{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:57:44Z","timestamp":1791910664186,"version":"4.3.4"},"reference-count":48,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,3,6]],"date-time":"2024-03-06T00:00:00Z","timestamp":1709683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Daridorexant (dari), as the first dual orexin receptor antagonist (DORA) marketed in Europe, offers a novel therapeutic approach to insomnia. However, data regarding its real-world safety are scarce. Thus, this study was aimed at assessing its safety profile using a large-scale pharmacovigilance database. Dari-related adverse drug reaction (ADR) reports from the Food and Drug Administration Adverse Event Reporting System were scrutinized, and ADRs were selected using reporting odds ratio (ROR) as a measure of disproportionality. Frequencies of events related to dari were compared to all other drugs (reference group, RG1) and only to other DORAs (RG2). Only significant disproportionalities to both RGs were evaluated in-depth. A total of 845 dari-related reports were selected; nightmares (n = 146; dari vs. RG1: ROR = 113.74; 95%CI [95.13, 136]; dari vs. RG2: ROR = 2.35; 95 CI% [1.93, 2.85]), depression (n = 22; dari vs. RG1: 2.13; [1.39, 3.25]; dari vs. RG2: ROR = 2.31; 95 CI% [1.45, 3.67]), and hangover (n = 20; dari vs. RG1: ROR = 127.92; 95 CI% [81.98, 199.62]; and dari vs. RG2: 3.38; [2.04, 5.61]) were considered as safety signals. These data provide valuable insights into the real-world safety profile of daridorexant, supporting the existence of safety signals related to nightmares, depression, and hangovers.<\/jats:p>","DOI":"10.3390\/ph17030342","type":"journal-article","created":{"date-parts":[[2024,3,6]],"date-time":"2024-03-06T04:03:50Z","timestamp":1709697830000},"page":"342","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Safety of Dual Orexin Receptor Antagonist Daridorexant: A Disproportionality Analysis of Publicly Available FAERS Data"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8345-8679","authenticated-orcid":false,"given":"Giuseppe","family":"Cicala","sequence":"first","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2019-4696","authenticated-orcid":false,"given":"Maria Antonietta","family":"Barbieri","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1681-1417","authenticated-orcid":false,"given":"Giulia","family":"Russo","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3210-7171","authenticated-orcid":false,"given":"Francesco","family":"Salvo","sequence":"additional","affiliation":[{"name":"Regional Pharmacovigilance Centre of Bordeaux, Department of Medical Pharmacology, Centre Hospitalier Universitaire de Bordeaux, F-33000 Bordeaux, France"},{"name":"AHeaD Team, U1219, Bordeaux Population Health, National Institute for Health and Medical Research (Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, INSERM), Universit\u00e9 de Bordeaux, F-33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2509-7449","authenticated-orcid":false,"given":"Edoardo","family":"Spina","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association.","DOI":"10.1176\/appi.books.9780890425596"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.jsmc.2022.03.003","article-title":"Epidemiology of Insomnia","volume":"17","author":"Morin","year":"2022","journal-title":"Sleep Med. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.jsmc.2019.10.002","article-title":"Insomnia and Cognitive Performance","volume":"15","author":"Brownlow","year":"2020","journal-title":"Sleep Med. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/s40271-020-00474-z","article-title":"Development and Validation of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ)","volume":"14","author":"Hudgens","year":"2021","journal-title":"Patient Patient-Centered Outcomes Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1177\/0269881119855343","article-title":"British Association for Psychopharmacology Consensus Statement on Evidence-Based Treatment of Insomnia, Parasomnias and Circadian Rhythm Disorders: An Update","volume":"33","author":"Wilson","year":"2019","journal-title":"J. Psychopharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1111\/jsr.12594","article-title":"European Guideline for the Diagnosis and Treatment of Insomnia","volume":"26","author":"Riemann","year":"2017","journal-title":"J. Sleep Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"125","DOI":"10.7326\/M15-2175","article-title":"Management of Chronic Insomnia Disorder in Adults: A Clinical Practice Guideline from the American College of Physicians","volume":"165","author":"Qaseem","year":"2016","journal-title":"Ann. Intern. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.jsmc.2020.11.002","article-title":"Adherence to Cognitive Behavior Therapy for Insomnia","volume":"16","author":"Agnew","year":"2021","journal-title":"Sleep Med. Clin."