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Purpose The aim of this study was to analyze the clinical characteristics of fatal adverse events (AEs) of rivaroxaban combined with aspirin and to underline the importance of the rational use of drugs. Methods The WHO global database of reported potential side effects of medicinal products (VigiBase) was searched for fatal AEs in the combined use of rivaroxaban and aspirin, and the clinical characteristics of those cases with sufficient information (vigiGrade completeness score ≥ 0.80) were analyzed. Results By January 19, 2020, 2309 fatal adverse event reports of rivaroxaban combined with aspirin from 21 countries were entered in VigiBase. One hundred and twenty cases contained further information, of which 42 were female (35%) and 78 were male (65%). The median age was 75 (range 34 to 93) years, and 109 cases (91%) were elderly patients (≥ 65 years). The AEs listed in the fatal case reports included bleeding in 114 cases (mainly intracranial hemorrhage and gastrointestinal hemorrhage, 59 and 46 respectively, accounting for 88%) and ischemic events in six cases (ischemic stroke in three, acute myocardial infarction in two, myocardial infarction combined with acute liver failure in one). Among the patients with bleeding events, 108 (95%) had existing risk factors for bleeding or for interacting with aspirin or rivaroxaban. These may be divided into the following: diseases (hypertension, renal impairment, history of stroke, peptic ulcer, or previous bleeding), drugs (high dose aspirin, antiplatelet drugs, anticoagulants, P-gp inhibitors/CYP3A4 inhibitors, non-steroidal anti-inflammatory drugs, steroids, and selective serotonin reuptake inhibitors), or other factors (e.g., elderly, low body weight, or excessive intake of ginger, fish oil, or alcohol). There were 45 cases with two or more of these risk factors in addition to rivaroxaban and aspirin. Patients with ischemic events are often in very high-risk groups of atherosclerotic cardiovascular disease (ASCVD) or self-discontinuation of treated drugs. Medication errors occurred in 24 patients (20%): excessive treatment in 17 cases, contraindication in three, frequency error in two, excessive treatment combined with contraindication in one, and self-discontinuation in one. Conclusions Fatal AEs related to rivaroxaban combined with aspirin, including bleeding and ischemic events, have been reported mostly in the elderly, and sometimes involved medication errors. The fatal AEs mainly manifested as serious bleeding, and most of them occurred in patients with concurrent multiple risk factors. Monitoring coagulation during rivaroxaban treatment is recommended in very high-risk ASCVD populations, and attention should be paid to prevention of medication errors.

Introduction Montelukast is a medicine indicated for use in asthma. Psychiatric disorders including nightmares have not been described in clinical trials but during recent years have been included in the product information as having been reported post-marketing, without further description of the events. Previous descriptions in the scientific literature were based on limited numbers of reports or lacked detailed case information. Objective The study aim was to further characterise post-marketing adverse drug reactions for nightmares, suspected to be induced by montelukast, to facilitate safer use of the medicine by providing additional information to patients and healthcare professionals. Methods We clinically reviewed reports of nightmares with montelukast present in VigiBase, World Health Organization’s global database of suspected adverse reactions to medicinal products, developed and maintained by the Uppsala Monitoring Centre, until 3 May, 2020. Results There were 1118 reports of nightmares with montelukast in VigiBase, which provided valuable descriptions of the nightmares as well as information about the impact on the daily lives, with many cases describing a severe impact of the nightmares. About half of the reports were classified as serious. Two thirds concerned children, with the largest age group represented being children aged 5–10 years. In most cases, the nightmares disappeared upon discontinuation of the drug but for some patients it took a long time until the nightmares ceased. Conclusions The nature and potential severity of this adverse drug reaction, as described in these reports, present important knowledge for patients and healthcare providers that could help reduce drug-induced harm. This study highlights the value of post-marketing reports for further characterisation of known adverse drug reactions. The benefit–risk balance should be continuously monitored while patients are taking montelukast.

