Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 08 June 2018

Indication(s)

1 INDICATIONS AND USAGE MEKINIST is a kinase inhibitor indicated as a single agent 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) 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) Limitations of Use: MEKINIST is not indicated for treatment of patients with melanoma who have progressed on prior BRAF-inhibitor therapy. (1.5) 1.1 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma MEKINIST® is indicated, as a single agent 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), (2.2)]. 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), (2.3)]. 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), (2.4)]. 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), (2.5)]. 1.5 Limitations of Use MEKINIST is not indicated for treatment of patients with melanoma who have progressed on prior BRAF-inhibitor therapy [see Clinical Studies (14.5)].

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contraindications
4 CONTRAINDICATIONS None. None (4)
Adverse reactions
6 ADVERSE REACTIONS The following 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 Thromboembolism [see Warnings and Precautions (5. 4 )] Cardiomyopathy [see Warnings and Precautions (5. 5 )] Ocular Toxicities [see Warnings and Precautions (5. 6 )] Interstitial Lung Disease [see Warnings and Precautions (5. 7 )] Serious Febrile Reactions [see Warnings and Precautions (5. 8 )] Serious Skin Toxicity [see Warnings and Precautions (5. 9 )] Hyperglycemia [see Warnings and Precautions (5. 10 )] 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 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) 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. The data described in the Warnings and Precautions section reflect exposure to MEKINIST administered as a single agent in 329 patients with various solid tumors and exposure to MEKINIST administered with dabrafenib in 559 patients with unresectable or metastatic melanoma and 93 patients with NSCLC. MEKINIST as a single agent was evaluated in 329 patients including 107 (33%) exposed for greater than or equal to 6 months and 30 (9%) exposed for greater than or equal to one year. MEKINIST as a single agent was studied in open-label, single-arm trials (N = 118) and in an open-label, randomized, active-controlled trial (N = 211; the METRIC study). The median age was 54 years, 60% were male, > 99% were White, and all patients had unresectable or metastatic melanoma. All patients received 2 mg once-daily doses of MEKINIST. Unresectable or Metastatic BRAF V600E or V600K Mutation Positive Melanoma MEKINIST Administered as a Single Agent Table 3 presents adverse reactions identified from analyses of the METRIC study, a randomized, open-label trial of patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma receiving MEKINIST (N = 211) 2 mg orally once daily or chemotherapy (N = 99) (either dacarbazine 1,000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 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 receiving MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication. The most common adverse reactions resulting in permanent discontinuation of MEKINIST were decreased left ventricular ejection fraction (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 common reasons cited for dose reductions of MEKINIST. Table 3. Selected Adverse Reactions Occurring in ≥ 10% of Patients Receiving MEKINIST in the METRIC Study and at a Higher Incidence (≥ 5%) than in the Chemotherapy Arm or ≥ 2% (Grades 3 or 4) Adverse Reactions 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 Stomatitisc 15 2 2 0 Abdominal paind 13 1 5 1 Vascular Lymphedemae 32 1 4 0 Hypertension 15 12 7 3 Hemorrhagef 13 < 1 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, 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. Other clinically important adverse reactions observed in less than or equal to 10% of patients (N = 329) treated with MEKINIST were: Cardiac Disorders: Bradycardia Gastrointestinal Disorders: Dry mouth Infections and Infestations: Folliculitis, rash pustular, cellulitis Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis Nervous System Disorders: Dizziness, dysgeusia Ocular Disorders: Blurred vision, dry eye Table 4. Laboratory Abnormalities Occurring at a Higher Incidence in Patients Treated with MEKINIST in the METRIC