Abstract
From 2002 to 2018, the number of patients with prostate cancer significantly increased from 679,023 to 1276,106 worldwide. Total prostatectomy (including robot-assisted prostatectomy), radiation therapy, and pharmacological treatment are commonly used to treat prostate cancer. The Chief of the Pharmaceutical Safety Division, that is, the Federation of Pharmaceutical Manufacturers’ Associations of Japan (FPMAJ), recently called for the revision of package inserts for ethical drugs. However, the pathogenesis of interstitial lung disease (ILD), a serious drug-induced adverse effect, remains unclear. Moreover, there have been no large-scale evaluations of potential complications associated with currently used antiandrogens, which are commonly employed to treat prostate cancer. Hence, ILD, as an adverse event, remains poorly understood. Therefore, we conducted a survey of reports in the Japanese Adverse Drug Event Report (JADER) database to investigate the potential association between the reporting of ILD and antiandrogen drug use in clinical practice. The occurrence of ILD was investigated by evaluating the relationship between antiandrogen drug use and ILD. Adverse event signals were detected with reporting odds ratios (RORs), using data from the JADER and FDA Adverse Event Reporting System (FAERS) databases, for the analysis of post-marketing adverse event reports. The JADER was used to examine the time profile of adverse event occurrence for each drug, whereas the FAERS was used to screen cases of unknown adverse events and analyze their trends of occurrence. The analysis of data from both databases revealed the 95% confidence interval lower limits of ROR for bicalutamide and flutamide to be > 1, and adverse event signals were detected following the use of either drug. While caution should be exercised for drugs that are new to the market, we conclude that drugs with similar therapeutic effects that have been in use for a long period should also be re-examined for potential adverse events.
Highlights
From 2002 to 2018, the number of patients with prostate cancer significantly increased from 679,023 to 1276,106 worldwide (Parkin et al, 2005; Torre et al, 2015; Bray et al, 2018)
To evaluate the signals of interstitial lung disease (ILD), the reporting odds ratios (RORs) and 95% confidence interval (CI) for ILD were calculated using the following formula, with the ROR adjusted for age, sex, and reporting year: ROR a/c, 95%CI exp log(ROR) ± 1.96 1 + 1 + 1 + 1 bd abcd where, a represents cases that belong to the group identified as ILD; b represents cases that did not belong to the group but were identified as ILD; c represents cases that belong to the group and were not identified as ILD; and d represents cases that did not belong to the group and were not identified as ILD (Rothman et al, 2004; Kanda, 2013)
The 95% CI lower limit of the ROR for bicalutamide and flutamide was >1, and adverse event signals were detected in both cases (Table 3)
Summary
From 2002 to 2018, the number of patients with prostate cancer significantly increased from 679,023 to 1276,106 worldwide (Parkin et al, 2005; Torre et al, 2015; Bray et al, 2018). Convulsive seizures, heart problems, and severe skin disorders have been reported as serious adverse effects (Astellas, 2018; Janssen Pharmaceutical, 2019) These agents inhibit the binding of androgens to androgen receptors and their nuclear translocation, thereby suppressing the growth of androgen-dependent tumors, leading to the development of castration-resistant, castration-free, distant metastasis-free, and androgen-dependent tumors (Clegg et al, 2012). These antagonists have been indicated for patients with prostate cancer, and they are expected to improve treatment efficacy (Clegg et al, 2012; Smith et al, 2018)
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