Drug Interactions between fluoxetine / olanzapine and vortioxetine

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 2D6 may significantly increase the plasma concentrations of vortioxetine, which is primarily metabolized by the isoenzyme. According to the product labeling, administration of vortioxetine with the potent CYP450 2D6 inhibitor bupropion resulted in greater than 2-fold increases in vortioxetine peak plasma concentration (Cmax) and systemic exposure (AUC) compared to administration of vortioxetine alone. High plasma levels of vortioxetine may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Symptoms of the 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.

MANAGEMENT: The dosage of vortioxetine should be reduced by one-half when used in combination with potent CYP450 2D6 inhibitors such as bupropion, cinacalcet, fluoxetine, paroxetine, quinidine, ritonavir, and terbinafine. Following discontinuation of the potent CYP450 2D6 inhibitor, vortioxetine dosage should be returned to the original level. Since fluoxetine and paroxetine are also selective serotonin reuptake inhibitors, additive serotonergic effects with vortioxetine should be considered, and concomitant use avoided if possible.

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.