Encorafenib is a kinase inhibitor. The chemical name is methyl N -{(2 S )-1-[(4-{3-[5-chloro-2-fluoro-3-(methanesulfonamido)phenyl]-1-(propan-2-yl)-1 H -pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl}carbamate. The molecular formula is C 22 H 27 ClFN 7 O 4 S 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 75 mg of encorafenib with the following inactive ingredients: copovidone, poloxamer 188, microcrystalline cellulose, succinic acid, crospovidone, colloidal silicon dioxide, magnesium stearate (vegetable origin). The capsule shell contains gelatin, titanium dioxide, iron oxide red, iron oxide yellow, ferrosoferric oxide, monogramming ink (pharmaceutical glaze, ferrosoferric oxide, propylene glycol). Chemical Structure

BRAFTOVI is a kinase inhibitor indicated: Melanoma • in combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-authorized test. Colorectal Cancer (CRC) • in combination with cetuximab and fluorouracil-based chemotherapy, for the treatment of adult patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA‑authorized test. • in combination with cetuximab, for the treatment of adult patients with mCRC with a BRAF V600E mutation, as detected by an FDA-authorized test, after prior therapy. Non-Small Cell Lung Cancer (NSCLC) • in combination with binimetinib, for the treatment of adult patients with metastatic non–small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-authorized test. Limitations of Use BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma, wild-type BRAF CRC, or wild-type BRAF NSCLC

BRAF V600E or V600K Mutation–Positive Unresectable or Metastatic Melanoma BRAFTOVI is indicated, in combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-authorized test

BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (mCRC) • BRAFTOVI is indicated, in combination with cetuximab and fluorouracil-based chemotherapy , for the treatment of adult patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA- authorized test . • BRAFTOVI is indicated, in combination with cetuximab, for the treatment of adult patients with mCRC with a BRAF V600E mutation, as detected by an FDA- authorized test, after prior therapy

BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC) BRAFTOVI is indicated, in combination with binimetinib, for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-authorized test

Limitations of Use BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma, wild-type BRAF CRC, or wild-type BRAF NSCLC .

Capsules: 75 mg, hard gelatin, stylized "A" on beige cap and "LGX 75mg" on white body. Capsules: 75 mg.

Melanoma • Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to the initiation of BRAFTOVI. • The recommended dose is 450 mg orally once daily in combination with binimetinib. CRC • Confirm the presence of BRAF V600E mutation in plasma or tumor specimens prior to the initiation of BRAFTOVI. • The recommended dose is 300 mg orally once daily in combination with o biweekly cetuximab and mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) or cetuximab and FOLFIRI (fluorouracil, leucovorin and irinotecan) o weekly cetuximab NSCLC • Confirm the presence of BRAF V600E mutation in tumor or plasma specimens prior to initiating BRAFTOVI. • The recommended dose is 450 mg orally once daily in combination with binimetinib. Take BRAFTOVI with or without food

Patient Selection BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma Confirm the presence of a BRAF V600E or V600K mutation in tumor specimens prior to initiating BRAFTOVI . Information on FDA-authorized tests for the detection of BRAF V600E and V600K mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics . BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC) Confirm the presence of a BRAF V600E mutation in plasma or tumor tissue prior to initiating BRAFTOVI . If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA- authorized tests for the detection of BRAF V600E mutations in CRC is available at: http://www.fda.gov/CompanionDiagnostics . BRAF V600E Mutation-Positive Metastatic Non‑Small Cell Lung Cancer (NSCLC) Confirm the presence of a BRAF V600E mutation in tumor or plasma specimens prior to initiating BRAFTOVI . If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA- authorized tests for the detection of BRAF V600E mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics

Recommended Dosage for BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma and for BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC) The recommended dosage of BRAFTOVI is 450 mg (six 75 mg capsules) orally once daily in combination with binimetinib until disease progression or unacceptable toxicity. Refer to the binimetinib prescribing information for recommended binimetinib dosing information

Recommended Dosage for BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC) The recommended dosage of BRAFTOVI is 300 mg (four 75 mg capsules) orally once daily until disease progression or unacceptable toxicity in combination with: • biweekly cetuximab and mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) or biweekly cetuximab and FOLFIRI (fluorouracil, leucovorin and irinotecan) • weekly cetuximab

Administration BRAFTOVI may be taken with or without food . Do not take a missed dose of BRAFTOVI within 12 hours of the next dose of BRAFTOVI. Do not take an additional dose if vomiting occurs after BRAFTOVI administration but continue with the next scheduled dose

