Drug Safety[JOURNAL]
Sun
200 papers
Health Information Exchanges (HIEs) as Novel Sources for Population-Based Post Marketing Surveillance of Medical Products: A Pilot Study from the FDA Sentinel Innovation Center.
Khurshid A, Kendrick D, Pillai HS … +12 more , Sun J, Oliveira E, Jaquish A, Dutcher SK, Bright P, Wang Y, Li J, Austin T, Heagerty PJ, Matheny ME, Schneeweiss S, Desai RJ
Drug Saf · 2026 Apr · PMID 41975169 · Publisher ↗
INTRODUCTION: Health information exchanges (HIEs) provide the capability to electronically move health care information among different health care information systems and store these data for downstream use cases. Howev...
INTRODUCTION: Health information exchanges (HIEs) provide the capability to electronically move health care information among different health care information systems and store these data for downstream use cases. However, use of data from HIEs for postmarketing surveillance of medical products has not previously been explored. OBJECTIVES: To conduct a pilot descriptive study characterizing data from MyHealth Access Network, a statewide HIE for Oklahoma, to understand its utility for conducting pharmacoepidemiology studies. MATERIALS AND METHODS: MyHealth Access Network connects 95% of all hospital activity, 100% of federally qualified health center activity, and most community behavioral health clinics, tribal health systems, and independent providers in the state. As a use case to understand data in MyHealth Access Network, we characterized patients aged ≥18 years with type 2 diabetes mellitus (T2DM), and treated with one of two common antidiabetic drug classes: sodium-glucose co-transporter 2 inhibitors (SGLT-2i) and dipeptidyl peptidase 4 inhibitors (DPP-4i) in a new user cohort design. A cohort entry date was defined based on records of medication initiation for either of the two drug classes, using dispensing data from insurance claims (when available) or prescribing data from electronic health records (EHRs) when claims were not available. Patient characteristics including demographics, comorbidities, comedications, clinical and lifestyle-related factors, and healthcare utilization factors were summarized for the two exposure groups. RESULTS: A total of 65,225 DPP-4i initiators and 98,863 SGLT-2i initiators met our inclusion criteria. The mean age was around 60 years and nearly half were women in both the groups. While there was a large proportion of those with unknown race information (31% DPP-4i, 24% SGLT-2i), the majority were White (47% DPP-4i, 57% SGLT-2i). The second most reported race category was American Indian or Alaskan Natives (15% DPP-4i, 10% SGLT-2i), which is in line with their representation in the 2024 US Census for Oklahoma. Hemoglobin A1c (HbA1c) results were available for 68% and 67% of the DPP-4i and SGLT-2i groups with mean ± SD of 8.0± 2.0% and 8.1 ± 1.9%, respectively. Serum creatinine was recorded for 72% DPP-4i and 71% SGLT-2i initiators with mean ± SD of 1.2 ± 0.8 mg/dL and 1.1 ± 0.5 mg/dL, respectively. DISCUSSION: Health information exchanges may offer a promising resource that can contribute to population-based postmarketing surveillance of medical products infrastructure owing to their longitudinal capture of information across various healthcare settings.
Reliability of Self-Reported Maternal Health and Mother-Infant Outcome Data in Web-Based Questionnaires.
Sillis L, Van Mechelen L, van Gelder MMHJ … +10 more , Lenie S, Allegaert K, Bogaerts A, De Vos M, Hompes T, Smits A, Van Calsteren K, Verbakel JY, Foulon V, Ceulemans M
Drug Saf · 2026 Apr · PMID 41963694 · Publisher ↗
OBJECTIVES: The BELpREG registry in Belgium collects self-reported real-world data on perinatal medication use and mother-infant outcomes. Given the importance of self-reported data for pregnancy safety studies, this stu...
OBJECTIVES: The BELpREG registry in Belgium collects self-reported real-world data on perinatal medication use and mother-infant outcomes. Given the importance of self-reported data for pregnancy safety studies, this study aims to assess the reliability of maternal health and mother-infant outcome data reported in BELpREG. METHODS: We compared self-reported maternal health and mother-infant outcomes in the BELpREG registry with medical record data from gynaecologists, general practitioners, and midwives. Participants included pregnant women enrolled in BELpREG, aged 18 years or older, who delivered between November 2022 and April 2024 and had medical record data provided by at least one healthcare professional (HCP). Comparisons for continuous variables such as pre-pregnancy body mass index (BMI), gestational age at delivery, and infant metrics at birth were analysed using intraclass correlation coefficients (ICCs). For dichotomous and categorical variables, including pregnancy complications, delivery characteristics, and hospital admissions, we used Cohen's Kappa and observed proportions of positive and negative agreement. RESULTS: This study included 175 participants with available medical record data. Medical records were mostly returned by gynaecologists (40%) and midwives (25.7%). Reliability was high for pregnancy complications, onset, and mode of delivery. Gestational age showed almost perfect concordance (ICC 0.99). Infant outcomes, including birth metrics and Apgar scores, were highly reliable (ICC > 0.90), with almost perfect categorisation into birth weight percentiles (Cohen's Kappa 0.97). Self-reported maternal BMI exhibited moderate reliability as a continuous measure (ICC 0.75), but almost perfect agreement when categorised (Cohen's Kappa 0.89). The low prevalence of hospital admissions, delivery complications, infant complications, postpartum complications, and birth defects limited the assessment of these outcomes. CONCLUSIONS: The BELpREG registry demonstrated high agreement between self-reported and HCP-reported data for most maternal health and mother-infant outcomes, supporting its use in future pregnancy safety studies.
Giant Cell Arteritis Following COVID-19 Vaccination: A Consumer-Stimulated Analysis.
