FDA Adverse Event Reporting System Research Articles

Abrocitinib-associated adverse events: a real-world pharmacovigilance study using the FAERS database

ABSTRACT Background Atopic dermatitis (AD) is a common chronic inflammatory skin disease. Janus kinase (JAK) modulates cytokines involved in AD pathophysiology, and JAK inhibitors have emerged as effective pharmacotherapeutic remedies for AD. Abrocitinib, an oral selective inhibitor of JAK1, is indicated for the management of moderate-to-severe AD. The current study evaluated the adverse events (AEs) associated with abrocitinib in a real-world setting. Methods To quantify the signals of abrocitinib-associated AEs, we used the US Food and Drug Administration Adverse Event Reporting System (FAERS) for this pharmacovigilance study with two established pharmacovigilance methods. Results A total of 1071 AEs of abrocitinib were investigated as the primary suspected from the FAERS to detect and characterize relevant safety signals. The analysis revealed 85 signals for abrocitinib. The most common AE for abrocitinib was drug ineffective. The signal strength of eczema herpeticum was 515.87 (277.80–957.98) and 510.59 (5148.65) and exhibited the highest strength for abrocitinib. Rare AEs such as aggravated condition, pruritus, and hypersensitivity were not listed on the label, and attention to these AEs is required. Conclusion The analysis of the AE signals may provide support for clinical monitoring and risk identification of abrocitinib.

Differences in Ocular Adverse Events Associated with phosphodiesterase-5 inhibitors: a real-world pharmacovigilance study

ABSTRACT Background Phosphodiesterase type 5 (PDE5) inhibitors are commonly prescribed for erectile dysfunction and pulmonary hypertension. While PDE5 inhibitors have shown remarkable efficacy in their intended therapeutic areas, there have been concerns regarding their potential ocular adverse events. Our study aims to characterize the ocular safety profiles of PDE5 inhibitors and explore the differences in ocular adverse events among PDE5 inhibitors. Research design and methods We analyzed reports on ocular adverse events associated with sildenafil, vardenafil and tadalafil submitted to the FDA Adverse Event Reporting System (FAERS) database from the first quarter of 2004 to the first quarter of 2023. Disproportionality analysis was conducted to evaluate reporting risk profiles. Results Among 61,211 reports qualifying for analysis, 5,127 involved sildenafil, 832 vardenafil, and 3,733 tadalafil. All PDE5 inhibitors showed increased reporting odds ratios (ROR) for ocular adverse events, with vardenafil highest (ROR 4.47) followed by sildenafil and tadalafil. Key ocular adverse events included cyanopsia, optic ischemic neuropathy, visual field defects, unilateral blindness and blindness. Sildenafil showed the highest disproportionality for cyanopsia (ROR 1148.11) while vardenafil and tadalafil showed the highest disproportionality for optic ischemic neuropathy. Time-to-onset analysis also revealed significant differences, with sildenafil having a later median time-to-onset compared to vardenafil and tadalafil. Conclusions This comprehensive pharmacovigilance study reveals distinct patterns of ocular adverse events associated with sildenafil, vardenafil, and tadalafil. These findings contribute to a better understanding of the safety profiles of PDE5 inhibitors and may guide healthcare professionals in clinical decision-making.

A real-world pharmacovigilance study of drug-induced QT interval prolongation: analysis of spontaneous reports submitted to FAERS

PurposeTo identify the most commonly reported drugs associated with QT interval prolongation in the FDA Adverse Event Reporting System (FAERS) and evaluate their risk for QT interval prolongation.MethodsWe employed the preferred term (PT) “electrocardiogram QT prolonged” from the Medical Dictionary for Regulatory Activities (MedDRA) 26.0 to identify adverse drug events (ADEs) of QT interval prolongation in the FAERS database from the period 2004–2022. Reporting odds ratio (ROR) was performed to quantify the signals of ADEs.ResultsWe listed the top 40 drugs that caused QT interval prolongation. Among them, the 3 drugs with the highest number of cases were quetiapine (1,151 cases, ROR = 7.62), olanzapine (754 cases, ROR = 7.92), and citalopram (720 cases, ROR = 13.63). The two most frequently reported first-level Anatomical Therapeutic Chemical (ATC) groups were the drugs for the nervous system (n = 19, 47.50%) and antiinfectives for systemic use (n = 7, 17.50%). Patients with missing gender (n = 3,482, 23.68%) aside, there were more females (7,536, 51.24%) than males (5,158, 35.07%) were involved. 3,720 patients (25.29%) suffered serious clinical outcomes resulting in deaths or life-threatening conditions. Overall, most drugs that caused QT interval prolongation had early failure types according to the assessment of the Weibull's shape parameter (WSP) analysis.ConclusionsOur study offered a list of drugs that frequently caused QT interval prolongation based on the FAERS system, along with a description of some risk profiles for QT interval prolongation brought on by these drugs. When prescribing these drugs in clinical practice, we should closely monitor the occurrence of ADE for QT interval prolongation.

