Information Component Research Articles

Cardiovascular Toxicities of Antiangiogenic Tyrosine Kinase Inhibitors: A Retrospective, Pharmacovigilance Study

Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are an essential therapeutic option in the management of various solid tumors, particularly renal cell carcinoma (RCC). However, post-marketing data regarding their potential cardiovascular toxicities are scant. To identify and characterize cardiovascular adverse events (CVAEs) of VEGFR-TKIs indicated for RCC. Disproportionality analysis of the US Food and Drug Administration adverse event reporting system (July 2014-December 2019) using the reporting odds ratio (ROR) and the lower bound of the Information component (IC) 95% credibility interval (IC025 > 0 is significant). We identified 51,836 adverse event reports of sunitinib, pazopanib, axitinib, cabozantinib, and lenvatinib in the full database [36% women; median age 65 years (range 57-73)]. CVAEs accounted for 11,784 (23%) of the reports, with hypertension [n = 5548 (11%), ROR = 6.55 (95% CI 6.37-6.74), IC025 = 2.48] and hemorrhages [n = 3710 (7.2%), ROR = 1.28 (1.24-1.32), IC025 = 0.28] being the most frequent types. Additional CVAEs were over-reported with VEGFR-TKIs treatment, including aortic dissection [n = 61 (0.1%), ROR = 3.50 (2.71-4.51)], pericardial diseases [n = 173 (0.3%), ROR = 1.98 (1.70-2.30)], cardiomyopathy [n = 61 (0.1%), ROR = 1.89 (1.47-2.43)], heart failure [n = 868 (1.7%), ROR = 1.35 (1.26-1.44)], and venous thromboembolism [n = 604 (1.2%), ROR = 1.33 (1.23-1.45), all IC025 > 0]. The major pericardial disorder was non-malignant pericardial effusion [n = 134 (77%)]. Aortic dissections were also over-reported in patients without concomitant elevated blood pressure [ROR = 2.68 (1.97-3.63), IC025 = 0.91]. Finally, CVAEs were reported more often following lenvatinib and sunitinib treatment compared to other VEGFR-TKIs. In post-marketing surveillance data, VEGFR-TKIs are associated with increased reporting of various CVAEs, including pericardial diseases, particularly non-malignant pericardial effusion, and aortic dissections. Moreover, VEGFR-TKIs differ in their CVAE reporting patterns. Clinicians should be conscious of these findings in the care of VEGFR-TKIs recipients.

Signal Detection of Adverse Drug Reactions of Cephalosporins Using Data from a National Pharmacovigilance Database.

This case-non-case study aims to detect signals not currently listed on cephalosporin drug labels. From 2009 to 2018, adverse event (AE) reports concerning antibacterial drugs (anatomical therapeutic chemical (ATC) code J01) in the Korea Adverse Events Reporting System (KAERS) database were examined. For signal detection, three indices of disproportionality, proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC), were calculated. The list of signals was compared with ADRs on the drug labels from the United States, United Kingdom, Japan, and South Korea. A total of 163,800 cephalosporin–AE combinations and 72,265 all other J01–AE combinations were analyzed. This study detected 472 signals and 114 new signals that are not included on the drug labels. Cefatrizine–corneal edema (PRR, 440.64; ROR, 481.67; IC, 3.84) and cefatrizine–corneal ulceration (PRR, 346.22; ROR, 399.70; IC, 4.40) had the highest PRR, ROR, and IC among all signals. Additionally, six serious AEs that were not listed on drug labels such as cefaclor-induced stupor (ten cases) and cefaclor-induced respiratory depression (four cases) were found. Detecting signals using a national pharmacovigilance database is useful for identifying unknown ADRs. This study identified signals of cephalosporins that warrant further investigation.

Signal detection of botulinum toxin type A (BoNT/A) using the Korea Adverse Event Reporting System Database, 1999-2016.

