Drug Safety[JOURNAL]
Sun
200 papers
Pharmacovigilance in the Community: A Special-Interest Group of the International Society of Pharmacovigilance.
Elhawary MA, Noss R, Alj L … +5 more , Younus M, Alkhakany M, Rostom H, Caro-Rojas A, Alshammari TM
Drug Saf · 2025 Mar · PMID 39779631 · Publisher ↗
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Drug-Induced Cognitive Impairment.
Reimers A, Odin P, Ljung H
Drug Saf · 2025 Apr · PMID 39718691 · Full text
Drug-induced cognitive impairment (DICI) is a well-established, yet under-recognised, complication of many types of pharmacological treatment. While there is a large body of scientific literature on DICI, most papers are...
Drug-induced cognitive impairment (DICI) is a well-established, yet under-recognised, complication of many types of pharmacological treatment. While there is a large body of scientific literature on DICI, most papers are about drug-induced dementia in the elderly and one specific drug class. However, DICI also comprises subclinical symptoms, domain-specific forms of cognitive impairment as well as mild cognitive impairment (MCI), and delirium. Even mild forms of DICI, if not recognised as such, can have deleterious and life-long consequences. In addition, DICI also occurs in younger adults and in children, and has been reported with many different drug classes. The aim of this review is to raise awareness of DICI by providing an overview on the type(s) and symptoms of observed DICI and the suspected underlying mechanism(s) for various drug classes: antiseizure medications, antidepressants, antiparkinsonian drugs, antipsychotics, lithium, benzodiazepines/Z-drugs, opioids, first-generation antihistamines, drugs for urinary incontinence, proton pump inhibitors, glucocorticoids, NSAIDs, statins, antihypertensives, and chemotherapeutic agents.
Advances in Drug Safety: Highlights from the 23rd Annual Meeting of the International Society of Pharmacovigilance.
Aimer O, Salas M, Hammad TA … +6 more , Mouchantaf R, Ilic K, Gossell-Williams M, Mehta U, Platt RW, Carleton B
Drug Saf · 2025 Mar · PMID 39692839 · Publisher ↗
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Use of Reporting Recommendation Intended for Pharmaceutical Risk Minimisation Evaluation Studies (RIMES) Checklist in Risk Minimisation/Mitigation Studies: A Review and Survey.
Duckworth SE, Druelles S, Brouwer E … +3 more , Brown DA, Hakkarainen KM, Guleria S
Drug Saf · 2025 Apr · PMID 39688763 · Publisher ↗
INTRODUCTION: The Reporting Recommendation Intended for Pharmaceutical Risk Minimisation Evaluation Studies (RIMES) checklist is endorsed by the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance...
INTRODUCTION: The Reporting Recommendation Intended for Pharmaceutical Risk Minimisation Evaluation Studies (RIMES) checklist is endorsed by the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) and is tailored for studies assessing Risk Minimisation Measures and Risk Evaluation and Mitigation Strategy (RMM/REMS) effectiveness; however, its awareness and usage remain unknown. We evaluated the implementation of the RIMES checklist in RMM/REMS effectiveness studies registered in the EUPAS register during 01 December 2017- 01 January 2024. Furthermore, the awareness and utilization of the RIMES checklist among researchers conducting RMM/REMS effectiveness studies was assessed. METHODS: The European Union Post-Authorisation Study (EUPAS) Register was reviewed to identify studies conducted in at least one European country within the specified timeframe. Data were extracted from the online EUPAS registrations, including uploaded study documents. Additionally, a survey was distributed through at International Society of Pharmacoepidemiology (ISPE) to assess awareness and checklist utilisation among researchers. Findings from both the review and the survey were reported descriptively. RESULTS: Among 44 studies included in the review, cross-sectional questionnaire-based surveys (n = 28, 64%), and retrospective cohort studies using secondary data (n = 13, 30%) were frequently used study designs. Oncology (n = 12, 27%) and pregnancy-related conditions (n = 7, 16%) were frequently reported therapeutic areas. Most studies were required by regulators and typically evaluated the additional RMM/REMS. The awareness and usage of the RIMES checklist was low, while the ENCePP checklist was used frequently. Some researchers considered the ENCePP checklist adequate for RMM/REMS studies, while few advocated for the RIMES checklist. CONCLUSION: The awareness and utilisation of the specific RIMES checklist designed for studies evaluating RMM/REMS was limited, indicating a need for improving awareness and utilisation of RIMES and harmonisation of existing guidance and frameworks for RMM/REMS effectiveness studies.
Post-licensure Safety Surveillance of 20-Valent Pneumococcal Conjugate Vaccine (PCV20) Among US Adults in the Vaccine Adverse Event Reporting System (VAERS).
Oliveira M, Marquez P, Ennulat C … +5 more , Blanc P, Welsh K, Nair N, Taminato M, Moro PL
Drug Saf · 2025 Mar · PMID 39666166 · Full text
BACKGROUND: On June 8, 2021, a new 20-valent pneumococcal conjugate vaccine (PCV20, PREVNAR 20, Pfizer, Inc.) was licensed for use in adults aged ≥ 18 years by the US Food and Drug Administration (FDA). OBJECTIVE: To des...
