Daridorexant is an oral dual orexin receptor antagonist (DORA) indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance in adults. It works by blocking orexin A and B from binding to OX1R and OX2R receptors, suppressing the wake drive. As with other hypnotic medications, patients should be aware of the possibility of complex sleep behaviors that may occur while taking daridorexant, such as sleepwalking, sleep-driving, and other activities while not fully awake. In addition, daridorexant may cause worsening of depression or suicidality, particularly in patients with pre-existing depression. Patients should be informed of the risks of complex sleep behaviors and changes in mood or suicidality prior to starting daridorexant and advised to seek medical help immediately if any of these effects occur. The risk of CNS depression and next day impairment may also occur with daridorexant, and patients should be alerted to the importance of getting a full night's sleep (a minimum of 7 hours of sleep before waking) and ensuring they feel awake before driving or operating machinery. The FDA approved daridorexant in January 2022.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Only administer within 30 minutes before going to bed, and only when there is at least 7 hours remaining before the planned time of awakening.
-Time to sleep onset may be delayed if taken with or soon after a meal.
The most common adverse reaction reported with use of daridorexant in a double-blind, placebo controlled clinical trial was headache, which occurred in 6% of patients taking the 25 mg/night and 7% of patients taking 50 mg/night compared to 5% of patients on placebo. Fatigue (which included reports of somnolence or drowsiness, sedation, hypersomnia, and lethargy) was reported in 6% of patients taking the 25 mg dose and 5% of patients on 50 mg compared to 4% of patients on placebo. Dizziness (which also included vertigo and labyrinthitis) was also a reported adverse reaction in the clinical trial, affecting 2% of patients on 25 mg and 3% of patients on 50 mg compared to 2% of patients on placebo. Abnormal dreams and bad dreams (nightmares) have been reported during postmarketing use of daridorexant. In order to minimize psychomotor impairment and other side effect risks, patients should follow all instructions for appropriate use, including to avoid consuming alcohol and other CNS depressants with daridorexant.
Nausea was reported in clinical trials of daridorexant, occurring in 3% of patients in the 50 mg/night group compared to 2% of patients on placebo. There were no reports of nausea in the 25 mg/night group.
In clinical trials of daridorexant, sleep paralysis (an inability to move or speak for several minutes prior to falling asleep or after waking) occurred in 0.5% of patients on the 25 mg dose and 0.3% of patients on the 50 mg dose compared to no patients in the placebo group. Hypnagogic/hypnopompic hallucinations (vivid and disturbing perceptions occurring at transitions from sleep to wake) were also reported in 0.6% of patients on 25 mg (compared to no reports in the 50 mg group or placebo). While not reported in clinical trials of daridorexant, patients taking orexin receptor antagonists may also experience cataplexy (periods of myasthenia lasting from seconds to a few minutes). Patients should be educated about these potential side effects.
Complex sleep-related behaviors, which includes sleepwalking (somnambulism), sleep-driving, and completing activities while not fully awake (such as making phone calls, having sex, or preparing and eating food) can occur with the use of hypnotic medications, including daridorexant. Patients often have no recollection of these events. These activities can occur at any point in treatment and in both hypnotic-naive and experienced patients. They may also occur with or without concomitant use of alcohol or other CNS depressants. Patients should discontinue use of daridorexant immediately if any of these complex sleep-related behaviors occur and contact their health care provider about these events.
In primarily depressed patients treated with sedative/hypnotics, worsening of depression and suicidal ideation, thoughts, and actions (including completed suicides) have been reported. Patients with psychiatric disorders, including insomnia, are at increased risk of suicide. Any emergence of changes in thinking, moods, or behavior while a patient is taking daridorexant should be evaluated.
Daridorexant may carry a potential risk of psychological dependence, misuse, and/or abuse. Abuse may be associated with an increased risk of somnolence, daytime drowsiness, impaired reaction time, and impaired driving skills. In a human abuse potential study, daridorexant (at doses of 50 mg, 100 mg, and 150 mg) was compared to zolpidem 30 mg, suvorexant 150 mg, and placebo. At 50 mg, daridorexant demonstrated lower "drug liking" ratings than zolpidem and suvorexant but the ratings were significantly higher than placebo. Higher doses of daridorexant (above the maximum recommended dose) showed similar ratings of "drug liking" to zolpidem and suvorexant. Chronic use of daridorexant in animal studies and clinical trials did not result in withdrawal signs or symptoms upon drug discontinuation, suggesting that daridorexant does not lead to physiological dependence.
Hypersensitivity reactions (including angioedema, rash, and urticaria) have been reported during postmarketing use of daridorexant.
Daridorexant is contraindicated in patients with a history of hypersensitivity to daridorexant or any components of daridorexant. Angioedema with pharyngeal involvement has been reported.
The use of daridorexant is contraindicated in patients with narcolepsy. Patients taking daridorexant may experience sleep paralysis (an inability to move or speak for several minutes) at the time of sleep-wake transitions or hypnagogic or hypnopompic hallucinations (vivid or disturbing perceptions). Symptoms similar to mild cataplexy have also occurred with orexin receptor antagonists like daridorexant and may cause periods of leg weakness that are brief, lasting only a few seconds to a few minutes. These episodes can occur at any time of day and may not be related to any identified trigger (e.g., laughter or surprise). Prescribers should discuss these possible events with patients prior to prescribing daridorexant.
Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, treatment of insomnia with daridorexant should be initiated only after careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new cognitive or behavioral changes may be the result of an unrecognized underlying psychiatric or physical disorder, and can emerge during the course of treatment with hypnotic drugs. A variety of cognitive and behavioral changes (e.g., amnesia, anxiety, hallucinations and other neuro-psychiatric symptoms) have been reported to occur in association with the use of hypnotics. As with other hypnotics, daridorexant should be administered with caution in patients exhibiting symptoms of depression. Patients with psychiatric disorders, including insomnia, are at increased risk of suicide. In primarily depressed patients treated with hypnotics, worsening of depression and suicidal ideation (including completed suicides) have been reported. Monitoring of suicide risk and protective measures may be required.
Patients should be instructed to avoid driving or operating machinery or performing other tasks requiring mental alertness after taking their dose. Next-day impairment is possible, particularly when daridorexant is taken with less than a full night of sleep remaining or if a higher than the recommended dose is taken. The risk is also increased during coadministration with other CNS depressants or with medications that increase systemic exposure to daridorexant. Prescribers should advise patients about the potential for next-day somnolence. Because daridorexant can cause drowsiness, the risk of falls is increased. Consider dose adjustment of daridorexant in patients taking other CNS depressants, and concurrent use of other hypnotics should be avoided. Additive adverse effects may occur when alcohol is coadministered with daridorexant; therefore, ethanol ingestion should be avoided. Hypnotics, including daridorexant, have the potential to cause complex sleep-related behaviors (e.g., sleep-driving, preparing food, having sex) while not fully awake and frequently having no memory of the event. These can occur with the first or any subsequent use of hypnotic medication use, regardless of whether the individual uses alcohol or other CNS depressants concomitantly. The risk of these effects should be discussed with patients before prescribing dardiorexant, and patients should discontinue use of the medication immediately if they experience any of these sleep behaviors.
