Drug Interaction Report

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: Caution is advised when pimavanserin is used with CYP450 3A4 inhibitors. Patients should be monitored for adverse effects such as peripheral edema and QT prolongation, and the pimavanserin dosage adjusted as necessary.

GENERALLY AVOID: Coadministration with potent or moderate inducers of CYP450 3A4 may decrease the plasma concentrations of pimavanserin, which is primarily metabolized by the isoenzyme. In a drug interaction study designed to measure pre- and post-pimavanserin levels following rifampin administration (a potent CYP450 3A4 inducer), Cmax and AUC were decreased by 71% and 91%, respectively, compared to pre-rifampin plasma concentrations. A physiologically based pharmacokinetic simulation with a moderate CYP450 3A4 inducer (efavirenz) predicted Cmax and AUC of pimavanserin will be decreased by approximately 60% and 70%, respectively.

MANAGEMENT: Coadministration of potent or moderate CYP450 3A4 inducers with pimavanserin should be avoided.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ivacaftor. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Elexacaftor and tezacaftor are also CYP450 3A4 substrates in vitro and may interact similarly with grapefruit juice, whereas lumacaftor is not expected to interact.

ADJUST DOSING INTERVAL: According to prescribing information, systemic exposure to ivacaftor increased approximately 2.5- to 4-fold, systemic exposure to elexacaftor increased approximately 1.9- to 2.5-fold, and systemic exposure to lumacaftor increased approximately 2-fold following administration with fat-containing foods relative to administration in a fasting state. Tezacaftor exposure is not significantly affected by administration of fat-containing foods.

MANAGEMENT: Patients treated with ivacaftor-containing medications should avoid consumption of grapefruit juice and any food that contains grapefruit or Seville oranges. All ivacaftor-containing medications should be administered with fat-containing foods such as eggs, avocados, nuts, meat, butter, peanut butter, cheese pizza, and whole-milk dairy products. A typical cystic fibrosis diet will satisfy this requirement.