BACKGROUND: On June 8, 2021, a new 20-valent pneumococcal conjugate vaccine (PCV20, PREVNAR 20, Pfizer, Inc.) was licensed for use in adults aged ≥ 18 years by the US Food and Drug Administration (FDA). OBJECTIVE: To describe reports to the Vaccine Adverse Event Reporting System (VAERS) after administration of the 20-valent pneumococcal conjugate vaccine in adults. METHODS: We searched the VAERS for reports of adverse events involving persons aged ≥ 19 years who received PCV20 during October 20, 2021, through December 31, 2023. Our evaluation included automated analysis of reports, clinical review of serious reports and pre-specified events of special interest, empirical Bayesian data mining to assess for disproportionate reporting, and estimation of reporting rates for reports of Guillain-Barré syndrome (GBS). RESULTS: The VAERS received 1976 reports after PCV20 administration in persons aged ≥ 19 years (6% of reports involved serious events). The most common adverse events among persons aged 19-64 years (n = 798) were injection-site reactions (231, 29%), pain (134, 17%), erythema (118, 15%), and fever (117, 15%). For persons aged ≥ 65 years (n = 1178), the most common adverse events were injection-site reactions (417, 35%), pain (180, 15%), pain in extremity (162, 14%), and erythema (158, 13%). A data mining alert (EB05 = 3.812) for the MedDRA Preferred Term "Guillain-Barre syndrome" was observed for serious reports. Clinical review verified 11 of 20 GBS reports; 7/11 vaccine recipients were aged ≥ 65 years. Among the 11 verified cases, the median time from vaccination to symptom onset was 14 days. Five persons received another vaccine on the same visit. The reporting rate of GBS after PCV20 receipt was 0.5 cases per million doses distributed. No other safety concern was identified. CONCLUSIONS: During the period of this post-licensure review of PCV20, we found most reports were non-serious and comprised mostly local and systemic (e.g., fever) reactions consistent with prelicensure studies. In serious reports, we also identified a data mining alert for GBS after receipt of PCV20, which Centers for Disease Control and Prevention and the FDA are investigating further. No other new or unexpected safety concern was identified.
Prenatal and Early Childhood Exposure to Proton Pump Inhibitors and Antibiotics and the Risk of Childhood Cancer: A Nationwide Population-Based Cohort Study.
Gudnadottir U, Fransson E, Ljungman G … +4 more , Wikman A, Vlieghe E, Engstrand L, Brusselaers N
Drug Saf · 2025 Apr · PMID 39666165 · Full text
BACKGROUND: Our microbiome is established during infancy, a time important for later health and long-term effects. Proton pump inhibitors and antibiotics are regularly prescribed during pregnancy. Both drugs cause microb...
BACKGROUND: Our microbiome is established during infancy, a time important for later health and long-term effects. Proton pump inhibitors and antibiotics are regularly prescribed during pregnancy. Both drugs cause microbiome disturbance and have been associated with increased cancer risk in adults, but effects of these drugs on the growing foetus and infant remain understudied. AIM: The aim of this study is to study the association between prenatal and early life proton pump inhibitor and antibiotics exposure and the risk of childhood cancer. METHODS: This study is a retrospective population-based cohort design, using registry data on all births (n = 722,372) in Sweden between 2006 and 2016, according to the STROBE checklist. For women who had multiple children in the timeframe of the study, only the first child during the time period was included in the cohort. Exposure was defined as either ≥ 1 proton pump inhibitor or antibiotics prescription during pregnancy, or during the first 2 years of life. Outcome was defined as cancer at any time during the follow-up or cancer after the age of 2 years for early life exposure. Multivariable Cox proportional hazard models were used to calculate hazard ratios. RESULTS: In total, 1091 (0.2%) children were diagnosed with malignant cancer during the follow-up. Prenatal exposure to proton pump inhibitors and antibiotics were not associated with an increased risk of cancer. Regarding early life exposure, proton pump inhibitors were associated with an increased risk of cancer at age two or older (adjusted hazard ratio [aHR] 3.68, 95% confidence interval [CI] 2.24-6.06). CONCLUSIONS: We did not find evidence that prenatal proton pump inhibitors and antibiotics were associated with overall childhood cancer. However, proton pump inhibitors during early life were associated with an increased risk of childhood cancer, but indication on drug use was not available and confounding by indication may be present.
Performance and Reproducibility of Large Language Models in Named Entity Recognition: Considerations for the Use in Controlled Environments.
Dietrich J, Hollstein A
Drug Saf · 2025 Mar · PMID 39661234 · Full text
INTRODUCTION: Recent artificial intelligence (AI) advances can generate human-like responses to a wide range of queries, making them a useful tool for healthcare applications. Therefore, the potential use of large langua...