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.

Risk of VMAT2 inhibitors on suicidality and parkinsonism: report utilizing the United States Food and Drug Administration adverse event reporting system.

Prescription of vesicular monoamine transporter 2 (VMAT2) inhibitors, valbenazine, deutetrabenazine, and tetrabenazine, is becoming increasingly common in persons treated with antipsychotics. Reported suicidality and parkinsonism are safety concerns with VMAT2 inhibitors. Herein, we aim to evaluate the aforementioned safety outcomes using the FDA Adverse Event Reporting System. Reporting odds ratios (RORs) and lower limits of 95% confidence intervals of information components (IC025) were calculated to quantify VMAT2 inhibitor-associated adverse events. Acetaminophen was the reference agent. Suicidal ideation was significantly associated with VMAT2 inhibitors, with RORs ranging from 2.38 to 10.67 and IC025 ranging from 0.73 to 2.39. Increased odds of suicidal behavior was observed with tetrabenazine (ROR 3.011, IC025 0.0087), but not deutetrabenazine or valbenazine. Decreased odds of suicide attempts and completed suicide were observed with VMAT2 inhibitors, with RORs ranging from 0.011 to 0.10 (all IC025 < 0). Increased odds of parkinsonism were reported for all VMAT2 inhibitors, with RORs and IC025 ranging from 19.49 to 25.37 and 1.66 to 2.93, respectively. The mixed results with VMAT2 inhibitor-associated suicidality and parkinsonism do not establish causal relationships. The parameters of suicidality may be explained by underlying psychiatric disorders.

Vitreoretinal Traction Syndrome, Nitrituria and Human Epidermal Growth Factor Receptor Negative Might Occur in the Aromatase-Inhibitor Anastrozole Treatment

Background. Anastrozole has been approved for treatment of hormone receptor-positive advanced or metastatic breast cancer by FDA. This study was to assess Anastrozole-related adverse events (AEs) of real-world through data mining of the US Food and drug administration adverse event reporting system (FAERS). Methods. Four different disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN) and the multiitem gamma Poisson shrinker (MGPS) algorithms were employed to quantify the signals of Anastrozole-associated AEs. Results. A total 25 system organ class (SOCs) and 300 significant disproportionality Preferred Terms (PTs) were found in this study. The top 5 most significant SOCs were Eye disorders, renal and urinary disorders, respiratory, thoracic and mediastinal disorders, investigations, and cardiac disorders. Unexpected significant AEs was vitreoretinal traction syndrome (ROR = 1108.22, PRR = 1103.98, IC025 = 9.51, EBGM05 = 389.98), nitrituria (ROR = 3561.82, PRR = 3557.28, IC025 = 10.38, EBGM05 = 318.83) and human epidermal growth factor receptor negative (ROR = 675.04, PRR = 674.01, IC025 = 9, EBGM05 = 204.57). Conclusion. The Unexpected significant AEs associated with anastrozole were identified in this study, warrants urgent clarification through additional prospective studies.

Safety analysis of Oseltamivir and Baloxavir Marboxil after market approval: a pharmacovigilance study based on the FDA adverse event reporting system

