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

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)].

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

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 moderate OSA requiring CPAP or severe OSA. QUVIVIQ has not been studied in patients with 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.

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.

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)

7.1 Effects of Other Drugs on QUVIVIQ

Table 2 describes clinically significant drug interactions where the concomitant use of other drugs affects QUVIVIQ.

7.2 Effects of QUVIVIQ on Other Drugs

Table 3 describes clinically significant drug interactions where the concomitant use of QUVIVIQ affects other drugs.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of QUVIVIQ have not been established in pediatric patients.

8.5 Geriatric Use

No dose adjustment is required in patients over the age of 65 years.

Of the total number of subjects in the clinical studies of QUVIVIQ with insomnia (N = 1854), approximately 39% (N = 727) were ≥ 65 years and 5.9% (N = 110) were ≥ 75 years. The likelihood of somnolence and fatigue increased with patient age.

Because QUVIVIQ can increase somnolence and drowsiness, patients, particularly the elderly, are at higher risk of falls [see Warnings and Precautions (5.1)].

8.6 Hepatic Impairment

QUVIVIQ has not been studied in patients with severe hepatic impairment (Child-Pugh score ≥ 10). Use in this population is not recommended [see Clinical Pharmacology (12.3)].

Reduce the dose of QUVIVIQ in patients with moderate hepatic impairment (Child-Pugh score 7–9) [see Dosage and Administration (2.3)]. Moderate hepatic impairment may increase daridorexant systemic exposure to a clinically relevant extent [see Clinical Pharmacology (12.3)], which may increase the frequency or severity of adverse reactions.

8.7 Patients with Compromised Respiratory Function

9.1 Controlled Substance

QUVIVIQ contains daridorexant, a Schedule IV controlled substance.

9.2 Abuse

Drug abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. The abuse potential of daridorexant was evaluated in preclinical models, recreational sedative drug users, and insomnia subjects.

In a human abuse potential study conducted in 63 recreational sedative drug users, the effect of single-dose administration of QUVIVIQ [50 mg, 100 mg (two times the maximum recommended dose), and 150 mg (three times the maximum recommended dose)], zolpidem (30 mg), suvorexant (150 mg), and placebo on subjective rating of "drug liking" was evaluated. At the dose of 50 mg, QUVIVIQ showed significantly lower "drug liking" ratings than zolpidem (30 mg) and suvorexant (150 mg), but significantly higher than placebo. At doses of 100 mg (two times the maximum recommended dose) and 150 mg (three times the maximum recommended dose), QUVIVIQ showed similar "drug liking" ratings to zolpidem (30 mg) and suvorexant (150 mg).

In placebo-controlled Phase 3 clinical studies in which 1232 subjects with insomnia were treated with QUVIVIQ for up to 12 months, there were no reports indicative of abuse liability. Because individuals with a history of abuse of or addiction to alcohol or other drugs may be at increased risk for abuse of or addiction to QUVIVIQ, follow such patients carefully.

9.3 Dependence

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms upon abrupt treatment discontinuation or a significant dose reduction of a drug.

In animal studies and clinical trials evaluating physical dependence, chronic administration of daridorexant did not produce withdrawal signs or symptoms upon drug discontinuation. This suggests that daridorexant does not produce physical dependence.

12.1 Mechanism of Action

The mechanism of action of daridorexant in the treatment of insomnia is presumed to be through antagonism of orexin receptors. The orexin neuropeptide signaling system plays a role in wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive.

12.2 Pharmacodynamics

Daridorexant binds to and inhibits the orexin receptors OX1R and OX2R (Ki = 0.47 and 0.93 nM, respectively).

12.3 Pharmacokinetics

Daridorexant plasma exposure is dose proportional from 25 mg to 50 mg. The daridorexant pharmacokinetic profile is similar following multiple-dose and single-dose administration with no accumulation.

Specific Populations

Age, sex, race (White, Black, Asian), body size, and mild to severe renal impairment (Cockcroft-Gault < 30 mL/min, not on dialysis) did not have a clinically significant effect on the pharmacokinetics of daridorexant. The effect of severe hepatic impairment (Child-Pugh score ≥ 10) on the pharmacokinetics of daridorexant has not been studied.

