Drug Interaction Report

MONITOR: Coadministration with drugs that are inhibitors of CYP450 2D6 may increase the plasma concentrations of atomoxetine, which is primarily metabolized by the isoenzyme. In patients who are extensive metabolizers of CYP450 2D6 (approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent), potent inhibitors of the isoenzyme such as fluoxetine and paroxetine have been shown to increase atomoxetine systemic exposure (AUC) by 6- to 8-fold and peak plasma concentration (Cmax) by 3- to 4-fold. These higher concentrations are similar to those observed in CYP450 2D6 poor metabolizers given the drug alone. In vitro studies suggest that coadministration of CYP450 2D6 inhibitors to poor metabolizers will not further increase atomoxetine plasma concentrations. The risk of QT prolongation may be increased with concomitant use of CYP450 2D6 inhibitors that also prolong the QT interval (e.g., abiraterone, osilodrostat, primaquine, propoxyphene, ranolazine). Additionally, the risk of serotonin syndrome may increase with concomitant use of CYP450 2D6 inhibitors that possess serotonergic activity (e.g., duloxetine, dexfenfluramine, fenfluramine).

MANAGEMENT: Pharmacologic response to atomoxetine should be monitored more closely whenever a CYP450 2D6 inhibitor is added to or withdrawn from therapy, as dosage adjustment of atomoxetine may be necessary in extensive metabolizers. If the CYP450 2D6 inhibitor also prolongs the QT interval, and/or has serotonergic activity, then obtaining more frequent electrocardiograms (ECGs) to monitor the QT interval as well as closer monitoring for signs and symptoms of serotonin syndrome is advised. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes (e.g., dizziness, lightheadedness, syncope, palpitations, irregular heartbeat, and/or shortness of breath) and/or symptoms of serotonin syndrome (e.g., altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, tremor). During coadministration, patients should also be advised to contact their doctor if they experience excessive adverse effects of atomoxetine such as dizziness, dry mouth, anorexia, sleep disturbances, and palpitations.

ADJUST DOSING INTERVAL: Food may significantly increase the oral bioavailability of some formulations of abiraterone acetate. Compared to administration in the fasted state, abiraterone peak plasma concentration (Cmax) and systemic exposure (AUC) were approximately 7- and 5-fold higher, respectively, when a single dose of abiraterone acetate was administered with a low-fat meal (7% fat; 300 calories) and approximately 17- and 10-fold higher, respectively, when it was administered with a high-fat meal (57% fat; 825 calories). Given the normal variation in the content and composition of meals, taking abiraterone acetate with meals has the potential to result in increased and highly variable exposures. The safety of these increased exposures during multiple dosing has not been assessed. However, the abiraterone acetate 125 mg tablet, commonly marketed as Yonsa, was found to have an approximately 6.5-fold higher Cmax and 4.4-fold higher AUC when a single dose of 500 mg (4 tablets) was administered with a high-fat meal (56% - 60% fat, 900 - 1000 calories) compared to overnight fasting in healthy volunteers. These differences were not considered clinically significant for this formulation.

MANAGEMENT: Some formulations of abiraterone acetate must be taken on an empty stomach. No food should be consumed for at least two hours before and one hour after the abiraterone acetate dose. However, the abiraterone acetate 125 mg tablet, commonly marketed as Yonsa, can be taken with or without food. The manufacturer's product labeling should be consulted for specific guidance.