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Allegra-D (Fexofenadine; Pseudoephedrine)
Fexofenadine; Pseudoephedrine
Allegra-D® | Allegra-D® 12 Hour | Allegra-D® 24 Hour
Classification:
Antihistamines
H1-blockers
Autonomic Agents
Sympathomimetics
Respiratory Agents
Adrenergic agonists
Description: Fexofenadine and pseudoephedrine are combined together in an oral preparation (Allegra-D®) used to relieve symptoms of seasonal allergic rhinitis. Fexofenadine is a nonsedating, selective peripheral H1-antagonist that dries nasal and sinus passages; it is the active metabolite of the antihistamine terfenadine. Both fexofenadine and terfenadine are non-sedating, however, 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. Pseudoephedrine is a sympathomimetic agent that causes vasoconstriction and decreases nasal and sinus congestion. Allegra-D® (60 mg fexofenadine and 120 mg pseudoephedrine) was approved by the FDA for twice daily administration on December 24, 1997. The FDA approved Allegra-D® 24-Hour, a once-daily formulation containing 180 mg fexofenadine and 240 mg pseudoephedrine, in 2004.
Mechanism of Action: Fexofenadine; pseudoephedrine is a combination product. Fexofenadine is an antihistamine and pseudoephedrine is a sympathomimetic agent.
Fexofenadine: 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. Fexofenadine is a metabolite of terfenadine which has been associated with QT prolongation and ventricular tachycardias (torsades de pointes). However, premarketing trials with fexofenadine have demonstrated no significant prolongation of the QT interval at doses of 60 - 240 mg twice daily in 900 patients or up to 400 mg twice daily in healthy subjects.
Pseudoephedrine: Pseudoephedrine is an agonist at both alpha- and, to a lesser degree, beta-adrenergic receptors. Like ephedrine, pseudoephedrine also has an indirect effect by releasing norepinephrine from its storage sites. By stimulating alpha-adrenergic receptors in the mucosa of the respiratory tract, pseudoephedrine shrinks swollen nasal mucous membranes; reduces tissue hyperemia, edema, and nasal congestion; and increases nasal airway patency. Also, drainage of sinus secretions is increased, and obstructed eustachian ostia may be opened. Oral administration of pseudoephedrine usually produces negligible effects on blood pressure. In some patients, especially those with preexisting cardiac disease receiving higher doses, pseudoephedrine may increase blood pressure or irritability of the heart muscle and may affect ventricular conduction.
Pharmacokinetics: The fexofenadine; pseudoephedrine product is administered orally. Allegra-D® is formulated to provide 60 mg of fexofenadine hydrochloride for immediate-release and 120 mg of pseudoephedrine hydrochloride for extended-release; Allegra-D® 24-Hour is formulated to provide 180 mg of fexofenadine hydrochloride for immediate-release and 240 mg of pseudoephedrine hydrochloride for extended-release. Coadministration of fexofenadine with pseudoephedrine has no effect on the bioavailability or pharmacokinetics of either drug. Coadministration of Allegra-D® or Allegra-D® 24-Hour brands of fexofenadine; pseudoephedrine with a high-fat meal significantly decreased fexofenadine plasma concentrations Cmax ( - 46%) and AUC ( - 42%). Time to maximum concentration (Tmax) was delayed by 50%. The rate or extent of pseudoephedrine absorption was not affected by food.
Fexofenadine: 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 (0.5 - 1.5% metabolized by CYP 3A4 isoenzymes), however, 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-D 24 Hour Extended Release Tablets(Tablet, Extended Release 180;240 mg;)
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 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.
Pseudoephedrine: Pseudoephedrine duration of action is dependent upon the dose and the extended release formulation (12 or 24 hours). Pseudoephedrine is presumed to cross the placenta, blood brain barrier, and may be distributed into breast milk. Pseudoephedrine is incompletely metabolized in the liver to norpseudoephedrine, the primary active metabolite of the parent. The drug and metabolite are excreted in the urine; with 55 - 75% excreted as unchanged drug. The elimination half-life of the drug ranges from 9 - 16 hours dependent primarily upon urinary pH. The rate of urinary excretion is accelerated upon urinary acidification to a pH near 5. Upon alkalization of the urine to a pH of approximately 8, some of the drug is reabsorbed into the kidney tubule and the rate of urinary excretion is slowed.
Renal impairment significantly reduces pseudoephedrine clearance. The effect of liver disease on pseudoephedrine pharmacokinetics is unknown. The effect of hemodialysis on the removal of pseudoephedrine is unknown.
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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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