Effects of hepatic impairment and renal impairment on the exposure to daridorexant are summarized in Figure 1.

Figure 1 Effects of hepatic impairment and renal impairment on daridorexant PK

Daridorexant dose: 25 mg. Data are GMRs and 90% CIs. Hepatic impairment PK variables are based on the unbound fraction of daridorexant. Reference = matched healthy subjects. AUC = area under the plasma concentration-time curve from zero to infinity; CI = confidence interval; Cmax = maximum plasma concentration; GMR = geometric mean ratio; PK = pharmacokinetics.

Drug Interaction Studies

The effects of other compounds on the exposure to daridorexant are summarized in Figure 2. The effects of daridorexant on the exposure to other compounds are summarized in Figure 3.

Effect of Other Compounds on QUVIVIQ

Figure 2 Effect of co-administered compounds on the PK of daridorexant

Daridorexant 50 mg was administered with interacting drugs, except with diltiazem (25 mg daridorexant). Interacting drugs were administered in multiple-dose fashion, except famotidine (single dose) and alcohol (5 h infusion at 0.6 g/L). Based on PBPK analysis: Concomitant use of itraconazole (a strong CYP3A4 inhibitor) increased daridorexant AUC by more than 400%. Concomitant use of rifampin (a strong CYP3A4 inducer) decreased daridorexant AUC by more than 50%. Data are GMRs and 90% CIs. Some 90% CIs are too narrow to be shown. AUC = area under the plasma concentration-time curve; CI = confidence interval; Cmax = maximum plasma concentration; GMR = geometric mean ratio; SSRI = selective serotonin reuptake inhibitor.

Effect of QUVIVIQ on Other Compounds

Figure 3 Effect of daridorexant on the PK of other compounds

AUC = area under the plasma concentration-time curve; BCRP = breast cancer resistance protein; CI = confidence interval; Cmax = maximum plasma concentration; CP = cytochrome P450 enzyme; P-gp = P-glycoprotein; SSRI = selective serotonin reuptake inhibitor.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

In dogs, daily oral administration of daridorexant at ≥ 30 mg/kg/day resulted in behavior characteristic of cataplexy when presented with positive stimulation. The no-observed-effect level (NOEL) for cataplexy is 20 mg/kg/day, which is approximately 3 times the MRHD of 50 mg, based on Cmax and AUC.

14.1 Controlled Clinical Studies

The efficacy of QUVIVIQ was evaluated in two multicenter, randomized, double-blind, placebo-controlled, parallel-group studies, Study 1 (NCT03545191) and Study 2 (NCT03575104).

A total of 1854 patients with Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5®) insomnia were randomized to receive QUVIVIQ or placebo once daily, in the evening, for 3 months. Study 1 randomized 930 subjects to QUVIVIQ 50 mg (N = 310), 25 mg (N = 310) or placebo (N = 310). Study 2 randomized 924 subjects to QUVIVIQ 25 mg (N = 309), 10 mg (N = 307), or placebo (N = 308). The 10 mg dose is not an approved dose.

At the end of the 3-month treatment period, both studies included a 7-day placebo run-out period, after which patients could enter a 9-month, double-blind, placebo-controlled extension study (Study 3, NCT03679884).

In Study 1, patients had a mean age of 55.4 years (range 18 to 88 years), with 39.1% of subjects ≥ 65 years of age, including 5.8% ≥ 75 years of age. Patients were identified as female or male and by US census-based racial and ethnic categories. The percentages of patients in the respective categories were: female sex (67.1%), White (90%), Black or African American (8%), Asian (1.0%), or Other race (< 1%).

In Study 2, patients had a mean age of 56.7 years (range 19 to 85 years), with 39.3% of subjects ≥ 65 years of age, including 6.1% ≥ 75 years of age. Patients were identified as female or male and by US census-based racial and ethnic categories. The percentages of patients in the respective categories were: female sex (69.0%), White (88%), Black or African American (8%), Asian (4%), or Other race (< 1%).

