Drug Interaction Report

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: 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.

ADJUST DOSING INTERVAL: Food may delay the gastrointestinal absorption of tamsulosin. The time to maximum plasma concentration (Tmax) is reached by 4 to 5 hours under fasted conditions and by 6 to 7 hours when tamsulosin is administered with food. The delay in Tmax has the desirable effect of smoothing the tamsulosin plasma concentration profile, thereby reducing fluctuation of the plasma peak and trough concentrations with multiple dosing. Food may also affect the extent of absorption of tamsulosin. It has been reported that taking tamsulosin under fasted conditions results in a 30% increase in bioavailability (AUC) and 40% to 70% increase in peak plasma concentration (Cmax) compared to fed conditions. The effects of food on the pharmacokinetics of tamsulosin are consistent regardless of whether tamsulosin is taken with a light meal or a high-fat meal.

MANAGEMENT: To ensure uniformity of absorption, tamsulosin should be administered approximately one-half hour following the same meal each day.

ADJUST DOSING INTERVAL: Food enhances the absorption and oral bioavailability of darunavir administered in combination with low-dose ritonavir. The mechanism is unknown. When administered with food, the peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of darunavir were approximately 30% higher than when administered in the fasting state. Darunavir exposure was similar for the range of meals studied. The total caloric content of the various meals evaluated ranged from 240 Kcal (12 grams fat) to 928 Kcal (56 grams fat).

MANAGEMENT: To ensure maximal oral absorption, darunavir coadministered with ritonavir should be taken with food. The type of food is not important.