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Daridorexant: Drug information

Daridorexant: Drug information
(For additional information see "Daridorexant: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Pharmacologic Category
  • Hypnotic, Miscellaneous;
  • Orexin Receptor Antagonist
Dosing: Adult

Note: Intended for short-term use (≤4 to 8 weeks), preferably in conjunction with nonpharmacologic therapies (ACP [Qaseem 2016]; Winkelman 2022). Limit long-term use to cases for which nonpharmacologic treatments are not available or not effective and benefits are felt to outweigh risks (AASM [Sateia 2017]).

Insomnia, sleep onset or sleep maintenance

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.

Dosing: Kidney Impairment: Adult

No dosage adjustment necessary.

Dosing: Hepatic Impairment: Adult

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).

Dosing: Older Adult

See adult dosing; use caution due to increased risk of adverse reactions.

Product Availability

Quviviq: FDA approved January 2022; anticipated availability in May 2022.

Medication Guide and/or Vaccine Information Statement (VIS)

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.

Administration: Adult

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.

Use: Labeled Indications

Insomnia, sleep onset or sleep maintenance: Treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance, in adults.

Adverse Reactions

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%), fatigue (≤6%), headache (6% to 7%)

<1%: Nervous system: Hallucination (hypnogenic hallucinations and hypnopompic hallucinations), sleep paralysis

Frequency not defined: Nervous system: Daytime sedation (including driving impairment)

Contraindications

Narcolepsy.

Warnings/Precautions

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.

Metabolism/Transport Effects

Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

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

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

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

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

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

Pregnancy Considerations

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.

Breastfeeding Considerations

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.

Monitoring Parameters

LFTs (baseline and as clinically indicated); respiratory rate (as clinically indicated).

Mechanism of Action

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).

Pharmacokinetics

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%.

Pharmacokinetics: Additional Considerations

Hepatic impairment: AUC may be increased in patients with moderate hepatic impairment (has not been studied in severe hepatic impairment).

REFERENCES

  1. Mignot E, Mayleben D, Fietze I, et al; investigators. Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. Lancet Neurol. 2022;21(2):125-139. doi:10.1016/S1474-4422(21)00436-1 [PubMed 35065036]
  2. Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD; Clinical Guidelines Committee of the American College of Physicians. Management of chronic insomnia disorder in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2016;165(2):125-133. doi:10.7326/M15-2175 [PubMed 27136449]
  3. Quviviq (daridorexant) [prescribing information]. Radnor, PA: Idorsia Pharmaceuticals US Inc; January 2022.
  4. 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. doi:10.1007/s00213-021-05954-0 [PubMed 34415378]
  5. Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307-349. doi:10.5664/jcsm.6470 [PubMed 27998379]
  6. Winkelman JW. Overview of the treatment of insomnia in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed January 18, 2022.
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