Daridorexant

Daridorexant (ACT-541468) is a dual orexin receptor antagonist (DORA) developed by Idorsia [5]. It was approved in 2022 by the US Food and Drug Administration and the European Medicines Agency [2] for adults with difficulty falling asleep, staying asleep or both [1].

Dose-finding. In 359 adults up to 64 years old, 5–50 mg for 30 days reduced wake after sleep onset and time to fall asleep in a dose-dependent way, sustained to the end of treatment [7]. In 58 adults aged 65–85, doses of 10, 25 and 50 mg cut wake after sleep onset by 32, 45 and 61 minutes against placebo over two nights each [8].

Phase 3. Two trials at 156 sites in 17 countries randomized 1,854 adults to 3 months of 50 mg, 25 mg or placebo (study 1) or 25 mg, 10 mg or placebo (study 2) [5]. On 50 mg, wake after sleep onset fell 23 and 18 minutes more than on placebo at months 1 and 3, latency to persistent sleep 11 and 12 minutes more, and self-reported total sleep rose 22 and 20 minutes more; self-rated daytime sleepiness also improved [5]. On 25 mg the effects were smaller and daytime sleepiness did not improve significantly; in study 2, 25 mg did not significantly shorten sleep onset after correction for multiple testing, and 10 mg had no effect on measured sleep [5]. People aged 65 and over, 39% of study 1, improved as much as younger adults, with a smaller placebo response [9]. Phase 3 trials in Japan (490 adults, 4 weeks) and China (206 adults, 1 month) found similar gains in self-reported and measured sleep [10][11].

Long term. Of the 1,684 people who finished the 3-month trials, 804 entered a 40-week placebo-controlled extension [6]. Adverse events were similar across groups, there was no withdrawal or rebound, and gains in self-rated daytime functioning on 50 mg stayed significant at weeks 12, 24 and 36, while the gain in total sleep was 20 minutes at week 12 and just missed significance afterward [6].

How it compares. In a 2025 network meta-analysis of the three licensed DORAs, 50 mg had the largest effect on self-reported total sleep at month 1, larger than 25 mg and lemborexant 5 mg, while 25 mg was the only daridorexant dose with more somnolence than placebo in the sensitivity analysis [12]. The 2022 Lancet network meta-analysis grouped daridorexant with licensed drugs that work acutely but have poor tolerability or no long-term data, though dropouts for side effects were more likely on zopiclone (odds ratio 3.45) [13]. A 2026 meta-analysis in people aged 65 and over found its adverse-event rate similar to placebo [14].

Other groups. In 60 people aged 55 and over with insomnia and nocturia, 50 mg added about 21 minutes of self-reported sleep over 4 weeks and reduced night-time voids in the first week, though not significantly by week 4 [15].

Orexin and hyperarousal. Orexin neurons fire during wakefulness and fall silent during sleep, and their loss causes narcolepsy [16][17]. Insomnia is associated with a state of hyperarousal, and orexin is a key promoter of arousal; orexin antagonists block this pathway temporarily rather than acting on GABA-A receptors [18].

Binding and design. Daridorexant blocks OX1 and OX2 receptors with Ki values of 0.47 and 0.93 nM [1]. It was chosen from a series of related DORAs by physiology-based modeling of how long each would occupy brain OX2 receptors in humans; the active dose of 25 mg was predicted from an occupancy threshold of about 65% derived from almorexant and suvorexant, and the predictions largely held in the first human trial [19][20].

Effect on the sleeping brain. In pooled phase 3 recordings from 1,466 patients, 50 mg reduced wake-to-wake transitions, made transitions from wake into N1, N2 and REM sleep more likely, and lowered high-frequency beta power during wake and light sleep, which the authors read as reduced hyperarousal; EEG spectra in N2, N3 and REM sleep and sleep spindles did not change, and 25 mg had weaker effects [21].

Metabolites. Its three major metabolites keep some affinity for orexin receptors but do not reach high enough brain concentrations to contribute to its effect [22].

Mechanism-based effects. Dogs given 30 mg/kg a day or more showed cataplexy-like behavior when stimulated, with no effect at 20 mg/kg [1], and the label lists sleep paralysis, hallucinations and cataplexy-like symptoms as class effects [1].

