ADVERSE REACTIONS SECTION.

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 Thromboembolism [see Warnings and Precautions (5. )] Cardiomyopathy [see Warnings and Precautions (5. )] Ocular Toxicities [see Warnings and Precautions (5. )] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5. )] Serious Febrile Reactions [see Warnings and Precautions (5. )] Serious Skin Toxicities [see Warnings and Precautions (5. )] Hyperglycemia [see Warnings and Precautions (5. 10 )] There are additional adverse reactions associated with dabrafenib. Refer to the dabrafenib prescribing information for additional information.. 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. )] Cardiomyopathy [see Warnings and Precautions (5. )] Ocular Toxicities [see Warnings and Precautions (5. )] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5. )] Serious Febrile Reactions [see Warnings and Precautions (5. )] Serious Skin Toxicities [see Warnings and Precautions (5. )] Hyperglycemia [see Warnings and Precautions (5. 10 )] Most common adverse reactions (>= 20%) for MEKINIST as 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.. 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). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The pooled safety populations described in the WARNINGS and PRECAUTIONS reflect exposure to MEKINIST as single agent in 329 patients with various solid tumors enrolled in METRIC, MEK113583, and MEK111054, and to MEKINIST administered with dabrafenib in 1087 patients enrolled in COMBI-d, COMBI-v, COMBI-AD, and BRF113928 with unresectable or metastatic melanoma, adjuvant melanoma or NSCLC. Among the 329 patients who received MEKINIST as single agent, 33% were exposed for months or longer and 9% were exposed for at least one year. Among the 1087 patients who received MEKINIST administered with dabrafenib, 70% were exposed for months or longer and 21% were exposed for greater than one year.Unresectable or Metastatic BRAF V600E or V600K Mutation-Positive MelanomaMEKINIST as Single AgentThe safety of MEKINIST was evaluated in the METRIC study, randomized, open-label trial of patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma who received MEKINIST (N 211) mg orally once daily or chemotherapy (N 99) (either dacarbazine 1000 mg/m2 every weeks or paclitaxel 175 mg/m2 every weeks) [see Clinical Studies (14.1)]. Patients with abnormal LVEF, history of acute coronary syndrome within 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. Tables and present adverse reactions and laboratory abnormalities, respectively, of MEKINIST as single agent in the METRIC study.Table 3. Select Adverse Reactions Occurring in >= 10% of Patients Who Received MEKINIST and at Higher Incidence (>= 5%) Than in the Chemotherapy Arm or >= 2% (Grades or 4) Adverse Reactions in METRICaNational Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. bGrade adverse reactions limited to rash (n 1) in trametinib arm and diarrhea (n 1) in chemotherapy arm. cIncludes stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation. dIncludes abdominal pain, lower abdominal pain, upper abdominal pain, and abdominal tenderness. eIncludes lymphedema, edema, and peripheral edema. fIncludes epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, melena, vaginal hemorrhage, hemorrhoidal hemorrhage, hematuria, and conjunctival hemorrhage.Adverse ReactionsMEKINISTChemotherapyN 211N 99AllGradesa (%)Grades3 and 4b(%)AllGradesa(%)Grades3 and 4b(%)Skin and subcutaneous tissue Rash578100 Acneiform dermatitis19< 110 Dry skin11000 Pruritus10210 Paronychia10010Gastrointestinal Diarrhea430162 Stomatitisc 15220 Abdominal paind 13151Vascular Lymphedemae 32140 Hypertension151273 Hemorrhagef 13< 100Other clinically important adverse reactions observed in <= 10% of patients (N 329) who received MEKINIST were:Cardiac: BradycardiaGastrointestinal: Dry mouthInfections: Folliculitis, rash pustular, cellulitisMusculoskeletal and Connective Tissue: RhabdomyolysisNervous System: Dizziness, dysgeusiaOcular: Blurred vision, dry eyeTable 4. Laboratory Abnormalities Occurring at Higher Incidence in Patients Who Received MEKINIST in the METRIC Study [Between-Arm Difference of >= 5% (All Grades) or >= 2% (Grades or 4)a]aOnly Grade adverse reactions were reported in either treatment arm.Laboratory AbnormalityMEKINISTChemotherapyN 211N 99AllGrades(%)Grades3 and 4(%)AllGrades(%)Grades3 and 4(%)Increased aspartate aminotransferase (AST)602161Hypoalbuminemia422231Increased alanine aminotransferase (ALT)393203Anemia382263Increased alkaline phosphatase242183MEKINIST with DabrafenibThe 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), multicenter, double-blind, randomized (1:1), active-controlled trial and the COMBI-v study (n 350), multicenter, open-label, randomized (1:1), active-controlled trial. In both trials, patients received MEKINIST mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. The trials excluded patients with abnormal LVEF, history of acute coronary syndrome within 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.