Drug Interaction Report

MONITOR: Concomitant use of pazopanib with simvastatin may increase the risk of ALT elevations, possibly due to additive hepatotoxic effects. In clinical trials, potentially severe and life-threatening hepatotoxicity manifested as increases in serum transaminases (ALT, AST) and bilirubin was observed with pazopanib use. Transaminase elevations occurred early in the course of treatment, with 92.5% of all cases of any grade occurring in the first 18 weeks. Across all monotherapy studies with pazopanib (n=977), ALT exceeding 3 times the upper limit of normal (ULN) was reported in 14% of patients who received pazopanib and ALT exceeding 8 times ULN was reported in 4%. Concurrent elevations in ALT greater than 3 times ULN and bilirubin greater than 2 times ULN regardless of alkaline phosphatase levels were detected in 1% of patients. Four of these patients had no other explanation for the elevations. Two of the total 977 patients (0.2%) died with disease progression and hepatic failure. Of the 41 patients who had concomitant use of simvastatin, 11 (27%) developed ALT exceeding 3 times ULN.

MANAGEMENT: Caution is advised if pazopanib is used in combination with simvastatin. Serum liver transaminases and bilirubin should be measured prior to initiation of pazopanib and regularly during treatment as recommended in the product labeling. If ALT elevations occur, simvastatin should be discontinued and guidelines for pazopanib dosage adjustments should be followed, or alternatives to pazopanib considered. Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, light colored stools, and jaundice. Insufficient data are available to assess the risk of pazopanib administered concomitantly with other HMG-CoA reductase inhibitors.

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.