Drug Safety[JOURNAL]
Sun
200 papers
NSAIDs Use During Herpes Zoster Infection and Stroke Risk: A Nationwide Case-Crossover Study.
Meng LC, Lai HY, Chuang HM … +3 more , Chen HM, Chen LK, Hsiao FY
Drug Saf · 2026 Jun · PMID 41686364 · Publisher ↗
BACKGROUND AND AIMS: Herpes zoster (HZ) infection and long-term non-steroidal anti-inflammatory drugs (NSAIDs) use are established risk factors for stroke and other cardiovascular diseases. Given the paucity of evidence...
BACKGROUND AND AIMS: Herpes zoster (HZ) infection and long-term non-steroidal anti-inflammatory drugs (NSAIDs) use are established risk factors for stroke and other cardiovascular diseases. Given the paucity of evidence regarding an association between NSAIDs use and HZ on stroke risk, this case-crossover study, utilizing a nationwide, population-based cohort, aimed to investigate the effect of HZ infection and concurrent NSAIDs use on the incidence of stroke. METHODS: Using Taiwan's National Health Insurance database (2014-2020), we identified 336,075 patients with incident stroke. A case-crossover design comparing exposure to HZ and NSAIDs between the focal period (1-30 days before stroke) and referent period (366-395 days before stroke) was employed. Conditional logistic regression estimated adjusted odds ratios (aORs) for stroke risk associated with NSAIDs use during HZ episodes. Pre-planned subgroup analyses further examined such effects on stroke subtypes (ischemic stroke, hemorrhagic stroke, and transient ischemic attack [TIA]), across age groups (< 50, 50-64, ≥ 65 years) and in patients with various comorbidities, including immunocompromised and autoimmune diseases, cardiometabolic risk factors, and renal and liver diseases. RESULTS: Combined HZ infection and NSAIDs use was associated with doubled stroke risk (aOR 2.05, 95% confidence interval [CI] 1.80-2.33) compared with periods without either exposure. For specific stroke types, the aORs were 1.94 (95% CI 1.65-2.29) for ischemic stroke, 1.81 (95% CI 1.34-2.43) for hemorrhagic stroke, and 2.81 (95% CI 2.06-3.85) for TIA. HZ episodes without NSAIDs (aOR 1.70, 95% CI 1.45-2.00) and NSAIDs use alone (aOR 1.42, 95% CI 1.40-1.44) showed lower but significant risk increment. In age-stratified analyses, individuals aged 65 years and older exhibited a significantly elevated stroke risk while concurrently utilizing NSAIDs during HZ episodes (aOR 2.19, 95% CI 1.92-2.62). Subgroup analyses demonstrated consistent elevated risks in patients with pre-existing comorbidities, particularly immunocompromised conditions (aOR 3.07, 95% CI 1.95-4.81) and renal disease (aOR 4.30, 95% CI 2.20-8.41). CONCLUSIONS: Our findings demonstrate a significant association between HZ infection and NSAIDs use on stroke risk, particularly among individuals aged 65 years and older or those with pre-existing immunocompromised, cardiometabolic, and chronic conditions. The optimization of pain management strategies during HZ episodes is paramount to mitigate the risk of stroke while ensuring effective management of HZ-associated pain.
Pharmacovigilance Through Fresh Eyes: The International Society of Pharmacovigilance Student Community's Role in Shaping the Future of Pharmacovigilance.
Saleh H, Amidu IM, Ziaudeen Z … +2 more , Walker RJ, Younus M
Drug Saf · 2026 Mar · PMID 41678038 · Publisher ↗
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VigiBase: Resource Profile Update with a Summary of Global Patterns and Trends in Adverse Event Reports for Medicines and Vaccines.
Brand JS, Gauffin O, Sartori D … +7 more , Fusaroli M, Sköld H, Bergvall T, Sandberg L, Wallberg M, Hjelmström P, Norén GN
Drug Saf · 2026 Jun · PMID 41618069 · Full text
VigiBase, the WHO global database of adverse event reports for medicines and vaccines, receives information on suspected adverse effects of medicinal products from countries, regions and territories that are members of t...
VigiBase, the WHO global database of adverse event reports for medicines and vaccines, receives information on suspected adverse effects of medicinal products from countries, regions and territories that are members of the WHO Programme for International Drug Monitoring. The database serves as a global resource for pharmacovigilance signal management and scientific development. Its initial establishment through the programme in 1968 has also contributed to the international harmonisation of adverse event report data. As of 31 December 2024, the database includes over 40 million individual case reports coded in standard terminologies (WHODrug and MedDRA). These reports, of which ~ 80% relate to medicines and ~ 20% to vaccines, come from over 160 countries. This profile paper aims to provide an update on the database infrastructure including data capture, management and analysis tools. It also presents a summary of global patterns and trends of key report characteristics, as well as strengths and limitations of the data to offer context to users and the global pharmacovigilance community.
Physician Awareness of FDA's Relaxation of REMS-Required Laboratory Testing Requirements and Changes in Prescribing Practices During the COVID-19 Pandemic.
Hwang CS, Lu Z, Russo M … +7 more , Zakoul H, Toyserkani GA, Zhou EH, LaCivita C, Dal Pan GJ, Kesselheim AS, Sarpatwari A
Drug Saf · 2026 May · PMID 41593404 · Publisher ↗
BACKGROUND: The US Food and Drug Administration (FDA) requires pharmaceutical manufacturers to implement Risk Evaluation and Mitigation Strategy (REMS) programs for certain medications that carry serious safety risks. On...
