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

Cheminformatics-aided pharmacovigilance: application to Stevens-Johnson Syndrome

Objective Quantitative Structure-Activity Relationship (QSAR) models can predict adverse drug reactions (ADRs), and thus provide early warnings of potential hazards. Timely identification of potential safety concerns could protect patients and aid early diagnosis of ADRs among the exposed. Our objective was to determine whether global spontaneous reporting patterns might allow chemical substructures associated with Stevens-Johnson Syndrome (SJS) to be identified and utilized for ADR prediction by QSAR models

The REporting of A Disproportionality Analysis for DrUg Safety Signal Detection Using Individual Case Safety Reports in PharmacoVigilance (READUS-PV): Explanation and Elaboration

In pharmacovigilance, disproportionality analyses based on individual case safety reports are widely used to detect safety signals. Unfortunately, publishing disproportionality analyses lacks specific guidelines, often leading to incomplete and ambiguous reporting, and carries the risk of incorrect conclusions when data are not placed in the correct context. The REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance (READUS-PV) statement was developed to address this issue by promoting transparent and comprehensive reporting of disproportionality studies. While the statement paper explains in greater detail the procedure followed to develop these guidelines, with this explanation paper we present the 14 items retained for READUS-PV guidelines, together with an in-depth explanation of their rationale and bullet points to illustrate their practical implementation. Our primary objective is to foster the adoption of the READUS-PV guidelines among authors, editors, peer reviewers, and readers of disproportionality analyses. Enhancing transparency, completeness, and accuracy of reporting, as well as proper interpretation of their results, READUS-PV guidelines will ultimately facilitate evidence-based decision making in pharmacovigilance

The Reporting of a Disproportionality Analysis for Drug Safety Signal Detection Using Individual Case Safety Reports in PharmacoVigilance (READUS-PV): Development and Statement

Background and aim: Disproportionality analyses using reports of suspected adverse drug reactions are the most commonly used quantitative methods for detecting safety signals in pharmacovigilance. However, their methods and results are generally poorly reported in published articles and existing guidelines do not capture the specific features of disproportionality analyses. We here describe the development of a guideline (REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance [READUS-PV]) for reporting the results of disproportionality analyses in articles and abstracts. Methods: We established a group of 34 international experts from universities, the pharmaceutical industry, and regulatory agencies, with expertise in pharmacovigilance, disproportionality analyses, and assessment of safety signals. We followed a three-step process to develop the checklist: (1) an open-text survey to generate a first list of items; (2) an online Delphi method to select and rephrase the most important items; (3) a final online consensus meeting. Results: Among the panel members, 33 experts responded to round 1 and 30 to round 2 of the Delphi and 25 participated to the consensus meeting. Overall, 60 recommendations for the main body of the manuscript and 13 recommendations for the abstracts were retained by participants after the Delphi method. After merging of some items together and the online consensus meeting, the READUS-PV guidelines comprise a checklist of 32 recommendations, in 14 items, for the reporting of disproportionality analyses in the main body text and four items, comprising 12 recommendations, for abstracts. Conclusions: The READUS-PV guidelines will support authors, editors, peer-reviewers, and users of disproportionality analyses using individual case safety report databases. Adopting these guidelines will lead to more transparent, comprehensive, and accurate reporting and interpretation of disproportionality analyses, facilitating the integration with other sources of evidence

Apokoinou i svenskt samtalsspråk : En familj av metoder för grammatisk konstruktion och för lösandet av kommunikativa projekt

I den här avhandlingen undersöks den grammatiska samtalskonstruktionen apokoinou i svenskt samtalsspråk. I kontrast till traditioner av normativ grammatik och teoretiska perspektiv på språk, där apokoinou och besläktade fenomen har exkluderats från grammatisk beskrivning eller blivit behandlade som produkter av olika typer av misstag, är apokoinou här re-specificerad som en i högsta grad funktionell grammatisk resurs och metod för att åstadkomma lokala kommunikativa projekt i samtal. Apokoinouyttranden definieras formellt som produkterna av en konstruktionsmetod där det finala segment i en möjligt avslutad syntaktisk enhet (pivån) är retro-konstruerad som det initiala segmentet i en efterföljande syntaktisk enhet. Utbyggnaden av pivån görs med en dubblering av en eller flera syntaktiska konstituenter från segmentet som föregår pivån samt med en prosodisk design som integrerar yttrandet i sin helhet. Ur ett strikt och normativt perspektiv på en avgränsad (skrift)mening som grundenhet medför denna dubblering att den finala fasen i hela yttrandet framstår som inkoherent med den initiala fasen. Apokoinouyttranden är dock inte inkoherenta för samtalsdeltagare, utan är en familj av metoder för att åstadkomma två handlingar efter varandra inom samma yttrande. Den andra handlingen kan skifta perspektiv på den lokala ämnesaspekten, bekräfta eller insistera på ett lokalt ämne eller handling, avsluta och avgränsa ett lokal projekt, samt återuppta oavslutade kommunikativa projekt efter mellanliggande aktiviteter. Dessa handlingar är alla mottagaranpassade lokala kommunikativa projekt i det avseendet att de är utformade att passa in i en vidare kommunikativ kontext samt att de ofta är interaktionellt åstadkomna inom och genom minimala handlingssekvenser. Dessa resultat har konsekvenser för grammatiskt teori. En av dessa konsekvenser är att grammatik måste uppfattas som villkor för dynamiska konstruktionsprocesser, inte endast som statiska och fixerade strukturer. En annan konsekvens är att grammatik organiseras lokalt snarare än på en maximalt generell nivå. Apokoinou bör också inkluderas i en svensk samtalsgrammatik som en av de grammatiska resurser som är tillgängliga för deltagare i samtal.This thesis investigates apokoinou in Swedish talk-in-interaction. In contrast to the traditions of normative grammar and theoretically based approaches to language, where apokoinou and related phenomena have been excluded from grammatical description altogether or been treated as the products of various kinds of mistakes, apokoinou is here re-specified as a highly functional grammatical resource and method to accomplish local communicative projects in talk. Apokoinou utterances are formally defined as the products of a construction method, where a segment that is final in a first possibly complete syntactic segment (the pivot) is retro-constructed as initial in a following second syntactic segment. The extension of the pivot segment is made by way of a doubling of syntactic constituents from the pre-pivot segment and with a prosodic design that integrates the whole utterance. From a strict and normative sentence-perspective, this doubling renders the final phase of the whole utterance incoherent with the initial phase. However, apokoinou utterances are not incoherent for participants, but a family of methods to accomplish two consecutive actions within one utterance. The second action can change perspective on some local topical aspect, confirm or insist on some local topic or action, close and demarcate a local project, and resume turns or skip-connect to pending local communicative projects after interstitial activities. These are all recipient designed local communicative projects in the sense of being designed to fit within the ongoing wider communicative context and they are often interactionally achieved in and through minimal sequences. These results have implications for grammatical theory. Among these are that grammar must be seen as conditions on dynamic constructional processes, not only as static and fixed structures, and that grammar is organized on a local level rather than on a maximally general level. Apokoinou should also be included in a grammar of Swedish conversational language as one of the grammatical resources available for participants in Swedish talk