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

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.