Mekinist

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, rash, headache, vomiting, musculoskeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, and dermatitis acneiform. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Safety Pool The pooled safety population described in the WARNINGS and PRECAUTIONS reflects exposure to MEKINIST 2 mg orally, once daily as a single agent in 329 patients with various solid tumors enrolled in METRIC, MEK113583, and MEK111054. Among these 329 patients who received MEKINIST as a single agent, 33% were exposed for 6 months or longer and 9% were exposed for greater than one year. The pooled safety population described in the WARNINGS and PRECAUTIONS also reflects exposure to MEKINIST 2 mg orally, once daily administered in combination with dabrafenib 150 mg orally, twice daily, in 1087 patients enrolled in COMBI-d, COMBI-v, COMBI-AD, and BRF113928 with unresectable or metastatic melanoma, adjuvant melanoma or NSCLC. Among these 1087 patients who received MEKINIST administered with dabrafenib, 70% were exposed for 6 months or longer and 21% were exposed for greater than one year. Pediatric Safety Pool The pediatric pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to weight-based MEKINIST orally, once daily administered in combination with dabrafenib in 166 pediatric patients across two trials: a multi-center, open-label, multi-cohort study in pediatric patients with BRAF V600E mutation-positive glioma requiring systemic therapy (Study G2201; n = 123) and a multi-center, open-label, multi-cohort study in pediatric patients with refractory or recurrent solid tumors with MAPK pathway activation (Study X2101; n = 43) [see Clinical Studies (14.6, 14.7)] . Among 166 patients who received MEKINIST administered with dabrafenib, 85% were exposed for 6 months and 69% were exposed for greater than one year. The most common (> 20%) adverse reactions were pyrexia (66%), rash (54%), headache (40%), vomiting (38%), musculoskeletal pain (36%), fatigue (31%), dry skin (31%), diarrhea (30%), nausea (26%), epistaxis and other bleeding events (25%), abdominal pain (24%), and dermatitis acneiform (23%). The most common (> 2%) Grade 3 or 4 laboratory abnormalities were decreased neutrophil count (20%), increased alanine aminotransferase (3.1%), and increased aspartate aminotransferase (3.1%). Unresectable or Metastatic BRAF V600E or V600K Mutation-Positive Melanoma MEKINIST as a Single Agent The safety of MEKINIST was evaluated in the METRIC study, a randomized, open-label trial of patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma who received MEKINIST (N = 211) 2 mg orally once daily or chemotherapy (N = 99) (either dacarbazine 1000 mg/m 2 every 3 weeks or paclitaxel 175 mg/m 2 every 3 weeks) [see Clinical Studies (14.1)] . Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, or current evidence of Class II or greater congestive heart failure (New York Heart Association) were excluded. The median duration of treatment with MEKINIST was 4.3 months. In this study, 9% of patients who received MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication. The most frequent adverse reactions resulting in permanent discontinuation of MEKINIST were decreased LVEF, pneumonitis, renal failure, diarrhea, and rash. Adverse reactions led to dose reductions in 27% of patients treated with MEKINIST. Rash and decreased LVEF were the most frequent reasons cited for dose reductions of MEKINIST. Table 6 and Table 7 present adverse reactions and laboratory abnormalities, respectively, of MEKINIST as a single agent in the METRIC study. Table 6. Select Adverse Reactions Occurring in ≥ 10% of Patients Who Received MEKINIST and at a Higher Incidence (≥ 5%) Than in the Chemotherapy Arm or ≥ 2% (Grades 3 or 4) Adverse Reactions in the METRIC Study a NCI CTCAE version 4.0. b Grade 4 adverse reactions limited to rash (n = 1) in trametinib arm and diarrhea (n = 1) in chemotherapy arm. c Includes stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation. d Includes abdominal pain, lower abdominal pain, upper abdominal pain, and abdominal tenderness. e Includes lymphedema, edema, and peripheral edema. f Includes epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, melena, vaginal hemorrhage, hemorrhoidal hemorrhage, hematuria, and conjunctival hemorrhage. Adverse Reactions MEKINIST Chemotherapy N = 211 N = 99 All Grades a (%) Grades 3 and 4 b (%) All Grades a (%) Grades 3 and 4 b (%) Skin and subcutaneous tissue Rash 57 8 10 0 Acneiform dermatitis 19 < 1 1 0 Dry skin 11 0 0 0 Pruritus 10 2 1 0 Paronychia 10 0 1 0 Gastrointestinal Diarrhea 43 0 16 2 Stomatitis c 15 2 2 0 Abdominal pain d 13 1 5 1 Vascular Lymphedema e 32 1 4 0 Hypertension 15 12 7 3 Hemorrhage f 13 < 1 0 0 Other clinically important adverse reactions observed in ≤ 10% of patients (N = 329) who received MEKINIST were: Cardiac: Bradycardia Gastrointestinal: Dry mouth Infections and infestations: Folliculitis, rash pustular, cellulitis Musculoskeletal and Connective Tissue: Rhabdomyolysis Nervous System: Dizziness, dysgeusia Ocular: Blurred vision, dry eye Table 7. Laboratory Abnormalities Occurring at a Higher Incidence in Patients Who Received MEKINIST in the METRIC Study [Between-Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3 or 4) a ] Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Only Grade 3 adverse reactions were reported in either treatment arm. Laboratory Abnormality MEKINIST Chemotherapy N = 211 N = 99 All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) Increased AST 60 2 16 1 Hypoalbuminemia 42 2 23 1 Increased ALT 39 3 20 3 Anemia 38 2 26 3 Increased alkaline phosphatase 24 2 18 3 MEKINIST with Dabrafenib The safety of MEKINIST when administered with dabrafenib was evaluated in 559 patients with previously untreated, unresectable or metastatic, BRAF V600 mutation-positive melanoma who received MEKINIST in two trials, the COMBI-d study (n = 209), a multi-center, double-blind, randomized (1:1), active-controlled trial and the COMBI-v study (n = 350), a multi-center, open-label, randomized (1:1), active-controlled trial. In both trials, patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. Both trials excluded patients with abnormal LVEF, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), history of RVO or RPED, QTcB interval ≥ 480 msec, uncontrolled hypertension, uncontrolled arrhythmias, active brain metastases, or known history of glucose-6-phosphate dehydrogenase deficiency [see Clinical Studies (14.1)] . Among these 559 patients, 197 (35%) were exposed to MEKINIST for > 6 months to 12 months while 185 (33%) were exposed to MEKINIST for > 1 year. The median age was 55 years (range: 18 to 91), 57% were male, and 98% were White, 72% had baseline ECOG performance status 0 and 28% had ECOG performance status 1, 64% had M1c stage disease, 35% had elevated lactate dehydrogenase (LDH) at baseline, and 0.5% had a history of brain metastases. The most common adverse reactions (≥ 20%) for MEKINIST in patients who received MEKINIST plus dabrafenib in the COMBI-d and COMBI-v studies were: pyrexia, nausea, rash, chills, diarrhea, vomiting, hypertension, and peripheral edema. The demographics and baseline tumor characteristics of patients enrolled in the COMBI-d study are summarized in Clinical Studies [see Clinical Studies (14.1)] . Patients who received MEKINIST plus dabrafenib had a median duration of exposure of 11 months (range: 3 days to 30 months) to MEKINIST. Among the 209 patients who received MEKINIST plus dabrafenib, 26% were exposed to MEKINIST for > 6 months to 12 months while 46% were exposed to MEKINIST for > 1 year. In the COMBI-d study, adverse reactions leading to discontinuation of MEKINIST occurred in 11% of patients who received MEKINIST plus dabrafenib; the most frequent were pyrexia (1.4%) and decreased ejection fraction (1.4%). Adverse reactions leading to dose reductions of MEKINIST occurred in 18% of patients who received MEKINIST plus dabrafenib; the most frequent were pyrexia (2.9%), neutropenia (1.9%), decreased ejection fraction (1.9%), and rash (1.9%). Adverse reactions leading to dose interruptions of MEKINIST occurred in 46% of patients who received MEKINIST plus dabrafenib; the most frequent were pyrexia (18%), chills (7%), vomiting (6%), and decreased ejection fraction (4.8%). Table 8 and Table 9 present selected adverse reactions and laboratory abnormalities, respectively, of MEKINIST observed in the COMBI-d study. Table 8. Adverse Reactions Occurring in ≥ 10% (All Grades) of Patients Who Received MEKINIST with Dabrafenib and at a Higher Incidence* Than in Patients Who Received Single-Agent Dabrafenib in COMBI-d a * ≥ 5% for All Grades or ≥ 2% for Grades 3–4 incidence in patients who received MEKINIST with dabrafenib compared with patients who received dabrafenib as a single agent. a NCI CTCAE version 4.0. b Includes peripheral edema, edema, lymphedema, localized edema, and generalized edema. c Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal discomfort. d Includes rash, generalized rash, pruritic rash, erythematous rash, papular rash, vesicular rash, macular rash, maculo-papular rash, and folliculitis rash. e Most common events (≥ 1%) include epistaxis, hematochezia, decreased hemoglobin, purpura, and rectal hemorrhage. Grade 4 events were limited to hepatic hematoma and duodenal ulcer hemorrhage (each n = 1 in the pooled combination arm). Adverse Reactions Pooled MEKINIST plus Dabrafenib N = 559 COMBI-d Study MEKINIST plus Dabrafenib N = 209 Dabrafenib N = 211 All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) General Pyrexia 54 5 57 7 33 1.9 Chills 31 0.5 31 0 17 0.5 Peripheral edema b 21 0.7 25 1.4 11 0.5 Gastrointestinal Nausea 35 0.4 34 0.5 27 1.4 Diarrhea 31 1.3 30 1.4 16 0.9 Vomiting 27 1.1 25 1.0 14 0.5 Abdominal pain c 18 0.9 26 1.0 14 2.4 Skin and subcutaneous tissue Rash d 32 1.1 42 0 27 1.4 Vascular Hypertension 26 11 25 6 16 6 Hemorrhage e 18 2.0 19 1.9 15 1.9 Nervous system Dizziness 11 0.2 14 0 7 0 Other clinically important adverse reactions for MEKINIST observed in less than 10% of patients who received MEKINIST in combination with dabrafenib (N = 559) were: Cardiac: Bradycardia Immunologic: Sarcoidosis Musculoskeletal and connective tissue: Rhabdomyolysis Table 9. Laboratory Abnormalities Worsening from Baseline Occurring at ≥ 10% (All Grades) of Patients Who Received MEKINIST with Dabrafenib and at a Higher Incidence* Than in Patients Who Received Single-Agent Dabrafenib in COMBI-d Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. * ≥ 5% for All Grades or ≥ 2% for Grades 3–4 incidence in patients who received MEKINIST with dabrafenib compared with patients who received dabrafenib as a single agent. a For these laboratory tests, the denominator is 556. b For these laboratory tests, the denominator is 208 for the combination arm, 207-209 for the dabrafenib arm. c Grade 4 adverse reactions limited to lymphopenia and hyperglycemia (each n = 4), increased ALT and increased AST (each n = 3), neutropenia (n = 2), and hyponatremia (n = 1) in the pooled combination arm; neutropenia, lymphopenia, increased ALT, increased AST, and hyperglycemia (each n = 1) in the COMBI-d study combination arm; neutropenia, thrombocytopenia, increased ALT, and increased AST (each n = 1) in the dabrafenib arm. Laboratory Abnormality Pooled MEKINIST plus Dabrafenib N = 559 a COMBI-d Study MEKINIST plus Dabrafenib N = 209 b Dabrafenib N = 211 b All Grades (%) Grades 3 and 4 c (%) All Grades (%) Grades 3 and 4 c (%) All Grades (%) Grades 3 and 4 c (%) Chemistry Hyperglycemia 60 4.7 65 6 57 4.3 Hypoalbuminemia 48 1.1 53 1.4 27 0 Hyponatremia 25 8 24 6 14 2.9 Hepatic Increased AST 59 4.1 60 4.3 21 1.0 Increased blood alkaline phosphatase 49 2.7 50 1.0 25 0.5 Increased ALT 48 4.5 44 3.8 28 1.0 Hematology Neutropenia 46 7 50 6 16 1.9 Anemia 43 2.3 43 2.4 38 4.3 Lymphopenia 32 8 38 9 28 7 Thrombocytopenia 21 0.7 19 0.5 10 0.5 Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma The safety of MEKINIST when administered with dabrafenib was evaluated in 435 patients with Stage III melanoma with BRAF V600E or V600K mutations following complete resection who received at least one dose of study therapy in the COMBI-AD study [see Clinical Studies (14.2)] . Patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily for 12 months. The trial excluded patients with abnormal LVEF; history of acute coronary syndromes, coronary angioplasty, or stenting within 6 months; Class II or greater congestive heart failure (New York Heart Association); QTc interval ≥ 480 msec; treatment refractory hypertension; uncontrolled arrhythmias; or history of RVO. Patients who received MEKINIST in combination with dabrafenib had a median duration of exposure of 11 months (range: 0 to 12) to MEKINIST. Among the 435 patients who received MEKINIST in combination with dabrafenib, 72% were exposed to MEKINIST for > 6 months. The median age of patients who received MEKINIST in combination with dabrafenib was 50 years (range: 18 to 89), 56% were male, 99% were White, 92% had baseline ECOG performance status 0, and 8% had baseline ECOG performance status 1. The most common adverse reactions (≥ 20%) in patients who received MEKINIST in combination with dabrafenib were: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia. Adverse reactions resulting in discontinuation and dose interruptions of MEKINIST occurred in 24% and 54% of patients, respectively; the most frequent for each were pyrexia and chills. Adverse reactions leading to dose reductions of MEKINIST occurred in 23% of patients; the most frequent were pyrexia and decreased ejection fraction. Table 10 summarizes the adverse reactions that occurred in at least 20% of the patients who received MEKINIST in combination with dabrafenib. Table 10. Adverse Reactions Occurring in ≥ 20% of Patients in the COMBI-AD Study a a NCI CTCAE version 4.0. b Includes pyrexia and hyperpyrexia. c Includes fatigue, asthenia, and malaise. d Includes headache and tension headache. e Includes rash, rash maculo-papular, rash macular, rash generalized, rash erythematous, rash papular, rash pruritic, nodular rash, rash vesicular, and rash pustular. f Includes myalgia, musculoskeletal pain, and musculoskeletal chest pain. Adverse Reactions MEKINIST plus Dabrafenib N = 435 Placebo N = 432 All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) General Pyrexia b 63 5 11 < 1 Fatigue c 59 5 37 < 1 Chills 37 1 4 0 Gastrointestinal Nausea 40 < 1 20 0 Diarrhea 33 < 1 15 < 1 Vomiting 28 < 1 10 0 Nervous system Headache d 39 1 24 0 Skin and subcutaneous tissue Rash e 37 < 1 16 < 1 Musculoskeletal and connective tissue Arthralgia 28 < 1 14 0 Myalgia f 20 < 1 14 0 Other clinically important adverse reactions observed in less than 20% of patients in the COMBI-AD study who received MEKINIST in combination with dabrafenib were: blurred vision (6%), decreased ejection fraction (5%), rhabdomyolysis (< 1%), and sarcoidosis (< 1%). The laboratory abnormalities are summarized in Table 11. Table 11. