Drug Interaction Report

MONITOR: Coadministration with tolvaptan may increase the serum concentrations of digoxin. The proposed mechanism is decreased clearance due to tolvaptan inhibition of the P-glycoprotein-mediated intestinal and/or renal efflux of digoxin. When digoxin (0.25 mg once daily for 12 days) was coadministered with tolvaptan (60 mg once daily on days 8 to 12), digoxin peak concentration (Cmax) and systemic exposure (AUC) increased by 30% and 20%, respectively, compared to administration alone. Digoxin had no significant effect on the pharmacokinetics of tolvaptan, which is also a P-gp substrate.

MANAGEMENT: Serum digoxin levels and pharmacologic effects should be closely monitored following the addition or withdrawal of tolvaptan, and the digoxin dosage adjusted as needed. Patients should be advised to seek medical attention if they experience signs of digoxin toxicity such as nausea, anorexia, visual disturbances, slow pulse, or irregular heartbeat.

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of tolvaptan. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. According to the product labeling, administration of tolvaptan with grapefruit juice resulted in a 1.8-fold increase in tolvaptan systemic exposure. The clinical significance is unknown, although increased pharmacologic effects may be expected. Too rapid correction of hyponatremia increases the risk of osmotic demyelination syndrome, which is associated with dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, and death.

MANAGEMENT: Patients treated with tolvaptan should avoid consumption of grapefruits and grapefruit juice.

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.