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1007\/s13311-021-01010-z","article-title":"Pharmacological Management of Insomnia","volume":"18","author":"Madari","year":"2021","journal-title":"Neurotherapeutics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1177\/2045125317753340","article-title":"Challenges of the Pharmacological Management of Benzodiazepine Withdrawal, Dependence, and Discontinuation","volume":"8","author":"Fluyau","year":"2018","journal-title":"Ther. Adv. Psychopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1093\/ijnp\/pyz007","article-title":"An Insight into Z-Drug Abuse and Dependence: An Examination of Reports to the European Medicines Agency Database of Suspected Adverse Drug Reactions","volume":"22","author":"Schifano","year":"2019","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e13902","DOI":"10.1111\/jsr.13902","article-title":"The Orexin Story and Orexin Receptor Antagonists for the Treatment of Insomnia","volume":"32","author":"Muehlan","year":"2023","journal-title":"J. Sleep Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1038\/nature04284","article-title":"Hypothalamic Regulation of Sleep and Circadian Rhythms","volume":"437","author":"Saper","year":"2005","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1017\/S1092852916000225","article-title":"Mechanism of Action of Suvorexant","volume":"21","author":"Stahl","year":"2016","journal-title":"CNS Spectr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"101573","DOI":"10.1016\/j.smrv.2021.101573","article-title":"The Efficacy and Safety of Dual Orexin Receptor Antagonists in Primary Insomnia: A Systematic Review and Network Meta-Analysis","volume":"61","author":"Xue","year":"2022","journal-title":"Sleep Med. Rev."},{"key":"ref_16","unstructured":"European Commission Union (2024, February 01). Register of Medicinal Products for Human Use. Available online: https:\/\/ec.europa.eu\/health\/documents\/community-register\/html\/index_en.htm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s40263-022-00980-8","article-title":"Long-Term Safety and Tolerability of Daridorexant in Patients with Insomnia Disorder","volume":"37","author":"Kunz","year":"2023","journal-title":"CNS Drugs"},{"key":"ref_18","unstructured":"European Medicines Agency (2022). Human Medicine European Public Assessment Reports Database, European Medicines Agency."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"47795","DOI":"10.4088\/JCP.23lr14892","article-title":"Potential Aggravation of Suicide Risk with Daridorexant","volume":"84","author":"Palagini","year":"2023","journal-title":"J. Clin. Psychiatry"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"44433","DOI":"10.4088\/JCP.22l14628","article-title":"Possible Suicidal Risk with Daridorexant, a New Treatment for Insomnia","volume":"84","author":"Nobile","year":"2022","journal-title":"J. Clin. Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"49178","DOI":"10.4088\/JCP.23br14923","article-title":"Dual Orexin Receptor Antagonists and Suicide Risk","volume":"84","author":"Salvo","year":"2023","journal-title":"J. Clin. Psychiatry"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1111\/j.1365-2125.2011.04037.x","article-title":"Benefits and Strengths of the Disproportionality Analysis for Identification of Adverse Drug Reactions in a Pharmacovigilance Database","volume":"72","author":"Montastruc","year":"2011","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1130636","DOI":"10.3389\/fpsyt.2023.1130636","article-title":"Tolerability Profile of Paliperidone Palmitate Formulations: A Pharmacovigilance Analysis of the EUDRAVigilance Database","volume":"14","author":"Cicala","year":"2023","journal-title":"Front. Psychiatry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1111\/bcp.13098","article-title":"The Value of Patient Reporting to the Pharmacovigilance System: A Systematic Review","volume":"83","author":"Cavaco","year":"2017","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_25","unstructured":"Weber, J.C.P. (1987). Side-Effects of Anti-Inflammatory Drugs, Springer."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kim, H.-J., Jeong, H.E., Bae, J.-H., Baek, Y.-H., and Shin, J.-Y. (2019). Characteristics and Trends of Spontaneous Reporting of Therapeutic Ineffectiveness in South Korea from 2000 to 2016. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0212905"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1111\/j.1365-2125.2006.02746.x","article-title":"Patient Reporting of Suspected Adverse Drug Reactions: A Review of Published Literature and International Experience","volume":"63","author":"Blenkinsopp","year":"2007","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1007\/s40265-022-01699-y","article-title":"Daridorexant: First Approval","volume":"82","author":"Markham","year":"2022","journal-title":"Drugs"},{"key":"ref_29","unstructured":"Food and Drug Administration (2023, May 03). QUVIVIQ Full Prescribing Information, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2022\/214985s000lbl.pdf."},{"key":"ref_30","unstructured":"Food and Drug Administration (2023, May 03). BELSOMRA Full Prescribing Information, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2014\/204569s000lbledt.pdf."