• Assess left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition (MUGA) scan before starting, after 1 month, and at 2–3 mo intervals during therapy. If asymptomatic and absolute ↓ LVEF of ≥10% from baseline and below institutional lower limits of normal from pretreatment value, withhold for up to 4 wks. If LVEF improves to normal within 4 wks,resume trametinib at lower dose, ↓ by 0.5 mg, or discontinue in patients taking 1 mg daily. If symptomatic HF, absolute ↓ LVEF >20% of baseline that is below institutional lower limits of normal, or absolute ↓ LVEF ≥10% of baseline that is below institutional lower limits of normal that does not improve to normal within 4 wks following interruption of therapy, permanently discontinue trametinib.
• Perform ophthalmalogic evaluation at baseline; compare if patient reports visual disturbance. If retinal pigment epithelial detachment (RPED) occurs, withhold trametinib for up to 3 wks. If RPED improves within 3 wks, resume trametinib at same or at a lower dose (0.5 mg) or discontinue in patients taking 1 mg daily. If retinal vein occlusion occurs or if Grade 2–3 RPED does not improve to at least Grade 1 within 3 wks, permanently discontinue trametinib.
• Assess for signs and symptoms of interstitial lung disease (cough, dyspnea, hypoxia, pleural effusion, infiltrates). Permanently discontinue trametinib if these occur.
• Monitor for skin toxicities and secondary infections every 2 mo during and for 6 mo following therapy. If intolerable Grade 2 rash that does not improve within 3 wks following dose reduction or if Grade 3 or 4 rash occurs, withhold trametinib (single-agent) or dabrafenib (combination therapy) for up to 3 wks. If improved within 3 wks, resume trametinib at a lower dose. If intolerable Grade 2 or Grade 3 or 4 rash that does not improve despite interruption of therapy for 3 wks, permanently discontinue trametinib (single-agent) or dabrafenib (combination therapy).
• Monitor BP periodically during therapy. May cause hypertension.
• Monitor temperature during therapy. May cause serious febrile reactions. If fever >104°F, do not modify dose of trametinib; withhold dabrafenib until fever resolves. Then resume at same or lower dose. If fever >104°F or complicated by rigors, hypotension, dehydration, or renal failure, withhold trametinib (single-agent) or dabrafenib (combination therapy) until fever resolves. Then resume at same or lower dose.
• Monitor for signs and symptoms venous thromboembolism (shortness of breath, chest pain, arm or leg swelling). Permanently discontinue trametinib and dabrafenib for life threatening pulmonary embolism. Withhold trametinib for uncomplicated deep vein thrombosis or pulmonary embolism for up to 3 wks; if improved to Grade 0–1, trametinib may be resumed at lower dose level. Do not modify dose of dabrafenib.
• Monitor for signs and symptoms of hemorrhage. Withhold trametinib for Grade 3 hemorrhagic events; if improved, resume at next lower dose level. Permanently discontinue therapy for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve.
• Monitor for signs and symptoms of colitis and GI perforation.
• Monitor patients receiving trametinib and dabrafenib closely for signs or symptoms of non-cutaneous malignancies.

Lab Test Considerations:

• Verify negative pregnancy before starting therapy.
• Confirm presence of BRAF V600E or V600K mutation in tumor specimens prior to starting therapy with trametinib. Information on FDA-approved tests for the detection of BRAF V600E mutations in melanoma or NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.
  • May cause ↑ AST, ALT, and alkaline phosphatase.
  • May cause hypoalbumemia.
  • May cause anemia.
  • Monitor blood sugar at baseline and periodically during therapy when administered with dabrafenib. May cause hyperglycemia.