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients in the COMBI-AD Study Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a The incidence is based on the number of patients who had both a baseline and at least one on-study laboratory measurement: MEKINIST plus dabrafenib (range: 429 to 431) and placebo arm (range: 426 to 428). Laboratory Abnormality MEKINIST plus Dabrafenib a N = 435 Placebo a N = 432 All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) Chemistry Hyperglycemia 63 3 47 2 Hypophosphatemia 42 7 10 < 1 Hypoalbuminemia 25 < 1 < 1 0 Hepatic Increased AST 57 6 11 < 1 Increased ALT 48 5 18 < 1 Increased blood alkaline phosphatase 38 1 6 < 1 Hematology Neutropenia 47 6 12 < 1 Lymphopenia 26 5 6 < 1 Anemia 25 < 1 6 < 1 Trial COMBI-APlus (Pyrexia Management Study) COMBI-APlus evaluated the impact of pyrexia-related outcomes of a revised pyrexia management algorithm in patients who received dabrafenib administered with trametinib in the adjuvant treatment of BRAF V600 mutation-positive melanoma after complete resection. The pyrexia management algorithm interrupted both dabrafenib and trametinib when patient’s temperature is ≥ 100.4°F. Grade 3-4 pyrexia occurred in 4.3% of patients, hospitalizations due to pyrexia occurred in 5.1% of patients, pyrexia with complications (dehydration, hypotension, renal dysfunction, syncope, severe chills) occurred in 2.2% of patients, and treatment discontinuation due to pyrexia occurred in 2.5% of patients. Metastatic, BRAF V600E Mutation-Positive Non-Small Cell Lung Cancer The safety of MEKINIST when administered with dabrafenib was evaluated in 93 patients with previously untreated (n = 36) and previously treated (n = 57) metastatic BRAF V600E mutation-positive NSCLC in a multi-center, multi-cohort, non-randomized, open-label trial (Study BRF113928). Patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. The trial excluded patients with abnormal LVEF, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), QTc interval ≥ 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, history of ILD or pneumonitis, or history or current RVO [see Clinical Studies (14.3)]. Among these 93 patients, 53 (57%) were exposed to MEKINIST and dabrafenib for > 6 months and 27 (29%) were exposed to MEKINIST and dabrafenib for ≥ 1 year. The median age was 65 years (range: 41 to 91), 46% were male, 85% were White; 32% had baseline ECOG performance status 0 and 61% had ECOG performance status 1; 98% had non-squamous histology; and 12% were current smokers, 60% were former smokers, and 28% had never smoked. The most common adverse reactions (≥ 20%) in these 93 patients were: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea. Adverse reactions leading to discontinuation of MEKINIST occurred in 19% of patients; the most frequent were pyrexia (2.2%), decreased ejection fraction (2.2%), and respiratory distress (2.2%). Adverse reactions leading to dose reductions of MEKINIST occurred in 30% of patients who received MEKINIST plus dabrafenib; the most frequent were pyrexia (5%), nausea (4.3%), vomiting (4.3%), diarrhea (3.2%), and neutropenia (3.2%). Adverse reactions leading to dose interruptions of MEKINIST occurred in 57% of patients who received MEKINIST plus dabrafenib; the most frequent were pyrexia (16%), vomiting (10%), neutropenia (8%), nausea (5%), and decreased ejection fraction (5%). Table 12 and Table 13 present adverse reactions and laboratory abnormalities, respectively, of MEKINIST in combination with dabrafenib in Study BRF113928. Table 12. Adverse Reactions Occurring in ≥ 20% (All Grades) of Patients Treated with MEKINIST plus Dabrafenib in Study BRF113928 a a NCI CTCAE version 4.0. b Includes fatigue, malaise, and asthenia. c Includes peripheral edema, edema, and generalized edema. d Includes rash, rash generalized, rash papular, rash macular, rash maculo-papular, and rash pustular. e Includes hemoptysis, hematoma, epistaxis, purpura, hematuria, subarachnoid hemorrhage, gastric hemorrhage, urinary bladder hemorrhage, contusion, hematochezia, injection site hemorrhage, pulmonary hemorrhage, and retroperitoneal hemorrhage. Adverse Reactions MEKINIST plus Dabrafenib N = 93 All Grades (%) Grades 3 and 4 (%) General Pyrexia 55 5 Fatigue b 51 5 Edema c 28 0 Chills 23 1.1 Gastrointestinal Nausea 45 0 Vomiting 33 3.2 Diarrhea 32 2.2 Decreased appetite 29 0 Skin and subcutaneous tissue Dry skin 31 1.1 Rash d 28 3.2 Vascular Hemorrhage e 23 3.2 Respiratory system Cough 22 0 Dyspnea 20 5 Table 13. Treatment-Emergent Laboratory Abnormalities Occurring in ≥ 20% (All Grades) of Patients Who Received MEKINIST plus Dabrafenib in Study BRF113928 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a For these laboratory tests, the denominator is 90. b For these laboratory tests, the denominator is 91. Laboratory Abnormality MEKINIST plus Dabrafenib N = 93 All Grades (%) Grades 3 and 4 (%) Chemistry a Hyperglycemia 71 9 Hyponatremia 57 17 Hypophosphatemia 36 7 Increased creatinine 21 1.1 Hepatic a Increased blood alkaline phosphatase 64 0 Increased AST 61 4.4 Increased ALT 32 6 Hematology b Leukopenia 48 8 Anemia 46 10 Neutropenia 44 8 Lymphopenia 42 14 Advanced BRAF V600E Mutation-Positive Tumors Study BRF117019 The safety of MEKINIST when administered with dabrafenib was evaluated in a multi-cohort, multi-center, non-randomized, open-label study in adult patients with cancers with the BRAF V600E mutation (Study BRF117019). A total of 206 patients were enrolled in the trial, 36 of whom were enrolled in the ATC cohort, 105 were enrolled in specific solid tumor cohorts, and 65 in other malignancies [see Clinical Studies (14.4, 14.6)] . Patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. Among these 206 patients, 101 (49%) were exposed to MEKINIST for ≥ 1 year and 103 (50%) were exposed to dabrafenib for ≥ 1 year. The median age was 60 years (range: 18 to 89); 56% were male; 79% were White; and 34% had baseline ECOG performance status 0 and 60% had ECOG performance status 1. Serious adverse reactions occurred in 45% of patients who received MEKINIST in combination with dabrafenib. Serious adverse reactions in > 5% of patients included pyrexia (11%) and pneumonia (6%). Fatal adverse reactions occurred in 3.9% of patients who received MEKINIST in combination with dabrafenib. Fatal adverse reactions that occurred in > 1% of patients included sepsis (1.9%). Permanent treatment discontinuation due to an adverse reaction occurred in 13% of patients. Adverse reactions which resulted in permanent treatment discontinuation in > 1% of patients included nausea (1.5%). Dosage interruptions due to an adverse reaction occurred in 55% of patients. Adverse reactions which required dosage interruption in > 5% of patients included pyrexia (22%), chills (9%), fatigue (6%), neutropenia (6%), and nausea (5%). Dose reductions due to an adverse reaction occurred in 44% of patients. Adverse reactions which required dose reductions in > 5% of patients included pyrexia (18%), chills (8%), and fatigue (6%). The most common (≥ 20%) adverse reactions, including laboratory abnormalities, are listed in Table 14 and Table 15. Table 14 summarizes the adverse reactions in Study BRF117019. Table 14. Adverse Reactions (≥ 20%) in Adult Patients Treated with MEKINIST Plus Dabrafenib in Study BRF117019 a NCI CTCAE version 4.0. b Includes fatigue, asthenia, and malaise. c Includes peripheral edema and peripheral swelling. d Includes rash, rash maculo-papular, rash erythematous, rash pustular, and rash papular. e Includes epistaxis, hematuria, contusion, hematoma, hemoptysis, conjunctival hemorrhage, hematochezia, rectal hemorrhage, hemorrhoidal hemorrhage, melaena, purpura, eye contusion, eye hemorrhage, gastric hemorrhage, gingival bleeding, hematemesis, hemorrhage intracranial, hemorrhagic stroke, hemothorax, increased tendency to bruise, large intestinal hemorrhage, mouth hemorrhage, petechiae, pharyngeal hemorrhage, prothrombin time prolonged, pulmonary hematoma, retinal hemorrhage, vaginal hemorrhage, and vitreous hemorrhage. f Includes cough and productive cough. g Includes myalgia, musculoskeletal chest pain, and musculoskeletal pain. Adverse Reactions MEKINIST plus Dabrafenib a (N = 206) All Grades (%) Grade 3 or 4 (%) General Pyrexia 55 4.95 Fatigue b 50 5 Chills 30 0.5 Peripheral edema c 22 0 Gastrointestinal Nausea 40 1.5 Constipation 27 0 Vomiting 27 1.5 Diarrhea 26 2.93 Skin and subcutaneous tissue Rash d 40 2.4 Nervous system Headache 30 1.5 Vascular Hemorrhage e 29 4.4 Respiratory system Cough f 29 0 Musculoskeletal and connective tissue Myalgia g 24 0.5 Arthralgia 23 0.5 Clinically relevant adverse reactions in < 20% of adult patients who received MEKINIST in combination with dabrafenib included ejection fraction decreased (8%), uveitis (1.9%) and hypersensitivity (1.9%). Table 15 summarizes the laboratory abnormalities in Study BRF117019. Table 15. Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Adult Patients Treated with MEKINIST Plus Dabrafenib in Study BRF117019 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a The denominator used to calculate the rate varied from 199 to 202 based on the number of patients with a baseline value and at least one post-treatment value. Laboratory Abnormality MEKINIST plus Dabrafenib a All Grades (%) Grade 3 or 4 (%) Chemistry Hyperglycemia 61 8 Decreased sodium 35 10 Decreased magnesium 24 0 Increased creatinine 21 1.5 Hepatic Increased alkaline phosphatase 51 5 Increased AST 51 4.6 Increased ALT 39 3 Hematology Decreased hemoglobin 44 9 BRAF V600E Mutation-Positive Solid Tumors in Pediatric Patients Study CTMT212X2101 (X2101) The safety of MEKINIST when administered with dabrafenib was evaluated in Study X2101, a multi-center, open-label, multi-cohort study in pediatric patients (n = 48) with refractory or recurrent solid tumors activation [see Clinical Studies (14.6)] . The median duration of exposure to MEKINIST in Parts C (dose escalation) and D (cohort expansion) was 20.8 and 24.4 months, respectively. The median duration of exposure to dabrafenib in Parts C and D was 20.8 and 24.9 months, respectively. The median age of pediatric patients who received MEKINIST with dabrafenib was 9 years (range: 1 to 17). Serious adverse reactions occurred in 46% of patients who received MEKINIST in combination with dabrafenib. Serious adverse reactions in > 5% of patients included pyrexia (25%) and ejection fraction decreased (6%). Permanent treatment discontinuation due to an adverse reaction occurred in 21% of patients. Adverse reactions which resulted in permanent treatment discontinuation in > 3% of patients included ALT increased (6%), AST increased (4.2%) and ejection fraction decreased (4.2%). Dosage interruptions due to an adverse reaction occurred in 73% of patients. Adverse reactions which required dosage interruption in > 5% of patients included pyrexia (56%), vomiting (19%), neutropenia (13%), rash (13%), ejection fraction decreased (6%), and uveitis (6%). Dose reductions due to an adverse reaction occurred in 25% of patients. Adverse reactions which required dose reductions in > 5% of patients included pyrexia (13%). The most common (≥ 20%) adverse reactions, including laboratory abnormalities, are listed in Table 16 and Table 17. Table 16 summarizes the adverse reactions in Study X2101. Table 16. Adverse Reactions (≥ 20%) in Pediatric Patients Treated with MEKINIST Plus Dabrafenib in Study X2101 a NCI CTCAE version 4.0. b Includes fatigue, asthenia, and malaise. c Includes rash, rash maculo-papular, rash erythematous, rash papular, rash pustular, and rash macular. d Includes dermatitis acneiform and acne. e Includes abdominal pain and abdominal pain upper. f Includes epistaxis, hematuria, contusion, hematoma, petechiae, rectal hemorrhage, and red blood cell count decreased. Adverse Reactions MEKINIST plus Dabrafenib a (N = 48) All Grades (%) Grade 3 or 4 (%) General Pyrexia 75 17 Fatigue b 48 0 Skin and subcutaneous tissue Rash c 73 2.1 Dry skin 48 0 Dermatitis acneiform d 40 0 Gastrointestinal Vomiting 52 4.2 Diarrhea 42 2.1 Abdominal pain e 33 4.2 Nausea 33 2.1 Constipation 23 0 Respiratory system Cough 44 0 Nervous system Headache 35 0 Vascular Hemorrhage f 33 0 Infections and infestations Paronychia 23 0 Table 17 summarizes the laboratory abnormalities in Study X2101. Table 17. Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Pediatric Patients Treated with MEKINIST Plus Dabrafenib in Study X2101 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a The denominator used to calculate the rate varied from 39 to 48 based on the number of patients with a baseline value and at least one post-treatment value. Laboratory Abnormality MEKINIST plus Dabrafenib a All Grades (%) Grade 3 or 4 (%) Chemistry Hyperglycemia 65 2.2 Hypoalbuminemia 48 2.1 Hypocalcemia 40 2.1 Decreased phosphate 38 0 Decreased magnesium 33 2.1 Hypernatremia 27 0 Hypokalemia 21 2.1 Hepatic Increased AST 55 4.2 Increased ALT 40 6 Increased alkaline phosphatase 28 6 Increased total bilirubin 21 2.1 Hematology Decreased hemoglobin 60 6 Decreased neutrophils 49 28 BRAF V600E Mutation-Positive Low-Grade Glioma in Pediatric Patients Study CDRB436G2201 (G2201) The safety of MEKINIST in combination with dabrafenib was evaluated in pediatric patients 1 to < 18 years of age in Study G2201. Patients with low-grade glioma (LGG) who required first systemic therapy were randomized (2:1) to MEKINIST plus dabrafenib (n = 73) or carboplatin plus vincristine (n = 33). Nine patients crossed over from the carboplatin plus vincristine arm to the MEKINIST and dabrafenib arm. Pediatric patients received weight-based MEKINIST orally once daily administered in combination with dabrafenib until disease progression or intolerable toxicity. Patients in the control arm received carboplatin and vincristine at doses of 175 mg/m 2 and 1.5 mg/m 2 , respectively in 10-week induction course followed by eight 6-week cycles of maintenance therapy or until disease progression or intolerable toxicity. Among patients with low-grade glioma who were randomized to MEKINIST plus dabrafenib (n = 73), 95% were exposed for 6 months or longer and 71% were exposed for greater than one year. The median age of these patients was 10 years (range: 1 to 17); 60% female; 75% White, 7% Asian, 2.7% Black or African American, 4% other race and 11% where race was unknown or not reported. Serious adverse reactions occurred in 40% of these patients. Serious adverse reactions in > 3% of patients included pyrexia (14%) and vomiting (4%). Permanent discontinuation of MEKINIST due to an adverse reaction occurred in 4% of patients. Adverse reactions which resulted in permanent discontinuation of MEKINIST included chills, fatigue, pyrexia, weight increased, and headache. Dosage interruptions of MEKINIST due to an adverse reaction occurred in 70% of patients. Adverse reactions which required a dosage interruption in > 5% of patients included pyrexia (52%). Dose reductions of MEKINIST due to an adverse reaction occurred in 12% of patients. Adverse reactions which required dose reductions in > 2% of patients included weight increased (2.7%). The most common (≥ 15%) adverse reactions were pyrexia (68%), rash (51%), headache (47%), vomiting (34%), musculoskeletal pain (34%), fatigue (33%), diarrhea (29%), dry skin (26%), nausea (25%), hemorrhage (25%), abdominal pain (25%), dermatitis acneiform (22%), dizziness (15%), upper respiratory tract infection (15%), and weight increased (15%). The most common (≥ 20%) laboratory abnormalities that worsened from baseline were leukopenia (59%), increased alkaline phosphatase (55%), anemia (46%), decreased neutrophils (44%), increased AST (37%), decreased magnesium (34%), increased magnesium (32%), decreased platelets (30%), increased ALT (29%), and increased lymphocytes (24%). Table 18 summarizes the adverse reactions in Study G2201. Table 18. Adverse Reactions (≥ 15%) in Pediatric LGG Patients Who Received MEKINIST in Combination with Dabrafenib in Study G2201 a a NCI CTCAE version 4.03. b Includes diarrhea, colitis, enterocolitis, and enteritis. c Includes abdominal pain and upper abdominal pain. d Includes stomatitis, cheilitis, mouth ulceration, aphthous ulcer, and glossitis. e Includes pyrexia and body temperature increased. f Includes fatigue and asthenia. g Includes headache and migraine with aura. h Includes dizziness and vertigo. i Includes peripheral neuropathy, peripheral motor neuropathy, peripheral sensorimotor neuropathy, paresthesia, neuralgia, hypoaesthesia, and peripheral sensory neuropathy. j Includes epistaxis, post-procedural hemorrhage, hematuria, upper gastrointestinal hemorrhage, and hemorrhage intracranial. k Includes rash, rash macular, rash maculo-papular, rash pustular, rash papular, rash erythematous, eczema, erythema multiforme, dermatitis, dermatitis exfoliative, skin exfoliation, palmar-plantar erythrodysaesthesia syndrome, and dermatitis bullous. l Includes dermatitis acneiform, acne, and acne pustular. m Includes back pain, myalgia, pain in extremity, arthralgia, bone pain, non-cardiac chest pain, neck pain, and musculoskeletal stiffness. Adverse Reactions MEKINIST plus Dabrafenib N = 73 Carboplatin plus Vincristine N = 33 All Grades (%) Grade ≥ 3 (%) All Grades (%) Grade ≥ 3 (%) Gastrointestinal Vomiting 34 1 48 3 Diarrhea b 29 0 18 6 Nausea 25 0 45 0 Abdominal pain c 25 0 24 0 Constipation 12 0 36 0 Stomatitis d 10 0 18 0 General Pyrexia e 68 8 18 3 Fatigue f 33 0 39 0 Nervous system Headache g 47 1 33 3 Dizziness h 15 0 9 3 Peripheral neuropathy i 7 0 45 6 Vascular Hemorrhage j 25 0 12 0 Skin and subcutaneous tissue Rash k 51 2.7 18 3 Dry skin 26 0 3 0 Dermatitis acneiform l 22 0 0 0 Alopecia 3 0 24 0 Musculoskeletal and connective tissue Musculoskeletal pain m 34 0 30 0 Pain in jaw 1.4 0 18 0 Metabolism and nutrition Decreased appetite 5 0 24 0 Respiratory, thoracic and mediastinal Oropharyngeal pain 11 0 18 0 Psychiatric Anxiety 1.4 0 15 3 Immune system Hypersensitivity 0 0 15 3 Infections and infestations Upper respiratory tract infection 15 0 6 0 Injury, poisoning and procedural complications Infusion related reaction 0 0 15 3 Investigations Weight increased 15 7 0 0 Table 19 summarizes the laboratory abnormalities in Study G2201. Table 19. Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Pediatric LGG Patients Who Received MEKINIST in Combination with Dabrafenib in Study G2201 a Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a The denominator used to calculate the rate varied from 70 to 73 in D+T arm and 9 to 33 in C + V arm based on the number of patients with a baseline value and at least one post-treatment value. Laboratory Abnormality MEKINIST plus Dabrafenib N = 73 Carboplatin plus Vincristine N = 33 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hepatic Increased alkaline phosphatase 55 0 13 0 Increased AST 37 1.4 55 0 Increased ALT 29 3 61 9 Chemistry Decreased magnesium 34 4.1 76 6 Increased magnesium 32 0 24 3 Increased potassium 15 4.2 21 6 Decreased calcium 14 4.1 22 9 Decreased potassium 8 1.4 70 0 Decreased phosphate 7 2.7 33 3 Decreased sodium 5 1.4 27 6 Increased serum fasting glucose 0 0 44 0 Hematology Decreased leukocytes 59 0 91 18 Decreased hemoglobin 46 0 94 36 Decreased neutrophils 44 17 84 75 Decreased platelets 30 0 73 18 Increased lymphocytes 24 0 13 3.1 Decreased lymphocytes 16 1.4 56 6 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of MEKINIST in combination with dabrafenib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dermatologic: SCAR (including DRESS and SJS) [see Warnings and Precautions (5.9)] Immune System: Hemophagocytic lymphohistiocytosis (HLH) [see Warnings and Precautions (5.12)]

