Drug Interactions between Luvox and tolvaptan

GENERALLY AVOID: Coadministration with inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of tolvaptan, which is almost exclusively metabolized by the isoenzyme. The interaction has been studied with ketoconazole, a potent CYP450 3A4 inhibitor. When a single 30 mg oral dose of tolvaptan was administered to 19 healthy volunteers following pretreatment with ketoconazole 200 mg/day for 3 days, tolvaptan peak plasma concentration (Cmax) increased by 3.5-fold and systemic exposure (AUC) increased by 5.4-fold, although 24-hour urine output increased by just 1.3-fold due to the saturable nature of tolvaptan's effect on urinary excretion rate. The impact of moderate CYP450 3A4 inhibitors has not been adequately assessed. According to the product labeling, grapefruit juice has been shown to increase tolvaptan exposure by 1.8-fold. However, the potency of grapefruit juice as an inhibitor of CYP450 3A4 depends on its strength, which was not specified.

MANAGEMENT: Concomitant use of tolvaptan with moderate CYP450 3A4 inhibitors should generally be avoided unless no alternatives exist and benefits outweigh potential risks. A lower dosage of tolvaptan should be considered. Serum sodium concentration and neurologic status should be closely monitored during coadministration. 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.

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