Macrolides and Torsadogenic Risk: Emerging Issues from the FDA Pharmacovigilance Database

Abstract

Introduction: Concern exists on the pro-arrhythmic potential of macrolides, namely Torsade de Pointes (TdP). Recent evidence has challenged the common opinion of considering azithromycin a safer therapeutic option, causing emerging regulatory and clinical interest. Materials and Methods:We analyzed cases of drug-induced TdP (2004TdP ( -2011 submitted to the publicly available FDA Adverse Event Reporting System (FAERS). Four groups of mutually exclusive events were identified in decreasing order of drug-attributable risk: 1) TdP; 2) QT interval abnormalities; 3) ventricular arrhythmia (VA); 4) Sudden Cardiac Death (SCD). They were combined into case definition A (TdP/QT abnormalities) and case definition B (VA/SCD). Both case-by-case analysis (information on concomitant drugs, especially QT-prolonging agents listed by Arizona CERT, and disproportionality approach (Reporting Odds Ratio, ROR, with 95%CI) were carried out.Results: Over the 8-year period, macrolides were associated with 183 and 419 cases of interest (case definition A and B, respectively). Clarithromycin was the most frequently reported (84 and 162 cases), followed by azithromycin (63 and 140). Only 27% of cases of TdP/QT abnormalities with azithromycin occurred in patients >65 years of age (63, 47 and 44% for clari-, ery-and telithromycin, respectively). In cases of TdP/QT abnormalities, concomitant QT-prolonging drugs (Arizona CERT lists 1 or 2) were recorded with a proportion very different among macrolides (11 to 89%). The highest percentage of fatal outcome was recorded for azithromycin (17%). Disproportionality was found for azithromycin, clarithromycin and telithromycin for both events of interest, whereas erithromycin showed disproportion only for TdP/QT abnormalities. Conclusions:Despite inherent limitations of spontaneous reporting analyses, the remarkable proportion of fatal cases and the occurrence of TdP-related events in middle-aged patients strengthen the view that caution is needed before considering azithromycin as a safer therapeutic option among macrolides. Before performing the analysis, several technical issues were handled with. This is the case for the drug mapping, duplicate removal and management of missing data [13]. Data of interest for the 2004-2011 period were collected from "DEMO" (demographic information), "DRUG", "REACTION" (adverse events coded according to the Medical Dictionary for Regulatory Activities terminology, MedDRA version 13.0) and "OUTCOME" files [14]. Macrolides and Torsadogenic Data analysisIn the light of the peculiar clinical setting in which TdP usually occurs (i.e., multi-factorial causative roles with different risk factors), a case listing was first generated in order to describe demographic information (e.g., age and sex) and concomitant drugs, which may act as potential confounders of the drug-event association by reducing the so-called "repolarization reserve" [15]. Specifically, each event of interest was assessed for co-administration of drugs with cardiovascular indications (i.e., Cla...

Erythromycin, QTc interval prolongation, and torsade de pointes: Case reports, major risk factors and illness severity

“…Moreover, whilst erythromycin showed disproportionality with respect to TdP/QT abnormalities, azithromycin and clarithryomycin showed disproportionality both with respect to TdP/QT abnormalities and for VA/SCD [Raschi et al 2013]. Notably, in this AERS analysis many cases of TdP/QT abnormalities with azithromycin occurred in middle-aged rather than elderly individuals, supporting the notion that azithromycin is not necessarily a safer macrolide option in generally healthy patients [Raschi et al 2013]. On the other hand, a separate analysis of a national Danish cohort of 1864 years of age failed to find an increased risk of death from cardiovascular causes with azithromycin use [Svanström et al 2013].…”

“…When VA and SCD were also taken into account, clarithromycin had a higher number of reports than azithromycin, with erythromycin having fewer reports than either other drug during this period [Raschi et al 2013]. Moreover, whilst erythromycin showed disproportionality with respect to TdP/QT abnormalities, azithromycin and clarithryomycin showed disproportionality both with respect to TdP/QT abnormalities and for VA/SCD [Raschi et al 2013]. Notably, in this AERS analysis many cases of TdP/QT abnormalities with azithromycin occurred in middle-aged rather than elderly individuals, supporting the notion that azithromycin is not necessarily a safer macrolide option in generally healthy patients [Raschi et al 2013].…”

“…Azithromycin has received a great deal of interest recently, however, following a high-profile study that showed a small but significantly increased risk of cardiovascular deaths during 5 days of azithromycin therapy [Ray et al 2012]. A recent data-mining study of the FDA AERS over the 8-year period from 2004 to 2011 [Raschi et al 2013] has reported more cases of TdP and QT interval abnormalities with azithromycin than for either clarithromycin or erythromycin. When VA and SCD were also taken into account, clarithromycin had a higher number of reports than azithromycin, with erythromycin having fewer reports than either other drug during this period [Raschi et al 2013].…”

“…A recent data-mining study of the FDA AERS over the 8-year period from 2004 to 2011 [Raschi et al 2013] has reported more cases of TdP and QT interval abnormalities with azithromycin than for either clarithromycin or erythromycin. When VA and SCD were also taken into account, clarithromycin had a higher number of reports than azithromycin, with erythromycin having fewer reports than either other drug during this period [Raschi et al 2013]. Moreover, whilst erythromycin showed disproportionality with respect to TdP/QT abnormalities, azithromycin and clarithryomycin showed disproportionality both with respect to TdP/QT abnormalities and for VA/SCD [Raschi et al 2013].…”