Shetty AN, Mallard JH, Hennessy D … +4 more , Wood N, Clothier HJ, Buttery JP, SAFESIG–GP Primary Health Network (PHN) Collaboration Group
Drug Saf · 2026 Jun · PMID 41961244 · Full text
INTRODUCTION: Giant cell arteritis (GCA) is an immune-mediated vasculitis of large and medium arteries, mainly affecting older adults. Prompted by a consumer concern, a few spontaneous reports after coronavirus disease 2...
INTRODUCTION: Giant cell arteritis (GCA) is an immune-mediated vasculitis of large and medium arteries, mainly affecting older adults. Prompted by a consumer concern, a few spontaneous reports after coronavirus disease 2019 (COVID-19) vaccination and Australian regulator signal, we investigated a possible association between GCA and vaccination. METHODS: This study analysed multiple data sources from January 2021 to September 2024. We reviewed spontaneous GCA reports submitted to the statewide vaccine safety service, Surveillance of Adverse Events following Vaccination in the Community (SAEFVIC), and applied self-controlled case series (SCCS) to two large Australian healthcare datasets [general practice (GP) and linked hospital data]. SCCS used a 1-42-day risk window, stratified by vaccine type, age, and sex. Incident GCA cases were identified via keyword matching and diagnostic codes [Systematized Nomenclature of Medicine Clinical Terms (SNOMED-CT)/International Classification of Diseases Tenth Revision, Australian Modification (ICD-10-AM)]. RESULTS: Six cases of GCA were spontaneously reported, four with onset within 42 days postvaccination, all following the adenoviral vectored Vaxzevria® {reporting rate 0.10 [95% confidence interval (CI) 0.03-0.27]}. The proportional reporting ratio signal detection method did not indicate a safety signal. Of 2700 incident cases of GCA identified across primary and hospital care datasets, 293 occurred within 42 days of COVID-19 vaccination. There was no increased risk of GCA following COVID-19 vaccination in either dataset [GP relative incidence (RI): 0.96 (95% CI 0.76, 1.21); hospital RI: 0.79 (95% CI 0.68, 0.91)], including by vaccine type, age, or sex. CONCLUSIONS: Using three Australian data sources, this study found no increase in GCA presentations within 6 weeks of COVID-19 vaccination. These consumer-stimulated findings support informed decisions, strengthen vaccine safety evidence, and help clinicians counsel patients.
Short-Term and Long-Term Safety Analyses of Brexpiprazole for Agitation Associated with Dementia due to Alzheimer's Disease: Timing and Duration of Adverse Events.
Porsteinsson AP, Chumki SR, Wang D … +6 more , Such P, Palma AM, Zhang Z, Shah A, Kalu U, Montano CB
Drug Saf · 2026 Apr · PMID 41961243 · Publisher ↗
INTRODUCTION: Agitation symptoms are a common and burdensome aspect of Alzheimer's dementia. Historically, agitation has been managed using off-label treatments such as atypical antipsychotics, but this approach is assoc...
INTRODUCTION: Agitation symptoms are a common and burdensome aspect of Alzheimer's dementia. Historically, agitation has been managed using off-label treatments such as atypical antipsychotics, but this approach is associated with safety concerns in older, more vulnerable patients. Brexpiprazole is an atypical antipsychotic that has been recently approved in several countries for the treatment of agitation associated with dementia due to Alzheimer's disease. Previous analyses show that brexpiprazole was efficacious and generally well tolerated for up to 24 weeks. Building upon previous work, this post hoc analysis aimed to evaluate the timing and duration of treatment-emergent adverse events (TEAEs) during brexpiprazole treatment. METHODS: In a 12-week analysis, data were pooled from three phase 3, randomized, double-blind, placebo-controlled trials of brexpiprazole in participants with agitation associated with dementia due to Alzheimer's disease. In a separate 24-week analysis, brexpiprazole data were combined from a 12-week randomized trial and a 12-week active-treatment extension trial. The median time from starting treatment to first reporting a TEAE and the median duration of all TEAEs were determined. RESULTS: A total of 1043 participants received at least one dose of trial medication. Over 12 weeks, brexpiprazole 2 or 3 mg/day (the approved therapeutic dosages in the United States, N = 366) compared to placebo (N = 388) had similar time to first TEAE (32 days and 28 days, respectively), similar duration of all TEAEs (6 days and 4 days), and longer time to discontinuation due to adverse events (47 days and 30 days). Over 24 weeks (N = 163), the time to first TEAE on brexpiprazole 2 or 3 mg/day was 52 days, and the duration of all TEAEs was 3 days. Among participants who did not report a TEAE in the 12-week parent trial, TEAEs were rare throughout the 12-week extension trial. CONCLUSIONS: These exploratory analyses reinforce that brexpiprazole is generally well tolerated over 12 weeks, and also over 24 weeks among patients who tolerated the first 12 weeks of treatment. The results provide a practical clinical insight into the safety of brexpiprazole over time in patients with agitation associated with dementia due to Alzheimer's disease. TRIAL REGISTRATION: Post hoc analysis of NCT01862640, NCT01922258, NCT03548584, NCT03594123 (ClinicalTrials.gov).
Estimating the Prevalence of Prescribed Medication Use in Pregnancy with a Systematic Review and Meta-analysis.
Sullivan C, Kerr A, Cahill M … +4 more , Flynn AC, O'Shaughnessy F, Cleary B, Bennett K
Drug Saf · 2026 Apr · PMID 41922857 · Publisher ↗
INTRODUCTION: Medication use in pregnancy is common, but decisions balancing the needs of maternal and fetal health can be complex. Ongoing monitoring of medication use in pregnancy is essential to ensure their continued...
