Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Idorsia Pharmaceuticals Deutschland GmbH, Marie-Curie-Strasse 8, 79539 Lörrach, Germany
Because of the general risk of falls in the elderly, daridorexant should be used with caution in this population, although clinical studies did not show an increase in the incidence of falls on daridorexant compared to placebo.
QUVIVIQ should be administered with caution in patients older than 75 years since efficacy and safety data in this population are limited.
Because daridorexant acts by reducing wakefulness, patients should be cautioned about engaging in potentially hazardous activities, driving, or operating heavy machinery unless they feel fully alert, especially in the first few days of treatment (see section 4.7).
Caution should be exercised when prescribing QUVIVIQ concomitantly with CNS-depressant medicinal products due to potentially additive effects, and a dose adjustment of either QUVIVIQ or the concomitant CNS depressants should be considered.
Patients should be cautioned about drinking alcohol during treatment with QUVIVIQ (see section 4.5).
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 daridorexant, mainly during the first weeks of treatment (see section 4.8).
Symptoms similar to mild cataplexy have been reported with dual orexin receptor antagonists.
Prescribers should explain the nature of these events to patients when prescribing QUVIVIQ. Should such events occur, patients need to be further evaluated and, depending on the nature and severity of the events, discontinuation of treatment should be considered.
In primarily depressed patients treated with hypnotics, worsening of depression and suicidal thoughts and actions have been reported. As with other hypnotics, QUVIVIQ should be administered with caution in patients exhibiting symptoms of depression.
Isolated cases of suicidal ideation have been reported in Phase 3 clinical studies, in subjects with preexisting psychiatric conditions and/or stressful living conditions, across all treatment groups, including placebo. Suicidal tendencies may be present in patients with depression and protective measures may be required.
QUVIVIQ should be administered with caution in patients with psychiatric co-morbidities since efficacy and safety data in this patient population are limited.
Daridorexant did not increase the frequency of apnoea/hypopnoea events or cause oxygen desaturation in patients with mild or moderate obstructive sleep apnoea (OSA), nor did it cause oxygen desaturation in patients with moderate chronic obstructive pulmonary disease (COPD). Daridorexant has not been studied in patients with severe OSA (apnoea-hypopnoea index ≥30 events per hour) or with severe COPD (FEV1 <40% of predicted).
Caution should be exercised when prescribing QUVIVIQ to patients with severe OSA and severe COPD.
There was no evidence of abuse or withdrawal symptoms indicative of physical dependence upon treatment discontinuation in clinical studies with daridorexant in subjects with insomnia.
In an abuse liability study of daridorexant (50, 100 and 150 mg) conducted in non-insomniac recreational drug users (n=72), daridorexant (100 and 150 mg) produced similar “drug liking” ratings as zolpidem (30 mg). Because individuals with a history of abuse or addiction to alcohol or other substances may be at increased risk for abuse of QUVIVIQ, these patients should be followed carefully.
Use is not recommended in patients with severe hepatic impairment (see sections 4.2 and 5.2).
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
In healthy subjects, co-administration of daridorexant 25 mg with the moderate CYP3A4 inhibitor diltiazem (240 mg once daily) increased daridorexant exposure parameters AUC and Cmax by 2.4 times and 1.4 times, respectively. In patients taking moderate CYP3A4 inhibitors (e.g., erythromycin, ciprofloxacin, cyclosporine), the recommended dose of QUVIVIQ is 25 mg.
No clinical study was conducted with a strong CYP3A4 inhibitor. Concomitant use of QUVIVIQ with strong inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, ritonavir) is contraindicated (see section 4.3).
The consumption of grapefruit or grapefruit juice in the evening should be avoided.
In healthy subjects, co-administration with efavirenz (600 mg once daily), a moderate CYP3A4 inducer, decreased daridorexant exposure parameters AUC and Cmax by 61% and 35%, respectively.
Based on these results, concomitant use with a moderate or strong CYP3A4 inducer substantially decreases exposure to daridorexant, which may reduce efficacy.
The solubility of daridorexant is pH-dependent. In healthy subjects, co-administration with famotidine (40 mg), an inhibitor of gastric acid secretion, decreased daridorexant Cmax by 39% while AUC remained unchanged.
No dose adjustment is required when QUVIVIQ is used concomitantly with treatments that reduce gastric acidity.
In healthy subjects, co-administration of 20 mg citalopram, a selective serotonin re-uptake inhibitor (SSRI), did not have any clinically relevant effect on the PK of 50 mg daridorexant.
In a clinical study conducted in healthy subjects receiving daridorexant and midazolam, a sensitive CYP3A4 substrate, daridorexant at a dose of 25 mg did not affect the PK of midazolam, indicating an absence of CYP3A4 induction or inhibition. QUVIVIQ can be administered with CYP3A4 substrates (e.g., simvastatin, ticagrelor) without dose adjustment.
Based on in vitro results (see section 5.2), daridorexant inhibited and induced CYP3A4. In the absence of clinical data with 50 mg, caution should be used in case of concomitant administration with CYP3A4 substrates, including oral contraceptives, with close safety and efficacy monitoring in case of medicinal products with a narrow therapeutic index that cannot be avoided.