BACKGROUND: The US Food and Drug Administration (FDA) requires pharmaceutical manufacturers to implement Risk Evaluation and Mitigation Strategy (REMS) programs for certain medications that carry serious safety risks. One possible REMS requirement is routine monitoring via laboratory tests. However, in March 2020, the FDA issued a temporary enforcement discretion policy enabling prescribers to apply medical judgment for completing REMS-required laboratory testing. OBJECTIVE: We aimed to assess whether physicians were aware of the FDA's temporary policy and if they changed their laboratory testing practices during the coronavirus disease 2019 pandemic. METHODS: We designed a survey of US physicians prescribing one of seven medications: ambrisentan, bosentan, clozapine, isotretinoin, lenalidomide, pomalidomide, and thalidomide. The study was conducted over two waves, May 2022 to October 2022 and October 2022 to January 2023. Multivariable logistic regression modeling was used to examine predictors of each outcome. RESULTS: The combined response rate between the two waves of survey administration was 21%. Among 949 physician respondents, 438 (47%; 927 question respondents) reported awareness and 192 (21%; 926 question respondents) reported changing practices. Among the 438 physicians who reported awareness, 176 (40%) reported changing practices. Characteristics associated with awareness included sex (female vs male, odds ratio [OR] = 1.92, 95% confidence interval [CI] 1.37-2.69); recency of medical school graduation (25-34 vs ≤ 15 years, OR = 0.50, 95% CI 0.31-0.81); practice setting (academic hospital vs outpatient group, OR = 0.58, 95% CI 0.37-0.88); prescribing experience (≥ 21 vs ≤10 patients, OR = 2.92, 95% CI 2.06-4.14); and timing of survey completion (wave 2 vs wave 1, OR = 0.47, 95% CI 0.34-0.66). Characteristics associated with practice changes included race (Asian vs White, OR = 0.62, 95% CI 0.38-0.99) and awareness of FDA's policy (yes vs no, OR = 14.07, 95% CI 7.93-24.96), in addition to sex (female vs male, OR = 1.99, 95% CI 1.31-3.01), recency of medical school graduation (≥ 35 vs < 15 years: OR = 0.53, 95% CI 0.30-0.93), and timing of survey completion (wave 2 vs wave 1: OR = 0.58, 95% CI 0.34-0.99). CONCLUSIONS: Although policy awareness was correlated with laboratory practice changes, fewer than half of physicians who were aware of the FDA's policy reported changing their practices.
Assessing the Use of Medical Insurance Claims and Electronic Health Records to Measure COVID-19 Vaccination During Pregnancy.
Coates MM, Rowe SL, Sullivan SG … +3 more , Munoz FM, Arah OA, Regan AK
Drug Saf · 2026 May · PMID 41587000 · Full text
INTRODUCTION: The safety and effectiveness of COVID-19 vaccination during pregnancy are commonly assessed using administrative health records, which may misclassify vaccine exposures. OBJECTIVE: The aim of this study was...
INTRODUCTION: The safety and effectiveness of COVID-19 vaccination during pregnancy are commonly assessed using administrative health records, which may misclassify vaccine exposures. OBJECTIVE: The aim of this study was to compare the capture of COVID-19 vaccines in commercial insurance claims records and electronic health records (EHR) before and during pregnancy in a cohort in the United States and demonstrate the implications of observed misclassification on vaccine safety and effectiveness estimates. METHODS: Analysis of de-identified data from the Optum Labs Data Warehouse (OLDW) included pregnancies ending after December 11, 2020, and beginning before January 1, 2023, among people aged 15-54 years who were continuously enrolled in health insurance and had EHR data available. We compared the capture of COVID-19 vaccines from insurance claims and EHR databases to the combined and deduplicated doses using clinical procedure and drug codes, assessing records over time and by gestational age, dose number, vaccine manufacturer, and socioeconomic variables. RESULTS: For 29,663 eligible pregnancies, we identified 25,124 COVID-19 vaccine doses (87% in claims and 35% in EHR). About 44% had received one or more doses of a COVID-19 vaccine before or during pregnancy in the combined data, compared with 41% in the insurance claims data and 16% in the EHR data. Records of vaccination relative to the combined data improved in the claims data and declined in the EHR data over time. Vaccine manufacturer information from records without procedure codes in EHR data was unreliable, and a greater proportion of combined doses were recorded in EHR when the cohort was restricted to people with more frequent EHR encounters. The magnitudes of exposure misclassification observed, particularly in EHR data, could substantially bias estimates of vaccine effectiveness and safety. CONCLUSIONS: Insurance claims data captured a larger proportion of COVID-19 vaccine doses than EHR data, and this proportion increased over time. Combining data from multiple administrative health records sources can improve COVID-19 vaccine measurement before and during pregnancy and may be important to reduce bias in studies of vaccine effects.
Risk of Cancer Comparing Warfarin and Direct Oral Anticoagulants: Population-Based Cohort Studies in England and Hong Kong.
