FEXOFENADINE
DESCRIPTION:
Fexofenadine hydrochloride, the active ingredient of ALLEGRA(TM), is a histamine
H1-receptor antagonist with the chemical name ()-4-(1-hydroxy- 4-(4-
(hydroxydiphenylmethyl)-1-piperidinyl)-butyl )-alpha,alpha-dimethyl
benzeneacetic acid hydrochloride.
The molecular weight is 538.13 and the empirical formula is C32H39NO4.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. ALLEGRA(TM) is
formulated as tab. for oral administration. Each tab. contains 120 mg & 180 mg
fexofenadine hydrochloride and the following excipients: croscamellose sodium,
gelatin, lactose, microcrystalline cellulose, and pregelatinized starch.
ACTIONS/CLINICAL PHARMACOLOGY:
MECHANISM OF ACTION
Fexofenadine, a metabolite of terfenadine, is an antihistamine with selective
peripheral H1-receptor antagonist activity. Fexofenadine 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.
PHARMACOKINETICS
Fexofenadine hydrochloride was rapidly absorbed following oral administration of
a single dose of two 60-mg capsules to healthy male volunteers with a mean time
to maximum plasma concentration occurring at 2.6 hours postdose. After
administration of a single 60-mg dose as an oral solution to healthy subjects,
the mean plasma concentration was 209 ng/mL. Mean steady-state peak plasma
concentrations of 286 ng/mL were observed when healthy volunteers were
administered multiple doses of fexofenadine hydrochloride (60 mg oral solution
every 12 hours for 10 doses). Fexofenadine pharmacokinetics were linear for oral
doses up to 120 mg twice daily. Although the absolute bioavailability of
fexofenadine hydrochloride capsules is unknown, the capsules are bioequivalent
to an oral solution. The mean elimination half-life of fexofenadine was 14.4
hours following administration of 60 mg, twice daily, to steady- state in normal
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.
Approximately 5% of the total dose was metabolized. Because the absolute
bioavailability of fexofenadine hydrochloride has not been established, it is
unknown if the fecal component represents unabsorbed drug or the result of
biliary excretion.
The pharmacokinetics of fexofenadine hydrochloride in seasonal allergic rhinitis
patients were similar to those in healthy subjects. Peak fexofenadine plasma
concentrations were similar between adolescent (12-16 years of age) and adult
patients.
Fexofenadine is 60% to 70% bound to plasma proteins, primarily albumin and
alpha1-acid glycoprotein.
SPECIAL POPULATIONS
Special population pharmacokinetics (for age and renal and hepatic impairment),
obtained after a single dose of 80 mg fexofenadine hydrochloride, were compared
to those from normal subjects in a separate study of similar design. While
subject weights were relatively uniform between studies, these special
population patients were substantially older than the healthy, young volunteers.
Thus, an age effect may be confounding the pharmacokinetic differences observed
in some of the special populations.
EFFECT OF AGE. In older subjects (>/=65 years old), peak plasma levels of
fexofenadine were 99% greater than those observed in normal volunteers (<65
years old). Mean elimination half-lives were similar to those observed in normal
volunteers.
RENALLY IMPAIRED. In patients 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 normal
volunteers. Peak plasma levels in patients on dialysis (creatinine clearance =
10 mL/min) were 82% greater and half-life was 31% longer than observed in normal
volunteers. Based on increases in bioavailability and half-life, a dose of 60 mg
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
patients with hepatic disease did not differ substantially from that observed in
healthy subjects.
EFFECT OF GENDER. Across several trials, no clinically significant gender-
related differences were observed in the pharmacokinetics of fexofenadine.
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.
EFFECTS ON QTC. In dogs, (10 mg/kg/day, orally for 5 days) and rabbits (10
mg/kg, intravenously over one hour) fexofenadine did not prolong QTc at plasma
concentrations that were at least 28 and 63 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 X 10 (raised to the power of -5) M of
fexofenadine. This concentration was at least 32 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 seasonal allergic rhinitis patients given fexofenadine
hydrochloride capsules in doses of 60 mg to 240 mg twice daily for two weeks or
in 40 healthy volunteers given fexofenadine hydrochloride as an oral solution at
doses up to 400 mg twice daily for 6 days.