Dosage Modifications for Adverse Reactions BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma or BRAF V600E Mutation-Positive Metastatic NSCLC If binimetinib is withheld, reduce BRAFTOVI to a maximum dose of 300 mg (four 75 mg capsules) once daily until binimetinib is resumed . Dose reductions for adverse reactions associated with BRAFTOVI are presented in Table 1. Table 1: Recommended Dose Reductions for BRAFTOVI for Adverse Reactions – Melanoma or NSCLC Action Recommended Dose First dose reduction 300 mg (four 75 mg capsules) orally once daily Second dose reduction 225 mg (three 75 mg capsules) orally once daily Subsequent modification Permanently discontinue if unable to tolerate BRAFTOVI 225 mg (three 75 mg capsules) once daily BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC) When BRAFTOVI is administered in combination with cetuximab and mFOLFOX6 or FOLFIRI • Continue BRAFTOVI with mFOLFOX6 or FOLFIRI if cetuximab is permanently discontinued. • Permanently discontinue BRAFTOVI if cetuximab and mFOLFOX6 or FOLFIRI are permanently discontinued. When BRAFTOVI is administered in combination with cetuximab • Permanently discontinue BRAFTOVI when cetuximab is permanently discontinued. Dose reductions for adverse reactions associated with BRAFTOVI are presented in Table 2. Table 2: Recommended Dose Reductions for BRAFTOVI for Adverse Reactions – CRC Action Recommended Dose First dose reduction 225 mg (three 75 mg capsules) orally once daily Second dose reduction 150 mg (two 75 mg capsules) orally once daily Subsequent modification Permanently discontinue if unable to tolerate BRAFTOVI 150 mg (two 75 mg capsules) once daily BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma, BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC), or BRAF V600E Mutation-Positive NSCLC Dosage modifications for adverse reactions associated with BRAFTOVI are presented in Table 3. Table 3: Recommended Dosage Modifications for BRAFTOVI for Adverse Reactions Severity of Adverse Reaction National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Dose Modification for BRAFTOVI New Primary Malignancies Noncutaneous RAS Mutation-positive Malignancies Permanently discontinue BRAFTOVI. Cardiomyopathy • Symptomatic congestive heart failure or absolute decrease in LVEF of greater than 20% from baseline that is also below LLN Reduce BRAFTOVI by one dose level . • If LVEF improves to at least institutional LLN and absolute decrease to less than or equal to 10% compared to baseline, continue BRAFTOVI at the reduced dose . • If no improvement, withhold BRAFTOVI until improves to at least institutional LLN and absolute decrease to less than or equal to 10% compared to baseline and then resume at the reduced dose or reduce dose an additional dose level. Hepatotoxicity • Grade 2 AST or ALT increased Maintain BRAFTOVI dose. • If no improvement within 4 weeks, withhold BRAFTOVI until improves to Grade 0-1 or to pretreatment/baseline levels and then resume at same dose. • Grade 3 or 4 AST or ALT increased See Other Adverse Reactions . Uveitis • Grade 1–3 If Grade 1 or 2 does not respond to specific ocular therapy, or for Grade 3 uveitis, withhold BRAFTOVI for up to 6 weeks. • If improved, resume at same or reduced dose. • If not improved, permanently discontinue BRAFTOVI. • Grade 4 Permanently discontinue BRAFTOVI. QTc Prolongation • QTcF greater than 500 ms and less than or equal to 60 ms increase from baseline Withhold BRAFTOVI until QTcF less than or equal to 500 ms. Resume at reduced dose. • If more than one recurrence, permanently discontinue BRAFTOVI. • QTcF greater than 500 ms and greater than 60 ms increase from baseline Permanently discontinue BRAFTOVI. Dermatologic [Other than Hand-foot Skin Reaction (HFSR)] • Grade 2 If no improvement within 2 weeks, withhold BRAFTOVI until Grade 0–1. Resume at same dose. • Grade 3 Withhold BRAFTOVI until Grade 0–1. Resume at same dose if first occurrence or reduce dose if recurrent. • Grade 4 Permanently discontinue BRAFTOVI. Other Adverse Reactions (including Hemorrhage) and HFSR Dose modification of BRAFTOVI when administered with binimetinib or with cetuximab is not recommended for new primary cutaneous malignancies; ocular events other than uveitis, iritis, and iridocyclitis; interstitial lung disease/pneumonitis; creatine phosphokinase (CPK) elevation; rhabdomyolysis; and venous thromboembolism. • Recurrent Grade 2 or • First occurrence of any Grade 3 Withhold BRAFTOVI for up to 4 weeks. • If improves to Grade 0–1 or to pretreatment/baseline level, resume at reduced dose. • If no improvement, permanently discontinue BRAFTOVI. • First occurrence of any Grade 4 Permanently discontinue BRAFTOVI or Withhold BRAFTOVI for up to 4 weeks. • If improves to Grade 0–1 or to pretreatment/baseline level, then resume at reduced dose. • If no improvement, permanently discontinue BRAFTOVI. • Recurrent Grade 3 Consider permanently discontinuing BRAFTOVI. • Recurrent Grade 4 Permanently discontinue BRAFTOVI. Refer to the binimetinib or cetuximab prescribing information for dose modifications for adverse reactions associated with each product, as appropriate

