The REporting of A Disproportionality Analysis for DrUg Safety Signal Detection Using Individual Case Safety Reports in PharmacoVigilance (READUS-PV): Explanation and Elaboration.

In pharmacovigilance, disproportionality analyses based on individual case safety reports are widely used to detect safety signals. Unfortunately, publishing disproportionality analyses lacks specific guidelines, often leading to incomplete and ambiguous reporting, and carries the risk of incorrect conclusions when data are not placed in the correct context. The REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance (READUS-PV) statement was developed to address this issue by promoting transparent and comprehensive reporting of disproportionality studies. While the statement paper explains in greater detail the procedure followed to develop these guidelines, with this explanation paper we present the 14 items retained for READUS-PV guidelines, together with an in-depth explanation of their rationale and bullet points to illustrate their practical implementation. Our primary objective is to foster the adoption of the READUS-PV guidelines among authors, editors, peer reviewers, and readers of disproportionality analyses. Enhancing transparency, completeness, and accuracy of reporting, as well as proper interpretation of their results, READUS-PV guidelines will ultimately facilitate evidence-based decision making in pharmacovigilance.

The Reporting of a Disproportionality Analysis for Drug Safety Signal Detection Using Individual Case Safety Reports in PharmacoVigilance (READUS-PV): Development and Statement.

BACKGROUND AND AIM: Disproportionality analyses using reports of suspected adverse drug reactions are the most commonly used quantitative methods for detecting safety signals in pharmacovigilance. However, their methods and results are generally poorly reported in published articles and existing guidelines do not capture the specific features of disproportionality analyses. We here describe the development of a guideline (REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance [READUS-PV]) for reporting the results of disproportionality analyses in articles and abstracts. METHODS: We established a group of 34 international experts from universities, the pharmaceutical industry, and regulatory agencies, with expertise in pharmacovigilance, disproportionality analyses, and assessment of safety signals. We followed a three-step process to develop the checklist: (1) an open-text survey to generate a first list of items; (2) an online Delphi method to select and rephrase the most important items; (3) a final online consensus meeting. RESULTS: Among the panel members, 33 experts responded to round 1 and 30 to round 2 of the Delphi and 25 participated to the consensus meeting. Overall, 60 recommendations for the main body of the manuscript and 13 recommendations for the abstracts were retained by participants after the Delphi method. After merging of some items together and the online consensus meeting, the READUS-PV guidelines comprise a checklist of 32 recommendations, in 14 items, for the reporting of disproportionality analyses in the main body text and four items, comprising 12 recommendations, for abstracts. CONCLUSIONS: The READUS-PV guidelines will support authors, editors, peer-reviewers, and users of disproportionality analyses using individual case safety report databases. Adopting these guidelines will lead to more transparent, comprehensive, and accurate reporting and interpretation of disproportionality analyses, facilitating the integration with other sources of evidence.

Impact of the vaccination against SARS-CoV-2 campaign on disproportionality indicator from the WHO pharmacovigilance database: A competition bias study from case/non-case analysis.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) vaccination campaign has resulted in numerous pharmacovigilance's safety reports which were recorded in the World Health Organization (WHO) pharmacovigilance database (VigiBase) and represent in July 2022 more than 10% of cases recorded. The information component (IC) is a statistical disproportionality measure based on the observed and expected numbers of case reports. A positive value of the lower endpoint of a 95% credibility interval for the information component (IC0.25) suggests a possible causal relationship between the drug and the adverse reaction. This study aimed to evaluate the impact of the wave of COVID-19 vaccines safety declarations on IC0.25 from Vigilyze and thus illustrate with a concrete example the competition bias. METHODS: We arbitrarily selected 21 adverse drug reactions using Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs), divided in two types: PTs known to be related to COVID-19 vaccines ("expected") and others (type "unexpected"). Data were extracted from VigiLyze. We created two groups: V+ (the full database, including COVID-19 vaccines reports) and V- (the same extraction without COVID-19 vaccine reports). IC0.25 was recomputed for the group V- and we compared the positive signal evolution in the two settings of selection (V+ and V- groups). RESULTS: The number of positive potential signals was significantly different in the groups V+ and V- for IC0.25. We observed that most of the "unexpected" PTs lost potential signal after the withdrawal of COVID-19 reports. On the contrary, the majority of 'expected' PTs had potential new signals after the withdrawal of COVID-19 reports. DISCUSSION: This study is one of the first to evaluate the effect of COVID-19 vaccines reporting on Automated Signal Detection of Pharmacovigilance. In this study, we observed that a wave of pharmacovigilance reporting can affect disproportionality estimators such as IC0.25 and then have an impact on automated signal detection; some signals disappear (almost with all PTs related to COVID-19 vaccines) and others appear (mostly with PTs not related to COVID-19 vaccines), illustrating the competition bias. CONCLUSION: We show that a health crisis involving a change in drug use can affect adverse drug reactions reporting and pharmacovigilance databases, leading to competition bias and a change in the disproportionality analyses. For health professionals who use quantitative disproportionality analysis, it is important not only to use the crude values of indicators but also the kind of PTs and the evolution of the signal over time (take into account major events such as crises).