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 and 28% had ECOG performance status 1, 64% had M1c stage disease, 35% had elevated lactate dehydrogenase (LDH) at baseline, and 0.5% had history of brain metastases.The most common adverse reactions (>= 20%) for MEKINIST in patients who received 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 who received MEKINIST plus dabrafenib had median duration of exposure of 11 months (range: 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 and Table present selected adverse reactions and laboratory abnormalities, respectively, of MEKINIST observed in the COMBI-d study.Table 5. Adverse Reactions Occurring in >= 10% (All Grades) of Patients Who Received MEKINIST With Dabrafenib and at Higher Incidence Than in Patients Who Received Single-Agent Dabrafenib in COMBI-da >= 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 single agent. aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. bIncludes peripheral edema, edema, lymphedema, localized edema, and generalized edema. cIncludes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal discomfort. dIncludes rash, generalized rash, pruritic rash, erythematous rash, papular rash, vesicular rash, macular rash, maculo-papular, and folliculitis rash. eMost common events (>= 1%) include epistaxis, hematochezia, decreased hemoglobin, purpura, and rectal hemorrhage. Grade events were limited to hepatic hematoma and duodenal ulcer hemorrhage (each = in the pooled combination arm).Adverse ReactionsPooled MEKINIST plus DabrafenibN 559COMBI-d StudyMEKINIST plus Dabrafenib = 209DabrafenibN 211AllGrades(%)Grades3 and 4(%)AllGrades(%)Grades3 and 4(%)AllGrades(%)Grades3 and 4(%)General Pyrexia545577331.9 Chills310.5310170.5 Peripheral edemab 210.7251.4110.5Gastrointestinal Nausea350.4340.5271.4 Diarrhea311.3301.4160.9 Vomiting271.1251.0140.5 Abdominal painc 180.9261.0142.4Skin Rashd 321.1420271.4Vascular Hypertension2611256166 Hemorrhagee 182.0191.9151.9Nervous system Dizziness110.214070Other clinically important adverse reactions for MEKINIST observed in less than 10% of patients who received MEKINIST in combination with dabrafenib (N 559) were:Cardiac: BradycardiaImmunologic: SarcoidosisMusculoskeletal: RhabdomyolysisTable 6. Laboratory Abnormalities Worsening From Baseline Occurring at >= 10% (All Grades) of Patients Who Received MEKINIST With Dabrafenib and at 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 single agent. aFor these laboratory tests the denominator is 556. bFor these laboratory tests the denominator is 208 for the combination arm, 207-209 for the dabrafenib arm. cGrade adverse reactions limited to lymphopenia and hyperglycemia (each = 4), increased ALT and increased AST (each = 3), neutropenia (n 2), and hyponatremia (n 1), in the pooled combination arm; neutropenia, lymphopenia, increased ALT, increased AST, hyperglycemia (each = 1) in the COMBI-d study combination arm; neutropenia, thrombocytopenia, increased ALT, and increased AST (each = 1) in the dabrafenib arm.Laboratory AbnormalityPooled MEKINIST plus DabrafenibN 559a COMBI-d StudyMEKINIST plus Dabrafenib = 209b DabrafenibN 211b AllGrades(%)Grades3 and 4c (%)AllGrades(%)Grades3 and 4c (%)AllGrades(%)Grades3 and 4c (%)Chemistry Hyperglycemia604.7656574.3 Hypoalbuminemia481.1531.4270 Hyponatremia258246142.9Hepatic Increased AST594.1604.3211.0 Increased blood alkaline phosphatase492.7501.0250.5 Increased ALT484.5443.8281.0Hematology Neutropenia467506161.9 Anemia432.3432.4384.3 Lymphopenia 328389287 Thrombocytopenia210.7190.5100.5Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive MelanomaThe 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 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 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 median duration of exposure of 11 months (range: 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 summarizes adverse reactions that occurred in at least 20% of the patients who received MEKINIST in combination with dabrafenib.Table 7. Adverse Reactions Occurring in >= 20% of Patients in COMBI-ADa 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 ReactionsMEKINIST plus DabrafenibN 435 Placebo = 432 AllGrades(%)Grades3 and 4(%)AllGrades(%)Grades3 and 4(%)General Pyrexiab 63511< Fatiguec 59537< Chills37140Gastrointestinal Nausea40< 1200 Diarrhea33< 115< Vomiting28< 1100Nervous system Headached 391240Skin Rashe 37< 116< 1Musculoskeletal Arthralgia28< 1140 Myalgiaf 20< 1140Other 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 8.Table 8. Laboratory Abnormalities Worsening From Baseline Occurring in >= 20% of Patients in COMBI-ADAbbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. aThe incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement:MEKINIST plus dabrafenib (range: 429 to 431) and placebo arm (range: 426 to 428).Laboratory AbnormalityMEKINIST plus Dabrafeniba = 435 Placeboa = 432 AllGrades(%)Grades3 and 4(%)AllGrades(%)Grades3 and 4(%)Chemistry Hyperglycemia633472 Hypophosphatemia42710< Hypoalbuminemia25< 1< 10Hepatic Increased AST57611< Increased ALT48518< Increased blood alkaline phosphatase3816< 1Hematology Neutropenia47612< Lymphopenia2656< Anemia25< 16< 1Trial COMBI-APlus (Pyrexia Management Study)COMBI-APlus evaluated the impact of pyrexia related outcomes of 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 patients temperature is >= 100.4F.