Food And Drug Administration Adverse Event Research Articles

Pharmacovigilance of esketamine nasal spray: an analysis of the FDA adverse event reporting system database.

Esketamine nasal spray (ESK-NS) is a new drug for treatment-resistant depression, and we aimed to detect and characterize the adverse events (AEs) of ESK-NS using the Food and Drug Administration (FDA) adverse event reporting system (FAERS) database between 2019 Q1 and 2023 Q4. Reporting odds ratio (ROR), proportional reporting ratio (PRR), and multi-item gamma Poisson shrinker (MGPS) were performed to detect risk signals from the FAERS data to identify potential ESK-NS-AEs associations. A total of 14,606 reports on AEs with ESK-NS as the primary suspected drug were analyzed. A total of 518 preferred terms signals and 25 system organ classes mainly concentrated in psychiatric disorders (33.20%), nervous system disorders (16.67%), general disorders and administration site conditions (14.21%), and others were obtained. Notably, dissociation (n = 1,093, ROR 2,257.80, PRR 899.64, EBGM 876.86) exhibited highest occurrence rates and signal intensity. Moreover, uncommon but significantly strong AEs signals, such as hand-eye coordination impaired, feeling guilty, and feelings of worthlessness, were observed. Additionally, dissociative disorder (n = 57, ROR 510.92, PRR 506.70, EBGM 386.60) and sedation (n = 688, ROR 172.68, PRR 155.53, and EBGM 142.05) both presented strong AE signals, and the former is not recorded in the Summary of Product Characteristics (SmPC). In clinical applications, close attention should be paid to the psychiatric disorders and nervous system disorders, especially dissociation. Meanwhile, clinical professionals should be alert for the occurrence of AEs signals not mentioned in the SmPC and take preventive measures to ensure the safety of clinical use.

Drug-induced interstitial lung disease: a real-world pharmacovigilance study of the FDA Adverse Event Reporting System from 2004 to 2021.

Drug-induced interstitial lung disease (DILD) is an increasingly common cause of morbidity and mortality. However, due to the lack of specificity, DILD detection remains an unsolved public health challenge. For the first time, we aimed to examine DILD reports submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) to identify demographic characteristics and top drugs associated with DILD at a group level (including age, sex, drug class, and country stratification) and individual drug level. A retrospective analysis of the FAERS database was examined by disproportionality analysis. We reviewed the FAERS database from 2004 to 2021, using search terms 'interstitial lung disease' and sorting cases by generic drug name. The reporting odds ratio, proportional reporting ratio, and Bayesian confidence propagation neural network were calculated as the measure of strength of association. There were 32,821 DILD reports in the FAERS. After excluding reports without age, sex, or country data according to the specific measurement, the median age of patients was 68 (interquartile range: 59), 54.77% were male, and 46.00% of reports came from Japan. The top drug classes related to DILD in the FAERS were antineoplastic, followed by cardiovascular and antirheumatic agents, in varying order in different sexes. Fam-trastuzumab deruxtecan-nxki, ramucirumab, and eribulin were the top three drugs with the highest strength of association. We also found some drugs without DILD in the labels, such as amiodarone, temsirolimus, and ursodiol. There are significant differences in DILD reports in various countries. For example, the United States and France reported more cardiovascular agents, whereas Canada reported more antirheumatic agents. We found the top drugs and drug classes that were associated with DILD in the FAERS, which provides a real-world window for different ages, sexes, and countries to formulate precise pharmacovigilance policies.

Adverse event profiles of CDK4/6 inhibitors: data mining and disproportionality analysis of the FDA adverse event reporting system.

Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are targeted therapies designed to selectively block CDK4/6, crucial regulators of the cell cycle. These inhibitors play a pivotal role in restoring cell cycle control, particularly in breast cancer cases marked by abnormal CDK regulation, ultimately inhibiting uncontrolled cell division and tumor growth. This analysis aimed to comprehensively examine adverse effects in CDK4/6 inhibitors using the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. Disproportionality analysis was conducted to analyze the adverse event (AE) reports related to CDK4/6 inhibitor submitted to the FAERS database. We collected AE reports regarding palbociclib, ribociclib, abemaciclib, trilaciclib, and dalpiciclib submitted to the FAERS from 2015Q1 to 2023Q1. We used the system organ class and the Standardized MedDRA Query to perform a comprehensive search for AEs at the preferred term (PT) level, using case reports as our data source. After removing duplicate reports, we performed disproportionality analysis and sensitivity analysis to identify safety signals. A total of 85,635 reports encompassing 280,211 AEs were extracted for analysis. Among 3681 scrutinized PTs, approximately 484 were detected as statistically significant signals associated with CDK4/6 inhibitors. It was noteworthy that palbociclib and ribociclib had comparable safety profiles, whereas abemaciclib exhibited distinctive safety patterns. Notably, our analysis found novel safety signals linked to CDK4/6 inhibitors, including nail-related disorders such as onychoclasis, nail disorder, and nail discoloration, and psychiatric concerns, including eating disorders and emotional disorder. Overall, the present study identified several new safety signals of CDK4/6 inhibitors, as well as differences among various drugs within the CDK4/6 category, through the use of the FDA FAERS, which deserve more careful monitoring in the clinic.

