FDA Adverse Event Reporting System Research Articles

Post-marketing safety concerns with lumateperone: a pharmacovigilance analysis based on the FDA adverse event reporting system (FAERS) database.

Lumateperone, a novel antipsychotic drug that was granted by the Food and Drug Administration (FDA) approval in December 2019, remains insufficiently explored for its adverse event profile. This study used the FDA Adverse Event Reporting System (FAERS) database to explore its potential safety issues. This study conducted a retrospective analysis of FAERS data from the fourth quarter of 2019 to the third quarter of 2023, extracting reports related to lumateperone. Disproportionality analysis using Reporting Odds Ratio (ROR) and Bayesian Confidence Propagation Neural Network (BCPNN) algorithms was employed to detect signals of adverse events (AEs). Our research processed 4,777 pertinent AE disclosures related to lumateperone, unveiling 125 signals that satisfied both ROR and BCPNN evaluative benchmarks across 26 System Organ Classes (SOCs). Intriguingly, 108 of these signals were categorized as unanticipated, spotlighting notable psychiatric manifestations such as mania (ROR = 73.82, 95% CI = 57.09-95.46; IC = 6.16, IC025 = 4.49), and hypomania (ROR = 34.74, 95% CI = 15.54-77.64; IC = 5.10, IC025 = 3.43), alongside non-psychiatric phenomena like urinary retention (ROR = 3.59, 95% CI = 1.80-7.19; IC = 1.84, IC025 = 0.18) and serotonin syndrome (ROR = 8.69, 95% CI = 4.81-15.72; IC = 3.11, IC025 = 1.45). This research provides real-world safety data on lumateperone post-marketing and is an important supplement to the information from clinical trial studies. Healthcare professionals should be vigilant for the risk of a manic switch in patients with bipolar depression who are administered lumateperone. More epidemiological studies are needed in the future to explore and further evaluate the risk-benefit issue of lumateperone.

Assessing the safety of bedaquiline: insight from adverse event reporting system analysis.

The development and marketing of Bedaquiline (BDQ) represent significant advancements in treating tuberculosis, particularly multidrug-resistant forms. However, comprehensive research into BDQ's real-world safety remains limited. We obtained BDQ related adverse event (AE) information from the US Food and Drug Administration's Adverse Event Reporting System (FAERS) to assess its safety and inform drug usage. The AE data for BDQ from 2012 Q4 to 2023 Q3 was collected and standardized. Disproportionality analysis, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Multi-item Gamma Poisson Shrinker (MGPS), and Bayesian Confidence Propagation Neural Network (BCPNN) was used to quantify signals of BDQ-related AEs. Logistic regression was used to analyze the individual data of hepatotoxicity and drug-induced liver injury, and multiple linear regression models were established. Additionally, network pharmacology was employed to identify the potential biological mechanisms of BDQ-induced liver injury. We identified 2017 case reports directly related to BDQ. Our analysis identified 341 Preferred Terms (PTs) characterizing these AEs across 27 System Organ Classes (SOC). An important discovery was the identification of AEs associated with ear and labyrinth disorders, which had not been documented in the drug's official leaflet before. Subgroup analysis revealed a negative correlation between BDQ-related liver injury and females (OR: 0.4, 95%CI: 0.3-0.6). In addition, via network pharmacology approach, a total of 76 potential targets for BDQ related liver injury were predicted, and 11 core target genes were selected based on the characterization of protein-protein interactions. The pathway linked to BDQ-induced liver injury was identified, and it was determined that the PI3K-Akt signaling pathway contained the highest number of associated genes. The analysis of the FAERS database revealed adverse events linked to BDQ, prompting the use of a network pharmacology approach to study the potential molecular mechanism of BDQ-induced liver injury. These findings emphasized the significance of drug safety and offered understanding into the mechanisms behind BDQ-induced liver injury. BDQ demonstrated distinct advantages, including reduced incidence of certain adverse events compared to traditional treatments such as injectable agents and second-line drugs. However, it is important to acknowledge the limitations of this analysis, including potential underreporting and confounding factors. This study provides valuable insights into the safety of BDQ and its role in the management of MDR-TB, emphasizing the need for continued surveillance and monitoring to ensure its safe and effective use.

