Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inducers of CYP450 2C8 and/or 3A4 may decrease the plasma concentrations of dabrafenib, which is primarily metabolized by these isoenzymes. Administration of rifampin (600 mg once a day), a potent CYP450 3A4 and moderate CYP450 2C8 inducer, with dabrafenib (150 mg twice a day) for 10 days resulted in a decreased dabrafenib AUC (34%) and Cmax (27%). The AUC of the metabolite hydroxy-dabrafenib was not affected; however, the AUC increased by 73% for the metabolite carboxy-dabrafenib and decreased by 30% for desmethyl-dabrafenib.

MANAGEMENT: Concomitant use of dabrafenib with potent CYP450 2C8 or 3A4 inducers should generally be avoided. Otherwise, patients should be closely monitored for potential loss of efficacy of dabrafenib.

GENERALLY AVOID: An isolated case report suggests that foods containing large amounts of tyramine may precipitate a hypertensive crisis in patients treated with St. John's wort. The mechanism of interaction is unknown, as St. John's wort is not thought to possess monoamine oxidase (MAO) inhibiting activity at concentrations achieved in vivo. The case patient was a 41-year-old man who had been taking St. John's wort for seven days prior to presentation at the emergency room with confusion and disorientation. The patient recalled last eating aged cheese and having a glass of red wine approximately 10 hours prior to admission. No other cause of delirium or hypertension could be identified. In addition, alcohol may potentiate some of the pharmacologic effects of St. John's wort. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Until further information is available, patients treated with St. John's wort should consider avoiding consumption of protein foods in which aging or breakdown of protein is used to increase flavor. These foods include cheese (particularly strong, aged or processed cheeses), sour cream, wine (particularly red wine), champagne, beer, pickled herring, anchovies, caviar, shrimp paste, liver (particularly chicken liver), dry sausage, figs, raisins, bananas, avocados, chocolate, soy sauce, bean curd, yogurt, papaya products, meat tenderizers, fava beans, protein extracts, and dietary supplements. Caffeine may also precipitate hypertensive crisis so its intake should be minimized as well. Patients should also be advised to avoid or limit consumption of alcohol.

ADJUST DOSING INTERVAL: Food may reduce as well as delay the absorption of dabrafenib. In study subjects, administration of dabrafenib with a high-fat meal decreased peak plasma concentration (Cmax) and systemic exposure (AUC) by 51% and 31%, respectively, and delayed median Tmax by approximately 3.6 hours compared to administration in the fasted state.

MANAGEMENT: Dabrafenib should be taken at least 1 hour before or 2 hours after a meal.