French pharmacovigilance survey of casirivimab - imdevimab monoclonal antibodies in coronavirus disease (COVID-19)

Introduction: Casirivimab and imdevimab (Ronapreve®) are two recombinant human monoclonal antibodies (mAbs) that bind to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, preventing the virus from entering cells. In March 2021, this drug was granted emergency use authorisation (EUA) in France for early treatment of COVID-19 in patients at increased risk of progression to severe COVID-19. In August/September 2021, the indication was expanded to COVID-19 prevention (pre- or post-exposure prophylaxis) and treatment of hospitalised patients requiring non-invasive oxygen therapy. The aim of the study was to better describe the adverse drug reaction (ADR) profile and detect safety signals of this new drug used in COVID-19 treatment. Methods: We described Adverse Drug Reaction (ADR) profile with casirivimab/imdevimab reported as suspect/interacting drug to the French pharmacovigilance network and the pharmaceutical company between 17/03/2021 and 30/06/2022. Data presented correspond to the 2 periods of the pharmacovigilance survey: the first carried out by the pharmaceutical company for curative and prophylactic uses and the second by Toulouse University regional pharmacovigilance center (RPVC). Results: A total of 384 cases were analysed and 256 were "serious". ADR profile was comparable between the 2 periods and between curative and prophylactic use, corresponding to expected ADRs such as infusion-related reactions and hypersensitivity, inefficiencies or worsened infections and deaths. Two potential pharmacovigilance signals were also studied: acute pulmonary oedemas and sudden deaths. Discussion: No pharmacovigilance signal emerged from this 15 months French pharmacovigilance survey. Moreover data from published studies are also reassuring. This pharmacovigilance survey was the first one for the new version of EUA and with a new ADR reporting process i.e declaration to the RPVC instead of the pharmaceutical company. Casirivimab/imdevimab is no longer used in France today but we continue to monitor this drug for any future evidence of resurgent activity on a new variant of Sars-CoV-2.

Pharmacovigilance des médicaments et des vaccins contre la COVID-19 durant la pandémie: comment le Réseau français des centres régionaux de pharmacovigilance a relevé le défi?

Résumé La pandémie secondaire au virus SARS-CoV2 s'est traduite, pour la pharmacovigilance institutionnelle française, par une « crise sanitaire » en 2 temps : la phase coronavirus disease 2019 - « COVID-19 » pendant laquelle les missions des centres régionaux de pharmacovigilance (CRPV) étaient de détecter un impact des médicaments sur cette maladie, qu'il s'agisse du rôle éventuellement aggravant de certains médicaments ou d'une modification du profil de sécurité de médicaments utilisés pour la prise en charge de la COVID-19. La seconde phase a fait suite à la mise à disposition des vaccins contre la COVID-19, pendant laquelle les missions des CRPV étaient de détecter le plus précocement possible, tout nouvel effet indésirable grave, source d'un potentiel signal qui modifierait le rapport bénéfices/risques d'un vaccin et nécessiterait la mise en place de mesures de sécurité sanitaire. Pendant ces 2 périodes, la détection de signal est restée le cœur de métier des CRPV. Les CRPV ont du s'organiser pour prendre en charge l'augmentation historique de la volumétrie de déclarations et de demandes d'avis. Les CRPV en charge du suivi des vaccins ont fait face à une activité démesurée sur une longue durée, afin de synthétiser l'ensemble des déclarations, d'identifier, en temps réel, l'émergence de signaux et de produire un rapport hebdomadaire. L'organisation nationale mise en place avec l'Agence nationale de sécurité du médicament et des produits de santé a permis de relever le challenge que représentait un tel suivi instantané des vaccins. Le Réseau français des CRPV a su s'adapter en faisant preuve d'agilité et de flexibilité et en démontrant son efficacité dans la détection précoce de signaux. Cette crise a également confirmé la supériorité de la détection manuelle/humaine des signaux en terme de puissance et d'efficience pour détecter rapidement un nouvel effet indésirable médicamenteux et prendre rapidement des mesures de réduction du risque. Pour maintenir la performance des CRPV français dans la détection de tels signaux et surveiller tous les médicaments comme ils doivent l'être un nouveau modèle de financement permettant de corriger l'inadéquation des moyens d'expertise des CRPV au regard de la volumétrie des déclarations est maintenant nécessaire.

