Drug Safety[JOURNAL]
Sun
200 papers
Teratogenic Risk Impact Mitigation (TRIM): Development of Explicit Criteria to Facilitate Decisions Regarding Teratogenic Risk Mitigation Strategies.
Ewig CLY, Wang Y, Smolinski NE … +34 more , Toyserkani GA, LaCivita C, Lackey L, Eggers S, Sahin L, Abu-Rustum RS, Bateman BT, Berard A, Chambers CD, Choby B, Conover EA, Greene MF, Hernández-Díaz S, Jamieson DJ, Običan SG, Polifka JE, Roussos-Ross K, Sheffield JS, Lavigne SV, Zimmermann EM, Laffan SB, DeLise AM, Gilsenan AW, Hammad TA, Hampp C, Hardy JR, Knox CA, Shields K, Smith MY, Sobel RE, Tassinari MS, Maro JC, Rasmussen SA, Winterstein AG
Drug Saf · 2025 Dec · PMID 40762949 · Full text
BACKGROUND: Preventing fetal exposure to teratogenic medications is an important target for risk mitigation efforts. Decisions about risk mitigation efforts specific to teratogenic medications are complex. OBJECTIVES: Th...
BACKGROUND: Preventing fetal exposure to teratogenic medications is an important target for risk mitigation efforts. Decisions about risk mitigation efforts specific to teratogenic medications are complex. OBJECTIVES: The Teratogenic Risk Impact and Mitigation (TRIM) tool was developed as an innovative decision support tool to facilitate prioritization of teratogenic medications for risk mitigation strategies. METHODS: We employed a modified Delphi study design involving experts across teratology, obstetrics/gynecology, and medication safety. Panelists proposed decision criteria in three focus groups, followed by e-Delphi rounds to reach a consensus on criteria regarding three dimensions: (1) completeness; (2) relevance; and (3) distinctiveness. Aggregated feedback from each round was used to inform revision of the criteria in subsequent rounds. RESULTS: A total of 33 candidate criteria proposed by 32 focus group participants were organized into ten distinct criteria for the Delphi process. Consensus (defined as > 85% agreement on all three dimensions) was reached after three e-Delphi rounds, resulting in six criteria: (1) background use among persons of reproductive potential; (2) overall medication benefit considering severity of the indication and availability of alternatives; (3) seriousness of the teratogenic outcome; (4) risk of the teratogenic outcome; (5) certainty regarding teratogenicity; and (6) the risk of exposure during pregnancy. CONCLUSIONS: We established measurable criteria to inform decisions when prioritizing teratogenic medications for risk mitigation programs. Criteria are consensus based and consistent with relevant regulatory guidance. Future work will operationalize these criteria and determine specific weights to facilitate medication-specific TRIM scores. Through its explicit framework, the TRIM tool may support consistent, transparent, and rational decision making and help optimize the contribution of risk mitigation programs to public health.
The Impact of COVID-19 and COVID-19 Vaccination on Detection, Assessment, and Management of Suspected Acute Drug-Induced Liver Injury Occurring during Clinical Trials: Consensus Recommendations from the IQ DILI Initiative.
Palmer M, Seekins D, Avigan M … +6 more , Marcinak J, Rockey DC, Regev A, Shastri VK, Lewis JH, Dash A
Drug Saf · 2026 Jan · PMID 40762948 · Full text
While the acute impact of the coronavirus disease 2019 (COVID-19) pandemic has waned, implications for clinical trials remain. In particular, guidance for evaluation of elevated liver tests due to COVID-19, its treatment...
While the acute impact of the coronavirus disease 2019 (COVID-19) pandemic has waned, implications for clinical trials remain. In particular, guidance for evaluation of elevated liver tests due to COVID-19, its treatments, and COVID-19 vaccination is lacking. The IQ DILI Initiative, composed of experts from academia, regulatory agencies, and industry herein propose recommendations to address this gap. Extensive literature review was conducted and structured discussions were held between IQ DILI industry members, regulators, and academic experts in hepatology and DILI. Liver-related manifestations in nonhospitalized patients with COVID-19 are highly varied. Evidence of liver injury may occur after COVID-19 symptoms resolve and testing is negative. Treatments for COVID-19 may cause liver injury or alter pharmacokinetics. COVID-19 vaccination has been associated with rare but clear hepatotoxicity, typically consistent with drug-induced autoimmune-like hepatitis, although other presentations, severity, latency, and time to resolution have been reported. Liver injury occurred with mRNA and viral vector vaccines, and in individuals with and without underlying autoimmune or liver diseases. Drug developers and investigators should be aware of the potential liver-related manifestations related to COVID-19, its treatments, and COVID-19 vaccination, as this may impact study eligibility and causality assessment during a trial. COVID-19 testing should be considered part of DILI causality assessment, as a positive test may prevent premature termination of the investigational drug. Since clinical trial participants may not consider vaccinations in their medical history, specific inquiry about their receipt is important when liver tests are abnormal during screening and as part of DILI causality assessment.
How does the Content and Dissemination of Communications on the Risks of Medicines Affect Prescriber Awareness, Knowledge, and Behaviour: A Systematic Review.
