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FEXOFENADINE HYDROCHLORIDE and PSEUDOEPHEDRINE HYDROCHLORIDE
Overview
What is FEXOFENADINE HYDROCHLORIDE and PSEUDOEPHEDRINE HYDROCHLORIDE?
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, is a histamine
H-receptor antagonist with the chemical name
(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,
α-dimethyl benzeneacetic acid hydrochloride and the following chemical
structure:
The molecular weight is 538.13 and the empirical formula is CHNO•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, is an adrenergic
(vasoconstrictor) agent with the chemical name
[S-(R*,R*)]-α-[1-(methylamino)ethyl]-benzenemethanol hydrochloride and the
following chemical structure:
The molecular weight is 201.70. The molecular formula is CHNO•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.
What does FEXOFENADINE HYDROCHLORIDE and PSEUDOEPHEDRINE HYDROCHLORIDE look like?
What are the available doses of FEXOFENADINE HYDROCHLORIDE and PSEUDOEPHEDRINE HYDROCHLORIDE?
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What should I talk to my health care provider before I take FEXOFENADINE HYDROCHLORIDE and PSEUDOEPHEDRINE HYDROCHLORIDE?
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How should I use FEXOFENADINE HYDROCHLORIDE and PSEUDOEPHEDRINE HYDROCHLORIDE?
Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride
Extended-Release Tablets are 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.
Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release
Tablets should be administered when both the antihistaminic properties of
fexofenadine hydrochloride and the nasal decongestant properties of
pseudoephedrine hydrochloride are desired (see ).
The recommended dose of Fexofenadine Hydrochloride and
Pseudoephedrine Hydrochloride Extended-Release Tablets is one tablet twice daily
administered on an empty stomach with water for adults and children 12 years of
age and older. It is recommended that the administration of Fexofenadine
Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets 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 and .)
Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release
Tablets must be swallowed whole and never crushed or chewed. Occasionally, the
inactive ingredients of Fexofenadine Hydrochloride and Pseudoephedrine
Hydrochloride Extended-Release Tablets may be eliminated in the feces in a form
that may resemble the original tablet. (See .)
What interacts with FEXOFENADINE HYDROCHLORIDE and PSEUDOEPHEDRINE HYDROCHLORIDE?
Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are contraindicated in patients with known hypersensitivity to any of its ingredients.
Due to its pseudoephedrine component, Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are 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 section). It is also contraindicated in patients with severe hypertension, or severe coronary artery disease, and in those who have shown 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.
What are the warnings of FEXOFENADINE HYDROCHLORIDE and PSEUDOEPHEDRINE HYDROCHLORIDE?
Lithium toxicity is closely related to serum lithium levels, and can occur at doses close to therapeutic levels (see ).
What are the precautions of FEXOFENADINE HYDROCHLORIDE and PSEUDOEPHEDRINE HYDROCHLORIDE?
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
and ).
Patients taking Fexofenadine Hydrochloride and Pseudoephedrine
Hydrochloride Extended-Release Tablets should receive the following information:
Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release
Tablets are prescribed for the relief of symptoms of seasonal allergic rhinitis.
Patients should be instructed to take Fexofenadine Hydrochloride and
Pseudoephedrine Hydrochloride Extended-Release Tablets only as prescribed. If nervousness, dizziness,
or sleeplessness occur, discontinue use and consult the doctor. Patients should
also be advised against the concurrent use of Fexofenadine Hydrochloride and
Pseudoephedrine Hydrochloride Extended-Release 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 advised to take the tablet on an
empty stomach with water. Patients should be directed to swallow the tablet
whole. Patients should be cautioned not to break or chew the tablet. Patients
should also be instructed to store the medication in a tightly closed container
in a cool, dry place, away from children.
Patients should be told that the inactive ingredients may occasionally be
eliminated in the feces in a form that may resemble the original tablet (see ).
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 hydrochloride with either ketoconazole or
erythromycin led to increased plasma concentrations of fexofenadine.
