Non-sedating H1-blockers
Description: Fexofenadine is an H1-receptor antagonist. It is the active metabolite of another H1-antagonist, terfenadine. Both fexofenadine and terfenadine are non-sedating, however, unlike terfenadine, fexofenadine does not cause QT prolongation when given in doses up to 800 mg/day or when administered concomitantly with ketoconazole or erythromycin. However, one case report documented ventricular tachycardia associated with QT prolongation during fexofenadine therapy in a patient with a history of prolonged QT interval. Fexofenadine was first approved by the FDA in July 25, 1996 for the treatment of seasonal allergic rhinitis in adults and children 12 years and older. The drug received subsequent approval for children as young as 6 years old in February 2000. The development and submission of Allegra™ to the FDA was completed in 2.8 years, compared to the industry average of 14 years. In France and the UK, the trade name is Telfast. Fexofenadine was approved for the treatment of chronic idiopathic urticaria in adults and children aged 6 and older in February 2000.
Mechanism of Action: Similar to other H1-blockers, fexofenadine does not prevent the release of histamine as do cromolyn and nedocromil, but competes with free histamine for binding at the H1-receptor. This competitive antagonism blocks the effects of histamine on H1-receptors in the GI tract, uterus, large blood vessels, and bronchial smooth muscle. Blockade of H1-receptors also suppresses the formation of edema, flare, and pruritus that result from histaminic activity. At higher concentrations, H1-receptor antagonism becomes relatively irreversible. Fexofenadine is lipophilic compared to first generation antihistamines and does not readily cross the blood-brain barrier. CNS depression is minimal compared with other H1-antagonists. Although fexofenadine is a metabolite of terfenadine which has been associated with QT prolongation and ventricular tachycardias (torsades de pointes), pre-marketing trials with fexofenadine demonstrated no significant prolongation of the QT interval; doses up to 800 mg/day have been studied.
Pharmacokinetics: Fexofenadine is administered orally and is rapidly absorbed (peak in 2 - 3 hours). The absolute bioavailability of fexofenadine is unknown. The onset of antihistamine effectiveness (evaluated by wheal and flare studies) is about 1 hour and persists for up to 12 hours. Protein binding ranges from 60 - 70%; fexofenadine is primarily bound to albumin and alpha1-acid glycoprotein. Based on radiolabeled studies, approximately 80% and 11% of a dose was recovered in the feces and urine, respectively. Approximately 5% of the total administered dose is metabolized. Because the absolute bioavailability has not been determined, it is unknown if the fecal component represents unabsorbed drug or biliary excretion of the drug. Therefore, it is unknown if either renal excretion and/or metabolism plays a significant role in systemic drug elimination. The mean elimination half-life is approximately 14.4 hours in normal volunteers receiving 60 mg twice daily.
Allegra Capsules(Cap 60 mg) 
Special Populations: The pharmacokinetics of fexofenadine is altered by renal disease and age, but not hepatic disease or gender. Peak plasma concentrations were 87% and 111% greater in patients with mild (CrCl 41 - 80 ml/min) to severe (CrCl 11 - 40 ml/min) renal impairment, respectively. Mean elimination half-lives were 59% and 72% longer, respectively, than in normal volunteers. Peak plasma concentrations in dialysis patients (CrCl <= 10 ml/min) were 82% greater and half-life was 31% longer than in normal volunteers. The effect of hemodialysis on the removal of fexofenadine is unknown. Hemodialysis did not effectively remove fexofenadine from blood (up to 1.7% removed) following terfenadine oral administration. In older subjects (> 65 years old), peak plasma levels of fexofenadine were 99% greater than those observed in younger subjects (< 65 years old). Mean elimination half-lives were similar to those observed in younger subjects. The AUC of fexofenadine following a 60 mg oral dose is 56% higher in children aged 7 - 12 years than for adults. Relative to adults receiving a 60 mg dose, fexofenadine plasma exposure is similar in children receiving a 30 mg dose of fexofenadine. The pharmacokinetics of fexofenadine hydrochloride in patients with hepatic disease did not differ substantially from that observed in healthy subjects. No clinically significant gender-related differences were observed in the pharmacokinetics of fexofenadine.
References
. Giraud T. QT lengthening and arrhythmias associated with fexofenadine. Lancet 1999;353:2072 - 3.
[ Revised 1/4/2006 10:06:00 PM ]
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