Note: Limit long-term use (>4 weeks) to cases for which nonpharmacologic treatments are not available or not effective and benefits are felt to outweigh risks (ACP [Qaseem 2016]).
Insomnia, sleep onset or sleep maintenance: Oral: 25 to 50 mg once daily within 30 minutes of bedtime and at least 7 hours before planned time of awakening. Maximum: 50 mg/day (Mignot 2022; manufacturer's labeling).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No dosage adjustment necessary.
Mild impairment (Child-Pugh class A): No dosage adjustment necessary.
Moderate impairment (Child-Pugh class B): Maximum 25 mg/day.
Severe impairment (Child-Pugh class C): Use is not recommended (has not been studied).
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as hydrochloride:
Quviviq: 25 mg, 50 mg
No
C-IV
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214985s000lbl.pdf#page=22, must be dispensed with this medication.
Oral: Administer within 30 minutes of bedtime with ≥7 hours remaining before planned time of awakening. Onset may be delayed if taken with or immediately after food.
Insomnia, sleep onset or sleep maintenance: Treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance, in adults.
Daridorexant is frequently associated with CNS depression, including daytime sedation, drowsiness, and fatigue, which may impair driving.
Mechanism: Dose-related; related to the pharmacologic action via orexin receptor antagonism which is believed to suppress wake drive (Ref).
Onset: Rapid; sleep onset occurs within 30 to 40 minutes (Ref). CNS-depressant effects may persist for up to several days after discontinuing use.
Risk factors:
• Daytime impairment is increased with less than a full night of sleep (ie, <7 hours)
• Higher than recommended doses
• Concomitant administration with other CNS depressants (eg, benzodiazepines, opioids, tricyclic antidepressants, alcohol)
• Older adults (risk of falling)
Events associated with complex sleep disorders, including hazardous sleep-related activities such as sleepwalking, sleep-driving, cooking and eating food, making phone calls, or having sex while asleep have been reported with other orexin receptor antagonists at therapeutic doses, with or without concomitant use of alcohol or other CNS depressants. Patients do not usually remember these events.
Onset: Varied; can occur at any time (following the first dose or any subsequent doses).
Daridorexant may infrequently cause hallucinations (hypnogenic hallucinations and hypnopompic hallucinations). In addition, sleep paralysis (inability to move or speak for several minutes during sleep-wake transitions) may occur. Mild cataplexy occurring during the night or day has been reported with other orexin receptor antagonists, and is not always associated with a triggering event (eg, laughter, surprise).
Mechanism: Unknown whether these events are specifically related to antagonism of orexin receptors; however, orexin neuron loss is associated with the symptoms of narcolepsy which suggests orexin receptor antagonists can theoretically produce narcolepsy symptoms, particularly cataplexy (Ref).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.
1% to 10%:
Gastrointestinal: Nausea (3%)
Nervous system: Dizziness (3%), drowsiness (≤6%) (table 1) , fatigue (≤6%) (table 2) , headache (6% to 7%)
Drug (Daridorexant) |
Placebo |
Dose |
Number of Patients (Daridorexant) |
Number of Patients (Placebo) |
Comments |
---|---|---|---|---|---|
6% |
4% |
25 mg once daily |
310 |
309 |
Described as "somnolence or fatigue" |
5% |
4% |
50 mg once daily |
308 |
309 |
Described as "somnolence or fatigue" |
Drug (Daridorexant) |
Placebo |
Dose |
Number of Patients (Daridorexant) |
Number of Patients (Placebo) |
Comments |
---|---|---|---|---|---|
6% |
4% |
25 mg once daily |
310 |
309 |
Described as "somnolence or fatigue" |
5% |
4% |
50 mg once daily |
308 |
309 |
Described as "somnolence or fatigue" |
<1%: Nervous system: Hallucination (hypnogenic hallucinations and hypnopompic hallucinations) (table 3) , sleep paralysis (table 4)
Drug (Daridorexant) |
Placebo |
Dose |
Number of Patients (Daridorexant) |
Number of Patients (Placebo) |
Comments |
---|---|---|---|---|---|
0.6% |
0% |
25 mg once daily |
310 |
309 |
Hypnagogic and hypnopompic hallucinations |
Drug (Daridorexant) |
Placebo |
Dose |
Number of Patients (Daridorexant) |
Number of Patients (Placebo) |
---|---|---|---|---|
0.5% |
0% |
25 mg once daily |
310 |
309 |
0.3% |
0% |
50 mg once daily |
308 |
309 |
Frequency not defined: Nervous system: Daytime sedation (including driving impairment)
Narcolepsy.
