Fact-Finding Survey of Lethal or Fatal Adverse Drug Events in the Japanese Adverse Drug Event Report Database, Fiscal Year 2004–2023 (Adults ≥ 20 Years)
Department of Practical Pharmacy, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi 274-8510, Chiba, Japan
*
Author to whom correspondence should be addressed.
Pharmacoepidemiology 2025, 4(4), 19; https://doi.org/10.3390/pharma4040019
Submission received: 31 July 2025
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Revised: 20 September 2025
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Accepted: 24 September 2025
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Published: 26 September 2025
Abstract
Background: While adverse drug events (ADEs) are a major public health concern, data on the occurrence of lethal or fatal ADEs in Japan are limited. Therefore, this study aimed to elucidate the characteristics and reporting trends of lethal or fatal ADEs by analyzing the Japanese Adverse Drug Event Report (JADER), a pharmacovigilance database. Methods: Of the individual ADE reports registered in the JADER database between April 2004 and March 2024 (fiscal year (FY) 2004–2023), all data involving individuals aged ≥ 20 years with complete data on sex and age were included in this analysis. Descriptive statistics were used to summarize the results. Results: The number of ADE cases registered in the JADER database increased approximately 2.3-fold from 21,824 in FY 2004 to 50,520 in FY 2023. Lethal or fatal ADE cases increased throughout the study period. In particular, the reporting rate of fatal ADEs reported in JADER appears to have increased in recent years. Lethal or fatal ADEs were reported more frequently among men and individuals aged ≥ 70 years. The recent increase in the reported rates of lethal or fatal ADEs may be largely influenced by the increased number of ADE reports associated with antineoplastic agents. The increase in the number of reports on immune checkpoint inhibitors is particularly notable. Conclusions: This study provides new insights into demographic and drug-related characteristics, as well as time trends associated with lethal or fatal ADEs in Japan. Further studies are needed to confirm these findings.
1. Introduction
Adverse drug reactions (ADRs) are a major public health concern worldwide that continues to put patients at risk. Although most ADRs are transient and minor, an increasing proportion of patients experience serious events related to drug therapy that can lead to poor clinical outcomes, such as hospitalization or death [1]. Previous studies have shown that adverse drug events (ADEs) are one of the most common causes of hospitalization [2,3,4]. Additionally, the number of serious ADEs reported to the U.S. Food and Drug Administration has continued to increase [5]. A global study using VigiBase®, the World Health Organization pharmacovigilance database, evaluated the association between fatal ADEs and suspected drugs, and identified antineoplastic and immunomodulating agents (Anatomical Therapeutic Chemical [ATC] classification L) as one of the most common causes [6]. However, including antineoplastic agents as potential offending agents makes interpretation of study results difficult due to the high cancer-related mortality rate. A study using the Korean Adverse Event Reporting System, after excluding antineoplastic agents, found that antibiotics were the most common cause of fatal ADEs [7]. Taking these differences into account, this study investigated the differences in characteristics within the framework of lethal ADE (clinical outcome = death) and fatal ADE (specifically the Medical Dictionary for Regulatory Activities [MedDRA] preferred terms [PTs], as described in the Section 4).
Drug utilization varies across countries, regions, and ethnic groups, and assessing the occurrence of ADEs requires consideration of demographic, clinical, and sociocultural aspects related to drug utilization in clinical practice. Therefore, analyses based on data from real-world settings on drug use and ADE reports in specific countries, regions, or ethnic groups may enable the development of measures that consider their characteristics and ultimately help ensure patient safety.
Many countries have voluntary ADE-reporting systems to ensure patient safety. In Japan, the Japanese Adverse Drug Event Report (JADER) database has been established, and data from April 2004 onwards are publicly available and freely accessible on the Pharmaceuticals and Medical Devices Agency website (https://www.pmda.go.jp, accessed on 30 August 2024). To date, various studies have been performed using the JADER database; however, no comprehensive investigation of lethal or fatal ADEs has been conducted. The recent development of highly effective drugs in various medical fields and the remarkable progress in treatment methods using these drugs may influence the occurrence of lethal or fatal ADEs. Gaining insight into the reporting trends of drugs in association with lethal or fatal ADEs is crucial for advancing patient safety. Therefore, in this study, we focused on lethal or fatal ADEs in Japan and analyzed ADE reports of patients aged 20 years and older registered in the JADER database over a 20-year period from fiscal year (FY) 2004 to FY 2023 to elucidate the characteristics and reporting trends.