A real-world pharmacovigilance analysis of eslicarbazepine acetate using the FDA adverse events reporting system (FAERS) database from 2013 (Q4) to 2024 (Q1).

The approval of eslicarbazepine acetate (ESL) by the Food and Drug Administration (FDA) in 2013 marked an advancement in the treatment of adult patients with partial-onset seizures. However, there still remains a paucity of real-world studies regarding the adverse events (AEs) associated with this compound. The principal aim of the present study was to scrutinize ESL-related AEs by leveraging data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. By extracting all available data since the FDA approval of ESL (2013Q4-2024Q1), disproportionality analysis was performed using reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN) and multi-item gamma Poisson shrinker (MGPS) algorithms. AE signals that simultaneously met the requirements of all four algorithms were identified as significant positive signals. Demographic information, time of onset and gender-specific signal detection were also examined. In addition, a special screening process for designated medical events (DME) was implemented to focus on the evaluation and comparison of safety signals within DME and System Organ Classification (SOC) level, as well as SMQ (Standardised MedDRA Queries) level. Stratified analysis by logistic regression is employed to examine the variations across different gender (male and female) and age groups (<18years old, 18-64years old, >65years old). A total of 5,719 AE reports and 1,907 reported cases were obtained. ESL related AEs were identified in relation to 27 SOCs, among which the significant positive SOCs were nervous system disorders, injury poisoning and procedural complications, etc. There were 86 severely disproportional preferred terms that complied with the four algorithms. Most AEs occurred within the first month after treatment. According to the 86 valuable positive signals with DME screening results, 3 signals of dermatitis exfoliative, stevens-johnson syndrome, drug reaction with eosinophilia and systemic symptoms were consistent with PT signals on the DME-list, with the 3 PTs focusing on skin and subcutaneous tissue disorders and hypersensitivity. Males are more commonly affected by seizures than females. Seizures, hyponatremia, and confusional states were more frequently observed in the elderly population, while aggression, irritability, DRESS (drug reaction with eosinophilia and systemic symptoms), and abnormal behavior were found to be more common in the pediatric population. Both the children and elderly groups exhibited a higher proportion of agitation than the adult group. Our research enhances the safety and tolerability profile of ESL, but the clinical use of ESL should be noticed and avoided in relation to AEs since it raises the risk of dermatitis exfoliative, stevens-johnson syndrome. Particular attention should be paid to DRESS in children and hyponatremia in the elderly.

The drug risks of cilostazol: A pharmacovigilance study of FDA Adverse Event Reporting System database.

Cilostazol is indicated for alleviating intermittent claudication (IC) in stable-phase peripheral arterial disease (PAD) patients. Conducting data mining on adverse events (AEs) of cilostazol in the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database to explore its potential medication risks and advance more rational and secure clinical medication practices. This study utilized the Open Vigil 2.1-MedDRA tool to retrieve and extract AE reporting data related to cilostazol from the FAERS database spanning the first quarter of 2004 to the first quarter of 2024. The primary methodology employed was the application of the reporting odds ratio (ROR) method to detect risk signals associated with AEs of cilostazol. A total of 2,130 AE reports involving cilostazol were identified as the primary suspect drug, with a total of 7,134 AEs reported. These reports were predominantly concentrated among patients aged 60 and above, with a higher occurrence in males compared to females. Japan ranked first among the reporting countries, and the majority of reports were submitted by healthcare professionals. Through the screening of cilostazol, a total of 323 positive risk signals for AEs were identified, encompassing 23 system organ classes (SOCs). A comparison with the existing cilostazol product label revealed 8 AEs that were not included based on the number of AE reports, and 19 AEs that were not included based on the strength of the risk signals. Cilostazol exhibited positive risk signals for AEs primarily affecting 8 organ systems based on the SOC classification. Among these, cardiac disorders ranked highest, with a total of 53 positive risk signals for cardiovascular-related AEs identified. In terms of the number of reports, cardiac failure ranked first, aligning with the black box warning issued by the FDA regarding cilostazol. The occurrence of adverse reactions related to cilostazol is primarily concentrated within the first month of treatment. However, a certain proportion of adverse reactions have been reported to occur after long-term use (exceeding 360 days) of cilostazol therapy. Our results have further enriched the observations from existing clinical and real-world studies, uncovering new AE signals for cilostazol, including fall, cerebral infarction, pneumonia, loss of consciousness, acute kidney injury, renal impairment, renal failure, cardiac vein perforation, basal ganglia haematoma, cerebral hyperperfusion syndrome, et al. This study also highlights the significant impact of cilostazol on the cardiovascular system, necessitating close attention to potential cardiovascular toxicities. In addition to focusing on the short-term adverse reactions following cilostazol administration, thorough research into its long-term safety profile is also imperative. This study provides recommendations and guidance for the rational and safe clinical use of cilostazol. In the future, prospective studies are needed to explore the occurrence of related AEs further.

