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.

ADJUST DOSING INTERVAL: Food does not appear to substantially alter the pharmacokinetics of tipranavir. When tipranavir capsules or oral solution was coadministered with ritonavir capsules at steady-state, no clinically significant changes in tipranavir peak plasma concentration (Cmax) and systemic exposure (AUC) were observed under fed conditions (500 to 682 kcal, 23% to 25% calories from fat) relative to fasted conditions. The effect of food on tipranavir exposure during coadministration with ritonavir tablets has not been evaluated. High-fat foods may enhance the gastrointestinal absorption of tipranavir. In a multiple-dose study, administration of tipranavir capsules with a high-fat meal (868 kcal, 53% from fat, 31% from carbohydrates) increased the oral bioavailability of tipranavir by 31% compared to administration with toast and skimmed milk, but did not significantly affect tipranavir Cmax. Thus, tipranavir may be safely taken with standard or high-fat meals.

MANAGEMENT: Tipranavir coadministered with low-dose ritonavir should be taken with food to improve the gastrointestinal tolerability of ritonavir. According to the product labeling, tipranavir coadministered with ritonavir capsules or solution can be taken with or without meals, whereas tipranavir coadministered with ritonavir tablets must be taken with meals.

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.