Arterial hypertension associated with PARPi: A meta-analysis of 41 placebo randomized controlled trials combined with a World Health Organization's pharmacovigilance study.

BACKGROUND: Arterial hypertension has been recently reported from randomized controlled trials (RCTs) assessing poly (ADP-ribose) polymerase inhibitor (PARPi). OBJECTIVE: In a context of increasing use of PARPi, it is crucial to properly assess risk and incidence of this adverse event for clinical practice. METHODS: We performed a systematic review and meta-analysis in MEDLINE, Cochrane CENTRAL and ClinicalTrials.gov up to January 4, 2023 with an ongoing surveillance up to June 7, 2023. RCTs comparing PARPi to placebo in adult patients with solid tumors were included if hypertension was reported. The primary outcome was the summary risk ratio (RR, with 95% CIs) of any hypertension of PARPi class in placebo RCTs. Secondary outcomes were the summary risk and incidence of hypertension of each individual PARPi. To provide clinical features of PARPi-associated hypertension, we independently queried the WHO's pharmacovigilance database, up to September 1, 2022. RESULTS: In total, 41 placebo RCTs (n = 15 264 adult patients) were included. PARPi class was not associated with an increased risk of hypertension compared with placebo. In individual analyses, the risk of hypertension was lower with olaparib than placebo (RR 0.77 [95% CI: 0.68-0.86], P < 0.01; I2  = 19%, χ2 P = 0.26). Niraparib monotherapy increased the risk of any (RR 2.84 [95% CI: 1.76-4.57], P < 0.01; I2  = 66%, χ2 P = 0.01) hypertension with a summary incidence of 19.87% (95% CI: 15.23-25.50). In real-life setting, niraparib-associated hypertension occurs within 20 days and was serious in 66%. Co-prescription of at least one antihypertensive or therapy-induced hypertension was reported in 20.5% or 14.4% of cases, respectively. CONCLUSIONS: In a context of extensive assessment of niraparib in combination, these data reinforce the need of a close monitoring of this adverse event to preserve its clinical benefit on patients' survival.

State of the Art of Probiotic Use in Neonatal Intensive Care Units in French-Speaking European Countries.

The effectiveness of probiotics in reducing the incidence of necrotizing enterocolitis has been supported by a very large number of studies. However, the utilization of probiotics in preterm infants remains a topic of debate. This study aims to assess the rate of probiotic use in European neonatal intensive care units (NICUs), compare administration protocols, and identify barriers and concerns associated with probiotic use. An online questionnaire was distributed via email to European NICUs between October 2020 and June 2021. Different questions related to the frequency of probiotic use were proposed. Data on probiotic administration protocols and reasons for non-utilization were collected. The majority of responses were from France and Switzerland, with response rates of 85% and 89%, respectively. A total of 21% of French NICUs and 100% of Swiss NICUs reported routine probiotic use. There was significant heterogeneity in probiotic administration protocols, including variations in probiotic strains, administration, and treatment duration. The main obstacles to routine probiotic use were the absence of recommendations, lack of consensus on strain selection, insufficient scientific evidence, and concerns regarding potential adverse effects. The rate of routine probiotic administration remains low in European NICUs, with heterogeneity among protocols. Further trials are necessary to elucidate optimal treatment modalities and ensure safety of administration.

Neurocognitive impairment in females with breast cancer treated with endocrine therapy and CDK4/6 inhibitors: a pharmacovigilance study using the World Health Organization's database.

