Ontralfy is indicated for the treatment of spasticity in adults.

{ "type": "p", "children": [], "text": "Ontralfy is indicated for the treatment of spasticity in adults." }

Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved [see Warnings and Precautions (5.2)].

The recommended starting dose is 2 mg (5 mL) by mouth every 6 to 8 hours, as needed, to a maximum of three doses in 24 hours.

Dosage can be gradually increased every 1 to 4 days by 2 mg (5 mL) to 4 mg (10 mL) at each dose based on clinical response and tolerability. The maximum total daily dosage is 36 mg (90 mL). Single doses greater than 16 mg (40 mL) have not been studied.

The pharmacokinetics of Ontralfy differ when taken with or without food [see Clinical Pharmacology (12.3)]. Ontralfy may be taken with or without food; however, consistent administration with respect to food is recommended to reduce variability in tizanidine plasma exposure. If administration with respect to food is changed, monitor patients for therapeutic effect or adverse reactions [see Clinical Pharmacology (12.3)].

Because of the short duration of therapeutic effect, treatment with Ontralfy should be reserved for those daily activities and times when relief of spasticity is most important.

In patients with creatinine clearance < 25 mL/min, use lower individual doses during titration. If higher doses are required, the individual doses rather than dosing frequency should be increased [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

In patients with hepatic impairment, use lower individual doses during titration. If higher doses are required, individual doses rather than dosing frequency should be increased [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

When discontinuing Ontralfy, particularly in patients who have been receiving high doses for long periods or who may be on concomitant treatment with narcotics, decrease the dosage by 2 mg (5 mL) to 4 mg (10 mL) per day to minimize the risk of withdrawal adverse reactions [see Drug Abuse and Dependence (9.3)].

Oral Solution: 2 mg/5 mL of tizanidine as a clear, colorless to pale yellow solution with a strawberry flavor.

{ "type": "p", "children": [], "text": "Oral Solution: 2 mg/5 mL of tizanidine as a clear, colorless to pale yellow solution with a strawberry flavor." }

Ontralfy is contraindicated in patients:

{ "type": "p", "children": [], "text": "Ontralfy is contraindicated in patients:" }

{ "type": "ul", "children": [ "taking strong CYP1A2 inhibitors [see Drug Interactions (7.1)].\n", "with a history of hypersensitivity to tizanidine or the ingredients in Ontralfy. Symptoms have included anaphylaxis and angioedema [see Warnings and Precautions (5.5)]\n" ], "text": "" }

Ontralfy is an α2-adrenergic agonist that can produce hypotension [see Adverse Reactions (6.1) and Drug Interactions (7.5)]. Syncope has been reported in patients treated with tizanidine in the postmarketing setting. The risk of hypotension may be minimized by dose titration; monitoring for signs and symptoms of hypotension prior to dosage increase may minimize the risks associated with hypotension. In addition, patients moving from a supine to fixed upright position may be at increased risk for hypotension and orthostatic effects.

Monitor for hypotension when Ontralfy is used in patients receiving concurrent antihypertensive therapy. It is not recommended that Ontralfy be used with other α2-adrenergic agonists. Clinically significant hypotension (decreases in both systolic and diastolic pressure) has been reported with concomitant administration of tizanidine and strong CYP1A2 inhibitors [see Clinical Pharmacology (12.3)]. Therefore, concomitant use of Ontralfy with strong CYP1A2 inhibitors is contraindicated [see Contraindications (4) and Drug Interactions (7.1)].

Ontralfy may cause hepatocellular liver injury. Liver function test abnormality and hepatotoxicity have been observed with tizanidine, the active moiety of Ontralfy [see Adverse Reactions (6.1, 6.2)]. Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected [see Dosage and Administration (2.1) and Use in Specific Populations (8.7)].

Ontralfy can cause sedation, which may interfere with everyday activity. In the multiple dose studies of tizanidine, the prevalence of patients with sedation peaked following the first week of titration and then remained stable for the duration of the maintenance phase of the study [see Adverse Reactions (6.1)]. The CNS depressant effects of Ontralfy with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive [see Drug Interactions (7.4)]. Monitor patients who take Ontralfy with another CNS depressant for symptoms of excess sedation.

Tizanidine use has been associated with hallucinations. Formed, visual hallucinations or delusions were reported in 5 of 170 patients (3%) in two North American controlled clinical studies of tizanidine. Most of the patients were aware that the events were unreal. One patient developed psychosis in association with the hallucinations. One patient among these 5 continued to have problems for at least 2 weeks following discontinuation of tizanidine. Hallucinations have also been reported with tizanidine use in the postmarketing setting. Consider discontinuing Ontralfy in patients who develop hallucinations.

Ontralfy can cause anaphylaxis. Signs and symptoms of hypersensitivity, including respiratory compromise, urticaria, and angioedema of the throat and tongue, have been reported. Ontralfy is contraindicated in patients with a history of hypersensitivity reactions to tizanidine [see Contraindications (4)].

Ontralfy can cause withdrawal adverse reactions, which include rebound hypertension, tachycardia, and hypertonia. To minimize the risk of these reactions, particularly in patients who have been receiving high doses of Ontralfy (20 to 28 mg daily) for long periods of time (9 weeks or more) or who may be on concomitant treatment with narcotics, the Ontralfy dosage should be decreased slowly [see Dosage and Administration (2.5)].

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The safety of Ontralfy has been established from adequate and well-controlled studies of tizanidine tablets in adult patients with spasticity [see Clinical Studies (14)]. Below is a presentation of the adverse reactions of tizanidine tablets in these adequate and well-controlled studies.

The safety of tizanidine has been evaluated in three double-blind, randomized, placebo-controlled clinical studies [see Clinical Studies (14)]. Two studies were conducted in patients with multiple sclerosis and one in patients with spinal cord injury. Each study had a 13-week active treatment period which included a 3-week titration phase to the maximum tolerated dose up to 36 mg/day in three divided doses, a 9-week plateau phase where the dose of tizanidine was held constant and a 1-week dose tapering period. In all, 264 patients received tizanidine and 261 patients received placebo. Across the three studies approximately 51% of patients were women, and the median dose during the plateau phase ranged from 20 to 28 mg/day.

The most common adverse reactions (>10% of patients treated with tizanidine) reported in multiple dose, placebo-controlled clinical studies involving 264 patients with spasticity were dry mouth, somnolence/sedation, asthenia (weakness, fatigue and/or tiredness), and dizziness. Three-quarters of the patients rated the reactions as mild to moderate and one-quarter of the patients rated the reactions as being severe. These adverse reactions appeared to be dose related.

Table 1 lists adverse reactions that were reported in greater than 2% of patients in three multiple dose, placebo-controlled studies who received tizanidine where the frequency in the tizanidine group was greater than the placebo group.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 1: Multiple Dose, Placebo-Controlled Studies Adverse Reactions Reported in &gt;2% of Patients Treated with Tizanidine Tablets and Incidence Greater than Placebo</span> </caption> <col align="left" valign="top" width="34%"/> <col align="center" valign="top" width="33%"/> <col align="center" valign="top" width="33%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" valign="bottom">Adverse Reaction</th><th align="center" class="Rrule">Placebo<br/>N = 261<br/>%</th><th align="center" class="Rrule">Tizanidine<br/>Tablet N = 264<br/>%</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>includes weakness, fatigue, and/or tiredness</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Dry mouth</td><td align="center" class="Rrule">10</td><td align="center" class="Rrule">49</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Somnolence</td><td align="center" class="Rrule">10</td><td align="center" class="Rrule">48</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Asthenia<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">41</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Dizziness</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">16</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">UTI</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">10</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Infection</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">6</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Liver test abnormality</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">6</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Constipation</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Vomiting</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Speech disorder</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Amblyopia (blurred vision)</td><td align="center" class="Rrule">&lt;1</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Urinary frequency</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Flu syndrome</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Dyskinesia</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Nervousness</td><td align="center" class="Rrule">&lt;1</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Pharyngitis</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule">Rhinitis</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">3</td> </tr> </tbody> </table></div>

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 a rate of 2% or less.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 2: Single Dose, Placebo-Controlled Study—Common Adverse Reactions Reported</span> </caption> <col align="left" valign="bottom" width="25%"/> <col align="center" valign="bottom" width="25%"/> <col align="center" valign="bottom" width="25%"/> <col align="center" valign="bottom" width="25%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">Adverse Reaction</th><th align="center" class="Rrule">Placebo<br/>N = 48<br/>%</th><th align="center" class="Rrule">Tizanidine Tablet,<br/>8 mg, N = 45<br/>%</th><th align="center" class="Rrule">Tizanidine Tablet,<br/>16 mg,<br/>N = 49<br/>%</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>includes weakness, fatigue, and/or tiredness</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Somnolence</td><td align="center" class="Rrule">31</td><td align="center" class="Rrule">78</td><td align="center" class="Rrule">92</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Dry mouth</td><td align="center" class="Rrule">35</td><td align="center" class="Rrule">76</td><td align="center" class="Rrule">88</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Asthenia<a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a></td><td align="center" class="Rrule">40</td><td align="center" class="Rrule">67</td><td align="center" class="Rrule">78</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Dizziness</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">22</td><td align="center" class="Rrule">45</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Hypotension</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">33</td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule">Bradycardia</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">10</td> </tr> </tbody> </table></div>

The following adverse reactions have been identified during post approval use of tizanidine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac Disorders: Ventricular tachycardia, decreased blood pressure

Hepatobiliary Disorders: Hepatotoxicity [see Warnings and Precautions (5.2)], hepatitis

Musculoskeletal and Connective Tissue Disorders: arthralgia

Nervous System Disorders: Convulsion, paresthesia, tremor, muscle spasms

Psychiatric Disorders: Hallucinations [see Warnings and Precautions (5.4)], depression

Skin and Subcutaneous Tissue Disorders: Stevens Johnson Syndrome, anaphylactic reaction [see Warnings and Precautions (5.6)], exfoliative dermatitis, rash

Concomitant use of Ontralfy with strong cytochrome P450 1A2 (CYP1A2) inhibitors (e.g., fluvoxamine, ciprofloxacin) is contraindicated. Changes in pharmacokinetics of tizanidine when administered with a strong CYP1A2 inhibitor resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment [see Contraindications (4) and Clinical Pharmacology (12.3)].