Fexofenadine had no effect on the pharmacokinetics of either erythromycin or
ketoconazole. In 2 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
healthy volunteers (n=24, each study). No differences in adverse events or
QT interval were observed when subjects were
administered fexofenadine hydrochloride alone or in combination with either
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 , and animal models. These studies indicate that
ketoconazole or erythromycin co-administration enhances fexofenadine
gastrointestinal absorption. This observed increase in the bioavailability of
fexofenadine may be due to transport-related effects, such as p-glycoprotein.
animal studies also suggest that in addition
to enhancing absorption, ketoconazole decreases fexofenadine gastrointestinal
secretion, while erythromycin may also decrease biliary excretion.
Due to the pseudoephedrine component, Fexofenadine Hydrochloride and
Pseudoephedrine Hydrochloride Extended-Release Tablets 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 (e.g., 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 Fexofenadine Hydrochloride and Pseudoephedrine
Hydrochloride Extended-Release Tablets concomitantly with other sympathomimetic
amines because combined effects on the cardiovascular system may be harmful to
the patient (see ).
Administration of 120 mg of fexofenadine hydrochloride (2 x 60 mg
capsule) within 15 minutes of an aluminum and magnesium containing antacid
(Maalox®) decreased fexofenadine AUC by 41% and C by
43%. Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride
Extended-Release Tablets should not be taken closely in time with aluminum and
magnesium containing antacids.
Fruit juices such as grapefruit, orange and apple may reduce the
bioavailability and exposure of fexofenadine. This is based on the results from
3 clinical studies using histamine induced skin wheals and flares coupled with
population pharmacokinetic analysis. The size of wheal and flare were
significantly larger when fexofenadine hydrochloride was administered with
either grapefruit or orange juices compared to water. Based on the literature
reports, the same effects may be extrapolated to other fruit juices such as
apple juice. The clinical significance of these observations is unknown. In
addition, based on the population pharmacokinetics analysis of the combined data
from grapefruit and orange juices studies with the data from a bioequivalence
study, the bioavailability of fexofenadine was reduced by 36%. Therefore, to
maximize the effects of fexofenadine, it is recommended that Fexofenadine
Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets should
be taken with water (see ).
There are no animal or
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 human daily
oral dose of Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride
Extended-Release Tablets.
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 (less than the maximum recommended human daily oral dose of
pseudoephedrine hydrochloride on a mg/m basis).
In (Bacterial Reverse Mutation, CHO/HGPRT
Forward Mutation, and Rat Lymphocyte Chromosomal Aberration assays) and (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 4 times the AUC at the maximum recommended human daily
oral dose of Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride
Extended-Release Tablets. In mice, fexofenadine produced no effect on male or
female fertility at average dietary doses up to 4438 mg/kg (approximately 15
times the maximum recommended human daily oral dose of Fexofenadine
Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets based
on comparison of the AUCs).
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 AUC at the maximum
recommended human daily oral dose of Fexofenadine Hydrochloride and
Pseudoephedrine Hydrochloride Extended-Release Tablets.
In mice, no adverse effects and no teratogenic effects during gestation were
observed with fexofenadine at dietary doses up to 3730 mg/kg (approximately 15
times the maximum recommended human daily oral dose of Fexofenadine
Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets based
on comparison of the AUCs).
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 4 times the AUC at
the maximum recommended human daily oral dose of Fexofenadine Hydrochloride and
Pseudoephedrine Hydrochloride Extended-Release Tablets. The dose of 300 mg/kg of
pseudoephedrine hydrochloride in rats was approximately 10 times the maximum
recommended human daily oral dose of Fexofenadine Hydrochloride and
Pseudoephedrine Hydrochloride Extended-Release Tablets on a mg/m 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 AUC at the
maximum recommended human daily oral dose of Fexofenadine Hydrochloride and
Pseudoephedrine Hydrochloride Extended-Release Tablets. The dose of 200 mg/kg of
pseudoephedrine hydrochloride was approximately 15 times the maximum recommended
human daily oral dose of Fexofenadine Hydrochloride and Pseudoephedrine
Hydrochloride Extended-Release Tablets on a mg/m
basis.
There are no adequate and well-controlled studies in pregnant women.
Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release
Tablets should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
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 4 times the AUC at the
maximum recommended human daily oral dose of Fexofenadine Hydrochloride and
Pseudoephedrine Hydrochloride Extended-Release Tablets.
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
Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release
Tablets are administered to nursing women.
Safety and effectiveness of Fexofenadine Hydrochloride and
Pseudoephedrine Hydrochloride Extended-Release Tablets in children below the age
of 12 years have not been established. In addition, the doses of the individual
components in Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride
Extended-Release Tablets exceed the recommended individual doses for pediatric
patients under 12 years of age. Fexofenadine Hydrochloride and Pseudoephedrine
Hydrochloride Extended-Release Tablets are not recommended for pediatric
patients under 12 years of age.
Clinical studies of Fexofenadine Hydrochloride and
Pseudoephedrine Hydrochloride Extended-Release Tablets did not include
sufficient numbers of subjects aged 65 and older to determine whether they
respond differently from younger subjects. Other reported clinical experience
has not identified differences in responses between the elderly and younger
subjects, although the elderly are more likely to have adverse reactions to
sympathomimetic amines.
The pseudoephedrine component of Fexofenadine Hydrochloride and
Pseudoephedrine Hydrochloride Extended-Release Tablets 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.
| Concomitant Drug | C (Peak plasma concentration) | AUC(0–12h)(Extent of systemic exposure) |
|---|---|---|
| Erythromycin(500 mg every 8 hrs) | +82% | +109% |
| Ketoconazole(400 mg once daily) | +135% | +164% |
What are the side effects of FEXOFENADINE HYDROCHLORIDE and PSEUDOEPHEDRINE HYDROCHLORIDE?
In one clinical trial (n=651) in which 215 subjects 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 subjects receiving
fexofenadine hydrochloride 60 mg alone (n=218 subjects) or in subjects receiving
pseudoephedrine hydrochloride 120 mg alone (n=218). A placebo group was not
included in this study.
The percent of subjects 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 subjects 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.
In placebo-controlled clinical trials, which included 2461
subjects receiving fexofenadine hydrochloride at doses of 20 mg to 240 mg twice
daily, adverse events were similar in fexofenadine hydrochloride and
placebo-treated subjects. 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 subjects 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
subjects with seasonal allergic rhinitis and chronic idiopathic urticaria at
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 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.
| Adverse Experience | 60 mg Fexofenadine Hydrochloride/120 mg Pseudoephedrine Hydrochloride Combination Tablet Twice Daily(n=215) | Fexofenadine Hydrochloride 60 mg Twice Daily(n=218) | Pseudoephedrine Hydrochloride 120 mg Twice Daily(n=218) |
|---|---|---|---|
| Headache | 13.0% | 11.5% | 17.4% |
| Insomnia | 12.6% | 3.2% | 13.3% |
| Nausea | 7.4% | 0.5% | 5.0% |
| Dry Mouth | 2.8% | 0.5% | 5.5% |
| Dyspepsia | 2.8% | 0.5% | 0.9% |
| Throat Irritation | 2.3% | 1.8% | 0.5% |
| Dizziness | 1.9% | 0.0% | 3.2% |
| Agitation | 1.9% | 0.0% | 1.4% |
| Back Pain | 1.9% | 0.5% | 0.5% |
| Palpitation | 1.9% | 0.0% | 0.9% |
| Nervousness | 1.4% | 0.5% | 1.8% |
| Anxiety | 1.4% | 0.0% | 1.4% |
| Upper Respiratory Infection | 1.4% | 0.9% | 0.9% |
| Abdominal Pain | 1.4% | 0.5% | 0.5% |
What should I look out for while using FEXOFENADINE HYDROCHLORIDE and PSEUDOEPHEDRINE HYDROCHLORIDE?
Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride
Extended-Release Tablets are contraindicated in patients with known
hypersensitivity to any of its ingredients.
Due to its pseudoephedrine component, Fexofenadine Hydrochloride and
Pseudoephedrine Hydrochloride Extended-Release Tablets are 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 section).
It is also contraindicated in patients with severe hypertension, or severe
coronary artery disease, and in those who have shown 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.
