By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved a third member of the dual orexin receptor antagonist (DORA) class to treat insomnia. The orexin neuropeptide system (orexin A and orexin B) plays a role in wakefulness.1 Blocking these receptors promotes sleep. Daridorexant will be distributed as Quviviq.
INDICATIONS
Daridorexant can be prescribed to adult patients with insomnia characterized by difficulty with sleep onset and/or sleep maintenance.1
DOSAGE
The recommended dosage is 25 mg to 50 mg once per night.1 It should be taken 30 minutes before going to bed, with at least seven hours remaining before planned awakening. High-fat and high-caloric meals delay the onset of daridorexant, which will delay the onset of sleep induction. Daridorexant is available as 25 mg and 50 mg tablets.
POTENTIAL ADVANTAGES
Daridorexant has the shortest elimination half-life (eight hours) of the three available DORAs (suvorexant, 12 hours; lemborexant, 15-17 hours).1-3 A half-life longer than 10 hours may carry the risk of hangover effects.4
POTENTIAL DISADVANTAGES
Daridorexant carries the same class warning and precautions as other DORAs, such as worsening of depression, suicidal ideation, sleep paralysis, complex sleep behavior, and potential effect on respiratory abilities in patients with compromised respiratory function.1 Daridorexant 50 mg showed statistically significant impairment vs. placebo in next-morning driving performance after the first dose.1 After four doses, the effect was not statistically significant vs. placebo. Daridorexant is metabolized by CYP3A4. Concomitant use with a strong CYP3A4 inhibitor or a strong or moderate inducer is not recommended.1 The most frequently reported adverse reactions (≤ 7%) were headache, somnolence or fatigue, dizziness, and nausea.1
COMMENTS
The efficacy of daridorexant was evaluated in two randomized, double-blind, placebo-controlled studies in subjects diagnosed with insomnia.1,5 Subjects were randomized to daridorexant 25 mg (n = 310 in study 1, n = 309 in study 2), 50 mg (n = 310 in study 1), and placebo (n = 310 and n = 308) once daily for three months. The primary endpoints were change from baseline in month 1 and month 3 in latency to persistent sleep (LPS) and wakefulness after sleep onset (WASO) measured by polysomnography in a sleep laboratory. The secondary endpoint was patient-reported subjective total sleep time (sTST). LPS showed a mean reduction of six to eight minutes for the 25 mg dose and 11 minutes for the 50 mg dose over placebo at month 1. The 25 mg dose resulted in a mean reduction in WASO of 12 minutes and 23 minutes over placebo for the 50 mg dose. Generally, these results were maintained at month 3. sTST improved by 13 to 16 minutes for the 25 mg dose and 22 minutes for the 50 mg dose. After discontinuation of treatment, LPS and WASO were better during the next night in a dose-dependent manner (mean of 19 minutes/15 minutes for the 25 mg dose and 25 minutes/16 minutes for the 50 mg dose). Withdrawal symptoms were not observed at treatment discontinuation.1 Impairment of nighttime respiratory function was not observed in patients with moderate COPD.6
CLINICAL IMPLICATIONS
DORAs improve sleep onset and maintenance, with limited impairment of daytime functioning, low likelihood of abuse potential, and preserve sleep architecture.4 They have a favorable profile compared to benzodiazepines and “Z drugs” (e.g., zolpidem, zopiclone, eszopiclone, and zaleplon). This is primarily because of their difference in mode of action (i.e., reducing wake promotion rather than inducing sedation). Daridorexant is the third DORA on the market, and there are no head-to-head comparisons among these agents. The cost is unavailable at the time of this review as the drug’s availability is expected in May 2022. It is pending controlled substance scheduling. Both suvorexant and lemborexant are schedule IV because of a risk of misuse.
REFERENCES
- Idorsia Pharmaceuticals US Inc. Quviviq prescribing information. January 2022.
- Merck Sharp & Dohme Corp. Belsomra prescribing information. March 2021.
- Eisai Inc. Dayvigo prescribing information. December 2019.
- Muehlan C, Vaillant C, Zenklusen I, et al. Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders. Expert Opin Drug Metab Toxicol 2020;16:1063-1078.
- Mignot E, Mayleben D, Fietze I, et al. Safety and efficacy of daridorexant in patients with insomnia disorder: Results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. Lancet Neurol 2022;21:125-139.
- Boof ML, Dingemanse J, Brunke M, et al. Effect of the novel dual orexin receptor antagonist daridorexant on night-time respiratory function and sleep in patients with moderate chronic obstructive pulmonary disease. J Sleep Res 2021;30:e13248.
Daridorexant can be prescribed to adult patients with insomnia characterized by difficulty with sleep onset and/or sleep maintenance.
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