Concomitant use of Ontralfy with moderate or weak CYP1A2 inhibitors (e.g., zileuton, antiarrhythmics [amiodarone, mexiletine, propafenone, and verapamil], cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine) should be avoided. If concomitant use is clinically necessary, and adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce Ontralfy dosage or discontinue Ontralfy therapy [see Clinical Pharmacology (12.3)].

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

Alcohol increases the exposure of tizanidine after administration of Ontralfy. This was associated with an increase in adverse reactions of tizanidine.

Concomitant use of Ontralfy with CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may cause additive CNS depressant effects, including sedation. Monitor patients who take Ontralfy with another CNS depressant for symptoms of excess sedation [see Clinical Pharmacology (12.3)].

Concomitant use of Ontralfy with other α2-adrenergic agonists is not recommended because hypotensive effects may be cumulative [see Warnings and Precautions (5.1)].

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

Risk Summary

There are no adequate data on the developmental risk associated with use of tizanidine in pregnant women. In animal studies, administration of tizanidine during pregnancy resulted in developmental toxicity (embryofetal and postnatal offspring mortality and growth deficits) at doses less than those used clinically, which were not associated with maternal toxicity (see Animal Data).

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% - 4% and 15% - 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Animal Data

Oral administration of tizanidine (0.3 to 100 mg/kg/day) to pregnant rats during the period of organogenesis resulted in embryofetal and postnatal offspring mortality and reductions in body weight at doses of 30 mg/kg/day and above. Maternal toxicity was observed at the highest dose tested. The no-effect dose for embryofetal developmental toxicity in rats (3 mg/kg/day) is similar to the maximum recommended human dose (MRHD) of 36 mg/day on a body surface area (mg/m2) basis.

Oral administration of tizanidine (1 to 100 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in embryofetal and postnatal offspring mortality at all doses. Maternal toxicity was observed at the highest dose tested. Oral administration of tizanidine (10 and 30 mg/kg/day) during the perinatal period of pregnancy (2-6 days prior to delivery) resulted in increased postnatal offspring mortality at both doses. A no-effect dose for embryofetal developmental toxicity in rabbit was not identified. The lowest dose tested (1 mg/kg/day) is less than the MRHD on a mg/m2 basis.

In a pre- and postnatal development study in rats, oral administration of tizanidine (3 to 30 mg/kg/day) resulted in increased postnatal offspring mortality. A no-effect dose for pre- and postnatal developmental toxicity was not identified. The lowest dose tested (3 mg/kg/day) is similar to the MRHD on a mg/m2 basis, respectively.

Risk Summary

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

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

There are no adequate and well-controlled studies in humans on the effect of Ontralfy 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)].

Safety and effectiveness in pediatric patients have not been established.

Juvenile Animal Toxicity Data

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

Tizanidine 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 did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Pharmacokinetic data showed that elderly subjects cleared tizanidine slower than the younger subjects [see Clinical Pharmacology (12.3)]. In elderly patients with renal insufficiency (creatinine clearance < 25 mL/min), tizanidine clearance is reduced compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. During titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. Monitor elderly patients because they may have an increased risk for adverse reactions associated with Ontralfy.

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

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

Ontralfy contains tizanidine, which is not a controlled substance.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Abuse potential was not evaluated in human studies. Rats were able to distinguish tizanidine from saline in a standard discrimination paradigm, after training, but failed to generalize the effects of morphine, cocaine, diazepam, or phenobarbital to tizanidine.

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. 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. 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 (2.5)].

Monkeys were shown to self-administer tizanidine in a dose-dependent manner, and abrupt cessation of tizanidine produced transient signs of withdrawal at doses > 35 times the maximum recommended human dose on a mg/m2 basis. These transient withdrawal signs (increased locomotion, body twitching, and aversive behavior toward the observer) were not reversed by naloxone administration.

A review of the safety surveillance database revealed cases of intentional and accidental tizanidine overdose. Some of the cases resulted in fatality and many of the intentional overdoses were with multiple drugs including CNS depressants. The clinical manifestations of tizanidine overdose were consistent with its known pharmacology. In the majority of cases a decrease in sensorium was observed including lethargy, somnolence, confusion and coma. Depressed cardiac function is also observed including most often bradycardia and hypotension. Respiratory depression is another common feature of tizanidine overdose.

{ "type": "p", "children": [], "text": "A review of the safety surveillance database revealed cases of intentional and accidental tizanidine overdose. Some of the cases resulted in fatality and many of the intentional overdoses were with multiple drugs including CNS depressants. The clinical manifestations of tizanidine overdose were consistent with its known pharmacology. In the majority of cases a decrease in sensorium was observed including lethargy, somnolence, confusion and coma. Depressed cardiac function is also observed including most often bradycardia and hypotension. Respiratory depression is another common feature of tizanidine overdose." }

Should overdose occur, ensure the adequacy of an airway and monitor cardiovascular and respiratory function. Dialysis is not likely to be an efficient method of removing tizanidine from the body [see Description (11)]. In general, symptoms resolve within one to three days following discontinuation of tizanidine and administration of appropriate therapy. Because of the similar mechanism of action, symptoms and management of tizanidine overdose are similar to that following clonidine overdose. For the most recent information concerning the management of overdose, contact a poison control center.

{ "type": "p", "children": [], "text": "Should overdose occur, ensure the adequacy of an airway and monitor cardiovascular and respiratory function. Dialysis is not likely to be an efficient method of removing tizanidine from the body [see Description (11)]. In general, symptoms resolve within one to three days following discontinuation of tizanidine and administration of appropriate therapy. Because of the similar mechanism of action, symptoms and management of tizanidine overdose are similar to that following clonidine overdose. For the most recent information concerning the management of overdose, contact a poison control center." }

Ontralfy contains tizanidine hydrochloride as the active ingredient, which is a central alpha2-adrenergic agonist. Its chemical name is 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole monohydrochloride. It has a molecular formula of C9H8ClN5S.HCl and a molecular weight of 290.2. Its structural formula is:

{ "type": "p", "children": [], "text": "Ontralfy contains tizanidine hydrochloride as the active ingredient, which is a central alpha2-adrenergic agonist. Its chemical name is 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole monohydrochloride. It has a molecular formula of C9H8ClN5S.HCl and a molecular weight of 290.2. Its structural formula is:" }

Tizanidine hydrochloride is a white to off-white, fine crystalline powder, which is odorless or with a faint characteristic odor. Tizanidine hydrochloride is slightly soluble in water and methanol; solubility in water decreases as the pH increases.

{ "type": "p", "children": [], "text": "Tizanidine hydrochloride is a white to off-white, fine crystalline powder, which is odorless or with a faint characteristic odor. Tizanidine hydrochloride is slightly soluble in water and methanol; solubility in water decreases as the pH increases." }

Ontralfy is supplied as an oral solution. Each 5 mL contains 2 mg tizanidine (equivalent to 2.29 mg tizanidine hydrochloride), and the inactive ingredients anhydrous citric acid, edetate disodium dihydrate, flavor, methylparaben sodium, propylparaben sodium, purified water, sodium citrate anhydrous, and sucralose. Each 5 mL of Ontralfy contains 2 mg of sodium.

{ "type": "p", "children": [], "text": "Ontralfy is supplied as an oral solution. Each 5 mL contains 2 mg tizanidine (equivalent to 2.29 mg tizanidine hydrochloride), and the inactive ingredients anhydrous citric acid, edetate disodium dihydrate, flavor, methylparaben sodium, propylparaben sodium, purified water, sodium citrate anhydrous, and sucralose. Each 5 mL of Ontralfy contains 2 mg of sodium." }

Tizanidine is a 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.

The CNS depressant effects of tizanidine and alcohol are additive [see Warnings and Precautions (5.3) and Drug Interactions (7.4)].

Tizanidine has linear pharmacokinetics over the doses studied in clinical development [1 mg (half the recommended dosage) to 20 mg]. Ontralfy oral solution has comparable bioavailability to tizanidine oral tablets under fasted and fed conditions and to tizanidine oral capsules under the fed condition.

Absorption

Following 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.

Effect of Food

In a single dose pharmacokinetic study in healthy adult subjects, the administration of Ontralfy following a standardized high-fat, high-calorie breakfast had minimal effect on the Cmax of tizanidine; however, AUC was increased by approximately 33% when compared to dosing under fasting condition. The median Tmax and mean elimination half-life (t1/2) are similar under both fasting and fed conditions.

Distribution

Tizanidine is extensively distributed throughout the body with a 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.

Elimination

Metabolism

Tizanidine has a 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.

Excretion

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 Populations

Geriatric Patients

No specific pharmacokinetic study was conducted to investigate age effects. Cross study comparison of pharmacokinetic data following single dose administration of 6 mg tizanidine showed that elderly subjects cleared the drug four times slower than younger subjects [see Use in Specific Populations (8.5)].

Patients with Hepatic Impairment

The influence of hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. Because tizanidine is extensively metabolized in the liver, hepatic impairment would be expected to have significant effects on pharmacokinetics of tizanidine [see Use in Specific Populations (8.7)].

Patients with Renal Impairment

Tizanidine 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 a longer duration of clinical effect. [see Use in Specific Populations (8.6)].

Gender Effects

No specific pharmacokinetic study was conducted to investigate gender effects. Retrospective analysis of pharmacokinetic data following single and multiple dose administration of 4 mg tizanidine, however, showed that gender had no effect on the pharmacokinetics of tizanidine.

Drug Interactions

CYP1A2 Inhibitors

The effects of coadministration of fluvoxamine or ciprofloxacin, both strong CYP1A2 inhibitors, 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, with coadministration of fluvoxamine. The Cmax and AUC of tizanidine increased by 7-fold and 10-fold, respectively, with coadministration of ciprofloxacin [see Contraindications (4)].

There have been no clinical studies evaluating the effects of other CYP1A2 inhibitors on tizanidine [see Drug Interactions (7.2)].

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 Contraceptives

No specific pharmacokinetic study was conducted to investigate interaction between oral contraceptives and Ontralfy. Retrospective analysis of population pharmacokinetic data following single and multiple dose administration of 4 mg tizanidine, however, showed that women concurrently taking oral contraceptives had 50% lower clearance of tizanidine compared to women not on oral contraceptives [see Drug Interactions (7.3)].

