Drug Interactions between dutasteride / tamsulosin and saquinavir

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of tamsulosin, which is primarily metabolized by the hepatic microsomal isoenzymes CYP450 3A4 and 2D6. Severe hypotension and priapism may occur. In 24 healthy volunteers, administration of a single 0.4 mg dose of tamsulosin with the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily for 5 days) resulted in a 2.2-fold increase in tamsulosin peak plasma concentration (Cmax) and 2.8-fold increase in systemic exposure (AUC). The magnitude of interaction may be increased further in individuals who have genetic polymorphisms of CYP450 2D6 resulting in reduced or absent enzyme activity, or so-called CYP450 2D6 poor metabolizers (approximately 7% of Caucasians and less than 2% of Asians and individuals of African descent). When a single 0.4 mg dose of tamsulosin was given to 24 healthy volunteers with the potent CYP450 2D6 inhibitor paroxetine (20 mg once daily for 9 days), tamsulosin Cmax and AUC increased by a factor of 1.3 and 1.6, respectively. A similar increase in exposure is expected in CYP450 2D6 poor metabolizers as compared to extensive metabolizers, hence a potentially greater impact of CYP450 3A4 inhibition.

MANAGEMENT: Since CYP450 2D6 poor metabolizers cannot be readily identified, concomitant use of tamsulosin with potent CYP450 3A4 inhibitors should generally be avoided. Some authorities recommend avoiding concomitant use of tamsulosin during and for 2 weeks after treatment with itraconazole. If tamsulosin administration is discontinued for several days or more at either the 0.4 or 0.8 mg dose, therapy should be reinitiated with the 0.4 mg once-daily dose and titrated gradually as needed.

MONITOR: Based on in vitro data, coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of dutasteride, which is metabolized by the isoenzyme. No clinical drug interaction studies have been conducted. However, a population pharmacokinetic analysis found decreased clearance of dutasteride when it is coadministered with the moderate CYP450 3A4 inhibitors, verapamil and diltiazem (37% and 44%, respectively). In contrast, no decrease in dutasteride clearance was seen during coadministration with amlodipine, a calcium channel blocker that is not a CYP450 3A4 inhibitor.

MANAGEMENT: The possibility of prolonged and/or increased pharmacologic effects of dutasteride should be considered during concomitant therapy with CYP450 3A4 inhibitors, particularly potent ones like itraconazole, ketoconazole, posaconazole, voriconazole, conivaptan, nefazodone, cobicistat, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics.