Drug Interaction Report

MONITOR: There is clinical evidence that sunitinib can prolong the PR interval of the electrocardiogram in some patients. Theoretically, coadministration with other agents that prolong the PR interval (e.g., beta blockers, calcium channel blockers, atazanavir, lopinavir, digoxin, lacosamide, mefloquine) may result in additive effects and increased risk of conduction disturbances and atrioventricular block. In a phase I clinical study of patients with advanced solid tumors who received sunitinib 150 mg on days 3 and 9 and 50 mg on days 4 to 8, mean placebo-adjusted changes in the PR interval were positive at all time points, with the maximum increase occurring 7 to 12 hours postdose, followed by a decline at 24 hours. Outlier analyses for the PR interval (>200 msec) showed a shift toward a higher proportion of outliers in patients treated with sunitinib. Excessive PR interval prolongation can result in AV block. On days 3 and 9, heart rate decreased progressively over the 24-hour period following sunitinib dosing, but was not affected by the positive control. During the study, an event of bradycardia occurred that was considered treatment-related, and dizziness was experienced by 7 of 48 patients. Bradycardia and AV block are recognized risk factors for torsade de pointes arrhythmia. Because sunitinib can also cause QTc prolongation, particular concerns exist with respect to its proarrhythmic potential.

MANAGEMENT: Caution is advised if sunitinib is used concomitantly with other agents that prolong the PR interval, especially in the elderly and patients with known conduction problems (e.g., marked first-degree AV block; second-degree or higher AV block; sick sinus syndrome without pacemaker) or severe cardiac disease such as myocardial ischemia or heart failure. Patients should be advised to notify their doctor if they experience dizziness, lightheadedness, fainting, or irregular heartbeat.

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.

Administration of digoxin with a high-fiber meal has been shown to decrease its bioavailability by almost 20%. Fiber can sequester up to 45% of the drug when given orally. Patients should be advised to maintain a regular diet without significant fluctuation in fiber intake while digoxin is being titrated.

Grapefruit juice may modestly increase the plasma concentrations of digoxin. The mechanism is increased absorption of digoxin due to mild inhibition of intestinal P-glycoprotein by certain compounds present in grapefruits. In 12 healthy volunteers, administration of grapefruit juice with and 30 minutes before, as well as 3.5, 7.5, and 11.5 hours after a single digoxin dose (0.5 mg) increased the mean area under the plasma concentration-time curve (AUC) of digoxin by just 9% compared to administration with water. Moreover, P-glycoprotein genetic polymorphism does not appear to influence the magnitude of the effects of grapefruit juice on digoxin. Thus, the interaction is unlikely to be of clinical significance.