Allegra-D Extended-Release Tablets
Manufacturer: sanofi-aventis
Prescribing Information as of January 2003
DESCRIPTION
ALLEGRA-D® (fexofenadine
hydrochloride and
pseudoephedrine hydrochloride) Extended-Release Tablets for oral
administration contain 60 mg fexofenadine hydrochloride for
immediate-release and 120 mg pseudoephedrine hydrochloride for
extended-release. Tablets also contain as excipients: microcrystalline
cellulose, pregelatinized starch, croscarmellose sodium, magnesium stearate,
carnauba wax, stearic acid, silicon dioxide, hypromellose and polyethylene
glycol.
Fexofenadine hydrochloride, one of the active ingredients of ALLEGRA-D,
is a histamine H 1 -receptor antagonist with the chemical name
(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-(alpha),
(alpha)-dimethyl benzeneacetic acid hydrochloride and the following chemical
structure:
The molecular
weight is 538.13 and the empirical formula is C 32 H 39
NO 4 ·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.
Pseudoephedrine hydrochloride, the other active ingredient of ALLEGRA-D,
is an adrenergic (vasoconstrictor) agent with the chemical name [S-(R*,R*)]-(alpha)-[1-(methylamino)ethyl]-benzenemethanol
hydrochloride and the following chemical structure:
The molecular weight is 201.70. The molecular formula is C 10
H 15 NO·HCl. Pseudoephedrine hydrochloride occurs as fine, white
to off-white crystals or powder, having a faint characteristic odor. It is
very soluble in water, freely soluble in alcohol, and sparingly soluble in
chloroform.
CLINICAL PHARMACOLOGY
Mechanism of Action
Fexofenadine hydrochloride, the major active metabolite of terfenadine,
is an antihistamine with selective peripheral H 1 -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 alpha
1 -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 and pseudoephedrine
hydrochloride when administered separately have been well characterized.
Fexofenadine pharmacokinetics were linear for oral doses of fexofenadine
hydrochloride up to 120 mg twice daily. The mean elimination half-life of
fexofenadine was 14.4 hours following administration of 60 mg fexofenadine
hydrochloride, twice daily, to steady-state in normal volunteers. Human mass
balance studies documented a recovery of approximately 80% and 11% of the [
14 C] 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 is 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 (alpha) 1 -acid glycoprotein.
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.
The bioavailability of fexofenadine hydrochloride and pseudoephedrine
hydrochloride from ALLEGRA-D 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 postdose.
Pseudoephedrine hydrochloride produced a mean single-dose pseudoephedrine
peak plasma concentration of 206 ng/mL which occurred 6 hours postdose.
Following multiple dosing to steady-state, a fexofenadine peak concentration
of 255 ng/mL was observed 2 hours postdose. Following multiple dosing to
steady-state, a pseudoephedrine peak concentration of 411 ng/mL was observed
5 hours postdose. Coadministration of ALLEGRA-D with a high-fat meal
decreased fexofenadine plasma concentrations C max (-46%) and AUC
(-42%). Time to maximum concentration (T max ) was delayed by
50%. The rate or extent of pseudoephedrine absorption was not affected by
food. It is recommended that the administration of ALLEGRA-D with food
should be avoided. (See DOSAGE AND ADMINISTRATION ).
Special Populations
Special population pharmacokinetics (for renal and hepatic impairment and
age), 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 younger
subjects (<65 years old). Mean elimination half-lives were similar to those
observed in younger subjects.
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
About 55-75% of an administered dose of pseudoephedrine hydrochloride is
excreted unchanged in the urine; the remainder is apparently metabolized in
the liver. Therefore, pseudoephedrine may accumulate in patients with renal
insufficiency.
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 patients with hepatic
disease did not differ substantially from that observed in healthy
subjects. 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 and40 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 not known.
Effects on QT c . In dogs, (10 mg/kg/day, orally for
5 days) and rabbits (10 mg/kg, intravenously over one hour) fexofenadine
hydrochloride did not prolong QT c 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 × 10 -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 QT c 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.