CLINICAL STUDIES
In three, 2-week, multi-center, randomized, double-blind, placebo-controlled
trials in patients 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 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 patients 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 patients with
seasonal allergic rhinitis who were exposed to ragweed pollen in an
environmental exposure unit.
INDICATIONS AND USAGE:
ALLEGRA(TM) is indicated for the relief of symptoms associated with seasonal
allergic rhinitis in adults and children 12 years of age and older. Symptoms
treated effectively include sneezing, rhinorrhea, itchy nose/palate/throat,
itchy/watery/red eyes.
CONTRAINDICATIONS:
ALLEGRA(TM) is contraindicated in patients with known hypersensitivity to any of
its ingredients.
PRECAUTIONS:
DRUG INTERACTIONS
In two separate studies, fexofenadine hydrochloride 120 mg twice daily (twice
the recommended dose) was co-administered with erythromycin 500 mg every 8 hours
or ketoconazole 400 mg once daily under steady-state conditions to normal,
healthy volunteers (n=24, each study). No differences in adverse events or QTc
interval were observed when subjects were administered fexofenadine
hydrochloride alone or in combination with erythromycin or ketoconazole. The
findings of these studies are summarized in the following table:
EFFECTS ON STEADY-STATE FEXOFENADINE PHARMACOKINETICS
AFTER 7 DAYS OF CO-ADMINISTRATION WITH FEXOFENADINE
HYDROCHLORIDE 120 MG EVERY 12 HOURS
(TWICE RECOMMENDED DOSE) IN NORMAL VOLUNTEERS (N=24)
Cmax,SS AUCSS(0-12h)
Concomitant (Peak Plasma (Extent Of
Drug Concentration) Systemic Exposure)
Erythromycin % ?%
(500 mg
every 8 hrs)
Ketoconazole ?% ?%
(400 mg
once daily)
The mechanisms of these interactions are unknown, and the potential for
interaction with other azole antifungal or macrolide agents has not been
studied. These changes in plasma levels were within the range of plasma levels
achieved in adequate and well-controlled clinical trials. Fexofenadine had no
effect on the pharmacokinetics of erythromycin or ketoconazole.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
The carcinogenic potential and reproductive toxicity of fexofenadine
hydrochloride were assessed using terfenadine studies with adequate fexofenadine
exposure (based on plasma area- under-the-curve (AUC) values). No evidence of
carcinogenicity was observed when mice and rats were given daily oral doses of
50 and 150 mg/kg of terfenadine for 18 and 24 months, respectively; these doses
resulted in plasma AUC values of fexofenadine that were up to four times the
human therapeutic value (based on a 60-mg twice-daily fexofenadine hydrochloride
dose).
In in-vitro (Bacterial Reverse Mutation, CHO/HGPRT Forward Mutation, and Rat
Lymphocyte Chromosomal Aberration assays) and in-vivo (Mouse Bone Marrow
Micronucleus assay) tests, fexofenadine hydrochloride revealed no evidence of
mutagenicity.
In rat fertility studies, dose-related reductions in implants and increases in
postimplantation losses were observed at oral doses equal to or greater than 150
mg/kg of terfenadine; these doses produced plasma AUC values of fexofenadine
that were equal to or greater than three times the human therapeutic value
(based on a 60-mg twice-daily fexofenadine hydrochloride dose).
PREGNANCY
TERATOGENIC EFFECTS: CATEGORY C. There was no evidence of teratogenicity in rats
or rabbits at oral terfenadine doses up to 300 mg/kg; these doses produced
fexofenadine plasma AUC values that were up to 4 and 37 times the human
therapeutic value (based on a 60-mg twice-daily fexofenadine hydrochloride
dose), respectively.
There are no adequate and well-controlled studies in pregnant women.