Study [Between-arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3 or 4)a] Test MEKINIST Chemotherapy N = 211 N = 99 All Grades Grades 3 and 4 All Grades Grades 3 and 4 Increased aspartate aminotransferase (AST) 60 2 16 1 Hypoalbuminemia 42 2 23 1 Increased alanine aminotransferase (ALT) 39 3 20 3 Anemia 38 2 26 3 Increased alkaline phosphatase 24 2 18 3 a No Grade 4 events were reported in either treatment arm. MEKINIST Administered with Dabrafenib The safety of MEKINIST, 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 multicenter, double-blind, randomized (1:1), active-controlled trial and the COMBI-v study (n = 350), a multicenter, 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. The trials excluded patients with abnormal left ventricular ejection fraction, 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 G6PD deficiency. 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 LDH at baseline, and 0.5% had a history of brain metastases. The most commonly occurring adverse reactions (≥ 20%) for MEKINIST in patients receiving MEKINIST plus dabrafenib 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 receiving MEKINIST plus dabrafenib had a median duration of exposure of 11 months (range: 3 days to 30 months) to MEKINIST. Among the 209 patients receiving 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 receiving MEKINIST plus dabrafenib; the most common were pyrexia (1.4%) and decreased ejection fraction (1.4%). Adverse reactions leading to dose reductions of MEKINIST occurred in 18% of patients receiving MEKINIST plus dabrafenib; the most common 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 receiving MEKINIST plus dabrafenib; the most common were pyrexia (18%), chills (7%), vomiting (6%) and decreased ejection fraction (4.8%). Table 5 and Table 6 present selected adverse drug reactions and laboratory abnormalities, respectively, of MEKINIST observed in the COMBI-d study. Table 5. Adverse Reactions Occurring in ≥ 10% (All Grades) of Patients Receiving MEKINIST with Dabrafenib and at a Higher Incidence* than in Patients Receiving Single-Agent Dabrafenib in the COMBI-d Studya 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 disorders and administrative site conditions Pyrexia 54 5 57 7 33 1.9 Chills 31 0.5 31 0 17 0.5 Edema peripheralb 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 painc 18 0.9 26 1.0 14 2.4 Nervous system Dizziness 11 0.2 14 0 7 0 Vascular Hypertension 26 11 25 6 16 6 Hemorrhaged 18 2.0 19 1.9 15 1.9 Skin Rashe 32 1.1 42 0 27 1.4 * ≥ 5% for All Grades or ≥ 2% for Grades 3–4 incidence in patients receiving MEKINIST with dabrafenib compared with patients receiving dabrafenib as a single agent a National Cancer Institute Common Terminology Criteria for Adverse Events, 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 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). e Includes rash, generalized rash, pruritic rash, erythematous rash, papular rash, vesicular rash, macular rash, maculo-papular, and folliculitis rash. Other clinically important adverse reactions for MEKINIST observed in less than 10% of patients receiving MEKINIST in combination with dabrafenib (N = 559) were: Cardiac Disorders: Bradycardia Musculoskeletal Disorders: Rhabdomyolysis Table 6. Laboratory Abnormalities Worsening from Baseline Occurring at ≥ 10% (All Grades) of Patients Receiving MEKINIST with Dabrafenib and at a Higher Incidence* than in Patients Receiving Single-Agent Dabrafenib in the COMBI-d Study Test Pooled MEKINIST plus Dabrafenib N = 559a COMBI-d Study MEKINIST plus Dabrafenib N = 209b Dabrafenib N = 211b All Grades (%) Grades 3 and 4c (%) All Grades (%) Grades 3 and 4c (%) All Grades (%) Grades 3 and 4c (%) 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 Liver Function Tests 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 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 *≥ 5% for All Grades or ≥ 2% for Grades 3–4 incidence in patients receiving MEKINIST with dabrafenib compared with patients receiving dabrafenib as a single agent AST = Aspartate aminotransferase; ALT = Alanine aminotransferase. 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, 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. 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 left ventricular ejection fraction; 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 retinal vein occlusion. 