Drug Interactions between amiodarone and dutasteride / tamsulosin

MONITOR: Coadministration with inhibitors of CYP450 3A4 and/or 2D6 may increase the plasma concentrations of tamsulosin, which is primarily metabolized in the liver by these isoenzymes. 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 a 2.8-fold increase in systemic exposure (AUC) compared to administration alone. Likewise, concomitant treatment with the potent CYP450 2D6 inhibitor paroxetine (20 mg once daily for 9 days) resulted in an increase in the Cmax and AUC of a single 0.4 mg dose of tamsulosin by a factor of 1.3 and 1.6, respectively. The effects of concomitant administration of a moderate CYP450 3A4 inhibitor such as erythromycin or a moderate CYP450 2D6 inhibitor such as terbinafine on the pharmacokinetics of tamsulosin have not been evaluated. The effects of coadministration of both a CYP450 3A4 and a CYP450 2D6 inhibitor have also not been evaluated. However, there is a potential for significant increase in tamsulosin exposure relative to coadministration with either inhibitor alone. Similarly, a significant increase in exposure may occur when tamsulosin is administered with a CYP450 3A4 inhibitor to 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).

MANAGEMENT: Caution is advised if tamsulosin is used concomitantly with moderate CYP450 3A4 inhibitors (e.g., amiodarone, aprepitant, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, fusidic acid, imatinib, isavuconazonium, verapamil) and/or moderate to potent CYP450 2D6 inhibitors (e.g., abiraterone, bupropion, celecoxib, cinacalcet, darifenacin, dronedarone, duloxetine, fluoxetine, lorcaserin, paroxetine, propafenone, quinidine, ranolazine, rolapitant, terbinafine), particularly at a dosage higher than 0.4 mg/day. The potential for increased risk of adverse effects such as postural hypotension, syncope, and priapism should be considered. It should be noted that rolapitant, a moderate CYP450 2D6 inhibitor, can increase plasma concentrations and the risk of adverse effects of tamsulosin for at least 28 days after administration of rolapitant. Patients should be advised to avoid rising abruptly from a sitting or recumbent position, and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Patients should also avoid driving or operating hazardous machinery until they know how the medication affects them.

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.