Drug Interactions between fesoterodine and letrozole / ribociclib

MONITOR: Coadministration with ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

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MONITOR: Coadministration with 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. The effects of less potent CYP450 3A4 inhibitors were not examined.

MANAGEMENT: Close clinical and laboratory monitoring is advised whenever a CYP450 3A4 inhibitor is added to or withdrawn from fesoterodine therapy, and the dosage adjusted if necessary. 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.

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