Expert Opinion on Drug Safety最新文献

Introduction: Hemophilia A is an inherited bleeding disorder caused by factor VIII (FVIII) deficiency, resulting in recurrent bleeding and progressive joint damage. Treatment has expanded beyond FVIII replacement to extended-half-life products, non-factor therapies, rebalancing agents, and gene therapy. These advances improve outcomes but introduce distinct long-term safety considerations.

Areas covered: This review evaluates long-term safety evidence from pivotal trials, extension studies, real-world registries, and recent international congress reports. It examines standard- and extended-half-life FVIII concentrates, efanesoctocog alfa, emicizumab, emerging rebalancing agents targeting natural anticoagulant pathways, and adeno-associated virus vector-based gene therapies.

Expert opinion: Established hemophilia A treatments generally have favorable long-term safety profiles and reduce treatment burden; however, mature safety data remain limited for newer agents. Inhibitor development remains the principal complication of FVIII replacement. Non-factor and rebalancing therapies carry potential thrombotic risks requiring appropriate monitoring. Gene therapy may provide durable FVIII expression after a single administration but raises concerns regarding hepatotoxicity, durability of expression, and uncertain long-term effects. Continued pharmacovigilance and individualized treatment selection are therefore essential as therapeutic options expand.

Background: The main purpose of this study is to observe and detect adverse reactions to the combination of topotecan, bevacizumab and cyclophosphamide, to learn more about possible adverse drug reactions (ADRs) and to help doctors make the right medication decisions and treatment plans.

Research design and methods: Adverse event signals were detected and quantified using data from the U.S. Food and Drug Administration's Adverse Event Reporting System using reporting ratios, proportions of reports (PRR), Bayesian Confidence Propagation Neural Networks (BCPN), and empirical Bayesian Geometric Mean (EBGM). Subgroup analyses were performed to compare adverse events associated with topotecan alone.

Results: The analysis of FAERS data revealed a total of 1,789 primary suspected adverse events (PS AEs) linked to topotecan. The Weibull shape parameter (β) for females was lower than for males across all age groups, indicating a potentially higher susceptibility to the adverse effects of topotecan in female patients.

Conclusions: This study proved several expected and new adverse drug reactions associated with the combination of topotecan, bevacizumab, and cyclophosphamide. While some ADRs, such as neutropenia and anemia, align with the known adverse profile of topotecan, the detection of novel signals, including potential gender-based differences in drug response, warrants further investigation.

Background: Drug-induced sinusitis has been widely reported as an adverse drug reaction in recent years, yet the pharmacogenetic mechanisms and risk factors associated with sinusitis remain elusive.

Objective: We aimed to identify the major drugs reported in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) in relation to sinusitis and to analyze their pharmacogenetic mechanisms through drug target analysis.

Methods: We conducted a review of the publicly available FAERS database from 2004 to the third quarter of 2023. We extracted genetic tools corresponding to each drug, utilized colocalization analysis, Mendelian randomization (MR) analysis, and cross-tissue drug target analysis to predict the impact of drug targets on sinusitis.

Results: Following the validation of drug-related risks, a total of 13 medications were ultimately identified, including TNF inhibitors: pomalidomide (ROR: 14.77), certolizumab pegol(ROR: 8.21), etanercept (ROR: 7.961), lenalidomide (ROR: 6.998), adalimumab (ROR: 6.677), infliximab (ROR: 3.939); C4B-targeted drugs: human immunoglobulin G (ROR:3.846) and other risk drugs were commonly reported. Co-localization analysis and MR analysis suggests associations between TNF, C4B, and LTA and sinusitis.

Conclusion: We demonstrated the risk of sinusitis associated with 13 drugs, including pomalidomide, and the impact of TNF and C4B drugs on sinusitis, which provides guidance for the use of related drugs and the prevention of sinusitis.

Background: BRAF/MEK inhibitors (BRAFi+MEKi) like may cause peripheral neuropathies (PN). This study analyzes FAERS data to assess PN signals across BRAFi+MEKi combinations.

Research design and methods: Disproportionality analysis was conducted to quantify the signals of BRAFi+MEKi-associated PN on FAERS database from January 2011 to December 2022. Additionally, we examined the onset times and prognosis of BRAFi+MEKi-associated PN.

