Evaluation of tolvaptan-associated hepatic disorder using different national pharmacovigilance databases

Abstract

Tolvaptan-associated hepatic disorder is a rare, but lethal adverse event; however, the precise risk and time of onset remain unclear. This study aimed to characterize the severity, time‑to‑onset, and outcomes of hepatic disorder based on patient age and sex. Patient data were acquired from the Japanese Adverse Drug Event Report database (JADER) and the JAPIC AERS database, which consists of the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) processed by the Japan Pharmaceutical Information Center. Hepatic disorder was classified as severe or nonsevere. Tolvaptan use was associated with hepatic disorder in analyses using the FAERS [Severe hepatic disorder: reporting odds ratio (ROR) 4.93, 95% confidence interval (CI) 4.33‒5.61; information component (IC) 2.11, 95% CI 1.92‒2.29; nonsevere hepatic disorder: ROR 6.78, 95% CI 6.01‒7.65; IC 2.51, 95% CI 2.33‒2.68] and the JADER (severe hepatic disorder: ROR 4.21, 95% CI 3.57‒4.97; IC 1.86, 95% CI 1.63‒2.10; nonsevere hepatic disorder: ROR 4.27, 95% CI 3.68‒4.95; IC 1.83, 95% CI 1.62‒2.04). A time‑to‑onset analysis revealed that the median onset time was significantly longer in patients aged < 60 years compared with patients aged ≥ 60, regardless of the severity (FAERS: severe hepatic disorder 7 vs. 58 days, p < 0.0001; nonsevere hepatic disorder 8 vs. 52.5 days, p < 0.0001; JADER: severe hepatic disorder 9.5 vs. 32 days, p = 0.0017; nonsevere hepatic disorder 9 vs. 89 days, p < 0.0001). Severe outcomes were observed, regardless of the severity of hepatic disorder. Patients should be monitored for liver function based on age to prevent fatal outcomes.

Keywords: Adverse event; Hepatic disorder; Liver; Pharmacovigilance; Spontaneous reporting system; Tolvaptan.

Fig. 1

Mosaic plot of outcomes for severe or nonsevere hepatic disorder stratified by age in the FAERS and JADER. The total number of outcomes may not necessarily match the total number of patients because patients reported ≥ 1 outcome. Severe outcomes such as “death,” “life-threatening,” “hospitalization,” and “not recovered” were included in the FAERS and JADER.

Fig. 2

Histogram and Weibull shape parameters of hepatic disorder for severity in the FAERS and JADER. Upper panel shows the box plots, which represent the median (the vertical line within the box). The ends of the box represent the 1st and 3rd quartile, respectively. The confidence diamond contains the mean and the upper and lower 95% CIs of the mean. The whiskers extend to the outermost data point that falls within the distances representing 1.5-fold the interquartile range.

Fig. 3

Kaplan–Meier curves for the incidence of hepatic disorder in patients aged < 60 years or ≥ 60 years based on severity of hepatic disorder in the FAERS and JADER. The x axis is limited to 540 days. Patients aged < 60 years had a significantly later onset of severe or nonsevere hepatic disorder than those aged ≥ 60 in the FAERS and JADER.