Perry LT, Mohammad A, Hooimeyer A … +2 more , McEwin EJ, Mintzes B
Drug Saf · 2026 Jan · PMID 40758211 · Full text
BACKGROUND: Medicines have important and sometimes lifesaving health benefits. They can also be the cause of harm and injury due to adverse drug reactions (ADRs). Effective communication of medicine risks is crucial to i...
BACKGROUND: Medicines have important and sometimes lifesaving health benefits. They can also be the cause of harm and injury due to adverse drug reactions (ADRs). Effective communication of medicine risks is crucial to informed prescribing decisions and the protection of patient health. Clinicians must receive, interpret, and then implement these communications to achieve desired outcomes; however, this has not always been successful. Therefore, it is important to understand how the content of risk communication about medicines and the methods of dissemination may affect prescribers' awareness, knowledge, and behaviours. AIMS: This systematic review provides an overview of the effect of content and dissemination of risk communications about medicines on prescribers' awareness, knowledge, and behaviour and ultimately on patient health. METHODS: A systematic review was conducted. Studies were included if they were randomised controlled trials investigating the effect of the content or dissemination of risk communications about medicines on prescribers' knowledge, awareness, and behaviour. MEDLINE, Embase, and PsycINFO via Ovid, Scopus, and Web of Science databases were searched up to December 2024. Data on intervention type, study design, prescriber type, and outcomes were extracted. Outcomes were synthesised, and meta-analysis was undertaken where results allowed for this. RESULTS: Twenty-three studies met the inclusion criteria: ten investigated the content of risk communication, ten investigated dissemination methods, and three investigated both. Twenty-one studies assessed prescribing behaviours, and one study each assessed clinicians' awareness and knowledge, respectively. Two studies evaluated how risk communication content and its delivery to clinicians affected patient health outcomes. Interventions included computerised clinical systems, risk assessment tools, alerting systems, targeted messaging, and education. Visual risk assessment tools and targeted education reduced ADR rates, improving patient health. Alerts to change clinical monitoring and assessment behaviour were modestly effective (relative risk [RR] 1.03; 95% confidence interval [CI] 1.01-1.05). Multicomponent approaches also positively affected prescribing behaviours. Targeted messages, such as audit and feedback, improved clinicians' awareness of risk communications. Computer alerts and risk assessments that were interruptive and easily accessed in workflows or provided actions or information to avoid or minimise risk to patients did not significantly change prescribing (RR 1.50; 95% CI 0.87-2.60 and RR 1.41; 95% CI 0.89-2.24). However, study heterogeneity and small sample sizes limited the power to detect differences. CONCLUSION: There is limited evidence from randomised controlled trials comparing the effectiveness of drug risk communication strategies targeting prescribers. No one content or dissemination intervention was wholly effective; however, key aspects of risk communication content and its dissemination to clinicians were identified, including multi-modal approaches. Further investigation is warranted.
Uncovering the Hidden Hurdles: Exploring Challenges in Pediatric Pharmacovigilance in the Netherlands.
Dittrich ATM, Kroeze Y, Willemsen MAAP … +3 more , Draaisma JMT, van Puijenbroek EP, Te Loo DMWM
Drug Saf · 2026 Jan · PMID 40753519 · Full text
INTRODUCTION: The use of drugs carries risks, as adverse drug reactions (ADRs) can occur. In the Netherlands, a voluntary pharmacovigilance system is in place, allowing healthcare professionals and patients to report (su...
INTRODUCTION: The use of drugs carries risks, as adverse drug reactions (ADRs) can occur. In the Netherlands, a voluntary pharmacovigilance system is in place, allowing healthcare professionals and patients to report (suspected) ADRs. Previous research has highlighted underreporting as a significant problem; however, barriers for ADR reporting are not clear. OBJECTIVES: The aim was to assess perceptions of ADR reporting among pediatricians (in training), to identify barriers hindering reporting, and to study differences between our hospital and other Dutch hospitals. METHODS: A cross-sectional survey was conducted among pediatricians (in training) in the Netherlands. The study questionnaire was based on a validated questionnaire and adjusted for the Dutch context, addressing aspects related to ADR reporting, attitudes toward ADRs in work environment, personal vision, reasons for nonreporting, and future perspectives. RESULTS: A dataset of 127 respondents was included. Of these, 93% reported knowing how to report an ADR. Overall, 95% believed that reporting ADRs has the potential to enhance knowledge and improve drug safety, and 93% acknowledged the overall importance of ADR reporting. However, 19% of respondents indicated that they had never reported an ADR. The most commonly cited reason (61%) for not reporting was prior knowledge of the ADR. Other barriers included uncertainty about whether a symptom constituted an ADR, the perception that the ADR was not severe, and time constraints. CONCLUSIONS: This study highlights the importance of addressing barriers to ADR reporting in pediatric healthcare. While healthcare professionals recognize the significance of ADR reporting, several impediments hinder their reporting efforts.
Epidemiology of Thrombotic Thrombocytopenia Syndrome 2011 to 2022: English Sentinel Network Cohort Studies.
Ordóñez-Mena JM, Kar D, Fan X … +10 more , Ferreira F, Anand SN, Layton D, Clifton D, Joy M, Thakur A, Alessi A, Lee A, Mather L, de Lusignan S
Drug Saf · 2025 Oct · PMID 40745250 · Full text
BACKGROUND AND OBJECTIVE: Thrombotic thrombocytopenia syndrome (TTS) is a rare condition following vaccination with adenovirus-vectored coronavirus disease 2019 (COVID-19) vaccines. This retrospective analysis of England...