2. Results
The number of ADE cases registered in the JADER database increased by approximately 2.3-fold from 21,824 in FY 2004 to 50,520 in FY 2023.
An overview of the cases of lethal or fatal ADEs is presented in Figure 1,Figure 2. Cases of lethal or fatal ADEs showed an increasing trend throughout the study period, reaching their highest number in FY 2021 (Figure 1a and Figure 2a). The number of reported cases of lethal ADEs increased sharply in FY 2021 (year-over-year: 163%) (Figure 1a). A strong correlation was found between the number of lethal ADEs and the number of all ADE cases for each year (r = 0.991, 95% CI = 0.978–0.997; p < 2.2 × 10−16) (Figure 1b). The proportion of cases with lethal ADEs for those aged ≥ 70 years increased throughout the study period, with 63.3% of cases aged ≥ 70 years in FY 2023 (Figure 1c). The proportion of reported lethal ADEs tended to increase with age, with significant differences observed between the 20–69 age group and the ≥ 70 years group (odds ratio = 1.61, 95% CI = 1.58–1.64; p < 2.2 × 10−16) (Figure 1d). The number of reported cases of fatal ADEs increased sharply in FY 2014 and FY 2021 (year-over-year: 221% and 160%, respectively) (Figure 2a). A strong correlation was found between the number of fatal ADEs and the number of all ADE cases for each year (r = 0.934, 95% CI = 0.837–0.974; p = 1.84 × 10−9) (Figure 2b), but this correlation was less robust than that observed for fatal ADEs. The percentage of cases with lethal ADEs aged ≥ 70 years increased throughout the study period, with 64.1% of cases aged ≥ 70 years in FY 2023 (Figure 2c). The proportion of reported fatal ADEs tended to increase with age, with significant differences observed between the 20–69 age group and the ≥ 70 years group (odds ratio = 1.69, 95% CI = 1.61–1.76; p < 2.2 × 10−16) (Figure 2d).
The time trends of crude and age-standardized reporting rates for lethal and fatal ADE cases are shown in Figure 1e and Figure 2e. The age-standardized lethal ADE reporting rates were similar between FY 2004 (77.8 per 1000 ADE case reports) and FY 2023 (79.7 per 1000 ADE case reports), with no considerable change in the reporting rate throughout the study period (Figure 1e). The reporting rate of age-standardized fatal ADE cases in FY 2023 was 18.7 per 1000 ADE case reports, an increase from that in 2004 (3.4 per 1000 ADE case reports). Particularly, the reporting rate of fatal ADEs among males increased from 3.9 per 1000 ADE case reports (FY 2004) to 23.3 per 1000 ADE case reports (FY 2023). A distinctive peak in the reporting rate of fatal ADEs was observed in 2014 (Figure 2e). Additionally, the number of fatal ADE cases from 2019 onward did not align with the regression curve calculated using data before 2018 (excluding 2014) (Figure 2b). Therefore, the reporting rate of fatal ADEs appears to have been higher from 2019 onward than in earlier years (Figure 2e).
The suspected drugs for lethal ADEs were compiled at 5-year intervals, and the 10 most frequently reported drugs are listed in Table 1. Across all periods, drugs belonging to ATC classification L (antineoplastic and immunosuppressive drugs) accounted for most of the reported drugs. Prednisolone (ATC classification H: systemic hormone preparations, excl. sex hormones and insulin) was ranked high throughout the study period. The suspected drugs for fatal ADEs were compiled at 5-year intervals, and the top 10 most frequently reported drugs are shown in Table 2. From FY 2019 to 2023, eight drugs belonging to ATC classification L (antineoplastic and immunomodulatory agents) were ranked. After accounting for the COVID-19 and vaccine era and excluding the impact of the increased use of COVID-19 vaccines, this number increased to nine. Drugs belonging to ATC classifications B (blood and blood forming organs), C (cardiovascular system), H (systemic hormone preparations, excl. sex hormones and insulins), N (nervous system), J (anti-infectives for systemic use), and V (various) were also ranked, and fatal ADE cases were characterized. In addition, in this study, drugs reported as “suspected drugs” or “drug interactions” were considered as “suspected drugs” in a broad sense. The rates of “drug interactions” in lethal and fatal ADE cases were 0.7% and 0.3%, respectively; therefore, their impact was limited (Supplementary Tables S1 and S2).
