Safety Evaluation of Irinotecan: A Real-World Disproportionality Analysis Using FAERS and JADER Databases During the Time Period 2004-2024

Siyu Lou¹Huayou Chen²Zhiwei Cui³Xiyuan Zhang⁴Chengyu Zhu¹Linmei Zhou¹Yingyong Ou^1*Fan Zou^1*

• ¹Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
• ²Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, China
• ³Department of Obstetrics and Gynecology, First Affiliated Hospital of Xi’an Jiaotong University, Xi'an, Shaanxi, China
• ⁴Department of General Medicine, Yanan university Affiliated hospital, Yanan, China

Irinotecan is a key treatment for colon, pancreatic, and ovarian cancers. However, maintaining its safety in clinical use necessitates ongoing vigilance. To address this, we performed a detailed analysis of adverse drug events (ADEs) related to irinotecan using data from the U.S. FDA Adverse Event Reporting System (FAERS) and the Japan Adverse Drug Event Report (JADER). Between 2004 and 2024, 11,344 and 7,822 reports of irinotecan-related ADEs were collected in FAERS and JADER, respectively. Reports from both databases involved 27 system organ classes (SOCs). The SOCs with the highest number of reported cases in FAERS and JADER were gastrointestinal disorders (n=6,888) and blood and lymphatic system disorders (n=3,389). Using four disproportionality methods, we identified 388 and 67 preferred terms (PTs) associated with irinotecan in FAERS and JADER, respectively, with 38 overlapping signals. These included some signals listed in the drug label such as neutropenia, diarrhea, thrombocytopenia, and stomatitis, as well as some unexpected signals such as second primary malignancy, hyperammonaemia, and hiccups. Specific positive signals in FAERS included skin toxicity [n=100, ROR 33.89 (27.79-41.34), PRR 33.80, EBGM05 28.03, IC025 4.76], aphasia [n=65, ROR 3.57 (2.8-4.55), PRR 3.56, EBGM05 2.90, IC025 1.47], and hepatic failure [n=56, ROR 3.09 (2.38-4.02), PRR 3.09, EBGM05 2.48, IC025 1.24], while in JADER, they included fatigue [n=73, ROR 4.69 (3.71-5.93), PRR 4.67, EBGM05 3.57, IC025 0.51], hyperammonaemia [n=67, ROR 7.24 (5.56-9.27), PRR 7.21, EBGM05 5.32, IC025 1.10], and cholinergic syndrome [n=27, ROR 5.54 (3.76-8.16), PRR 5.53, EBGM05 3.61, IC025 0.74]. In both FAERS (n=2,119, 53.1%) and JADER (n=5,366, 61.7%), these adverse events occurred within one month of irinotecan treatment. The median time to onset of irinotecan-associated ADEs was 28 days (9, 76) in FAERS and 17 days (9, 57) in JADER, respectively (median [Q1, Q3]). Our analysis revealed suspected ADEs associated with irinotecan dosing and identified several unexpected signals. By comparing the differences in signals and ADE occurrences between the two databases, we highlighted the importance of continued clinical monitoring of irinotecan, enhanced pharmacovigilance, awareness of regional variations, and further research.