BACKGROUND AND OBJECTIVE: Thrombotic thrombocytopenia syndrome (TTS) is a rare condition following vaccination with adenovirus-vectored coronavirus disease 2019 (COVID-19) vaccines. This retrospective analysis of England primary care data aimed to estimate TTS event rates before, during, and after the COVID-19 pandemic, and following AZD1222 (ChAdOx1-nCoV-19) vaccination. METHODS: Primary care data on TTS events were collected using the Oxford-Royal College of General Practitioners Research and Surveillance Centre sentinel network. TTS events were defined as thromboembolism with coincident (± 7 days) thrombocytopenia events using Systematized Nomenclature of Medicine clinical terms (the current Brighton Collaboration definition could not be used in the study as data related to specific parameters [e.g., D-dimer or PF4 antibodies] were not available in the primary care database). Multivariable logistic regression analyses were performed to assess the association between covariates and TTS. RESULTS: Incident TTS rates per 100,000 person-years were: 0.42 in a pre-COVID-19 cohort (1 January, 2011-31 December, 2019; 9,062,313 individuals); 0 in 39,448 individuals with confirmed COVID-19 (1 July-31 December, 2020); 0.48 and 0.47 during the pre-vaccination pandemic period spanning 1 January-14 August, 2020 (13,245,710 individuals) and 15 August-31 December, 2020 (13,347,462 individuals); 2.41 in an AZD1222-vaccinated cohort (5,544,761 individuals; 1 January, 2021-4 July, 2022). Multivariable logistic regression analysis of TTS events (- 7/+ 42 days event-window; pre-COVID-19 cohort) showed greater odds in older individuals and high-risk groups as defined by the Joint Committee on Vaccination and Immunization. Thrombotic thrombocytopenia syndrome was rare in all cohorts. Differential covariate distributions precluded comparisons of TTS rates across cohorts. Covariate distributions within thromboembolism and thrombocytopenia cases were comparable to those of TTS cases. CONCLUSIONS: Our study, using a previous definition of TTS, reinforces the very rare nature of TTS before and during the pandemic, and before and after the introduction of the AZD1222 vaccine; it also confirms the established very low incident event rate in individuals vaccinated with AZD1222.
Observed Versus Expected Analysis-How Does It Fit in the Pharmacovigilance Toolkit?
Van Holle L
Drug Saf · 2025 Dec · PMID 40742669 · Publisher ↗
Observed versus expected (O/E) analyses have been used in an unprecedented scale for the safety monitoring of the COVID-19 mass vaccination. The extent of their usage changed its nature, which consisted of a mixture of m...
Observed versus expected (O/E) analyses have been used in an unprecedented scale for the safety monitoring of the COVID-19 mass vaccination. The extent of their usage changed its nature, which consisted of a mixture of medical expertise and epidemiology, into something more algorithmic and automated. By doing so, the observed versus expected analysis became closer to disproportionality analysis (DPA), which is also a type of observed versus expected analysis that differs in the way the expected is calculated. A qualitative assessment of the strengths and limitations of both methods concludes that the algorithmic O/E is more likely to underestimate under-reporting, is more likely to be sensitive to asymmetrical differences in the definition of the condition of interest, and is more dependent on a greater variety of data sources or medical knowledge that might not be accurate for emerging safety issues (exposure, background incidence rate, and risk window). Provided some adjustment (stratification and/or subgrouping) of the routine disproportionality into a targeted disproportionality occurs, which would account for the epidemiological specifics of the vaccine and event-of-interest, the targeted DPA has the potential to be promoted from a signal detection method into a signal evaluation method that could advantageously replace the algorithmic O/E analysis. Research on the setup of a sensitivity analysis framework integrating several standardized choices of disproportionality settings, along with measures (qualitative or quantitative) of the biases for each choice, could be more beneficial for the pharmacovigilance field than studies designed to estimate the background incidence rates of adverse events of special interest for the sole purpose of being used in O/E analyses.
Correction: An Evaluation of Duplicate Adverse Event Reports Characteristics in the Food and Drug Administration Adverse Event Reporting System.
Janiczak S, Tanveer S, Tom K … +4 more , Zhang R, Ma Y, Wolf L, Muñoz MA
Drug Saf · 2025 Dec · PMID 40711728 · Full text
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Real-World Data Insights into Antidepressant Prescription and Adherence During Pregnancy in Catalonia (Spain).
Bellas L, Camacho-Arteaga L, Giner-Soriano M … +4 more , Albert-Prats-Uribe, Gómez-Lumbreras A, Aguilera C, Agustí A
Drug Saf · 2025 Dec · PMID 40632487 · Full text
BACKGROUND: Affective disorders, particularly depression, are common among women of childbearing age, and pregnancy often exacerbates symptoms. Antidepressants are often required for treatment, but adherence during pregn...