Acetaminophen

Tizanidine delayed the Tmax of acetaminophen by 16 minutes. Acetaminophen did not affect the pharmacokinetics of tizanidine.

Alcohol

Alcohol increased the AUC and Cmax of tizanidine by approximately 20% and 15%, respectively [see Drug Interactions (7.4)].

Carcinogenesis

Tizanidine was administered to mice for 78 weeks at oral doses up to 16 mg/kg/day, which is 2 times the maximum recommended human dose (MRHD) of 36 mg/day on a body surface area (mg/m2) basis. Tizanidine was administered to rats for 104 weeks at oral doses up to 9 mg/kg/day, which is 2.5 times the MRHD on a mg/m2 basis. There was no increase in tumors in either species.

Mutagenesis

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

Impairment of Fertility

Oral administration of tizanidine to rats prior to and during mating and continuing during early pregnancy in females resulted in reduced fertility in male and female rats at doses of 30 and 10 mg/kg/day, respectively. No effect on fertility was observed at doses of 10 (male) and 3 (female) mg/kg/day, which are approximately 3 times and similar to the MRHD, respectively, on a mg/m2 basis.

Single-Dose Study in Patients with Multiple Sclerosis with Spasticity

In Study 1, 140 patients with spasticity caused by multiple sclerosis were randomized to receive single oral doses of 8 mg or 16 mg tizanidine, or placebo. Patients and assessors were blinded 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).

Response was assessed by physical examination; muscle tone was rated on a 5-point scale (Ashworth score) as follows:

Spasm counts were also collected.

Assessments were made at 1, 2, 3 and 6 hours after treatment. A statistically significant reduction of the Ashworth score for tizanidine compared to placebo was detected at 1, 2 and 3 hours after treatment. Figure 1 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale. The greatest reduction in muscle tone was 1 to 2 hours after treatment. By 6 hours after treatment, muscle tone in the 8 mg and 16 mg tizanidine groups was indistinguishable from muscle tone in patients who received placebo. Within a given patient, improvement in muscle tone was correlated with plasma concentration. Plasma concentrations were variable from patient to patient at a given dose. Although 16 mg produced a larger effect, adverse reactions including hypotension were more common and more severe than in the 8 mg group. There were no differences in the number of spasms occurring in each group.

Figure 1: 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 a 7-week study (Study 2), 118 patients with spasticity secondary to spinal cord injury were randomized to either placebo or tizanidine. Steps similar to those taken in the first study were employed to ensure the integrity of blinding.

Patients were titrated over 3 weeks up to a 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 4 additional weeks (i.e., maintenance phase). Throughout the maintenance phase, muscle tone was assessed on the Ashworth scale within a 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 a statistically significant reduction in muscle tone and frequency of spasms in the tizanidine treated group compared to placebo. The reduction in muscle tone was not associated with a reduction in muscle strength (a desirable outcome) but also did not lead to any consistent advantage of tizanidine treated patients on measures of activities of daily living. Figure 2 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale.

Figure 2: 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 Muscle Tone from Baseline)

Ontralfy contains 2 mg/5 mL tizanidine. It is a clear, colorless to pale yellow solution with strawberry flavor and is supplied in bottles of 473 mL with child-resistant closure (NDC 82919-626-16).

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Dispense in containers with child-resistant closure.

Serious Drug Interactions

Advise patients they should not take Ontralfy 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 healthcare providers when they start or stop taking any medication because of the risks associated with interaction between Ontralfy and other medicines [see Contraindications (4) and Drug Interactions (7)].

Ontralfy Dosing and Administration

Tell patients to take Ontralfy exactly as prescribed (consistently either with or without food) [see Dosage and Administration (2.2)]. Inform patients that they should not take more Ontralfy than prescribed because of the risk of adverse events at single doses greater than 8 mg or total daily doses greater than 36 mg. Tell patients that they should not suddenly discontinue Ontralfy, because rebound hypertension and tachycardia may occur [see Warnings and Precautions (5.6)].

Hypotension

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

Sedation

Tell patients that Ontralfy may cause them to become sedated or somnolent and they should be careful when performing activities that require alertness, such as driving a vehicle or operating machinery [see Warnings and Precautions (5.3)]. Tell patients that the sedation may be additive when Ontralfy 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 Ontralfy decreases spasticity and caution should be used.

Hypersensitivity Reactions

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

Manufactured for: Fidelity BioPharma Co., New Haven, CT 065102024 Fidelity BioPharma Co. All rights reserved.

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NDC 82919-626-16

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Ontralfy™(tizanidine oral solution)2 mg/5 mL

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WHERE INNOVATION MATTERS

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16 fl. oz. (473 mL)Rx only

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Tizanidine hydrochloride is a central alpha-2-adrenergic agonist indicated for the management of spasticity. Because of the short duration of therapeutic effect, treatment with tizanidine hydrochloride capsules should be reserved for those daily activities and times when relief of spasticity is most important [see Dosage and Administration ( 2.1)] .

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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 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 hydrochloride capsules 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.

Tizanidine hydrochloride capsules 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)] .

Tizanidine hydrochloride capsules 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)]

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)] .

Capsules

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2 mg: Size 5 Hard gelatin capsule filled with off white to pale yellow granular powder. Cap: Blue opaque, imprinted with " ^" in black ink and Body: Light Blue opaque imprinted with "043" in black ink

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4 mg: Size 3 Hard gelatin capsule filled with off white to pale yellow granular powder. Cap: Blue opaque, imprinted with "^" in black ink and Body: White opaque imprinted with "044" in black ink

{ "type": "p", "children": [], "text": "4 mg: Size 3 Hard gelatin capsule filled with off white to pale yellow granular powder. Cap: Blue opaque, imprinted with \"^\" in black ink and Body: White opaque imprinted with \"044\" in black ink" }

6 mg: Size 2 Hard gelatin capsule filled with off white to pale yellow granular powder. Cap: Blue opaque, imprinted with "^" in black ink and Body: Light blue opaque imprinted with "045" in black ink

{ "type": "p", "children": [], "text": "6 mg: Size 2 Hard gelatin capsule filled with off white to pale yellow granular powder. Cap: Blue opaque, imprinted with \"^\" in black ink and Body: Light blue opaque imprinted with \"045\" in black ink" }

Tizanidine hydrochloride capsules is contraindicated in patients taking potent inhibitors of CYP1A2, such as fluvoxamine or ciprofloxacin [see Drug Interactions ( 7.1, 7.2)] .

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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 is used in patients receiving concurrent antihypertensive therapy. It is not recommended that tizanidine 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. Therefore, concomitant use of tizanidine with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated [see Contraindications ( 4) and Drug Interactions ( 7.1, 7.2)] .

Tizanidine may cause hepatocellular liver injury. Tizanidine 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 ( 2.3) and Use in Specific Populations ( 8.7)]

Tizanidine 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 with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take tizanidine with another CNS depressant for symptoms of excess sedation. [see Drug Interactions ( 7.5, 7.6)]

Tizanidine 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 in patients who develop hallucinations.

Because of potential drug interactions, tizanidine 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 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 therapy is clinically evident. In such a case, use with caution. [see Drug Interactions ( 7.3) and Clinical Pharmacology ( 12.3)]

Tizanidine 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 and seek immediate medical care should these signs and symptoms occur. [see Contraindications ( 4)]

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. [see Dosage and Administration ( 2.2) and Use in Specific Populations ( 8.6)]

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 ( 2.2)]

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

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 a 13-week active treatment period which included a 3-week titration phase to the maximum tolerated dose up to 36 mg/day in three divided doses, a 9-week plateau phase where the dose of tizanidine was held constant and a 1-week dose tapering. 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 1lists 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 greater than the placebo group. For comparison purposes, the corresponding frequency of the event (per 100 patients) among placebo treated patients is also provided.

<div class="scrollingtable"><table cellpadding="3.6pt" width="75%"> <caption> <span>Table 1: Multiple Dose, Placebo-Controlled Studies - Frequent (&gt;2%) Adverse Reactions Reported for Which Tizanidine Tablets Incidence is Greater than Placebo</span> </caption> <col width="43%"/> <col width="20%"/> <col width="23%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>(weakness, fatigue, and/or tiredness)</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule" valign="bottom"> <p class="First"> <span class="Bold">Event</span> </p> </td><td align="center" class="Botrule" valign="bottom"> <p class="First"> <span class="Bold">Placebo <br/> N = 261 <br/> % </span> </p> </td><td align="center" class="Botrule" valign="bottom"> <p class="First"> <span class="Bold">Tizanidine Tablet <br/> N = 264 <br/> % </span> </p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First">Dry mouth</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">49</p> </td> </tr> <tr> <td valign="top"> <p class="First">Somnolence</p> </td><td align="center" valign="top"> <p class="First">10</p> </td><td align="center" valign="top"> <p class="First">48</p> </td> </tr> <tr> <td valign="top"> <p class="First">Asthenia <a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> </p> </td><td align="center" valign="top"> <p class="First">16</p> </td><td align="center" valign="top"> <p class="First">41</p> </td> </tr> <tr> <td valign="top"> <p class="First">Dizziness</p> </td><td align="center" valign="top"> <p class="First">4</p> </td><td align="center" valign="top"> <p class="First">16</p> </td> </tr> <tr> <td valign="top"> <p class="First">UTI</p> </td><td align="center" valign="top"> <p class="First">7</p> </td><td align="center" valign="top"> <p class="First">10</p> </td> </tr> <tr> <td valign="top"> <p class="First">Infection</p> </td><td align="center" valign="top"> <p class="First">5</p> </td><td align="center" valign="top"> <p class="First">6</p> </td> </tr> <tr> <td valign="top"> <p class="First">Constipation</p> </td><td align="center" valign="top"> <p class="First">1</p> </td><td align="center" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td valign="top"> <p class="First">Liver test abnormality</p> </td><td align="center" valign="top"> <p class="First">2</p> </td><td align="center" valign="top"> <p class="First">6</p> </td> </tr> <tr> <td valign="top"> <p class="First">Vomiting</p> </td><td align="center" valign="top"> <p class="First">0</p> </td><td align="center" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td valign="top"> <p class="First">Speech disorder</p> </td><td align="center" valign="top"> <p class="First">0</p> </td><td align="center" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td valign="top"> <p class="First">Amblyopia (blurred vision)</p> </td><td align="center" valign="top"> <p class="First">&lt;1</p> </td><td align="center" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td valign="top"> <p class="First">Urinary frequency</p> </td><td align="center" valign="top"> <p class="First">2</p> </td><td align="center" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td valign="top"> <p class="First">Flu syndrome</p> </td><td align="center" valign="top"> <p class="First">2</p> </td><td align="center" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td valign="top"> <p class="First">Dyskinesia</p> </td><td align="center" valign="top"> <p class="First">0</p> </td><td align="center" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td valign="top"> <p class="First">Nervousness</p> </td><td align="center" valign="top"> <p class="First">&lt;1</p> </td><td align="center" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td valign="top"> <p class="First">Pharyngitis</p> </td><td align="center" valign="top"> <p class="First">1</p> </td><td align="center" valign="top"> <p class="First">3</p> </td> </tr> <tr class="Last"> <td valign="top"> <p class="First">Rhinitis</p> </td><td align="center" valign="top"> <p class="First">2</p> </td><td align="center" valign="top"> <p class="First">3</p> </td> </tr> </tbody> </table></div>

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 a rate of 2% or less.