INTRODUCTION: Recent artificial intelligence (AI) advances can generate human-like responses to a wide range of queries, making them a useful tool for healthcare applications. Therefore, the potential use of large language models (LLMs) in controlled environments regarding efficacy, reproducibility, and operability will be of paramount interest. OBJECTIVE: We investigated if and how GPT 3.5 and GPT 4 models can be directly used as a part of a GxP validated system and compared the performance of externally hosted GPT 3.5 and GPT 4 against LLMs, which can be hosted internally. We explored zero-shot LLM performance for named entity recognition (NER) and relation extraction tasks, investigated which LLM has the best zero-shot performance to be used potentially for generating training data proposals, evaluated the LLM performance of seven entities for medical NER in zero-shot experiments, selected one model for further performance improvement (few-shot and fine-tuning: Zephyr-7b-beta), and investigated how smaller open-source LLMs perform in contrast to GPT models and to a small fine-tuned T5 Base. METHODS: We performed reproducibility experiments to evaluate if LLMs can be used in controlled environments and utilized guided generation to use the same prompt across multiple models. Few-shot learning and quantized low rank adapter (QLoRA) fine-tuning were applied to further improve LLM performance. RESULTS AND CONCLUSION: We demonstrated that zero-shot GPT 4 performance is comparable with a fine-tuned T5, and Zephyr performed better than zero-shot GPT 3.5, but the recognition of product combinations such as product event combination was significantly better by using a fine-tuned T5. Although Open AI launched recently GPT versions to improve the generation of consistent output, both GPT variants failed to demonstrate reproducible results. The lack of reproducibility together with limitations of external hosted systems to keep validated systems in a state of control may affect the use of closed and proprietary models in regulated environments. However, due to the good NER performance, we recommend using GPT for creating annotation proposals for training data as a basis for fine-tuning.
Call to action: Pharmaceutical residues in the environment: threats to ecosystems and human health.
Lunghi C, Valetto MR, Caracciolo AB … +22 more , Bramke I, Caroli S, Bottoni P, Castiglioni S, Crisafulli S, Cuzzolin L, Deambrosis P, Giunchi V, Grisotto J, Marcomini A, Moretti U, Murgia V, Pandit J, Polesello S, Poluzzi E, Romizi R, Scarpa N, Scroccaro G, Sorrentino R, Sundström A, Wilkinson J, Paolone G
Drug Saf · 2025 Apr · PMID 39656351 · Publisher ↗
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Trends in Proton Pump Inhibitor Use in Sweden by Sex and Age: A Drug Utilisation Study.
Brusselaers N, Gudnadottir U, Engstrand L … +1 more , Lilja HE
Drug Saf · 2025 Apr · PMID 39645619 · Full text
BACKGROUND: Proton pump inhibitors (PPIs) are among the most popular drugs worldwide. Yet, there are concerns on long-term safety and poor adherence to prescription guidelines. Off-label use in children and increasing ma...
BACKGROUND: Proton pump inhibitors (PPIs) are among the most popular drugs worldwide. Yet, there are concerns on long-term safety and poor adherence to prescription guidelines. Off-label use in children and increasing maintenance use in older adults may be particularly worrisome. OBJECTIVES: To assess differences in PPI use by age, sex calendar year and PPI type, and to explore potential underlying indications (ulcerogenic drugs, and indications) in Sweden. METHODS: Proton pump inhibitor drug utilisation study based on the Swedish nationwide prescribed drug (2006-2023) and patient registries (2006-2022). RESULTS: Proton pump inhibitors were used by 14.4% (women) and 10.5% (men) of adults; and 1.0-1.5% of children and adolescents (aged < 20 years). Proton pump inhibitor use was higher in women in all age-groups except small children (aged < 5 years). Proton pump inhibitor use has increased in all age groups, especially in young children (aged < 10 years) and the oldest groups (aged > 65 years). Proton pump inhibitor users aged > 85 years filled most prescriptions with an annual average of 9.5 (men), 11.6 (women) prescriptions. Most prescriptions were for omeprazole and esomeprazole: 63.7% and 23.5% in adults; 23.5% and 44.7% in children (2023). Prescriptions for other drugs for peptic ulcers/reflux became rare, with 99% of prescriptions in this category being PPIs by 2023. Gastro-intestinal diagnoses were predominantly recorded in men, became less prevalent and only explained part of PPI use, while ulcerogenic drugs were common (particularly in women), suggesting PPIs are regularly used for gastroprotection. CONCLUSION: Proton pump inhibitor use has doubled in children and increased 50% in adults over the study period, in both sexes, while recorded gastrointestinal indications decreased. Alternative therapies were rarely prescribed in Sweden.
Early Detection of Hearing Impairment Signals Post-mRNA COVID-19 Vaccination: A Disproportionality Analysis Study on French Pharmacovigilance Database.
Boulefaa D, Bagheri H, Salvo F … +7 more , Rabier MB, Geniaux H, Lepelley M, Rocher F, Mahe J, Grandvillemuin A, Thai-Van H
Drug Saf · 2025 Mar · PMID 39638989 · Full text
INTRODUCTION: Improving adverse events following immunisation (AEFI) detection is vital for vaccine safety surveillance, as an early safety signal can help minimize risks. In February 2022, the World Health Organization...
