Post-marketing Data Research Articles

Safety and Tolerability of Nintedanib in Patients with Fibrosing Interstitial Lung Diseases: Post-marketing Data.

Nintedanib is approved for the treatment of idiopathic pulmonary fibrosis (IPF), other forms of progressive pulmonary fibrosis (PPF), and systemic sclerosis-associated interstitial lung disease (ILD). We present global post-marketing safety data for nintedanib in these fibrosing ILDs. Data on adverse events in patients with fibrosing ILDs who were treated with nintedanib were collected via spontaneous reporting and solicited reporting in various studies (excluding clinical trials).Data were collected from 15 October 2014 (first regulatory approval) to 15 October 2023. Adverse events were coded using the Medical Dictionary for Regulatory Activities. Cumulative exposure to nintedanib was estimated using sales data. Cumulative exposure to nintedanib was 380,557 patient-years. Diarrhoea was reported at a rate of 227.5 per 1000 patient-years. Only 2.6% of diarrhoea events were reported as serious. Of 39,788 (33.6%) diarrhoea events with a known time to onset, almost 60% occurred within the first 3months of treatment. The rate of serious liver enzyme and bilirubin elevations (including drug-induced liver injury) was 4.0 per 1000 patient-years. Bleeding was reported at a rate of 24.2 per 1000 patient-years. Most (81.3%) bleeding events were non-serious. The rates of myocardial infarction, ischaemic stroke, and venous thromboembolism were 3.3, 3.3, and 2.0 per 1000 patient-years, respectively. Gastrointestinal perforation was reported at a rate of 0.9 per 1000 patient-years. Post-marketing safety data on established and potential adverse events associated with nintedanib in patients with fibrosing ILDs, collected over 9years, demonstrated a safety profile that was similar to that established in clinical trials and provided in the product labels. Education of patients about the adverse events that may be associated with nintedanib, and the effective management of adverse events when they occur, is important to minimise the impact of adverse events and help patients remain on treatment.

Sex differences in reporting of statin-associated diabetes mellitus to the US Food and Drug Administration

Abstract Background Statins have been reported to precipitate diabetes mellitus (DM) in some patients. Limited evidence suggests that this occurs in women more frequently than men, but direct comparisons of rates of reporting of statin-associated DM between men and women are lacking. Purpose To determine whether there are sex-specific differences in post-marketing reporting of statin-associated DM. Methods We conducted a retrospective pharmacovigilance analysis of spontaneously reported adverse drug events (ADEs) submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System between January 1997 and September 2023. A Proportional Reporting Ratio (PRR) was used to identify the rate of reported statin-associated DM ADEs relative to the rate of DM ADEs reported with all other medications. We compared signals of disproportionate reporting (SDRs) between men and women using a modified relative odds ratio (ROR). Results During the study period, there were two-fold as many reports of statin-associated DM in women than in men (14,793 versus 7,307, respectively), despite the fact there were only 7% more non-DM statin ADEs reported in women compared to men (512,134 versus 480,849, respectively). Compared to the background rate of reporting for all ADEs (0.6%), statin-induced DM was disproportionally reported for all subjects in aggregate (2.1%, PRR=3.7) as well as for men only (1.5%, PRR=2.4) and for women only (2.9%, PRR=5.3). Significant PRRs for DM were observed with each statin and for all statins collectively (Figure 1). Statins were reported as the primary- or secondary-suspected cause of DM in women with considerably greater frequency than in men (58% versus 29%, respectively). Rates of reporting of statin-associated DM were higher in women than in men for all statins, with the greatest difference being observed with atorvastatin (ROR 3.0), and the lowest difference being observed with rosuvastatin (ROR 1.2) (Figure 1). Conclusions Post-marketing ADE surveillance data suggest a markedly higher rate of incident DM associated with statins than with other medications and a higher rate of reporting of statin-associated DM in women than in men. Future studies should consider sex-moderated mechanisms of statin-associated DM.Figure 1

Adverse events analysis of Relugolix (Orgovyx®) for prostate cancer based on the FDA Adverse Event Reporting System (FAERS).

