Introduction

The global population is aging rapidly, and adverse drug reactions (ADRs) have become a major concern in geriatric medicine. Older adults are particularly vulnerable to ADRs owing to the physiological changes associated with aging, such as reduced renal and hepatic clearance, altered body composition, and increased pharmacodynamic sensitivity [1]. These age-related factors are in addition to the comorbidities and polypharmacy commonly observed in older adults [2]. Consequently, ADRs in older adults are more likely to lead to hospitalization, functional decline, organ failure, and death, placing a significant burden on patients, caregivers, and the healthcare system [3]. International studies have shown that ADRs account for ≤10% of hospitalizations in older adults, highlighting the clinical significance of ADRs [4].

Although South Korea has one of the fastest aging populations in the world [5], evidence of the national burden and characteristics of ADRs in older adults is limited. Existing Korean studies have primarily examined specific treatment groups or clinical settings [6] and have failed to provide a comprehensive understanding of drug safety issues in older adults. As the proportion of older adults is expected to increase, a more accurate understanding of the characteristics and outcomes of ADRs in older adults is urgently needed to inform patient safety planning and health policy development.

The Korea Adverse Event Reporting System (KAERS) is a nationwide pharmacovigilance database that collects data on suspected ADRs reported by healthcare professionals, pharmaceutical companies, and consumers. This system provides a valuable opportunity to analyze ADRs at the population level by capturing diverse drug classes and a wide range of clinical patterns. While voluntary reporting has inherent limitations such as underreporting and reporting bias, the data are essential to identify trends, characterize high-risk populations, and develop prevention strategies.

This study aimed to analyze reported ADRs in Korean patients aged ≥65 years using KAERS data collected over a 10-year period (2005–2015). Specifically, this study aimed to identify patient demographics and drug use patterns, the frequency and predictors of serious ADRs, and key clinical implications for improving medication safety in older adults. By providing a comprehensive overview of ADRs in this vulnerable population, this study aimed to provide evidence that can guide clinicians, policymakers, and pharmacovigilance systems toward safer prescriptions and monitoring for older adults.

Methods

Ethics statements: This study was approved by the Institutional Review Board (IRB) of Busan Paik Hospital (IRB No: 2016-0226), and the requirement for informed consent was waived.

1. Data source

This study used data from the KAERS, a nationwide spontaneous reporting database managed by the Korea Institute of Drug Safety and Risk Management. The KAERS collects voluntary reports of suspected ADRs from healthcare professionals, pharmaceutical companies, and consumers across Korea. Each report includes patient demographics, suspected drugs, concomitant medications, adverse events coded by World Health Organization (WHO) Adverse Reaction Terminology, and causality assessments.

2. Study population and inclusion criteria

We included reports submitted between January 1, 2005, and December 31, 2015. Eligible cases met the following criteria (Fig. 1): (1) patients aged ≥65 years at the time of ADR occurrence; (2) causality assessment classified as “certain,” “probable,” or “possible”; and (3) oral drug administration.

Serious ADRs were defined, in accordance with International Conference on Harmonization E2A [7] and WHO-Uppsala Monitoring Centre criteria [8], as any case that met at least one of the following conditions: death, a life-threatening event, hospitalization or prolongation of hospitalization, persistent or significant disability/incapacity, congenital anomaly, or other medically important condition.

3. Statistical analysis

Descriptive statistics were used to summarize the patient characteristics, implicated drugs, and reported system organ classes (SOCs). Categorical variables are expressed as frequencies and percentages, and continuous variables as mean±standard deviation or median (interquartile range [IQR]). Comparisons of serious versus nonserious ADRs by SOC and drug class were conducted using the chi-square or Fisher exact tests, as appropriate.

Multivariable logistic regression analysis was performed at the patient level to identify independent predictors of serious ADRs, including age group, sex, and the number of drugs. Odds ratios (ORs) and 95% confidence intervals (CIs) were also determined. In addition, a disproportionality analysis was conducted at the event level to explore potential drug–ADR signals. Reporting ORs (RORs) and proportional reporting ratios with 95% CIs were calculated for the selected drug–SOC pairs. Signals were defined when the lower limit of the 95% CI of the ROR exceeded one, and at least three cases were reported.

All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA) and R version 4.5.1 (R Foundation for Statistical Computing, Vienna, Austria). Statistical significance was set at p<0.05.