All sedative/hypnotic medications have CNS depressant effects. The benefits of treatment with daridorexant should be weighed against the potential for adverse respiratory effects in patients with compromised respiratory function or preexisting pulmonary disease. Daridorexant has not been studied in patients with moderate obstructive sleep apnea (OSA) requiring CPAP or severe OSA. Daridorexant has not been studied in patients with severe chronic obstructive pulmonary disease (COPD).
Daridorexant is a controlled substance and should be used with caution in patients who may be at increased risk of substance abuse or addiction. Because individuals with a history of alcoholism or abuse or addiction to other drugs may be at increased risk for abuse of or addiction to daridorexant, follow such patients carefully. In an abuse potential study comparing subjective ratings of "drug liking", patients with a history of recreational sedative use showed lower preference for daridorexant at prescribed doses compared to zolpidem (30 mg) and suvorexant (150 mg) but significantly higher "drug liking" ratings for daridorexant than placebo. At daridorexant doses of 100 and 150 mg (2 and 3 times the maximum recommended dose, respectively), ratings of likeability were similar to zolpidem and suvorexant. In placebo-controlled, phase 3 clinical trials, patients with insomnia received daridorexant for up to 12 months; there were no reported concerns of abuse in these trials. In animal studies and clinical trials assessing physical dependence, there were no reported withdrawal signs or symptoms following discontinuation, indicating that physical dependence is not likely to occur with the use of daridorexant.
Daridorexant has not been studied in patients with severe hepatic disease (Child Pugh score 10 or greater) and is not recommended for use in this population. For patients with moderate hepatic impairment (Child Pugh score 7 to 9), a reduced dosage is recommended.
Clinical studies of daridorexant for insomnia included geriatric adults 65 years of age and older and no dosage adjustment was necessary based on age. However, during clinical trials, the risk of somnolence and fatigue did increase with patient age. Because daridorexant can increase somnolence and drowsiness, patients, particularly geriatric individuals, are at higher risk of falls. The U.S. Omnibus Budget Reconciliation Act (OBRA) regulates the use of sedative/hypnotic agents for residents of long-term care facilities (LTCFs); when a drug is being used to induce sleep or treat a sleep disorder, the facility should attempt periodic tapering of the medication as stated in the OBRA guidelines or provide documentation of continued medical necessity.
There are no clinical data regarding the use of daridorexant during human pregnancy to evaluate for drug-associated risks of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal studies, oral administration of daridorexant to pregnant rats and rabbits at the time of organogenesis did not cause malformation or fetal toxicity at doses 8 to 10 times the maximum recommended human dose (MRHD) of 50 mg. When administered to pregnant rats during gestation and lactation, there were no maternal or developmental toxicities noted at doses up to 9 times the MRHD. A pregnancy registry will monitor pregnancy outcomes in women exposed to daridorexant during pregnancy. Women and healthcare providers can call Idorsia Pharmaceuticals at 1-833-400-9611 for registry information.
Use daridorexant with caution during breast-feeding. There are no clinical studies or data regarding the presence of daridorexant in breast milk, effects on the breastfed infant, or possible changes on milk production. Infants exposed to breast milk that contains daridorexant should be monitored for excessive sedation. Daridorexant and its metabolites were present in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breast-feeding, mother's clinical need for daridorexant, and potential adverse effects in the infant should all be considered when deciding whether to use daridorexant in a breast-feeding mother.
For the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance:
Oral dosage:
Adults: 25 mg to 50 mg PO once per night within 30 minutes of going to bed and with at least 7 hours remaining before the planned time of awakening. Adjust to clinical response and tolerability. Max: 50 mg/night. Time to sleep onset may be delayed if taken with or immediately following a meal. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Maximum Dosage Limits:
-Adults
50 mg/day PO.
-Geriatric
50 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Moderate hepatic impairment (Child-Pugh score 7 to 9): Do not exceed 25 mg PO once each night.
Severe hepatic impairment (Child-Pugh score 10 or higher): Use is not recommended.
Patients with Renal Impairment Dosing
No dosage adjustments are needed.
*non-FDA-approved indication
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with daridorexant. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and daridorexant is a P-gp inhibitor.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of daridorexant is necessary. If daridorexant is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with daridorexant may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If daridorexant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Daridorexant is a weak inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with daridorexant may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of daridorexant could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If daridorexant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Daridorexant is a weak inhibitor of CYP3A.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of daridorexant is necessary; avoid when hydrocodone is used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like daridorexant can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If daridorexant is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of daridorexant is necessary. If daridorexant is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like daridorexant can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If daridorexant is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Adagrasib: (Major) Avoid concomitant use of daridorexant and adagrasib. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Afatinib: (Moderate) If the concomitant use of daridorexant and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of daridorexant. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-gp substrate and daridorexant is a P-gp inhibitor. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC of afatinib was 119% when coadministered with the same P-gp inhibitor, and 111% when the inhibitor was administered 6 hours after afatinib.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of daridorexant is necessary. If daridorexant is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A substrate, and coadministration with CYP3A inhibitors like daridorexant can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If daridorexant is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
Alprazolam: (Major) Avoid coadministration of alprazolam and daridorexant due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with daridorexant, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A substrate and daridorexant is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
Amitriptyline: (Moderate) Monitor for excessive sedation and somnolence during coadministration of daridorexant and tricyclic antidepressants. Dosage adjustments of daridorexant and the tricyclic antidepressant may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with daridorexant is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; daridorexant is a P-gp inhibitor.
Amobarbital: (Major) Avoid concomitant use of daridorexant and amobarbital. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Additive CNS effects, such as sedation and psychomotor impairment, are also possible. Daridorexant is a CYP3A substrate and amobarbital is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of daridorexant and clarithromycin. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Anxiolytics; Sedatives; and Hypnotics: (Major) Use of daridorexant with other sedatives and hypnotics should generally be avoided due to duplication of treatments and due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with daridorexant, a reduction in dose of one or both agents may be needed.
Apalutamide: (Major) Avoid concomitant use of daridorexant and apalutamide. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased daridorexant overall exposure by over 50%.
