b'QUVIVIQ (daridorexant) tablets, for oral use, CIVQUVIVIQ (daridorexant) tablets, for oral use, CIVQUVIVIQ (daridorexant) tablets, for oral use, CIVQUVIVIQ (daridorexant) tablets, for oral use, CIV Initial U.S. Approval: 2022Clinical Trials ExperienceTable 2Clinically Important Drug Interactions with QUVIVIQReduce the dose of QUVIVIQ in patients with moderate hepatic impairment Brief Summary of prescribing Information for QUVIVIQ (daridorexant) CIV.Because clinical trials are conducted under widely varying conditions, adverse(Child-Pugh score 79) [see Dosage and Administration in the full prescribing 11Alcohol and Other CNS DepressantsINDICATIONS AND USAGEreaction rates observed in clinical trials of a drug cannot be directly comparedinformation].QUVIVIQ is indicated for the treatment of adult patients with insomnia, characterizedto rates in clinical trials of another drug and may not reflect the rates observedClinicalConcomitant use of alcohol or other CNS depressants withModerate hepatic impairment may increase daridorexant systemic exposure to a by difficulties with sleep onset and/or sleep maintenance [see Clinical Studies inin practice.Implications: QUVIVIQ may lead to additive impairment of psychomotorclinically relevant extent [see Clinical Pharmacology in the full prescribing the full prescribing information].The safety of QUVIVIQ was evaluated in three placebo-controlled clinical studies performance and risk of CNS depression [see Clinicalinformation], which may increase the frequency or severity of adverse reactions. CONTRAINDICATIONS(two 3-month studies of identical design [Study 1 and Study 2], and a 9-monthPharmacology in the full prescribing information]. Patients with Compromised Respiratory FunctionQUVIVIQ is contraindicated in patients with narcolepsy.extension study [Study 3]). Study 1 evaluated 50 mg and 25 mg doses ofPrevention orAvoid alcohol consumption with QUVIVIQ [see Warnings andObstructive sleep apnea WARNINGS AND PRECAUTIONSQUVIVIQ, while Study 2 evaluated a 25 mg dose and a 10 mg dose of QUVIVIQ.Management: Precautions]. The respiratory depressant effect of QUVIVIQ was evaluated after one night and CNS-Depressant Effects and Daytime ImpairmentThe 10 mg dose is not an approved dose. A total of 1232 patients (includingUse with caution in patients receiving CNS depressants. Considerafter five consecutive nights of treatment in a randomized, placebo-controlled, QUVIVIQ is a central nervous system (CNS) depressant that can impair daytimeapproximately 40% elderly patients [ 65 years old]), received QUVIVIQ 50 mgdose adjustment of QUVIVIQ and/or the CNS depressant(s) iftwo-period crossover study in 25 patients with mild to moderate OSA (apnea-wakefulness even when used as prescribed. CNS-depressant effects may persist(N = 308); 25 mg (N = 618); or 10 mg (an unapproved dose) (N = 306). A totalused concomitantly [see Warnings and Precautions]. hypopnea index [AHI] 5 to 30 events per hour) not requiring CPAP. Following in some patients for up to several days after discontinuing QUVIVIQ. Prescribersof 576 patients were treated with QUVIVIQ for at least 6 months and 331 for atonce-daily dosing of 50 mg, the mean treatment difference (daridorexantshould advise patients about the potential for next-day somnolence.least 12 months.USE IN SPECIFIC POPULATIONSplacebo) on Day 5 for AHI was 0.74 (90% CI, -1.43 to 2.92). Driving ability was impaired in some subjects taking QUVIVIQ 50 mg [seeMost Common Adverse ReactionsPregnancyDue to study limitations, including the short duration of the study, clinically Clinical Studies in the full prescribing information]. The risk of daytimeThe most common reported adverse reaction (in at least 5% of patients andPregnancy Exposure Registrymeaningful respiratory effects of QUVIVIQ in OSA cannot be excluded, including impairment is increased if QUVIVIQ is taken with less than a full night of sleepgreater than placebo) during double-blind treatment in Study 1 was headache.There will be a pregnancy exposure registry that monitors pregnancy outcomesfor long-term treatment. remaining or if a higher than recommended dose is taken [see Dosage andTable 1 shows adverse reactions that occurred in at least 2% of patients treated within women exposed to QUVIVIQ during pregnancy. Pregnant women exposed toQUVIVIQ has not been studied in patients with severe OSA (AHI30) or those Administration in the full prescribing information]. If QUVIVIQ is taken in theseQUVIVIQ and more frequently than in patients who received placebo in Study 1.QUVIVIQ and healthcare providers are encouraged to call Idorsia Pharmaceuticals Ltdrequiring CPAP [see Warnings and Precautions]. circumstances, caution patients against driving and other activities requiringTable 1Adverse Reactions Reported in2% of QUVIVIQ-treated Patientsat 1-833-400-9611.Chronic obstructive pulmonary