Drug Interaction Report

MONITOR: Although this combination is used therapeutically and recommended for certain indications (e.g., melanoma, anaplastic thyroid cancer, non-small cell lung cancer), concomitant use of dabrafenib and trametinib may be associated with increased risk of severe and possibly life-threatening adverse events. These include skin toxicities (e.g., Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms), intracranial and gastrointestinal hemorrhage, venous thromboembolism, and serious febrile events. In an open label study patients with metastatic melanoma with BRAF V600 mutations (n=247) were treated with dabrafenib alone or dabrafenib and trametinib. Serious pyrexia with severe chills or hypotension or that required hospitalization occurred in 19 to 25% of patients treated with the combination as compared to 2% of patients in the monotherapy group.

MANAGEMENT: The manufacturer's product labeling should be consulted for recommendations on dosage adjustments or discontinuation in the event of severe toxicities. Patients should be instructed to contact their doctor if they experience unusual bleeding or bruising or severe weakness; fever; red, purple or intolerable rash; shortness of breath, chest pain, or arm or leg swelling.

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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.

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ADJUST DOSING INTERVAL: Food may reduce as well as delay the absorption of trametinib. In study subjects, administration of a single dose of trametinib with a high-fat, high-calorie meal decreased peak plasma concentration (Cmax) and systemic exposure (AUC) by 70% and 24%, respectively, and delayed Tmax by approximately 4 hours compared to administration in the fasted state.

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

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The recommended maximum number of medicines in the 'multikinase inhibitors' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'multikinase inhibitors' category:

• dabrafenib
• trametinib

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.