QUVIVIQ

1 INDICATIONS AND USAGE QUVIVIQ is indicated for the treatment of adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenance [see Clinical Studies (14.1) ] . QUVIVIQ is an orexin receptor antagonist indicated for the treatment of adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage is 25 mg to 50 mg once per night, taken orally within 30 minutes before going to bed, with at least 7 hours remaining prior to planned awakening. ( 2.1 ) Time to sleep onset may be delayed if taken with or soon after a meal. ( 2.1 ) Hepatic Impairment: ( 2.3 ) Moderate hepatic impairment: Maximum recommended dosage is 25 mg no more than once per night. Severe hepatic impairment: Not recommended. 2.1 Recommended Dosage The recommended dosage range is 25 mg to 50 mg of QUVIVIQ taken orally no more than once per night within 30 minutes of going to bed (with at least 7 hours remaining prior to planned awakening). Time to sleep onset may be delayed if taken with or soon after a meal [see Clinical Pharmacology (12.3) ] . 2.2 Dosage Recommendations for Concomitant Use with CYP3A4 Inhibitors or CYP3A4 Inducers Co-administration with Strong CYP3A4 Inhibitors Avoid concomitant use of QUVIVIQ with strong inhibitors of CYP3A4 [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . Co-administration with Moderate CYP3A4 Inhibitors The recommended dosage of QUVIVIQ is 25 mg no more than once per night when used with moderate inhibitors of CYP3A4 [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . Co-administration with Strong or Moderate CYP3A4 Inducers Avoid concomitant use of QUVIVIQ with strong or moderate CYP3A4 inducers [see Drug Interactions (7.1) ] . 2.3 Dosage Recommendations for Patients with Hepatic Impairment The maximum recommended dosage in patients with moderate hepatic impairment (Child-Pugh score 7–9) is 25 mg of QUVIVIQ no more than once per night [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] . QUVIVIQ is not recommended in patients with severe hepatic impairment (Child-Pugh score ≥ 10) [see Use in Specific Populations (8.6) ] .

4 CONTRAINDICATIONS QUVIVIQ is contraindicated: in patients with narcolepsy. in patients with a history of hypersensitivity to daridorexant or any components of QUVIVIQ. Angioedema with pharyngeal involvement has been reported [see Adverse Reactions (6.2) ] . Narcolepsy. ( 4 ) Known hypersensitivity to daridorexant or other components of QUVIVIQ. ( 4 )

5 WARNINGS AND PRECAUTIONS CNS-Depressant Effects and Daytime Impairment: Impairs alertness and motor coordination including morning impairment. Risk increases when used with other central nervous system (CNS) depressants. For patients taking QUVIVIQ, caution against next-day driving and other activities requiring complete mental alertness. ( 5.1 ) Worsening of Depression/Suicidal Ideation: Worsening of depression or suicidal thinking may occur. ( 5.2 ) Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-like Symptoms: May occur with use of QUVIVIQ. ( 5.3 ) Complex Sleep Behaviors: Behaviors including sleepwalking, sleep driving, and engaging in other activities while not fully awake may occur. Discontinue immediately if complex sleep behavior occurs. ( 5.4 ) Compromised Respiratory Function: Effect on respiratory function should be considered. ( 5.5 , 8.7 ) Need to Evaluate for Co-morbid Diagnoses: Reevaluate if insomnia persists after 7 to 10 days. ( 5.6 ) 5.1 CNS-Depressant Effects and Daytime Impairment QUVIVIQ is a central nervous system (CNS) depressant that can impair daytime wakefulness even when used as prescribed. CNS-depressant effects may persist in some patients for up to several days after discontinuing QUVIVIQ. Prescribers should advise patients about the potential for next-day somnolence. Driving ability was impaired in some subjects taking QUVIVIQ 50 mg [see Clinical Studies (14.2) ] . The risk of daytime impairment is increased if QUVIVIQ is taken with less than a full night of sleep remaining or if a higher than recommended dose is taken [see Dosage and Administration (2.1) ] . If QUVIVIQ is taken in these circumstances, caution patients against driving and other activities requiring complete mental alertness. Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression, which can cause daytime impairment. Dosage adjustments of QUVIVIQ and of concomitant CNS depressants may be necessary when administered together because of potentially additive effects. The use of QUVIVIQ with other drugs to treat insomnia is not recommended . Advise patients not to consume alcohol in combination with QUVIVIQ because co-administration of QUVIVIQ with alcohol resulted in additive effects on psychomotor performance [see Drug Interactions (7.1) ]. Because QUVIVIQ can cause drowsiness, patients, particularly the elderly, are at a higher risk of falls. 5.2 Worsening of Depression/Suicidal Ideation Patients with psychiatric disorders, including insomnia, are at increased risk of suicide. In primarily depressed patients treated with hypnotics, worsening of depression and suicidal thoughts and actions (including completed suicides) have been reported. As with other hypnotics, QUVIVIQ should be administered with caution in patients exhibiting symptoms of depression. Monitoring of suicide risk and protective measures may be required. 5.3 Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-like Symptoms Sleep paralysis, an inability to move or speak for up to several minutes during sleep-wake transitions, and hypnagogic/hypnopompic hallucinations, including vivid and disturbing perceptions, can occur with the use of QUVIVIQ [see Adverse Reactions (6.1) ] . Prescribers should explain the nature of these events to patients when prescribing QUVIVIQ. Symptoms similar to mild cataplexy have been reported with orexin receptor antagonists. Such symptoms can include periods of leg weakness lasting from seconds to a few minutes, can occur either at night or during the day, and may not be associated with an identified triggering event (e.g., laughter or surprise). 5.4 Complex Sleep Behaviors Complex sleep behaviors, including sleepwalking, sleep driving, and engaging in other activities while not fully awake (e.g., preparing and eating food, making phone calls, having sex), have been reported to occur with the use of hypnotics, including orexin receptor antagonists such as QUVIVIQ. These events can occur in hypnotic-naïve as well as in hypnotic-experienced persons. Patients usually do not remember these events. Complex sleep behaviors may occur following the first or any subsequent use of hypnotics, such as QUVIVIQ, with or without the concomitant use of alcohol and other CNS depressants [see Drug Interactions (7.1) ]. Discontinue QUVIVIQ immediately if a patient experiences a complex sleep behavior. 5.5 Patients with Compromised Respiratory Function QUVIVIQ has been studied in mild to severe OSA not using CPAP, and in patients with moderate COPD. The effects of QUVIVIQ on respiratory function should be considered if prescribed to patients with compromised respiratory function. QUVIVIQ has not been studied in patients with mild or severe COPD [see Use in Specific Populations (8.7) ]. 5.6 Need to Evaluate for Co-morbid Diagnoses Because sleep disturbances may be the presenting manifestation of a medical and/or psychiatric disorder, treatment of insomnia 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 abnormalities may be the result of an unrecognized underlying psychiatric or medical disorder and can emerge during the course of treatment with sleep-promoting drugs such as QUVIVIQ.