Background and objectivesAmidst limited influenza treatment options, evaluating the safety of Oseltamivir and Baloxavir Marboxil is crucial, particularly given their comparable efficacy. This study investigates post-market safety profiles, exploring adverse events (AEs) and their drug associations to provide essential clinical references.MethodsA meticulous analysis of FDA Adverse Event Reporting System (FAERS) data spanning the first quarter of 2004 to the fourth quarter of 2022 was conducted. Using data mining techniques like reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Propagation Neural Network, and Multiple Gamma Poisson Shrinkage, AEs related to Oseltamivir and Baloxavir Marboxil were examined. Venn analysis compared and selected specific AEs associated with each drug.ResultsIncorporating 15,104 Oseltamivir cases and 1,594 Baloxavir Marboxil cases, Wain analysis unveiled 21 common AEs across neurological, psychiatric, gastrointestinal, dermatological, respiratory, and infectious domains. Oseltamivir exhibited 221 significantly specific AEs, including appendicolith [ROR (95% CI), 459.53 (340.88 ∼ 619.47)], acne infantile [ROR (95% CI, 368.65 (118.89 ∼ 1143.09)], acute macular neuroretinopathy [ROR (95% CI), 294.92 (97.88 ∼ 888.64)], proctitis [ROR (95% CI), 245.74 (101.47 ∼ 595.31)], and Purpura senile [ROR (95% CI), 154.02 (81.96 ∼ 289.43)]. designated adverse events (DMEs) associated with Oseltamivir included fulminant hepatitis [ROR (95% CI), 12.12 (8.30-17.72), n=27], ventricular fibrillation [ROR (95% CI), 7.68 (6.01–9.83), n=64], toxic epidermal necrolysis [ROR (95% CI), 7.21 (5.74–9.05), n=75]. Baloxavir Marboxil exhibited 34 specific AEs, including Melaena [ROR (95% CI), 21.34 (14.15–32.18), n = 23], cystitis haemorrhagic [ROR (95% CI), 20.22 (7.57-54.00), n = 4], ileus paralytic [ROR (95% CI), 18.57 (5.98–57.71), n = 3], and haemorrhagic diathesis [ROR (95% CI), 16.86 (5.43–52.40)), n = 3]. DMEs associated with Baloxavir Marboxil included rhabdomyolysis [ROR (95% CI), 15.50 (10.53 ∼ 22.80), n = 26].ConclusionMonitoring fulminant hepatitis during Oseltamivir treatment, especially in patients with liver-related diseases, is crucial. Oseltamivir’s potential to induce abnormal behavior, especially in adolescents, necessitates special attention. Baloxavir Marboxil, with lower hepatic toxicity, emerges as a potential alternative for patients with liver diseases. During Baloxavir Marboxil treatment, focused attention on the occurrence of rhabdomyolysis is advised, necessitating timely monitoring of relevant indicators for those with clinical manifestations. The comprehensive data aims to provide valuable insights for clinicians and healthcare practitioners, facilitating an understanding of the safety profiles of these influenza treatments in real-world scenarios.

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

ObjectiveLumateperone, 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.MethodsThis 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).ResultsOur 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).ConclusionThis 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

BackgroundThe 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.PurposeWe 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.MethodsThe 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.ResultsWe 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.ConclusionThe 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.

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.

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 for the first quarter of 2019 through the second quarter of 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 A total of 112 elagolix-induced AE signals were detected in 17 system organ classes (SOCs) that simultaneously met the thresholds of 4 algorithms. 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 adverse events 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. The majority of cases occurred within 1 month after initiation of elagolix treatment. 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.

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.

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

Background and Objective Chronic myeloid leukemia (CML) is a hematological malignancy with an excellent prognostic outcome. After advancements in CML treatment and the introduction of different tyrosine kinase inhibitors (TKI), 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. and compare the events reported with different TKI. Method The Nationwide Readmission Database (NRD) was searched from January 2016 to December 2020. for the study population. Adults of age ≥ 18 years with or without CML hospitalized for with a primary diagnosis of acute myocardial infarction, ST-segment elevation myocardial infarction (STEMI), and non-ST-segment elevation myocardial infarction (NSTEMI) and underwent PCI were included. The patients were identified using ICD-10 codes. The baseline characteristics and outcomes of the CML and non-CML patients who underwent PCI were compared. The primary outcomes were in-hospital mortality and 30-day readmission rates. The secondary outcomes were the PCI complications rates. Data regarding TKI reports of STEMI and acute coronary syndrome were obtained from The FDA Adverse Event Reporting System (FARES). Results Out of 2,727,619 patients with myocardial infarction, 2,124 CML patients were identified. A total of 888 CML patients underwent PCI. The mean age was 68.34 ± 11.14, with 62.46 % above 65 years. The analysis showed no significant difference between CML and non-CML patients after PCI for death (OR? 0.93 (95% CI 0.49-1.80), P=0.527) and 30-day readmission (OR? 1.41 (95% CI 0.99-2.01), P=0.056) rates. CML patients were significantly older (mean age 68.34 ± 11.14 versus 64.40 ± 12.61, p &lt; 0.001) than non-CML patients without a difference in sex distribution. Hypertension (85.45% versus 78.64%), diabetes (45.48% versus 37.29), stroke (11.84% versus 7.78) at baseline were significantly higher in CML group. Prior myocardial infarction events (20.51% versus 15.17%) and prior PCI procedure (24.47% versus 16.89%) were significantly higher in CML group. CML had a significantly longer hospital stay (4.66 ± 4.40 versus 3.75 ± 4.62 days, p = 0.001). The primary outcomes did not differ between the comparison groups. Conclusion This analysis showed no statistically significant difference in mortality, 30-day readmission, and complication rates post PCI between CML and non-CML patients. However, interestingly, CML patients may experience lower coronary artery dissection and ischemic stroke rates 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

ObjectiveAs 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.Research design and methodsWe 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.ResultsIn 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 &amp;lt;18 years, 18–64 years, and≥ 65 years 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.ConclusionBy 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.

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.