Fexofenadine: A New Nonsedating Antihistamine
By William T. Elliott, MD, and James Chan, PharmD, PhD
The fda has approved fexofenadine (allegra, Hoechst Marion Roussel), the active carboxylate derivative of terfenadine (Seldane), for the treatment of allergic rhinitis. The drug was developed by Sepracor, a company that specializes in developing drug analogs. The rights to the drug were then sold to Hoechst Marion Roussell (HMR), the company that holds the patent for terfenadine.
As opposed to terfenadine, fexofenadine does not carry the "black box" warning from the FDA. The warning was a result of QTc interval prolongation seen with terfenadine and the resultant cardiac arrhythmias seen in hepatic impairment or when the drug was given concomitantly with other drugs that inhibit terfenadine’s metabolism.
HMR is introducing fexofenadine at the same time that their patent on terfenadine is expiring. The FDA has also recently taken action to withdraw terfenadine from the market just weeks after the first generic was approved. HMR, while officially challenging the FDA’s action, is heavily marketing fexofenadine as a safer form of terfenadine.
Fexofenadine is indicated for the treatment of seasonal allergic rhinitis.
Fexofenadine is absorbed rapidly after oral administration with peak plasma levels reached within three hours. The elimination half-life is 14 hours, and it can be dosed twice daily. Data on the effectiveness of the drug is in abstract form only, but it does seem to be an effective inhibitor of peripheral H1 receptors.1,2
Fexofenadine (terfenadine carboxylate) is the major active metabolite of terfenadine, but it does not appear to share the cardiotoxic action of terfenadine based on in vitro studies.3,4 No statistically significant increase in mean QTc interval was observed in healthy subjects given fexofenadine up to 400 mg twice daily for six days.1 When fexofenadine, administered at twice the recommended dose (120 mg bid), was coadministered with erythromycin (500 mg qid) or ketoconazole (400 mg qd) under steady state conditions, no difference in adverse events or QTc interval were observed.
Like other nonsedating antihistamines, terfenadine, loratadine, and astemizole, fexofenadine does not generally cause somnolence at recommended doses.
While there does not appear to be a pharmacodynamic interaction with fexofenadine and erythromycin or ketoconazole, a significant pharmacokinetic interaction exists. The coadministration of fexofenadine and erythromycin or ketoconazole results in significant increases in steady state peak plasma levels (82% to 135%) and area under the plasma time curve (AUC; 109% to 164%). This is similar to the pharmacokinetic interaction observed with loratadine. The clinical relevance of this interaction is not known.
Fexofenadine is supplied in 60 mg capsules. The recommended dose is 60 mg twice a day. The dose should be reduced to once daily in patients with diminished renal function.
Fexofenadine is the major active metabolite of terfenadine, but, unlike terfenadine, it does not have the potential for prolonging the QTc interval. The twice daily dosing of fexofenadine permits creative dosing with fexofenadine in the morning and a traditional antihistamine at bedtime as well as dosing on an as-needed basis. Fexofenadine is currently the least costly nonsedating antihistamine.
Ironically, the introduction of fexofenadine may signal the end of terfenadine's availability, as the FDA explores the wisdom of keeping terfenadine on the market now that a safer alternative is available.
1. Allegra Product Information. Hoechst Marion Roussell, Inc.; July 1996.
2. Med Lett 1996;38:95-96.
3. Woosley RL, et al. JAMA 1993;269:1532-1536.
4. Woosley RL. Annu Rev Pharmacol Toxicol 1996;36:233-52.