The PT level ADEs for which the clinical outcome was determined to be “death” in cases with lethal ADEs were compiled, and the top 10 are shown in Table 3. A total of 91,080 ADEs were reported across 63,413 lethal ADE cases, indicating that not every case was associated with a single ADE report. The most frequently reported event was “death (PT code 10011906),” followed by “interstitial lung disease (PT code 10022611).”
3. Discussion
In this study, we analyzed the reporting trends of lethal or fatal ADEs in Japan based on data registered in JADER and characterized their features.
The reporting rate of lethal or fatal ADEs tended to increase with age, with the reporting rates being significantly higher in patients aged ≥ 70 years than in those aged 20–69 years. Additionally, the reporting rate of lethal or fatal ADEs was higher in men than in women. Previous studies have shown that the risk of serious drug-related ADEs is higher in older patients and men, supporting the results of our study [8,9].
The age-standardized reporting rate for fatal ADEs exhibited a different pattern from that of lethal ADEs. In particular, a notable peak in the reporting rate for fatal ADEs was observed in FY 2014. Although not shown in the data, a substantial proportion of fatal ADE reports related to imatinib mesilate (n = 78, 88.6%) and deferasirox (n = 49, 83.1%) were concentrated in FY 2014. ADE reports are not necessarily submitted immediately after the occurrence of ADEs. The concentration of reports on fatal ADEs related to imatinib mesilate (launched in Japan in December 2001) and deferasirox (launched in Japan in June 2008) in FY 2014 may have been one of the causes of the unusual increase in the reporting rate in that year. Therefore, potential overreporting or underreporting should be considered for each year.
The most frequently reported drugs in lethal or fatal ADE cases in Japan have changed over time. It has been suggested that the increase in the reporting rates of lethal or fatal ADEs since FY 2019 may be largely influenced by the increase in the number of reports of drugs belonging to ATC classification L (antineoplastic and immunosuppressive drugs). In a study using VigiBase®, the drug class most frequently associated with fatal ADEs was antineoplastic agents (ATC classification L01) [6]. A study using the Korea Adverse Event Reporting System found that, when antineoplastic agents were excluded because of the high cancer-related mortality, antibacterial drugs were the most common suspected drugs of fatal ADEs [7]. Taking these differences into account, we investigated the differences in their characteristics within the frameworks of fatal and lethal ADEs. Compared to lethal ADE, drugs classified as non-antineoplastic agents ranked higher as suspected drugs of fatal ADE. However, recently, there has been a notable increase in individual fatal ADE reports with antineoplastic agents reported as the suspected drugs. The increase in the number of reports on immune checkpoint inhibitors is particularly notable. A pooled study of VigiBase® analyses, multicenter analysis, and meta-analysis concluded that although the number of fatal events reported with immune checkpoint inhibitors is notable in VigiBase®, the risk of fatal immune-related adverse events in patients with advanced cancer remains very low and should not discourage patients from using these potentially curative therapies [10]. Matsuo et al. used JADER to investigate the association between antineoplastic agents and adverse cardiovascular events and reported that antineoplastic agents are associated with fatal ADEs such as Torsade de pointes/QT prolongation [11]. Voluntary ADE-reporting systems capture ADE reports rather than their true incidence, and the high ranking of antineoplastic agents may also be attributable to both symptom severity and the rigor of surveillance. The recent coronavirus disease 2019 (COVID-19) pandemic may have influenced the reporting of fatal ADEs, as many patients refrained from visiting medical facilities [12,13]. Furthermore, safety monitoring of COVID-19 vaccines at the national level in Japan [14] led to an increase in ADE reports, which may also have affected the reporting of fatal ADEs [11,15]. Our previous report showed that ADEs registered in JADER decreased in FY 2020 compared with FY 2019, followed by a sharp increase in FY 2021 [16]. A similar pattern was observed in this study, with a temporary decrease or stagnation in lethal or fatal ADEs in FY 2020, followed by a marked increase in FY 2021.