Aprepitant, Fosaprepitant: (Major) Limit the daridorexant dose to 25 mg if coadministered with aprepitant/fosaprepitant. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and aprepitant/fosaprepitant is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Aripiprazole: (Moderate) Monitor for aripiprazole-related adverse reactions during concomitant use of daridorexant. Patients receiving both a CYP2D6 inhibitor plus daridorexant may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP3A and CYP2D6 substrate; daridorexant is a weak CYP3A inhibitor.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid concomitant use of daridorexant and butalbital. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Additive CNS effects, such as sedation and psychomotor impairment, are also possible. Daridorexant is a CYP3A substrate and butalbital is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with daridorexant may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of daridorexant could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If daridorexant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Daridorexant is a weak inhibitor of CYP3A.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of daridorexant is necessary. If daridorexant is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like daridorexant can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If daridorexant is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Major) Avoid concomitant use of daridorexant and atazanavir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Atazanavir; Cobicistat: (Major) Avoid concomitant use of daridorexant and atazanavir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%. (Major) Avoid concomitant use of daridorexant and cobicistat. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with daridorexant is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; daridorexant is a P-gp inhibitor.
Belladonna; Opium: (Moderate) Concomitant use of opium with daridorexant may cause excessive sedation and somnolence. Limit the use of opium with daridorexant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Benzhydrocodone; Acetaminophen: (Moderate) Consider a reduced dose of benzhydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of daridorexant is necessary. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like daridorexant can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of benzhydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If daridorexant is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to benzhydrocodone.
Berotralstat: (Major) Limit the daridorexant dose to 25 mg if coadministered with berotralstat. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving daridorexant. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving daridorexant. Concurrent use may increase betrixaban exposure resulting in an increased bleeding risk; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a P-gp substrate; daridorexant is a P-gp inhibitor. Coadministration of other P-gp inhibitors increased betrixaban exposure by 2 to 3-fold.
Bexarotene: (Major) Avoid concomitant use of daridorexant and bexarotene. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and bexarotene is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with daridorexant may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and daridorexant is a P-gp inhibitor.
Bosentan: (Major) Avoid concomitant use of daridorexant and bosentan. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with daridorexant is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and daridorexant is a weak CYP3A inhibitor.
Buprenorphine: (Moderate) Concomitant use of buprenorphine and daridorexant can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when daridorexant is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping daridorexant, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If daridorexant is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and daridorexant is a CYP3A inhibitor.
Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and daridorexant can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when daridorexant is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping daridorexant, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If daridorexant is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and daridorexant is a CYP3A inhibitor.
Butalbital; Acetaminophen: (Major) Avoid concomitant use of daridorexant and butalbital. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Additive CNS effects, such as sedation and psychomotor impairment, are also possible. Daridorexant is a CYP3A substrate and butalbital is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid concomitant use of daridorexant and butalbital. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Additive CNS effects, such as sedation and psychomotor impairment, are also possible. Daridorexant is a CYP3A substrate and butalbital is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid concomitant use of daridorexant and butalbital. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Additive CNS effects, such as sedation and psychomotor impairment, are also possible. Daridorexant is a CYP3A substrate and butalbital is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%. (Moderate) Concomitant use of codeine with daridorexant may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of daridorexant could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If daridorexant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Daridorexant is a weak inhibitor of CYP3A.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid concomitant use of daridorexant and butalbital. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Additive CNS effects, such as sedation and psychomotor impairment, are also possible. Daridorexant is a CYP3A substrate and butalbital is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%. (Moderate) Concomitant use of codeine with daridorexant may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of daridorexant could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If daridorexant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Daridorexant is a weak inhibitor of CYP3A.
Butorphanol: (Moderate) Concomitant use of butorphanol with daridorexant may cause excessive sedation and somnolence. Limit the use of butorphanol with daridorexant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Carbamazepine: (Major) Avoid concomitant use of daridorexant and carbamazepine. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Concomitant use may also increase carbamazepine concentrations. Daridorexant is a CYP3A substrate and inhibitor and carbamazepine is a CYP3A substrate and strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased daridorexant overall exposure by over 50%.
Celecoxib; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with daridorexant is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of daridorexant, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Cenobamate: (Major) Avoid concomitant use of daridorexant and cenobamate. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Ceritinib: (Major) Avoid concomitant use of daridorexant and ceritinib. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and ceritinib is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Chloramphenicol: (Major) Avoid concomitant use of daridorexant and chloramphenicol. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Chlordiazepoxide: (Major) Monitor for excessive sedation and somnolence during use of daridorexant with chlordiazepoxide. Dosage adjustments may be necessary when administered together because of potentially additive CNS effects. Use of more than 2 hypnotics should be avoided due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with daridorexant, a reduction in dose of one or both agents may be needed. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Chlordiazepoxide; Amitriptyline: (Major) Monitor for excessive sedation and somnolence during use of daridorexant with chlordiazepoxide. Dosage adjustments may be necessary when administered together because of potentially additive CNS effects. Use of more than 2 hypnotics should be avoided due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with daridorexant, a reduction in dose of one or both agents may be needed. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants. (Moderate) Monitor for excessive sedation and somnolence during coadministration of daridorexant and tricyclic antidepressants. Dosage adjustments of daridorexant and the tricyclic antidepressant may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Chlordiazepoxide; Clidinium: (Major) Monitor for excessive sedation and somnolence during use of daridorexant with chlordiazepoxide. Dosage adjustments may be necessary when administered together because of potentially additive CNS effects. Use of more than 2 hypnotics should be avoided due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with daridorexant, a reduction in dose of one or both agents may be needed. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with daridorexant may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of daridorexant could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If daridorexant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Daridorexant is a weak inhibitor of CYP3A.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of daridorexant is necessary; avoid when hydrocodone is used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like daridorexant can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If daridorexant is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Ciprofloxacin: (Major) Limit the daridorexant dose to 25 mg if coadministered with ciprofloxacin. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and ciprofloxacin is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Cisapride: (Major) Avoid concomitant use of cisapride and daridorexant; use increases cisapride exposure and the risk for adverse effects such as QT/QTc prolongation and torsade de pointes (TdP). Cisapride is a CYP3A substrate and daridorexant is a weak CYP3A inhibitor. Concomitant use of cisapride with CYP3A inhibitors is disallowed under the Propulsid Limited Access Program.
Clarithromycin: (Major) Avoid concomitant use of daridorexant and clarithromycin. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Clomipramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of daridorexant and tricyclic antidepressants. Dosage adjustments of daridorexant and the tricyclic antidepressant may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Clonazepam: (Major) Monitor for excessive sedation and somnolence during use of daridorexant with clonazepam. Dosage adjustments may be necessary when administered together because of potentially additive CNS effects. Use of more than 2 hypnotics should be avoided due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with daridorexant, a reduction in dose of one or both agents may be needed. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with daridorexant and monitor for adverse reactions. If daridorexant is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A; daridorexant is a weak CYP3A inhibitor.
