Dizzinessc

 15 3 4 0

 Peripheral neuropathyc

 12 1 13 2

Vascular Disorders

 Hemorrhagec

 19 3 9 2

a Grades per National Cancer Institute CTCAE v4.03. b Grade 4 adverse reactions limited to fatigue (n=1), pruritus (n=1) and rash (n=1) in the BRAFTOVI with binimetinib arm. c Represents a composite of multiple, related preferred terms.

BRAFTOVI when used as a single agent increases the risk of certain adverse reactions compared toBRAFTOVI in combination with binimetinib. In patients receiving BRAFTOVI 300 mg orally once daily as

a single agent, the following adverse reactions were observed at a higher rate (≥ 5%) compared to patientsreceiving BRAFTOVI in combination with binimetinib: palmar-plantar erythrodysesthesia syndrome (51%

vs. 7%), hyperkeratosis (57% vs. 23%), dry skin (38% vs. 16%), erythema (16% vs. 7%), rash (41% vs.

22%), alopecia (56% vs. 14%), pruritus (31% vs. 13%), arthralgia (44% vs. 26%), myopathy (33% vs. 23%),

back pain (15% vs. 9%), dysgeusia (13% vs. 6%), and acneiform dermatitis (8% vs. 3%). 

 

Other clinically important adverse reactions occurring in < 10% of patients who received BRAFTOVI in

combination with binimetinib were:

Nervous system disorders: Facial paresis

Gastrointestinal disorders: Pancreatitis

Skin and subcutaneous tissue disorders: Panniculitis

Immune system disorders: Drug hypersensitivity

Table 4: Laboratory Abnormalities Occurring in ≥ 10% (All Grades) of Patients Receiving

BRAFTOVI in Combination with Binimetinib in COLUMBUSa

Laboratory Abnormality

BRAFTOVI

with binimetinib

N=192

Vemurafenib

N=186

All

Grades

(%)

Grades

3 and 4

(%)

All

Grades

(%)

Grades

3 and 4

(%)

Hematology

 Anemia 36 3.6 34 2.2

 Leukopenia 13 0 10 0.5

 Lymphopenia 13 2.1 30 7

 Neutropenia 13 3.1 4.8 0.5

Chemistry

 Increased Creatinine 93 3.6 92 1.1

Increased Gamma Glutamyl Transferase 45 11 34 4.8

 Increased ALT 29 6 27 2.2

 Increased AST 27 2.6 24 1.6

 Hyperglycemia 28 5 20 2.7

Increased Alkaline Phosphatase 21 0.5 35 2.2

 Hyponatremia 18 3.6 15 0.5

 Hypermagnesemia 10 1.0 26 0.5

a Grades per National Cancer Institute CTCAE v4.03.

7 DRUG INTERACTIONS

7.1 Effect of Other Drugs on BRAFTOVI

Strong or Moderate CYP3A4 InhibitorsConcomitant administration of BRAFTOVI with a strong or moderate CYP3A4 inhibitor increasedencorafenib plasma concentrations and may increase encorafenib adverse reactions [see Clinical

Pharmacology (12.3)]. 

Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors,including grapefruit juice. If coadministration of strong or moderate CYP3A4 inhibitors cannot be avoided,

modify dose as recommended [see Dosage and Administration (2.4)].

Strong or Moderate CYP3A4 Inducers

Concomitant administration of BRAFTOVI with a strong or moderate CYP3A4 inducer may decreaseencorafenib plasma concentrations and may decrease encorafenib efficacy [see Clinical Pharmacology

(12.3)]. Avoid concomitant administration of strong or moderate CYP3A4 inducers with BRAFTOVI.

7.2 Effect of BRAFTOVI on Other Drugs