4 CONTRAINDICATIONS None. None. ( 4 )

11 DESCRIPTION Trametinib dimethyl sulfoxide is a kinase inhibitor. The chemical name is acetamide, N-[3-[3-cyclopropyl-5-[(2-fluoro-4- iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl- 2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]-, compound with 1,1’-sulfinylbis[methane] (1:1). It has a molecular formula C 26 H 23 FIN 5 O 4 •C 2 H 6 OS with a molecular mass of 693.53 g/mol. Trametinib dimethyl sulfoxide has the following chemical structure: Trametinib dimethyl sulfoxide is a white to almost white powder. It is practically insoluble in the pH range of 2 to 8 in aqueous media. MEKINIST (trametinib) tablets for oral use are supplied as 0.5 mg and 2 mg tablets for oral administration. Each 0.5 mg tablet contains 0.5635 mg trametinib dimethyl sulfoxide equivalent to 0.5 mg of trametinib non-solvated parent. Each 2 mg tablet contains 2.254 mg trametinib dimethyl sulfoxide equivalent to 2 mg of trametinib non-solvated parent. The inactive ingredients of MEKINIST tablets are: Tablet Core: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate (vegetable source), mannitol, microcrystalline cellulose, and sodium lauryl sulfate. Coating: hypromellose, iron oxide red (2 mg tablets), iron oxide yellow (0.5 mg tablets), polyethylene glycol, polysorbate 80 (2 mg tablets), and titanium dioxide. MEKINIST (trametinib) for oral solution is a white or almost white powder which produces a clear colorless solution when reconstituted with water. Each bottle contains 4.7 mg of trametinib equivalent to 5.3 mg trametinib dimethyl sulfoxide. Each mL of reconstituted trametinib solution contains 0.05 mg of trametinib non-solvated parent. The inactive ingredients of MEKINIST for oral solution are betadex sulfobutyl ether sodium, citric acid monohydrate, dibasic sodium phosphate, methylparaben, potassium sorbate, sucralose, and strawberry flavor. Trametinib Structure-01

