AHFS Class:

• Orexin Receptor Antagonists 28:24.40

Generic Name(s):

• Daridorexant

Daridorexant hydrochloride, an orexin receptor antagonist, is a hypnotic agent.1,8,9

Insomnia

Daridorexant is used for the treatment of insomnia, characterized by difficulty with sleep onset and/or sleep maintenance, in adults.1,2 In controlled clinical studies, daridorexant improved sleep onset and sleep maintenance compared with placebo.1,2

Clinical Experience

Efficacy of daridorexant in the management of insomnia was established in 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of 3 months' duration (studies 1 and 2) in adults who met DSM-5 criteria for insomnia disorder.1,2 The primary efficacy end points in both studies were the change from baseline to month 1 and month 3 in latency to persistent sleep (LPS, a measure of sleep induction) and wake after sleep onset (WASO, a measure of sleep maintenance), measured objectively by polysomnography in a sleep laboratory.1,2 Self-reported total sleep (sTST) at 1 and 3 months was a secondary end point in both studies.1,2

In study 1, a total of 930 patients were randomized to receive daridorexant 50 mg, daridorexant 25 mg, or placebo once nightly for 3 months.1,2 Patients had a mean age of 55.4 years (range: 18-88 years); 39.1%were ≥65 years of age, 5.8% were ≥75 years of age, 67.1% were female, 90% were white, 8% were Black or African American, and 1% were Asian.1 Both the 50- and 25-mg doses of daridorexant were more effective than placebo as measured by polysomnography (LPS, WASO) and sTST at 1 and 3 months.1,2

In study 2, a total of 924 patients were randomized to receive daridorexant 25 mg, daridorexant 10 mg, or placebo once nightly for 3 months.1,2 Patients had a mean age of 56.7 years (range: 19-85 years); 39.3% were ≥65 years of age, 6.1% were ≥75 years of age, 69% were female, 88% were white, 8% were Black or African American, and 4% were Asian.1 Daridorexant 25 mg was more effective than placebo as measured by polysomnography (LPS, WASO) and sTST at 1 and 3 months.1,2 Daridorexant 10 mg was not superior to placebo in these outcome measures and is not an approved dose of the drug.1,2

General

Pretreatment Screening

• Because sleep disturbances may be a manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after careful evaluation of the patient.1

Patient Monitoring

• Monitor for somnolence and CNS depressant effects.1

Administration

Daridorexant is administered orally no more than once per night, within 30 minutes before going to bed and ≥7 hours before the planned time of awakening.1

Administration with or soon after a meal decreases the rate of drug absorption and may delay the onset of effect.1

Dosage

Dosage of daridorexant hydrochloride is expressed in terms of daridorexant.1

Insomnia

For the management of insomnia, the recommended adult dosage of daridorexant is 25-50 mg administered no more than once per night within 30 minutes before bedtime, with at least 7 hours remaining prior to planned awakening.1

Dosage Modification for Concomitant Therapy

When administered concomitantly with a moderate cytochrome P-450 (CYP) 3A4 inhibitor, the recommended maximum dosage of daridorexant is 25 mg taken no more than once per night.1 Avoid concomitant use of strong CYP3A4 inhibitors or strong or moderate CYP3A4 inducers.1

When used concomitantly with other CNS depressants, dosage adjustment of daridorexant or the other CNS depressant may be necessary because of potential additive effects.1

Special Populations

Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh score 7-9), the maximum recommended dose of daridorexant is 25 mg no more than once per night.1 Use of daridorexant is not recommended in patients with severe hepatic impairment (Child-Pugh score ≥10).1

Renal Impairment

The manufacturer makes no specific dosage recommendations for patients with renal impairment.1

Geriatric Patients

Adjustment of daridorexant dosage in geriatric patients is not necessary based solely on age.1

Contraindications

• Narcolepsy.1

Warnings/Precautions

CNS Depressant Effects and Daytime Impairment

Daridorexant, like other hypnotic agents, has CNS depressant effects and may impair daytime wakefulness even when used as prescribed.1 Such effects may persist for up to several days after discontinuance of the drug.1 Advise patients receiving daridorexant about the potential for next day somnolence.1 The CNS depressant effects of daridorexant may increase the risk of falls, particularly in geriatric patients.1

The risk of daytime impairment is increased if daridorexant is taken with less than a full night of sleep remaining, if a higher than recommended dose of daridorexant is administered, or if daridorexant is used concomitantly with other CNS depressants.1 Patients taking daridorexant under these circumstances should be cautioned against driving and other activities requiring complete mental alertness the day after use.1