Sympathomimetic amines should be used with caution in patients with
hypertension, diabetes mellitus, ischemic heart disease, increased intraocular
pressure, hyperthyroidism, renal impairment, or prostatic hypertrophy (see ). Sympathomimetic amines may
produce central nervous system stimulation with convulsions or cardiovascular
collapse with accompanying hypotension.
What might happen if I take too much FEXOFENADINE HYDROCHLORIDE and PSEUDOEPHEDRINE HYDROCHLORIDE?
Most reports of fexofenadine hydrochloride overdose contain
limited information. However, dizziness, drowsiness, and dry mouth have been
reported. For the pseudoephedrine hydrochloride component of Fexofenadine
Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets,
information on acute overdose is limited to the marketing history of
pseudoephedrine hydrochloride. Single doses of fexofenadine hydrochloride up to
800 mg (6 healthy volunteers at this dose level), and doses up to 690 mg twice
daily for one month (3 healthy 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. Following
administration of terfenadine, hemodialysis did not effectively remove
fexofenadine, the major active metabolite of terfenadine, from blood (up to 1.7%
removed). 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 human daily oral dose of Fexofenadine Hydrochloride and
Pseudoephedrine Hydrochloride Extended-Release Tablets on a mg/m basis.) The median oral lethal dose in newborn rats was 438
mg/kg (approximately 30 times the maximum recommended human daily oral dose of
Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release
Tablets on a mg/m 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 on a mg/m
basis). The oral median lethal dose of pseudoephedrine hydrochloride in rats was
1674 mg/kg (approximately 55 times the maximum recommended human daily oral dose
of Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release
Tablets on a mg/m basis).
How should I store and handle FEXOFENADINE HYDROCHLORIDE and PSEUDOEPHEDRINE HYDROCHLORIDE?
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP] .Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets contain 60 mg fexofenadine hydrochloride for immediate release and 120 mg pseudoephedrine hydrochloride for extended release. Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are available in high-density polyethylene (HDPE) bottles of 10 (); bottles of 30 () and bottles of 60 ().Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are two-layer tablets, one white layer and one tan layer with a clear film coating on the tablets. The tablets are engraved with "93 T13" on the white layer.Store Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets at 20–25°C (68–77°F). (See USP Controlled Room Temperature.)Rev. June 2009Manufactured by:sanofi-aventis U.S. LLCBridgewater, NJ 08807Manufactured for:TEVA PHARMACEUTICALS USASellersville, PA 18960©2009 sanofi-aventis U.S. LLC50090574Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets contain 60 mg fexofenadine hydrochloride for immediate release and 120 mg pseudoephedrine hydrochloride for extended release. Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are available in high-density polyethylene (HDPE) bottles of 10 (); bottles of 30 () and bottles of 60 ().Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are two-layer tablets, one white layer and one tan layer with a clear film coating on the tablets. The tablets are engraved with "93 T13" on the white layer.Store Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets at 20–25°C (68–77°F). (See USP Controlled Room Temperature.)Rev. June 2009Manufactured by:sanofi-aventis U.S. LLCBridgewater, NJ 08807Manufactured for:TEVA PHARMACEUTICALS USASellersville, PA 18960©2009 sanofi-aventis U.S. LLC50090574Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets contain 60 mg fexofenadine hydrochloride for immediate release and 120 mg pseudoephedrine hydrochloride for extended release. Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are available in high-density polyethylene (HDPE) bottles of 10 (); bottles of 30 () and bottles of 60 ().Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are two-layer tablets, one white layer and one tan layer with a clear film coating on the tablets. The tablets are engraved with "93 T13" on the white layer.Store Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets at 20–25°C (68–77°F). (See USP Controlled Room Temperature.)Rev. June 2009Manufactured by:sanofi-aventis U.S. LLCBridgewater, NJ 08807Manufactured for:TEVA PHARMACEUTICALS USASellersville, PA 18960©2009 sanofi-aventis U.S. LLC50090574Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets contain 60 mg fexofenadine hydrochloride for immediate release and 120 mg pseudoephedrine hydrochloride for extended release. Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are available in high-density polyethylene (HDPE) bottles of 10 (); bottles of 30 () and bottles of 60 ().Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are two-layer tablets, one white layer and one tan layer with a clear film coating on the tablets. The tablets are engraved with "93 T13" on the white layer.Store Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets at 20–25°C (68–77°F). (See USP Controlled Room Temperature.)Rev. June 2009Manufactured by:sanofi-aventis U.S. LLCBridgewater, NJ 08807Manufactured for:TEVA PHARMACEUTICALS USASellersville, PA 18960©2009 sanofi-aventis U.S. LLC50090574Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets contain 60 mg fexofenadine hydrochloride for immediate release and 120 mg pseudoephedrine hydrochloride for extended release. Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are available in high-density polyethylene (HDPE) bottles of 10 (); bottles of 30 () and bottles of 60 ().Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are two-layer tablets, one white layer and one tan layer with a clear film coating on the tablets. The tablets are engraved with "93 T13" on the white layer.Store Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets at 20–25°C (68–77°F). (See USP Controlled Room Temperature.)Rev. June 2009Manufactured by:sanofi-aventis U.S. LLCBridgewater, NJ 08807Manufactured for:TEVA PHARMACEUTICALS USASellersville, PA 18960©2009 sanofi-aventis U.S. LLC50090574Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets contain 60 mg fexofenadine hydrochloride for immediate release and 120 mg pseudoephedrine hydrochloride for extended release. Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are available in high-density polyethylene (HDPE) bottles of 10 (); bottles of 30 () and bottles of 60 ().Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are two-layer tablets, one white layer and one tan layer with a clear film coating on the tablets. The tablets are engraved with "93 T13" on the white layer.Store Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets at 20–25°C (68–77°F). (See USP Controlled Room Temperature.)Rev. June 2009Manufactured by:sanofi-aventis U.S. LLCBridgewater, NJ 08807Manufactured for:TEVA PHARMACEUTICALS USASellersville, PA 18960©2009 sanofi-aventis U.S. LLC50090574Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets contain 60 mg fexofenadine hydrochloride for immediate release and 120 mg pseudoephedrine hydrochloride for extended release. Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are available in high-density polyethylene (HDPE) bottles of 10 (); bottles of 30 () and bottles of 60 ().Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are two-layer tablets, one white layer and one tan layer with a clear film coating on the tablets. The tablets are engraved with "93 T13" on the white layer.Store Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets at 20–25°C (68–77°F). (See USP Controlled Room Temperature.)Rev. June 2009Manufactured by:sanofi-aventis U.S. LLCBridgewater, NJ 08807Manufactured for:TEVA PHARMACEUTICALS USASellersville, PA 18960©2009 sanofi-aventis U.S. LLC50090574Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets contain 60 mg fexofenadine hydrochloride for immediate release and 120 mg pseudoephedrine hydrochloride for extended release. Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are available in high-density polyethylene (HDPE) bottles of 10 (); bottles of 30 () and bottles of 60 ().Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are two-layer tablets, one white layer and one tan layer with a clear film coating on the tablets. The tablets are engraved with "93 T13" on the white layer.Store Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets at 20–25°C (68–77°F). (See USP Controlled Room Temperature.)Rev. June 2009Manufactured by:sanofi-aventis U.S. LLCBridgewater, NJ 08807Manufactured for:TEVA PHARMACEUTICALS USASellersville, PA 18960©2009 sanofi-aventis U.S. LLC50090574Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets contain 60 mg fexofenadine hydrochloride for immediate release and 120 mg pseudoephedrine hydrochloride for extended release. Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are available in high-density polyethylene (HDPE) bottles of 10 (); bottles of 30 () and bottles of 60 ().Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are two-layer tablets, one white layer and one tan layer with a clear film coating on the tablets. The tablets are engraved with "93 T13" on the white layer.Store Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets at 20–25°C (68–77°F). (See USP Controlled Room Temperature.)Rev. June 2009Manufactured by:sanofi-aventis U.S. LLCBridgewater, NJ 08807Manufactured for:TEVA PHARMACEUTICALS USASellersville, PA 18960©2009 sanofi-aventis U.S. LLC50090574
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Fexofenadine hydrochloride, the major active metabolite of
terfenadine, is an antihistamine with selective peripheral H-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-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.