To detect signals of potential adverse events (AEs) after botulinum toxin (BTX) treatment using the Korea Institute of Drug Safety & Risk Management-Korea adverse event reporting system database (KIDS-KD). The individual case safety reports (ICSRs) submitted to KIDS-KD from 1999 to 2016 were analyzed. To detect safety signals, disproportionality analysis was introduced, and the three indices (proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC)) were calculated based on the reported preferred terms (WHO-ART, preferred term (PT)). The signals detected were compared with drug labels from Korea and the USA. A total of 5,896 AE reports were collected in January 1999 - December 2016 in the Korea Adverse Event Reporting System (KAERS) databases. Among the total of 103,785 drug-AE pairs, 1,413 were attributed to BTX. The disproportionality analysis produced 44 PTs as safety signals and detected 7 unlabeled PTs that were not listed on the labels. After matching for age and sex (1:2), the adjusted ROR of ineffective medicine and depression in BTX was 21.60 (95% confidence interval (CI), 19.12-24.41) and 6.02 (95% CI, 3.41-10.64) respectively. The number of AE reports after BTX has increased, the majority of which were from females. Safety signals such as "medicine ineffective" and "concentration impaired" may be due to increasing off-label use, which warrants long-term surveillance, especially among females after BTX injection.

Effect of antipsychotics on breast tumors by analysis of the Japanese Adverse Drug Event Report database and cell-based experiments

BackgroundSince antipsychotics induce hyperprolactinemia via the dopamine D2 receptor, long-term administration may be a risk factor for developing breast tumors, including breast cancer. On the other hand, some antipsychotic drugs have been reported to suppress the growth of breast cancer cells in vitro. Thus, it is not clear whether the use of antipsychotics actually increases the risk of developing or exacerbating breast tumors. The purpose of this study was to clarify the effects of antipsychotic drugs on the onset and progression of breast tumors by analyzing an adverse event spontaneous reporting database and evaluating the proliferation ability of breast cancer cells.MethodsJapanese Adverse Drug Event Report database (JADER) reports from April 2004 to April 2019 were obtained from the Pharmaceuticals and Medical Devices Agency (PMDA) website. Reports of females only were analyzed. Adverse events included in the analysis were hyperprolactinemia and 60 breast tumor-related preferred terms. The reporting odds ratio (ROR), proportional reporting ratio (PRR), and information component (IC) were used to detect signals. Furthermore, MCF-7 cells were treated with haloperidol, risperidone, paliperidone, sulpiride, olanzapine and blonanserin, and cell proliferation was evaluated by WST-8 assay.ResultsIn the JADER analysis, the IC signals of hyperprolactinemia were detected with sulpiride (IC, 3.73; 95% CI: 1.81–5.65), risperidone (IC, 3.69; 95% CI: 1.71–5.61), and paliperidone (IC, 4.54; 95% CI: 2.96–6.12). However, the IC signal of breast tumors was not observed with any antipsychotics. In cell-based experiments, MCF-7 cells were treated with six antipsychotics at concentrations of 2 and 32 μM, and none of the drugs showed any growth-promoting effects on MCF-7 cells. On the other hand, blonanserin markedly suppressed the growth of MCF-7 cells at a concentration of 32 μM, and the effect was concentration dependent.ConclusionsAnalysis of the JADER using the IC did not show breast tumor signals due to antipsychotic drugs. In in vitro experiments, antipsychotics did not promote MCF-7 cell proliferation whereas blonanserin suppressed MCF-7 cell growth. Further research on the effects of blonanserin on the onset and progression of breast tumor is expected.

Safety of antipsychotic drugs: A systematic review of disproportionality analysis studies

