Drug Interaction Report

MONITOR: Coadministration with dabrafenib may decrease the plasma concentrations of drugs that are primarily metabolized by CYP450 3A4 and/or 2C9, including many antidiabetic agents such as nateglinide, repaglinide, linagliptin, saxagliptin, and sulfonylureas. Dabrafenib has been found in vitro and in vivo to be an inducer of CYP450 3A4 and 2C9 using the probe substrates midazolam and warfarin, respectively. Onset of induction is likely to occur after 3 days of repeat dosing with dabrafenib; however, transient inhibition of these isoenzymes may be observed during the first few days of treatment. According to the product labeling, hyperglycemia is a commonly reported side effect during treatment with dabrafenib, which may require dosage increases of insulin and oral hypoglycemic agents or initiation of such therapy. It is unclear whether dabrafenib itself can impair glucose metabolism, or if the hyperglycemia is primarily due to a pharmacokinetic interaction between dabrafenib and some antidiabetic agents.

MANAGEMENT: Caution is advised when dabrafenib is prescribed to patients with diabetes, particularly those receiving antidiabetic agents that are metabolized by CYP450 3A4 and/or 2C9. Close clinical monitoring of glycemic control is recommended following initiation or discontinuation of dabrafenib, and the dosages of concomitant antidiabetic agents adjusted as necessary. Patients should be advised to notify their physician if their blood glucose is consistently high or if they experience symptoms of severe hyperglycemia such as excessive thirst and increases in the volume or frequency of urination. Likewise, patients should be observed for hypoglycemia when dabrafenib is withdrawn from their therapeutic regimen.

ADJUST DOSING INTERVAL: Exenatide slows gastric emptying and may reduce the extent and rate of absorption of concomitantly administered oral medications. When acetaminophen 1000 mg was administered simultaneously with exenatide 10 mcg and also one hour, 2 hours, and 4 hours after exenatide injection, acetaminophen systemic exposure (AUC) was decreased by 21%, 23%, 24%, and 14%, respectively; peak plasma concentration (Cmax) was decreased by 37%, 56%, 54%, and 41%, respectively; and time to peak plasma concentration (Tmax) was increased from 0.6 hours in the control period to 0.9 hours, 4.2 hours, 3.3 hours, and 1.6 hours, respectively. These values were not significantly changed when acetaminophen was given one hour before exenatide injection.

MANAGEMENT: Concomitantly administered oral medications that are dependent on threshold concentrations for efficacy (e.g., antibiotics, contraceptives) or that require rapid gastrointestinal absorption (e.g., hypnotics, pain medications) should be administered at least 1 hour before exenatide. If such medications are to be administered with food, patients should be advised to take them with a meal or snack when exenatide is not administered.

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.