<div class="scrollingtable"><table cellpadding="3.6pt" width="75%"> <caption> <span>Table 2: Single Dose, Placebo-Controlled Study - Common Adverse Reactions Reported</span> </caption> <col width="25%"/> <col width="16%"/> <col width="23%"/> <col width="21%"/> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>(weakness, fatigue, and/or tiredness)</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule" valign="bottom"> <p class="First"> <span class="Bold">Event</span> </p> </td><td align="center" class="Botrule" valign="bottom"> <p class="First"> <span class="Bold">Placebo <br/> N = 48 <br/> % </span> </p> </td><td align="center" class="Botrule" valign="bottom"> <p class="First"> <span class="Bold">Tizanidine Tablet, <br/> 8mg, N = 45 <br/> % </span> </p> </td><td align="center" class="Botrule" valign="bottom"> <p class="First"> <span class="Bold">Tizanidine Tablet, <br/> 16 mg, N = 49 <br/> % </span> </p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First">Somnolence</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">31</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">78</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">92</p> </td> </tr> <tr> <td valign="top"> <p class="First">Dry mouth</p> </td><td align="center" valign="top"> <p class="First">35</p> </td><td align="center" valign="top"> <p class="First">76</p> </td><td align="center" valign="top"> <p class="First">88</p> </td> </tr> <tr> <td valign="top"> <p class="First">Asthenia <a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a> </p> </td><td align="center" valign="top"> <p class="First">40</p> </td><td align="center" valign="top"> <p class="First">67</p> </td><td align="center" valign="top"> <p class="First">78</p> </td> </tr> <tr> <td valign="top"> <p class="First">Dizziness</p> </td><td align="center" valign="top"> <p class="First">4</p> </td><td align="center" valign="top"> <p class="First">22</p> </td><td align="center" valign="top"> <p class="First">45</p> </td> </tr> <tr> <td valign="top"> <p class="First">Hypotension</p> </td><td align="center" valign="top"> <p class="First">0</p> </td><td align="center" valign="top"> <p class="First">16</p> </td><td align="center" valign="top"> <p class="First">33</p> </td> </tr> <tr class="Last"> <td valign="top"> <p class="First">Bradycardia</p> </td><td align="center" valign="top"> <p class="First">0</p> </td><td align="center" valign="top"> <p class="First">2</p> </td><td align="center" valign="top"> <p class="First">10</p> </td> </tr> </tbody> </table></div>

The following adverse reactions have been identified during post approval use of tizanidine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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 post marketing 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. Based on the information provided regarding these reactions, a causal relationship with tizanidine cannot be entirely excluded. The events are listed in order of decreasing clinical significance; severity in the post marketing setting is not reported.

Concomitant use of fluvoxamine and tizanidine 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)]

Concomitant use of ciprofloxacin and tizanidine 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)] .

Because of potential drug interactions, concomitant use of tizanidine 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 therapy. [see Warnings and Precautions ( 5.5) and Clinical Pharmacology ( 12.3)]

Concomitant use of tizanidine with oral contraceptives is not recommended. However, if concomitant use is clinically necessary, initiate tizanidine 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 therapy. [see Clinical Pharmacology ( 12.3)]

Alcohol increases the overall amount of drug in the bloodstream after a dose of tizanidine. This was associated with an increase in adverse reactions of tizanidine. The CNS depressant effects of tizanidine and alcohol are additive. [see Clinical Pharmacology ( 12.3)]

The sedative effects of tizanidine with CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take tizanidine with another CNS depressant for symptoms of excess sedation. [see Clinical Pharmacology ( 12.3)]

Because hypotensive effects may be cumulative, it is not recommended that tizanidine be used with other α 2-adrenergic agonists. [see Warnings and Precautions ( 5.1)]

Pregnancy Category C

Tizanidine has not been studied in pregnant women. Tizanidine should be given to pregnant women only if the benefit outweighs the risk to the unborn fetus. Reproduction studies performed in rats at a dose of 3 mg/kg, equal to the maximum recommended human dose on a mg/m 2basis, and in rabbits at 30 mg/kg, 16 times the maximum recommended human dose on a mg/m 2basis, 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 2basis 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 2basis.

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

Safety and effectiveness in pediatric patients have not been established.

Tizanidine 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 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 6 mg tizanidine showed that younger subjects cleared the drug four times faster than the elderly subjects. In elderly patients with renal insufficiency (creatinine clearance < 25 mL/min), tizanidine clearance is reduced by more than 50% compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. During titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. Monitor elderly patients because they may have an increased risk for adverse reactions associated with tizanidine.

Tizanidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. In patients with renal insufficiency (creatinine clearance < 25 mL/min) clearance was reduced by more than 50%. In these patients, during titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. These patients should be monitored closely for the onset or increase in severity of the common adverse events (dry mouth, somnolence, asthenia and dizziness) as indicators of potential overdose. [see Dosage and Administration ( 2.2), Warnings and Precautions ( 5.7) and Clinical Pharmacology ( 12.3)] .

The influence of hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. Because tizanidine is extensively metabolized in the liver, hepatic impairment would be expected to have significant effects on pharmacokinetics of tizanidine. [see Dosing and Administration ( 2.3), Warnings and Precautions ( 5.2), and Clinical Pharmacology ( 12.3)] .

Abuse potential was not evaluated in human studies. Rats were able to distinguish tizanidine from saline in a standard discrimination paradigm, after training, but failed to generalize the effects of morphine, cocaine, diazepam, or phenobarbital to tizanidine.

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 a dose-dependent manner, and abrupt cessation of tizanidine produced transient signs of withdrawal at doses > 35 times the maximum recommended human dose on a mg/m 2basis. These transient withdrawal signs (increased locomotion, body twitching, and aversive behavior toward the observer) were not reversed by naloxone administration.

A review of the safety surveillance database revealed cases of intentional and accidental tizanidine overdose. Some of the cases resulted in fatality and many of the intentional overdoses were with multiple drugs including CNS depressants. The clinical manifestations of tizanidine overdose were consistent with its known pharmacology. In the majority of cases a decrease in sensorium was observed including lethargy, somnolence, confusion and coma. Depressed cardiac function is also observed including most often bradycardia and hypotension. Respiratory depression is another common feature of tizanidine overdose.

{ "type": "p", "children": [], "text": "A review of the safety surveillance database revealed cases of intentional and accidental tizanidine overdose. Some of the cases resulted in fatality and many of the intentional overdoses were with multiple drugs including CNS depressants. The clinical manifestations of tizanidine overdose were consistent with its known pharmacology. In the majority of cases a decrease in sensorium was observed including lethargy, somnolence, confusion and coma. Depressed cardiac function is also observed including most often bradycardia and hypotension. Respiratory depression is another common feature of tizanidine overdose." }

Should overdose occur, basic steps to ensure the adequacy of an airway and the monitoring of cardiovascular and respiratory systems should be undertaken. Tizanidine is a lipid-soluble drug, which is only slightly soluble in water and methanol. Therefore, dialysis is not likely to be an efficient method of removing drug from the body. In general, symptoms resolve within one to three days following discontinuation of tizanidine and administration of appropriate therapy. Due to the similar mechanism of action, symptoms and management of tizanidine overdose are similar to that following clonidine overdose. For the most recent information concerning the management of overdose, contact a poison control center.

{ "type": "p", "children": [], "text": "Should overdose occur, basic steps to ensure the adequacy of an airway and the monitoring of cardiovascular and respiratory systems should be undertaken. Tizanidine is a lipid-soluble drug, which is only slightly soluble in water and methanol. Therefore, dialysis is not likely to be an efficient method of removing drug from the body. In general, symptoms resolve within one to three days following discontinuation of tizanidine and administration of appropriate therapy. Due to the similar mechanism of action, symptoms and management of tizanidine overdose are similar to that following clonidine overdose. For the most recent information concerning the management of overdose, contact a poison control center." }

Tizanidine Hydrochloride is a central alpha2-adrenergic agonist. Tizanidine Hydrochloride is a almost white to slightly yellow, crystalline powder. Tizanidine is slightly soluble in water and methanol. Its chemical name is 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole monohydrochloride. Tizanidine’s molecular formula is C 9H 8ClN 5S-HCl, its molecular weight is 290.2 and its structural formula is:

{ "type": "p", "children": [], "text": "Tizanidine Hydrochloride is a central alpha2-adrenergic agonist. Tizanidine Hydrochloride is a almost white to slightly yellow, crystalline powder. Tizanidine is slightly soluble in water and methanol. Its chemical name is 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole monohydrochloride. Tizanidine’s molecular formula is C\n \n 9H\n \n 8ClN\n \n 5S-HCl, its molecular weight is 290.2 and its structural formula is:\n\n " }

Tizanidine Hydrochloride Capsules are supplied as 2, 4, and 6 mg capsules for oral administration. Tizanidine Hydrochloride Capsules contain the active ingredient, tizanidine hydrochloride (2.29 mg equivalent to 2 mg tizanidine base, 4.58 mg equivalent to 4 mg tizanidine base, and 6.87 mg equivalent to 6 mg tizanidine base), and the inactive ingredients, microcrystalline cellulose, lactose monohydrate, hypromellose, colloidal silicon dioxide, croscarmellose sodium, stearic acid, gelatin, titanium dioxide, FD&C Blue 1 and FD&C Red 40. The imprinting ink contains shellac, isopropyl alcohol, propylene glycol, dehydrated alcohol, butyl alcohol, strong ammonia solution, black iron oxide and potassium hydroxide.

