These Highlights Do Not Include All The Information Needed To Use Ontralfy™ Safely And Effectively. See Full Prescribing Information For Ontralfy.

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.

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.

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 .

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.

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 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.

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.

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.

Ontralfy is an α ₂-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 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 69528-310-16).

Safety and effectiveness in pediatric patients have not been established.

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.

The efficacy of Ontralfy is supported by evidence from a relative bioavailability study in healthy adult subjects comparing Ontralfy to tizanidine tablets under fasted and fed conditions [see Clinical Pharmacology (12.3)]. The clinical studies described below were conducted using tizanidine tablets.

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).

Ontralfy is contraindicated in patients:

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

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)]

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 Ontralfy dosage or discontinue. ( 7.2, 12.3)

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)] .

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.

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.

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 is indicated for the treatment of spasticity in adults.

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)].

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.

Ontralfy contains tizanidine, which is not a controlled substance.

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 .

• Hypotension: monitor for signs and symptoms of hypotension, in particular in patients receiving concurrent antihypertensives; Ontralfy should not be used with other α ₂-adrenergic agonists. ( 5.1, 7.5)
• Risk of liver injury: monitor ALTs; discontinue Ontralfy if liver injury occurs. ( 5.2)
• Sedation: Ontralfy may interfere with everyday activities; sedative effects of Ontralfy, alcohol, and other central nervous system (CNS) depressants are additive. ( 5.3, 7.4)
• Hallucinations: consider discontinuation of Ontralfy. ( 5.4)

• 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)
• The pharmacokinetics of Ontralfy differ 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. ( 2.2, 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 Ontralfy, decrease dose by 2 mg (5 mL) to 4 mg (10 mL) per day to minimize the risk of withdrawal adverse reactions. ( 2.5)

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

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

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 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)].

• Pregnancy: Based on animal data, may cause fetal harm. ( 8.1)
• Geriatric use: Ontralfy should be used with caution in elderly patients because clearance is decreased four-fold. ( 8.5)

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)].

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.

Table 1:  Multiple Dose, Placebo-Controlled Studies Adverse Reactions Reported in >2% of Patients Treated with Tizanidine Tablets and Incidence Greater than Placebo

* includes weakness, fatigue, and/or tiredness

In the single dose, placebo-controlled study involving 142 patients with spasticity due to multiple sclerosis (Study 1) [see Clinical Studies (14)] , the patients were specifically asked if they had experienced any of the four most common adverse reactions: dry mouth, somnolence (drowsiness), asthenia (weakness, fatigue and/or tiredness), and dizziness. In addition, hypotension and bradycardia were observed. The occurrence of these reactions is summarized in Table 2. Other events were, in general, reported at a rate of 2% or less.

Table 2: Single Dose, Placebo-Controlled Study—Common Adverse Reactions Reported

* includes weakness, fatigue, and/or tiredness

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)].

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)].

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.

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 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)].

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.

NDC 69528-310-16

Ontralfy™

(tizanidine oral solution)

2 mg/5 mL

16 fl. oz. (473 mL)

Rx only

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)].

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)].

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

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.

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.

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 .

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.

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 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.

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.

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.

Ontralfy is an α ₂-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 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 69528-310-16).

Safety and effectiveness in pediatric patients have not been established.

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.

The efficacy of Ontralfy is supported by evidence from a relative bioavailability study in healthy adult subjects comparing Ontralfy to tizanidine tablets under fasted and fed conditions [see Clinical Pharmacology (12.3)]. The clinical studies described below were conducted using tizanidine tablets.

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).

Ontralfy is contraindicated in patients:

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

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)]

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 Ontralfy dosage or discontinue. ( 7.2, 12.3)

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)] .

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.

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.

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 is indicated for the treatment of spasticity in adults.

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)].

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.

Ontralfy contains tizanidine, which is not a controlled substance.

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 .

• Hypotension: monitor for signs and symptoms of hypotension, in particular in patients receiving concurrent antihypertensives; Ontralfy should not be used with other α ₂-adrenergic agonists. ( 5.1, 7.5)
• Risk of liver injury: monitor ALTs; discontinue Ontralfy if liver injury occurs. ( 5.2)
• Sedation: Ontralfy may interfere with everyday activities; sedative effects of Ontralfy, alcohol, and other central nervous system (CNS) depressants are additive. ( 5.3, 7.4)
• Hallucinations: consider discontinuation of Ontralfy. ( 5.4)

• 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)
• The pharmacokinetics of Ontralfy differ 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. ( 2.2, 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 Ontralfy, decrease dose by 2 mg (5 mL) to 4 mg (10 mL) per day to minimize the risk of withdrawal adverse reactions. ( 2.5)

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

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

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 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)].

• Pregnancy: Based on animal data, may cause fetal harm. ( 8.1)
• Geriatric use: Ontralfy should be used with caution in elderly patients because clearance is decreased four-fold. ( 8.5)

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)].

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.

Table 1:  Multiple Dose, Placebo-Controlled Studies Adverse Reactions Reported in >2% of Patients Treated with Tizanidine Tablets and Incidence Greater than Placebo

* includes weakness, fatigue, and/or tiredness

In the single dose, placebo-controlled study involving 142 patients with spasticity due to multiple sclerosis (Study 1) [see Clinical Studies (14)] , the patients were specifically asked if they had experienced any of the four most common adverse reactions: dry mouth, somnolence (drowsiness), asthenia (weakness, fatigue and/or tiredness), and dizziness. In addition, hypotension and bradycardia were observed. The occurrence of these reactions is summarized in Table 2. Other events were, in general, reported at a rate of 2% or less.

Table 2: Single Dose, Placebo-Controlled Study—Common Adverse Reactions Reported

* includes weakness, fatigue, and/or tiredness

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)].

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)].

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.

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 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)].

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.

NDC 69528-310-16

Ontralfy™

(tizanidine oral solution)

2 mg/5 mL

16 fl. oz. (473 mL)

Rx only

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)].

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)].

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