reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

5.7 Hemorrhage

Hemorrhage can occur when MEKTOVI is administered in combination with encorafenib. In COLUMBUS,hemorrhage occurred in 19% of patients receiving MEKTOVI in combination with encorafenib. Grade 3 or

greater hemorrhage occurred in 3.2% of patients. The most frequent hemorrhagic events weregastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage

(1%). 

Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6 of patients.

Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage andAdministration (2.3), Adverse Reactions (6.1)].

5.8 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, MEKTOVI can cause fetal harm whenadministered to a pregnant woman. Binimetinib was embryotoxic and abortifacient when administered to

rabbits during the period of organogenesis at doses greater than or equal to those resulting in exposuresapproximately 5 times the human exposure at the recommended clinical dose of 45 mg twice daily.

Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effectivecontraception during treatment with MEKTOVI and for at least 30 days after the final dose [see Use in

Specific Populations (8.1, 8.3)].

5.9 Risks Associated with Combination Treatment

MEKTOVI is indicated for use in combination with encorafenib. Refer to the encorafenib prescribinginformation for additional risk information that applies to combination use treatment.

6 ADVERSE REACTIONS

The following adverse reactions are described elsewhere in the labeling:

 Cardiomyopathy [see Warnings and Precautions (5.1)]

 Venous Thromboembolism [see Warnings and Precautions (5.2)]

 Ocular Toxicities [see Warnings and Precautions (5.3)]

 Interstitial Lung Disease [see Warnings and Precautions (5.4)]

 Hepatotoxicity [see Warnings and Precautions (5.5)]

 Rhabdomyolysis [see Warnings and Precautions (5.6)]

 Hemorrhage [see Warnings and Precautions (5.7)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in theclinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not

reflect the rates observed in practice.

The data described in Warnings and Precautions [see Warnings and Precautions (5)] reflect exposure of192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma to MEKTOVI (45 mg

twice daily) in combination with encorafenib (450 mg once daily) in a randomized open-label, active-controlled trial (COLUMBUS) or, for rare events, exposure of 690 patients with BRAF V600 mutation­positive melanoma to MEKTOVI (45 mg twice daily) in combination with encorafenib at doses between

300 mg and 600 mg once daily across multiple clinical trials.