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Longitudinal trends of Individual Case Safety Report (ICSR) reporting of remdesivir, tocilizumab and all COVID-19-specific medicines (including remdesivir and tocilizumab) to the respective
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IntroductionThe safety profile of remdesivir, conditionally approved for COVID-19, was limited at its 2020 introduction. Adverse drug reactions (ADRs) for medicines are collected in VigiBase, the WHO Global Database of Individual Case Safety Reports (ICSRs).Objective
This study aimed to provide a descriptive analysis of COVID-19 ICSR data focusing...
Context in source publication
Context 1
... longitudinal trends of ICSR reporting of remdesivir, tocilizumab and all COVID-19 medicines during the study period are visualized in Fig. 1. The very first COVID-19-related ICSR was reported to an NC on 30 January 2020 and was indeed a remdesivir report. Global reporting between January and April was dominated by medicines from the WHO-initiated Solidarity trial; besides remdesivir, hydroxychloroquine, chloroquine, azithromycin and lopinavir/ritonavir were also reported. ...
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Citations
... 16 It is also possible that this real-world Veteran cohort had greater comorbidity than those enrolled in clinical trials. Remdesivir-associated liver injury has been observed in other real-world cohorts of critically ill patients with COVID-19 17 and pharmacovigilance studies 18,19 ; it has been associated with liver failure 20 and increased mortality. 21 Our study was not designed to analyze clinical outcomes of those observed to exhibit ALT elevations in the remdesivir-treated group. ...
Remdesivir is the first US Food and Drug Administration (FDA)‐approved drug for the treatment of coronavirus disease 2019 (COVID‐19). We conducted a retrospective pharmacogenetic study to examine remdesivir‐associated liver enzyme elevation among Million Veteran Program participants hospitalized with COVID‐19 between March 15, 2020, and June 30, 2021. Pharmacogene phenotypes were assigned using Stargazer. Linear regression was performed on peak log‐transformed enzyme values, stratified by population, adjusted for age, sex, baseline liver enzymes, comorbidities, and 10 population‐specific principal components. Patients on remdesivir had higher peak alanine aminotransferase (ALT) values following treatment initiation compared with patients not receiving remdesivir. Remdesivir administration was associated with a 33% and 24% higher peak ALT in non‐Hispanic White (NHW) and non‐Hispanic Black (NHB) participants (p < 0.001), respectively. In a multivariable model, NHW CYP2C19 intermediate/poor metabolizers had a 9% increased peak ALT compared with NHW normal/rapid/ultrarapid metabolizers (p = 0.015); this association was not observed in NHB participants. In summary, remdesivir‐associated ALT elevations appear to be multifactorial, and further studies are needed.
... Three separate disproportionality analyses of RDV found bradycardia among the commonly reported adverse drug reac-tions (ADRs) in COVID-19 patients [5,28,29]. RDV was the most common medication reported in the WHO Global Database of Individual Case Safety Reports (ICSRs) related to COVID-19 from January 1, 2020 to December 31, 2020; 4.6% (n = 237) of those ICSRs reported bradycardia as the ADR following RDV treatment [29]. The clinical consequences of bradycardia after RDV administration have not been wellestablished. ...
... Three separate disproportionality analyses of RDV found bradycardia among the commonly reported adverse drug reac-tions (ADRs) in COVID-19 patients [5,28,29]. RDV was the most common medication reported in the WHO Global Database of Individual Case Safety Reports (ICSRs) related to COVID-19 from January 1, 2020 to December 31, 2020; 4.6% (n = 237) of those ICSRs reported bradycardia as the ADR following RDV treatment [29]. The clinical consequences of bradycardia after RDV administration have not been wellestablished. ...
Background:
The coronavirus disease 2019 (COVID-19) pandemic has required timely and informed decisions about treatment recommendations for clinical practice. One such drug used for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is remdesivir (RDV), and several cardiac side effects have been reported including bradyarrhythmia (e.g., transient sinus bradycardia, symptomatic sinus bradycardia, complete atrioventricular (AV) block). The current study aimed to explore the association between RDV treatment for SARS-CoV-2 infection and the risk of bradyarrhythmia by presenting a review and meta-analysis of available published studies.