Due to the limitations of clinical trials, some delayed and rare adverse events (AEs) may remain undetected, and safety information can be supplemented through post-market data analysis. This study aims to comprehensively analyze the AEs associated with Relugolix (Orgovyx®) using data from the FAERS database, and gain a better understanding of the potential risks and side effects of Relugolix (Orgovyx®) therapy. Data of Relugolix (Orgovyx®) were collected from the FAERS database covering the period from the fourth quarter of 2020 to the third quarter of 2023. Disproportionality analysis was performed by calculating the reporting odds ratios (ROR), proportional reporting ratio (PRR), Bayesian analysis confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) to detect positive signals. Totally, 5,382,189 reports were collected from the FAERS database, 4,397 reports of Relugolix (Orgovyx®) were identified as the 'primary suspected (PS)' AEs. Relugolix (Orgovyx®) induced AEs occurred in 26 organ systems. 58 significant disproportionality preferred terms (PTs) satisfying with the four algorithms were retained at the same time. Unexpected significant AEs such as Pollakiuria, and Prostatic specific antigen increased also occur. The median time of onset was 60 days. The majority of the AEs occurred within the first 30 days after Relugolix (Orgovyx®) initiation. Common AEs included Hot flush, Fatigue, Asthenia, Constipation, and Myalgia. These AEs should be focused on when using the drug to avoid serious consequences. In addition, the study results also suggested that the drug may exist Pollakiuria, Prostatic specific antigen increased and other AEs not mentioned in the manual, to supplement the AEs in the manual. This study is helpful for clinicians and pharmacists to improve their understanding of Relugolix (Orgovyx®) related AEs, and take timely prevention and treatment measures to ensure drug safety for patients.

A Clustering Ensemble Method for Drug Safety Signal Detection in Post-Marketing Surveillance.

Post-marketing surveillance refers to the process of monitoring the safety of drugs once they reach the market, after the successful completion of clinical trials. In this work, we investigate a computational approach using data mining tools to detect safety signals from post-market safety databases, or in other words, to identify adverse events (AEs) with disproportionately high reporting rates compared to other AEs, associated with a particular drug or a drug class. Essentially, we view this as a problem of cluster analysis-based anomaly detection on post-market safety data, where the goal is to 'unsupervisedly' detect the anomalous or the signal AEs. Our findings demonstrate the potential of using a clustering ensemble method to detect drug safety signals. It employs multiple clustering or anomaly detection algorithms, followed by a performance comparison of the candidate algorithms based on a collection of appropriate measures of goodness of clustering results. The method is general enough to include any number of clustering or anomaly detection algorithms and goodness measures, and performs better than any of the candidate algorithms in identifying the signal AEs. Extensive simulation studies illustrate that the ensemble method detects the AE signals from synthetic post-market safety datasets pretty accurately across the different scenarios explored. Based on the cases reported to the FDA Adverse Event Reporting System (FAERS) between 2013 and 2022, we further demonstrate that the ensemble method successfully identifies and confirms most of the adverse events that are known to occur most frequently in reaction to antiepileptic drugs and -lactam antibiotics.

Exploring and comparing renal adverse effects between PARP inhibitors based on a real-world analysis of post-marketing surveillance data

Exploring and comparing renal adverse effects between PARP inhibitors based on a real-world analysis of post-marketing surveillance data

The risk of depression, anxiety, and suicidal behavior in patients with obesity on glucagon like peptide-1 receptor agonist therapy.

