Allegra--D 24 Hour

Fexofenadine hydrochloride, the major active metabolite of terfenadine, is an antihistamine with selective peripheral H₁-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 alpha₁-adrenergic-receptor blocking effects were observed. Moreover, no sedative or other central nervous system effects were observed. Radiolabeled tissue distribution studies in rats indicated that fexofenadine does not cross the blood-brain barrier.

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.

The pharmacokinetics of fexofenadine hydrochloride in subjects with seasonal allergic rhinitis were similar to those in healthy volunteers.

Clinical efficacy and safety studies were not conducted with ALLEGRA-D 24 HOUR Extended-Release Tablets. The effectiveness of ALLEGRA-D 24 HOUR for the treatment of seasonal allergic rhinitis is based on an extrapolation of the demonstrated efficacy of ALLEGRA 180 mg and the nasal decongestant properties of pseudoephedrine hydrochloride.

In one 2-week, multicenter, randomized, double-blind clinical trial in subjects 12 to 65 years of age with seasonal allergic rhinitis (n=863), fexofenadine hydrochloride 180 mg once 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. 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.

Because ALLEGRA-D 24 HOUR is a once-daily, fixed-dose combination that cannot be titrated and renal insufficiency increases the bioavailability and prolongs the half-life of fexofenadine hydrochloride and pseudoephedrine hydrochloride, ALLEGRA-D 24 HOUR tablets should generally be avoided in patients with renal insufficiency (see CLINICAL PHARMACOLOGY, and DOSAGE AND ADMINISTRATION).

Patients taking ALLEGRA-D 24 HOUR tablets should receive the following information: ALLEGRA-D 24 HOUR tablets are prescribed for the relief of symptoms of seasonal allergic rhinitis. Patients should be instructed to take ALLEGRA-D 24 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 24 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.

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 was co-administered with either 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_c 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 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 24 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 24 HOUR concomitantly with other sympathomimetic amines because combined effects on the cardiovascular system may be harmful to the patient (see WARNINGS).

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 2 and 3 times, respectively, the exposure from the maximum recommended human daily oral dose of ALLEGRA-D 24 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 (approximately 3 times the maximum recommended human daily oral dose of ALLEGRA-D 24 HOUR based on comparison of the AUCs of fexofenadine). 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 (approximately 3 times the maximum recommended human daily oral dose of ALLEGRA-D 24 HOUR based on comparison of the AUCs). In mice, fexofenadine produced no effect on male or female fertility at average dietary doses up to 4438 mg/kg (approximately 10 times the maximum recommended human daily oral dose of ALLEGRA-D 24 HOUR based on comparison of the AUCs).

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 24 HOUR is administered to nursing women.

Safety and effectiveness of ALLEGRA-D 24 HOUR in children below the age of 12 years have not been established. In addition, the doses of the individual components in ALLEGRA-D 24 HOUR exceed the recommended individual doses for pediatric patients under 12 years of age. ALLEGRA-D 24 HOUR is not recommended for pediatric patients under 12 years of age.

Clinical studies of ALLEGRA-D 24 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 patients, although the elderly are more likely to have adverse reactions to sympathomimetic amines.

The pseudoephedrine component of ALLEGRA-D 24 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, it may be useful to monitor renal function.

In a placebo-controlled clinical study in the United States, which included 570 subjects with seasonal allergic rhinitis aged 12 years and older receiving fexofenadine hydrochloride tablets at doses of 120 or 180 mg once daily, adverse events were similar in fexofenadine hydrochloride and placebo-treated subjects. The following table lists adverse experiences that were reported by greater than 2% of subjects treated with fexofenadine hydrochloride tablets at doses of 180 mg once daily and that were more common with fexofenadine hydrochloride than placebo.

Events that have been reported during controlled clinical trials involving subjects with seasonal allergic rhinitis 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, 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.