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. Patients receiving MEKINIST in combination with dabrafenib had a median duration of exposure of 11 months (range: 0 to 12) to MEKINIST. Among the 435 patients receiving MEKINIST in combination with dabrafenib, 72% were exposed to MEKINIST for > 6 months. The most commonly occurring adverse reactions (≥ 20%) in patients receiving 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 common for each were pyrexia and chills. Adverse reactions leading to dose reductions of MEKINIST occurred in 23% of patients; the most common were pyrexia and ejection fraction decrease. Table 7 summarizes adverse reactions that occurred in at least 20% of the patients receiving MEKINIST in combination with dabrafenib. Table 7. Adverse Reactions Occurring in ≥ 20% of Patients in the COMBI-AD Studya aNCI CTCAE version 4.0 bIncludes pyrexia and hyperpyrexia cIncludes fatigue, asthenia, and malaise dIncludes headache and tension headache eIncludes rash, rash maculo-papular, rash macular, rash generalized, rash erythematous, rash papular, rash pruritic, nodular rash, rash vesicular, and rash pustular fIncludes 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 Pyrexiab 63 5 11 < 1 Fatiguec 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 Headached 39 1 24 0 Skin Rashe 37 < 1 16 < 1 Musculoskeletal Arthralgia 28 < 1 14 0 Myalgiaf 20 < 1 14 0 Other clinically important adverse reactions observed in less than 20% of patients in the COMBI-AD study receiving MEKINIST in combination with dabrafenib were blurred vision (6%), ejection fraction decreased (5%) and rhabdomyolysis (< 1%). The most common laboratory abnormalities are summarized in Table 8. Table 8. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients in the COMBI-AD study aThe 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) Test MEKINIST plus Dabrafeniba N = 435 Placeboa N = 432 All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) Hematology Neutropenia 47 6 12 < 1 Lymphopenia 26 5 6 < 1 Anemia 25 < 1 6 < 1 Liver Function Tests Increased AST 57 6 11 < 1 Increased ALT 48 5 18 < 1 Increased blood alkaline phosphatase 38 1 6 < 1 Chemistry Hyperglycemia 63 3 47 2 Hypophosphatemia 42 7 10 < 1 Hypoalbuminemia 25 < 1 < 1 0 Metastatic, BRAF V600E Mutation-Positive NSCLC 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 multicenter, 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 left ventricular ejection fraction, 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 interstitial lung disease or pneumonitis, or history or current retinal vein occlusion [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 commonly occurring 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 resulting in discontinuation of MEKINIST occurred in 19% of patients; the most common were pyrexia (2.2%), ejection fraction decreased (2.2%), and respiratory distress (2.2%). Adverse reactions leading to dose reductions of MEKINIST occurred in 30% of patients receiving MEKINIST plus dabrafenib; the most common 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 receiving MEKINIST plus dabrafenib; the most common were pyrexia (16%), vomiting (10%), neutropenia (8%), nausea (5%), and ejection fraction decreased (5%). Table 9 and Table 10 present adverse drug reactions and laboratory abnormalities, respectively, of MEKINIST in combination with dabrafenib in Study BRF113928. Table 9. Adverse Reactions Occurring in ≥ 20% (All Grades) of Patients Treated with MEKINIST plus Dabrafenib in Study BRF113928a Adverse Reactions MEKINIST plus Dabrafenib N = 93 All Grades (%) Grades 3 and 4 b (%) General Pyrexia 55 5 Fatigueb 51 5 Edemac 28 0 Chills 23 1.1 Gastrointestinal Nausea 45 0 Vomiting 33 3.2 Diarrhea 32 2.2 Decreased appetite 29 0 Respiratory system Cough 22 0 Dyspnea 20 5 Skin Dry skin 31 1.1 Rashd 28 3.2 Vascular Hemorrhagee 23 3.2 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. Table 10. Treatment-Emergent Laboratory Abnormalities Occurring in ≥ 20% (All Grades) of Patients Receiving MEKINIST plus Dabrafenib in Study BRF113928 Test MEKINIST plus Dabrafenib N = 93 All Grades (%) Grades 3 and 4 (%) Hematology a Leukopenia 48 8 Anemia 46 10 Neutropenia 44 8 Lymphopenia 42 14 Liver Function Tests b Increased blood alkaline phosphatase 64 0 Increased AST 61 4.4 Increased ALT 32 6 Chemistry b Hyperglycemia 71 9 Hyponatremia 