First treatment for non-24-hour-sleep-wake disorder approved by FDA

July 10, 2014

Two trials involving 100 totally blind individuals with circadian rhythm sleep disorders established the efficacy of the new product.

Diana SobierajIn January 2014, FDA approved tasimelteon (Hetlioz; Vanda Pharmaceuticals) for the treatment of non-24-hour-sleep-wake disorder. Non-24-hour-sleep-wake-disorder is a circadian rhythm sleep disorder in which a person’s biological clock fails to synchronize to the external 24-hour cycle, the result of a lack of signaling that usually occurs with the perception of light. This disorder occurs in approximately 50% of blind individuals. Tasimelteon is a melatonin receptor agonist at the MT1 and MT2 receptors, which are thought to be involved in the control of circadian rhythms, although product labeling states the exact mechanism in unknown. Currently, there are no contraindications for the use of tasimelteon.

Efficacy

The efficacy of tasimelteon is based on two randomized, double-blind, placebo-controlled trials of totally blind subjects. The first trial, Safety and Efficacy of Tasimelteon (SET), randomized 84 blind patients with non-24-hour-sleep-wake disorder to receive either tasimelteon 20 mg or placebo one hour before bedtime for up to six months. Main outcomes included entrainment of the major melatonin metabolite aMT6s to a 24-hour rhythm, nighttime and daytime sleep. A significantly greater number of patients taking tasimelteon were entrained compared to placebo (20% versus 2.6%, P=0.017). Compared with placebo, clinical response in patients taking tasimelteon, as measured through entrainment plus predefined criteria on clinical response scales, was also significantly greater. Total nighttime sleep improved and total daytime napping decreased in patients taking tasimelteon compared to placebo.

The Randomized Withdrawal Study of the Safety and Efficacy of Tasimelteon (RESET) was designed to evaluate the maintenance effects of tasimelteon in blind patients with non-24-hour-sleep-wake disorder. Patients were started on tasimelteon 20 mg nightly in an open-label fashion, and those who were considered responders were randomized to continue tasimelteon or receive placebo for two months. Responders were patients who became entrained to a 24-hour cycle measured through aMT6s levels. Twenty patients were randomized, and a significantly greater proportion of patients taking tasimelteon maintained entrainment compared to placebo (90% versus 20%, P=0.0026). Total nighttime sleep was significantly greater and total daytime napping was significantly lower in patients taking tasimelteon compared to placebo.

 

Safety

In the SET and RESET trials, discontinuation rates of tasimelteon or placebo due to an adverse event were similar at 6% and 4%, respectively. Adverse events with an incidence of >5% and which occurred in patients taking tasimelteon at a rate at least twice as high as placebo included headache, alanine aminotransferase increase, nightmare/abnormal dreams, upper respiratory infection, and urinary tract infection.

Tasimelteon may impair the performance of activities requiring complete mental alertness; therefore, patients should limit overall activities after taking tasimelteon and prepare to go to bed. 

Dosing

Tasimelteon is dosed 20 mg before bedtime, at the same time each night. If a patient cannot take the medication at approximately the same time on a given occasion, the dose should be skipped. Since the maximal concentration and time to reach the maximal concentration were impaired by food, patients should take tasimelteon without food. The capsule should be swallowed whole.

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. Safety and effectiveness in pediatric patients have not been established. 

No dose adjustments are suggested in patients with any degree of renal impairment or with mild or moderate liver impairment. However, the drug has not been evaluated in patients with severe liver impairment; therefore, tasimelteon is not recommended for this population. 

Because patients show individual differences in circadian rhythms, they should be informed that daily use of tasimelteon for several weeks or months may be necessary before full benefit is realized.

Concurrent administration of tasimelteon with fluvoxamine or other strong CYP1A2 inhibitors or rifampin and other CYP3A4 inducers is not recommended, since this may lead to possible large increases or decreases, respectively, in tasimelteon concentrations.