INTRODUCTION: Improving adverse events following immunisation (AEFI) detection is vital for vaccine safety surveillance, as an early safety signal can help minimize risks. In February 2022, the World Health Organization reported a preliminary signal on sudden sensorineural hearing loss (SSNHL) following coronavirus disease 2019 (COVID-19) vaccination, 54 million persons in France received at least one dose, covering 78.8% of the population within a year. OBJECTIVE: The primary objective of this study was to identify a method of disproportionality analysis capable to detect a safety signal for hearing impairment (HI) as early as possible during the initial phases of the COVID-19 vaccination campaign. Secondly, we described all cases of SSNHL reported during vaccine booster campaigns in France. METHODS: Data from January 2011 to February 2022 were extracted from the French pharmacovigilance database. Cases were all spontaneous reports of AEFI for elasomeran and tozinameran, while non-cases were AEFI reported for other vaccines. Disproportionality analysis for HI was performed monthly during 2021, to estimate a reporting odds ratio (ROR). Four different methods were used for ROR estimation. Furthermore, we reviewed cases of SSNHL following messenger RNA COVID-19 vaccinations reported during booster campaigns, from 2 February 2022 to 1 March 2023, based on a comprehensive medical evaluation. RESULTS: Using a standard methodology, we identified a signal on 31 July 2021 (ROR 1.50, 95% confidence interval [CI] [1.06-2.18]). Multivariate analysis adjusted for sex, age, ototoxic drugs and excluding reference reports of common AEFI for vaccines allowed us to detect the HI signal as early as 31 March 2021 (ROR 2.67, 95% CI [1.36-5.57]). The SSNHL reporting rate was estimated to be 0.83/1,000,000 doses for tozinameran and 4.3/1,000,000 for elasomeran during the booster campaigns. CONCLUSION: Using a well-structured disproportionality analysis could have enhanced early detection of safety signals and contribute to risk minimizing measures. According to descriptive data, HI following mRNA COVID-19 vaccines remains rare.
Prenatal Exposure to Proton Pump Inhibitors and Risk of Serious Infections in Offspring During the First Year of Life: A Nationwide Cohort Study.
Tisseyre M, Collier M, Beeker N … +3 more , Kaguelidou F, Treluyer JM, Chouchana L
Drug Saf · 2025 Mar · PMID 39630354 · Publisher ↗
INTRODUCTION AND OBJECTIVE: Proton pump inhibitor (PPI) use in children increases the risk of infections, prompting inquiry into the impact of prenatal PPIs exposure on serious infections in offspring. As a research gap...
INTRODUCTION AND OBJECTIVE: Proton pump inhibitor (PPI) use in children increases the risk of infections, prompting inquiry into the impact of prenatal PPIs exposure on serious infections in offspring. As a research gap in this area exists, this study aimed to address it by assessing the association between prenatal PPIs exposure and serious infections in infants during their first year of life. METHODS: Using the French health insurance data warehouse (SNDS) (2013-2018), we conducted a retrospective cohort study on singleton, full-term liveborn non-immunocompromised infants, stratified by PPI use during the first three months of life (early-life use). Proton pump inhibitor dispensing in ambulatory care settings during pregnancy defined exposure. Outcomes concerned any serious infections in offspring aged between 3 and 12 months. Adjusted odds ratios (aORs) were estimated using logistic regression with multivariable models to control for potential confounders. RESULTS: Of the 2,485,545 infants included, 497,060 (23.3%) were prenatally exposed to PPIs and 97,767 (4.6%) had PPI use during the first three months of life. Prenatal PPI exposure was associated with serious infections in offspring (aOR, 1.09 [95% CI, 1.07-1.10]) in infants without early-life PPIs use. No association was found for infants with early-life PPI use (aOR, 1.05 [95% CI, 1.00-1.11]). Gastrointestinal infections were the sole site with persistent significance. CONCLUSION: Prenatal PPI exposure is common and is not associated with a major risk of serious infections in infants during their first year. However, even after adjusting for several confounding factors, a weak association remains, especially in infants without early-life PPI use. While offering reassurance, adherence to clinical guidelines is still crucial.
Adverse Drug Events in Ambulatory Care: A Cross-Sectional Study.
Plasek JM, Amato MG, Salem A … +5 more , Foer D, Lipsitz S, Jackson GP, Bates DW, Zhou L
Drug Saf · 2025 Apr · PMID 39621298 · Full text
BACKGROUND: Adverse drug events (ADEs) are understudied in the ambulatory care setting. We aim to estimate the prevalence and characteristics of ADEs in outpatient care using electronic health records (EHRs). METHODS: Th...