Results: A total of 268 reports of BRAFi+MEKi-associated PN were identified in the study, with a median age range of 60.00 to 69.00 years. All three combination therapies exhibited positive signals for PN, and notably, Encorafenib and Binimetinib (E+B) displayed the strongest association with PN (ROR 3.05[2.47,3.76], IC1.57[1.26]). The associations between PN and different BRAFi+MEKi combinations remained persisted in the gender and age stratification analysis, with all three combination therapies showing an elevated number of disproportionality signals in males compared to females.

Conclusion: According to our findings, BRAFi+MEKi-associated PN tends to occur several months after initiation and may lead to serious outcomes. Male sex is more likely to be a risk factor associated with PN. Prompt identification and intervention for BRAFi+MEKi-associated PN are crucial, and additional fundamental research is required to validate the underlying mechanism as observed in our study.

Introduction: Immune checkpoint inhibitors (ICIs) have transformed the treatment of multiple malignancies and significantly increased survival; however, by enhancing antitumor immunity, they can also cause off-target immune-related adverse events (irAEs), some of which become refractory to standard first-line corticosteroids. Refractory irAEs (r-irAEs) require timely recognition and personalized, organ-specific escalation strategies based on toxicity severity and mechanistic insights.

Areas covered: In this narrative review, we synthesize current evidence across organ systems on the epidemiology, clinical features, diagnostic evaluation, and management of r-irAEs, with a particular focus on second- and third-line immunosuppressive options. We summarize findings from retrospective cohorts, prospective studies, guideline statements, and high-quality case series relevant to steroid-refractory irAEs and highlight practical considerations for escalation. The literature search was performed in PubMed and Embase for publications from January 2010 through August 2025.

Expert opinion: Tailored treatment strategies and structured escalation algorithms are needed to optimize outcomes for patients with r-irAEs. Integration of emerging biomarkers, endoscopic and histologic findings, and tumor microenvironment features may facilitate earlier recognition of steroid-refractory disease and more individualized escalation of immunosuppression.

Background: Direct oral anticoagulants (DOACs) are commonly used to prevent and treat thromboembolic diseases. This study aimed to assess and compare dementia related adverse events (AEs) associated with DOACs.

Research design and methods: AEs related to DOACs from January 2014 to June 2023 were extracted from the FDA Adverse Event Reporting System (FAERS) database. Disproportionality analysis methods, including reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Propagation Neural Network, and Multi-Item Gamma Poisson Shrinker, were used to evaluate the association between DOACs and dementia-related AEs.

Results: There were 12,692,968 AEs reported in FAERS after deduplication. Among these, 165, 206, 1574, and 12 dementia-related AEs that were attributed to dabigatran, rivaroxaban, apixaban, and edoxaban, respectively. Apixaban showed the strongest association with dementia-related AEs (ROR 7.66, 95% confidence interval (CI) 7.27-8.06), while rivaroxaban had the lowest ROR (0.95, 95%CI 0.83-1.09). Women exhibited higher RORs for all DOACs, with apixaban showing the most significant correlation. Subgroup analysis indicated a significant link between apixaban and dementia, dementia Alzheimer's type and senile dementia.

Conclusions: Apixaban appears most associated with dementia-related AEs among DOACs, whereas rivaroxaban poses a lower risk. Further research is needed to validate these findings through large-scale prospective studies.

Background: Mannitol, an osmotic diuretic, is widely used to treat edema, intracranial hypertension, and cerebral edema. This study analyzed mannitol-related adverse events (AEs) using the FDA adverse event reporting system (FAERS) data to identify potential safety signals.

Research design and methods: A retrospective pharmacovigilance study was conducted using FAERS data from Q1 2013 to Q4 2023. Signal detection algorithms, including the reporting odds ratio (ROR) and proportional reporting ratio (PRR), were employed to identify and evaluate mannitol-related AEs. The analysis focused on the frequency, severity, and clinical relevance of reported AEs.