For lethal ADEs, the leading PT-level ADE with a clinical outcome of death was “death (PT code: 10011906),” and the second leading was “interstitial lung disease (PT code: 10022611).” Drug-induced interstitial lung disease is becoming an increasingly common cause of morbidity and mortality [17]. Various antineoplastic agents have been suspected of being associated with ILD. ILD associated with the use of antineoplastic drugs may respond to appropriate treatment, although fatal cases have been reported [18,19]. Previous studies have indicated that many ADE reports are related to interstitial lung disease in Japan [20,21,22]. This may have influenced the results of this study. Additionally, “malignant neoplasm progression (PT code: 10051398)” ranked eighth. This suggests that the high cancer mortality rate may affect the number of lethal ADEs attributed to the suspected drugs.
This study had some limitations. As in every pharmacovigilance study dealing with spontaneous ADE reports, findings in our study reflect reporting rather than incidence, and are subject to time-dependent reporting dynamics (e.g., the Weber effect) [23]. Consequently, the analysis primarily focuses on the reporting rate rather than the actual occurrence rate of ADEs. Additionally, underreporting and selective reporting influence trends in reporting over time. Notably, the increase in reporting rates for fatal ADEs in FY 2014 appeared to be largely driven by specific drugs. Studies utilizing spontaneous reporting systems preclude the definitive causal attribution of reported ADEs to specific drugs. Furthermore, this study did not evaluate the influence of dosage, treatment duration, comorbidities, and concomitant medications on the occurrence of ADEs. Nevertheless, analysis of the pharmacovigilance database in a particular country or region/ethnic group is useful to explain its main characteristics and ultimately help ensure patient safety. Furthermore, given the increasing prevalence of research utilizing spontaneous ADE reports in recent years, it is essential to comprehensively understand the structural and contextual characteristics of the databases that compile such reports.
4. Materials and Methods
4.1. Data Source
Of the individual ADE reports registered in the JADER database from April 2004 to March 2024 (FY 2004–2023), all data involving individuals aged 20 and older with complete data on sex and age were included in this analysis. A previous report showed that the male-to-female ratio in these data was approximately 1, with no significant fluctuations observed throughout the study period [16].
In JADER, age is reported in increments of 10 years; thus, in this study, patient data were tabulated into eight age groups: 20–29, 30–39, 40–49, 50–59, 60–69, 70–79, 80–89, and ≥ 90 years. ADEs in the JADER database are based on PTs in MedDRA. The ADEs in the JADER database were defined based on the MedDRA/Japanese (https://www.meddra.org/how-to-use/support-documentation/japanese, accessed on 30 August 2024) version 27.0. The clinical outcomes of ADEs are classified into five categories: “death,” “sequelae,” “not recovered,” “improvement,” and “recovery.” Drugs are classified into three categories based on their involvement in the occurrence of ADEs: “suspected drugs,” drug interactions,” and “concomitant drugs.”
4.2. Cases of Lethal or Fatal ADEs
We defined lethal ADE cases as reports whose clinical outcome was recorded as “death (n = 63,413)” in JADER; this terminology did not imply causality. In contrast, fatal ADE cases (n = 8605) were defined as cases in which six PTs were reported, “brain death (PT code: 10049054),” “cardiac death (PT code: 10049993),” “clinical death (PT code: 10083493),” “death (PT code: 10011906),” “sudden cardiac death (PT code: 10049418),” and “sudden death (PT code: 10042434),” based on previous reports [6] and MedDRA Term Selection: Point to Consider (ICH-endorsed) [24]. In this study, lethal ADEs encompassed a broader range of situations than fatal ADEs. Figure 3 shows a Euler diagram of the relationship between lethal and fatal ADE cases in JADER. Among them, the 21 cases classified as “fatal not lethal” had missing or incomplete clinical outcome data. In this study, these cases were excluded from the analysis of lethal ADEs, but their impact was minimal, accounting for only 0.03% of the total lethal or fatal ADE cases (Supplementary Table S3).
4.3. Suspected Drugs in a Broad Sense
In this study, the term “suspected drugs” was redefined more broadly to encompass drugs reported either as “suspected drugs” or as “drug interactions.” This is because some cases in the JADER database contained reports of drug interactions only, without any suspected drugs.
