Binimetinib

Asymptomatic, absolute decrease in LVEF of greater than 10% from baseline that is also below lower limit of normal (LLN)LVEF is at or above the lower limit of normal andAbsolute decrease from baseline is 10% or less andPatient is asymptomatic.If the LVEF does not recover within 4 weeks permanently discontinue MEKTOVI. Symptomatic congestive heart failure or absolute decrease in LVEF of greater than 20% from baseline that is also below LLNUncomplicated deep venous thrombosis (DVT) or pulmonary embolism (PE)If improves to Grade 0-1, resume at a reduced dose.If no improvement, permanently discontinue MEKTOVI.Life threatening PESymptomatic serous retinopathy/Retinal pigment epithelial detachmentsIf improves and becomes asymptomatic, resume at same dose.If not improved, resume at a lower dose level or permanently discontinue MEKTOVI. Any Grade Grade 1-3If improved, resume at same or reduced dose. If not improved, permanently discontinue MEKTOVI.Grade 4Grade 2If improved to Grade 0-1, resume at a reduced dose.If not resolved within 4 weeks, permanently discontinue MEKTOVI.Grade 3 or Grade 4Grade 2 AST or ALT increasedIf no improvement within 2 weeks, withhold MEKTOVI until improved to Grade 0-1 or to pretreatment/baseline levels and then resume at the same dose.Grade 3 or 4 AST or ALT increasedGrade 4 asymptomatic CPK elevation or Any Grade CPK elevation with symptoms or with renal impairmentIf improved to Grade 0-1 resume at a reduced dose.If not resolved within 4 weeks, permanently discontinue MEKTOVI.Grade 2Grade 3Grade 4Recurrent Grade 2 orFirst occurrence of any Grade 3If improves to Grade 0-1 or to pretreatment/baseline levels, resume at reduced dose.If no improvement, permanently discontinue MEKTOVI.First occurrence of any Grade 4If improves to Grade 0-1 or to pretreatment/baseline levels, then resume at a reduced dose.If no improvement, permanently discontinue MEKTOVI.Recurrent Grade 3Recurrent Grade 4

Table 2: Recommended Dosage Modifications for MEKTOVI for Adverse Reactions

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Severity of Adverse ReactionNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.	Dose Modification for MEKTOVI
Cardiomyopathy [see Warnings and Precautions (5.2)]
Withhold MEKTOVI for up to 4 weeks, evaluate LVEF every 2 weeks. Resume MEKTOVI at a reduced dose if the following are present:
Permanently discontinue MEKTOVI.
Venous Thromboembolism [see Warnings and Precautions (5.3)]
Withhold MEKTOVI.
Permanently discontinue MEKTOVI.
Serous Retinopathy [see Warnings and Precautions (5.4)]
Withhold MEKTOVI for up to 10 days.
Retinal Vein Occlusion (RVO) [see Warnings and Precautions (5.4)]
Permanently discontinue MEKTOVI.
Uveitis [see Warnings and Precautions (5.4)]
If Grade 1 or 2 does not respond to specific ocular therapy, or for Grade 3 uveitis, withhold MEKTOVI for up to 6 weeks.
Permanently discontinue MEKTOVI.
Interstitial Lung Disease [see Warnings and Precautions (5.5)]
Withhold MEKTOVI for up to 4 weeks.
Permanently discontinue MEKTOVI.
Hepatotoxicity [see Warnings and Precautions (5.6)]
Maintain MEKTOVI dose.
See Other Adverse Reactions.
Rhabdomyolysis or Creatine Phosphokinase (CPK) elevations [see Warnings and Precautions (5.7)]
Withhold MEKTOVI dose for up to 4 weeks.
Dermatologic [other than palmar plantar erythrodysesthesia syndrome (PPES)] [see Adverse Reactions (6.1)]
If no improvement within 2 weeks, withhold MEKTOVI until Grade 0-1. Resume at same dose if first occurrence or reduce dose if recurrent.
Withhold MEKTOVI until Grade 0-1. Resume at same dose if first occurrence or reduce dose if recurrent.
Permanently discontinue MEKTOVI.
Other Adverse Reactions (including Hemorrhage) [see Warnings and Precautions (5.8), Adverse Reactions (6.1)]Dose modification of MEKTOVI when administered with encorafenib is not recommended for the following adverse reactions: palmar-plantar erythrodysesthesia syndrome (PPES), non-cutaneous RAS mutation-positive malignancies, and QTc prolongation.
Withhold MEKTOVI for up to 4 weeks.
Permanently discontinue MEKTOVI, or Withhold MEKTOVI for up to 4 weeks.
Consider permanently discontinuing MEKTOVI.
Permanently discontinue MEKTOVI.