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 CancerThe 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 multicenter, multi-cohort, non-randomized, open-label trial (Study BRF113928). Patients received MEKINIST 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 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 >= year. The median age was 65 years (range: 41 to 91), 46% were male, 85% were white; 32% had baseline ECOG performance status 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 resulting in 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 and Table 10 present adverse 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 aNCI CTCAE version 4.0.bIncludes fatigue, malaise, and asthenia.cIncludes peripheral edema, edema, and generalized edema.dIncludes rash, rash generalized, rash papular, rash macular, rash maculo-papular, and rash pustular.eIncludes hemoptysis, hematoma, epistaxis, purpura, hematuria, subarachnoid hemorrhage, gastric hemorrhage, urinary bladder hemorrhage, contusion, hematochezia, injection site hemorrhage, pulmonary hemorrhage, and retroperitoneal hemorrhage.Adverse ReactionsMEKINIST plus DabrafenibN 93AllGrades(%)Grades3 and 4b(%)General Pyrexia555 Fatigueb 515 Edemac 280 Chills231.1Gastrointestinal Nausea450 Vomiting333.2 Diarrhea322.2 Decreased appetite290Skin Dry skin311.1 Rashd 283.2Vascular Hemorrhagee 233.2Respiratory system Cough220 Dyspnea205Table 10. Treatment-Emergent Laboratory Abnormalities Occurring in >= 20% (All Grades) of Patients Who Received MEKINIST Plus Dabrafenib in Study BRF113928Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. aFor these laboratory tests the denominator is 90. bFor these laboratory tests the denominator is 91.Laboratory AbnormalityMEKINIST plus DabrafenibN 93AllGrades(%)Grades3 and 4(%)Chemistrya Hyperglycemia719 Hyponatremia5717 Hypophosphatemia367 Increased creatinine211.1Hepatica Increased blood alkaline phosphatase640 Increased AST614.4 Increased ALT326Hematologyb Leukopenia488 Anemia4610 Neutropenia448 Lymphopenia4214Locally Advanced or Metastatic, BRAF V600E Mutation-Positive, Anaplastic Thyroid CancerThe safety of MEKINIST when administered with dabrafenib was evaluated in 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, 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 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 >= 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.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of MEKINIST in combination with dabrafenib. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Dermatologic: SCAR (including DRESS and SJS).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Trametinib is reversible inhibitor of mitogen-activated extracellular signal-regulated kinase (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.. 12.2 Pharmacodynamics. Administration of mg and mg MEKINIST 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 ElectrophysiologyThe heart rate-corrected QT (QTc) prolongation potential of trametinib was assessed in dedicated study in 32 patients who received placebo on Day and MEKINIST mg once daily on Days 2-14 followed by MEKINIST 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 single- and repeat-oral administration in patients with solid tumors and BRAF V600 mutation-positive metastatic melanoma.AbsorptionAfter oral administration of MEKINIST, the median time to achieve peak plasma concentrations (Tmax) is 1.5 hours post-dose. The mean absolute bioavailability of single oral dose of MEKINIST mg is 72%. The increase in Cmax was dose proportional after single dose of 0.125 mg (0.0625 times the approved recommended dosage) to 10 mg (5 times the approved recommended dosage) while the increase in AUC was greater than dose proportional. After repeat doses of 0.125 mg to mg daily, both Cmax and AUC increase proportionally with dose. Inter-subject variability in AUC and Cmax at steady state is 22% and 28%, respectively.Effect of FoodAdministration of single dose of MEKINIST with high-fat, high-calorie meal (approximately 1000 calories) decreased trametinib AUC by 24%, Cmax by 70%, and delayed Tmax by approximately hours as compared with fasted conditions.DistributionTrametinib is 97.4% bound to human plasma proteins. The apparent volume of distribution (Vc/F) is 214 L.EliminationThe estimated elimination half-life of trametinib based on the population PK model is 3.9 to 4.8 days. The apparent clearance is 4.9 L/h.MetabolismTrametinib 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 single dose of [14C]-trametinib, approximately 50% of circulating radioactivity is represented as the parent compound. However, based on metabolite profiling after repeat dosing of trametinib, >= 75% of drug-related material in plasma is the parent compound.ExcretionFollowing oral administration of [14C]-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 PopulationsAge, sex, body weight, and renal impairment (eGFR 15 to 89 mL/min/1.73 m2) do not have clinically important effect on the exposure of trametinib. There are insufficient data to evaluate potential differences in the exposure of trametinib by race or ethnicity.Patients with Hepatic Impairment: Based on results from pharmacokinetic study in patients with mild to severe hepatic impairment defined by bilirubin and AST levels, mild, moderate, and severe hepatic impairment had no significant effect in trametinib exposure or apparent drug clearance compared with patients with normal hepatic function [see Use in Specific Populations (8.6)].Drug Interaction StudiesEffect of Dabrafenib on Trametinib: Coadministration of trametinib mg daily with dabrafenib 150 mg twice daily resulted in no change in AUC of trametinib as compared with administration of trametinib.Effect of Trametinib on CYP Substrates: Based on in vitro studies, trametinib is an inhibitor of CYP2C8, but is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 at clinically relevant systemic concentration of 0.04 uM. Trametinib is an inducer of CYP3A in vitro. Based on cross-study comparisons, oral administration of MEKINIST mg once daily with sensitive CYP3A4 substrate had no clinically important effect on the AUC and Cmax of the sensitive CYP3A4 substrate.Effect of Transporters on Trametinib: Trametinib is substrate of P-glycoprotein (P-gp) and BSEP. Inhibition of P-gp is unlikely to result in clinically important increase in trametinib concentrations as trametinib exhibits high passive permeability and bioavailability. Trametinib is not 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 clinically relevant systemic concentration of 0.04 uM.

CLINICAL STUDIES SECTION.

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. 14.1 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma MEKINIST as Single AgentThe safety and efficacy of MEKINIST were evaluated in an international, multicenter, 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 BRAF inhibitor or MEK inhibitor was not permitted. Patients were randomized to receive MEKINIST mg orally once daily (N 214) or chemotherapy (N 108) consisting of either dacarbazine 1000 mg/m2 intravenously every weeks or paclitaxel 175 mg/m2 intravenously every 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 central testing site using 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(R)-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 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 statistically significant increase in PFS in the patients treated with MEKINIST. Table 11 and Figure summarize the PFS results.Table 11. Efficacy Results in the METRIC StudyAbbreviations: CI, confidence interval; DoR, duration of response; HR, hazard ratio; NR, not reached. aPike estimator.Investigator-Assessed EndpointsMEKINISTN 214ChemotherapyN 108Progression-Free Survival Number of Events (%)117 (55%)77 (71%) Progressive Disease107 (50%)70 (65%) Death10 (5%)7 (6%) Median, months (95% CI)4.8 (4.3, 4.9)1.5 (1.4, 2.7) HRa (95% CI)0.47 (0.34, 0.65) value (log-rank test)< 0.0001Confirmed Tumor Responses Overall Response Rate (95% CI)22% (17%, 28%)8% (4%, 15%) Complete Response, (%)4 (2%)0 Partial Response, (%)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 StudyIn supportive analyses based on independent radiologic review committee (IRRC) assessment, the PFS results were consistent with those of the primary efficacy analysis.MEKINIST with DabrafenibCOMBI-d StudyThe 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 mg once daily plus dabrafenib 150 mg twice daily or dabrafenib 150 mg twice daily plus matching placebo. Randomization was stratified by LDH level (greater than the 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 years), 53% were male, 99% were white, 72% had ECOG performance status of 0, 4% had Stage IIIc, 66% had M1c disease, 65% had normal LDH, and patients had 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 12 and Figure summarize the efficacy results.Table 12. Efficacy Results in the COMBI-d StudyAbbreviations: CI, confidence interval; DoR, duration of response; HR, hazard ratio; NR, not reached; ORR, overall response rate. aPFS and ORR were assessed by investigator. bBased on stratified log-rank test.EndpointMEKINIST plus DabrafenibN 211Placebo plus DabrafenibN 212Progression-Free Survivala 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) valueb 0.035Overall 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) valueb 0.01Overall Response Ratea ORR (95% CI)66% (60%, 73%)51% (44%, 58%) value< 0.001 Complete Response10%8% Partial