Regulatory Authority in Pharmacovigilance

Abstract: Based on their Gross National Income (GNI) per capita, the World Bank has categorized 80 economies as HighIncome. Global pharmacovigilance rules are primarily driven by three major regulatory stakeholders: the Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Pharmaceuticals and Medical Devices Agency (PMDA). This article's goal is to provide an overview of pharmacovigilance systems and procedures in high-income nations, especially those that are also International Conference on Harmonization (ICH) members. Every high-income nation is a part of the WHO PIDM. Medication safety precautions are directly correlated with a nation's income level. The 10 intrepid members of the Uppsala Monitoring Center are from affluent nations and were among the first to act following the thalidomide catastrophe, establishing drug appraisal committees, launching ADR reporting forms, and implementing safety protocols. Although VigiBase is accessible, several nations have their own databases for data management and analysis, such as the FDA Adverse Event Reporting System, the French pharmacovigilance database, the EU's Eudravigilance system, and Canada's Vigilance online database. Strong pharmacovigilance systems are present in all high-income nations. The two international leaders in pharmacovigilance are the USFDA and EMA. The majority of wealthy nations adhere to EMA regulations. The degree of affluence in a nation directly affects the safety of medicines.

A systematic analysis and data mining of opioid-related adverse events submitted to the FAERS database.

The opioid epidemic has become a serious national crisis in the United States. An indepth systematic analysis of opioid-related adverse events (AEs) can clarify the risks presented by opioid exposure, as well as the individual risk profiles of specific opioid drugs and the potential relationships among the opioids. In this study, 92 opioids were identified from the list of all Food and Drug Administration (FDA)-approved drugs, annotated by RxNorm and were classified into 13 opioid groups: buprenorphine, codeine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, tapentadol, and tramadol. A total of 14,970,399 AE reports were retrieved and downloaded from the FDA Adverse Events Reporting System (FAERS) from 2004, Quarter 1 to 2020, Quarter 3. After data processing, Empirical Bayes Geometric Mean (EBGM) was then applied which identified 3317 pairs of potential risk signals within the 13 opioid groups. Based on these potential safety signals, a comparative analysis was pursued to provide a global overview of opioid-related AEs for all 13 groups of FDA-approved prescription opioids. The top 10 most reported AEs for each opioid class were then presented. Both network analysis and hierarchical clustering analysis were conducted to further explore the relationship between opioids. Results from the network analysis revealed a close association among fentanyl, oxycodone, hydrocodone, and hydromorphone, which shared more than 22 AEs. In addition, much less commonly reported AEs were shared among dihydrocodeine, meperidine, oxymorphone, and tapentadol. On the contrary, the hierarchical clustering analysis further categorized the 13 opioid classes into two groups by comparing the full profiles of presence/absence of AEs. The results of network analysis and hierarchical clustering analysis were not only consistent and cross-validated each other but also provided a better and deeper understanding of the associations and relationships between the 13 opioid groups with respect to their adverse effect profiles.

