{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T12:44:54Z","timestamp":1787834694026,"version":"build-2784847793"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T00:00:00Z","timestamp":1671062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017686","name":"Fujian Provincial Health Technology Project","doi-asserted-by":"publisher","award":["2020CXB014"],"award-info":[{"award-number":["2020CXB014"]}],"id":[{"id":"10.13039\/501100017686","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Triazole antifungal drugs (TAD) are widely used to treat invasive fungal infections due to their broad antifungal spectrum and low toxicity. Despite their preference in the clinic, multiple Adverse Events (AE) are still reported each year. Objective: We aimed to characterize the distribution of Adverse Events associated with Triazole antifungal drugs in different systems and to identify Important Medical Events (IME) signals for Triazole antifungal drugs. Methods: The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) was queried for Adverse Events related to Triazole antifungal drugs from 2012 to 2022. The Adverse Events caused by all other drugs and non-TAD antifungal drugs were analyzed as references. Reporting odds ratio and Bayesian confidence propagation neural network of information components were used to evaluate the association between Triazole antifungal drugs and Important Medical Events. Visual signal spectrum is mapped to identify potential adverse reaction signals. Results: Overall, 10,262 Adverse Events were reported to be associated with Triazole antifungal drugs, of which 5,563 cases were defined as Important Medical Events. Common adverse drug reactions (ADR) mentioned in the instructions such as delirium and hypokalemia were detected, as well as unlabeled ADRs such as rhabdomyolysis and hepatitis fulminant. Cholestasis, drug-induced liver injury, QT interval prolongation and renal impairment have notable signals in all Triazole antifungal drugs, with 50 percent of patients developing a severe clinical outcome. Isavuconazole had the lowest signal intensity and demonstrated a superior safety profile. Conclusion: Most results are generally consistent with previous studies and are documented in the prescribing instructions, but some IMEs are not included, such as hepatitis fulminant. Additional pharmaco-epidemiological or experimental studies are required to validate the small number of unlabeled ADRs. TAD-related Important Medical Eventshave a considerable potential to cause clinically serious outcomes. Clinical use of Triazole antifungal drugs requires more attention.<\/jats:p>","DOI":"10.3389\/fphar.2022.1039867","type":"journal-article","created":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T07:52:41Z","timestamp":1671090761000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":25,"title":["Pharmacovigilance of triazole antifungal agents: Analysis of the FDA adverse event reporting system (FAERS) database"],"prefix":"10.3389","volume":"13","author":[{"given":"Jianxing","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zipeng","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baohua","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maobai","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruichao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1080\/17425255.2017.1391213","article-title":"Pharmacogenomics of triazole antifungal agents: Implications for safety, tolerability and efficacy","volume":"13","author":"Amsden","year":"2017","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1016\/j.cmi.2017.03.023","article-title":"Evaluation of the in vitro activity of isavuconazole and comparator voriconazole against 2635 contemporary clinical Candida and Aspergillus isolates","volume":"23","author":"Astvad","year":"2017","journal-title":"Clin. Microbiol. Infect."},{"key":"B3","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1007\/s40265-019-01127-8","article-title":"Adverse effects associated with long-term administration of azole antifungal agents","volume":"79","author":"Benitez","year":"2019","journal-title":"Drugs"},{"key":"B4","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1111\/j.1442-200X.2010.03286.x","article-title":"Twice-weekly fluconazole prophylaxis in premature infants: Association with cholestasis","volume":"53","author":"Bhat","year":"2011","journal-title":"Pediatr. Int."},{"key":"B5","doi-asserted-by":"publisher","first-page":"263","DOI":"10.2165\/00002018-200225040-00004","article-title":"Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: An overview","volume":"25","author":"De Ponti","year":"2002","journal-title":"Drug Saf."},{"key":"B6","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1086\/324620","article-title":"Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis","volume":"34","author":"Denning","year":"2002","journal-title":"Clin. Infect. Dis."},{"key":"B7","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s40360-017-0115-z","article-title":"A case report of intravenous posaconazole in hepatic and renal impairment patient with invasive Aspergillus terreus infection: Safety and role of therapeutic drug monitoring","volume":"18","author":"Dilokpattanamongkol","year":"2017","journal-title":"BMC Pharmacol. Toxicol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"324","DOI":"10.3390\/jof6040324","article-title":"Isavuconazole: Mechanism of action, clinical efficacy, and resistance","volume":"6","author":"Ellsworth","year":"2020","journal-title":"J. Fungi."