An artificial intelligence algorithm for co-clustering to help in pharmacovigilance before and during the COVID-19 pandemic.

AIMS: Monitoring drug safety in real-world settings is the primary aim of pharmacovigilance. Frequent adverse drug reactions (ADRs) are usually identified during drug development. Rare ones are mostly characterized through post-marketing scrutiny, increasingly with the use of data mining and disproportionality approaches, which lead to new drug safety signals. Nonetheless, waves of excessive numbers of reports, often stirred up by social media, may overwhelm and distort this process, as observed recently with levothyroxine or COVID-19 vaccines. As human resources become rarer in the field of pharmacovigilance, we aimed to evaluate the performance of an unsupervised co-clustering method to help the monitoring of drug safety. METHODS: A dynamic latent block model (dLBM), based on a time-dependent co-clustering generative method, was used to summarize all regional ADR reports (n = 45 269) issued between 1 January 2012 and 28 February 2022. After analysis of their intra and extra interrelationships, all reports were grouped into different cluster types (time, drug, ADR). RESULTS: Our model clustered all reports in 10 time, 10 ADR and 9 drug collections. Based on such clustering, three prominent societal problems were detected, subsequent to public health concerns about drug safety, including a prominent media hype about the perceived safety of COVID-19 vaccines. The dLBM also highlighted some specific drug-ADR relationships, such as the association between antiplatelets, anticoagulants and bleeding. CONCLUSIONS: Co-clustering and dLBM appear as promising tools to explore large pharmacovigilance databases. They allow, 'unsupervisedly', the detection, exploration and strengthening of safety signals, facilitating the analysis of massive upsurges of reports.

A Hybrid Algorithm Combining Population Pharmacokinetic and Machine Learning for Isavuconazole Exposure Prediction.

OBJECTIVES: Maximum a posteriori Bayesian estimation (MAP-BE) based on a limited sampling strategy and a population pharmacokinetic (POPPK) model is used to estimate individual pharmacokinetic parameters. Recently, we proposed a methodology that combined population pharmacokinetic and machine learning (ML) to decrease the bias and imprecision in individual iohexol clearance prediction. The aim of this study was to confirm the previous results by developing a hybrid algorithm combining POPPK, MAP-BE and ML that accurately predicts isavuconazole clearance. METHODS: A total of 1727 isavuconazole rich PK profiles were simulated using a POPPK model from the literature, and MAP-BE was used to estimate the clearance based on: (i) the full PK profiles (refCL); and (ii) C24h only (C24h-CL). Xgboost was trained to correct the error between refCL and C24h-CL in the training dataset (75%). C24h-CL as well as ML-corrected C24h-CL were evaluated in a testing dataset (25%) and then in a set of PK profiles simulated using another published POPPK model. RESULTS: A strong decrease in mean predictive error (MPE%), imprecision (RMSE%) and the number of profiles outside ± 20% MPE% (n-out20%) was observed with the hybrid algorithm (decreased in MPE% by 95.8% and 85.6%; RMSE% by 69.5% and 69.0%; n-out20% by 97.4% and 100% in the training and testing sets, respectively. In the external validation set, the hybrid algorithm decreased MPE% by 96%, RMSE% by 68% and n-out20% by 100%. CONCLUSION: The hybrid model proposed significantly improved isavuconazole AUC estimation over MAP-BE based on the sole C24h and may improve dose adjustment.

Drug-related catatonia in youths: real-world insights from the WHO Safety Database.

