Potential Adverse Events Reported With the Janus Kinase Inhibitors Approved for the Treatment of Rheumatoid Arthritis Using Spontaneous Reports and Online Patient Reviews

The aim of this study was to analyze the potential adverse events (AEs) caused by Janus kinase (JAK) inhibitors, including tofacitinib, baricitinib, and upadacitinib, used to treat rheumatoid arthritis using spontaneous AE reports from the FDA (FAERS) and interpreting them in correlation with those from Korea (KAERS) and an online patient review (WebMD). Potential AEs were identified based on a disproportionality analysis using the proportional reporting ratio (PRR), reporting odds ratio (ROR), and the information component (IC). A total of 23,720 reports were analyzed from FAERS database, of which 91.5% were reports on tofacitinib. Potentially important medical AEs related to infections were reported frequently, as well as thromboembolism-related AEs. The AEs, such as malignancy, interstitial lung diseases, myocardial infarction, and gastrointestinal disorder, also reported. In an online patient review report, the ineffectiveness of the drug and gastrointestinal AEs were frequently reported. Infection with baricitinib and symptoms related to pain or edema due to upadacitinib were the main discomfort experienced by patients. In conclusion, the results of this study highlight the possible safety issues associated with JAK inhibitors. Routine clinical observations and further research using various real-world databases are needed.

Systematic review of spontaneous reports of myocarditis and pericarditis in transplant recipients and immunocompromised patients following COVID-19 mRNA vaccination

Objectives: To determine whether spontaneous reporting rates of myocarditis and pericarditis differed in immunocompromised patients compared to the whole population overall, and in terms of demographics, vaccine dose, and time-to-onset. Design: Systematic review of spontaneously reported data from the European Union/European Economic Area (EU/EEA) and the United States (US). Data Sources: EudraVigilance (EU/EEA) and Vaccine Adverse Event Reporting System (VAERS; US) spontaneous reporting databases were searched from date of vaccine launch to 30 November 2021. Eligibility criteria: Publicly available spontaneous reporting data for 'Myocarditis' and 'Pericarditis' from EU/EEA and US following COVID-19 mRNA vaccines. Reports with comorbidities or concurrent medication indicative of transplantation, HIV infection, or cancer ('immunocompromised' population) were compared with each overall database population. Data extraction and synthesis: Two researchers extracted data. Spontaneously reported events of myocarditis and pericarditis were presented for immunocompromised populations for each data source, stratified by age, sex, dose, and time-to-onset (where available). Seriousness of each event was determined according to the ICH E2A definition. Proportional Reporting Ratio (PRR) was calculated. Results: There were 106 reports of myocarditis and pericarditis amongst immunocompromised individuals overall. Seriousness was comparable between the immunocompromised and overall populations in both databases. No trends in age or sex were observed amongst immunocompromised individuals. Most reports (54.4%) to VAERS followed a second vaccine dose and 70.2% of events occurred within 14 days. The frequency of reporting was similar to the wider population (PRR=1.36 [95% CI= 0.89-1.82] for VAERS population). Conclusions: Myocarditis and pericarditis following COVID-19 vaccination are very rare, and benefits of COVID-19 vaccination continue to outweigh any perceived risks. Reporting rates of myocarditis and pericarditis were similar in immunocompromised individuals, however defining characteristics differed compared to the whole population; therefore, continued monitoring of adverse events following vaccination remains vital to understand differences between population subgroups.

Development of a Network-Based Signal Detection Tool: The COVID-19 Adversome in the FDA Adverse Event Reporting System

Introduction: The analysis of pharmacovigilance databases is crucial for the safety profiling of new and repurposed drugs, especially in the COVID-19 era. Traditional pharmacovigilance analyses–based on disproportionality approaches–cannot usually account for the complexity of spontaneous reports often with multiple concomitant drugs and events. We propose a network-based approach on co-reported events to help assessing disproportionalities and to effectively and timely identify disease-, comorbidity- and drug-related syndromes, especially in a rapidly changing low-resources environment such as that of COVID-19.Materials and Methods: Reports on medications administered for COVID-19 were extracted from the FDA Adverse Event Reporting System quarterly data (January–September 2020) and queried for disproportionalities (Reporting Odds Ratio corrected for multiple comparisons). A network (the Adversome) was estimated considering events as nodes and conditional co-reporting as links. Communities of significantly co-reported events were identified. All data and scripts employed are available in a public repository.Results: Among the 7,082 COVID-19 reports extracted, the seven most frequently suspected drugs (remdesivir, hydroxychloroquine, azithromycin, tocilizumab, lopinavir/ritonavir, sarilumab, and ethanol) have shown disproportionalities with 54 events. Of interest, myasthenia gravis with hydroxychloroquine, and cerebrovascular vein thrombosis with azithromycin. Automatic clustering identified 13 communities, including a methanol-related neurotoxicity associated with alcohol-based hand-sanitizers and a long QT/hepatotoxicity cluster associated with azithromycin, hydroxychloroquine and lopinavir-ritonavir interactions.Conclusion: Findings from the Adversome detect plausible new signals and iatrogenic syndromes. Our network approach complements traditional pharmacovigilance analyses, and may represent a more effective signal detection technique to guide clinical recommendations by regulators and specific follow-up confirmatory studies.

