Drug Interaction Report

MONITOR CLOSELY: Coadministration with the hepatitis C virus (HCV) NS3/4A protease inhibitors, boceprevir and telaprevir, may significantly increase the plasma concentrations of cyclosporine. The risk of nephro- and neurotoxicity associated with cyclosporine may be increased. The mechanism involves inhibition of CYP450 3A4, the isoenzyme responsible for the intestinal and hepatic metabolism of cyclosporine. Enhanced cyclosporine oral bioavailability due to inhibition of intestinal P-glycoprotein efflux transporter may also contribute. In 9 study subjects, administration of a single 10 mg dose of cyclosporine during treatment with telaprevir 750 mg every 8 hours for 11 days increased the dose-normalized cyclosporine peak plasma concentration (Cmax) and systemic exposure (AUC) by an average of 32% and 364%, respectively, compared to administration of a single 100 mg dose of cyclosporine alone. When a single 100 mg dose of cyclosporine was coadministered with boceprevir 800 mg three times a day for 7 days, cyclosporine Cmax increased by 2.0-fold and AUC increased by 2.7-fold. No significant effect on the pharmacokinetics of boceprevir was observed.

MANAGEMENT: Caution is advised if cyclosporine is used in combination with boceprevir or telaprevir. Cyclosporine blood levels and renal function should be checked frequently and the dosage adjusted accordingly, particularly following initiation or discontinuation of the HCV NS3/4A protease inhibitor. Patients should be advised to notify their physician if they experience possible signs of cyclosporine toxicity such as nausea, vomiting, diarrhea, abdominal pain, dizziness, fatigue, headache, tremors, and convulsions. Some authorities recommend against the use of telaprevir in organ transplant candidates or recipients.

GENERALLY AVOID: Administration with grapefruit juice (compared to water or orange juice) has been shown to increase blood concentrations of cyclosporine with a relatively high degree of interpatient variability. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

GENERALLY AVOID: Administration with red wine or purple grape juice may decrease blood concentrations of cyclosporine. In 12 healthy volunteers, 12 ounces total of a merlot consumed 15 minutes prior to and during cyclosporine administration (single 8 mg/kg dose of Sandimmune) decreased cyclosporine peak blood concentration (Cmax) and systemic exposure (AUC) by 38% and 30%, respectively, compared to water. The time to reach peak concentration (Tmax) doubled, and oral clearance increased 50%. Similarly, one study were 12 healthy patients were administered purple grape juice and a single dose of cyclosporine showed a 30% and a 36% decrease in cyclosporine systemic exposure (AUC) and peak blood concentration (Cmax), respectively. The exact mechanism of interaction is unknown but may involve decreased cyclosporine absorption.

MONITOR: Food has been found to have variable effects on the absorption of cyclosporine. There have been reports of impaired, unchanged, and enhanced absorption during administration with meals relative to the fasting state. The mechanisms are unclear. Some investigators found an association with the fat content of food. In one study, increased fat intake resulted in significantly increased cyclosporine bioavailability and clearance. However, the AUC and pharmacodynamics of cyclosporine were not significantly affected, thus clinical relevance of these findings may be minimal.

MANAGEMENT: Patients receiving cyclosporine therapy should be advised to either refrain from or avoid fluctuations in the consumption of grapefruits and grapefruit juice. Until more data are available, the consumption of red wine or purple grape juice should preferably be avoided or limited. All oral formulations of cyclosporine should be administered on a consistent schedule with regard to time of day and relation to meals so as to avoid large fluctuations in plasma drug levels.

ADJUST DOSING INTERVAL: Food significantly enhances the oral bioavailability of telaprevir. When given with a meal containing 533 kcal and 21 g fat, telaprevir systemic exposure (AUC) increased by 237% compared to administration under fasting conditions. The type of meal also affects the exposure to telaprevir. Relative to fasting, telaprevir AUC increased by approximately 117% with a low-fat meal (249 kcal; 3.6 g fat) and 330% with a high-fat meal (928 kcal; 56 g fat). In Phase 3 clinical trials, telaprevir doses were administered within 30 minutes of completing a meal or snack containing approximately 20 grams of fat.

MANAGEMENT: Telaprevir should be administered with food containing approximately 20 grams of fat. Patients should be advised that the fat content of the meal or snack is critical to the absorption of telaprevir. Food taken with telaprevir should be ingested within 30 minutes prior to each dose. Examples of some foods that could be taken with telaprevir include: bagel with cream cheese; half cup of nuts; 3 tablespoons of peanut butter; 1 cup of ice cream; 2 ounces of American or cheddar cheese; 2 ounces of potato chips; or half cup of trail mix.