Fexofenadine (Allegra) Interactions
Antacids- Erythromycin
- food
- grapefruit juice
- Ketoconazole
- Rifampin
- St. John’s Wort, Hypericum perforatum
Fexofenadine (Allegra) Interactions
NOTE: Fexofenadine is a substrate for P-glycoprotein transport.
Most food does not interact significantly with fexofenadine; the drug may be administered with or without food. However, some fruit juices appear to impair the absorption of fexofenadine. Apple juice, orange juice, and grapefruit juice have been reported to decrease the AUC and Cmax of fexofenadine by roughly 60 - 70%, but individual variability in the changes have been noted in various studies. According to the manufacturer, the bioavailability of fexofenadine is estimated to be reduced by 36% during coadministration with grapefruit or orange juice. The mechanism of the interaction is proposed to be an inhibition of intestinal P-glycoprotein transport systems by the juices, resulting in decreased systemic drug absorption. Histamine-induced skin evaluations indicate that the size of wheal and flare reactions are significantly greater when fexofenadine is coadministered with either grapefruit or orange juice compared to water. The clinical significance of these observations is unknown. To maximize the effects of fexofenadine, the manufacturer recommends that fexofenadine be taken with water (see Dosage). Since fexofenadine effectiveness may be reduced, it is prudent for patients to avoid coadministration with grapefruit, orange, or apple juices.
Unlike terfenadine, fexofenadine has not been associated with QT prolongation or ventricular arrhythmias when coadministered with erythromycin or ketoconazole. In two separate studies of 24 healthy subjects, fexofenadine 120 mg twice daily (twice the recommended dose) was coadministered with erythromycin 500 mg every 8 hours or ketoconazole 400 mg once daily for seven days. No differences in adverse events or QTc interval were observed when subjects were administered fexofenadine alone or in combination with potent CYP 3A4 inhibitors, erythromycin or ketoconazole. Erythromycin increased steady-state fexofenadine peak concentrations by 82% and increased AUC by 109%. Ketoconazole increased steady-state fexofenadine peak concentrations by 135% and increased AUC by 164%. Fexofenadine had no effect on the pharmacokinetics of erythromycin or ketoconazole. The mechanism of these interactions has been evaluated using in vitro, in situ, and in vivo animal models. These studies indicate that ketoconazole or erythromycin coadministration 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. According to the manufacturer, the associated changes in fexofenadine plasma levels following erythromycin or ketoconazole were within the range of plasma levels achieved in adequate and well-controlled clinical trials. Given the magnitude of the increases in AUC, it is prudent to use caution and monitor patients receiving fexofenadine and erythromycin or ketoconazole until additional data are available.
Coadministration with antacids (containing aluminum or magnesium) within 15 minutes decreases the AUC and Cmax of fexofenadine by 41% and 43%, respectively. Separate administration is recommended.
Although fexofenadine is considered a ‘non-sedating’ H1-blocker, sedation has been noted in individual patients receiving fexofenadine or other second generation, non-sedating H1-blockers. For this reason, it would be prudent to monitor for drowsiness during concurrent use with other CNS depressants such as tricyclic antidepressants, barbiturates, benzodiazepines, opiate agonists, antipsychotics, ethanol, other H1-blockers, and anxiolytics, sedatives, and hypnotics.
Rifampin may decrease plasma concentrations of fexofenadine and potentially reduce its antihistaminic effects. A 6-day course of rifampin (600 mg/day) has been reported to increase the oral clearance of fexofenadine (single dose) by 2 to 3-fold in 24 healthy subjects. Rifampin does not alter the renal clearance or half-life of fexofenadine. In theory, rifampin may activate P-glycoprotein transport in the small intestine, and thereby decreases the oral absorption of fexofenadine (a substrate of P-glycoprotein transport). Although the therapeutic range of fexofenadine is broad, monitor for potential decreased therapeutic effects of fexofenadine if rifampin is initiated.
Conflicting studies have shown that St. John’s Wort may increase, decrease, or not change the plasma concentrations and AUC of fexofenadine. Results vary between single and multiple dose studies. The mechanisms proposed have included CYP3A4 induction and/or altered P-glycoprotein efflux transport of fexofenadine. The clinical importance of this theoretical interaction has not been established; further study is needed.
[ Last revised: 12/30/2005 10:37:00 AM ]
References
. Hansten PD, Horn JR. Cytochrome P450 Enzymes and Drug Interactions, Table of Cytochrome P450 Substrates, Inhibitors, Inducers and P-glycoprotein and footnotes. In: The Top 100 Drug Interactions - A guide to Patient Management. 2005 Edition. Edmonds, WA: H&H Publications; 2005:157 - 170.
. Izzo AA. Drug interactions with St. John’s Wort (Hypericum perforatum): a review of the clinical evidence. Int J Clin Pharmacol Ther. 2004;42:139 - 48.
. Allegra® (fexofenadine) package insert. Kansas City, MO: Aventis Pharmaceuticals; 2005 Oct.
. Dresser GK, Bailey DG, Leake BF, et al. Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther 2002;71:11 - 20.
. Hamman MA, Bruce MA, Haehner-Daniels BD, et al. The effect of rifampin administration on the disposition of fexofenadine. Clin Pharmacol Ther 2001;69:114 - 21.
. Wang Z, Hamman MA, Huang SM, et al. Effect of St John’s wort on the pharmacokinetics of fexofenadine. Clin Pharmacol Ther 2002;71:414 - 20.
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