Post-Marketing Safety Profile of Vortioxetine Using a Cluster Analysis and a Disproportionality Analysis of Global Adverse Event Reports

INTRODUCTION: Vortioxetine, a multimodal serotonergic drug, is widely used as treatment for major depressive disorder. Although on the market since late 2013, the data of the relative safety of vortioxetine, especially compared to selective serotonin reuptake inhibitors, are still scarce. OBJECTIVE: The aim of this study was to explore the adverse event reporting pattern of vortioxetine through a cluster analysis. Furthermore, to compare the adverse event reporting pattern for vortioxetine with that of the selective serotonin reuptake inhibitors. METHODS: Individual case safety reports for vortioxetine in VigiBase up to 1 November, 2019 were subjected to consensus clustering, to identify and describe natural groupings of reports based on their reported adverse events. A vigiPoint exploratory analysis compared vortioxetine to the selective serotonin reuptake inhibitors in terms of relative frequencies for a wide range of covariates, including patient sex and age, reported drugs and adverse events, and reporting country. Important differences were identified using odds ratios with adaptive statistical shrinkage. RESULTS: Thirty-six clusters containing at least five reports were identified and analysed. The two largest clusters included 48% of the vortioxetine reports and appeared to represent gastrointestinal adverse events and hypersensitivity adverse events. Other distinct clusters were related to, respectively, fatigue, aggression/suicidality, convulsion, medication errors, arthralgia/myalgia, increased weight, paraesthesia and anticholinergic effects. Some of these clusters are not labelled for vortioxetine, such as arthralgia/myalgia and paraesthesia, but are known adverse events for selective serotonin reuptake inhibitors. A vigiPoint analysis revealed a higher proportion of reports from consumers and non-health professionals for vortioxetine as well as higher relative reporting rates of gastrointestinal symptoms, pruritus and mood-related symptoms, consistent with the cluster analysis. CONCLUSIONS: A pattern of co-reported adverse events that is consistent with labelled adverse events for vortioxetine and the safety profile for selective serotonin reuptake inhibitors in general was revealed. Clusters of unlabelled adverse events were identified that reflect clinical entities that might represent signals of previously unknown adverse events. More extensive analyses of spontaneous reports may help to further understand the reporting pattern of adverse events. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40264-021-01139-y

Does patient reporting lead to earlier detection of drug safety signals? A retrospective comparison of time to reporting between patients and healthcare professionals in a global database:A Retrospective Comparison of Time to Reporting Between Patients and Healthcare Professionals in a Global Database

OBJECTIVE: To explore if there is a difference between patients and healthcare professionals (HCPs) in time to reporting drug-adverse drug reaction (ADR) associations which led to drug safety signals. DESIGN: This was a retrospective comparison of time to reporting selected drug-ADR associations which led to drug safety signals between patients and healthcare professionals. SETTING: ADR reports were selected from the World Health Organization Global database of individual case safety reports, VigiBase. Reports were selected based on drug-ADR associations of actual drug safety signals. MAIN OUTCOME MEASURES: Primary outcome was the difference in time to reporting between patients and HCPs. The date of the first report for each individual signal was used as time zero. The difference in time between the date of the reports and time zero was calculated. Statistical differences in timing were analysed on the corresponding survival curves using a Mann-Whitney U test. RESULTS: In total 2822 reports were included, of which 52.7% were patient reports, with a median of 25% for all included signals. For all signals, median time to signal detection was 10.4 years. Overall, HCPs reported earlier than patients: median 7.0 vs 8.3 years (p <0.001). CONCLUSIONS: Patients contributed a large proportion of reports on drug-ADR pairs that eventually became signals. HCPs reported 1.3 year earlier than patients. These findings strengthen the evidence on the value of patient reporting in signal detection, and highlight an opportunity to encourage patients to report suspected ADRs even earlier in the future

Effects of varying magnetosheath flow and dissipation on the two-dimensional reconnection structure at the magnetopause

In this Master's thesis the effect of magnetic reconnection at the magnetopause is investigated while considering non-ideal effects such as resistivity and viscosity. The analysis is conducted at the dayside magnetopause, but off the subsolar point resulting in a non-zero magnetosheath flow influencing the flow structure. Also a velocity gradient is introduced affecting the structure further. It is shown the the structure of the magnetic field and streamlines are dramatically changed from the symmetric ideal case.Validerat; 20101217 (root

Dark Matter in the Galactic Halo : A Search Using Neutrino Induced Cascades in the DeepCore Extension of IceCube

