BRAFTOVI

2 DOSAGE AND ADMINISTRATION Melanoma • Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to the initiation of BRAFTOVI. ( 2.1 ) • The recommended dose is 450 mg orally once daily in combination with binimetinib. ( 2.2 ) CRC • Confirm the presence of BRAF V600E mutation in plasma or tumor specimens prior to the initiation of BRAFTOVI. ( 2.1 ) • 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) ( 2.3 ) o weekly cetuximab ( 2.3 ) NSCLC • Confirm the presence of BRAF V600E mutation in tumor or plasma specimens prior to initiating BRAFTOVI. ( 2.1 ) • The recommended dose is 450 mg orally once daily in combination with binimetinib. ( 2.2 ) Take BRAFTOVI with or without food. ( 2.4 ) 2.1 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 [see Warnings and Precautions (5.2) , Clinical Studies (14.1) ] . 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 [see Warnings and Precautions (5.2) , Clinical Studies (14.2 , 14.3) ]. 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 [see Warnings and Precautions (5.2) , Clinical Studies (14.3) ] . 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 . 2.2 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. 2.3 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) [see Clinical Studies (14.2) ] • weekly cetuximab [see Clinical Studies (14.2) ]. 2.4 Administration BRAFTOVI may be taken with or without food [see Clinical Pharmacology (12.3) ] . 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. 2.5 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 [see Warnings and Precautions (5.9) ] . 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 [see Warnings and Precautions (5.1) ] Noncutaneous RAS Mutation-positive Malignancies Permanently discontinue BRAFTOVI. Cardiomyopathy [see Warnings and Precautions (5.3) ] • 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 [see Dosage and Administration (2.3) ] . • 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 [see Dosage and Administration (2.3) ] . • 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 [see Warnings and Precautions (5.4) ] • 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 [see Warnings and Precautions (5.6) ] • 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 [see Warnings and Precautions (5.7) ] • 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)] [see Adverse Reactions (6.1) ] • 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) [see Warnings and Precautions (5) ] and HFSR [see Adverse Reactions (6.1) ] 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. 2.6 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 [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . 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.

See official label

1 INDICATIONS AND USAGE 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.