{ "type": "p", "children": [], "text": "Tizanidine Hydrochloride Capsules are supplied as 2, 4, and 6 mg capsules for oral administration. Tizanidine Hydrochloride Capsules contain the active ingredient, tizanidine hydrochloride (2.29 mg equivalent to 2 mg tizanidine base, 4.58 mg equivalent to 4 mg tizanidine base, and 6.87 mg equivalent to 6 mg tizanidine base), and the inactive ingredients, microcrystalline cellulose, lactose monohydrate, hypromellose, colloidal silicon dioxide, croscarmellose sodium, stearic acid, gelatin, titanium dioxide, FD&C Blue 1 and FD&C Red 40. The imprinting ink contains shellac, isopropyl alcohol, propylene glycol, dehydrated alcohol, butyl alcohol, strong ammonia solution, black iron oxide and potassium hydroxide." }

Tizanidine is a 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.

Absorption and Distribution

Following 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 a 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 Capsules and Tizanidine Tablets

Tizanidine capsules and tizanidine tablets are bioequivalent to each other under fasting conditions, but not under fed conditions. A single dose of either two 4 mg tablets or two 4 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 hours after dosing with a half-life of approximately 2 hours. When two 4 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 1 hour and 25 minutes. In contrast, when two 4 mg capsules were administered with food, the mean maximal plasma concentration was decreased by 20%, the median time to peak plasma concentration was increased 2 to 3 hours. Consequently, the mean C maxfor the capsule when administered with food is approximately 66% the C maxfor 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 a 15% to 20% increase in C maxand AUC of tizanidine and a 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 Tablets and Tizanidine Capsules (2 X 4 mg) Under Fasted and Fed Conditions

Metabolism and Excretion

Tizanidine has linear pharmacokinetics over the doses studied in clinical development (1–20 mg). Tizanidine has a 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.

Special Populations

Age Effects

No specific pharmacokinetic study was conducted to investigate age effects. Cross study comparison of pharmacokinetic data following single dose administration of 6 mg tizanidine showed that younger subjects cleared the drug four times faster than the elderly subjects. Tizanidine has not been evaluated in children. [see Use in Specific Populations ( 8.4, 8.5)]

Hepatic Impairment

The influence of hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. Because tizanidine is extensively metabolized in the liver, hepatic impairment would be expected to have significant effects on pharmacokinetics of tizanidine. Tizanidine is not recommended in this patient population [see Use in Specific Populations ( 8.7)]

Renal Impairment

Tizanidine 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 a longer duration of clinical effect. Tizanidine should be used with caution in renally impaired patients [see Warnings and Precautions ( 5.7) and Use in Specific Populations ( 8.6)] .

Gender Effects

No specific pharmacokinetic study was conducted to investigate gender effects. Retrospective analysis of pharmacokinetic data, however, following single and multiple dose administration of 4 mg Tizanidine showed that gender had no effect on the pharmacokinetics of tizanidine.

Race Effects

Pharmacokinetic differences due to race have not been studied.

Drug Interactions

CYP1A2 Inhibitors

The interaction between tizanidine 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 a single 4 mg dose of tizanidine was studied in 10 healthy subjects. The C max, AUC, and half-life of tizanidine increased by 12-fold, 33-fold, and 3-fold, respectively. The effect of ciprofloxacin on the pharmacokinetics of a single 4 mg dose of tizanidine was studied in 10 healthy subjects. The C maxand AUC of tizanidine increased by 7-fold and 10-fold, respectively. [see 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, antiarrythmics (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 vitrostudies 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 Contraceptives

No specific pharmacokinetic study was conducted to investigate interaction between oral contraceptives and tizanidine. Retrospective analysis of population pharmacokinetic data following single and multiple dose administration of 4 mg tizanidine, 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 T maxof 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 C maxby approximately 15%. This was associated with an increase in side effects of tizanidine. The CNS depressant effects of tizanidine and alcohol are additive.

Carcinogenesis

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

Mutagenesis

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

Impairment of fertility

Oral administration of tizanidine resulted in reduced fertility in male and female rats following doses of 30 and 10 mg/kg/day, respectively. No effect on fertility was observed at doses of 10 (male) and 3 (female) mg/kg/day, which are approximately 8 and 3 times, respectively, the MRHD on a mg/m 2basis).

Tizanidine’s 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 1 and 2).

{ "type": "p", "children": [], "text": "Tizanidine’s 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 1 and 2)." }

Single-Dose Study in Patients with Multiple Sclerosis with Spasticity

{ "type": "p", "children": [], "text": "\nSingle-Dose Study in Patients with Multiple Sclerosis with Spasticity\n" }

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, 8 mg or 16 mg of tizanidine.

{ "type": "p", "children": [], "text": "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, 8 mg or 16 mg of tizanidine." }

Response was assessed by physical examination; muscle tone was rated on a 5 point scale (Ashworth score), with a score of 0 used to describe normal muscle tone. A score of 1 indicated a slight spastic catch while a score of 2 indicated more marked muscle resistance. A score of 3 was used to describe considerable increase in tone, making passive movement difficult. A muscle immobilized by spasticity was given a score of 4. Spasm counts were also collected.

{ "type": "p", "children": [], "text": "Response was assessed by physical examination; muscle tone was rated on a 5 point scale (Ashworth score), with a score of 0 used to describe normal muscle tone. A score of 1 indicated a slight spastic catch while a score of 2 indicated more marked muscle resistance. A score of 3 was used to describe considerable increase in tone, making passive movement difficult. A muscle immobilized by spasticity was given a score of 4. Spasm counts were also collected." }

Assessments were made at 1, 2, 3 and 6 hours after treatment. A statistically significant reduction of the Ashworth score for tizanidine compared to placebo was detected at 1, 2 and 3 hours after treatment. Figure 2below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale. The greatest reduction in muscle tone was 1 to 2 hours after treatment. By 6 hours after treatment, muscle tone in the 8 and 16 mg tizanidine groups was indistinguishable from muscle tone in placebo treated patients. Within a given patient, improvement in muscle tone was correlated with plasma concentration. Plasma concentrations were variable from patient to patient at a given dose. Although 16 mg produced a larger effect, adverse events including hypotension were more common and more severe than in the 8 mg group. There were no differences in the number of spasms occurring in each group.

{ "type": "p", "children": [], "text": "Assessments were made at 1, 2, 3 and 6 hours after treatment. A statistically significant reduction of the Ashworth score for tizanidine compared to placebo was detected at 1, 2 and 3 hours after treatment.\n \n Figure 2below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale. The greatest reduction in muscle tone was 1 to 2 hours after treatment. By 6 hours after treatment, muscle tone in the 8 and 16 mg tizanidine groups was indistinguishable from muscle tone in placebo treated patients. Within a given patient, improvement in muscle tone was correlated with plasma concentration. Plasma concentrations were variable from patient to patient at a given dose. Although 16 mg produced a larger effect, adverse events including hypotension were more common and more severe than in the 8 mg group. There were no differences in the number of spasms occurring in each group.\n\n " }

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)

{ "type": "p", "children": [], "text": "\nFigure 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)\n" }

Seven-Week Study in Patients with Spinal Cord Injury with Spasticity

{ "type": "p", "children": [], "text": "\nSeven-Week Study in Patients with Spinal Cord Injury with Spasticity\n" }

In a 7-week study (Study 2), 118 patients with spasticity secondary to spinal cord injury were randomized to either placebo or tizanidine. Steps similar to those taken in the first study were employed to ensure the integrity of blinding.

{ "type": "p", "children": [], "text": "In a 7-week study (Study 2), 118 patients with spasticity secondary to spinal cord injury were randomized to either placebo or tizanidine. Steps similar to those taken in the first study were employed to ensure the integrity of blinding." }

Patients were titrated over 3 weeks up to a 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 4 additional weeks (i.e., maintenance phase). Throughout the maintenance phase, muscle tone was assessed on the Ashworth scale within a period of 2.5 hours following either the morning or afternoon dose. The number of daytime spasms was recorded daily by patients.

{ "type": "p", "children": [], "text": "Patients were titrated over 3 weeks up to a 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 4 additional weeks (i.e., maintenance phase). Throughout the maintenance phase, muscle tone was assessed on the Ashworth scale within a 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 a statistically significant reduction in muscle tone and frequency of spasms in the tizanidine treated group compared to placebo. The reduction in muscle tone was not associated with a reduction in muscle strength (a desirable outcome) but also did not lead to any consistent advantage of tizanidine treated patients on measures of activities of daily living. Figure 3below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale.

{ "type": "p", "children": [], "text": "At endpoint (the protocol-specified time of outcome assessment), there was a statistically significant reduction in muscle tone and frequency of spasms in the tizanidine treated group compared to placebo. The reduction in muscle tone was not associated with a reduction in muscle strength (a desirable outcome) but also did not lead to any consistent advantage of tizanidine treated patients on measures of activities of daily living.\n \n Figure 3below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale.\n\n " }

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 Muscle Tone from Baseline)

{ "type": "p", "children": [], "text": "\nFigure 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 Muscle Tone from Baseline)\n" }

Tizanidine Hydrochloride Capsules are available as two-piece hard gelatin capsules containing tizanidine hydrochloride 4.58 mg, equivalent to 4 mg tizanidine base.

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in containers with child resistant closure.

Serious Drug Interactions

{ "type": "p", "children": [], "text": "\nSerious Drug Interactions\n" }

Advise patients they should not take tizanidine 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 and other medicines.