INTRODUCTION: Medication use in pregnancy is common, but decisions balancing the needs of maternal and fetal health can be complex. Ongoing monitoring of medication use in pregnancy is essential to ensure their continued safe and appropriate use in this population. OBJECTIVE: The aim of this review is to estimate the prevalence of prescribed medication use in pregnancy. METHODS: This review was carried out in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol was registered in the PROSPERO database (CRD42024533866). PubMed, Medline, Cinahl (EBSCO), APA PsychINFO (EBSCO), Embase (Ovid), Scopus, and Web of Science databases were systematically searched for relevant articles published from January 2010 to May 2025. Inclusion criteria specified that studies provided a value for prescribed medication use in the general population of pregnant women during part or all of the gestational period. Articles were independently dual screened, and relevant data were extracted and validated from included studies. Quality and bias of the studies were assessed using the Joanna Briggs Institute critical appraisal tool for prevalence studies. A narrative synthesis was conducted for all studies. A random-effects meta-analysis with logit transformation was used to pool prevalence estimates (95% confidence interval, CI) where sufficient studies defined medication use in a similar way. Cochran's Q, I, and τ were used to measure heterogeneity. RESULTS: A total of 13,416 unique articles were identified and screened. Seventy studies were included. The pooled prevalence for prescribed medication alone during pregnancy was 56% (CI 44-67%, p < 0.01, I = 100%, τ = 1.30), based on 23 studies and a population of 7.3 million. The pooled prevalence for prescribed medications alone for the first, second, and third trimesters was 31% (CI 22-40%, p < 0.01, I = 100%, τ = 0.65) from 14 studies, 30% (CI 21-42%, p < 0.01, I = 100%, τ = 0.56) from 9 studies, and 34% (CI 22-49%, p < 0.01, I = 100%, τ = 0.77) from 8 studies, respectively. The pooled prevalence for prescribed medications including prescribed vitamins and minerals was 83% (CI 75-89%, p < 0.01, I = 100%, τ = 1.66) based on 26 studies and a population of 4.9 million. For this more inclusive group, the pooled prevalence for the first, second, and third trimesters was 52% (CI 44-61%, p < 0.01, I = 100%, τ = 0.46) from 14 studies, 56% (CI 42-70%, p < 0.01, I = 100%, τ = 0.88), and 59% (CI 42-74%, p < 0.01, I = 100%, τ = 1.25) both from 10 studies, respectively. Methods used to estimate prevalence varied greatly owing to differences in the definition of prescribed medications, the measured exposure period, and the pregnancy outcomes included. CONCLUSIONS: From this review, it was evident that a large proportion of women use prescribed medications during pregnancy, but estimates vary greatly. A more standardized approach to studying medication use in pregnancy is needed to allow for consistent and standardised estimates that are comparable across populations.
A Scoping Review of Case-Level Causality Assessment Tools Developed Between 2008 and 2023; Strengths, Weaknesses and Potential Future Improvements.
Cooper D, Ansari MT, Aurelius T … +10 more , Bobbins A, Dhanda S, Gravel CA, Hauben M, Morris D, Morton K, Platt R, Van Puijenbroek E, Yeomans A, Davies M
Drug Saf · 2026 Mar · PMID 41910704 · Publisher ↗
BACKGROUND: Various approaches to causality assessment have been developed that generally fall into the following three categories; expert judgement/global introspection, algorithms or probabilistic/Bayesian methods (or...
BACKGROUND: Various approaches to causality assessment have been developed that generally fall into the following three categories; expert judgement/global introspection, algorithms or probabilistic/Bayesian methods (or a combination of these). Causality assessment tools (CATs) are designed to assess the likelihood that a medicine has caused an adverse event in a specific individual. OBJECTIVE: To provide an up-to-date assessment of existing CATs, the International Working Group on New Developments in Pharmacovigilance conducted a scoping review to identify CATs developed or updated between 2008 and 2023. The objective was to describe key components and strengths and weaknesses and to categorise CATs based on therapeutic area, clinical setting or patient population to support selection of the most appropriate tool within a specific context. We also discuss additional considerations for the assessment of adverse drug reactions seen with biologics. METHODS: Searches were conducted in Embase and MEDLINE and to identify relevant grey literature. Review articles that described CATs developed between 1 January, 2008 until 31 December, 2023 (including updates to pre-existing CATs) were included. The key components of each CAT identified were extracted in addition to its strengths, weaknesses and other performance characteristics. RESULTS: In total, 48 articles and 7 grey literature sources were eligible for inclusion; 18 CATs were identified, categorised as: global introspection (n = 1, 6%), algorithmic (n = 12, 67 %), hybrid (n = 4, 22%) and probabilistic (n = 1, 6 %). Algorithmic CATs included those for use in specific outcomes (severe cutaneous adverse reaction n = 1, drug-induced liver injury n = 4), or in specific populations/settings (paediatric n = 1, neonatal intensive care units n = 1). One CAT (World Health Organization tool for assessing adverse events following immunization, WHO-AEFI) was designed for use with vaccines. CONCLUSIONS: Causality assessment tools designed to assess certain outcomes, such as drug-induced liver injury and severe cutaneous adverse reaction, may benefit from the future inclusion of biomarkers as predictors of risk. For specific biologics, such as immune checkpoint inhibitors where there is a heightened risk of immune-mediated AEs, there may be a role for biomarkers to help identify immune checkpoint inhibitor-induced toxicity. Additional considerations for causality may include drug quality, potential for medication error and assessment of adherence to risk minimisation measures.
Guillain-Barré Syndrome Following Recombinant Zoster Vaccine in US Medicare Adults Age 65 Years or Older.
Dos Reis S, Chiang YY, Amill-Rosario A … +8 more , Lee H, Johnson A, Ryan K, Oraichi D, Seifert H, Yun H, Gamble S, Spence O
Drug Saf · 2026 Jul · PMID 41910703 · Full text
BACKGROUND AND OBJECTIVE: Pre- and post-marketing studies detected Guillain-Barré syndrome following recombinant zoster vaccine. This study evaluated new-onset Guillain-Barré syndrome following recombinant zoster vaccine...
