Drug Interaction Report

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of tolvaptan, which is primarily metabolized by the isoenzyme. When tolvaptan was administered with the potent CYP450 3A4 inducer rifampin, tolvaptan peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by approximately 85%. The interaction has not been studied with other, less potent inducers.

MANAGEMENT: The potential for diminished pharmacologic effects of tolvaptan should be considered during coadministration with CYP450 3A4 inducers. Alternative treatments may be required if an interaction is suspected.

MONITOR: Isolated case reports have suggested that the ingestion of alcohol during griseofulvin therapy may rarely cause disulfiram-like reactions, flushing, tachycardia, or increased effects of alcohol. The mechanism is unknown.

MANAGEMENT: Patients should be advised of the possibility of increased adverse effects or a disulfiram-like reaction.

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.