Daridorexant 50mg tablets

BACKGROUND: In order to appraise the risk-benefit balance of the three available dual orexin receptor antagonists (DORAs; daridorexant, lemborexant, and suvorexant) for the management of adults with insomnia, we conducted a systematic review and random-effects model network meta-analysis. METHODS: Included were all published double-blind, randomized, placebo-controlled trials of these agents. Outcomes included subjective time to sleep onset at month 1 (sTSO, primary), subjective total sleep time at month 1 (sTST, co-primary), subjective wake after sleep onset at month 1, Insomnia Severity Index scores at month 1, all-cause discontinuation, discontinuation due to adverse events, and the incidence of individual adverse events such as somnolence, dizziness, falls, headache, nasopharyngitis, and upper respiratory tract infection. RESULTS: This meta-analysis included eight trials (5198 adults, average age = 56.33 years, 67.84% female). The treatment arms included daridorexant 25 mg/day (DAR25), daridorexant 50 mg/day (DAR50), lemborexant 5 mg/day (LEM5), lemborexant 10 mg/day (LEM10), suvorexant 20 mg/day (15 mg/day for people ≥65years, SUV20/15), and placebo. All active-treatments outperformed placebo in terms of all efficacy outcomes. The standardized mean difference (95% CI) in primary outcomes ranged from; sTSO: -0.430 (-0.568, -0.292) for LEM10 to -0.164 (-0.296, -0.031) for SUV20/15 and sTST: -0.475 (-0.593, -0.357) for DRA50 to -0.206 ( -0.330, -0.082) for LEM5. An additional sensitivity analysis suggested that DRA25, LEM10, and SUV20/15 were associated with a higher incidence of somnolence compared to a placebo. CONCLUSIONS: Considering that there is no evidence that DORAs are associated with physiological tolerance, withdrawal symptoms, or rebound insomnia when abruptly discontinued, and that sleep architecture is not adversely affected, the DORAs appear to be a favorable choice in managing insomnia disorder in adults.

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INTRODUCTION: Chronic insomnia disorder (CID) significantly impacts well-being and daily functioning. Daridorexant, a double orexin receptor blocker, has shown efficacy in randomized clinical trials and has been recently approved for the treatment of CID in adult patients. This retrospective observational study aimed to describe real-world data on daridorexant effectiveness and safety in adult patients with CID. METHODS: Consecutive patients initiating on-label daridorexant at the Sleep Medicine Centre, University Hospital of Rome Tor Vergata were enrolled. Baseline and 30-day follow-up (FU) evaluations included patients' and CID characteristics, comorbidities, and clinicians' and patients' subjective ratings of changes with the Clinical and Patient Global Impression-Improvement scores (CGI-Is and PGI-Is), as well as Insomnia Severity Index (ISI) scores in a subgroup of patients. RESULTS: Sixty-nine patients initiated 50-mg daily dosage. At FU, 58% of both patients and clinicians rated CID as improved on CGI-Is and PGI-Is, with no differences based on comorbidities, sex, or number of previous medications. No significant predictors of CGI-Is and PGI-Is improvement were identified. At FU, ISI scores (n = 24) significantly decreased from 18.25 ± 3.21 to 12.08 ± 6.12 (Z = 8.000; p < 0.001). Of these, eight patients (33.3%) had absence of insomnia symptoms, and no patients reported a worsening in ISI score categories. CONCLUSIONS: This study suggests daridorexant to be effective and safe in real-world CID treatment whether used as a first-ever treatment, switch, or add-on, as reflected by subjective and objective measures and the absence of serious treatment-related adverse events. Future research on larger cohorts should explore daridorexant potential across diverse patient characteristics.

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This double-blind, placebo-controlled, two-way crossover trial evaluated the efficacy and safety of daridorexant in patients with chronic insomnia and comorbid nocturia. In total, 60 patients aged ≥55 years with insomnia complaints for ≥3 months, Insomnia Severity Index (ISI) ≥13 and ≥3 voids/night for ≥1 month were randomised (1:1) to daridorexant 50 mg/placebo for 4 weeks followed by crossover after a 14-21-day washout period. The primary endpoint was change from baseline to Week (W) 4 in self-reported total sleep time (sTST). Other endpoints included change in ISI score, sleep depth and quality (visual analogue scale scores), nocturnal voids (mean number, time to first) and daytime functioning (Insomnia Daytime Symptoms and Impacts Questionnaire score [IDSIQ]). At W4, daridorexant significantly increased sTST versus placebo (least-squares mean difference [LSMD] 20.9 min, 95% confidence interval [CI] 8.0-33.7; p = 0.002); significant improvements were also seen at W1-3. Compared with placebo, daridorexant significantly decreased (p < 0.001) ISI at both timepoints, W2 (LSMD -3.7, 95% CI -5.1 to -2.3) and W4 (LSMD -3.3, 95% CI -4.7 to -1.8) and significantly improved (p < 0.05) sleep depth (W1, 2, 3, 4), sleep quality (W1, 2, 3) and IDSIQ total score (W1, 3). Daridorexant versus placebo reduced the number of voids (LSMD [95% CI]: W1-0.6 [-0.9 to -0.3], p < 0.001; W4-0.3 [-0.7 to +0.1], p = 0.090) and increased median time to first void (difference to placebo, W1: +31 min, p = 0.0027; W4: +23 min, p = 0.2026). No adverse events of special interest (falls/urinary incontinence) were reported during daridorexant treatment. In conclusion, in patients with chronic insomnia and nocturia, daridorexant improves both conditions with a favourable safety profile.

