{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:50:17Z","timestamp":1753890617835,"version":"3.41.2"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,17]],"date-time":"2023-07-17T00:00:00Z","timestamp":1689552000000},"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:p><jats:bold>Introduction:<\/jats:bold> In December 2020, the Italian Medicines Agency (AIFA) in collaboration with the Italian Regional Centers of Pharmacovigilance evaluated four individual case safety reports (ICSRs) reporting obinutuzumab and non-overt disseminated intravascular coagulation (DIC) as a new possible signal. In this study, we described the process of signal management for obinutuzumab-associated non-overt DIC.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> In accordance with the Guideline on Good Pharmacovigilance Practices Module IX, we described the process of the Italian and European Union signal management process in five steps: signal detection, signal validation, signal confirmation, signal analysis, and prioritization and signal assessment.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> In the signal detection phase, four cases of obinutuzumab-associated non-overt DIC met the criteria for signal definition (ROR 213.6 and IC025 77). In the signal validation phase, both the Italian and European databases of spontaneously reported adverse drug reactions were investigated with supporting evidence from medical literature. Four patients (two men and two women aged 67\u201377) were in treatment with obinutuzumab for chronic lymphocytic leukemia, and they developed a subclinical DIC within 24\u00a0h from the administration of the drug. The DIC spontaneously resolved in all cases. Three more ICSRs were reported in the EudraVigilance database. The medical literature provided poor evidence of the possible association between obinutuzumab and DIC. The signal was subsequently validated, first by AIFA and then by EMA. The signal was confirmed by the Pharmacovigilance Risk Assessment Committee (PRAC) Rapporteur in the \u201csignal confirmation\u201d phase, and it entered \u201csignal analysis and prioritization\u201d and \u201csignal assessment\u201d. In these phases, the PRAC assessed and confirmed DIC as a possible adverse reaction to obinutuzumab. Finally, the Summary of Product characteristics was updated with this new risk.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Despite the intrinsic difficulties linked to the nature of the event itself, the process of signal detection and the issuing of the risk minimization measures by the Italian Medicines Agency as part of the EU procedures have proven to be efficient.<\/jats:p>","DOI":"10.3389\/fdsfr.2023.1194683","type":"journal-article","created":{"date-parts":[[2023,7,17]],"date-time":"2023-07-17T09:45:38Z","timestamp":1689587138000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Signal management and risk minimization strategy: a case study on obinutuzumab and non-overt disseminated intravascular coagulation"],"prefix":"10.3389","volume":"3","author":[{"given":"Giulia","family":"Valdiserra","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadia","family":"Mores","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosalba Elisabetta","family":"Rocchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Sottosanti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrizia","family":"Felicetti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pasquale","family":"Marchione","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Laurenti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Fresa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giampaolo","family":"Bucaneve","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emiliano","family":"Cappello","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Bonaso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Ferraro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irma","family":"Convertino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Tuccori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1007\/S11239-020-02147-Y","article-title":"Drug-induced disseminated intravascular coagulation: A pharmacovigilance study on World health organization\u2019s database","volume":"50","author":"Bonaldo","year":"2020","journal-title":"J. Thromb. Thrombolysis"},{"key":"B2","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1007\/s40264-017-0564-8","article-title":"Muscular adverse drug reactions associated with proton pump inhibitors: A disproportionality analysis using the Italian national Network of pharmacovigilance database","volume":"40","author":"Capogrosso Sansone","year":"2017","journal-title":"Drug Saf."