Drug Interaction Report

ADJUST DOSE: Coadministration with inhibitors of P-glycoprotein (P-gp) may increase the oral bioavailability of tolvaptan, which has been shown in vitro to be a substrate of the efflux transporter. Pharmacokinetic and clinical data are not available, however.

MANAGEMENT: Caution is advised if tolvaptan is prescribed in combination with P-glycoprotein inhibitors, especially potent ones such as amiodarone, cyclosporine, or quinidine. Serum sodium concentration and neurologic status should be closely monitored, and the tolvaptan dosage adjusted accordingly. 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. Discontinuation or interruption of tolvaptan therapy should be considered in patients who develop too rapid a rise in serum sodium.

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.

GENERALLY AVOID: Coadministration with grapefruit juice is likely to increase the plasma concentrations of ponatinib, which is primarily metabolized by CYP450 3A4. However, the interaction has not been studied. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

MANAGEMENT: The consumption of grapefruit, grapefruit juice, and supplements that contain grapefruit extract should be avoided during treatment with ponatinib.