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Daridorexant, a dual orexin receptor antagonist, is approved for the treatment of insomnia disorder in adults. Approximately 30%-35% of patients with insomnia disorder also have obstructive sleep apnoea (OSA) of any severity. It is unclear whether sleep medications provide safe and effective treatment for insomnia in these patients. This post hoc analysis evaluated the efficacy and safety of daridorexant 25 and 50 mg on objective and self-reported insomnia variables and self-reported daytime functioning in patients with untreated mild OSA and comorbid insomnia disorder (COMISA). This analysis included participants with insomnia disorder enrolled in the Phase 3 study assessing either daridorexant 25 or 50 mg with an apnoea/hypopnoea index 5-< 15 events/h ('mild OSA'). Wake after sleep onset (WASO), latency to persistent sleep (LPS), self-reported total sleep time (sTST) and the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) were assessed at Months 1 and 3. Safety endpoints were treatment-emergent adverse events, daytime somnolence and next-morning residual effects. In participants with mild OSA, daridorexant improved WASO, LPS, sTST and IDSIQ total score over time. The average treatment effect size for all efficacy parameters was numerically greater with daridorexant 50 mg than with daridorexant 25 mg; daridorexant 25 mg was not always greater than placebo. No safety concerns were reported for daridorexant 50 or 25 mg. In participants with comorbid insomnia and untreated mild OSA, daridorexant 50 mg versus placebo improved all sleep parameters over time and was well tolerated. Daridorexant warrants further investigation in COMISA. Trial Registration: ClinicalTrials.gov identifier: NCT03545191.

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BACKGROUND: Medications, including dual orexin receptor antagonists (DORAs), benzodiazepines (BZDs), Z-drugs and melatonin receptor agonists, are common medications for insomnia disorder, but holistic comparisons of their efficacy and safety are not quite clear. OBJECTIVE: To investigate the efficacy and safety profiles of agents for treating insomnia disorder and further establish a clinical algorithm in terms of type of insomnia based on the "time window" generated from adjusting for certain confounding factors. METHODS: Relevant randomized controlled trials (RCTs) were retrieved from PubMed, Embase, Scopus, the Cochrane Library, Web of Science, and ClinicalTrials.gov from inception to April 15, 2025. The standard mean difference (SMD) was generated for consecutive variants, including the wake after sleep onset(WASO), latency to persistent sleep(LPS), total sleep time(TST), and sleep efficiency(SE), for pairwise comparisons via Bayesian network meta-regression (NMR) analyses adjusted for the follow-up period and age by RStudio 4.4.2. Pharmacovigilance (PV) was investigated by leveraging the FAERS database, and odds ratios (ORs) were generated for dichotomous and ordinal variants for pairwise comparisons via STATA 18.0 MP. RESULT: = 0.066; 95 % CI: 1.091 to 1.411). In terms of dyspnoea, eszopiclone (OR ranging from 0.556 to 0.669) had significantly lower constituent ratios than daridorexant, melatonin and zolpidem did. Melatonin (OR = 1.568, 95 % CI = 1.192 to 2.061, p = 0.001) and zolpidem (OR = 1.302, 95 % CI = 1.026 to 1.653, p = 0.03) had a significantly higher constituent ratio than suvorexant. The proportion of patients with severe dyspnoea caused by daridorexant (OR = 0.256, 95 % CI = 0.096 to 0.678, p = 0.006) was significantly lower than that caused by suvorexant and lemborexant. For adverse reaction outcomes, zaleplon (OR = 9.888, 95 % CI = 1.124 to 86.944, p = 0.039) had a significantly higher effect than daridorexant on severe dyspnoea. CONCLUSION: Comprehensively considering the efficacy effect size, time windows (follow-up period, age, and types of insomnia), PV, severity of imperative adverse events, we propose prioritizing the use of daridorexant 25 mg/d for insomnia characterized by difficulty maintaining sleep and insufficient sleep duration. For insomnia characterized by difficulty falling asleep, we recommend prioritizing the use of lemborexant 10 mg/day or zolpidem 10 mg/day. For overall poor sleep efficiency, we recommend using lemborexant. Drug selection should be based on the types of insomnia and drug safety. More head-to-head clinical trials are needed to confirm those findings.