This large community-based cohort study investigates the impact of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), specifically Liraglutide and Semaglutide, on the risk of developing psychiatric conditions such as depression, anxiety, and suicidal behaviors in patients with obesity. Utilizing post-marketing data, this research compares patients prescribed GLP-1 RAs (cases) with those not taking these medications (controls). The analysis spanned data from January 1, 2015, to December 31, 2023. To minimize selection bias, we employed 1:1 propensity score matching to account for demographic factors such as age, sex, race, and comorbidities. After matching, the study included 162,253 case and control patients. This study showed a significant association between GLP-1 RA treatment and an 98% increased risk of any psychiatric disorders. Notably, patients on GLP-1 RAs exhibited a 195% higher risk of major depression, a 108% increased risk for anxiety, and a 106% elevated risk for suicidal behavior. These findings underscore the critical need for physicians to thoroughly assess patient history before prescribing GLP-1 RAs and highlight the urgent requirement for further prospective clinical trials to fully understand the implications of GLP-1 RA use on mental health in the obese patient population.

Immune Checkpoint Inhibitor Therapy for Kidney Transplant Recipients - A Review of Potential Complications and Management Strategies.

Immune checkpoint inhibitor (ICI) therapy has enabled a paradigm shift in Oncology, with the treatment of metastatic cancer in certain tumor types becoming akin to the treatment of chronic disease. Kidney transplant recipients (KTR) are at increased risk of developing cancer compared to the general population. Historically, KTR were excluded from ICI clinical trials due to concern for allograft rejection and decreased anti-tumor efficacy. While early post-marketing data revealed an allograft rejection risk of 40%-50%, 2 recent small prospective trials have demonstrated lower rates of rejection of 0%-12%, suggesting that maintenance immunosuppression modification prior to ICI start modulates rejection risk. Moreover, objective response rates induced by ICI for the treatment of advanced or metastatic skin cancer, the most common malignancy in KTR, have been comparable to those achieved by immune intact patients. Non-invasive biomarkers may have a role in risk-stratifying patients before starting ICI, and monitoring for rejection, though allograft biopsy is required to confirm diagnosis. This clinically focused review summarizes current knowledge on complications of ICI use in KTR, including their mechanism, risk mitigation strategies, non-invasive biomarker use, approaches to treatment of rejection, and suggestions for future directions in research.

8348 A Rare Case Of Liraglutide-Associated Angioedema Requiring Emergent Intubation

Abstract Disclosure: T. Amin: None. A. Mararenko: None. J. Cheng: None. R. Ong: None. S. Holland: None. K. Hu: None. Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists are widely used in the management of type 2 diabetes mellitus to enhance glycaemic control. While generally considered safe, recent reports indicate an increasing frequency of adverse drug reactions, with gastrointestinal symptoms such as pancreatitis becoming more prevalent. This case report highlights a rare occurrence of angioedema induced by the GLP-1 receptor agonist, Liraglutide. Case A 58-year-old Type 2 diabetic male presented with rapidly progressing tongue swelling, abdominal discomfort, and watery diarrhea, six hours after initiating Liraglutide therapy. On presentation, he was hemodynamically stable, afebrile, maintaining adequate oxygenation on room air. On examination, the patient was in moderate distress with generalized tongue swelling protruding out, with no swelling of eyelids or lips. No rashes were noted on exposed skin and clear breath sounds without wheezing on lung examination. Due to concern for an impending airway compromise, the patient was intubated. Chart review showed he had an episode of self-resolving tongue swelling a few months back, at which time he was taken off his Angiotensin receptor blocker. 2 weeks ago, he was started on a new brand of GLP-1 receptor agonist (Liraglutide) to achieve optimal glycemic control. No other drug allergies or allergic reactions were reported. C1-Esterase panel, eosinophil count, and inflammatory markers were within normal limits.On admission, Liraglutide was discontinued, he was placed on a basal-bolus insulin regimen, received methylprednisolone, famotidine, and diphenhydramine Subsequent improvement allowed for extubation on the third day, and the patient was discharged with plans to discontinue Liraglutide and an epinephrine pen for precautionary use. Conclusion: This case represents a rare and severe manifestation of angioedema associated with Liraglutide use in a diabetic patient. While angioedema has been infrequently reported with other GLP-1 receptor agonists such as Exenatide and Dulaglutide , our case underscores the importance of clinicians' awareness regarding this potential life-threatening complication with Liraglutide. Post-marketing surveillance data suggest that anaphylactic reactions with Liraglutide may occur rarely, emphasizing the need for vigilance among healthcare providers. Presentation: 6/2/2024