We investigated the generic names of the top 10 suspected drugs in cases of lethal or fatal ADEs and mapped them to the first level of the ATC classification. The first level of the code, consisting of one letter, indicates the main anatomical group, of which there are 14. Drugs were classified according to the ATC classification system as defined by the WHO Collaborating Center for Drug Statistics Methodology (ATC/DDD, https://atcddd.fhi.no/atc_ddd_index/, accessed on 1 September 2025). Duplicate entries of the same drug within a single report were consolidated and counted only once.
4.4. Data Pipeline
JADER consists of four tables: “demo,” “reac,” “drug,” and “hist”. These tables are interconnected via shared identification numbers, allowing integration of information. JADER linkages used “demo,” “reac,” “drug,” and “hist” tables as described previously [25]. In this study, three tables—“demo,” “reac,” and “drug”—were used. Figure 4 shows the study flow diagram.
4.5. Statistical Analysis
Descriptive statistics were used to summarize the results. Pearson’s correlation coefficient was calculated to evaluate the correlation between the two variables. Fisher’s exact test was used to test proportions. Age-standardized lethal or fatal ADE reporting rates were computed by direct standardization to the reference population as recommended by WHO/International Agency for Research on Cancer [26]. The numerator is the number of lethal or fatal ADE cases in each age group, and the denominator is the total number of ADE cases in that age group. The patient population from the ADE cases in FY 2004 was used as the standard population. All analyses were performed using R software version 4.2.2 (https://www.r-project.org, accessed on 8 May 2025), and a p-value < 0.05 was considered statistically significant.
5. Conclusions
This study provides new insights into demographic and drug-related characteristics, as well as time trends associated with lethal or fatal ADEs in Japan. Lethal or fatal ADE cases increased throughout the study period. In particular, the reporting rate of fatal ADEs reported in JADER appears to have increased in recent years. Lethal or fatal ADEs were reported more frequently among men and individuals aged ≥ 70 years. The recent increase in the reported rates of lethal or fatal ADEs may be largely influenced by the increased number of ADE reports on antineoplastic agents. The increase in the number of reports on immune checkpoint inhibitors is particularly notable. Further studies using other methodologies are required to confirm these findings.
Supplementary Materials
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/pharma4040019/s1, Table S1: Top 10 drugs among lethal ADE cases restricted to “suspected drugs”. Table S2: Top 10 drugs among fatal ADE cases restricted to “suspected drugs”. Table S3: Comparison of lethal and fatal ADE cases.
Author Contributions
Conceptualization, H.T. and T.I.; methodology, H.T.; formal analysis, H.T.; writing—original draft preparation, H.T.; writing—review and editing, H.T. and T.I.; and project administration, T.I. All authors have read and agreed to the published version of the manuscript.
Funding
The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.
Institutional Review Board Statement
This was a database-related observational study with no direct access to any research subjects; thus, no ethical approval was sought. All results in this study were obtained from data from the JADER database. All data from JADER were fully anonymized by the relevant regulatory authorities prior to access. This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects.
Informed Consent Statement
Not applicable.
Data Availability Statement
The datasets generated and/or analyzed in the current study are available in the JADER database (https://www.pmda.go.jp/safety/info-services/drugs/adr-info/suspected-adr/0004.html, accessed on 30 August 2024).
Conflicts of Interest
All authors declare no conflicts of interest for this paper.
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Figure 1.
Characteristics of lethal adverse drug event reports. (a) Time trend in the number of lethal adverse drug events; (b) correlation between the number of lethal adverse drug event cases and the total number of adverse drug event cases; (c) changes in the age distribution of cases with lethal adverse drug events; (d) proportion of lethal adverse drug events in each age group; (e) time trends of crude and age-standardized reporting rates for lethal adverse drug events. Rates per 1000 adverse drug event case reports; standard = fiscal year 2004 adverse drug event case population. Panel (a) shows red triangles highlighting a marked increase in lethal adverse drug event reports in fiscal year 2021. The red dotted line in panel (b) represents the regression curve.
Figure 1.
Characteristics of lethal adverse drug event reports. (a) Time trend in the number of lethal adverse drug events; (b) correlation between the number of lethal adverse drug event cases and the total number of adverse drug event cases; (c) changes in the age distribution of cases with lethal adverse drug events; (d) proportion of lethal adverse drug events in each age group; (e) time trends of crude and age-standardized reporting rates for lethal adverse drug events. Rates per 1000 adverse drug event case reports; standard = fiscal year 2004 adverse drug event case population. Panel (a) shows red triangles highlighting a marked increase in lethal adverse drug event reports in fiscal year 2021. The red dotted line in panel (b) represents the regression curve.
