{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T11:12:29Z","timestamp":1772104349950,"version":"3.50.1"},"reference-count":31,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,10,5]],"date-time":"2025-10-05T00:00:00Z","timestamp":1759622400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Background: Trelegy Ellipta is a widely prescribed triple inhaler therapy for chronic obstructive pulmonary disease (COPD). Although its clinical efficacy is well established, evidence on sex-specific differences in adverse event (AE) profiles from real-world pharmacovigilance data remains limited. In addition, some AEs may reflect underlying disease characteristics rather than drug exposure, which complicates interpretation of safety signals. Objective: To explore sex-related differences in AEs associated with Trelegy Ellipta using the FDA Adverse Event Reporting System (FAERS). The study aimed to identify potential safety signals while accounting for alternative explanations, including comorbidity burden and disease-related variation. Methods: We retrospectively analyzed FAERS reports from January 2018 to April 2025, identifying 4555 AEs attributed to Trelegy Ellipta. Events were coded by System Organ Class (SOC) and stratified by patient sex. Frequencies were compared between male (n = 1621) and female (n = 2934) patients using chi-square tests, and associations were expressed as reporting odds ratios (RORs) with 95% confidence intervals (CIs). Results: Male patients more frequently reported hypertension (63.4% vs. 47.0%; p = 0.01), pneumonia (87.8% vs. 76.8%; p &lt; 0.001), anxiety (91.0% vs. 66.9%; p &lt; 0.001), sleep disorders (20.1% vs. 6.8%; p &lt; 0.001), and hyperglycemia (92.7% vs. 52.1%; p &lt; 0.001). Female patients more often reported headache (56.7% vs. 32.6%; p &lt; 0.001), depression (33.1% vs. 9.0%; p &lt; 0.001), and osteoporosis (41.7% vs. 2.4%; p &lt; 0.001). Further variation was observed across neurological, musculoskeletal, and respiratory categories, suggesting a multidimensional pattern of sex differences. Conclusions: This FAERS-based analysis indicates distinct sex-specific safety signals for Trelegy Ellipta, particularly in cardiovascular, neuropsychiatric, and steroid-related domains. These findings are hypothesis-generating and highlight the importance of incorporating sex-disaggregated analyses into future pharmacovigilance and clinical studies.<\/jats:p>","DOI":"10.3390\/medsci13040221","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T08:10:51Z","timestamp":1759738251000},"page":"221","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Sex-Specific Safety Signals of Trelegy Ellipta: A FAERS Pharmacovigilance Analysis"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8363-621X","authenticated-orcid":false,"given":"Josef","family":"Yayan","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy, and Sleep Medicine, Department of Internal Medicine, HELIOS Clinic Wuppertal, Witten\/Herdecke University, 42283 Witten, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Biancosino","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, HELIOS Clinic Wuppertal, Witten\/Herdecke University, 42283 Witten, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5250-5658","authenticated-orcid":false,"given":"Marcus","family":"Kr\u00fcger","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Martha-Maria Hospital Halle-D\u00f6lau, 06120 Halle, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2862-3325","authenticated-orcid":false,"given":"Kurt","family":"Rasche","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Sleep Medicine, Department of Internal Medicine, HELIOS Clinic Wuppertal, Witten\/Herdecke University, 42283 Witten, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,5]]},"reference":[{"key":"ref_1","unstructured":"Agarwal, A.K., Raja, A., and Brown, B.D. (2025, August 28). Chronic Obstructive Pulmonary Disease, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK559281\/."},{"key":"ref_2","first-page":"CD012620","article-title":"Dual combination therapy versus long-acting bronchodilators alone for chronic obstructive pulmonary disease (COPD): A systematic review and network meta-analysis","volume":"12","author":"Oba","year":"2018","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1056\/NEJMoa1713901","article-title":"Once-daily single-inhaler triple versus dual therapy in patients with COPD","volume":"378","author":"Lipson","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1007\/s40265-014-0269-6","article-title":"Fluticasone furoate\/vilanterol: A review of its use in chronic obstructive pulmonary disease","volume":"74","author":"McKeage","year":"2014","journal-title":"Drugs"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"44","DOI":"10.29390\/cjrt-2021-041","article-title":"Chronic obstructive pulmonary disease patients\u2019 experience using Trelegy as compared with other inhalers","volume":"58","author":"Mashaal","year":"2022","journal-title":"Can. J. Respir. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ruan, Z., Wang, C., Yuan, S., Fan, Y., Xu, B., Cong, X., Li, D., and Miao, Q. (2025). High-risk adverse events in two types of single inhaler triple-therapy: A pharmacovigilance study based on the FAERS database. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1460407"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"143","DOI":"10.2165\/00003088-200948030-00001","article-title":"Sex differences in pharmacokinetics and pharmacodynamics","volume":"48","author":"Soldin","year":"2009","journal-title":"Clin. Pharmacokinet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1513\/AnnalsATS.202211-975OC","article-title":"Predictors of patient-reported and pharmacy refill measures of maintenance inhaler adherence in veterans with chronic obstructive pulmonary disease","volume":"21","author":"Pattock","year":"2024","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1753466618760779","DOI":"10.1177\/1753466618760779","article-title":"Single-inhaler triple therapy utilizing the once-daily combination of fluticasone furoate, umeclidinium and vilanterol in the management of COPD: The current evidence base and future prospects","volume":"12","author":"Malerba","year":"2018","journal-title":"Ther. Adv. Respir. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1186\/s12931-019-1213-9","article-title":"Single-inhaler triple therapy in patients with chronic obstructive pulmonary disease: A systematic review","volume":"20","author":"Langham","year":"2019","journal-title":"Respir. Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sportiello, L., and Capuano, A. (2024). Sex and gender differences and pharmacovigilance: A knot still to be untied. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1397291"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s00392-021-01915-x","article-title":"Gender-specific differences in COPD symptoms and their impact for the diagnosis of cardiac comorbidities","volume":"112","author":"Trudzinski","year":"2023","journal-title":"Clin. Res. Cardiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"695","DOI":"10.2147\/COPD.S149404","article-title":"Factors associated with appropriate inhaler use in patients with COPD\u2014Lessons from the REAL survey","volume":"13","author":"Price","year":"2018","journal-title":"Int. J. Chron. Obstruct. Pulmon. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"106280","DOI":"10.1016\/j.rmed.2020.106280","article-title":"Impact of patients\u2019 perception of COPD and treatment on adherence and health-related quality of life in real-world: Study in 53 community pharmacies","volume":"176","author":"Grau","year":"2021","journal-title":"Respir. Med."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Doi, K., Hirano, T., Oishi, K., Fukatsu-Chikumoto, A., Ohteru, Y., Hamada, K., Ohata, S., Murata, Y., Yamaji, Y., and Asami-Noyama, M. (2024). Gender Difference in the Relationship between Extrapulmonary Factors and Reduced Lung Function in Early Adulthood. J. Clin. Med., 13.","DOI":"10.3390\/jcm13061769"},{"key":"ref_16","first-page":"2335","article-title":"The importance of inhaler devices: The choice of inhaler device may lead to suboptimal adherence in COPD patients","volume":"10","author":"Sicras","year":"2015","journal-title":"Int. J. Chron. Obstruct. Pulmon. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"85","DOI":"10.2174\/1874306401408010085","article-title":"Inhaled corticosteroids and bone health","volume":"8","author":"Chee","year":"2014","journal-title":"Open Respir. Med. J."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zucker, I., and Prendergast, B.J. (2020). Sex differences in pharmacokinetics predict adverse drug reactions in women. Biol. Sex Differ., 11.","DOI":"10.1186\/s13293-020-00308-5"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.therap.2022.10.002","article-title":"Sex differences in adverse drug reactions: Are women more impacted?","volume":"78","author":"Lacroix","year":"2023","journal-title":"Therapies"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1111\/bcp.13923","article-title":"Sex differences in adverse drug reactions reported to the National Pharmacovigilance Centre in the Netherlands: An explorative observational study","volume":"85","author":"Denig","year":"2019","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1097\/MCP.0000000000000554","article-title":"Inhaled corticosteroids and fractures in chronic obstructive pulmonary disease: Current understanding and recommendations","volume":"25","author":"Moon","year":"2019","journal-title":"Curr. Opin. Pulm. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1111\/j.1365-2222.2009.03354.x","article-title":"The role of female sex hormones in the development and severity of allergic and non-allergic asthma","volume":"39","author":"Heijink","year":"2009","journal-title":"Clin. Exp. Allergy"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1038\/clpt.2012.50","article-title":"Novel data-mining methodologies for adverse drug event discovery and analysis","volume":"91","author":"Harpaz","year":"2012","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.jsps.2016.09.008","article-title":"Pharmacovigilance system in Saudi Arabia","volume":"25","author":"Alshammari","year":"2017","journal-title":"Saudi Pharm. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"S73","DOI":"10.4103\/0976-500X.120957","article-title":"Clinical and economic burden of adverse drug reactions","volume":"4","author":"Sultana","year":"2013","journal-title":"J. Pharmacol. Pharmacother."},{"key":"ref_26","first-page":"e596","article-title":"2019 ACC\/AHA guideline on the primary prevention of cardiovascular disease","volume":"140","author":"Arnett","year":"2019","journal-title":"Circulation"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"69","DOI":"10.2337\/dc17-1414","article-title":"Long-term trends in antidiabetes drug usage in the U.S.: Real-world evidence in patients newly diagnosed with type 2 diabetes","volume":"41","author":"Montvida","year":"2018","journal-title":"Diabetes Care"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Brabete, A.C., Greaves, L., Maximos, M., Huber, E., Li, A., and L\u00ea, M.L. (2022). A sex- and gender-based analysis of adverse drug reactions: A scoping review of pharmacovigilance databases. Pharmaceuticals, 15.","DOI":"10.3390\/ph15030298"},{"key":"ref_29","unstructured":"U.S. Food and Drug Administration (2025, August 28). FDA\u2019s Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data, Available online: https:\/\/www.fda.gov\/media\/109618\/download."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Hendriksen, L.C., van der Linden, P.D., Lagro-Janssen, A.L.M., van den Bemt, P.M.L.A., Siiskonen, S.J., Teichert, M., Kuiper, J.G., Herings, R.M.C., Stricker, B.H., and Visser, L.E. (2021). Sex differences associated with adverse drug reactions resulting in hospital admissions. Biol. Sex Differ., 12.","DOI":"10.1186\/s13293-021-00377-0"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1016\/j.jacc.2018.02.070","article-title":"Participation of women in clinical trials supporting FDA approval of cardiovascular drugs","volume":"71","author":"Scott","year":"2018","journal-title":"J. Am. Coll. Cardiol."}],"container-title":["Medical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3271\/13\/4\/221\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T08:30:33Z","timestamp":1759739433000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3271\/13\/4\/221"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,5]]},"references-count":31,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["medsci13040221"],"URL":"https:\/\/doi.org\/10.3390\/medsci13040221","relation":{},"ISSN":["2076-3271"],"issn-type":[{"value":"2076-3271","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,5]]}}}