mg tizanidine hydrochloride showed that gender had no effect on the pharmacokinetics of tizanidine.Race EffectsPharmacokinetic differences due to race have not been studied.Drug InteractionsCYP1A2 InhibitorsThe interaction between tizanidine hydrochloride and either fluvoxamine or ciprofloxacin is most likely due to inhibition of CYP1A2 by fluvoxamine or ciprofloxacin. The effect of fluvoxamine on the pharmacokinetics of single mg dose of tizanidine hydrochloride was studied in 10 healthy subjects. The Cmax, AUC, and half-life of tizanidine increased by 12-fold, 33-fold, and 3-fold, respectively. The effect of ciprofloxacin on the pharmacokinetics of single mg dose of tizanidine hydrochloride was studied in 10 healthy subjects. The Cmax and AUC of tizanidine increased by 7-fold and 10-fold, respectively s ee Contraindications 4 )]. Although there have been no clinical studies evaluating the effects of other CYP1A2 inhibitors on tizanidine, other CYP1A2 inhibitors, such as zileuton, other fluoroquinolones, antiarrhythmics (amiodarone, mexiletine, propafenone and verapamil), cimetidine, famotidine, oral contraceptives, acyclovir and ticlopidine, may also lead to substantial increases in tizanidine blood concentrations [see Warnings and Precautions 5.5 )].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.Oral ContraceptivesNo specific pharmacokinetic study was conducted to investigate interaction between oral contraceptives and tizanidine hydrochloride. Retrospective analysis of population pharmacokinetic data following single and multiple dose administration of mg tizanidine hydrochloride, however, showed that women concurrently taking oral contraceptives had 50% lower clearance of tizanidine compared to women not on oral contraceptives [see Warnings and Precautions (5.5)].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.. Figure 1.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no adequate data on the developmental risk associated with use of tizanidine hydrochloride 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.DataAnimal 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 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. 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 mg/m2 basis.In pre- and postnatal development study in rats, oral administration of tizanidine (3 to 30 mg/kg/day) resulted in increased postnatal offspring mortality. 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 mg/m2 basis, respectively.

SPL UNCLASSIFIED SECTION.

2.1 Dosing Information. Tizanidine hydrochloride capsules 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 hydrochloride capsules and tizanidine hydrochloride tablets are bioequivalent to each other under fasting conditions (more than hours after meal), but not under fed conditions (within 30 minutes of 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 mg. Because the effect of tizanidine hydrochloride peaks at approximately to hours post-dose and dissipates between to hours post-dose, treatment can be repeated at to hour intervals, as needed, to maximum of three doses in 24 hours. Dosage can be gradually increased by mg to mg at each dose, with to days between dosage increases, until 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm (8.1) Geriatric use: Tizanidine hydrochloride should be used with caution in elderly patients because clearance is decreased four-fold (8.5). Pregnancy: Based on animal data, may cause fetal harm (8.1) Geriatric use: Tizanidine hydrochloride should be used with caution in elderly patients because clearance is decreased four-fold (8.5). 8.1 Pregnancy. Risk SummaryThere are no adequate data on the developmental risk associated with use of tizanidine hydrochloride 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.DataAnimal 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 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. 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 mg/m2 basis.In pre- and postnatal development study in rats, oral administration of tizanidine (3 to 30 mg/kg/day) resulted in increased postnatal offspring mortality. 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 mg/m2 basis, respectively.. 8.2 Lactation. Risk SummaryThere 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 mothers clinical need for tizanidine hydrochloride and any potential adverse effects on the breastfed infant from tizanidine hydrochloride or from the underlying maternal condition.. 8.3 Females and Males of Reproductive Potential. There are no adequate and well-controlled studies in humans on the effect of tizanidine hydrochloride 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)]. 8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.. 8.5 Geriatric Use. Tizanidine hydrochloride 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 tizanidine hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Cross-study comparison of pharmacokinetic data following single dose administration of mg tizanidine hydrochloride 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 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 tizanidine hydrochloride.. 8.6 Impaired Renal Function. Tizanidine hydrochloride 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, individual doses should be reduced during titration. 