Indapamide can cause hypokalaemia and hyponatraemia. Rhabdomyolysis associated with these electrolyte abnormalities has been reported.The aim of this study was to assess causal association between the use of indapamide and the occurrence of rhabdomyolysis using the Bradford Hill criteria.Variables in the rhabdomyolysis case reports and literature were reviewed. Bradford Hill criteria were used in the assessment of causal association.Up to 11 November 2020, there were 28 unique cases in VigiBase from 13 countries reporting indapamide-associated rhabdomyolysis. In 18 of these cases, hypokalaemia (n = 14) or hyponatremia (n = 8) was a co-reported event, including four cases where both of these events were reported. Indapamide was the only suspected drug in nine of these 18 cases and positive dechallenge was mentioned in 13 of them. In addition, there were risk factors such as falls, concomitant drugs with risk of hypokalaemia, or muscle injury. In two cases, liquorice (containing glycyrrhizin) was concomitantly used with indapamide before hypokalaemia and rhabdomyolysis occurred. Thiazide diuretics, known to cause hypokalaemia, showed similar disproportionality patterns as indapamide regarding rhabdomyolysis and myopathy, while calcium channel blockers (not causing hypokalaemia), had lower disproportionality values than indapamide.Based on the review of case series and causality assessment using Bradford Hill criteria, indapamide may cause rhabdomyolysis due to hypokalaemia or hyponatremia. Considering the seriousness of the reported cases, health care professionals should be aware of this potential risk following indapamide intake, particularly when there are risk factors for hypokalaemia and hyponatremia such as excessive liquorice consumption. A similar risk of muscle injuries may apply to thiazide diuretics as well.

Objective The aim of this study was to assess the causality of anti-TNFα agents-associated pleuropericarditis in VigiBase with a focus on its diverse types. Methods All variables contained in the pleuropericarditis reports were reviewed. Well-documented reports, vigiGrade completeness score ≥ 0.80 or with an informative narrative, were analyzed and with a focus on the clinical features of the cases. Bradford-Hill criteria were used in the case series assessment of causality. Results From 1968 up to 18 December 2019, there were 94 unique cases from 18 countries reporting pleuropericarditis with anti-TNFα agents as a suspected or interacting medicine. Among the 94 reports, 42 were identified as well-documented and further assessed for clinical features. Of the 42 cases, 39 were serious, including three fatal and seven life-threatening. In 35 cases, an anti-TNFα agent was the only suspected drug. Positive de- and re-challenge were reported in 95% and 17% of the 42 cases, respectively. The times to onset (TTO) varied greatly among individual cases, ranging from one month to 75 months (mean = 24 months). The most commonly involved anti-TNFα agents were adalimumab, infliximab and etanercept; and the mostly reported pleuropericarditis types were classified as autoimmune-related with (n = 17) or without (n = 15) co-reported drug-induced lupus (DIL), or infection-related (n = 8). While adalimumab was the most reported in the infection-related cases (7/8), infliximab was the most frequent in the autoimmune-related cases, in particular co-reported with DIL (9/17). There were four cases where the reaction occurred one to two months after the anti-TNFα agents (infliximab and adalimumab) were stopped. Based on the review of the case series using Bradford-Hill criteria the anti-TNFα agents associated pleuropericarditis are considered as a class effect. Conclusions To clinically recognize and manage these potentially life-threatening serious cardiopulmonary complications, health care professionals should be aware of this possible risk. Meanwhile, attention should be paid to the clinical features of pleuropericarditis cases, since they may cause diagnostic and therapeutic difficulties. Considering the long elimination time, clinicians need to be reminded to remain vigilant for the adverse reactions even after discontinuing anti-TNFα therapy.

Angioedema occurring in the head and neck region is a rare and sometimes life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Few studies have investigated the association of common variants with this extreme reaction, but none have explored the combined influence of rare variants yet. Adjudicated cases of ACEI-induced angioedema (ACEI-AE) or ARB-induced angioedema (ARB-AE) and controls were recruited at five different centers. Sequencing of 1,066 samples (408 ACEI-AE, ARB-AE, and 658 controls) was performed using exome-enriched sequence data. A common variant of the F5 gene that causes an increase in blood clotting (rs6025, p.Arg506Gln, also called factor V Leiden), was significantly associated with both ACEI-AE and ARB-AE (odds ratio: 2.85, 95% confidence interval (CI), 1.89–4.25). A burden test analysis of five rare missense variants in F5 was also found to be associated with ACEI-AE or ARB-AE, P = 2.09 × 10−3. A combined gene risk score of these variants, and the common variants rs6025 and rs6020, showed that individuals carrying at least one variant had 2.21 (95% CI, 1.49–3.27, P = 6.30 × 10−9) times the odds of having ACEI-AE or ARB-AE. The increased risk due to the common Leiden allele was confirmed in a genome-wide association study from the United States. A high risk of angioedema was also observed for the rs6020 variant that is the main coagulation defect-causing variant in black African and Asian populations. We found that deleterious missense variants in F5 are associated with an increased risk of ACEI-AE or ARB-AE.

