Adverse effects of posaconazole on adrenal steroid biosynthesis: An integrative approach using FAERS-based pharmacovigilance and systematic review with meta-analysis of randomised controlled trials

• Pseudoaldosteronism signal detected only for posaconazole and itraconazole. • Hypokalaemia is commonly reported in posaconazole-related pseudoaldosteronism. • Posaconazole had a higher hypokalaemia risk than voriconazole in RCT meta-analysis. • Bradford Hill criteria supported posaconazole as a cause of pseudoaldosteronism. Posaconazole, a broad-spectrum azole antifungal agent, is used for prophylaxis and treatment of invasive fungal infections (IFIs). However, it has been associated with pseudoaldosteronism—a syndrome involving hypertension, hypokalaemia, and QT prolongation—likely mediated by adrenal steroid biosynthesis inhibition. This study aimed to assess the association between posaconazole and pseudoaldosteronism using a triangulated approach integrating real-world pharmacovigilance data, clinical trial evidence, and a structured causality framework. A disproportionality analysis of real-world pharmacovigilance data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) was performed to detect signals for pseudoaldosteronism, hypokalaemia, hypertension, and QT prolongation. Co-reported adverse events in pseudoaldosteronism cases were identified and counted. Clinical trial evidence was synthesised through a systematic review and meta-analysis (SR/MA) of randomised controlled trials comparing posaconazole with other antifungal agents. Causality was assessed based on the Bradford Hill criteria (BHC). In the FAERS analysis, posaconazole and itraconazole consistently showed signals for pseudoaldosteronism. Among reports of posaconazole, 29.8% (95% confidence interval [CI]: 22.1–38.4%) of pseudoaldosteronism cases co-occurred with hypokalaemia. The MA showed that posaconazole significantly increased the risk of hypokalaemia than did voriconazole (risk ratio: 10.41; 95% CI: 2.00–54.27; I 2 = 0%). Synthesizing our findings from the FAERS analysis and SR/MA supported a causal relationship based on the BHC. This study supports a causal association between posaconazole and pseudoaldosteronism by integrating clinical data from FAERS and SR/MA. Clinicians should closely monitor serum potassium during posaconazole therapy and consider pseudoaldosteronism in patients with hypokalaemia.