Drug Interaction Report

GENERALLY AVOID: Coadministration with moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of tolvaptan. According to the prescribing information, tolvaptan is extensively metabolized in the liver almost exclusively by CYP450 3A4. Tolvaptan peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 80% and 200%, respectively, when the moderate CYP450 3A4 inhibitor fluconazole was given in a 400 mg dose one day prior and a 200 mg dose concomitantly with tolvaptan.

MANAGEMENT: Concomitant use of tolvaptan with moderate CYP450 3A4 inhibitors should generally be avoided. A 50% reduction of the total daily tolvaptan dosage is recommended when used in the treatment of adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD), along with close monitoring of serum sodium and volume status. The prescribing information for both the specific tolvaptan product and the concomitant medication should be consulted for more detailed guidance.

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: Pomegranates and grapefruit may increase the systemic exposure to ribociclib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in these fruits. Increased exposure to ribociclib may increase the risk of adverse effects such as infections, neutropenia, leukopenia, anemia, thrombocytopenia, anorexia, nausea, vomiting, diarrhea, stomatitis, alopecia, fatigue, headache, and abnormal liver function may be increased.

MANAGEMENT: Patients receiving ribociclib should avoid consumption of pomegranates or pomegranate juice and grapefruit or grapefruit juice during treatment.