BRAFTOVI has the potential to render hormonal contraceptives ineffective [see Drug Interactions (7.2)].

Infertility

Males

Based on findings in male rats at doses approximately 13 times the human exposure at the 450 mg clinicaldose, use of BRAFTOVI may impact fertility in males [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

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

8.5 Geriatric Use

Of the 690 patients with BRAF mutation-positive melanoma who received BRAFTOVI at doses between300 mg and 600 mg once daily in combination with binimetinib (45 mg twice 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 BRAFTOVI plus binimetinib were observed in elderly patients as compared to

younger patients [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

Dose adjustment for BRAFTOVI is not recommended in patients with mild hepatic impairment (Child-PughClass A) [see Clinical Pharmacology (12.3)]. A recommended dose has not been established for patients

with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment.

8.7 Renal Impairment

No dose adjustment is recommended for patients with mild to moderate renal impairment (CLcr 30 to< 90 mL/min) [see Clinical Pharmacology (12.3)]. A recommended dose has not been established for

patients with severe renal impairment (CLcr < 30 mL/min).

10 OVERDOSAGE

Since encorafenib is 86% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatmentof overdose with BRAFTOVI.

11 DESCRIPTION

Encorafenib is a kinase inhibitor. The chemical name is methyl N-{(2S)-1-[(4-{3-[5-chloro-2-fluoro-3­(methanesulfonamido)phenyl]-1-(propan-2-yl)-1H-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2­

yl}carbamate. The molecular formula is C22H27ClFN7O4S and the molecular weight is 540 daltons. The

chemical structure of encorafenib is shown below:

Encorafenib is a white to almost white powder. In aqueous media, encorafenib is slightly soluble at pH 1,very slightly soluble at pH 2, and insoluble at pH 3 and higher.

BRAFTOVI (encorafenib) capsules for oral use contain 50 mg or 75 mg of encorafenib with the followinginactive ingredients: copovidone, poloxamer 188, microcrystalline cellulose, succinic acid, crospovidone,

colloidal silicon dioxide, magnesium stearate (vegetable origin). The capsule shell contains gelatin, titaniumdioxide, iron oxide red, iron oxide yellow, ferrosoferric oxide, monogramming ink (pharmaceutical glaze,

ferrosoferric oxide, propylene glycol).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Encorafenib is a kinase inhibitor that targets BRAF V600E, as well as wild-type BRAF and CRAF in invitro cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene,

such as BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cellgrowth. Encorafenib was also able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1,