BACKGROUND: Adverse drug events (ADEs) are understudied in the ambulatory care setting. We aim to estimate the prevalence and characteristics of ADEs in outpatient care using electronic health records (EHRs). METHODS: This cross-sectional study included EHR data for patients who had an outpatient encounter at an academic medical center from 1 October 2018 through 31 December 2019. We developed a stratified sampling strategy based on a comprehensive set of 994 ADE-related International Classification of Disease (ICD-10) codes to identify clinical encounters and notes likely to contain ADEs. Within each ICD-10 likelihood group, clinical notes were randomly sampled and annotated for present or possible ADE-drug relationships and severity. The overall estimated population prevalence of ADEs presenting in the outpatient setting was calculated. The generalizability of the findings was assessed by comparing ICD-10 code frequencies against a large commercial database. RESULTS: The study included 3126 notes (unique patient encounters) from 2882 unique patients. Of these, 1383 patient encounters (44.2%) had a present or possible ADE documented (6308 mentions). Of the 6038 ADEs mentioned, 14.1% were hypersensitivity reactions, 1.1% were life-threatening, 22.4% were serious, and 60.4% were significant. Main causal agents included anti-infectives (19.3%), central nervous system agents (12.8%), and cardiovascular agents (11.5%). The overall prevalence of present ADEs mentioned in the clinical notes was estimated to be 1.97 per 100 patient encounters (or 2.52 per 100 patient encounters when possible ADEs are included). CONCLUSIONS: This study identified the overall population prevalence per encounter of ADEs in the outpatient population by leveraging ICD-10 codes and investigating ADEs documented in clinical notes. Understanding the ADE characteristics in a large corpus of outpatient documentation advances pharmacovigilance knowledge, enhancing the detection, monitoring, and prevention of ADEs in ambulatory care.
Fracture-Related Safety Reporting of JAK Inhibitors: An Analysis from the WHO Global VigiBase.
Martinez de la Torre A, Clausen AB, Burden AM … +1 more , Weiler S
Drug Saf · 2025 Feb · PMID 39604587 · Full text
INTRODUCTION: The Janus kinase (JAK) inhibitors are treatment options for autoimmune diseases. Numerous safety concerns have been raised. The European Medicines Agency updated the product information of tofacitinib to in...
INTRODUCTION: The Janus kinase (JAK) inhibitors are treatment options for autoimmune diseases. Numerous safety concerns have been raised. The European Medicines Agency updated the product information of tofacitinib to include the risk of fractures-but not for other JAK inhibitors. We conducted a global pharmacovigilance analysis of previously investigated JAK inhibitors to investigate a potential class effect. METHODS: Individual case safety reports (ICSRs) for all licensed JAK inhibitors were identified from the global WHO pharmacovigilance database. The primary outcome of interest was a bone fracture. Disproportionality analyses using reporting odds ratios (RORs) were conducted. RESULTS: We identified 122,037 ICSRs for tofacitinib, 27,786 ICSRs for upadacitinib, 14,616 ICSRs for baricitinib, 830 for filgotinib, and 350 for abrocitinib. Among the ICSRs, we identified 2198 (1.8%), 634 (2.3%), and 144 (1.0%) reports, where a bone fracture was reported for tofacitinib, upadacitinib, and baricitinib, respectively. Few reports were available for the newest drugs filgotinib (10) and abrocitinib (1). JAK inhibitors were associated with increased reporting for fracture: tofacitinib (ROR 3.34, 95% confidence interval [CI] 3.20-3.48), upadacitinib (ROR 4.23, 95% CI 3.80-4.48), baricitinib (ROR 1.80, 95% CI 1.52-2.11) and filgotinib (ROR 2.24, 95% CI 1.11-3.94). Patients with bone fractures were more often female, older and had a higher number of co-reported medications. They were more likely to use glucocorticoids, opioids, and bisphosphonates. CONCLUSION: The results from this pharmacovigilance analysis, based on a spontaneous reporting database associated with inherent limitations, suggest a potential risk of fractures with JAK inhibitors, indicating that a class effect cannot be ruled out.
Challenges in the Implementation of EU Risk Minimisation Measures for Medicinal Products in Clinical Practice Guidelines: Mixed Methods Multi-Case Study.
Møllebæk M, Gardarsdottir H, Bikou AG … +14 more , Kodrič A, Silva AM, Andersen A, Kontogiorgis C, Poplavska E, Ahmadizar F, Dermiki-Gkana F, Rutkovska I, Vaz IR, Kos M, Barão P, Grupstra R, Alves TL, Almarsdóttir AB
Drug Saf · 2025 Feb · PMID 39570566 · Full text
INTRODUCTION: Risk minimisation measures (RMMs) aim to ensure safe use of medicines, but their implementation in clinical practice is complicated by the diversity of stakeholders whose clinical decision making they seek...