Fexofenadine hydrochloride should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
NONTERATOGENIC EFFECTS. Dose-related decreases in pup weight gain and survival
were observed in rats exposed to oral doses equal to and greater than 150 mg/kg
of terfenadine; at these doses the plasma AUC values of fexofenadine were equal
to or greater than 3 times the human therapeutic values (based on a 60-mg twice-
daily fexofenadine hydrochloride dose).
NURSING MOTHERS
There are no adequate and well-controlled studies in women during lactation.
Because many drugs are excreted in human milk, caution should be exercised when
fexofenadine hydrochloride is administered to a nursing woman.
PEDIATRIC USE
Safety and effectiveness of ALLEGRA(TM) in pediatric patients under the age of
12 years have not been established. Across well-controlled clinical trials in
patients with seasonal allergic rhinitis, a total of 205 patients between the
ages of 12 to 16 years received doses ranging from 20 mg to 240 mg twice daily
for up to two weeks. Adverse events were similar in this group compared to
patients above the age of 16 years.
GERIATRIC USE
In placebo-controlled trials, 42 patients, age 60 to 68 years, received doses of
20 mg to 240 mg of fexofenadine twice daily for up to two weeks. Adverse events
were similar in this group to patients under age 60 years.
DRUG INTERACTIONS:
In two separate studies, fexofenadine hydrochloride 120 mg twice daily (twice
the recommended dose) was co-administered with erythromycin 500 mg every 8 hours
or ketoconazole 400 mg once daily under steady-state conditions to normal,
healthy volunteers (n=24, each study). No differences in adverse events or QTc
interval were observed when subjects were administered fexofenadine
hydrochloride alone or in combination with erythromycin or ketoconazole. The
findings of these studies are summarized in the following table:
EFFECTS ON STEADY-STATE FEXOFENADINE PHARMACOKINETICS
AFTER 7 DAYS OF CO-ADMINISTRATION WITH FEXOFENADINE
HYDROCHLORIDE 120 MG EVERY 12 HOURS
(TWICE RECOMMENDED DOSE) IN NORMAL VOLUNTEERS (N=24)
Cmax,SS AUCSS(0-12h)
Concomitant (Peak Plasma (Extent Of
Drug Concentration) Systemic Exposure)
Erythromycin % ?%
(500 mg
every 8 hrs)
Ketoconazole ?% ?%
(400 mg
once daily)
The mechanisms of these interactions are unknown, and the potential for
interaction with other azole antifungal or macrolide agents has not been
studied. These changes in plasma levels were within the range of plasma levels
achieved in adequate and well-controlled clinical trials. Fexofenadine had no
effect on the pharmacokinetics of erythromycin or ketoconazole.
(See Also PRECAUTIONS section.)
ADVERSE REACTIONS:
In placebo-controlled clinical trials, which included 2461 patients receiving
fexofenadine hydrochloride at doses of 20 mg to 240 mg twice daily, adverse
events were similar in fexofenadine hydrochloride and placebo-treated patients.
The incidence of adverse events, including drowsiness, was not dose related and
was similar across subgroups defined by age, gender, and race. The percent of
patients who withdrew prematurely because of adverse events was 2.2% with
fexofenadine hydrochloride vs 3.3% with placebo. All adverse events that were
reported by greater than 1% of patients who received the recommended daily dose
of fexofenadine hydrochloride (60 mg twice-daily), and that were more common
with fexofenadine than placebo, are listed in the following table.
ADVERSE EXPERIENCES REPORTED IN PLACEBO-CONTROLLED
SEASONAL ALLERGIC RHINITIS
CLINICAL TRIALS AT RATES OF GREATER THAN 1%
Placebo
Fexofenadine 60 Mg Twice
Twice Daily Daily
Adverse Experience (n=679) (n=671)
Viral Infection (cold, flu) 2.5% 1.5%
Nausea 1.6% 1.5%
Dysmenorrhea 1.5% 0.3%
Drowsiness 1.3% 0.9%
Dyspepsia 1.3% 0.6%
Fatigue 1.3% 0.9%
Adverse events occurring in greater than 1% of fexofenadine hydrochloride-
treated patients (60 mg twice daily), but that were more common in the placebo-
treated group, include headache and throat irritation.
