key: cord-0960213-njq5pc58
authors: Sarayani, Amir; Cicali, Brian; Henriksen, Carl H.; Brown, Joshua D.
title: Safety signals for QT prolongation or Torsades de Pointes associated with azithromycin with or without chloroquine or hydroxychloroquine
date: 2020-04-19
journal: Res Social Adm Pharm
DOI: 10.1016/j.sapharm.2020.04.016
sha: 4fa9614e16685e241014d6cfa748576eb83ff777
doc_id: 960213
cord_uid: njq5pc58

Abstract Background Combinations of hydroxychloroquine (HCQ) and azithromycin have been promoted as treatments for COVID-19 based on small, uncontrolled clinical trials that have not assessed potential risks. Risks of treatment include QT segment prolongation, Torsades de Pointes (TdP), and death. This comparative pharmacovigilance analysis evaluated the risk of these events. Methods Data from the U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) (>13 million total reports) were used. Queries extracted reports based on exposures of HCQ/chloroquine (CQ) alone, azithromycin alone, HCQ/CQ + azithromycin, amoxicillin alone, HCQ/CQ + amoxicillin alone. Amoxicillin served as a control. Events of interest included death and TdP/QT prolongation as well as accidents/injuries and depression as control events. Proportional Reporting Ratios (PRR) and 95% confidence intervals (CI) were calculated where a lower limit of the of 95% CI (Lower95CI) value of ≥2.0 is interpreted as a potential safety signal. Results Lower95CIs for HCQ/CQ alone showed no potential safety signals for TdP/QT prolongation, death, or any of the control events included. The PRRs and 95% CIs for TdP/QT prolongation was 1.43 (1.29–2.59) with HCQ/CQ use alone and 4.10 (3.80–4.42) for azithromycin alone. For the combined HCQ/CQ + azithromycin group, the PRR and 95% CI was 3.77 (1.80–7.87). For the control of amoxicillin, there were no safety signals when used alone or in combination with HCQ/CQ. Conclusions HCQ/CQ use was not associated with a safety signal in this analysis of FAERS data. However, azithromycin used alone was associated with TdP/QT prolongation events and should be used with caution.

Background: Combinations of hydroxychloroquine (HCQ) and azithromycin have been 7 promoted as treatments for COVID-19 based on small, uncontrolled clinical trials that have not 8 assessed potential risks. Risks of treatment include QT segment prolongation, Torsades de 9

Pointes (TdP), and death. This comparative pharmacovigilance analysis evaluated the risk of 10 these events. and TdP/QT prolongation as well as accidents/injuries and depression as control events. 16

Proportional Reporting Ratios (PRR) and 95% confidence intervals (CI) were calculated where a 17 lower limit of the of 95% CI (Lower95CI) value of ≥2.0 is interpreted as a potential safety signal. Hydroxychloroquine (HCQ) has been promoted as a potential treatment for severe acute 33 respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its presentation as COVID-19 34 disease. 1,2 HCQ has several possible mechanisms of action that may promote its use as an 35 antiviral against SARS-CoV-2 via reductions in virus entry and replication as well as 36 immunosuppressive effects to mitigate cytokine storm in severe disease. immunosuppressive activity in in-vitro studies, 6,7 which has led to widespread but so far 46 unfounded claims not only for treatment but also for prevention. Medical professionals have 47 cautioned against concomitant use due to a lack of evidence and safety concerns. These safety 48 concerns have primarily centered on the risk of drug-induced QT interval prolongation, which 49 can lead to tachycardias such as Torsades de Pointes (TdP) and sudden cardiac death. 8 50 51 Risk of QT prolongation and TdP has been reported for both HCQ/CQ and azithromycin when 52 used alone. 9,10 However, whether or not the combined use of these medications could lead to 53 additive or synergistic effects on QT prolongation is unknown. In the absence of direct safety 54 data for COVID-19 patients, the purpose of this analysis was to assess the disproportionality in 55 reporting of TdP and QT prolongation for these medications when used alone and in 56 combination. 57 for each study drug are reported in Table 1 . Lower95CIs for HCQ/CQ alone showed no potential 99 safety signals for TdP/QT prolongation, death, or any of the control events included (Table 2) . In an analysis of FAERS adverse drug event reports, HCQ/CQ appeared not to be associated 149 with a safety signal related to TdP/QT prolongation when used alone. Azithromycin alone or 150 when used with HCQ/CQ was associated with a potential safety signal. From the perspective of 151 this specific adverse drug event, HCQ/CQ use appears to be relatively safe, but further 152 evidence is needed to affirm its effectiveness for COVID-19 and SARS-CoV-2 infection. 153 

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