Wang Z, Yu Q, Matthewman J … +10 more , Tazare J, Majano SB, Brown J, Cheung KS, Chui CSL, Chan EWY, Bhaskaran K, Wong ICK, Douglas IJ, Wong AYS
Drug Saf · 2026 Jun · PMID 41553598 · Publisher ↗
BACKGROUND: Previous evidence suggests a potential protective effect of warfarin against cancer, compared to non-users. However, it may be prone to immortal time bias and residual confounding. OBJECTIVE: We aimed to exam...
BACKGROUND: Previous evidence suggests a potential protective effect of warfarin against cancer, compared to non-users. However, it may be prone to immortal time bias and residual confounding. OBJECTIVE: We aimed to examine the association between cancer and warfarin, compared with active comparator (direct oral anticoagulants). METHODS: We conducted studies using population-based databases from England and Hong Kong to investigate the association between warfarin and hazard of cancer using a new-user active-comparator cohort design. People with atrial fibrillation aged ≥ 18 years who had first received anticoagulant treatment during 01/01/2011-31/12/2019 were involved. RESULTS: No evidence supported the association between warfarin and hazard of overall cancer, compared with direct oral anticoagulants in both settings (England: hazard ratio [HR] = 1.03, 95% confidence interval [CI] 0.94-1.13; Hong Kong: HR = 0.89, 95% CI 0.79-1.01). A lower hazard of female breast (HR = 0.49, 95% CI 0.30-0.79), ovarian (HR = 0.07, 95% CI 0.01-0.58), and pancreatic (HR = 0.46, 95% CI 0.22-0.96) cancers and a higher hazard of kidney cancer (HR = 3.57, 95% CI 1.64-7.76) were found in Hong Kong, comparing warfarin with direct oral anticoagulants, but these were not replicated in England. CONCLUSIONS: This study does not find a protective effect of warfarin against cancer versus direct oral anticoagulants. The risks of site-specific cancers including pancreatic, kidney, and sex-specific cancers between oral anticoagulants shown in the Hong Kong setting only may require further investigation in other independent datasets.
Perspective on Better Access to Data and Data Integration in Pharmacovigilance: Information from a Focus Group.
van Hunsel F, Lane S, Cooper D … +9 more , Aurelius T, Bobbins A, Dickinson H, Hauben M, Morris D, van Puijenbroek E, Yeomans A, Younus M, Shakir S
Drug Saf · 2026 Jun · PMID 41533330 · Full text
A focus group organised by the Drug Safety Research Unit (DSRU) International Working Group (IWG) on New Developments in Pharmacovigilance discussed current challenges and opportunities in pharmacovigilance (PV), emphasi...
A focus group organised by the Drug Safety Research Unit (DSRU) International Working Group (IWG) on New Developments in Pharmacovigilance discussed current challenges and opportunities in pharmacovigilance (PV), emphasising the need for a multimodal approach in data analysis and accessibility of diverse data sources for drug safety surveillance. Nine participants, selected purposefully for their multisectoral expertise in PV, discussed the value of various data types, including data from clinical trials and real-world data (RWD), each offering distinct strengths and limitations. Key challenges identified included data standardisation, quality variability, technological barriers and ethical concerns, particularly with data derived from social media. Emerging tools such as knowledge graphs were highlighted for their potential to enhance data integration and signal detection, however further research is required. The group also addressed disparities in data access, with particular attention to regulatory restrictions, limited infrastructure in low-resource settings and restricted access to industry-held data. Proposed solutions included fostering greater data transparency, establishing secure data-sharing platforms and forming collaborative consortia to facilitate responsible and ethical data use. Overall, the discussion underscored the need for improved integration, access and methodological rigour to strengthen PV practices and enhance global drug safety monitoring.
Unveiling the Limits of Anticholinergic Burden Scales: A Study of Adverse Drug Reactions in the French Pharmacovigilance Database.
Pecquet PE, Moragny J, Gras V … +4 more , Schiro P, Pinel S, Laville SM, Liabeuf S
Drug Saf · 2026 May · PMID 41528420 · Full text
BACKGROUND AND HYPOTHESIS: The anticholinergic burden is the cumulative effect of drugs with anticholinergic properties and is typically measured using one of several anticholinergic scales. We hypothesised that these sc...
BACKGROUND AND HYPOTHESIS: The anticholinergic burden is the cumulative effect of drugs with anticholinergic properties and is typically measured using one of several anticholinergic scales. We hypothesised that these scales may not fully capture all the relevant adverse drug reactions (ADRs). By accessing the French national pharmacovigilance database (FPVD) and focusing on drug classes known to induce anticholinergic ADRs, the objectives of the present study were to describe the reported ADRs, characterise the drugs involved, and examine the drugs' classification within anticholinergic scales. METHODS: Cases were extracted from the FPVD (1985-2024) when the suspected drug (i) had a high anticholinergic score, according to one or more of 22 anticholinergic burden scales, or (ii) belonged to the same class as the drug identified in (i). The anticholinergic ADRs investigated were confusion, glaucoma, tachycardia, urinary retention, constipation, intestinal obstruction and mydriasis. RESULTS: Of the 101,365 cases reported in the FPVD, regarding the selected drugs, 9629 (9.5%) involved at least one anticholinergic ADR investigated. Patients who experienced at least one anticholinergic ADR had a median age of 61 years (interquartile range: 38-79), and the majority were women (58%). Confusion was the most frequently reported anticholinergic ADR (4603 cases, of which 81% were classified as serious), followed by tachycardia (n = 1541 cases, 70% serious), and urinary retention (1061 cases, 75% serious). It is noteworthy that 98% of the 561 reported cases of intestinal obstruction were classified as serious. The drug classes with the highest number of reports were (by far) anxiolytics, antidepressants, and antipsychotics. Some drugs linked to anticholinergic ADRs in the FPVD were not present in (or were assigned a low score by) commonly used anticholinergic scales, such as the Anticholinergic Cognitive Burden. CONCLUSIONS: Anticholinergic ADRs affect both older and younger adults. The existing scoring systems might not fully capture the range of medications involved in real-world anticholinergic-related events.
