• Assess skin prior to starting therapy and every 2 mo during and for 6 mo following therapy for new lesions. If new lesions appear, evaluate and remove as needed. If Grade 2 (intolerable), Grade 3, or Grade 4 rash or other skin reactions occur, withhold or reduce dose.
• Monitor for bleeding and hemorrhage periodically during therapy. If Grade 3 hemorrhage occurs, hold therapy for up to 4 wk. If improved to Grade 0 or 1, resume at next lower dose. If not improved within 4 wk, permanently discontinue. If Grade 4 hemorrhage occurs, permanently discontinue therapy.
• Monitor left ventricular ejection fraction (LVEF) prior to initiation, 1 mo after initiation, and every 3 mo until discontinuation. If asymptomatic, absolute ↓ LVEF from baseline of >10% and <institutional lower limit of normal (LLN), hold therapy for 2 wk; repeat LVEF. Resume at next lower dose if all of following are present: LVEF is ≥LLN and absolute ↓ from baseline LVEF ≤10%. Discontinue permanently if any of following are present: LVEF is <LLN or absolute ↓ from baseline LVEF >10%. If symptomatic LVEF ↓ from baseline, hold therapy for up to 4 wk, repeat LVEF. Resume at next lower dose if all of following are present: symptoms resolve and LVEF is ≥LLN and absolute ↓ from baseline LVEF is ≤10%. Discontinue permanently if any of following are present: symptoms persist, or LVEF <LLN, or absolute ↓ from baseline LVEF >10%. If restarting cobimetinib after a dose reduction or interruption, evaluate LVEF at approximately 2 wk, 4 wk, 10 wk, and 16 wk, and as clinically indicated.
• Perform ophthalmological evaluations periodically during therapy and if patient reports new or worsening visual disturbances. If serious retinopathy occurs, hold therapy for up to 4 wk. If signs and symptoms improve, resume at next lower dose. If not improved or symptoms recur at lower dose within 4 wk, permanently discontinue. If retinal vein occlusion occurs, permanently discontinue therapy.
• Assess for photosensitivity during therapy. If Grade 2 (intolerable), Grade 3, or Grade 4 photosensitivity occurs, withhold therapy up to 4 wk. If improved to Grade 0 or 1, resume at next lower dose. If not improved within 4 wk, permanently discontinue.

Lab Test Considerations:

• Confirm presence of BRAF V600E or V600K mutation in tumor specimens starting therapy with cobimetinib with vemurafenib. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.May cause ↑ AST, ALT, alkaline phosphatase, and GGT. Monitor liver function tests before starting and monthly during therapy, and as clinically indicated. For 1st occurrence of Grade 4 hepatotoxicity, hold therapy up to 4 wk. If improved to Grade 0 or 1, resume at next lower dose. If not improved to Grade 0 or 1 within 4 wk, permanently discontinue. If Grade 4 hepatotoxicity recurs, discontinue therapy permanently.
  • Obtain CK and serum creatinine levels at baseline and periodically during therapy. If Grade 4 CK ↑ or any CK ↑ and myalgia occur, hold therapy up to 4 wk. If improved to Grade 3 or lower, resume at next lower dose level. If not improved within 4 wk, permanently discontinue.
  • May cause hypophosphatemia, hyponatremia, hypoalbuminemia, hypokalemia, hyperkalemia, and hypocalcemia.
  • May cause anemia, lymphopenia, and thrombocytopenia.