BACKGROUND AND OBJECTIVE: Pre- and post-marketing studies detected Guillain-Barré syndrome following recombinant zoster vaccine. This study evaluated new-onset Guillain-Barré syndrome following recombinant zoster vaccine in older US adults. METHODS: Using the Medicare Chronic Condition Warehouse administrative data, we implemented a self-controlled risk interval case-only design with a 1- to 42-day risk window and a 43- to 84-day control window following recombinant zoster vaccine. Participants were Medicare beneficiaries aged ≥65 years who received at least one dose of the recombinant zoster vaccine two-dose regimen from 2018 to 2020. New-onset Guillain-Barré syndrome was identified using an algorithm requiring an International Classification of Disease, Tenth Revision diagnosis code of G61.0 in the primary position in an inpatient setting or in any other setting followed by an inpatient encounter within 7 days, with no Guillain-Barré syndrome in the preceding 365 days. Conditional Poisson regression models estimated the relative risk and 95% confidence intervals (CIs). We estimated the attributable risk and 95% CI. Sensitivity analyses examined dose-specific effects, 60- to 183-day dose spacing, and coronavirus disease 2019 and seasonality. RESULTS: Of 3,383,799 eligible participants, 75 experienced new-onset Guillain-Barré syndrome. The primary analysis detected a relative risk of 3.15 (95% CI 1.82, 5.68) and an attributable risk of 6.59 per 1,000,000 doses (95% CI 4.35, 7.96). The dose-specific analysis detected a relative risk of 5.33 (95% CI 2.59, 12.36) for dose 1. The coronavirus disease 2019 and seasonality analyses revealed an increased risk. Dose 2 and the 60- to 183-day dose spacing were not significant. CONCLUSIONS: The elevated risk of new-onset Guillain-Barré syndrome among US Medicare beneficiaries aged ≥65 years was detected after recombinant zoster vaccine dose 1 but not dose 2.
US Risk Evaluation and Mitigation Strategies with Elements to Assure Safe Use: A Longitudinal Analysis of REMS Modifications (2008-2022).
Morrato EH, Campagna EJ, LaCivita C … +1 more , Toyserkani GA
Drug Saf · 2026 Jul · PMID 41874837 · Full text
INTRODUCTION: Risk evaluation and mitigation strategies (REMS) are risk management healthcare interventions required by the US Food and Drug Administration (FDA) for certain prescription medicines with serious safety con...
INTRODUCTION: Risk evaluation and mitigation strategies (REMS) are risk management healthcare interventions required by the US Food and Drug Administration (FDA) for certain prescription medicines with serious safety concerns to protect public health and ensure that the benefits outweigh its risks. REMS are expected to evolve over a drug's lifecycle on the basis of new pharmacovigilance evidence and changing healthcare delivery context. OBJECTIVE: The aim of this study is to characterize the frequency and types of REMS modifications over time to inform health policy and pharmacovigilance practice. METHODS: A retrospective longitudinal case series study was conducted using publicly available data on program characteristics and change history from the FDA's public website (REMS@FDA). All REMS programs with elements to assure safe use (ETASU; N = 100) approved by the FDA between 1 January 2008 and 31 December 2022 were linked longitudinally into "REMS Classes" based on common drug class and/or moiety (N = 67). Median follow-up per program was 7.4 (interquartile range [IQR] 2.3-11.6) years after the index REMS approval. Type of REMS modification was coded and categorized as major or minor using the FDA's guidance to the industry. Frequency and type of modification and time to first major modification were assessed. RESULTS: The median number of new REMS Classes approved per year was four. In the last 5 years of observation (2017-2022), REMS were being exclusively introduced concurrently with product approval. The median number of modifications per year per REMS class was 1.2 (IQR 0.7-1.6), representing 671 modifications and 364 unique dates. The median time to first modification was 15.4 (IQR 6.9-25.8) months and did not vary by when the index REMS was approved. Of the REMS classes, 96% (n = 64) had at least one modification by end of observation. As the cumulative number of REMS classes increased over time, modifications to approved REMS classes outpaced the approval of new REMS classes 17:1. The most common types of modifications were changes to REMS goals and/or design (n = 221) and changes to REMS materials (n = 167). However, no clear patterns were observed to suggest a specific type of early modification was more common than another. Among the 32 REMS classes approved in the first 5 years following the FDA Amendments Act of 2007 (FDAAA; 2008-2012), approximately one half (n = 14) had evolved to a shared system REMS by end of observation and one third (n = 10) had been released (median time to release 7.0 years, IQR 4.7-7.2 years). CONCLUSIONS: REMS modifications were common and demonstrated responsiveness to new evidence about the drug and adaptation to changing patterns of healthcare delivery within a learning health system.
International Society of Pharmacovigilance Advances over Time: Strategies and Results of the Advisory Board from 2022 to 2025.
Caro-Rojas A
Drug Saf · 2026 May · PMID 41874836 · Publisher ↗
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Disseminated Intravascular Coagulation Following Idarucizumab and Andexanet Alfa: Assessment of a Signal of Disproportionate Reporting From the Food and Drugs Administration Adverse Event Reporting System (FAERS) Database.
Roberto G, Parmeggiani L, Flaccavento A … +5 more , Vannacci A, Mannaioni G, Gini R, Virgili G, Tuccori M
Drug Saf · 2026 Jun · PMID 41865355 · Full text
BACKGROUND: Idarucizumab and andexanet alfa are licensed for the emergency reversal of the antithrombotic effect of direct oral anticoagulants (DOAC). Given their recent commercialization and rare use in clinical practic...