{ "type": "p", "children": [], "text": "Advise patients they should not take tizanidine 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 and other medicines." }

Tizanidine Dosing

{ "type": "p", "children": [], "text": "\nTizanidine Dosing\n" }

Tell patients to take tizanidine 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 than prescribed because of the risk of adverse events at single doses greater than 8 mg or total daily doses greater than 36 mg. Tell patients that they should not suddenly discontinue tizanidine, because rebound hypertension and tachycardia may occur.

{ "type": "p", "children": [], "text": "Tell patients to take tizanidine 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 than prescribed because of the risk of adverse events at single doses greater than 8 mg or total daily doses greater than 36 mg. Tell patients that they should not suddenly discontinue tizanidine, because rebound hypertension and tachycardia may occur." }

Effects of Tizanidine

{ "type": "p", "children": [], "text": "\nEffects of Tizanidine\n" }

Warn patients that they may experience hypotension and to be careful when changing from a lying or sitting to a standing position. Tell patients that tizanidine may cause them to become sedated or somnolent and they should be careful when performing activities that require alertness, such as driving a vehicle or operating machinery. Tell patients 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. 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 decreases spasticity and caution should be used.

{ "type": "p", "children": [], "text": "Warn patients that they may experience hypotension and to be careful when changing from a lying or sitting to a standing position. Tell patients that tizanidine may cause them to become sedated or somnolent and they should be careful when performing activities that require alertness, such as driving a vehicle or operating machinery. Tell patients 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. 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 decreases spasticity and caution should be used." }

Distributed by: Advagen Pharma Ltd 666 Plainsboro Road Suite 605 Plainsboro, NJ 08536, USA.

{ "type": "p", "children": [], "text": "Distributed by: \n Advagen Pharma Ltd \n 666 Plainsboro Road \n Suite 605 \n Plainsboro, NJ 08536, USA.\n " }

Manufactured by: Rubicon Research Private Limited Ambernath, Dist: Thane, 421506 India.

{ "type": "p", "children": [], "text": "Manufactured by: \n Rubicon Research Private Limited \n Ambernath, Dist: Thane, 421506 India.\n " }

Rev. 03,09/2020

{ "type": "p", "children": [], "text": "Rev. 03,09/2020" }

 Tizanidine is indicated for the treatment of spasticity in adults.

Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved [see Warnings and Precautions ( 5.2)] .

The recommended starting dose is 2 mg by mouth every 6 to 8 hours, as needed, to a maximum of three doses in 24 hours. Dosage can be gradually increased every 1 to 4 days by 2 mg to 4 mg at each dose based on clinical response and tolerability. The maximum total daily dosage is 36 mg. Single doses greater than 16 mg have not been studied. There are pharmacokinetic differences when administering Tizanidine between the fed or fasted state [see Clinical Pharmacology ( 12.3)] . Tizanidine may be taken with or without food; however, consistent administration with respect to food is recommended to reduce variability in tizanidine plasma exposure. Because of the short duration of therapeutic effect, treatment with Tizanidine should be reserved for those daily activities and times when relief of spasticity is most important.

In patients with creatinine clearance < 25 mL/min, use lower individual doses during titration. If higher doses are required, the individual doses rather than dosing frequency should be increased [see Use in Specific Populations ( 8.6) and Clinical Pharmacology ( 12.3)] .

In patients with hepatic impairment, use lower individual doses during titration. If higher doses are required, individual doses rather than dosing frequency should be increased [see Use in Specific Populations ( 8.7) and Clinical Pharmacology (12.3)] .

When discontinuing Tizanidine, particularly in patients who have been receiving high doses for long periods or who may be on concomitant treatment with narcotics, decrease the dosage by 2 mg to 4 mg per day to minimize the risk of withdrawal adverse reactions [see Drug Abuse and  Dependence ( 9.3)] .

There are pharmacokinetic differences when: 1) switching between administration of Tizanidine with or without food 2) switching between dosage forms if being administered with food. If these situations occur, monitor patients for therapeutic effect or adverse reactions [see Dosage and Administration ( 2.2) and Clinical Pharmacology ( 12.3)] .

Tablets

Tizanidine tablets USP, 2 mg are white to off-white, round, flat, bevel edged uncoated tablets debossed with "U" and "168" on one side and bisecting score on other side.

Tizanidine tablets USP, 4 mg are white to off-white, round, flat, bevel edged uncoated tablets debossed with "U" and "169" on one side and quadrisecting score on other side.

Tizanidine is contraindicated in patients:           taking strong CYP1A2 inhibitors [see Drug Interactions ( 7.1)].           with a history of hypersensitivity to tizanidine or the ingredients in Tizanidine. Symptoms have included anaphylaxis and angioedema [see Warnings and Precautions ( 5.5)].

Tizanidine is an α2-adrenergic agonist that can produce hypotension [see Adverse Reactions ( 6.1) and Drug Interactions ( 7.5)] . Syncope has been reported in patients treated with tizanidine in the postmarketing setting. The risk of hypotension may be minimized by dose titration; monitoring for signs and symptoms of hypotension prior to dosage increase may minimize the risks associated with hypotension. In addition, patients moving from a supine to fixed upright position may be at increased risk for hypotension and orthostatic effects.

Monitor for hypotension when Tizanidine is used in patients receiving concurrent antihypertensive therapy. It is not recommended that Tizanidine be used with other α2-adrenergic agonists. Clinically significant hypotension (decreases in both systolic and diastolic pressure) has been reported with concomitant administration of tizanidine and strong CYP1A2 inhibitors [see  Clinical Pharmacology ( 12.3)] . Therefore, concomitant use of Tizanidine with strong CYP1A2 inhibitors is contraindicated [see Contraindications ( 4) and Drug Interactions ( 7.1)] . ( 7.1)] .

Tizanidine may cause hepatocellular liver injury. Liver function test abnormality and hepatotoxicity have been observed with Tizanidine [see Adverse Reactions ( 6.1, 6.2)] . Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected [see Dosage and Administration ( 2.1) and Use in Specific Populations ( 8.7)].

Tizanidine can cause sedation, which may interfere with everyday activity. In the multiple dose studies of Tizanidine, the prevalence of patients with sedation peaked following the first week of titration and then remained stable for the duration of the maintenance phase of the study [see Adverse Reactions ( 6.1)] . The CNS depressant effects of tizanidine with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive [see Drug Interactions ( 7.4)] . Monitor patients who take Tizanidine with another CNS depressant for symptoms of excess sedation.

Tizanidine use has been associated with hallucinations. Formed, visual hallucinations or delusions were reported in 5 of 170 patients (3%) in two North American controlled clinical studies. Most of the patients were aware that the events were unreal. One patient developed psychosis in association with the hallucinations. One patient among these 5 continued to have problems for at least 2 weeks following discontinuation of tizanidine. Hallucinations have also been reported with tizanidine use in the postmarketing setting. Consider discontinuing Tizanidine in patients who develop hallucinations.

Tizanidine can cause anaphylaxis. Signs and symptoms of hypersensitivity, including respiratory compromise, urticaria, and angioedema of the throat and tongue, have been reported. Tizanidine is contraindicated in patients with a history of hypersensitivity reactions to tizanidine [see Contraindications ( 4)] .

Tizanidine can cause withdrawal adverse reactions, which include rebound hypertension, tachycardia, and hypertonia. To minimize the risk of these reactions, particularly in patients who have been receiving high doses of Tizanidine (20 to 28 mg daily) for long periods of time (9 weeks or more) or who may be on concomitant treatment with narcotics, the Tizanidine dosage  should be decreased slowly [see Dosage and Administration ( 2.5)].

The following clinically significant adverse reactions are described elsewhere in other sections of the prescribing information:

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

The safety of Tizanidine has been evaluated in three double-blind, randomized, placebo-controlled clinical studies [see Clinical Studies ( 14)] . Two studies were conducted in patients with multiple sclerosis and one in patients with spinal cord injury. Each study had a 13-week active treatment period which included a 3-week titration phase to the maximum tolerated dose up to 36 mg/day in three divided doses, a 9-week plateau phase where the dose of tizanidine was held constant and a 1-week dose tapering period. In all, 264 patients received tizanidine and 261 patients received placebo. Across the three studies approximately 51% of patients were women, and the median dose during the plateau phase ranged from 20 to 28 mg/day.

The most common adverse reactions (>10% of patients treated with Tizanidine) reported in multiple dose, placebo-controlled clinical studies involving 264 patients with spasticity were dry mouth, somnolence/sedation, asthenia (weakness, fatigue and/or tiredness), and dizziness. Three-quarters of the patients rated the reactions as mild to moderate and one-quarter of the patients rated the reactions as being severe. These adverse reactions appeared to be dose related.

Table 1 lists adverse reactions that were reported in greater than 2% of patients in three multiple dose, placebo-controlled studies who received Tizanidine where the frequency in the Tizanidine group was greater than the placebo group.

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 a rate of 2% or less.