7 DRUG INTERACTIONS Strong CYP3A4 inhibitors: Avoid concomitant use. ( 2.2 , 7.1 ) Moderate CYP3A4 inhibitors: Maximum recommended dose is 25 mg. ( 2.2 , 7.1 ) Moderate or Strong CYP3A4 inducers: Avoid concomitant use. ( 7.1 ) 7.1 Effects of Other Drugs on QUVIVIQ Table 2 describes clinically significant drug interactions where the concomitant use of other drugs affects QUVIVIQ. Table 2 Effects of Other Drugs on QUVIVIQ Strong or Moderate CYP3A4 Inhibitors Clinical Implications: Concomitant use with a strong or moderate CYP3A4 inhibitor increases exposure to daridorexant [see Clinical Pharmacology (12.3) ] , which may increase the risk of QUVIVIQ adverse reactions. Prevention or Management: The recommended dose of QUVIVIQ is 25 mg when used with a moderate CYP3A4 inhibitor [see Dosage and Administration (2.2) ] . Concomitant use of QUVIVIQ with a strong inhibitor of CYP3A4 is not recommended [see Dosage and Administration (2.2) ] . Strong and Moderate CYP3A4 Inducers Clinical Implications: Concomitant use with a strong or moderate CYP3A4 inducer decreases exposure to daridorexant [see Clinical Pharmacology (12.3) ] , which may reduce the efficacy of QUVIVIQ. Prevention or Management: Concomitant use of QUVIVIQ with a strong or moderate inducer of CYP3A4 is not recommended [see Dosage and Administration (2.2) ] . Alcohol and Other CNS Depressants Clinical Implications: Concomitant use of alcohol or other CNS depressants with QUVIVIQ may lead to additive impairment of psychomotor performance and risk of CNS depression [see Clinical Pharmacology (12.2) ] . Prevention or Management: Avoid alcohol consumption with QUVIVIQ [see Warnings and Precautions (5.1) ] . Use with caution in patients receiving CNS depressants. Consider dose adjustment of QUVIVIQ and/or the CNS depressant(s) if used concomitantly [see Warnings and Precautions (5.1) ] . 7.2 Effects of QUVIVIQ on Other Drugs Table 3 describes clinically significant drug interactions where the concomitant use of QUVIVIQ affects other drugs. Table 3 Effects of QUVIVIQ on Other Drugs CYP3A4 Substrates Clinical Implications: Concomitant use of QUVIVIQ with CYP3A4 substrates increases the exposure to CYP3A4 substrate [see Clinical Pharmacology (12.3) ] . Prevention or Management: Use with caution in patients receiving CYP3A4 substrates with narrow therapeutic index. P-gp Substrates Clinical Implications: Concomitant use of QUVIVIQ with P-gp substrates increases the exposure to P-gp substrate [see Clinical Pharmacology (12.3) ] . Prevention or Management: Use with caution in patients receiving P-gp substrates with a narrow therapeutic index.

6 ADVERSE REACTIONS The following are discussed in detail in other sections of the labeling: CNS-Depressant Effects and Daytime Impairment [see Warnings and Precautions (5.1) ] Worsening of Depression/Suicidal Ideation [see Warnings and Precautions (5.2) ] Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-like Symptoms [see Warnings and Precautions (5.3) ] Complex Sleep Behaviors [see Warnings and Precautions (5.4) ] Patients with Compromised Respiratory Function [see Warnings and Precautions (5.5) ] The most common adverse reactions (reported in ≥ 5% of patients treated with QUVIVIQ and at an incidence ≥ than placebo) were headache and somnolence or fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Idorsia Pharmaceuticals Ltd at toll-free phone 1-833-400-9611 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The safety of QUVIVIQ was evaluated in three placebo-controlled clinical studies (two 3-month studies of identical design [Study 1 and Study 2], and a 9-month extension study [Study 3]). Study 1 evaluated 50 mg and 25 mg doses of QUVIVIQ, while Study 2 evaluated a 25 mg dose and a 10 mg dose of QUVIVIQ. The 10 mg dose is not an approved dose. A total of 1232 patients (including approximately 40% elderly patients [≥ 65 years old]), received QUVIVIQ 50 mg (N = 308); 25 mg (N = 618); or 10 mg (an unapproved dose) (N = 306). A total of 576 patients were treated with QUVIVIQ for at least 6 months and 331 for at least 12 months. Most Common Adverse Reactions The most common reported adverse reaction (in at least 5% of patients and greater than