Catatonia is characterized by psychomotor alterations and reduced contact with the environment. Initially linked to schizophrenia, it also occurs in mood disorders or organic conditions. In children, catatonia remains poorly delineated, despite dramatically increasing the risk of premature death. As data on pediatric drug-induced catatonia bears many uncertainties, we aimed to characterize its age-dependent patterns, using real-world data from the WHO safety database (VigiBase®).VigiBase® was queried for all reports of catatonia registered up to December 8th 2022. Reports involving patients <18 years were classified into 3 groups: ≤23 months, 2-11 years, and 12-17 years. Disproportionality analyses relied on the Reporting Odds Ratio (ROR), and the positivity of the lower end of the 95% confidence interval of the Information Component (IC) was required to suspect a signal. Catatonia was evoked in 421 pediatric reports. In infants, vaccines were leading. In children, the main signals involved haloperidol (ROR 104.3; 95% CI 45.6-238.5), ondansetron (ROR 40.5; 95% CI 16.5-99.5), and ciclosporin (ROR 27.4; 95% CI 13.8-54.1). In adolescents, chlorpromazine (ROR 199.1; 95% CI 134.8-294.1), benzatropine (ROR 193; 95% CI 104.1-361.6), and olanzapine (ROR 135.7; 95% CI 104.6-175.9) reached the highest RORs. In infants, catatonia was related to vaccines, it was ascribed to multiple drugs in children, and mainly to psychotropic drugs in adolescents. Less suspected drugs, such as ondansetron, were highlighted. Despite limitations inherent in spontaneous reporting systems, this study supports that a careful anamnesis is warranted to separate catatonia associated with medical conditions from drug-induced catatonia in pediatric patients.

Calcitonin gene-related peptide-targeting drugs and Raynaud's phenomenon: a real-world potential safety signal from the WHO pharmacovigilance database.

BACKGROUND: Migraine is responsible for significant disability and societal burden. Recently, drugs targeting the calcitonin gene-related peptide (CGRP) pathway raised new hopes. CGRP, a potent vasodilator, plays a key role in the pathogenesis of migraine attacks. The deficiency of CGRP is involved in Raynaud's phenomenon, which consists of abnormal vasoconstriction of the digits. We aimed to assess the potential association of Raynaud's phenomenon with CGRP-targeting drugs, analyzing real-world data from the World Health Organization (VigiBase®). METHODS: We queried all reports of Raynaud's phenomenon involving a CGRP-targeting drug. We sought disproportionate reporting of Raynaud's phenomenon with these drugs. For this purpose, we relied on the calculation of the Information Component (IC). A positive lower end of the 95% confidence interval (CI) of the IC defines a statistically significant association. As migraine patients are prone to Raynaud's phenomenon, we also calculated the IC of Raynaud's phenomenon with CGRP-targeting drugs compared to 5HT1B/D agonists (triptans), and beta-blockers used in the treatment of migraine. RESULTS: Overall, 99 reports of Raynaud's phenomenon involving CGRP-targeting drugs have been yielded in VigiBase®. The most reported CGRP-targeting drug was erenumab, with 56 reports (56.6%). The median time to onset was 84 days. No fatality was notified, but one patient suffered from gangrene and extremity necrosis. As a whole, CGRP-targeting drugs were significantly associated with Raynaud's phenomenon, with an IC of 3.3 (95%CI: 3.0-3.5). There was a disproportionate reporting of Raynaud's phenomenon with CGRP-targeting drugs compared to triptans (IC 0.4; 95%CI: 0.1-0.6) and to beta-blockers (IC 0.5; 95%CI: 0.2-0.7) as well. CONCLUSIONS: There is a significant disproportionality signal of Raynaud's phenomenon with CGRP-targeting. This signal stands out when CGRP-targeting drugs are compared to other drugs used in patients with migraine. This study is limited by missing data in pharmacovigilance reports. CGRP-targeting drugs may be subject to Weber effect and reporting bias. Nonetheless, CGRP blockade might be the last straw that disrupts the physiological balance of vascular response in patients at-risk of Raynaud's phenomenon. Pending further data regarding vascular safety of CGRP-targeting drugs, caution is warranted in these patients.

Immune checkpoint inhibitors-induced nephropathy: a French national survey.

