FDA Adverse Event Reporting System Research Articles

A real-world disproportionality analysis of FDA adverse event reporting system (FAERS) events for avatrombopag

A real-world disproportionality analysis of FDA adverse event reporting system (FAERS) events for avatrombopag

Pharmacovigilance insights into drug-induced cystitis: analysis of FDA data from 2004 to 2024.

Drug-induced cystitis (DIC) significantly impacts patient quality of life and treatment outcomes. This study investigates the incidence and characteristics of DIC using data from the FDA Adverse Event Reporting System (FAERS). We reviewed FAERS reports related to cystitis from Q1 2004 to Q1 2024, compiling a list of potential causative drugs. The top 50 drugs with the highest number of cystitis reports were ranked. Statistical disproportionality analyses, including Proportional Reporting Ratio (PRR) and Reporting Odds Ratio (ROR), were used to detect unusually high reporting frequencies of cystitis associated with specific drugs. From 17,703,515 FAERS reports spanning 2004-2024, 36399 involved cystitis. The majority of implicated drugs were antineoplastics. Busulfan, BCG, and mitomycin had the highest ROR and PRR values. Additionally, drugs such as defibrotide sodium, milrinone, and dyazide, which do not have cystitis listed on their labels, were identified, highlighting the need for increased clinical vigilance and awareness. The findings underscore the importance of ongoing pharmacovigilance in identifying and characterizing DIC. Further clinical studies are warranted to validate these associations and to develop strategies for mitigating the risk of DIC, thereby improving patient safety and treatment outcomes.

Hepatitis associated with immune checkpoint inhibitors-based combinations of other therapies: A real-world pharmacovigilance analysis based on the FDA adverse event reporting system (FAERS) database.

The combination regimen with immune checkpoint inhibitors (ICIs) and other therapies has been widely applied for patients with non-small-cell lung cancer (NSCLC). To date, no literature has systematically addressed the risk of hepatitis associated with the combination therapy. We conducted this pharmacovigilance analysis using the Food and Drug Administration Adverse Event Reporting System (FAERS). A total of 587,016 NSCLC reports were extracted from FAERS database spanning from the first quarter of 2013 to the second quarter of 2023. After filtering duplicate reports, logistic regression model was used to detect safety signals, and multivariable logistic regression model was used to confirm the interaction between ICI and other drugs. Of the 81,512 patients with NSCLC, 2785 cases developed hepatitis. Multivariable logistic regression analyses revealed that the adjusted ROR of ICI combined with targeted therapy (TT) was the highest 1.64 (95% CI, 1.32-2.02; P < 0.0001) among all therapies, while that of TT and ICI treatment were 1.07 (95% CI, 0.98-1.17; P = 0.1097) and 1.12 (95% CI, 1.03-1.22; P = 0.0111), respectively. The adjusted ROR for the interaction effect was 1.64 (95% CI, 1.32-2.02; P < 0.0001). Furthermore, the adjusted ROR of ICI combined with KRAS-targeted drugs was the highest 3.03 (95% CI, 1.49-5.93; P = 0.0016) among all targeted drugs, with an adjusted ROR of 3.03 (95% CI, 1.49-5.93; P = 0.0016), indicating a meaningful interaction of these two kinds of drugs. We confirmed that combination treatment of ICI and TT is associated with the amplified risk of hepatitis, which is partly due to the interaction between ICI and TT, and the KRAS-targeted drugs may harbor the highest potential for hepatitis induction among TT drugs when combined with ICI. Besides, the combination treatment of ICI- and KRAS-targeted drugs also increases the incidence of colitis, pulmonary embolism and dehydration.

Real-world research on beta-blocker usage trends in China and safety exploration based on the FDA Adverse Event Reporting System (FAERS).