BACKGROUND: Affective disorders, particularly depression, are common among women of childbearing age, and pregnancy often exacerbates symptoms. Antidepressants are often required for treatment, but adherence during pregnancy is variable. Although some studies suggest potential risks to the foetus, many cannot rule out confounding by indication. In this context, understanding real-world patterns of antidepressant prescription and adherence during pregnancy is essential to inform clinical practice and ensure adequate mental healthcare. OBJECTIVE: The aim of the present study was to characterise the use of antidepressants in a cohort of pregnant women using electronic health records. METHODS: This observational cohort drug-utilisation study assessed antidepressant prescription patterns, adherence and persistence among pregnant women using data from the SIDIAP (Information System for the Development of Research in Primary Care) database in Catalonia from January 2011 to June 2020. RESULTS: Among 99,605 pregnancies, 14.9% involved antidepressant prescriptions, but only 5.8% of these were collected from pharmacies. The median pregnancy duration was 38.4 weeks, and the median maternal age was 33.5 years. Anxiety was the most common health issue associated with an antidepressant prescription. Paroxetine was the most frequently prescribed antidepressant, although sertraline usage increased over time. Antidepressant prescriptions and adherence decreased during pregnancy, with an increase in the postpartum period. About 11.6% of pregnancies involved a concurrent prescription of another antidepressant, and 29.2% of women resumed antidepressant use after pregnancy. Women who initiated antidepressants during pregnancy were more likely to persist with treatment than those with pre-existing prescriptions. CONCLUSIONS: Our study describes antidepressant use during pregnancy in Catalonia. It is remarkable that there is a notable gap between antidepressant prescriptions and dispensations. Given the risks of untreated maternal depression, strengthening primary care with adequate resources and personalised support is essential for improving perinatal mental healthcare.
The Value of Sensitivity Analyses in Assessing the Risk of Two Rare Neurological Adverse Events and Pseudoephedrine Use.
Alexander GC, Chingcuanco F, Garg A … +1 more , Budnitz D
Drug Saf · 2025 Oct · PMID 40629215 · Full text
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Temporal Changes in Reporting of Neurodevelopmental Outcomes After Maternal Exposure to Valproate: A Contribution of the ConcePTION Project.
Gkolfi D, van Rijt-Weetink YRJ, Taavola-Gustafsson H … +7 more , Sandberg L, Raemaekers BC, van Hunsel FPAM, Passier ALM, Bromley RL, Yates LM, van Puijenbroek EP
Drug Saf · 2025 Dec · PMID 40624327 · Full text
BACKGROUND: Understanding changes over time in the quantity and characteristics of reports submitted to pharmacovigilance centres is crucial for accurately interpreting safety signals associated with exposure during preg...
BACKGROUND: Understanding changes over time in the quantity and characteristics of reports submitted to pharmacovigilance centres is crucial for accurately interpreting safety signals associated with exposure during pregnancy. OBJECTIVE: We aimed to assess temporal changes in the outcome measures for signal detection, specifically the number and clustering of reported adverse events concerning maternal valproate exposure and neurodevelopmental outcomes in offspring. METHODS: An observational study using VigiBase analysed changes in the number of reports and event clustering related to neurodevelopmental outcomes in offspring following valproate exposure during pregnancy. Reports from the start of VigiBase till 3 April, 2023 were identified using the VigiBase pregnancy algorithm. Time trend graphs illustrated reporting behavioural changes, with particular focus on the impact of major scientific publications and regulatory decisions. Report clusters, identified by the vigiGroup method, were randomised and independently reviewed by three qualified reviewers for clinical relevance to neurodevelopmental outcomes, morphological disorders or other entities. RESULTS: Over time, an increase in reports mentioning neurodevelopmental outcomes and a more diverse pattern of adverse events for valproate has been reported. An increase in the number of reports following key publications and international regulatory guidelines was visible. CONCLUSIONS: Our study revealed an increase over time in reporting and awareness of neurodevelopmental outcomes and valproate exposure during pregnancy, following important publications and regulatory decisions. However, the extent to which these developments contributed to the observed increase remains unclear.
The Effect of Opioid Agonist Treatment on Injection-Related Sequelae: A Population-Based Observational Study.
Lim J, Bruneau J, Platt RW … +1 more , Panagiotoglou D
Drug Saf · 2025 Nov · PMID 40608239 · Publisher ↗
INTRODUCTION: Opioid agonist treatment (OAT) reduces drug-related poisonings and injection-related infections among people with opioid use disorder (OUD). Despite buprenorphine-naloxone (BNX) and methadone (MET) both bei...
INTRODUCTION: Opioid agonist treatment (OAT) reduces drug-related poisonings and injection-related infections among people with opioid use disorder (OUD). Despite buprenorphine-naloxone (BNX) and methadone (MET) both being first-line OAT options in Canada, their comparative effectiveness in preventing recurrent injection-related infections and poisonings remains unclear. OBJECTIVES: This study compared the effectiveness of buprenorphine-naloxone and methadone in reducing recurrent risks of injection-related bacterial infections and opioid-related poisoning among people on OAT. METHODS: We used administrative health data from Québec, Canada to create our cohort of adult patients (aged 18-65 years) on OAT maintenance between 2014 and 2019. We applied a time-dependent Cox proportional hazards model for our time-varying exposure definition to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the recurrent risks of injection-related bacterial infections and opioid-related poisoning, adjusting for age, sex, socio-demographic, and clinical factors. We also compared the effectiveness of buprenorphine-naloxone and methadone during the OAT induction phase (i.e., first 30 days of treatment). RESULTS: The study population included 2010 patients (mean age: 41.21 years, 67.41% male). Compared to methadone, buprenorphine-naloxone was associated with 45% lower recurrent risk of opioid-related poisoning (HR: 0.55; 95% CI 0.35-0.86). Overall, the association between buprenorphine-naloxone and recurrent risk of injection-related bacterial infections suggested a weak protective effect (HR: 0.80; 95% CI 0.59-1.09). During the induction phase, there was limited evidence of differences between buprenorphine-naloxone and methadone for the recurrent risks of injection-related bacterial infections (HR: 0.91; 95% CI 0.51-1.60) and opioid-related poisoning (HR: 1.07; 95% CI 0.51-2.24). CONCLUSION: Among patients in OAT maintenance, buprenorphine-naloxone was associated with lower risk of recurrent opioid-related poisoning compared to methadone, but not for injection-related infections. This advantage was not observed during induction, suggesting the need for improved treatment retention early in OAT.