<div class="scrollingtable"><table class="Noautorules" width="439"> <caption> <span>Table 1: Multiple Dose, Placebo-Controlled Studies-Adverse Reactions Reported in &gt;2% of Patients Treated with Tizanidine Tablets and Incidence Greater than Placebo</span> </caption> <col width="217"/> <col width="95"/> <col width="127"/> <tfoot> <tr> <td align="left" colspan="3"> <p class="First Footnote">*(includes weakness, fatigue, and/or tiredness)</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold">Adverse Reaction</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold">Placebo</span> <br/> <span class="Bold">N = 261</span> <br/> <span class="Bold"> %</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold">Tizanidine</span><span class="Bold">Tablet N = 264</span> <br/> <span class="Bold">%</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Dry mouth <br/> </td><td align="center" class="Botrule Rrule">10 <br/> </td><td align="center" class="Botrule Rrule">49 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Somnolence <br/> </td><td align="center" class="Botrule Rrule">10 <br/> </td><td align="center" class="Botrule Rrule">48 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Asthenia* <br/> </td><td align="center" class="Botrule Rrule">16 <br/> </td><td align="center" class="Botrule Rrule">41 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Dizziness <br/> </td><td align="center" class="Botrule Rrule">4 <br/> </td><td align="center" class="Botrule Rrule">16 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">UTI <br/> </td><td align="center" class="Botrule Rrule">7 <br/> </td><td align="center" class="Botrule Rrule">10 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Infection <br/> </td><td align="center" class="Botrule Rrule">5 <br/> </td><td align="center" class="Botrule Rrule">6 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Liver test abnormality <br/> </td><td align="center" class="Botrule Rrule">2 <br/> </td><td align="center" class="Botrule Rrule">6 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Constipation <br/> </td><td align="center" class="Botrule Rrule">1 <br/> </td><td align="center" class="Botrule Rrule">4 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Vomiting <br/> </td><td align="center" class="Botrule Rrule">0 <br/> </td><td align="center" class="Botrule Rrule">3 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Speech disorder <br/> </td><td align="center" class="Botrule Rrule">0 <br/> </td><td align="center" class="Botrule Rrule">3 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Amblyopia (blurred vision) <br/> </td><td align="center" class="Botrule Rrule">&lt;1 <br/> </td><td align="center" class="Botrule Rrule">3 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Urinary frequency <br/> </td><td align="center" class="Botrule Rrule">2 <br/> </td><td align="center" class="Botrule Rrule">3 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Flu syndrome <br/> </td><td align="center" class="Botrule Rrule">2 <br/> </td><td align="center" class="Botrule Rrule">3 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Dyskinesia <br/> </td><td align="center" class="Botrule Rrule">0 <br/> </td><td align="center" class="Botrule Rrule">3 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Nervousness <br/> </td><td align="center" class="Botrule Rrule">&lt;1 <br/> </td><td align="center" class="Botrule Rrule">3 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Pharyngitis <br/> </td><td align="center" class="Botrule Rrule">1 <br/> </td><td align="center" class="Botrule Rrule">3 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Rhinitis <br/> </td><td align="center" class="Botrule Rrule">2 <br/> </td><td align="center" class="Botrule Rrule">3 <br/> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table class="Noautorules" width="448"> <caption> <span>Table 2: Single Dose, Placebo-Controlled Study—Common Adverse Reactions Reported</span> </caption> <col width="132"/> <col width="76"/> <col width="120"/> <col width="120"/> <tfoot> <tr> <td align="left" colspan="4"> <p class="First Footnote">*includes weakness, fatigue, and/or tiredness</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold">A</span><span class="Bold">dverse Reaction</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold">Placebo</span> <br/> <span class="Bold">N = 48</span> <br/> <span class="Bold">%</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold">Tizanidine</span><span class="Bold">Tablet, 8mg, N = 45</span> <br/> <span class="Bold">%</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold">Tizanidine</span><span class="Bold">Tablet, 16 mg, N = 49</span> <br/> <span class="Bold">%</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Somnolence <br/> </td><td align="center" class="Botrule Rrule">31 <br/> </td><td align="center" class="Botrule Rrule">78 <br/> </td><td align="center" class="Botrule Rrule">92 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Dry mouth <br/> </td><td align="center" class="Botrule Rrule">35 <br/> </td><td align="center" class="Botrule Rrule">76 <br/> </td><td align="center" class="Botrule Rrule">88 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Asthenia* <br/> </td><td align="center" class="Botrule Rrule">40 <br/> </td><td align="center" class="Botrule Rrule">67 <br/> </td><td align="center" class="Botrule Rrule">78 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Dizziness <br/> </td><td align="center" class="Botrule Rrule">4 <br/> </td><td align="center" class="Botrule Rrule">22 <br/> </td><td align="center" class="Botrule Rrule">45 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Hypotension <br/> </td><td align="center" class="Botrule Rrule">0 <br/> </td><td align="center" class="Botrule Rrule">16 <br/> </td><td align="center" class="Botrule Rrule">33 <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Bradycardia <br/> </td><td align="center" class="Botrule Rrule">0 <br/> </td><td align="center" class="Botrule Rrule">2 <br/> </td><td align="center" class="Botrule Rrule">10 <br/> </td> </tr> </tbody> </table></div>

The following adverse reactions have been identified during post approval use of Tizanidine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac Disorders: Ventricular tachycardia, decreased blood pressure

Hepatobiliary Disorders: Hepatotoxicity [see Warnings and Precautions ( 5.2)] , hepatitis Musculoskeletal and Connective Tissue Disorders: arthralgia

Nervous System Disorders: Convulsion, paresthesia, tremor, muscle spasms

Psychiatric Disorders: Hallucinations [see Warnings and Precautions ( 5.4)] , depression

Skin and Subcutaneous Tissue Disorders: Stevens Johnson Syndrome, anaphylactic reaction [see Warnings and Precautions ( 5.5)] , exfoliative dermatitis, rash

Concomitant use of Tizanidine with strong cytochrome P450 1A2 (CYP1A2) inhibitors (e.g., fluvoxamine, ciprofloxacin) is contraindicated. Changes in pharmacokinetics of tizanidine when administered with a strong CYP1A2 inhibitor resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment [see Contraindications ( 4) and Clinical Pharmacology ( 12.3)] .

Concomitant use of Tizanidine with moderate or weak CYP1A2 inhibitors (e.g., zileuton, antiarrhythmics [amiodarone, mexiletine, propafenone, and verapamil], cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine) should be avoided. If concomitant use is clinically necessary, and adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce Tizanidine dosage or discontinue Tizanidine therapy [see Clinical Pharmacology ( 12.3)] .

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

Alcohol increases the exposure of tizanidine after administration of Tizanidine. This was associated with an increase in adverse reactions of Tizanidine.

Concomitant use of Tizanidine with CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may cause additive CNS depressant effects, including sedation. Monitor patients who take Tizanidine with another CNS depressant for symptoms of excess sedation [see Clinical Pharmacology( 12.3)]

Concomitant use of Tizanidine with other α2-adrenergic agonists is not recommended because hypotensive effects may be cumulative [see Warnings and Precautions ( 5.1)] .

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

Risk Summary

There are no adequate data on the developmental risk associated with use of tizanidine in pregnant women. In animal studies, administration of tizanidine during pregnancy resulted in developmental toxicity (embryofetal and postnatal offspring mortality and growth deficits) at doses less than those used clinically, which were not associated with maternal toxicity (see Animal Data).

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% - 4% and 15% - 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Animal Data

Oral administration of tizanidine (0.3 to 100 mg/kg/day) to pregnant rats during the period of organogenesis resulted in embryofetal and postnatal offspring mortality and reductions in body weight at doses of 30 mg/kg/day and above. Maternal toxicity was observed at the highest dose tested. The no-effect dose for embryofetal developmental toxicity in rats (3 mg/kg/day) is similar to the maximum recommended human dose (MRHD) of 36 mg/day on a body surface area (mg/m 2) basis.

Oral administration of tizanidine (1 to 100 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in embryofetal and postnatal offspring mortality at all doses. Maternal toxicity was observed at the highest dose tested. Oral administration of tizanidine (10 and 30 mg/kg/day) during the perinatal period of pregnancy (2-6 days prior to delivery) resulted in increased postnatal offspring mortality at both doses. A no-effect dose for embryofetal developmental toxicity in rabbit was not identified. The lowest dose tested (1 mg/kg/day) is less than the MRHD on a mg/m 2basis.

In a pre- and postnatal development study in rats, oral administration of tizanidine (3 to 30 mg/kg/day) resulted in increased postnatal offspring mortality. A no-effect dose for pre- and postnatal developmental toxicity was not identified. The lowest dose tested (3 mg/kg/day) is similar to the MRHD on a mg/m 2basis, respectively.

Risk Summary

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

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

There are no adequate and well-controlled studies in humans on the effect of tizanidine 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)].

Safety and effectiveness in pediatric patients have not been established.

Juvenile Animal Toxicity Data

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

Tizanidine 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 did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Pharmacokinetic data showed that younger subjects cleared tizanidine faster than the elderly subjects [see Clinical Pharmacology ( 12.3)] . In elderly patients with renal insufficiency (creatinine clearance <25 mL/min), tizanidine clearance is reduced compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. During titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. Monitor elderly patients because they may have an increased risk for adverse reactions associated with Tizanidine.

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

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

Tizanidine contains tizanidine, which is not a controlled substance.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Abuse potential was not evaluated in human studies. Rats were able to distinguish tizanidine from saline in a standard discrimination paradigm, after training, but failed to generalize the effects of morphine, cocaine, diazepam, or phenobarbital to tizanidine.

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. 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. 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 ( 2.5)].

Monkeys were shown to self-administer tizanidine in a dose-dependent manner, and abrupt cessation of tizanidine produced transient signs of withdrawal at doses > 35 times the maximum recommended human dose on a mg/m 2basis. These transient withdrawal signs (increased locomotion, body twitching, and aversive behavior toward the observer) were not reversed by naloxone administration.

A review of the safety surveillance database revealed cases of intentional and accidental tizanidine overdose. Some of the cases resulted in fatality and many of the intentional overdoses were with multiple drugs including CNS depressants. The clinical manifestations of tizanidine overdose were consistent with its known pharmacology. In the majority of cases a decrease in sensorium was observed including lethargy, somnolence, confusion and coma. Depressed cardiac function is also observed including most often bradycardia and hypotension. Respiratory depression is another common feature of tizanidine overdose.

Should overdose occur, ensure the adequacy of an airway and monitor cardiovascular and respiratory function. Dialysis is not likely to be an efficient method of removing tizanidine from the body [see Description ( 11)] . In general, symptoms resolve within one to three days following discontinuation of tizanidine and administration of appropriate therapy. Because of  the similar mechanism of action, symptoms and management of tizanidine overdose are similar to that following clonidine overdose. For the most recent information concerning the management of overdose, contact a poison control center.

Tizanidine Tablets contains tizanidine hydrochloride as the active ingredient, which is a central alpha 2-adrenergic agonist. Its chemical name is 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3- benzothiadiazole monohydrochloride. It has a molecular formula of C 9H 8ClN 5S-HCl and a molecular weight of 290.2. Its structural formula is:

Tizanidine hydrochloride is a white to off-white, fine crystalline powder, which is odorless or with a faint characteristic odor. Tizanidine hydrochloride is slightly soluble in water and methanol; solubility in water decreases as the pH increases

Tizanidine tablets, are for oral administration and contain 2 or 4 mg tizanidine  (equivalent to 2.288 mg and 4.576 mg tizanidine hydrochloride, respectively), and the inactive ingredients anhydrous lactose, colloidal silicon dioxide, microcrystalline cellulose, and stearic acid.