Antipsychotic drugs are commonly prescribed, mainly for the treatment of schizophrenia and other psychotic disorders. Disproportionality analysis of pharmacovigilance data from national and international databases have been recently utilized to investigate the side-effect profiles of antipsychotics and have provided unique insights of their safety. Among several national and international spontaneous reporting databases the databases of the World Health Organization (VigiBase), of the European Medicines Agency (EudraVigilance) and the US Food and Drug Administration (FAERS) incorporate millions of Individual Case Safety Reports. The aim of our study was to systematically review published disproportionality analyses on antipsychotic drugs, in order to summarize the current state of methodology and potential strengths of this analysis while highlighting safety signal generated for these pharmacological group. PubMed was searched using a search algorithm combining terms for antipsychotic drugs and disproportionality analysis. A total of 39 articles were found to be eligible corresponding to 38 original disproportionality studies. Different measures of disproportionality were used in each study: reporting odds ratio (ROR), proportional reporting ratio (PRR), empirical Bayes geometric mean (EBGM) and the information component (IC). Despite the inherent limitations of the pharmacovigilance databases disproportionality analysis provides complemented evidence from RCTs on the safety of antipsychotics, especially regarding participants often excluded from RCTs, such as pregnant and breastfeeding women, children and participants with drug abuse, comorbidities or concomitant medications.

Lung Cancer Adverse Events Reports for Angiotensin-Converting Enzyme Inhibitors: Data Mining of the FDA Adverse Event Reporting System Database

Because of contradictory evidence from clinical trials, the association between angiotensin-converting enzyme inhibitors (ACEIs) and lung cancer needs further evaluation. As such, the current study is to assess disproportionate reporting of primary malignant lung cancer among reports for ACEIs submitted to the FDA adverse event reporting system utilizing a pharmacovigilance approach. We conducted a disproportionality analysis of primary malignant lung cancer adverse events associated with 10 ACEIs by calculating the reported odds ratios (ROR) and information component (IC) with 95% confidence intervals (CI). ROR was adjusted for sex, age, and reporting year by logistic regression analyses. From January 2004 to March 2020, a total of 622 cases of lung cancer adverse event reports were identified for ACEIs users. Significant disproportionate association was found for ACEIs as a drug class (ROR: 1.22, 95% CI: 1.13–1.32; IC: 0.28, 95% CI: 0.17–0.39. adjusted ROR: 1.23, 95% CI: 1.02–1.49). After stratification based on gender, a subset analysis suggested that female patients exhibited a significant disproportionate association, while male patients did not. Sensitivity analyses that limited the data by reporting region, comorbidity, and reporting year also showed similar trends. Statistical significant lung cancer signals were detected among patients who received ACEI, especially female patients. The disproportionality analysis of the FAERS database suggests mildly increased reporting of lung cancer among ACEI users. Further robust epidemiological studies are necessary to confirm this relationship.

Repurposing haloperidol for the treatment of rheumatoid arthritis: an integrative approach using data mining techniques

Introduction:Treatment of rheumatoid arthritis (RA) has advanced with the introduction of biological disease-modifying antirheumatic drugs. However, more than 20% of patients with RA still have moderate or severe disease activity. Hence, novel antirheumatic drugs are required. Recently, drug repurposing, a process of identifying new indications for existing drugs, has received great attention. Furthermore, a few reports have shown that antipsychotics are capable of affecting several cytokines that are also modulated by existing antirheumatic drugs. Therefore, we investigated the association between antipsychotics and RA by data mining using real-world data and bioinformatics databases.Methods:Disproportionality and sequence symmetry analyses were employed to identify the associations between the investigational drugs and RA using the US Food and Drug Administration Adverse Event Reporting System (2004–2016) and JMDC administrative claims database (January 2005–April 2017; JMDC Inc., Tokyo, Japan), respectively. The reporting odds ratio (ROR) and information component (IC) were used in the disproportionality analysis to indicate a signal. The adjusted sequence ratio (SR) was used in the sequence symmetry analysis to indicate a signal. The bioinformatics analysis suite, BaseSpace Correlation Engine (Illumina, CA, USA) was employed to explore the molecular mechanisms associated with the potential candidates identified by the drug-repurposing approach.Results:A potential inverse association between the antipsychotic haloperidol and RA, which exhibited significant inverse signals with ROR, IC, and adjusted SR, was found. Furthermore, the results suggested that haloperidol may exert antirheumatic effects by modulating various signaling pathways, including cytokine and chemokine signaling, major histocompatibility complex class-II antigen presentation, and Toll-like receptor cascade pathways.Conclusion:Our drug-repurposing approach using data mining techniques identified haloperidol as a potential antirheumatic drug candidate.

