Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating MEKTOVI [see Use inSpecific Populations (8.1)].

Contraception

MEKTOVI can cause fetal harm when administered to a pregnant woman [see Use in SpecificPopulations (8.1)].

Females

Advise females of reproductive potential to use effective contraception during treatment with MEKTOVIand for at least 30 days after the final dose.

8.4 Pediatric Use

The safety and effectiveness of MEKTOVI have not been established in pediatric patients.

8.5 Geriatric Use

Of the 690 patients with BRAF mutation-positive melanoma who received MEKTOVI (45 mg twice daily)in combination with encorafenib at doses between 300 mg and 600 mg once daily across multiple clinical

trials, 20% were aged 65 to 74 years and 8% were aged 75 years and older. No overall differences in thesafety or effectiveness of MEKTOVI plus encorafenib were observed in elderly patients as compared to

younger patients [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

Binimetinib concentrations may increase in patients with moderate or severe hepatic impairment. Doseadjustment for MEKTOVI is not recommended in patients with mild hepatic impairment (total bilirubin > 1

and ≤ 1.5 × ULN and any AST or total bilirubin ≤ ULN and AST > ULN). Reduce the dose of MEKTOVIfor patients with moderate (total bilirubin > 1.5 and ≤ 3 × ULN and any AST) or severe (total bilirubin

levels > 3 × ULN and any AST) hepatic impairment [see Dosage and Administration (2.4), ClinicalPharmacology (12.3)].

10 OVERDOSAGE

Since binimetinib is 97% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatmentof overdose with MEKTOVI.

11 DESCRIPTION

Binimetinib is a kinase inhibitor. The chemical name is 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2­hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide. The molecular formula is C17H15BrF2N4O3 and

the molecular weight is 441.2 daltons. The chemical structure of binimetinib is shown below: 

 

Binimetinib is a white to slightly yellow powder. In aqueous media, binimetinib is slightly soluble at pH 1,very slightly soluble at pH 2, and practically insoluble at pH 4.5 and higher.

MEKTOVI (binimetinib) tablets for oral use contain 15 mg of binimetinib with the following inactiveingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate

(vegetable source), and colloidal silicon dioxide. The coating contains polyvinyl alcohol, polyethyleneglycol, titanium dioxide, talc, ferric oxide yellow, and ferrosoferric oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Binimetinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) andMEK2 activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK)

pathway. In vitro, binimetinib inhibited extracellular signal-related kinase (ERK) phosphorylation in cell-free assays as well as viability and MEK-dependent phosphorylation of BRAF-mutant human melanoma cell

lines. Binimetinib also inhibited in vivo ERK phosphorylation and tumor growth in BRAF-mutant murinexenograft models.