Daridorexant

Breast Feeding; Lactation; Milk, Human; Hypnotics and Sedatives; Orexin Receptor Antagonists; Sleep Aids, Pharmaceutical

EMA approved medicines: Human medicine

H413 (100%): May cause long lasting harmful effects to aquatic life [Hazardous to the aquatic environment, long-term hazard]

P273, and P501 (click each P-code to see the statement)

The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

In two controlled trials conducted in support of approval of daridorexant in the United States, there were no changes in serum ALT, AST, alkaline phosphatase or bilirubin levels during treatment and no instances of drug induced liver injury. Since its approval and more widespread clinical use, there have been no published reports of clinically apparent liver injury attributed to daridorexant. Indeed, the two previously approved orexin receptor antagonists available in the United States were also found to be free of hepatic adverse effects.

N - Nervous system

QN - Nervous system

Daridorexant binds to and antagonizes the orexin receptors OX1R and OX2R (Ki = 0.47 and 0.93 nM, respectively) equipotentally. In clinical trials, daridorexant improved sleep onset and sleep maintenance, and patient-reported total sleep time. Patient-reported daytime sleepiness was also reportedly reduced. At a dose four times the maximum recommended dose, daridorexant does not prolong the QTc interval to any clinically relevant extent. Daridorexant is currently being assessed for a controlled substance schedule in the US. In a human abuse potential study, daridorexant showed some abuse potential at doses higher than the recommended dose (100-150 mg), indicated by similar “drug liking” ratings to zolpidem (30 mg) and suvorexant in recreational sedative drug users. However, at clinically relevant concentrations, daridorexant does not bind to abuse-associated CNS targets. In animal studies and clinical trials evaluating physical dependence, chronic administration of daridorexant did not produce withdrawal signs or symptoms upon drug discontinuation, indicating that the drug does not produce physical dependence.

The sleep and wake cycle is regulated by complex interactions between sleep-promoting systems, including inhibitory GABA activity, and wake-promoting systems, including orexins, acetylcholine and monoaminergic systems. Orexin, also called hypocretin, is a wake-promoting neuropeptide produced by a small group of neurons in the lateral hypothalamus. Orexin stabilizes wakefulness by activating orexin neurons with the highest activity during active wakefulness and minimal activity during sleep. Orexin neurons project to other wake-promoting neurons that also express orexin receptors: these include the histaminergic neurons of the tuberomammillary nucleus, noradrenergic neurons of the locus coeruleus, serotoninergic neurons of the dorsal raphe, dopaminergic neurons of the ventral tegmental area, and cholinergic neurons of the basal forebrain and the pedunculopontine and laterodorsal tegmental nuclei. These wake-promoting neurons are part of the ascending reticular activating system that operates under a feedback loop in the sleep and wake cycle. There are two identified types of orexin (OXA and OXB) that bind to orexin type 1 and 2 receptors (OX1R and OX2R), which are G-protein coupled receptors. OXA binds more preferentially to OX1R, while OX2R shows a dual affinity for OXA and OXB. The defined role of each orexin receptor is still unclear; however, there is some evidence suggesting that OX2R regulates sleep and wake, while OX1R have some role in sleep maintenance. Daridorexant blocks the binding of wake-promoting neuropeptides OXA and OXB to OX1R and OX2R, thereby suppressing wake drive. Daridorexant selectively targets orexin neurons and inhibits downstream neuronal pathways that promote wakefulness; however, it does not affect neuronal pathways that cause side effects commonly seen in positive allosteric GABA-A receptor modulators.