Immune checkpoint inhibitors (ICIs), aiming to foster cancer-targeted immune response, proved to be effective in several advanced malignancies at the price of immune-related adverse events affecting various organs, notably the kidneys. Herein, a retrospective descriptive analysis was performed on all biopsy-confirmed cases of ICI-induced nephropathy notified to the French Pharmacovigilance database to date. Data were gathered about patients' characteristics, acute kidney injuries and histopathological features. A total of 63 biopsy-proven cases were included for analysis. Immune-related nephropathy occurred after a mean of 105.5 ± 98.6 (standard deviation) days after the introduction of the ICI. Kidney Disease: Improving Global Outcomes acute kidney injury stage 3 occurred in 36.5% of patients, and the mean peak serum creatinine was 288 µmol/L. Histopathology suggested acute tubule-interstitial nephritis in 52 patients (83%), while signs of acute tubular necrosis were found in 18 (29%) and glomerular involvement in 5 of them (8%). Another immune-related adverse event was documented in 25 patients (39.7%). Patients were treated with corticosteroids in 88.9% of cases. All in all, 27.0% fully recovered, 54.0% partially recovered, 12.7% did not recover. Rechallenge was attempted in 19 patients and one patient relapsed. Three-quarters of patients received a medication known to cause acute tubule-interstitial nephritis. The major limits of this study are those inherent to pharmacovigilance studies, such as its retrospective nature and incomplete data. Although it cannot pretend drawing any pathophysiological conclusion, this study depicts the clinical and histopathological pictures of ICI-induced nephropathies in a large cohort of biopsied patients with all grades of severity.

Therapeutic Drug Monitoring of Direct Oral Anticoagulants May Increase Their Benefit-Risk Ratio.

The attractiveness of direct oral anticoagulants (DOACs) over vitamin K antagonists, in addition to a better benefit-risk ratio, stems from the fact that no therapeutic drug monitoring is deemed necessary. This has been recently mitigated by the fact that increased dabigatran (D) plasma levels have been associated with hemorrhages, and is currently under scrutiny of the European Medicines Agency. We aimed to evaluate, in real conditions of use, whether patients with out-of-range DOAC blood concentrations (too high or too low) were associated with bleeding or thrombosis. Patients treated with D or rivaroxaban (R) were prospectively included in a hospital cohort. D and R plasma levels were measured by high-pressure liquid chromatography-tandem mass spectrometry-at the physician's demand. We defined concentration range as "expected" within the 95% confidence interval of the mean concentration obtained from pivotal trials, and "out of range" when concentrations were outside of that interval. A blind assessment of concentrations versus occurrence of bleeding or thrombosis was performed by means of univariate and multivariate analysis. Three hundred and twenty-two patients (mean age 78.5 years ± 13.1), treated with D or R were included consecutively. They had a mean CHA2DS2-VASc at 4.4 ± 1.7 and a mean HAS-BLED score at 1.7 ± 0.9. Irrespective of the DOAC prescribed, patients presenting with out-of-range concentrations had significantly more bleeding or thrombosis than patients with expected concentrations (P < 0.001). Patients with bleeding were more prone to have concentrations beyond the 95 percentile (N = 62, P < 0.001), whereas patients with thrombosis were more likely to have concentrations below the fifth percentile (N = 26, P < 0.05). The main risks associated with hemorrhages were abnormal concentrations, a high HAS-BLED score, the patient's age, and the creatinine blood level. For thrombosis, a concentration below the fifth percentile was the only risk factor that was significant in our cohort. While D and R under current recommendation have a better benefit-risk ratio than warfarin, their safe usage could be further optimized by some degree of therapeutic monitoring.

Are current guidelines adapted for patient eligibility to PrEP? A case report.