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1424","DOI":"10.1016\/J.EUF.2021.07.001","article-title":"Drug-induced urinary retention: An analysis of a national spontaneous adverse drug reaction reporting database","volume":"8","author":"Crisafulli","year":"2022","journal-title":"Eur. Urol. Focus"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1007\/S40264-017-0553-Y","article-title":"Overview of the safety of anti-VEGF drugs: Analysis of the Italian spontaneous reporting system","volume":"40","author":"Cutroneo","year":"2017","journal-title":"Drug Saf."},{"key":"B5","unstructured":"EudraVigilance expert working group"},{"key":"B6","unstructured":"Gazyvaro | European medicines agency"},{"key":"B7","unstructured":"Guideline on good pharmacovigilance practices (GVP) Module IX-Signal management2017"},{"key":"B8","unstructured":"MabThera | European medicines agency"},{"key":"B9","unstructured":"Ocrevus | European medicines agency"},{"key":"B10","unstructured":"PRAC recommendations on signal_September 20212021"},{"key":"B11","unstructured":"PRAC recommendations on signals_March 2022"},{"key":"B12","unstructured":"Signal management"},{"key":"B13","unstructured":"Obinutuzumab | FDA2022"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1763","DOI":"10.1038\/leu.2016.41","article-title":"Role of CD20 expression and other pre-treatment risk factors in the development of infusion-related reactions in patients with CLL treated with obinutuzumab","volume":"30","author":"Freeman","year":"2016","journal-title":"Leukemia"},{"key":"B15","doi-asserted-by":"publisher","first-page":"2646","DOI":"10.1182\/blood-2015-09-670802","article-title":"Cytokine release in patients with CLL treated with obinutuzumab and possible relationship with infusion-related reactions","volume":"126","author":"Freeman","year":"2015","journal-title":"Blood"},{"key":"B16","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1002\/HON.2837","article-title":"Non-overt disseminated intravascular coagulopathy associated with the first obinutuzumab administration in patients with chronic lymphocytic leukemia","volume":"39","author":"Fresa","year":"2021","journal-title":"Hematol. Oncol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1007\/s40265-014-0340-3","article-title":"Obinutuzumab: A review of its use in patients with chronic lymphocytic leukaemia","volume":"75","author":"Hoy","year":"2015","journal-title":"Drugs"},{"key":"B18","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1111\/ijlh.12830","article-title":"Pathogenesis and diagnosis of disseminated intravascular coagulation","volume":"40","author":"Levi","year":"2018","journal-title":"Int. J. Lab. Hematol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1182\/BLOOD-2017-10-804096","article-title":"How I treat disseminated intravascular coagulation","volume":"131","author":"Levi","year":"2018","journal-title":"Blood"},{"key":"B20","doi-asserted-by":"publisher","first-page":"bbab347","DOI":"10.1093\/BIB\/BBAB347","article-title":"Detection algorithms and attentive points of safety signal using spontaneous reporting systems as a clinical data source","volume":"22","author":"Noguchi","year":"2021","journal-title":"Brief. Bioinform."},{"key":"B21","doi-asserted-by":"publisher","first-page":"bcr2016218443","DOI":"10.1136\/BCR-2016-218443","article-title":"Disseminated intravascular coagulation-like reaction following rituximab infusion","volume":"2017","author":"Rafei","year":"2017","journal-title":"BMJ Case Rep."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1055\/s-0037-1616068","article-title":"Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation","volume":"86","author":"Taylor","year":"2001","journal-title":"J. Thromb. Haemost."},{"key":"B23","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1111\/J.1538-7836.2007.02313.X","article-title":"The scoring system of the scientific and standardisation committee on disseminated intravascular coagulation of the international society on thrombosis and haemostasis: A 5-year overview","volume":"5","author":"Toh","year":"2007","journal-title":"J. Thromb. Haemost."},{"key":"B24","doi-asserted-by":"publisher","first-page":"e435","DOI":"10.1038\/bcj.2016.42","article-title":"Obinutuzumab-induced coagulopathy in chronic lymphocytic leukaemia with trisomy 12","volume":"6","author":"Walter","year":"2016","journal-title":"Blood Cancer J."}],"container-title":["Frontiers in Drug Safety and Regulation"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fdsfr.2023.1194683\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T15:31:57Z","timestamp":1732289517000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fdsfr.2023.1194683\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,17]]},"references-count":24,"alternative-id":["10.3389\/fdsfr.2023.1194683"],"URL":"https:\/\/doi.org\/10.3389\/fdsfr.2023.1194683","relation":{},"ISSN":["2674-0869"],"issn-type":[{"type":"electronic","value":"2674-0869"}],"subject":[],"published":{"date-parts":[[2023,7,17]]},"article-number":"1194683"}}