Daridorexant

Caution should be exercised when prescribing daridorexant concomitantly with CNS-depressant medicinal products due to potentially additive effects, and a dose adjustment of either daridorexant or the concomitant CNS depressants should be considered.

Patients should be cautioned about drinking alcohol during treatment with daridorexant.

In healthy subjects, concomitant intake with alcohol led to a prolonged absorption of daridorexant (t_max increased by 1.25 h). Daridorexant exposure (C_max and AUC) and t_½ were unchanged. Co-administration of 50 mg daridorexant with alcohol led to additive effects on psychomotor performance.

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 daridorexant with BCRP substrates (e.g., rosuvastatin, imatinib) should be handled with caution.

Based on in vitro studies, 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 daridorexant 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, co-administration with efavirenz (600 mg once daily), a moderate CYP3A4 inducer, decreased daridorexant exposure parameters AUC and C_max 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.

Based on in vitro results, 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 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. Daridorexant can be administered with CYP3A4 substrates (e.g., simvastatin, ticagrelor) without dose adjustment.

Based on in vitro results, 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.

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 C_max by 2.4 times and 1.4 times, respectively. In patients taking moderate CYP3A4 inhibitors (e.g., erythromycin, ciprofloxacin, cyclosporine), the recommended dose of daridorexant is 25 mg.

The consumption of grapefruit or grapefruit juice in the evening should be avoided.

In patients with severe hepatic impairment, daridorexant has not been studied and is not recommended.

Worsening of depression and suicidal ideation

In primarily depressed patients treated with hypnotics, worsening of depression and suicidal thoughts and actions have been reported. As with other hypnotics, daridorexant 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.

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 daridorexant, these patients should be followed carefully.

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 daridorexant to patients with severe OSA and severe COPD.

There are no data on the use of daridorexant in pregnant women. Animal studies did not indicate harmful effects with respect to reproductive toxicity.

Consequently, daridorexant 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.

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 daridorexant therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data concerning the effect of exposure to daridorexant on human fertility. Animal studies indicate no impact on male or female fertility.

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. In order to minimise this risk, a period of approximately 9 hours is recommended between taking daridorexant and driving or using machines.

Summary of safety profile

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.

Tabulated list of adverse reactions

The table below 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.

Adverse reactions:

Description of selected adverse reactions

Somnolence

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 and hallucinations

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.