The frequency and magnitude of laboratory abnormalities were similar in
fexofenadine hydrochloride and placebo-treated patients.
OVERDOSAGE:
Information regarding acute overdosage is limited to experience from clinical
trials conducted during the development of ALLEGRA(TM). Single doses of
fexofenadine hydrochloride up to 800 mg (6 normal volunteers at this dose
level), and doses up to 690 mg twice daily for one month (3 normal volunteers at
this dose level), were administered without the development of clinically
significant adverse events.
In the event of overdose, consider standard measures to remove any unabsorbed
drug. Symptomatic and supportive treatment is recommended.
Hemodialysis did not effectively remove fexofenadine from blood (up to 1.7%
removed) following terfenadine administration.
No deaths occurred at oral doses of fexofenadine hydrochloride up to 5000 mg/kg
in mice (170 times the maximum recommended human daily oral dose based on
mg/M(squared)) and up to 5000 mg/kg in rats (330 times the maximum recommended
human daily oral dose based on mg/M(squared)). Additionally, no clinical signs
of toxicity or gross pathological findings were observed. In dogs, no evidence
of toxicity was observed at oral doses up to 2000 mg/kg (450 times the maximum
recommended human daily oral dose based on mg/M(squared)).
DOSAGE AND ADMINISTRATION:
The recommended dose of ALLEGRA(TM) is 60 mg twice daily for adults and children
12 years of age and older.
A dose of 60 mg once daily is recommended as the starting dose in patients with
decreased renal function. (See ACTIONS/CLINICAL PHARMACOLOGY.)
CLINICAL STUDIES:
In three, 2-week, multi-center, randomized, double-blind, placebo-controlled
trials in patients 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 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 patients 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 patients with
seasonal allergic rhinitis who were exposed to ragweed pollen in an
environmental exposure unit.
(See Also ACTIONS/CLINICAL PHARMACOLOGY section.)
FEXOFENADINE
DESCRIPTION:
Fexofenadine hydrochloride, the active ingredient of ALLEGRA(TM), is a histamine
H1-receptor antagonist with the chemical name ()-4-(1-hydroxy- 4-(4-
(hydroxydiphenylmethyl)-1-piperidinyl)-butyl )-alpha,alpha-dimethyl
benzeneacetic acid hydrochloride.
The molecular weight is 538.13 and the empirical formula is C32H39NO4.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. ALLEGRA(TM) is
formulated as tab. for oral administration. Each tab. contains 120 mg & 180 mg
fexofenadine hydrochloride and the following excipients: croscamellose sodium,
gelatin, lactose, microcrystalline cellulose, and pregelatinized starch.
ACTIONS/CLINICAL PHARMACOLOGY:
MECHANISM OF ACTION
Fexofenadine, a metabolite of terfenadine, is an antihistamine with selective
peripheral H1-receptor antagonist activity. Fexofenadine 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.
PHARMACOKINETICS
Fexofenadine hydrochloride was rapidly absorbed following oral administration of
a single dose of two 60-mg capsules to healthy male volunteers with a mean time
to maximum plasma concentration occurring at 2.6 hours postdose. After
administration of a single 60-mg dose as an oral solution to healthy subjects,
the mean plasma concentration was 209 ng/mL. Mean steady-state peak plasma
concentrations of 286 ng/mL were observed when healthy volunteers were
administered multiple doses of fexofenadine hydrochloride (60 mg oral solution
every 12 hours for 10 doses). Fexofenadine pharmacokinetics were linear for oral
doses up to 120 mg twice daily. Although the absolute bioavailability of
fexofenadine hydrochloride capsules is unknown, the capsules are bioequivalent
to an oral solution. The mean elimination half-life of fexofenadine was 14.4
hours following administration of 60 mg, twice daily, to steady- state in normal
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.
Approximately 5% of the total dose was metabolized. Because the absolute
bioavailability of fexofenadine hydrochloride has not been established, it is
unknown if the fecal component represents unabsorbed drug or the result of
biliary excretion.