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. Take MEKINIST at least 1 hour before or at least 2 hours after a meal. ( 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)] . An FDA-approved test for the detection of BRAF V600E mutation in ATC is not currently available. 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 dosage for MEKINIST tablets in pediatric patients who weigh at least 26 kg is based on body weight (Table 1) [see Dosage and Administration (2.3)] . A recommended dosage of MEKINIST tablets has not been established in patients who weigh less than 26 kg. Table 1. Recommended Dosage for MEKINIST Tablets in Pediatric Patients (Weight-based) Body Weight Recommended Dosage 26 to 37 kg 1 mg orally once daily 38 to 50 kg 1.5 mg orally once daily 51 kg or greater 2 mg orally once daily MEKINIST for Oral Solution The recommended dosage for MEKINIST for oral solution is based on body weight (Table 2) [see Dosage and Administration (2.3)] . Table 2. Recommended Dosage for MEKINIST for Oral Solution (Weight-based) Body Weight Recommended Dosage Total Volume of Oral Solution Once Daily (Trametinib Content) 8 kg 6 mL (0.3 mg) 9 kg 7 mL (0.35 mg) 10 kg 7 mL (0.35 mg) 11 kg 8 mL (0.4 mg) 12 to 13 kg 9 mL (0.45 mg) 14 to 17 kg 11 mL (0.55 mg) 18 to 21 kg 14 mL (0.7 mg) 22 to 25 kg 17 mL (0.85 mg) 26 to 29 kg 18 mL (0.9 mg) 30 to 33 kg 20 mL (1 mg) 34 to 37 kg 23 mL (1.15 mg) 38 to 41 kg 25 mL (1.25 mg) 42 to 45 kg 28 mL (1.4 mg) 46 to 50 kg 32 mL (1.6 mg) ≥ 51 kg 40 mL (2 mg) The recommended duration of treatment for patients with unresectable or metastatic melanoma or solid tumors, metastatic NSCLC, or locally advanced or metastatic anaplastic thyroid cancer is until disease progression or unacceptable toxicity. The recommended duration of treatment in the adjuvant melanoma setting is until disease recurrence or unacceptable toxicity for up to 1 year. The recommended duration of treatment for pediatric patients with LGG is until disease progression or until unacceptable toxicity. Refer to the dabrafenib prescribing information for recommended dabrafenib dosing information. 2.3 Administration Take MEKINIST at the same time each day, approximately 24 hours apart. Take MEKINIST at least 1 hour before or 2 hours after a meal [see Clinical Pharmacology (12.3)] . Do not take a missed dose of MEKINIST within 12 hours of the next dose of MEKINIST. If vomiting occurs after MEKINIST administration, do not take an additional dose. Take the next dose at its scheduled time. MEKINIST Tablets Do not crush or break MEKINIST tablets. MEKINIST for Oral Solution MEKINIST for oral solution is intended for administration by a caregiver. Prior to use of the oral solution, ensure caregivers receive training on proper dosing and administration of MEKINIST for oral solution. Preparation and Administration To prepare MEKINIST for oral solution, tap the bottle until powder flows freely. Add 90 mL distilled or purified water to the powder in the bottle and invert or gently shake the bottle with re-attached cap for up to 5 minutes until powder is fully dissolved yielding a clear solution. Separate the dosing adapter from the oral syringe. Insert dosing adapter into bottle neck after reconstitution of the solution. Write the discard after date. Once reconstituted, MEKINIST oral solution can be used for 35 days. Administer MEKINIST for oral solution from oral dosing syringe or feeding tube. After reconstitution, store in original bottle below 25°C (77°F) and do not freeze. 2.4 Dosage Modifications for Adverse Reactions Dose reductions for adverse reactions associated with MEKINIST are presented in Tables 3 and 4. Table 3. Recommended Dosage Reductions for MEKINIST Tablets for Adverse Reactions Recommended Dosage 1 mg orally once daily 1.5 mg orally once daily 2 mg orally once daily First dose reduction 0.5 mg orally once daily 1 mg orally once daily 1.5 mg orally once daily Second dose reduction N/A 0.5 mg orally once daily 1 mg orally once daily Subsequent modification Permanently discontinue MEKINIST tablets if unable to tolerate a maximum of two dose reductions. Table 4. Recommended Dosage Reductions for MEKINIST for Oral Solution for Adverse Reactions Body Weight (Recommended dosage) First Dose Reduction Second Dose Reduction 8 kg [6 mL (0.3 mg)] 5 mL 3 mL 9 kg [7 mL (0.35 mg)] 5 mL 4 mL 10 kg [7 mL (0.35 mg)] 5 mL 4 mL 11 kg [8 mL (0.4 mg)] 6 mL 4 mL 12 to 13 kg [9 mL (0.45 mg)] 7 mL 5 mL 14 to 17 kg [11 mL (0.55 mg)] 8 mL 6 mL 18 to 21 kg [14 mL (0.7 mg)] 11 mL 7 mL 22 to 25 kg [17 mL (0.85 mg)] 13 mL 9 mL 26 to 29 kg [18 mL (0.9 mg)] 14 mL 9 mL 30 to 33 kg [20 mL (1 mg)] 15 mL 10 mL 34 to 37 kg [23 mL (1.15 mg)] 17 mL 12 mL 38 to 41 kg [25 mL (1.25 mg)] 19 mL 13 mL 42 to 45 kg [28 mL (1.4 mg)] 21 mL 14 mL 46 to 50 kg [32 mL (1.6 mg)] 24 mL 16 mL ≥ 51 kg [40 mL (2 mg)] 30 mL 20 mL Permanently discontinue MEKINIST for oral solution if unable to tolerate a maximum of two dose reductions. Dosage modifications for adverse reactions associated with MEKINIST are presented in Table 5. Table 5. Recommended Dosage Modifications for MEKINIST for Adverse Reactions a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. b See Tables 3 and 4 for recommended dose reductions of MEKINIST. c Dose modifications are not recommended for MEKINIST when administered with dabrafenib for the following adverse reactions of dabrafenib: non-cutaneous malignancies and uveitis. Dose modification of MEKINIST is not required for new primary cutaneous malignancies. Severity of Adverse Reaction a Dosage Modification for MEKINIST b Hemorrhage [see Warnings and Precautions (5.2)] Grade 3 Withhold MEKINIST. If improved, resume MEKINIST at lower dose. If not improved, permanently discontinue MEKINIST. Grade 4 Permanently discontinue MEKINIST. Venous Thromboembolic Events [see Warnings and Precautions (5.4)] Uncomplicated deep venous thrombosis (DVT) or pulmonary embolism (PE) Withhold MEKINIST for up to 3 weeks. If improved to Grade 0-1, resume MEKINIST at lower dose. If not improved, permanently discontinue MEKINIST. Life-threatening PE Permanently discontinue MEKINIST. Cardiomyopathy [see Warnings and Precautions (5.5)] Asymptomatic, absolute decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline and is below institutional lower limit of normal (LLN) from pretreatment value Withhold MEKINIST for up to 4 weeks. If improved to normal LVEF value, resume MEKINIST at lower dose. If not improved to normal LVEF value, permanently discontinue MEKINIST. Symptomatic cardiomyopathy Absolute decrease in LVEF of greater than 20% from baseline that is below LLN Permanently discontinue MEKINIST. Ocular Toxicities [see Warnings and Precautions (5.6)] Retinal pigment epithelial detachments (RPED) Withhold MEKINIST for up to 3 weeks. If improved, resume MEKINIST at same or lower dose. If not improved, permanently discontinue MEKINIST or resume MEKINIST at lower dose. Retinal vein occlusion (RVO) Permanently discontinue MEKINIST. Pulmonary [see Warnings and Precautions (5.7)] Interstitial lung disease (ILD)/pneumonitis Permanently discontinue MEKINIST. Febrile Reactions [see Warnings and Precautions (5.8)] Fever of 100.4°F to 104°F (or first symptoms in case of recurrence) Withhold MEKINIST until fever resolves, then resume MEKINIST at same or lower dose. Fever higher than 104°F Fever complicated by rigors, hypotension, dehydration, or renal failure Withhold MEKINIST until febrile reactions resolve for at least 24 hours, then resume MEKINIST at lower dose. Or Permanently discontinue MEKINIST. Skin Toxicities [see Warnings and Precautions (5.9)] Intolerable Grade 2 Grade 3 or 4 Withhold MEKINIST for up to 3 weeks. If improved, resume MEKINIST at lower dose. If not improved, permanently discontinue MEKINIST. Severe cutaneous adverse reactions (SCARs) Permanently discontinue MEKINIST. Other Adverse Reactions c Intolerable Grade 2 Any Grade 3 Withhold MEKINIST. If improved to Grade 0-1, resume MEKINIST at lower dose. If not improved, permanently discontinue MEKINIST. First occurrence of any Grade 4 Withhold MEKINIST until improves to Grade 0-1, then resume at lower dose. Or Permanently discontinue MEKINIST. Recurrent Grade 4 Permanently discontinue MEKINIST. Refer to the dabrafenib prescribing information for dose modifications for adverse reactions associated with dabrafenib.

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 and with no satisfactory locoregional treatment options. ( 1.4 , 2.1 ) the treatment of adult and pediatric patients 6 years 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 indicated, as a single agent in BRAF-inhibitor treatment-naïve patients or 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 [see Dosage and Administration (2.1)] . 1.2 Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma MEKINIST is indicated, in combination with dabrafenib, for 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 [see Dosage and Administration (2.1)]. 1.3 BRAF V600E Mutation-Positive Metastatic NSCLC MEKINIST is indicated, in combination with dabrafenib, for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test [see Dosage and Administration (2.1)] . 1.4 BRAF V600E Mutation-Positive Locally Advanced or Metastatic Anaplastic Thyroid Cancer MEKINIST is indicated, in combination with dabrafenib, for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options [see Dosage and Administration (2.1)] . 1.5 BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors MEKINIST is indicated, in combination with dabrafenib, for the treatment of adult and pediatric patients 6 years 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 [see Dosage and Administration (2.1)] . This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.6)] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). 1.6 BRAF V600E Mutation-Positive Low-Grade Glioma MEKINIST is indicated, in combination with dabrafenib, for 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 [see Dosage and Administration (2.1)] . 1.7 Limitations of Use MEKINIST is not indicated for treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition [see Indications and Usage (1.5), Clinical Pharmacology (12.1)] .

10 OVERDOSAGE The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of RPEDs for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST.

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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Trametinib is a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. Trametinib inhibits cell growth of various BRAF V600 mutation-positive tumors in vitro and in vivo. Trametinib and dabrafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Use of trametinib and dabrafenib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive tumor cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation-positive tumor xenografts compared with either drug alone. In the setting of BRAF-mutant colorectal cancer, induction of EGFR-mediated MAPK pathway re-activation has been identified as a mechanism of intrinsic resistance to BRAF inhibitors [see Indications and Usage (1.7)] . 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 clinically relevant QTc prolongation was detected in the 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. 12.3 Pharmacokinetics The pharmacokinetics of trametinib were characterized following a single dose and multiple doses in patients with solid tumors and BRAF V600 mutation-positive metastatic melanoma. Following administration of MEKINIST tablets 0.125 mg (0.0625 times the approved recommended adult dosage) to 4 mg (2 times the approved recommended adult dosage) daily, both C max and AUC increase proportionally with dose. Inter-subject variability in AUC and C max at steady state is 22% and 28%, respectively. Absorption The median time to achieve peak plasma concentrations (T max ) is 1.5 hours post-dose. The mean absolute bioavailability of MEKINIST tablets is 72% and MEKINIST for oral solution is 81%. Effect of Food Following administration of MEKINIST tablets, a high-fat, high-calorie meal (approximately 1000 calories) decreased trametinib AUC by 24%, C max by 70%, and delayed T max by approximately 4 hours as compared with fasted conditions. Distribution Trametinib is 97.4% bound to human plasma proteins. The apparent volume of distribution (V c /F) is 214 L. Elimination The estimated elimination half-life is 3.9 to 4.8 days. The apparent clearance is 4.9 L/h. Metabolism Trametinib is metabolized predominantly via deacetylation alone or with mono-oxygenation or in combination with glucuronidation biotransformation pathways in vitro. Deacetylation is mediated by carboxylesterases (i.e., carboxylesterase 1b/c and 2) and may also be mediated by other hydrolytic enzymes. Following a single dose of [ 14 C]-trametinib, approximately 50% of circulating radioactivity is represented as the parent compound; however, ≥ 75% of drug-related material in plasma is the parent compound based on metabolite profiling after repeat dosing of trametinib. Excretion Following oral administration of [ 14 C]-trametinib, greater than 80% of excreted radioactivity was recovered in the feces while less than 20% of excreted radioactivity was recovered in the urine with less than 0.1% of the excreted dose as parent. Specific Populations Age (18 to 93 years), sex, body weight (36 to 170 kg), and renal impairment (eGFR 15 to 89 mL/min/1.73 m 2 ) have no clinically significant effect on the exposure of trametinib. There are insufficient data to evaluate potential differences in the exposure of trametinib by race or ethnicity. Pediatric Patients: The pharmacokinetics of trametinib in glioma and other solid tumors were evaluated in 244 patients aged 1 to < 18 years old following a single dose or multiple doses. Pharmacokinetic parameters in patients aged 1 to < 18 years are within range of values previously observed in adults given the same dose based on weight. Weight (6 to 156 kg) was found to have a statistically significant effect on trametinib oral clearance in this population. Patients with Hepatic Impairment: Hepatic impairment (defined by bilirubin and AST levels) had no significant effect in trametinib exposure or apparent drug clearance compared with patients with normal hepatic function. Drug Interaction Studies Effect of Dabrafenib on Trametinib : Coadministration of MEKINIST tablets 2 mg daily with dabrafenib resulted in no change in AUC of trametinib. Effect of Trametinib on CYP Substrates: Coadministration of MEKINIST tablets 2 mg once daily with a sensitive CYP3A4 substrate had no clinically relevant effect on the AUC and C max of the sensitive CYP3A4 substrate. Based on in vitro studies, trametinib is an inhibitor of CYP2C8, but is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at a clinically relevant systemic concentration. Effect of Transporters on Trametinib: Trametinib is a substrate of P-glycoprotein (P-gp) and BSEP. Inhibition of P-gp is unlikely to result in a clinically important increase in trametinib concentrations as trametinib exhibits high passive permeability and bioavailability. Trametinib is not a substrate of BCRP, OATP1B1, OATP1B3, OATP2B1, OCT1, MRP2, or MATE1 in vitro. Effect of Trametinib on Transporters: Based on in vitro studies, trametinib is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, BSEP, MRP2, or MATE1 at a clinically relevant systemic concentration.

12.1 Mechanism of Action Trametinib is a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. Trametinib inhibits cell growth of various BRAF V600 mutation-positive tumors in vitro and in vivo. Trametinib and dabrafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Use of trametinib and dabrafenib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive tumor cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation-positive tumor xenografts compared with either drug alone. In the setting of BRAF-mutant colorectal cancer, induction of EGFR-mediated MAPK pathway re-activation has been identified as a mechanism of intrinsic resistance to BRAF inhibitors [see Indications and Usage (1.7)] .

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 clinically relevant QTc prolongation was detected in the 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.

12.3 Pharmacokinetics The pharmacokinetics of trametinib were characterized following a single dose and multiple doses in patients with solid tumors and BRAF V600 mutation-positive metastatic melanoma. Following administration of MEKINIST tablets 0.125 mg (0.0625 times the approved recommended adult dosage) to 4 mg (2 times the approved recommended adult dosage) daily, both C max and AUC increase proportionally with dose. Inter-subject variability in AUC and C max at steady state is 22% and 28%, respectively. Absorption The median time to achieve peak plasma concentrations (T max ) is 1.5 hours post-dose. The mean absolute bioavailability of MEKINIST tablets is 72% and MEKINIST for oral solution is 81%. Effect of Food Following administration of MEKINIST tablets, a high-fat, high-calorie meal (approximately 1000 calories) decreased trametinib AUC by 24%, C max by 70%, and delayed T max by approximately 4 hours as compared with fasted conditions. Distribution Trametinib is 97.4% bound to human plasma proteins. The apparent volume of distribution (V c /F) is 214 L. Elimination The estimated elimination half-life is 3.9 to 4.8 days. The apparent clearance is 4.9 L/h. Metabolism Trametinib is metabolized predominantly via deacetylation alone or with mono-oxygenation or in combination with glucuronidation biotransformation pathways in vitro. Deacetylation is mediated by carboxylesterases (i.e., carboxylesterase 1b/c and 2) and may also be mediated by other hydrolytic enzymes. Following a single dose of [ 14 C]-trametinib, approximately 50% of circulating radioactivity is represented as the parent compound; however, ≥ 75% of drug-related material in plasma is the parent compound based on metabolite profiling after repeat dosing of trametinib. Excretion Following oral administration of [ 14 C]-trametinib, greater than 80% of excreted radioactivity was recovered in the feces while less than 20% of excreted radioactivity was recovered in the urine with less than 0.1% of the excreted dose as parent. Specific Populations Age (18 to 93 years), sex, body weight (36 to 170 kg), and renal impairment (eGFR 15 to 89 mL/min/1.73 m 2 ) have no clinically significant effect on the exposure of trametinib. There are insufficient data to evaluate potential differences in the exposure of trametinib by race or ethnicity. Pediatric Patients: The pharmacokinetics of trametinib in glioma and other solid tumors were evaluated in 244 patients aged 1 to < 18 years old following a single dose or multiple doses. Pharmacokinetic parameters in patients aged 1 to < 18 years are within range of values previously observed in adults given the same dose based on weight. Weight (6 to 156 kg) was found to have a statistically significant effect on trametinib oral clearance in this population. Patients with Hepatic Impairment: Hepatic impairment (defined by bilirubin and AST levels) had no significant effect in trametinib exposure or apparent drug clearance compared with patients with normal hepatic function. Drug Interaction Studies Effect of Dabrafenib on Trametinib : Coadministration of MEKINIST tablets 2 mg daily with dabrafenib resulted in no change in AUC of trametinib. Effect of Trametinib on CYP Substrates: Coadministration of MEKINIST tablets 2 mg once daily with a sensitive CYP3A4 substrate had no clinically relevant effect on the AUC and C max of the sensitive CYP3A4 substrate. Based on in vitro studies, trametinib is an inhibitor of CYP2C8, but is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at a clinically relevant systemic concentration. Effect of Transporters on Trametinib: Trametinib is a substrate of P-glycoprotein (P-gp) and BSEP. Inhibition of P-gp is unlikely to result in a clinically important increase in trametinib concentrations as trametinib exhibits high passive permeability and bioavailability. Trametinib is not a substrate of BCRP, OATP1B1, OATP1B3, OATP2B1, OCT1, MRP2, or MATE1 in vitro. Effect of Trametinib on Transporters: Based on in vitro studies, trametinib is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, BSEP, MRP2, or MATE1 at a clinically relevant systemic concentration.

