Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of pazopanib, which is primarily metabolized by the isoenzyme. In healthy subjects, administration of a single dose of pazopanib eye drop with the potent CYP450 3A4 inhibitor ketoconazole resulted in a 150% increase in pazopanib peak plasma concentration (Cmax) and a 220% increase in systemic exposure (AUC). Although not studied, the interaction may increase the risk of QT interval prolongation and torsade de pointes arrhythmia as well as severe and fatal hepatotoxicity associated with the use of pazopanib.

MANAGEMENT: Concomitant use of pazopanib with potent CYP450 3A4 inhibitors should generally be avoided. Some authorities recommend avoiding concomitant use of pazopanib during and for 2 weeks after treatment with itraconazole. If coadministration is unavoidable, a reduction of the pazopanib dosage to 400 mg once daily should be considered. Based on pharmacokinetic studies, this dosage is predicted to adjust the pazopanib systemic exposure (AUC) to the range observed without inhibitors. However, clinical data are lacking. Patients should have liver function tests (ALT, AST, bilirubin), electrocardiograms, and serum electrolyte levels performed at baseline and regular intervals as recommended in the product labeling. Further dosage reductions may be needed if adverse effects occur during therapy. Patients should be advised to notify their physician if they experience signs and symptoms of hepatotoxicity such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, and jaundice. In addition, they should seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope. Following discontinuation of the potent CYP450 3A4 inhibitor, a washout period of approximately one week should be allowed before the pazopanib dosage is adjusted upward.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of pazopanib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Although not studied, the interaction may increase the risk of QT interval prolongation and torsade de pointes arrhythmia as well as severe and fatal hepatotoxicity associated with the use of pazopanib.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of pazopanib. The mechanism of interaction is unknown. Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2-fold increase in peak plasma concentration (Cmax) and systemic exposure (AUC).

MANAGEMENT: Patients treated with pazopanib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Pazopanib should be administered at least one hour before or two hours after a meal.

ADJUST DOSING INTERVAL: Food reduces the oral absorption and bioavailability of voriconazole. According to the product labeling, administration of multiple doses of voriconazole with high-fat meals decreased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) by 34% and 24%, respectively, when the drug is administered as a tablet, and by 58% and 37%, respectively, when administered as the oral suspension.

MANAGEMENT: To ensure maximal oral absorption, voriconazole tablets and oral suspension should be taken at least one hour before or after a meal.