Figure 2.
Characteristics of fatal adverse drug event reports. (a) Time trend in the number of fatal adverse drug events; (b) correlation between the number of fatal adverse drug event cases and the number of total adverse drug event cases; (c) changes in the age distribution of cases with fatal adverse drug events; (d) proportion of fatal adverse drug events in each age group; (e) time trends of crude and age-standardized reporting rates for fatal adverse drug events. Rates per 1000 adverse drug event case reports; standard = fiscal year 2004 adverse drug event case population. Panels (a,e) show red triangles highlighting a marked increase in fatal adverse drug event reports in fiscal year 2014. In panel (b), the red dotted line represents the regression curve based on all data, while the blue dashed line represents the curve excluding data from fiscal years 2014 and 2019–2023.
Figure 2.
Characteristics of fatal adverse drug event reports. (a) Time trend in the number of fatal adverse drug events; (b) correlation between the number of fatal adverse drug event cases and the number of total adverse drug event cases; (c) changes in the age distribution of cases with fatal adverse drug events; (d) proportion of fatal adverse drug events in each age group; (e) time trends of crude and age-standardized reporting rates for fatal adverse drug events. Rates per 1000 adverse drug event case reports; standard = fiscal year 2004 adverse drug event case population. Panels (a,e) show red triangles highlighting a marked increase in fatal adverse drug event reports in fiscal year 2014. In panel (b), the red dotted line represents the regression curve based on all data, while the blue dashed line represents the curve excluding data from fiscal years 2014 and 2019–2023.
Figure 3.
Euler diagram of the relationship between cases of lethal adverse drug events and cases of fatal adverse drug events in Japanese Adverse Drug Event Report database. Detailed data are provided in the Supplementary Table S3.
Figure 3.
Euler diagram of the relationship between cases of lethal adverse drug events and cases of fatal adverse drug events in Japanese Adverse Drug Event Report database. Detailed data are provided in the Supplementary Table S3.
Figure 4.
The study flow diagram. ADEs, adverse drug events; PTs, preferred terms. a Cases with lethal ADEs were defined as reports whose clinical outcome was recorded as “death.” b Cases with fatal ADEs were defined as cases in which six PTs were reported: “brain death,” “cardiac death,” “clinical death,” “death,” “sudden cardiac death,” and “sudden death.”
Figure 4.
The study flow diagram. ADEs, adverse drug events; PTs, preferred terms. a Cases with lethal ADEs were defined as reports whose clinical outcome was recorded as “death.” b Cases with fatal ADEs were defined as cases in which six PTs were reported: “brain death,” “cardiac death,” “clinical death,” “death,” “sudden cardiac death,” and “sudden death.”
Table 1.
Top 10 suspected drugs reported in cases with lethal adverse drug events.
| Fiscal Year | Rank | Suspected Drug | ATC Classification | Cases (Reporting Rate, %) |
|---|---|---|---|---|
| 2004–2008 (n = 9415) | 1 | Prednisolone | H | 510 (5.4) |
| 2 | Methotrexate | L | 461 (4.9) | |
| 3 | Gefitinib | L | 363 (3.9) | |
| 4 | Fluorouracil | L | 343 (3.6) | |