BACKGROUND: Despite effective antiretroviral therapy developed over the last decade, HIV infection remains a major worldwide public health problem. Recently, a promising preventive treatment has been made available for HIV prophylaxis, PrEP for pre-ExPosure Prophylaxis. Indeed, it was shown to significantly reduce the risk of HIV infection in patients exposed to high risk of infection such as men having sex with men (MSM), heterosexuals and people who inject drugs. Several issues pertaining to PrEP remain uncertain including short and long-term adverse events, drug resistance, risk compensation and resurgence of other sexually transmitted infections. CASE PRESENTATION: We report a case of a 52-year-old MSM eligible for PrEP as he was exposed to a high risk of HIV infection, presented no clinical symptoms of HIV primary infection and was seronegative for HIV. PrEP therapy was then initiated with fixed association of emtricitabine-tenofovir disoproxil. One month later, HIV tests using two different assays were positive, despite perfect compliance reported by the patient and confirmed by plasma drug level. A retrospective search for plasma viral RNA in the blood sample before PrEP initiation turned out positive. Genotyping and treatment sensitivity performed on sample after one month of PrEP showed a virus resistance to lamivudine and emtricitabine. Similar cases in the literature and pivotal studies have reported HIV infections in patients initiating or undergoing PrEP. These patients where either infected but still seronegative, displaying no clinical symptoms upon enrollment, or became infected during PrEP. Reasons are mainly poor compliance to treatment, resistance to PrEP, and lack of diagnosis before PrEP. Guidelines advocate safe sex behavior before initiation, search for clinical signs of HIV primary infection and two different serologic tests performed with one-month interval. DISCUSSION AND CONCLUSIONS: Our patient newly HIV infected received PrEP as he was still seronegative. Current recommendations fail to screen recently HIV infected, but still seronegative patients who are initiating PrEP. This issue raises strong concerns regarding the lack of adequate selection for eligibility to PrEP and may contribute to exposing partners to HIV infection and select viral mutations. Infection risk could be minimized by search for plasma viral HIV RNA at pre-inclusion, at least for patients suspected of unsafe behaviors such as non-respect of the non-exposure period before PrEP initiation.

[Comparative relevance of declaration of side effects by patients and health professionals]. / Pertinence comparée des notifications d'effets indésirables de patients et professionnels de santé.

INTRODUCTION: Drug-induced adverse events have been accessible to patient's spontaneous reporting in France and such notifications have been steadily increasing since 2011. However, these notifications are still shrouded with medical perplexity and are sometimes subjected to partial caution in their interpretation by the patient's physician. We aimed to evaluate and compare prospectively the relevance of such spontaneous notifications with those provided by healthcare professionals to the French Pharmacovigilance Center of Nice-Alpes-Côte d'Azur. METHODS: Spontaneous reporting of drug adverse events notified by patients and health care professionals were compared in terms of critical (name, date, effect, drug involved, chronological compatibility) and non-critical (posology, dosage) information, whereas the plausibility of the cases were assessed in weekly multispecialty staffs. Each patient's notification was matched with the immediate pre- and post-notifications declared by health care providers. RESULTS: Spontaneous notifications from 61 patients were compared with 122 notifications from health care providers. Neither the critical information necessary for declaring the case in the national database (7/61 versus 16/122, P=0.75), nor the uncritical elements allowing to assess the case (30/61 versus 51/122, P=0.22), its plausibility or the causality of the drug (P=0.10) differed significantly between the two groups. 107 cases out of 122 (88%) notified by health care providers were classified as serious, as compared with 19 out of 61 (15%) of patient's ones (P<0.001). CONCLUSION: Despite concerns from pharmacovigilance specialists in France, the medical relevance of spontaneous reported drug-associated adverse events does not differ from that of health care providers.

Drug-induced cardiac toxicity and adverse drug reactions, a narrative review.

Drug-induced cardiotoxicity is a primary concern in both drug development and clinical practice. Although the heart is not a common target for adverse drug reactions, some drugs still cause various adverse cardiac events, with sometimes severe consequences. Direct cardiac toxicity encompasses functional and structural changes of the cardiovascular system due to possible exposure to medicines. This phenomenon extends beyond cardiovascular drugs to include non-cardiovascular drugs including anticancer drugs such as tyrosine kinase inhibitors, anthracyclines and immune checkpoint inhibitors (ICIs), as well as various antipsychotics, venlafaxine, and even some antibiotics (such as macrolides). Cardiac ADRs comprise an array of effects, ranging from heart failure and myocardial ischemia to valvular disease, thrombosis, myocarditis, pericarditis, arrhythmias, and conduction abnormalities. The underlying mechanisms may include disturbances of ionic processes, induction of cellular damage via impaired mitochondrial function, and even hypercoagulability. To mitigate the impact of drug-induced cardiotoxicity, multi-stage evaluation guidelines have been established, following the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines for in vitro and in vivo testing. Despite preclinical safeguards, post-marketing surveillance remains critical, as certain cardiotoxic drugs may escape initial scrutiny. Indeed, historical data show that cardiovascular ADRs contribute to almost 10% of market withdrawals. The impact of drug-induced cardiotoxicity on cardiac issues, particularly heart failure, is often underestimated, with incidence rates ranging from 11.0% to over 20.0%. We here comprehensively examine different patterns of drug-induced cardiotoxicity, highlighting current concerns and emerging pharmacovigilance signals. Understanding the underlying mechanisms and the associated risk factors is critical in order to promptly identify, effectively manage, and proactively prevent drug-induced cardiac adverse events. Collaborative efforts between physicians and cardiologists, coupled with thorough assessment and close monitoring, are essential to ensuring patient safety in the face of potential drug-induced cardiotoxicity.

Lipschütz ulcer following first dose of COVID-19 tozinameran vaccine: Report of a case and review of a World Health Organization pharmacovigilance database.

Lipschütz ulcer (LU) is a condition known for painful vulvar ulcers, typically affecting young women and often linked to infectious agents. Recent reports have indicated a potential connection between LU and COVID-19 vaccination, particularly after the second or booster doses. This study presents a case of LU following the first dose of tozinameran in a young woman who had a previous SARS-CoV-2 infection and investigates similar cases globally. An 18-year-old woman experienced vulvar pain and ulcers 2-days after her initial COVID-19 vaccine dose. After ruling out infections through serological tests, a diagnosis of LU was made, and her symptoms resolved after 10 days. A literature search and VigiBase® analysis revealed 11 cases of LU following COVID-19 vaccination, and 519 vulvovaginal ulcer cases associated with these vaccines were identified in Vigibase®, with a median onset of 2 days. Most LU cases occurred after the second dose or booster shots. The primary hypothesis for this association is a type 3 hypersensitivity reaction mediated by immune complexes, possibly triggered by prior exposure, as many cases occurred after the second dose. Interestingly, the presented case suggests that prior COVID-19 infection could serve as sensitization. In conclusion, this study highlights the potential occurrence of LU after the initial COVID-19 vaccine dose in young patients with prior COVID-19 infection. While the risk of recurrence after subsequent vaccinations or infections remains uncertain, the benefits of vaccination outweigh the risks. Clinicians and patients should be aware of this potential issue to make informed decisions regarding vaccination.

Cardiac and metabolic safety profile of antipsychotics in youths: A WHO safety database analysis.

A significant heterogeneity prevails in antipsychotics (APs) safety monitoring recommendations. Youths are deemed more vulnerable to cardiometabolic side effects. We aimed to assess age-dependent reporting of cardiac and metabolic disorders in youths, relying on the WHO safety database (VigiBase®). VigiBase® was queried for all reports of cardiac, glucose, lipid and nutritional disorders involving APs. Patients <18 years were classified as pediatric population. Disproportionality analyses relied on the Information Component (IC): the positivity of the lower end of its 95 % confidence interval was required to suspect a signal. We yielded 4,672 pediatric reports. In disproportionality analysis, nutritional disorders were leading in youths (IC 3.9 [3.9-4.0]). Among healthcare professionals' reports, stronger signals were detected in youths than in adults. Children had the greatest signal with nutritional disorders (IC 4.7 [4.6-4.8]). In adolescents, aripiprazole was ascribed to non-alcoholic steatohepatitis (NASH). Our findings, based on real-world data, support the hypothesis of a greater propensity for nutritional disorders in youths, despite limitations of pharmacovigilance studies. We suggest specific safety profiles, such as aripiprazole and NASH. Pending more answers from population-based studies, a careful anamnesis should seek for risk factors before AP initiation. A cautious monitoring is warranted to allow earlier identification of side effects.

Dental Adverse Effects of Anti-CD20 Therapies.