Salt and tablets. Quviviq tablets contain daridorexant hydrochloride, which is very slightly soluble in water; each 25 or 50 mg tablet holds 27 or 54 mg of the salt [1].

Absorption. Solubility depends on stomach pH, so famotidine lowered the peak by 39%, though total exposure did not change [23]. A heavy meal slows absorption without reducing exposure [1][2]. Body composition, age and alkaline phosphatase changed exposure by less than 20% in pooled modeling, and kidney impairment did not change it [1][2]. Moderate liver impairment may raise exposure enough to cap the dose at 25 mg [1].

Common effects. In phase 3 study 1, adverse events affected 38% on 50 mg and 25 mg against 34% on placebo, most often nasopharyngitis and headache [5]. Headache occurred in 7% on 50 mg against 5% on placebo, somnolence or fatigue in 5–6% against 4%, and nausea in 3% against 2% [1]. In the Japanese trial somnolence rose with dose, to 6.8% on 50 mg against 1.8% on placebo [10]. In people aged 65 and over, somnolence, dizziness and falls on 50 mg each occurred in one person, against one, one and four on placebo [9]. One death from cardiac arrest on 25 mg was judged unrelated [5].

Narcolepsy-like effects. Sleep paralysis occurred in 0.3–0.5% and hallucinations at sleep onset or waking in 0.6% on 25 mg, with none on placebo [1]; no cataplexy or complex sleep behavior was reported in the 40-week extension [6]. Sleep paralysis was its strongest signal in US adverse-event reports [29].

Next-day effects and driving. In a simulator study in 60 healthy adults aged 50–79, the morning after the first dose of 50 mg lane weaving rose by 2.19 cm, and its upper confidence limit crossed the 2.6 cm threshold matched to an alcohol effect; 44% were impaired against 15% improved, and people rated their own driving worse [27]. After four nights the effect was 0.26 cm and not different from placebo [27]. A network meta-analysis of driving studies found daridorexant 100 mg worse than placebo after a single dose [30]. When healthy adults were woken 4 hours after 25 or 50 mg, body sway increased and memory was worse than on placebo, but they woke to sound as readily [1]. In the extension study, morning sleepiness scores did not worsen [6].

Stopping. No withdrawal symptoms appeared after up to a year [1][6], and sleep did not fall below its pre-treatment level [6]. The benefit faded quickly, though: on the first night off 50 mg, wake after sleep onset was 25 minutes longer than on the last treated night [1].

Breathing. Over 5 nights of 50 mg, the apnea–hypopnea index did not rise in mild-to-moderate sleep apnea (difference 0.74 events an hour) [24] or severe sleep apnea (−3.7) [25], and oxygen saturation did not fall in moderate COPD [26]; total sleep time rose in each study [24][25][26]. It has not been studied in mild or severe COPD [1].

Abuse and overdose. In 63 recreational sedative users, drug liking for 50 mg (73 out of 100) was higher than for placebo but lower than for suvorexant 150 mg and zolpidem 30 mg, while 100 and 150 mg were liked about as much as those comparators [31]; daridorexant is in Schedule IV [1]. Among 51 overdoses reported to French poison centers, with a median dose of 200 mg, those taking daridorexant alone mainly became drowsy; severe cases, including coma, involved other drugs or alcohol, and nobody died [32].

Other findings. It is contraindicated after hypersensitivity, as angioedema involving the throat has been reported [1]. At 4 times the top dose it did not prolong the QTc interval [1]. Animal studies found no fetal harm at 8–10 times human exposure, and breast milk carried less than 0.22% of the mother's dose [1][33].

Daridorexant is cleared mainly by CYP3A4: the label advises against strong inhibitors, recommends 25 mg with moderate inhibitors, and advises against strong or moderate inducers [1]. The moderate inducer efavirenz cut its exposure by 61% [23]. Famotidine lowered its peak level but not total exposure, so acid-reducing drugs need no dose change [23]. Alcohol at 0.6 g/L added to its effects on balance and alertness, and citalopram did not [1]. It raises exposure to drugs cleared by CYP3A4 and P-glycoprotein, so narrow-margin drugs in those pathways need care [1].