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OBJECTIVES: To evaluate the efficacy and safety of daridorexant in women aged 47-55 years with insomnia disorder, an age group representative of the menopause transition. STUDY DESIGN: In this randomized, double-blind, placebo-controlled study (NCT03545191), conducted in 10 countries between May 2018 and May 2020, 930 patients with insomnia disorder were randomized using interactive response technology (1:1:1) to receive a single film-coated tablet of daridorexant 25 mg, 50 mg, or placebo every evening for 3 months. Subgroup analyses were performed among the 117 women aged 47-55 (25 mg n = 43; 50 mg n = 35; placebo n = 39). MAIN OUTCOME MEASURES: Efficacy endpoints included change from baseline to Month 3 of treatment in polysomnography-measured wake after sleep onset (WASO) and latency to persistent sleep (LPS), self-reported total sleep time (sTST), and insomnia-related daytime impairment, as recorded on the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). Safety endpoints included adverse events and score on a visual analog scale for morning sleepiness. Efficacy was analyzed in all randomized subjects, and safety in all who received at least one treatment dose. RESULTS: At Month 3, daridorexant 50 mg vs placebo decreased WASO and LPS by a least-squares mean (LSM) of 13.8 min (95 % CI -29.0, 1.4) and 14.7 min (-30.0, 0.6) respectively, increased sTST by an LSM of 21.8 min (-3.9, 47.4) and decreased (improved) IDSIQ total score by an LSM of 4.1 (-14.4, 6.3). No marked deviations from the effect in the overall population were observed. The incidence of somnolence/fatigue was low and comparable across groups. Morning sleepiness improved in all groups. CONCLUSIONS: These analyses suggest that daridorexant 50 mg provides benefit in sleep outcomes and daytime functioning in women aged 47-55 with insomnia disorder. Daridorexant 50 mg is well tolerated in this population, with no increased risk of next-morning sleepiness or somnolence. GOV IDENTIFIER: NCT03545191.

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The orexin (hypocretin) system plays a central role in regulating the sleep-wake cycle through two neuropeptides, orexin-A and orexin-B, which act on OX1R and OX2R receptors. Emerging evidence links heightened orexin signaling with the pathophysiology of chronic insomnia. This review outlines the neurobiology of the orexinergic system, compares the pharmacological profile of dual orexin receptor antagonists (DORAs) to traditional GABAergic hypnotics, and evaluates the clinical efficacy and safety of Suvorexant, Lemborexant, and Daridorexant. DORAs function by selectively dampening orexin-driven arousal, thereby facilitating sleep onset and maintenance without disrupting natural sleep architecture. Clinical trials have shown that these agents significantly reduce sleep latency and enhance sleep continuity, with a favorable side effect profile. Overall, DORAs represent a distinct and clinically advantageous option for insomnia treatment, with growing interest in their potential utility across mood, anxiety, and neurodegenerative disorders.

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Daridorexant is a dual orexin receptor antagonist for the treatment of insomnia. We report results from the first two randomised, double-blind clinical studies of daridorexant in Japanese subjects. In the Phase 1 study, daridorexant (10, 25, 50 mg) or placebo were administered in the morning for 4 days in 24 young (mean age 26.9 years) and 24 older (mean age 69.7 years) healthy Japanese adults. Daridorexant reached a peak plasma concentration within 1.0 h across every dose and age group. For all doses, the mean plasma concentration of daridorexant showed a similar change between the age groups. Exposure parameters increased dose-dependently with minimal/no accumulation upon repeated dosing. The terminal half-life was ~8 h. In the Phase 2, four-period, four-way crossover study, 47 Japanese subjects (mean age 50.4 years) with insomnia disorder were randomised to receive four treatments (daridorexant 10, 25, 50 mg, placebo) during four treatment periods, each consisting of two treatment nights (5-12 day washout between treatment periods). Subjects continued their fourth treatment for 12 further days. A statistically significant dose-response relationship (multiple-comparison procedure-modelling, p < 0.0001) was found in the reduction of polysomnography-measured wake after sleep onset (WASO; primary endpoint) and latency to persistent sleep (secondary endpoint) from baseline to days 1/2. Statistically significant dose-response relationships were also observed for secondary subjective endpoints from baseline to days 1/2 (sWASO, latency to sleep onset). All daridorexant doses were well tolerated, with no treatment discontinuations and no next-morning residual effects. These results supported further investigation of daridorexant in Japanese patients with insomnia disorder.

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