Pharmacovigilance study of immunomodulatory drug-related adverse events using spontaneous reporting system databases

Abstract

The aim of this study was to evaluate the country-specific reporting status profile of immunomodulatory drugs (IMiDs)-related adverse events (ImrAEs) in real-world clinical practice, using data from the Japanese Adverse Drug Event Report (JADER) and Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) databases. Immunomodulatory drugs, including thalidomide and its derivatives, are a new class of anticancer and anti-inflammatory drugs. IMiD risk management programs have instituted sufficient measures to prevent fetal effects but do not address adverse effects experienced by patients themselves. To date, no study has compared ImrAE profiles across countries. Adverse events were defined using the preferred terms in the Medical Dictionary for Regulatory Activities. The number of reported adverse events related to IMiDs in each country (the United States and Japan) was investigated. In both Japan and the United States, myelosuppression, pneumonia, and neuropathy peripheral have been reported as adverse events suspected to be associated with IMiDs. Adverse event profiles differed between the countries. The number of adverse event reports for thalidomide increased transiently in the United States in 2008 following the multiple myeloma indication, and then exhibited a downward trend. The number of adverse event reports for lenalidomide and pomalidomide has increased in the United States since their launch. The number of transient reports increased in Japan in 2015, when pomalidomide was launched. In this study, the profile of ImrAEs was revealed using the FAERS and JADER databases. Our comparative safety study indicated the importance of comparing the safety profiles of IMiDs using post-marketing real-world data. It is important to focus on the adverse events experienced by patients taking IMiDs, as well as the effects of IMiDs on fetuses.

Keywords: FDA adverse event reporting system database; Japanese adverse drug event report database; immunomodulatory drug; lenalidomide; pomalidomide; thalidomide.

Figure 1.

Schedule for the expansion of IMiD indications in the US, Japan, and EU.

Figure 2.

Launch schedule for IMiD RMP in the US, Japan, and EU.

Figure 3.

Percentage of IMiD-related adverse events (ImrAEs) reported in the US and Japan. The yellow line represents the US, and the blue line represents Japan.

Figure 4.

Box plot and Weibull shape parameter (β) of ImrAEs: (a) Pneumonia, (b) White blood cell count decreased, (c) Deep vein thrombosis, (d) Platelet count decreased, (e) Neutrophil count decreased, (f) Thrombocytopenia, (g) Neutropenia, and (h) Anaemia. Histogram and Weibull shape parameter of ImrAE for each drug in the ATC classification. Right panel shows box plots, which represent the median (the horizontal line within the box). The ends of the box represent the 25th and 75th quantiles, also expressed as 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 of 1.5 times the length of the inner quartiles. The bracket outside the box indicates the shortest half, which is the densest 50% of the observations. Abbreviation: 95%CI, 95% confidence interval.