Response56%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 StudyCOMBI-MB StudyThe activity of MEKINIST with dabrafenib for the treatment of BRAF V600E or V600K mutation-positive melanoma, metastatic to the brain, was evaluated in non-randomized, open-label, multicenter, 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 cm in diameter, ocular melanoma, or primary mucosal melanoma. Patients received MEKINIST 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 confirmed intracranial response per RECIST v1.1, modified to allow up to five intracranial target lesions at least mm in diameter, as assessed by independent review.The COMBI-MB study enrolled 121 patients with BRAF V600E (85%) or V600K (15%) mutation. The median age was 54 years (range: 23 to 84 years), 58% were male, 100% were white, 8% were from the United States, 65% had normal LDH value at baseline, and 97% had an ECOG performance status of 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 complete response rate of 4.1% and partial response rate of 46%. The median duration of intracranial response was 6.4 months (range: to 31 months). 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, multicenter, 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(R)-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 anticancer treatment, including radiotherapy. Patients were randomized (1:1) to receive MEKINIST mg once daily in combination with dabrafenib 150 mg twice daily or two placebos for up to year. Randomization was stratified by BRAF mutation status (V600E or V600K) and American Joint Committee on Cancer (AJCC; 7th 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 months for the first two years and every months thereafter.In COMBI-AD, 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 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 13 and Figure 3.Table 13. Efficacy Results in COMBI-AD in the Adjuvant Treatment of MelanomaAbbreviations: HR, hazard ratio; CI, confidence interval; NE, not estimable. aPike estimator obtained from the stratified log-rank test. bLog-rank test stratified by disease stage IIIa vs. IIIb vs. IIIc and BRAF V600 mutation type V600E vs. V600K.MEKINIST plus DabrafenibN 438PlaceboN 432Relapse-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) valueb 0.0001Figure 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 multicenter, 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 and 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 could not have received prior systemic therapy for metastatic disease. Patients in Cohort received dabrafenib 150 mg twice daily. Patients in Cohorts and received MEKINIST 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 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: 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 14.Table 14. Efficacy Results Based on Independent Review in Study BRF113928Abbreviations: CI, confidence interval; DoR, duration of response; NE, not estimable.TreatmentDabrafenibMEKINIST plus DabrafenibPopulationPreviously TreatedN 78Previously TreatedN 57Treatment NaiveN 36Overall Response Rate ORR (95% CI)27% (18%, 38%)63% (49%, 76%)61% (44%, 77%) Complete Response1%4%3% Partial Response26%60%58%Duration of Responsen 21n 36n 22 Median DoR, months (95% CI)9.9 (4.2, NE)12.6 (5.8, NE)NE (6.9, NE) with DoR >= months52%64%59%In subgroup analysis of patients with retrospectively centrally confirmed BRAF V600E mutation-positive NSCLC with the Oncomine(TM) Dx Target Test, the ORR results were similar to those presented in Table 14.. 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, multicenter, 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 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: 47-85); 44% were male, 50% white, 44% Asian; and 94% had ECOG performance status of or 1. Prior anti-cancer treatments included surgery and external beam radiotherapy (83% each), and systemic therapy (67%).Efficacy results are summarized in Table 15.Table 15. Efficacy Results in the ATC Cohort Based on Independent Review of Study BRF117019Abbreviations: ATC, anaplastic thyroid cancer; CI, confidence interval; DoR, duration of response; ORR, overall response rate; NE, not estimable.ATC Cohort PopulationN 36Overall Response Rate ORR (95% CI)53% (35.5%, 69.6%) Complete Response6% Partial Response47%Duration of Responsen 19Median DoR, months (95% CI)13.6 (3.8, NE) with DoR >= months68% with DoR >= 12 months53%. 14.5 Lack of Clinical Activity in Metastatic Melanoma Following BRAF-Inhibitor Therapy. The clinical activity of MEKINIST as single agent was evaluated in single-arm, multicenter, international trial in 40 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma who had received prior treatment with BRAF inhibitor. All patients received MEKINIST at dose of 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 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 confirmed partial or complete response as determined by the clinical investigators.