},{"key":"B9","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1128\/AAC.01525-13","article-title":"Incidence density of invasive fungal infections during primary antifungal prophylaxis in newly diagnosed acute myeloid leukemia patients in a tertiary cancer center, 2009 to 2011","volume":"58","author":"Gomes","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1517\/17425255.2011.627854","article-title":"Triazole antifungal agents drug-drug interactions involving hepatic cytochrome P450","volume":"7","author":"Gubbins","year":"2011","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"B11","first-page":"40890","article-title":"International conference on harmonisation; electronic transmission of postmarket individual case safety reports for drugs and biologics, excluding vaccines; availability of Food and drug administration regional implementation specifications for ICH E2B(R3h) reporting to the food and drug administration adverse event reporting system","volume":"81","year":"2016","journal-title":"Fed. Regist."},{"key":"B12","doi-asserted-by":"publisher","first-page":"28","DOI":"10.2133\/dmpk.dmpk-12-rv-085","article-title":"Impact of genetic polymorphisms in CYP2C9 and CYP2C19 on the pharmacokinetics of clinically used drugs","volume":"28","author":"Hirota","year":"2013","journal-title":"Drug Metab. Pharmacokinet."},{"key":"B13","doi-asserted-by":"publisher","first-page":"3695101","DOI":"10.1155\/2020\/3695101","article-title":"Fournier gangrene associated with sodium-glucose cotransporter-2 inhibitors: A pharmacovigilance study with data from the U.S. FDA adverse event reporting system","volume":"2020","author":"Hu","year":"2020","journal-title":"J. Diabetes Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1016\/j.drudis.2016.09.015","article-title":"Pharmacogenomics of the cytochrome P450 2C family: Impacts of amino acid variations on drug metabolism","volume":"22","author":"Isvoran","year":"2017","journal-title":"Drug Discov. Today"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1111\/myc.13148","article-title":"Breakthrough invasive fungal infections: Who is at risk?","volume":"63","author":"Jenks","year":"2020","journal-title":"Mycoses"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1772","DOI":"10.1093\/jac\/dkw045","article-title":"Trough concentration of voriconazole and its relationship with efficacy and safety: A systematic review and meta-analysis","volume":"71","author":"Jin","year":"2016","journal-title":"J. Antimicrob. Chemother."},{"key":"B17","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s13054-015-0753-8","article-title":"Evaluation of sulfobutylether-\u03b2-cyclodextrin (SBECD) accumulation and voriconazole pharmacokinetics in critically ill patients undergoing continuous renal replacement therapy","volume":"19","author":"Kiser","year":"2015","journal-title":"Crit. Care"},{"key":"B18","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1080\/14740338.2017.1270264","article-title":"Clinical hepatotoxicity associated with antifungal agents","volume":"16","author":"Kyriakidis","year":"2017","journal-title":"Expert Opin. Drug Saf."},{"key":"B19","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1016\/S0140-6736(15)01159-9","article-title":"Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): A phase 3, randomised-controlled, non-inferiority trial","volume":"387","author":"Maertens","year":"2016","journal-title":"Lancet"},{"key":"B20","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1124\/mol.116.103390","article-title":"Role of multidrug resistance protein 3 in antifungal-induced cholestasis","volume":"90","author":"Mahdi","year":"2016","journal-title":"Mol. Pharmacol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1828","DOI":"10.4254\/wjh.v7.i14.1828","article-title":"Voriconazole and the liver","volume":"7","author":"Mih\u0103il\u0103","year":"2015","journal-title":"World J. Hepatol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2259","DOI":"10.1097\/QAD.0000000000001961","article-title":"Effect of oral fluconazole 1200 mg\/day on QT interval in African adults with HIV-associated cryptococcal meningitis","volume":"32","author":"Molloy","year":"2018","journal-title":"AIDS"},{"key":"B23","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1002\/cpt.583","article-title":"Clinical pharmacogenetics implementation consortium (CPIC) guidelines for CYP2C19 and voriconazole therapy","volume":"102","author":"Moriyama","year":"2017","journal-title":"Clin. Pharmacol. Ther."},{"key":"B24","doi-asserted-by":"publisher","first-page":"27","DOI":"10.2147\/dhps.s6321","article-title":"Clinical safety and tolerability issues in use of triazole derivatives in management of fungal infections","volume":"2","author":"Neofytos","year":"2010","journal-title":"Drug Healthc. Patient Saf."},{"key":"B25","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.idc.2015.10.012","article-title":"Antifungal agents: Spectrum of activity, Pharmacology, and clinical indications","volume":"30","author":"Nett","year":"2016","journal-title":"Infect. Dis. Clin. North Am."},{"key":"B26","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1177\/0962280211403604","article-title":"Shrinkage observed-to-expected ratios for robust and transparent large-scale pattern discovery","volume":"22","author":"Nor\u00e9n","year":"2013","journal-title":"Stat. Methods Med. Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.2165\/00003495-200464100-00005","article-title":"QT prolongation with antimicrobial agents: Understanding the significance","volume":"64","author":"Owens","year":"2004","journal-title":"Drugs"},{"key":"B28","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1093\/clinids\/18.3.484","article-title":"Aspergillus fumigatus pneumonia in neutropenic patients receiving fluconazole for infection due to Candida species: is amphotericin B combined with fluconazole the appropriate answer?","volume":"18","author":"Pahls","year":"1994","journal-title":"Clin. Infect. Dis."