Correction: Advancing Pharmacovigilance Practice in Africa: Moving from Data Collection to Data-Driven Decision Making-Report from the 4th ISoP Africa Chapter Meeting.
Ndagije HB, Ampaire S, Sabblah GT … +17 more , Ogar C, Pandit JM, Kotecha N, Russom M, Nambasa VP, Ambale C, Aywak D, Bassi PU, Mathenge W, Meyer JC, Khaemba C, Kwikiriza E, Mayengo J, Atuhaire J, Nahamya D, Aimer O, Caro-Rojas A
Drug Saf · 2026 Jan · PMID 41505025 · Full text
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Evaluating COVID-19 Vaccine Masking and Unmasking Methods in Two National Pharmacovigilance Databases.
Rachwal O, Gutiérrez-Lobón M, Cueto NS … +6 more , Ventura AN, Fernández-Fernández C, van Hunsel FPAM, Scholl JHG, Gordillo-Marañón M, van Puijenbroek EP
Drug Saf · 2026 May · PMID 41501319 · Full text
BACKGROUND: The COVID-19 mass vaccination led to a substantial increase in spontaneous reports submitted to pharmacovigilance (PV) databases, potentially introducing masking effects that could conceal safety signals. OBJ...
BACKGROUND: The COVID-19 mass vaccination led to a substantial increase in spontaneous reports submitted to pharmacovigilance (PV) databases, potentially introducing masking effects that could conceal safety signals. OBJECTIVES: To examine the masking effect of COVID-19 vaccines on disproportionality analyses and to compare two unmasking interventions in the Dutch (Lareb database) and Spanish (Farmacovigilancia Española, Datos de Reacciones Adversas, FEDRA) national PV databases: removal of all drug-event combinations (DEC) involving a COVID-19 vaccine versus excluding influential outliers DECs only. METHODS: The masking effect was explored retrospectively on the basis of the number of signals of disproportionate reporting (SDR). DECs involving a COVID-19 vaccine were excluded using crude and outlier techniques, and reporting odds ratios were recalculated. Subsets of important medical events (IME) were analysed in both databases. RESULTS: Both crude and influential outlier removal methods led to reductions in the number of reports, DECs and SDRs. Both in the Lareb database and FEDRA, crude removal excluded 2.1% of DECs, while the outlier method excluded 0.1%. Crude removal had a greater impact on SDRs, reducing them by 9.8% in the Lareb database and 3.9% in FEDRA, compared with 5.7% and 1.1% with the outlier method. In the Lareb database, 1301 SDRs (20 IME-related) were unmasked using crude removal, and 1942 (95 IME-related) with the outlier method. FEDRA showed 1453 and 1226 SDRs unmasked, including 41 and 70 IME-related. CONCLUSIONS: COVID-19 vaccines caused substantial masking in both databases. Both strategies effectively revealed new SDRs, though their impact varied. The choice of approach should be tailored to the database context.
Standardizing and Comparing Management Recommendations for Potential Drug-Drug Interactions Across Different Interaction Checkers.
Crupi L, Letinier L, Jouhet V … +10 more , Cossin S, Pariente A, Mathieu C, Martin GL, Konschelle F, Rouanet J, Carollo M, Trifirò G, Esposito E, Salvo F
Drug Saf · 2026 May · PMID 41491904 · Publisher ↗
BACKGROUND: Potential drug-drug interactions (pDDIs) are frequent in clinical care, particularly among older patients. Accurate identification and management of pDDIs are essential for patient safety. Prescribers often r...
BACKGROUND: Potential drug-drug interactions (pDDIs) are frequent in clinical care, particularly among older patients. Accurate identification and management of pDDIs are essential for patient safety. Prescribers often rely on interaction checkers (ICs) to screen for pDDIs. However, these tools may provide inconsistent recommendations, potentially leading to suboptimal clinical decisions. OBJECTIVE: This study aimed to develop a standardized approach for classifying and prioritizing pDDIs based on the clinical relevance of their management recommendations and to compare how these pDDIs are categorized across ICs. METHODS: A scale was developed through a structured iterative process to classify pDDIs into four management categories (high priority, intermediate priority, low priority, data unavailable), based on the management recommendations extracted from six ICs. This scale was applied to 218 real-world pDDIs identified from 1923 patients, and the agreement was primarily assessed using Gwet's AC1. MAIN RESULTS: Overall agreement among the ICs was moderate (Gwet's AC1 = 0.44; 95% CI 0.39-0.50), with values ranging from 0.58 (0.51, 0.65) to 0.38 (0.31, 0.44) in leave-one-out analyses. The agreement was higher in binary analyses dichotomizing the scale into high- and intermediate-priority versus low-priority pDDIs (AC1 = 0.72; 95% CI 0.65-0.79), and in the classification of high-priority versus all other pDDIs (AC1 = 0.62; 95% CI 0.54-0.69). CONCLUSION: This study developed and tested a structured approach to systematically compare pDDI management across ICs and prioritize clinically relevant interactions. Its application revealed a generally limited agreement between ICs, pointing to the need for harmonized approaches and further studies to support more consistent, evidence-aligned pDDI management.