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The pooled safety populations described in the WARNINGS and PRECAUTIONS reflect exposure to MEKINIST as single agent in 329 patients with various solid tumors enrolled in METRIC, MEK113583, and MEK111054, and to MEKINIST administered with dabrafenib in 1087 patients enrolled in COMBI-d, COMBI-v, COMBI-AD, and BRF113928 with unresectable or metastatic melanoma, adjuvant melanoma or NSCLC. Among the 329 patients who received MEKINIST as single agent, 33% were exposed for months or longer and 9% were exposed for at least one year. Among the 1087 patients who received MEKINIST administered with dabrafenib, 70% were exposed for months or longer and 21% were exposed for greater than one year.Unresectable or Metastatic BRAF V600E or V600K Mutation-Positive MelanomaMEKINIST as Single AgentThe safety of MEKINIST was evaluated in the METRIC study, randomized, open-label trial of patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma who received MEKINIST (N 211) mg orally once daily or chemotherapy (N 99) (either dacarbazine 1000 mg/m2 every weeks or paclitaxel 175 mg/m2 every weeks) [see Clinical Studies (14.1)]. Patients with abnormal LVEF, history of acute coronary syndrome within 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. Tables and present adverse reactions and laboratory abnormalities, respectively, of MEKINIST as single agent in the METRIC study.Table 3. Select Adverse Reactions Occurring in >= 10% of Patients Who Received MEKINIST and at Higher Incidence (>= 5%) Than in the Chemotherapy Arm or >= 2% (Grades or 4) Adverse Reactions in METRICaNational Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. bGrade adverse reactions limited to rash (n 1) in trametinib arm and diarrhea (n 1) in chemotherapy arm. cIncludes stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation. dIncludes abdominal pain, lower abdominal pain, upper abdominal pain, and abdominal tenderness. eIncludes lymphedema, edema, and peripheral edema. fIncludes epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, melena, vaginal hemorrhage, hemorrhoidal hemorrhage, hematuria, and conjunctival hemorrhage.Adverse ReactionsMEKINISTChemotherapyN 211N 99AllGradesa (%)Grades3 and 4b(%)AllGradesa(%)Grades3 and 4b(%)Skin and subcutaneous tissue Rash578100 Acneiform dermatitis19< 110 Dry skin11000 Pruritus10210 Paronychia10010Gastrointestinal Diarrhea430162 Stomatitisc 15220 Abdominal paind 13151Vascular Lymphedemae 32140 Hypertension151273 Hemorrhagef 13< 100Other clinically important adverse reactions observed in <= 10% of patients (N 329) who received MEKINIST were:Cardiac: BradycardiaGastrointestinal: Dry mouthInfections: Folliculitis, rash pustular, cellulitisMusculoskeletal and Connective Tissue: RhabdomyolysisNervous System: Dizziness, dysgeusiaOcular: Blurred vision, dry eyeTable 4. Laboratory Abnormalities Occurring at Higher Incidence in Patients Who Received MEKINIST in the METRIC Study [Between-Arm Difference of >= 5% (All Grades) or >= 2% (Grades or 4)a]aOnly Grade adverse reactions were reported in either treatment arm.Laboratory AbnormalityMEKINISTChemotherapyN 211N 99AllGrades(%)Grades3 and 4(%)AllGrades(%)Grades3 and 4(%)Increased aspartate aminotransferase (AST)602161Hypoalbuminemia422231Increased alanine aminotransferase (ALT)393203Anemia382263Increased alkaline phosphatase242183MEKINIST with DabrafenibThe 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), multicenter, double-blind, randomized (1:1), active-controlled trial and the COMBI-v study (n 350), multicenter, open-label, randomized (1:1), active-controlled trial. In both trials, patients received MEKINIST mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. The trials excluded patients with abnormal LVEF, history of acute coronary syndrome within 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.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 and 28% had ECOG performance status 1, 64% had M1c stage disease, 35% had elevated lactate dehydrogenase (LDH) at baseline, and 0.5% had history of brain metastases.The most common adverse reactions (>= 20%) for MEKINIST in patients who received 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 who received MEKINIST plus dabrafenib had median duration of exposure of 11 months (range: 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 and Table present selected adverse reactions and laboratory abnormalities, respectively, of MEKINIST observed in the COMBI-d study.Table 5. Adverse Reactions Occurring in >= 10% (All Grades) of Patients Who Received MEKINIST With Dabrafenib and at Higher Incidence Than in Patients Who Received Single-Agent Dabrafenib in COMBI-da >= 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 single agent. aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. bIncludes peripheral edema, edema, lymphedema, localized edema, and generalized edema. cIncludes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal discomfort. dIncludes rash, generalized