Drug Interaction Report

GENERALLY AVOID: Pimavanserin may cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In a thorough QTc study conducted in 252 healthy subjects, the maximum mean change in QTc interval from baseline was 13.5 msec at twice the therapeutic dosage given to steady state. In 6-week premarketing placebo-controlled effectiveness studies, mean increases in QTc interval were approximately 5 to 8 msec in patients receiving the recommended pimavanserin dosage of 34 mg once daily. Sporadic QTcF values >=500 msec and change from baseline values >=60 msec were observed in subjects treated with pimavanserin, although the incidence was generally similar to that reported for placebo groups. There were no reports of torsade de pointes arrhythmia or differences from placebo in any other adverse reactions associated with delayed ventricular repolarization. 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 such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). The extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of pimavanserin, which is primarily metabolized by the isoenzyme. According to the product labeling, pimavanserin peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.5- and 3-fold, respectively, when given with the potent CYP450 3A4 inhibitor ketoconazole. The interaction has not been studied with other, less potent inhibitors. High plasma levels of pimavanserin may increase the risk of QT interval prolongation, which has been associated with ventricular arrhythmias including torsade de pointes and sudden death.

MANAGEMENT: Coadministration of pimavanserin with other drugs that can prolong the QT interval should generally be avoided. Caution is advised if concomitant use of pimavanserin is required and no alternatives are available, in accordance with the labeling recommendation for use in combination with CYP450 3A4 inhibitors. Patients should be monitored for adverse effects such as peripheral edema and QT prolongation, have regular ECGs to monitor for arrhythmias when the QT interval is prolonged, and the pimavanserin dosage adjusted as necessary. 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.

GENERALLY AVOID: Grapefruit products may significantly increase the plasma concentrations and effects of mavorixafor, which is primarily metabolized by the isoenzyme CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. A study examining mavorixafor in combination with the strong CYP450 3A4 and P-glycoprotein inhibitor, itraconazole, suggests an increase in mavorixafor's systemic exposure (AUC) of approximately 2-fold. Clinical data with grapefruit products are not available. Pharmacokinetic interactions involving grapefruit are subject to a high degree of interpatient variability and can also be affected by the product and amount consumed; therefore, the extent to which a given patient may be affected is difficult to predict. Additionally, since mavorixafor is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

ADJUST DOSING INTERVAL: Food may significantly reduce the peak plasma concentration (Cmax) and systemic exposure (AUC) of mavorixafor. When a single-dose of mavorixafor (400 mg) was administered with a high-fat meal (1000 calories, 50% fat) to healthy subjects, the Cmax and AUC decreased by 66% and 55%, respectively. Similarly, when the same dose was given with a low-fat meal (500 calories, 25% fat) to healthy subjects, mavorixafor's Cmax and AUC decreased by 55% and 51%, respectively. Additionally, a single dose of mavorixafor (400 mg) administered with a low-fat meal to healthy subjects following an overnight fast resulted in a 14% higher Cmax and an 18% lower AUC than those obtained from subjects who fasted for an additional 4 hours after the dose.

MANAGEMENT: Mavorixafor should be taken on an empty stomach after an overnight fast, 30 minutes before food. Patients should be advised to avoid eating or drinking products containing grapefruit, as this could increase the risk of experiencing adverse effects from mavorixafor such as QT prolongation.