The pharmacokinetics of fexofenadine hydrochloride in subjects
with seasonal allergic rhinitis were similar to those in healthy
volunteers.
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 the 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 Fexofenadine Hydrochloride and Pseudoephedrine
Hydrochloride Extended-Release Tablets with a high fat meal decreased the
bioavailability of fexofenadine by approximately 50% (AUC 42% and Cmax 46%).
Time to maximum concentration (T) was delayed by 50%.
The rate or extent of pseudoephedrine absorption was not affected by food.
Therefore, Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride
Extended-Release Tablets should be taken on an empty stomach with water (see ).
Fexofenadine is 60% to 70% bound to plasma proteins, primarily
albumin and α-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 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 [C]
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.
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.
In older subjects (greater than or equal to 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.
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 less than or equal to 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 ).
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.
Across several trials, no clinically significant gender-related
differences were observed in the pharmacokinetics of fexofenadine
hydrochloride.
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.
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
QT 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 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 QT
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
QT 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 QT 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.
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.
Non-Clinical Toxicology
Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are contraindicated in patients with known hypersensitivity to any of its ingredients.Due to its pseudoephedrine component, Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are 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 section). It is also contraindicated in patients with severe hypertension, or severe coronary artery disease, and in those who have shown 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.
Sympathomimetic amines should be used with caution in patients with hypertension, diabetes mellitus, ischemic heart disease, increased intraocular pressure, hyperthyroidism, renal impairment, or prostatic hypertrophy (see ). Sympathomimetic amines may produce central nervous system stimulation with convulsions or cardiovascular collapse with accompanying hypotension.
Combined use of haloperidol and lithium. An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN and FBS) followed by irreversible brain damage has occurred in a few patients treated with lithium plus haloperidol. A causal relationship between these events and the concomitant administration of lithium and haloperidol has not been established; however, patients receiving such combined therapy should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear.
The possibility of similar adverse interactions with other antipsychotic medication exists.
Lithium may prolong the effects of neuromuscular blocking agents. Therefore, neuromuscular blocking agents should be given with caution to patients receiving lithium.
Caution should be used when lithium and diuretics or angiotensin converting enzyme (ACE) inhibitors are used concomitantly because sodium loss may reduce the renal clearance of lithium and increase serum lithium levels with risk of lithium toxicity. When such combinations are used, the lithium dosage may need to be decreased, and more frequent monitoring of lithium plasma levels is recommended.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDS): Lithium levels should be closely monitored when patients initiate or discontinue NSAID use. In some cases, lithium toxicity has resulted from interactions between an NSAID and lithium. Indomethacin and piroxicam have been reported to increase significantly steady-state plasma lithium concentrations. There is also evidence that other nonsteriodal anti-inflammatory agents, including the selective cyclooxygenase-2 (COX-2) inhibitors, have the same effect. In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg BID with celecoxib 200 mg BID as compared to subjects receiving lithium alone.
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 and ).
Patients taking Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets should receive the following information: Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are prescribed for the relief of symptoms of seasonal allergic rhinitis. Patients should be instructed to take Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets only as prescribed. If nervousness, dizziness, or sleeplessness occur, discontinue use and consult the doctor. Patients should also be advised against the concurrent use of Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release 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 advised to take the tablet on an empty stomach with water. Patients should be directed to swallow the tablet whole. Patients should be cautioned not to break or chew the tablet. Patients should also be instructed to store the medication in a tightly closed container in a cool, dry place, away from children.
Patients should be told that the inactive ingredients may occasionally be eliminated in the feces in a form that may resemble the original tablet (see ).
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 hydrochloride with either ketoconazole or erythromycin led to increased plasma concentrations of fexofenadine. Fexofenadine had no effect on the pharmacokinetics of either erythromycin or ketoconazole. In 2 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 healthy volunteers (n=24, each study). No differences in adverse events or QT interval were observed when subjects were administered fexofenadine hydrochloride alone or in combination with either 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 , and animal models. These studies indicate that ketoconazole or erythromycin co-administration enhances fexofenadine gastrointestinal absorption. This observed increase in the bioavailability of fexofenadine may be due to transport-related effects, such as p-glycoprotein. animal studies also suggest that in addition to enhancing absorption, ketoconazole decreases fexofenadine gastrointestinal secretion, while erythromycin may also decrease biliary excretion.
