Risk of QT prolongation and torsade de pointes associated with exposure to hydroxyzine: re‐evaluation of an established drug

Anne‐Françoise Schlit,Jürgen W G Bentz,Aurore Colomar,Luca Cariolato,Rossen Boev,Branderley Claudio,Annie Delaunois,Victor S Sloan,Jean‐Pierre Valentin,Christopher Peters

doi:10.1002/prp2.309

Anne‐Françoise Schlit, Jürgen W G Bentz + Show 8 more

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https://doi.org/10.1002/prp2.309

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Abstract

Several noncardiac drugs have been linked to cardiac safety concerns, highlighting the importance of post‐marketing surveillance and continued evaluation of the benefit‐risk of long‐established drugs. Here, we examine the risk of QT prolongation and/or torsade de pointes (TdP) associated with the use of hydroxyzine, a first generation sedating antihistamine. We have used a combined methodological approach to re‐evaluate the cardiac safety profile of hydroxyzine, including: (1) a full review of the sponsor pharmacovigilance safety database to examine real‐world data on the risk of QT prolongation and/or TdP associated with hydroxyzine use and (2) nonclinical electrophysiological studies to examine concentration‐dependent effects of hydroxyzine on a range of human cardiac ion channels. Based on a review of pharmacovigilance data between 14th December 1955 and 1st August 2016, we identified 59 reports of QT prolongation and/or TdP potentially linked to hydroxyzine use. Aside from intentional overdose, all cases involved underlying medical conditions or concomitant medications that constituted at least 1 additional risk factor for such events. The combination of cardiovascular disorders plus concomitant treatment of drugs known to induce arrhythmia was identified as the greatest combined risk factor. Parallel patch‐clamp studies demonstrated hydroxyzine concentration‐dependent inhibition of several human cardiac ion channels, including the ether‐a‐go‐go‐related gene (hERG) potassium ion channels. Results from this analysis support the listing of hydroxyzine as a drug with “conditional risk of TdP” and are in line with recommendations to limit hydroxyzine use in patients with known underlying risk factors for QT prolongation and/or TdP.

Highlights

A growing number of noncardiac drugs have been found to delay cardiac repolarization, causing QT interval prolongation1 and predisposing patients to an increased risk of potentially fatal ventricular arrhythmias, known as torsade de pointes (TdP)
It is only in recent years that non-clinical studies and post-marketing safety analyses have suggested a potential increased risk of QT interval prolongation and/or TdP associated with exposure to hydroxyzine (Acosta-Materan et al 2016; Redfern et al 2003; Valentin et al 2010)
A cumulative review of case reports from the sponsor pharmacovigilance safety database, using a narrow standard MedDRA query (SMQ) for QT prolongation and/or TdP, identified 59 case reports potentially linked to hydroxyzine treatment up to 1st August 2016, with an average reporting rate of 3.81 QT prolongation and/or TdP events/1,000,000 patient-years of exposure

Summary

Introduction

A growing number of noncardiac drugs have been found to delay cardiac repolarization, causing QT interval prolongation and predisposing patients to an increased risk of potentially fatal ventricular arrhythmias, known as torsade de pointes (TdP) Patients had an elevated baseline risk of QT prolongation, for example due to concomitant treatment with medications that potentially prolonged the QT interval (e.g., antiarrhythmics, antipsychotics), or the presence of underlying heart conditions (Yap and Camm 2003; Kannankeril et al 2010) These drugs include the second-generation, non-sedating antihistamines astemizole and terfenadine, withdrawn from the market in Europe and the United States (in 1997 and 1999, respectively) due to cardiac safety concerns (Kannankeril et al 2010; World Health Organization, 2011; Davila et al 2006)

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