Post-marketing safety concerns with elagolix: a disproportionality analysis of the FDA adverse event reporting system

ABSTRACT Objective Elagolix is approved for the treatment of moderate-to-severe pain associated with endometriosis. However, the long-term safety of elagolix in a large sample of real-world patients is unknown. Methods The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) reports were collected and analyzed from January 2019 to June 2023. Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms, were employed in data mining to quantify the signals of elagolix-related adverse events (AEs). Results After removing the non-drug-related AE signals, we detected several AE signals such as hot flushes, bone pain, suicidal ideation, depression, and increased liver enzymes, which were known during the clinical trial phase. In addition to this, we detected several unexpected important AEs that were not mentioned in the drug insert, including cystitis interstitial, parosmia, and epiploic appendagitis. The median onset time of elagolix-associated AEs was 28.5 days. Conclusion Our study provides a comprehensive picture of the safety of elagolix in the post-marketing setting, while also identifying potential new AE signals. These findings emphasize the importance of continued monitoring of the potential risks of elagolix.

Safety of marketed biosimilar monoclonal antibody cancer treatments in the US: a disproportionality analysis using the food and drug administration adverse event reporting system (FAERS) database

ABSTRACT Background By 31 December 2022, the United States Food and Drug Administration (FDA) has approved 12 biosimilar monoclonal antibody cancer treatments. This study detected disproportionate adverse event (AE) reporting signals and compared safety profile of individual biosimilars to their originator biologics and between each pair of biosimilars. Research design and methods The FDA Adverse Event Reporting System data (6/1/2018–12/31/2022) were used to identify AE reports for rituximab, bevacizumab, trastuzumab, and their marketed biosimilars. Reporting odds ratios and empirical Bayesian geometric mean were computed to detect reporting disproportionality in serious, death, and specific AEs between studied biologics/biosimilars and all other drugs. Results Significant AE reporting signals were identified: 1) death for biological rituximab, pruritus for biosimilar rituximab-pvvr, and infusion-related reactions for biological rituximab and biosimilar rituximab-pvvr (significantly higher ROR for rituximab-pvvr than biological rituximab, p < .0001); 2) death for biological bevacizumab and biosimilar bevacizumab-bvzr (significantly higher ROR for bevacizumab-bvzr than biological bevacizumab, p < .0001), hypertension, platelet count decreased (PCD), and proteinuria for biological bevacizumab and biosimilar bevacizumab-awwb (significantly higher ROR of PCD for bevacizumab-awwb than originator bevacizumab, p = .001); and 3) rash for biosimilar trastuzumab-anns. Conclusions Findings call for large, longitudinal studies to examine causality of certain AEs with rituximab-pvvr and bevacizumab biosimilars.

A real-world pharmacovigilance analysis of the FDA adverse event reporting system events for polatuzumab vedotin

ABSTRACT Background Polatuzumab vedotin is the first antibody-drug conjugate approved by the US Food and Drug Administration (FDA) for patients with diffuse large B-cell lymphoma. This study evaluated adverse events (AEs) associated with polatuzumab vedotin by data mining of the FDA Adverse Event Reporting System (FAERS). Methods This study included AEs registered in FAERS between 2019 Q2 and 2023 Q2. Four algorithms were used to quantify the signals of polatuzumab vedotin-associated AEs, including reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker. Results A total of 7,609,450 reports were collected from the FAERS database, and 1,388 reports of polatuzumab vedotin were identified as primary suspected AEs. Polatuzumab vedotin-associated AEs involved 26 organ systems. According to the four algorithms, 108 significant disproportionality AEs were retained simultaneously. Unexpected significant AEs included gastrointestinal hemorrhage, ileus, gastrointestinal perforation, cholecystitis, hypogammaglobulinemia, hepatitis B reactivation, hypercalcemia, hydronephrosis, cystitis hemorrhagic, interstitial lung disease, and thrombophlebitis. The median time to onset of polatuzumab vedotin-associated AEs was 20 (interquartile range 4–56) days. Conclusions Our study identified significant new AE signals for polatuzumab vedotin through real-world disproportionality analysis data and may provide additional evidence for risk identification of polatuzumab vedotin.