The effect of daridorexant 50 or 100 mg on next-morning driving performance was evaluated in a randomized, active- and placebo-controlled, crossover study in 60 healthy adults, half of whom were ≥65 years of age.1,4 Daridorexant had clinically important effects on standard driving performance tests compared with placebo when assessed 9 hours following bedtime administration of the first 50- or 100-mg dose in both geriatric subjects and younger adults.1,4 Although the mean effect on driving performance was not statistically significant (compared to placebo) after 4 consecutive nights of treatment with either dose of daridorexant, driving ability was impaired in some subjects taking the drug.1,4 Because of potential individual variation in sensitivity to daridorexant, patients receiving the drug should be cautioned about the potential for next-morning driving impairment.1,4

Concomitant use of daridorexant with other CNS depressants (e.g., alcohol, benzodiazepines, opiates, tricyclic antidepressants) increases the risk of CNS depression.1 Dosage adjustment of daridorexant and/or other CNS depressants may be necessary if the drugs are used concomitantly.1 Concomitant use of daridorexant with alcohol or other drugs to treat insomnia is not recommended.1 Concomitant administration of daridorexant with alcohol results in additive effects on psychomotor performance; advise patients not to consume alcohol in combination with the drug.1

Worsening of Depression and Suicidal Ideation

Worsening of depression and suicidal thoughts and actions (including completed suicides) have been reported in primarily depressed patients receiving sedative and hypnotic agents.1 Patients with psychiatric disorders, including insomnia, are at increased risk of suicide.1 Use daridorexant with caution in patients exhibiting symptoms of depression; monitoring of suicide risk and protective measures may be required.1

Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-like Symptoms

Sleep paralysis (an inability to move or speak for up to several minutes during sleep-wake transition) and hypnagogic/hypnopompic hallucinations, including vivid and disturbing perceptions, may occur in patients taking daridorexant.1 In addition, symptoms similar to mild cataplexy (e.g., leg weakness lasting from seconds to a few minutes) may occur either at night and/or during the day and may not be associated with an identified triggering event (e.g., laughter or surprise).1 Patients should be informed of the possibility of these effects.1

Complex Sleep Behaviors

Complex sleep behaviors, including sleep-walking, sleep-driving, and engaging in other activities while not fully awake (e.g., preparing and eating food, making phone calls, having sex) have been reported following use of hypnotic agents, including orexin receptor antagonists (e.g., daridorexant).1 Patients usually did not remember experiencing these complex sleep behaviors.1 These events can occur in hypnotic agent-naive as well as in hypnotic agent-experienced patients, and can occur following the first dose or at any time during treatment with daridorexant, with or without concomitant use of alcohol or other CNS depressants.1

Discontinue daridorexant immediately if a complex sleep behavior occurs.1

Patients with Compromised Respiratory Function

Effects of daridorexant on respiratory function should be considered if the drug is used in patients with compromised respiratory function.1

In a randomized, placebo-controlled crossover study in 25 patients with mild to moderate obstructive sleep apnea (OSA) not requiring continuous positive airway pressure (CPAP), daridorexant 50 mg given nightly was associated with a negligible increase in the average number of episodes of apnea and hypopnea per hour of sleep (mean apnea-hypopnea index [AHI]12 treatment difference of 0.74 for daridorexant compared with placebo) after 5 nights of use.1,5 However, clinically meaningful respiratory depressant effects in patients with OSA, including with long-term treatment, cannot be excluded.1 Daridorexant has not been studied in patients with moderate OSA requiring CPAP or severe OSA.1

In a randomized, placebo-controlled crossover study in 25 patients with moderate chronic obstructive pulmonary disease (COPD), daridorexant 50 mg was associated with a minimal numerical decrease (0.18%) in oxygen saturation after 5 nights of use; however, clinically meaningful respiratory depressant effects in patients with compromised respiratory function cannot be excluded.1 Daridorexant has not been studied in patients with severe COPD.1

Adequate Patient Evaluation

Because sleep disturbances may be a manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after careful evaluation of the patient.1 Failure of insomnia to remit after 7-10 days of daridorexant therapy, worsening of insomnia, or emergence of new cognitive or behavioral abnormalities may indicate the presence of an underlying psychiatric, physical, and/or medical condition requiring evaluation.1