| 5 | Tacrolimus Hydrate | L | 325 (3.5) | |
| 6 | Cyclosporin | L | 322 (3.4) | |
| 7 | Tegafur/gimeracil/oteracil potassium | L | 313 (3.3) | |
| 8 | Cisplatin | L | 305 (3.2) | |
| 9 | Paclitaxel | L | 245 (2.6) | |
| 10 | Docetaxel hydrate | L | 227 (2.4) | |
| 2009–2013 (n = 12,246) | 1 | Prednisolone | H | 720 (5.9) |
| 2 | Methotrexate | L | 533 (4.4) | |
| 3 | Bevacizumab | L | 445 (3.6) | |
| 4 | Sorafenib tosilate | L | 433 (3.5) | |
| 5 | Tacrolimus Hydrate | L | 338 (2.8) | |
| 6 | Tegafur/gimeracil/oteracil potassium | L | 311 (2.5) | |
| 7 | Cyclosporin | L | 287 (2.3) | |
| 8 | Anti-human thymocyte immunoglobulin, rabbit | L | 281 (2.3) | |
| 9 | Fluorouracil | L | 277 (2.3) | |
| 10 | Cisplatin | L | 267 (2.2) | |
| 2014–2018 (n = 18,563) | 1 | Prednisolone | H | 1067 (5.7) |
| 2 | Nivolumab | L | 675 (3.6) | |
| 3 | Methotrexate | L | 667 (3.6) | |
| 4 | Pembrolizumab | L | 572 (3.1) | |
| 5 | Apixaban | B | 513 (2.8) | |
| 6 | Dexamethasone | H | 467 (2.5) | |
| 7 | Bevacizumab | L | 429 (2.3) | |
| 8 | Tacrolimus hydrate | L | 422 (2.3) | |
| 9 | Lenalidomide hydrate | L | 361 (1.9) | |
| 10 | Rivaroxaban | B | 352 (1.9) | |
| 2019–2023 (n = 23,189) | 1 | Coronavirus (SARS-CoV-2) RNA vaccine (COMIRNATY®) | J | 1863 (8.0) |
| 2 | Nivolumab | L | 1761 (7.6) | |
| 3 | Pembrolizumab | L | 1353 (5.8) | |
| 4 | Ipilimumab | L | 1134 (4.9) | |
| 5 | Prednisolone | H | 977 (4.2) | |
| 6 | Carboplatin | L | 622 (2.7) | |
| 7 | Bevacizumab | L | 602 (2.6) | |
| 8 | Roxadustat | B | 569 (2.5) | |
| 9 | Methotrexate | L | 542 (2.3) | |
| 10 | Atezolizumab | L | 537 (2.3) | |
| 11 a | Dexamethasone | H | 472 (2.0) |
ATC classification B = blood and blood forming organs; H = systemic hormone preparations, excl. Sex hormones and insulin; J = anti-infectives for systemic use; L = antineoplastic and immunomodulatory agents. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ATC, Anatomical Therapeutic Chemical. a the top 11 suspected drugs from fiscal years 2019–2023 are shown, considering the context of COVID-19 and the vaccine era.
Table 2.
Top 10 suspected drugs reported in cases with fatal adverse drug events.
| Fiscal Year | Rank | Suspected Drug | ATC Classification | Cases (Reporting Rate, %) |
|---|---|---|---|---|
| 2004–2008 (n = 510) | 1 | Valsartan | C | 26 (5.1) |
| 2 | Donepezil hydrochloride | N | 23 (4.5) | |
| 3 | Risperidone | N | 19 (3.7) | |
| 4 | Aripiprazole | N | 17 (3.3) | |
| 5 | Olanzapine | N | 16 (3.1) | |
| 5 | Oseltamivir phosphate | J | 16 (3.1) | |
| 7 | Carvedilol | C | 13 (2.5) | |
| 7 | Etanercept | L | 13 (2.5) | |
| 7 | Telmisartan | C | 13 (2.5) | |
| 10 | Ribavirin | J | 12 (2.4) | |
| 10 | Flunitrazepam | N | 12 (2.4) | |
| 2009–2013 (n = 1007) | 1 | Sorafenib tosilate | L | 35 (3.5) |
| 2 | Risperidone | N | 28 (2.8) | |
| 3 | Emulsified influenza HA vaccine (A/H1N1) | J | 27 (2.7) | |
| 4 | Darbepoetin alfa | B | 20 (2.0) | |
| 5 | Valsartan | C | 18 (1.8) | |
| 5 | Tocilizumab | L | 18 (1.8) | |
| 7 | Fludarabine phosphate | L | 17 (1.7) | |
| 8 | Olanzapine | N | 16 (1.6) | |
| 8 | Lamotrigine | N | 16 (1.6) | |
| 8 | Epoetin beta pegol | B | 16 (1.6) | |
| 8 | Donepezil hydrochloride | N | 16 (1.6) | |
| 2014–2018 (n = 2394) | 1 | Pembrolizumab | L | 82 (3.4) |
| 1 | Imatinib mesilate | L | 82 (3.4) | |