Monitoring the safety of drugs and COVID-19 vaccines by the French Pharmacovigilance Centers during the pandemic: A win-win bet with Health Authorities!

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) pandemic virus was a "health crisis" and a significant burden also for the French pharmacovigilance system. It took its toll in 2 phases, the first being in early 2020 when very little was known, and during which the missions of the 31 Regional Pharmacovigilance Centers (RPVCs) from university hospitals were to detect adverse reactions of drugs used in the context of the disease. Whether as a possible aggravating role on COVID-19, or displaying a different safety profile during its course, or to assess safety of curative treatment, this phase preceded that of the arrival of dedicated vaccines. Then the RPVCs' missions were to detect, as early as possible, any new serious adverse effect leading to a potential signal that would modify the benefit/risk ratio of a vaccine and require the implementation of health safety measures. During these two distinct periods, signal detection remained the core business of the RPVCs. Each RPVC had to organize itself to handle an unprecedented surge of declarations and requests for advice, from health care professionals and patients alike. "Leading" RPVCs, who were in charge of monitoring vaccines, had to deal with an extraordinary workload (still going on to this date), to generate in real-time and on a weekly basis, a summary of all the adverse drug reaction (ADR) reports as well as an extended analysis of the different safety signals. The organization put in place at the beginning of the health crisis, adapted to the context of the vaccines, allowed to meet the challenge of real-time pharmacovigilance monitoring, and to identify many safety signals. Efficient "short-circuits exchanges" with the French Regional Pharmacovigilance Centers Network (RPVCN) were paramount to the National Agency for the Safety of Medicines and Health Products (ANSM) to develop an optimal collaborative partnership. The French RPVCN has shown at this occasion both agility and flexibility, swiftly adapting to vaccine- and media-related unrest, and demonstrated its effectiveness in the early detection of safety signals. This crisis also confirmed the superiority of manual/human signal detection over automated ones, as the most effective and powerful tool to date to rapidly detect and validate a new ADR and enable to elaborate rapid risk reduction measures. To maintain the performance of French RPVCN in signal detection and to monitor all drugs as they should, and as expected by our fellow citizens, a new funding model should be considered.

[Monitoring the safety of drugs and COVID-19 vaccines by the French Pharmacovigilance Centers during the pandemic: a win-win bet with Health Authorities!] / Pharmacovigilance des médicaments et des vaccins contre la COVID-19 durant la pandémie : comment le Réseau français des centres régionaux de pharmacovigilance a relevé le défi ?

The pandemic subsequent to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus resulted, for the French institutional pharmacovigilance, in a "health crisis" in 2 phases: the coronavirus disease 2019 - "COVID-19" phase during which the missions of the Regional Pharmacovigilance Centres (RPVC) were to detect a possible impact of drugs on this disease, as whether existed a possible aggravating role of certain drugs, or the safety profile of drugs used for the management of COVID-19 could evolve. The second phase followed the availability of COVID-19 vaccines, during which the RPVCs' missions were to detect as early as possible any new serious adverse effect, source of a potential signal that would modify the benefit/risk ratio of a vaccine and require the implementation of health safety measures. During these two periods, signal detection remained the core business of the RPVCs. The RPVCs had to organize themselves to handle an historical surge of declarations and requests for advice, whereas the RPVCs in charge of monitoring vaccines had to deal with an extraordinary dense activity over a long period of time, in order to produce in real time and on a weekly basis, a summary of all the declarations and an analysis of safety signals. The national organization put in place made it possible to meet the challenge of real-time pharmacovigilance monitoring of 4 vaccines with conditional marketing authorizations. Short-circuit efficient exchanges with the French Regional Pharmacovigilance Centres Network was paramount for the French National Agency for medicines and health products (Agence nationale de sécurité du médicament et des produits de santé) to develop an optimal collaborative partnership. The RPVC network has shown agility and flexibility, has been able to adapt swiftly and demonstrated its effectiveness in the early detection of safety signals. This crisis confirmed the superiority of manual/human signal detection as the most effective and powerful tool to date, to rapidly detect a new adverse drug reaction and enable to elaborate rapid measures of risk reduction. In order to maintain the performance of French RPVCs in signal detection and to monitor all drugs as they should and as expected by our fellow citizens, a new funding model correcting the inadequacy of RPVCs' expertise resources in relation to the volume of reports should be considered.