Signals of Adverse Reactions to Herbal Medicines: Evidence and Document Analysis Based on a Scoping Review.
Sartori D, Aronson JK, Brand JS … +4 more , Gauffin O, Hedfors Vidlin S, Norén GN, Onakpoya IJ
Drug Saf · 2025 Dec · PMID 40601107 · Full text
BACKGROUND: To date, signals of adverse reactions to herbal medicines have not been systematically reviewed, limiting pharmacovigilance of herbal medicines because of a lack of data. OBJECTIVES: We sought to analyse the...
BACKGROUND: To date, signals of adverse reactions to herbal medicines have not been systematically reviewed, limiting pharmacovigilance of herbal medicines because of a lack of data. OBJECTIVES: We sought to analyse the available evidence on signals involving herbal medicines and to determine to what extent they had been documented at the European Union (EU) level and in the USA. METHODS: We used the results of a published scoping review of interventional and non-interventional studies that reported signals of adverse reactions to drugs. We assigned Anatomical Therapeutic Chemical classification to all drugs, and identified herbal medicines when they fell under the Anatomical Therapeutic Chemical V90. We ascertained the presence of the adverse reaction, or related adverse reactions, for each signal in reference documents for healthcare professionals: the US Botanical Safety Handbook and the EU monographs and US Dietary Supplement Fact Sheets; and in those for consumers: the US Dietary Supplement Label Database. We summarised the data descriptively, treating US documents as one and comparing harms across pairs of US and EU documents by signal. Documents were deemed concordant if they both included the same or related adverse reactions, or if neither did. We also compared adverse reactions across US documents for healthcare professionals with those for consumers. RESULTS: Of the 10,861 signals covered by the scoping review, 53 (0.49%) concerned herbal medicines, all based on case reports. Reference documents from both the US and EU were available for 37 signals. Most of the documents were concordant (73%), and ten (27%) were discordant: six adverse reactions were mentioned only in US documents, three only in EU monographs, and one was warned against in US documents but not in EU documents. Twenty-one signals could be followed up in the Botanical Safety Handbook and Dietary Supplement Fact Sheets. Most (68%) US documents for healthcare professionals were concordant. When the Botanical Safety Handbook and Dietary Supplement Fact Sheets did not include an adverse reaction, neither did the Dietary Supplement Label Database. However, when they did, only 20% of the labels for consumers did too. The proportion of labels mentioning adverse reactions otherwise available in documents intended for healthcare professionals ranged widely, reflecting differences across multiple labels for the same products. CONCLUSIONS: Very few signals of adverse reactions from the wider scoping review concerned herbal medicines, and were all based on case reports. Information was mostly concordant across documents in the EU and USA. As manufacturers are solely responsible for the contents of the Dietary Supplement Label Database, regulatory oversight may be required to ensure that consistent and comprehensive information on the harms of herbal medicines is made available to consumers in the USA.
Strategies and Challenges in Coding Ambiguous Information Using MedDRA: An Exploration Among Norwegian Pharmacovigilance Officers.
Garmann T, Samdal H, Sartori D … +3 more , Jahanlu D, Andersen F, Rocca E
Drug Saf · 2025 Nov · PMID 40593291 · Full text
INTRODUCTION: The Medical Dictionary for Regulatory Activities (MedDRA) is an international standardized medical terminology used to code various types of medical information, including safety reports of suspected advers...
INTRODUCTION: The Medical Dictionary for Regulatory Activities (MedDRA) is an international standardized medical terminology used to code various types of medical information, including safety reports of suspected adverse reactions to medicines. Quantitative studies have highlighted varying levels of coding inconsistency across MedDRA-relevant platforms, though the possible grounds of such inconsistency remain unclear. OBJECTIVE: We explored the reasoning and strategies employed by pharmacovigilance officers when coding selected ambiguous adverse events to MedDRA, categorized the types of coding inconsistencies, and explored sources of the inconsistencies. METHODS: Pharmacovigilance officers from the Norwegian public health sector were invited to participate in a survey-based, cross-sectional study followed by focus group interviews. The survey consisted of 11 coding tasks, with varying degrees of ambiguity, purposively sampled from the Norwegian pharmacovigilance registry. Participants selected the appropriate MedDRA terms and graded the difficulty level of each task on a scale from 1 (least difficult) to 4 (most difficult). Terms selected by participants were compared with a Standard Term Selection (STS), agreed upon by the authors in consultation with a MedDRA trainer. Inconsistencies with the STS were classified as omission (missing term), substitution (extra term selected in the presence of an omission), and addition (extra term selected and none omitted). In focus groups, participants discussed challenges in the coding tasks and the strategies they used to overcome them. Interview transcripts were analyzed using thematic analysis. RESULTS: In total, 26 coders (79% of the eligible population) completed the survey. Of the survey answers, 36% were identical to the STS; answers consistent with the STS varied across the specific coding tasks and did not align with the perceived difficulty of the tasks. The most common inconsistency (30% of the survey answers) arose from substituting one of multiple MedDRA terms. Of the survey answers, 18% included omissions without substitutions, and 6% added unnecessary terms to the STS. Eight of the 26 coders (31%) participated in the focus group interviews. Focus group themes revealed that substitutions were explained by difficulties in translating lay language to medical terminology, finding accurate English translations for Norwegian medical terms, and fitting complex descriptions into MedDRA terms. This was explained by themes related to ambiguity-resolution strategies. Themes explaining omissions included strategies for resolving ambiguity, contextual thinking, causal and pharmacological reasoning in the coding process, and information categorization. CONCLUSIONS: Tailored training programs and clear institutional guidelines are needed to target the sources of coding inconsistencies suggested by this study.