BACKGROUND: Idarucizumab and andexanet alfa are licensed for the emergency reversal of the antithrombotic effect of direct oral anticoagulants (DOAC). Given their recent commercialization and rare use in clinical practice, current evidence on rare thromboembolic adverse events following idarucizumab or andexanet alfa administration is insufficient to draw definitive conclusions. OBJECTIVE: The aim of this study was to perform a signal detection analysis based on data from a large spontaneous reporting database to identify possible safety signals concerning rare, serious and unexpected thromboembolic events reported following the administration of idarucizumab and andexanet alfa, respectively. METHODS: A disproportionality analysis was performed based on Individual Case Safety Reports (ICSRs) submitted from any US or non-US country between 2004 and 2022 to the FDA Adverse Event Reporting System (FAERS). A case/non-case approach was applied: cases were ICSRs containing the event of interest, non-cases were the remaining reports. The odds of exposure to idarucizumab and andexanet alfa, respectively, in cases versus non-cases was measured. Reporting odds ratio (ROR) and 95% confidence intervals (95% CI) were calculated for 434 Preferred Terms from three relevant sub-standardized MedDRA queries. Signals of disproportionate reporting (SDR) were drug-event pairs reported in three or more ICSRs, with the lower 95% CI of RORs > 1. SDRs corresponding to unexpected and biologically plausible drug-event pairs were selected for further evaluation through a case-by-case assessment. Original ICSRs, including case narratives, were obtained from the FDA. The WHO-UMC system for standardized case causality assessment was used to guide and classify the expert-based judgement of individual cases. RESULTS: A total of 11,561,146 ICSRs submitted to FAERS between 2004 and 2022 were analysed. Idarucizumab and andexanet alfa were listed as suspected drugs in 1463 and 399 reports, respectively. A total of 21 SDRs for idarucizumab and 19 for andexanet alfa were obtained. Eleven ICSRs containing the drug-event pair idarucizumab-disseminated intravascular coagulation (DIC) (ROR 14.5; 95% CI 8.0-26.3) and four containing andexanet-alfa-DIC (ROR 19.4; 95% CI 7.2-51.9) were selected for case-by-case assessment. Two additional andexanet-alfa-DIC ICSRs submitted in 2023 were identified using the FAERS Public Dashboard, although one was a duplicate. Nine of the 11 for idarucizumab and four of the five for andexanet alfa were original ICSRs with a case narrative available. Age was reported in ten idarucizumab cases (mean 79 years) and four andexanet alfa cases (mean 71 years). Nine idarucizumab cases and four andexanet alfa cases were fatal. Causality was judged 'possible' for five idarucizumab cases and three andexanet alfa cases which occurred within 1 day from administration. The remaining ICSRs were classified as 'unlikely' or 'conditional/unclassifiable'. CONCLUSIONS: The disproportionality analysis of the FAERS allowed us to highlight the associations between idarucizumab-DIC and andexanet-alfa-DIC, which might otherwise have remained unobserved due to the rarity of DIC and the low utilization of idarucizumab and andexanet alfa. Although the case-by-case evaluation was limited by the intrinsic indication bias, a causal link remained possible in those cases that occurred soon after administration. Since DIC is a life-threatening and often fatal condition, further investigation is warranted while close follow-up of high-risk patients may be considered to promptly detect any sign of coagulopathy following the administration of DOAC reversal agents. Any such observed adverse events should be reported to the relevant pharmacovigilance system in a timely manner.
International Medicinal Product Information Documents: A Quantitative Content Analysis of Instructions for Preventing, Mitigating, and Monitoring Adverse Drug Reactions.
Sartori D, Fusaroli M, Aronson JK … +2 more , Norén GN, Onakpoya IJ
Drug Saf · 2026 Mar · PMID 41863710 · Publisher ↗
INTRODUCTION: Medicinal product information documents (PIDs) detail clinical characteristics and instructions for monitoring, preventing, and mitigating adverse drug reactions (ADRs). They vary across countries, but ther...
INTRODUCTION: Medicinal product information documents (PIDs) detail clinical characteristics and instructions for monitoring, preventing, and mitigating adverse drug reactions (ADRs). They vary across countries, but there have been no recent international comparisons. We have therefore quantified and compared the completeness of the information given in drug labelling from different countries. METHODS: From the websites of 35 regulatory agencies, we retrieved the PIDs of medicinal products that were involved in signals communicated by regulators in 2014-2019. We developed a data extraction framework based on the Dose-relatedness, Time course, Susceptibility (DoTS) clinical classification of ADRs and used its implications for prevention and mitigation to score the completeness of related instructions in PIDs. To extract and classify monitoring instructions, we used a modified Systematic Instructions for Monitoring (SIM) method. PIDs had sufficiently complete instructions for prevention when the DoTS score was ≥ 5/12, and sufficiently complete monitoring instructions when the SIM score was ≥ 3/6. We used proportions of PIDs having a score ≥ 1 to determine the relative availability of clinical characteristics or instructions in a country, compared with all other countries. We quantified their pairwise disagreements using Jaccard's distance and identified clusters with similar patterns of completeness using agglomerative hierarchical clustering. RESULTS: PIDs were available on the websites of 18 of 35 regulatory agencies. They concerned 364 distinct medicinal products, which were involved in 627 signals. Across all countries, the instructions for prevention or mitigation met sufficient completeness for a median of 30% of PIDs (IQR 28-33%), while instructions for monitoring were sufficiently complete for a median of 22% (IQR 19-25%). The information given by the European Union (EU) and Canada had the highest relative availability of clinical characteristics and prevention or mitigation instructions, with a proportion of 0.86. Canadian and EU PIDs also had the highest relative availability of monitoring instructions, with proportions of 0.79 and 0.70. Two clusters of countries showed low disagreements: Malaysia and Singapore; Australia and New Zealand. CONCLUSIONS: This study suggests that PIDs often do not contain complete instructions for prevention, mitigation, and monitoring of ADRs. Extending existing regulatory cooperation globally would enable regulators to access clinical characteristics and instructions from different regions.
Strengthening Pharmacovigilance in Latin America: Multidisciplinary Insights from Two ISoP Latin American Chapter Symposia.
