Introduction
Daridorexant is a novel dual orexin receptor antagonist approved for the treatment of insomnia in adults. Marketed under the brand name QUVIVIQ®, it represents a newer class of sleep medications that target the orexin neurotransmitter system rather than acting as generalized central nervous system depressants like traditional sedative-hypnotics.
Mechanism of Action
Daridorexant selectively antagonizes both orexin receptor types (OX1R and OX2R). Orexins (hypocretins) are neuropeptides produced in the hypothalamus that promote wakefulness. By blocking the binding of orexins to their receptors, daridorexant suppresses wake drive, thereby facilitating sleep initiation and maintenance without causing widespread neuronal depression.
Indications
- Treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance in adults
Dosage and Administration
Recommended dosage: 25-50 mg once per night Administration: Taken orally within 30 minutes before bedtime with at least 7 hours remaining before planned awakening Special populations:- Hepatic impairment: 25 mg maximum dose for moderate hepatic impairment (Child-Pugh B); contraindicated in severe hepatic impairment
- Renal impairment: No dosage adjustment needed for mild to moderate impairment; use with caution in severe impairment
- Geriatric patients: Consider starting with 25 mg dose
- CYP3A4 inhibitors: Reduce dose to 25 mg when used with moderate CYP3A4 inhibitors
Pharmacokinetics
Absorption: Rapid absorption with median Tmax of 1.5-2 hours; high-fat meal delays absorption by approximately 1.5 hours Distribution: Volume of distribution ~31 L; protein binding ~99.7% Metabolism: Primarily metabolized by CYP3A4 with minor contributions from CYP2C9; forms inactive metabolites Elimination: Half-life ~8 hours; primarily excreted in feces (57%) and urine (28%)Contraindications
- Narcolepsy
- Severe hepatic impairment
- Concomitant use with strong CYP3A4 inhibitors
- History of hypersensitivity to daridorexant or any component of the formulation
Warnings and Precautions
CNS Depression: May impair next-day alertness and performance; caution patients about driving or operating machinery Sleep Paralysis/Hallucinations: May occur along with hypnagogic/hypnopompic experiences Cataplexy-like Symptoms: Rare reports of muscle weakness or periods of leg weakness Complex Sleep Behaviors: May include sleepwalking, sleep driving, and other activities without full awareness Depression/Suicidal Thoughts: Worsening of depression or emergence of suicidal ideation may occur Respiratory Depression: Use with caution in patients with compromised respiratory function Abuse Potential: Schedule IV controlled substance; potential for abuse and dependenceDrug Interactions
Strong CYP3A4 inhibitors: Contraindicated (e.g., clarithromycin, itraconazole) Moderate CYP3A4 inhibitors: Reduce daridorexant dose to 25 mg (e.g., fluconazole, diltiazem) CYP3A4 inducers: May decrease daridorexant exposure (e.g., rifampin, carbamazepine) CNS depressants: Additive effects with alcohol, benzodiazepines, opioids, and other sedatives Digoxin: May increase digoxin concentrations (P-gp interaction)Adverse Effects
Common (≥2%):- Headache (6%)
- Somnolence (5%)
- Fatigue (4%)
- Dizziness (3%)
- Nausea (2%)
- Complex sleep behaviors
- Daytime somnolence
- Sleep paralysis
- Hypnagogic/hypnopompic hallucinations
- Cataplexy-like symptoms
- Worsening depression/suicidal ideation
Monitoring Parameters
- Sleep quality and duration assessment
- Next-day alertness and cognitive function
- Mood changes, especially in patients with depression
- Signs of complex sleep behaviors
- Hepatic function in patients with liver impairment
- Adherence and potential misuse patterns
Patient Education
- Take only when you can get a full night's sleep (at least 7 hours)
- Avoid alcohol and other CNS depressants while taking daridorexant
- Do not engage in potentially hazardous activities after taking until you know how it affects you
- Report any unusual sleep behaviors, sleep paralysis, or hallucinations
- Inform healthcare providers about all medications you're taking
- Do not increase dose without medical supervision
- Gradually taper under medical supervision if discontinuing after prolonged use
- Store securely to prevent misuse by others
References
1. FDA prescribing information: QUVIVIQ (daridorexant). 2022 2. Mignot E, Mayleben D, Fietze I, et al. Safety and efficacy of daridorexant in patients with insomnia disorder: two phase 3 randomized controlled trials. Lancet Neurol. 2022;21(2):125-139 3. Roch C, Bergamini G, Steiner MA, Clozel M. Nonclinical pharmacology of daridorexant: a new dual orexin receptor antagonist for the treatment of insomnia. Psychopharmacology (Berl). 2021;238(10):2693-2708 4. Boss C, Roch C. Orexin receptor antagonists: historical perspectives and future opportunities. Curr Top Med Chem. 2021;21(15):1324-1344 5. ClinicalTrials.gov: Phase 3 studies of daridorexant (NCT03545191, NCT03575104)