},{"key":"B29","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1093\/cid\/civ1194","article-title":"Executive summary: Clinical practice guideline for the management of candidiasis: 2016 update by the infectious diseases society of America","volume":"62","author":"Pappas","year":"2016","journal-title":"Clin. Infect. Dis."},{"key":"B30","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1002\/pds.1001","article-title":"The reporting odds ratio and its advantages over the proportional reporting ratio","volume":"13","author":"Rothman","year":"2004","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"B31","doi-asserted-by":"publisher","first-page":"796","DOI":"10.7150\/ijms.6048","article-title":"Data mining of the public version of the FDA adverse event reporting system","volume":"10","author":"Sakaeda","year":"2013","journal-title":"Int. J. Med. Sci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1002\/pds.4115","article-title":"The value of time-to-onset in statistical signal detection of adverse drug reactions: A comparison with disproportionality analysis in spontaneous reports from The Netherlands","volume":"25","author":"Scholl","year":"2016","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1818","DOI":"10.1128\/AAC.01217-06","article-title":"In vitro activities of isavuconazole and other antifungal agents against Candida bloodstream isolates","volume":"51","author":"Seifert","year":"2007","journal-title":"Antimicrob. Agents Chemother."},{"key":"B34","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1111\/j.1476-5381.2009.00191.x","article-title":"Drug-induced QT interval shortening: Potential harbinger of proarrhythmia and regulatory perspectives","volume":"159","author":"Shah","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1016\/j.ejmech.2007.01.006","article-title":"Synthesis of novel triazole derivatives as inhibitors of cytochrome P450 14alpha-demethylase (CYP51)","volume":"42","author":"Sun","year":"2007","journal-title":"Eur. J. Med. Chem."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1311","DOI":"10.1007\/s00228-020-02909-w","article-title":"Borrowing external information to improve Bayesian confidence propagation neural network","volume":"76","author":"Tada","year":"2020","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1002\/kjm2.12325","article-title":"Posaconazole-induced pseudohyperaldosteronism","volume":"37","author":"Tantiprawan","year":"2021","journal-title":"Kaohsiung J. Med. Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1080\/14787210.2016.1199272","article-title":"Antifungal agents and liver toxicity: A complex interaction","volume":"14","author":"Tverdek","year":"2016","journal-title":"Expert Rev. anti. Infect. Ther."},{"key":"B39","doi-asserted-by":"publisher","first-page":"674","DOI":"10.3109\/08880018.2013.775616","article-title":"Voriconazole induced bradycardia","volume":"30","author":"Uluda\u011f","year":"2013","journal-title":"Pediatr. Hematol. Oncol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1002\/pds.668","article-title":"A comparison of measures of disproportionality for signal detection in spontaneous reporting systems for adverse drug reactions","volume":"11","author":"van Puijenbroek","year":"2002","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"B41","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1007\/s40264-019-00899-y","article-title":"Investigating overlap in signals from EVDAS, FAERS, and VigiBase","volume":"43","author":"Vogel","year":"2020","journal-title":"Drug Saf."},{"key":"B42","doi-asserted-by":"publisher","first-page":"697330","DOI":"10.3389\/fphar.2021.697330","article-title":"Adverse effects associated with currently commonly used antifungal agents: A network meta-analysis and systematic review","volume":"12","author":"Yang","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1124\/mol.110.067256","article-title":"Itraconazole-induced cholestasis: Involvement of the inhibition of bile canalicular phospholipid translocator MDR3\/ABCB4","volume":"79","author":"Yoshikado","year":"2011","journal-title":"Mol. Pharmacol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s12072-017-9793-2","article-title":"CSH guidelines for the diagnosis and treatment of drug-induced liver injury","volume":"11","author":"Yu","year":"2017","journal-title":"Hepatol. Int."},{"key":"B45","doi-asserted-by":"publisher","first-page":"237","DOI":"10.18433\/jpps32867","article-title":"Torsade de Pointes\/QT prolongation associated with antifungal triazoles: A pharmacovigilance study based on the U.S. FDA adverse event reporting system (FAERS)","volume":"25","author":"Yu","year":"2022","journal-title":"J. Pharm. Pharm. Sci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1186\/s40425-019-0754-2","article-title":"Endocrine toxicity of immune checkpoint inhibitors: A real-world study leveraging US Food and drug administration adverse events reporting system","volume":"7","author":"Zhai","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"B47","doi-asserted-by":"publisher","first-page":"766125","DOI":"10.3389\/fphar.2021.766125","article-title":"Safety of SGLT2 inhibitors: A pharmacovigilance study from 2013 to 2021 based on FAERS","volume":"12","author":"Zhou","year":"2021","journal-title":"Front. Pharmacol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.1039867\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T07:52:45Z","timestamp":1671090765000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.1039867\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,15]]},"references-count":47,"alternative-id":["10.3389\/fphar.2022.1039867"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.1039867","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,15]]},"article-number":"1039867"}}