Characteristics of Drug-RElated Hospitalizations for Nursing HOme Residents: Cross-Sectional RENHO Study.
Lopez A, Alfarano C, Lepetit M … +8 more , Chebane L, Redjimi N, Couret A, Fabre D, Gardette V, Berdaï D, Lapeyre-Mestre M, Bagheri H
Drug Saf · 2025 Sep · PMID 40588648 · Full text
BACKGROUND: Nursing home residents with advancing age are often exposed to polypharmacy, a well-known risk factor for adverse drug reactions (ADRs), which increases the risk of hospitalization. Therefore, we assessed the...
BACKGROUND: Nursing home residents with advancing age are often exposed to polypharmacy, a well-known risk factor for adverse drug reactions (ADRs), which increases the risk of hospitalization. Therefore, we assessed the characteristics of and factors associated with ADR-related emergency department (ED) admissions among nursing home residents. METHODS: We carried out a cross-sectional study using the Toulouse University Hospital discharge database to identify nursing home residents ED admissions from 1 April, 2019 to 31 March, 2020. Information was updated for 2 years after inclusion (re-admissions). Emergency department medical files were analyzed to identify factors associated with these admissions (including demographics, functional dependency level, comorbidities, body mass index, ED admission in the previous 12 previous months, and number of drugs). RESULTS: We identified 1514 patients (corresponding to 2024 ED admissions), 409 of whom (27.0%) were admitted at least once for an ADR. Thirty-six nursing home residents were re-admitted in 2020 and/or 2021 for ADRs, half of whom were for the same ADR. The most frequent ADRs were falls (114, 24.3%), hemorrhagic events (106, 22.6%), and constipation (47, 10.0%) involving benzodiazepines and Z-drugs (170, 16.0%), antidepressants (125, 11.9%), antithrombotic drugs (110, 10.3%), and opioids (82, 7.7%). About 12% of ADRs were assessed as avoidable. Factors significantly associated with ADR-related ED admissions were the number of drugs (odds ratio 1.09; 95% confidence interval 1.05-1.13), previous ED admissions (odds ratio 3.47; 95% confidence interval 2.46-4.90), and overweight (odds ratio 1.54; confidence interval 1.15-2.06). CONCLUSIONS: Drug-induced iatrogenic disease could lead to ED admission for nursing home residents in approximately one-quarter of cases, 12% of which were assessed as avoidable. A previous history of ED admission and polypharmacy remain key associated factors. The awareness-raising campaigns for health professionals should be strengthened to prevent avoidable drug-induced ADRs.
Association of GLP1-Receptor Agonists with Risk of Hepatocellular Carcinoma: A Retrospective Cohort Study.
Titus J, Katukuri V, Boktor M … +1 more , Mansi IA
Drug Saf · 2025 Oct · PMID 40587039 · Publisher ↗
BACKGROUND: The use of glucagon-like peptide-1 receptor agonists (GLP-1RA) has exponentially increased owing to their favorable cardio-renal-metabolic effects. Some studies have raised concerns about a potential associat...
BACKGROUND: The use of glucagon-like peptide-1 receptor agonists (GLP-1RA) has exponentially increased owing to their favorable cardio-renal-metabolic effects. Some studies have raised concerns about a potential association between GLP-1RA use and malignancy. This study aimed to examine the association between GLP-1RA use and risk of hepatocellular carcinoma (HCC). METHODS: This retrospective propensity score (PS)-matched cohort study used data from the Veterans Health Administration (years 2006-2021). Using a new-user active comparator design, the study included adults who initiated a GLP-1RA or dipeptidyl peptidase-4 inhibitor (DPP4i) as an active comparator and had no prior history of HCC or liver transplantation. The primary outcome was incident HCC. We developed a PS that included 133 variables encompassing diabetes severity, hepatic conditions, liver disease scores, vital signs, laboratory investigations, comorbidity scores, and use of other medication classes. RESULTS: Of 147,969 GLP-1RA and 263,664 DPP4i users, 100,248 pairs of GLP-1RA and DPP4i users were PS-matched. Hepatocellular carcinoma occurred in 302 (0.30%) GLP-1RA users and in 230 (0.23%) DPP4i users (odds ratio [OR]: 1.31, 95% confidence interval [95% CI]: 1.11-1.56). Secondary analysis, which stratified patients by duration of medication use, showed an increased risk of HCC in association with GLP-1RA use > 6 months, but similar HCC risk if medication use was < 6 months (OR: 0.96; 95% CI 0.68-1.35). CONCLUSIONS: Glucagon-like peptide-1 receptor agonists use was associated with a modest but statistically significant increase in HCC risk versus DPP4i use. Although the reported benefits of GLP-1RA seem to far exceed this modest increased risk, further studies are warranted due to exponentially increasing GLP-1RA use and their broadening indications.
