{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T06:36:28Z","timestamp":1765521388896,"version":"3.48.0"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Drug Saf. Regul."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Roflumilast, a selective phosphodiesterase-4 inhibitor, is prescribed to reduce exacerbations in severe COPD, but its real-world safety profile remains insufficiently characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a retrospective pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS). Reports from 2004 to 2025Q1 listing roflumilast as the primary suspect were extracted, deduplicated, and analyzed. Disproportionality analysis employed four algorithms\u2014Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS). Safety signals were defined by established thresholds. Time-to-onset and Weibull modeling were applied to assess temporal patterns.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 3,140 reports were identified, primarily involving older COPD patients. The median time-to-onset was 4 days (IQR 0\u201334), with 72% occurring within 30 days. Thirty Preferred Terms met signal criteria. Frequent signals included diarrhoea, weight decreased, nausea, dyspnoea, insomnia, and headache. Psychiatric events such as depression and suicidal ideation were notable. The strongest disproportionality was observed for gastroduodenal ulcer (ROR 47.1) and COPD (ROR 25.7). System Organ Class enrichment was most evident in gastrointestinal, psychiatric, and respiratory disorders.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion\/Conclusion<\/jats:title>\n                    <jats:p>This real-world analysis confirms roflumilast\u2019s established adverse effects (gastrointestinal upset, weight loss, insomnia) and highlights concerning psychiatric signals. Most events occurred early, underscoring the need for close monitoring during treatment initiation. The use of multiple disproportionality methods enhances signal detection robustness and supports ongoing pharmacovigilance in clinical practice.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fdsfr.2025.1721656","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T06:32:47Z","timestamp":1765521167000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A real-world disproportionality analysis of roflumilast using the US food and drug administration adverse event reporting system data"],"prefix":"10.3389","volume":"5","author":[{"given":"Baiqing","family":"Huang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yirou","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenli","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaorui","family":"Gu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xisheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"972","DOI":"10.9734\/bjpr\/2013\/5633","article-title":"Pharmacovigilance analysis of adverse psychiatric events and suicidality reported for roflumilast, an Add-On COPD therapy","volume":"3","author":"Ali","year":"2013","journal-title":"J. Pharm. Res. Int."},{"key":"B2","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1016\/S0140-6736(09)61255-1","article-title":"Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials","volume":"374","author":"Calverley","year":"2009","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2227","DOI":"10.1016\/S0140-6736(22)00470-6","article-title":"Chronic obstructive pulmonary disease","volume":"399","author":"Christenson","year":"2022","journal-title":"Lancet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.21037\/jtd.2019.04.49","article-title":"Efficacy and safety profile of roflumilast in a real-world experience","volume":"11","author":"Cilli","year":"2019","journal-title":"J. Thorac. Dis."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1001\/jama.2022.14663","article-title":"Roflumilast for chronic plaque psoriasis","volume":"328","author":"Cordoro","year":"2022","journal-title":"JAMA"},{"key":"B6","doi-asserted-by":"publisher","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":"B7","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1038\/nrd3276","article-title":"Roflumilast","volume":"9","author":"Fabbri","year":"2010","journal-title":"Nat. Rev. Drug Discov."},{"key":"B8","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1016\/S0140-6736(12)60304-3","article-title":"Side-effects of roflumilast","volume":"379","author":"Gupta","year":"2012","journal-title":"Lancet."},{"key":"B9","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.pupt.2016.02.004","article-title":"Comparison of the clinical effects of combined salmeterol\/fluticasone delivered by dry powder or pressurized metered dose inhaler","volume":"37","author":"Hojo","year":"2016","journal-title":"Pulm. Pharmacol. Ther."},{"key":"B10","doi-asserted-by":"publisher","first-page":"CD002309","DOI":"10.1002\/14651858.CD002309.pub6","article-title":"Phosphodiesterase-4 inhibitors for chronic obstructive pulmonary disease","volume":"5","author":"Janjua","year":"2020","journal-title":"Cochrane Database Syst. Rev."},{"key":"B11","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1007\/s13318-016-0343-4","article-title":"Pharmacokinetics of roflumilast and its active metabolite roflumilast N-Oxide in healthy Chinese subjects after single and multiple oral doses","volume":"42","author":"Li","year":"2017","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.3389\/fphar.2018.01048","article-title":"Phosphodiesterase-4 inhibitors for the treatment of inflammatory diseases","volume":"9","author":"Li","year":"2018","journal-title":"Front. Pharmacol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"213","DOI":"10.3978\/j.issn.2072-1439.2013.05.11","article-title":"Roflumilast: a green signal is yet to come","volume":"5","author":"Lone","year":"2013","journal-title":"J. Thorac. Dis."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e22843","DOI":"10.7759\/cureus.22843","article-title":"Effectiveness of roflumilast in treating chronic obstructive pulmonary disease: a systematic review and meta-analysis","volume":"14","author":"Naseem","year":"2022","journal-title":"Cureus"},{"key":"B15","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1177\/1753465812466167","article-title":"Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis","volume":"7","author":"Oba","year":"2013","journal-title":"Ther. Adv. Respir. Dis."},{"key":"B16","doi-asserted-by":"publisher","first-page":"16661","DOI":"10.1038\/s41598-025-01583-1","article-title":"A pharmacovigilance analysis of post-marketing safety of durvalumab","volume":"15","author":"Tan","year":"2025","journal-title":"Sci. Rep."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2779","DOI":"10.1007\/s00125-012-2632-z","article-title":"The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db\/db mice","volume":"55","author":"Vollert","year":"2012","journal-title":"Diabetologia"},{"key":"B18","doi-asserted-by":"publisher","first-page":"81","DOI":"10.2147\/COPD.S89849","article-title":"Roflumilast: a review of its use in the treatment of COPD","volume":"11","author":"Wedzicha","year":"2016","journal-title":"Int. J. Chron. Obstruct Pulmon Dis."},{"key":"B19","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1378\/chest.12-2332","article-title":"Cardiovascular safety in patients receiving roflumilast for the treatment of COPD","volume":"144","author":"White","year":"2013","journal-title":"Chest"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.3390\/ph17081028","article-title":"Adverse event profiles of adalimumab in children: a disproportionality analysis","volume":"17","author":"Zhang","year":"2024","journal-title":"Pharm. (Basel)"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1333662","DOI":"10.3389\/fphar.2024.1333662","article-title":"A real-world disproportionality analysis of everolimus: data mining of the public version of FDA adverse event reporting system","volume":"15","author":"Zhao","year":"2024","journal-title":"Front. Pharmacol."}],"container-title":["Frontiers in Drug Safety and Regulation"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fdsfr.2025.1721656\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T06:32:49Z","timestamp":1765521169000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fdsfr.2025.1721656\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,12]]},"references-count":21,"alternative-id":["10.3389\/fdsfr.2025.1721656"],"URL":"https:\/\/doi.org\/10.3389\/fdsfr.2025.1721656","relation":{},"ISSN":["2674-0869"],"issn-type":[{"value":"2674-0869","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,12]]},"article-number":"1721656"}}