Cardiac safety of second‐generation H1‐antihistamines when updosed in chronic spontaneous urticaria

Abstract The symptoms of chronic urticaria, be it chronic spontaneous urticaria ( CSU ) or chronic inducible urticaria (CindU), are mediated primarily by the actions of histamine on H 1 receptors located on endothelial cells (the weal) and on sensory nerves (neurogenic flare and pruritus). Thus, second‐generation H 1 antihistamines (sg AH s) are the primary treatment of these conditions. However, many patients are poorly responsive to licensed doses of antihistamines. In these patients, the current EAACI / GA 2 LEN / EDF / WAO guideline for urticaria suggests updosing of sg AH s up to fourfold. However, such updosing is off‐label and the responsibility resides with the prescribing physician. Therefore, the safety of the drug when used above its licensed dose is of paramount importance. An important aspect of safety is potential cardiotoxicity. This problem was initially identified some 20 years ago with cardiotoxic deaths occurring with astemizole and terfenadine, two early sg AH s. In this review, we discuss the mechanisms and assessments of potential cardiotoxicity of H 1 antihistamines when updosed to four times their licensed dose. In particular, we have focused on the potential of H 1 antihistamines to block hERG (human Ether‐a‐go‐go‐Related Gene) voltage‐gated K + channels, also known as Kv11.1 channels according to the IUPHAR classification. Blockade of these channels causes QT prolongation leading to torsade de pointes that may possibly degenerate into ventricular fibrillation and sudden death. We considered in detail bilastine, cetirizine, levocetirizine, ebastine, fexofenadine, loratadine, desloratadine, mizolastine and rupatadine and concluded that all these drugs have an excellent safety profile with no evidence of cardiotoxicity even when updosed up to four times their standard licensed dose, provided that the prescribers carefully consider and rule out potential risk factors for cardiotoxicity, such as the presence of inherited long QT syndrome, older age, cardiovascular disorders, hypokalemia and hypomagnesemia, or the use of drugs that either have direct QT prolonging effects or inhibit sg AH metabolism.