Temporal Trends of Anticholinergic Drug Exposure Among Older Adults: A 25-Year Population-Based Study.
Evelo A, Licher S, Stricker BH … +2 more , Visser LE, Ruiter R
Drug Saf · 2025 Oct · PMID 40579658 · Full text
BACKGROUND: Exposure to anticholinergic drugs is associated with adverse outcomes, particularly among older adults. Limiting the anticholinergic burden (ACB) among older patients has been advocated for decades, but relia...
BACKGROUND: Exposure to anticholinergic drugs is associated with adverse outcomes, particularly among older adults. Limiting the anticholinergic burden (ACB) among older patients has been advocated for decades, but reliable population-level data on temporal trends are lacking. Here, we estimated the cumulative incidence and incidence rates (IRs) of a cumulative ACB score of three or more (cACB ≥ 3) among older adults in a community-dwelling population and described the changes in IR over the past 25 years. METHODS: Within the population-based Rotterdam Study, pharmacy dispensing records were obtained from 11,038 individuals aged 65+ years from 1996 to 2020. The cACB score was calculated with the Anticholinergic Cognitive Burden Scale and supplemented with drugs on the ACB scale by the Expertisecentre PHarmacotherapy in OldeR people (EPHOR). Age- and sex-specific IRs were calculated, and non-overlapping 5-year episodes were defined to determine time trends in IRs. RESULTS: The cumulative incidence of a cACB ≥ 3 was 25.3% between 1996 and 2020. Compared with 1996-2000, the IR of cACB ≥ 3 had declined by 54% between the 2016-2022 episode (IR ratio: 0.46, 95% confidence interval (CI): 0.41-0.52). Participants aged 86-90 years had more than 1.5 times the rate of a cACB ≥ 3 compared with participants aged 66-70 years (IR ratio: 1.67, 95% CI 1.46-1.91). CONCLUSIONS: Exposure to anticholinergic drugs has decreased by over 50% between 1996 and 2020 in this population of community-dwelling adults. However, the oldest old had and remained to have the highest risk of a cACB ≥ 3 during our study period. Thus, prescribers and pharmacists should continue to regularly review the prescription of drugs with an ACB, especially among those vulnerable to adverse outcomes.
Sex Differences in Electrolyte Disturbances Among Diuretic Users According to Renal Function and Age.
Maida N, Kondo S, Hayashi N … +3 more , Iwata H, Kobayashi N, Yamaura K
Drug Saf · 2025 Oct · PMID 40560472 · Full text
INTRODUCTION: Diuretics are widely used in Japan for the treatment of hypertension and heart failure. Electrolyte disturbance is a common adverse reaction to diuretics and may be life-threatening. Previous studies have s...
INTRODUCTION: Diuretics are widely used in Japan for the treatment of hypertension and heart failure. Electrolyte disturbance is a common adverse reaction to diuretics and may be life-threatening. Previous studies have shown that diuretic-induced electrolyte disturbance is more common in women. Electrolyte balance is regulated by the kidneys, and renal function tends to decline with advancing age. OBJECTIVE: The aim of this study was to identify patients at high risk of adverse reactions to diuretics, considering the effects of sex, renal function, and age on susceptibility to diuretic-induced electrolyte disturbance. METHODS: Claims data for 67,135 patients on diuretics in Japan were sourced from DeSC Healthcare, Inc. The data covered the period from April 2020 to March 2021. RESULTS: Analysis of patient numbers using the chi-squared test showed that hyperkalemia was more common in men than in women (326 vs. 271; p = 0.003) and that hypokalemia was more common in women than in men (413 vs. 285; p < 0.001). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for women considering age and renal function (estimated glomerular filtration rate [eGFR]). In elderly patients aged ≥ 75 years, the odds of developing hypokalemia in women compared to men were 1.47 (95% CI 1.13-1.91) for eGFR 60-30 mL/min/1.73 m and 2.05 (95% CI 1.08-4.10) for eGFR < 30 mL/min/1.73 m. CONCLUSION: Among women aged ≥ 75 years, those in lower eGFR groups (60-30 and < 30) had higher odds of hypokalemia compared to men. These data highlight the importance of monitoring for adverse reactions to diuretics, particularly hypokalemia, in elderly women with low eGFR.
Correction: Major Adverse Cardiovascular Events Related to JAK Inhibitors: A Disproportionality Analysis Using the WHO Global Individual Case Safety Database.
Di Napoli R, Richez C, Scavone C … +5 more , Singier A, Demourgues M, Mascolo A, Capuano A, Salvo F
Drug Saf · 2025 Aug · PMID 40549135 · Full text
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Uncovering Pregnancy Exposures in Pharmacovigilance Case Report Databases: A Comprehensive Evaluation of the VigiBase Pregnancy Algorithm.
