Post-marketing safety signals of Wilson’s disease therapies: evidence from FAERS and VigiBase

Wilson’s disease is a rare autosomal copper metabolism recessive disorder that requires lifelong pharmacological treatment. D-penicillamine and trientine are the most commonly used copper chelators. However, their post-marketing safety reporting patterns remain insufficiently characterized. We conducted a pharmacovigilance study using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the World Health Organization’s VigiAccess database. Because FAERS allows case-level signal detection whereas VigiAccess provides only aggregated data, analyses were intentionally restricted to parallel signal characterization, precluding event-matched or head-to-head comparisons. To reduce indication bias and ensure disease-specific assessment, FAERS analyses were restricted to reports explicitly listing “hepato-lenticular degeneration” as the indication for use. Temporal, geographical, and demographic trends were evaluated, and disproportionality analyses—including the reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC), and multi-item gamma-Poisson shrinker (MGPS)—were performed to identify and validate adverse drug event (ADE) signals. A total of 641 cases were retrieved from FAERS and 4,560 from VigiAccess. Trientine accounted for most cases in FAERS, whereas D-penicillamine predominated in VigiAccess. Temporal analysis showed earlier reporting peaks for D-penicillamine in VigiAccess, while trientine displayed a progressive rise after 2000. Regional differences were evident, with Europe dominating VigiAccess reports and Asia/America contributing more strongly to FAERS. Disproportionality analyses revealed significant signals: trientine was associated with hepatic failure, abdominal pain, tremor, nausea, and fatigue, while D-penicillamine demonstrated signals for dystonia, arthritis, tremor, and nausea. Extremely high estimates for hepato-lenticular degeneration likely reflect confounding by indication. Our findings characterize drug-specific safety reporting patterns for copper chelators used in Wilson’s disease within two complementary pharmacovigilance systems. Rather than establishing relative safety, the observed differences reflect distinct reporting profiles shaped by database structure, regulatory context, and clinical use. Integrating national and international pharmacovigilance data provides complementary insights into post-marketing safety signals and may support tailored clinical monitoring strategies without implying head-to-head comparative risk.