57 17 Hypophosphatemia 36 7 Increased creatinine 21 1.1 a For these laboratory tests the denominator is 91. b For these laboratory tests the denominator is 90. Locally Advanced or Metastatic, BRAF V600E-Mutation Positive, Anaplastic Thyroid Cancer (ATC) The safety of MEKINIST when administered with dabrafenib was evaluated in a nine-cohort, multicenter, non-randomized, open-label study in patients with rare cancers with the BRAF V600E mutation, including locally advanced or metastatic ATC (Study BRF117019). At the time of the safety analysis, a total of 100 patients were enrolled in the trial, 16 of whom were enrolled in the ATC cohort. The primary safety population included all patients who received at least one dose of MEKINIST or dabrafenib. Patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. Among these 100 patients, 46 (46%) were exposed to MEKINIST and dabrafenib for > 6 months and 23 (23%) were exposed to MEKINIST and dabrafenib for ≥ 1 year. The median age was 59.5 years (range: 18 to 85); 62% were male; 85% were White; and 31% had baseline ECOG performance status 0 and 59% had ECOG performance status 1. The adverse reaction profile among all patients and among patients in the ATC cohort was similar to that observed in other approved indications.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION The recommended dosage regimen of MEKINIST is 2 mg orally once daily. 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 and 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)]. 2.2 Recommended Dosage for Unresectable or Metastatic Melanoma The recommended dosage of MEKINIST is 2 mg orally taken once daily, as a single agent or in combination with dabrafenib, until disease progression or unacceptable toxicity. Refer to the dabrafenib prescribing information for recommended dabrafenib dosing information. 2.3 Recommended Dosage for the Adjuvant Treatment of Melanoma The recommended dosage of MEKINIST is 2 mg orally taken once daily in combination with dabrafenib until disease recurrence or unacceptable toxicity for up to 1 year. Refer to the dabrafenib prescribing information for recommended dabrafenib dosing information. 2.4 Recommended Dosage for NSCLC The recommended dose of MEKINIST is 2 mg orally taken once daily in combination with dabrafenib until disease recurrence or unacceptable toxicity. Refer to the dabrafenib prescribing information for recommended dabrafenib dosing information. 2.5 Recommended Dosage for ATC The recommended dose of MEKINIST is 2 mg orally taken once daily in combination with dabrafenib until disease recurrence or unacceptable toxicity. Refer to the dabrafenib prescribing information for recommended dabrafenib dosing information. 2.6 Administration Take MEKINIST doses 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. 2.7 Dosage Modifications for Adverse Reactions Dose reductions for adverse reactions associated with MEKINIST are presented in Table 1. Table 1. Recommended Dose Reductions for MEKINIST for Adverse Reactions Action Recommended Dose First Dose Reduction 1.5 mg orally once daily Second Dose Reduction 1 mg orally once daily Subsequent Modification Permanently discontinue if unable to tolerate MEKINIST 1 mg orally once daily Dosage modifications for adverse reactions associated with MEKINIST are presented in Table 2. Table 2. Recommended Dosage Modifications for MEKINIST for Adverse Reactions Severity of Adverse Reaction a MEKINIST b Venous Thromboembolism Uncomplicated DVT or PE Withhold MEKINIST for up to 3 weeks. If improved to Grade 0-1, resume at a lower dose level. If not improved, permanently discontinue. Life threatening PE Permanently discontinue MEKINIST. Cardiac Asymptomatic, absolute decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline and is below institutional lower limits of normal (LLN) from pretreatment value Withhold MEKINIST for up to 4 weeks. If improved to normal LVEF value, resume at a lower dose level. If not improved to normal LVEF value, permanently discontinue. Symptomatic congestive heart failure Absolute decrease in LVEF of greater than 20% from baseline that is below LLN Permanently discontinue MEKINIST. Ocular Toxicities Retinal pigment epithelial detachments (RPED) Withhold MEKINIST for up to 3 weeks. If improved, resume MEKINIST at same or lower dose level. If not improved, discontinue or resume at a lower dose. Retinal vein