ABSTRACT
Introduction: Nirmatrelvir/ritonavir (Paxlovid®) is currently one of the few therapeutic options for coronavirus disease 2019 (COVID-19) curative treatment in non-oxygen-requiring adult patients at-high risk of progressing to severe disease. This recently approved boosted antiviral therapy presents a significant risk of drug-drug interactions (DDI). As part of the enhanced surveillance program in France for COVID-19 drugs and vaccines, the French national pharmacovigilance database (BNPV [base nationale de pharmacovigilance]) was queried in order to better characterize the drug safety profile, with a special focus on DDI. The aim of the study was to describe the adverse drug reactions reported through the BNPV. Method: All nirmatrelvir/ritonavir reports validated in the BNPV from the first authorization in France (January, 20th 2022) to December, 3rd 2022 (date of the query) were considered. An analysis of the scientific literature (PubMed®) and from the WHO pharmacovigilance database (Vigibase) was also performed. Results.- Over this period (11 months), 228 reports (40% of serious reports) were registered with a sex ratio of 1.9 female/1 male and a mean age of 66 years old. DDI reports account for more than 13% of reports (N = 30) and were mainly related to immunosuppressive drugs overexposure (N = 16). A total of 10/228 reports with fatal outcomes were reported in complex clinical settings. The main reported unexpected adverse drug reaction (ADRs) were high blood pressure (N = 7), confusion (N = 5), acute kidney injuries (AKI, N = 7) and various skin reactions (N = 22). Apart from situations of disease recurrence (not found in this analysis), data from Pubmed® and Vigibase also reported the above-mentioned events of interest. Conclusion: Overall, this analysis shows that nirmatrelvir/ritonavir safety profile was conform to current summary of product characteristics (SmPC). The main concern was the risk of DDI. Therefore, SmPC and expert recommendations should be systematically consulted before initiation of this antiviral, which is particularly indicated in polypharmacy patients. A case-by-case multidisciplinary approach including a clinical pharmacologist is required in these complex situations. Blood pressure elevation, confusion, cutaneous reactions and AKIs were the main unexpected ADRs of interest to follow, but need to be confirmed with a qualitative approach over time and new reports.
ABSTRACT
INTRODUCTION: Nirmatrelvir/ritonavir (Paxlovid®) is currently one of the few therapeutic options for coronavirus disease 2019 (COVID-19) curative treatment in non-oxygen-requiring adult patients at-high risk of progressing to severe disease. This recently approved boosted antiviral therapy presents a significant risk of drug-drug interactions (DDI). As part of the enhanced surveillance program in France for COVID-19 drugs and vaccines, the French national pharmacovigilance database (BNPV [base nationale de pharmacovigilance]) was queried in order to better characterize the drug safety profile, with a special focus on DDI. The aim of the study was to describe the adverse drug reactions reported through the BNPV. METHOD: All nirmatrelvir/ritonavir reports validated in the BNPV from the first authorization in France (January, 20th 2022) to December, 3rd 2022 (date of the query) were considered. An analysis of the scientific literature (PubMed®) and from the WHO pharmacovigilance database (Vigibase) was also performed. RESULTS: Over this period (11 months), 228 reports (40% of serious reports) were registered with a sex ratio of 1.9 female/1 male and a mean age of 66 years old. DDI reports account for more than 13% of reports (n=30) and were mainly related to immunosuppressive drugs overexposure (n=16). A total of 10/228 reports with fatal outcomes were reported in complex clinical settings. The main reported unexpected adverse drug reaction (ADRs) were high blood pressure (n=7), confusion (n=5), acute kidney injuries (AKI, n=7) and various skin reactions (n=22). Apart from situations of disease recurrence (not found in this analysis), data from Pubmed® and Vigibase also reported the above-mentioned events of interest. CONCLUSION: Overall, this analysis shows that nirmatrelvir/ritonavir safety profile was conform to current summary of product characteristics (SmPC). The main concern was the risk of DDI. Therefore, SmPC and expert recommendations should be systematically consulted before initiation of this antiviral, which is particularly indicated in polypharmacy patients. A case-by-case multidisciplinary approach including a clinical pharmacologist is required in these complex situations. Blood pressure elevation, confusion, cutaneous reactions and AKIs were the main unexpected ADRs of interest to follow, but need to be confirmed with a qualitative approach over time and new reports.
ABSTRACT
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.