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 [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.
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
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 17 and 38 times, respectively,
the therapeutic plasma concentrations in man (based on a 60 mg twice daily fexofenadine hydrochloride dose). 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
21 times the therapeutic plasma concentration in man (based on a 60
mg twice 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
In a 2-week, multicenter,
randomized, double-blind, active-controlled trial in subjects 12–65
years of age with seasonal allergic rhinitis due to ragweed allergy
(n=651), the 60 mg fexofenadine hydrochloride/120 mg pseudoephedrine
hydrochloride combination tablet administered twice daily significantly
reduced the intensity of sneezing, rhinorrhea, itchy nose/palate/throat,
itchy/watery/red eyes, and nasal congestion.
In three, 2-week, multicenter, randomized, double-blind, placebo-controlled
trials in subjects 12–68 years of age with seasonal allergic
rhinitis (n=1634), fexofenadine hydrochloride 60 mg twice 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. Statistically significant reductions in symptom
scores were observed following the first 60 mg dose, with the effect
maintained throughout the 12-hour interval. In general, there was
no additional reduction in total symptom scores with higher doses
of fexofenadine hydrochloride up to 240 mg twice daily. 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. Onset
of action for reduction in total symptom scores, excluding nasal congestion,
was observed at 60 minutes compared to placebo following a single
60 mg fexofenadine hydrochloride dose administered to subjects with
seasonal allergic rhinitis who were exposed to ragweed pollen in an
environmental exposure unit.
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