Methods:
We presented a review of published literature and meta-analysis of observational studies (MOOSE). A narrative summary of RDV and bradyarrhythmia in COVID-19 infection and pooled analysis of observational studies that meet inclusion criteria was included. Studies included were published between January 2020 and December 2021 (identified through PubMed and ScienceDirect) and examined the association between treatment with RDV in SARS-CoV-2 infection and the risk of bradyarrhythmia.
Results:
Three studies (two retrospective cohort studies and one prospective cohort study) met inclusion criteria for pooled meta-analysis of bradyarrhythmia and RDV therapy in COVID-19 patients. Treatment with RDV was associated with increased risk of sinus bradycardia when compared to controls (odds ratio 3.27 (95% confidence interval 1.90 - 5.63)). In the pooled analysis, the incidence of bradycardia in those that received RDV was 34.07% vs. 18.13% among controls. Thirteen case reports, three case series, and three disproportionality analyses were identified in review of the literature.
Conclusion:
Data from real-world observational studies suggest that treating COVID-19 patients with RDV may predispose the development of bradyarrhythmia. The importance of this observation is of uncertain clinical significance as some observational studies have reported more favorable outcomes among patients who experience bradycardia after RDV therapy. The current study is limited by the small number of studies that could be meaningfully pooled and more well-designed cohort studies are needed to explore this association.
... To increase the sensitivity of subsequent quantitative analyses and reduce the confounding of related disease background, a population-focused study (Rocca et al., 2021) was performed in some subsets of the FAERS database containing COVID-19 and DM reports between the first quarter of 2020 (2020q1) and the third quarter of 2021 (2021q3), which included at least one drug prescribed for COVID-19 among "PS" drugs. ...
Background : The information is relatively scarce regarding the occurrence of drug-induced acute kidney injury (AKI) when anti-coronavirus disease 2019 (COVID-19) drugs are prescribed for patients with diabetes mellitus (DM).
Objective : The objective of this study was to evaluate a pharmacovigilance signal for AKI upon the use of common drugs prescribed for COVID-19 treatment, especially in patients with DM.
Methods : The FDA Adverse Event Reporting System (FAERS) database were used, and data from the first quarter of 2020 to the third quarter of 2021 were retrieved. A disproportionality analysis was performed to determine whether AKI was more frequently reported with anti-COVID-19 drugs compared to that with other drugs in different populations. Further, reporting odds ratios (RORs) and their 95% confidence intervals (CIs) were used to calculate disproportionality. Results: We identified 33,488 COVID-19 patients and 2397 COVID-19 patients with DM. AKI was the most frequent adverse drug reaction (ADR) reported in this patient population. The primary suspected drugs related to AKI in more than half of the reports (75.60%, 127/168) were four common anti-COVID-19 drugs (remdesivir, tocilizumab, hydroxychloroquine, and lopinavir/ritonavir). Compared with other drugs in the same time window, remdesivir and lopinavir/ritonavir were associated with an increased risk of AKI in all COVID-19 patients (ROR: 3.97, 95% CI: 3.51–4.50; ROR: 4.02, 95% CI: 3.11–5.19, respectively). In COVID-19 patients with DM, remdesivir was significantly associated with AKI (ROR: 5.65, 95% CI: 4.06–7.87); meanwhile, there was a new AKI signal associated with tocilizumab (ROR: 2.37, 95% CI: 1.19–4.72). After sensitivity analyses in COVID-19 patients with DM, consistent results for remdesivir were observed; however, the AKI signals for tocilizumab were unstable.
Conclusion: Our study confirmed the association of AKI with the usage of common anti-COVID-19 drugs (especially remdesivir and tocilizumab) in DM patients. These safety signals suggested more individualized treatments for COVID-19 patients with comorbidities. Cross-disciplinary collaborative is needed to improve current strategy of clinical treatment and develop new approaches to management.