Disproportionality analysis in VigiBase as a drug repositioning method for the discovery of potentially useful drugs in Alzheimer's disease.

Disproportionality analysis is a validated method for detecting significant associations between drugs and adverse events (AEs) in pharmacovigilance databases. We applied this approach in VigiBase to establish the safety profile displayed by the anticholinesterase drugs used in AD and searched the database for drugs with similar safety profiles. The detected drugs with potential activity against acetylcholinesterase and butyrylcholinesterases (BuChEs) were then evaluated to confirm their anticholinesterase potential. We identified 22 drugs with safety profiles similar to AD medicines. Among these drugs, 4 (clozapine, aripiprazole, sertraline and S-duloxetine) showed a human BuChE inhibition rate of over 70% at 10-5 M. Their human BuChE half maximal inhibitory concentration values were compatible with clinical anticholinesterase action in humans at their normal doses. The most active human BuChE inhibitor in our study was S-duloxetine, with a half maximal inhibitory concentration of 1.2μM. Combined with its ability to inhibit serotonin (5-HT) reuptake, the use of this drug could represent a novel multitarget directed ligand therapeutic strategy for AD. We identified 4 drugs with repositioning potential in AD using drug safety profiles derived from a pharmacovigilance database. This method could be useful for future drug repositioning efforts.

Abstract 12978: Identification of Cardiovascular Adverse Effects Associated With Midostaurin - A WHO Pharmacovigilance Database Analysis

Introduction: Midostaurin is an oral multiple tyrosine kinase inhibitor (TKI) approved for treatment of acute myeloid leukemia and systemic mastocytosis. Clinical trials have shown efficacy of midostaurin with few adverse events. Although midostaurin does cause QT-prolongation, other associated cardiovascular complications are unknown. The purpose of this study is to identify and characterize cardiovascular adverse events associated with midostaurin. Methods: We used VigiBase, WHO's global database of individual case safety reports, to evaluate the association between midostaurin and cardiovascular adverse events using the reporting odds ratio (ROR) and the information component (IC). IC is an indicator value for disproportionate Bayesian reporting that compares observed and expected values to find associations between drugs and adverse events. IC 025 is the lower end of the IC 95% credibility interval and an IC 025 value of more than zero is deemed significant. Results: We identified 153 adverse cardiovascular events reported in patients who received midostaurin. Midostaurin treatment was associated with higher reporting of QT prolongation (48 cases, IC 025 4.15), heart failure (38 cases, IC 025 1.90), atrial fibrillation (20 cases, IC 025 1.53), and pericardial disease (12 cases, IC 025 1.23). A majority of these adverse events occurred within 50 days of midostaurin initiation with midostaurin being the only suspected culprit medication. Fatalities occurred in 8.7%, 43.2%, and 42.1% of cases of QT prolongation, heart failure, and atrial fibrillation, respectively. Conclusions: Midostaurin can lead to severe and sometimes fatal cardiac toxicities in a subset of patients. Baseline electrocardiograms and echocardiograms would be prudent in patients starting midostaurin to characterize and monitor these adverse effects.

Amiodarone and Parkinsonism: a pharmacovigilance study.

Some case reports have described parkinsonism with amiodarone. We investigated a putative association between parkinsonism and exposure to amiodarone. We used the WHO pharmacovigilance database (VigiBase® ). All adverse drug reactions with 'Parkinson-like events' and amiodarone were included. Four disproportionality analyses were performed: 1/after inclusion of all reports, 2/according to sex, 3/for the twenty last years (2000-2019), and 4/after exclusion of concomitant drugs known to induce parkinsonism (antipsychotic, antivertigo, antiemetic antinauseant drugs, flunarizine). Results are expressed as reporting odds ratios (ROR; 95% CI) and information component (IC). No significant association was found in the whole population [ROR=0.83 (0.65-1.06), IC=-0.7 (IC025 =-0.65)], in men, in women, for the 2000-2019years, or after exclusion of drugs inducing parkinsonism. We failed to find any signal of parkinsonism with amiodarone. We suggest that reports of parkinsonism with amiodarone could be mainly explained by other underlying causes.

