Analysis of clinical factors associated with Kampo formula-induced pseudoaldosteronism based on self-reported information from the Japanese Adverse Drug Event Report database

Abstract

Drug-induced pseudoaldosteronism is a typical adverse effect of Kampo formulas. Previous research described the potential risks of Kampo formula-linked pseudoaldosteronism. However, few studies assessed the risk factors using a real-world database and a data-mining approach. Using the Japanese Adverse Drug Event Report database, we extracted pseudoaldosteronism reports for 148 Kampo formulas covered by Japanese national health insurance. Adverse events were decided according to the preferred terminology of the Medical Dictionary for Regulatory Activities/Japanese version 25.1. We calculated reporting odds ratio (RORs) and identified Kampo formulas as suspected causes of pseudoaldosteronism. Moreover, we evaluated clinical factors associated with Kampo formula-induced pseudoaldosteronism via logistic regression. From April 2004 to November 2022, 6334 adverse events related to the Kampo formulas were reported. We selected 2471 reports containing complete clinical data, including 210 reports on pseudoaldosteronism. In the pseudoaldosteronism group, 69.0% of patients were female, and 85.2% were ≥70 years old. The formulas most commonly associated with pseudoaldosteronism were Shakuyakukanzoto, Yokukansan, and Ryokeijutsukanto (ROR [95% confidence interval {CI}] = 18.3 [13.0–25.9], 8.1 [5.4–12.0], and 5.5 [1.4–21.9], respectively). Logistic analysis identified female sex (odds ratio [OR] [95% CI] = 1.7 [1.2–2.6]; P = 0.006), older age (≥70, 5.0 [3.2–7.8]; P < 0.001), low body weight (<50 kg, 2.2 [1.5–3.2]; P < 0.001), diuretics usage (2.1 [1.3–4.8]; P = 0.004), hypertension (1.6 [1.1–2.4]; P = 0.014), and dementia (7.0 [4.2–11.6]; P < 0.001) as pseudoaldosteronism-related factors. Additionally, the daily Glycyrrhiza dose (OR = 2.1 [1.9–2.3]; P < 0.001) and duration of administration (>14 days, OR = 2.8 [1.7–4.5]; P < 0.001) were associated with adverse events. We did not observe an interaction between aging and hypertension. Careful follow-up is warranted during long-term Glycyrrhiza-containing Kampo formula use in patients with multiple clinical factors for pseudoaldosteronism.