Neuropsychiatric Adverse Events with Monoclonal Antibodies Approved for Multiple Myeloma: An Analysis from the FDA Adverse Event Reporting System.

Background/Objectives: Monoclonal antibodies (mAbs) have revolutionized multiple myeloma (MM) treatment. However, post-marketing data on their neuropsychiatric safety are limited. This study aimed to evaluate neuropsychiatric adverse events (AEs) related to mAbs used for MM through a retrospective pharmacovigilance analysis using the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) database. Methods: Individual case safety reports (ICSRs) from 2015 to 2023 with at least one neuropsychiatric AE and one of the MM-approved mAbs as the suspected drug (i.e., daratumumab, elotuzumab, isatuximab, belantamab mafodotin, teclistamab, elranatamab, and talquentamab) were analyzed using descriptive and disproportionality approaches. Results: Unknown signals of disproportionate reporting (SDR) included the following: cerebral infarction for daratumumab (n = 45; reporting odds ratio (ROR) = 2.39, 95% confidence interval (CI) = 1.79-3.21; information component (IC) = 1.54, IC025-IC075 = 1.05-1.9), elotuzumab (25; 7.61, 5.13-11.28; 3.03, 2.37-3.51), and isatuximab (10; 2.56, 1.38-4.76; 1.67, 0.59-2.4); mental status changes for daratumumab (40; 2.66, 1.95-3.63; 1.67, 1.14-2.04) and belantamab mafodotin (10; 4.23, 2.28-7.88; 2.3, 1.22-3.03); an altered state of consciousness for daratumumab (32; 1.97, 1.39-2.78; 1.32, 0.73-1.74) and belantamab mafodotin (6; 2.35, 1.05-5.23; 1.6, 0.19-2.52); Guillain-Barre syndrome (GBS) for daratumumab (23; 6.42, 4.26-9.69; 2.81, 2.11-3.3), isatuximab (8; 10.72, 5.35-21.48; 3.57, 2.35-4.37), and elotuzumab (3; 4.74, 1.53-14.7; 2.59, 0.52-3.8); and orthostatic intolerance for daratumumab (10; 12.54, 6.71-23.43; 3.75, 2.67-4.48) and elotuzumab (4; 28.31, 10.58-75.73; 5, 3.24-6.08). Conclusions: Our analysis highlighted several previously unacknowledged SDRs for MM-approved mAbs. Given the complex and not entirely understood etiology of some neuropsychiatric AEs, including GBS, further investigations are necessary.

Safety assessment of KRAS (G12C) inhibitors based on the FDA Adverse Event Reporting System (FAERS) database: A real-world pharmacovigilance study