Abuse Potential and Dependence

Daridorexant is a schedule IV controlled substance (C-IV).1,6

In an abuse-potential study conducted in recreational sedative drug users, administration of higher than recommended doses of daridorexant (100-150 mg) produced subjective responses (e.g., “drug liking”) similar to those produced by higher doses of zolpidem tartrate (30 mg) and suvorexant (150 mg).1 Because patients with a history of drug or alcohol abuse or addiction may be at increased risk for abuse of and addiction to daridorexant, such patients should be monitored carefully when receiving the drug.1

In clinical studies of 3 months' duration, there was evidence suggesting possible rebound insomnia following discontinuance of daridorexant.3 However, clinical studies of the drug provided no evidence of physical dependence with prolonged use, and no withdrawal symptoms were reported following drug discontinuance.1

Specific Populations

Pregnancy

There are no adequate data on the use of daridorexant in pregnant women to evaluate the risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.1

In animal reproduction studies, fetal toxicity or malformation was not observed at dosages resulting in up to 8 and 10 times the exposures achieved with the maximum recommended human dosage in rats and rabbits, respectively.1

In rats administered daridorexant during pregnancy and lactation, no adverse fetal or developmental effects were observed at dosages resulting in up to 9 times the exposures achieved with the maximum recommended human dosage.1

A pregnancy registry has been established to monitor pregnancy outcomes in women exposed to daridorexant during pregnancy; clinicians and patients are encouraged to call 833-400-9611.1

Lactation

Daridorexant and its metabolites are distributed into milk in rats; it is not known whether the drug or its metabolites are distributed into human milk.1 The effects of the drug on the breast-fed infant or on milk production also are unknown.1 Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for the drug and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

The manufacturer states that infants exposed to daridorexant through breast milk should be monitored for excessive sedation.1

Pediatric Use

Safety and efficacy of daridorexant have not been established in pediatric patients.1

Geriatric Use

In controlled clinical studies, approximately 39% of patients who received daridorexant were ≥65 years of age and 5.9% were ≥75 years of age.1,2 The incidence of somnolence and fatigue increased with patient age.1

The CNS depressant effects of daridorexant may increase the risk of falls, particularly in geriatric patients.1

Hepatic Impairment

In individuals with moderate hepatic impairment (Child-Pugh score 7-9), exposure of daridorexant may be increased to a clinically important extent, possibly resulting in increased frequency or severity of adverse reactions; therefore, the initial and maximum dosage of daridorexant in such patients is 25 mg no more than once per night.1

Daridorexant has not been studied in patients with severe hepatic impairment (Child-Pugh score ≥10) and use of the drug in such patients is not recommended.1

Renal Impairment

Mild to severe renal impairment (estimated GFR <30 mL/minute, not on dialysis) does not have a clinically important effect on daridorexant pharmacokinetics.1,7 Dialysis is unlikely to effectively remove daridorexant since the drug is highly protein bound.1,7

Common Adverse Effects

Common adverse effects reported in ≥5% of patients receiving daridorexant include headache and somnolence or fatigue.1

Daridorexant is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.1 The drug is a weak inhibitor of CYP3A4.3

Daridorexant and its major metabolites are not substrates of any major influx or efflux transporters.3 Daridorexant is a weak inhibitor of breast cancer resistance protein (BCRP).3

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 Inhibitors

Concomitant use with a strong or moderate CYP3A4 inhibitor increases exposure to daridorexant, which may increase the risk of adverse reactions.1

In patients receiving moderate CYP3A4 inhibitors, the maximum recommended dose of daridorexant is 25 mg no more than once per night.1

Concomitant use of daridorexant and strong CYP3A4 inhibitors is not recommended.1 Strong CYP3A4 inhibitors are expected to increase daridorexant AUC by >5-fold.3

Diltiazem

Concomitant administration of daridorexant (single 25-mg dose) and the moderate CYP3A4 inhibitor diltiazem (multiple 240-mg doses) increased the AUC and peak concentrations of daridorexant by approximately 2.4- and 1.4-fold, respectively.1,3

Itraconazole

Concomitant administration of daridorexant (single 50-mg dose) and the strong CYP3A4 inhibitor itraconazole (400 mg once daily) is predicted to increase the AUC of daridorexant by >4-fold.1,3

CYP3A4 Inducers

Concomitant use of daridorexant with a strong or moderate CYP3A4 inducer results in decreased systemic exposure and possibly reduced efficacy of daridorexant.1

Concomitant use of daridorexant and a strong or moderate CYP3A4 inducer is not recommended.1

