warnings and cautions
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. PRECAUTIONS General 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 ). Information for Patients 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. 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 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: 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 C max SS (Peak plasma concentration) AUC ss(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 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 ). 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 C max by 43%. ALLEGRA-D 24 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 bioequivalence study data, the bioavailability of fexofenadine was reduced by 36%. Therefore, to maximize the effects of fexofenadine, it is recommended that ALLEGRA-D 24 HOUR should be taken with water (see DOSAGE AND ADMINISTRATION ). 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 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/m 2 basis). In in vitro (Bacterial Reverse Mutation, CHO/HGPRT Forward Mutation, and Rat Lymphocyte Chromosomal Aberration assays) and in vivo (Mouse Bone Marrow Micronucleus assay) tests, fexofenadine hydrochloride revealed no evidence of mutagenicity. Reproduction and fertility studies with terfenadine in rats produced no effect on male or female fertility at oral doses up to 300 mg/kg/day (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). Pregnancy Teratogenic Effects Category C Terfenadine alone was not teratogenic in rats at oral doses up to 300 mg/kg (approximately 3 times the maximum recommended human daily oral dose of ALLEGRA-D 24 HOUR based on comparison of the AUCs of fexofenadine) and in rabbits at oral doses up to 300 mg/kg (approximately 25 times the maximum recommended human daily oral dose of ALLEGRA-D 24 HOUR based on comparison of the AUCs of fexofenadine). In mice, no adverse effects and no teratogenic effects during gestation were observed with fexofenadine at dietary doses up to 3730 mg/kg (approximately 10 times the maximum recommended human daily oral dose of ALLEGRA-D 24 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 3 times the AUC of the maximum recommended human daily oral dose of ALLEGRA-D 24 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 24 HOUR on a mg/m 2 basis. In rabbits, an oral combination dose of 100/200 mg/kg produced decreased fetal weight. By extrapolation, the AUC of fexofenadine for 100 mg/kg orally of terfenadine was approximately 8 times the human AUC of the maximum recommended human daily oral dose of ALLEGRA-D 24 HOUR. The dose of 200 mg/kg of pseudoephedrine hydrochloride was approximately 15 times the maximum recommended human daily oral dose of ALLEGRA-D 24 HOUR on a mg/m 2 basis. There are no adequate and well-controlled studies in pregnant women. ALLEGRA-D 24 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 3 times the human AUC of the maximum recommended human daily oral dose of ALLEGRA-D 24 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 24 HOUR is administered to nursing women. Pediatric Use 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. Geriatric Use 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.