Allegra-D

Allegra-D information, interactions and side effects, ALLEGRA-D® 12 HOUR (fexofenadine hcl and pseudoephedrine hcl) (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 (fexofenadine hcl and pseudoephedrine hcl) 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:

Allegra-D

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 (fexofenadine hcl and pseudoephedrine hcl) 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:

Allegra-D2

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.

INDICATIONS

ALLEGRA-D (fexofenadine hcl and pseudoephedrine hcl) 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 (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR should be administered when both the antihistaminic properties of fexofenadine hydrochloride and the nasal decongestant properties of pseudoephedrine hydrochloride are desired.

DOSAGE AND ADMINISTRATION

The recommended dose of ALLEGRA-D (fexofenadine hcl and pseudoephedrine hcl) 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 (fexofenadine hcl and pseudoephedrine hcl) 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.

ALLEGRA-D (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of ALLEGRA-D (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR may be eliminated in the feces in a form that may resemble the original tablet.

HOW SUPPLIED

ALLEGRA-D (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR Extended-Release Tablets contain 60 mg fexofenadine hydrochloride for immediate release and 120 mg pseudoephedrine hydrochloride for extended release. ALLEGRA-D (fexofenadine hcl and pseudoephedrine hcl) 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 (fexofenadine hcl and pseudoephedrine hcl) 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 (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR Extended-Release Tablets at 20-25°C (68-77°F).

SIDE EFFECTS

ALLEGRA-D (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR

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.

Adverse Experiences Reported in One Active-Controlled Seasonal Allergic Rhinitis Clinical Trial at Rates of Greater than 1%

 

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%

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 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

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, cardiac arrhythmias and ischemic colitis 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.

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 (fexofenadine hcl and pseudoephedrine hcl) 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 (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR concomitantly with other sympathomimetic amines because combined effects on the cardiovascular system may be harmful to the patient.

Drug Interactions with Antacids

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 Cmax by 43%. ALLEGRA-D (fexofenadine hcl and pseudoephedrine hcl) 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.

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. Sympathomimetic amines may produce central nervous system stimulation with convulsions or cardiovascular collapse with accompanying hypotension.

PRECAUTIONS

General

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.

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 human daily oral dose of ALLEGRA-D (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR.

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/m2 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 4 times the AUC at the maximum recommended human daily oral dose of ALLEGRA-D (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR. 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 ALLEGRA-D (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR based on comparison of the AUCs).

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 (fexofenadine hcl and pseudoephedrine hcl) 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 (fexofenadine hcl and pseudoephedrine hcl) 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 (fexofenadine hcl and pseudoephedrine hcl) 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 (fexofenadine hcl and pseudoephedrine hcl) 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 (fexofenadine hcl and pseudoephedrine hcl) 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 (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR on a mg/m2 basis.

There are no adequate and well-controlled studies in pregnant women. ALLEGRA-D (fexofenadine hcl and pseudoephedrine hcl) 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 (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR.

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 (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR is administered to nursing women.

Pediatric Use

Safety and effectiveness of ALLEGRA-D (fexofenadine hcl and pseudoephedrine hcl) 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 (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR exceed the recommended individual doses for pediatric patients under 12 years of age. ALLEGRA-D (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR is not recommended for pediatric patients under 12 years of age.

Geriatric Use

Clinical studies of ALLEGRA-D (fexofenadine hcl and pseudoephedrine hcl) 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 (fexofenadine hcl and pseudoephedrine hcl) 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.

OVERDOSE

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 (fexofenadine hcl and pseudoephedrine hcl) 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 (fexofenadine hcl and pseudoephedrine hcl) 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 (fexofenadine hcl and pseudoephedrine hcl) 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 (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR on a mg/m2 basis).

CONTRAINDICATIONS

ALLEGRA-D (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR is contraindicated in patients with known hypersensitivity to any of its ingredients.

Due to its pseudoephedrine component, ALLEGRA-D (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR 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. 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.

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