Results

1. Case selection

In total, 889,997 ADR reports were recorded in the KAERS database between 2005 and 2015. Among these, we included patients aged ≥65 years (209,381 reports, 23.5%). Within this subset, 199,770 reports were assessed as “certain,” “probable,” or “possible.” Finally, by selecting reports involving oral drug administration, a total of 118,023 ADR reports were identified. These reports constituted the final study population for the descriptive, comparative, and regression analyses (Fig. 1).

2. Report characteristics

In total, 60,529 older patients with oral ADRs were included in this study. Among them, 25,255 (42.1%) were male and 34,801 (57.9%) were female. The mean age was 73.6±6.2 years (median, 73 years; IQR, 69–78 years). By age group, 35,679 patients (60.1%) were 65–74 years old, 20,314 (34.2%) were 75–84 years old, and 3,371 (5.7%) were ≥85 years old. Regarding the number of drugs, 49,195 cases (81.3%) involved one drug, 10,186 (16.8%) involved two to four drugs, and 1,098 (1.9%) involved five or more drugs. The most frequently reported SOCs were gastrointestinal disorders (42,548 cases, 36.1%), skin and appendage disorders (18,306 cases, 15.5%), and central and peripheral nervous system disorders (15,086 cases, 12.8%). Other SOCs included general disorders (9,149, 7.8%), psychiatric disorders (8,539, 7.2%), metabolic and nutritional disorders (3,516, 3.0%), urinary system disorders (3,284, 2.8%), respiratory system disorders (2,910, 2.5%), liver and biliary system disorders (2,429, 2.1%), and platelet, bleeding, and clotting disorders (2,343, 2.0%). At Anatomical Therapeutic Chemical (ATC) level 2, the top drug classes were analgesics (N02; 24,332 cases, 20.7%), antibacterials for systemic use (J01; 8,866, 7.5%), antimycobacterials (J04; 8,425, 7.1%), anti-inflammatory and antirheumatic products (M01; 6,635, 5.6%), and antineoplastic agents (L01; 5,925, 5.0%). Other frequent classes included drugs for acid-related disorders (A02; 5,802, 4.9%), antithrombotic agents (B01; 5,292, 4.5%), psychoanaleptics (N06; 3,620, 3.1%), and psycholeptics (N05; 3,734, 3.2%). Causality assessment showed 2,949 cases (2.5%) classified as “certain,” 29,990 cases (25.4%) as “probable,” and 85,084 cases (72.1%) as “possible.” A total of 7,199 cases (6.1%) were classified as serious ADRs, whereas 110,824 (93.9%) were classified as nonserious ADRs. Among the serious ADRs, 4,119 (3.5%) involved hospitalization or prolonged hospitalization, 3,017 (2.6%) were other medically important conditions, 352 (0.3%) were life-threatening, 325 (0.3%) resulted in death, and 158 (0.1%) involved disability or functional impairment. No congenital anomalies were reported. According to the reporting source, the majority of ADR cases were reported by regional pharmacovigilance centers (100,304 cases, 85.0%), followed by manufacturers/importers (14,212, 12.0%), healthcare institutions (2,826, 2.4%), pharmacies (630, 0.5%), and public health centers (41, <0.1%). Direct reports from consumers (n=2) and others (n=5) were rare (Table 1).

3. Characteristics and risk factors of serious adverse drug reactions

Across the SOCs, the proportion of serious ADRs was statistically significant (p<0.0001). The highest proportions of serious cases were observed in liver and biliary system disorders (18.9%), platelet, bleeding and clotting disorders (12.0%), and respiratory system disorders (16.7%). Gastrointestinal disorders were the most frequently reported SOC (42,548 cases), with 932 serious ADRs (2.2%). At ATC drug class level 2, the frequency of serious ADRs was significantly different (p<0.0001). The proportion of serious ADRs was highest for antineoplastic agents (L01, 20.7%), followed by antithrombotic agents (B01, 14.5%), and antimycobacterials (J04, 7.6%). Analgesics (N02) accounted for the largest number of ADRs (24,332 cases), of which 659 (2.7%) were serious (Table 2).