Beta-blockers are widely used, with continuously updated clinical recommendations. However, their application faces challenges in personalized treatment and safety. The study aimed to investigate the frequency and patterns of prescribing beta-blockers in China and to explore potential adverse event risk signals associated with beta-blockers, providing reference for rational medication use in clinical settings. Prescription data for beta-blockers from January 2018 to June 2023 were extracted through the Hospital Prescription Analysis Collaborative Project in China to analyze clinical usage trends. While adverse drug reaction reports for beta-blockers were obtained from the FDA Adverse Event Reporting System (FAERS) database. The classification and standardization of adverse drug event (ADE) reports were based on the preferred terms (PT) and corresponding system organ classes (SOC) from the Medical Dictionary for Regulatory Activities (MedDRA). Signal detection utilized a proportion imbalance method. In clinical practice, metoprolol dominated beta-blocker prescriptions in China, accounting for 62.2%. Beta-blockers were primarily prescribed to the elderly (65.7%) and male patients (57.0%). However, off-label use of beta-blockers was relatively widespread. For instance, sotalol was prescribed for hypertension at 18.25%, while esmolol was used for angina and heart failure at rates of 12.94% and 14.98%, respectively. In addition, we identified newly discovered adverse reactions associated with beta-blockers, such as BRASH syndrome (metoprolol: n = 186, ROR = 391.285; carvedilol: n = 72, ROR = 256.459), acute kidney injury (bisoprolol: n = 247, ROR = 5.641), premature baby (labetalol: n = 110, ROR = 91.385), and sleep disorder (propranolol: n = 254, ROR = 10.98). Metoprolol led the beta-blocker market in China. Attention was warranted regarding the newly discovered adverse reactions, such as the risk of acute kidney injury with bisoprolol and the potential for BRASH syndrome with metoprolol and carvedilol.

Comparative Safety of Ultrasound Enhancing Agents: A Systematic Review and Bayesian Network Meta-Analysis: Comparative Safety Evaluation of Optison.

Ultrasound enhancing agents (UEAs), including Optison, Definity, and Lumason, enhance the diagnostic performance of echocardiography, particularly in patients with suboptimal acoustic windows. However, there remains a paucity of comparative safety assessments among the Food and Drug Administration (FDA)-approved UEAs. A PRISMA-guided systematic literature review performed in August 2023 searched Medline, Embase, Cochrane Library, and grey literature. Randomized and non-randomized comparative evidence on safety of contrast enhanced procedures were included. A feasibility assessment ensured homogeneity across studies by comparing patient characteristics and outcomes. Bayesian hierarchical network meta-regression was employed to indirectly compare published safety outcomes across different UEAs. In addition, adverse events (AEs) between 2019-2023 for each UEA were retrieved from the FDA Adverse Events Reporting System (FAERS), and comparative safety outcomes were derived using annual UEA administration in the US. Screening of 4146 records rendered 19 studies for inclusion in the indirect comparison analysis after feasibility assessment. Optison demonstrated favorable safety in direct comparisons with Definity and Lumason across the majority of investigated AEs. Network meta-regression results on serious adverse events (SAEs) within 30 minutes revealed odds ratios (ORs) of 0.59 (95% confidence interval: 0.27-1.23) and 0.63 (0.29-1.33) for Optison vs. Lumason and Definity, respectively, indicating a decreased risk of SAEs for Optison vs. Lumason and Definity, further supported by statistically significant ORs within FAERS: 0.01 (0-0.02), P<0.001 and 0.15 (0.05-0.48), P=0.001, for Optison vs. Lumason and Definity, respectively. In conclusion, our results restate the favorable comparative safety profile of Optison, providing new evidence to inform clinical decision-making.

Adverse events associated with oseltamivir and baloxavir marboxil in against influenza virus therapy: A pharmacovigilance study using the FAERS database.

Influenza virus is a widespread pathogen that poses significant health risks to humans. Oseltamivir and Baloxavir Marboxil are commonly utilized medications for both treating and preventing influenza infections. Despite their widespread use, there remains a need to thoroughly investigate their safety profiles and potential adverse reactions. This study aims to comprehensively analyze the adverse events associated with oseltamivir and baloxavir marboxil in real-world clinical settings, with the goal of assessing their safety and potential risks in the management of influenza virus infections. We conducted a retrospective analysis utilizing data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database, spanning from the first quarter of 2004 to the third quarter of 2023. The analysis encompassed examination of drug utilization patterns, types of adverse events reported, patient demographics, and other pertinent factors. From the first quarter of 2004 to the third quarter of 2023, FAERS collected over 17,035,521 adverse event reports (AE reports). Among these reports, there were 38,384 reports associated with oseltamivir, and 3,364 reports associated with baloxavir marboxil. Oseltamivir and Baloxavir Marboxil were primarily used for the treatment of influenza virus infections, accounting for 62.43% and 67.49% of their total usage, respectively. The main adverse reactions reported for oseltamivir were vomiting (case reports = 1402) followed by confusional state (case reports = 353), while for baloxavir marboxil, adverse reactions mainly centered around off-label use (case reports = 378) and intentional product use issues (case reports = 278). In terms of systemic adverse reactions, oseltamivir primarily affected psychiatric disorders (n = 45), whereas baloxavir marboxil mainly impacted the gastrointestinal system (n = 7). Additionally, regarding adverse reactions in pregnant women, the occurrence of normal newborns was a significant signal for oseltamivir, suggesting a certain level of safety during maternal use. Conversely, reports of adverse reactions such as respiratory arrest were documented for baloxavir marboxil, while no such reports were associated with oseltamivir. This study provides a comprehensive analysis of the adverse reactions observed with the clinical use of oseltamivir and baloxavir marboxil, revealing the safety and risks associated with these two drugs in the treatment and prevention of influenza virus infections. Firstly, although both drugs are used for influenza treatment, they exhibit different types of adverse reactions. Oseltamivir predominantly affects the psychiatric system, while baloxavir marboxil primarily impacts the gastrointestinal system. Additionally, oseltamivir demonstrates a certain level of safety for use in pregnant women, while reports of adverse reactions such as respiratory arrest are associated with baloxavir marboxil. Despite the clinical significance of this study, limitations exist due to the voluntary nature of data reporting, which may lead to reporting biases and incomplete information. Future research could employ more rigorous prospective study designs, integrating clinical trials and epidemiological studies, to more accurately assess the safety risks of oseltamivir and baloxavir marboxil.