Cobicistat: (Major) Avoid concomitant use of daridorexant and cobicistat. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Cobimetinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with daridorexant is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-gp substrate; daridorexant is a P-gp inhibitor.
Codeine: (Moderate) Concomitant use of codeine with daridorexant may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of daridorexant could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If daridorexant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Daridorexant is a weak inhibitor of CYP3A.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with daridorexant may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of daridorexant could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If daridorexant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Daridorexant is a weak inhibitor of CYP3A.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with daridorexant may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of daridorexant could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If daridorexant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Daridorexant is a weak inhibitor of CYP3A.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with daridorexant may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of daridorexant could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If daridorexant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Daridorexant is a weak inhibitor of CYP3A.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with daridorexant may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of daridorexant could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If daridorexant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Daridorexant is a weak inhibitor of CYP3A.
Colchicine: (Major) Avoid concomitant use of colchicine and daridorexant due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and daridorexant is a P-gp inhibitor.
Conivaptan: (Major) Limit the daridorexant dose to 25 mg if coadministered with conivaptan. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Crizotinib: (Major) Limit the daridorexant dose to 25 mg if coadministered with crizotinib. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Cyclosporine: (Major) Limit the daridorexant dose to 25 mg and closely monitor cyclosporine whole blood trough concentrations as appropriate if coadministered together. The dose of cyclosporine may need to be adjusted. Concomitant use may increase the exposure of both drugs and the risk for adverse effects. Daridorexant is a CYP3A substrate and weak CYP3A and P-gp inhibitor; cyclosporine is a CYP3A and P-gp substrate and moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with daridorexant is necessary in patients with creatinine clearance (CrCl) greater than 50 mL/minute. Avoid coadministration in patients with CrCl less than 50 mL/minute when dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery. Avoid coadministration in patients with CrCl less than 30 mL/minute in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function. Dabigatran is a P-gp substrate and daridorexant is a P-gp inhibitor. Concomitant use has been observed to increase dabigatran overall exposure by 1.4-fold.
Dabrafenib: (Major) Avoid concomitant use of daridorexant and dabrafenib. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and dabrafenib is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Danazol: (Major) Limit the daridorexant dose to 25 mg if coadministered with danazol. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and danazol is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Darunavir: (Major) Avoid concomitant use of daridorexant and darunavir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Darunavir; Cobicistat: (Major) Avoid concomitant use of daridorexant and cobicistat. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%. (Major) Avoid concomitant use of daridorexant and darunavir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concomitant use of daridorexant and cobicistat. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%. (Major) Avoid concomitant use of daridorexant and darunavir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%. (Moderate) Coadministration of tenofovir alafenamide with daridorexant may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and daridorexant is a P-gp inhibitor.
Delavirdine: (Major) Avoid concomitant use of daridorexant and delavirdine. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and delavirdine is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Desipramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of daridorexant and tricyclic antidepressants. Dosage adjustments of daridorexant and the tricyclic antidepressant may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with daridorexant is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and daridorexant is a CYP3A inhibitor.
Digoxin: (Moderate) Increase monitoring of serum digoxin concentrations and watch for potential signs and symptoms of clinical toxicity when starting, adjusting, or discontinuing daridorexant. Concurrent use may increase digoxin exposure. Digoxin is a P-gp substrate with a narrow therapeutic index and daridorexant is a P-gp inhibitor.
Diltiazem: (Major) Limit the daridorexant dose to 25 mg if coadministered with diltiazem. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Concomitant use of diltiazem increased daridorexant overall exposure 2.4-fold in drug interaction studies.
Disopyramide: (Moderate) Monitor for an increase in disopyramide-related adverse reactions if coadministration with daridorexant is necessary as concurrent use may increase disopyramide exposure. Disopyramide is a CYP3A substrate and daridorexant is a weak CYP3A inhibitor. Although specific drug interaction studies have not been done for disopyramide, cases of life-threatening interactions have been reported when disopyramide was coadministered with moderate and strong CYP3A inhibitors.
Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with daridorexant is necessary as concurrent use may increase dofetilide exposure. Daridorexant is a weak CYP3A inhibitor. Dofetilide is a minor CYP3A substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A inhibitors may increase the risk of arrhythmia (torsade de pointes).
Dolutegravir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with daridorexant. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and daridorexant is a P-gp inhibitor.
Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with daridorexant. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and daridorexant is a P-gp inhibitor.
Dolutegravir; Rilpivirine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with daridorexant. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and daridorexant is a P-gp inhibitor.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with daridorexant may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and daridorexant is a P-gp inhibitor.
Doxepin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of daridorexant and tricyclic antidepressants. Dosage adjustments of daridorexant and the tricyclic antidepressant may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Doxorubicin Liposomal: (Major) Avoid coadministration of daridorexant with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a P-gp substrate and daridorexant is a P-gp inhibitor. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of daridorexant with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a P-gp substrate and daridorexant is a P-gp inhibitor. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Dronedarone: (Major) Limit the daridorexant dose to 25 mg if coadministered with dronedarone. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and dronedarone is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Duvelisib: (Major) Limit the daridorexant dose to 25 mg if coadministered with duvelisib. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and duvelisib is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Edoxaban: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of daridorexant is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and daridorexant is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with daridorexant. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of daridorexant. Increased concentrations of edoxaban may occur during concomitant use of daridorexant; monitor for increased adverse effects of edoxaban.
Efavirenz: (Major) Avoid concomitant use of daridorexant and efavirenz. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. During drug interaction studies, concomitant use of efavirenz decreased daridorexant overall exposure by over 50%.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of daridorexant and efavirenz. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. During drug interaction studies, concomitant use of efavirenz decreased daridorexant overall exposure by over 50%. (Moderate) Coadministration of tenofovir disoproxil fumarate with daridorexant may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and daridorexant is a P-gp inhibitor.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of daridorexant and efavirenz. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. During drug interaction studies, concomitant use of efavirenz decreased daridorexant overall exposure by over 50%. (Moderate) Coadministration of tenofovir disoproxil fumarate with daridorexant may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and daridorexant is a P-gp inhibitor.
Elagolix: (Major) Avoid concomitant use of daridorexant and elagolix. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and elagolix is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of daridorexant and elagolix. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and elagolix is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Eliglustat: (Major) Coadministration of eliglustat and daridorexant is not recommended in poor CYP2D6 metabolizers (PMs). In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Eliglustat is a CYP3A and CYP2D6 substrate; daridorexant is a weak CYP3A inhibitor. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration of eliglustat with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concomitant use of daridorexant and cobicistat. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%. (Moderate) Coadministration of tenofovir alafenamide with daridorexant may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and daridorexant is a P-gp inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of daridorexant and cobicistat. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%. (Moderate) Coadministration of tenofovir disoproxil fumarate with daridorexant may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and daridorexant is a P-gp inhibitor.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with daridorexant may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and daridorexant is a P-gp inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with daridorexant may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and daridorexant is a P-gp inhibitor.
Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with daridorexant may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and daridorexant is a P-gp inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with daridorexant may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and daridorexant is a P-gp inhibitor.
Encorafenib: (Major) Avoid concomitant use of daridorexant and encorafenib. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased daridorexant overall exposure by over 50%.
Enzalutamide: (Major) Avoid concomitant use of daridorexant and enzalutamide. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and enzalutamide is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased daridorexant overall exposure by over 50%.
Erythromycin: (Major) Limit the daridorexant dose to 25 mg if coadministered with erythromycin. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and erythromycin is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Eslicarbazepine: (Major) Avoid concomitant use of daridorexant and eslicarbazepine. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and eslicarbazepine is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Estazolam: (Major) Monitor for excessive sedation and somnolence during use of daridorexant with estazolam. Dosage adjustments may be necessary when administered together because of potentially additive CNS effects. Use of more than 2 hypnotics should be avoided due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with daridorexant, a reduction in dose of one or both agents may be needed. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Eszopiclone: (Major) Use of daridorexant with other sedatives and hypnotics should generally be avoided due to duplication of treatments and due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with daridorexant, a reduction in dose of one or both agents may be needed.
Ethanol: (Major) Advise patients to avoid the use of alcohol with daridorexant as concurrent use increases the risk for additive CNS depression and impairment.
Etravirine: (Major) Avoid concomitant use of daridorexant and etravirine. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and etravirine is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with daridorexant is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-gp substrate and daridorexant is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with daridorexant is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; daridorexant is a P-gp inhibitor.
Fedratinib: (Major) Limit the daridorexant dose to 25 mg if coadministered with fedratinib. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Felodipine: (Moderate) Concurrent use of felodipine and daridorexant should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A substrate and daridorexant is a weak CYP3A inhibitor. Concurrent use of another weak CYP3A inhibitor increased felodipine AUC and Cmax by approximately 50%.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of daridorexant is necessary. If daridorexant is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like daridorexant can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If daridorexant is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or daridorexant; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and daridorexant is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A inhibitors, including daridorexant, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the potential outcomes of combination therapy with multiple weak CYP3A inhibitors and flibanserin should be discussed with the patient.
Fluconazole: (Major) Limit the daridorexant dose to 25 mg if coadministered with fluconazole. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Flurazepam: (Major) Monitor for excessive sedation and somnolence during use of daridorexant with flurazepam. Dosage adjustments may be necessary when administered together because of potentially additive CNS effects. Use of more than 2 hypnotics should be avoided due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with daridorexant, a reduction in dose of one or both agents may be needed. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Fluvoxamine: (Major) Limit the daridorexant dose to 25 mg if coadministered with fluvoxamine. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Fosamprenavir: (Major) Limit the daridorexant dose to 25 mg if coadministered with fosamprenavir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and fosamprenavir is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Fosphenytoin: (Major) Avoid concomitant use of daridorexant and fosphenytoin. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased daridorexant overall exposure by over 50%.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with coadministration of glecaprevir and daridorexant as increased plasma concentrations of glecaprevir may occur resulting in increased risk of glecaprevir-related adverse events. Glecaprevir is a substrate of P-gp and daridorexant is a P-gp inhibitor. (Moderate) Monitor for an increase in pibrentasvir-related adverse effects if concomitant use of daridorexant is necessary. Concomitant use may increase pibrentasvir exposure. Pibrentasvir is a substrate of P-gp and daridorexant is a P-gp inhibitor.
Grapefruit juice: (Major) Avoid concomitant use of daridorexant and grapefruit juice. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and grapefruit juice is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of daridorexant is necessary; avoid when hydrocodone is used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like daridorexant can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If daridorexant is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of daridorexant is necessary; avoid when hydrocodone is used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like daridorexant can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If daridorexant is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of daridorexant is necessary; avoid when hydrocodone is used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like daridorexant can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If daridorexant is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of daridorexant is necessary. If daridorexant is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like daridorexant can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If daridorexant is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Idelalisib: (Major) Avoid concomitant use of daridorexant and idelalisib. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and idelalisib is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Imatinib: (Major) Limit the daridorexant dose to 25 mg if coadministered with imatinib. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and imatinib is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Imipramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of daridorexant and tricyclic antidepressants. Dosage adjustments of daridorexant and the tricyclic antidepressant may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Indinavir: (Major) Avoid concomitant use of daridorexant and indinavir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and indinavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Isavuconazonium: (Major) Limit the daridorexant dose to 25 mg if coadministered with isavuconazonium. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and isavuconazonium is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concomitant use of daridorexant and rifampin. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and rifampin is a strong CYP3A inducer. Concomitant use of rifampin decreased daridorexant overall exposure by over 50% in drug interaction studies.
Isoniazid, INH; Rifampin: (Major) Avoid concomitant use of daridorexant and rifampin. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and rifampin is a strong CYP3A inducer. Concomitant use of rifampin decreased daridorexant overall exposure by over 50% in drug interaction studies.
Isradipine: (Minor) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with daridorexant is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and daridorexant is a weak CYP3A inhibitor.
Itraconazole: (Major) Avoid concomitant use of daridorexant and itraconazole. Daridorexant is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. In drug interaction studies, concomitant use of itraconazole increased daridorexant overall exposure by over 400%, increasing the risk for daridorexant-related adverse effects.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of daridorexant is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and daridorexant is a weak CYP3A inhibitor.
Ketoconazole: (Major) Avoid concomitant use of daridorexant and ketoconazole. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with daridorexant may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and daridorexant is a P-gp inhibitor.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of daridorexant and clarithromycin. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Lapatinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with daridorexant is necessary. Lapatinib is a P-gp substrate and daridorexant is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
Lefamulin: (Major) Avoid coadministration of daridorexant with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; concomitant use may also increase daridorexant exposure. Daridorexant may be administered with intravenous lefamulin. If concomitant use with oral lefamulin is necessary, limit the daridorexant dose to 25 mg. Lefamulin is a P-gp substrate and oral lefamulin is a moderate CYP3A inhibitor and daridorexant is a CYP3A substrate and P-gp inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Lemborexant: (Major) Limit the dose of lemborexant to 5 mg PO once daily if coadministered with daridorexant as concomitant use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A substrate; daridorexant is a weak CYP3A inhibitor. Coadministration with a weak CYP3A inhibitor is predicted to increase lemborexant exposure by less than 2-fold. Use together is not recommended as both are in the same class and used to treat insomnia.
Lenacapavir: (Major) Limit the daridorexant dose to 25 mg if coadministered with lenacapavir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and lenacapavir is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Letermovir: (Major) Limit the daridorexant dose to 25 mg if coadministered with letermovir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and letermovir is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold. Letermovir/cyclosporine combinations are strong 3A inhibitors and should not be used in combination with daridorexant.