INTRODUCTION: Risk minimisation measures (RMMs) aim to ensure safe use of medicines, but their implementation in clinical practice is complicated by the diversity of stakeholders whose clinical decision making they seek to inform. Clinical practice guidelines (CPGs) are considered integral in clinical decision making. OBJECTIVES: To determine the extent to which RMMs are included in the relevant CPGs and to describe factors that determine RMM inclusion. METHODS: A multi-case study design using quantitative document analysis of CPGs combined with qualitative interviews with informants from organisations that issue CPGs. Cases from five therapeutic areas (TAs) with a regulatory requirement for further RMMs were studied individually in six EU member states (Denmark, Greece, Latvia, Netherlands, Portugal and Slovenia). Clinical practice guidelines were analysed using pre-defined coding frameworks. Interviewees were sampled purposively for experience and knowledge about CPG development and RMM inclusion. Verbatim interview transcripts were analysed inductively. RESULTS: In total, 136 CPGs were analysed, and RMM information about TAs was included in 25% of CPGs. Based on 71 interviews we found that factors that determine RMM inclusion in CPGs include clinicians' low awareness of RMMs despite awareness of RMMs' safety concern, low expectation of RMMs' clinical utility, and unfamiliarity with pharmacovigilance data supporting RMMs and perceived incompatibility of CPGs' scope and purpose and RMM information. CONCLUSIONS: The inclusion of RMM information in relevant CPGs is remarkably limited. It may be explained by characteristics of CPGs and of RMMs as well as lack of connection between national regulators and organisations and authors developing CPGs. More collaboration between stakeholders, national regulators and the EMA may advance implementation.
Signals of Possibly Persistent Gustatory, Olfactory and Auditory Adverse Drug Reactions to Antibiotic Drugs: A Disproportionality Analysis Using the EudraVigilance Database.
Ferraro S, Cappello E, Fornili M … +4 more , Convertino I, Bonaso M, Lucenteforte E, Tuccori M
Drug Saf · 2025 Mar · PMID 39514152 · Publisher ↗
BACKGROUND: In 2018, the European Medicines Agency issued some risk minimisation measures related to unresolved adverse drug reactions (ADRs) reported for fluoroquinolones, including sensory ADRs. Spontaneous reporting d...
BACKGROUND: In 2018, the European Medicines Agency issued some risk minimisation measures related to unresolved adverse drug reactions (ADRs) reported for fluoroquinolones, including sensory ADRs. Spontaneous reporting databases frequently report unresolved outcomes for gustatory, olfactory and auditory (GOA) ADRs. However, such a high volume of unresolved GOA ADRs could reflect an under-investigated clinical issue or an intrinsic difficulty in the outcome assessment. OBJECTIVES: The objectives of the study were: (1) to investigate whether unresolved outcomes are reported more frequently for GOA ADRs than for other ADRs to systemic antibiotics and (2) to identify possible signals of unresolved GOA ADRs for systemic antibiotics. METHODS: We used the EudraVigilance database to extract the number of ADRs to systemic antibiotics of the Anatomical Therapeutic Chemical class J01 up to February 2019. We classified ADRs in "non-GOA ADRs" and "GOA ADRs". Adverse drug reactions were categorised in three groups according to the outcome: defined, persistent/permanent (unresolved) and undetermined ADRs. We performed disproportionality analyses with the case/non-case methodology, by calculating the crude reporting odds ratio (ROR) and 95% confidence interval (CI). Cases were all persistent/permanent ADRs, and non-cases were defined and undetermined ADRs. For the first objective, index groups were gustatory or olfactory or auditory ADRs, while reference group included all non-GOA ADRs. For the second objective, we performed a disproportionality analysis by using the sub-set of GOA ADRs. Index and reference groups varied with subgroups of drugs and drug class, so that each drug and drug class was compared with the others. We conducted two sensitivity analyses for each analysis by varying the case definition. RESULTS: We extracted 748,798 ADRs, including 10,770 GOA ADRs. The first analysis showed that GOA ADRs were reported more frequently as unresolved events compared with all other ADRs (ROR: 2.68 95% CI 2.51-2.85; ROR: 5.20 95% CI 4.66-5.81; and ROR: 2.64 (95% CI 2.51-2.79, respectively). Gustatory ADRs were reported more frequently as unresolved for doxycycline (ROR: 1.69, 95% CI 1.18-2.41, p = 0.0038), azithromycin (ROR: 2.07, 95% CI 1.58-2.72, p < 0.0001) and levofloxacin (ROR: 1.59, 95% CI 1.22-2.07, p < 0.001) compared with GOA ADRs of all other antibiotics. Olfactory ADRs were reported more frequently as unresolved for doxycycline (ROR: 2.4, 95% CI 1.26-4.58, p = 0.0078) and levofloxacin (ROR: 1.92, 95% CI 1.28-2.86, p = 0.0014). Auditory ADRs were reported more frequently as unresolved for doxycycline (ROR: 1.52, 95% CI 1.09-2.12, p = 0.013) and clarithromycin (ROR: 1.31, 95% CI 1.09-1.59, p = 0.0049). CONCLUSIONS: We tested and used an appropriate expected frequency standard, which allows us to identify possible signals of unresolved GOA ADRs to antibiotic drugs in the EudraVigilance database. This approach could be used to generate signals of persistent or even irreversible events for other drugs or adverse reactions. However, these signals must be confirmed with a thorough clinical assessment.
Teratogenic Risk Impact and Mitigation (TRIM): Study Protocol for the Development of a Decision Support Tool to Prioritize Medications for Risk Mitigation.