Quantitative Structure-Activity Relationship Models to Predict Cardiac Adverse Effects.

Drug-induced cardiotoxicity represents one of the most common causes of attrition of drug candidates in preclinical and clinical development. For this reason, the evaluation of cardiac toxicity is essential during drug development and regulatory review. In the present study, drug-induced postmarket adverse event combinations from the FDA Adverse Event Reporting System were extracted for 2002 drugs using 243 cardiac toxicity-related preferred terms (PTs). These PTs were combined into 12 groups based on their clinical relevance to serve as training sets. The optimal classification scheme was determined using a combination of data sources that included drug labeling information, published literature, clinical study data, and postmarket surveillance data. Two commercial QSAR platforms were used to construct 12 models, including general cardiac toxicity, cardiac ischemia, heart failure, cardiac valve disease, myocardial disease, pericardial disease, structural heart disease, cardiac arrhythmia, Torsades de Pointes, long QT syndrome, atrial fibrillation and ventricular arrhythmia, and cardiac arrest. The cross-validated performance for the new models reached a sensitivity of up to 80% and negative predictivity of up to 80%. These new models covering a wide range of cardiac endpoints will provide fast, reliable, and comprehensive predictions of potential cardiotoxic compounds in drug discovery and regulatory safety assessment.

Association between different GLP-1 receptor agonists and acute pancreatitis: case series and real-world pharmacovigilance analysis

ObjectiveGlucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown notable advancements in managing blood sugar control. Nevertheless, there remains a gap in real-world data regarding the variation in acute pancreatitis (AP) risk among different GLP-1 RAs. Our study aimed to characterize and evaluate AP associated with different GLP-1 RAs (exenatide, lixisenatide, liraglutide, albiglutide, semaglutide, dulaglutide and tirzepatide) in a public adverse events database and to review the relevant case reports.MethodsWe described a case series of patients experiencing AP while on GLP-1 RAs. Additionally, we utilized various algorithms including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) to analyze data from the Food and Drug Administration’s Adverse Event Reporting System (FAERS) regarding suspected adverse events of AP linked to GLP-1 RAs from January 2005 to September 2023.ResultsOur case series comprised thirty-nine patients who experienced AP events while on GLP-1 RAs. Within the FAERS database, we retrieved a total of 6,751 individual case safety reports (ICSRs) involving various GLP-1 RAs. The median age of the patients included in our study was 57 years (range: 14–99), with 98.3% of cases classified as serious. Signals indicating AP were observed across all GLP-1 RAs, with particular emphasis on exenatide and liraglutide.ConclusionThere is a notable reporting signal of AP associated with all GLP-1 RAs. Healthcare providers must remain vigilant and closely monitor this potentially life-threatening adverse event.

Risks of malignancies related to disease-modifying antirheumatic drugs in rheumatoid arthritis: a pharmacovigilance analysis using the FAERS database

