Adverse Event Profile of Azacitidine: Analysis by Route of Administration Using Japanese Pharmacovigilance Database

Abstract

Introduction: Azacitidine is a useful drug for myelodysplastic syndromes and acute myeloid leukemia. In clinical trials, hematologic toxicity and infection have been observed as adverse events (AEs) of this drug. However, information on the time to onset of high risk AEs and subsequent outcomes, as well as differences in the frequency of AEs due to the route of administration is lacking. In this study, we investigated azacitidine-induced AEs comprehensively using the Japanese Adverse Event Reporting Database (JADER) published by the Pharmaceuticals and Medical Devices Agency, with disproportionate analysis of AE incidence trends, time to onset, and subsequent outcomes. In addition, we analyzed the differences in AEs by route of administration and the number of days until the occurrence of AEs and generated hypotheses.

Methods: The study used JADER data reported from April 2004 to June 2022. Risk estimation was conducted using reported odds ratio. A signal was detected when the lower limit of the 95% confidence interval of the calculated ROR was ≥1.

Results: A total of 34 signals were detected as AEs due to azacitidine. Among them, 15 were hematologic toxicities and 10 were infections, which demonstrated a particularly high rate of death. Signals of AEs such as tumor lysis syndrome (TLS) and cardiac failure, which have been described in case reports, were also detected, and the rate of death after onset was high. In addition, more AEs generally occurred within the first month of treatment.

Conclusion: The results of this study suggest that more attention should be paid to cardiac failure, hematologic toxicity, infection, and TLS. Because many patients in clinical trials have discontinued treatment due to serious AEs before the therapeutic effect became apparent, appropriate supportive care, dose reduction, and drug withdrawal are important for the continuation of treatment.

Keywords: Azacitidine; DNA methylation Inhibitors; Japanese Adverse Drug Event Report; Myelodysplastic syndromes; Pharmacovigilance.