Adverse events of givosiran in the treatment of acute hepatic porphyria: a pharmacovigilance study using the FAERS and VigiAccess databases

Acute hepatic porphyria is a rare metabolic disorder characterized by life-threatening acute attacks and chronic neurological symptoms. Givosiran is an RNA interference therapeutic approved by the FDA in 2019 to treat AHP by inhibiting hepatic ALAS1 expression. This study aims to provide a comprehensive pharmacovigilance analysis of givosiran to evaluate its safety profile in real-world clinical settings.

A retrospective disproportionality analysis was conducted using the FAERS database (from inception to Q4 2025) and the VigiAccess database (from inception to January 2026). Four algorithms—ROR, PRR, EBGM, and BCPNN—were employed to detect positive signals. Secondary analyses included clinical prioritization of signals and TTO analysis using the Weibull distribution test.

Overall,1,286 adverse event reports identifying givosiran as the primary suspect were extracted from FAERS, while the external validation using VigiAccess retrieved 1,326 reports. Among the FAERS reports with available data, female patients were more frequently reported, however, most cases lacked gender information. This demographic trend was supported by VigiAccess data, where reports were predominantly from the Americas (1,024 cases) and Europe (297 cases), with females accounting for 189 cases. Disproportionality analysis identified several adverse events consistent with previously recognized risks, including increased blood homocysteine, renal impairment, and pancreatitis. In addition, multiple signals not currently included in the product labeling—such as abdominal pain, seizure, and mental disorder—were consistently detected across both databases and warrant further investigation. Clinical prioritization categorized acute pancreatitis, seizure, abdominal pain, and renal impairment as moderate priority signals. TTO analysis revealed a mean onset of 544.36 days, with a Weibull shape parameter (β) of 1.01 (95% CI: 0.73–1.26), indicating a random failure-type risk pattern where the hazard remains constant over time. Sensitivity analysis excluding several PTs potentially related to the underlying manifestations of acute hepatic porphyria yielded consistent results, with major metabolic, pancreatic, and hepatic signals remaining statistically significant. Validation in VigiAccess identified 35 signals, confirming key risks such as blood homocysteine Increased and pancreatitis.

This study corroborates the known risks of givosiran, including elevated blood homocysteine and renal impairment, using both the FAERS and VigiAccess databases, and identifies significant associations of givosiran with pancreatitis and seizures. The consistent detection of these signals across two independent databases further supports their credibility. The random failure-type risk pattern indicates that continuous safety monitoring should be maintained throughout the entire treatment course.