The pharmacokinetics of fexofenadine hydrochloride in seasonal allergic rhinitis
patients were similar to those in healthy subjects. Peak fexofenadine plasma
concentrations were similar between adolescent (12-16 years of age) and adult
patients.
Fexofenadine is 60% to 70% bound to plasma proteins, primarily albumin and
alpha1-acid glycoprotein.
SPECIAL POPULATIONS
Special population pharmacokinetics (for age and renal and hepatic impairment),
obtained after a single dose of 80 mg fexofenadine hydrochloride, were compared
to those from normal subjects in a separate study of similar design. While
subject weights were relatively uniform between studies, these special
population patients were substantially older than the healthy, young volunteers.
Thus, an age effect may be confounding the pharmacokinetic differences observed
in some of the special populations.
EFFECT OF AGE. In older subjects (>/=65 years old), peak plasma levels of
fexofenadine were 99% greater than those observed in normal volunteers (<65
years old). Mean elimination half-lives were similar to those observed in normal
volunteers.
RENALLY IMPAIRED. In patients 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 normal
volunteers. Peak plasma levels in patients on dialysis (creatinine clearance =
10 mL/min) were 82% greater and half-life was 31% longer than observed in normal
volunteers. Based on increases in bioavailability and half-life, a dose of 60 mg
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
patients with hepatic disease did not differ substantially from that observed in
healthy subjects.
EFFECT OF GENDER. Across several trials, no clinically significant gender-
related differences were observed in the pharmacokinetics of fexofenadine.
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.
EFFECTS ON QTC. In dogs, (10 mg/kg/day, orally for 5 days) and rabbits (10
mg/kg, intravenously over one hour) fexofenadine did not prolong QTc at plasma
concentrations that were at least 28 and 63 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 X 10 (raised to the power of -5) M of
fexofenadine. This concentration was at least 32 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 seasonal allergic rhinitis patients given fexofenadine
hydrochloride capsules in doses of 60 mg to 240 mg twice daily for two weeks or
in 40 healthy volunteers given fexofenadine hydrochloride as an oral solution at
doses up to 400 mg twice daily for 6 days.
CLINICAL STUDIES
In three, 2-week, multi-center, randomized, double-blind, placebo-controlled
trials in patients 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 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 patients 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 patients with
seasonal allergic rhinitis who were exposed to ragweed pollen in an
environmental exposure unit.
INDICATIONS AND USAGE:
ALLEGRA(TM) is indicated for the relief of symptoms associated with seasonal
allergic rhinitis in adults and children 12 years of age and older. Symptoms
treated effectively include sneezing, rhinorrhea, itchy nose/palate/throat,
itchy/watery/red eyes.
CONTRAINDICATIONS:
ALLEGRA(TM) is contraindicated in patients with known hypersensitivity to any of
its ingredients.
PRECAUTIONS:
DRUG INTERACTIONS
In two separate studies, fexofenadine hydrochloride 120 mg twice daily (twice
the recommended dose) was co-administered with erythromycin 500 mg every 8 hours
or ketoconazole 400 mg once daily under steady-state conditions to normal,
healthy volunteers (n=24, each study). No differences in adverse events or QTc
interval were observed when subjects were administered fexofenadine
hydrochloride alone or in combination with erythromycin or ketoconazole. The
findings of these studies are summarized in the following table:
EFFECTS ON STEADY-STATE FEXOFENADINE PHARMACOKINETICS
AFTER 7 DAYS OF CO-ADMINISTRATION WITH FEXOFENADINE
HYDROCHLORIDE 120 MG EVERY 12 HOURS
(TWICE RECOMMENDED DOSE) IN NORMAL VOLUNTEERS (N=24)
Cmax,SS AUCSS(0-12h)
Concomitant (Peak Plasma (Extent Of
Drug Concentration) Systemic Exposure)
Erythromycin % ?%
(500 mg
every 8 hrs)
Ketoconazole ?% ?%
(400 mg
once daily)
The mechanisms of these interactions are unknown, and the potential for
interaction with other azole antifungal or macrolide agents has not been
studied. These changes in plasma levels were within the range of plasma levels
achieved in adequate and well-controlled clinical trials. Fexofenadine had no
effect on the pharmacokinetics of erythromycin or ketoconazole.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
The carcinogenic potential and reproductive toxicity of fexofenadine
hydrochloride were assessed using terfenadine studies with adequate fexofenadine
exposure (based on plasma area- under-the-curve (AUC) values). No evidence of
carcinogenicity was observed when mice and rats were given daily oral doses of
50 and 150 mg/kg of terfenadine for 18 and 24 months, respectively; these doses
resulted in plasma AUC values of fexofenadine that were up to four times the
human therapeutic value (based on a 60-mg twice-daily fexofenadine hydrochloride
dose).
