Thromboembolic Events with Cyclin-Dependent Kinase 4/6 Inhibitors in the FDA Adverse Event Reporting System

We analyzed thromboembolic events, recognized (AESIs), with cyclin-dependent kinase (CDK)4/6 inhibitors, using the Food and Drug Administration adverse event reporting system. Methods: Thromboembolic events were characterized in terms of spectrum [venous and arterial thromboembolism (VTE; ATE)] and clinical features by combining the disproportionality approach [reporting odds ratio (ROR) with 95% confidence interval (CI)] with individual case assessment. Results: A total of 1722 thromboembolic events were retained. Increased VTE reporting emerged for CDK4/6 inhibitors in the exploratory analyses (n = 659; ROR = 1.51; 95% CI = 1.39–1.63), with consistent disproportionality in the consolidated analyses (e.g., deep vein thrombosis with abemaciclib: 17; 1.98; 1.22–3.19). Higher-than-expected ATE reporting was found for ribociclib, including myocardial infarction (41; 1.82; 1.33–2.48), with rapid onset (median latency 1 vs. 6 months for other CDK4/6 inhibitors). Causality was highly probable or probable in 83.2% of cases, with a negligible proportion of pre-existing drug- and patient-related risk factors except for cardiovascular comorbidities (26%). Conclusions: Although causal association cannot be firmly inferred, oncologists should proactively monitor the occurrence of VTE with CDK4/6 inhibitors. The unexpected distinctive increased ATE reporting with ribociclib deserves urgent clarification though large comparative population-based studies. We support pharmacovigilance for the post-marketing characterization of AESIs, thus promoting real-time safe prescribing in oncology

Immune Checkpoint Inhibitors and Pregnancy: Analysis of the VigiBase® Spontaneous Reporting System

In pregnancy, immune checkpoint pathways are involved in the maintenance of fetomaternal immune tolerance. Preclinical studies have shown that immune checkpoint inhibitors (ICIs) increase the risk of fetal death. Despite the fact that using ICIs in pregnant women and women of childbearing potential is not recommended, some case reports of ICI exposure in pregnancy have been published showing favorable fetal outcomes. This study aimed to gain further insight into ICI safety in pregnancy by querying VigiBase®, the World Health Organization’s spontaneous reporting system. We performed raw and subgroup disproportionality analyses using the reporting odds ratio and comparing ICIs with the entire database, other antineoplastic agents, and other antineoplastic agents gathered in VigiBase® since 2011. Across 103 safety reports referring to ICI exposure during the peri-pregnancy period, 56 reported pregnancy-related outcomes, of which 46 were without concomitant drugs as potential confounding factors. No signals of disproportionate reporting were found for spontaneous abortion, fetal growth restriction, and prematurity. In light of the expanding indications of ICIs, continuous surveillance by clinicians and pharmacovigilance experts is warranted, along with pharmacoepidemiological studies on other sources of real-world evidence, such as birth records, to precisely assess ICI exposure during the peri-pregnancy period and further characterize relevant outcomes

Immune Checkpoint Inhibitors and Pregnancy: Analysis of the VigiBase® Spontaneous Reporting System

: In pregnancy, immune checkpoint pathways are involved in the maintenance of fetomaternal immune tolerance. Preclinical studies have shown that immune checkpoint inhibitors (ICIs) increase the risk of fetal death. Despite the fact that using ICIs in pregnant women and women of childbearing potential is not recommended, some case reports of ICI exposure in pregnancy have been published showing favorable fetal outcomes. This study aimed to gain further insight into ICI safety in pregnancy by querying VigiBase®, the World Health Organization's spontaneous reporting system. We performed raw and subgroup disproportionality analyses using the reporting odds ratio and comparing ICIs with the entire database, other antineoplastic agents, and other antineoplastic agents gathered in VigiBase® since 2011. Across 103 safety reports referring to ICI exposure during the peri-pregnancy period, 56 reported pregnancy-related outcomes, of which 46 were without concomitant drugs as potential confounding factors. No signals of disproportionate reporting were found for spontaneous abortion, fetal growth restriction, and prematurity. In light of the expanding indications of ICIs, continuous surveillance by clinicians and pharmacovigilance experts is warranted, along with pharmacoepidemiological studies on other sources of real-world evidence, such as birth records, to precisely assess ICI exposure during the peri-pregnancy period and further characterize relevant outcomes

Liver Injury with Nintedanib: A Pharmacovigilance-Pharmacokinetic Appraisal

Drug-induced liver injury (DILI) with nintedanib has emerged as an adverse event of special interest in premarketing clinical trials. We characterized DILI with nintedanib in the real world and explored the underlying pharmacological basis. First, we assessed serious hepatic events reported to the Food and Drug Administration's Adverse Event Reporting System by combining the disproportionality approach [reporting odds ratio (ROR) with 95% confidence interval (CI)] with individual case assessment. Demographic and clinical features were inspected (seriousness, onset, discontinuation, dechallenge/rechallenge, concomitant drugs) to implement an ad hoc causality assessment scoring system. Second, we appraised physiochemical and pharmacokinetic parameters possibly predictive of DILI occurrence. Significant disproportionality was found for nintedanib as compared to pirfenidone (N = 91; ROR = 4.77; 95% CI = 3.15-7.39). Asian population, low body weight (59 kg), and rapid DILI onset (13.5 days) emerged as clinical features. Hospitalization and discontinuation were found in a significant proportion of cases (32% and 36%, respectively). In 24% of the cases, at least two potentially hepatotoxic drugs (statins, proton pump inhibitors, antibiotics) were recorded. Causality was at least possible in 92.3% of the cases. High lipophilicity and predicted in silico inhibition of liver transporters emerged as potential pharmacokinetic features supporting the biological plausibility. Although causality cannot be demonstrated, clinicians should consider early monitoring and medication review on a case-by-case basis