Due to the pseudoephedrine component, Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets 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 (e.g., 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 Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets concomitantly with other sympathomimetic amines because combined effects on the cardiovascular system may be harmful to the patient (see ).
Administration of 120 mg of fexofenadine hydrochloride (2 x 60 mg capsule) within 15 minutes of an aluminum and magnesium containing antacid (Maalox®) decreased fexofenadine AUC by 41% and C by 43%. Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets should not be taken closely in time with aluminum and magnesium containing antacids.
Fruit juices such as grapefruit, orange and apple may reduce the bioavailability and exposure of fexofenadine. This is based on the results from 3 clinical studies using histamine induced skin wheals and flares coupled with population pharmacokinetic analysis. The size of wheal and flare were significantly larger when fexofenadine hydrochloride was administered with either grapefruit or orange juices compared to water. Based on the literature reports, the same effects may be extrapolated to other fruit juices such as apple juice. The clinical significance of these observations is unknown. In addition, based on the population pharmacokinetics analysis of the combined data from grapefruit and orange juices studies with the data from a bioequivalence study, the bioavailability of fexofenadine was reduced by 36%. Therefore, to maximize the effects of fexofenadine, it is recommended that Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets should be taken with water (see ).
There are no animal or 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 human daily oral dose of Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets.
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 (less than the maximum recommended human daily oral dose of pseudoephedrine hydrochloride on a mg/m basis).
In (Bacterial Reverse Mutation, CHO/HGPRT Forward Mutation, and Rat Lymphocyte Chromosomal Aberration assays) and (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 4 times the AUC at the maximum recommended human daily oral dose of Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets. In mice, fexofenadine produced no effect on male or female fertility at average dietary doses up to 4438 mg/kg (approximately 15 times the maximum recommended human daily oral dose of Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets based on comparison of the AUCs).
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 AUC at the maximum recommended human daily oral dose of Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets.
In mice, no adverse effects and no teratogenic effects during gestation were observed with fexofenadine at dietary doses up to 3730 mg/kg (approximately 15 times the maximum recommended human daily oral dose of Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets based on comparison of the AUCs).
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 4 times the AUC at the maximum recommended human daily oral dose of Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets. The dose of 300 mg/kg of pseudoephedrine hydrochloride in rats was approximately 10 times the maximum recommended human daily oral dose of Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets on a mg/m 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 AUC at the maximum recommended human daily oral dose of Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets. The dose of 200 mg/kg of pseudoephedrine hydrochloride was approximately 15 times the maximum recommended human daily oral dose of Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets on a mg/m basis.
There are no adequate and well-controlled studies in pregnant women. Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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 4 times the AUC at the maximum recommended human daily oral dose of Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets.
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 Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are administered to nursing women.
Safety and effectiveness of Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets in children below the age of 12 years have not been established. In addition, the doses of the individual components in Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets exceed the recommended individual doses for pediatric patients under 12 years of age. Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets are not recommended for pediatric patients under 12 years of age.
Clinical studies of Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects, although the elderly are more likely to have adverse reactions to sympathomimetic amines.
The pseudoephedrine component of Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets 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.
In one clinical trial (n=651) in which 215 subjects 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 subjects receiving fexofenadine hydrochloride 60 mg alone (n=218 subjects) or in subjects receiving pseudoephedrine hydrochloride 120 mg alone (n=218). A placebo group was not included in this study.
The percent of subjects 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 subjects 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.
In placebo-controlled clinical trials, which included 2461 subjects receiving fexofenadine hydrochloride at doses of 20 mg to 240 mg twice daily, adverse events were similar in fexofenadine hydrochloride and placebo-treated subjects. 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 subjects 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 subjects with seasonal allergic rhinitis and chronic idiopathic urticaria at 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 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.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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