Background
Gastrointestinal adverse drug reactions (GADRs) of direct-acting antiviral agents (DAAs) in patients with chronic hepatitis C are underestimated.AimThis study aimed to comprehensively evaluate the gastrointestinal safety of DAAs in patients with chronic hepatitis C.Method
The US FDA Adverse Event Reporting System database was searched for GADR cases reported from 01 to 2012 to 30 September 2021. Twelve DAA types used for hepatitis C virus were included. The top 30 GADRs were assessed based on the use of DAAs, number of cases, and clinical features. A case–non-case disproportionality approach was used to confirm pharmacovigilance signals, whereby reporting odds ratios (ROR) with 95% CI were calculated.ResultsNausea (70.01/1000), diarrhoea (39.10/1000), and vomiting (31.68/1000) accounted for the highest number of cases. The pooled median time-to-onset of the top 30 GADRs was 13 days (Q1-Q3: 2–38) and the proportion of drug discontinuation was 19.17%. The highest number of DAA-related cases involved ledipasvir/sofosbuvir (21.86%), sofosbuvir/velpatasvir (21.77%), and sofosbuvir (13.41%). When DAAs were considered as a class drug, after adjusting for age, sex, concomitant diseases and drugs that potentially induced GADRs, significant RORs for specific GADRs were noted, including abdominal discomfort (1.62, 95% CI 1.32–1.99), constipation (1.54, 95% CI 1.26–1.89), dyspepsia (1.25, 95% CI 1.01–1.55), abdominal distension (1.36, 95% CI 1.05–1.75), faeces discoloured (1.77, 95% CI 1.15–2.73), and gastric ulcer (2.37, 95% CI 1.28–4.41).Conclusion
Clinicians should have a deeper understanding of GADRs to improve the gastrointestinal tolerance of patients with chronic hepatitis C.
Introduction:
An association between tumor necrosis factor (TNF)-α inhibitors and hypoglycemia has been detected in a few case reports and small case series; however, no relevant pharmacovigilance data have been published yet.
Objective:
The objective of this study was to detect and characterize relevant safety signals between hypoglycemia and TNF-α inhibitor use.
Methods:
Indication-focused disproportionality analysis was conducted to detect increased reporting of TNF-α-associated hypoglycemia compared with all other reports with the same indication during the same time period. Reporting odds ratios (RORs) with 95% confidence intervals (CIs) were calculated to determine disproportionality. To reduce potential confounding factors, adjusted RORs were further calculated by logistic regression to control for age, sex, diabetes status, and concomitant drugs that potentially affect blood glucose levels.
Results:
In all, 1086 adverse drug reactions related to TNF-α inhibitors were reported as 'hypoglycemia'. There were no disproportionality signals of hypoglycemia in TNF-α inhibitor users with indication of inflammatory bowel disease. When TNF-α inhibitors were considered as a class, disproportion for hypoglycemia only emerged in indication of psoriasis (n = 267, ROR 1.20, 95% CI 1.02-1.41). In further analyses of specific TNF-α inhibitor type, significant RORs for hypoglycemia were found in indication of rheumatic disease, including adalimumab in ankylosing spondylitis (n = 37, ROR 1.97, 95% CI 1.28-3.04), psoriasis (n = 160, ROR 1.64, 95% CI 1.37-1.97), and rheumatoid arthritis (n = 230, ROR 1.35, 95% CI 1.16-1.56) and infliximab in psoriasis (n = 18, ROR 2.14, 95% CI 1.33-3.42). After adjusting for confounding factors, only the signals of adalimumab were stable.
Conclusions:
Our study identified some potential pharmacovigilance signals between hypoglycemia and TNF-α inhibitors, which warrants further validation.
Over the last 2 years, there has been gradual and sustained progress toward our understanding of pharmacotherapy for coronavirus disease 2019 (COVID-19) as a result of large- and small-scale randomized controlled trials. Numerous new and repurposed treatments have been evaluated; some have demonstrated benefit in clinically important outcomes like mortality and hospitalization, and optimism for oral antiviral treatments is growing. Given the rapidly evolving landscape of COVID-19 treatments, frontline clinicians should use treatment and management guidelines to guide their approach to each patient, with the individual's severity and location of illness in mind to appreciate the nuances in clinical evidence.
