Allegra-D 60 MG /120 MG 12HR Extended Release Oral Tablet
WARNINGS
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 CONTRAINDICATIONS).
Sympathomimetic amines may produce central nervous system stimulation with convulsions or cardiovascular collapse with accompanying hypotension.
DRUG INTERACTIONS
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 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 QTc 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.
Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Co-Administration with Fexofenadine Hydrochloride 120 mg Every 12 Hours (two times the recommended twice daily dose) in Healthy Volunteers (n=24) Concomitant Drug Cmax SS (Peak plasma concentration) AUCSS(0–12h) (Extent of systemic exposure) Erythromycin (500 mg every 8 hrs) +82% +109% Ketoconazole (400 mg once daily) +135% +164% 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.
This observed increase in the bioavailability of fexofenadine may be due to transport-related effects, such as p-glycoprotein.
In vivo 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, ALLEGRA-D 12 HOUR is 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 ALLEGRA-D 12 HOUR concomitantly with other sympathomimetic amines because combined effects on the cardiovascular system may be harmful to the patient (see WARNINGS).
Drug Interactions with Antacids Administration of 120 mg of fexofenadine hydrochloride (2 × 60 mg capsule) within 15 minutes of an aluminum and magnesium containing antacid (Maalox®) decreased fexofenadine AUC by 41% and Cmax by 43%.
ALLEGRA-D 12 HOUR should not be taken closely in time with aluminum and magnesium containing antacids.
Interactions with Fruit Juices 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 ALLEGRA-D 12 HOUR should be taken with water (see DOSAGE AND ADMINISTRATION).
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 12 HOUR, 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 ALLEGRA-D 12 HOUR on a mg/m2 basis.) The median oral lethal dose in newborn rats was 438 mg/kg (approximately 30 times the maximum recommended human daily oral dose of ALLEGRA-D 12 HOUR on a mg/m2 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/m2 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 ALLEGRA-D 12 HOUR on a mg/m2 basis).
DESCRIPTION
ALLEGRA-D® 12 HOUR (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 12 HOUR, is a histamine H1-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 C32H39NO4•HCl.
Fexofenadine hydrochloride is a white to off-white crystalline powder.
It is freely soluble in methanol and ethanol, slightly soluble in chloroform and water, and insoluble in hexane.
Fexofenadine hydrochloride is a racemate and exists as a zwitterion in aqueous media at physiological pH.
Pseudoephedrine hydrochloride, the other active ingredient of ALLEGRA-D 12 HOUR, 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 C10H15NO•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.
Chemical Structure Chemical Structure
CLINICAL STUDIES
Clinical Studies In a 2-week, multicenter, randomized, double-blind, active-controlled trial in subjects 12–65 years of age with seasonal allergic rhinitis due to ragweed allergy (n=651), the 60 mg fexofenadine hydrochloride/120 mg pseudoephedrine hydrochloride combination tablet administered twice daily significantly reduced the intensity of sneezing, rhinorrhea, itchy nose/palate/throat, itchy/watery/red eyes, and nasal congestion.
In three, 2-week, multicenter, randomized, double-blind, placebo-controlled trials in subjects 12–68 years of age with seasonal allergic rhinitis (n=1634), fexofenadine hydrochloride 60 mg twice daily significantly reduced total symptom scores (the sum of the individual scores for sneezing, rhinorrhea, itchy nose/palate/throat, itchy/watery/red eyes) compared to placebo.
Statistically significant reductions in symptom scores were observed following the first 60 mg dose, with the effect maintained throughout the 12-hour interval.
In general, there was no additional reduction in total symptom scores with higher doses of fexofenadine hydrochloride up to 240 mg twice daily.
Although the number of subjects in some of the subgroups was small, there were no significant differences in the effect of fexofenadine hydrochloride across subgroups of subjects defined by gender, age, and race.
Onset of action for reduction in total symptom scores, excluding nasal congestion, was observed at 60 minutes compared to placebo following a single 60 mg fexofenadine hydrochloride dose administered to subjects with seasonal allergic rhinitis who were exposed to ragweed pollen in an environmental exposure unit.
HOW SUPPLIED
ALLEGRA-D 12 HOUR Extended-Release Tablets contain 60 mg fexofenadine hydrochloride for immediate release and 120 mg pseudoephedrine hydrochloride for extended release.
ALLEGRA-D 12 HOUR Extended-Release Tablets are available in high-density polyethylene (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 12 HOUR 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 “06/012D” on the white layer.
Store ALLEGRA-D 12 HOUR Extended-Release Tablets at 20–25°C (68–77°F).
(See USP Controlled Room Temperature.)
GERIATRIC USE
Geriatric Use Clinical studies of ALLEGRA-D 12 HOUR 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 ALLEGRA-D 12 HOUR 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.
INDICATIONS AND USAGE
ALLEGRA-D 12 HOUR 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.
ALLEGRA-D 12 HOUR should be administered when both the antihistaminic properties of fexofenadine hydrochloride and the nasal decongestant properties of pseudoephedrine hydrochloride are desired (see CLINICAL PHARMACOLOGY).
PEDIATRIC USE
Pediatric Use Safety and effectiveness of ALLEGRA-D 12 HOUR in children below the age of 12 years have not been established.
In addition, the doses of the individual components in ALLEGRA-D 12 HOUR exceed the recommended individual doses for pediatric patients under 12 years of age.
ALLEGRA-D 12 HOUR is not recommended for pediatric patients under 12 years of age.
PREGNANCY
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 AUC at the maximum recommended human daily oral dose of ALLEGRA-D 12 HOUR.
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 ALLEGRA-D 12 HOUR 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 ALLEGRA-D 12 HOUR.
The dose of 300 mg/kg of pseudoephedrine hydrochloride in rats was approximately 10 times the maximum recommended human daily oral dose of ALLEGRA-D 12 HOUR on a mg/m2 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 ALLEGRA-D 12 HOUR.
The dose of 200 mg/kg of pseudoephedrine hydrochloride was approximately 15 times the maximum recommended human daily oral dose of ALLEGRA-D 12 HOUR on a mg/m2 basis.
There are no adequate and well-controlled studies in pregnant women.
ALLEGRA-D 12 HOUR 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 4 times the AUC at the maximum recommended human daily oral dose of ALLEGRA-D 12 HOUR.
NUSRING MOTHERS
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 12 HOUR is administered to nursing women.
INFORMATION FOR PATIENTS
Information for Patients Patients taking ALLEGRA-D 12 HOUR tablets should receive the following information: ALLEGRA-D 12 HOUR tablets are prescribed for the relief of symptoms of seasonal allergic rhinitis.
Patients should be instructed to take ALLEGRA-D 12 HOUR 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 12 HOUR 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 DOSAGE AND ADMINISTRATION).
DOSAGE AND ADMINISTRATION
The recommended dose of ALLEGRA-D 12 HOUR 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 ALLEGRA-D 12 HOUR 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.) ALLEGRA-D 12 HOUR must be swallowed whole and never crushed or chewed.
Occasionally, the inactive ingredients of ALLEGRA-D 12 HOUR may be eliminated in the feces in a form that may resemble the original tablet.
(See PRECAUTIONS, Information for Patients.)