Winterstein AG, Ewig CLY, Wang Y … +11 more , Smolinski NE, Toyserkani GA, LaCivita C, Lackey L, Eggers S, Zhou EH, Diaby V, Sarayani A, Thai T, Maro JC, Rasmussen SA
Drug Saf · 2025 Feb · PMID 39499480 · Full text
INTRODUCTION: Preventing prenatal exposure to teratogenic medications is an important goal of regulatory risk mitigation efforts. In the USA, as of March 2024, 11 teratogenic medications have a required Risk Evaluation a...
INTRODUCTION: Preventing prenatal exposure to teratogenic medications is an important goal of regulatory risk mitigation efforts. In the USA, as of March 2024, 11 teratogenic medications have a required Risk Evaluation and Mitigation Strategy (REMS) program. It is unclear whether these programs target those medications with the most significant impact on public health and adverse pregnancy outcomes. OBJECTIVES: This study aims to develop an innovative decision support tool that uses explicit, quantifiable criteria to facilitate prioritization of teratogenic medications for risk mitigation strategies. METHODS: The Teratogenic Risk Impact and Mitigation (TRIM) decision support tool will be developed by a national panel via a modified Delphi approach to define measurable criteria, and a multi-criteria decision analysis to estimate criteria weights within a discrete choice experiment. The TRIM scores will then be calculated for 12 teratogenic drugs with active or eliminated REMS programs and for 12 teratogenic drugs without REMS. These drugs will be identified based on highest prenatal exposure prevalence in claims data of privately and publicly insured individuals. Data for the TRIM criteria levels for these 24 drugs will be identified from evidence searches and ad hoc analyses of the same claims data. CONCLUSIONS: Teratogenic Risk Impact and Mitigation is intended to inform regulatory decision making about the need for risk mitigation programs for teratogenic medications by providing explicit, quantifiable, evidence-based criteria. The TRIM scores of 24 teratogenic drugs may provide benchmarks for considering REMS for marketed and new teratogenic medications.
Views on the Development and Use of a New Digital Adverse Drug Event Reporting Platform in Australia: A Qualitative Study.
Gebreyohannes EA, Thornton C, Thiessen M … +4 more , de Vries ST, Coombs G, Hwang I, Lim R
Drug Saf · 2025 Feb · PMID 39487335 · Full text
BACKGROUND: Reporting of adverse drug events (ADEs) to regulatory authorities remains low, particularly among consumers. OBJECTIVES: To explore stakeholders' views on the development and use of a digital platform to impr...
BACKGROUND: Reporting of adverse drug events (ADEs) to regulatory authorities remains low, particularly among consumers. OBJECTIVES: To explore stakeholders' views on the development and use of a digital platform to improve ADE reporting by consumers to the regulatory authority in Australia, i.e., the Therapeutic Goods Administration. METHODS: A qualitative study was conducted using semi-structured interviews, focus group discussions (FGDs), and co-design workshops with consumers, healthcare professionals (HCPs), and regulators. The interview recordings were transcribed verbatim, coded, and analysed thematically according to the Capability, Opportunity, Motivation, Behaviour model. Findings of the FGDs and co-design workshops were incorporated to enhance and complement the insights gathered from the interviews. RESULTS: A total of 39 participants took part in the study (54 % consumers, 41 % HCPs, and 5 % regulators). Uncovered themes related to ADE reporting in general were: difficulty recognizing ADEs and health literacy, awareness about reporting ADEs (Capability); visibility of ADE reporting, professionals' views on consumer ADE reporting, consumer education (Opportunity); the common good, benefit to the reporter, identifying ADEs worth reporting, and concern about reporting (Motivation). Additional identified themes specific to a new digital platform were: physical abilities (Capability); features that facilitate intuitive use, convenience and accessibility, user experience, integration with existing systems, trust, sharing experiences with others (Opportunity); and concern about using a reporting platform, and feedback loop (Motivation). CONCLUSIONS: A cross-section of attitudes and values were obtained regarding ADE reporting in general and a new ADE reporting digital platform for consumers in Australia, which will inform its development, implementation and evaluation.
Investigation of the Role of Chemical Analysis in Causality Assessment of Herbal and Dietary Supplement-Induced Liver Injury.
Halegoua-DeMarzio D, Navarro VJ, Davis A … +20 more , Ahmad J, Avula B, Barnhart H, Barritt AS, Bonkovsky HL, Chen VL, Choi G, Fontana RJ, Ghabril MS, Khan I, Koh C, Odin J, Rockey DC, Rostami H, Serrano J, Sherker AH, Stolz A, Tillmann HL, Vuppalanchi R, Drug-Induced Liver Injury Network
Drug Saf · 2025 Feb · PMID 39354283 · Full text
BACKGROUND: The attribution of drug-induced liver injury (DILI) to specific herbal and dietary supplements (HDS) is confounded by inaccurate labels and undisclosed ingredients. The US Drug-Induced Liver Injury Network (...
