Hetlioz

1 INDICATIONS AND USAGE HETLIOZ is a melatonin receptor agonist. HETLIOZ capsules are indicated for the treatment of: Non-24-Hour Sleep-Wake Disorder (Non-24) in adults Nighttime sleep disturbances in Smith-Magenis Syndrome (SMS) in patients 16 years of age and older HETLIOZ LQ oral suspension is indicated for the treatment of: Nighttime sleep disturbances in SMS in pediatric patients 3 years to 15 years of age

1.1Non-24-Hour Sleep-Wake Disorder

(Non-24) HETLIOZ capsules are indicated for the treatment of Non-24 in adults.

1.2Nighttime Sleep Disturbances in Smith-Magenis Syndrome

(SMS) HETLIOZ capsules are indicated for the treatment of nighttime sleep disturbances in SMS in patients 16 years of age and older. HETLIOZ LQ oral suspension is indicated for the treatment of nighttime sleep disturbances in SMS in pediatric patients 3 to 15 years of age.

Indicated Population Dosage Form Body Weight Recommended Dosage Non-24 Adults Capsules Not applicable 20 mg one hour prior to bedtime Nighttime sleep disturbances in SMS Patients 16 years of age and older Capsules Not applicable 20 mg one hour prior to bedtime Pediatric Patients 3 to 15 years of age Oral Suspension ≤ 28 kg 0.7 mg/kg one hour before bedtime ≥ 28 kg 20 mg one hour prior to bedtime HETLIOZ capsules and HETLIOZ LQ oral suspension are not substitutable Administer at the same time every night ( 2.2 , 2.3 ) Take without food

2.1Non-Interchangeability

between HETLIOZ Capsules and HETLIOZ LQ Oral Suspension HETLIOZ capsules and HETLIOZ LQ oral suspension are not substitutable .

2.2Recommended Dosage for

HETLIOZ Capsules for Non-24 Adults The recommended dosage of HETLIOZ capsules in adults is 20 mg one hour before bedtime, at the same time every night. Because of individual differences in circadian rhythms, drug effect may not occur for weeks or months.

2.3Recommended Dosage for

HETLIOZ Capsules and HETLIOZ LQ Oral Suspension for Nighttime Sleep Disturbances in SMS Patients 16 years of Age and Older The recommended dosage of HETLIOZ capsules in patients 16 years and older is 20 mg one hour before bedtime, at the same time every night. Pediatric Patients 3 Years to 15 Years of Age The recommended dosage of HETLIOZ LQ oral suspension in pediatric patients 3 years to 15 years of age is based on body weight ( Table 1 ). Administer HETLIOZ one hour before bedtime, at the same time every night.

Table 1: Recommended Dosage of HETLIOZ LQ Oral Suspension for the Treatment of Nighttime Sleep Disturbances in SMS in Pediatric Patients 3 Years to 15 Years of Age Body Weight Daily Dose (oral suspension) ≤28 kg 0.7 mg/kg one hour before bedtime >28 kg 20 mg one hour before bedtime

2.4Important Administration Information Administer

HETLIOZ capsules and HETLIOZ LQ oral suspension without food . If a patient is unable to take HETLIOZ at approximately the same time on a given night, they should skip that dose and take the next dose as scheduled. HETLIOZ LQ Oral Suspension See " Instructions for Use " for complete administration instructions. Shake HETLIOZ LQ oral suspension well for at least 30 seconds before every administration.

Remove seal and insert press-in bottle adapter (included in the package) into the neck of the bottle until a tight seal is made. Turn the bottle upside down and withdraw the prescribed amount of HETLIOZ LQ oral suspension from the bottle. Leave the press-in bottle adapter in place on bottle neck and replace cap on bottle.

Store refrigerated. After opening, discard after 5 weeks (for the 48 mL bottle) and after 8 weeks (for the 158 mL bottle).