ObjectivesKRAS (G12C) inhibitors (sotorasib and adagrasib) have approved treatment in patients with KRAS (G12C)-mutated non-small cell lung cancer (NSCLC). The post-marketing data concerning KRAS (G12C) inhibitors remain limited, and the outcomes of relevant studies are yet to yield conclusive evidence supporting the long-term safety of KRAS (G12C) inhibitors. Materials and methodsThis investigation comprehensively assessed adverse events (AEs) attributed to KRAS (G12C) inhibitors by employing advanced data mining techniques, utilizing the FDA Adverse Event Reporting System (FAERS). The dataset encompasses the period from the first quarter of 2021 to the first quarter of 2024. A disproportionality analysis was conducted to quantify the correlation between KRAS (G12C) inhibitors and AEs. The metrics employed for the evaluation of disproportionality comprise the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the information component (IC), and the empirical Bayesian geometric mean (EBGM). ResultsA total of 2,253 and 486 reports were identified as related to sotorasib and adagrasib, with the identification of 51 and 26 preferred terms, respectively. The most frequent AEs of sotorasib comprised diarrhoea (ROR 5.27), hepatotoxicity (ROR 38.09), alanine aminotransferase increased (ROR 17.41), aspartate aminotransferase increased (ROR 20.88), and hepatic function abnormal (ROR 19.88). The most common AEs of adagrasib included diarrhoea (ROR 4.21), nausea (ROR 3.84), vomiting (ROR 5.36), decreased appetite (ROR 4.79), and dehydration (ROR 7.00). A relatively reduced risk of hepatotoxicity but a increased risk of serious AEs in adagrasib compared to sotorasib (P < 0.001). ConclusionOur findings would provide valued evidence for healthcare professionals to recognize AEs associated with KRAS (G12C) inhibitors and differences between sotorasib and adagrasib, and guide their clinical practice.

A real-world disproportionality analysis of baloxavir marboxil: post-marketing pharmacovigilance data

ABSTRACT Objective Baloxavir marboxil (hereafter referred to as baloxavir) is the only cap-dependent endonuclease inhiabitor approved for the treatment and prevention of influenza. However, as a new drug marketed in 2018, the long-term safety of baloxavir in large sample population was unclear. This study aims to evaluate baloxavir-associated adverse events (AEs) through data mining of the international pharmacovigilance database of US FDA Adverse Event Reporting System (FAERS). Methods Disproportionality analysis was conducted to assess the association between baloxavir and its AEs. Data were collected from FAERS from March 2018 to June 2023. After standardizing the data, signal quantification techniques including ROR, PRR, BCPNN and MGPS were used for analysis. Results A total of 49 significant baloxavir-related preferred terms (PTs) in 20 system organ classes (SOCs) were identified in our data analysis. Compared to baloxavir’s FDA label, some new PTs emerged, with the top 10 being pneumonia, loss of consciousness, rhabdomyolysis, seizure, altered state of consciousness, hepatic function abnormal, delirium, depressed level of consciousness, encephalopathy and cardio-respiratory arrest. Conclusion In clinical application of baloxavir, attention should be paid to the new AE signals in addition to the those recorded in the labels, so as to ensure the safety of the patients.

Improved Apriori Method for Safety Signal Detection Using Post-Marketing Clinical Data

Improved Apriori Method for Safety Signal Detection Using Post-Marketing Clinical Data

The discovery and development of gefapixant as a novel antitussive therapy

ABSTRACT Introduction Gefapixant, a P2X 3 receptor antagonist, shows considerable potential in managing refractory or unexplained chronic cough. Clinical trials have consistently demonstrated its efficacy in significantly reducing cough frequency and alleviating associated symptoms. However, its adverse effect profile, particularly taste disturbances such as dysgeusia and hypogeusia, the incidence of which is dose-dependent, poses a significant challenge to patient compliance and overall treatment satisfaction. Areas covered The authors review the mechanism of action of gefapixant, the dose-dependent nature of its adverse effects and the findings from various clinical trials, including Phase 1, Phase 2, and Phase 3 studies. The authors also cover its regulatory status, post-marketing data, and its main competitors. Expert opinion Gefapixant represents a significant advancement in treating chronic cough. However, balancing efficacy and tolerability is crucial. Lower effective doses and potential combination therapies may mitigate taste disturbances. Patient education and close monitoring during treatment are also important for optimal outcomes. Further research is needed to refine dosing strategies to minimize side effects while maintaining therapeutic efficacy. This research and personalized treatment approaches are key to optimizing gefapixant therapy, ensuring improved management of chronic cough while reducing adverse effects. However, pharmaceutical trials and proposals must be adapted to align with each regulatory body’s specific requirements and concerns.