Primary efficacy endpoints for both studies were the change from baseline to Month 1 and Month 3 in Latency to Persistent Sleep (LPS) and Wake After Sleep Onset (WASO), measured objectively by polysomnography in a sleep laboratory. LPS is a measure of sleep induction and WASO is a measure of sleep maintenance.

Secondary endpoint included in the statistical testing hierarchy with Type 1 error control was patient-reported Total Sleep Time (sTST), evaluated every morning at home using a validated Sleep Diary Questionnaire (SDQ).

In Study 1, doses of 25 and 50 mg QUVIVIQ showed a statistically significant improvement vs placebo on polysomnography (LPS, WASO) and self-reported total sleep (sTST), at Month 1 and Month 3 (Table 4).

In Study 2, QUVIVIQ 25 mg showed a statistically significant improvement vs placebo on WASO and sTST at Month 1 and Month 3 (Table 5). QUVIVIQ 10 mg did not show a statistically significant improvement on LPS, WASO, or sTST at Month 1 or Month 3.

The efficacy of QUVIVIQ was similar across subgroups based on age, sex, race, and region.

The effects of QUVIVIQ on LPS, WASO, and sTST were observed at Month 1 and were maintained through Month 3. The change from baseline of sTST by week in Study 1 is presented in Figure 4.

Figure 4 Change from Baseline of sTST by Week (Study 1)

14.2 Special Safety Studies

16.1 How Supplied

QUVIVIQ tablets are available as:

• 25 mg, light purple, arc-triangle shaped film-coated tablets debossed with "25" on one side, and "i" on the other side.
  NDC 80491-7825-3, bottle of 30 with child-resistant closure
• 50 mg: light orange, arc-triangle shaped film-coated tablets debossed with "50" on one side, and "i" on the other side.
  NDC 80491-7850-3, bottle of 30 with child-resistant closure

16.2 Storage and Handling

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

Administration Instructions

Advise patients to take QUVIVIQ only in the evening within 30 minutes before going to bed and only if they can stay in bed for a full night (at least 7 hours) before being active again [see Dosage and Administration (2.1)].

Advise patients that the effect of QUVIVIQ may be delayed if taken with or soon after a meal [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)].

CNS-Depressant Effects and Daytime Impairment

Advise patients that QUVIVIQ can impair daytime wakefulness even when used as prescribed. 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. If QUVIVIQ is taken in these circumstances, caution patients against driving and other activities requiring complete mental alertness. Advise patients that increased drowsiness may increase the risk of falls in some patients [see Warnings and Precautions (5.1), Clinical Studies (14.2)].

Worsening of Depression/Suicidal Ideation

Tell patients to report any worsening of depression or suicidal thoughts immediately [see Warnings and Precautions (5.2)].

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

Advise patients and their families that QUVIVIQ may cause sleep paralysis, which is an inability to move or speak for several minutes during sleep-wake transitions and hypnagogic/hypnopompic hallucinations, including vivid and disturbing perceptions. Symptoms similar to mild cataplexy have occurred with orexin receptor antagonists [see Warnings and Precautions (5.3)].

Complex Sleep Behaviors

Instruct patients and their families that hypnotics may cause complex sleep behaviors, including sleep-walking, sleep driving, preparing and eating food, making phone calls, or having sex while not being fully awake. Tell patients to discontinue QUVIVIQ and notify their healthcare provider immediately if they develop any of these symptoms [see Warnings and Precautions (5.4)].

Concomitant Medications

Ask patients about alcohol consumption, medicines they are taking, and drugs they may be taking without a prescription. Advise patients to avoid consuming alcohol with QUVIVIQ [see Warnings and Precautions (5.1), Drug Interactions (7.1), Clinical Pharmacology (12.2)].

Pregnancy

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to QUVIVIQ during pregnancy [see Use in Specific Populations (8.1)].

Tolerance, Abuse, and Dependence

Tell patients not to increase the dose of QUVIVIQ on their own, and to inform you if they believe the drug "does not work" [see Drug Abuse and Dependence (9)].