tizanidine hydrochloride

Recent Major Changes - Recent Major Changes Indications and Usage (1) 02/2025 Dosage and Administration (2.1, 2.2, 2.3, 2.4, 2.5, 2.6) 02/2025 Contraindications (4) 02/2025 Warnings and Precautions (5.1, 5.2, 5.4, 5.5) 02/2025

1 INDICATIONS AND USAGE 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 )] . 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. ( 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 tizanidine hydrochloride capsules, decrease dose slowly to minimize the risk of withdrawal adverse reactions (2.5) 2.1 Recommended Evaluation and Testing Before and After Initiating Tizanidine Hydrochloride Capsules 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 tizanidine hydrochloride capsules between the fed or fasted state [see Clinical Pharmacology (12.3)]. Tizanidine hydrochloride capsules 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 hydrochloride capsules 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 Tizanidine Hydrochloride Capsules When discontinuing tizanidine hydrochloride capsules, 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: 1) switching between administration of tizanidine hydrochloride capsules 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)].

3 DOSAGE FORMS AND STRENGTHS Capsules 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 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 8 mg: Size 2 Hard gelatin capsule filled with off white to pale yellow granular powder. Cap: Blue opaque imprinted with "Λ" in black ink and Body: White opaque, imprinted with "A46" in black ink • Capsules: 2 mg, 4 mg, 6 mg or 8 mg ( 3 )

4 CONTRAINDICATIONS Tizanidine Hydrochloride Capsules are contraindicated in patients: taking strong CYP1A2 inhibitors [see Drug Interactions ( 7.1 )]. with a history of hypersensitivity to tizanidine or the ingredients in tizanidine hydrochloride capsules. 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 tizanidine hydrochloride capsules ( 4 , 5.5 )

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in other sections of the prescribing information: Hypotension [ see Warnings and Precautions (5.1 )] Liver Injury [ see Warnings and Precautions (5.2) ] Sedation [ see Warnings and Precautions (5.3) ] Hallucinosis/Psychotic-Like Symptoms [ see Warnings and Precautions (5.4) ] Hypersensitivity Reactions [ see Warnings and Precautions (5.6) ] The most common adverse reactions (greater than 2% of 264 patients taking tizanidine and greater than in placebo-treated patients in three multiple dose, placebo-controlled studies) were dry mouth, somnolence, asthenia, dizziness, urinary tract infection, constipation, liver function tests abnormal, vomiting, speech disorder, amblyopia, urinary frequency, flu syndrome, SGPT/ALT increased, dyskinesia, nervousness, pharyngitis, and rhinitis ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC at 1-877-748-1970 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. 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 to 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 1 lists 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. Table 1. Multiple Dose, Placebo-Controlled Studies - Frequent (> 2%) Adverse Reactions Reported for Which Tizanidine Tablets Incidence is Greater than Placebo *(weakness, fatigue, and/or tiredness) Event Placebo N = 261 % Tizanidine Tablet N = 264 % Dry mouth 10 49 Somnolence 10 48 Asthenia* 16 41 Dizziness 4 16 UTI 7 10 Infection 5 6 Constipation 1 4 Liver test abnormality 2 6 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 Rea …

7 DRUG INTERACTIONS 7.1 Fluvoxamine Concomitant use of fluvoxamine and tizanidine hydrochloride is contraindicated. Changes in pharmacokinetics of tizanidine when administered with fluvoxamine resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment [see Contraindications (4) and Clinical Pharmacology (12.3)] . 7.2 Ciprofloxacin Concomitant use of ciprofloxacin and tizanidine hydrochloride is contraindicated. Changes in pharmacokinetics of tizanidine when administered with ciprofloxacin resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment [see Contraindications (4) and Clinical Pharmacology (12.3)]. 7.3 CYP1A2 Inhibitors other than Fluvoxamine and Ciprofloxacin Because of potential drug interactions, concomitant use of tizanidine hydrochloride 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 to 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 hydrochloride therapy [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)] . 7.4 Oral Contraceptives Concomitant use of tizanidine hydrochloride with oral contraceptives is not recommended. However, if concomitant use is clinically necessary, initiate tizanidine hydrochloride with a single 2 mg dose and increase in 2 to 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 hydrochloride therapy [see Clinical Pharmacology (12.3)]. 7.5 Alcohol Alcohol increases the overall amount of drug in the bloodstream after a dose of tizanidine hydrochloride. This was associated with an increase in adverse reactions of tizanidine hydrochloride. The CNS depressant effects of tizanidine hydrochloride and alcohol are additive [see Clinical Pharmacology (12.3)]. 7.6 Other CNS Depressants The sedative effects of tizanidine hydrochloride with CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take tizanidine hydrochloride with another CNS depressant for symptoms of excess sedation [see Clinical Pharmacology (12.3)]. 7.7 α 2 -adrenergic Agonists Because hypotensive effects may be cumulative, it is not recommended that tizanidine hydrochloride be used with other α 2 -adrenergic agonists [see Warnings and Precautions (5.1)].