Differences in hypersensitivity reactions and gadolinium deposition disease/symptoms associated with gadolinium exposure to gadolinium-based contrast agents: new insights based on global databases VigiBase, FAERS, and IQVIA-MIDAS

BackgroundHypersensitivity reactions (HSRs) can occur unexpectedly and be life-threatening when gadolinium-based contrast agents (GBCAs) are used. Gadolinium deposition disease (GDD) and symptoms associated with gadolinium exposure (SAGE) have been controversial for a long time. However, similar studies are currently incomplete or outdated. Therefore, comparing the safety of different GBCAs in terms of HSRs and GDD/SAGE using the latest post-marketing safety data should yield further insights into safely using GBCAs.MethodsThe safety differences between all GBCAs to GDD and the spectrum of GBCA-related HSRs were all compared and analyzed by using the World Health Organization database VigiBase and the FDA Adverse Event Reporting System (FAERS) database in this study. A further analysis of SAGE was also conducted using FAERS data. The lower limit of the reporting odds ratio (ROR) 95% confidence interval was used for signal detection. Moreover, the frequency of HSRs was calculated by dividing the number of reports in VigiBase by the total sales volume (measured in millions) from 2008 to 2022 in the IQVIA Multinational Integrated Data Analysis System. All adverse events were standardized using the Medical Dictionary for Drug Regulatory Activities (MedDRA) 26.0.ResultsThis study shows that all GBCAs have the potential to induce HSRs, with nonionic linear GBCAs exhibiting a comparatively lower signal. According to standardized MedDRA query stratification analysis, gadobutrol had a greater ROR025 for angioedema. The ROR025 of gadobenate dimeglumine and gadoteridol is larger for anaphylactic/anaphylactoid shock conditions. Regarding severe cutaneous adverse reactions, only gadoversetamide and gadodiamide showed signals in FAERS and VigiBase. There were also differences in the frequency of HSRs between regions. Regarding GDD, gadoterate meglumine, and gadoteridol had a lower ROR025. An analysis of the 29 preferred terms linked to SAGE indicated that special consideration should be given to the risk of skin induration associated with gadoversetamide, gadopentetate dimeglumine, gadobenate dimeglumine, gadodiamide, and gadoteridol. Additionally, gadodiamide and gadoteridol pose a greater risk of skin tightness compared to other GBCAs.ConclusionsThe risk differences among GBCAs using data from several sources were compared in this study. However, as a hypothesis-generating method, a clear causal relationship would require further research and validation.

Safety of fingolimod in patients with relapsing remitting multiple sclerosis: A descriptive analysis of data from the EudraVigilance database

The most prevalent disease course of Multiple Sclerosis (MS) is relapsing remitting multiple sclerosis (RRMS). Fingolimod (Gilenya®) was the first oral disease-modifying therapy to RRMS. Patients affected by MS require long-term treatment, making the ongoing evaluation of the safety profile of fingolimod imperative. The aim of this study was to analyze the post-marketing pharmacovigilance data of fingolimod in Europe.Data of 12-year period (1 January 2011–19 June 2023) were obtained from EudraVigilance, and a descriptive analysis using drug-reaction pairs was performed.A total of 22,957 reports were collected. The most reported adverse events (AEs) were related to nervous system disorders SOC (multiple sclerosis relapse n = 2271; 3.51%, headache n = 921; 1.42%, central nervous system lesion n = 893; 1,38%, dizziness 769; 1,19%, hypoaesthesia 487; 0.75% and multiple sclerosis 449; 0.69%), followed by investigations (lymphocyte count decreased n = 1648; 2.55%, white blood cell count decreased n = 833; 1.29%), blood and lymphatic system disorder (lymphopenia n = 1146; 1.77%), and general disorders and administration site condition (fatigue n = 1106; 1.71%, gait disturbance 564; 0.87%). A percentage of 23.00% of serious adverse events (SAEs), among the most reported were multiple sclerosis relapse (n = 2271; 15.27%), macular oedema (n = 793; 5.33%), bradycardia (n = 678; 4.56%), leukopenia (n = 533; 3.58%), and multiple sclerosis (n = 449; 3.02%).Most of AEs were non-serious, some SAEs related to cardiac, ophthalmic and infectious disorders emerged: their prevalence, along with the alignment of reported AEs with existing literature, supports the overall safety of fingolimod. Considering the rare and long-term ADRs that may arise in patients chronically treated for MS, continuous pharmacovigilance remains essential.

