Quviviq
(daridorexant)Dosage & Administration
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Quviviq Prescribing Information
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)].
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)].
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)].
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)].
QUVIVIQ (daridorexant) tablets are available as:
25 mg: light purple, arc-triangle shaped, film-coated tablet debossed with "25" on one side and "i" (Idorsia logo) on the other side, containing 25 mg daridorexant.
50 mg: light orange, arc-triangle shaped, film-coated tablet debossed with "50" on one side and "i" (Idorsia logo) on the other side, containing 50 mg daridorexant.
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.
Lactation
Risk Summary
Daridorexant is present in human breast milk in low amounts. In a clinical lactation study, daridorexant was detected in human milk at a mean daily infant dose of 0.0016 mg/kg, with a relative infant dose of <1% the maternal weight-adjusted dose (see Data). There are no data on the effects of daridorexant on the breastfed infant or its effects on milk production.
Infants exposed to QUVIVIQ through breastmilk should be monitored for excessive sedation. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for QUVIVIQ and any potential adverse effects on the breastfed infant from QUVIVIQ or from the underlying maternal condition.
Data
A lactation study in 10 healthy adult lactating women evaluated the concentrations of daridorexant in plasma and breast milk following a single dose of 50 mg daridorexant. The calculated mean daily infant dose is 0.0016 mg/kg based on an assumed infant body weight of 6 kg, and the relative infant dose is 0.22% of the maternal weight-adjusted dose. Approximately 87% of the total amount of daridorexant present in milk was detected by 24 hours after administration. The amount of daridorexant present in breast milk at steady state is expected to be similar to that after a single dose.
Pediatric Use
The safety and effectiveness of QUVIVIQ have not been established in pediatric patients.
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)].
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.
Patients with Compromised Respiratory Function
Obstructive Sleep Apnea
The respiratory depressant effect of QUVIVIQ was evaluated after one night and after five consecutive nights of treatment with QUVIVIQ 50 mg in a randomized, placebo-controlled, two-period crossover study in 25 patients with mild to moderate OSA (apnea-hypopnea index [AHI] 5 to 30 events per hour of sleep) not using CPAP. Following once-daily dosing of 50 mg in the evening, the mean treatment difference (daridorexant – placebo) on Day 5 for AHI was 0.74 (90% CI, -1.43 to 2.92).
QUVIVIQ was also evaluated after 5 consecutive nights of treatment with QUVIVIQ 50 mg in a randomized, placebo-controlled, double-blind, two-period crossover study in 16 patients with severe OSA (apnea-hypopnea index ≥ 30 events per hour of sleep; studied range 30.8–82.2 events per hour) not using CPAP. Following once daily dosing of 50 mg in the evening, the mean treatment difference (daridorexant – placebo) on Day 5 for AHI was -3.74 (90% CI, -11.71 to 4.23).
Due to study limitations, including the short duration of the studies, clinically meaningful respiratory effects of QUVIVIQ in OSA cannot be excluded, including for long-term treatment [see Warnings and Precautions (5.5)].
Chronic Obstructive Pulmonary Disease
The respiratory depressant effect of QUVIVIQ was evaluated after one night and after five consecutive nights of treatment with QUVIVIQ 50 mg in a randomized, placebo-controlled, two-period crossover study in 25 patients with moderate COPD (FEV1/FVC ratio ≤ 70% and 40% ≤ FEV1 < 80% of predicted). Following once-daily dosing of 50 mg in the evening, the mean SpO2 treatment difference (daridorexant – placebo) on Day 5 was 0.18% (90% CI, -0.21 to 0.57).
QUVIVIQ has not been studied in patients with mild (FEV1 ≥ 80% predicted) or severe COPD (FEV1 < 40% of predicted).
Clinically meaningful respiratory effects of QUVIVIQ in patients with compromised respiratory function cannot be excluded [see Warnings and Precautions (5.5)].
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)].
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.
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.
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).
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.
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)].
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.