Importance: Endocrine therapies (ETs) and inhibitors of cyclin-dependent kinases-4/6 (iCDK4/6s) are a standard treatment in breast cancer. However, data on potential neurocognitive impacts remain inconsistent for ET and are scarce for iCDK4/6s. Objective: To evaluate whether ET and iCDK4/6s are associated with neurocognitive impairment (NCI). Methods: We used observational, real-world cases of NCI from the World Health Organization's database VigiBase® to perform disproportionality analysis. Cases were defined as any symptom of NCI in females treated with ETs or iCDK4/6s. The study period was from the date of the first adverse event reported in VigiBase® with iCDK4/6s (1 January 2014) until the date of data extraction (16 March 2022). In our primary analysis, we calculated the reporting odds ratio (ROR) adjusted for age to identify a potential association between NCI and individual ETs in isolation or in combination with iCDK4/6s. We also performed subgroup analyses by the NCI class. Results: We identified 2.582 and 1.943 reports of NCI associated with ETs and iCDK4/6s, respectively. NCI was significantly associated with each ET [anastrozole: n = 405, aROR = 1.52 (95% CI: 1.37-1.67); letrozole: n = 741, aROR = 1.37 (95% CI: 1.27-1.47); exemestane: n = 316, aROR = 1.37 (95% CI: 1.22-1.53); tamoxifen: n = 311, aROR = 1.25 (95% CI: 1.12-1.40); and fulvestrant: n = 319, aROR = 1.19 (95% CI: 1.06-1.33)] and only with palbociclib for iCDK4/6s [n = 1,542, aROR = 1.41 (95% CI: 1.34-1.48)]. Conclusion: These findings suggest that in females treated for breast cancer, all ETs may be associated with NCI. However, amongst iCDK4/6s, NCI may be specific to palbociclib. NCI most frequently involved learning and memory as well as language. Neurocognitive impact of treatments requires better consideration and management.

Infections associated with clozapine: a pharmacovigilance study using VigiBase®.

Introduction: Clozapine is primarily reserved for treatment-resistant schizophrenia due to safety concerns associated with its use. Infections have been reported with clozapine, which may lead to elevated serum levels of the drug. However, the existing literature on this topic is limited. Therefore, we conducted a study using VigiBase® to investigate the potential over-reporting of infections associated with clozapine, to explore the presence of dose-dependency, and to investigate the underlying mechanism. Methods: Disproportionality analyses were performed using VigiBase to assess the association between clozapine and all types of infections, the association between clozapine-associated infections and neutropenia, the association between clozapine-associated infections and agranulocytosis, the dose-effect relationship between clozapine and infections, and the interaction between clozapine and the main strong CYP450 inhibitors using reports carried out until 11 April 2023. Results: A statistically significant signal of infections was observed with clozapine, as indicated by an information component of 0.43 [95% CI: (0.41-0.45)]. The most commonly reported infections were respiratory and gastrointestinal in nature. Neutropenia showed weaker association with clozapine-associated reports of infections compared to other clozapine-associated reports [X2 (1, N = 204,073) = 454; p < 0.005], while agranulocytosis demonstrated a stronger association with clozapine-associated reports of infections [X2 (1, N = 204,073) = 56; p < 0.005]. No evidence of dose-dependency was observed. Among the 17 tested CYP inhibitors, significant drug-drug interactions were found with clarithromycin, metronidazole, valproic acid, lansoprazole, omeprazole, amiodarone, and esomeprazole. Discussion: Our study revealed a significant safety signal between clozapine use and infections, predominantly respiratory and gastrointestinal infections. The co-administration of clozapine with valproic acid or proton pump inhibitors may potentially contribute to an increased risk of infection. Further vigilance is warranted in clinical practice, and consideration of therapeutic drug monitoring of clozapine in cases involving concomitant use of these drugs or in the presence of infections may be beneficial.

Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis.

Immune checkpoint inhibitors (ICI) have transformed the therapeutic landscape in oncology. However, ICI can induce uncommon life-threatening autoimmune T-cell-mediated myotoxicities, including myocarditis and myositis. The thymus plays a critical role in T cell maturation. Here we demonstrate that thymic alterations are associated with increased incidence and severity of ICI myotoxicities. First, using the international pharmacovigilance database VigiBase, the Assistance Publique Hôpitaux de Paris-Sorbonne University data warehouse (Paris, France) and a meta-analysis of clinical trials, we show that ICI treatment of thymic epithelial tumors (TET, and particularly thymoma) was more frequently associated with ICI myotoxicities than other ICI-treated cancers. Second, in an international ICI myocarditis registry, we established that myocarditis occurred earlier after ICI initiation in patients with TET (including active or prior history of TET) compared to other cancers and was more severe in terms of life-threatening arrythmias and concurrent myositis, leading to respiratory muscle failure and death. Lastly, we show that presence of anti-acetylcholine-receptor antibodies (a biological proxy of thymic-associated autoimmunity) was more prevalent in patients with ICI myocarditis than in ICI-treated control patients. Altogether, our results highlight that thymic alterations are associated with incidence and seriousness of ICI myotoxicities. Clinico-radio-biological workup evaluating the thymus may help in predicting ICI myotoxicities.

