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Pharmacologic response to atomoxetine should be monitored more closely whenever a CYP450 2D6 inhibitor is added to or withdrawn from therapy, as dosage adjustment of atomoxetine may be necessary in extensive metabolizers.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.

GENERALLY AVOID: Alcohol may potentiate the central nervous system and cardiovascular effects of centrally-acting appetite suppressants. In one study, concurrent administration of methamphetamine (30 mg intravenously) and ethanol (1 gm/kg orally over 30 minutes) increased heart rate by 24 beats/minute compared to methamphetamine alone. This increases cardiac work and myocardial oxygen consumption, which may lead to more adverse cardiovascular effects than either agent alone. Subjective effects of ethanol were diminished in the eight study subjects, but those of methamphetamine were not affected. The pharmacokinetics of methamphetamine were also unaffected except for a decrease in the apparent volume of distribution at steady state.

MANAGEMENT: Concomitant use of centrally-acting appetite suppressants and alcohol should be avoided if possible, especially in patients with a history of cardiovascular disease. Patients should be counselled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.