The association between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and suicidality: reports to the Food and Drug Administration Adverse Event Reporting System (FAERS)

ABSTRACT Introduction Recently, the European Medicines Agency (EMA) received reports of suicidal thoughts and self-injury associated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide and semaglutide. Research design and methods Herein, we sought to evaluate suicidality associated with all GLP-1 RAs relative to other glucose-lowering agents currently approved by the United States Food and Drug Administration (FDA). Reports of suicidal ideation, “depression/suicidal”, suicidal behavior, suicidal attempts, and completed suicide associated with GLP-1 RA exposure reported to the FDA between 2005 and October 2023 were obtained from the FDA Adverse Event Reporting System (FAERS). We present data using the reporting odds ratio (ROR). The ROR was considered significant when the lower limit of the 95% confidence interval (CI) was greater than 1.0. Results Disproportionate reporting of suicidal ideation and “depression/suicidal” was observed with semaglutide and liraglutide. Disproportionate reporting of suicidal behavior, suicide attempts, and completed suicide was not observed for any of the FDA-approved GLP-1 RAs. Conclusions Using the Bradford Hill criteria, however, and taking into consideration confounders, no causal link between GLP-1 RAs and suicidality exists.

The association between aspirin use and immune-related adverse events in specific cancer patients receiving ICIs therapy: analysis of the FAERS database.

Background: The promise of immune checkpoint inhibitors (ICIs) therapy in cancer treatment is tempered by the occurrence of immune-related adverse events (irAEs). Many patients undergoing ICIs also take aspirin, but the association between aspirin and irAEs is not well understood. Methods: This study analyzed adverse reaction data associated with the use of ICIs in the US Food and Drug Administration (FDA) Adverse Event Reporting System FDA Adverse Event Reporting System database, from the approval date of each drug until 1 October 2022. Multivariate logistic regression was employed to assess the association of aspirin use with irAEs in patients receiving ICIs. Results: The results indicated that aspirin use was associated with an increased risk of irAEs in a pan-cancer analysis, with a more pronounced association in specific cancer types such as lung cancer, mesothelioma, and pancreatic cancer. However, in lymphoma, aspirin use was associated with a reduced risk of irAEs. Furthermore, aspirin use was associated with an increased risk of certain irAEs, such as anemia, colitis, myocarditis, myositis, pancreatitis, pericarditis, and pneumonia, while it was associated with a reduced risk of rash, Stevens-Johnson syndrome, and thyroiditis. Conclusion: This study has unveiled an association between aspirin use and irAEs in cancer patients receiving ICIs therapy, emphasizing the need for individualized consideration of patients' medication history when devising cancer treatment plans to enhance efficacy and reduce risks.

Post-marketing safety surveillance of sacituzumab govitecan: an observational, pharmacovigilance study leveraging FAERS database.

Background and objective: Sacituzumab govitecan (SG), the first antibody-drug conjugate targeting human trophoblast cell-surface antigen 2 (Trop-2), has been approved by the Food and Drug Administration (FDA) for the treatment of advanced or metastatic breast cancer and urothelial cancer. However, there is currently a dearth of information regarding the safety profiles of SG in a large sample cohort. The objective of the present study is to investigate SG-related adverse events (AEs) in real-world settings leveraging the FDA Adverse Event Reporting System (FAERS) database to guide the safety management of clinical medication. Methods: The FAERS database was retrospectively queried to extract reports associated with SG from April 2020 to March 2023. To identify and evaluate potential AEs in patients receiving SG, various disproportionality analyses such as reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) were employed. Results: Overall, 2069 reports of SG as the "primary suspect" were identified. Noteworthy, SG was significantly associated with an increased risk of blood lymphatic system disorders (ROR, 7.18; 95% CI, 6.58-7.84) and hepatobiliary disorders (ROR, 2.68; 95% CI, 2.17-3.30) at the System Organ Class (SOC) level. Meanwhile, 61 significant disproportionality preferred terms (PTs) simultaneously complied with all four algorithms were adopted. Therein, anemia, thrombocytopenia, neutropenia, leukopenia, diarrhea, asthenia, alopecia, and electrolyte imbalance were consistent with the common AEs described in the clinical trials and specification of SG. Furthermore, unexpected significant AEs include colitis (ROR, 12.09; 95% CI, 9.1-16.08), heart rate increased (ROR, 5.11; 95% CI, 3.84-6.79), sepsis (ROR, 4.77; 95% CI, 3.59-6.34), cholestasis (ROR, 6.28; 95% CI, 3.48-11.36), blood bilirubin increased (ROR, 4.65; 95% CI, 2.42-8.94) and meningitis (ROR, 7.23; 95% CI, 2.71-19.29) were also be detected. The median time to onset of SG-related AEs was 14 [interquartile range (IQR), 7-52] days, with the majority occurring within the initial month of SG treatment. Conclusion: Our study validates the commonly known AEs and also found some potentially emerging safety issues related to SG in real-world clinical practice, which could provide valuable vigilance evidence for clinicians and pharmacists to manage the safety issues of SG.

