Ontralfy Drug Information

Ontralfy is indicated for the treatment of spasticity in adults.

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.

Recommended Dosage in Patients with Hepatic Impairment

In patients with hepatic impairment, use lower individual doses during titration.

Discontinuation of Ontralfy

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.

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 practice. The safety of Ontralfy has been established from adequate and well-controlled studies of tizanidine tablets in adult patients with spasticity. 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. 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 2 3 includes weakness, fatigue, and/or tiredness In the single dose, placebo-controlled study involving 142 patients with spasticity due to multiple sclerosis (Study 1), 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.

Postmarketing Experience

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, hepatitis Musculoskeletal and Connective Tissue Disorders: arthralgia Nervous System Disorders: Convulsion, paresthesia, tremor, muscle spasms Psychiatric Disorders: Hallucinations, depression Skin and Subcutaneous Tissue Disorders: Stevens Johnson Syndrome, anaphylactic reaction, exfoliative dermatitis, rash

Strong CYP1A2 Inhibitors

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.

Moderate or Weak CYP1A2 Inhibitors

Concomitant use of Ontralfy with moderate or weak CYP1A2 inhibitors (e.g., zileuton, antiarrhythmics, 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.

Oral Contraceptives

Concomitant use of Ontralfy with oral contraceptives is not recommended.

Alcohol and Other CNS Depressants

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. 7.5 α2-Adrenergic Agonists Concomitant use of Ontralfy with other α2-adrenergic agonists is not recommended because hypotensive effects may be cumulative.

Antihypertensive Medications

Concomitant use of Ontralfy with antihypertensive medications may cause additive hypotensive effects. Monitor patients who take Ontralfy with antihypertensive medications for hypotension.

Pregnancy 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 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. 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.

Pediatric Use Safety and effectiveness in pediatric patients have not been established. Juvenile Animal Toxicity Data Oral administration of tizanidine 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.

Ontralfy is contraindicated in patients: taking strong CYP1A2 inhibitors. with a history of hypersensitivity to tizanidine or the ingredients in Ontralfy. Symptoms have included anaphylaxis and angioedema Concomitant use with strong CYP1A2 inhibitors Patients with a history of hypersensitivity to tizanidine or the ingredients in Ontralfy

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. 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.