Biogen

1 INDICATIONS AND USAGE MEKINIST is a kinase inhibitor indicated as a single agent for the treatment of BRAF-inhibitor treatment-naïve patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. ( 1.1 , 2.1 ) MEKINIST is indicated, in combination with dabrafenib, for: the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. ( 1.1 , 2.1 ) the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection. ( 1.2 , 2.1 ) the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test. ( 1.3 , 2.1 ) the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation, as detected by an FDA-approved test, and with no satisfactory locoregional treatment options. ( 1.4 , 2.1 ) the treatment of adult and pediatric patients 1 year of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ( 1.5 , 2.1 ) the treatment of pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. ( 1.6 , 2.1 ) Limitations of Use : MEKINIST is not indicated for treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition. ( 1.7 , 12.1 ) 1.1 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma MEKINIST ® is…

2 DOSAGE AND ADMINISTRATION The recommended dosage of MEKINIST in adult patients is 2 mg orally once daily. The recommended dosage for MEKINIST in pediatric patients is based on body weight. ( 2 ) 2.1 Patient Selection Melanoma Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with MEKINIST as a single agent or in combination with dabrafenib [see Clinical Studies (14.1, 14.2)] . Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics . NSCLC Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.3)] . Information on FDA-approved tests for the detection of BRAF V600E mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics . ATC Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.4)] . Information on FDA-approved tests for the detection of BRAF V600E mutations in ATC is available at: http://www.fda.gov/CompanionDiagnostics . Solid Tumors Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.6)] . An FDA-approved test for the detection of BRAF V600E mutation in solid tumors other than melanoma and NSCLC is not currently available. Low-Grade Glioma Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.7)] . An FDA-approved test for the detection of BRAF V600E mutation in LGG is not currently available. 2.2 Recommended Dosage MEKINIST Tablets Adult Patients The recommended dosage for MEKINIST tablets in adult patients is 2 mg orally taken once daily [see Dosage and Administration (2.3)] . Pediatric Patients The recommended…

12.2 Pharmacodynamics Administration of MEKINIST tablets 1 mg and 2 mg to patients with BRAF V600 mutation-positive melanoma resulted in dose-dependent changes in tumor biomarkers, including inhibition of phosphorylated ERK, inhibition of Ki67 (a marker of cell proliferation), and increases in p27 (a marker of apoptosis). Cardiac Electrophysiology The heart rate-corrected QT (QTc) prolongation potential of trametinib was assessed in a dedicated study in 32 patients who received placebo on Day 1 and MEKINIST tablets 2 mg once daily on Days 2-14 followed by MEKINIST tablets 3 mg on Day 15. No large changes in the mean QTc interval (i.e., > 20 ms) were detected in the study. A decrease from baseline in HR by 9 beats/min (90% CI: -11.4 to -6.1) and an increase from baseline in PR by 20 ms (90% CI: 13.0 to 27.4) relative to placebo was observed at two hours post-dose in the same study. In clinical trials in patients who received MEKINIST with dabrafenib, QTc prolongation > 500 ms occurred in 0.8% of patients and QTc increased by > 60 ms from baseline in 3.8% of patients.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: New Primary Malignancies [see Warnings and Precautions ( 5.1)] Hemorrhage [see Warnings and Precautions (5.2)] Colitis and Gastrointestinal Perforation [see Warnings and Precautions (5.3)] Venous Thromboembolic Events [see Warnings and Precautions (5. 4 )] Cardiomyopathy [see Warnings and Precautions (5. 5 )] Ocular Toxicities [see Warnings and Precautions (5. 6 )] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5. 7 )] Serious Febrile Reactions [see Warnings and Precautions (5. 8 )] Serious Skin Toxicities [see Warnings and Precautions (5. 9 )] Hyperglycemia [see Warnings and Precautions (5. 10 )] Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions (5. 12 )] There are additional adverse reactions associated with dabrafenib. Refer to the dabrafenib prescribing information for additional information. Most common adverse reactions (≥ 20%) for MEKINIST as a single agent include rash, diarrhea, and lymphedema. ( 6.1 ) Most common adverse reactions (≥ 20%) for MEKINIST in combination with dabrafenib include: Unresectable or metastatic melanoma: pyrexia, nausea, rash, chills, diarrhea, vomiting, hypertension, and peripheral edema. ( 6.1 ) Adjuvant treatment of melanoma: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia. ( 6.1 ) NSCLC: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea. ( 6.1 ) Adult patients with solid tumors: pyrexia, fatigue, nausea, rash, chills, headache, hemorrhage, cough, vomiting, constipation, diarrhea, myalgia, arthralgia, and edema. ( 6.1 ) Pediatric patients with solid tumors: pyrexia, rash, vomiting, fatigue, dry skin, cough, diarrhea, dermatitis acneiform, headache, abdominal pain, nausea, hemorrhage, constipation, and paronychia. ( 6.1 ) Pediatric patients with LGG: pyrexia,…

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS New Primary Malignancies, Cutaneous and Non-Cutaneous : Can occur when MEKINIST is used with dabrafenib. Monitor patients for new malignancies prior to, or while on therapy, and following discontinuation of treatment. ( 5.1 ) Hemorrhage : Major hemorrhagic events can occur. Monitor for signs and symptoms of bleeding. ( 5.2 ) Colitis and Gastrointestinal Perforation : Colitis and gastrointestinal perforation can occur in patients receiving MEKINIST. ( 5.3 ) Venous Thromboembolic Events : Deep vein thrombosis (DVT) and pulmonary embolism (PE) can occur in patients receiving MEKINIST. ( 5.4 , 2.4 ) Cardiomyopathy : Assess left ventricular ejection fraction (LVEF) before treatment, after one month of treatment, then every 2 to 3 months thereafter. ( 5.5 , 2.4 ) Ocular Toxicities : Perform ophthalmological evaluation for any visual disturbances. For Retinal Vein Occlusion (RVO), permanently discontinue MEKINIST. ( 5.6 , 2.4 ) Interstitial Lung Disease (ILD)/Pneumonitis : Withhold MEKINIST for new or progressive unexplained pulmonary symptoms. Permanently discontinue MEKINIST for treatment-related ILD or pneumonitis. ( 5.7 , 2.4 ) Serious Febrile Reactions : Can occur when MEKINIST is used with dabrafenib. ( 5.8 , 2.4 ) Serious Skin Toxicities : Monitor for skin toxicities and for secondary infections. Permanently discontinue MEKINIST for intolerable Grade 2 or for Grade 3 or 4 rash not improving within 3 weeks despite interruption of MEKINIST. Permanently discontinue for severe cutaneous adverse reactions (SCARs). ( 5.9 , 2.4 ) Hyperglycemia : Monitor serum glucose levels in patients with preexisting diabetes or hyperglycemia. ( 5.10 ) Hemophagocytic Lymphohistiocytosis (HLH) : Interrupt treatment for suspected HLH. Discontinue treatment if HLH is confirmed. ( 5.12 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. ( 5.13 , 8.1 , 8.3 ) 5.1…

7 DRUG INTERACTIONS MEKINIST is indicated for use in combination with dabrafenib. Refer to the dabrafenib prescribing information for additional risk information that applies to combination use treatment.