Based on in vitro results (see section 5.2), daridorexant induced CYP2C9. In the absence of clinical data, caution should be used in case of concomitant administration with CYP2C9 substrates with close efficacy monitoring in case of medicinal products with a narrow therapeutic index.
In a clinical study conducted in healthy subjects receiving daridorexant 25 mg and rosuvastatin, a BCRP substrate, daridorexant did not affect the PK of rosuvastatin, indicating an absence of inhibition of BCRP. In the absence of clinical data at 50 mg, simultaneous administration of QUVIVIQ with BCRP substrates (e.g., rosuvastatin, imatinib) should be handled with caution.
Based on in vitro studies (see section 5.2), daridorexant is an inhibitor of several transporters, including P-gp, with the strongest inhibition seen on BCRP. In the absence of clinical data, simultaneous administration of QUVIVIQ with P-gp substrates (e.g., digoxin, dabigatran) should be handled with caution, with close monitoring in case of medicinal products with a narrow therapeutic index (e.g., digoxin).
In healthy subjects, concomitant intake with alcohol led to a prolonged absorption of daridorexant (tmax increased by 1.25 h). Daridorexant exposure (Cmax and AUC) and t½ were unchanged.
In healthy subjects, the PK of citalopram at steady state was not affected by co-administration of 50 mg daridorexant.
Co-administration of 50 mg daridorexant with alcohol led to additive effects on psychomotor performance.
No relevant interaction on psychomotor performance was observed when 50 mg daridorexant was co-administered with 20 mg citalopram in healthy subjects at steady state.
Interaction studies have only been performed in adults.
There are no data on the use of daridorexant in pregnant women. Animal studies did not indicate harmful effects with respect to reproductive toxicity (see section 5.3).
Consequently, QUVIVIQ should be used during pregnancy only if the clinical condition of the pregnant woman requires treatment with daridorexant.
It is unknown whether daridorexant or its metabolites are excreted in human milk. Available data in animals have shown excretion of daridorexant and its metabolites in milk (see section 5.3).
A risk of excessive somnolence to the breastfed infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from QUVIVIQ therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
There are no data concerning the effect of exposure to daridorexant on human fertility. Animal studies indicate no impact on male or female fertility (see section 5.3).
Hypnotics have a major influence on the ability to drive and use machines.
A randomised, double-blind, placebo- and active-controlled, cross-over study evaluated the effects of nighttime administration of daridorexant on next-morning driving performance, using a driving simulator, 9 hours after dosing in non-insomniac, healthy subjects aged from 50 to 79 years. Testing was conducted after 1 night (initial dosing) and after 4 consecutive nights of treatment with daridorexant 50 mg. Zopiclone 7.5 mg was used as an active comparator.
In the morning after first-dose administration, daridorexant impaired simulated driving performance as measured by the Standard Deviation of the Lateral Position (SDLP). No effect on driving performance was detected after 4 consecutive nights of administration. Zopiclone significantly impaired simulated driving performance at both time points.
Patients should be cautioned about engaging in potentially hazardous activities, driving, or operating heavy machinery unless they feel fully alert, especially in the first few days of treatment (see section 4.4). In order to minimise this risk, a period of approximately 9 hours is recommended between taking QUVIVIQ and driving or using machines.
The most frequently reported adverse reactions were headache and somnolence. The majority of adverse reactions were mild to moderate in intensity. No evidence of a doserelationship for the frequency or severity of adverse reactions was observed. The adverse reaction profile in elderly subjects was consistent with younger subjects.
Table 1 shows adverse reactions that occurred in Study 1 and Study 2.
The frequency of adverse reactions is defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
The safety of daridorexant was evaluated in three placebo-controlled Phase 3 clinical studies. A total of 1847 subjects (including approximately 40% elderly subjects [≥65 years old]) received daridorexant 50 mg (N=308); 25 mg (N=618); or 10 mg (N=306), or placebo (N=615). A total of 576 subjects were treated with daridorexant for at least 6 months and 331 for at least 12 months.
Table 1. Adverse reactions:
| System organ class | Adverse reaction | Frequency |
|---|---|---|
| Psychiatric disorders | Hallucination | Uncommon |
| Nervous system disorders | Headache | Common |
| Somnolence | Common | |
| Dizziness | Common | |
| Sleep paralysis | Uncommon | |
| Gastrointestinal disorders | Nausea | Common |
| General disorders and administration site conditions | Fatigue | Common |
Somnolence was reported in 3% and 2% of subjects treated with daridorexant 25 mg and 50 mg, respectively, compared to 2% of subjects on placebo.
Sleep paralysis was reported in 0.5% and 0.3% subjects receiving daridorexant 25 mg and 50 mg, respectively, compared to no reports for placebo. Hypnagogic and hypnopompic hallucinations were reported in 0.6% subjects receiving daridorexant 25 mg compared to no cases with daridorexant 50 mg or placebo. Sleep paralysis and hallucinations occur mainly during the first weeks of treatment.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