Concerns related to adverse effects:
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving). Next-day somnolence may occur when taken as prescribed. Daytime driving impairment risk increases when taken with less than a full night's sleep, and/or when a higher than recommended dose is taken. CNS depression may increase the risk of falls, particularly in older adults. CNS depression may persist for several days following discontinuation of therapy.
• Complex sleep behaviors: Complex sleep behaviors, including sleep walking, sleep driving, preparing and eating food, making phone calls, or having sex while not fully awake, may occur following use of daridorexant. Patients usually do not remember these events. May occur with first use or any subsequent use with or without the use of alcohol or other CNS depressants. Discontinue immediately if a patient experiences a complex sleep behavior.
• Sleep-related effects: Sleep paralysis (inability to move or speak for up to several minutes during sleep-wake transitions), hypnagogic/hypnopompic hallucinations, and mild cataplexy may occur. Cataplexy symptoms may include periods of leg weakness lasting from seconds to a few minutes, can occur both at night and during the day, and may not be associated with a triggering event (eg, laughter, surprise).
Disease-related concerns:
• Depression: Use with caution in patients with depression; worsening of depression, including suicide or suicidal ideation, has been reported with the use of hypnotics.
• Hepatic impairment: Use with caution in patients with moderate hepatic impairment (Child-Pugh class B); frequency and severity of adverse reactions may be increased. Use is not recommended in patients with severe hepatic impairment (Child-Pugh class C).
• Respiratory disease: Use with caution in patients with respiratory compromise; has not been studied in patients with moderate obstructive sleep apnea (OSA) requiring continuous positive airway pressure, severe OSA, or severe chronic obstructive pulmonary disease.
Special populations:
• Older adults: Use with caution due to increased risk of somnolence, fatigue, drowsiness, and falls.
Other warnings/precautions:
• Appropriate use: Symptomatic treatment of insomnia should be initiated only after careful evaluation of potential causes of sleep disturbance. Failure of sleep disturbance to resolve after 7 to 10 days may indicate psychiatric and/or medical illness.
Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): May enhance the CNS depressant effect of Daridorexant. Risk X: Avoid combination
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CNS Depressants: Daridorexant may enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Daridorexant. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Daridorexant. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Daridorexant. Management: Limit the daridorexant dose to 25 mg, no more than once per night, when combined with moderate CYP3A4 inhibitors. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Daridorexant. Risk X: Avoid combination
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Melatonin: May enhance the sedative effect of Hypnotics (Nonbenzodiazepine). Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: Hypnotics (Nonbenzodiazepine) may enhance the CNS depressant effect of Oxybate Salt Products. Risk X: Avoid combination
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification
Adverse events were not observed in animal reproduction studies when daridorexant was administered during the period of organogenesis to rats and rabbits in doses equivalent to 8 and 10 times the maximum recommended human dose, respectively.
Data collection to monitor pregnancy and infant outcomes following exposure to daridorexant is ongoing. Health care providers are encouraged to enroll patients exposed to daridorexant during pregnancy in the pregnancy registry (1-833-400-9611). Patients may also enroll themselves.
It is not known if daridorexant is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Infants exposed via breast milk should be monitored for excessive sedation.
LFTs (baseline and as clinically indicated); respiratory rate (as clinically indicated).
Daridorexant blocks the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R, which is thought to suppress wake drive (Roch 2021; manufacturer's labeling).
Onset: ~35 to 40 minutes (25 mg); ~30 minutes (50 mg) (Mignot 2022).
Distribution: Vd: 31 L.
Protein binding: Plasma: 99.7%.
Metabolism: Primarily hepatic via CYP3A4 (89%).
Bioavailability: 62%.
Half-life elimination: ~8 hours.
Time to peak: 1 to 2 hours; administration with a high-fat, high-calorie meal may delay by an additional 1.3 hours.
Excretion: Feces: ~57%; urine: ~28%.
Hepatic impairment: AUC may be increased in patients with moderate hepatic impairment (has not been studied in severe hepatic impairment).
Tablets (Quviviq Oral)
25 mg (per each): $18.28
50 mg (per each): $18.28
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