JPERM

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Histamine is one of the most essential biochemical molecules involved in various responses, including inflammation, neurotransmission, and cell proliferation, in diverse organs. Clinical manifestations of allergic diseases are often triggered or initiated by histamine. In order to prevent histamine reactions in allergic disease, clinicians have attempted to develop antagonist of histamine receptors. Due to its effectiveness, antihistamine has been widely used in the treatment of allergic diseases, such as allergic rhinitis and urticaria by inhibiting histamine actions. Although antihistamines are generally safe, there are patients who experience unexpected side effects, such as sedation, cardiotoxicity, hepatotoxicity, nephrotoxicity, and change of appetite. Due to their ability to penetrate through blood-brain barrier, first-generation antihistamines potentially impair alertness, cognition, and memory. The safety profiles of the second-generation antihistamines are relatively superior to the first-generation antihistamines; the second-generation antihistamines cause relatively less central nervous system adverse reactions. However, serious cardiotoxicity of early second-generation antihistamines, such as terfenadine and astemizole, was reported. Moreover, widely-used second-generation antihistamine, cetirizine and loratadine, can present hepatotoxicity. In addition, body weight gain caused by both first- and second-generation antihistamines had been reported. In recent decades, pharmacologic mechanisms that are involved in these sides effect of antihistamine have been elucidated. Understanding detailed mechanisms and consequences of commonly observed side effects may help clinicians prescribe antihistamines safely. Herein, we summarize the mechanisms of histamine action, roles of antihistamines, and their common side effects in order to provide better understanding of antihistamines in clinical practice.

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After enacting the 21st Century Cures Act of 2016, real-world data (RWD) and realworld evidence (RWE) have been increasingly used to support drug development and approval worldwide. The importance of RWD/RWE is growing for decisionmaking, while the reliability of RWD/RWE is still a concern regarding the quality of data, reproducibility, and transparency. Regulatory agencies have published diverse guidelines to encourage the appropriate use of RWD/RWE, but there are differences in practical information detailing methodological and analytic approaches among countries. We compared guidelines focusing on study design and data analysis for RWD/RWE in the United States, Europe, South Korea from 2017 to 2022. We summarized RWD/RWE guidelines according to the timeline and conducted a GAP analysis from the following perspectives: (1) the roadmap for the use of RWD/RWE; (2) the current guideline for study design and data analysis; (3) features of guideline. Based on our findings, we suggest a future direction for developing governance in terms of study design and data analysis to enhance the utilization of RWD/RWE in South Korea.

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Objective: Drug-induced rhabdomyolysis can cause acute kidney injury and rate of polypharmacy is high in the elderly. This study aimed to assess the incidence of rhabdomyolysis with combination therapy of CYP3A4 substrates (S) and inhibitors (I) in the elderly in Korea. Methods: Patients were selected from the 2017 elderly patient data (the Korean Health Insurance Review and Assessment Service - Aged Population Sample). The list of CYP3A4 S and I was taken from the Indiana university of pharmacy and converted to Korean ATC codes. Further selection criteria were a medication possession ratio greater than 80%, duration of medication 7 days or longer, and duration of follow-up 3 months or longer. The incidence and odds ratio of rhabdomyolysis with top 50 pairs of the combination of drugs were assessed. Comparative analysis of the association of rhabdomyolysis with patient characteristics and comorbidities was analyzed using Chi-square test. Logistic regression models were used to analyze the association with rhabdomyolysis for each variable. Results: Rhabdomyolysis was identified in 78 cases in 24,240 patients with 7 days or longer use (DC7), and 19 cases in 3,444 patients with 30 days or longer use (DC30) of CYP3A4 S and I. The comorbidities of severe liver disease and rheumatoid disease had a significant association. Among patients with DC7, the drug pairs (S,I) with significant adjusted odds ratio (aOR) were [clopidogrel, cimetidine] (0.32; 95% CI, 0.10–0.96). Among patients with DC30, the drug pairs with significant aOR were [atorvastatin and fluconazole] (16.13; 95% CI, 2.40–108.36), [alprazolam and amiodarone] (10.74; 95% CI, 1.62–71.38), [zolpidem tartrate and ciprofloxacin] (9.61; 95% CI, 1.38–66.83), [lansoprazole and amiodarone] (7.51; 95% CI, 1.04–54.23). Conclusion: In the elderly, the combination uses of CYP3A4 substrate and inhibitor with 30 days or longer use of atorvastatin and fluconazole had the highest risk of rhabdomyolysis with risk factors of comorbidities of liver disease or rheumatoid disease.

