Zanaflex

Indications and Usage ( 1 ) 11/2024 Dosage and Administration ( 2.1 , 2.2 , 2.3 , 2.4 , 2.5 , 2.6 ) 11/2024 Contraindications ( 4 ) 11/2024 Warnings and Precautions ( 5.1 , 5.2 , 5.4 , 5.5 ) 11/2024

1 INDICATIONS AND USAGE Zanaflex is indicated for the treatment of spasticity in adults. Zanaflex is a central alpha-2-adrenergic agonist indicated for the treatment of spasticity. ( 1 )

2 DOSAGE AND ADMINISTRATION Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved. ( 2.1 ) Recommended starting dose: 2 mg by mouth every 6 to 8 hours, as needed, up to a maximum of 3 doses in 24 hours ( 2.2 ) Dosage can be increased by 2 mg to 4 mg per dose every 1 to 4 days; maximum total daily dosage is 36 mg ( 2.2 ) Tizanidine pharmacokinetics differs between tablets and capsules, and when taken with or without food. These differences could result in a change in tolerability and control of symptoms. Consistent administration with respect to food is recommended. If substitution between dosage forms is necessary, take into consideration these pharmacokinetic differences. ( 2.2 , 2.6 , 12.3 ) Patients with renal impairment (creatinine clearance <25 mL/min) or hepatic impairment: use lower individual doses during titration. If higher doses are required, individual doses rather than dosing frequency should be increased. ( 2.3 , 2.4 ) To discontinue Zanaflex, decrease dose slowly to minimize the risk of withdrawal adverse reactions ( 2.5 ) 2.1 Recommended Evaluation and Testing Before and After Initiating Zanaflex Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved [see Warnings and Precautions ( 5.2 )] . 2.2 Recommended Dosage 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 Zanaflex between the fed or fasted state [see Clinical Pharmacology ( 12.3 )] . Zanaflex 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 Zanaflex should be reserved for those daily activities and times when relief of spasticity is most important. 2.3 Recommended Dosage in Patients with Renal Impairment 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 )] . 2.4 Recommended Dosage in Patients with Hepatic Impairment 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 )] . 2.5 Discontinuation of Zanaflex When discontinuing Zanaflex, 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 )] . 2.6 Switching Between With/Without Food and Different Tizanidine Dosage Forms There are pharmacokinetic differences when: switching between administration of Zanaflex with or without food 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 )] .

3 DOSAGE FORMS AND STRENGTHS Capsules 2 mg: Light blue opaque body with a light blue opaque cap with “2 MG” printed on the cap 4 mg: White opaque body with a blue opaque cap with “4 MG” printed on the cap 6 mg: Blue opaque body with a white stripe and blue opaque cap with “6 MG” printed on the cap Tablets 4 mg white, uncoated tablets with a quadrisecting score on one side and debossed with “A594” on the other side Capsules: 2 mg, 4 mg, or 6 mg ( 3 ) Tablets: 4 mg ( 3 )

4 CONTRAINDICATIONS Zanaflex is contraindicated in patients taking strong CYP1A2 inhibitors [see Drug Interactions ( 7.1 )] . with a history of hypersensitivity to tizanidine or the ingredients in Zanaflex. Symptoms have included anaphylaxis and angioedema [see Warnings and Precautions ( 5.5 )] Concomitant use with strong CYP1A2 inhibitors ( 4 , 7.1 ) Patients with a history of hypersensitivity to tizanidine or the ingredients in Zanaflex. ( 4 , 5.5 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in other sections of the prescribing information: Hypotension [see Warnings and Precautions ( 5.1 )] Liver Injury [see Warnings and Precautions ( 5.2 )] Sedation [see Warnings and Precautions ( 5.3 )] Hallucinosis/Psychotic-Like Symptoms [see Warnings and Precautions ( 5.4 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.5 )] Withdrawal Adverse Reactions [see Warnings and Precautions ( 5.6 )] The most common adverse reactions (greater than 10% of patients taking tizanidine and greater than in patients taking placebo) were dry mouth, somnolence, asthenia, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Legacy Pharma Inc. at 1-8007277151 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of 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 Zanaflex 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 Zanaflex) 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 Zanaflex where the frequency in the Zanaflex group was greater than the placebo group. Table 1: Multiple Dose, Placebo-Controlled Studies-Adverse Reactions Reported in >2% of Patients Treated with Zanaflex Tablets and Incidence Greater than Placebo Adverse Reaction Placebo N = 261 % Zanaflex Tablet N = 264 % Dry mouth 10 49 Somnolence 10 48 Asthenia includes weakness, fatigue, and/or tiredness 16 41 Dizziness 4 16 UTI 7 10 Infection 5 6 Liver test abnormality 2 6 Constipation 1 4 Vomiting 0 3 Speech disorder 0 3 Amblyopia (blurred vision) <1 3 Urinary frequency 2 3 Flu syndrome 2 3 Dyskinesia 0 3 Nervousness <1 3 Pharyngitis 1 3 Rhinitis 2 3 In the single dose, placebo-controlled study involving 142 patients with spasticity 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. Table 2: Single Dose, Placebo-Controlled Study-Common Adverse Reactions Reported Adverse Reaction Placebo N = 48 % Zanaflex Tablet, 8mg, N = 45 % Zanaflex Tablet, 16 mg, N = 49 % Somnolence 31 78 92 Dry mouth 35 76 88 Asthenia includes weakness, fatigue, and/or tiredness 40 67 78 Dizziness 4 22 45 Hypotension 0 16 33 Brady …