Levoketoconazole: (Major) Avoid concomitant use of daridorexant and ketoconazole. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Levorphanol: (Major) Concomitant use of levorphanol with daridorexant may cause excessive sedation and somnolence. Limit the use of levorphanol with daridorexant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with daridorexant is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and daridorexant is a weak CYP3A inhibitor.
Lidocaine; Epinephrine: (Moderate) Monitor for lidocaine toxicity if coadministration with daridorexant is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and daridorexant is a weak CYP3A inhibitor.
Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with daridorexant is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and daridorexant is a weak CYP3A inhibitor.
Lomitapide: (Major) Decrease the dose of lomitapide by one-half not to exceed 30 mg/day PO if coadministration with daridorexant is necessary. Concomitant use may significantly increase the serum concentration of lomitapide. Lomitapide is a CYP3A substrate and daridorexant is a weak CYP3A inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A inhibitors.
Lonafarnib: (Major) Avoid concomitant use of daridorexant and lonafarnib. Concomitant use may increase the exposure of both drugs and the risk for adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Daridorexant is a CYP3A substrate and weak CYP3A inhibitor and lonafarnib is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with daridorexant. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and daridorexant is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with daridorexant. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and daridorexant is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Lopinavir; Ritonavir: (Major) Avoid concomitant use of daridorexant and ritonavir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Lorazepam: (Major) Monitor for excessive sedation and somnolence during use of daridorexant with lorazepam. Dosage adjustments may be necessary when administered together because of potentially additive CNS effects. Use of more than 2 hypnotics should be avoided due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with daridorexant, a reduction in dose of one or both agents may be needed. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Lorlatinib: (Major) Avoid concomitant use of daridorexant and lorlatinib. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and lorlatinib is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Lovastatin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with daridorexant is necessary. Concomitant use may increase lovastatin exposure. Lovastatin is a P-gp substrate; daridorexant is a P-gp inhibitor.
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of daridorexant and lumacaftor; ivacaftor. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and lumacaftor/ivacaftor is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased daridorexant overall exposure by over 50%.
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of daridorexant and lumacaftor; ivacaftor. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and lumacaftor/ivacaftor is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased daridorexant overall exposure by over 50%.
Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with daridorexant is necessary. Concomitant use may increase maraviroc exposure. Maraviroc is a P-gp substrate; daridorexant is a P-gp inhibitor.
Mavacamten: (Major) Avoid concomitant use of daridorexant and mavacamten. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and mavacamten is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Mefloquine: (Moderate) Monitor for an increase in mefloquine-related adverse effects if concomitant use of daridorexant is necessary. Concomitant use may increase mefloquine exposure. Mefloquine is a CYP3A and P-gp substrate and daridorexant is a weak CYP3A and P-gp inhibitor.
Meperidine: (Moderate) Consider a reduced dose of meperidine with frequent monitoring for respiratory depression and sedation if concurrent use of daridorexant is necessary. If daridorexant is discontinued, meperidine plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to meperidine. Meperidine is a substrate of CYP3A and daridorexant is a weak CYP3A inhibitor. Concomitant use with daridorexant can increase meperidine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of meperidine.
Meprobamate: (Major) Use of daridorexant with other sedatives and hypnotics should generally be avoided due to duplication of treatments and due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with daridorexant, a reduction in dose of one or both agents may be needed.
Methadone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of daridorexant is necessary. If daridorexant is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; daridorexant is a weak CYP3A inhibitor. Concomitant use with daridorexant can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone.
Methohexital: (Major) Avoid coadministration of daridorexant and methohexital as concurrent use may decrease daridorexant exposure which may reduce efficacy. Additive CNS effects, such as sedation and psychomotor impairment, are also possible. Lemborexant is a CYP3A4 substrate; methohexital is a moderate CYP3A4 inducer.
Midazolam: (Moderate) Use caution when midazolam is coadministered with daridorexant. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and daridorexant is a weak CYP3A inhibitor. Concomitant use has been observed to increase midazolam overall exposure by 1.4-fold.
Mifepristone: (Major) Avoid concomitant use of daridorexant and mifepristone. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and mifepristone is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Mitotane: (Major) Avoid concomitant use of daridorexant and mitotane. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and mitotane is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased daridorexant overall exposure by over 50%.
Morphine: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with daridorexant is necessary; decrease the dose of morphine as necessary. Morphine is a P-gp substrate and daridorexant is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
Morphine; Naltrexone: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with daridorexant is necessary; decrease the dose of morphine as necessary. Morphine is a P-gp substrate and daridorexant is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
Nafcillin: (Major) Avoid concomitant use of daridorexant and nafcillin. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and nafcillin is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Nalbuphine: (Moderate) Concomitant use of nalbuphine with daridorexant may cause excessive sedation and somnolence. Limit the use of nalbuphine with daridorexant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Naldemedine: (Moderate) Monitor for naldemedine-related adverse reactions if coadministered with daridorexant. Naldemedine plasma concentrations may increase during concomitant use. Naldemedine is a P-gp substrate; daridorexant is a P-gp inhibitor.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and daridorexant. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and daridorexant is a weak CYP3A and P-gp inhibitor.
Nefazodone: (Major) Avoid concomitant use of daridorexant and nefazodone. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Nelfinavir: (Major) Avoid concomitant use of daridorexant and nelfinavir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and nelfinavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Netupitant, Fosnetupitant; Palonosetron: (Major) Limit the daridorexant dose to 25 mg if coadministered with netupitant. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Nilotinib: (Major) Limit the daridorexant dose to 25 mg if coadministered with nilotinib. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Nimodipine: (Moderate) Monitor blood pressure and reduce the dose of nimodipine as clinically appropriate if coadministration with daridorexant is necessary. Concurrent use may increase nimodipine exposure. Nimodipine is a CYP3A substrate and daridorexant is a weak CYP3A inhibitor.
Nintedanib: (Moderate) Monitor for nintedanib-related adverse reactions if concomitant use of daridorexant is necessary. Concomitant use may increase nintedanib exposure. Nintedanib is a P-gp substrate, and a minor substrate of CYP3A and daridorexant is a dual P-gp and CYP3A inhibitor. Coadministration with another dual P-gp and CYP3A inhibitor increased nintedanib AUC by 60%.
Nirmatrelvir; Ritonavir: (Major) Avoid concomitant use of daridorexant and ritonavir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Nirogacestat: (Major) Limit the daridorexant dose to 25 mg if coadministered with nirogacestat. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with daridorexant due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A substrate and daridorexant is a CYP3A inhibitor. Coadministration with another CYP3A inhibitor increased the AUC of nisoldipine by 30% to 45%.