placebo) during double-blind treatment in Study 1 was headache. Table 1 shows adverse reactions that occurred in at least 2% of patients treated with QUVIVIQ and more frequently than in patients who received placebo in Study 1. Table 1 Adverse Reactions Reported in ≥ 2% of QUVIVIQ-treated Patients and Greater than in Placebo-treated Patients in a 3-Month Placebo-Controlled Study (Study 1) QUVIVIQ QUVIVIQ Placebo 25 mg 50 mg (N=310) (N=308) (N=309) % % % Nervous System Disorders Headache The following terms were combined: Headache includes: headache, tension headache, migraine, migraine with aura, head discomfort Somnolence or fatigue includes: somnolence, sedation, fatigue, hypersomnia, lethargy Dizziness includes: dizziness, vertigo, labyrinthitis Nausea includes: nausea, vomiting, procedural nausea 6 7 5 Somnolence or fatigue 6 5 4 Dizziness 2 3 2 Gastro-intestinal disorders Nausea 0 3 2 Other Adverse Reactions Observed During Clinical Trials (Study 1 and Study 2) Other adverse reactions of < 2% frequency but greater than placebo are shown below. The following do not include adverse reactions 1) for which a drug cause was remote, 2) that were so general as to be uninformative, or 3) that were not considered to have clinically significant implications. Sleep paralysis was reported in 0.5% and 0.3% of patients receiving QUVIVIQ 25 mg and 50 mg, respectively, compared to no reports for placebo. Hypnagogic and hypnopompic hallucinations were reported in 0.6% of patients receiving QUVIVIQ 25 mg compared to no cases with QUVIVIQ 50 mg or placebo. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of QUVIVIQ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Psychiatric disorders : Nightmares or abnormal dreams Immune system disorders: Hypersensitivity (including angioedema, rash, urticaria)

8.1 Pregnancy Pregnancy Exposure Registry There will be a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to QUVIVIQ during pregnancy. Pregnant women exposed to QUVIVIQ and healthcare providers are encouraged to call Idorsia Pharmaceuticals Ltd at 1-833-400-9611. Risk Summary There are no available data on QUVIVIQ use in pregnant women to evaluate for drug-associated risks of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of daridorexant to pregnant rats and rabbits during the period of organogenesis did not cause fetal toxicity or malformation at doses up to 8 and 10 times the maximum recommended human dose (MRHD) of 50 mg, respectively, based on AUC. Oral administration of daridorexant to pregnant and lactating rats did not cause any maternal or developmental toxicity at doses up to 9 times the MRHD, based on AUC (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Daridorexant was administered orally to pregnant rats during the period of organogenesis at doses of 30, 100, and 300 mg/kg/day, which are approximately 1, 3, and 8 times the MRHD of 50 mg, respectively, based on AUC. Daridorexant did not cause any maternal or embryofetal toxicities or fetal malformation at doses up to 300 mg/kg/day. The NOAEL for maternal and fetal toxicity is 300 mg/kg/day, which is approximately 8 times the MRHD of 50 mg, based on AUC. Daridorexant was administered orally to pregnant rabbits during the period of organogenesis at doses of 30, 60, and 120 mg/kg/day, which are approximately 3, 4, and 10 times the MRHD of 50 mg, respectively, based on AUC. Daridorexant did not cause any fetal toxicity or malformation at doses up to 120 mg/kg/day. Daridorexant caused maternal toxicities of decreased weight gain and food consumption at the dose of 120 mg/kg/day. The NOAELs for maternal and fetal toxicity are 60 and 120 mg/kg/day, respectively, which are approximately 4 and 10 times the MRHD of 50 mg, respectively, based on AUC. Daridorexant was administered orally to pregnant rats during gestation and lactation at doses of 50, 100, and 300 mg/kg/day, which are approximately 1, 3, and 9 times the MRHD of 50 mg, respectively, based on AUC. Daridorexant did not cause any maternal or developmental toxicities at doses up to 300 mg/kg/day. The NOAEL for maternal and developmental toxicity is 300 mg/kg/day, which is approximately 9 times the MRHD of 50 mg, based on AUC.