disease complete mental alertness.and Greater than in Placebo-treated Patients in a 3-Month Placebo- Risk SummaryThe respiratory depressant effect of QUVIVIQ was evaluated after one night and Co-administration with other CNS depressants (e.g., benzodiazepines, opioids,Controlled Study (Study 1)There are no available data on QUVIVIQ use in pregnant women to evaluate forafter five consecutive nights of treatment in a randomized, placebo-controlled, tricyclic antidepressants, alcohol) increases the risk of CNS depression, whichQUVIVIQQUVIVIQPlacebodrug-associated risks of major birth defects, miscarriage, or other adversetwo-period crossover study in 25 patients with moderate COPD (FEV 1 /FVC ratio can cause daytime impairment. Dosage adjustments of QUVIVIQ and of25 mg50 mg maternal or fetal outcomes. In animal reproduction studies, oral administration 70% and 40%FEV 1 80% of predicted). Following once-daily dosing ofconcomitant CNS depressants may be necessary when administered together(N=310)(N=308)(N=309)of daridorexant to pregnant rats and rabbits during the period of organogenesis50 mg, the mean SpO 2treatment difference (daridorexantplacebo) on Day 5 because of potentially additive effects. The use of QUVIVIQ with other drugs to% % % did not cause fetal toxicity or malformation at doses up to 8 and 10 times thewas 0.18% (90% CI, -0.21 to 0.57). treat insomnia is not recommended. Advise patients not to consume alcohol inmaximum recommended human dose (MRHD) of 50 mg, respectively, based onQUVIVIQ has not been studied in patients with severe COPD (FEV 1 40% of combination with QUVIVIQ because co-administration of QUVIVIQ with alcoholNervous System Disorders AUC. Oral administration of daridorexant to pregnant and lactating rats did notpredicted). resulted in additive effects on psychomotor performance [see Drug Interactions].Headache* 6 7 5 cause any maternal or developmental toxicity at doses up to 9 times the MRHD, Because QUVIVIQ can cause drowsiness, patients, particularly the elderly, are atSomnolence or fatigue* 6 5 4 based on AUC (see Data).Clinically meaningful respiratory effects of QUVIVIQ in patients with compromised a higher risk of falls.The estimated background risk of major birth defects and miscarriage for therespiratory function cannot be excluded [see Warnings and Precautions]. Worsening of Depression/Suicidal IdeationDizziness* 2 3 2 indicated population is unknown. All pregnancies have a background risk ofDRUG ABUSE AND DEPENDENCE Patients with psychiatric disorders, including insomnia, are at increased risk ofGastro-intestinal disorders birth defect, loss, or other adverse outcomes. In the U.S. general population,Controlled Substance suicide. In primarily depressed patients treated with hypnotics, worsening ofNausea* 0 3 2 the estimated background risk of major birth defects and miscarriage inQUVIVIQ contains daridorexant, a Schedule IV controlled substance. depression and suicidal thoughts and actions (including completed suicides)*The following terms were combined:clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Abuse have been reported. As with other hypnotics, QUVIVIQ should be administeredHeadache includes: headache, tension headache, migraine, migraine with aura,DataDrug abuse is the intentional, non-therapeutic use of a drug, even once, for its with caution in patients exhibiting symptoms of depression. Monitoring ofhead discomfort Animal Datadesirable psychological or physiological effects. The abuse potential of suicide risk and protective measures may be required.Somnolence or fatigue includes: somnolence, sedation, fatigue, hypersomnia,daridorexant was evaluated in preclinical models, recreational sedative drug Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-likelethargyDaridorexant was administered orally to pregnant rats during the period ofusers, and insomnia subjects. SymptomsDizziness includes: dizziness, vertigo, labyrinthitis organogenesis at doses of 30, 100, and 300 mg/kg/day, which are approximatelyIn a human abuse potential study conducted in 63 recreational sedative drug users, Sleep paralysis, an inability to move or speak for up to several minutes duringNausea includes: nausea, vomiting, procedural nausea 1, 3, and 8 times the MRHD of 50 mg, respectively, based on AUC. Daridorexantthe effect of single-dose administration of QUVIVIQ [50 mg, 100 mg (two timessleep-wake transitions, and hypnagogic/hypnopompic hallucinations, includingdid not cause any maternal or embryofetal toxicities or fetal malformation at dosesthe maximum recommended dose), and 150 mg (three times the maximum Other Adverse Reactions Observed During Clinical Trials (Study 1 and Study 2)up to 300 mg/kg/day. The NOAEL for maternal and fetal toxicity is 300 mg/kg/day,recommended dose)], zolpidem (30 mg), suvorexant (150 mg), and placebo on vivid and