Interstitial Lung Disease With Non-Vitamin K Oral Anticoagulants-A Clinical Concern?

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risk benefit profile of novel anti diabetic drugs current perspectives

We are facing a paradigm shift in the era of antidiabetics, because agents marketed after 2008 (i.e., after the rosiglitazone saga) are not only required to reduce levels of HbA1, but also to demonstrate beneficial or at least neutral effect with regard to cardiovascular (CV) outcomes (Figure 1). This is of paramount relevance, considering that the risk of developing CV disease is two-fold higher in patients with diabetes compared with individuals without diabetes [1]. Thus, pharmacovigilance is gaining a crucial role in guiding research and supporting clinical practice

Data Mining Techniques in Pharmacovigilance: Analysis of the Publicly Accessible FDA Adverse Event Reporting System (AERS)

Pharmacovigilance is a clinically oriented discipline, which may guide appropriate drug use through a balanced assessment of drug safety. Although much has been done in recent years, efforts are needed to expand the border of pharmacovigilance. We have provided insight into the FDA_Adverse Events Reporting Systems (FDA_AERS), a worldwide publicly available pharmacovigilance archive, to exemplify how to address major methodological issues. We believe that fostering discussion among researchers will increase transparency and facilitate definition of the most reliable approaches. By virtue of its large population coverage and free availability, the FDA_AERS has the potential to pave the way to a new way of looking to signal detection in PhV. Our key messages are: (1) before applying statistical tools (i.e., Data Mining Approaches - DMAs) to pharmacovigilance database for signal detection, all aspects related to data quality should be considered (e.g., drug mapping, missing data and duplicates); (2) at present, the choice of a given DMA mostly relies on local habits, expertise and attitude and there is room for improvement in this area; (3) DMA performance may be highly situation dependent; (4) over-reliance on these methods may have deleterious consequences, especially with the so-called "designated medical events", for which a case-by-case analysis is mandatory and complements disproportionality; and (5) the most appropriate selection of pharmacovigilance tools needs to be tailored to each situation, being mindful of the numerous biases and confounders that may influence performance and incremental utility of DMAs

Janus Kinase Inhibitors and Coronavirus Disease (COVID)-19: Rationale, Clinical Evidence and Safety Issues

: We are witnessing a paradigm shift in drug development and clinical practice to fight the novel coronavirus disease (COVID-19), and a number of clinical trials have been or are being testing various pharmacological approaches to counteract viral load and its complications such as cytokine storm. However, data on the effectiveness of antiviral and immune therapies are still inconclusive and inconsistent. As compared to other candidate drugs to treat COVID-19, Janus Kinase (JAK) inhibitors, including baricitinib and ruxolitinib, possess key pharmacological features for a potentially successful repurposing: convenient oral administration, favorable pharmacokinetic profile, multifunctional pharmacodynamics by exerting dual anti-inflammatory and anti-viral effects. Baricitinib, originally approved for rheumatoid arthritis, received Emergency Use Authorization in November 2020 by the Food and Drug Administration in combination with remdesivir for the treatment of COVID-19 in hospitalized patients ≥ 2 years old who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation. By July 2021, the European Medicines Agency is also expected to issue the opinion on whether or not to extend its use in hospitalised patients from 10 years of age who require supplemental oxygen. Ruxolitinib, approved for myelofibrosis, was prescribed in patients with COVID-19 within an open-label Emergency Expanded Access Plan. This review will address key milestones in the discovery and use of JAK inhibitors in COVID-19, from artificial intelligence to current clinical evidence, including real world experience, and critically appraise emerging safety issues, namely infections, thrombosis, and liver injury. An outlook to ongoing studies (clinicaltrials.gov) and unpublished pharmacovigilance data is also offered

Recurrence of pericarditis after influenza vaccination: a case report and review of the literature

BACKGROUND: This case report describes a patient with pericarditis likely attributed to influenza vaccination (positive rechallenge), with a literature review. CASE PRESENTATION: A 87-year old patient developed pericarditis after influenza vaccination, with acute chest pain, without ECG abnormalities or increased cardiac enzyme levels. Echocardiogram showed moderate pericardial effusion. Recovery was obtained through steroids One year later, few days after re-immunization, the patient experienced the same symptoms and was admitted to hospital with diagnosis of recurrence of pericarditis with severe pericardial effusion, again treated with steroids. Other possible causes were ruled out and the cardiologist recommended against influenza vaccinations in the future; the patient did not experience recurrence of pericarditis in the following 6 years. Cases of pericarditis following influenza immunization in the literature were also reviewed. CONCLUSIONS: Pericarditis following immunization for influenza is very rarely reported in the literature. In a few cases, influenza vaccination seems likely responsible. We suggest considering recent immunization in patient's history as part of the differential diagnosis in elderly with chest pain

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