A one year study designed to evaluate safety and tolerability of 240 mg
of fexofenadine hydrochloride (n=240) compared to placebo (n=237) in healthy
subjects, did not reveal a statistically significant increase in the mean QT
c 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 patients with seasonal allergic rhinitis demonstrated no
statistically significant increase in the mean QT c 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 patients 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 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
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 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-D 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/
and/or throat, itchy/watery/red eyes, and nasal congestion.
ALLEGRA-D should be administered when both the antihistaminic properties
of fexofenadine hydrochloride and the nasal decongestant properties of
pseudoephedrine hydrochloride are desired (see CLINICAL
PHARMACOLOGY ).
CONTRAINDICATIONS
ALLEGRA-D is contraindicated in patients with known hypersensitivity to
any of its ingredients.
Due to its pseudoephedrine component, ALLEGRA-D is contraindicated in
patients with narrow-angle glaucoma or urinary retention, and in patients
receiving monoamine oxidase (MAO) inhibitor therapy or within fourteen (14)
days of stopping such treatment (see Drug Interactions
section). It is also contraindicated in patients with
severe hypertension, or severe
coronary artery disease, and in those who have shown hypersensitivity or
idiosyncrasy to its components, to adrenergic agents, or to other drugs of
similar chemical structures. Manifestations of patient idiosyncrasy to
adrenergic agents include: insomnia, dizziness, weakness, tremor, or
arrhythmias.
WARNINGS
Sympathomimetic amines should be used judiciously and sparingly in
patients with hypertension,
diabetes mellitus, ischemic
heart disease, increased intraocular pressure, hyperthyroidism, renal
impairment, or prostatic hypertrophy (see CONTRAINDICATIONS
). Sympathomimetic amines may produce central nervous system stimulation
with convulsions or cardiovascular collapse with accompanying hypotension.
PRECAUTIONS
General
Due to its pseudoephedrine component, ALLEGRA-D should be used with
caution in patients with hypertension, diabetes mellitus, ischemic heart
disease, increased intraocular pressure, hyperthyroidism, renal impairment,
or prostatic hypertrophy (see WARNINGS and
CONTRAINDICATIONS ). Patients with decreased renal function should be
given a lower initial dose (one tablet per day) because they have reduced
elimination of fexofenadine and pseudoephedrine (See CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION ).
Information for Patients
Patients taking ALLEGRA-D tablets should receive the following
information: ALLEGRA-D tablets are prescribed for the relief of symptoms of
seasonal allergic rhinitis. Patients should be instructed to take ALLEGRA-D
tablets only as prescribed. Do not exceed the recommended dose. If
nervousness, dizziness, or sleeplessness occur, discontinue use and consult
the doctor. Patients should also be advised against the concurrent use of
ALLEGRA-D tablets with over-the-counter antihistamines and decongestants.
The product should not be used by patients who are hypersensitive to it
or to any of its ingredients. Due to its pseudoephedrine component, this
product should not be used by patients with narrow-angle glaucoma, urinary
retention, or by patients receiving a monoamine oxidase (MAO) inhibitor or
within 14 days of stopping use of MAO inhibitor. It also should not be used
by patients with severe hypertension or severe
coronary artery disease.
Patients should be told that this product should be used in pregnancy or
lactation only if the potential benefit justifies the potential risk to the
fetus or nursing infant. Patients should be cautioned not to break or chew
the tablet. Patients should be directed to swallow the tablet whole.
Patients should be instructed not to take the tablet with food. Patients
should also be instructed to store the medication in a tightly closed
container in a cool, dry place, away from children.
Drug Interactions
Fexofenadine hydrochloride and pseudoephedrine hydrochloride do not
influence the pharmacokinetics of each other when administered concomitantly.
Fexofenadine has been shown to exhibit minimal (ca. 5%) metabolism.
However, co-administration of fexofenadine with ketoconazole and
erythromycin led to increased plasma levels of fexofenadine. Fexofenadine
had no effect on the pharmacokinetics of erythromycin and ketoconazole. In
two separate studies, fexofenadine HCl 120 mg BID (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
QT c interval were observed when subjects were administered
fexofenadine HCl alone or in combination with erythromycin or ketoconazole.
