Mechanism of Action

Fexofenadine hydrochloride, the major active metabolite of terfenadine, is an antihistamine with selective peripheral H1-receptor antagonist activity. Fexofenadine hydrochloride inhibited antigen-induced bronchospasm in sensitized guinea pigs and histamine release from peritoneal mast cells in rats. In laboratory animals, no anticholinergic or alpha1-adrenergic-receptor blocking effects were observed. Moreover, no sedative or other central nervous system effects were observed. Radiolabeled tissue distribution studies in rats indicated that fexofenadine does not cross the blood-brain barrier.

Pseudoephedrine hydrochloride is an orally active sympathomimetic amine and exerts a decongestant action on the nasal mucosa. Pseudoephedrine hydrochloride is recognized as an effective agent for the relief of nasal congestion due to allergic rhinitis. Pseudoephedrine produces peripheral effects similar to those of ephedrine and central effects similar to, but less intense than, amphetamines. It has the potential for excitatory side effects.

Pharmacokinetics

The pharmacokinetics of fexofenadine hydrochloride in subjects with seasonal allergic rhinitis were similar to those in healthy volunteers.

Absorption

Fexofenadine hydrochloride and pseudoephedrine hydrochloride administered as ALLEGRA-D 24 HOUR tablets are absorbed at a similar rate and are equally available under single-dose and steady-state conditions as the separate administration of the components. Coadministration of fexofenadine and pseudoephedrine does not significantly affect the bioavailability of either component. The administration of ALLEGRA-D 24 HOUR tablets 30 minutes or 1.5 hour after a high-fat meal decreased the bioavailability of fexofenadine by approximately 50% (AUC 42% and Cmax 54%). Pseudoephedrine pharmacokinetics were unaffected when coadministered with a high-fat meal. Therefore, ALLEGRA-D 24 HOUR should be taken on an empty stomach with water (See DOSAGE AND ADMINISTRATION).

A pharmacokinetic study following single and multiple oral doses over 7 days of ALLEGRA-D 24 HOUR in 66 healthy volunteers showed that fexofenadine, the immediate release component of ALLEGRA-D 24 HOUR, was rapidly absorbed with mean maximum plasma concentrations of 634 ng/mL and 674 ng/mL after single and multiple doses, respectively. The median time to maximum concentration of fexofenadine was 1.8-2.0 hours post-dose. In the same study, the mean maximum plasma concentrations of pseudoephedrine, the extended-release component of ALLEGRA-D 24 HOUR, were 394 ng/mL and 495 ng/mL after single and multiple doses, respectively, with median time to maximum concentration of 12 hours post-dose. Pseudoephedrine concentrations at the end of the dosing interval (mean: 172 ng/mL) at steady state were equivalent to those observed from a comparator pseudoephedrine hydrochloride 240 mg tablet.

Distribution

Fexofenadine hydrochloride is 60% to 70% bound to plasma proteins, primarily albumin and α1- acid glycoprotein. The protein binding of pseudoephedrine in humans is not known. Pseudoephedrine hydrochloride is extensively distributed into extravascular sites (apparent volume of distribution between 2.6 and 3.5 L/kg).

Metabolism

Approximately 5% of the total dose of fexofenadine hydrochloride and less than 1% of the total oral dose of pseudoephedrine hydrochloride were eliminated by hepatic metabolism.

Elimination

The mean terminal elimination half-life of fexofenadine was 14.6 hours following administration of ALLEGRA-D 24 HOUR tablets in healthy volunteers, which is consistent with observations from separate administration. Human mass balance studies documented a recovery of approximately 80% and 11% of the [¹⁴C]-fexofenadine hydrochloride dose in the feces and urine, respectively. Because the absolute bioavailability of fexofenadine hydrochloride has not been established, it is unknown if the fecal component is primarily unabsorbed drug or the result of biliary excretion. The mean terminal half-life of pseudoephedrine was 7 hours following single- dose administration of ALLEGRA-D 24 HOUR tablets.

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