| 3 | Nivolumab | L | 76 (3.2) | |
| 4 | Lenalidomide hydrate | L | 63 (2.6) | |
| 5 | Dexamethasone | H | 57 (2.4) | |
| 6 | Risperidone | N | 53 (2.2) | |
| 7 | Deferasirox | V | 52 (2.2) | |
| 8 | Paliperidone palmitate | N | 50 (2.1) | |
| 9 | Darbepoetin alfa | B | 48 (2.0) | |
| 10 | Apixaban | B | 46 (1.9) | |
| 2019–2023 (n = 4694) | 1 | Nivolumab | L | 539 (11.5) |
| 2 | Ipilimumab | L | 397 (8.5) | |
| 3 | Coronavirus (SARS-CoV-2) RNA vaccine (COMIRNATY®) | J | 327 (7.0) | |
| 4 | Pembrolizumab | L | 224 (4.8) | |
| 5 | Lenalidomide hydrate | L | 213 (4.5) | |
| 6 | Bevacizumab | L | 162 (3.5) | |
| 7 | Venetoclax | L | 158 (3.4) | |
| 8 | Atezolizumab | L | 124 (2.6) | |
| 9 | Roxadustat | B | 108 (2.3) | |
| 10 | Durvalumab | L | 107 (2.3) | |
| 11 a | Pomalidomide | L | 105 (2.2) |
ATC classification: B = blood and blood forming organs; C = cardiovascular system; H = systemic hormone preparations. Sex hormones and insulin; J = anti-infectives for systemic use; L = antineoplastic and immunomodulatory agents; N = nervous system; V = various. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ATC, Anatomical Therapeutic Chemical. a the top 11 suspected drugs from fiscal years 2019–2023 are shown, considering the context of COVID-19 and the vaccine era.
Table 3.
Top 10 PT level adverse drug events for which the clinical outcome was determined to be “death” in cases of lethal adverse drug events.
Table 3.
Top 10 PT level adverse drug events for which the clinical outcome was determined to be “death” in cases of lethal adverse drug events.
| Rank | Adverse Drug Event (PT Code) | Cases (Reporting Rate, %) |
|---|---|---|
| 1 | Death (10011906) | 7232 (11.4) |
| 2 | Interstitial lung disease (10022611) | 5900 (9.3) |
| 3 | Pneumonia (10035664) | 2939 (4.6) |
| 4 | Sepsis (10040047) | 2103 (3.3) |
| 5 | Cerebral hemorrhage (10008111) | 1499 (2.4) |
| 6 | Multiple organ dysfunction syndrome (10077361) | 1434 (2.3) |
| 7 | Cardiac failure (10007554) | 1298 (2.0) |
| 8 | Malignant neoplasm progression (10051398) | 1265 (2.0) |
| 9 | Respiratory failure (10038695) | 1250 (2.0) |
| 10 | Disseminated intravascular coagulation (10013442) | 1242 (2.0) |
PT, preferred term.
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Tanaka, H.; Ishii, T. Fact-Finding Survey of Lethal or Fatal Adverse Drug Events in the Japanese Adverse Drug Event Report Database, Fiscal Year 2004–2023 (Adults ≥ 20 Years). Pharmacoepidemiology 2025, 4, 19. https://doi.org/10.3390/pharma4040019
AMA Style
Tanaka H, Ishii T. Fact-Finding Survey of Lethal or Fatal Adverse Drug Events in the Japanese Adverse Drug Event Report Database, Fiscal Year 2004–2023 (Adults ≥ 20 Years). Pharmacoepidemiology. 2025; 4(4):19. https://doi.org/10.3390/pharma4040019
Chicago/Turabian StyleTanaka, Hiroyuki, and Toshihiro Ishii. 2025. "Fact-Finding Survey of Lethal or Fatal Adverse Drug Events in the Japanese Adverse Drug Event Report Database, Fiscal Year 2004–2023 (Adults ≥ 20 Years)" Pharmacoepidemiology 4, no. 4: 19. https://doi.org/10.3390/pharma4040019
APA StyleTanaka, H., & Ishii, T. (2025). Fact-Finding Survey of Lethal or Fatal Adverse Drug Events in the Japanese Adverse Drug Event Report Database, Fiscal Year 2004–2023 (Adults ≥ 20 Years). Pharmacoepidemiology, 4(4), 19. https://doi.org/10.3390/pharma4040019
