Drug Interactions between Farydak and Stivarga

ADJUST DOSING INTERVAL: Depending on the amount of fat, food may enhance the oral bioavailability of both regorafenib and its active metabolites, M-2 and M-5. In 24 healthy male subjects, administration of regorafenib with a high-fat meal (945 calories; 54.6 g fat) increased the mean systemic exposure (AUC) of regorafenib by 48% but decreased the mean AUC of M-2 and M-5 by 20% and 51%, respectively, compared to administration under the fasted state. In contrast, administration with a low-fat meal (319 calories; 8.2 g fat) increased the mean AUC of regorafenib, M-2 and M-5 by 36%, 40% and 23%, respectively, compared to administration during fasting.

GENERALLY AVOID: Coadministration with grapefruit juice may alter the pharmacokinetics of regorafenib and its active metabolites. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. The interaction has not been studied specifically with grapefruit juice, but has been reported with the potent CYP450 3A4 inhibitor, ketoconazole. In 18 healthy male study subjects, administration of a single 160 mg dose of regorafenib on day 5 of treatment with ketoconazole (400 mg daily for 18 days) resulted in a 33% increase in mean regorafenib systemic exposure (AUC) compared to administration of regorafenib alone. Additionally, there was a 93% decrease each in the mean AUC of the M-2 and M-5 metabolites. Both have been shown to have similar in vitro pharmacological activity and steady-state concentrations as regorafenib, thus the net clinical effect of these pharmacokinetic changes is unknown.

MANAGEMENT: To ensure optimal oral absorption, regorafenib should be administered with a low-fat breakfast that contains less than 30% fat. Examples of a low-fat breakfast include: 2 slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of jelly, plus 8 ounces of skim milk (319 calories; 8.2 g fat); or 1 cup of cereal, 8 ounces of skim milk, 1 slice of toast with jam, apple juice, and 1 cup of coffee or tea (520 calories; 2 g fat). Patients should be advised to avoid consuming grapefruit or grapefruit juice during treatment with regorafenib.

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GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of panobinostat. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Increased exposure to panobinostat may increase the risk of adverse effects such as nausea, vomiting, diarrhea, anorexia, peripheral edema, cardiotoxicity, ECG abnormalities, electrolyte disturbances, bleeding complications, hepatotoxicity, and myelosuppression.

Food may delay the rate of absorption of panobinostat, but does not significantly affect the overall extent of absorption. When a single oral dose of panobinostat was administered to 36 patients with advanced cancer 30 minutes after a high-fat meal, panobinostat peak plasma concentration (Cmax) and systemic exposure (AUC) were approximately 44% and 16% lower, respectively, compared to administration under fasting conditions. The median time to maximum concentration (Tmax) was prolonged by 2.5 hours.

MANAGEMENT: Patients should avoid consumption of grapefruit or grapefruit juice during treatment with panobinostat. The manufacturer also recommends avoiding star fruit, Seville oranges, pomegranate, and pomegranate juice. Panobinostat may be administered with or without food.

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