Allegra D-12 Hour

ALLEGRA D-12 HOUR- fexofenadine hydrochloride and pseudoephedrine hydrochloride tablet, extended release
sanofi-aventis U.S. LLC

DESCRIPTION

ALLEGRA-D® 12 HOUR (fexofenadine hydrochloride and pseudoephedrine hydrochloride) Extended-Release Tablets for oral administration contain 60 mg fexofenadine hydrochloride for immediate release and 120 mg pseudoephedrine hydrochloride for extended release. Tablets also contain as excipients: microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, magnesium stearate, carnauba wax, stearic acid, silicon dioxide, hypromellose and polyethylene glycol.

Fexofenadine hydrochloride, one of the active ingredients of ALLEGRA-D 12 HOUR, is a histamine H1 -receptor antagonist with the chemical name (±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethyl benzeneacetic acid hydrochloride and the following chemical structure:

Chemical Structure
(click image for full-size original)

The molecular weight is 538.13 and the empirical formula is C32 H39 NO4 •HCl. Fexofenadine hydrochloride is a white to off-white crystalline powder. It is freely soluble in methanol and ethanol, slightly soluble in chloroform and water, and insoluble in hexane. Fexofenadine hydrochloride is a racemate and exists as a zwitterion in aqueous media at physiological pH.

Pseudoephedrine hydrochloride, the other active ingredient of ALLEGRA-D 12 HOUR, is an adrenergic (vasoconstrictor) agent with the chemical name [S-(R*,R*)]-α-[1-(methylamino)ethyl]-benzenemethanol hydrochloride and the following chemical structure:

Chemical Structure

The molecular weight is 201.70. The molecular formula is C10 H15 NO•HCl. Pseudoephedrine hydrochloride occurs as fine, white to off-white crystals or powder, having a faint characteristic odor. It is very soluble in water, freely soluble in alcohol, and sparingly soluble in chloroform.

CLINICAL PHARMACOLOGY

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. At the recommended oral dose, it has little or no pressor effect in normotensive adults.

Pharmacokinetics

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

Absorption

The pharmacokinetics of fexofenadine hydrochloride and pseudoephedrine hydrochloride when administered separately have been well characterized. Fexofenadine pharmacokinetics were linear for oral doses of fexofenadine hydrochloride up to a total daily dose of 240 mg (120 mg twice daily). Peak fexofenadine plasma concentrations were similar between adolescent (12–16 years of age) and adult subjects.

The bioavailability of fexofenadine hydrochloride and pseudoephedrine hydrochloride from ALLEGRA-D 12 HOUR Extended-Release Tablets is similar to that achieved with separate administration of the components. Coadministration of fexofenadine and pseudoephedrine does not significantly affect the bioavailability of either component.

Fexofenadine hydrochloride was rapidly absorbed following single-dose administration of the 60 mg fexofenadine hydrochloride/120 mg pseudoephedrine hydrochloride tablet with median time to mean maximum fexofenadine plasma concentration of 191 ng/mL occurring 2 hours post-dose. Pseudoephedrine hydrochloride produced a mean single-dose pseudoephedrine peak plasma concentration of 206 ng/mL which occurred 6 hours post-dose. Following multiple dosing to steady-state, a fexofenadine peak concentration of 255 ng/mL was observed 2 hours post-dose. Following multiple dosing to steady-state, a pseudoephedrine peak concentration of 411 ng/mL was observed 5 hours post-dose. The administration of ALLEGRA-D 12 HOUR with a high fat meal decreased the bioavailability of fexofenadine by approximately 50% (AUC 42% and Cmax 46%). Time to maximum concentration (Tmax ) was delayed by 50%. The rate or extent of pseudoephedrine absorption was not affected by food. Therefore, ALLEGRA-D 12 HOUR should be taken on an empty stomach with water (see DOSAGE AND ADMINISTRATION).

Distribution

Fexofenadine 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 elimination half-life of fexofenadine was 14.4 hours following administration of 60 mg fexofenadine hydrochloride, twice daily, to steady-state in healthy volunteers. Human mass balance studies documented a recovery of approximately 80% and 11% of the [14 C] 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.

Pseudoephedrine has been shown to have a mean elimination half-life of 4–6 hours which is dependent on urine pH. The elimination half-life is decreased at urine pH lower than 6 and may be increased at urine pH higher than 8.

Special Populations

Pharmacokinetics in special populations (for renal, hepatic impairment, and age), obtained after a single dose of 80 mg fexofenadine hydrochloride, were compared to those from healthy subjects in a separate study of similar design.

Effect of Age

In older subjects (≥65 years old), peak plasma levels of fexofenadine were 99% greater than those observed in younger subjects (<65 years old). Mean fexofenadine elimination half-lives were similar to those observed in younger subjects.

Renally Impaired

In subjects with mild (creatinine clearance 41–80 mL/min) to severe (creatinine clearance 11–40 mL/min) renal impairment, peak plasma levels of fexofenadine were 87% and 111% greater, respectively, and mean elimination half-lives were 59% and 72% longer, respectively, than observed in healthy volunteers. Peak plasma levels in subjects on dialysis (creatinine clearance ≤10 mL/min) were 82% greater and half-life was 31% longer than observed in healthy volunteers.

No data are available on the pharmacokinetics of pseudoephedrine in renally-impaired subjects. However, most of the oral dose of pseudoephedrine hydrochloride (43–96%) is excreted unchanged in the urine. A decrease in renal function is, therefore, likely to decrease the clearance of pseudoephedrine significantly, thus prolonging the half-life and resulting in accumulation.

Based on increases in bioavailability and half-life of fexofenadine hydrochloride and pseudoephedrine hydrochloride, a dose of one tablet once daily is recommended as the starting dose in patients with decreased renal function (see DOSAGE AND ADMINISTRATION).

Hepatically Impaired

The pharmacokinetics of fexofenadine hydrochloride in subjects with hepatic disease did not differ substantially from that observed in healthy volunteers. The effect on pseudoephedrine pharmacokinetics is unknown.

Effect of Gender

Across several trials, no clinically significant gender-related differences were observed in the pharmacokinetics of fexofenadine hydrochloride.

Pharmacodynamics

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