ObjectivesOver the years when disease-modifying antirheumatic drugs (DMARDs) have been used in rheumatoid arthritis patients, reports of malignancies have emerged. This study aims to investigate the association between malignancies and DMARDs by using data extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS).MethodsFAERS data (January 2019 to December 2023) were reviewed. For each drug-event pair, the disproportionality analysis was conducted to evaluate the risk of malignancy. Multivariate logistic regression was implemented to mitigate potential biases. Moreover, the time to onset of malignancy was also evaluated.ResultsWe conducted a detailed search for rheumatoid arthritis indications and identified a total of 17,412 adverse event reports associated with malignancies, with selective DMARDs designated as the role code “primary suspect”. At the preferred term level, there were 198 positive signals, among which the lower limit of the 95% confidence interval for the information component is 3.55 for squamous cell carcinoma of the skin, 2.39 for breast cancer, and 2.27 for lymphoproliferative disorder. In comparison to other DMARDs, targeted synthetic DMARDs were associated with a broader range of malignancies at both preferred term and Standardized MedDRA Queries levels. The number of adverse events reported in female patients is approximately 2–3 times higher than men, and the median age across the population was approximately 62 years. In terms of onset time, the conventional synthetic DMRADs exhibited a relatively longer median time, ranging from 3.58 to 7.08 years, while the targeted synthetic DMARDs demonstrated a shorter median time of 0.83–1.67 years.ConclusionOur study uncovers varying degrees of malignancy risks related to DMARDs, with a significantly higher risk observed in targeted synthetic DMARDs. Additionally, novel malignancy signals, not documented in product labels, have been detected. In the future, further research will be necessary to validate our findings.

Disseminated intravascular coagulation is an underestimated but fatal adverse event associated with blinatumomab therapy: A pharmacovigilance analysis of FAERS.

Hematologic adverse events (AEs) are common and serious toxicities in patients with hematologic malignancies undergoing blinatumomab therapy. However, restrictive selection criteria in pivotal clinical trials can lead to an underestimation of rare but fatal toxicities. In this study, we systematically analyzed hematologic AEs associated with blinatumomab using the Food and Drug Administration Adverse Event Reporting System (FAERS) from October 2014 to December 2023. Disproportionate analysis was performed to identify overreported AEs, with a reporting odds ratio (ROR), and a lower bound of the 95% confidence interval (ROR025) exceeding one considered significant. Additionally, adjusted mortality rates and risk ratios (RR) of the top 10 reported hematologic AEs were calculated using a logistic regression model. Among 4745 blinatumomab-related cases, 418 (8.81%) involved hematologic AEs. We identified 22 significantly overreporting hematologic AEs compared to the full database, with myelosuppression (n = 39 [9.33%], ROR025 = 8.04), disseminated intravascular coagulation (DIC, n = 31 [7.42%], ROR025 = 15.14), and bone marrow failure (n = 14 [3.35%], ROR025 = 3.41) notably underestimated in clinical trials. DIC resulted in a substantial mortality rate of 45.16%. Finally, DIC was found to be independently associated with death in a multivariable logistic regression analysis (RR = 2.47 [95% CI: 1.11-3.83]). These findings could aid clinicians in the early detection of these rarely reported but fatal hematologic AEs, thereby reducing the risk of severe toxicities in blinatumomab recipients.

Abstract 4137177: A pharmacovigilance investigation from the FAERS database on patients using pembrolizumab and its association with cardiac arrhythmias

Background: Arrhythmia is always a concern in oncological treatments. The advent of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, enhancing the immune system's ability to combat malignancies. They are being more frequently used, revealing a range of immune-related adverse events (irAEs). This study aims to investigate the incidence of cardiac arrhythmias in patients receiving Pembrolizumab. Methods: We conducted a retrospective analysis of the FDA Adverse Event Reporting System (FAERS) database, focusing on reports submitted between 2006 to 2024. Cases involving patients treated with ICs were identified, and information related to cardiac arrhythmias was extracted using the Medical Dictionary for Regulatory Activities (MedDRA). Patients ≥ 18 years of age treated with ICIs were included in this study. A disproportionality analysis was conducted to identify arrhythmia events associated with pembrolizumab by comparing it with other immune checkpoint inhibitors (nivolumab, ipilimumab, and atezolizumab) and the entire FAERS database using the reporting odds ratio (ROR) and information component (IC). Results: A comprehensive analysis of 61,236 reported cases of pembrolizumab use revealed a total of 3,901 cases with cardiac complications. Among these, 672 cases (17.22 %) of arrhythmias were reported, with 452 individuals (67.26%) requiring hospitalization and 172 cases (25.59%) resulting in fatalities. Atrial fibrillation emerged as the most prevalent arrhythmia (49.7%). The occurrence of ventricular tachycardia with an ROR of 1.67 (1.18–2.35) and an IC of 0.44 (0.01–1.46) and complete atrio-ventricular block with an ROR of 1.57 (1.19–2.08) and an IC of 0.40 (0.04–1.24) were statistically significant. The reported arrhythmias associated with pembrolizumab are tabulated in Table 1 . The majority of events were reported in males, as shown in Figure 1 . Conclusion: This research offers significant insights into the connection between ICIs and cardiac arrhythmias, utilizing real-world data from the FAERS database. Healthcare providers should monitor cardiac events in patients receiving ICIs and aim to achieve a balance between anticancer effectiveness and cardiovascular safety. Further investigation is necessary to better understand the underlying mechanisms of arrhythmia and enhance risk stratification strategies for this specific patient group.

