Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of sunitinib and its pharmacologically active metabolite, both of which are substrates of the isoenzyme. In healthy volunteers, concurrent administration of a single dose of sunitinib with the potent CYP450 3A4 inhibitor, ketoconazole, resulted in a 49% and 51% increase in the combined (i.e., sunitinib plus its primary active metabolite) peak plasma concentration (Cmax) and systemic exposure (AUC) values, respectively, compared to administration of sunitinib alone. Because sunitinib 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.

MANAGEMENT: Alternative agents with no or minimal CYP450 3A4-inhibiting activity are recommended in patients treated with sunitinib. Some authorities recommend avoiding concomitant use of sunitinib during and for 2 weeks after treatment with itraconazole. A dose reduction for sunitinib to a minimum of 37.5 mg daily for gastrointestinal stromal tumor (GIST) and metastatic renal cell carcinoma (mRCC) or 25 mg daily for pancreatic neuroendocrine tumors (pNET) should be considered if it must be coadministered with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics.

ADJUST DOSING INTERVAL: Food may reduce the systemic bioavailability of amprenavir from fosamprenavir oral suspension. The mechanism of interaction has not been described. According to the product labeling, administration of fosamprenavir oral suspension (1400 mg single dose) with a high-fat meal (967 kcal, 67 g fat, 33 g protein, 58 g carbohydrate) reduced amprenavir peak plasma concentration (Cmax) by 46% and systemic exposure (AUC) by 28% compared to administration in a fasted state. The time to reach peak plasma level (Tmax) was delayed by 0.72 hours. In contrast, the same high-fat meal did not affect the pharmacokinetics of amprenavir from fosamprenavir tablets.

MANAGEMENT: Fosamprenavir suspension should be administered on an empty stomach in adults, but with food in pediatric patients to aid palatability and compliance. If emesis occurs within 30 minutes after dosing the suspension, the dose should be repeated. Fosamprenavir tablets may be taken with or without food.

GENERALLY AVOID: Consumption of grapefruit or grapefruit juice during sunitinib therapy may increase the plasma concentrations of sunitinib. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism by certain compounds present in grapefruit.

MANAGEMENT: Although clinical data are lacking, it may be advisable to avoid the consumption of large amounts of grapefruit or grapefruit juice during sunitinib therapy.