Drug Interaction Report

MONITOR: Use of tipranavir in combination with estrogens may be associated with an increased risk of skin rash. The mechanism has not been described. Mild to moderate rashes including urticarial rash, maculopapular rash, and possible photosensitivity have been reported in 14% of females and 8% to 10% of males receiving tipranavir in combination with low-dose ritonavir in phase 2 and 3 trials. However, in one drug interaction trial, 33% of healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir/ritonavir developed a rash. Rash accompanied by joint pain or stiffness, throat tightness, or generalized pruritus has also been reported in both men and women.

MANAGEMENT: Women who use estrogens should be advised of a potentially increased risk of skin rash during concomitant treatment with tipranavir. If a rash occurs, it is usually mild to moderate. Nevertheless, patients should be instructed to contact their physician promptly, as a temporary discontinuation of tipranavir or the estrogen may be necessary.

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.

Coadministration with grapefruit juice may increase the bioavailability of oral estrogens. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits. In a small, randomized, crossover study, the administration of ethinyl estradiol with grapefruit juice (compared to herbal tea) increased peak plasma drug concentration (Cmax) by 37% and area under the concentration-time curve (AUC) by 28%. Based on these findings, grapefruit juice is unlikely to affect the overall safety profile of ethinyl estradiol. However, as with other drug interactions involving grapefruit juice, the pharmacokinetic alterations are subject to a high degree of interpatient variability. Also, the effect on other estrogens has not been studied.