Pharmacovigilance Due Diligence in Drug Development: A Practical Playbook for Risk Identification, Compliance Assessment, and Strategic Decision Making.
Youssef A, Hammad TA
Drug Saf · 2026 May · PMID 41400880 · Full text
In the pharmaceutical industry, due diligence (DD) is a critical, cross-functional process used to evaluate the scientific and regulatory viability of products, particularly during in-licensing or acquisition. Among the...
In the pharmaceutical industry, due diligence (DD) is a critical, cross-functional process used to evaluate the scientific and regulatory viability of products, particularly during in-licensing or acquisition. Among the various dimensions assessed, safety evaluation plays a pivotal role in determining whether a product is likely to achieve regulatory approval, maintain a favourable benefit-risk balance, and support sustainable market access. This article focuses on the unique role of pharmacovigilance (PV) and safety experts in the DD process. It outlines the key safety-related questions that must be addressed, highlights potential red flags-such as organ-specific toxicities, labelling liabilities, or risk management burdens-and provides practical considerations for evaluating the robustness of the safety data package. Drawing on extensive industry experience and regulatory precedents, this manuscript offers structured guidance for an area where no formal framework exists. It emphasizes the importance of forecasting the likelihood of achieving a positive benefit-risk profile and identifying foreseeable safety-related barriers-ranging from boxed warnings to withdrawal risk-that could delay approval or diminish product value. By proposing a systematic approach to safety DD, including a playbook and an inclusive checklist with colour-coded categorization framework, this paper aims to support more informed, proactive, and risk-calibrated decision making in pharmaceutical transactions.
Causal Inference Tools for Pharmacovigilance: Using Causal Graphs to Identify and Address Biases in Disproportionality Analysis.
Fusaroli M, Mitchell J, Rudolph A … +2 more , Rocca E, Fusaroli R
Drug Saf · 2026 Apr · PMID 41381798 · Full text
INTRODUCTION: Disproportionality analysis, finding associations in the co-reporting of drugs and events, is widely used in pharmacovigilance to detect potential safety signals of adverse drug reactions. However, inherent...
INTRODUCTION: Disproportionality analysis, finding associations in the co-reporting of drugs and events, is widely used in pharmacovigilance to detect potential safety signals of adverse drug reactions. However, inherent biases and unique data features often cause disproportionality to diverge from causation, and a comprehensive framework to address these issues is lacking. OBJECTIVE: We showcase how directed acyclic graphs (DAGs) can enhance disproportionality analysis-related inferences, better qualifying its limitations and catalysing its inclusion in the broader evidence landscape. METHODS: We introduce a DAG-based causal framework to systematically document and address biases in disproportionality analyses (e.g., confounding, colliders, measurement and reporting biases). We illustrate its application to case studies from the Food & Drug Administration (FDA) Adverse Event Reporting System-using the Information Component as a disproportionality metric and restriction as conditioning. RESULTS: Directed acyclic graphs facilitate the formalisation of existing knowledge and causal assumptions, optimise the design of disproportionality analysis to mitigate biases-thereby enhancing sensitivity and specificity-improve transparency, better enable the formulation of critiques, highlight limitations of disproportionality and guide follow-up studies to address residual confounding and broader evidence synthesis. CONCLUSION: Using DAGs to map and mitigate biases requires caution and does not allow to obtain definitive answers to causal questions. Still, it results in more reliable and knowledge-based safety signals, reducing and mapping the gap between what we find (association) and what we look for (causation). Additional research should further tailor DAGs to pharmacovigilance challenges, map the generative mechanisms of pharmacovigilance data, and better integrate disproportionality analysis results into evidence-synthesis workflows.
GP Consultations for Herpes Zoster After COVID-19 Vaccination: A Self-Controlled Cohort Study Based on Electronic Health Record Data from the Netherlands.
Jajou R, van Puijenbroek E, Overbeek J … +4 more , Hek K, Mulder E, van Hunsel F, Kant A
Drug Saf · 2026 May · PMID 41379294 · Full text
BACKGROUND AND OBJECTIVE: Several systematic reviews and meta-analyses have been published with conflicting results on the risk of herpes zoster after coronavirus disease 2019 (COVID-19) vaccination. We aimed to study th...
