The Value of a Broad Therapeutic Index for Antihistamines*

The therapeutic index of a histamine-1 (H1)antihistamine is the benefit-to-risk ratio of the medication and defines the range of doses and plasma concentrations over which the drug is effective and safe. In allergic rhinoconjunctivitis and urticaria, although the efficacy profiles of currently available H1-antihistamines are similar, these agents differ greatly with regard to safety, and this contributes to their different therapeutic indices. Compared with their first-generation predecessors, the orally administered second-generation H1-antihistamines such as cetirizine, desloratadine, fexofenadine, levocetirizine, and loratadine have fewer central nervous system (CNS) adverse effects. However, differences exist among second-generation H1-antihistamines in terms of their effect on the CNS, with some agents having potential for dose-related CNS effects when the manufacturer’s recommended dose is exceeded. Similarly, in terms of cardiac safety, although all currently marketed H1-antihistamines are safer than astemizole or terfenadine, some of the medications in this class may be more likely than others to cause cardiac toxicity under certain circumstances. A broad therapeutic index is important not only when considering the potential effects of concomitant administration of medications, herbal products, and foods on the H1-antihistamine bioavailability and efficacy, but also because patients may spontaneously increase their H1-antihistamine dose in order to obtain symptom relief. Fexofenadine is an example of an H1-antihistamine that has a broad therapeutic index beyond the manufacturer’s recommended doses of 120 mg or 180 mg once daily. Fexofenadine has been shown to be effective at doses as low as 20 mg twice daily and to not cause sedation or cardiac toxicity at doses as high as 690 mg twice daily. (Advanced Studies in Medicine. 2002;2(24):872-876)