Abstract 4147627: A Pharmacovigilance Study of Bempedoic Acid: Balancing Risks and Benefits

Introduction: Bempedoic acid has been approved by FDA since Feb 2020 as an adjunct to maximally tolerated statin therapy for the reduction of LDL-C, specifically in individuals afflicted by atherosclerotic cardiovascular disease (ASCVD) and heterozygous familial hypercholesterolemia (HeFH). Bempedoic acid is also a viable alternative for patients intolerant to statins. Most recently, it has been approved to use for primary prevention of hyperlipidemia, alone or in combination with a statin. It is important to study its side effect profile as it is anticipated to be used more frequentlynin the future. Methods: We explored reported adverse events (AEs) of bempedoic acid using FDA Adverse Event Reporting System (FAERS). A total of 1202 adverse effects were reported until March 31, 2024. 69.97% AEs were reported by healthcare professionals (HCPs), which were further analyzed. AEs were analyzed in men (32.53%) vs women (53.24%) and in three age groups of 18-64, 65-85, and &gt;85 years. Results: A total of 586 (48.7%) events were serious adverse effects. Most common side effects were myalgia which included muscle pain, extremity pain and muscle spasm (25.04%), arthralgia including back pain and bone pain (18.47%), nausea (6.6%), headache(5.5%), gout (4.4%). Among the patients with adverse effects, 4.75% had cardiac side effects which included atrial fibrillation (12%), palpitation (29%), angina pectoris (18%), Myocardial Infarction (5%). Discussion: A thorough understanding of bempedoic acid's complex pharmacology empowers healthcare professionals to tailor treatment plans based on individual patient requirements. This enables informed decision-making in prescribing, optimizing dosage regimens, and mitigating potential adverse reactions. Most studies have been relatively short term in order to confirm the long term side effect profile. It would be beneficial to be cautious in using this medication for patients with above mentioned clinical conditions like myalgia, arthralgia, gout, rhabdomyolysis, atrial fibrillation, angina pectoris. Conclusion: Long term pharmacovigilance is needed to assess the safety profile of bempedoic acid over extended use. With the current increasing use of bempedoic acid, there is a need for more data on safety profiles. In future, further randomized trials are required to better assess the safety profile.

A real−world pharmacovigilance study of FDA Adverse Event Reporting System events for pralsetinib

BackgroundPralsetinib, a selective oral inhibitor of rearranged during transfection (RET) fusion proteins and oncogenic RET mutants, has shown significant efficacy in treating RET fusion-positive non-small cell lung cancer and thyroid cancer. However, since pralsetinib was approved in the United States in September 2020, there have been limited reports of post-marketing adverse events (AEs). In this study, we aimed to analyze the AE signals with pralsetinib on the basis of the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) to provide instructions in clinical practice.MethodsAll AE reports were obtained from the FAERS database from the first quarter (Q3) of 2020 to the second quarter (Q2) of 2024. Various signal quantification techniques were used for analysis, including reporting odds ratios, proportional reporting ratios, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker (MGPS)-based empirical Bayesian geometric mean.ResultsOut of 8,341,673 case reports in the FAERS database, 1,064 reports of pralsetinib as the “primary suspected (PS)” AEs were recorded, covering 26 system organ classes and 256 preferred terms. Of the reports, 62.5% were from consumers rather than healthcare professionals. The most common systems were general disorders and administration site conditions (n = 704), investigations (n = 516), and gastrointestinal disorders (n = 405). A total of 95 significant disproportionality preferred terms (PTs) conformed to the four algorithms simultaneously. AEs that ranked the top three at the PT level were hypertension (n = 80), asthenia (n = 79), and anemia (n = 65). Of the 95 PTs with significant disproportionation, unexpected significant AEs such as increased blood calcitonin, increased myocardial necrosis marker, and bacterial cystitis were observed, which were not mentioned in the drug’s instructions. The median onset time of pralsetinib-associated AEs was 41 days [interquartile range (IQR) 14–86 days]. The majority of the AEs occurred in 30 days (42.86%).ConclusionOur pharmacovigilance analysis of real-world data from the FEARS database revealed the safety signals and potential risks of pralsetinib usage. These results can provide valuable evidence for further clinical application of pralsetinib and are important in enhancing clinical medication safety.