disturbing perceptions, can occur with the use of QUVIVIQ [see AdverseOther adverse reactions of 2% frequency but greater than placebo are shownwhich is approximately 8 times the MRHD of 50 mg, based on AUC.subjective rating of drug liking was evaluated. At the dose of 50 mg, QUVIVIQ Reactions]. Prescribers should explain the nature of these events to patientsbelow. The following do not include adverse reactions 1) for which a drug causeDaridorexant was administered orally to pregnant rabbits during the period ofshowed significantly lower drug liking ratings than zolpidem (30 mg) and when prescribing QUVIVIQ.was remote, 2) that were so general as to be uninformative, or 3) that were notorganogenesis at doses of 30, 60, and 120 mg/kg/day, which are approximatelysuvorexant (150 mg), but significantly higher than placebo. At doses of 100 mg Symptoms similar to mild cataplexy have been reported with orexin receptorconsidered to have clinically significant implications.3, 4, and 10 times the MRHD of 50 mg, respectively, based on AUC. Daridorexant(two times the maximum recommended dose) and 150 mg (three times the antagonists. Such symptoms can include periods of leg weakness lasting from Sleep paralysis was reported in 0.5% and 0.3% of patients receiving QUVIVIQdid not cause any fetal toxicity or malformation at doses up to 120 mg/kg/day.maximum recommended dose), QUVIVIQ showed similar drug liking ratings seconds to a few minutes, can occur either at night or during the day, and may25 mg and 50 mg, respectively, compared to no reports for placebo.Daridorexant caused maternal toxicities of decreased weight gain and foodto zolpidem (30 mg) and suvorexant (150 mg). not be associated with an identified triggering event (e.g., laughter or surprise) Hypnagogic and hypnopompic hallucinations were reported in 0.6% of patientsconsumption at the dose of 120 mg/kg/day. The NOAELs for maternal and fetalIn placebo-controlled Phase 3 clinical studies in which 1232 subjects with Complex Sleep Behaviorsreceiving QUVIVIQ 25 mg compared to no cases with QUVIVIQ 50 mg or placebo.toxicity are 60 and 120 mg/kg/day, respectively, which are approximately 4 andinsomnia were treated with QUVIVIQ for up to 12 months, there were no reports Complex sleep behaviors, including sleepwalking, sleep driving, and engaging inPost-Marketing Experience10 times the MRHD of 50 mg, respectively, based on AUC.indicative of abuse liability. Because individuals with a history of abuse of or other activities while not fully awake (e.g., preparing and eating food, makingThe following adverse reactions have been identified during post-approval useDaridorexant was administered orally to pregnant rats during gestation andaddiction to alcohol or other drugs may be at increased risk for abuse of or phone calls, having sex), have been reported to occur with the use of hypnotics,of QUVIVIQ. Because these reactions are reported voluntarily from a populationlactation at doses of 50, 100, and 300 mg/kg/day, which are approximately 1, 3,addiction to QUVIVIQ, follow such patients carefully. including orexin receptor antagonists such as QUVIVIQ. These events can occurof uncertain size, it is not always possible to reliably estimate their frequency orand 9 times the MRHD of 50 mg, respectively, based on AUC. Daridorexant didDependence in hypnotic- nave as well as in hypnotic-experienced persons. Patients usuallyestablish a causal relationship to drug exposure.not cause any maternal or developmental toxicities at doses up to 300 mg/kg/day.Physical dependence is a state that develops as a result of physiological do not remember these events. Complex sleep behaviors may occur followingThe NOAEL for maternal and developmental toxicity is 300 mg/kg/day, which isadaptation in response to repeated drug use, manifested by withdrawal signs the first or any subsequent use of hypnotics, such as QUVIVIQ, with or withoutPsychiatric disorders: Abnormal dreams or nightmaresapproximately 9 times the MRHD of 50 mg, based on AUC.and symptoms upon abrupt treatment discontinuation or a significant dose the concomitant use of alcohol and other CNS depressants [see Drug Interactions].Immune system disorders: Hypersensitivity (such as rash, urticaria)Lactationreduction of a drug. Discontinue QUVIVIQ immediately if a patient experiences a complex sleep behavior.DRUG INTERACTIONSRisk SummaryIn animal studies and clinical trials evaluating physical dependence, chronic Patients with Compromised Respiratory FunctionDrugs Having Clinically Important Interactions with QUVIVIQ There are no data on the presence of daridorexant in human milk, the effects onadministration of daridorexant did not produce withdrawal signs or symptoms The effects of QUVIVIQ on respiratory function should be considered if prescribedTable 2Clinically Important Drug Interactions with QUVIVIQthe breastfed