Exploring Novel Adverse Events of Nefecon

BackgroundNefecon, the first innovative drug approved by both the US FDA and European EMA for IgA nephropathy, lacked comprehensive real-world assessments of its adverse events (AEs). MethodsWe leveraged post-marketing data of Nefecon from the US FDA Adverse Event Reporting System, employing disproportionate analysis to detect positive signals at the system organ class (SOCs) and preferred terms (PTs) levels. Duplicate AEs related to budesonide and those previously reported in studies were excluded through the use of the Medical Dictionary of Regulatory Activities. Our analysis encompassed time to onset (TTO), Weibull shape parameter (WSP) evaluation, cumulative incidence, clinical prioritization evaluation and subgroup analysis based on gender and age. ResultsA total of 1515 individuals with IgA nephropathy were included. Eight positive SOC signals and 23 positive PT signals were identified, including four PTs (asthenia, malaise, product dose omission issue, and anxiety) representing novel AEs newly identified in this study. None of the positive PTs were classified as high clinical priority, with only acne, hypertension, swelling face, and weight increased considered as moderate clinical priority events. The median time to TTO was 31 days. All WSP test results indicated an early failure type profile. Lastly, subgroup analysis provided further insights into the relative risk of specific AEs. ConclusionsNefecon demonstrates a favorable safety profile, with no high-priority clinical events identified. The identification of novel AEs and subgroup-specific high-risk events fills a gap in existing studies and offers valuable insights for early clinical vigilance.

A real-world disproportionality analysis of semaglutide: Post-marketing pharmacovigilance data.

The recent adverse reactions associated with semaglutide have led the Food and Drug Administration (FDA) to issue a "black box warning", and it is necessary to analyze all reports of adverse reactions to improve the safety of its clinical use. Statistical analyses and signal mining were performed by obtaining the adverse event reports related to semaglutide in the FAERS database from the first quarter of 2018 to the fourth quarter of 2023. We used disproportionality and Bayesian analysis to examine clinical and demographic attributes, trends reported quarterly, and contrasts between two distinct indications (obesity and type 2 diabetes). We found 10 unexpected adverse signals related to "pancreatic cancer", "intestinal obstruction", "cholecystitis", and "polycystic ovary" and both the two different indications had the same serious adverse reaction events occurring. This study identified many unexpected signals of serious adverse reactions, suggesting the importance of continuous post-marketing surveillance of semaglutide to understand its potential risks.

Safety of 300IR house dust mite sublingual tablet from pooled clinical trial and post-marketing data

