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 Close clinical and laboratory monitoring is advised whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy.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.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.

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.

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.