Analysis of the US FDA adverse event reporting system to identify adverse cardiac events associated with hydroxychloroquine in older adults.

The purpose of this study is to analyze the US FDA Adverse Event Reporting System (FAERS) to identify adverse cardiac events of hydroxychloroquine in older adults. A case/non-case method was used to determine adverse events associated with hydroxychloroquine as the primary suspect drug between January 1, 2004, and December 31, 2019, for older adults (≥65 years). Adverse events are preferred terms (PTs) defined in MedDRA. We used frequentist approaches, including the reporting odds ratio (ROR) and the proportional reporting ratio (PRR) to measure disproportionality. We used Bayesian approaches to derive information component (IC) value and Empirical Bayesian Geometric Mean (EBGM) score. Signals were defined as the number of reports > 3 and the lower limit of 95% confidence intervals (CI) of ROR ≥ 2, PRR ≥ 2, IC > 0, EBGM > 1. We identified 334 adverse cardiac events comprising 71 different MedDRA PTs from 2004 to 2019 for hydroxychloroquine in older adults. Strong disproportionality signals were noted for "Restrictive cardiomyopathy" (ROR = 272.43 (138.09-537.47); EBGM = 149.78 (77.34-264.67), "Right ventricular hypertrophy" (219.49 (85.32-564.70); 102.74 (39.67-222.81), "Cardiac septal hypertrophy" (226.77 (78.65-653.80); 93.82 (32.19-219.81), "Myocardial fibrosis" (57.29 (21.06-155.85); 42.99 (14.74-100.75), and "Cardiotoxicity" (43.90 (26.66-72.27); 40.28 (24.02-63.72). The risk of cardiomyopathy and myocardial disorders is high following exposure to hydroxychloroquine in older adults. Due to the current lack of safety data from randomized controlled trials as well as large observational studies to confirm the risk of adverse cardiac events associated with hydroxychloroquine, findings from analyses of post-marketing data may serve as interim guidance.

Cardiotoxicity Associated with Gemcitabine: Literature Review and a Pharmacovigilance Study.

Background: Gemcitabine is a nucleoside analog, widely used either alone or in combination, for the treatment of multiple cancers. However, gemcitabine may also be associated with cardiovascular adverse-drug-reactions (CV-ADR). Methods: First, we searched for all cases of cardiotoxicity associated with gemcitabine, published in MEDLINE on 30 May 2019. Then, we used VigiBase, the World Health Organization’s global database of individual case safety reports, to compare CV-ADR reporting associated with gemcitabine against the full database between inception and 1 April 2019. We used the information component (IC), an indicator value for disproportionate Bayesian reporting. A positive lower end of the 95% credibility interval for the IC (IC025) ≥ 0, is deemed significant. Results: In VigiBase, 46,898 reports were associated with gemcitabine on a total of 18,908,940 in the full database. Gemcitabine was associated with higher reporting for myocardial ischemia (MI, n: 119), pericardial diseases (n: 164), supraventricular arrhythmias (SVA, n: 308) and heart failure (HF, n: 484) versus full database with IC025 ranging between 0.40 and 2.81. CV-ADR were associated with cardiovascular death in up to 17% of cases. Conclusion: Treatment with gemcitabine is associated with potentially lethal CV-ADRs, including MI, pericardial diseases, SVA and HF. These events should be considered in patient care and clinical trial design.

Psoriasis associated with ACE inhibitors: an analysis of the FAERS database.