20230526

21

3 DOSAGE FORMS AND STRENGTHS MEKINIST tablets: 0.5 mg tablets: Yellow, modified oval, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘TFC’ on the opposing face. 0.5 mg tablets: Yellow, ovaloid, biconvex, unscored film-coated tablets with beveled edges and with the Novartis logo debossed on one side and ‘TT’ on the other side. 2 mg tablets: Pink, round, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘HMJ’ on the opposing face. 2 mg tablets: Pink, round, biconvex, unscored film-coated tablets with beveled edges and with the Novartis logo debossed on one side and ‘LL’ on the other side. MEKINIST for oral solution: White to almost white powder containing 4.7 mg of trametinib per bottle. Each mL of reconstituted strawberry-flavored trametinib solution contains 0.05 mg of trametinib. MEKINIST Tablets: 0.5 mg, 2 mg ( 3 ) MEKINIST for Oral Solution: 4.7 mg ( 3 )

Mekinist trametinib TRAMETINIB DIMETHYL SULFOXIDE TRAMETINIB SILICON DIOXIDE CROSCARMELLOSE SODIUM HYPROMELLOSES MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE SODIUM LAURYL SULFATE FERRIC OXIDE RED FERRIC OXIDE YELLOW POLYETHYLENE GLYCOL POLYSORBATE 80 GS;TFC Mekinist trametinib TRAMETINIB DIMETHYL SULFOXIDE TRAMETINIB SILICON DIOXIDE CROSCARMELLOSE SODIUM HYPROMELLOSES MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE SODIUM LAURYL SULFATE FERRIC OXIDE RED FERRIC OXIDE YELLOW TITANIUM DIOXIDE GS;HMJ Mekinist trametinib TRAMETINIB DIMETHYL SULFOXIDE TRAMETINIB SILICON DIOXIDE CROSCARMELLOSE SODIUM HYPROMELLOSES MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE SODIUM LAURYL SULFATE FERRIC OXIDE YELLOW POLYETHYLENE GLYCOL TITANIUM DIOXIDE IMPRINT;TT biconvex, with beveled edges Mekinist trametinib TRAMETINIB DIMETHYL SULFOXIDE TRAMETINIB SILICON DIOXIDE CROSCARMELLOSE SODIUM HYPROMELLOSES MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE SODIUM LAURYL SULFATE FERRIC OXIDE RED POLYETHYLENE GLYCOL POLYSORBATE 80 TITANIUM DIOXIDE IMPRINT;LL biconvex, with beveled edges Mekinist trametinib TRAMETINIB DIMETHYL SULFOXIDE TRAMETINIB BETADEX SULFOBUTYL ETHER SODIUM CITRIC ACID MONOHYDRATE SODIUM PHOSPHATE, DIBASIC, UNSPECIFIED FORM METHYLPARABEN POTASSIUM SORBATE SUCRALOSE STRAWBERRY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with trametinib have not been conducted. Trametinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, and micronuclei in the bone marrow of rats. Trametinib may impair fertility in humans. In female rats given trametinib for up to 13 weeks, increased follicular cysts and decreased corpora lutea were observed at doses ≥ 0.016 mg/kg/day (approximately 0.3 times the human exposure at the recommended adult dose based on AUC). In rat and dog toxicity studies up to 13 weeks in duration, there were no treatment effects observed on male reproductive tissues [see Use in Specific Populations (8.3)] .

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with trametinib have not been conducted. Trametinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, and micronuclei in the bone marrow of rats. Trametinib may impair fertility in humans. In female rats given trametinib for up to 13 weeks, increased follicular cysts and decreased corpora lutea were observed at doses ≥ 0.016 mg/kg/day (approximately 0.3 times the human exposure at the recommended adult dose based on AUC). In rat and dog toxicity studies up to 13 weeks in duration, there were no treatment effects observed on male reproductive tissues [see Use in Specific Populations (8.3)] .

NDA217513

Mekinist

trametinib

0078-1161

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL NDC 0078-0666-15 Mekinist ® (trametinib) Tablets 0.5 mg* Rx only 30 Tablets NOVARTIS PRINCIPAL DISPLAY PANEL NDC 0078-0666-15 Mekinist® (trametinib) Tablets 0.5 mg* Rx only 30 Tablets NOVARTIS

Indications and Usage, BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors ( 1.5 ) 6/2022 Indications and Usage, BRAF V600E Mutation-Positive Low-Grade Glioma ( 1.6 ) 3/2023 Indications and Usage, Limitations of Use ( 1.7 ) 6/2022 Dosage and Administration, Patient Selection ( 2.1 ) 3/2023 Dosage and Administration, Recommended Dosage ( 2.2 ) 3/2023 Dosage and Administration, Administration ( 2.3 ) 3/2023 Dosage and Administration, Dosage Modifications for Adverse Reactions ( 2.4 ) 3/2023 Warnings and Precautions, New Primary Malignancies ( 5.1 ) 3/2023 Warnings and Precautions, Hemorrhage ( 5.2 ) 3/2023 Warnings and Precautions, Colitis and Gastrointestinal Perforation ( 5.3 ) 3/2023 Warnings and Precautions, Venous Thromboembolic Events ( 5.4 ) 3/2023 Warnings and Precautions, Cardiomyopathy ( 5.5 ) 3/2023 Warnings and Precautions, Ocular Toxicities ( 5.6 ) 3/2023 Warnings and Precautions, Serious Febrile Reactions ( 5.8 ) 3/2023 Warnings and Precautions, Serious Skin Toxicities ( 5.9 ) 3/2023 Warnings and Precautions, Hyperglycemia ( 5.10 ) 3/2023 Warnings and Precautions, Hemophagocytic Lymphohistiocytosis ( 5.12 ) 5/2023

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). New Primary Cutaneous and Non-cutaneous Malignancies Advise patients that MEKINIST administered with dabrafenib can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their healthcare provider immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)] . Hemorrhage Advise patients that MEKINIST administered with dabrafenib increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.2)] . Colitis and Gastrointestinal Perforation Advise patients that MEKINIST can cause colitis and gastrointestinal perforation and to contact their healthcare provider for signs or symptoms of colitis or gastrointestinal perforation [see Warnings and Precautions (5.3)] . Venous Thromboembolic Events Advise patients that MEKINIST administered with dabrafenib increases the risks of PE and DVT. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)] . Cardiomyopathy Advise patients that MEKINIST can cause cardiomyopathy and to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)] . Ocular Toxicities Advise patients that MEKINIST can cause severe visual disturbances that can lead to blindness and to contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)] . Interstitial Lung Disease/Pneumonitis Advise patients that MEKINIST can cause ILD (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs, such as cough or dyspnea [see Warnings and Precautions (5.7)] . Serious Febrile Reactions Advise patients that MEKINIST administered with dabrafenib can cause serious febrile reactions. Instruct patients to contact their healthcare provider if they develop a fever while taking MEKINIST with dabrafenib [see Warnings and Precautions (5.8)] . Serious Skin Toxicities Advise patients that MEKINIST can cause serious skin toxicities, which may require hospitalization, and to contact their healthcare provider for progressive or intolerable rash. Advise patients to contact their healthcare provider immediately if they develop signs and symptoms of a severe skin reaction [see Warnings and Precautions (5.9)] . Hypertension Advise patients that MEKINIST can cause hypertension and that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension, such as severe headache, blurry vision, or dizziness [see Adverse Reactions (6.1)] . Diarrhea Advise patients that MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment [see Adverse Reactions (6.1)] . Embryo-Fetal Toxicity Advise pregnant women and males of reproductive potential of the potential risk to a fetus [see Warnings and Precautions (5.13), Use in Specific Populations (8.1, 8.3)] . Advise females to contact their healthcare provider of a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with MEKINIST and for 4 months after the last dose. Advise male patients with female partners of reproductive potential to use condoms during treatment with MEKINIST and for 4 months after the last dose. Lactation Advise women not to breastfeed during treatment with MEKINIST and for 4 months after the last dose [see Use in Specific Populations (8.2)] . Infertility Advise females of reproductive potential of the potential risk for impaired fertility [see Use in Specific Populations (8.3)] . Administration Instruct patients to take MEKINIST at least 1 hour before or at least 2 hours after a meal [see Dosage and Administration (2.3)] . THxID ® BRAF assay is a trademark of bioMérieux. Oncomine ™ Dx Target Test is a trademark of Life Technologies Corporation, a part of Thermo Fisher Scientific Inc. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2023-29

