Drug Interaction Report

MONITOR: Coadministration with tolvaptan may increase the plasma concentrations of drugs that are substrates of P-glycoprotein (P-gp). The proposed mechanism is decreased clearance due to inhibition of P-glycoprotein-mediated drug efflux in the intestine, liver, and/or kidney by tolvaptan. When the P-gp probe substrate 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: Caution is advised when tolvaptan is prescribed with drugs that are P-gp substrates, particularly those with a narrow therapeutic range such as digoxin and dabigatran etexilate. Alternatives should be considered whenever possible. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate following the initiation or discontinuation of tolvaptan. The prescribing information for the coadministered drug should be consulted for specific dosing recommendations.

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.