INTRODUCTION: Over the past few years, anti-CD20 therapies like rituximab, ocrelizumab or ofatumumab have seen an increase in interest in the treatment of neurological autoimmune disorders such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), or resistant forms of generalized myasthenia gravis (MG). They are generally well-tolerated, but recent reports have highlighted severe dental disorders in patients undergoing anti-CD20 therapies. The aim was to describe a series of cases and to compare with the available scientific literature. METHODS: We reviewed 6 patient cases with dental disorders during anti-CD20 therapy that were reported to the pharmacovigilance center. A disproportionality analysis was also conducted on Vigibase® for each anti-CD20 and each adverse effect described in the cases. RESULTS: Six cases of dental and gingival conditions in relatively young patients were reported (median age: 40.5 years old [min: 34; max: 79]). Oral conditions were developed in four patients with MS treated with ocrelizumab and in two patients receiving rituximab (one patient with MG and one with NMOSD). The onset of oral conditions ranged from 10 days to 2 years after treatment initiation. Notably, all patients treated with ocrelizumab experienced gingival recession. Various dental pathologies were observed, including tooth loss, dental pain, caries, brittle teeth, dental fractures, dental abscesses, and periodontitis. Analysis of Vigibase® revealed 284 worldwide cases of dental and gingival conditions under ocrelizumab, 386 cases under rituximab, and 80 under ofatumumab. Significant associations were found between these therapies and dental pathologies, particularly tooth abscesses and infections. CONCLUSION: To our knowledge, this is the first case series reporting dental conditions developed in patients long-term treated with anti-CD20 treatments. This issue, literature data, and Vigilyze® analysis might be considered a safety signal that necessitates being confirmed with more robust data, such as a retrospective study with a control group. Meanwhile, proactive measures are essential like frequent dental checkups and dental hygienic measures to prevent oral health problems associated with anti-CD20 therapies.

What should be done to combat misinformation about health products?

The increasing role of digital technology, social media, the wide range of channels and the volume of information, the role of medicine as a societal subject, public information that is insufficient and poorly suited to situations of uncertainty are all observations which led to the theme of this round table. After discussing the definition of disinformation, which is not limited to fake news, and talking about contributors who misinform, whether intentionally or not, the participants of this round table made nine recommendations (R) to combat disinformation about health products: create a collaborative platform, information/training on health products, a platform with five major characteristics, namely accessibility, flexibility, objectivity, transparency and independence, as well as media suited to the different targets (R1); promote basic knowledge on health products: education/training to restore the particularly poor image of medication, and teach the public how to use basic concepts appropriately (R2); improve communication to the public based on the observation that information is the main weapon against misinformation and entails, in particular, coordinating communication from the different institutions to make public information more audible, making institutional messages clearer, ensuring they are more factual and prioritising them (R3); know how to communicate using the correct codes and tools (R4), because, to be understood, the substance and the form are inseparable; develop research on communication in the field of health products (R5); acquire tools to identify and regulate as soon as possible (R6); keep check of content by developing critical thinking (R7); define quality criteria for information sources (R8); identify, assess and reference initiatives for the public that could be placed on the platform (R9).

Optimization of Rituximab Therapy in Adult Patients With PLA2R1-Associated Membranous Nephropathy With Artificial Intelligence.

Introduction: Rituximab is a first-line treatment for membranous nephropathy. Nephrotic syndrome limits rituximab exposure due to urinary drug loss. Rituximab underdosing (serum level <2 µg/ml at month-3) is a risk factor for treatment failure. We developed a machine learning algorithm to predict the risk of underdosing based on patients' characteristics at rituximab infusion. We investigated the relationship between the predicted risk of underdosing and the cumulative dose of rituximab required to achieve remission. Methods: Rituximab concentrations were measured at month-3 in 92 sera from adult patients with primary membranous nephropathy, split into a training (75%) and a testing set (25%). A forward-backward machine-learning procedure determined the best combination of variables to predict rituximab underdosing in the training data set, which was tested in the test set. The performances were evaluated for accuracy, sensitivity, and specificity in 10-fold cross-validation training and test sets. Results: The best variables combination to predict rituximab underdosing included age, gender, body surface area (BSA), anti-phospholipase A2 receptor type 1 (anti-PLA2R1) antibody titer on day-0, serum albumin on day-0 and day-15, and serum creatinine on day-0 and day-15. The accuracy, sensitivity, and specificity were respectively 79.4%, 78.7%, and 81.0% (training data set), and 79.2%, 84.6% and 72.7% (testing data set). In both sets, the algorithm performed significantly better than chance (P < 0.05). Patients with an initial high probability of underdosing experienced a longer time to remission with higher rituximab cumulative doses required to achieved remission. Conclusion: This algorithm could allow for early intensification of rituximab regimen in patients at high estimated risk of underdosing to increase the likelihood of remission.