Contribution of aldehyde oxidase to methotrexate-induced hepatotoxicity: in vitro and pharmacoepidemiological approaches

ABSTRACT Background Methotrexate (MTX) is partially metabolized by aldehyde oxidase (AOX) in the liver and its clinical impact remains unclear. In this study, we aimed to demonstrate how AOX contributes to MTX-induced hepatotoxicity in vitro and clarify the relationship between concomitant AOX inhibitor use and MTX-associated liver injury development using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Methods We assessed intracellular MTX accumulation and cytotoxicity using HepG2 cells. We used the FAERS database to detect reporting odds ratio (ROR)-based MTX-related hepatotoxicity event signals. Results AOX inhibition by AOX inhibitor raloxifene and siRNA increased the MTX accumulation in HepG2 cells and enhanced the MTX-induced cell viability reduction. In the FAERS analysis, the ROR for MTX-related hepatotoxicity increased with non-overlap of 95% confidence interval when co-administered with drugs with higher Imax, u (maximum unbound plasma concentration)/IC50 (half-maximal inhibitory concentration for inhibition of AOX) calculated based on reported pharmacokinetic data. Conclusion AOX inhibition contributed to MTX accumulation in the liver, resulting in increased hepatotoxicity. Our study raises concerns regarding MTX-related hepatotoxicity when co-administered with drugs that possibly inhibit AOX activity at clinical concentrations.

Myocardial Infarction in Chronic Myeloid Leukemia: Results from the Nationwide Readmission Database

Introduction: Chronic myeloid leukemia (CML) is a hematological malignancy with an excellent prognostic outcome. After the advancements in CML treatment and the introduction of different tyrosine kinase inhibitors (TKIs), the life expectancy of CML patients has become equivalent to that of the general population. As a result, coronary artery disease is anticipated to be the leading cause of death among CML patients. Moreover, TKI use is associated with a risk of endothelial dysfunction, thrombosis, and cardiovascular events, including myocardial infarction. In this study, we compare the outcomes of percutaneous coronary intervention (PCI) in patients with CML to their matched non-CML counterparts. Method: This is a retrospective cohort study using the Nationwide Readmission Database from January 2016 to December 2020. Adults with or without CML hospitalized for acute myocardial infarction and underwent PCI were included. The patients were identified using ICD-10 codes. The primary outcomes were in-hospital mortality and 30-day readmission rates. The secondary outcomes were PCI complications rates. Results: Out of 2,727,619 patients with myocardial infarction, 2,124 CML patients were identified. A total of 888 CML patients underwent PCI. CML patients were significantly older (mean age: 68.34 ± 11.14 vs. 64.40 ± 12.61 years, p < 0.001) than non-CML patients without a difference in sex distribution. Hypertension (85.45% vs. 78.64%), diabetes (45.48% vs. 37.29), stroke (11.84% vs. 7.78) at baseline were significantly higher in the CML group. Prior myocardial infarction events (20.51% vs. 15.17%) and prior PCI procedure (24.47% vs. 16.89%) were significantly higher in the CML group. CML patients had a significantly longer hospital stay (4.66 ± 4.40 vs. 3.75 ± 4.62 days, p = 0.001). The primary outcomes did not differ between the comparison groups. The risk of post-PCI complications did not differ between the comparison groups in the propensity matched analysis except for coronary artery dissection (odds ratio [OR]: 0.10; 95% confidence interval [CI]: 0.02–0.65, p = 0.016) and ischemic stroke (OR: 0.35; 95% CI: 0.14–0.93, p = 0.034) which were lower in the CML group. Conclusion: This analysis showed no statistically significant difference in mortality, 30-day readmission, and post PCI complications rates between CML and non-CML patients. However, interestingly, CML patients may experience lower coronary artery dissection and ischemic stroke events than those without CML diagnosis.

Toxicity burden patterns of MET-selective tyrosine kinase inhibitors: evidence from real-world pharmacovigilance.

MET exon 14 skipping alterations and MET amplifications are recognized as oncogenic and targetable genetic changes in cancer patients. The treatment of MET-selective tyrosine kinase inhibitors (TKIs) in this specific population has shown encouraging therapeutic results. However, a comprehensive understanding of the potential toxicities linked to these agents is still lacking.The present pharmacovigilance analysis was carried out using the FDA Adverse Event Reporting System database to assess notable adverse events associated with MET-selective TKIs.Gastrointestinal disorders, respiratory toxicity, hepatotoxicity, and disturbances in metabolism and nutrition demonstrated a substantial prevalence and significance among the adverse event (AE) categories. Particularly notable were the occurrences of peripheral oedema, nausea, dysphagia, fatigue, and dyspnoea, which emerged as the foremost five reported AEs. The majority of these AEs were observed within the initial months of initiating treatment with MET-selective TKIs and persistently thereafter. Notably, our investigation unveiled a significant correlation between the usage of capmatinib and the incidence of hearing loss and difficulty in swallowing.Diligent monitoring and the implementation of supportive care strategies are essential in managing the toxicities associated with MET-selective TKIs, particularly those related to gastrointestinal disorders, respiratory toxicity, hepatotoxicity, and ototoxicity.