Abstract 16751: Novel Psoriasis Agents Associated Cardiotoxicity: Analysis of FAERS

Introduction: Psoriasis is a chronic skin condition characterised by hyper-proliferation of epidermal keratinocytes, resulting in erythematous and scaling lesions. The US Food and Drug Administration (FDA) has approved nine biological agents to address the burden of psoriasis, but their cardiovascular risks remain poorly studied. Methods: This retrospective pharmacovigilance study utilised the FDA Adverse Event Reporting System database to analyse adverse events associated with newly approved therapeutic agents for psoriasis. We employed disproportionally signal analysis, calculating the reporting odds ratio (ROR) with a 95% confidence interval. Results: Among the vast FAERS database, which contained more than 25 million adverse events, a total of 334,399 events were associated with newly approved therapeutic agents for psoriasis. Cardiac adverse events accounted for 3,852 cases, including pericarditis, atrial fibrillation, and coronary artery disease. Secukinumab had the highest number of reported adverse events, followed by brodalumab, while tildrakizumab had the lowest. Coronary artery disease was the most reported adverse event (1,438 cases), followed by pericarditis (572 cases) and atrial fibrillation (384 cases). Secukinumab had the highest incidence of coronary artery disease, pericarditis, and atrial fibrillation. Risankizumab showed a significant association with an increased risk of coronary artery disease and atrial fibrillation, while tildrakizumab and Ixekizumab were associated with atrial fibrillation. Secukinumab was associated with an elevated risk of pericarditis. Conclusions: The study uncovers unknown cardiovascular adverse effects related to biologic agents used in psoriasis treatment. These findings emphasise the importance of monitoring and evaluating the cardiovascular safety profiles of biologic agents used in psoriasis treatment.

Incidence of Parkinsonism As a Complication of Anti-BCMA CAR-T Cell Therapy in Multiple Myeloma

Introduction: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR T) therapy has revolutionized the treatment for relapsed/refractory multiple myeloma (RRMM). Two BCMA-directed CAR T products, Idecabtagene Vicleucel (ide-cel) and Ciltacabtagene Autoleucel (cilta-cel), have received approval from the U.S. Food and Drug Administration (FDA). While these therapies have demonstrated remarkable efficacy, concerns regarding treatment-related neurotoxicities have emerged. The specific adverse effect of Parkinsonism associated with BCMA-directed CAR T therapy has not been adequately studied. Methods: We conducted an analysis utilizing the FDA Adverse Events Reports System (FAERS) database, covering the years 2021-2023. Our search focused on the reported incidence of Parkinsonism associated with BCMA-directed CAR T therapy. Results: Upon reviewing the FDA data, we identified a total of 177 patients with reported nervous system disorders related to Ide-cel therapy. Out of these patients, 2 had reported incidents of Parkinsonism. Similarly, for Cilta-cel therapy, there were 81 patients with reported nervous system disorders, with 5 reported incidents of Parkinsonism. Out of the total 7 reported patients with Parkinsonism, 5 were males, 2 were females, the average age was 67, the average weight was 68.9 kg, and 3 patients were also noted to have associated cytokine release syndrome. Conclusion: Our analysis of FAERS data highlights the occurrence of Parkinsonism associated with BCMA-directed CAR T-cell therapy. Further studies are required to quantify the need for neurological surveillance after initiating treatment with these novel agents.

Varicella zoster virus reactivation reported with isatuximab use

Isatuximab is a CD38-directed antibody indicated for the treatment of relapsed or refractory multiple myeloma. The Division of Pharmacovigilance at the U.S. Food and Drug Administration (FDA) reviewed case reports from postmarketing sources, including the FDA Adverse Event Reporting System (FAERS), PubMed, and Embase, to investigate a potential association between isatuximab and the risk of varicella zoster virus (VZV) reactivation. We identified 20 reports of which 15 met our case definition and causality criteria. All 15 patients (80% male, median age = 60 years) received isatuximab for a hematologic neoplasm; eight (53%) for previously untreated multiple myeloma. All cases described additional risk factors for VZV reactivation, including concomitant proteasome inhibitor and/or immunomodulatory drug (n = 10, 67%) use. Based on this postmarket analysis, the U.S. Prescribing Information for isatuximab was updated to include this new safety information, including recommendations for antiviral prophylaxis.

The Safety Profiles of Two First-Generation NTRK Inhibitors: Analysis of Individual Case Safety Reports from the FDA Adverse Event Reporting System (FAERS) Database.