CTLA-4 Pathway Is Instrumental in Giant Cell Arteritis.

BACKGROUND: Giant cell arteritis (GCA) causes severe inflammation of the aorta and its branches and is characterized by intense effector T-cell infiltration. The roles that immune checkpoints play in the pathogenesis of GCA are still unclear. Our aim was to study the immune checkpoint interplay in GCA. METHODS: First, we used VigiBase, the World Health Organization international pharmacovigilance database, to evaluate the relationship between GCA occurrence and immune checkpoint inhibitors treatments. We then further dissected the role of immune checkpoint inhibitors in the pathogenesis of GCA, using immunohistochemistry, immunofluorescence, transcriptomics, and flow cytometry on peripheral blood mononuclear cells and aortic tissues of GCA patients and appropriated controls. RESULTS: Using VigiBase, we identified GCA as a significant immune-related adverse event associated with anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) but not anti-PD-1 (anti-programmed death-1) nor anti-PD-L1 (anti-programmed death-ligand 1) treatment. We further dissected a critical role for the CTLA-4 pathway in GCA by identification of the dysregulation of CTLA-4-derived gene pathways and proteins in CD4+ (cluster of differentiation 4) T cells (and specifically regulatory T cells) present in blood and aorta of GCA patients versus controls. While regulatory T cells were less abundant and activated/suppressive in blood and aorta of GCA versus controls, they still specifically upregulated CTLA-4. Activated and proliferating CTLA-4+ Ki-67+ regulatory T cells from GCA were more sensitive to anti-CTLA-4 (ipilimumab)-mediated in vitro depletion versus controls. CONCLUSIONS: We highlighted the instrumental role of CTLA-4 immune checkpoint in GCA, which provides a strong rationale for targeting this pathway.

Mapping Strategies to Assess and Increase the Validity of Published Disproportionality Signals: A Meta-Research Study.

BACKGROUND AND AIM: Disproportionality analysis is traditionally used in spontaneous reporting systems to generate working hypotheses about potential adverse drug reactions: the so-called disproportionality signals. We aim to map the methods used by researchers to assess and increase the validity of their published disproportionality signals. METHODS: From a systematic literature search of published disproportionality analyses up until 1 January 2020, we randomly selected and analyzed 100 studies. We considered five domains: (1) rationale for the study, (2) design of disproportionality analyses, (3) case-by-case assessment, (4) use of complementary data sources, and (5) contextualization of the results within existing evidence. RESULTS: Among the articles, multiple strategies were adopted to assess and enhance the results validity. The rationale, in 95 articles, was explicitly referred to the accrued evidence, mostly observational data (n = 46) and regulatory documents (n = 45). A statistical adjustment was performed in 34 studies, and specific strategies to correct for biases were implemented in 33 studies. A case-by-case assessment was complementarily performed in 35 studies, most often by investigating temporal plausibility (n = 26). Complementary data sources were used in 25 articles. In 78 articles, results were contextualized using accrued evidence from the literature and regulatory documents, the most important sources being observational (n = 45), other disproportionalities (n = 37), and case reports (n = 36). CONCLUSIONS: This meta-research study highlighted the heterogeneity in methods and strategies used by researchers to assess the validity of disproportionality signals. Mapping these strategies is a first step towards testing their utility in different scenarios and developing guidelines for designing future disproportionality analysis.

Hypoxia Associated With Dihydropyridine Calcium Channel Inhibitors: A Pharmacovigilance Study in VigiBase.