Cardiovascular adverse events associated with antibody-drug conjugates (ADCs): a pharmacovigilance study based on the FAERS database.

As a novel drug formulation, antibody drug conjugates (ADCs) are widely used in various types of cancer. However, clinically, there is a lack of attention to the CVD produced by them, as well as a lack of research on the real-world situation. Using the Food and Drug Administration Adverse Event Reporting System (FAERS) database, to ensure its clinical safety application, we analyzed post-marketing data on antitumor ADCs to identify risk factors and drugs associated with the risk of cardiovascular events. We used OpenVigil 2.1 to conduct a database query for adverse events (AEs) reported to the FAERS database between the time the drug was launched and the second quarter of 2023. Cardiovascular adverse events (AEs) were grouped into fourteen narrow categories using the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs), and the reporting odds ratio (ROR) and the proportional reporting ratio (PRR) for reporting the association between different drugs and cardiovascular disease (CVD) risk were calculated. In the FAERS database, 1863 AEs associated with CVD we studied were identified in patients receiving ADC therapy. Most reports came from people aged ≥65, but a significant number of cases were found to be unknown. The number of patients with antibody-drug conjugates (ADCs)-related CVD cases aged <18years, 18-64years, and≥ 65years was 52 (2.79%), 586 (31.45%), and 613 (32.90%), respectively. The proportion of female patients (834, 44.77%) was higher than that of male patients (752, 40.37%). Death (770 reports), disability (9 reports), Hospitalization initial or prolonged (407 reports), and life-threatening reactions (187 reports). Of the 770 deaths reported, 103 (31.7%) were associated with brentuximab vedotin, 10 (24.4%) with sacituzumab govitecan, 22 (19.3%) with enfortumab vedotin, and 35 (34.7%) with trastuzumab emtansine.49 (41.2%) cases were associated with polatuzumab vedotin, 62 (29%) with trastuzumab deruxtecan, 423 (54.3%) with gemtuzumab ozogamicin, and 66 (38.8%) with inotuzumab ozogamicin. In a disproportionate number of SMQS, cardiac failure (n = 277) and embolic and thrombotic events, venous (n = 446) were the most frequently reported CVD-related AEs in ADCs. By mining the FAERS database, we provided relevant information on the association between ADC use and cardiovascular-associated AEs. ADCs were associated with increased cardiovascular toxicity, deserving distinct monitoring and appropriate management. Further research is needed to confirm these findings and assess causality.

A pharmacovigilance study of adverse events associated with polymyxins based on the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database

ABSTRACT Background Polymyxins have been regarded as last-line treatment for multidrug-resistant gram-negative bacterial infections. Nonetheless, concerns regarding toxicity persist. This study aimed to explore and compare potential adverse events (AEs) between colistin and polymyxin B (PMB). Methods Outpatient antibiotic use associated with acute upper respiratory infections in China: a nationwide cross-sectional study Polymyxins-related AEs were retrieved from the U.S. Food and Drug Administration Adverse Event Reporting System between 2004 and 2022. Potential signals were estimated by the reporting odds ratio (ROR), and subgroup analyses were preformed to adjust for potential factors in AEs with significant disproportionality. Results Analysis of 3,915 records involving 718 patients revealed a higher disproportionality of renal and urinary disorders (ROR 1.62, 95% CI 1.01–2.59) and acute kidney injury (ROR 1.75, 95% CI 1.07–2.87) with colistin treatment. Conversely, colistin exhibited a lower risk for neurotoxicity (ROR 0.47, 95% CI 0.30–0.73). Seven cases of skin hyperpigmentation were reported with PMB, whereas none were reported with colistin. Over 80% of cases involving polymyxin-related AEs occurred during the first two weeks of therapies, with a median onset time of 4.5 days. Conclusions Outpatient antibiotic use associated with acute upper respiratory infections in China: a nationwide cross-sectional study Patients received colistin displayed a higher potential risk of nephrotoxicity but a lower risk of neurotoxicity. Clinicians should be vigilant in monitoring the AEs of hyperpigmentation disorders induced by PMB.