Many case reports have been published concerning the development or exacerbation of psoriasis after administration of angiotensin-converting enzyme (ACE) inhibitors. The aim of the present study was to investigate the association between psoriasis and ACE inhibitors using the US Food and Drug Administration Adverse Event Reporting System (FAERS) data. After excluding patients with psoriasis-related primary diseases, the association of psoriasis with 14 ACE inhibitors was examined using disproportional analyses reporting odds ratio (ROR) and information component (IC). Signals were detected for all 14 ACE inhibitors combined (ROR: 1.25, 95% confidence interval [CI]: 1.14-1.37; IC: 0.31, 95% CI: 0.17-0.44) and individually for lisinopril (ROR: 1.20, 95% CI: 1.05-1.37; IC: 0.25, 95% CI: 0.06-0.45), perindopril (ROR: 1.86, 95% CI: 1.38-2.52; IC: 0.86, 95% CI: 0.43-1.30), and ramipril (ROR: 1.63, 95% CI: 1.36-1.96; IC: 0.69, 95% CI: 0.42-0.96). ACE inhibitors are widely used in patients with hypertension, heart failure, and diabetes mellitus, which are considered comorbidities of psoriasis. Our results suggest that the involvement of ACE inhibitors should be considered in patients on ACE inhibitor therapy who have developed (or show exacerbated) psoriasis.

Post-Marketing Safety Concerns with Esketamine: A Disproportionality Analysis of Spontaneous Reports Submitted to the FDA Adverse Event Reporting System

Introduction: Esketamine nasal spray received approval for treatment-resistant depression in March 2019. Objective: Using the FDA Adverse Event Reporting System (FAERS) database (March 2019–March 2020), we analysed esketamine-related adverse events (AEs) to detect and characterize relevant safety signals. Methods: We used the consolidated case/non-case approach to estimate the reporting odds ratio (ROR) and information component (IC) with relevant confidence intervals (95% CI) for esketamine-related AEs with ≥4 counts. Comparisons between serious and non-serious AEs were performed using non-parametric tests. Results: The FAERS database contained 962 cases of esketamine-related AEs, with signals detected for several AEs, such as dissociation (ROR = 1,612.64, 95% CI = 1,354.63, 1,919.79; IC = 8.19, 95% CI = 7.96, 8.35), sedation (ROR = 238.46, 95% CI = 202.98, 280.15; IC = 7, 95% CI = 6.75, 7.18), feeling drunk (ROR = 96.17, 95% CI = 61.42, 150.57; IC = 4.84, 95% CI = 4.09, 5.36), suicidal ideation (ROR = 24.03, 95% CI = 18.72, 30.84; IC = 4.31, 95% CI = 3.9, 4.61), and completed suicide (ROR = 5.75, 95% CI = 3.18, 10.41; IC = 2.25, 95% CI = 1.23, 2.94). Signals for suicidal and self-injurious ideation, but not suicide attempt and completed suicide, remained when comparing esketamine to venlafaxine. Females and patients receiving antidepressant polypharmacy, co-medication with mood stabilizers, antipsychotics, benzodiazepines, or somatic medications were more likely to suffer from serious versus non-serious AEs (χ² = 125.29, p < 0.001, χ² = 9.08, p = 0.003, χ² = 8.14, p = 0.004, χ² = 19.48, p < 0.001, χ² = 25.62, p < 0.001, and χ² = 16.79, p < 0.001, respectively). Conclusions: Esketamine may carry a clear potential for serious AEs, which deserves urgent clarification by means of further prospective studies.

Comparison of Data Mining Methods for the Signal Detection of Adverse Drug Events with a Hierarchical Structure in Postmarketing Surveillance.

There are several different proposed data mining methods for the postmarketing surveillance of drug safety. Adverse events are often classified into a hierarchical structure. Our objective was to compare the performance of several of these different data mining methods for adverse drug events data with a hierarchical structure. We generated datasets based on the World Health Organization’s Adverse Reaction Terminology (WHO-ART) hierarchical structure. We evaluated different data mining methods for signal detection, including several frequentist methods such as reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC), the likelihood ratio test-based method (LRT), and Bayesian methods such as gamma Poisson shrinker (GPS), Bayesian confidence propagating neural network (BCPNN), the new IC method, and the simplified Bayesian method (sB), as well as the tree-based scan statistic through an extensive simulation study. We also applied the methods to real data on two diabetes drugs, voglibose and acarbose, from the Korea Adverse event reporting system. Only the tree-based scan statistic method maintained the type I error rate at the desired level. Likelihood ratio test-based methods and Bayesian methods tended to be more conservative than other methods in the simulation study and detected fewer signals in the real data example. No method was superior to the others in terms of the statistical power and sensitivity of detecting true signals. It is recommended that those conducting drug‒adverse event surveillance use not just one method, but make a decision based on several methods.