Due to their negative effects on hypoxic pulmonary vasoconstriction, dihydropyridine calcium channel inhibitors (DCCIs) can lead to hypoxia in patients with a pulmonary shunt. To date, only preclinical studies and case reports have focused on this potential adverse drug reaction. We aimed to assess the reporting association between DCCIs and hypoxia using the World Health Organization pharmacovigilance database (VigiBase). We performed a disproportionality analysis to evaluate the strength of the reporting association between i.v. clevidipine and nicardipine, thought to be a surrogate of patients in the intensive care unit, and hypoxia. The information component and the lower end of its 95% credibility interval were used to evaluate disproportionality. A description of the cases was made. Secondary outcomes included the association between all DCCIs and hypoxia compared with other treatments with similar indications, urapidil and labetalol, regardless of the route of administration. Association between oral nicardipine and hypoxia was also searched. A statistically significant signal of hypoxia was found for intravenous clevidipine and nicardipine. The time to onset was reported with a median of 2 days (interquartile range 1.5-4.5). Four dechallenges were performed with intravenous nicardipine, leading to the resolution of the symptoms. Regardless of the route of administration, a signal of hypoxia was also found for nimodipine but not for other drugs, including comparators. For nicardipine no signal of hypoxia was found with the oral route of administration. Our pharmacovigilance database analysis showed a significant association between the use of intravenous DCCIs and hypoxia.

Atrial Fibrillation Incidence Associated With Exposure to Anticancer Drugs Used as Monotherapy in Clinical Trials.

Background: The incidence of atrial fibrillation (AF) associated with anticancer drugs in cancer patients remains incompletely defined. Objectives: The primary outcome was the annualized incidence rate of AF reporting associated with exposure to 1 of 19 anticancer drugs used as monotherapy in clinical trials. The authors also report the annualized incidence rate of AF reported in the placebo arms of these trials. Methods: The authors systematically searched ClinicalTrials.gov for phase 2 and 3 cancer trials studying 19 different anticancer drugs of interest used as monotherapy, up to September 18, 2020. The authors performed a random-effects meta-analysis to compute summary AF annualized incidence rate with its 95% CI using log transformation and inverse variance weighting. Results: A total of 191 clinical trials (47.1% were randomized) of 16 anticancer drugs across 26,604 patients were included. Incidence rates could be calculated for 15 drugs administered singly as monotherapy. Summary annualized incidence rates of AF reporting associated with exposure to 1 of the 15 anticancer drugs used as monotherapy were derived; these ranged from 0.26 to 4.92 per 100 person-years. The 3 highest annualized incidence rates of AF reporting were found for ibrutinib 4.92 (95% CI: 2.91-8.31), clofarabine 2.38 (95% CI: 0.66-8.55), and ponatinib 2.35 (95% CI: 1.78-3.12) per 100 person-years. Summary annualized incidence rate of AF reporting in the placebo arms was 0.25 per 100 person-years (95% CI: 0.10-0.65). Conclusions: AF reporting is not a rare event associated with anticancer drugs in clinical trials. A systematic and standardized AF detection should be considered in oncological trials, particularly those studying anticancer drugs associated with high AF rates. (Incidence of atrial fibrillation associated with anticancer drugs exposure in monotherapy, A safety meta-analysis of phase 2 and 3 clinical trials; CRD42020223710).

Rhabdomyolysis with Co-Administration of Statins and Antiplatelet Therapies-Analysis of the WHO Pharmacovigilance Database.

PURPOSE: While statins and antiplatelet therapies are largely prescribed together worldwide, limited information is available on the safety of their association regarding rhabdomyolysis occurrence. We aimed to assess the reporting of rhabdomyolysis in patients treated with a combination of statin and antiplatelet therapy, compared to statin alone. METHODS: We used the World Health Organization pharmacovigilance database (VigiBase®) to compare the rhabdomyolysis reporting between statin (atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin) plus antiplatelet therapy (acetylsalicylic acid, clopidogrel, prasugrel and ticagrelor) groups versus statin alone groups, for each statin and antiplatelet therapy. Study setting was restricted to patients aged 45 or older, including reports up until 1st September, 2021. We computed reporting Odds-Ratio (ROR) and their 95% confidence interval (CI) to quantify the disproportionality between groups, adjusted on age and sex. RESULTS: Among the 11,431,708 reports of adverse reactions, we extracted 9,489 cases of rhabdomyolysis in patients treated with statins, of whom 2,464 (26%) were also treated with antiplatelet therapy. The reporting of rhabdomyolysis was increased when ticagrelor was associated with atorvastatin (ROR 1.30 [1.02-1.65]) or rosuvastatin (ROR 1.90 [1.42-2.54]) compared to the respective statin alone but did not change when aspirin, clopidogrel or prasugrel were considered. CONCLUSION: Rhabdomyolysis reporting was increased when ticagrelor -but not other antiplatelet agents- was notified with the most prescribed statins in practice. This finding needs to be considered by physicians especially in high-risk patients.

Sport resumption and quality of life after surgical correction of anomalous origin of a coronary artery from the opposite sinus.