The first-generation tropomyosin receptor kinase (TRK) inhibitors, larotrectinib and entrectinib, represent exciting new developments in cancer treatment that offer relevant, rapid, and long-lasting clinical benefits. Larotrectinib and entrectinib are recommended as first-line treatments for locally advanced or metastatic non-small cell lung cancer (NSCLC) patients with positive TRK gene fusions. In this study, using the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database between 2019 and 2022, a retrospective analysis was conducted to evaluate the safety profiles of these drugs. During our study period, 807 individual case safety reports (ICSRs) related to larotrectinib or entrectinib were retrieved from the FAERS database, of which 48.7% referred to females and 24.7% referred to adult patients (18-64 years) with a median age of 61.0 years. A total of 1728 adverse drug reactions (ADRs) were identified. The most frequently reported ADRs were dizziness and pain, which belong to the System Organ Classes (SOCs) "nervous system disorders" and "general disorders and administration site conditions". Regarding all ADRs, the median time to onset was 37.0 days for larotrectinib and 12.0 days for entrectinib. No evident safety concerns emerged in the long-term safety profiles (>365 days). Only 18 ICSRs were related to pediatric populations (≤16 years), of which 94.0% of the ICSRs were related to larotrectinib. The median age was 10.5 years, while most patients were female (44.4%). Our results show favorable risk-benefit profiles for larotrectinib and entrectinib. Considering the increased use of neurotrophic tyrosine receptor kinase (NTRK) inhibitors, continuous safety monitoring of larotrectinib and entrectinib is required for the detection of possible new adverse drug reactions.

Adverse event profile of CGRP monoclonal antibodies: findings from the FDA adverse event reporting database

ABSTRACT Background Four CGRP Monoclonal Antibodies (mAbs) have been approved for migraine prophylaxis by the Food and Drug Administration (FDA) since 2018. However, there are concerns about the safety of these four drugs for real-world use. Objective To compare the adverse event profiles of four CGRP-mAbs with FAERS data. Methods The study was based on records from the FAERS database. Only reports containing one of the active ingredients with CGRP-mAbs were included in this study. Disproportionality analyses including but not limited to reporting odds ratio (ROR) and information components (IC) were conducted to identify drug-AE associations. Results In total, 58110 reports were identified for CGRP-mAbs. 80 overlapping signals were disproportionately reported. They affected a range of organs and systems, including the gastrointestinal and cardiovascular systems, skin, and hair. Additionally, the rare cardiovascular adverse events were significantly different among the four CGRP-mAbs. Conclusion We identified numerous shared underlying signals (overlapping signals) for CGRP-mAbs as suspected drugs in multiple systems and organs. The unlabeled common signals may indicate potential safety issues. In addition, the underlying safety signals varied among the four CGRP-mAbs, particularly in the cardiovascular system, and further studies are needed to confirm these associations and the potential clinical implications.

Immune-mediated colitis associated with ocrelizumab: A new safety risk

Background: An association between certain immunomodulatory therapies (rituximab, ipilimumab, and other immune checkpoint inhibitors) and inflammatory (non-ischemic and non-infectious) colitis in oncologic and non-oncologic patient populations is well documented in the medical literature. Objective: The purpose of this case series is to describe adverse event reports of new onset, inflammatory colitis in association with ocrelizumab in patients with multiple sclerosis submitted to U.S. Food and Drug Administration (FDA) or published in the medical literature. Methods: The FDA Adverse Event Reporting System (FAERS) and medical literature were searched. Results: A review of postmarketing cases from FAERS and published medical literature identified 38 cases consistent with inflammatory, non-ischemic, and non-infectious colitis in association with ocrelizumab. The median time-to-onset was 8 months. Cases were reported using the following diagnostic terms: Crohn’s disease (13), unspecified colitis (11), microscopic colitis (5), ulcerative colitis (5), medication-induced colitis (3), and autoimmune colitis (2). Conclusions: This case series highlights ocrelizumab induced immune-mediated colitis that can be clinically severe and potentially life-threatening. Based on the findings of this review, the ocrelizumab Prescribing Information was amended to include immune-mediated colitis in the Warnings and Precautions section.

A real-world pharmacovigilance analysis of FDA adverse event reporting system database for upadacitinib.