BackgroundThe 300IR house dust mite (HDM) sublingual immunotherapy (SLIT) tablet is approved for treatment of HDM-induced allergic rhinitis (AR). To provide a comprehensive review of the 300IR HDM-SLIT tablet safety profile based on randomized controlled trial (RCT) pooled data and post-marketing (PM) pharmacovigilance data. MethodsSubjects (5–65 years) with confirmed HDM-AR with or without controlled asthma were treated with 300IR or placebo in 8 RCTs. Reported treatment-emergent adverse events (TEAEs) were pooled and analyzed descriptively in subsets of adults/adolescents and children. Adverse reactions (ADRs) collected from spontaneous reporting and PM studies through a pharmacovigilance system since the first marketing authorization were also analyzed. ResultsAcross RCTs, 1853 subjects were treated with the 300IR HDM-SLIT tablet and 1846 with placebo. In both subsets of adults/adolescents and children whichever their asthma status, treatment-related TEAEs of higher incidence in active groups vs placebo were mostly consistent with mild or moderate local application-site reactions. They were mainly reported on the first days of treatment and decreased over time. 4 severe laryngopharyngeal reactions (2 requiring adrenaline/epinephrine) and 1 moderate eczema considered serious rapidly resolved with medications; no anaphylaxis was reported. In PM settings, ADRs reported in more than 235,000 patients were in line with RCT findings. Severe systemic reactions occurred rarely; 12 anaphylactic reactions resolved safely (5 with adrenaline). No new safety signal was raised. ConclusionSafety data from RCTs and more than 7 years of real-life experience confirmed the favorable safety profile of 300IR HDM-SLIT tablet in patients across different regions, regardless of age and asthma status. Clinical trial registrationsNCT00674700; Retrospectively registered 06 May 2008.NCT01199133; Retrospectively registered 09 September 2010.NCT01527188; Retrospectively registered 01 February 2012.NCT02443805; Registered 29 April 2015/EudraCT 2014-004223-46; Registered 16 September 2015.jRCT2080221872/JapicCTI-121917; Registered 01 August 2012.jRCT2080222929/JapicCTI-15298; Registered 04 August 2015.

The underlying mechanism of chimeric antigen receptor (CAR)-T cell therapy triggering secondary T-cell cancers: Mystery of the Sphinx?

The U.S. Food and Drug Administration (FDA) has reported cases of T-cell malignancies, including CAR-positive lymphomas, in patients receiving B cell maturation antigen (BCMA)- or CD19-targeted autologous CAR-T cell immunotherapy. These reports were derived from clinical trials and/or post-marketing adverse event data. This finding has attracted widespread attention. Therefore, it is essential to explore the potential mechanisms by which chimeric antigen receptor (CAR)-T cell therapy triggers secondary T-cell cancers to further guarantee the safety of CAR-T cell therapy.

Post-marketing Safety Concerns of Teprotumumab: A Real-World Pharmacovigilance Assessment.

Teprotumumab is the only drug approval by The US Food and Drug Administration (FDA) for the treatment of thyroid eye disease (TED), which targets the insulin-like growth factor-1 receptor. This study aimed to identify potential safety signals of teprotumumab by analyzing post-marketing safety data from the FDA Adverse Event Reporting System (FAERS) database in 2023. The case/non-case approach was used to estimate the reporting odds ratio (ROR) and information component (IC) with relevant confidence intervals (95% CI) for adverse events (AEs) that numbered three or more. Total of 2158 cases were included in the analysis. Main safety signals identified were ear and labyrinth disorders, reproductive system and breast disorders, metabolism and nutrition disorders and gastrointestinal disorders. Specifically, autophony (ROR [95% CI] = 4188.34 [1403.29-12500.8]), eyelid retraction (ROR [95% CI] = 2094.17 [850.69-5155.29]), deafness permanent (ROR [95% CI] = 1552.35 [789.07-3053.98]), deafness bilateral (ROR [95% CI] = 73.12 [41.14-129.97]), inflammatory bowel disease (ROR [95% CI] = 23.26 [13.46-40.19]), hyperglycaemic hyperosmolar nonketotic syndrome (ROR [95% CI] = 17.75 [5.70-55.28]) and amenorrhoea (ROR [95% CI] = 47.98 [36.22-63.54]) showed significant safety signals of teprotumumab. This study identified ear and labyrinth disorders, reproductive system and breast disorders, as specific safety signals of teprotumumab. Clinicians and pharmacists should be vigilant regarding these AEs. However, available data are currently insufficient, and further pharmacovigilance and surveillance are needed to fully understand this issue.