Drug Interaction Report

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of fesoterodine's active metabolite, 5-hydroxymethyl tolterodine, which is partially metabolized by the isoenzyme. The possibility of prolonged and/or increased pharmacologic effects of fesoterodine should be considered. Because 5-hydroxymethyl tolterodine is also metabolized by CYP450 2D6, the clinical significance of the interaction may be greater in patients who are CYP450 2D6-deficient, or so-called poor metabolizers of CYP450 2D6 (approximately 7% of Caucasians and less than 2% of Asians and individuals of African descent) who may rely more on the 3A4 metabolic pathway for clearance of the drug. In one study, administration of fesoterodine (8 mg single oral dose) with the potent CYP450 3A4 inhibitor ketoconazole (200 mg twice a day for 5 days) increased the mean peak plasma concentration (Cmax) of 5-hydroxymethyl tolterodine by 2.0-fold and its systemic exposure (AUC) by 2.3-fold in 2D6 extensive metabolizers compared to administration without ketoconazole. In 2D6 poor metabolizers, 5-hydroxymethyl tolterodine Cmax increased by 2.1-fold and AUC increased by 2.5-fold during coadministration with ketoconazole. However, Cmax and AUC were 4.5- and 5.7-fold higher, respectively, in poor metabolizers taking ketoconazole compared to extensive metabolizers who were not taking ketoconazole. In another study where subjects were administered fesoterodine with ketoconazole 200 mg once a day for 5 days, the Cmax and AUC of 5-hydroxymethyl tolterodine were increased 2.2-fold in 2D6 extensive metabolizers and 1.5- and 1.9-fold, respectively, in 2D6 poor metabolizers. Cmax and AUC were 3.4- and 4.2-fold higher, respectively, in subjects who were poor metabolizers taking ketoconazole compared to extensive metabolizers who were not taking ketoconazole.

MANAGEMENT: The dosage of fesoterodine should not exceed 4 mg/day when used with potent CYP450 3A4 inhibitors. Close clinical and laboratory monitoring is advised whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. Patients should be advised to contact their physician if they experience potential adverse effects of fesoterodine such as irregular heartbeat, blurry vision, difficulty urinating, dry mouth, headache, drowsiness, dizziness, gastrointestinal upset, or constipation. The product labeling for itraconazole (a potent CYP450 3A4 inhibitor) states that concomitant use with fesoterodine is contraindicated in patients with moderate to severe renal or hepatic impairment during and for 2 weeks after treatment with itraconazole. In addition, some authorities consider the coadministration of posaconazole with fesoterodine as contraindicated.

ADJUST DOSING INTERVAL: Administration of atazanavir with food enhances oral bioavailability and reduces pharmacokinetic variability. According to the manufacturer, administration with a light meal increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of a single 400 mg dose of atazanavir by 57% and 70%, respectively, relative to the fasting state. Administration with a high-fat meal resulted in a mean increase of 35% in atazanavir AUC and no change in Cmax compared to fasting. The coefficient of variation of AUC and Cmax decreased by approximately one-half when given with either a light or high-fat meal compared to the fasting state.

MANAGEMENT: To ensure maximal oral absorption, atazanavir should be administered with or immediately after a meal.

MONITOR: Coadministration with moderate inhibitors of CYP450 3A4 such as grapefruit juice may increase the plasma concentrations of fesoterodine's active metabolite, 5-hydroxymethyl tolterodine, which is partially metabolized by the isoenzyme. The possibility of prolonged and/or increased pharmacologic effects of fesoterodine should be considered. Because 5-hydroxymethyl tolterodine is also metabolized by CYP450 2D6, the clinical significance of the interaction may be greater in patients who are CYP450 2D6-deficient, or so-called poor metabolizers of CYP450 2D6 (approximately 7% of Caucasians and less than 2% of Asians and individuals of African descent) who may rely more on the 3A4 metabolic pathway for clearance of the drug.

MANAGEMENT: Caution is advised if fesoterodine is administered with grapefruit or grapefruit juice. Patients should be advised to notify their physician if they experience potential adverse effects of fesoterodine such as irregular heartbeat, blurry vision, difficulty urinating, dry mouth, headache, drowsiness, dizziness, gastrointestinal upset, or constipation.