Dose Modifications for Coadministration with Strong or Moderate CYP3A4 Inhibitors Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors. If coadministration is unavoidable, reduce the BRAFTOVI dose according to the recommendations in Table 4. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the BRAFTOVI dose that was taken prior to initiating the CYP3A4 inhibitor . Table 4: Recommended Dose Reductions for BRAFTOVI for Coadministration with Strong or Moderate CYP3A4 Inhibitors Current Daily Dose Current daily dose refers to recommended dose of BRAFTOVI based on indication or reductions for adverse reactions based on dosing recommendations in Table 1 (Melanoma) and Table 2 (CRC). Dose for Coadministration with Moderate CYP3A4 Inhibitor Dose for Coadministration with Strong CYP3A4 Inhibitor 450 mg 225 mg (three 75 mg capsules) 150 mg (two 75 mg capsules) 300 mg 150 mg (two 75 mg capsules) 75 mg 225 mg 75 mg 75 mg 150 mg 75 mg 75 mg Encorafenib exposure at the 75 mg QD BRAFTOVI dosage when coadministered with a strong CYP3A4 inhibitor is expected to be higher than at the 150 mg QD dosage in the absence of a CYP3A4 inhibitor and similar to exposure at the 225 mg QD dosage in the absence of a CYP3A4 inhibitor. Monitor patients closely for adverse reactions and use clinical judgment when using BRAFTOVI with strong CYP3A4 inhibitors at the 150 mg dose level.

• New Primary Malignancies, cutaneous and noncutaneous : Can occur. Monitor for malignancies and perform dermatologic evaluations prior to, while on therapy, and following discontinuation of treatment. • Tumor Promotion in BRAF Wild-Type Tumors : Increased cell proliferation can occur with BRAF inhibitors. • Cardiomyopathy : Assess left ventricular ejection fraction (LVEF) before initiating treatment with BRAFTOVI and binimetinib, and after one month of treatment, then every 2 to 3 months thereafter. The safety of BRAFTOVI in combination with binimetinib has not been established in patients with LVEF below 50%. • Hepatotoxicity : Monitor liver function tests before and during treatment with BRAFTOVI and binimetinib and as clinically indicated. • Hemorrhage : Major hemorrhagic events can occur in patients receiving BRAFTOVI and binimetinib. • Uveitis : Perform ophthalmologic evaluation at regular intervals and for any visual disturbances. • QT Prolongation : Monitor electrolytes before and during treatment. Correct electrolyte abnormalities and control for cardiac risk factors for QT prolongation. Withhold BRAFTOVI for QTc of 500 ms or greater. • Embryo-Fetal Toxicity : Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective nonhormonal method of contraception. ( 5.8 , 8.1 , 8.3 ) • Risks Associated with BRAFTOVI as a Single Agent : If binimetinib is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended. • Risks Associated with Combination Treatment : BRAFTOVI is indicated for use as part of a regimen in combination with binimetinib or cetuximab. 5.1 New Primary Malignancies New primary malignancies, cutaneous and noncutaneous, have been observed in patients treated with BRAF inhibitors and can occur with BRAFTOVI. Cutaneous Malignancies In COLUMBUS, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6%, and basal cell carcinoma occurred in 1.6% of patients who received BRAFTOVI in combination with binimetinib. Median time to first occurrence of cuSCC/KA was 5.8 months (range 1 to 9 months) . For patients who received BRAFTOVI as a single agent, cuSCC/KA was reported in 8%, basal cell carcinoma in 1%, and a new primary melanoma in 5% of patients. In BEACON CRC, cuSCC/KA occurred in 1.4% of patients with CRC, and a new primary melanoma occurred in 1.4% of patients who received BRAFTOVI in combination with cetuximab. In PHAROS, cuSCC and skin papilloma, each occurred in 2% of patients who received BRAFTOVI in combination with binimetinib. In BREAKWATER, the following cutaneous malignancies occurred in patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6: melanocytic nevus in 5.6%, skin papilloma in 3% , basal cell carcinoma in 1.3%, squamous cell carcinoma of skin in 0.9%, keratoacanthoma in 0.4% and malignant melanoma in situ in 0.4%. In patients who received BRAFTOVI in combination with cetuximab and FOLFIRI, skin papilloma occurred in 2.8% and keratoacanthoma in 1.4% of patients. Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Noncutaneous Malignancies Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms . Monitor patients receiving BRAFTOVI for signs and symptoms of noncutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive noncutaneous malignancies