rash, pruritic rash, erythematous rash, papular rash, vesicular rash, macular rash, maculo-papular, and folliculitis rash. eMost common events (>= 1%) include epistaxis, hematochezia, decreased hemoglobin, purpura, and rectal hemorrhage. Grade events were limited to hepatic hematoma and duodenal ulcer hemorrhage (each = in the pooled combination arm).Adverse ReactionsPooled MEKINIST plus DabrafenibN 559COMBI-d StudyMEKINIST plus Dabrafenib = 209DabrafenibN 211AllGrades(%)Grades3 and 4(%)AllGrades(%)Grades3 and 4(%)AllGrades(%)Grades3 and 4(%)General Pyrexia545577331.9 Chills310.5310170.5 Peripheral edemab 210.7251.4110.5Gastrointestinal Nausea350.4340.5271.4 Diarrhea311.3301.4160.9 Vomiting271.1251.0140.5 Abdominal painc 180.9261.0142.4Skin Rashd 321.1420271.4Vascular Hypertension2611256166 Hemorrhagee 182.0191.9151.9Nervous system Dizziness110.214070Other clinically important adverse reactions for MEKINIST observed in less than 10% of patients who received MEKINIST in combination with dabrafenib (N 559) were:Cardiac: BradycardiaImmunologic: SarcoidosisMusculoskeletal: RhabdomyolysisTable 6. Laboratory Abnormalities Worsening From Baseline Occurring at >= 10% (All Grades) of Patients Who Received MEKINIST With Dabrafenib and at 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 single agent. aFor these laboratory tests the denominator is 556. bFor these laboratory tests the denominator is 208 for the combination arm, 207-209 for the dabrafenib arm. cGrade adverse reactions limited to lymphopenia and hyperglycemia (each = 4), increased ALT and increased AST (each = 3), neutropenia (n 2), and hyponatremia (n 1), in the pooled combination arm; neutropenia, lymphopenia, increased ALT, increased AST, hyperglycemia (each = 1) in the COMBI-d study combination arm; neutropenia, thrombocytopenia, increased ALT, and increased AST (each = 1) in the dabrafenib arm.Laboratory AbnormalityPooled MEKINIST plus DabrafenibN 559a COMBI-d StudyMEKINIST plus Dabrafenib = 209b DabrafenibN 211b AllGrades(%)Grades3 and 4c (%)AllGrades(%)Grades3 and 4c (%)AllGrades(%)Grades3 and 4c (%)Chemistry Hyperglycemia604.7656574.3 Hypoalbuminemia481.1531.4270 Hyponatremia258246142.9Hepatic Increased AST594.1604.3211.0 Increased blood alkaline phosphatase492.7501.0250.5 Increased ALT484.5443.8281.0Hematology Neutropenia467506161.9 Anemia432.3432.4384.3 Lymphopenia 328389287 Thrombocytopenia210.7190.5100.5Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive MelanomaThe 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 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 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 median duration of exposure of 11 months (range: 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 summarizes adverse reactions that occurred in at least 20% of the patients who received MEKINIST in combination with dabrafenib.Table 7. Adverse Reactions Occurring in >= 20% of Patients in COMBI-ADa 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 ReactionsMEKINIST plus DabrafenibN 435 Placebo = 432 AllGrades(%)Grades3 and 4(%)AllGrades(%)Grades3 and 4(%)General Pyrexiab 63511< Fatiguec 59537< Chills37140Gastrointestinal Nausea40< 1200 Diarrhea33< 115< Vomiting28< 1100Nervous system Headached 391240Skin Rashe 37< 116< 1Musculoskeletal Arthralgia28< 1140 Myalgiaf 20< 1140Other 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 8.Table 8. Laboratory Abnormalities Worsening From Baseline Occurring in >= 20% of Patients in COMBI-ADAbbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. aThe incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement:MEKINIST plus dabrafenib (range: 429 to 431) and placebo arm (range: 426 to 428).Laboratory AbnormalityMEKINIST plus Dabrafeniba = 435 Placeboa = 432 AllGrades(%)Grades3 and 4(%)AllGrades(%)Grades3 and 4(%)Chemistry Hyperglycemia633472 Hypophosphatemia42710< Hypoalbuminemia25< 1< 10Hepatic Increased AST57611< Increased ALT48518< Increased blood alkaline phosphatase3816< 1Hematology Neutropenia47612< Lymphopenia2656< Anemia25< 16< 1Trial COMBI-APlus (Pyrexia Management Study)COMBI-APlus evaluated the impact of pyrexia related outcomes of 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 patients temperature is >= 100.4F.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 CancerThe 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 multicenter, multi-cohort, non-randomized, open-label trial (Study BRF113928). Patients received MEKINIST 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 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 >= year. The median age was 65 years (range: 41 to 91), 46% were male, 85% were white; 32% had baseline ECOG performance status 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 resulting in 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 and Table 10 present adverse 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 aNCI CTCAE version 4.0.bIncludes fatigue, malaise, and asthenia.cIncludes peripheral edema, edema, and