Emerging Toxicities of Antibody-Drug Conjugates for Breast Cancer: Clinical Prioritization of Adverse Events from the FDA Adverse Event Reporting System.

Antibody-drug conjugates (ADCs) are gaining widespread use in the treatment of breast cancer, although toxicity remains an underexplored issue in the real-world clinical setting. Individual case safety reports collected in large pharmacovigilance databases can advance our knowledge on their safety profile in routine clinical practice. We prioritized adverse events (AEs) reported with ADCs approved for breast cancer using the Food andDrugAdministration Adverse Event Reporting System (FAERS). We assessed clinical priority of AEs reported in FAERS (February 2013-March 2022) for trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan (SG) by attributing a score to each AE disproportionally reported with ADCs. Four criteria were assessed: clinical relevance, reporting rate, reported case fatality rate, and stability of disproportionality signals (consistency of the reporting odds ratio across multiple analyses using three different comparators). We retained 6589 reports (77.4% referring to T-DM1 as suspect), and 572 AEs generated a disproportionality signal in at least one analysis. The majority of these AEs (62%) were classified as moderate clinical priorities (e.g., interstitial lung disease with T-DXd, thrombocytopenia, peripheral neuropathy with T-DM1, febrile neutropenia, and large intestine perforation with SG). Three AEs emerged as high clinical priorities (6 points): septic shock and neutropenic colitis with SG (N = 8 and 13, with median onset 13 and 10 days, respectively), without co-reported immunosuppressive agents; and pulmonary embolism with T-DM1 (N = 31, median onset 109 days, 52% with reported metastasis). The heterogeneous spectrum of post-marketing toxicities for ADCs used in breast cancer, as emerging from the FAERS, is largely in line with preapproval evidence. Although causality cannot be proved, we call for increased awareness by oncologists on potential serious unexpected reactions, including early onset of septic shock and neutropenic colitis with SG, and late emergence of pulmonary embolism with T-DM1.

Signal detection of adverse reactions for bendamustine based on FDA adverse event reporting system

ABSTRACT Background This study aimed to analyze the adverse events to bendamustine using data obtained from the Food and Drug Administration open public data project (openFDA) and to provide a reference for its use in clinical practice. Research design and methods Adverse events (AEs) due to bendamustine usage reported from 1 January 2008 to 31 March 2023 were collected from the FDA Adverse Event Reporting System (FAERS). The reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian plausible propagation neural network (BCPNN), and multinomial gamma-Poisson distribution shrinking (MGPS) algorithms were used to identify signs of adverse reactions caused by bendamustine. Results A total of 4214 AE reports where bendamustine was considered as the first suspected drug were obtained from FAERS. The analysis revealed 214 AE risk signals, among which 141 met the criteria but they were not listed as possible side effects on the drug information sheet provided in the package. Conclusion Our findings identified numerous common AEs with previously reported clinical observations. We also identified some signs of potential new AEs, indicating the need of careful clinical monitoring of patients treated with bendamustine and further risk identification research about this drug.

Abstract PO3-12-04: Pulmonary Complication related to Trastuzumab Deruxtecan. A pharmacovigilance study from 2022-2023 FAERS Database

