Cardiac Safety of Intranasal Chlorpheniramine: An Exposure-Based Risk Assessment

Background: H1-antihistamines are widely used for allergic and upper respiratory conditions; however, several agents included in this class have been associated with cardiac electrophysiological adverse effects, including QT interval prolongation and torsades de pointes (TdP). These effects are largely exposure-dependent and mechanistically linked to inhibition of cardiac ion channels. Chlorpheniramine maleate (CPM), a first-generation H1-antihistamine, has been implicated in arrhythmic events primarily under conditions of increased systemic exposure, prompting interest in whether alternative routes of administration may lower cardiac risk. Methods: This narrative review integrates mechanistic, preclinical, clinical, pharmacokinetic, and regulatory evidence. Information was extracted from PubMed, Google Scholar, and Scielo using search terms such as cardiotoxicity, chlorpheniramine, QT prolongation, intranasal administration, and cardiac arrhythmias, with no language restriction. Results: Comparative pharmacokinetic evidence shows that, on a dose-normalized basis, intranasal and oral chlorpheniramine exhibit comparable bioavailability; however, in a clinical context, intranasal doses (1.12-2.24 mg) are lower than oral daily doses (4-12 mg/day), resulting in a lower systemic exposure (Cmax and AUC) with intranasal administration. Available pharmacovigilance or epidemiological data have not specifically evaluated intranasal chlorpheniramine, and the number of dedicated safety trials remains limited. Conclusions: Preclinical, in vitro, mechanistic studies suggest that intranasal administration of chlorpheniramine should confer superior cardiac safety compared to the oral route. However, clinical data from human studies directly comparing the cardiac safety of intranasal chlorpheniramine versus systemic chlorpheniramine is extremely limited. More data from clinical trials, case-control studies, and regulatory databases are needed to validate these theoretical claims.