Drug Interaction Report

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 2D6 may significantly 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 potent CYP450 2D6 inhibitors that also prolong the QT interval (e.g., fluoxetine, methotrimeprazine). Additionally, the risk of serotonin syndrome may increase with concomitant use of potent CYP450 2D6 inhibitors that possess serotonergic activity (e.g., bupropion, fluoxetine, paroxetine).

MANAGEMENT: Pharmacologic response to atomoxetine should be monitored more closely whenever a potent CYP450 2D6 inhibitor such as fluoxetine, paroxetine, or quinidine is added to or withdrawn from therapy, as dosage adjustment of atomoxetine may be necessary in extensive metabolizers. The initial recommended dose should only be increased up to the usual target dose if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. If the potent 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 some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled 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.