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01.05.2007 | Original Research Article

An Evaluation of the Cardiovascular Safety Profile of Duloxetine

Findings from 42 Placebo-Controlled Studies

verfasst von: Dr Joachim Wernicke, Alberto Lledó, Joel Raskin, Daniel K. Kajdasz, Fujun Wang

Erschienen in: Drug Safety | Ausgabe 5/2007

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Abstract

Background and objective: In recent years, new classes of medication, such as the serotonin-noradrenaline reuptake inhibitors (SNRIs), have been developed for use in the treatment of major depressive disorder (MDD). For many years, treatment options were largely limited to the use of monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). However, there have been published reports of orthostatic hypotension, arrhythmias and corrected QT (QTc) interval changes in patients treated with TCAs. As new medications become available, it is important to understand how their cardiovascular safety profile compares with that of more established agents to aid clinicians and patients in choosing the best treatment options. This study was designed to evaluate the cardiovascular safety profile of the SNRI duloxetine through evaluation of cardiovascular-related parameters and adverse events (AEs).

Methods: The cardiovascular safety of duloxetine was assessed using all placebocontrolled duloxetine clinical trial data as of December 2005. This consisted of data from 42 placebo-controlled clinical trials of 8504 patients who were treated with duloxetine. Additional information from a high-dose clinical pharmacology study and postmarketing safety surveillance are also presented. Of the placebocontrolled trials included in this analysis, clinical indications under investigation included MDD (15 studies), diabetic peripheral neuropathic pain (3 studies), fibromyalgia (2 studies), generalised anxiety disorder (3 studies) and lower urinary tract disorders (19 studies, all related to incontinence). Cardiovascular safety was evaluated based on vital signs, ECGs and the incidence of treatment-emergent AEs potentially related to cardiovascular safety. These safety parameters were analysed across all indications. To identify both serious and non-serious cardiovascular-related AEs, as well as AEs reported as the reason for discontinuation, a comprehensive list of terms derived from the Medical Dictionary for Regulatory Activities (version 8.0) was generated and used to search the duloxetine databases for cardiovascular-related events.

Results: Calculation of change from baseline to maximum in ECG parameters showed significant differences between treatment groups for all parameters, with decreases from baseline in RR, QRS and QT intervals for patients receiving duloxetine and increases from baseline for patients treated with placebo. These shifts were related to small heart rate changes, but the mean differences were not considered clinically relevant. Categorical analyses of shifts from normal to abnormal (or abnormal to normal) for heart rate and QT corrected for heart rate using Fridericia’s formula (QTcF) values showed that most patients did not shift from their baseline category. Patients with MDD who were treated for up to 1 year with duloxetine had blood pressure changes early in treatment that then stabilised. Even in patients with elevated blood pressure at baseline in these clinical trials, no increased risk of sustained blood pressure elevation with duloxetine treatment was found.

Conclusion: Overall, the findings presented here support our conclusions that use of duloxetine does not appear to be associated with significant cardiovascular risks in patients with conditions for which the drug has been approved or studied.

¹Heart rate (bpm) categories were <50, ≥50 to ≤59, ≥60 to ≤79, ≥80 to ≤100, ≥101 to ≤120; QTcF (msec) categories were <390, ≥391 to ≤419, ≥420 to ≤449, ≥450 to ≤479, ≥480 to ≤500, >500.

²Diastolic pressure (mm Hg) categories were <50, ≥50 to ≤59, ≥60 to ≤69, ≥70 to ≤79, ≥80 to ≤89, ≥90 to ≤99, ≥100; systolic pressure (mm Hg) categories were <80, ≥80 to ≤99, ≥100 to ≤119, ≥120 to ≤139, ≥140 to ≤159, ≥160 to ≤179, ≥180

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Titel: An Evaluation of the Cardiovascular Safety Profile of Duloxetine
Findings from 42 Placebo-Controlled Studies
verfasst von: Dr Joachim Wernicke
Alberto Lledó
Joel Raskin
Daniel K. Kajdasz
Fujun Wang
Publikationsdatum: 01.05.2007
Verlag: Springer International Publishing
Erschienen in: Drug Safety / Ausgabe 5/2007
Print ISSN: 0114-5916
Elektronische ISSN: 1179-1942
DOI: https://doi.org/10.2165/00002018-200730050-00007

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An Evaluation of the Cardiovascular Safety Profile of Duloxetine

Findings from 42 Placebo-Controlled Studies

Abstract

Live-Webinar "Chronische Unterbauch- und Viszeralschmerzen in der Praxis managen"

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Abstract

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