Cardiovascular Pharmacology
Cardiovascular Safety of FexofenadineHCl

https://doi.org/10.1016/S0002-9149(99)00124-1Get rights and content

Abstract

Fexofenadine HCl is the acid metabolite of terfenadine (Seldane). The effect of this recently approved nonsedating antihistamine on the corrected QT interval (QTc) was evaluated in dose-tolerance, safety, and drug-interaction studies with healthy volunteers, and in clinical studies in patients with seasonal allergic rhinitis (SAR). Twelve-lead electrocardiographic data were collected once before and after dosing or serially throughout these studies. Outliers were defined as QTc >440 ms with a ≥10 ms increase from baseline. The recommended fexofenadine HCl dose is 60 mg twice daily. Fexofenadine HCl doses up to 800 mg once daily or 690 mg twice daily for 28 days resulted in no dose-related increases in QTc. Longer term studies indicated no statistically significant QTc increases compared with placebo in patients receiving fexofenadine HCl 80 mg twice daily for 3 months, 60 mg twice daily for 6 months, or 240 mg once daily for 12 months. Interaction studies showed no significant increases in QTc when fexofenadine HCl 120 mg twice daily was administered in combination with erythromycin (500 mg 3 times daily) or ketoconazole (400 mg once daily) after dosing to steady state (6.5 days). Clinical trials in patients with SAR (n = 1,160) treated with 40, 60, 120, or 240 mg twice-daily fexofenadine HCl or placebo indicated no dose-related increases in QTc and no statistically significant increases in mean QTc compared with placebo. In controlled trials with approximately 6,000 persons, no case of fexofenadine-associated torsades de pointes was observed. The frequency and magnitude of QTc outliers were similar between fexofenadine HCl and placebo in all studies. Based on a large clinical database, we conclude that fexofenadine HCl has no significant effect on QTc, even at doses >10-fold higher than that is efficacious for SAR.

Section snippets

Methods

To avoid inter-reader variability, all electrocardiographs were read by a single cardiologist, who was blinded to the treatment assignment. The electrocardiographs were analyzed by RR and QT intervals by means of a standard, automated process. All QTc measurements were made on ≥3 successive QTc intervals, and a cycle was measured on the corresponding RR intervals. In general, the QTc measurements were made in lead II; however, occasionally another appropriate lead was selected if lead II was

Clinical trials in patients with seasonal allergic rhinitis

Two double-blind, randomized, 2-week placebo-controlled parallel studies were conducted with a total of 1,160 patients (870 received fexofenadine HCl and 290 received placebo) with SAR symptoms (Table I). 11, 12 Doses of 40, 60, 120, and 240 mg fexofenadine HCl twice daily were compared with placebo for a dosing period of 2 weeks. Electrocardiographs were collected before randomization and at 1 to 3 hours following the final dose, when plasma levels of fexofenadine were expected to be highest.

Discussion

Extensive electrocardiographic data from >2,100 patients who received fexofenadine HCl or placebo in controlled clinical trials demonstrates that fexofenadine does not increase QTc even when administered long-term in doses 10-fold that of the recommended dosage (60 mg twice daily). Moreover, no case of torsade de pointes ventricular tachycardia was observed in approximately 6,000 patients who received fexofenadine during clinical development of the drug.

The risk factor for ventricular

Acknowledgements

The authors thank Sheila Owens for assistance in the development of this manuscript.

References (23)

  • Hoechst Marion Roussel, Inc. Seldane. Physicians Desk Reference, Montvale NJ....
  • Cited by (86)

    • Treatment of chronic spontaneous urticaria: Immunomodulatory approaches

      2018, Clinical Immunology
      Citation Excerpt :

      However, rupatadine seems to be more effective than cetirizine [34], while levocetirizine seems to be more effective than rupatadine in another study [35]. There are studies showing the benefit and safety of increasing up to 4 times conventional doses of bilastine (20 mg), desloratadine (5 mg), levocetirizine (5 mg), fexofenadine (180 mg) in difficult-to-treat CU [36–41]. Concerning rupatadine (10 mg), one study showed safety of increasing up to 4 times the conventional doses [42] but the real benefit could only be proved in CU when increasing up to 2 times conventional doses [43].

    • A new cytochrome P450 belonging to the 107L subfamily is responsible for the efficient hydroxylation of the drug terfenadine by Streptomyces platensis

      2011, Archives of Biochemistry and Biophysics
      Citation Excerpt :

      Hydroxyterfenadine undergoes subsequent CYP2J2-dependent oxidation into the corresponding carboxylic acid, fexofenadine, the active metabolite. The prodrug terfenadine was superseded by fexofenadine several years ago, because of the cardiotoxicity of terfenadine at high doses [9]. However, despite structural similarities of these two compounds, the synthetic route used to prepare terfenadine was found to be poorly efficient for fexofenadine synthesis and gave very low yields (<10%) [10–12].

    View all citing articles on Scopus
    View full text