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more closely whenever a potent CYP450 2D6 inhibitor such as fluoxetine, paroxetine, or quinidine is added to or withdrawn from therapy, as dosage adjustment of atomoxetine may be necessary in extensive metabolizers.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.

MONITOR: It is uncertain whether olanzapine causes clinically significant prolongation of the QT interval. In pooled studies of adults as well as pooled studies of adolescents, there were no significant differences between olanzapine and placebo in the proportion of patients experiencing potentially important changes in ECG parameters, including QT, QTcF (Fridericia-corrected), and PR intervals. In clinical trials, clinically meaningful QTc prolongations (QTcF >=500 msec at any time post-baseline in patients with baseline QTcF <500 msec) occurred in 0.1% to 1% of patients treated with olanzapine, with no significant differences in associated cardiac events compared to placebo. Published studies have generally reported no significant effect of olanzapine on QTc interval, although both QTc prolongation and QTc shortening have also been reported. There have been a few isolated case reports of QT prolongation in patients receiving olanzapine. However, causality is difficult to establish due to confounding factors such as concomitant use of drugs that cause QT prolongation and underlying conditions that may predispose to QT prolongation (e.g., hypokalemia, congenital long QT syndrome, preexisting conduction abnormalities).

MANAGEMENT: Some authorities recommend caution when olanzapine is used with drugs that are known to cause QT prolongation. ECG monitoring may be advisable in some cases, such as in patients with a history of cardiac arrhythmias or congenital or family history of long QT syndrome. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

MONITOR: Serotonin syndrome has been reported following the concomitant use of atomoxetine with other serotonergic medicinal products. The use of agents with serotonergic activity (such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), tetracyclic antidepressants, tricyclic antidepressants, 5-HT1 receptor agonists (triptans), ergot alkaloids, lithium, St. John's wort, phenylpiperidine opioids, dextromethorphan, and tryptophan, among others) may potentiate the risk of serotonin syndrome, a rare but serious and potentially fatal condition. Symptoms of serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucination, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.

MONITOR: Atomoxetine can cause dose-related prolongation of the QT interval. There is the potential for an increased risk of QTc interval (QT interval corrected for heart rate) prolongation when atomoxetine is administered with other QT prolonging drugs (e.g., neuroleptics, class IA and III antiarrhythmics, moxifloxacin, erythromycin, methadone, mefloquine, tricyclic antidepressants, lithium or cisapride) and drugs that cause electrolyte imbalance (e.g., thiazide diuretics). In a study of 120 healthy male CYP450 2D6 poor metabolizers receiving atomoxetine (20 mg and 60 mg twice daily for 7 days), no large QTc changes were observed (i.e., >60 msec increase or QTc >480 msec); however, there were slight increases in the QTc interval with increased atomoxetine concentrations. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors including, but not limited to cardiac disease, uncontrolled hypothyroidism, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation may vary depending on the dosage(s) and specific drug(s) involved.

MANAGEMENT: If coadministration of atomoxetine with other agents that both prolong the QT interval and possess or enhance serotonergic activity is required, some authorities advise patients should have more frequent electrocardiograms (ECGs) than normally recommended, and be monitored closely for, and counseled about the signs and symptoms of serotonin syndrome (e.g., altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor), as well as prolonged QT interval (irregular heartbeat, dizziness, lightheadedness, fainting), especially during initiation and dose escalations. Due to variability and occasionally prolonged half-lives of these coadministered agents, consulting individual product labeling for specific guidance is advised.

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.

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.