Results: Among 39,061,894 reports, 1,014 mentioned mannitol. Common AEs included increased intracranial pressure, hyperosmolar state, hyperchloremia, and hypernatremia. 80% of AEs fell under 'renal and urinary disorders' (295 cases), 'skin and subcutaneous tissue disorders' (371 cases). Specific preferred terms (PTs) linked with mannitol included 'hyperosmolar state', (ROR = 665.98 (95% CI: 272.28-1628.95), PRR = 664.53 (95% CI: 269.75-1637.1)), 'hyperchloremia,' 'hypernatremia' (ROR = 25.18 (95% CI: 17.66-35.9), PRR = 24.85 (95% CI: 17.46-35.36)).

Conclusions: This study underscores the need for vigilant monitoring of mannitol use. Further research is required to understand the mechanisms behind unexpected AEs and establish a comprehensive safety profile.

Background: Diroximel fumarate (DRF) is an oral fumarate used to treat relapsing forms of multiple sclerosis (RMS). This study comprehensively analyzed the adverse events (AEs) associated with DRF for treating RMS based on data from the FDA Adverse Event Reporting System (FAERS) database.

Research design and methods: This study collected data on AEs associated with DRF treatment of RMS from the FAERS database between 2019 and 2024. We used reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS) for signal detection.

Results: This study collected 7,944,554 AE reports, of which 7,868 were associated with DRF. A total of 120 preferred terms (PTs) were included in the analysis, relating to 27 system organ classes (SOCs). This study identified several clinically significant new potential AEs, including decreased immune responsiveness (n = 26, ROR 4.45, PRR 4.45, IC 2.15, EBGM 4.43), female breast cancer (n = 50, ROR 4.07, PRR 4.07, IC 2.02, EBGM 4.05), transient blindness (n = 19, ROR 7.27, PRR 7.26, IC 2.85, EBGM 7.21) and others.

Conclusions: Our study identified several potentially important AEs that were not mentioned in the DRF instructions. However, further epidemiologic studies are needed to validate these findings.

Background: Fluconazole, a widely used antifungal agent, has been associated with various adverse events (AEs). This study aimed to analyze the safety profiles of fluconazole using the FDA Adverse Event Reporting System (FAERS) database to provide insights for its safe use.

Research design and methods: Fluconazole-related AEs from 2004 to 2024Q2 were extracted from the FAERS database. The Reporting Odds Ratio (ROR) method was employed to detect and analyze safety signals. Additionally, the impact of COVID-19 on fluconazole safety was also examined.

Results: A total of 7,720 AEs were identified, with 40.3% being serious. The most common AEs involved skin, gastrointestinal, and administration site reactions. High doses of fluconazole were linked to increased teratogenic risks. Weekly dosing regimens and doses below 200 mg/day were associated with fewer severe AEs. During the COVID-19 pandemic, there was a notable rise in reports of drug inefficacy and hepatic/renal damage. Additionally, 45 new adverse reactions were identified.

Conclusions: The study highlights the importance of monitoring liver, kidney, and cardiovascular functions during fluconazole use, especially in high-risk populations. The findings underscore the need for careful dosing and consideration of drug interactions, particularly during the COVID-19 pandemic, to ensure safe and effective use of fluconazole.

Introduction: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) remain underused in clinical practice, one of the reasons may be the fear of adverse events which have been emphasized during the first years of use. This comprehensive review aims to give an update on the safety and tolerability profile of SGLT2is.

Areas covered: An extensive literature search identified randomized controlled trials, observational cohort studies and pharmacovigilance reports that investigated the safety of SGLT2is in patients with type 2 diabetes (T2D), with or without comorbidities or presenting at-risk conditions.

Expert opinion: Some adverse events pointed out initially have been confirmed, especially a higher risk of genital infections, though not the initial fear of urinary tract infections. A euglycemic diabetic ketoacidosis remains exceptional in patients with T2D. Volume depletion is a rare event that may be anticipated. Of note, several severe adverse events that led to warnings by regulatory agencies have not been confirmed in further studies: bone fractures, lower-limb amputations, severe perineal infections, acute renal injury. The safety profile of SGLT2is appears globally reassuring even in special at-risk populations. However, data remain rather scarce in patients with severe comorbidities and in very old or frail people, so that caution use is classically recommended.