Pharmacoepidemiology, Volume 4, Issue 4 (December 2025) – 7 articles

Background/Objectives: Human immunodeficiency virus (HIV) continues to be a global public health concern. Several antiretroviral drugs have been approved for the treatment, post-exposure, and pre-exposure prophylaxis of HIV. Darunavir (DRV) is a protease inhibitor (PI) approved for the management of HIV globally. This study aims to generate safety signals for DRV through data mining and analysis of adverse events (AEs) reported to the United Kingdom (UK) Medicines and Healthcare products Regulatory Agency (MHRA) Yellow Card Scheme. Methods: Disproportionality analysis was conducted using reporting odds ratio (ROR), proportional reporting ratio (PRR), and Bayesian confidence propagation neural network (BCPNN) approaches to identify potential safety signals. Results: The MHRA database contained n = 779 reports (n = 1791 AEs) attributed to DRV. The majority of AEs were reported for males. Positive safety signals were identified at both the system organ class (SOC, n = 5) and preferred term level (PT, n = 95). At SOC level, endocrine disorders emerged as a signal of interest n = 33 cases (ROR: 8.17, 95% CI: 5.78–11.56; PRR:7.96, 95% CI: 5.68–11.15; and IC: 2.85, IC025: 2.51). Among the results, 40 new potential safety signals are not listed on the product labelling in the UK. These include serious AEs such as cerebrovascular accident, brain injury, thrombosis, and pregnancy, puerperium, and perinatal AEs. Conclusions: This study provides additional real-world safety data for DRV in the UK and paves the way for future observational studies to investigate the identified safety signals. Full article

Background: Medication safety in pregnancy, puerperium, and perinatal periods is underexplored because these populations are excluded from clinical trials. EudraVigilance offers post-marketing evidence, but disproportionality analyses focus on isolated drug event pairs and may miss syndromic patterns. We applied a network- and cluster-based framework to EudraVigilance reports on antiviral use in pregnancy to improve surveillance and identify meaningful constellations. Methods: We retrieved all individual case safety reports (ICSRs) from January 2015 to June 2025, including pregnancy, puerperium, or perinatal terms, focusing on suspect antivirals. After parsing terms, disproportionality metrics were computed as a benchmark. A bipartite drug–event network was built and projected to event–event co-occurrence networks; Louvain community detection identified clusters. Clusters were characterized by size, drug mix, seriousness, overlap with disproportionality signals, and stratification across periods. Results: The dataset comprised 106,924 ICSRs and 232,067 unique pairs. Disproportionality yielded 6142 signals, mainly involving antiretrovirals (ritonavir, lamivudine, zidovudine, emtricitabine/tenofovir). Network analysis revealed clusters grouping maternal and fetal/neonatal outcomes (e.g., fetal death, low birth weight), and transplacental transfer, highlighting structures not visible in pairwise analyses. Several clusters combined high-frequency exposures with clinically relevant outcomes, suggesting early-warning potential. Conclusions: Combining disproportionality with network- and cluster-based pharmacovigilance adds value for monitoring pregnancy medication safety. Beyond individual signals, this approach reveals meaningful clusters and “bridge” reactions connecting adverse-event domains, offering a richer framework for perinatal surveillance. Despite spontaneous-reporting limits, findings generate hypotheses for mechanistic and pharmacoepidemiologic follow-up and support network methods as complements to traditional pharmacovigilance. Full article

Introduction: Acute iron poisoning is a potentially life-threatening condition that primarily affects the gastrointestinal, hepatic and cardiovascular systems. While it most often occurs accidentally in children, intentional overdoses in adolescents and adults remain an important clinical concern. Case description: We report the case of a 14-year-old male patient with a history of depression who intentionally ingested 100 ferrous sulfate tablets (equivalent to 118 mg/kg of elemental iron). The patient was admitted to the emergency department three hours after ingestion. He presented with vomiting tablet remnants, headache, and mild abdominal pain. Supportive measures included intestinal irrigation with polyethylene glycol (PEG), gastric protection, and N-acetylcysteine intravenous administration. The iron chelator therapy with deferoxamine was not possible because the medication was unavailable, so treatment with the oral iron chelator (deferasirox) was initiated. The iron levels gradually decreased, with no evidence of liver or cardiovascular involvement. The patient was discharged on day 20 post-ingestion with outpatient psychiatric follow-up. Discussion: This case highlights the importance of early initiation of gastrointestinal decontamination with PEG to limit systemic iron absorption. The use of deferasirox as an alternative chelating agent in the absence of deferoxamine has been associated with a favorable response. Conclusions: The rational use of oral chelators, gastrointestinal decontamination, and hepatoprotective therapies in acute iron poisoning might prevent major complications and improve prognosis. Alternative therapies can be valuable when an antidote is not immediately available; however, further clinical research is required before making a recommendation. Full article

