Tasimelteon

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

1.1 Non-24-Hour Sleep-Wake Disorder (Non-24) HETLIOZ capsules are indicated for the treatment of Non-24 in adults.

1.2 Nighttime 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.

Capsules: 20 mg size 1 dark blue opaque, hard gelatin capsules printed with “VANDA 20 mg” in white. Oral suspension: 4 mg/mL white to slightly yellow opaque suspension in 48 mL or 158 mL bottles. Capsules: 20 mg ( 3 ) Oral suspension: 4 mg/mL ( 3 )

None. None ( 4 )

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 ( 5.1 )

5.1 Somnolence 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.

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 ( 6.1 ) 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 .

6.1 Clinical 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.

Strong CYP1A2 inhibitors (e.g., fluvoxamine): Avoid use of HETLIOZ in combination with strong CYP1A2 inhibitors because of increased exposure ( 7.1 , 12.3 ) Strong CYP3A4 inducers (e.g., rifampin): Avoid use of HETLIOZ in combination with rifampin or other CYP3A4 inducers, because of decreased exposure ( 7.2 , 12.3 )

7.1 Strong CYP1A2 Inhibitors (e.g., fluvoxamine) Avoid use of HETLIOZ in combination with fluvoxamine or other strong CYP1A2 inhibitors because of a potentially large increase in tasimelteon exposure and greater risk of adverse reactions [see Clinical Pharmacology ( 12.3 )].

7.2 Strong CYP3A4 Inducers (e.g., rifampin) Avoid use of HETLIOZ in combination with rifampin or other CYP3A4 inducers because of a potentially large decrease in tasimelteon exposure with reduced efficacy [see Clinical Pharmacology ( 12.3 )].

7.3 Beta-adrenergic Receptor Antagonists (e.g., acebutolol, metoprolol) Beta-adrenergic receptor antagonists have been shown to reduce the production of melatonin via specific inhibition of beta-1 adrenergic receptors. Nighttime administration of beta-adrenergic receptor antagonists may reduce the efficacy of HETLIOZ.

Hepatic impairment : HETLIOZ has not been studied in patients with severe hepatic impairment and is not recommended in these patients ( 8.6 )

8.1 Pregnancy 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) (see Data ). 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.

8.2 Lactation Risk Summary There are no data on the presence of tasimelteon or its metabolites in human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HETLIOZ and any potential adverse effects on the breastfed infant from HETLIOZ or from the underlying maternal condition.

8.4 Pediatric Use Safety and effectiveness of HETLIOZ for the treatment of Non-24 in pediatric patients have not been established. Safety and effectiveness of HETLIOZ LQ oral suspension for the treatment of nighttime sleep disturbances in Smith-Magenis Syndrome (SMS) have been established in pediatric patients 3 years and older. Use is based on a placebo-controlled crossover study of pediatric and adult patients [see Clinical Studies ( 14.2 )]. Safety and effectiveness of HETLIOZ for the treatment of nighttime sleep disturbances in SMS have not been established in patients younger than 3 years old. Juvenile Animal Toxicity Data Juvenile rats received oral doses of tasimelteon at 50, 150, or 450 mg/kg from weaning (day 21) through adulthood (day 90). These doses are approximately 12 to 108 times the maximum recommended human dose (MRHD) of 20 mg based on a mg/m 2 body surface area. Toxicity was observed mainly at the highest dose and included mortality (females only), tremors, unsteady gait, decrease in growth and development compared to controls. The former reflected as decreases in bone growth, bone mineral content, bone ossification, and a delay in attainment of sexual maturation. Tasimelteon had no effect on fertility, reproduction, or learning and memory. The No Observed Adverse Effect Level (NOAEL) is 150 mg/kg/day, which is approximately 178 times the MRHD based on AUC.

8.5 Geriatric Use The risk of adverse reactions may be greater in elderly (>65 years) patients than younger patients because exposure to tasimelteon is increased by approximately 2-fold compared with younger patients.

8.6 Hepatic Impairment Dose adjustment is not necessary in patients with mild or moderate hepatic impairment. HETLIOZ has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, HETLIOZ is not recommended for use in patients with severe hepatic impairment [see Clinical Pharmacology ( 12.3 )].

8.7 Smokers Smoking causes induction of CYP1A2 levels. The exposure of tasimelteon in smokers was lower than in non-smokers and therefore the efficacy of HETLIOZ may be reduced in smokers [see Clinical pharmacology ( 12.3 )].

The mechanism by which tasimelteon exerts its therapeutic effect in patients with Non-24 or nighttime sleep disturbances in SMS is unclear. However, tasimelteon is an agonist at melatonin MT 1 and MT 2 receptors which are thought to be involved in the control of circadian rhythms.