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm (8.1) Geriatric use: Tizanidine hydrochloride capsules 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 tizanidine hydrochloride in pregnant women. In animal studies, administration of tizanidine during pregnancy resulted in developmental toxicity (embryofetal and postnatal offspring mortality and growth deficits) at doses less than those used clinically, which were not associated with maternal toxicity (see Animal Data ). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 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 to 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 tizanidine hydrochloride and any potential adverse effects on the breastfed infant from tizanidine hydrochloride or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential There are no adequate and well-controlled studies in humans on the effect of tizanidine hydrochloride on female or male reproductive potential. Oral administration of tizanidine to male and female rats resulted in adverse effects on fertility [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 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 Tizanidine hydrochloride is known to be substantially excrete …

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.

11 DESCRIPTION Tizanidine hydrochloride capsules contains tizanidine hydrochloride as the active ingredient, which is a central alpha 2 - 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. 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 Capsules are supplied as 2, 4, 6 and 8 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, 6.87 mg equivalent to 6 mg tizanidine base and 9.16 mg equivalent to 8 mg tizanidine base), and the inactive ingredients, microcrystalline cellulose, lactose monohydrate, hypromellose, colloidal silicon dioxide, croscarmellose sodium, stearic acid, 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. "Image Description"

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

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Tizanidine hydrochloride capsules Tizanidine hydrochloride capsules are available in three strengths as two-piece hard gelatin capsules containing tizanidine hydrochloride 2.29 mg, 4.58 mg and 6.87 mg, equivalent to 2 mg, 4 mg and 6 mg tizanidine base. • Tizanidine capsules 2 mg have a hard gelatin size "3" light blue opaque capsule, imprinted "2MG" with white ink on cap and "Tiza" & "circle of thin line" with white ink on body, containing light yellow to yellow color pellets. Tizanidine capsules 2 mg are supplied as follows. Bottle of 10 capsules (NDC 76420-900-10 repackaged from NDC 67877-610-XX) Bottle of 20 capsules (NDC 76420-900-20 repackaged from NDC 67877-610-XX) Bottle of 30 capsules (NDC 76420-900-30 repackaged from NDC 67877-610-XX) Bottle of 60 capsules (NDC 76420-900-60 repackaged from NDC 67877-610-XX) Bottle of 90 capsules (NDC 76420-900-90 repackaged from NDC 67877-610-XX) Bottle of 150 capsules (NDC 76420-900-15 relabeled from NDC 67877-610-15) Bottle of 500 capsules (NDC 76420-900-05 relabeled from NDC 67877-610-05) Blister pack of 10 capsules (NDC 76420-900-01 relabeled from NDC 67877-610-33) • Tizanidine capsules 4 mg have a hard gelatin capsule size "3" blue opaque cap, imprinted "4MG" with white ink and "Tiza" & white opaque body "circle of thin line" with black ink, containing light yellow to yellow color pellets. Tizanidine capsules 4 mg are supplied as follows. Bottle of 10 capsules (NDC 76420-901-10 repackaged from NDC 67877-611-XX) Bottle of 20 capsules (NDC 76420-901-20 repackaged from NDC 67877-611-XX) Bottle of 30 capsules (NDC 76420-901-30 repackaged from NDC 67877-611-XX) Bottle of 60 capsules (NDC 76420-901-60 repackaged from NDC 67877-611-XX) Bottle of 90 capsules (NDC 76420-901-90 repackaged from NDC 67877-611-XX) Bottle of 150 capsules (NDC 76420-901-15 relabeled from NDC 67877-611-15) Bottle of 500 capsules (NDC 76420-901-05 relabeled from NDC 67877-611-05) Blister pack of 10 capsules (NDC 76420-901-01 relabeled from NDC 67877-611-33) • Tizanidine capsules 6 mg have a hard gelatin size "2" blue opaque capsule, imprinted "6MG" with white ink on cap and "Tiza" & "circle of thin line" with white ink on body, containing light yellow to yellow color pellets. Tizanidine capsules 6 mg are supplied as follows. Bottle of 10 capsules (NDC 76420-902-10 repackaged from NDC 67877-612-XX) Bottle of 20 capsules (NDC 76420-902-20 repackaged from NDC 67877-612-XX) Bottle of 30 capsules (NDC 76420-902-30 repackaged from NDC 67877-612-XX) Bottle of 60 capsules (NDC 76420-902-60 repackaged from NDC 67877-612-XX) Bottle of 90 capsules (NDC 76420-902-90 repackaged from NDC 67877-612-XX) Bottle of 150 capsules (NDC 76420-902-15 relabeled from NDC 67877-612-15) Bottle of 500 capsules (NDC 76420-902-05 relabeled from NDC 67877-612-05) Blister pack of 10 capsules (NDC 76420-902-01 relabeled from NDC 67877-612-33) Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Dispense in containers with child resistant closure.