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.

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.

Pharmacovigilance follow-up of patients in the context of the COVID-19 pandemic.

INTRODUCTION: In the context of COVID-19 pandemic, a national pharmacovigilance survey was set up in March 2020. The purpose of this survey was to ensure continuous monitoring of adverse drug reactions (ADRs) in patients with COVID-19, not only related to the drugs used in this indication but also related to all drugs administered to these patients or suspected of having promoted the infection. MATERIAL AND METHODS: This descriptive study was based on data extracted from the French Pharmacovigilance Database from 1 January 2020 to 30 September 2021. Misuse was also analysed through the MESANGE project. The ADRs were classified according to three groups: "drugs used to treat COVID-19", "other drugs administered to COVID-19 positive patients" and "drugs suspected of having promoted COVID-19". The data were also presented according to 2 periods (period one was from January to June 2020 and period two from July 2020 onwards). RESULTS: Among 2189 included cases, 67.1% were serious. Cases were mainly related to "other drugs administrated to COVID-19 positive patients" (58.5%) followed by "drugs used to treat COVID-19" (33.7%) and "drugs suspected of having promoted COVID-19" (7.8%). Drugs used to treat COVID-19 and their main safety profile were different depending on the period: mostly hydroxychloroquine (51%) with heart injury and lopinavir/ritonavir (42%) with liver injury for the first period, and dexamethasone (46%) with hyperglycemia and tocilizumab (28%) with liver injury for the second period. The drugs suspected of worsening COVID-19 differed in both periods especially for non-steroidal anti-inflammatory drugs mainly reported in period 1 (41.5% versus 8.2% in period 2). Other immunosuppressive drugs were in the majority in the second period (85.7%), with mainly methotrexate (15.3%), anti-CD20 (15.3%) and anti-TNF alpha (10.5%). No confirmed safety signal was identified among other drugs administered to patients with COVID-19. The profile of ADRs and suspected drugs was similar between the 2 periods. The study of misuse in outpatient settings identified in both periods mainly hydroxychloroquine, azithromycin, ivermectin and zinc±vitamin C. DISCUSSION: This survey, based on real-time pharmacological and medical assessment of ADRs and weekly meetings in a specific national committee, made it possible to identify relevant safety signals which contribute to patient care with no delay. The main safety signal highlighted was serious cardiac damage under hydroxychloroquine, alone or combined with azithromycin and also with lopinavir/ritonavir. This signal has contributed to the evolution of the recommendations for these 2 drugs. The methodology of this survey has been taken over and is still going on for the pharmacovigilance monitoring of vaccines against COVID-19, for monoclonal antibodies used against COVID-19 and also for Paxlovid® (nirmatrelvir/ritonavir) which benefit from dedicated surveys.

Sex differences in adverse drug reactions: Are women more impacted?

Pharmacovigilance and pharmacoepidemiology studies regarding the sex difference in adverse drug reactions are numerous, and it is now a challenge to take them into account in order to increase drug safety. Here, we present an overview of this topic through data on epidemiology, mechanisms, and methods used for assessing sex differences in drug safety. Because the literature is extensive, we choose to expose a few examples of studies for cardiovascular drugs, anti-infectious, psychotropics, antidiabetics, anticancer drugs and some specific drugs to illustrate our purpose. Many studies show a higher risk in women for most of drugs involving in sex differences. However, physiological, methodological and subjective points have to be taken into account to interpret these results. Clinical trials must also enroll more women to better evaluate sex differences both in efficacy and pharmacovigilance. Nevertheless, when there is a pharmacological rationale underlying the observed association between sex and drug safety profile, it is now unavoidable to think about its consideration for a personalized prescription.