Severity of adverse reactiona

Binimetinib

Cutaneous reactions

• Grade2

Binimetinib should be maintained.

If rash worsens or does not improve within 2 weeks with treatment, binimetinib should be withheld until improved to Grade 0 or 1 and then resumed at the same dose if first occurrence or resumed at a reduced dose if recurrent Grade2.

• Grade 3

Binimetinib should be withheld until improved to Grade 0 or 1 and resumed at the same dose if first occurrence or resumed at a reduced dose if recurrent Grade 3.

• Grade 4

Binimetinib should be permanently discontinued.

Ocular events

• Symptomatic retinal pigment epithelial detachments (RPED) (Grade 2 or 3)

Binimetinib should be withheld for up to 2 weeks and ophthalmic monitoring should be repeated including visual acuity assessment.

• If improved to Grade 0 or 1, binimetinib should be resumed at same dose.

• If improved to Grade 2, binimetinib should be resumed at a lower dose.

• If not improved to Grade 2, binimetinib should be permanently discontinued.

• Symptomatic RPED (Grade 4) associated with reduced visual acuity (Grade 4)

Binimetinib should be permanently discontinued.

• Retinal vein occlusion (RVO)

Binimetinib should be permanently discontinued.

Severity of adverse reaction3

Binimetinib

Cardiac events

• Grade 2 Left ventricular ejection fraction (LVEF) decrease or asymptomatic, absolute decrease in LVEF of greater than 10 % from baseline that is below lower limit of normal (LLN)

LVEF should be eva luated every 2 weeks.

• If asymptomatic:

Binimetinib should be withheld for up to 4 weeks. Binimetinib should be resumed at a reduced dose if all of the following are present within 4 weeks:

o LVEF is at or above the LLN

o Absolute decrease from baseline is 10 % or less.

• If the LVEF does not recover within 4 weeks, binimetinib should be permanently discontinued.

• Grade 3 or 4 LVEF decrease or symptomatic left ventricular dysfunction (LVD)

Binimetinib should be permanently discontinued.

LVEF should be eva luated every 2 weeks until recovery.

Rhabdomyolysis/Creatine phosphokinase (CK) elevation

• Grade 3 (CK > 5 - 10x upper limit of normal (ULN)) asymptomatic

Binimetinib dose should be maintained and it should be ensured that patient is adequately hydrated.

• Grade 4 (CK > 10x ULN) asymptomatic

Binimetinib should be withheld until improved to Grade 0 or 1. It should be ensured that patient has adequate hydration.

• Grade 3 or grade 4 (CK > 5x ULN) with muscle symptoms or renal impairment

Binimetinib should be withheld until improved to Grade 0 or 1.

• If resolved within 4 weeks, binimetinib should be resumed at a reduced dose, or

• Binimetinib should be permanently discontinued.

Venous thromboembolism (VTE)

• Uncomplicated deep vein thrombosis (DVT) or pulmonary embolism (PE) ≤ Grade 3

Binimetinib should be withheld.

• If improved to Grade 0 or 1, binimetinib should be resumed at a reduced dose, or

• If not improved, binimetinib should be permanently discontinued.

• Grade 4 PE

Binimetinib should be permanently discontinued.