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Objective: Heparin, a high-risk medication with narrow therapeutic range, poses a significant risk to patient safety due to fatal accidents resulting from administration errors. This study aimed to analyze the cases of bleeding accompanied by prolonged activated partial thromboplastin time (aPTT) in patients undergoing continuous intravenous heparin infusion. Methods: We retrospectively reviewed the medical records of 200 adult patients who received continuous intravenous heparin infusion at Seoul National University Hospital from August 1, 2018 to July 31, 2021, and exhibited a prolonged aPTT exceeding 150 seconds. Bleeding was classified into major or minor bleeding. We classified the reasons for aPTT prolongation into four main categories: ‘protocol-related factors’, ‘human errors’, ‘administration of heparin bolus due to medical procedure’, and ‘individual variability’. This categorization was established through a thorough analysis of individual cases, including structural assessments. Results: Among the 200 patients, 62 (31.0%) patients experienced bleeding, with 20 (32.3%) exhibiting major bleeding. Notably, 37 (59.7%) of bleeding patients were concurrently administered other antithrombotic agents. The analysis revealed that 32 (16.0%) cases of aPTT prolongation were attributed to ‘protocol-related factors’, 73 (36.5%) to ‘human error’, and 83 (41.5%) to ‘individual variability’. Conclusion: This study showed that 'human error' and ‘protocol-related factors’ collectively contributed to more than 50% of prolonged aPTT among heparin users. To ensure safer heparin administration, it is strongly recommended to focus on optimizing heparin protocols and implementing strategies to reduce human errors.

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While health insurance claims data in Korea have the potential as evidence for drug regulatory decision-making, its effective utilization remains limited. This study aims to identify the challenges encountered by researchers in utilizing claims data and discuss improvement strategies. We summarized practical difficulties encountered by researchers who have experience using claims data from the National Health Insurance Service and the Health Insurance Review and Assessment Service. Challenges encountered by researchers included difficulties in acquiring drug data, delays in data provision, limited provision of information on specific conditions, drugs, and treatments, small data capacity, short data usage periods, and spatiotemporal considerations when accessing data. To maximize the utility of claims data in drug regulatory decision-making, continuous communication between researchers and data providers is necessary for addressing these challenges.

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Objective: We aimed to identify factors associated with adverse event (AE) reports in statin-associated muscle symptoms (SAMS) using hierarchical clustering of patients in the Korea Institute of Drug Safety and Risk Management - Korea Adverse Event Reporting System database (KIDS-KAERS DB) (2105A0027). Methods: To explore the characteristics and risk factors of SAMS reports, we analysed the KIDSKAERS DB from 2016 to 2020. We included reports with a causality category level of “possible” or higher. Hierarchical clustering analysis was used to identify distinctive patterns within the dataset, with a particular focus on variables such as sex, age, statin type, contraindicated drugs and concomitant drugs. The reporting characteristics were described according to the cluster. Results: Four clusters of AE reports were distinguished by hierarchical clustering: atorvastatin- and rosuvastatinassociated AE (cluster 1), pitavastatin- and simvastatin-associated AE (cluster 2), rosuvastatin-associated AE (cluster 3), and atorvastatin-associated AE (cluster 4). Cluster 1 had a relatively higher proportion of men (57 cases, 50.9%) and a higher mean age (64.8 years) than the other clusters. Concomitant drug use was more common in cluster 1 (56 cases, 50.0%) than in other clusters (33.5%–46.2%), and all serious AEs were observed in cluster 1. Conclusion: Using hierarchical clustering, we found four distinct clusters based on SAMS report characteristics. Our findings further emphasize that patients prescribed statins, especially elderly male patients taking rosuvastatin and atorvastatin concomitantly with other medications, should be closely monitored for the development of rhabdomyolysis

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Objective: This study aimed to examine the causality of hepatotoxicity related to sulfamethoxazole/trimethoprim (SMX/TMP) in pediatric patients with acute lymphoblastic leukemia (ALL). Methods: We retrospectively analyzed medical records of pediatric ALL patients, who were transitioned from SMX/TMP to aerosolized pentamidine (AP) for Pneumocystis jirovecii pneumonia prevention due to suspected hepatotoxicity between 2010 and 2023. The Roussel Uclaf causality assessment method (RUCAM) was used to assess hepatotoxicity due to SMX/ TMP, emphasizing cases considered “high probability” (RUCAM ≥ 6). Results: Of the 176 pediatric ALL patients who switched from SMX/TMP to AP, 112 did so due to elevated liver enzyme levels, and 38 of these (33.9%) were classified as “high probability” for hepatotoxicity according to RUCAM. Hepatotoxicity induced by SMX/TMP is characterised by an average ALT level of 430.6 IU/L, a total bilirubin level of 1.2 mg/dL at onset, typically manifesting after 223.1 days and resolving within 110.7 days. Multivariable analysis identified significant factors such as age (1–5 years), obesity, onset time (≤ 20 days), recovery time (≤ 20 days), and treatments with L-asparaginase and 6-mercaptopurine as associated with an increased risk of hepatotoxicity. Conclusion: This study found that 21.6% of pediatric ALL patients who discontinued SMX/TMP for prophylaxis had hepatotoxicity with a ‘probable or higher’ causality due to SMX/TMP. Identifying factors associated with ‘probable or higher’ causality for SMX/TMP-induced hepatotoxicity in these patients may be valuable for future research in this domain.