French pharmacovigilance survey of casirivimab - imdevimab monoclonal antibodies in coronavirus disease (COVID-19).

INTRODUCTION: Casirivimab and imdevimab (Ronapreve®) are two recombinant human monoclonal antibodies (mAbs) that bind to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, preventing the virus from entering cells. In March 2021, this drug was granted emergency use authorisation (EUA) in France for early treatment of COVID-19 in patients at increased risk of progression to severe COVID-19. In August/September 2021, the indication was expanded to COVID-19 prevention (pre- or post-exposure prophylaxis) and treatment of hospitalised patients requiring non-invasive oxygen therapy. The aim of the study was to better describe the adverse drug reaction (ADR) profile and detect safety signals of this new drug used in COVID-19 treatment. METHODS: We described ADR profile with casirivimab/imdevimab reported as suspect/interacting drug to the French pharmacovigilance network and the pharmaceutical company between 17/03/2021 and 30/06/2022. Data presented correspond to the 2 periods of the pharmacovigilance survey: the first carried out by the pharmaceutical company for curative and prophylactic uses and the second by Toulouse university regional pharmacovigilance center (RPVC). RESULTS: A total of 384 reports were analysed and 256 were "serious". ADR profile was comparable between the 2 periods and between curative and prophylactic use, corresponding to expected ADRs such as infusion-related reactions and hypersensitivity, inefficiencies or worsened infections and deaths. Two potential pharmacovigilance signals were also studied: acute pulmonary oedemas and sudden deaths. DISCUSSION: No pharmacovigilance signal emerged from this 15 months French pharmacovigilance survey. Moreover data from published studies are also reassuring. This pharmacovigilance survey was the first one for the new version of EUA and with a new ADR reporting process i.e. declaration to the RPVC instead of the pharmaceutical company. Casirivimab/imdevimab is no longer used in France today but we continue to monitor this drug for any future evidence of resurgent activity on a new variant of Sars-CoV-2.

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.

Safety profile of the lopinavir/ritonavir combination before and during the SARS-CoV-2 pandemic.

INTRODUCTION: When the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic began, there were no effective treatments assessed by clinical trials. In this context, in France, the French Public Health Council issued, from 5 March, 2020, several proposed recommendations for the therapeutic management of this new disease. This included the use of combination lopinavir/ritonavir, which is usually indicated as HIV treatment. Thanks to the reporting of adverse drug reactions (ADRs) to the French Regional Pharmacovigilance Centers, several safety signals including hepatobiliary and cardiovascular were quickly identified. OBJECTIVE: This study aimed to compare the ADRs reported with lopinavir/ritonavir used in its usual indication prior to the pandemic with the ADRs reported with the coronavirus disease 2019 (COVID-19) indication. METHODS: Cases of ADRs were extracted from the French Pharmacovigilance Database. ADRs were compared between the two periods: pre-COVID (1985 to 31 December 2019) and COVID (1 January 2020 to 21 July 2020). RESULTS: Patients with COVID-19 were found to have a different safety profile, with significantly more damage to the liver (43% of ADRs), heart (10.6%) and kidneys (7.1%). The ADRs reported before the pandemic were mainly gastrointestinal and cutaneous. CONCLUSIONS: This different safety profile may be related to the effect of the virus on the organs, the patient profile (age, medical history…) and the drugs associated with lopinavir/ritonavir. Our study should serve as a reminder that the safety profile of a drug can depend on its use. Spontaneous reporting and pharmacovigilance have a critical role in alerting health professionals to "new" ADRs reported with well-known drugs.