Vargas-Neri JL, Caro-Rojas A, Castañeda-Hernández G … +18 more , Cuello-Meza CC, Duarte B, Fontana D, Galicia-Quintanar C, Hall-Ramírez V, Salas D, Salas M, Segura-Uribe JJ, Tarapues M, Zuluaga-Arias HP, Aceves-González C, Bautista-Arteaga J, Carreño-Quintero W, Daza-Paz D, González-Achury DM, Ramírez-Pedreros RA, Galvis-Sánchez DA, Terán-Mercado LD
Drug Saf · 2026 Mar · PMID 41863709 · Publisher ↗
Pharmacovigilance in Latin America has witnessed notable progress in recent years, marked by advancements in regulatory frameworks, regional cooperation, and increased academic involvement. However, heterogeneity among c...
Pharmacovigilance in Latin America has witnessed notable progress in recent years, marked by advancements in regulatory frameworks, regional cooperation, and increased academic involvement. However, heterogeneity among countries, uneven institutional development, and limited resources still hinder its full impact on public health. In this context, the Latin American Chapter of the International Society of Pharmacovigilance (ISoP LATAM) has played a key role in organizing two regional symposia: Cartagena, Colombia (2023), and Merida, Mexico (2025). Through multidisciplinary roundtables and open forums, ISoP LATAM has brought together regulators, academia, healthcare professionals, researchers, patient organizations, and industry representatives to promote dialogue, identify opportunities, and propose measures to improve pharmacovigilance in the region. Discussion included regulatory harmonization and convergence, the adoption of international standards for risk management and safety reporting, and the integration of artificial intelligence and real-world evidence into pharmacovigilance systems. Participants emphasized the importance of addressing medication errors through a Human Factors/Ergonomics approach, strengthening the monitoring and regulation of biosimilars, and creating differentiated frameworks for recognizing therapeutic failures. The expansion of pharmaceutical care and the systematic inclusion of pharmacovigilance education across the health sciences' curriculum were highlighted as priorities. The reflections from these symposia emphasize the crucial role of ISoP LATAM in providing a platform for open and multidisciplinary discussions. Shifting the focus from solely regulatory topics to a broader public health perspective and expanding the agenda to include emerging fields such as pharmacogenomics, ecopharmacovigilance, and patient engagement-while ensuring fair access to technological innovations-will be vital for enhancing drug safety in Latin America.
Liver Safety of the Dual Neurokinin-1/-3 Receptor Antagonist Elinzanetant.
Lewis JH, Andrade RJ, Larrey D … +5 more , Horsmans Y, Anderson RA, Trajanovic M, Groettrup-Wolfers E, Zuurman L
Drug Saf · 2026 Mar · PMID 41849128 · Publisher ↗
BACKGROUND: Elinzanetant is a selective dual neurokinin (NK)-1/-3 receptor antagonist for the treatment of moderate-to-severe vasomotor symptoms associated with menopause or caused by endocrine therapy. Elinzanetant has...
BACKGROUND: Elinzanetant is a selective dual neurokinin (NK)-1/-3 receptor antagonist for the treatment of moderate-to-severe vasomotor symptoms associated with menopause or caused by endocrine therapy. Elinzanetant has been approved by health authorities in several countries. The occurrence of elevated liver enzymes has been observed in clinical use with NK-3 receptor antagonists, e.g., fezolinetant and pavinetant, with recommendations for liver monitoring in the fezolinetant labeling information. Therefore, a thorough evaluation of the liver safety data from clinical trials with elinzanetant was undertaken. OBJECTIVE: To summarize available hepatic safety data from the clinical development program of elinzanetant. METHODS: The potential risk of drug-induced liver injury (DILI) associated with elinzanetant was evaluated on the basis of the analysis of 24 phase 1 studies, three phase 2 studies (RELENT-1, SWITCH-1, NIRVANA), and four randomized, placebo-controlled phase 3 studies (OASIS 1‒4). Liver safety assessments were conducted throughout the studies as per protocol. In the phase 3 studies, a liver safety monitoring board (LSMB) performed an independent and blinded review of cases meeting close liver observation criteria, in alignment with US Food and Drug Administration DILI Guidance and the Council for International Organizations of Medical Sciences 2020 consensus on DILI. An independent data and safety monitoring board monitored the general safety of the participants. RESULTS: In the clinical program (phases 1‒3), there was no imbalance between the elinzanetant and placebo groups in alanine aminotransferase (ALT) elevations up to 5×, 10×, or 20× the upper limit of normal (ULN). In the pooled studies that included postmenopausal women, during weeks 1‒52 of treatment, ALT or aspartate transaminase (AST) elevations ≥ 3× ULN were observed in 1.2% of participants treated with elinzanetant 120 mg and in 1.0% of participants treated with placebo. In addition, there were no cases meeting Hy's law, and no indication of cholestatic injury. The LSMB assessed two cases on elinzanetant (2 out of 1697 participants, 0.12%) and one case on placebo (1 out of 1028, 0.10%) as probably related to study drug. For the cases on elinzanetant, one participant had a peak ALT level 7.4× ULN and the other had a peak ALT 3.5× ULN. Alkaline phosphatase and total bilirubin levels remained within reference range; both cases were mild and reversible. The peak ALT for the participant on placebo was 3.6× ULN. No case was classified as highly likely or definite. CONCLUSIONS: The aggregated phase 1‒3 clinical data, supported by preclinical toxicology and individual case adjudications of participants with elevated liver enzymes, suggest that there is a low risk of liver toxicity for elinzanetant. On the basis of these data, liver test monitoring was considered unnecessary in clinical practice by the LSMB (video abstract available online). Supplementary file2 (MP4 73923 KB).
9 ISoP Intelligent Automation Boston Seminar: From Innovation to Impact. Building Trustworthy AI in Pharmacovigilance 4-5 December 2025 | Cambridge, USA & Virtual.