SWEDEGENE is a Swedish nation-wide sample collection established to facilitate studies of clinical and genetic risk factors for adverse drug reactions (ADRs). Most cases are recruited among patients reported to the ADR registry at the Swedish Medical Products Agency by health-care professionals. Clinical data are collected both from medical and laboratory records and through interviews using standardized questionnaires. Genome-wide scans and whole-genome sequencing are done, and association studies are conducted using mainly controls from the Swedish TwinGene biobank with data on diagnoses and prescribed drugs. SWEDEGENE was established in 2008 and currently contains DNA and information from about 2550 adults who have experienced specific ADRs, and from 580 drug exposed controls. Results from genome-wide association studies have now been published, and data from whole-genome sequencing are being analyzed. SWEDEGENE has the potential to offer a new means of developing individualized and safe drug therapy through patient pre-treatment screening.

COVID-19 is associated with a prothrombotic phenotype characterised by coagulopathy and endothelial dysfunction [1–4]. Following some cases of thrombosis after vaccination, Oxford-AstraZeneca vaccine (AZD1222) was temporarily suspended by some European countries. The European medicines agency (EMA) concluded that the benefits of the vaccine in combating COVID-19 outbreak continue to outweigh the risk of side effects. On March 19, 2021, Germany reported 13 cases of sinus or cerebral vein thrombosis with more than 1.6 million AstraZeneca COVID-19 vaccine doses administered. Some of these patients also had a heparin-induced thrombocytopenia (HIT)-like syndrome, which does suggest an immunological event as one of the potential origin of thrombosis., we observed an imbalance between venous and arterial thrombotic events in mRNA vaccines while with AZ1222 they are evenly shared. Our analysis highlights cerebral vein thrombosis with the three vaccin.

Purpose Clinically, interstitial lung disease (ILD) is a heterogeneous group of over 150 respiratory disorders. In the context of its signal evaluation work, the European Medicines Agency's (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has seen geographic clustering of case reports of ILD from Japan. To explore this further, EudraVigilance (EV), the EMA's database of adverse drug reactions (ADRs), was analysed. The results have been used to inform on implications for pharmacovigilance including signal detection and evaluation activities. Methods EV was queried for reports of respiratory ADRs coded using MedDRA for the period 1994–2014 for all medicinal products. Descriptive statistics and non-parametric (chi-square) independence tests were produced to compare reporting of ILD from Japan versus the rest of the world. Results As of 31 December 2014, there were 26 551 case reports of ILD in EV of which 17 526 (66%) originated in Japan. The reporting rate of ILD for Japan has been consistently higher over the period. The odds that a case report from Japan in EV refers to ILD is OR = 20.7, 95% CI 20.2, 21.3 (p

Aim: We conducted a genome-wide association study on angiotensin-converting enzyme inhibitor-induced cough and used our dataset to replicate candidate genes identified in previous studies. Patients & methods: A total of 124 patients and 1345 treated controls were genotyped using Illumina arrays. The genome-wide significance level was set to p < 5 × 10-8. Results: We identified nearly genome-wide significant associations in CLASP1, PDE11A, KCNMB2, TGFA, SLC38A6 and MMP16. The strongest association was with rs62151109 in CLASP1 (odds ratio: 3.97; p = 9.44 × 10-8). All top hits except two were located in intronic or noncoding DNA regions. None of the candidate genes were significantly associated in our study. Conclusion: Angiotensin-converting enzyme inhibitor-induced cough is potentially associated with genes that are independent of bradykinin pathways.

Background: Angioedema is a rare and serious adverse drug reaction (ADR) to angiotensin-converting enzyme (ACE) inhibitor treatment. Dry cough is a common side effect of ACE inhibitors and has been identified as a possible risk factor for angioedema. Objective: We compared characteristics between patients with ACE inhibitor–induced angioedema and cough with the aim of identifying risk factors that differ between these adverse events. Methods: Data on patients with angioedema or cough induced by ACE inhibitors were collected from the Swedish database of spontaneously reported ADRs or from collaborating clinicians. Wilcoxon rank sum test, Fisher’s exact test, and odds ratios (ORs) with 95% CIs were used to test for between-group differences. The significance threshold was set to P -5, and OR = 3.7, 95% CI = 2.0-7.0, P = 1.7 × 10-5. Angioedema cases were seen more often in male patients (OR = 2.2, 95% CI = 1.4-3.6, P = 1.3 × 10-4) and had longer time to onset and higher doses than those with cough ( P = 3.2 × 10-10 and P = 2.6 × 10-4). A multiple model containing the variables smoking, concurrent calcium channel blocker treatment, male sex, and time to onset accounted for 26% of the variance between the groups. Conclusion: Smoking, comedication with selective calcium channel blockers, male sex, and longer treatment time were associated with ACE inhibitor–induced angioedema rather than cough.