occlusion Permanently discontinue MEKINIST. Pulmonary Interstitial lung disease/pneumonitis Permanently discontinue MEKINIST. Febrile Drug Reaction Fever higher than 104°F Fever complicated by rigors, hypotension, dehydration, or renal failure Withhold MEKINIST until fever resolves. Then resume MEKINIST at same or lower dose level. Dermatologic Intolerable Grade 2 Grade 3 or 4 Withhold MEKINIST for up to 3 weeks. If improved, resume at a lower dose level. If not improved, permanently discontinue. Other Adverse Reactionsc Intolerable Grade 2 Any Grade 3 Withhold MEKINIST If improved to Grade 0-1, resume at a lower dose level. If not improved, permanently discontinue. First occurrence of any Grade 4 Withhold MEKINIST until adverse reaction improves to Grade 0-1. Then resume at a lower dose level. Or Permanently discontinue. Recurrent Grade 4 Permanently discontinue MEKINIST. a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. b See Table 1 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. Refer to the dabrafenib prescribing information for dose modifications for adverse reactions associated with dabrafenib.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Do not breast feed. (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 and findings from animal reproduction studies, MEKINIST can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. 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 clinical dose (see Data). If MEKINIST is used during pregnancy, or if the patient becomes pregnant while taking MEKINIST, advise the patient of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, 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 based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended 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 dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended 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 infant, or on milk production. Because of the potential for serious adverse reactions in breastfed infants from MEKINIST, 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 Contraception Based on its mechanism of action and findings from animal reproduction studies, 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. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST. 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 dose [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of MEKINIST as a single agent or in combination with dabrafenib have not been established in pediatric patients. Juvenile Animal 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 Clinical trials of MEKINIST as a single agent did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Of the 994 patients with melanoma randomized to receive MEKINIST plus dabrafenib in the COMBI-d, COMBI-v, and COMBI-AD studies, 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 elderly patients as compared to younger patients across the melanoma studies. The incidences of peripheral edema (26% vs. 12%) and anorexia (21% vs. 9%) increased in elderly patients as compared to younger patients in the metastatic melanoma studies. Clinical studies of MEKINIST in NSCLC did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment No dose adjustment is recommended in patients with mild hepatic impairment [see Clinical Pharmacology (12.3)]. The appropriate dose of MEKINIST has not been established in patients with moderate or severe hepatic impairment. 8.7 Renal Impairment No dose adjustment is recommended in patients with mild or moderate renal impairment [see Clinical Pharmacology (12.3)]. The appropriate dose of MEKINIST has not been established in patients with severe renal impairment.

Interactions

7 DRUG INTERACTIONS No formal clinical trials have been conducted to evaluate human cytochrome P450 (CYP) enzyme-mediated drug interactions with trametinib [see Clinical Pharmacology (12.3)]. MEKINIST is indicated for use in combination with dabrafenib. Refer to the dabrafenib labeling for additional risk information that applies to combination use treatment.

More information

Category Value
Authorisation number NDA204114
Agency product number BSB9VJ5TUT
Orphan designation No
Product NDC 0078-0666,0078-0668
Date First Approved 29-05-2013
Date Last Revised 04-05-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 1425118
Marketing authorisation holder Novartis Pharmaceuticals Corporation