May cause somnolence: After taking HETLIOZ, patients should limit their activity to preparing for going to bed, because HETLIOZ can impair the performance of activities requiring complete mental alertness

5.1Somnolence After

taking HETLIOZ, patients should limit their activity to preparing for going to bed. HETLIOZ can potentially impair the performance of activities requiring complete mental alertness.

None. None

8.1Pregnancy Risk Summary Available

postmarketing case reports with HETLIOZ use in pregnant women are not sufficient to evaluate drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In pregnant rats, no embryofetal developmental toxicity was observed at exposures of 50 mg/kg/day, or up to 24 times higher than the human exposure at the maximum recommended human dose (MRHD) . The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. 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.

Data Animal Data In pregnant rats administered tasimelteon at oral doses of 5, 50, or 500 mg/kg/day during the period of organogenesis, there were no effects on embryofetal development. The highest dose tested is approximately 240 times the MRHD of 20 mg/day, based on mg/m 2 body surface area. In pregnant rabbits administered tasimelteon at oral doses of 5, 30, or 200 mg/kg/day during the period of organogenesis, embryolethality and embryofetal toxicity (reduced fetal body weight and delayed ossification) were observed at the highest dose tested.

The highest dose is approximately 200 times the MRHD. Oral administration of tasimelteon at 50, 150, or 450 mg/kg/day to rats throughout organogenesis resulted in persistent reductions in body weight, delayed sexual maturation, and physical development, and neurobehavioral impairment in offspring at the highest dose tested which is approximately 220 times the MRHD based on mg/m2 body surface area. Reduced body weight in offspring was also observed at the mid-dose. The no effect dose (NOEL), (50 mg/kg/day) is approximately 25 times the MRHD based on mg/m 2 body surface area.

The most common adverse reactions (incidence >5% and at least twice as high on HETLIOZ than on placebo) were headache, increased alanine aminotransferase, nightmares or unusual dreams, and upper respiratory or urinary tract infection To report SUSPECTED ADVERSE REACTIONS, contact Vanda Pharmaceuticals Inc. at 1-844-438-5469 or www.hetlioz.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience Because

clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. More than 2080 subjects have been treated with at least one dose of HETLIOZ, of which more than 380 have been treated for > 26 weeks and more than 170 have been treated for > 1 year. Non-24-Hour Sleep-Wake Disorder (Non-24) A 26-week, parallel-arm placebo-controlled study (Study 1) evaluated HETLIOZ (n=42) compared to placebo (n=42) in patients with Non-24.

A randomized-withdrawal, placebo- controlled study of 8 weeks duration (Study 2) also evaluated HETLIOZ (n=10), compared to placebo (n=10), in patients with Non-24. In placebo-controlled studies, 6% of patients exposed to HETLIOZ discontinued treatment due to an adverse event, compared with 4% of patients who received placebo. Table 2 shows the incidence of adverse reactions from Study 1. *Adverse reactions with an incidence > 5% and at least twice as high on HETLIOZ than on placebo are displayed.

Table 2: Adverse Reactions in Study 1 HETLIOZ N=42 Placebo N=42 Headache 17 % 7 % Alanine aminotransferase increased 10 % 5 % Nightmare/abnormal dreams 10 % 0 % Upper respiratory tract infection 7 % 0 % Urinary tract infection 7 % 2 % Nighttime Sleep Disturbances in Smith-Magenis Syndrome (SMS) A 9-week, double-blind, randomized, placebo-controlled, two-period crossover study evaluated HETLIOZ (capsules and oral suspension; n=25) compared to placebo (n=26) in the treatment of nighttime sleep disturbances in patients with Smith-Magenis Syndrome. Pediatric patients (n=11, age 3 to 15 years) received HETLIOZ LQ oral suspension, and patients ≥16 years of age (n=14) received HETLIOZ capsules. Adverse reactions were similar in patients treated for Non-24 and patients with Smith-Magenis syndrome treated for nighttime sleep disturbances.

Adverse reactions were also similar in pediatric patients (3 years to 15 years) who received HETLIOZ LQ oral suspension, and patients ≥16 years of age who received HETLIOZ capsules.