Herbal medicinal products are increasingly used alongside conventional medicines, raising the risk of potential interactions such as pharmacodynamic drug–herb interactions (PD-DHIs) that can cause serious adverse drug reactions (ADRs). This review aims to present available pharmacological, clinical and pharmacoepidemiological literature regarding potential DHIs associated with serotonin syndrome or cardiac arrhythmias. Furthermore, it assesses the current evidence using the Oxford Centre for Evidence-Based Medicine (CEBM) 2009 framework. Serotonin syndrome most often results from combining serotonergic herbs (e.g., St. John’s wort) with antidepressants like serotonin reuptake inhibitors (SSRIs), as supported by repeated case reports and mechanistic plausibility (CEBM Level 3, Grade C). Other herbs such as black cohosh, ginseng, Syrian rue, turmeric, rhodiola, ashwagandha, and L-tryptophan/5-HTP have been linked to serotonin syndrome when used with SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), or monoamine oxidase inhibitors (MAOIs), but evidence is limited (Levels 4–5, Grade D). For cardiac arrhythmias, PD-DHIs arise when herbs interact with drugs that alter cardiac electrophysiology—such as QT-prolonging agents, psychotropics, antiarrhythmics or digoxin—thereby amplifying arrhythmogenic risk. Ephedra with sympathomimetics is strongly associated with arrhythmias (Level 2–3, Grade B). Licorice may potentiate digoxin and QT-prolonging drugs via hypokalemia (Level 4, Grade C). Other related PD-DHIs include aconite with antiarrhythmics, bitter orange or caffeine with QT-prolonging psychotropics, yohimbine with cardiovascular agents, and aloe or senna with digoxin. Overall, the evidence for PD-DHIs varies from moderate to weak but large-scale pharmacoepidemiological data is scarce. Future approaches, including artificial intelligence with explainable machine learning and network pharmacology, may integrate mechanistic, clinical, and real-world data to improve early detection or prediction of PD-DHIs. However, several specific challenges must be addressed. Therefore, it is crucial for healthcare providers in both clinical and community settings to increase their awareness of these interactions and ADRs to ensure the safe use of herbal remedies alongside conventional therapies. Full article

Immunocompromised outpatients, including people living with HIV/AIDS (PLWH), diabetes, cancer, and organ transplant recipients, are at high risk of antimicrobial resistance (AMR) due to their weakened immune systems and use of immunosuppressive therapies. The high prevalence of prophylactic and therapeutic antibiotic use in this vulnerable population, coupled with frequent contact with healthcare facilities and limited outpatient antimicrobial resistance surveillance systems, contributes to the increase in antimicrobial resistance. The majority of available data pertains to inpatients, and there is a lack of comprehensive outpatient information on pathogen distribution, resistance patterns, and diagnostic challenges. Moreover, nonspecific clinical presentations, diminished inflammatory responses, and limitations of traditional diagnostic methods complicate infection diagnosis in this population. Increasing resistance surveillance, developing rapid diagnostic tools, and implementing accurate and personalized approaches are key strategies to reduce the burden of disease, mortality, and healthcare costs in the immunocompromised outpatient population. This study was designed as a narrative review based on a comprehensive search of major databases and guidelines. It aims to examine the available evidence and address the challenges associated with AMR in immunocompromised outpatients. Full article

Background: Adherence to tyrosine kinase inhibitors (TKIs), the first-line treatment for renal cell carcinoma (RCC), is critical to ensure intended treatment outcomes. However, 75% of patients with RCC have persistency gaps (>7 days) within the first 90 days after initiating TKIs. This study explored factors affecting TKI adherence in RCC patients to inform future interventions. Methods: A retrospective cohort study was conducted at a specialist oncology hospital in Northwest England from October 2020 to October 2022 on patients with RCC treated with TKIs. TKI prescriptions and persistence gaps (>7 days) were identified from electronic dispensing records. Factors associated with persistence gaps were retrieved by reviewing patients’ clinical records. We used descriptive statistics to summarise the results and Kaplan–Meier analysis to assess the probability and the time to the first gap, stratified by adverse drug effect (ADE)-related and non-ADE-related gaps. Results: Among 165 included patients, 611 persistence gaps were identified. ADEs accounted for 59% (n = 464) of 787 recorded factors, with diarrhoea being the most frequent ADE (9.5%). Patients holding leftover TKIs were the primary (15.1%) non-ADE factor for persistency gaps. At least one gap was observed with 82% of patients (n = 135); 19% had ≥5 ADE-related gaps, and 25% had ≥5 non-ADE-related gaps. ADE-related gaps typically occurred within the first three months (50%), while non-ADE-related gaps were not time-dependent. Conclusions: ADEs, including diarrhoea and pain-related reactions, were the most frequently reported issues affecting TKI persistency in patients with RCC. These ADEs are likely to impact patients’ quality of life and adherence. Future qualitative research is warranted to explore patients’ care needs and additional factors such as health literacy and self-efficacy. Full article

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. Full article