Aimer O, Hammad TA, Petracek J … +4 more , Fouda M, Caro-Rojas A, Bate A, Kugener VF
Drug Saf · 2026 Jun · PMID 41843291 · Publisher ↗
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Critical Appraisal of Artificial Intelligence for Rare-Event Recognition: Principles and Pharmacovigilance Case Studies.
Norén GN, Meldau EL, Ellenius J
Drug Saf · 2026 Jul · PMID 41811678 · Full text
Many high-stakes artificial intelligence (AI) applications target low-prevalence events, where apparent accuracy can conceal limited real-world value. Relevant AI models range from expert-defined rules and traditional ma...
Many high-stakes artificial intelligence (AI) applications target low-prevalence events, where apparent accuracy can conceal limited real-world value. Relevant AI models range from expert-defined rules and traditional machine learning to generative large language models (LLMs) constrained for classification. As the effort and expertise required to develop modern AI decrease, there is a risk that organizations devote too little time to understanding their limitations and sources of error. We outline key dimensions for critical appraisal of AI in rare-event recognition, including problem framing and test set design, prevalence-aware statistical evaluation, robustness assessment, and integration into human workflows. In addition, we propose an approach to structured case-level examination (SCLE), to complement statistical performance evaluation, and a set of considerations to guide procurement or development of AI models for rare-event recognition. We instantiate the framework in pharmacovigilance, drawing on three studies: rule-based retrieval of pregnancy-related reports, duplicate detection combining machine learning with probabilistic record linkage, and automated redaction of person names using an LLM. We highlight pitfalls specific to the rare-event setting including optimism from unrealistic class balance and lack of difficult positive controls in test sets-and show how cost-sensitive targets align model performance with operational value. While grounded in pharmacovigilance practice, the principles generalize to domains where positives are scarce, and error costs may be asymmetric.
Maternal and Pediatric Use of Vaccines for Mpox: A Living Systematic Review and Meta-analysis of Safety and Effectiveness.
Ciapponi A, Ballivian J, Berrueta M … +15 more , Sambade JM, Castellana N, Bardach A, Brizuela M, Caravario J, Comande D, Couto E, Mazzoni A, Parker E, Salva F, Stegelmann K, Xiong X, Stergachis A, Munoz FM, Buekens P
Drug Saf · 2026 Jul · PMID 41792577 · Full text
BACKGROUND: Mpox is a re-emerging zoonotic infection caused by an Orthopoxvirus closely related to smallpox. The 2022-23 global outbreak prompted rapid use of vaccinia-based vaccines, historically developed for smallpox...
BACKGROUND: Mpox is a re-emerging zoonotic infection caused by an Orthopoxvirus closely related to smallpox. The 2022-23 global outbreak prompted rapid use of vaccinia-based vaccines, historically developed for smallpox and those of the latest generation used for mpox prevention. Assessing their safety and effectiveness in pregnant persons and children is critical to guide policies protecting populations at an elevated risk of severe illness. OBJECTIVE: This study assessed the safety and effectiveness of mpox and historical smallpox vaccines, administered during pregnancy and childhood. METHODS: We conducted a living systematic review and meta-analysis (PROSPERO CRD42024591322/CRD42024586205) following Cochrane, World Health Organization, and Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) standards. We searched biweekly across major databases, trial registries, preprints, and gray literature (inception to September 2025) for studies evaluating the safety and effectiveness of vaccinia-based smallpox vaccines, including historical (first- and second-generation) and modern (third-generation) vaccines, in maternal and pediatric populations. Reviewers independently conducted study selection, data extraction, and risk-of-bias assessment. Meta-analyses employed random-effects models, and results are presented through an interactive dashboard and a living platform. RESULTS: We included 27 clinical studies (1949-2025), involving 1,406,771 children/adolescents (eight studies) and 11,482 pregnant persons (19 studies). Most maternal data came from first-generation vaccines (Lister, Finnish, Dryvax, APSV). These vaccines were not associated with an increased risk of spontaneous abortion (risk ratio [RR] 1.02, 95% confidence interval [CI] 0.70-1.48), stillbirth (RR 1.02, 95% CI 0.70-1.48), or preterm birth (RR 1.08, 95% CI 0.78-1.50), but were linked to a higher risk of congenital anomalies (RR 1.25, 95% CI 1.01-1.54). Fifty-two fetal vaccinia cases were reported globally up to 1978, with none since. Evidence on second- (ACAM2000) and third-generation (MVA-BN) non-replicating vaccines remains limited. In children, serious adverse events were rare, and MVA-BN caused only mild self-limiting reactions. No study assessed vaccine effectiveness in pregnant persons, while limited pediatric data suggested possible protection after post-exposure prophylaxis. CONCLUSIONS: Vaccinia-based vaccines appear generally safe in pregnancy and children. However, evidence on the safety and effectiveness of third-generation mpox vaccines is still scarce. High-quality prospective studies and strengthened pharmacovigilance are urgently needed to inform policy and clinical decision making.
Correction: 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 Jul · PMID 41790353 · Full text
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QT Prolongation Risk of Antibody-Drug Conjugates.
Xu XS, Sanghavi K, Feng S … +3 more , Liu S, Barrett J, Gupta M
Drug Saf · 2026 Jul · PMID 41772369 · Publisher ↗
Antibody-drug conjugates (ADCs) have emerged as an important therapeutic class in oncology, offering targeted delivery of potent cytotoxic agents to cancer cells, thereby reducing systemic toxicity. However, the potentia...