Comparative study of the adverse event profile of hydroxychloroquine before and during the Sars-CoV2 pandemic.

AIMS: At the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, there were no clinically-tested medications for the effective treatment of coronavirus disease. In this context, on 5 March 2020, the French Public Health Council issued several recommendations for the therapeutic management of this new disease, including the use of hydroxychloroquine (HCQ). An unexpected cardiovascular safety signal was quickly identified as being more frequent than expected thanks to the reports of adverse drug reactions (ADRs) submitted to French regional pharmacovigilance centres (RPVC). The objective of this study was to compare all ADRs reported with HCQ used in its usual indication, collected before the pandemic period (1985 to 31 December, 2019) with those reported with the coronavirus disease 2019 (COVID-19) indication (1 January to 21 July, 2020). METHODS: For this purpose, reports were extracted from the French pharmacovigilance database and analysed for these two periods. RESULTS: Our study showed a different safety profile in COVID-19 patients with more cardiac disorders (57% of ADRs versus 5% before the pandemic period), especially QT interval prolongation, resulting from an interaction with azithromycin in more than 20% of cases. Hepatobiliary disorders were also significantly more frequent. CONCLUSIONS: These observations could be associated with the effect of the virus itself on the various organs, the profile of the patients treated, and concomitant drug treatments.

French organization for the pharmacovigilance of COVID-19 vaccines: A major challenge.

In this special issue, we present the main highlights of the first weeks of pharmacovigilance monitoring of coronavirus disease 2019 (COVID-19) vaccines in this unprecedented situation in France: the deployment of a vaccination during an epidemic period with the aim of vaccinating the entire population and the intense pharmacovigilance and surveillance of these vaccines still under conditional marketing authorizations. In this unprecedented situation, the cross approach and interaction between the French pharmacovigilance network and French National Agency for the Safety of Medicines and Health Products (ANSM) has been optimized to provide a real-time safety related to COVID-19 vaccines. Every week, pair of regional pharmacovigilance centers gathered safety data from the French pharmacovigilance network, to acutely expertise all the adverse drug reactions (ADRs) reported with each COVID-19 vaccine within a direct circuit with ANSM. Results of this expertise are presented and discussed with ANSM in order to raise safety signals and take appropriate measures if necessary. These reports are then published online. At the 25th of March 2021, more than 9 815 000 doses were injected and 20,265 ADRs were reported, mostly non-serious (76%). Several potential or confirmed signals were raised at the european level for those vaccines and others ADRs are under special attentions. This underlines the adaptiveness of the French pharmacovigilance system to both the identification of new patient profiles experiencing ADRs and the evolution of the vaccine strategy. Such an efficiency is necessary to manage a careful and acute surveillance of these new COVID-19 vaccines for and to face the pandemic at the same time.

French Pharmacovigilance Public System and COVID-19 Pandemic.

The current COVID-19 pandemic is an exceptional health situation including for drug use. As there was no known effective drug for COVID-19 at the beginning of the pandemic, different candidates were proposed. In this short article, we present the French public pharmacovigilance activities during this health crisis. Although COVID-19 is a confounding factor per se, owing to its potential for multi-organ damage including the heart and kidney, the quality of the transmitted data in adverse drug reaction reports, the timeliness of feedback from clinicians, and the real-time pharmacological and medical analysis by the French network of the regional pharmacovigilance centers made it possible to swiftly identify relevant safety signals. The French National Agency of Medicine was thus able to validate the data and convey their findings very early. This decentralized organization based on medical and pharmacological evaluation of case reports has proven to be efficient and responsive in this unique and challenging healthcare emergency.