Daridorexant

Daridorexant is indicated for the treatment of adults with insomnia characterized by difficulties with sleep onset and/or sleep maintenance. Daridorexant has also been found to improve daytime functioning at a dose of 50mg but not at 25mg. A major systematic review and network meta-analysis of insomnia medications published in 2022 found that daridorexant had an effect size (standardized mean difference (SMD)) against placebo for treatment of insomnia at 4weeks of 0.23 (95% –0.01 to 0.48). Treatment with daridorexant is generally safe and well tolerated for up to one year, with improvements in sleep and daytime functioning persisting throughout treatment. The Department of Defense (DOD) is testing the effectiveness of daridorexant in patients with post-traumatic stress disorder (PTSD) as the link between insomnia and PTSD is well established. Available forms In the United States and Canada, daridorexant is available in the form of 25 and 50mg oral tablets. It is provided as the salt daridorexant hydrochloride, with each tablet containing 27 or 54mg of this substance (equivalent to 25 or 50mg daridorexant). ==Contraindications==

Daridorexant is contraindicated in people with narcolepsy. It is not recommended in people with severe hepatic impairment, whereas a lower maximum dose is recommended in people with moderate hepatic impairment. Concomitant use of daridorexant with strong CYP3A4 inhibitors and moderate to strong CYP3A4 inducers is not recommended and should be avoided due to unfavorable modification of daridorexant exposure. ==Side effects==

Side effects of daridorexant include headache (6% at 25mg vs. 7% at 50mg vs. 5% for placebo), somnolence or fatigue (includes somnolence, sedation, fatigue, hypersomnia, and lethargy) (6% at 25mg vs. 5% at 50mg vs. 4% for placebo), dizziness (2% at 25mg vs. 3% at 50mg vs. 2% for placebo), and nausea (0% at 25mg vs. 3% at 50mg vs. 2% for placebo). Orexin receptor antagonists can affect the reward system and produce drug-liking responses in humans. At higher doses of 100 and 150mg (greater than the recommended maximum dose), drug liking with daridorexant was similar to that with zolpidem (30mg) and suvorexant (150mg). No reports indicative of misuse liability were observed in clinical trials with daridorexant, although these studies excluded participants with history of drug or alcohol misuse. ==Overdose==

There is limited clinical experience with overdose of daridorexant. Overdose of the medication at a dose of up to four times the maximum recommended dose may result in adverse effects including somnolence, muscle weakness, cataplexy-like symptoms, sleep paralysis, attention disturbances, fatigue, headache, and constipation. There is no specific antidote to overdose of daridorexant. == Interactions ==

CYP3A4 inhibitors and inducers can increase and decrease exposure to daridorexant, respectively. The weak CYP3A4 inhibitor ranitidine (150mg) is predicted to increase overall exposure to daridorexant by 1.5-fold; the moderate CYP3A4 inhibitor diltiazem (240mg) increased exposure to daridorexant by 2.4-fold; and the strong CYP3A4 inhibitor itraconazole, on the basis of physiologically-based pharmacokinetic modeling, would be expected to increase daridorexant exposure by more than 4-fold. Gastric pH modifiers like famotidine can decrease peak levels of daridorexant without affecting total exposure. Alcohol and selective serotonin reuptake inhibitors (SSRIs) like citalopram have not shown significant pharmacokinetic interactions with daridorexant. Coadministration of daridorexant with other sedatives like benzodiazepines, opioids, tricyclic antidepressants, and alcohol may increase the risk of central nervous system depression and daytime impairment. Daridorexant has not been found to significantly influence the pharmacokinetics of other drugs including midazolam (a CYP3A4 substrate), rosuvastatin (a BCRP substrate), and the SSRI citalopram (primarily a CYP2C19 substrate). ==Pharmacology==

Pharmacodynamics Daridorexant acts as a selective dual antagonist of the orexin (hypocretin) receptors OX1 and OX2. Elimination Daridorexant is eliminated primarily by feces (57%) then by urine (28%). The duration of action of daridorexant in terms of sedative effects is approximately 8hours with a 50mg dose. ==Chemistry==

Daridorexant is a small-molecule compound. Its molecular formula is C23H23N6O2Cl and its molecular weight is 450.93g/mol (or 487.38g/mol for the hydrochloride). Daridorexant hydrochloride is a white to light yellowish powder. Daridorexant is a lipophilic compound and daridorexant hydrochloride is very slightly soluble in water. ==History==

Daridorexant was originated by Actelion Pharmaceuticals and was further developed by Idorsia. It was patented in 2013 and was first described in the scientific literature in 2017. It was in development for 25 years by the husband-wife team Jean-Paul and Martine Clozel. Daridorexant was approved for medical use in the United States in January 2022 (The earlier orexin receptor antagonists suvorexant and lemborexant are not available in the European Union.) Regulatory review is also ongoing in Canada and Switzerland and is planned for the United Kingdom. ==Society and culture==

Legal status Daridorexant is a schedule IV controlled substance under the Controlled Substances Act in the United States. Daridorexant (Quviviq) was approved by Health Canada in April 2023. == References ==