Abstract 4135303: Acute Pericarditis Secondary to Secukinumab Therapy

Background: Pericarditis is the most common pericardial disease worldwide and has a high recurrence rate of 15-30%. It is primarily idiopathic but can arise from infectious and non-infectious causes; drug related cases are rare. Secukinumab, a fully human anti-interleukin-17A monoclonal antibody used for treating psoriasis, has been identified through the FDA Adverse Event Reporting System as potentially inducing pericarditis, though literature is scant. We report a case of acute pericarditis related to secukinumab use. Case presentation: A 28-year-old male with history of psoriasis on secukinumab therapy presented with sharp, central chest pain, and progressive shortness of breath for 3 weeks. He was evaluated for similar chest pain 3 weeks prior; CT chest showed small pericardial effusion and he was managed with analgesics without improvement. This admission, he had tachycardia, and ECG showed sinus rhythm with diffuse ST elevation and PR depression (Figure 1A). Troponin I levels were normal and inflammatory markers were elevated. Transthoracic echocardiogram (TTE) revealed a large pericardial effusion without tamponade physiology (Figure 1B). CT chest confirmed large pericardial effusion, increased in size compared to CT done 3 weeks prior (Figure 2). He was diagnosed with pericarditis and started on ibuprofen and colchicine which improved his symptoms. Search for viral etiology including testing for COVID, influenza A and B, RSV, hepatitis and HIV were negative. Immunological workup for ANA and rheumatoid factor was negative. Thus, secukinumab was thought to be the likely culprit. Follow-up TTE in 3 months showed resolution of pericardial effusion. Conclusion: This case underscores the importance of considering medication-induced pericarditis in patients presenting with typical symptoms, especially when on treatment with drugs like secukinumab. Given the growing evidence from pharmacovigilance databases and the severe potential outcomes of untreated pericarditis, clinicians should maintain vigilance for such adverse effects. Further research is warranted to clarify the mechanisms by which secukinumab may contribute to pericardial inflammation in order to optimize management strategies in affected patients.

Off-Label Use of Monoclonal Antibodies for Eosinophilic Esophagitis in Humans: A Scoping Review

Background: Eosinophilic esophagitis (EoE) is a rare, chronic immune-mediated disorder with limited treatment options. Despite the U.S. Food and Drug Administration (FDA) approval of dupilumab for EoE, other monoclonal antibodies remain unapproved and are used off-label with limited evidence on their efficacy and safety. This systematic review rigorously and comprehensively evaluates the evidence for monoclonal antibody therapies used off-label to treat EoE. Methods: We conducted a systematic review across PubMed, EMBASE, Cochrane Central, and ClinicalTrials.gov, assessing the efficacy and safety of off-label monoclonal antibodies in EoE through clinical outcomes and the FDA Adverse Event Reporting System (FAERS) data. Results: Among ten monoclonal antibodies reviewed, mepolizumab that targets IL-5 showed the most promise with a moderate recommendation based on Level 2 evidence. Others like omalizumab (anti-IgE), dectrekumab (anti-IL-13), and reslizumab (anti-IL-5) showed limited utility. Safety evaluations via the FAERS database revealed significant adverse drug reactions, including serious events like asthmatic crises, pneumonia, and adrenal insufficiency for mepolizumab and reslizumab, as well as chronic obstructive pulmonary disease and gastroenteritis for omalizumab. Dectrekumab’s safety profile remains unclear due to a lack of data. Conclusions: While mepolizumab demonstrates potential as an off-label treatment, none of the antibodies reviewed have FDA approval for EoE. Clinicians should consider the balance between local and systemic effects and exercise caution, closely monitoring for adverse effects, particularly in patients with respiratory comorbidities. Continued research is crucial to establish a more robust evidence base for these therapies.

Evaluation of pitolisant, sodium oxybate, solriamfetol, and modafinil for the management of narcolepsy: a retrospective analysis of the FAERS database