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 tizanidine hydrochloride common adverse events (dry mouth, somnolence, asthenia and dizziness) as indicators of potential overdosage [see Dosage and Administration (2.2), Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)]. 8.7 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. s ee Dosing and Administration 2.3 ), Warnings and Precautions 5.2 ), and Clinical Pharmacology 12.3 )].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypotension: monitor for signs and symptoms of hypotension, in particular in patients receiving concurrent antihypertensives; tizanidine hydrochloride should not be used with other 2-adrenergic agonists (5.1, 7.7) Risk of liver injury: monitor ALTs; discontinue tizanidine hydrochloride if liver injury occurs (5.2) Sedation: Tizanidine hydrochloride may interfere with everyday activities; sedative effects of tizanidine hydrochloride, alcohol, and other CNS depressants are additive (5.3, 7.5, 7.6) Hallucinations: consider discontinuation of tizanidine hydrochloride (5.4) Less potent inhibitors of CYP1A2: may cause hypotension, bradycardia, or excessive drowsiness, use caution if tizanidine hydrochloride is used with less potent inhibitors of CYP1A2, e.g., zileuton, other fluoroquinolones, antiarrhythmics cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine (5.5, 7.3, 12.3) Renal impairment (creatinine clearance 25 mL/min): use tizanidine hydrochloride with caution, and monitor closely for dry mouth, somnolence, asthenia and dizziness as indicators of potential overdose (5.7). Hypotension: monitor for signs and symptoms of hypotension, in particular in patients receiving concurrent antihypertensives; tizanidine hydrochloride should not be used with other 2-adrenergic agonists (5.1, 7.7) Risk of liver injury: monitor ALTs; discontinue tizanidine hydrochloride if liver injury occurs (5.2) Sedation: Tizanidine hydrochloride may interfere with everyday activities; sedative effects of tizanidine hydrochloride, alcohol, and other CNS depressants are additive (5.3, 7.5, 7.6) Hallucinations: consider discontinuation of tizanidine hydrochloride (5.4) Less potent inhibitors of CYP1A2: may cause hypotension, bradycardia, or excessive drowsiness, use caution if tizanidine hydrochloride is used with less potent inhibitors of CYP1A2, e.g., zileuton, other fluoroquinolones, antiarrhythmics cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine (5.5, 7.3, 12.3) Renal impairment (creatinine clearance 25 mL/min): use tizanidine hydrochloride with caution, and monitor closely for dry mouth, somnolence, asthenia and dizziness as indicators of potential overdose (5.7). 5.1 Hypotension. Tizanidine is an 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 supine to fixed upright position may be at increased risk for hypotension and orthostatic effects. Monitor for hypotension when tizanidine hydrochloride is used in patients receiving concurrent antihypertensive therapy. It is not recommended that tizanidine hydrochloride be used with other 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 mg of tizanidine hydrochloride. Therefore, concomitant use of tizanidine hydrochloride with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated [see Contraindications 4 and Drug Interactions 7.1 7.2 )].. 5.2 Risk of Liver Injury. Tizanidine hydrochloride may cause hepatocellular liver injury. Tizanidine hydrochloride should be used with caution in patients with any hepatic impairment. Monitoring of aminotransferase levels is recommended for baseline and month after maximum dose is achieved, or if hepatic injury is suspected see Dosage and Administration 2.3 and Use in Specific Populations 8.7 )]. 5.3 Sedation. Tizanidine hydrochloride 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 hydrochloride with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take tizanidine hydrochloride with another CNS depressant for symptoms of excess sedation. s ee Drug Interactions 7.5 7.6 )] 5.4 Hallucinosis/Psychotic-Like Symptoms. Tizanidine hydrochloride use has been associated with hallucinations. Formed, visual hallucinations or delusions have been reported in 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 continued to have problems for at least weeks following discontinuation of tizanidine. Consider discontinuing tizanidine hydrochloride in patients who develop hallucinations.. 5.5 Interaction with CYP1A2 Inhibitors. Because of potential drug interactions, tizanidine hydrochloride 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 hydrochloride is taken with other CYP1A2 inhibitors, such as zileuton, fluoroquinolones other than ciprofloxacin (which is contraindicated), antiarrhythmics (amiodarone, mexiletine, propafenone), cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine). Concomitant use should be avoided unless the necessity for tizanidine therapy is clinically evident. In such case, use with caution s ee Drug Interactions 7.3 and Clinical Pharmacology 12.3 )]. 5.6 Hypersensitivity Reactions. Tizanidine hydrochloride 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 hydrochloride and seek immediate medical care should these signs and symptoms occur s ee Contraindications 4 )]. 5.7 Increased Risk of Adverse Reactions in Patients with Renal Impairment. Tizanidine hydrochloride 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 s ee Dosage and Administration 2.2 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 mg per day) s ee Dosage and Administration 2.2 )].