Predicting the side effects of drugs using matrix factorization on spontaneous reporting database

The severe side effects of some drugs can threaten the lives of patients and financially jeopardize pharmaceutical companies. Computational methods utilizing chemical, biological, and phenotypic features have been used to address this problem by predicting the side effects. Among these methods, the matrix factorization method, which utilizes the side-effect history of different drugs, has yielded promising results. However, approaches that encapsulate all the characteristics of side-effect prediction have not been investigated to date. To address this gap, we applied the logistic matrix factorization algorithm to a database of spontaneous reports to construct a prediction with higher accuracy. We expressed the distinction in the importance of drug-side effect pairs by a weighting strategy and addressed the cold-start problem via an attribute-to-feature mapping method. Consequently, our proposed model improved the prediction accuracy by 2.5% and efficiently handled the cold-start problem. The proposed methodology is expected to benefit applications such as warning systems in clinical settings.

Spontaneous Reporting of Adverse Drug Reactions in a Pediatric Population in a Tertiary Hospital

The pediatric population is a vulnerable group for adverse drug reactions (ADRs), and data on spontaneous reporting of ADRs in the hospital setting are scarce. We conducted a retrospective analysis of ADRs in pediatric patients spontaneously reported by health care professionals to a Pharmacovigilance Program in a tertiary hospital between 2010 and 2020, and we compared characteristics of ADRs between pediatric age subgroups. From 1787 spontaneously reported ADRs in an 11-year period, 103 (5.85%) were pediatric ADRs. The median age of patients with ADRs was 8.4 years (range 1 day–17 years) and 57.3% were male. The most frequent ADRs reported were nervous system disorders (13.6%) and the most frequently involved drugs were antineoplastics and immunodulators (32.4%). A 59.2% of the ADRs were serious and 55.3% were classified as being type B reactions. Medication errors were involved in 7.8% of the ADRs and 11.9% of the suspected drugs were used off-label. Spontaneous reports of ADRs in newborns, infants, and toddlers were more serious and less often described in the product data sheet than in children and adolescents (p < 0.001 and p = 0.004 respectively). Medication errors were more frequent in patients under two years of age. These results should be interpreted with caution due to under-reporting and biases in spontaneous reporting of ADRs.

Inhaled Drug Therapy-Associated Adverse Reactions in Obstructive Respiratory Diseases: A Review of a Decade of Reporting to the Portuguese Pharmacovigilance System

Inhaled medication used for treatment of chronic obstructive lung diseases (asthma, chronic obstructive pulmonary disease-COPD, and Asthma-COPD overlap) may be associated with adverse drug reactions (ADRs). The aim of this study was to characterise spontaneous reports (SRs) of suspected ADRs received by the Portuguese Pharmacovigilance System (PPS), from 2007 to 2017. Methods: Retrospective observational study of SRs associated with single substance and combination inhalers, analysed in terms of pharmacological class of the involved drugs, sex and age range of the involved patients, and seriousness and type of ADRs. Results: 230 SRs were analysed, accounting for a total of 599 suspected ADRs. Inhaled corticosteroid/long-acting beta-2 agonist combination had the highest frequency in SRs (32.2%) and in ADRs (32.7%). There was a slight predominance in men (51.3%) and non-elderly adults were the most affected age group (39.1%). Most SRs were serious (70.4%). In total, “respiratory, thoracic and mediastinal diseases” ADRs were the most reported (19.5%), with “dyspnea” being the most frequent (4.8%). Conclusions: Most SRs were associated with controller medications and were expected. Most ADRs involved non-elderly adults, were serious and of respiratory nature and many were due to overuse of reliever medication.

Application of Association Rules Analysis in Mining Adverse Drug Reaction Signals

Adverse drug reactions (ADRs) are increasingly becoming a serious public health problem. Spontaneous reporting systems (SRSs) are an important way for many countries to monitor ADRs produced in the clinical use of drugs, and they are the main data source for ADR signal detection. The traditional signal detection methods are based on disproportionality analysis (DPA) and lack the application of data mining technology. In this paper, we selected the spontaneous reports from 2011 to 2018 in Jiangsu Province of China as the research data and used association rules analysis (ARA) to mine signals. We defined some important metrics of the ARA according to the two-dimensional contingency table of ADRs, such as Confidence and Lift, and constructed performance evaluation indicators such as Precision, Recall, and F1 as objective standards. We used experimental methods based on data to objectively determine the optimal thresholds of the corresponding metrics, which, in the best case, are Confidence = 0.007 and Lift = 1. We obtained the average performance of the method through 10-fold cross-validation. The experimental results showed that F1 increased from 31.43% in the MHRA method to 40.38% in the ARA method; this was a significant improvement. To reduce drug risk and provide decision making for drug safety, more data mining methods need to be introduced and applied to ADR signal detection.