Psychiatric Adverse Reactions to Anaplastic Lymphoma Kinase Inhibitors in Non-Small-Cell Lung Cancer: Analysis of Spontaneous Reports Submitted to the FDA Adverse Event Reporting System

open7siBackground The development of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) has improved the survival outcomes of patients with advanced ALK-rearranged non-small-cell lung cancer (NSCLC). The adverse events (AEs) related to ALK inhibitors are fairly well known; notably, about 20% of patients receiving lorlatinib experienced cognitive effects and behavioral alterations in pivotal trials. Therefore, psychiatric disorders could represent AEs of special interest for all ALK TKIs, deserving careful assessment in the post-marketing setting. Objective We conducted a real-world pharmacovigilance study on psychiatric AEs with marketed ALK inhibitors in subjects with advanced NSCLC. Patients and methods We performed an observational, retrospective analysis of spontaneous reports submitted to the Food and Drug Administration Adverse Events Reporting System (FAERS, as of December 2020), selecting psychiatric AEs to ALK TKIs approved in NSCLC (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib). These AEs were independently scrutinized by three oncologists applying predefined exclusion criteria, described in terms of clinical/demographic features and assessed for drug-related causality according to an adaptation of the WHO–UMC system, a standardized probabilistic algorithm. Results Among 584 reported psychiatric AEs, 95 cases were selected as potentially treatment related, with higher reporting frequency for lorlatinib (26, 2.8%), followed by brigatinib (10, 1.2%), alectinib (18, 0.7%), ceritinib (12, 0.6%), and crizo- tinib (29, 0.3%). Reported psychiatric symptoms were mood disorders (39), psychotic disorders (24), and anxiety, agitation, and irritability (25). In the majority (74%) of cases, psychiatric AEs were serious and required hospitalization in about 32% of patients; 15.8% of retained cases were considered as highly probable and 69.5% as probable. Drug discontinuation was recorded in 31.6% of the reported cases, with the highest proportion for lorlatinib (65.4%). Conclusion Notwithstanding limitations, our study found a higher proportion of psychiatric AEs with lorlatinib, but also raised the hypothesis of psychiatric reactions as a class effect of ALK TKIs.openSisi, Monia; Fusaroli, Michele; De Giglio, Andrea; Facchinetti, Francesco; Ardizzoni, Andrea; Raschi, Emanuel; Gelsomino, FrancescoSisi, Monia; Fusaroli, Michele; De Giglio, Andrea; Facchinetti, Francesco; Ardizzoni, Andrea; Raschi, Emanuel; Gelsomino, Francesc

Cardiovascular Toxicity of Immune Checkpoint Inhibitors: A Guide for Clinicians

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment and care of patients with cancer owing to unique features, including the occurrence of the so-called immune-related adverse events (irAEs). A multidisciplinary team, possibly including a cardio-oncology specialist, is warranted to achieve a favorable patient outcome. Cardiovascular toxicity, especially myocarditis, emerged as a life-threatening irAE in the real-word setting, and the European Society of Cardiology has recently published the first guideline on cardio-oncology to increase awareness and promote a standardized approach to tackle this complex multimodal issue, including diagnostic challenges, assessment, treatment, and surveillance of patients with cancer receiving ICIs. In this article, through a question & answer format made up of case vignettes, we offer a clinically oriented overview on the latest advancements of ICI-related cardiovascular toxicity, focusing on myocarditis and associated irAEs (myositis and myasthenia gravis within the so-called overlap syndrome), with the purpose of assisting clinicians and healthcare professionals in daily clinical practice

Investigating deliberate self-poisoning in the FDA Adverse Event Reporting System: clinical features and lethal dose estimation.

Repository with poster and interactive network for the article "Deliberate self-poisoning: real-time characterization of suicidal habits and toxidromes in the Food and Drug Administration Adverse Event Reporting System.", accepted in Drug Safety. Please note that the network does not work unless downloade

Unveiling the Hidden Toll of Drug-Induced Impulse Control Disorders.

Often underestimated in treatment decisions and monitoring, adverse drug reactions have a profound impact on patients’ lives. Impulse Control Disorders (ICDs) induced by dopaminergic agents can lead to divorce, financial strain, and legal issues. This is the linked repository to a study aiming to comprehensively assess the burden of ICDs triggered by pramipexole and aripiprazole and identify key symptoms that could be targeted to mitigate their consequences