Objectives: We sought to assess the resumption of sport, exercise performances, and quality of life (QoL) in adults and children after surgical repair of anomalous coronary arteries originating from the opposite sinus (ACAOS). Materials and methods: Patients who underwent surgical repair for ACAOS between 2002 and 2022 were retrospectively identified. Information about sports activity and exercise performance based on metabolic equivalents of task (METs) calculated at the last exercise stress test, were collected. QoL was assessed using age-appropriate questionnaires (Paediatric QoL Inventory, cardiac module version 3.0 for patients <18 years; SF-36 QoL Inventory for adults). Patients' METS and patients' QoL-scores were compared to reference population using the Wilcoxon test. Results: 45 patients were enrolled (males 71%, adults 49%, anomalous right coronary 84%). Median age at surgery was 15 years; median follow-up after surgery was 2.3 years [4 months-12 years]. All post-operative exercise stress tests were normal, METs and VO2 max patients' values did not differ from healthy children or adults (Exercise intensity: 12.5 ± 4.7 vs. 13.4 ± 2 METS, p = 0.3; VO2 max: 43.6 ± 16.6 vs. 46.9 ± 7 ml/kg/min, p = 0.37). For adults, QoL-scores were similar between ACAOS patients and controls. For children, there was no significant difference between the study patients' scores and those of the reference population, except for physical appearance proxy-report (p = 0.02). Conclusion: In our study, the practice of sports, exercise stress testing and QoL were not adversely affected after ACAOS repair.

Drug-associated acquired hemophilia A: an analysis based on 185 cases from the WHO pharmacovigilance database.

INTRODUCTION: Acquired hemophilia A (AHA) is a rare autoimmune hemorrhagic disease occurring in several underlying conditions. Drug-associated AHA (D-AHA) is poorly addressed nowadays. AIM: This work aims to identify and characterize which drugs are associated with AHA using the WHO global database of reported potential effects of medicinal products (VigiBase). METHODS: First, we realized a disproportionality analysis using the information component (IC) to identify D-AHA in VigiBase. IC compares observed- and expected-values in order to find associations between drugs and adverse drug reactions (ADRs) using disproportionate Bayesian reporting. IC025 is the lower end of a 95% credibility interval for the IC. Then, we collected cases of drugs significantly associated with AHA from July 2004 to November 2021. RESULTS: 14 drugs with IC025 > 0 were identified representing a total of 185 cases. D-AHA occurred more frequently in men (59%) than women (41%). The median (min-max) age at onset was 75 years (8-98). The median [Q1-Q3] time to onset of D-AHA from the start of the suspected drug was 30 days [9.5-73.75] and 10% of cases resulted in a fatality. The drugs associated with the highest IC025 (IC025 > 2) were Clopidogrel, Alemtuzumab, Omalizumab. This study retrieved for the first time three usually used drugs (3/14) that exhibit a significant pharmacovigilance signal for D-AHA. CONCLUSION: This worldwide pharmaco-epidemiologic study updates the list of the drugs associated with AHA. The clinician should be aware of these possible severe ADR, which might require larger epidemiological and pathophysiologic studies.

Association between road traffic accidents and drugs belonging to the antiseizure medications class: A pharmacovigilance analysis in VigiBase.

AIMS: Due to their central mechanism of action, antiseizure medications (ASMs) could lead to adverse effects likely to impair driving skills. Their extended use to neuropsychiatric disorders makes it a class of drugs to monitor for their road traffic accidental (RTA) potential. We aimed to assess the reporting association between ASMs and RTAs using the World Health Organization pharmacovigilance database (VigiBase). METHODS: We performed a disproportionality analysis to compute adjusted reporting odds ratios to evaluate the strength of reporting association between ASMs and RTAs. A univariate analysis using the reporting odds-ratio was used to assess drug-drug interactions between ASMs and RTAs. RESULTS: There were 1 341 509 reports associated with at least 1 ASM in VigiBase of whom 2.91‰ were RTAs reports. Eight ASMs were associated with higher reporting of RTAs compared to others (ranging from 1.35 [95% confidence interval 1.11-1.64] for lamotrigine to 4.36 [95% confidence interval 3.56-5.32] for cannabis). Eight significant drug-drug interactions were found between ASMs and the onset of RTA, mainly involving CYP450 induction. CONCLUSION: A significant safety signal between RTAs and some ASMs was identified. Association of several ASMs might further increase the occurrence of RTA. ASMs prescription in patients with identified risk factors of RTA should be considered with caution. Study number: ClinicalTrials.gov, NCT04480996.