Hetlioz Drug Information
Generic name: TASIMELTEON
Melatonin Receptor Agonist [EPC]
Uses of Hetlioz
Non-24-Hour Sleep-Wake Disorder (Non-24)
HETLIOZ capsules are indicated for the treatment of Non-24 in adults.
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.
Dosage & Administration of Hetlioz
| Capsules | |
| Capsules | |
| Oral Suspension | |
| ≥ 28 kg | 20 mg one hour prior to bedtime |
Side Effects of Hetlioz
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.
Warnings & Cautions for Hetlioz
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.
Drug Interactions with Hetlioz
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.
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.
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.
Pregnancy Safety for Hetlioz
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.
Pediatric Use of Hetlioz
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 . 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.
Overdosage Information for Hetlioz
There is limited premarketing clinical experience with the effects of an overdosage of HETLIOZ. As with the management of any overdose, general symptomatic and supportive measures should be used, along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Respiration, pulse, blood pressure, and other appropriate vital signs should be monitored, and general supportive measures employed.
While hemodialysis was effective at clearing HETLIOZ and the majority of its major metabolites in patients with renal impairment, it is not known if hemodialysis will effectively reduce exposure in the case of overdose. As with the management of any overdose, the possibility of multiple drug ingestion should be considered. Contact a poison control center for current information on the management of overdose.
Clinical Studies of Hetlioz
Non-24-Hour Sleep-Wake Disorder (Non-24)
The effectiveness of HETLIOZ in the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24) was established in two randomized double-masked, placebo-controlled, multicenter, parallel-group studies (Studies 1 and 2) in totally blind patients with Non-24. In study 1, 84 patients with Non-24 (median age 54 years) were randomized to receive HETLIOZ 20 mg or placebo, one hour prior to bedtime, at the same time every night for up to 6 months. Study 2 was a randomized withdrawal trial in 20 patients with Non-24 (median age 55 years) that was designed to evaluate the maintenance of efficacy of HETLIOZ after 12-weeks. Patients were treated for approximately 12 weeks with HETLIOZ 20 mg one hour prior to bedtime, at the same time every night.
Patients in whom the calculated time of peak melatonin level (melatonin acrophase) occurred at approximately the same time of day (in contrast to the expected daily delay) during the run-in phase were randomized to receive placebo or continue treatment with HETLIOZ 20 mg for 8 weeks. Study 1 and Study 2 evaluated the duration and timing of nighttime sleep and daytime naps via patient-recorded diaries. During Study 1, patient diaries were recorded for an average of 88 days during screening, and 133 days during randomization.
During Study 2, patient diaries were recorded for an average of 57 days during the run-in phase, and 59 days during the randomized-withdrawal phase. Because symptoms of nighttime sleep disruption and daytime sleepiness are cyclical in patients with Non-24, with severity varying according to the state of alignment of the individual patient’s circadian rhythm with the 24-hour day (least severe when fully aligned, most severe when 12 hours out of alignment), efficacy endpoints for nighttime total sleep time and daytime nap duration were based on the 25% of nights with the least nighttime sleep, and the 25% of days with the most daytime nap time. In Study 1, patients in the HETLIOZ group had, at baseline, an average 195 minutes of nighttime sleep and 137 minutes of daytime nap time on the 25% of most symptomatic nights and days, respectively.
Treatment with HETLIOZ resulted in a significant improvement, compared with placebo, for both of these endpoints in Study 1 and Study 2 (see Table 3 ). Table 3: Effects of HETLIOZ 20 MG on Nighttime Sleep Time and Daytime Nap Time in Study 1 and Study 2 Study 1 Study 2 Change from Baseline HETLIOZ 20 MG N=42 Placebo N=42 HETLIOZ 20 MG N=10 Placebo N=10 Nighttime sleep time on 25% most symptomatic nights (minutes) 50 22 -7 -74 Daytime nap time on 25% most symptomatic days (minutes) -49 -22 -9 50 A responder analysis of patients with both ≥ 45 minutes increase in nighttime sleep and ≥ 45 minutes decrease in daytime nap time was conducted in Study 1: 29% (n=12) of patients treated with HETLIOZ, compared with 12% (n=5) of patients treated with placebo met the responder criteria.
Nighttime Sleep Disturbances in Smith-Magenis Syndrome (SMS)
The effectiveness of HETLIOZ in the treatment of nighttime sleep disturbances in Smith-Magenis Syndrome (SMS) was established in a 9-week, double-blind, placebo- controlled cross-over study in adults and pediatric patients with SMS (Study 3; NCT 02231008). Patients 16 years of age and older received HETLIOZ 20 mg capsules, and pediatric patients 3 years to 15 years of age received a weight-based dose of oral suspension. Study 3 had two 4-week periods, separated by a 1-week washout interval. Patients were randomized to a treatment sequence of HELTIOZ in the first period and placebo in the second period, or placebo in the first period and HETLIOZ in the second period.
Patients were to take the study drug one hour prior to bedtime. The primary endpoints in Study 3 were nighttime total sleep time and nighttime sleep quality from a parent/guardian-recorded diary. Nighttime total sleep time was reported as a time unit in hours and minutes.
Nighttime sleep quality was rated as follows: 5 = excellent; 4 = good; 3 = average; 2 = fair; 1 = poor. The efficacy comparisons for nighttime sleep quality and total sleep time were based on the 50% of nights with the worst sleep quality and the 50% of nights with the least nighttime sleep in each 4-week period. In accordance with the cross-over design, the efficacy comparisons were within patient.
A total of 25 patients were randomized in Study 3. During screening, the mean quality score of the 50% of nights with the worst sleep quality was 2.1, and the total sleep time of 50% of nights with the least nighttime sleep was 6.4 hours. Compared to placebo, treatment with HETLIOZ resulted in a statistically significant improvement in the 50% worst nights’ sleep quality. Although improvement on the 50% worst total nighttime sleep time numerically favored HETLIOZ treatment, the difference was not statistically significant ( Table 4 ). Table 4: Primary Efficacy Results for Effects of HETLIOZ on Nighttime Sleep Quality and Nighttime Total Sleep Time in Patients with Smith-Magenis Syndrome (Study 3) SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval unadjusted for multiplicity. a LS Means are the model-based averages based on the 50% worst days per 4-week period. b Difference (drug minus placebo) in least-squares means. * Endpoint on which HETLIOZ was statistically significant different from placebo after controlling for multiple comparisons.
Primary Efficacy Measures Treatment Group LS Mean a (SE) Placebo-subtracted Difference b (95% CI) Average of 50% Worst Daily Nighttime Sleep Quality * HETLIOZ (n=25) 2.8
Placebo (n=25) 2.4 -- Average of 50% Worst Daily Nighttime Total Sleep
Time, hours HETLIOZ (n=25) 7.0 0.3 (-0.0, 0.6) Placebo (n=25) 6.7 --
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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