Abstract Background: The horizon of Trastuzumab Deruxtecan (T-DXd), an antibody-drug conjugate, has been expanding. After its promising results in HER2-positive/HER2-low Breast cancer, it has been on trial for other cancers, such as HER2-negative breast cancers, Gastrointestinal, lung, colorectal, urothelial, etc., and it has shown promising results in clinical trials. However, there have been reports of pulmonary adverse events associated with T-DXd, including interstitial lung disease (ILD) and pneumonitis. Understanding the occurrence and characteristics of these pulmonary complications is essential for optimizing patient care and ensuring the safe use of T-DXd. Using the FAERS (FDA Adverse Event Reporting System) database for 2022-2023 aims to see T-DXd-related pulmonary complications and guide healthcare professionals in monitoring and managing these adverse events effectively. Methods: We conducted a retrospective analysis of all reported cases of respiratory complications in patients using TDXD, utilizing data reported to the FDA Adverse Event Reporting System (FAERS) database for January 2022 to March 2023. We included patients of more than 18; these cases were identified and classified using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. Results: In this study, a total of 296 cases of adverse events were reported in patients using TDXD. Among these cases, 74 (27%) were respiratory adverse events. The most frequently observed respiratory complications were interstitial lung disease (ILD) and pneumonitis, with 21 cases each, accounting for 56% of the total respiratory complications. Out of the 14 reported deaths in this cohort, pneumonitis was the most commonly seen respiratory complication, occurring in 8 patients, followed by pulmonary embolism and ILD, each reported in 4 patients. Conclusion: Respiratory complications were the most frequent among the reported adverse events, accounting for 27% of all cases. ILD and pneumonitis were the most common complications, with 14 deaths reported in this group. These findings underline the importance of closely monitoring and managing pulmonary adverse events in patients treated with T-DXd. Healthcare professionals can use this information to optimize patient care and ensure the safe use of T-DXd. However, it is important to note that this study was based on a database and has limitations such as underreporting bias and lack of a control group, which hinders establishing a causal relationship. Additional research is needed to identify risk factors and improve patient outcomes. Citation Format: Niraj Neupane, Himal Kharel, Sangharsha Thapa. Pulmonary Complication related to Trastuzumab Deruxtecan. A pharmacovigilance study from 2022-2023 FAERS Database [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-12-04.

Drug Repurposing Using FDA Adverse Event Reporting System (FAERS) Database.

Drug repurposing is an emerging approach to reassigning existing pre-approved therapies for new indications. The FDA Adverse Event Reporting System (FAERS) is a large database of over 28 million adverse event reports submitted by medical providers, patients, and drug manufacturers and provides extensive drug safety signal data. In this review, four common drug repurposing strategies using FAERS are described, including inverse signal detection for a single disease, drug-drug interactions that mitigate a target ADE, identifying drug-ADE pairs with opposing gene perturbation signatures and identifying drug-drug pairs with congruent gene perturbation signatures. The purpose of this review is to provide an overview of these different approaches to FAERS-based drug repurposing using existing successful applications in the literature. With the fast expansion of adverse drug event reports, FAERS-based drug repurposing represents a versatile and promising strategy for discovering new uses for existing therapies.

Assessing the Impact of Morphine on Adverse Outcomes in ACS Patients Treated with P2Y12 Inhibitors: Insights from Multiple Real-World Evidence.

Mechanistic studies showed that morphine may impair the antiplatelet effect of P2Y12 inhibitors. However, Several clinical studies with cardiovascular events as an outcome are contradictory, and the broader impact of this drug interaction on additional organ systems remains uncertain. With multisource data, this study sought to determine the effects of morphine interaction with P2Y12 inhibitors on major adverse outcomes comprehensively, and identify the warning indicators. Interaction signals were sought in 187,919 safety reports from the FDA Adverse Event Reporting System (FAERS) database, utilizing reporting odds ratios (repOR). In a cohort of 5240 acute coronary syndrome patients, the analyses were validated, and the biological effects of warning indicators were further studied with Mendelian randomization and mediation analysis. Potential risk of renal system adverse events in patients cotreated with morphine is significantly higher in FAERS (repOR 4.83, 95% CI 4.42-5.28, false discovery rate adjusted-P =3.55*10-209). The analysis of in-house patient cohorts validated these results with an increased risk of acute kidney injury (adjusted OR: 1.65; 95% CI: 1.20 to 2.26), and we also found a risk of myocardial infarction in patients treated with morphine (adjusted OR: 1.55; 95% CI: 1.14 to 2.11). The Morphine group exhibited diminished Plateletcrit (PCT) levels post-surgery and lower PCT levels were associated with an increased risk of AKI. The administration of morphine in patients treated with P2Y12 receptor inhibitors should be carefully evaluated. PCT may serve as a potential warning indicator for morphine-related renal injury.

Dental Disorders Reported to the FDA Adverse Event Reporting System in Association with Buprenorphine: An Analysis by Ingredient Composition and Route of Administration.