Can tramadol really induce hyponatraemia? A pharmacovigilance study.

Several papers have described hyponatraemia with tramadol. However, in most reports, several confounding factors can be found. We used the WHO pharmacovigilance database (VigiBase®) to investigate if tramadol alone could be associated with hyponatraemia. All 1992-2019 ICSRs (individual case safety reports) with the preferred term (PT) "hyponatraemia" and tramadol were included. Two disproportionality analyses were performed: (1) after inclusion of all reports, and (2) after exclusion of concomitant hyponatraemic drugs. Results are expressed as reporting odds ratios (ROR; 95% CI) and information component (IC). Of 19 747 604 ICSRs, 225 575 were included. A significant association was found between tramadol use and reports of hyponatraemia (ROR = 1.49 [1.39-1.60], IC = 0.57 [IC025 = 0.47]). After exclusion of hyponatraemic drugs, the previously found association disappeared. The study failed to find any pharmacovigilance signal of hyponatraemia with tramadol alone. We suggest that reports of hyponatraemia with tramadol can be explained principally by other underlying causes of hyponatraemia, especially other concomitant hyponatraemic drugs.

Mapping endocrine toxicity spectrum of immune checkpoint inhibitors: a disproportionality analysis using the WHO adverse drug reaction database, VigiBase

PurposeOur study aimed to map endocrine toxicity spectrum of immune checkpoint inhibitors (ICIs).MethodsWe obtained data from VigiBase, between January 1, 2011 and March 6, 2019. All endocrine adverse drug reactions (ADRs) were classified by group queries according to the Medical Dictionary for Regulatory Activities. Disproportionality analysis was performed with information component (IC) and reporting odds ratio (ROR). We used IC to identify meaningful endocrinopathies associated with ICIs and ROR to compare differences between ICI subgroups of ADRs. IC025 (lower end of the 95% confidence interval of IC) is considered significant if larger than 0.ResultsIn all, 6089 reports for endocrinopathies associated with ICIs were involved, with a male to female ratio of 1.5:1. The disproportionality analysis indicated significance of not only common endocrinopathies: thyroid dysfunction, hypophysitis/hypopituitarism, adrenal insufficiency, T1DM, fulminant T1DM (IC025: 4.12–6.62), but also rare endocrinopathies: hypoparathyroidism, diabetes insipidus, hypogonadism (IC025: 1.56–2.04). Increased risk of ADR reporting emerged in anti-CTLA-4 (e.g., hypophysitis/hypopituitarism, adrenal insufficiency) or in anti-PD-1/PD-L1 (e.g., thyroid dysfunction, T1DM, fulminant T1DM). In general, combination therapy (anti-CTLA-4 plus anti-PD-1/PD-L1) had a stronger association with endocrinopathies than monotherapy (ROR: 2.8, 95% CI: 2.5–3.1). Onset time of common endocrinopathies differed between different ICI therapies, typically within 12 weeks in anti-CTLA-4 monotherapy but diffusely ranging from 0 to 48 weeks in anti-PD-1 monotherapy.ConclusionsOur study shows rising reporting frequencies of endocrinopathies caused by ICIs, especially aggravated in combination therapy. Clinicians should be early aware of latent endocrine toxicity and different onset time of endocrinopathies when implementing ICI therapies.

