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.
The pharmacokinetics of fexofenadine hydrochloride in subjects with seasonal allergic rhinitis were similar to those in healthy volunteers.
Fexofenadine hydrochloride and pseudoephedrine hydrochloride administered as
ALLEGRA-D 24 HOUR (fexofenadine hcl 180 and pseudoephendrine hcl 240) 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 (fexofenadine hcl 180 and pseudoephendrine hcl 240) 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 (fexofenadine hcl 180 and pseudoephendrine hcl 240) in 66 healthy volunteers showed that fexofenadine, the
immediate release component of ALLEGRA-D 24 HOUR (fexofenadine hcl 180 and pseudoephendrine hcl 240) , 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 (fexofenadine hcl 180 and pseudoephendrine hcl 240) , 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.
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).
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.
The mean terminal elimination half-life of fexofenadine was 14.6 hours following
administration of ALLEGRA-D 24 HOUR (fexofenadine hcl 180 and pseudoephendrine hcl 240) 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 (fexofenadine hcl 180 and pseudoephendrine hcl 240) tablets.
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.
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 volunteers 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. (See PRECAUTIONS and 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.
Wheal and Flare. Human histamine skin wheal and flare studies following single and twice daily doses of 20 mg and 40 mg fexofenadine hydrochloride demonstrated that the drug exhibits an antihistamine effect by 1 hour, achieves maximum effect at 2-3 hours, and an effect is still seen at 12 hours. There was no evidence of tolerance to these effects after 28 days of dosing. The clinical significance of these observations is unknown.
Effects on QTc. In dogs (30 mg/kg orally twice daily for 5 days) and
rabbits (10 mg/kg intravenously over 1 hour), fexofenadine hydrochloride did
not prolong QTc at plasma concentrations that were at least 7 and 15 times,
respectively, the therapeutic plasma concentrations in man (based on a 180 mg
once daily fexofenadine hydrochloride dose when administered as ALLEGRA-D 24
HOUR). No effect was observed on calcium channel current, delayed K+
channel current, or action potential duration in guinea pig myocytes, Na+
current in rat neonatal myocytes, or on the delayed rectifier K+
channel cloned from human heart at concentrations up to 1 x 10-5
M of fexofenadine. This concentration was at least 8 times the therapeutic plasma
concentration in man (based on a 180 mg once daily fexofenadine hydrochloride
No statistically significant increase in mean QTc interval compared to placebo was observed in 714 subjects with seasonal allergic rhinitis given fexofenadine hydrochloride capsules in doses of 60 mg to 240 mg twice daily for 2 weeks or in 40 healthy volunteers given fexofenadine hydrochloride as an oral solution at doses up to 400 mg twice daily for 6 days.
A 1-year study designed to evaluate safety and tolerability of 240 mg of fexofenadine hydrochloride (n=240) compared to placebo (n=237) in healthy volunteers, did not reveal a statistically significant increase in the mean QTc interval for the fexofenadine hydrochloride treated group when evaluated pretreatment and after 1, 2, 3, 6, 9, and 12 months of treatment.
Administration of the 60 mg fexofenadine hydrochloride/120 mg pseudoephedrine
hydrochloride combination tablet for approximately 2 weeks to 213 subjects with
seasonal allergic rhinitis demonstrated no statistically significant increase
in the mean QTc interval compared to fexofenadine hydrochloride administered
alone (60 mg twice daily, n=215), or compared to pseudoephedrine hydrochloride
(120 mg twice daily, n=215) administered alone.
Clinical efficacy and safety studies were not conducted with ALLEGRA-D 24 HOUR (fexofenadine hcl 180 and pseudoephendrine hcl 240) Extended-Release Tablets. The effectiveness of ALLEGRA-D 24 HOUR (fexofenadine hcl 180 and pseudoephendrine hcl 240) for the treatment of seasonal allergic rhinitis is based on an extrapolation of the demonstrated efficacy of ALLEGRA 180 mg and the nasal decongestant properties of pseudoephedrine hydrochloride.
In one 2-week, multicenter, randomized, double-blind clinical trial in subjects 12 to 65 years of age with seasonal allergic rhinitis (n=863), fexofenadine hydrochloride 180 mg once daily significantly reduced total symptom scores (the sum of the individual scores for sneezing, rhinorrhea, itchy nose/palate/throat, itchy/watery/red eyes) compared to placebo. Although the number of subjects in some of the subgroups was small, there were no significant differences in the effect of fexofenadine hydrochloride across subgroups of subjects defined by gender, age, and race.