BACKGROUND: The attribution of drug-induced liver injury (DILI) to specific herbal and dietary supplements (HDS) is confounded by inaccurate labels and undisclosed ingredients. The US Drug-Induced Liver Injury Network (DILIN) determines the attribution of injury to an agent through its structured expert opinion causality assessment process, but without the use of chemical analysis data of HDS. We aimed to determine the impact of chemical analysis of HDS products on prior causality assessment scores. METHODS: Obtained samples of HDS consumed by DILIN-enrolled patients were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS). Chemical analysis data were compared to label accuracy and detect whether the product contained botanical and non-botanical compounds. A comparison of the causality scores reassessed with chemical analysis was compared with the original scores. RESULTS: A total of 54 previously adjudicated cases with chemical analysis available were reassessed for causality with chemical analysis data; reviewers were blinded to original causality scores. Using the chemical analysis data, 37% (n = 20) of the 54 cases were scored with a higher likelihood of DILI compared with the original causality scores; 14 of the 20 (70%) moved from probable to highly likely; 52% had no change in causality score; and 11% of cases were scored as a lower likelihood of DILI. CONCLUSIONS: Our study demonstrates that there is value in using HDS chemical analysis data in the causality assessment process for DILI. In more than a third of cases, chemical analysis of products led to an increased confidence in DILI attribution to HDS. These findings suggest that chemical analysis is an important tool in causality assessment for HDS agents, specifically in challenging situations, and further studies are needed to confirm its applicability in clinical practice.
Safeguarding Patients in the AI Era: Ethics at the Forefront of Pharmacovigilance.
Jain A, Salas M, Aimer O … +1 more , Adenwala Z
Drug Saf · 2025 Feb · PMID 39331228 · Publisher ↗
Artificial intelligence is increasingly being used in pharmacovigilance. However, the use of artificial intelligence in pharmacovigilance raises ethical concerns related to fairness, non-discrimination, compliance, and r...
Artificial intelligence is increasingly being used in pharmacovigilance. However, the use of artificial intelligence in pharmacovigilance raises ethical concerns related to fairness, non-discrimination, compliance, and responsibility as the central ethical principles in risk assessment and regulatory requirements. This paper explores these concerns and provides a roadmap to how to address these challenges by considering data collection, privacy protection, transparency and accountability, model training, and explainability in artificial intelligence decision making for drug safety surveillance. A number of responsible approaches have been identified including an ethics framework and best practices to enhance artificial intelligence use in healthcare. The document also recognizes some initiatives that have demonstrated the importance of ethics in artificial intelligence pharmacovigilance. Nevertheless, the major needs mentioned in this paper are transparency, accountability, data protection, and fairness, which stress the necessity of collaboration to construct a cognitive framework aimed at integrating ethical artificial intelligence into pharmacovigilance. In conclusion, innovation should be balanced with ethical responsibility to enhance public health outcomes as well as patient safety.
An Integrated Approach for Representing Knowledge on the Potential of Drugs to Cause Acute Kidney Injury.
Fernández-Llaneza D, Vos RMP, Lieverse JE … +5 more , Gosselt HR, Kane-Gill SL, van Gelder T, Klopotowska JE, LEAPfROG Consortium
Drug Saf · 2025 Jan · PMID 39327387 · Full text
INTRODUCTION AND OBJECTIVE: The recent rise in acute kidney injury (AKI) incidence, with approximately 30% attributed to potentially preventable adverse drug events (ADEs), poses challenges in evaluating drug-induced AKI...
INTRODUCTION AND OBJECTIVE: The recent rise in acute kidney injury (AKI) incidence, with approximately 30% attributed to potentially preventable adverse drug events (ADEs), poses challenges in evaluating drug-induced AKI due to polypharmacy and other risk factors. This study seeks to consolidate knowledge on the drugs with AKI potential from four distinct sources: (i) bio(medical) peer-reviewed journals; (ii) spontaneous reporting systems (SRS); (iii) drug information databases (DIDs); and (iv) NephroTox website. By harnessing the potential of these underutilised sources, our objective is to bridge gaps and enhance the understanding of drug-induced AKI. METHODS: By searching Medline, studies with lists of drugs with AKI potential established through consensus amongst medical experts were selected. A final list of 63 drugs was generated aggregating the original studies. For these 63 drugs, the AKI reporting odds ratios (RORs) using three SRS databases, the average frequency of ADEs from four different DIDs and the number of published studies identified via NephroTox was reported. RESULTS: Drugs belonging to the antivirals, antibacterials, and non-steroidal anti-inflammatory pharmacological classes exhibit substantial consensus on AKI potential, which was also reflected in strong ROR signals, frequent to very frequent AKI-related ADEs and a high number of published studies reporting adverse kidney events as identified via NephroTox. Renin-angiotensin aldosterone system inhibitors and diuretics also display comparable signal strengths, but this can be attributed to expected haemodynamic changes. More variability is noted for proton-pump inhibitors. CONCLUSIONS: By integrating four disjointed sources of knowledge, we have created a novel, comprehensive resource on drugs with AKI potential, contributing to kidney safety improvement efforts.
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