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1007\/s00784-019-03029-1","article-title":"Investigation of the Relationship between Sleep Disorders and Xerostomia","volume":"24","author":"Apessos","year":"2020","journal-title":"Clin. Oral Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"224","DOI":"10.3109\/00016357.2015.1099730","article-title":"Sleep Quality in Patients with Xerostomia: A Prospective and Randomized Case-Control Study","volume":"74","author":"Berdugo","year":"2016","journal-title":"Acta Odontol. Scand."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"A52","DOI":"10.1093\/sleepadvances\/zpab014.141","article-title":"P097 Incidence of Abnormal Dreams and Nightmares with Lemborexant in Adults with Insomnia: Results from Two Phase 3 Studies","volume":"2","author":"Roth","year":"2021","journal-title":"SLEEP Adv."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e1918254","DOI":"10.1001\/jamanetworkopen.2019.18254","article-title":"Comparison of Lemborexant with Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults with Insomnia Disorder","volume":"2","author":"Rosenberg","year":"2019","journal-title":"JAMA Netw. Open"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"zsaa123","DOI":"10.1093\/sleep\/zsaa123","article-title":"Long-Term Efficacy and Tolerability of Lemborexant Compared with Placebo in Adults with Insomnia Disorder: Results from the Phase 3 Randomized Clinical Trial SUNRISE 2","volume":"43","author":"Yardley","year":"2020","journal-title":"Sleep"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s40479-014-0023-4","article-title":"Nightmares Affect the Experience of Sleep Quality but Not Sleep Architecture: An Ambulatory Polysomnographic Study","volume":"2","author":"Paul","year":"2015","journal-title":"Borderline Pers. Disord. Emot. Dysregul."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"101332","DOI":"10.1016\/j.smrv.2020.101332","article-title":"Effects of Orexin Receptor Antagonism on Human Sleep Architecture: A Systematic Review","volume":"53","author":"Clark","year":"2020","journal-title":"Sleep Med. Rev."},{"key":"ref_38","unstructured":"Dal Sacco, D. (2022). Dream Recall Frequency and Psychosomatics. Acta Biomed., 93."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1007\/s13311-020-00966-8","article-title":"Nightmare Disorder and Isolated Sleep Paralysis","volume":"18","author":"Stefani","year":"2021","journal-title":"Neurotherapeutics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"bcr-2017-222037","DOI":"10.1136\/bcr-2017-222037","article-title":"Adverse Reaction with Suvorexant for Insomnia: Acute Worsening of Depression with Emergence of Suicidal Thoughts","volume":"2017","author":"Petrous","year":"2017","journal-title":"BMJ Case Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.euroneuro.2007.01.005","article-title":"Reduced Orexin Levels in the Cerebrospinal Fluid of Suicidal Patients with Major Depressive Disorder","volume":"17","author":"Brundin","year":"2007","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"329","DOI":"10.31887\/DCNS.2008.10.3\/dnutt","article-title":"Sleep Disorders as Core Symptoms of Depression","volume":"10","author":"Nutt","year":"2008","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1323057","DOI":"10.3389\/fdsfr.2023.1323057","article-title":"Conducting and Interpreting Disproportionality Analyses Derived from Spontaneous Reporting Systems","volume":"3","author":"Cutroneo","year":"2024","journal-title":"Front. Drug Saf. Regul."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Khaleel, M.A., Khan, A.H., Ghadzi, S.M.S., Adnan, A.S., and Abdallah, Q.M. (2022). A Standardized Dataset of a Spontaneous Adverse Event Reporting System. Healthcare, 10.","DOI":"10.3390\/healthcare10030420"},{"key":"ref_45","unstructured":"Food and Drug Administration (2023, November 30). Questions and Answers on FDA\u2019s Adverse Event Reporting System (FAERS), Available online: https:\/\/www.fda.gov\/drugs\/surveillance\/questions-and-answers-fdas-adverse-event-reporting-system-faers."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"109","DOI":"10.2165\/00002018-199920020-00002","article-title":"The Medical Dictionary for Regulatory Activities (MedDRA)","volume":"20","author":"Brown","year":"1999","journal-title":"Drug Saf."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/s40801-021-00278-z","article-title":"Adverse Drug Reactions with HER2-Positive Breast Cancer Treatment: An Analysis from the Italian Pharmacovigilance Database","volume":"9","author":"Barbieri","year":"2022","journal-title":"Drugs Real World Outcomes"},{"key":"ref_48","unstructured":"Khouri, C., Salvo, F., Raschi, E., and Fusaroli, M. (2024, January 15). Reporting of A Disproportionality Analysis for DrUg Safety\u2014READUS. Available online: https:\/\/readus-statement.org\/."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/3\/342\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:09:53Z","timestamp":1760105393000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/3\/342"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,6]]},"references-count":48,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["ph17030342"],"URL":"https:\/\/doi.org\/10.3390\/ph17030342","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,6]]}}}