Objective: To mine the adverse drug event (ADE) signals of upadacitinib based on the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database to provide a reference for the safe clinical use of the drug. Methods: The ADE data for upadacitinib from Q1 2004 to Q1 2023 in the FAERS database were retrieved, and data mining was performed using the reporting odds ratio and proportional reporting ratio. Results: A total of 21,213 ADE reports for the primary suspect drug upadacitinib were obtained, involving 444 ADEs. Patients aged ≥60years (21.48%) and female (70.11%) patients were at a higher risk of ADEs with upadacitinib. After data cleaning, 182 ADE signals from 19 system organ classes (SOCs) were obtained. Six of these SOCs that occurred more frequently and were not mentioned in the drug labeling information included renal and urinary system (1.09%), reproductive and breast diseases (1.14%), ear and labyrinth disorders (0.57%), psychiatric disease (0.57%), blood and lymphatic system disorders (0.57%), and endocrine disorders (0.57%). The top ten most frequent ADE signals reported for upadacitinib were mainly related to: infections and infestations (7), investigations (2), and skin and subcutaneous tissue disorders (1). The top 10 ADEs in signal intensity ranking were lip neoplasm, ureteral neoplasm, eczema herpeticum, vulvar dysplasia, mediastinum neoplasm, eosinopenia, herpes zoster cutaneous disseminated, eye ulcer, acne cystic, and Moraxella infection. The top 10 high-frequency events leading to serious adverse events were urinary tract infection (2.74%), herpes zoster (1.63%), diverticulitis (1.19%), bronchitis (0.68%), nasopharyngitis (0.68%), localised infection (0.66%), nephrolithiasis (0.66%), pulmonary thrombosis (0.66%), blood cholesterol increased (0.55%), and Pneumocystis jirovecii pneumonia (0.53%). Conclusion: Clinicians should be vigilant to upadacitinib-induced events in systems not covered in the drug labeling information and to new and highly signaled ADEs to ensure the safe and effective use of upadacitinib.

Safety profiles of methylphenidate, amphetamine, and atomoxetine: analysis of spontaneous reports submitted to the food and drug administration adverse event reporting system.

Background: Methylphenidate, atomoxetine, and Amphetamine are the three most commonly used medications approved by the United States Food and Drug Administration (FDA) for the treatment of attention deficit/hyperactivity disorder (ADHD). However, a comprehensive analysis of their safety profiles across various age groups and genders in real-world contexts has yet to be conducted. In this study, a pharmacovigilance analysis was performed using the FDA Adverse Event Reporting System (FAERS) database to examine differences in adverse events between methylphenidate, atomoxetine, and Amphetamine. Methods: From January 2014 to September 2022, FAERS reports listing "Methylphenidate," "Dexmethylphenidate," "Atomoxetine," "Amphetamine," "Lisdexamfetamine," "Dextroamphetamine," and "Methamphetamine" as primary suspects were analyzed after removing duplicate reports. We used the standardized Medical Dictionary for Regulatory Activities (MedDRA) query generalized search for adverse events at the preferred term level based on case reports. After filtering duplicate reports, disproportionality analysis was used to detect safety signals according to the proportional reporting ratio (PRR). In order to delve into potential safety concerns, we undertook a two-step analysis of the data. Initially, the data was segmented based on age cohorts: 0-5years, 6-12years, 13-18years, and individuals aged ≥19years. Following this, after partitioning the data into males and females within the 0-18years age group, and similarly for those aged ≥19years, further analysis was conducted. Results: The pharmacovigilance analysis uncovered substantial safety signals in the standardized MedDRA queries. Methylphenidate was associated with dyskinesia (PRR = 21.15), myocardial infarction (PRR = 12.32), and hypertension (PRR = 8.95) in children aged 0-5, 6-12, and 13-18years, respectively, as well as neonatal exposures via breast milk (PRR = 14.10) in adults aged ≥19years. Atomoxetine was linked to hostility/aggression (PRR = 15.77), taste and smell disorders (PRR = 6.75), and hostility/aggression (PRR = 6.74) in children aged 0-5, 6-12, and 13-18years, respectively, as well as hostility/aggression (PRR = 14.00) in adults aged ≥19years. Amphetamine was associated with psychosis and psychotic disorders (PRR = 16.78), hostility/aggression (PRR = 4.39), and Other ischaemic heart disease (PRR = 10.77) in children aged 0-5years, 6-12years, and 13-18years, respectively, and hostility/aggression in adults aged ≥19years (PRR = 9.16). Significant and noteworthy adverse event signals were also identified at the preferred term level. Specifically, methylphenidate was associated with myocardial infarction, acute myocardial infarction, coronary artery dissection, electrocardiogram QT prolonged, growth retardation, self-destructive behavior, suicidal ideation, and completed suicide. Atomoxetine was linked to electrocardiogram QT prolonged, growth retardation, and tic. Amphetamine was recorded for coronary artery dissection, suicidal ideation, and completed suicide. It was observed that male patients, including both children and adults, showed a more significant and frequent occurrence of adverse events compared to females, particularly in terms of cardiac disorders. The intensity and quantity of adverse event signals were distinctly different between the two genders, with males having a higher number of signals. All detected safety signals were confirmed using signals obtained from the disproportionality analysis. Conclusion: This pharmacovigilance analysis demonstrated significant variations in the safety profiles of methylphenidate, atomoxetine, and Amphetamine across different age groups and between different genders. Following an in-depth analysis of the FAERS database, we discerned prominent safety signals. Notably, the strength of the signals associated with coronary artery dissection induced by methylphenidate and amphetamine, as well as those related to suicide, demand particular attention. Consequently, it remains imperative to persist in monitoring these medications, assessing the associated risks, and carrying out comparative studies particularly geared towards ADHD drugs.