This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: May 2023 INSTRUCTIONS FOR USE MEKINIST ® (MEK-in-ist) (trametinib) for oral solution This “Instructions for Use” contains information on how to give MEKINIST. Important information you need to know before giving MEKINIST oral solution MEKINIST for oral solution should only be given by a caregiver. Read this “Instructions for Use” carefully before you start giving MEKINIST for the first time and each time you get a refill. There may be new information. This “Instructions for Use” does not take the place of talking with your healthcare provider about you or your child’s medical condition and treatment. Instructions for reconstitution are on the folding box. Reconstitution of powder into solution must be performed by pharmacists only. Your healthcare provider or pharmacist should show the caregiver how to measure and give a dose of MEKINIST correctly. Always give MEKINIST exactly as the healthcare provider tells you to. If you have any questions about how to give a dose of MEKINIST, talk to the healthcare provider or pharmacist. You will receive the MEKINIST prescription in an amber-colored bottle that contains the oral solution that the pharmacist has already mixed. If you receive MEKINIST as a powder, contact the healthcare provider or pharmacist. If at any time MEKINIST oral solution gets on your or your child’s skin, wash the area well with soap and water. If at any time MEKINIST oral solution gets in your or your child’s eyes, rinse the eyes well with cool water. Ask the healthcare provider or pharmacist about how to safely dispose of MEKINIST oral solution. When MEKINIST is prepared as an oral solution, it can be used for 35 days. Throw away (dispose of) any remaining oral solution after 35 days. If you spill any MEKINIST oral solution, follow the instructions at the end of this Instructions for Use in the section called “How to clean up any spilled MEKINIST oral solution.” The MEKINIST pack should contain: The MEKINIST pack should contain: Reusable oral syringe parts: MEKINIST oral solution Store the bottle of oral solution at room temperature below 25°C (77°F). Do not freeze MEKINIST oral solution. Store the bottle of oral solution upright with the cap tightly closed. Keep MEKINIST oral solution in the box it comes in and away from direct light. When MEKINIST is prepared as an oral solution, it can be used for 35 days . Throw away (dispose of) any remaining oral solution after 35 days. Do not use the oral solution after the expiration date written or printed by the pharmacist on the label has passed. Keep MEKINIST oral solution and all medicines out of the reach of children. Oral syringe Store the oral syringe with the MEKINIST oral solution. Keep oral syringes out of the reach of children. Section A. Measuring and giving a dose of MEKINIST oral solution Gather your supplies: To give a dose of MEKINIST oral solution, you will need: 1 bottle adapter (already inserted into the bottle neck) 1 amber bottle containing oral solution 1 reusable oral syringe Call the healthcare provider or pharmacist if you do not have one or more of these items. If any of the MEKINIST oral solution comes into contact with your skin or eyes when you are following the steps below, follow the instructions in the section “Important information you need to know before giving MEKINIST oral solution” above. If any MEKINIST oral solution spills, follow the instructions in the section “ How to clean up any spilled MEKINIST oral solution ” at the end of this Instructions for Use. Step 1. Wash and dry your hands before measuring and giving a dose of MEKINIST oral solution. Step 2. Place your supplies on a clean, flat work surface. Step 3. Check if you have powder or liquid solution in the bottle. If you have powder , do not give MEKINIST and contact your pharmacist or healthcare provider. If you have solution , continue to step 4 below. Your pharmacist prepared the solution to an exact concentration. Do not add any more water to the solution you received from the pharmacy. Step 4. Check the expiration date of the oral solution that is handwritten or printed on the bottle label. Do not give MEKINIST oral solution if the expiration date has passed or there is no date on the bottle label. Note: if you are unsure of the expiration date, contact your healthcare provider or pharmacist. Step 5. Gently swirl the bottle for 30 seconds to mix the solution. If foam appears, put the amber bottle on a flat surface and let it sit there until the foam disappears. Step 6. When the foam has disappeared inside the amber bottle, remove the child-resistant cap by pushing down on the cap and turning it in the direction of the arrow (counter-clockwise), as shown. Then place the amber bottle back on your flat work surface. Step 7. Check if there is a bottle adapter already inserted in the bottle neck. Do not remove the bottle adapter. If not inserted, separate the adapter from the syringe and insert it. Contact the healthcare provider if you are unsure or the adapter is missing. Step 8. Next, pick up the oral syringe. Push the plunger up into the oral syringe as far as it will go to remove all the air inside. Step 9. Use one hand to hold the amber bottle containing the prepared oral solution steady. With your other hand, insert the tip of the oral syringe into the opening of the bottle adapter. Make sure the oral syringe is securely attached. Important: Due to air pressure, the plunger may move by itself when you measure your dose during step 10. Hold the end of the plunger to prevent it from moving. Step 10. Carefully turn the amber bottle upside down and pull down on the plunger to draw the oral solution into the oral syringe. To measure your dose, keep the tip of the oral syringe facing up. Pull down on the plunger until the top of the black stopper lines up with your prescribed dose in mLs on the syringe barrel. If large air bubbles appear in the syringe, push the oral solution back into the amber bottle and then pull down on the plunger again to draw up your dose. See figure below. Keep doing this until there are no air bubbles present. Small air bubbles are okay. Step 11. Continue to hold the plunger in place, and carefully turn the amber bottle upright. Put the amber bottle onto your flat work surface again. While still holding the plunger and barrel, remove the oral syringe from the bottle adapter by gently pulling straight up. Check again to be sure that the top of the black stopper is at your prescribed dose. If not, repeat steps 9, 10 and 11 again. Note: Your dose may be different than the dose shown in this figure. If you are giving a dose of MEKINIST oral solution by mouth, move to step 12. If you are giving a dose of MEKINIST oral solution through a feeding tube, go to Section B. Step 12. Important: If giving a dose of MEKINIST oral solution to a child, make sure they are sitting upright. Place the tip of the oral syringe inside the mouth. The tip should touch the inside of either cheek. Slowly push down on the plunger all the way to give the full dose of MEKINIST. Warning: Giving MEKINIST oral solution directly into the throat or pushing down on the plunger too fast may cause choking. Step 13. Check to make sure that there is no MEKINIST oral solution left in the oral syringe. If there is any solution left in the oral syringe, give it. Note: If your dose in mLs is more than the syringe can hold, repeat steps 8 through 14 until the total prescribed dose is given. Step 14. When finished, close the amber bottle. Do not remove the bottle adapter. Place the cap back on the amber bottle and turn it in the direction of the arrow (clockwise), as shown, to close it. Make sure the cap is securely attached onto the amber bottle. Step 15. Clean the reusable oral syringe. See the instructions in Section C “Cleaning the reusable oral syringe.” SECTION B. Giving a dose of MEKINIST through a feeding tube This section is for use only if you are going to give a dose of MEKINIST oral solution through a feeding tube . Before giving a dose of MEKINIST oral solution through a feeding tube, carefully read the following information, then move to step 1. MEKINIST oral solution may be given through a feeding tube, as directed by the healthcare provider. Only use a nasogastric (NG) or gastric (G-tube) feeding tube with a minimum size of French 4. Always use the 20mL oral syringe provided in this pack to give a dose of MEKINIST oral solution. You may need an ENFIT adapter (not included in pack) to connect the 20mL oral syringe to the feeding tube. Step 1. Flush the feeding tube according to the manufacturer’s instructions right away before giving a dose of MEKINIST oral solution. Step 2. Follow steps 1 through 11 in Section A, then move to step 3 in this section. Step 3. Connect the 20mL oral syringe containing MEKINIST oral solution to the feeding tube. You may need an ENFIT adapter to connect the syringe to the tube. Step 4. Apply steady pressure to the plunger to give the dose of MEKINIST oral solution through the feeding tube. Step 5. Check to be sure that there is no MEKINIST oral solution left in the oral syringe. If there is any MEKINIST oral solution left in the oral syringe, repeat steps 3 through 5. Step 6. Flush the tube again according to the manufacturer’s instructions. Step 7. Go to Section C for instructions on “Cleaning the reusable oral syringe.” SECTION C. Cleaning the reusable oral syringe Note: Keep the oral syringe separate from other kitchen items. Step 1. Fill a glass with warm, soapy water. Step 2. Place the tip of the oral syringe into the glass of warm soapy water. Pull up and then push down on the plunger to pull the soapy water in and out of the oral syringe 4 to 5 times. Step 3. Remove the plunger from the barrel. Step 4. Rinse the glass, plunger and barrel under warm tap water. Leave the oral syringe plunger and barrel on a clean paper towel to air dry. When your oral syringe is dry, store it with the MEKINIST oral solution. Step 5. Always keep the oral syringe out of the reach of children. Note: Use a new oral syringe for each new bottle of MEKINIST. Store the oral syringe with the MEKINIST oral solution. Keep oral syringes out of the reach of children. How to throw away (dispose of) MEKINIST that is expired or no longer needed, or old oral syringes Throw away (dispose of) unused solution into the trash. Do not pour solution down the drain. Ask the healthcare provider or pharmacist about how to safely throw away (dispose of) MEKINIST if you are not sure. Use a new oral syringe for each new bottle of MEKINIST. Throw away (dispose of) the used oral syringe into the trash. Ask the healthcare provider or pharmacist how to safely throw away (dispose of) the oral syringe if you are not sure. How to clean up any spilled MEKINIST oral solution. If you accidentally spill any MEKINIST oral solution, clean up the spill as follows: 1. Put on plastic gloves. 2. Soak up the spilled oral solution completely using an absorbent material, such as paper towels. 3. Place the used absorbent material into a sealable plastic bag, such as a food storage bag. 4. Wipe all surfaces exposed to the solution with alcohol wipes or pour rubbing alcohol onto a paper towel and then wipe the exposed surfaces with the paper towel. 5. Place the bag, gloves and used alcohol wipes or paper towel into another second plastic bag and seal. 6. Dispose of the bags into the trash. 7. Wash your hands well with soap and water. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2023-31 Mekinist-IFU-illustrations-1 Mekinist-IFU-illustrations-2 Mekinist-IFU-illustrations-3 Mekinist-IFU-illustrations-4 Mekinist-IFU-illustrations-5 Mekinist-IFU-illustrations-6 Mekinist-IFU-illustrations-7 Mekinist-IFU-illustrations-8 Mekinist-IFU-illustrations-9 Mekinist-IFU-illustrations-10 Mekinist-IFU-illustrations-11 Mekinist-IFU-illustrations-12 Mekinist-IFU-illustrations-13 Mekinist-IFU-illustrations-14 Mekinist-IFU-illustrations-15 Mekinist-IFU-illustrations-16 Mekinist-IFU-illustrations-17 Mekinist-IFU-illustrations-18 Mekinist-IFU-illustrations-19 Mekinist-IFU-illustrations-20 Mekinist-IFU-illustrations-21 Mekinist-IFU-illustrations-22 Mekinist-IFU-illustrations-23 Mekinist-IFU-illustrations-24 Mekinist-IFU-illustrations-25 Mekinist-IFU-illustrations-26