Efavirenz

Concomitant administration of daridorexant (single 50-mg dose) and the moderate CYP3A4 inducer efavirenz (multiple 600-mg daily doses) decreased daridorexant AUC and peak concentrations by 61 and 35%, respectively.1,3

Rifampin

Concomitant administration of daridorexant (single 50-mg dose) and the strong CYP3A4 inducer rifampin (600 mg daily) is predicted to result in a substantial (>50%) decrease in the AUC of daridorexant.1,3

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP3A4 Substrates

Daridorexant is not expected to affect the pharmacokinetics of CYP3A4 substrates; dosage adjustments of other CYP3A4 substrates are not recommended.3

Midazolam

Concomitant administration of daridorexant (single 25-mg dose) and the CYP3A4 substrate midazolam (multiple 2-mg doses) increased the AUC of midazolam approximately 1.1-fold; no effects on midazolam AUC were observed on day 4 of multiple-dose administration of daridorexant 25 mg.1

Drugs Affected by Transporter Systems

Drugs Affected by BCRP

Daridorexant is not expected to affect the pharmacokinetics of BCRP substrates; no dosage adjustments are necessary when such drugs are used concomitantly with daridorexant.3

Rosuvastatin

Concomitant administration of daridorexant (25 mg nightly) and the BCRP substrate rosuvastatin (multiple 10-mg doses) decreased rosuvastatin AUC by approximately 10%.1

Drugs Affecting Gastric Acidity

Concomitant use of drugs affecting gastric acidity is not expected to substantially affect the pharmacokinetics of daridorexant; no dosage adjustment of daridorexant is recommended with such concomitant use.3

Famotidine

Concomitant administration of daridorexant (single 50-mg dose) and famotidine (single 40-mg dose) reduced daridorexant peak concentrations by approximately 40%, but had no effect on daridorexant AUC.1

CNS Depressants

Concomitant use of daridorexant and other CNS depressants (e.g., alcohol, benzodiazepines, opiates, tricyclic antidepressants) may result in additive impairment of psychomotor performance and CNS depression.1 When daridorexant is used concomitantly with other CNS depressant drugs, dosage reduction of daridorexant and/or the other CNS depressant may be necessary.1 Concomitant use of daridorexant with other hypnotic agents is not recommended.1

Alcohol

An additive effect on psychomotor impairment was observed following single-dose administration of daridorexant 50 mg with alcohol (blood concentration 0.6 g/L); no clinically important pharmacokinetic interaction was observed.1 Alcohol consumption should be avoided in patients receiving daridorexant.1

Citalopram

No clinically important effects on psychomotor performance were observed when daridorexant 50 mg was administered in healthy subjects receiving citalopram (20 mg daily) at steady state.1 An increase in daridorexant AUC of approximately 10% and no effect on citalopram AUC were observed.1 No dosage adjustment is recommended when daridorexant is used concomitantly with citalopram.3

Description

Daridorexant is a dual orexin-1 and orexin-2 receptor antagonist.1,8,9 The mechanism of action of daridorexant in the treatment of insomnia is thought to be related to antagonism of orexin receptors.1,8,9 Orexin (also known as hypocretin) receptors located in the brain promote and maintain wakefulness; these receptors are activated by the binding of orexin A and B, neuropeptides produced in the lateral hypothalamus.1,8,9,10,11 Loss of orexin-producing neurons and decreased CSF orexin concentrations have been associated with narcolepsy in humans, while increased orexin activity may be associated with insomnia.1,8,9,10,11 Daridorexant binds to orexin-1 and orexin-2 receptors and blocks the binding of orexin A and B; blockade of these receptors is thought to suppress the wake drive and promote sleep.1,8,9

Daridorexant plasma exposure is dose-proportional at oral doses of 25-50 mg.1 The pharmacokinetic profile of daridorexant is similar following multiple-dose and single-dose administration with no accumulation observed.1 Peak plasma concentrations occur within 1-2 hours following oral administration of daridorexant.1 Absolute oral bioavailability of the drug is 62%.1 When daridorexant is administered with a high-fat and high-calorie meal in healthy subjects, time to maximum plasma concentrations is delayed by 1.3 hours and maximum plasma concentrations are decreased by 16%; however, total exposure is not affected.1 Daridorexant is 99.7% bound to plasma proteins, and the terminal half-life of the drug is approximately 8 hours.1 Daridorexant undergoes extensive metabolism and is primarily metabolized by cytochrome P-450 (CYP) 3A4 (89%), with other CYP isoenzymes individually contributing to <3% of the drug's metabolic clearance.1 The primary route of excretion is via feces (approximately 57%), followed by urine (approximately 28%), primarily as metabolites; trace amounts of the parent drug are excreted in feces and urine.1 Age, sex, race, body size, and renal impairment do not have a clinically important effect on the pharmacokinetics of daridorexant.1,7