BACKGROUND AND OBJECTIVE: Several systematic reviews and meta-analyses have been published with conflicting results on the risk of herpes zoster after coronavirus disease 2019 (COVID-19) vaccination. We aimed to study the risk of herpes zoster after COVID-19 vaccination using electronic health record data of general practices, from a large cohort in the Netherlands. METHODS: Persons aged ≥ 12 years who received at least one COVID-19 vaccination and were registered in the general practice databases of PHARMO and Nivel Primary Care Database were included. This study used a self-controlled design comparing the risk of herpes zoster in the risk period (28 days after COVID-19 vaccination) with the control period. Poisson regression was used to calculate incidence rate ratios, adjusting for severe acute respiratory syndrome coronavirus 2 infection. RESULTS: There were 2,098,683 COVID-19 vaccinated persons aged ≥ 12 years included, of whom 1,058,646 (50.4%) were female. An increased risk for herpes zoster was found after all the doses grouped together and the third dose of all COVID-19 vaccination (adjusted incidence rate ratio: all doses 1.07, 95% confidence interval [CI] 1.02-1.13 and third dose 1.21, 95% CI 1.05-1.38). After stratification on vaccine type, all doses and the third dose of messenger RNA vaccination (adjusted incidence rate ratio: all doses 1.06, 95% CI 1.00-1.12 and third dose 1.21, 95% CI 1.05-1.40) showed an increased risk. CONCLUSIONS: Our study showed a slight increased risk of herpes zoster when taking into account all doses and all types of vaccines. After stratification on vaccine type, no increased risk of herpes zoster after the primary vaccination series and a slightly elevated risk after the third/booster vaccination with a messenger RNA vaccine were found.
MCSG: A Method for Simultaneous Disproportionality Analysis and Background Rate Estimation in Large Pharmacovigilance Databases.
Bright M, Kontsioti E, Pirmohamed M … +2 more , Zhou Y, Maskell S
Drug Saf · 2026 Apr · PMID 41351764 · Publisher ↗
BACKGROUND: Databases for safety monitoring of medicinal products contain records of a huge number of pairings of drugs and adverse events (AEs). Existing disproportionality methods for safety monitoring in such database...
BACKGROUND: Databases for safety monitoring of medicinal products contain records of a huge number of pairings of drugs and adverse events (AEs). Existing disproportionality methods for safety monitoring in such databases estimate background rates of AE occurrence in ways that may be susceptible to masking effects that can hinder signal detection, particularly in the context of large overall counts of AE or drug occurrence in the data. OBJECTIVES: To develop a new statistical model for determining the background rate against which individual drug-AE pairs are to be evaluated, which is robust against masking effects, and to incorporate this into an algorithm which simultaneously estimates background rates and detects drug-AE pair counts that deviate significantly from these rates. METHODS: We constructed a hierarchical Bayesian model for background rates, and background rate samples were drawn from the model parameters using an iterative Markov Chain Monte Carlo (MCMC) method. At each iteration, any counts whose probability is low given current background rate estimation were removed from the computation that sampled the next set of background rates. The algorithm, called Markov Chain Signal Generation (MCSG), was implemented using a combination of Python and the probabilistic programming language Stan. RESULTS: The MCSG algorithm outperformed routinely used quantitative approaches for signal detection on both synthetic data designed to include a drug-AE pair with very strong masking effects and a reference set featuring 69 unique active substances and 792 unique AEs. On a synthetic dataset where selected pairs occurred at rates deviating from a constant background, MCSG accurately identified these pairs in the presence of strong masking signals. On a subset of some real data from the FDA Adverse Event Report System (FAERS), it effectively identified a reference set of positive and negative controls and was able to identify drug-AE pairs suggested in the literature. CONCLUSION: We have demonstrated a new approach to signal generation, which avoids the confounding effect of masking more effectively than currently used methods. The algorithm is best used in a setting of multiple drug-AE pairs, the majority of which are expected to have counts at background rate, although with substantial datasets the algorithm can take minutes or hours to run. It is therefore particularly suitable for infrequent, large-scale analysis (for example, quarterly analysis of the entirety of a pharmacovigilance database).
Unsuspected Adverse Drug Reactions to Dermatologic Medications: An Epidemiological Hypothesis-Free Screening Study of Real-World Data in Denmark.
Delvin T, Bygum A, Lund LC … +2 more , Andersen JH, Hallas J
Drug Saf · 2026 May · PMID 41348382 · Publisher ↗
BACKGROUND: Many adverse drug reactions (ADRs) to dermatological drugs may be underrecognized due to limitations in traditional surveillance. Systematic, hypothesis-free screening for such ADRs using real-world data is a...