Nortriptyline: (Moderate) Monitor for excessive sedation and somnolence during coadministration of daridorexant and tricyclic antidepressants. Dosage adjustments of daridorexant and the tricyclic antidepressant may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Oliceridine: (Moderate) Concomitant use of oliceridine with daridorexant may cause excessive sedation and somnolence. Limit the use of oliceridine with daridorexant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid concomitant use of daridorexant and rifabutin. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Oxazepam: (Major) Monitor for excessive sedation and somnolence during use of daridorexant with oxazepam. Dosage adjustments may be necessary when administered together because of potentially additive CNS effects. Use of more than 2 hypnotics should be avoided due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with daridorexant, a reduction in dose of one or both agents may be needed. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of daridorexant is necessary. If daridorexant is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like daridorexant can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If daridorexant is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Pazopanib: (Major) Avoid coadministration of pazopanib and daridorexant due to the potential for increased pazopanib exposure. Pazopanib is a P-gp substrate; daridorexant is a P-gp inhibitor. Consider selection of an alternative concomitant medication with no or minimal potential to inhibit P-gp.
Pentazocine; Naloxone: (Moderate) Concomitant use of pentazocine with daridorexant may cause excessive sedation and somnolence. Limit the use of pentazocine with daridorexant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Perphenazine; Amitriptyline: (Moderate) Monitor for excessive sedation and somnolence during coadministration of daridorexant and tricyclic antidepressants. Dosage adjustments of daridorexant and the tricyclic antidepressant may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Pexidartinib: (Major) Avoid concomitant use of daridorexant and pexidartinib. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and pexidartinib is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Phenobarbital: (Major) Avoid concomitant use of daridorexant and phenobarbital. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Additive CNS effects, such as sedation and psychomotor impairment, are also possible. Daridorexant is a CYP3A substrate and phenobarbital is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased daridorexant overall exposure by over 50%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concomitant use of daridorexant and phenobarbital. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Additive CNS effects, such as sedation and psychomotor impairment, are also possible. Daridorexant is a CYP3A substrate and phenobarbital is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased daridorexant overall exposure by over 50%.
Phenytoin: (Major) Avoid concomitant use of daridorexant and phenytoin. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased daridorexant overall exposure by over 50%.
Pimozide: (Major) Avoid concomitant use of pimozide and daridorexant. Concomitant use may result in elevated pimozide concentrations resulting in QT prolongation, ventricular arrhythmias, and sudden death. Pimozide is CYP3A substrate, and daridorexant is a weak CYP3A inhibitor.
Pitavastatin: (Moderate) Monitor for an increase in pitavastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with daridorexant is necessary. Concomitant use may increase pitavastatin exposure. Pitavastatin is a P-gp substrate; daridorexant is a P-gp inhibitor.
Posaconazole: (Major) Avoid concomitant use of daridorexant and posaconazole. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Concomitant use may also increase posaconazole exposure. Daridorexant is a CYP3A substrate and P-gp inhibitor and posaconazole is a P-gp substrate and strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Pralsetinib: (Major) Avoid concomitant use of daridorexant with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a P-gp substrate and daridorexant is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased the overall exposure of pralsetinib by 81%.
Primidone: (Major) Avoid concomitant use of daridorexant and primidone. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Additive CNS effects, such as sedation and psychomotor impairment, are also possible. Daridorexant is a CYP3A substrate and primidone is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased daridorexant overall exposure by over 50%.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and daridorexant due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and daridorexant is a P-gp inhibitor.
Propafenone: (Moderate) Monitor for increased propafenone toxicity if coadministered with daridorexant; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and daridorexant with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate; daridorexant is a weak CYP3A inhibitor.
Protriptyline: (Moderate) Monitor for excessive sedation and somnolence during coadministration of daridorexant and tricyclic antidepressants. Dosage adjustments of daridorexant and the tricyclic antidepressant may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Quazepam: (Major) Monitor for excessive sedation and somnolence during use of daridorexant with quazepam. Dosage adjustments may be necessary when administered together because of potentially additive CNS effects. Use of more than 2 hypnotics should be avoided due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with daridorexant, a reduction in dose of one or both agents may be needed. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Ranolazine: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with daridorexant is necessary and consider a ranolazine dosage adjustment. Concomitant use may increase ranolazine exposure. Ranolazine is a P-gp substrate; daridorexant is a P-gp inhibitor.
Relugolix: (Major) Avoid concomitant use of relugolix and oral daridorexant. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is necessary, administer daridorexant at least 6 hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of daridorexant is required; if treatment is interrupted for more than seven days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Relugolix is a P-gp substrate and daridorexant is a P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral daridorexant. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is necessary, administer daridorexant at least 6 hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of daridorexant is required; if treatment is interrupted for more than seven days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Relugolix is a P-gp substrate and daridorexant is a P-gp inhibitor.
Remifentanil: (Major) Concomitant use of remifentanil with daridorexant may cause excessive sedation and somnolence. Limit the use of remifentanil with daridorexant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Remimazolam: (Major) Monitor for excessive sedation and somnolence during use of daridorexant with remimazolam. Dosage adjustments may be necessary when administered together because of potentially additive CNS effects. Use of more than 2 hypnotics should be avoided due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with daridorexant, a reduction in dose of one or both agents may be needed. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Repotrectinib: (Major) Avoid concomitant use of daridorexant and repotrectinib. Coadministration may decrease daridorexant exposure and reduce its efficacy and increase repotrectinib exposure and the risk for repotrectinib-related adverse effects. Daridorexant is a CYP3A substrate and P-gp inhibitor; repotrectinib is a P-gp substrate and moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Ribociclib: (Major) Avoid concomitant use of daridorexant and ribociclib. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Ribociclib; Letrozole: (Major) Avoid concomitant use of daridorexant and ribociclib. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Rifabutin: (Major) Avoid concomitant use of daridorexant and rifabutin. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Rifampin: (Major) Avoid concomitant use of daridorexant and rifampin. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and rifampin is a strong CYP3A inducer. Concomitant use of rifampin decreased daridorexant overall exposure by over 50% in drug interaction studies.
Rifapentine: (Major) Avoid concomitant use of daridorexant and rifapentine. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and rifapentine is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased daridorexant overall exposure by over 50%.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with daridorexant is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and daridorexant is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with daridorexant; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and daridorexant is a P-gp inhibitor.
Ritonavir: (Major) Avoid concomitant use of daridorexant and ritonavir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Saquinavir: (Major) Avoid concomitant use of daridorexant and saquinavir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Concomitant use may also increase saquinavir exposure. Daridorexant is a CYP3A substrate and P-gp inhibitor and saquinavir is a P-gp substrate and strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Secobarbital: (Major) Avoid concomitant use of daridorexant and secobarbital. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Additive CNS effects, such as sedation and psychomotor impairment, are also possible. Daridorexant is a CYP3A substrate and secobarbital is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Silodosin: (Major) Avoid coadministration of silodosin and daridorexant due to the potential for increased silodosin exposure. In vitro data indicate that silodosin is a P-gp substrate; daridorexant is a P-gp inhibitor.
Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with daridorexant is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; daridorexant is a P-gp inhibitor.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of daridorexant. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and daridorexant is a weak CYP3A and P-gp inhibitor.
Sotorasib: (Major) Avoid concomitant use of daridorexant and sotorasib. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
St. John's Wort, Hypericum perforatum: (Major) Avoid concomitant use of daridorexant and St. John's Wort. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased daridorexant overall exposure by over 50%.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if daridorexant must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of daridorexant is necessary. If daridorexant is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A substrate, and coadministration with a weak CYP3A inhibitor like daridorexant can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If daridorexant is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with daridorexant is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; daridorexant is a weak CYP3A inhibitor.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with daridorexant is necessary. Talazoparib is a P-gp substrate and daridorexant is a P-gp inhibitor.
Tapentadol: (Major) Concomitant use of tapentadol with daridorexant may cause excessive sedation and somnolence. Limit the use of tapentadol with daridorexant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Temazepam: (Major) Monitor for excessive sedation and somnolence during use of daridorexant with temazepam. Dosage adjustments may be necessary when administered together because of potentially additive CNS effects. Use of more than 2 hypnotics should be avoided due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with daridorexant, a reduction in dose of one or both agents may be needed. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with daridorexant is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and daridorexant is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with daridorexant may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and daridorexant is a P-gp inhibitor.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with daridorexant may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and daridorexant is a P-gp inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with daridorexant may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and daridorexant is a P-gp inhibitor.
Ticagrelor: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with daridorexant as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-gp substrate and daridorexant is a P-gp inhibitor.
Tipranavir: (Major) Avoid concomitant use of daridorexant and tipranavir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Concomitant use may also increase tipranavir exposure. Daridorexant is a CYP3A substrate and P-gp inhibitor and tipranavir is a P-gp substrate and strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Topotecan: (Major) Avoid coadministration of daridorexant with oral topotecan due to increased topotecan exposure; daridorexant may be administered with intravenous topotecan. Coadministration increases the risk of topotecan-related adverse reactions. Oral topotecan is a P-gp substrate and daridorexant is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with daridorexant is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of daridorexant, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with daridorexant is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of daridorexant, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Trandolapril; Verapamil: (Major) Limit the daridorexant dose to 25 mg if coadministered with verapamil. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with daridorexant. Coadministration may increase the exposure of triazolam. Triazolam is a sensitive CYP3A substrate and daridorexant is a weak CYP3A inhibitor.
Tricyclic antidepressants: (Moderate) Monitor for excessive sedation and somnolence during coadministration of daridorexant and tricyclic antidepressants. Dosage adjustments of daridorexant and the tricyclic antidepressant may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Trimipramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of daridorexant and tricyclic antidepressants. Dosage adjustments of daridorexant and the tricyclic antidepressant may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Tucatinib: (Major) Avoid concomitant use of daridorexant and tucatinib. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with daridorexant. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A and P-gp substrate; daridorexant is a weak CYP3A and P-gp inhibitor.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with daridorexant due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of daridorexant. Venetoclax is a P-gp substrate; daridorexant is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Verapamil: (Major) Limit the daridorexant dose to 25 mg if coadministered with verapamil. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Vincristine Liposomal: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of daridorexant is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and daridorexant is a P-gp inhibitor.
Vincristine: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of daridorexant is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and daridorexant is a P-gp inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with daridorexant is necessary. Vinorelbine is a CYP3A substrate and daridorexant is a weak CYP3A inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of daridorexant and clarithromycin. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Voriconazole: (Major) Avoid concomitant use of daridorexant and voriconazole. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Voxelotor: (Major) Limit the daridorexant dose to 25 mg if coadministered with voxelotor. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with daridorexant is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP3A substrate and daridorexant is a weak CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zaleplon: (Major) Use of daridorexant with other sedatives and hypnotics should generally be avoided due to duplication of treatments and due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with daridorexant, a reduction in dose of one or both agents may be needed.
Zolpidem: (Major) Use of daridorexant with other sedatives and hypnotics should generally be avoided due to duplication of treatments and due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with daridorexant, a reduction in dose of one or both agents may be needed.
Daridorexant exerts its activity through antagonism of orexin receptors. Daridorexant binds to and blocks orexin receptors OX1R and OX2R, preventing the binding of orexin A and orexin B. These neuropeptides are responsible for promoting wakefulness; thus, daridorexant suppresses the wake drive. Daridorexant does not prolong the QTc interval to any clinically relevant extent at a dose 4 times the maximum recommended dose.
Daridorexant is administered orally. Daridorexant has a volume of distribution of 31 L and is 99.7% bound to plasma proteins. It undergoes extensive metabolism, primarily via CYP3A4 (89%), and is excreted in the feces (57%) and urine (28%). The half life of daridorexant is 8 hours.
Affected Cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4
Daridorexant is a substrate of CYP3A4. Concomitant use with a moderate or strong 3A4 inhibitor increases exposure to daridorexant, which may increase the risk of adverse reactions. Concomitant use of daridorexant is not recommended with strong inhibitors of 3A4, and dose reduction is needed with concomitant use of moderate CYP3A4 inhibitors. Use of daridorexant with moderate or strong 3A4 inducers should also be avoided, as this combination may decrease the efficacy of daridorexant.
-Route-Specific Pharmacokinetics
Oral Route
Following oral administration, daridorexant reaches peak plasma concentrations within 1 to 2 hours. Plasma exposure is dose proportional from 25 mg to 50 mg. The bioavailability of daridorexant is 62%. When studied in healthy subjects, intake of a high-fat, high calorie meal delayed time to peak by 1.3 hours and decreased the maximum concentration by 16%, but overall exposure to the medication remained the same.
-Special Populations
Hepatic Impairment
Moderate hepatic impairment (Child-Pugh score 7 to 9) may cause a clinically relevant increase systemic exposure; dose reduction is recommended. Daridorexant has not been studied in patients with severe hepatic impairment (Child-Pugh score 10 or greater) and use is not recommended in this population.
Renal Impairment
Renal impairment did not have a clinically significant effect on the pharmacokinetics of daridorexant.
Pediatrics
Pharmacokinetic data are not available for pediatric patients.
Geriatric
Age did not have a clinically significant effect on the pharmacokinetics of daridorexant
Gender Differences
Sex did not have a clinically significant effect on the pharmacokinetics of daridorexant.
Ethnic Differences
Race did not have a clinically significant effect on the pharmacokinetics of daridorexant.