Tumor Promotion in BRAF Wild-Type Tumors In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells, which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation prior to initiating BRAFTOVI

Cardiomyopathy Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients treated with BRAFTOVI in combination with binimetinib. In COLUMBUS, evidence of cardiomyopathy (decreased in LVEF below the institutional LLN with an absolute decreased in LVEF ≥10% below baseline as detected by echocardiography or MUGA) occurred in 7% of patients receiving BRAFTOVI plus binimetinib. Grade 3 left ventricular dysfunction occurred in 1.6% of patients. The median time to first occurrence of left ventricular dysfunction (any grade) in patients receiving BRAFTOVI in combination with binimetinib was 3.6 months (range 0 to 21 months). Cardiomyopathy resolved in 87% of patients receiving BRAFTOVI plus binimetinib. In PHAROS, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an absolute decrease in LVEF ≥10% below baseline as detected by echocardiography or MUGA) occurred in 11% of patients receiving BRAFTOVI in combination with binimetinib. Grade 3 left ventricular dysfunction occurred in 1% of patients. Cardiomyopathy resolved in 82% of patients receiving BRAFTOVI plus binimetinib. Assess ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, one month after initiating treatment, and every 2 to 3 months during treatment. The safety of BRAFTOVI in combination with binimetinib has not been established in patients with baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely when treated with BRAFTOVI. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction

Hepatotoxicity Hepatotoxicity can occur when BRAFTOVI is administered in combination with binimetinib. In COLUMBUS, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving BRAFTOVI in combination with binimetinib was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. In PHAROS, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving BRAFTOVI in combination with binimetinib was 10% for AST, 9% for ALT, and 3.2% for alkaline phosphatase. In BREAKWATER, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6 was 2.6% for alkaline phosphatase, and 1.3% each for ALT and AST. In patients receiving BRAFTOVI in combination with cetuximab and FOLFIRI, the incidence of Grade 3 or 4 increases in liver function laboratory tests was 1.5% each for ALT and AST. Monitor liver laboratory tests before initiation of BRAFTOVI, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction

Hemorrhage In COLUMBUS, hemorrhage occurred in 19% of patients receiving BRAFTOVI in combination with binimetinib; Grade 3 or greater hemorrhage occurred in 3.2% of patients. The most frequent hemorrhagic events were gastrointestinal, 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. In BEACON CRC, hemorrhage occurred in 19% of patients receiving BRAFTOVI in combination with cetuximab; Grade 3 or higher hemorrhage occurred in 1.9% of patients, including fatal gastrointestinal hemorrhage in 0.5% of patients. The most frequent hemorrhagic events were epistaxis (6.9%), hematochezia (2.3%), and rectal hemorrhage (2.3%). In PHAROS, hemorrhage occurred in 12% of patients receiving BRAFTOVI in combination with binimetinib including fatal hemorrhage intracranial (1%); Grade 3 or 4 hemorrhage occurred in 4.1% of patients. The most frequent hemorrhagic events were anal hemorrhage and hemothorax (2% each). In BREAKWATER, hemorrhage occurred in 34 % of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6; Grade 3 or 4 hemorrhage occurred in 3% of patients. In patients receiving BRAFTOVI in combination with cetuximab and FOLFIRI, hemorrhage occurred in 21% of patients. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction

Uveitis Uveitis, including iritis and iridocyclitis, has been reported in patients treated with BRAFTOVI in combination with binimetinib. In COLUMBUS, the incidence of uveitis among patients treated with BRAFTOVI in combination with binimetinib was 4%. In PHAROS, the incidence of uveitis among patients treated with BRAFTOVI in combination with binimetinib was 1%. In BREAKWATER, the incidence of uveitis among patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6 was 0.4%. Assess for visual symptoms at each visit. Perform an ophthalmologic evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction

QT Prolongation BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients . In COLUMBUS, an increase in QTcF to >500 ms was measured in 0.5% (1/192) of patients who received BRAFTOVI in combination with binimetinib. In PHAROS, an increase in QTcF to >500 ms was measured in 2.1% (2/95) of patients who received BRAFTOVI in combination with binimetinib. In BREAKWATER, an increase of QTcF >500 ms was measured in 4% (9/226) of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6. In patients receiving BRAFTOVI in combination with cetuximab and FOLFIRI, an increase of QTcF >500 ms was measured in 1.5% (1/65) of patients. Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc >500 ms

Embryo-Fetal Toxicity Based on its mechanism of action, BRAFTOVI can cause fetal harm when administered to a pregnant woman. Encorafenib produced embryo-fetal developmental changes in rats and rabbits and was an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 26 (in the rat) and 178 (in the rabbit) times the human exposure at the recommended dose of 450 mg, with no clear findings at lower doses. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use an effective, nonhormonal method of contraception since BRAFTOVI can render hormonal contraceptives ineffective, during treatment and for 2 weeks after the last dose of BRAFTOVI

Risks Associated with BRAFTOVI as a Single Agent BRAFTOVI when used as a single agent is associated with an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with binimetinib. In COLUMBUS, Grades 3 or 4 dermatologic reactions occurred in 21% of patients treated with BRAFTOVI single agent compared to 2% of patients treated with BRAFTOVI in combination with binimetinib . If binimetinib is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended

Risks Associated with Combination Treatment BRAFTOVI is indicated for use as part of a regimen in combination with binimetinib, in combination with cetuximab, in combination with cetuximab and mFOLFOX6 or FOLFIRI . Refer to the prescribing information for binimetinib, cetuximab and individual product components of mFOLFOX6 and FOLFIRI for additional risk information.

• Strong or moderate CYP3A4 inhibitors: Avoid coadministration. If unavoidable, reduce BRAFTOVI dosage. • Strong CYP3A4 inducers: Avoid coadministration. • Sensitive CYP3A4 substrates: Avoid coadministration with CYP3A4 substrates (including hormonal contraceptives) for which a decrease in plasma concentration may lead to reduced efficacy of the substrate. • Transporters: Dose reductions of drugs that are substrates of OATP1B1, OATP1B3, or BCRP may be required when used concomitantly with BRAFTOVI. ( 7.2 , 12.3 ) 7.1 Effect of Other Drugs on BRAFTOVI Strong or Moderate CYP3A4 Inhibitors Coadministration of BRAFTOVI with a strong or moderate CYP3A4 inhibitor increases encorafenib plasma concentrations and may increase encorafenib adverse reactions. Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors, including grapefruit juice. If coadministration is unavoidable, reduce the BRAFTOVI dose . Strong CYP3A4 Inducers Coadministration of BRAFTOVI with a strong CYP3A4 inducer may decrease encorafenib plasma concentrations and may decrease encorafenib efficacy. Avoid coadministration of BRAFTOVI with strong CYP3A4 inducers

Effect of BRAFTOVI on Other Drugs Sensitive CYP3A4 Substrates BRAFTOVI is a strong CYP3A4 inducer at steady-state. Concomitant use of BRAFTOVI may decrease the plasma concentrations of CYP3A4 substrates (including hormonal contraceptives), , which may reduce the efficacy of these substrates. Avoid the coadministration of BRAFTOVI with CYP3A4 substrates for which a decrease in plasma concentration may lead to reduced efficacy of the substrate. If the coadministration cannot be avoided, see the CYP3A4 substrate product labeling for recommendations. OATP1B1, OATP1B3, or BCRP Substrates Coadministration of BRAFTOVI with OATP1B1, OATP1B3, or BCRP substrates can result in increased concentrations of the substrates, and may increase toxicity of these agents. When used in combination, monitor patients closely for signs and symptoms of increased exposure and consider adjusting the dose of these substrates

Drugs That Prolong the QT Interval BRAFTOVI is associated with dose-dependent QTc interval prolongation . Avoid coadministration of BRAFTOVI with drugs known to prolong the QT/QTc interval.