BACKGROUND: Many adverse drug reactions (ADRs) to dermatological drugs may be underrecognized due to limitations in traditional surveillance. Systematic, hypothesis-free screening for such ADRs using real-world data is an underutilized approach in dermatology. OBJECTIVE: The aim was to systematically screen commonly used dermatological drugs for potential unknown ADR signals using nationwide Danish health register data and to evaluate sequence symmetry analysis (SSA) as an epidemiological screening method in pharmacovigilance. This evaluation focuses on identifying key signals for dedicated follow-up studies, not on an exhaustive analysis of all potential associations. METHODS: A nationwide, register-based, hypothesis-free screening study using Danish national health registers was conducted. The study cohort comprised 5,877,711 Danish residents prescribed dermatological drugs or relevant immunosuppressants linked to a dermatological indication between 1996 and 2022. Data were analyzed from 1995 to 2024. Exposures were the first dispensation of included dermatological drugs. The primary outcome measure was the trend-adjusted sequence ratio (SR), an estimate of the incidence rate ratio for rare events, with 95% confidence intervals (CIs), for incident drug-drug and drug-diagnosis pairs within ±12-month windows of exposure initiation. To assess directionality, supplementary case-crossover (CCO) analyses were performed on top-ranked signals, estimating odds ratios (ORs) with 95% CIs. RESULTS: The screening of 22.5 million incident exposure prescriptions yielded 4010 drug-drug and 22,234 drug-diagnosis pairs. After filtering and review, several potential unknown ADR signals were identified and prioritized. Signals were manually reviewed and categorized by clinical experts to identify plausible novel ADRs. Notable associations (adjusted SR [95% CI]; CCO OR [95% CI]) included isotretinoin with systemic corticosteroids (1.44 [1.35-1.53]; 1.78 [1.61-1.98]) and hemorrhoid treatments (1.58 [1.49-1.68]; 1.83 [1.68-1.98]); azathioprine with bone-modifying drugs (1.42 [1.33-1.53]; 1.57 [1.36-1.81]); terbinafine with lipid-lowering therapy (1.04 [1.01-1.08]; 1.14 [1.07-1.20]) and vitamin B12/folate use (1.20 [1.14-1.26]; 1.12 [1.02-1.22]); and clobetasol with atrial fibrillation/flutter (1.11 [1.06-1.17]; 1.07 [1.00-1.14]). CONCLUSIONS: Systematic hypothesis-free screening using SSA on nationwide real-world data can effectively identify potential unknown ADRs for dermatological drugs. The specific signals found in this study potentially have clinical implications and warrant further targeted investigations to support causality. This approach supports the implementation of routine real-world data screening to supplement traditional pharmacovigilance.
Hepatic Effects, Potential Drug-Induced Liver Injury, and Other Liver Safety Considerations of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in the New Era of Expanding Non-oncology Indications: Literature Review and Expert Consensus.
Fettiplace A, Regev A, Kiazand A … +11 more , Heinzel-Pleines U, Bahjat M, Garg A, Kikuchi L, Li H, Hamidi A, Alpers DH, Tillmann H, Larrey D, Di Bisceglie AM, Lewis JH
Drug Saf · 2026 Jun · PMID 41345813 · Full text
Chimeric antigen receptor T-cell (CAR-T) therapy is a rapidly expanding key therapeutic category, originally pioneered for haematological malignancies, now being developed into treatments for solid tumours and non-malign...
Chimeric antigen receptor T-cell (CAR-T) therapy is a rapidly expanding key therapeutic category, originally pioneered for haematological malignancies, now being developed into treatments for solid tumours and non-malignant immune-mediated conditions. Chimeric antigen receptor T-cell therapies have some relatively unique toxicities which can affect the liver, in addition to potential drug-induced liver injury and hepatitis B virus reactivation. This manuscript was developed by the IQ Consortium (International Consortium for Innovation and Quality in Pharmaceutical Development) Drug-induced Liver Injury (DILI) Initiative that consists of members from 17 pharmaceutical companies, in collaboration with academic and regulatory DILI experts. The aim was to produce a comprehensive guide to summarise the hepatic effects of CAR-T, and to propose an approach to the investigation of liver test changes. The clinical characteristics of liver test changes in association with cytokine release syndrome and immune-effector cell haemophagocytic lymphohistiocytosis are described, to enable these anticipated hepatic effects to be distinguished from other causes of abnormal liver tests. The frequency and timing of many primary and secondary liver conditions that may present after CAR-T therapy are described. This review provides the first detailed description of both anticipated and unpredictable hepatic effects of CAR-T cell therapies and is intended to assist in the future characterisation of hepatic effects of CAR-T therapies as programmes move into areas with a different benefit/risk profile, such as autoimmune or other non-oncology indications.
Systematic Review of Active Safety Surveillance of Vaccines and Medicines in Low- and Middle-Income Countries.
Stergachis A, Sevene E, Alam MGS … +5 more , Chandler RE, Precioso A, Mudigonda S, Nordenberg D, Chen RT
Drug Saf · 2026 Apr · PMID 41307832 · Full text
BACKGROUND: Functional active safety surveillance is essential for post-authorization assessment and life-cycle safety evidence generation of vaccines and medicines. Data collected through active surveillance methods are...
BACKGROUND: Functional active safety surveillance is essential for post-authorization assessment and life-cycle safety evidence generation of vaccines and medicines. Data collected through active surveillance methods are routinely used for post-approval surveillance of novel vaccines and medicines. Implementing these methods in low- and middle-income countries remains challenging. OBJECTIVE: This systematic review identified and assessed existing active safety surveillance in low- and middle-income countries, including key features, strengths, and limitations. METHODS: A search of EMBASE and PubMed Google Scholar databases was conducted. The protocol was registered with PROSPERO and adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. Findings were synthesized narratively and categorized by surveillance systems characteristics. RESULTS: Of 13,027 records identified, 423 publications met inclusion criteria. Articles spanned 96 low- and middle-income countries, with India (96), China (57), Brazil (30), Iran (26), Ethiopia (21), Indonesia (20), Uganda (18), Kenya (17), and Ghana (16), most represented. The majority focused on vaccines (211). A total of 127 articles utilized mobile technologies for follow-up, online data collection, and/or adverse event reporting. Fifteen percent of vaccine surveillance systems described in articles demonstrated flexibility to incorporate new vaccines, 34% reported multi-sectoral collaborations, and 10% involved multiple countries. Gaps identified include small sample sizes, lack of sustainability, limited flexible surveillance, staffing challenges, and limited use of standard case definitions and digital technologies. CONCLUSIONS: Active safety surveillance in low- and middle-income countries has made progress but still faces challenges. The capture and management of safety data through harmonized digital tools that promote consistency in recording and reporting and cross-country collaborations are crucial in further strengthening active safety surveillance in low- and middle-income countries.
