Allegra (Fexofenadine Hydrochloride) - Drug Interactions, Contraindications, Overdosage

Rev.

sanofi-aventis U.S. LLC
Bridgewater, NJ 08807

ALLEGRA ODT manufactured for:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807

©2006 sanofi-aventis U.S. LLC

DRUG INTERACTIONS

Drug Interaction with Erythromycin and Ketoconazole

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 in healthy adult subjects. Fexofenadine had no effect on the pharmacokinetics of either erythromycin or ketoconazole. In 2 separate studies in healthy adult subjects, fexofenadine hydrochloride 120 mg twice daily (240 mg total daily dose) was co-administered with either erythromycin 500 mg every 8 hours or ketoconazole 400 mg once daily under steady-state conditions to healthy adult subjects (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 in healthy adult subjects (n=24)

Concomitant Drug	CmaxSS (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.

Drug Interactions with Antacids

In healthy adult subjects, 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%. Fexofenadine hydrochloride 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 Tablets should be taken with water (see Pharmacokinetics and DOSAGE AND ADMINISTRATION).

ALLEGRA ODT can be taken with or without water. (See Pharmacokinetics and DOSAGE AND ADMINISTRATION.)

OVERDOSAGE

Reports of fexofenadine hydrochloride overdose have been infrequent and contain limited information. However, dizziness, drowsiness, and dry mouth have been reported. Single doses of fexofenadine hydrochloride up to 800 mg (6 healthy subjects at this dose level), and doses up to 690 mg twice daily for 1 month (3 healthy subjects at this dose level) or 240 mg once daily for 1 year (234 healthy subjects at this dose level) were administered without the development of clinically significant adverse events as compared to placebo.

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).

No deaths occurred at oral doses of fexofenadine hydrochloride up to 5000 mg/kg in mice (110 times the maximum recommended daily oral dose in adults and children based on mg/m²) and up to 5000 mg/kg in rats (230 times the maximum recommended daily oral dose in adults and 210 times the maximum recommended daily oral dose in children based on mg/m²). Additionally, no clinical signs of toxicity or gross pathological findings were observed. In dogs, no evidence of toxicity was observed at oral doses up to 2000 mg/kg (300 times the maximum recommended daily oral dose in adults and 280 times the maximum recommended daily oral dose in children based on mg/m²).

CONTRAINDICATIONS

ALLEGRA tablets, ALLEGRA ODT and ALLEGRA oral suspension are contraindicated in patients with known hypersensitivity to fexofenadine and any of the ingredients of ALLEGRA. Rare cases of hypersensitivity reactions with manifestations such as angioedema, chest tightness, dyspnea, flushing and systemic anaphylaxis have been reported.