Please use this identifier to cite or link to this item: https://www.um.edu.mt/library/oar/handle/123456789/55728
Title: Detecting signals of electrocardiogram QT prolongation and QT shortening : regulatory implications
Authors: Tanti, Amy
Keywords: Long QT syndrome -- Malta
Arrhythmia -- Malta
Drugs -- Side effects -- Malta
Electrocardiography -- Malta
Heart beat
Issue Date: 2017
Citation: Tanti, A. (2017). Detecting signals of electrocardiogram QT prolongation and QT shortening : regulatory implications (Doctoral dissertation).
Abstract: Drug-induced changes to the conductivity of the human ether-a-go-go related gene (hERG) potassium channels, affect cardiac repolarisation and put patients at risk of fatal cardiac arrhythmias such as Torsade de Pointes. Healthcare professionals and patients benefit from knowing which medicinal products cause this adverse event, in order to minimise co-prescribing of such drugs or to carry out appropriate monitoring. The aim of this study was to detect and characterize the QT change liability of authorised medicinal products. The methodology was in two parts. Study 1 involved extracting signals from the Eudravigilance database, and in study 2 an in-depth assessment of unexpected signals through review of literature, preclinical, adverse drug reaction and clinical trial data was performed. Proportional reporting ratios were used to identify statistical associations between drugs and QT change and expectedness was checked through the product information (PI). A list for the frequency of expectedness was created. Drugs not expected to cause QT changes were evaluated within the Bradford Hill criteria for association. Four hundred and seventeen candidates with a potential signal of QT modulation were identified. Of these, 12 products did not have QT change as an expected adverse event and so were assessed. Results from the assessment showed that changes to the PI of mirabegron, asenapine and pantoprazole could be warranted and signals on QT prolongation for mirabegron and asenapine were reported to the European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC). In March 2017, the PRAC rapporteurs for these active substances (Spain and United Kingdom) agreed to take regulatory action and update the SPCs within the next periodic safety review procedures, starting in quarter four 2017. For pantoprazole, an emergent signal of hypokalaemia may warrant further separate investigation. For QT shortening, fingolimod and olanzapine were assessed, and the data for these two drugs did not lead to a recommendation for change to the PI due to lack of robust evidence. In conclusion, this study presents a number of outputs; (1) inferences on (a) mirabegron, (b) asenapine and (c) pantoprazole, (2) assessment recommendations for preclinical assessors and marketing authorisation holders looking at hERG studies, (3) reflections on the pharmacological basis of short QT, and (4) an innovative proposal for a QT drugs list with risk categorisation.
Description: PharmD
URI: https://www.um.edu.mt/library/oar/handle/123456789/55728
Appears in Collections:Dissertations - FacM&S - 2017
Dissertations - FacM&SPha - 2017

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