Summary Background Drug-induced agranulocytosis is a potentially life-threatening adverse reaction. Genome-wide association studies (GWASs) in ethnic Chinese people in Taiwan and Hong Kong have shown an association between agranulocytosis induced by antithyroid drugs and the HLA alleles HLA-B*38:02 and HLA-DRB1*08:03 . We aimed to identify genetic variants associated with antithyroid drug-induced agranulocytosis in a white European population. Methods We did a GWAS in 234 European adults with any non-chemotherapy drug-induced agranulocytosis (absolute neutrophil count ≤0·5 × 10 9 /L [≤500/μL]) and 5170 population controls. 39 of the 234 patients had agranulocytosis that was induced by antithyroid drugs (thiamazole [methimazole], carbimazole, or propylthiouracil). After imputation and HLA allele prediction, 9 380 034 single nucleotide polymorphisms (SNPs) and 180 HLA alleles were tested for association. The genome-wide significance threshold was p −8 . Findings Agranulocytosis induced by non-chemotherapy drugs in general was significantly associated with the HLA region on chromosome 6, with odds ratios (ORs) of 3·24 (95% CI 2·31–4·55, p=1·20 × 10 −11 ) for HLA-B*27:05 and 3·57 (2·61–4·90, p=2·32 × 10 −15 ) for the top SNP (rs114291795). Drug-specific analysis showed that the association with HLA-B*27:05 was largely driven by cases induced by antithyroid drugs. In a multiple logistic regression model, the OR for HLA-B*27:05 was 7·30 (3·81–13·96) when antithyroid drug-induced agranulocytosis was compared with population controls (p=1·91 × 10 −9 ) and 16·91 (3·44–83·17) when compared with a small group of hyperthyroid controls (p=5·04 × 10 −4 ). Three SNPs were strongly associated with antithyroid drug-induced agranulocytosis: rs652888 (OR 4·73, 95% CI 3·00–7·44, p=1·92 × 10 −11 ) and rs199564443 (17·42, 7·38–41·12, p=7·04 × 10 −11 ), which were independent of HLA-B*27:05 , and rs1071816 (5·27, 3·06–9·10, p=2·35 × 10 −9 ) which was in moderate linkage disequilibrium with HLA-B*27:05 . In heterozygous carriers of all three SNPs, the predicted probability of antithyroid drug-induced agranulocytosis was about 30% (OR 753, 95% CI 105–6812). To avoid one case of agranulocytosis, based on the possible risk reduction if all three SNPs are genotyped and carriers are treated or monitored differently from non-carriers, roughly 238 patients would need to be genotyped. Interpretation In white European people, antithyroid drug-induced agranulocytosis was associated with HLA-B*27:05 and with other SNPs on chromosome 6. In the future, carriers of these variants could be placed under intensified monitoring or offered alternative treatment for hyperthyroidism. Funding Swedish Research Council, Swedish Heart and Lung Foundation, Clinical Research Support at Uppsala University, German Federal Institute for Drugs and Medical Devices, Carlos III Spanish Health Institute, European Regional Development Fund, UK National Institute for Health Research, The Selander's Foundation, Thureus Foundation, European Commission, and Science for Life Laboratory.

Clinically, interstitial lung disease (ILD) is a heterogeneous group of over 150 respiratory disorders. In the context of its signal evaluation work, the European Medicines Agency's (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has seen geographic clustering of case reports of ILD from Japan. To explore this further, EudraVigilance (EV), the EMA's database of adverse drug reactions (ADRs), was analysed. The results have been used to inform on implications for pharmacovigilance including signal detection and evaluation activities.EV was queried for reports of respiratory ADRs coded using MedDRA for the period 1994-2014 for all medicinal products. Descriptive statistics and non-parametric (chi-square) independence tests were produced to compare reporting of ILD from Japan versus the rest of the world.As of 31 December 2014, there were 26 551 case reports of ILD in EV of which 17 526 (66%) originated in Japan. The reporting rate of ILD for Japan has been consistently higher over the period. The odds that a case report from Japan in EV refers to ILD is OR = 20.7, 95% CI 20.2, 21.3 (p 0.001), compared to OR = 0.60, 95% CI 0.54, 0.67 (p 0.001) for pulmonary fibrosis.A geographic imbalance between Japan and the rest of the world in reporting respiratory ADRs as ILD is confirmed. Consequently, the PRAC has developed approaches to address this in relation to signals of ILD it assesses to allow for more targeted risk minimisation including updates to the product information in the EU setting. Copyright © 2016 John WileySons, Ltd.