7 DRUG INTERACTIONS Moderate or weak CYP1A2 inhibitors: avoid concomitant use; may cause hypotension, bradycardia, or excessive drowsiness; if concomitant use is necessary and adverse reactions occur, reduce Zanaflex dosage or discontinue. ( 7.2 , 12.3 ) 7.1 Strong CYP1A2 Inhibitors Concomitant use of Zanaflex 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 )] . 7.2 Moderate or Weak CYP1A2 Inhibitors Concomitant use of Zanaflex 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 Zanaflex dosage or discontinue Zanaflex therapy [see Clinical Pharmacology ( 12.3 )] . 7.3 Oral Contraceptives Concomitant use of Zanaflex 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 Zanaflex therapy [see Clinical Pharmacology ( 12.3 )] . 7.4 Alcohol and Other CNS Depressants Alcohol increases the exposure of tizanidine after administration of Zanaflex. This was associated with an increase in adverse reactions of Zanaflex. Concomitant use of Zanaflex with CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may cause additive CNS depressant effects, including sedation. Monitor patients who take Zanaflex with another CNS depressant for symptoms of excess sedation [see Clinical Pharmacology ( 12.3 )] . 7.5 α 2 -Adrenergic Agonists Concomitant use of Zanaflex with other α2-adrenergic agonists is not recommended because hypotensive effects may be cumulative [see Warnings and Precautions ( 5.1 )] . 7.6 Antihypertensive Medications Concomitant use of Zanaflex with antihypertensive medications may cause additive hypotensive effects [see Warnings and Precautions ( 5.1 )] . Monitor patients who take Zanaflex with antihypertensive medications for hypotension.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ) Geriatric use: Zanaflex should be used with caution in elderly patients because clearance is decreased four-fold ( 8.5 ) 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with use of Zanaflex 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 2 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/m 2 basis, respectively. 8.2 Lactation 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 Zanaflex and any potential adverse effects on the breastfed infant from Zanaflex or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential There are no adequate and well-controlled studies in humans on the effect of Zanaflex on female or male reproductive potential. Oral administration of tizanidine to male and female rats resulted in adverse effects on fertility [see Nonclinical Toxicology ( 13.1 )]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 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. 8.5 Geriatric Use Zanaflex is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impair …

12.1 Mechanism of Action 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.

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

11 DESCRIPTION Zanaflex ® 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 9 H 8 ClN 5 S-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. Zanaflex capsules are for oral administration and contain 2, 4, or 6 mg tizanidine (equivalent to 2.29 mg, 4.58 mg, and 6.87 mg tizanidine hydrochloride, respectively), and the inactive ingredients colorants, gelatin, hypromellose, silicon dioxide, sugar spheres, and titanium dioxide. Zanaflex tablets are for oral administration and contain 4 mg tizanidine (equivalent to 4.58 mg tizanidine hydrochloride), and the inactive ingredients anhydrous lactose, colloidal silicon dioxide, microcrystalline cellulose, and stearic acid. Structural Formula

10 OVERDOSAGE A review of the safety surveillance database revealed cases of intentional and accidental Zanaflex 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Zanaflex Capsules Zanaflex (tizanidine) capsules are two-piece hard gelatin shells containing 2 mg, 4 mg, or 6 mg tizanidine in bottles of 150 capsules available as follows. The 2 mg capsules have a light blue opaque body with a light blue opaque cap with “2 MG” printed on the cap: NDC 83107-001-15 The 4 mg capsules have a white opaque body with a blue opaque cap with “4 MG” printed on the cap: NDC 83107-002-15 The 6 mg capsules have a blue opaque body with a white stripe and blue opaque cap with “6 MG” printed on the capsules: NDC 83107-003-15 Zanaflex Tablets Zanaflex (tizanidine) tablets are uncoated containing 4 mg tizanidine in bottles of 150 tablets. The tablets have a quadrisecting score on one side and are debossed with “A594” on the other side: NDC 83107-004-15. 16.2 Storage and Handling 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.