Causes of Drug-Induced Severe Cutaneous Adverse Reaction Epidermal Necrolysis (EN): An Analysis Using FDA Adverse Event Reporting System (FAERS) Database.

The purpose of the study is to analyze FAERS data to identify drugs associated with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), determine demographics, drug classes involved, most likely resulted in death, and highlight emerging trends in SJS/TEN reactions. We reviewed the publicly available FAERS database from 2004-2021. Using search terms "Stevens-Johnson syndrome" or "Toxic epidermal necrolysis", we identified the reports of SJS/TEN or SJS/TEN followed by death that might associated with specific drugs. Then the amounts and trends were counted analyzed. During the study period of 2004-2021, the Food and Drug Administration (FDA) received a total of 14,363,139 reports of adverse reactions, among which 24,976 were linked to SJS or TEN. After excluding the cases with incomplete or insufficient information on age, gender, or country of origin, the median median age of patients was 53.82 (IQR = 57.52), the females accounted for 56.59% (12,827 cases) and 8,507 (38.34%) originated in the United States. The top 50 drugs were associated with 15,149 cases (60.65%). The subsequent fatal outcome occurring in 4878 out of 24,976 cases (19.53%). Top 3 drug classes associated with SJS/TEN in FAERS were antiepileptics, non-steroidal anti-inflammatory drugs (NSAIDs) and others. Top drug classes associated with SJS/TEN deaths were antineoplastic agents and cephalosporins. Linear regression showed that the annual percentage of monoclonal antibody-related SJS/TEN reactions increased at an average rate of 0.25% (95% confidence interval: 0.18, 0.32) from 0.00% in 2004 to 4.79% in 2021, faster than any other drug class except antigout drug (allopurinol). By using the publicly available FAERS data, we have identified some important themes and trends in drug-related SJS/TEN reactions. Monoclonal antibodies and proton pump inhibitors are drugs with emerging trends causing SJS/TEN. Additionally, cephalosporin antibiotics have a higher mortality rate following SJS/TEN.

Cardiac arrhythmias associated with anaplastic lymphoma kinase (ALK) inhibitors: an analysis of the FDA Adverse Event Reporting System (FAERS)

ABSTRACT Background Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) may provoke cardiac arrhythmias. We conducted this pharmacovigilance analysis to research cardiac arrhythmias associated with ALK-TKIs using the Food and Drug Administration Adverse Event Reporting System (FAERS). Research design and methods The first ALK-TKI, named crizotinib, was approved by the Food and Drug Administration (FDA) on 26 August 2011 for the treatment of ALK-rearranged non-small cell lung cancer (NSCLC). We evaluated ALK-TKIs-induced cardiac arrhythmias, by using the reporting odds ratio (ROR) and information component (IC) for mining the adverse event report signals in the FAERS database between January 2016 and June 2022. Results We identified a total of 362 ALK-TKIs-related cardiac arrhythmia reports which appeared to influence more men (64.44%) than women (30.76%), with a median age of 68 (interquartile range [IQR] 7–74) years. Compared with the full database, ALK-TKIs were detected with pharmacovigilance of cardiac arrhythmias (ROR025 = 1.26, IC025 = 0.26). Crizotinib and alectinib were found to be related to higher reporting of arrhythmias. The median time to onset (TTO) among five ALK-TKI therapies was significantly different (p = 0.044). Conclusion ALK-TKIs present different frequencies of cardiac arrhythmias reporting, with only crizotinib and alectinib producing positive signals in high-level group term (HLGT) level arrhythmia. The time interval between the initial of drug treatment to the onset of arrhythmia varies greatly and cannot be predicted.