14 CLINICAL STUDIES Figure 1. Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival (ITT Population) in the METRIC Study Figure 2. Kaplan-Meier Curves of Overall Survival in the COMBI-d Study Figure 3. Kaplan-Meier Curves for Relapse-Free Survival in COMBI-AD in the Adjuvant Treatment of Melanoma Figure 4. Kaplan-Meier Curves for Progression-Free Survival in Study G2201 (LGG cohort) 14.1 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma MEKINIST as a Single Agent The safety and efficacy of MEKINIST were evaluated in an international, multi-center, randomized (2:1), open-label, active-controlled trial (the METRIC study; NCT01245062) in 322 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. In the METRIC study, patients were not permitted to have more than one prior chemotherapy regimen for advanced or metastatic disease; prior treatment with a BRAF inhibitor or MEK inhibitor was not permitted. Patients were randomized to receive MEKINIST 2 mg orally once daily (N = 214) or chemotherapy (N = 108) consisting of either dacarbazine 1000 mg/m 2 intravenously every 3 weeks or paclitaxel 175 mg/m 2 intravenously every 3 weeks. Treatment continued until disease progression or unacceptable toxicity. Randomization was stratified according to prior use of chemotherapy for advanced or metastatic disease (yes vs. no) and LDH level (normal vs. greater than ULN). Tumor tissue was evaluated for BRAF mutations at a central testing site using a clinical trial assay. Tumor samples from 289 patients (196 patients treated with MEKINIST and 93 chemotherapy-treated patients) were also tested retrospectively using an FDA-approved companion diagnostic test, THxID ® -BRAF assay. The major efficacy outcome measure was progression-free survival (PFS). The median age for randomized patients was 54 years, 54% were male, greater than 99% were White, and all patients had baseline ECOG performance status of 0 or 1. Most patients had metastatic disease (94%), were Stage M1c (64%), had elevated LDH (36%), had no history of brain metastasis (97%), and received no prior chemotherapy for advanced or metastatic disease (66%). The distribution of BRAF V600 mutations was BRAF V600E (87%), V600K (12%), or both (less than 1%). The median durations of follow-up prior to initiation of alternative treatment were 4.9 months for patients treated with MEKINIST and 3.1 months for patients treated with chemotherapy. Fifty-one (47%) patients crossed over from the chemotherapy arm at the time of disease progression to receive MEKINIST. The METRIC study demonstrated a statistically significant increase in PFS in the patients treated with MEKINIST. Table 20 and Figure 1 summarize the PFS results. Table 20. Efficacy Results in the METRIC Study Abbreviations: CI, confidence interval; DoR, duration of response; HR, hazard ratio; NR, not reached. a Pike estimator. Investigator - A ssessed Endpoints MEKINIST N = 214 Chemotherapy N = 108 P rogression- F ree S urvival Number of events (%) 117 (55%) 77 (71%) Progressive disease 107 (50%) 70 (65%) Death 10 (5%) 7 (6%) Median, months (95% CI) 4.8 (4.3, 4.9) 1.5 (1.4, 2.7) HR a (95% CI) 0.47 (0.34, 0.65) P value (log-rank test) < 0.0001 Confirmed Tumor Responses Overall response rate (95% CI) 22% (17%, 28%) 8% (4%, 15%) Complete response, n (%) 4 (2%) 0 Partial response, n (%) 43 (20%) 9 (8%) Duration of Response Median DoR, months (95% CI) 5.5 (4.1, 5.9) NR (3.5, NR) Figure 1. Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival (ITT Population) in the METRIC Study In supportive analyses based on independent radiologic review committee (IRRC) assessment, the PFS results were consistent with those of the primary efficacy analysis. MEKINIST with Dabrafenib COMBI-d Study The safety and efficacy of MEKINIST administered with dabrafenib were evaluated in an international, randomized, double-blind, active-controlled trial (the COMBI-d study; NCT01584648). The COMBI-d study compared dabrafenib plus MEKINIST to dabrafenib plus placebo as first-line treatment for patients with unresectable (Stage IIIc) or metastatic (Stage IV) BRAF V600E or V600K mutation-positive cutaneous melanoma. Patients were randomized (1:1) to receive MEKINIST 2 mg once daily plus dabrafenib 150 mg twice daily or dabrafenib 150 mg twice daily plus matching placebo. Randomization was stratified by LDH level (> ULN vs. ≤ ULN) and BRAF mutation subtype (V600E vs. V600K). The major efficacy outcome was investigator-assessed PFS per RECIST v1.1 with additional efficacy outcome measures of overall survival (OS) and confirmed overall response rate (ORR). In the COMBI-d study, 423 patients were randomized to MEKINIST plus dabrafenib (n = 211) or dabrafenib plus placebo (n = 212). The median age was 56 years (range: 22 to 89), 53% were male, > 99% were White, 72% had ECOG performance status of 0, 4% had Stage IIIc, 66% had M1c disease, 65% had a normal LDH, and 2 patients had a history of brain metastases. All patients had tumor containing BRAF V600E or V600K mutations as determined by centralized testing with the FDA-approved companion diagnostic test; 85% had BRAF V600E mutation-positive melanoma and 15% had BRAF V600K mutation-positive melanoma. The COMBI-d study demonstrated statistically significant improvements in PFS and OS. Table 21 and Figure 2 summarize the efficacy results. Table 21. Efficacy Results in the COMBI-d Study Abbreviations: CI, confidence interval; DoR, duration of response; HR, hazard ratio; NR, not reached; ORR, overall response rate. a PFS and ORR were assessed by investigator. b Based on stratified log-rank test. Endpoint MEKINIST plus D abrafenib N = 211 Placebo plus Dabrafenib N = 212 Progression-Free Survival a Number of events (%) 102 (48%) 109 (51%) Median, months (95% CI) 9.3 (7.7, 11.1) 8.8 (5.9, 10.9) HR (95% CI) 0.75 (0.57, 0.99) P value b 0.035 Overall Survival Number of deaths (%) 99 (47%) 123 (58%) Median, months (95% CI) 25.1 (19.2, NR) 18.7 (15.2, 23.1) HR (95% CI) 0.71 (0.55, 0.92) P value b 0.01 Overall Response Rate a ORR (95% CI) 66% (60%, 73%) 51% (44%, 58%) P value < 0.001 Complete response 10% 8% Partial response 56% 42% Median DoR, months (95% CI) 9.2 (7.4, NR) 10.2 (7.5, NR) Figure 2. Kaplan-Meier Curves of Overall Survival in the COMBI-d Study COMBI-MB Study The activity of MEKINIST with dabrafenib for the treatment of BRAF V600E or V600K mutation-positive melanoma, metastatic to the brain, was evaluated in a non-randomized, open-label, multi-center, multi-cohort trial (the COMBI-MB study; NCT02039947). Eligible patients were required to have at least one measurable intracranial lesion and to have no leptomeningeal disease, parenchymal brain metastasis greater than 4 cm in diameter, ocular melanoma, or primary mucosal melanoma. Patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. The major efficacy outcome measure was intracranial response rate, defined as the percentage of patients with a confirmed intracranial response per RECIST v1.1, modified to allow up to five intracranial target lesions at least 5 mm in diameter, as assessed by independent review. The COMBI-MB study enrolled 121 patients with a BRAF V600E (85%) or V600K (15%) mutation. The median age was 54 years (range: 23 to 84), 58% were male, 100% were White, 8% were from the United States, 65% had a normal LDH value at baseline, and 97% had an ECOG performance status of 0 or 1. Intracranial metastases were asymptomatic in 87% and symptomatic in 13% of patients, 22% received prior local therapy for brain metastases, and 87% also had extracranial metastases. The intracranial response rate was 50% (95% CI: 40, 60), with a complete response rate of 4.1% and a partial response rate of 46%. The median duration of intracranial response was 6.4 months (range: 1 to 31). Of the patients with an intracranial response, 9% had stable or progressive disease as their best overall response. 14.2 Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma The safety and efficacy of MEKINIST administered with dabrafenib were evaluated in an international, multi-center, randomized, double-blind, placebo-controlled trial (COMBI-AD; NCT01682083) that enrolled patients with Stage III melanoma with BRAF V600E or V600K mutations as detected by the THxID ® -BRAF assay and pathologic involvement of regional lymph node(s). Enrollment required complete resection of melanoma with complete lymphadenectomy within 12 weeks prior to randomization. The trial excluded patients with mucosal or ocular melanoma, unresectable in-transit metastases, distant metastatic disease, or prior systemic anti-cancer treatment, including radiotherapy. Patients were randomized (1:1) to receive MEKINIST 2 mg once daily in combination with dabrafenib 150 mg twice daily or two placebos for up to 1 year. Randomization was stratified by BRAF mutation status (V600E or V600K) and American Joint Committee on Cancer (AJCC; 7 th Edition) Stage (IIIa, IIIb, or IIIc). The major efficacy outcome measure was relapse-free survival (RFS) defined as the time from randomization to disease recurrence (local, regional, or distant metastasis), new primary melanoma, or death from any cause, whichever occurred first as assessed by the investigator. Patients underwent imaging for tumor recurrence every 3 months for the first two years and every 6 months thereafter. In COMBI-AD, a total of 870 patients were randomized: 438 to the MEKINIST in combination with dabrafenib and 432 to placebo. Median age was 51 years (range: 18 to 89), 55% were male, 99% were White, and 91% had an ECOG performance status of 0. Disease characteristics were AJCC Stage IIIa (18%), Stage IIIb (41%), Stage IIIc (40%), stage unknown (1%); BRAF V600E mutation (91%), BRAF V600K mutation (9%); macroscopic lymph nodes (65%); and tumor ulceration (41%). The median duration of follow-up (time from randomization to last contact or death) was 2.8 years. COMBI-AD showed a statistically significant improvement in RFS in patients randomized to MEKINIST in combination with dabrafenib arm compared to those randomized to placebo. Efficacy results are presented in Table 22 and Figure 3. Table 22. Efficacy Results in COMBI-AD in the Adjuvant Treatment of Melanoma Abbreviations: HR, hazard ratio; CI, confidence interval; NE, not estimable. a Pike estimator obtained from the stratified log-rank test. b Log-rank test stratified by disease stage – IIIA vs. IIIB vs. IIIC – and BRAF V600 mutation type – V600E vs. V600K. Endpoint MEKINIST plus Dabrafenib N = 438 Placebo N = 432 Relapse-Free Survival Number of events (%) 166 (38) 248 (57) Median, months (95% CI) NE (44.5, NE) 16.6 (12.7, 22.1) HR (95% CI) a 0.47 (0.39, 0.58) P value b < 0.0001 Figure 3. Kaplan-Meier Curves for Relapse-Free Survival in COMBI-AD in the Adjuvant Treatment of Melanoma 14.3 BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer The safety and efficacy of dabrafenib alone or administered with MEKINIST were evaluated in a multi-center, three-cohort, non-randomized, activity-estimating, open-label trial (Study BRF113928; NCT01336634). Key eligibility criteria were locally confirmed BRAF V600E mutation-positive metastatic NSCLC, no prior exposure to BRAF or MEK inhibitor, and absence of EGFR mutation or ALK rearrangement (unless patients had progression on prior tyrosine kinase inhibitor therapy). Patients enrolled in Cohorts A and B were required to have received at least one previous platinum-based chemotherapy regimen with demonstrated disease progression but no more than three prior systemic regimens. Patients in Cohort C could not have received prior systemic therapy for metastatic disease. Patients in Cohort A received dabrafenib 150 mg twice daily. Patients in Cohorts B and C received MEKINIST 2 mg once daily and dabrafenib 150 mg twice daily. The major efficacy outcome was ORR per RECIST v1.1 as assessed by independent review committee (IRC) and duration of response. There were a total of 171 patients enrolled which included 78 patients enrolled in Cohort A, 57 patients enrolled in Cohort B, and 36 patients enrolled in Cohort C. The characteristics of the population were: a median age of 66 years; 48% male; 81% White, 14% Asian, 3% Black, and 2% Hispanic; 60% former smokers, 32% never smokers, and 8% current smokers; 27% had ECOG performance status (PS) of 0, 63% had ECOG PS of 1, and 11% had ECOG PS of 2; 99% had metastatic disease of which 6% had brain metastasis at baseline and 14% had liver metastasis at baseline; 11% had systemic anti-cancer therapy in the adjuvant setting, 58% of the 135 previously treated patients had only one line of prior systemic therapy for metastatic disease; 98% had non-squamous histology. Efficacy results are summarized in Table 23. Table 23. Efficacy Results Based on Independent Review in Study BRF113928 Abbreviations: CI, confidence interval; DoR, duration of response. a Represents final analysis results (cutoff date of 24 Feb 2021) for the primary analysis responder cohorts. Treatment Dabrafenib MEKINIST plus Dabrafenib Population Previously Treated N = 78 Previously Treated N = 57 Treatment Naïve N = 36 Overall Response Rate a ORR (95% CI) 27% (18%, 38%) 61% (48%, 74%) 61% (44%, 77%) Complete response 1% 5% 8% Partial response 26% 56% 53% Duration of Response a n = 21 n = 35 n = 22 Median DoR, months (95% CI) 18.0 (4.2, 40.1) 9.0 (5.8, 26.2) 15.2 (7.8, 23.5) In a subgroup analysis of patients with retrospectively centrally confirmed BRAF V600E mutation-positive NSCLC with the Oncomine ™ Dx Target Test, the ORR results were similar to those presented in Table 16. 14.4 BRAF V600E Mutation-Positive Locally Advanced or Metastatic Anaplastic Thyroid Cancer The safety and efficacy of MEKINIST administered with dabrafenib was evaluated in an activity-estimating, nine-cohort, multi-center, non-randomized, open-label trial (Study BRF117019; NCT02034110) in patients with rare cancers with the BRAF V600E mutation, including locally advanced, unresectable, or metastatic ATC with no standard locoregional treatment options. Trial BRF117019 excluded patients who could not swallow or retain the medication; who received prior treatment with BRAF or MEK inhibitors; with symptomatic or untreated CNS metastases; or who had airway obstruction. Patients received MEKINIST 2 mg once daily and dabrafenib 150 mg twice daily. The major efficacy outcome measure was ORR per RECIST v1.1 as assessed by independent review committee (IRC) and duration of response (DoR). Thirty-six patients were enrolled and were evaluable for response in the ATC cohort. The median age was 71 years (range: 47 to 85); 44% were male, 50% White, 44% Asian; and 94% had ECOG performance status of 0 or 1. Prior anti-cancer treatments included surgery and external beam radiotherapy (83% each), and systemic therapy (67%). Efficacy results are summarized in Table 24. Table 24. Efficacy Results in the ATC Cohort Based on Independent Review of Study BRF117019 Abbreviations: ATC, anaplastic thyroid cancer; CI, confidence interval; DoR, duration of response; ORR, overall response rate; NE, not estimable. ATC Cohort Population N = 36 Overall Response Rate ORR (95% CI) 53% (35.5%, 69.6%) Complete response 6% Partial response 47% Duration of Response n = 19 Median DoR, months (95% CI) 13.6 (3.8, NE) % with DoR ≥ 6 months 68% % with DoR ≥ 12 months 53% 14.5 Lack of Clinical Activity in Metastatic Melanoma Following BRAF-Inhibitor Therapy The clinical activity of MEKINIST as a single agent was evaluated in a single-arm, multi-center, international trial in 40 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma who had received prior treatment with a BRAF inhibitor. All patients received MEKINIST at a dose of 2 mg orally once daily until disease progression or unacceptable toxicity. The median age was 58 years, 63% were male, all were White, 98% had baseline ECOG PS of 0 or 1, and the distribution of BRAF V600 mutations was V600E (83%), V600K (10%), and the remaining patients had multiple V600 mutations (5%), or unknown mutational status (2%). No patient achieved a confirmed partial or complete response as determined by the clinical investigators. 14.6 BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors The safety and efficacy of MEKINIST in combination with dabrafenib for the treatment of BRAF V600E mutation-positive unresectable or metastatic solid tumors were evaluated in Trials BRF117019, NCI-MATCH, and CTMT212X2101, and supported by results in COMBI-d, COMBI-v [see Clinical Studies (14.2)] , and BRF113928 [see Clinical Studies (14.4)] . In adult studies, patients received MEKINIST 2 mg once daily and dabrafenib 150 mg twice daily. The major efficacy outcome measures were ORR per RECIST v1.1, RANO [HGG] or modified RANO [LGG] criteria and duration of response (DoR). BRF117019 Study and NCI-MATCH Study Study BRF117019 (NCT02034110) [see Clinical Studies (14.5)] is a multi-cohort, multi-center, non-randomized, open-label trial in adult patients with selected tumors with the BRAF V600E mutation, including high grade glioma (HGG) (n = 45), biliary tract cancer (BTC) (n = 43), low grade glioma (LGG) (n = 13), adenocarcinoma of small intestine (ASI) (n = 3), gastrointestinal stromal tumor (GIST) (n = 1), and anaplastic thyroid cancer [see Clinical Studies (14.5)] . Patients were enrolled based on local assessments of BRAF V600E mutation status; a central laboratory confirmed the BRAF V600E mutation in 93 of 105 patients. Arm H (EAY131-H) of the NCI-MATCH study (NCT02465060) is a single-arm, open-label study that enrolled patients with a BRAF V600E mutation. Patients with melanoma, thyroid cancer, or CRC were excluded. BRAF mutation status for enrollment was determined either by central or local laboratory test. The study included adult patients with solid tumors including gastrointestinal tumors (n = 14), lung tumors (n = 7), gynecologic or peritoneal tumors (n = 6), CNS tumors (n = 4), and ameloblastoma of mandible (n = 1). Among the 131 patients enrolled in BRF117019 and NCI-MATCH with the tumor types shown in Table 21, the baseline characteristics were: median age of 51 years with 20% age 65 or older; 56% female; 85% White, 9% Asian, 3% Black, 3% Other; and 37% ECOG 0, 56% ECOG 1, and 6% ECOG 2. Of the 131 patients, 90% received prior systemic therapy. Efficacy results in patients with solid tumors are summarized in Table 25. Table 25. Efficacy Results Based on Independent Review in Study BRF117019 and NCI-MATCH Arm H Abbreviations: PR, partial response. a Excludes NSCLC (n = 6) and ATC (n = 36) (previously approved tumor types for MEKINIST in combination with dabrafenib). b Median DoR 9.8 months (95% CI: 5.3, 20.4). c Median DoR 13.6 months (95% CI: 5.5, 26.7). d Denotes a right-censored DoR. Tumor Type a N Objective Response Rate Duration of Response % 95% CI Range (months) Biliary tract cancer b 48 46 (31, 61) 1.8 d , 40 d High grade glioma c 48 33 (20, 48) 3.9, 44 Glioblastoma 32 25 (12, 43) 3.9, 27 Anaplastic pleomorphic xanthoastrocytoma 6 67 (22, 96) 6, 43 Anaplastic astrocytoma 5 20 (0.5, 72) 15 Astroblastoma 2 100 (16, 100) 15, 23 d Undifferentiated 1 PR (2.5, 100) 6 Anaplastic ganglioglioma 1 0 NA NA Anaplastic oligodendroglioma 1 0 NA NA Low grade glioma 14 50 (23, 77) 6, 29 d Astrocytoma 4 50 (7, 93) 7, 23 Ganglioglioma 4 50 (7, 93) 6, 13 Pleomorphic xanthoastrocytoma 2 50 (1.3, 99) 6 Pilocytic astrocytoma 2 0 NA NA Choroid plexus papilloma 1 PR (2.5, 100) 29 d Gangliocytoma/ganglioglioma 1 PR (2.5, 100) 18 d Low grade serous ovarian carcinoma 5 80 (28, 100) 12, 42 d Adenocarcinoma small intestine 4 50 (7, 93) 7, 8 Adenocarcinoma pancreas 3 0 NA NA Mixed ductal/adenoneuroendocrine carcinoma 2 0 NA NA Neuroendocrine carcinoma of colon 2 0 NA NA Ameloblastoma of mandible 1 PR (2.5, 100) 30 Combined small cell-squamous carcinoma of lung 1 PR (2.5, 100) 5 Mucinous-papillary serous adenocarcinoma of peritoneum 1 PR (2.5, 100) 8 Adenocarcinoma of anus 1 0 NA NA Gastrointestinal stromal tumor 1 0 NA NA CTMT212X2101 (X2101) Study Study X2101 (NCT02124772) was a multi-center, open-label, multi-cohort study in pediatric patients with refractory or recurrent solid tumors. Part C was a dose escalation of MEKINIST in combination with dabrafenib in patients with a BRAF V600E mutation. Part D was a cohort expansion phase of MEKINIST in combination with dabrafenib in patients with LGG with a BRAF V600E mutation. The major efficacy outcome measure was ORR as assessed by independent review committee per RANO criteria. The efficacy of MEKINIST in combination with dabrafenib was evaluated in 48 pediatric patients, including 34 patients with LGG and 2 patients with HGG. For patients with BRAF V600E mutant LGG and HGG in Parts C and D, the median age was 10 years (range: 1 to 17); 50% were male, 75% White, 8% Asian, 3% Black; and 58% had Karnofsky/Lansky performance status of 100. Prior anti-cancer treatments included surgery (83%), external beam radiotherapy (2.8%), and systemic therapy (92%). The ORR was 25% (95% CI: 12%, 42%). For the 9 patients who responded, DoR was ≥ 6 months for 78% of patients and ≥ 24 months for 44% of patients. CDRB436G2201 (G2201) Study – High-Grade Glioma Cohort Study G2201 (NCT02684058) was a multi-center, randomized, open-label, Phase II study of dabrafenib and trametinib in chemotherapy naïve pediatric patients with BRAF V600E mutant low-grade glioma (LGG) and patients with relapsed or progressive BRAF V600E mutant HGG. Patients with HGG were enrolled in a single-arm cohort. The major efficacy outcome measure for the HGG cohort was ORR as assessed by independent review committee per RANO 2010 criteria. The efficacy of MEKINIST in combination with dabrafenib was evaluated in 41 pediatric patients with relapsed or progressive HGG. For patients with BRAF V600E mutant HGG enrolled in the HGG cohort, the median age was 13 years (range: 2 to 17); 56% were female, 61% White, 27% Asian, 2.4% Black and 37% had Karnofsky/Lansky performance status of 100. Prior anti-cancer treatments included surgery (98%), radiotherapy (90%), and chemotherapy (81%). The ORR was 56% (95% CI: 40, 72). The median DoR was not reached (95% CI: 9.2, NE). For the 23 patients who responded in the HGG cohort, DoR was ≥ 6 months for 78% of patients, ≥ 12 months for 48% of patients, and ≥ 24 months for 22% of patients. 14.7 BRAF V600E Mutation-Positive Low-Grade Glioma CDRB436G2201 (G2201) Study – Low-Grade Glioma Cohort The safety and efficacy of MEKINIST in combination with dabrafenib for the treatment of BRAF V600E mutation-positive low-grade glioma (LGG) in pediatric patients aged 1 to < 18 years of age were evaluated in the multi-center, open-label trial (Study CDRB436G2201; NCT02684058). Patients with LGG (WHO grades 1 and 2) who required first systemic therapy were randomized in a 2:1 ratio to dabrafenib plus trametinib (D + T) or carboplatin plus vincristine (C + V). BRAF mutation status was identified prospectively via a local assessment or a central laboratory test. In addition, retrospective testing of available tumor samples by the central laboratory was performed to evaluate BRAF V600E mutation status. Patients received age- and weight-based dosing of MEKINIST and dabrafenib until loss of clinical benefit or until unacceptable toxicity. Carboplatin and vincristine were dosed based on body surface area at doses 175 mg/m 2 and 1.5 mg/m 2 (0.05 mg/kg for patients < 12 kg), respectively, as one 10-week induction course followed by eight 6-week cycles of maintenance therapy. The major efficacy outcome measure was overall response rate (ORR) by independent review based on RANO LGG (2017) criteria. Additional efficacy outcome measures were progression-free survival and overall survival. The primary analysis was performed when all patients had completed at least 32 weeks of therapy. In the LGG cohort, 110 patients were randomized to D + T (n = 73) or C + V (n = 37). Median age was 9.5 years (range: 1 to 17); 60% were female. Study G2201 showed a statistically significant improvement in ORR and PFS in patients with LGG randomized to D + T compared to those randomized to C + V. Efficacy results are shown in Table 26. Table 26. Efficacy Results Based on Independent Review in Study G2201 (LGG cohort) Abbreviations: CI, confidence interval; NE, not estimable. a Based on Clopper-Pearson exact confidence interval b Based on Kaplan-Meier method c Based on proportional hazards model MEKINIST plus Dabrafenib N = 73 Carboplatin plus Vincristine N = 37 Overall Response Rate ORR% (95% CI) a 46.6 (34.8, 58.6) 10.8 (3.0, 25.4) P value < 0.001 Complete response, n (%) 2 (2.7) 1 (2.7) Partial response, n (%) 32 (44) 3 (8) Duration of Response Median (95% CI) b , months 23.7 (14.5, NE) NE (6.6, NE) % with observed DoR ≥ 12 months 56 50 % with observed DoR ≥ 24 months 15 25 Progression-Free Survival Median (95% CI) b , months 20.1 (12.8, NE) 7.4 (3.6, 11.8) Hazard ratio (95% CI) c 0.31 (0.17, 0.55) P value < 0.001 Figure 4. Kaplan-Meier Curves for Progression-Free Survival in Study G2201 (LGG cohort) At the time of the interim analysis of overall survival (OS), conducted when all patients had completed at least 32 weeks of treatment or had discontinued earlier, there was one death on the C + V arm. The OS results at interim analysis did not reach statistical significance.