Tizanidine is a 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.

The CNS depressant effects of tizanidine and alcohol are additive [see Warnings and Precautions ( 5.3) and Drug Interactions ( 7.4)] .

Tizanidine has linear pharmacokinetics over the doses studied in clinical development [1 mg(half the recommended dosage) to 20 mg].

Tizanidine capsules and tablets are bioequivalent to each other under fasting conditions, but not under fed conditions (see Absorption, Effect of Food).

Absorption

Following 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.

Effect of Food

There are pharmacokinetic differences between tizanidine capsules and tizanidine tablets with respect to administration with food.

A single dose of either two 4 mg tablets or two 4 mg capsules was administered under fed and fasting conditions in an open-label, four-period, randomized crossover study in 96 volunteers, of whom 81 were eligible for the statistical analysis. Pharmacokinetics under fed conditions were different than under fasting conditions and vary by dosage form.

Tablets or Capsules – Fasting

Tablets – Fed

Capsules – Fed

Capsule Content Sprinkled on Applesauce

            Compared to administration of an intact capsule while fasting:

Figure 1: Mean Tizanidine Concentration vs. Time Profiles ForTizanidine Tablets and Capsules (2 × 4 mg) Under Fasted and Fed Conditions

Distribution

Tizanidine is extensively distributed throughout the body with a 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.

Elimination

Metabolism

Tizanidine has a 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.

Excretion

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 Populations

Geriatric Patients

No specific pharmacokinetic study was conducted to investigate age effects. Cross study comparison of pharmacokinetic data following single dose administration of 6 mg Tizanidine showed that younger subjects cleared the drug four times faster than the elderly subjects. [see Use in Specific Populations ( 8.5)].

Patients with Hepatic Impairment

The influence of hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. Because tizanidine is extensively metabolized in the liver, hepatic impairment would be expected to have significant effects on pharmacokinetics of tizanidine [see Use in Specific Populations ( 8.7)].

Patients with Renal Impairment

Tizanidine 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 a longer duration of clinical effect [see Use in Specific Populations ( 8.6)].

Gender Effects

No specific pharmacokinetic study was conducted to investigate gender effects. Retrospective analysis of pharmacokinetic data following single and multiple dose administration of 4 mg Tizanidine, however, showed that gender had no effect on the pharmacokinetics of tizanidine.

Drug Interactions

CYP1A2 Inhibitors

The effects of coadministration of fluvoxamine or ciprofloxacin, both strong CYP1A2 inhibitors, 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, with coadministration of fluvoxamine. The Cmax and AUC of tizanidine increased by 7-fold and 10-fold, respectively, with coadministration of ciprofloxacin [see Contraindications ( 4)] .

There have been no clinical studies evaluating the effects of other CYP1A2 inhibitors on

tizanidine [see Drug Interactions ( 7.2)] .

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 Contraceptives

No specific pharmacokinetic study was conducted to investigate interaction between oral contraceptives and Tizanidine. Retrospective analysis of population pharmacokinetic data following single and multiple dose administration of 4 mg Tizanidine, however, showed that women concurrently taking oral contraceptives had 50% lower clearance of tizanidine compared to women not on oral contraceptives [see Drug Interactions  ( 7.3)].

Acetaminophen

Tizanidine delayed the T maxof acetaminophen by 16 minutes. Acetaminophen did not affect the pharmacokinetics of tizanidine.

Alcohol

Alcohol increased the AUC and Cmax of tizanidine by approximately 20% and 15%, respectively [see Drug Interactions ( 7.4)] .

Carcinogenesis

Tizanidine was administered to mice for 78 weeks at oral doses up to 16 mg/kg/day, which is 2 times the maximum recommended human dose (MRHD) of 36 mg/day on a body surface area (mg/m 2) basis.. Tizanidine was administered to rats for 104 weeks at oral doses up to 9 mg/kg/day, which is 2.5 times the MRHD on a mg/m 2basis. There was no increase in tumors in either species.

Mutagenesis

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

Impairment of Fertility

Oral administration of tizanidine to rats prior to and during mating and continuing during early pregnancy in females resulted in reduced fertility in male and female rats at doses of 30 and 10 mg/kg/day, respectively. No effect on fertility was observed at doses of 10 (male) and 3 (female) mg/kg/day, which are approximately 3 times and similar to the MRHD, respectively, on a mg/m 2basis.

The efficacy of Tizanidine for the treatment of spasticity was demonstrated in two adequate and well-controlled studies in patients with multiple sclerosis or spinal cord injury (Studies 1 and 2).

Single-Dose Study in Patients with Multiple Sclerosis with Spasticity

In Study 1, 140 patients with spasticity caused by multiple sclerosis were randomized to receive single oral doses of 8 mg or 16 mg of Tizanidine, or placebo. Patients and assessors were blinded 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).

Response was assessed by physical examination; muscle tone was rated on a 5-point scale (Ashworth score) as follows:

Spasm counts were also collected. Assessments were made at 1, 2, 3 and 6 hours after treatment. A statistically significant reduction of the Ashworth score for Tizanidine compared to placebo was detected at 1, 2, and 3 hours after treatment. Figure 2 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale. The greatest reduction in muscle tone was 1 to 2 hours after treatment. By 6 hours after treatment, muscle tone in the 8 mg and 16 mg Tizanidine groups was indistinguishable from muscle tone in patients who received placebo. Within a given patient, improvement in muscle tone was correlated with plasma concentration. Plasma concentrations were variable from patient to patient at a given dose. Although 16 mg produced a larger effect, adverse reactions including hypotension were more common and more severe than in the 8 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 a 7-week study (Study 2), 118 patients with spasticity secondary to spinal cord injury were randomized to either placebo or tizanidine. Steps similar to those taken in the first study were employed to ensure the integrity of blinding.

Patients were titrated over 3 weeks up to a 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 4 additional weeks (i.e., maintenance phase). Throughout the maintenance phase, muscle tone was assessed on the Ashworth scale within a 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 a statistically significant reduction in muscle tone and frequency of spasms in the tizanidine treated group compared to placebo. The reduction in muscle tone was not associated with a reduction in muscle strength (a desirable outcome) but also did not lead to any consistent advantage of tizanidine treated patients on measures of activities of daily living. Figure 3 below shows a 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 Muscle Tone from Baseline)

Tizanidine tablets, USP are available as white to off-white, round, flat, bevel edged uncoated tablets containing 4 mg of tizanidine.

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Tizanidine tablets USP,  4 mg white to off white, round, flat, beveledged uncoated tablet with "U" on one side and "169" debossed on one side and quadrisecting score on other side.

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NDC: 70518-1598-00

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NDC: 70518-1598-01

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NDC: 70518-1598-02

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NDC: 70518-1598-03

{ "type": "p", "children": [], "text": "NDC: 70518-1598-03" }

NDC: 70518-1598-04

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PACKAGING: 30 in 1 BLISTER PACK

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PACKAGING: 60 in 1 BOTTLE PLASTIC

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PACKAGING: 15 in 1 BOTTLE PLASTIC

{ "type": "p", "children": [], "text": "PACKAGING: 15 in 1 BOTTLE PLASTIC" }

PACKAGING: 30 in 1 BOTTLE PLASTIC

{ "type": "p", "children": [], "text": "PACKAGING: 30 in 1 BOTTLE PLASTIC" }

PACKAGING: 90 in 1 BOTTLE PLASTIC

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Store at 20° - 25°C (68° - 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F)  [see USP Controlled Room Temperature].

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Dispense in tight, light-resistant container [see USP].

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Repackaged and Distributed By:

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Remedy Repack, Inc.

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625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

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Serious Drug Interactions

Advise patients they should not take Tizanidine 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 healthcare providers when they start or stop taking any medication because of the risks associated with interaction between Tizanidine and other medicines [see Contraindications ( 4) and Drug Interactions ( 7)] .

Tizanidine Dosing and Administration

Tell patients to take Tizanidine exactly as prescribed (consistently either with or without food) and not to switch between tablets and capsules [see Dosage and Administration ( 2)] . Inform patients that they should not take more Tizanidine than prescribed because of the risk of adverse events at single doses greater than 8 mg or total daily doses greater than 36 mg. Tell patients that they should not suddenly discontinue Tizanidine, because rebound hypertension and tachycardia may occur [see Warnings and Precautions ( 5.6)] .

Hypotension

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

Sedation

Tell patients that Tizanidine may cause them to become sedated or somnolent and they should be careful when performing activities that require alertness, such as driving a vehicle or operating machinery [see Warnings and Precautions ( 5.3)] . Tell patients that the sedation may be additive when Tizanidine 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 decreases spasticity and caution should be used.

Hypersensitivity Reactions

Inform patients of the signs and symptoms of severe allergic reactions and instruct them to discontinue Tizanidine and seek immediate medical care should these signs and symptoms occur

[see Warnings and Precautions ( 5.5)] .

Manufactured by:

UNICHEM LABORATORIES LTD.

Pilerne Ind. Estate,

Pilerne, Bardez, Goa 403511, India

Manufactured for:

East Brunswick, NJ 08816

01-R-05/2025

13016355

DRUG: Tizanidine

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GENERIC: Tizanidine

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DOSAGE: TABLET

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ADMINSTRATION: ORAL

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NDC: 70518-1598-0

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NDC: 70518-1598-1

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NDC: 70518-1598-2

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NDC: 70518-1598-3

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NDC: 70518-1598-4

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COLOR: white

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SHAPE: ROUND

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SCORE: Four equal pieces

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SIZE: 10 mm

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IMPRINT: U;169

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PACKAGING: 30 in 1 BLISTER PACK

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PACKAGING: 60 in 1 BOTTLE PLASTIC

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PACKAGING: 15 in 1 BOTTLE PLASTIC

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PACKAGING: 30 in 1 BOTTLE PLASTIC

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PACKAGING: 90 in 1 BOTTLE PLASTIC

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ACTIVE INGREDIENT(S):

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INACTIVE INGREDIENT(S):

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{ "type": "ul", "children": [ "ANHYDROUS LACTOSE", "CELLULOSE, MICROCRYSTALLINE", "SILICON DIOXIDE", "STEARIC ACID" ], "text": "" }