Sandberg L, Vidlin SH, K-Pápai L … +8 more , Savage R, Raemaekers BC, Taavola-Gustafsson H, Rudolph A, Quirant L, Bergvall T, Wallberg M, Ellenius J
Drug Saf · 2025 Oct · PMID 40549134 · Full text
BACKGROUND: Information on the safety of medicine use during pregnancy is limited at the time of marketing, making post-marketing surveillance essential. However, the lack of a specific indicator for pregnancy-related ca...
BACKGROUND: Information on the safety of medicine use during pregnancy is limited at the time of marketing, making post-marketing surveillance essential. However, the lack of a specific indicator for pregnancy-related case reports within the international standard for transmission of individual case safety reports complicates the retrieval of such reports in pharmacovigilance databases. To address this, an algorithm to identify reports of exposures during pregnancy was developed in VigiBase, the World Health Organization global database of adverse event reports. OBJECTIVE: We aimed to evaluate and characterise the VigiBase pregnancy algorithm. METHODS: The rule-based algorithm uses multiple structured data elements in the International Council of Harmonisation (ICH) E2B transmission format that could potentially hold pregnancy-related information, to determine if a case report qualifies as a pregnancy case. Free text information is not considered. Three datasets were used for the evaluation. The "Full dataset" comprised deduplicated VigiBase data up to January 2023. The "Downsampled dataset" was a subsample of the Full dataset, adjusted to increase the prevalence of pregnancy reports by excluding individuals aged 45 years or older and male individuals aged 18 years or older, used to evaluate recall (i.e. sensitivity). The "Random dataset" was a straight random sample of the Full dataset, used to evaluate precision (i.e. positive predictive value). As a baseline for comparison, the Standardised Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) "Pregnancy and neonatal topics (narrow)" was used. To provide a gold standard for the evaluation, case reports were manually annotated as either "pregnancy case" or "non-pregnancy case", for all reports in the Downsampled dataset, and for the reports flagged as pregnancy cases by the algorithm or the SMQ baseline in the Random dataset. RESULTS: In the Downsampled dataset with 7874 annotated reports, 253 reports were annotated as pregnancy cases. Of those, the algorithm recalled 75% (95% confidence interval [CI] 69-80), increasing to 91% (95% CI 86-95) when restricting the analysis to reports adhering to the ICH E2B format. Preprocessing obstacles of incomplete mapping of specific pregnancy terms to MedDRA led to most false negatives followed by pregnancy information confined to free text information. The SMQ baseline had a lower recall of 62% (95% CI 56-68). In the Random dataset with 30,000 reports, the algorithm flagged 344 reports, among which 316 were annotated as pregnancy cases, leading to a precision of 92% (95% CI 88-95). The main reasons for false positives were postpartum indications, non-pregnancy-specific events or information miscoded as pregnancy related. The SMQ baseline had a lower precision of 74% (95% CI 69-78). CONCLUSIONS: The VigiBase pregnancy algorithm demonstrates robust performance, highlighting its potential to facilitate pharmacovigilance related to pregnancy. Our evaluation establishes a valuable benchmark for future research and emphasises the need for global harmonisation of standards for reporting pregnancy exposures.
Identifying New Candidate Predictors of Mortality in Japanese Patients with Severe Drug Eruptions.
Sato S, Ooka T, Zamami Y … +5 more , Hamano H, Hayashi F, Eguchi E, Funakubo N, Ohira T
Drug Saf · 2025 Nov · PMID 40536665 · Publisher ↗
UNLABELLED: BACKGROUND AND OBJECTIVES: SCORe of Toxic Epidermal Necrolysis (SCORTEN) and ABCD-10 have been developed as scoring systems for predicting mortality associated with Stevens-Johnson syndrome (SJS) or toxic epi...
UNLABELLED: BACKGROUND AND OBJECTIVES: SCORe of Toxic Epidermal Necrolysis (SCORTEN) and ABCD-10 have been developed as scoring systems for predicting mortality associated with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). These scores were developed based on a small number of patients; hence, their generalizability requires further exploration. The present study used three algorithms, including a machine learning method, to construct a mortality prediction model for SJS/TEN and to identify new candidate predictors of mortality from severe drug eruptions. METHODS: Data from 5966 patients with SJS or TEN were extracted from the Japanese Adverse Drug Event Report Database. A mortality prediction model was then constructed using stepwise regression, L1 regularized-logistic regression, and random forests based on the patient characteristics (e.g., age, sex, primary disease, adverse events, drug classification, route of administration) and outcomes (death). RESULTS AND DISCUSSION: The mortality prediction models for SJS/TEN identified sex (men), primary disease (hyperlipidemia, diabetes mellitus, renal dysfunction, and malignant tumors), adverse events (renal dysfunction, liver dysfunction, respiratory dysfunction, bacteremia/sepsis, disseminated intravascular coagulation syndrome, shock, and multiple organ failure), number of concomitant drugs, and route of administration (injection) as common factors associated with mortality. CONCLUSIONS: Our findings showed that sex, hyperlipidemia as the primary disease, number of concomitant drugs, use of antipyretic analgesics, and route of administration may be considered as predictors of mortality in patients with SJS/TEN. The external validity of these factors needs to be examined in the future.
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