infant, or the effects on milk production. Daridorexant and itsupon drug discontinuation. This suggests that daridorexant does not produce to patients with compromised respiratory function. QUVIVIQ has not beenmetabolites were present in the milk of lactating rats. When a drug is present inphysical dependence. studied in patients with moderate OSA requiring CPAP or severe OSA. QUVIVIQStrong or Moderate CYP3A4 Inhibitors animal milk, it is likely that the drug will be present in human milk.OVERDOSAGE has not been studied in patients with severe COPD [see Use in Specific Populations].ClinicalConcomitant use with a strong or moderate CYP3A4 inhibitorInfants exposed to QUVIVIQ through breastmilk should be monitored forThere is limited clinical experience with QUVIVIQ overdose. In clinical pharmacology Need to Evaluate for Co-morbid DiagnosesImplications: increases exposure to daridorexant [see Clinical Pharmacologyexcessive sedation. The developmental and health benefits of breastfeedingstudies, healthy subjects were administered single doses of up to 200 mg (4 times Because sleep disturbances may be the presenting manifestation of a medicalin the full prescribing information], which may increase the riskthe maximum recommended dose) of QUVIVIQ. The following adverse reactions and/or psychiatric disorder, treatment of insomnia should be initiated only afterof QUVIVIQ adverse reactions. should be considered along with the mothers clinical need for QUVIVIQ and anywere observed: somnolence, muscle weakness, cataplexy-like symptoms, sleep careful evaluation of the patient. The failure of insomnia to remit after 7 to Prevention orThe recommended dose of QUVIVIQ is 25 mg when used with apotential adverse effects on the breastfed infant from QUVIVIQ or from theparalysis, disturbance in attention, fatigue, headache, and constipation. 10 days of treatment may indicate the presence of a primary psychiatric and/orManagement: moderate CYP3A4 inhibitor [see Dosage and Administration inunderlying maternal condition. medical illness that should be evaluated. Worsening of insomnia or thethe full prescribing information]. Pediatric UseThere is no specific antidote to an overdosage of QUVIVIQ. In the event of an emergence of new cognitive or behavioral abnormalities may be the result of anThe safety and effectiveness of QUVIVIQ have not been established in pediatricoverdose, general symptomatic and supportive medical care, along with immediate unrecognized underlying psychiatric or medical disorder and can emerge duringConcomitant use of QUVIVIQ with a strong inhibitor of CYP3A4patients.gastric lavage where appropriate, should be provided and patients should be carefully the course of treatment with sleep-promoting drugs such as QUVIVIQ.is not recommended [see Dosage and Administration in the fullmonitored. Dialysis is unlikely to be effective as daridorexant is highly protein prescribing information]. Geriatric Usebound. Consult a Certified Poison Control Center for the most up to date information ADVERSE REACTIONSStrong and Moderate CYP3A4 Inducers No dose adjustment is required in patients over the age of 65 years.on the management of overdosage (1-800-222-1222 or www.poison.org). The following are discussed in detail in other sections of the labeling:Of the total number of subjects in the clinical studies of QUVIVIQ with insomniaCNS-Depressant Effects and Daytime Impairment [see Warnings andClinicalConcomitant use with a strong or moderate CYP3A4 inducer(N = 1854), approximately 39% (N = 727) were65 years and 5.9% (N = 110) wereDistributed by: Precautions]Implications: decreases exposure to daridorexant [see Clinical Pharmacology 75 years. The likelihood of somnolence and fatigue increased with patient age.Idorsia Pharmaceuticals US Inc.Worsening of Depression/Suicidal Ideation [see Warnings and Precautions]in the full prescribing information], which may reduce theBecause QUVIVIQ can increase somnolence and drowsiness, patients, particularlyOne Radnor Corporate Center, Suite 101 Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-likeefficacy of QUVIVIQ. the elderly, are at higher risk of falls [see Warnings and Precautions].100 Matsonford Rd Symptoms [see Warnings and Precautions]Prevention orConcomitant use of QUVIVIQ with a strong or moderate inducerHepatic ImpairmentRadnor, PA 19087 Complex Sleep Behaviors [see Warnings and Precautions]Management: of CYP3A4 is not recommended [see Dosage and AdministrationQUVIVIQ has not been studied in patients with severe hepatic impairment IDRS01192022Patients with Compromised Respiratory Function [see Warnings andin the full prescribing information]. (Child-Pugh score10). Use in this population is not recommended [seePatent: www.idorsia.com/patents Precautions](continued) Clinical Pharmacology in the full prescribing information].US-DA-00283 04/2023'