Prior research has suggested buprenorphine-containing medications may be associated with an increased risk of dental disorders. However, published data describing adverse dental reactions in buprenorphine users by active ingredient composition and route of administration are limited. The purpose of this study was to evaluate the influence of formulation on spontaneous reporting of dental disorders among patients treated with buprenorphine. Adverse event reports submitted to the United States Food and Drug Administration Adverse Event Reporting System (FAERS) between 2015 and 2022 were analyzed. Reporting odds ratios (ROR) and 95% confidence intervals (CI) were calculated to measure disproportionality of dental disorder reporting as classified by 39 Medical Dictionary for Regulatory Activities preferred terms. Compared to pooled reports for all other drugs across FAERS, both buprenorphine monotherapy (ROR 3.09; 95% CI 2.61-3.66) and combination buprenorphine/naloxone (ROR 14.61; 95% CI 13.34-16.01) were associated with positive disproportionality signals. Signals of disproportionate dental disorder reporting were also detected for buprenorphine medicines administered by sublingual (ROR 20.03; 95% CI 18.04-22.24), buccal (ROR 4.46; 95% CI 3.00-6.61) and oral (ROR 7.17; 95% CI 5.03-10.22) routes, but not for other modalities. In considering active ingredient and route together, sublingual buprenorphine monotherapies (ROR 23.55; 95% CI 17.84-31.11) and sublingual buprenorphine/naloxone (ROR 19.47; 95% CI 17.39-21.80) were each associated with disproportionate reporting of dental disorders. Subject to the limitations of spontaneous adverse event data, this study identified significantly disproportionate reporting of dental disorders to FAERS among patients treated with buprenorphine- containing medications, including formulations administered by sublingual, buccal and oral routes. These findings are consistent with prior data and suggest that regular oral care and proper dental hygiene be emphasized for patients undergoing therapy with orally dissolving buprenorphine.

Association of immunomodulatory therapies with COVID-19 mortality in rheumatoid arthritis: An analysis of the FDA adverse event reporting system

BackgroundThe COVID-19 pandemic significantly affects patients with RA and other rheumatic diseases. Our study aims to explore the factors associated with COVID-19-related fatality among Rheumatoid Arthritis (RA) patients, especially immunomodulatory therapies, using the international Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). MethodsReportes from FAERS were extracted from February 2020 to September 2022, and uesd for this cross-sectional analysis. The investigative outcome was COVID-19-related death. Age, sex, region, event date, and immunomodulatory medications classies were included as co-variates in multivariable logistic regression. In view of the different targeting and affinity of individual JAKi, Tofacitinib, Upadacitinib and Baricitinib was respectively analyzed. ResultsIn all, 3808 cases (mean age 58.85 years, 82.8 ​% female), 267 (7.0 ​%) died. JAKi therapies (41.2 ​%), followed by TNFi (37.7 ​%), IL-1i (12.2 ​%), IL-6i (4.1 ​%) and Anti-CD20 (3 ​%) were reported. Risk factors associated with COVID-19-related death in RA patients were age (odds ratio [OR]: 1.06; 95 ​% confidence interval [CI]: 1.05–1.08; p ​< ​0.01), male sex (1.71, 1.26–2.33; p ​= ​0.01) and anti-CD20 therapies (5.05; 1.40–18.19; p ​= ​0.013). With TNFi conference, anti-CD20 was still a risk predictor (4.29; 2.39–7.70; p ​< ​0.01). Other DMARDs except for anti-CD20, did not confer a significant association with mortality, compared with csDMARDs or TNFi. Individual JAKi showed no obvious difference in the risk of death, compared with csDMARDs or TNFis. ConclusionsConclusions Using FAERS open access data for risk prediction of death, anti-CD20 therapies were recognized as a risk factor for COVID-19-related fatalities among RA patients, other immunomodulatory therapies were not associated with mortality, compared with csDMARDs or TNFis.

Beyond the Label: Real-World Side Effects Experienced With FDA-Approved Drugs for Non-Melanoma Skin Cancers.

With immunotherapy historically focused on cutaneous melanoma, there has been a new wave of systemic medications available for treating non-melanoma skin cancers including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and Merkel cell carcinoma (MCC). The immune checkpoint inhibitors approved by the FDA target programmed cell death protein 1 (PD-1) and the Hedgehog (Hh) signaling pathway. These medications have expanded treatment options; however, side effects are an important consideration. We used the FDA Adverse Events Reporting System (FAERS) to characterize the most prevalent, real-world side effects experienced by patients on these agents. Muscle spasms (23.45%), alopecia (16.06%), ageusia (12.02%), taste disorder (11.91%), and fatigue (11.67%) were the five most common side effects reported with medications used for BCC treatment. Logistic regression analysis showed males on vismodegib for BCC having greater odds of experiencing muscle spasms (aOR 1.33, P&lt;0.001) and ageusia (aOR 1.34,&nbsp; P&lt;0.001) versus females, who were more likely to exhibit alopecia (aOR 1.82, P&lt;0.001) and nausea (aOR 1.96, P&lt;0.001). With SCC treatment, the 5 most reported adverse events were fatigue (5.58%), rash (3.59%), asthenia (3.59%), pruritus (3.19%), and pyrexia (2.79%). Patients taking cemiplimab-rwlc for BCC compared to SCC were more likely to experience disease progression (aOR 10.98, P=0.02). With medication labels providing an excessively daunting list of side effects, we characterize practical side effects seen in patients receiving systemic treatments for non-melanoma skin cancers.&nbsp; J Drugs Dermatol. 2024;23(5):301-305. doi:10.36849/JDD.7968.