Thrombotic Adverse Events Reported for Moderna, Pfizer and Oxford-AstraZeneca COVID-19 Vaccines: Comparison of Occurrence and Clinical Outcomes in the EudraVigilance Database

Vaccination against COVID-19 is the cornerstone of controlling and mitigating the ongoing pandemic. Thrombotic adverse events linked to Moderna, Pfizer and the Oxford-AstraZeneca vaccine have been documented and described as extremely rare. While the Oxford-AstraZeneca vaccine has received much of the attention, the other vaccines should not go unchallenged. This study aimed to determine the frequency of reported thrombotic adverse events and clinical outcomes for these three COVID-19 vaccines, namely, Moderna, Pfizer and Oxford-AstraZeneca. A retrospective descriptive analysis was conducted of spontaneous reports for Moderna, Pfizer and Oxford-AstraZeneca COVID-19 vaccines submitted to the EudraVigilance database in the period from 17 February to 14 June 2021. There were 729,496 adverse events for the three vaccines, of which 3420 were thrombotic, mainly Oxford-AstraZeneca (n = 1988; 58.1%) followed by Pfizer (n = 1096; 32.0%) and Moderna (n = 336; 9.8%). As serious adverse events, there were 705 reports of pulmonary embolism for the three vaccines, of which 130 reports (18.4%) were for Moderna, 226 reports (32.1%) for Pfizer and 349 (49.5%) for Oxford-AstraZeneca vaccines. The occurrence of pulmonary embolism is significantly associated with a fatal outcome (p ≤ 0.001). Sixty-three fatalities were recorded (n = 63/3420; 1.8%), of which Moderna (n = 6), Pfizer (n = 25) and Oxford-AstraZeneca (n = 32).

Thrombotic adverse events reported for Moderna, Pfizer and Oxford-AstraZeneca COVID-19 vaccines: comparison of occurrence and clinical outcomes in the EudraVigilance database

SummaryBackgroundVaccination against COVID-19 is the cornerstone to control and mitigate the ongoing pandemic. Thrombotic adverse events linked to Moderna, Pfizer and the Oxford-AstraZeneca vaccine have been documented and described as extremely rare. While the Oxford-AstraZeneca vaccine has received much of the attention, the other vaccines should not go unchallenged. This study aimed to determine the frequency of reported thrombotic adverse events and clinical outcomes for these three COVID-19 vaccines, namely, Moderna, Pfizer and Oxford-AstraZenecaMethodsA retrospective descriptive analysis was conducted of spontaneous reports for Moderna, Pfizer and Oxford-AstraZeneca COVID-19 vaccines submitted to the EudraVigilance database in the period from 17 February to 14 June 2021.FindingsThere were 729,496 adverse events for the three vaccines, of which 3,420 were thrombotic, mainly Oxford-AstraZeneca (n=1,988, 58·1%) followed by Pfizer (n=1,096, 32·0%) and Moderna (n=336, 9·8%). As serious adverse events, there were 705 reports of pulmonary embolism for the three vaccines, of which 130 reports (18·4%) were for Moderna, 226 reports (32·1%) for Pfizer and 349 (49·5%) for Oxford-AstraZeneca vaccines. The occurrence of pulmonary embolism is significantly associated with a fatal outcome (P=<0·001). Sixty-three fatalities were recorded (63/3420, 1.8%), of which Moderna (n=6), Pfizer (n=25) and Oxford-AstraZeneca (n=32).InterpretationThrombotic adverse events reported for the three vaccines remains extremely rare with multiple causative factors reported elsewhere as precipitating these events. Practicing vigilance and proper clinical management for the affected vaccines, as well as continuing to report adverse events, are essential.FundingNo funding was sought for this study.Research in contextEvidence before this studyDuring the first quarter of 2021, several European countries suspended the use of the Oxford–AstraZeneca vaccine amid reports of blood clot events and the death of a vaccinated person. This was followed by several reports of fatalities related to pulmonary embolism and other thrombotic events including thrombocytopenia which has been referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT). The European Medicines Agency on 18 March 2021 concluded that the Oxford– AstraZeneca vaccine was safe, effective and the benefits outweighed the risks.Added value of this studyThis study investigated the occurrence of thrombotic adverse events and their clinical outcomes of the three approved and most used COVID-19 vaccines namely Moderna, Pfizer and Oxford-AstraZeneca, using one of the largest spontaneous adverse events databases, namely EudraVigilance. Out of 729,496 adverse events reported for the three vaccines in the study period, only 3420 (0.47%) potential thrombotic adverse events were reported, the majority associated with Oxford-AstraZeneca (n=1,988, 58.1%).Implications of all the available evidenceMore than 4·89 billion doses of different COVID-19 vaccines have been administered across the globe.Despite thrombotic adverse events reported for the three vaccines in focus for this study - Moderna, Pfizer and Oxford-AstraZeneca - being extremely rare, so continuing to report adverse events is essential. On the basis of scientific evidence showing that benefit outweighs risk, people continue to be urged to accept the vaccination when offered.