Daridorexant (Quviviq™)

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Background: Daridorexant is an orexin receptor antagonist approved by the FDA for use in adults with insomnia characterized with sleep onset and sleep maintenance difficulties. The orexin neuropeptide pathway plays a role in wakefulness. By antagonizing the OX1R and OX2R receptors, daridorexant disrupts this pathway and promotes sleep.

Safety: Daridorexant is contraindicated in patients with narcolepsy, as narcolepsy is associated with a loss of orexin neuron function.1 It is not recommended in patients with severe hepatic impairment. Daridorexant is a CYP3A4 substrate, so strong inhibitors or liver failure may prolong its action and increase these effects.2 Of note, the first orexin receptor antagonist on the market, suvorexant, shows more daytime somnolence at 20 mg (5.1 percent) than either available dose of daridorexant.3

A 2020 randomized controlled trial found no evidence of withdrawal symptoms after treatment cessation.4 Compared to zolpidem, daridorexant showed significantly less cognitive impairment at all doses, and compared to suvorexant only doses exceeding FDA-approved doses produced more cognitive impairment. A dosedependent relationship was also seen in drug-liking effects for daridorexant, reflecting potential for abuse, though even at supratherapeutic doses this effect was lower compared to supratherapeutic doses of suvorexant and zolpidem.5 However, these studies did not enroll adults older than 65.

Tolerability: In a phase 3 clinical trial comparing daridorexant 25 mg and 50 mg to placebo, the most commonly reported adverse effects were nasopharyngitis (7 percent), headache (6 percent), fatigue (4 percent) and dizziness (2 percent). Accidental overdose was reported in 3 percent of participants in the daridorexant 50 mg arm.6 Next-day somnolence has been reported at therapeutic doses, up to several days after discontinuing daridorexant, reportedly occurring in 4 percent of participants treated with 25 mg and only 2 percent of participants in the 50 mg arm. The rate of adverse effects was similar in adults older than 65 as in those younger than 65.6 Concomitant administration with other CNS depressants may increase this risk. Sleep paralysis, hypnagogic or hypnopompic hallucinations, and other complex sleep behaviors such as sleepwalking or sleep-driving have also been reported with daridorexant (<1 percent).2 A meta-analysis comparing several pharmacotherapies for insomnia showed slightly higher incidence of all reported adverse events in daridorexant (46 percent) compared to doxepin (40 percent) and melatonin (42 percent).7

Efficacy: The primary endpoints in the Phase 3 clinical trial were the change from baseline in Wakefulness After Sleep Onset (WASO) and Latency to Persistent Sleep (LPS) measured in minutes at months 1 and 3. This was assessed by polysomnography in a sleep laboratory. Daridorexant showed a dose-dependent effect on both scores: at month 1 the 25 mg dose showed least squares mean of 18 minute reduction in WASO, and the 50 mg dose showed a 29 minute reduction compared to 6 minutes for placebo. After 3 months this effect persisted, with 25 mg maintaining 12 minutes less wakefulness than placebo [95 percent CI: -17, -6] and 18 minutes for the 50 mg dose [95percent CI: -24, -13]. Latency to Persistent Sleep also improved by 8 minutes over placebo [95percent CI: -13, -4] for 25 mg and 11 minutes over placebo [95percent CI: -16, -7] for 50 mg after 1 month. This effect is also durable at 3 months: 25 mg dose maintaining a 7.6-minute reduction over placebo [95percent CI: -12, -3] and 50 mg showing 11.7 minute reduction over placebo [95percent CI: -16, -7]. Of note, participants were only permitted to continue Cognitive Behavioral Therapy (CBT) for any indication provided they had started CBT more than one month before the study period began and agreed to continue throughout the entire course of the study. This is considered first-line therapy but is often inaccessible or undesired by patients.6

Price: Currently there are no generic equivalents to Quviviq available in the U.S. The estimated retail cash price for a 30-day supply (30 tablets) is $560. There is currently a manufacturer coupon to reduce copays, but the benefit varies by insurance plan and is not available for Medicare or Medicaid beneficiaries.8

Simplicity: Daridorexant is available as brand name Quviviq in 25 mg and 50 mg oral tablets. It is dosed once daily within 30 minutes of bedtime and should only be taken when more than 7 hours remain before planned awakening.

Bottom Line: Daridorexant is an effective treatment for insomnia, showing a similar effect to suvorexant on WASO and LPS scores. Based on available data, its safety profile is more favorable compared to suvorexant or other hypnotics. The lack of