ObjectiveNarcolepsy, a rare neurological disorder believed to have an autoimmune etiology, necessitates lifelong management. This study aimed to provide evidence supporting the safety of pharmacological treatment for narcolepsy.MethodsFive-year data on pitolisant, sodium oxybate, solriamfetol, and modafinil were extracted from the FDA Adverse Event Reporting System (FAERS) self-reporting database for the period spanning from 2019 to 2023. Various statistical methods, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network analysis (BCPNN), and multi-item gamma Poisson shrinker (MGPS), were employed to quantify the signals. Finally, a comparative analysis was conducted between demographic data, outcomes, and inherent associations among the medications and the signals.ResultsAfter data analysis, we obtained 50 signals (a cumulative count of 762 cases) for pitolisant, 640 signals (corresponding to 46,962 cases) for sodium oxybate, 40 signals (equivalent to 1,228 cases) for solriamfetol, and finally, 72 signals (representing 632 cases) for modafinil. The majority of these patients were female. Psychiatric and nervous system disorders were identified as the predominant adverse drug events (ADEs). For sodium oxybate, it is crucial to consider psychiatric disorders (such as suicidal ideation), respiratory disorders (including sleep apnea syndrome and respiratory depression), and signs of pregnancy and congenital familial diseases. For solriamfetol, noteworthy new ADEs include drug inefficacy, suicidal ideation, restless legs syndrome, and somnambulism. Furthermore, a relationship has been observed between modafinil use and restricted fetal growth, spontaneous abortion, cognitive disorders, and drug inefficacy and abuse.ConclusionThe majority of observed adverse reactions in this study were consistent with those listed in the product instructions. However, potential novel or notable ADE signals were identified through real-world pharmacovigilance analysis. It is anticipated that this paper will offer additional information regarding safe and rational medication for narcolepsy.

Delayed immune-related adverse events profile associated with immune checkpoint inhibitors: a real-world analysis

BackgroundImmune-related adverse events (irAEs) typically occur within 3 months of initiating immune-checkpoint inhibitors (ICIs), which has been extensively documented. But the clinical profiles of late-onset irAEs remain inadequately characterized. Therefore, this study aims to quantify the correlation between delayed irAEs and ICIs, and to delineate the profiles of delayed toxicities associated with ICIs using data from the Food and Drug Administration Adverse Event Reporting System (FAERS).MethodsData from the January 2011 to December 2023 in FAERS database were extracted. Four signal detection indices, reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN) and multi-item gamma Poisson shrinker (MGPS), were employed to evaluate the associations between ICIs and delayed irAEs.ResultsA total of 147,854 cases were included in this study, of which 3,738 cases related to delayed irAEs were identified. Generally, 8 signals at System Organ Class (SOC) level were found to be associated with ICIs. Males had a slightly higher reporting frequencies for respiratory disorders (ROR975 = 0.95) and blood and lymphatic system disorders (ROR025 = 1.22), but lower reporting frequencies for immune system disorders (ROR025 = 1.16). Three monotherapy (anti-PD-1, anti-PD-L1 and anti-CTLA-4) were all associated with significant increasing gastrointestinal disorders (ROR025 = 1.66, 1.16, 1.99) and metabolism disorders (ROR025 = 2.26, 1.74, 3.13). Anti-PD-1 therapy exhibited higher rates of respiratory toxicities (ROR025 = 1.46 versus 0.82) and skin toxicities (ROR025 = 1.27 versus 0.94) compared with anti-CTLA-4 therapy. At PT levels, pneumonitis (ROR025: from 11.85 to 29.27) and colitis (ROR025: from 2.11 to 24.84) were the most notable PT signals associated with all three ICI regimens. For outcomes of delayed irAEs, gastrointestinal disorders showed the highest proportion (51.06%) of death.ConclusionOur pharmacovigilance analysis indicates that a small percentage of patients receiving ICIs therapy experience delayed irAEs, which are challenging to manage and may result in severe consequences. Prompt identification and intervention of these delayed irAEs are crucial in clinical practice.

Drug use and acute kidney injury: a Drug-Wide Association study (DWAS) in Denmark and Sweden

Abstract Background Knowledge of which medications may lead to acute kidney injury (AKI) is limited, relying mostly on spontaneous reporting in pharmacovigilance systems. We here conducted an exploratory drug-wide association study (DWAS) to screen for associations between dispensed drugs and AKI risk. Methods Using two large Danish and Swedish data linkages, we identified AKI hospitalizations occurring between April 1997 to December 2021 in Denmark and between March 2007 to December 2021 in Sweden. We used a case-time control design comparing drug dispensing in the three months prior to the AKI with earlier periods for the same patient. Odds Ratios (ORs) for the association between each drug and AKI were estimated using conditional logistic regression and adjusting for the presence of comorbidities. We sought replication of signals in both health systems and explored the plausibility of findings through pharmacovigilance system analysis in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, appearance in the RESCUE list of medications that report AKI as a side effect, PUBMED evidence review and causality assessment through direct acyclic graphs. Results We included 20 622 adults in Denmark and 13 852 in Sweden hospitalized for AKI. In total, 16 unique medications were identified in both cohorts as associated to increased AKI occurrence. Of these, 10 medications had higher reporting odd ratios in the FAERS database, and 9 were listed by RESCUE or appeared in PUBMED. This analysis identified some medications with known AKI risks (i.e. likely true positives such as furosemide, penicillin, spironolactone, and omeprazole), medications that may have initiated in response to conditions that lead to AKI (i.e. false positives like metoclopramide provided to treat nausea/vomiting) and other candidates (e.g. opioids) that warrant further evaluation in subsequent studies. Conclusions This hypothesis-generating study identifies medications with potential involvement in AKI that require confirmation and validation.

