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 H1 receptors located on endothelial cells (the weal) and on sensory nerves (neurogenic flare and pruritus). Thus, second‐generation H1 antihistamines (sgAHs) are the primary treatment of these conditions. However, many patients are poorly responsive to licensed doses of antihistamines. In these patients, the current EAACI/GA2LEN/EDF/WAO guideline for urticaria suggests updosing of sgAHs 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 sgAHs. In this review, we discuss the mechanisms and assessments of potential cardiotoxicity of H1 antihistamines when updosed to four times their licensed dose. In particular, we have focused on the potential of H1 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 sgAH metabolism.

Bilastine: a lifetime companion for the treatment of allergies

“…In contrast, cetirizine 10 mg increased the number of errors at ground level and, at the simulated altitude (4000 m), additional impairment was observed in cetirizine 10 mg recipients in a distributive attention test 56 . Bilastine has no significant effect on QTc interval 58,59 , and there is no evidence of cardiotoxicity even when updosed up to four times the standard licensed dose 60 . Based on the European Medicines Agency (EMA) periodic safety update report of post-marketing activity, a cumulative review of hypersensitivity reactions was performed for bilastine.…”

The clinical evidence of second-generation H1-antihistamines in the treatment of allergic rhinitis and urticaria in children over 2 years with a special focus on rupatadine

“…Therefore, concomitant administration of rupatadine with known CYP3A4 inhibitors (e.g. grapefruit, ketoconazole, erythromycin) is not recommended [51][52][53][54][55][56][57][58][59][60][61]. In contrast, no clinically relevant changes in plasma levels were observed when rupatadine and azithromycin were coadministered [57].…”

“…Systemic exposure to rupatadine after food intake increased by 23% compared with that under fasting conditions and Tmax was delayed by 1 hour, but exposure to its metabolites remained unaffected. These changes did not show clinical consequences, and therefore, rupatadine can be administered with or without food [16,17,[51][52][53][54][55][56][57][58][59][60][61].…”

The efficacy and safety of compound glycyrrhizin combined with desloratadine in the treatment of chronic urticaria: protocol for a systematic review of randomized controlled trials

“…[1] The most commonly used drug is the second-generation H1 receptor antagonist, which can control the occurrence of CU during clinical use. Mauro Cataldi et al [7] considered in detail Second-Generation H1-Antihistamines such as cetirizine, ebastine, fexofenadine, loratadine, desloratadine, mizolastine, and rupatadine and concluded that all these drugs have an excellent safety pro le with no evidence of cardiotoxicity even when updated up to four times their standard licensed dose. [7] The main option in therapies aimed at symptomatic relief is to reduce the effect of mast cell mediators such as histamine, PAF, and others on the target organs.…”

“…Mauro Cataldi et al [7] considered in detail Second-Generation H1-Antihistamines such as cetirizine, ebastine, fexofenadine, loratadine, desloratadine, mizolastine, and rupatadine and concluded that all these drugs have an excellent safety pro le with no evidence of cardiotoxicity even when updated up to four times their standard licensed dose. [7] The main option in therapies aimed at symptomatic relief is to reduce the effect of mast cell mediators such as histamine, PAF, and others on the target organs. Many symptoms of urticaria are mediated primarily by the actions of histamine on H1-receptors located on endothelial cells and on sensory nerves.…”