In the univariable analysis, male sex (OR, 1.34; 95% CI, 1.25–1.44; p<0.0001) and the number of drugs (OR, 0.83; 95% CI, 0.79–0.87; p<0.0001) were significantly associated with serious ADRs, whereas age group was not statistically significant. Regarding the reporting source, manufacturers/importers (OR, 9.06; 95% CI, 8.36–9.81; p<0.0001), regional pharmacovigilance centers (OR, 0.15; 95% CI, 0.14–0.17; p<0.0001), and healthcare institutions (OR, 0.65; 95% CI, 0.48–0.88; p=0.0051) were statistically significant, while pharmacies, public health centers, and others were not. In the multivariable logistic regression with stepwise selection, male sex was significantly associated with serious ADRs (adjusted OR [aOR], 1.11; 95% CI, 1.03–1.19; p=0.0093) and the number of drugs showed an association with serious ADRs (aOR, 0.86; 95% CI, 0.82–0.90; p<0.0001). Regarding reporting source, manufacturers/importers (aOR, 8.58; 95% CI, 7.91–9.31; p<0.0001) was a statistically significant factor for serious ADRs (aOR, 0.15; 95% CI, 0.14–0.17; p<0.0001) (Table 3).

The distribution of seriousness differed according to causality assessment (p<0.0001). Among the reports classified as “certain,” “probable,” and “possible,” 7.1%, 7.3%, and 5.6% were serious, respectively (Table 4).

4. Disproportionality analysis

Disproportionality analysis identified representative drug–SOC pairs with elevated RORs. The top 10 signals are presented in Fig. 2. Notable associations included antibacterials for systemic use with application-site disorders (a, the number of reports in which both the drug and SOC were jointly reported=465), antiepileptics with nervous system disorders (a=4), immunosuppressants with neoplasms (a=9), and drugs for the treatment of bone diseases with musculoskeletal disorders (a=264). Additional signals were observed for diuretics with metabolic and nutritional disorders (a=1,650), anabolic agents with liver and biliary system disorders (a=12), antineoplastic agents with fetal disorders (a=3), sex hormones with female reproductive disorders (a=12), urologicals with male reproductive disorders (a=180), and thyroid therapy with endocrine disorders (a=207). All these drug–SOC combinations showed RORs with 95% CIs exceeding unity.

Discussion

This study analyzed ADRs among older patients in Korea from 2005 to 2015 using the KAERS database. In total, 118,023 oral ADR reports were included, of which 6.1% were classified as serious. To the best of our knowledge, this is the first nationwide analysis focusing on oral ADRs in the elderly population in Korea.

The most frequently reported organ system disorders were gastrointestinal and skin disorders, whereas analgesics, antimicrobials, and antituberculosis drugs were the major drug classes. Serious ADRs were most frequently associated with hospitalization or prolonged hospitalization, followed by other medically important conditions, life-threatening events, and death. High proportions of serious ADRs were observed in liver and biliary system disorders, respiratory disorders, and bleeding/clotting disorders. Antineoplastic and antithrombotic agents showed the highest proportions of serious outcomes [4,9].

In the multivariable analysis, male sex was significantly associated with serious ADRs, whereas age group was not. The number of medications inversely correlated with serious outcomes, which may be partially explained by selective reporting or differences in drug class distribution. These results suggest that the risk of serious ADRs is influenced more by drug characteristics than by the number of drugs alone [1,2]. Our results are consistent with previous international reports that identified antineoplastic, antithrombotic, and anti-infective agents as high-risk drug classes in older adults [4,9,10]. Although previous studies focused on specific medications or clinical settings [11,12], this study provides a comprehensive overview of drug classes and organ systems.

A strength of this study is that it utilized a 10-year nationwide pharmacovigilance database and focused on the rapidly growing elderly population in Korea. However, the limitations include underreporting, reporting bias, and a lack of denominator data inherent in the voluntary reporting system [13]. Furthermore, this study included data up to 2015, which may not fully reflect current prescription trends. Nevertheless, the major drug classes and risk factors identified are expected to remain largely unchanged [14].

In conclusion, ADRs remain a significant problem in older patients, particularly those treated with antineoplastic and antithrombotic agents. Male sex was also found to be an independent risk factor. These findings highlight the need for strengthened pharmacovigilance and safe prescription practices in older patients in Korea.

Article information

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

Fig. 1.

Flow chart of study population selection. KAERS, Korea Adverse Event Reporting System.

Fig. 2.

Forest plot of system organ class (SOC)-level adverse drug reaction signals with representative Anatomical Therapeutic Chemical (ATC) drug classes. ROR, reporting odds ratio; CI, confidence interval.

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References

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