Post-marketing safety analysis of nafamostat: A retrospective pharmacovigilance study using the Japanese Adverse Drug Event Report (JADER) database

Nafamostat is a broad-spectrum serine protease inhibitor approved for pancreatitis, disseminated intravascular coagulation, and extracorporeal circulation anticoagulation. It also showed potential anti-SARS-CoV-2 activity during the COVID-19 pandemic, leading to expanded clinical use. This study aimed to explore post-marketing adverse event (AE) signals of nafamostat based on the Japanese Adverse Drug Event Report database so as to provide evidence for clinical safety management. Retrospective analysis was performed on AE reports retrieved from the Japanese Adverse Drug Event Report database between Q1 2004 and Q3 2024. Four disproportionality analysis algorithms, including reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker, were adopted to detect AE signals. The distribution of AEs across system organ classes and preferred terms was summarized, and the time to onset was analyzed using the Weibull shape parameter test. A total of 2051 valid AE reports with nafamostat as the primary suspected drug were included, covering 20 system organ classes. The most prominent signals were observed in immune system disorders (n = 997) and vascular disorders (n = 370). Twenty-four preferred terms met the screening criteria of all 4 algorithms, among which anaphylactic shock (n = 746), shock (n = 341), and hyperkalemia (n = 200) were the most frequently reported. Six potential novel signals not recorded in the drug label were identified, namely acquired factor V deficiency, increased viral load, burning sensation, retroperitoneal hemorrhage, abdominal wall hematoma, and device-related thrombosis. Further bias analysis confirmed that 3 signals were false-positive results caused by confounding by indication or protopathic bias, while burning sensation had clear biological plausibility. The median time to onset was 1 day (interquartile range: 1-9 days); 58.55% of AEs occurred on the 1st day of administration, and 82.63% developed within 30 days. The Weibull test indicated that the AE risk peaked at the initial medication stage and gradually decreased over time. This real-world study clarified the safety profile of nafamostat, identifying severe allergic reactions and hyperkalemia as the main AEs. Of 6 initially detected unlabeled signals, 3 were confirmed as false-positive due to confounding bias, while the remaining 3 (bleeding complications and abnormal burning sensation) warrant clinical monitoring. Close monitoring within 24 hours after administration is highly recommended to reduce drug-related risks.