The findings of these studies are summarized in the following table:
The changes in plasma levels were within the range of plasma levels
achieved in adequate and well-controlled clinical trials.
The mechanism of these interactions has been evaluated in in vitro
, in situ and in vivo animal models. These studies indicate
that ketoconazole or erythromycin co-administration enhances fexofenadine
gastrointestinal absorption. In vivo animal studies also suggest that
in addition to enhancing absorption, ketoconazole decreases fexofenadine
gastrointestinal secretion, while erythromycin may also decrease biliary
excretion.
ALLEGRA-D tablets (pseudoephedrine component) are contraindicated in
patients taking monoamine oxidase inhibitors and for 14 days after stopping
use of an MAO inhibitor. Concomitant use with antihypertensive drugs which
interfere with sympathetic activity (eg, methyldopa, mecamylamine, and
reserpine) may reduce their antihypertensive effects. Increased ectopic
pacemaker activity can occur when pseudoephedrine is used concomitantly with
digitalis.
Care should be taken in the administration of ALLEGRA-D concomitantly
with other sympathomimetic amines because combined effects on the
cardiovascular system may be harmful to the patient (see
WARNINGS ).
Carcinogenesis, Mutagenesis, Impairment of Fertility
There are no animal or in vitro studies on the combination product
fexofenadine hydrochloride and pseudoephedrine hydrochloride to evaluate
carcinogenesis, mutagenesis, or impairment of fertility.
The carcinogenic potential and reproductive toxicity of fexofenadine
hydrochloride were assessed using terfenadine studies with adequate
fexofenadine exposure (area-under-the plasma concentration versus time curve
[AUC]). No evidence of carcinogenicity was observed when mice and rats were
given daily oral doses up to 150 mg/kg of terfenadine for 18 and 24 months,
respectively. In both species, 150 mg/kg of terfenadine produced AUC values
of fexofenadine that were approximately 3 times the human AUC at the maximum
recommended daily oral dose in adults.
Two-year feeding studies in rats and mice conducted under the auspices of
the National Toxicology Program (NTP) demonstrated no evidence of
carcinogenic potential with ephedrine sulfate, a structurally related drug
with pharmacological properties similar to pseudoephedrine, at doses up to
10 and 27 mg/kg, respectively (approximately 1/3 and 1/2, respectively, the
maximum recommended daily oral dose of pseudoephedrine hydrochloride in
adults on a mg/m 2 basis).
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.
Reproduction and fertility studies with terfenadine in rats produced no
effect on male or female fertility at oral doses up to 300 mg/kg/day.
However, reduced implants and post implantation losses were reported at 300
mg/kg. A reduction in implants was also observed at an oral dose of 150
mg/kg/day. Oral doses of 150 and 300 mg/kg of terfenadine produced AUC
values of fexofenadine that were approximately 3 and 4 times, respectively,
the human AUC at the maximum recommended daily oral dose in adults.
Pregnancy
Teratogenic Effects: Category C. Terfenadine alone was not
teratogenic in rats and rabbits at oral doses up to 300 mg/kg; 300 mg/kg of
terfenadine produced fexofenadine AUC values that were approximately 4 and
30 times, respectively, the human AUC at the maximum recommended daily oral
dose in adults.
The combination of terfenadine and pseudoephedrine hydrochloride in a
ratio of 1:2 by weight was studied in rats and rabbits. In rats, an oral
combination dose of 150/300 mg/kg produced reduced fetal weight and delayed
ossification with a finding of wavy ribs. The dose of 150 mg/kg of
terfenadine in rats produced an AUC value of fexofenadine that was
approximately 3 times the human AUC at the maximum recommended daily oral
dose in adults. The dose of 300 mg/kg of pseudoephedrine hydrochloride in
rats was approximately 10 times the maximum recommended daily oral dose in
adults on a mg/m 2 basis. In rabbits, an oral combination dose of
100/200 mg/kg produced decreased fetal weight. By extrapolation, the AUC of
fexofenadine for 100 mg/kg orally of terfenadine was approximately 10 times
the human AUC at the maximum recommended daily oral dose in adults. The dose
of 200 mg/kg of pseudoephedrine hydrochloride was approximately 15 times the
maximum recommended daily oral dose in adults on a mg/m 2 basis.
