Post-marketing safety concerns with pirfenidone and nintedanib: An analysis of individual case safety reports from the FDA adverse event reporting system (FAERS) database and the Japanese Adverse Drug Event Report (JADER) databases

Tao Wang¹Zhiwei Cui²Yingyong Ou¹Siyu Lou¹Huayou Chen³Chengyu Zhu¹Linmei Zhou¹Fan Zou^1*

• ¹Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
• ²Department of Obstetrics and Gynecology, First Affiliated Hospital of Xi’an Jiaotong University, Xi'an, Shaanxi, China
• ³The Second Affiliated Hospital of Hainan Medical University, Hainan, China

To date, only two drugs, pirfenidone and nintedanib, are approved for the treatment of patients with IPF. In addition, very few studies have reported on the safety profile of either drug in large populations. This study aims to identify and compare ADEs associated with pirfenidone and nintedanib in real-world settings by analyzing data from the FAERS. In addition, we utilized data from the JADER database for external validation Methods: The ADE reports on both drugs in FAERS and JADER were collected. After deduplication, Bayesian and non-Bayesian methods for disproportionality analysis were used for signal detection. TTO analysis were performed. In total, 35,804 and 20,486 ADE reports were identified from the FAERS database for pirfenidone and nintedanib. At the SOC level, both drugs have a positive signal value for "gastrointestinal disorders," "respiratory, thoracic, and mediastinal disorders," and "metabolism and nutrition disorders." Some positive signals were consistent with the drug labels, including nausea, decreased appetite, and weight decreased identified in pirfenidone, as well as diarrhea, decreased appetite, abdominal pain upper, and epistaxis identified in nintedanib. We also identified unexpected signals not listed on the drug label, such as decreased gastric pHsunburn, and pneumothorax for pirfenidone, and constipation, flatulence for nintedanib. The median onset time for ADEs was 146 days for pirfenidone and 45 days for nintedanib, respectively. Although the two antifibrotics differed in the proportion of periods in which the ADEs occurred, these ADEs were likely to continue even after a year of treatment. In the external validation of JADER, the number of reports for pirfenidone and nintedanib were 265, and 1,327, respectively. The disproportionality analysis at the SOC and PT levels supports the FAERS results.This study systematically investigates and compares the ADEs and their onset times at the SOC and specific PT levels for pirfenidone and nintedanib. Our results demonstrate provide valuable pharmacological insights for the similarities and differences between the safety profiles of the two drugs and highlight the importance of monitoring and managing the toxicity profile associated with antifibrotic drugs.