Cardiovascular Toxicities Associated With Hydroxychloroquine and Azithromycin

Keywords: azithromycin;cardiotoxicity;hydroxychloroquine;phamacovigilance EN azithromycin cardiotoxicity hydroxychloroquine phamacovigilance 303 305 3 07/23/20 20200721 NES 200721 Although hydroxychloroquine and azithromycin, alone or in combination, have been proposed for treatment of patients with coronavirus disease 2019 (COVID-19),[1] their potential cardiovascular toxicities had limited consideration in this new clinical environment The proportion that resulted in death for TdP/VT cases was 8 4% (7/83) with hydroxychloroquine and 20 2% (52/257) with azithromycin versus 0% (0/53) and 5 4% (12/223) for LQT without TdP/VT with hydroxychloroquine and azithromycin, respectively ( I P i 0 001 for both) [Extracted from the article] Copyright of Circulation is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission However, users may print, download, or email articles for individual use This abstract may be abridged No warranty is given about the accuracy of the copy Users should refer to the original published version of the material for the full abstract (Copyright applies to all Abstracts )

Safety Surveillance of Pneumococcal Vaccine Using Three Algorithms: Disproportionality Methods, Empirical Bayes Geometric Mean, and Tree-Based Scan Statistic.

Introduction: Diverse algorithms for signal detection exist. However, inconsistent results are often encountered among the algorithms due to different levels of specificity used in defining the adverse events (AEs) and signal threshold. We aimed to explore potential safety signals for two pneumococcal vaccines in a spontaneous reporting database and compare the results and performances among the algorithms. Methods: Safety surveillance was conducted using the Korea national spontaneous reporting database from 1988 to 2017. Safety signals for pneumococcal vaccine and its subtypes were detected using the following the algorithms: disproportionality methods comprising of proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC); empirical Bayes geometric mean (EBGM); and tree-based scan statistics (TSS). Moreover, the performances of these algorithms were measured by comparing detected signals with the known AEs or pneumococcal vaccines (reference standard). Results: Among 10,380 vaccine-related AEs, 1135 reports and 101 AE terms were reported following pneumococcal vaccine. IC generated the most safety signals for pneumococcal vaccine (40/101), followed by PRR and ROR (19/101 each), TSS (15/101), and EBGM (1/101). Similar results were observed for its subtypes. Cellulitis was the only AE detected by all algorithms for pneumococcal vaccine. TSS showed the best balance in the performance: the highest in accuracy, negative predictive value, and area under the curve (70.3%, 67.4%, and 64.2%). Conclusion: Discrepancy in the number of detected signals was observed between algorithms. EBGM and TSS calibrated noise better than disproportionality methods, and TSS showed balanced performance. Nonetheless, these results should be interpreted with caution due to a lack of a gold standard for signal detection.

Colitis following the use of immune checkpoint inhibitors: A real-world analysis of spontaneous reports submitted to the FDA adverse event reporting system

BackgroundAlthough colitis has been reported in patients treated with immune checkpoint inhibitors (ICIs), associations between colitis and ICIs had not been thoroughly assessed in real-world studies. Here, we identified and characterized significant colitis-associated with ICIs. MethodsBased on the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2004 to December 2019, the disproportionality analysis and Bayesian analysis, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN) and the multi-item gamma Poisson shrinker (MGPS) algorithms were adopted to data mining of the suspected adverse events of colitis after ICIs administrating. Clinical characteristics of patients with ICIs-associated colitis and the time to onset of colitis following different ICI regimens were collected. ResultsA total of 3786 reports of colitis adverse events were identified with ICIs. Seven ICI monotherapies were associated with the reporting of colitis. Statistically significant ROR, PRR, information component (IC), and empirical Bayesian geometric mean (EBGM) emerged for all ICI monotherapies and combination therapies. ICIs-associated colitis affected mostly male (53.51%), with a wide mean age range (60.65 to 72 years). Colitis adverse events were commonly reported in patients with melanoma and lung cancer. Adverse outcomes of colitis concerning ICI were mainly outcomes of hospitalization-initiated or prolonged and other serious. Among colitis cases, 17.43% cases of colitis concerning ICI lead to death. The adverse event ofcolitis occurred earliest in ipilimumab monotherapy with a median time to onset of 64.21 days (IQR: 27–69 days) among all monotherapies. ConclusionsICI may lead to severe and disabling ICIs-associated colitis during therapy. Analysis of FAERS data identified signals for adverse events of colitis with ICI regimens. Practitioners should consider the factors that may increase the likelihood of colitis. The findings support a continued surveillance and risk factor identification studies.