Ocular adverse events associated with GLP-1 receptor agonists: a real-world study based on the FAERS database and network pharmacology

ABSTRACT Objective This study evaluates the risk of ocular adverse events (AEs) associated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) using data from the FDA Adverse Event Reporting System (FAERS) and network pharmacology methods. Methods FAERS data from 2004 to 2024 were analyzed for ocular AEs linked to GLP-1 RA treatments. Disproportionality analysis (Reporting Odds Ratio, ROR) was used to identify signals, and a drug-gene interaction network explored potential mechanisms. Results Among 17,785,793 FAERS reports, semaglutide and lixisenatide were significantly associated with ocular AEs, with RORs of 1.25 (95% CI, 1.20-1.31) and 1.96 (95% CI, 1.70-2.27), respectively. Commonly reported AEs included blurred vision, visual impairment, and diabetic retinopathy, with some AEs occurring as early as 10 days after treatment initiation. Gene enrichment analysis highlighted potential links between GLP-1-related genes and ocular AEs. Conclusion The widespread use of GLP-1 RAs has raised concerns regarding their ophthalmic safety. This study contributes new evidence from real-world data, suggesting that semaglutide and lixisenatide are associated with significant risks of ocular AEs. Further experimental studies are warranted to elucidate the underlying mechanisms and confirm these associations.

Drug risks associated with sarcopenia: a real-world and GWAS study

IntroductionDrug-induced sarcopenia has not received adequate attention. Meanwhile, there is growing recognition of the importance of effective pharmacovigilance in evaluating the benefits and risks of medications.AimsThe primary aim of this study is to investigate the potential association between drug use and sarcopenia through an analysis of adverse event reports from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and to evaluate the genetic factors contributing to drug-induced sarcopenia using summary-data-based Mendelian randomization (SMR).MethodsWe obtained reports of adverse drug reactions from FAERS. Primary outcomes included sarcopenia and potential sarcopenia. We calculated the Proportional reporting ratio (PRR) to assess the risk of specific adverse events associated with various drugs, applying chi-square tests for statistical significance. Additionally, we used SMR based on Genome-wide association study (GWAS) to evaluate the potential associations between drug target genes of some significant medications and sarcopenia outcomes. The outcome data for sarcopenia included metrics as hand grip strength and appendicular lean mass (ALM).ResultsA total of 55 drugs were identified as inducing potential sarcopenia, and 3 drugs were identified as inducing sarcopenia. The top 5 drugs causing a potential risk of sarcopenia were levofloxacin (PRR = 9.96, χ2 = 1057), pregabalin (PRR = 7.20, χ2 = 1023), atorvastatin (PRR = 4.68, χ2 = 903), duloxetine (PRR = 4.76, χ2 = 527) and venlafaxine (PRR = 5.56, χ2 = 504), and the 3 drugs that had been proved to induced sarcopenia included metformin (PRR = 7.41, χ2 = 58), aspirin (PRR = 5.93, χ2 = 35), and acetaminophen (PRR = 4.73, χ2 = 25). We identified electron-transfer flavoprotein dehydrogenase (ETFDH) and protein Kinase AMP-Activated Non-Catalytic Subunit Beta 1 (PRKAB1) as the primary drug target genes for metformin, while Prostaglandin-endoperoxide Synthase 1 (PTGS1) and Prostaglandin-endoperoxide Synthase 2 (PTGS2) were considered the primary action target genes for aspirin and acetaminophen according to DrugBank database. SMR showed that the expression abundance of ETFDH was negatively correlated with right hand grip strength (blood: OR = 1.01, p-value = 1.27e-02; muscle: OR = 1.01, p-value = 1.42e-02) and negatively correlated with appendicular lean mass (blood: OR = 1.03, p-value = 7.73e-08; muscle: OR = 1.03, p-value = 1.67e-07).ConclusionsWe find that metformin, aspirin, and acetaminophen are specifically noted for their potential to induce sarcopenia based on the analyses conducted. We perform signal mining for drug-associated sarcopenia events based on real-world data and provides certain guidance for the safe use of medications to prevent sarcopenia.