There are no adequate and well-controlled studies in pregnant women.
ALLEGRA-D 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 an oral dose of 150 mg/kg
of terfenadine; this dose produced an AUC of fexofenadine that was
approximately 3 times the human AUC at the maximum recommended daily oral
dose in adults.
Nursing Mothers
It is not known if fexofenadine is excreted in human milk. Because many
drugs are excreted in human milk, caution should be used when fexofenadine
hydrochloride is administered to a nursing woman. Pseudoephedrine
hydrochloride administered alone distributes into breast milk of lactating
human females. Pseudoephedrine concentrations in milk are consistently
higher than those in plasma. The total amount of drug in milk as judged by
AUC is 2 to 3 times greater than the plasma AUC. The fraction of a
pseudoephedrine dose excreted in milk is estimated to be 0.4% to 0.7%. A
decision should be made whether to discontinue nursing or to discontinue the
drug, taking into account the importance of the drug to the mother. Caution
should be exercised when ALLEGRA-D is administered to nursing women.
Pediatric Use
Safety and effectiveness of ALLEGRA-D in pediatric patients under the age
of 12 years have not been established.
Geriatric Use
Clinical studies of ALLEGRA-D did not include sufficient numbers of
patients aged 65 and older to determine whether they respond differently
from younger patients. Other reported clinical experience has not identified
differences in responses between the elderly and younger patients, although
the elderly are more likely to have adverse reactions to sympathomimetic
amines. In general, dose selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range, reflecting the greater
frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or other drug therapy.
The pseudoephedrine component of ALLEGRA-D is known to be substantially
excreted by the kidney, and the risk of toxic reactions to this drug may be
greater in patients with impaired renal function. Because elderly patients
are more likely to have decreased renal function, care should be taken in
dose selection, and it may be useful to monitor renal function.
ADVERSE REACTIONS
ALLEGRA-D
In one clinical trial (n=651) in which 215 patients with seasonal
allergic rhinitis received the 60 mg fexofenadine hydrochloride/120 mg
pseudoephedrine hydrochloride combination tablet twice daily for up to 2
weeks, adverse events were similar to those reported either in patients
receiving fexofenadine hydrochloride 60 mg alone (n=218 patients) or in
patients receiving pseudoephedrine hydrochloride 120 mg alone (n=218). A
placebo group was not included in this study.
The percent of patients who withdrew prematurely because of adverse
events was 3.7% for the fexofenadine hydrochloride/pseudoephedrine
hydrochloride combination group, 0.5% for the fexofenadine hydrochloride
group, and 4.1% for the pseudoephedrine hydrochloride group. All adverse
events that were reported by greater than 1% of patients who received the
recommended daily dose of the fexofenadine hydrochloride/pseudoephedrine
hydrochloride combination are listed in the following table.
Many of the adverse events occurring in the fexofenadine hydrochloride/pseudoephedrine
hydrochloride combination group were adverse events also reported
predominately in the pseudoephedrine hydrochloride group, such as insomnia,
headache, nausea, dry mouth, dizziness, agitation, nervousness, anxiety, and
palpitation.
Fexofenadine Hydrochloride
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.
Events that have been reported during controlled clinical trials
involving seasonal allergic rhinitis and chronic idiopathic urticaria
patients with incidences less than 1% and similar to placebo and have been
rarely reported during postmarketing surveillance include: insomnia,
nervousness, and sleep disorders or paroniria. In rare cases, rash,
urticaria, pruritus and hypersensitivity reactions with manifestations such
as angioedema, chest tightness, dyspnea, flushing and systemic anaphylaxis
have been reported.