A search for Weakly Interacting Massive Particles (WIMPs) annihilating in the dark matter halo of the Milky Way was performed, using data from the IceCube Neutrino Observatory and its low-energy extension DeepCore. The data were collected during one year between 2011 to 2012 corresponding to 329.1 days of detector livetime. If WIMPs in the dark matter halo undergo pairwise annihilation they may produce a neutrino signal detectable at the Earth. Assuming annihilation into bb, W+W-, τ+τ-, μ+μ-, νν and a neutrino flavor ratio of 1:1:1 at the detector, cascade events from all neutrino flavors were used to search for an excess of neutrinos matching a dark matter signal spectrum. Two dark matter density profiles for the halo were used; the cored Burkert profile and the cusped NFW profile. No excess of neutrinos from the Galactic halo was observed, and upper limits were set for the thermally averaged product of the WIMP self-annihilation cross section and velocity, &lt;σAv&gt;, in the WIMP mass range 30 GeV to 10 TeV. For the bb annihilation channel and the NFW halo profile, the 90% C.L. upper limits are 9.03×10-22 cm3 s-1 for the mass WIMP 100 GeV and 4.08×10-22 cm3 s-1 for the WIMP mass 3000 GeV. The corresponding upper limits for the μ+μ- annihilation channel are 4.40×10-23 cm3 s-1 and 3.20×10-23 cm3 s-1.IceCub

Montelukast and Nightmares : Further Characterisation Using Data from VigiBase

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

Characterization of VigiBase reports on tinnitus associated with bisoprolol : An exploratory and descriptive study

The aim of this descriptive and explorative study was to assess individual case safety reports of bisoprolol associated with tinnitus and investigate their added value in information about adverse drug reactions (ADRs) in relation to information provided in medicine labels. The global reports from VigiBase, the WHO database of individual case safety reports, as of May 3, 2020, were analyzed for information about bisoprolol associated with tinnitus as an ADR affecting the quality of life of the patients. There were 123 reports of the ADR tinnitus reported with intake of bisoprolol in VigiBase. These described experiences of tinnitus and how this impacted on patients' daily life, for example, it could be long-lasting and may have negative impact on sleeping, and even ability to work and keep a job. There were also reports describing the management of the reaction, for example, recovery upon stopping the treatment, and improvement of the symptoms following a decreased dose or change of medicine batch. Based on reports in VigiBase, the ADR tinnitus associated with bisoprolol suggests vigilance for the onset of the event and that, if it occurs, a dose reduction or stopping the treatment could be necessary. The information provided in the reports shows the value of individual case safety reports collected post marketing, in providing descriptive information of the experience and management of the ADR

Safety Concerns Reported by Patients Identified in a Collaborative Signal Detection Workshop using VigiBase : Results and Reflections from Lareb and Uppsala Monitoring Centre

Introduction: Patient reporting in pharmacovigilance is important and contributes to signal detection. However, descriptions of methodologies for using patient reports in signal detection are scarce, and published experiences of how patient reports are used in pharmacovigilance are limited to a few individual countries. Objective: Our objective was to explore the contribution of patient reports to global signal detection in VigiBase. Methods Data were retrieved from VigiBase in September 2016. Drug-event-combination series were restricted to those with[50% patient reports, defined as reporter type "Consumer/non-health professional'' per E2B reporting standard. vigiRank was applied to patient reports to prioritize combinations for assessment. Product information for healthcare professionals (HCPs) as well as patient information leaflets (PILs) were used as reference for information on adverse drug reactions (ADRs). Staff from the Uppsala Monitoring Centre and the Netherlands Pharmacovigilance Centre Lareb categorized the combinations. Potential signals proceeded to a more in-depth clinical review to determine whether the safety concern should be communicated as a "signal.'' Results: Of the 212 combinations assessed, 20 (9%) resulted in eight signals communicated within the World Health Organization (WHO) programme for international drug monitoring. Review of PILs revealed insufficient ADR descriptions for patients and examples of poor consistency with product information for HCPs. Patient narratives provided details regarding the experience and impact of ADRs and evidence that patients make causality and personal risk assessments. Conclusions: Safety concerns described in patient reports can be identified in a global database including previously unknown ADRs as well as new aspects of known ADRs. Patient reports provide unique information valuable in signal assessment and should be included in signal detection. Novel approaches to highlighting patient reports in statistical signal detection can further improve the contribution of patient reports to pharmacovigilance

Effects of varying magnetosheath flow and dissipation on the two-dimensional reconnection structure at the magnetopause

The stationary Riemann problem including dissipation in form of resistivity and viscosity for the reconnection structure at the dayside magnetopause is considered. Including tangential velocity shear and gradients across the complete reconnection structure from the magnetosheath side into the magnetosphere, it is shown how dissipation affects the thickness of the intermediate shock wave in the vicinity of a reconnection site. We present how plasma flow structure undergoes a significant change for a nonzero uniform plasma velocity and velocity gradient. It is also shown how the reconnection rate changes and leads to a cutoff when the velocity becomes Alfvénic.Validerad; 2009; 20090519 (lgwe