Thyroid Hyperplasia and Neoplasm Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists in the Food and Drug Administration Adverse Event Reporting System: Retrospective Analysis.

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are one of the most commonly used drugs for type 2 diabetes mellitus. Clinical guidelines recommend GLP-1 RAs as an adjunct to diabetes therapy in patients with chronic kidney disease, presence or risk of atherosclerotic cardiovascular disease, and obesity. The weight loss observed in clinical trials has been explored further in healthy individuals, putting GLP-1 RAs on track to be the next weight loss treatment. Although the adverse event profile is relatively safe, most GLP-1 RAs come with a labeled boxed warning for the risk of thyroid cancers, based on animal models and some postmarketing case reports in humans. Considering the increasing popularity of this drug class and its expansion into a new popular indication, a further review of the most recent postmarketing safety data was warranted to quantify thyroid hyperplasia and neoplasm instances. GLP-1 RA patient reports from the US Food and Drug Administration (FDA) Adverse Event Reporting System database were analyzed using reporting odds ratios and 95% CIs. In this study, we analyzed over 18 million reports from the US FDA Adverse Event Reporting System and provided evidence of significantly increased propensity for thyroid hyperplasias and neoplasms in patients taking GLP-1 RA monotherapy when compared to patients taking sodium-glucose cotransporter-2 (SGLT-2) inhibitor monotherapy. GLP-1 RAs, regardless of indication, are associated with an over 10-fold increase in thyroid neoplasm and hyperplasia adverse event reporting when compared to SGLT-2 inhibitors.

Tacrolimus Related Acute Pancreatitis: An Observational, Retrospective, Pharmacovigilance Study

PurposeRecent case reports have drawn attention to the emergence of acute pancreatitis, a potentially life-threatening complication associated with tacrolimus. This study uses the Food and Drug Administration Adverse Event Reporting System (FAERS) to investigate the risk signal of acute pancreatitis associated with calcineurin inhibitors (CNIs), with a focus on tacrolimus. MethodsWe conducted an observational retrospective pharmacovigilance study utilizing the FAERS database, encompassing data from its inception to the third quarter of 2023. The assessment of the association between CNIs and acute pancreatitis was carried out using the Information Component (IC) and Reporting Odds Ratio (ROR). Logistic regression analysis was employed to elucidate factors contributing to fatal outcomes. All analyses were performed using R version 3.2.5. FindingWe identified 221 cases of acute pancreatitis linked to CNIs. The median age of individuals experiencing acute pancreatitis induced by tacrolimus was 43, with a predominant occurrence among male patients. Our study showed a significant association between CNIs and acute pancreatitis (ROR 1.82 [1.60–2.08], IC 0.85 [3.66–3.92]). Comparing tacrolimus and cyclosporine, the signal for tacrolimus seemed to be higher. Further analysis revealed that, with the exception of patients aged 60 and above, the signal for tacrolimus remained stable. Contrastingly, the signal for cyclosporine was unstable and limited to the male group and individuals aged less than 20 years. In cases of CNIs-related acute pancreatitis, the mortality rate was 31.67% (70/221 cases). Logistic regression analysis indicated that a younger age acts as a protective factor for death due to CNIs-related acute pancreatitis (OR 0.943, 95% CI 0.915–0.972, P = 0.000). ImplicationsOur study has identified a safety signal for tacrolimus in relation to acute pancreatitis. Additionally, we observed advanced age as a significant risk factor for tacrolimus-related acute pancreatitis, leading to mortality. Given the widespread use of tacrolimus, it is crucial for healthcare providers to be vigilant and informed about the potential association with acute pancreatitis.