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.
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.
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 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 (less than 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.
Pharmacodynamics
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 × 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 dose).
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 Studies
Clinical efficacy and safety studies were not conducted with
ALLEGRA-D 24 HOUR Extended-Release Tablets. The effectiveness of ALLEGRA-D 24
HOUR 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.
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