In in-vitro (Bacterial Reverse Mutation, CHO/HGPRT Forward Mutation, and Rat
Lymphocyte Chromosomal Aberration assays) and in-vivo (Mouse Bone Marrow
Micronucleus assay) tests, fexofenadine hydrochloride revealed no evidence of
mutagenicity.
In rat fertility studies, dose-related reductions in implants and increases in
postimplantation losses were observed at oral doses equal to or greater than 150
mg/kg of terfenadine; these doses produced plasma AUC values of fexofenadine
that were equal to or greater than three times the human therapeutic value
(based on a 60-mg twice-daily fexofenadine hydrochloride dose).
PREGNANCY
TERATOGENIC EFFECTS: CATEGORY C. There was no evidence of teratogenicity in rats
or rabbits at oral terfenadine doses up to 300 mg/kg; these doses produced
fexofenadine plasma AUC values that were up to 4 and 37 times the human
therapeutic value (based on a 60-mg twice-daily fexofenadine hydrochloride
dose), respectively.
There are no adequate and well-controlled studies in pregnant women.
Fexofenadine hydrochloride should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
NONTERATOGENIC EFFECTS. Dose-related decreases in pup weight gain and survival
were observed in rats exposed to oral doses equal to and greater than 150 mg/kg
of terfenadine; at these doses the plasma AUC values of fexofenadine were equal
to or greater than 3 times the human therapeutic values (based on a 60-mg twice-
daily fexofenadine hydrochloride dose).
NURSING MOTHERS
There are no adequate and well-controlled studies in women during lactation.
Because many drugs are excreted in human milk, caution should be exercised when
fexofenadine hydrochloride is administered to a nursing woman.
PEDIATRIC USE
Safety and effectiveness of ALLEGRA(TM) in pediatric patients under the age of
12 years have not been established. Across well-controlled clinical trials in
patients with seasonal allergic rhinitis, a total of 205 patients between the
ages of 12 to 16 years received doses ranging from 20 mg to 240 mg twice daily
for up to two weeks. Adverse events were similar in this group compared to
patients above the age of 16 years.
GERIATRIC USE
In placebo-controlled trials, 42 patients, age 60 to 68 years, received doses of
20 mg to 240 mg of fexofenadine twice daily for up to two weeks. Adverse events
were similar in this group to patients under age 60 years.
DRUG INTERACTIONS:
In two separate studies, fexofenadine hydrochloride 120 mg twice daily (twice
the recommended dose) was co-administered with erythromycin 500 mg every 8 hours
or ketoconazole 400 mg once daily under steady-state conditions to normal,
healthy volunteers (n=24, each study). No differences in adverse events or QTc
interval were observed when subjects were administered fexofenadine
hydrochloride alone or in combination with erythromycin or ketoconazole. The
findings of these studies are summarized in the following table:
EFFECTS ON STEADY-STATE FEXOFENADINE PHARMACOKINETICS
AFTER 7 DAYS OF CO-ADMINISTRATION WITH FEXOFENADINE
HYDROCHLORIDE 120 MG EVERY 12 HOURS
(TWICE RECOMMENDED DOSE) IN NORMAL VOLUNTEERS (N=24)
Cmax,SS AUCSS(0-12h)
Concomitant (Peak Plasma (Extent Of
Drug Concentration) Systemic Exposure)
Erythromycin % ?%
(500 mg
every 8 hrs)
Ketoconazole ?% ?%
(400 mg
once daily)
The mechanisms of these interactions are unknown, and the potential for
interaction with other azole antifungal or macrolide agents has not been
studied. These changes in plasma levels were within the range of plasma levels
achieved in adequate and well-controlled clinical trials. Fexofenadine had no
effect on the pharmacokinetics of erythromycin or ketoconazole.