Advice to Patients

• Advise patients to take daridorexant only once per night within 30 minutes of going to bed and only when able to stay in bed for ≥7 hours before being active again.1 Advise patients that taking daridorexant with or immediately after a meal may delay its effect.1
• Advise patients to not take daridorexant if alcohol has been consumed.1
• Inform patients that daridorexant can cause CNS depressant effects and impair daytime wakefulness even when used as prescribed.1 CNS depressant effects may increase the risk of falls in some patients.1 The risk of daytime impairment is increased if daridorexant is taken with less than a full night of sleep remaining or if a higher than recommended dose is taken; patients should be cautioned to avoid driving or other activities requiring complete mental alertness if the drug is taken under these circumstances.1
• Advise patients to be alert to and immediately report worsening depression or suicidal ideation.1
• Inform patients and their families that sleep paralysis, hypnagogic/hypnopompic hallucinations, and mild cataplexy-like symptoms may occur.1
• Advise patients of the risk of complex sleep behaviors, including sleep-walking, sleep-driving, preparing and eating food, making phone calls, or having sex while not being fully awake.1 Advise patients to discontinue daridorexant and immediately contact a clinician if a complex sleep behavior occurs.1
• Inform patients about the abuse potential of the drug.1 Advise patients to not increase the dose unless otherwise instructed by a clinician and to inform a clinician if insomnia worsens or does not improve.1
• Advise women to inform their clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise patients of the existence of a pregnancy registry that monitors pregnancy outcomes in women exposed to the drug during pregnancy.1
• Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant or past illnesses (e.g., depression, substance abuse, sleep apnea).1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Idorsia Pharmaceuticals US Inc. Daridorexant hydrochloride (Quviviq^®) tablets prescribing information. Radnor, PA; 2022 Oct. [Web]

2. Mignot E, Mayleben D, Fietze I et al. 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; 21:125-39. [PubMed 35065036]

3. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 214985Orig1s000: Integrated review. From FDA website. [Web]

4. Muehlan C, Brooks S, Vaillant C et al. Driving Performance after Bedtime Administration of Daridorexant, Assessed in a Sensitive Simulator. Clin Pharmacol Ther . 2022; 111:1334-42. [PubMed 35426136]

5. Boof ML, Dingemanse J, Lederer K et al. Effect of the new dual orexin receptor antagonist daridorexant on nighttime respiratory function and sleep in patients with mild and moderate obstructive sleep apnea. Sleep . 2021; 44:zsaa275. [PubMed 33305817]

6. Drug Enforcement Administration, Department of Justice. Schedules of controlled substances: placement of daridorexant into Schedule IV. 21 CFR Part 1308. Final Rule. [Docket No. DEA-949] Fed Regist. 2022; 87:20313-8. [Web]

7. Berger B, Muehlan C, Klein G et al. Pharmacokinetics of daridorexant, a dual orexin receptor antagonist, are not affected by renal impairment. Clin Transl Sci . 2021; 14:2132-8. [PubMed 34121345]

8. Ziemichód W, Grabowska K, Kurowska A et al. A Comprehensive Review of Daridorexant, a Dual-Orexin Receptor Antagonist as New Approach for the Treatment of Insomnia. Molecules . 2022; 27:6041. [PubMed 36144776]

9. Markham A. Daridorexant: First Approval. Drugs . 2022; 82:601-7. [PubMed 35298826]

10. Wang C, Wang Q, Ji B et al. The Orexin/Receptor System: Molecular Mechanism and Therapeutic Potential for Neurological Diseases. Front Mol Neurosci . 2018; 11:220. [PubMed 30002617]

11. Janto K, Prichard JR, Pusalavidyasagar S. An Update on Dual Orexin Receptor Antagonists and Their Potential Role in Insomnia Therapeutics. J Clin Sleep Med . 2018; 14:1399-1408. [PubMed 30092886]

12. American Academy of Sleep Medicine. Obstructive sleep apnea. From AASM website. Accessed 2022 Dec 28. [Web]