Prescription Drugs Subject to a Risk Evaluation and Mitigation Strategy: Patient Perspectives on Risk Communication and the Value of Educational Materials.
Chimonas S, Cosenza C, Kesselheim AS … +5 more , Toyserkani GA, Oswell KH, LaCivita C, Dal Pan GJ, Sarpatwari A
Drug Saf · 2026 Jun · PMID 41307831 · Full text
BACKGROUND: The US Food and Drug Administration (FDA)-mandates Risk Evaluation and Mitigation Strategy (REMS) programs for certain drugs with serious side effects help ensure that the benefits of use outweigh the risks....
BACKGROUND: The US Food and Drug Administration (FDA)-mandates Risk Evaluation and Mitigation Strategy (REMS) programs for certain drugs with serious side effects help ensure that the benefits of use outweigh the risks. REMS materials-including enrollment forms, fact sheets, and medication guides-inform patients and caregivers about drug risks and program requirements. OBJECTIVE: To explore how effectively REMS materials communicate drug risk information and program requirements to patients and caregivers and to identify patients' and caregivers' preferences for risk communication. METHODS: Interviews with patients and caregivers of patients prescribed REMS-covered drugs focused on REMS materials. Transcripts were coded manually, with answers to closed-ended questions tabulated in Excel. RESULTS: The study included 43 patients and six caregivers across eight REMS-covered drugs: alemtuzumab, ambrisentan, clozapine, isotretinoin, lenalidomide, pegvaliase, pomalidomide, and sodium oxybate. Most participants were female (N = 42, 86%), white/non-Hispanic (N = 40, 82%), and college educated (N = 37, 76%). The average age was 40 years, with 27 (55%) having annual family incomes over $100,000. Most participants learned about REMS-covered drugs via printed information (N = 36, 73%), mostly REMS materials; conversations with providers about drug risks and benefits (N = 29, 59%); and websites found on their own (N = 42, 86%). Nearly all participants (N = 47, 96%) felt well-informed about drug risks and benefits, and most participants taking self-administered drugs (N = 28, 67%) reported understanding safe use "very well." However, knowledge gaps emerged around REMS-related risks and reasons for safe use measures; some participants misunderstood REMS enrollment forms as legal protections, not safety measures. Patients also widely varied in their valuations of REMS materials, with some feeling informed and empowered and others confused or intimidated. Preferences for risk communication varied; most participants (N = 36, 73%) wanted to receive information verbally from providers, with several wanting visual aids, summaries, and other resources. DISCUSSION: Gaps in patients' and caregivers' understanding of REMS programs and drug risks highlight the merits of reviewing communication materials and strategies. Clear, concise, and comprehensive educational documents could promote understanding and adherence to REMS requirements.
Medications Associated with Increased Risk of Hypoglycemia in Older Adults on Sulfonylureas: A High-Throughput Case-Crossover-Based Screening Study.
Bea S, Patorno E, Hahn G … +3 more , Paik JM, Wexler DJ, Bykov K
Drug Saf · 2026 Apr · PMID 41307830 · Full text
BACKGROUND: Sulfonylureas (SU) are widely used for diabetes management in older adults but can cause hypoglycemia, which may be worsened by drug interactions. We applied high-throughput data mining to identify medication...
BACKGROUND: Sulfonylureas (SU) are widely used for diabetes management in older adults but can cause hypoglycemia, which may be worsened by drug interactions. We applied high-throughput data mining to identify medications that could increase hypoglycemia risk when taken with SU. METHODS: Using Medicare, MarketScan, and Optum Clinformatics (2003-2022), we identified patients aged ≥ 65 years who experienced a severe hypoglycemic event after at least 90 days on SU. We evaluated all medications dispensed in the 90 days before the event using a case-crossover (CCO) design. We adjusted for time-varying confounding and direct effect of the evaluated medications (precipitant) using a case-case time-control (CCTC) approach and metformin as control. We computed odds ratios (ORs) for its association with hypoglycemia. The false discovery rate (FDR) was controlled at 0.05 to adjust for multiple testing. To reduce confounding from other diabetes medications, we analyzed non-diabetes and diabetes medications separately. RESULTS: Among 1607 candidate drugs received before experiencing hypoglycemia, 86 non-diabetes medications showed a CCO OR ≥ 1.00. With metformin as control, sulfamethoxazole/trimethoprim (CCTC OR 1.76, p < 0.01, FDR q < 0.01) and metronidazole (CCTC OR 2.17, p < 0.01, FDR q = 0.04) were associated with severe hypoglycemia. Among 10 diabetes medications, insulin showed increased association (CCO OR 1.22, p < 0.01); however, once adjusted for the drug's direct effects, CCTC OR was 1.03 (p = 0.47, FDR q = 0.47). CONCLUSIONS: Using a high-throughput data mining approach, we identified two antibiotics (sulfamethoxazole/trimethoprim and metronidazole) that may increase hypoglycemia risk in older adults on sulfonylureas. Given the exploratory nature of this study, these findings warrant further investigation.
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