Antibody-drug conjugates (ADCs) have emerged as an important therapeutic class in oncology, offering targeted delivery of potent cytotoxic agents to cancer cells, thereby reducing systemic toxicity. However, the potential for cardiac toxicity, particularly QT interval prolongation, remains a critical safety concern during ADC development and clinical use. We review the mechanisms underlying ADC-induced QT prolongation, including payload-related direct ion channel interactions and indirect effects mediated by systemic exposure. By systematically examining clinical and preclinical data across ADC classes, including auristatins, maytansinoids, topoisomerase inhibitors, and DNA alkylators, we highlight the risk evaluation of 14 US Food and Drug Administration-approved ADCs, along with their regulatory review outcomes and labeling recommendations. Most approved ADCs appear to have a low corrected QT prolongation risk at therapeutic doses; clear signals are largely confined to inotuzumab and gemtuzumab ozogamicin, whereas auristatin-, maytansinoid-, and topoisomerase-1-based ADCs have shown minimal or no corrected QT changes. Regulatory approaches to ADC QT assessment are flexible and largely driven by payload novelty: novel payloads generally require comprehensive non-clinical testing and early dedicated QT studies, whereas established payloads can often rely on prior safety data, permitting extrapolation without new QT studies and use of pooled clinical data plus concentration-QT analyses when exposure and the linker-payload structure align with historical experience. Finally, we outline a practical framework for integrating translational and regulatory considerations for evaluating QT interval prolongation risk into the development of ADCs for patients with cancer, aiming to enhance cardiac safety for patients and improve the design of preclinical and clinical studies.
Genetically Informed Research Designs in Perinatal Pharmacoepidemiology: A Methodological Overview.
Carson AC, Zidan M, Olstad EW … +6 more , Gervin K, Galesloot TE, Scholte I, Ystrøm E, Nordeng H, van Gelder MMHJ
Drug Saf · 2026 Jul · PMID 41770489 · Full text
Despite the widespread use of medications during pregnancy, ethical and methodological barriers to clinical trials make observational studies necessary for evaluating medication safety in this population. Observational s...
Despite the widespread use of medications during pregnancy, ethical and methodological barriers to clinical trials make observational studies necessary for evaluating medication safety in this population. Observational studies are prone to biases that often limit their validity due to the lack of randomization; integrating genetic information through discordant sibling designs, polygenic scores, and Mendelian randomization can address several confounding issues. However, application of these three approaches in perinatal pharmacoepidemiology has been limited. Complementing traditional designs with these genetically informed research designs can tackle common biases and strengthen causal inference. This paper focuses on applying genetically informed research designs to child outcomes in perinatal pharmacoepidemiology by reviewing various methods, discussing their strengths and limitations, and examining their application to date, as well as considerations for implementing them in future research. Such considerations include the availability of genetic data, the complexity of integrating genetic data with existing epidemiological data, and selection of appropriate genetic instruments for analyses. Incorporating causal inference in perinatal pharmacoepidemiology can ultimately contribute to enhancing safe medication use during pregnancy.
The Evaluation of Transformer Models for the Detection of Adverse Drug Events: A Benchmark Study Using Dutch Free-Text Documents of Hospitalized Patients.
Murphy RM, Mishra N, de Keizer NF … +5 more , Dongelmans DA, Jager KJ, Abu-Hanna A, Klopotowska JE, Calixto I
Drug Saf · 2026 Jul · PMID 41723790 · Full text
INTRODUCTION: Adverse drug events (ADEs) are a leading cause of preventable patient harm in hospitals. Because they are often recorded only in clinical free-text documents, retrieval and quantification are significantly...
INTRODUCTION: Adverse drug events (ADEs) are a leading cause of preventable patient harm in hospitals. Because they are often recorded only in clinical free-text documents, retrieval and quantification are significantly limited. Automating ADE detection with natural language processing (NLP) is promising. Recent work shows that bidirectional encoder representations from transformers (BERT)-based models outperform bidirectional long short-term memory (Bi-LSTM) models and even larger generative pretrained transformers while being more computationally efficient. However, most ADE-NLP research focuses on the English language, often applies metrics less suitable for rare outcomes such as ADEs, and lacks external validation. OBJECTIVES: To evaluate four transformer models for the detection of ADEs by reusing Dutch clinical free-text documents and create a benchmark with realistic clinical scenarios, appropriate performance measures, and external validation. METHODS: We used three anonymized datasets: (1) Dutch ADE corpus with 102 densely annotated progress notes of patients admitted to the intensive care unit (ICU) from one Dutch academic hospital, (2) ICU AKI corpus with 411 sparsely annotated ICU notes from the same hospital, and (3) WINGS corpus with 100 discharge letters of internal medicine patients from two Dutch non-academic hospitals, labeled for ADE presence. A Bi-LSTM model and four transformer-based Dutch or multilingual encoder models (BERTje, RobBERT-base, MedRoBERTa.nl, NuNER) were trained for named entity recognition (NER) and relation classification (RC) using the Dutch ADE corpus. We used fivefold cross validation with 60%/20%/20% train/validation/test splits and performed hyperparameter tuning on the first fold for NER and across all folds for RC. We evaluated our ADE RC models internally using gold standard (two-step task) and predicted entities (end-to-end task). In addition, all models were externally validated using WINGS Corpus on detecting ADEs at the document level. We report both micro- and macro-averaged F1 scores, to account for ADE rarity. RESULTS: In our internal validation, MedRoBERTa.nl achieved the best performance, with macro-averaged F1 score of 0.63 using gold standard entities and 0.62 using predicted entities, while all models reached micro-averaged F1 scores ± 0.99. MedRoBERTa.nl also performed the best in our external validation, with recall range 0.67-0.74 using predicted entities (end-to-end task), meaning that between 67% and 74% of discharge letters with ADEs were detected. CONCLUSIONS: The Dutch domain-specific MedRoBERTa.nl showed the best performance in detecting ADEs in Dutch clinical texts, and in line with previous studies in English language settings, outperformed Bi-LSTM. The inclusion of external validation highlights its generalization potential. Our findings also underline the need for further model improvement and use of performance measures suited to rare outcomes such as ADEs, as micro-averaged F1 scores inflate performance compared with macro-averaged F1 scores. We provide a robust and clinically meaningful benchmark approach for NLP-based ADE detection in clinical free-text documents. Our approach can serve as a guidance for future NLP benchmarks in ADE domain.
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