(See Also PRECAUTIONS section.)
ADVERSE REACTIONS:
In placebo-controlled clinical trials, which included 2461 patients receiving
fexofenadine hydrochloride at doses of 20 mg to 240 mg twice daily, adverse
events were similar in fexofenadine hydrochloride and placebo-treated patients.
The incidence of adverse events, including drowsiness, was not dose related and
was similar across subgroups defined by age, gender, and race. The percent of
patients who withdrew prematurely because of adverse events was 2.2% with
fexofenadine hydrochloride vs 3.3% with placebo. All adverse events that were
reported by greater than 1% of patients who received the recommended daily dose
of fexofenadine hydrochloride (60 mg twice-daily), and that were more common
with fexofenadine than placebo, are listed in the following table.
ADVERSE EXPERIENCES REPORTED IN PLACEBO-CONTROLLED
SEASONAL ALLERGIC RHINITIS
CLINICAL TRIALS AT RATES OF GREATER THAN 1%
Placebo
Fexofenadine 60 Mg Twice
Twice Daily Daily
Adverse Experience (n=679) (n=671)
Viral Infection (cold, flu) 2.5% 1.5%
Nausea 1.6% 1.5%
Dysmenorrhea 1.5% 0.3%
Drowsiness 1.3% 0.9%
Dyspepsia 1.3% 0.6%
Fatigue 1.3% 0.9%
Adverse events occurring in greater than 1% of fexofenadine hydrochloride-
treated patients (60 mg twice daily), but that were more common in the placebo-
treated group, include headache and throat irritation.
The frequency and magnitude of laboratory abnormalities were similar in
fexofenadine hydrochloride and placebo-treated patients.
OVERDOSAGE:
Information regarding acute overdosage is limited to experience from clinical
trials conducted during the development of ALLEGRA(TM). Single doses of
fexofenadine hydrochloride up to 800 mg (6 normal volunteers at this dose
level), and doses up to 690 mg twice daily for one month (3 normal volunteers at
this dose level), were administered without the development of clinically
significant adverse events.
In the event of overdose, consider standard measures to remove any unabsorbed
drug. Symptomatic and supportive treatment is recommended.
Hemodialysis did not effectively remove fexofenadine from blood (up to 1.7%
removed) following terfenadine administration.
No deaths occurred at oral doses of fexofenadine hydrochloride up to 5000 mg/kg
in mice (170 times the maximum recommended human daily oral dose based on
mg/M(squared)) and up to 5000 mg/kg in rats (330 times the maximum recommended
human daily oral dose based on mg/M(squared)). Additionally, no clinical signs
of toxicity or gross pathological findings were observed. In dogs, no evidence
of toxicity was observed at oral doses up to 2000 mg/kg (450 times the maximum
recommended human daily oral dose based on mg/M(squared)).
DOSAGE AND ADMINISTRATION:
The recommended dose of ALLEGRA(TM) is 60 mg twice daily for adults and children
12 years of age and older.
A dose of 60 mg once daily is recommended as the starting dose in patients with
decreased renal function. (See ACTIONS/CLINICAL PHARMACOLOGY.)
CLINICAL STUDIES:
In three, 2-week, multi-center, randomized, double-blind, placebo-controlled
trials in patients 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 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 patients 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 patients with
seasonal allergic rhinitis who were exposed to ragweed pollen in an
environmental exposure unit.
(See Also ACTIONS/CLINICAL PHARMACOLOGY section.)