Pseudoephedrine Hydrochloride
Pseudoephedrine hydrochloride may cause mild CNS stimulation in
hypersensitive patients. Nervousness, excitability, restlessness, dizziness,
weakness, or insomnia may occur. Headache, drowsiness, tachycardia,
palpitation, pressor activity, and cardiac arrhythmias have been reported.
Sympathomimetic drugs have also been associated with other untoward effects
such as fear, anxiety, tenseness, tremor, hallucinations, seizures, pallor,
respiratory difficulty, dysuria, and cardiovascular collapse.
OVERDOSAGE
Most reports of fexofenadine hydrochloride overdose contain limited
information. However, dizziness, drowsiness, and dry mouth have been
reported. For the pseudoephedrine hydrochloride component of ALLEGRA-D,
information on acute overdose is limited to the marketing history of
pseudoephedrine hydrochloride. 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 large doses, sympathomimetics may give rise to giddiness, headache,
nausea, vomiting, sweating, thirst, tachycardia, precordial pain,
palpitations, difficulty in micturition, muscular weakness and tenseness,
anxiety, restlessness, and insomnia. Many patients can present a toxic
psychosis with delusions and hallucinations. Some may develop cardiac
arrhythmias, circulatory collapse, convulsions, coma, and respiratory
failure.
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.
The effect of hemodialysis on the removal of pseudoephedrine is unknown.
No deaths occurred in mature mice and rats at oral doses of fexofenadine
hydrochloride up to 5000 mg/kg (approximately 170 and 340 times,
respectively, the maximum recommended daily oral dose in adults on a mg/m
2 basis.) The median oral lethal dose in newborn rats was 438
mg/kg (approximately 30 times the maximum recommended daily oral dose in
adults on a mg/m 2 basis). In dogs, no evidence of toxicity was
observed at oral doses up to 2000 mg/kg (approximately 450 times the maximum
recommended human daily oral dose in adults on a mg/m 2 basis).
The oral median lethal dose of pseudoephedrine hydrochloride in rats was
1674 mg/kg (approximately 55 times the maximum recommended daily oral dose
in adults on a mg/m 2 basis).
DOSAGE AND ADMINISTRATION
The recommended dose of ALLEGRA-D is one tablet twice daily for adults
and children 12 years of age and older. It is recommended that the
administration of ALLEGRA-D with food should be avoided. A dose of one
tablet once daily is recommended as the starting dose in patients with
decreased renal function. (See CLINICAL PHARMACOLOGY and PRECAUTIONS .)
HOW SUPPLIED
ALLEGRA-D (fexofenadine hydrochloride and pseudoephedrine hydrochloride)
Extended-Release Tablets contain 60 mg fexofenadine hydrochloride for
immediate-release and 120 mg pseudoephedrine hydrochloride for
extended-release. ALLEGRA-D (fexofenadine hydrochloride and pseudoephedrine
hydrochloride) Extended-Release Tablets are available in: high-density
polyethylene (HDPE) bottles of 60 (NDC 0088-1090-41) with a polypropylene
child-resistant cap containing a pulp/wax liner with heat-sealed foil inner
seal; HDPE bottles of 100 (NDC 0088-1090-47) with a polypropylene screw cap
containing a pulp/wax liner with heat-sealed foil inner seal; HDPE bottles
of 500 (NDC 0088-1090-55) with a polypropylene screw cap containing a pulp/wax
liner with heat-sealed foil inner seal; and aluminum foil-backed clear
blister packs of 100 (NDC 0088-1090-49).
ALLEGRA-D is a two-layer tablet, one white layer and one tan layer with a
clear film coating on the tablet. The tablets are engraved with "Allegra-D"
on the white layer.
Store ALLEGRA-D Extended-Release Tablets at 20-25°C (68-77°F). (See USP
Controlled Room Temperature.)
Rx only
Prescribing Information as of January 2003
Aventis Pharmaceuticals Inc.
Kansas City, MO 64137 USA
US Patents 4,254,129; 5,375,693; 5,578,610.
©2003 Aventis Pharmaceuticals Inc.
www.allegra.com
alldp0103p
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