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Objective: This study aimed to evaluate the association between nirmatrelvir/ritonavir, molnupiravir and adverse events and identify safety signals not previously known. Methods: To identify major adverse events and safety signals associated with nirmatrelvir/ritonavir and molnupiravir, we conducted pharmacovigilance study using drug-related adverse events reported to KIDS KAERS DB (2305A0011). Disproportionality analysis were performed using reporting odds ratio (ROR) and information component (IC) method to detected new safety signals not listed in drug label. Results: Adverse events related to nirmatrelvir/ritonavir and molnupiravir were frequently reported in women and person aged ≥ 65, and mostly reported as not serious. Following nirmatrelvir/ritonavir administration, ‘sensory abnormalities’ (20.18%), ‘diarrhoea’ (13.76%), and ‘nausea and vomiting symptoms’ (9.87%) were most commonly reported, while for molnupiravir, ‘nausea and vomiting symptoms’ (15.92%), ‘neurological signs and symptoms’ (15.92%), ‘urticarias’ (10.45%) were predominantly reported. Disproportionality analysis revealed a significant association of nirmatrelvir/ritonavir with ‘sensory abnormalities’ (ROR [95% CI] = 223.74 [207.24–241.55]), ‘interactions’ (ROR [95% CI] = 37.35 [15.10–92.35]), ‘faecal abnormalities’ (ROR [95% CI] = 32.33 [18.68–56.36]). Adverse events not listed on drug label included ‘olfactory nerve disorders’, ‘appitite disorder’, ‘hallucinations’ and urinary adverse events. For molnupiravir, strong association were observed with cardiovascular adverse events such as ‘heart rate and pulse investigations’ (ROR [95% CI] = 58.60 [18.96–181.16]) and ‘vascular tests’ (ROR [95% CI] = 10.97 [4.09–29.47]), which were not included in drug label. Conclusion: Adverse events following the use of nirmatrelvir/ritonavir and molnupiravir were generally not serious, but some safety signals not listed on drug label were newly detected and warranted attention. We expected this study to provide basic data of safety for oral antivirals of COVID-19 and may contribute to the development of future drug safety guidelines.

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Objective: This study aimed to estimate the rate of high-alert medication (HAM) use in nationwide representative claims data and compare the rates by types of healthcare settings. Methods: This cross-sectional study used data obtained from 2019 and 2020 Health Insurance Review and Assessment Service National Patient Sample (HIRA-NPS) and National Inpatient Sample (HIRA-NIS). The study focused on essential HAMs from the HAM list for acute, long-term, and primary care settings. The usage was quantified in terms of the number of patients receiving the medications at least once, the proportion within the entire patient population, and the ratio of prescription days for HAMs to total days. We also analyzed the rate of inpatients who received HAMs in HIRA-NIS. Results: Among 1,888,831 patients included in the database, 480,852 patients (25.5%) received HAMs at least once annually, with oral benzodiazepine derivatives being the most commonly prescribed. Substantial variations were observed in HAM usage across healthcare settings with the highest prevalence observed in long-term care hospitals (32.4%) followed by acute care hospitals (24.8%) and primary care clinics (15.3%). Among inpatient populations, injectable benzodiazepines, anesthetics, and neuromuscular blockers were frequently prescribed. Conclusion: This study offers insights into the utilization of HAMs across various healthcare settings. It highlights the need for targeted interventions and management strategies to ensure the safe use of these medications, particularly in long-term care settings.

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Objective: Fimasartan, an angiotensin II receptor blocker (ARB) with superior potency and longer-lasting effects than losartan, demonstrates a good safety profile. However, recent case reports have emerged, linking fimasartan to hepatotoxicity. The aim of the study is to compare the occurrence of liver injury induced by fimasartan. Methods: Patients prescribed with fimasartan and losartan from 2011 to 2021 were identified from electronic health recordbased Common Data Model (CDM) of Seoul National University Hospital. Using clinical data warehouse, clinical information was collected and employed to cross-reference the results retrieved from the CDM. To assess causality and compare the incidence of drug-induced liver injury (DILI), 100 randomly selected patients with liver function abnormalities were evaluated. Results: The CDM analysis included 3,063 patients on fimasartan and 9,688 patients on losartan, among which 302 patients (2.37%) exhibited liver function abnormalities within the first year of ARB therapy. Specifically, 107 (3.49%) patients on fimasartan showed elevated serum alanine aminotransferase or aspartate aminotransferase, compared to 195 (2.01%) patients on losartan. However, when causality was assessed, patients with causality graded as probable or certain did not show any significant difference between the two medications. Conclusion: Although patients taking fimasartan exhibited a slightly higher incidence of mild liver enzyme elevations, this study did not find a significant difference in the occurrence of DILI. Consequently, fimasartan is less safe than losartan in terms of hepatotoxicity cannot be asserted. However, similar to other ARBs, fimasartan poses a risk of DILI, underscoring the importance of monitoring liver function tests to promote safer use of the medication.