8.5 Geriatric Use Of the 214 patients with melanoma who received single agent MEKINIST in the METRIC study, 27% were aged 65 years and older and 4% were over 75 years old [see Clinical Studies (14.1)] . This study of single agent MEKINIST in melanoma did not include sufficient numbers of geriatric patients to determine whether they respond differently from younger adults. Of the 994 patients with melanoma who received MEKINIST plus dabrafenib in the COMBI-d, COMBI-v, and COMBI-AD studies [see Clinical Studies (14.1, 14.2)] , 21% were aged 65 years and older and 5% were aged 75 years and older. No overall differences in the effectiveness of MEKINIST plus dabrafenib were observed in geriatric patients as compared to younger adults across these melanoma studies. The incidences of peripheral edema (26% vs. 12%) and anorexia (21% vs. 9%) increased in geriatric patients as compared to younger adults in these studies. Of the 93 patients with NSCLC who received MEKINIST in Study BRF113928, there were insufficient numbers of geriatric patients aged 65 and older to determine whether they respond differently from younger adults [see Clinical Studies (14.4)] . Of the 26 patients with ATC who received MEKINIST in Study BRF117019, 77% were aged 65 years and older and 31% were aged 75 years and older [see Clinical Studies (14.4)] . This study in ATC did not include sufficient numbers of younger adults to determine whether they respond differently compared to geriatric patients.

8.4 Pediatric Use BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors and LGG The safety and effectiveness of MEKINIST in combination with dabrafenib have been established in pediatric patients 6 years 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; and patients 1 year of age and older with LGG with BRAF V600E mutation who require systemic therapy. Use of MEKINIST in combination with dabrafenib for these indications is supported by evidence from studies X2101 and G2201 that enrolled 171 patients (1 to < 18 years) with BRAF V600 mutation-positive advanced solid tumors, of which 4 (2.3%) patients were 1 to < 2 years of age, 39 (23%) patients were 2 to < 6 years of age, 54 (32%) patients were 6 to < 12 years of age, and 74 (43%) patients were 12 to < 18 years of age [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.6, 14.7)] . The safety and effectiveness of MEKINIST in combination with dabrafenib have not been established in pediatric patients younger than 1 year old with LGG with BRAF V600E mutation, and in patients < 6 years old with unresectable or metastatic solid tumors with BRAF V600E mutations. The safety and effectiveness of MEKINIST as a single agent in pediatric patients have not been established. Juvenile Animal Toxicity Data In a repeat-dose toxicity study in juvenile rats, decreased bone length and corneal dystrophy were observed at doses resulting in exposures as low as 0.3 times the human exposure at the recommended adult dose based on AUC. Additionally, a delay in sexual maturation was noted at doses resulting in exposures as low as 1.6 times the human exposure at the recommended adult dose based on AUC.

8.1 Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1)] and findings from animal reproduction studies, MEKINIST can cause fetal harm when administered to a pregnant woman. There is insufficient data in pregnant women exposed to MEKINIST to assess the risks. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended adult clinical dose (see Data) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day [approximately 0.3 times the human exposure at the recommended adult dose based on area under the curve (AUC)]. In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended adult dose, there was maternal toxicity and an increase in post-implantation loss. In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended adult dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended adult dose based on AUC) there was an increase in post-implantation loss, including total loss of pregnancy, compared with control animals.

8 USE IN SPECIFIC POPULATIONS Lactation : Do not breastfeed. ( 8.2 ) Females and Males of Reproductive Potential : May impair fertility. Counsel patients on pregnancy planning and prevention. ( 8.3 ) 8.1 Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1)] and findings from animal reproduction studies, MEKINIST can cause fetal harm when administered to a pregnant woman. There is insufficient data in pregnant women exposed to MEKINIST to assess the risks. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended adult clinical dose (see Data) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day [approximately 0.3 times the human exposure at the recommended adult dose based on area under the curve (AUC)]. In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended adult dose, there was maternal toxicity and an increase in post-implantation loss. In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended adult dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended adult dose based on AUC) there was an increase in post-implantation loss, including total loss of pregnancy, compared with control animals. 8.2 Lactation Risk Summary There are no data on the presence of trametinib in human milk, or the effects of trametinib on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with MEKINIST and for 4 months following the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating MEKINIST. Contraception Based on data from animal studies and its mechanism of action, MEKINIST can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1 )]. Females Advise female patients of reproductive potential to use effective contraception during treatment with MEKINIST and for 4 months after the last dose. Males To avoid potential drug exposure to pregnant partners and female partners of reproductive potential, advise male patients (including those who have had vasectomies) with female partners of reproductive potential to use condoms during treatment with MEKINIST and for 4 months after the last dose. Infertility Females Advise female patients of reproductive potential that MEKINIST may impair fertility. Increased follicular cysts and decreased corpora lutea were observed in female rats at dose exposures equivalent to 0.3 times the human exposure at the recommended adult dose [see Nonclinical Toxicology (13.1)] . 8.4 Pediatric Use BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors and LGG The safety and effectiveness of MEKINIST in combination with dabrafenib have been established in pediatric patients 6 years 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; and patients 1 year of age and older with LGG with BRAF V600E mutation who require systemic therapy. Use of MEKINIST in combination with dabrafenib for these indications is supported by evidence from studies X2101 and G2201 that enrolled 171 patients (1 to < 18 years) with BRAF V600 mutation-positive advanced solid tumors, of which 4 (2.3%) patients were 1 to < 2 years of age, 39 (23%) patients were 2 to < 6 years of age, 54 (32%) patients were 6 to < 12 years of age, and 74 (43%) patients were 12 to < 18 years of age [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.6, 14.7)] . The safety and effectiveness of MEKINIST in combination with dabrafenib have not been established in pediatric patients younger than 1 year old with LGG with BRAF V600E mutation, and in patients < 6 years old with unresectable or metastatic solid tumors with BRAF V600E mutations. The safety and effectiveness of MEKINIST as a single agent in pediatric patients have not been established. Juvenile Animal Toxicity Data In a repeat-dose toxicity study in juvenile rats, decreased bone length and corneal dystrophy were observed at doses resulting in exposures as low as 0.3 times the human exposure at the recommended adult dose based on AUC. Additionally, a delay in sexual maturation was noted at doses resulting in exposures as low as 1.6 times the human exposure at the recommended adult dose based on AUC. 8.5 Geriatric Use Of the 214 patients with melanoma who received single agent MEKINIST in the METRIC study, 27% were aged 65 years and older and 4% were over 75 years old [see Clinical Studies (14.1)] . This study of single agent MEKINIST in melanoma did not include sufficient numbers of geriatric patients to determine whether they respond differently from younger adults. Of the 994 patients with melanoma who received MEKINIST plus dabrafenib in the COMBI-d, COMBI-v, and COMBI-AD studies [see Clinical Studies (14.1, 14.2)] , 21% were aged 65 years and older and 5% were aged 75 years and older. No overall differences in the effectiveness of MEKINIST plus dabrafenib were observed in geriatric patients as compared to younger adults across these melanoma studies. The incidences of peripheral edema (26% vs. 12%) and anorexia (21% vs. 9%) increased in geriatric patients as compared to younger adults in these studies. Of the 93 patients with NSCLC who received MEKINIST in Study BRF113928, there were insufficient numbers of geriatric patients aged 65 and older to determine whether they respond differently from younger adults [see Clinical Studies (14.4)] . Of the 26 patients with ATC who received MEKINIST in Study BRF117019, 77% were aged 65 years and older and 31% were aged 75 years and older [see Clinical Studies (14.4)] . This study in ATC did not include sufficient numbers of younger adults to determine whether they respond differently compared to geriatric patients. 8.6 Hepatic Impairment No dose adjustment is recommended in patients with mild (bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or bilirubin > 1x to 1.5x ULN and any AST) hepatic impairment. A recommended dosage of MEKINIST has not been established for patients with moderate (bilirubin > 1.5x to 3x ULN and any AST) or severe (bilirubin > 3x to 10x ULN and any AST) hepatic impairment. Consider the risk-benefit profile of MEKINIST related to dosing prior to determining whether to administer MEKINIST to patients with moderate or severe hepatic impairment. In patients with moderate hepatic impairment, 3 patients who received a starting dose of 1.5 mg orally once daily and two patients who received a starting dose of 2 mg orally once daily did not experience dose limiting toxicities (DLTs) during the first cycle of therapy. In patients with severe hepatic impairment, 3 patients who received a starting dose of 1 mg orally once daily did not experience DLTs during the first cycle; one patient who received a starting dose of 1.5 mg orally once daily experienced a DLT (grade 3 acneiform rash). Compared to patients with normal hepatic function, there was no increase in exposure of trametinib in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3)] .

16 HOW SUPPLIED/STORAGE AND HANDLING MEKINIST tablets: 0.5 mg tablets: Yellow, modified oval, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘TFC’ on the opposing face and are available in bottles of 30 (NDC 0078-0666-15). 0.5 mg tablets: Yellow, ovaloid, biconvex, unscored film-coated tablets with beveled edges and with the Novartis logo debossed on one side and ‘TT’ on the other side; available in bottles of 30 (NDC 0078-1105-15). 2 mg tablets: Pink, round, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘HMJ’ on the opposing face and are available in bottles of 30 (NDC 0078-0668-15). 2 mg tablets: Pink, round, biconvex, unscored film-coated tablets with beveled edges and with the Novartis logo debossed on one side and ‘LL’ on the other side; available in bottles of 30 (NDC 0078-1112-15). Store refrigerated at 2°C to 8°C (36°F to 46°F). Dispense in original bottle. Do not remove desiccant. Protect from moisture and light. Do not place medication in pill boxes. MEKINIST for oral solution: White or almost white powder in amber glass bottles, co-packaged with a press-in bottle adapter and an oral dosing syringe. Each bottle contains 4.7 mg of trametinib equivalent to 5.3 mg trametinib dimethyl sulfoxide. Each mL of reconstituted strawberry flavored trametinib solution contains 0.05 mg of trametinib non-solvated parent. (NDC 0078-1161-47). Store refrigerated at 2°C to 8°C (36°F to 46°F). Store in the original carton to protect from light and moisture. After reconstitution, store in the original bottle below 25°C (77°F) and do not freeze. Discard any unused solution 35 days after reconstitution.