generalized edema.dIncludes rash, rash generalized, rash papular, rash macular, rash maculo-papular, and rash pustular.eIncludes hemoptysis, hematoma, epistaxis, purpura, hematuria, subarachnoid hemorrhage, gastric hemorrhage, urinary bladder hemorrhage, contusion, hematochezia, injection site hemorrhage, pulmonary hemorrhage, and retroperitoneal hemorrhage.Adverse ReactionsMEKINIST plus DabrafenibN 93AllGrades(%)Grades3 and 4b(%)General Pyrexia555 Fatigueb 515 Edemac 280 Chills231.1Gastrointestinal Nausea450 Vomiting333.2 Diarrhea322.2 Decreased appetite290Skin Dry skin311.1 Rashd 283.2Vascular Hemorrhagee 233.2Respiratory system Cough220 Dyspnea205Table 10. Treatment-Emergent Laboratory Abnormalities Occurring in >= 20% (All Grades) of Patients Who Received MEKINIST Plus Dabrafenib in Study BRF113928Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. aFor these laboratory tests the denominator is 90. bFor these laboratory tests the denominator is 91.Laboratory AbnormalityMEKINIST plus DabrafenibN 93AllGrades(%)Grades3 and 4(%)Chemistrya Hyperglycemia719 Hyponatremia5717 Hypophosphatemia367 Increased creatinine211.1Hepatica Increased blood alkaline phosphatase640 Increased AST614.4 Increased ALT326Hematologyb Leukopenia488 Anemia4610 Neutropenia448 Lymphopenia4214Locally Advanced or Metastatic, BRAF V600E Mutation-Positive, Anaplastic Thyroid CancerThe safety of MEKINIST when administered with dabrafenib was evaluated in 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, 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 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 >= 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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dosage of MEKINIST is mg orally once daily. Take MEKINIST at least hour before or at least hours after meal. (2). The recommended dosage of MEKINIST is mg orally once daily. Take MEKINIST at least hour before or at least hours after meal. (2). 2.1 Patient Selection. MelanomaConfirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with MEKINIST as 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.NSCLCConfirm 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.ATCConfirm 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.. Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with MEKINIST as 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.. 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.. 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.. 2.2 Recommended Dosage for Unresectable or Metastatic Melanoma. The recommended dosage of MEKINIST is mg orally taken once daily, as 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 mg orally taken once daily in combination with dabrafenib until disease recurrence or unacceptable toxicity for up to year. Refer to the dabrafenib prescribing information for recommended dabrafenib dosing information.. 2.4 Recommended Dosage for NSCLC. The recommended dosage of MEKINIST is 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 dosage of MEKINIST is 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 hour before or hours after meal [see Clinical Pharmacology (12.3)].Do not take missed dose of MEKINIST within 12 hours of the next dose of MEKINIST.. Take MEKINIST doses approximately 24 hours apart.. Take MEKINIST at least hour before or hours after meal [see Clinical Pharmacology (12.3)].. Do not take 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 ReactionsActionRecommended DoseFirst Dose Reduction1.5 mg orally once dailySecond Dose Reduction1 mg orally once dailySubsequent ModificationPermanently discontinue if unable to tolerate MEKINIST mg orally once dailyDosage modifications for adverse reactions associated with MEKINIST are presented in Table 2.Table 2. Recommended Dosage Modifications for MEKINIST for Adverse ReactionsaNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.bSee Table for recommended dose reductions of MEKINIST.cDose 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 Reactiona Dosage Modification for MEKINISTb Hemorrhage [see Warnings and Precautions (5.2)]Grade 3Withhold MEKINIST. If improved, resume MEKINIST at lower dose.If not improved, permanently discontinue MEKINIST. Grade 4Permanently discontinue MEKINIST.Venous Thromboembolism [see Warnings and Precautions (5.4)]Uncomplicated deep venous thrombosis (DVT) or pulmonary embolism (PE)Withhold MEKINIST for up to weeks. If improved to Grade 0-1, resume MEKINIST at lower dose.If not improved, permanently discontinue MEKINIST. Life threatening PEPermanently 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 valueWithhold MEKINIST for up to weeks.If improved to normal LVEF value, resume MEKINIST at lower dose. If not improved to normal LVEF value, permanently discontinue MEKINIST. Symptomatic cardiomyopathyAbsolute decrease in LVEF of greater than 20% from baseline that is below LLNPermanently discontinue MEKINIST.Ocular Toxicities [see Warnings and Precautions (5.6)]Retinal pigment epithelial detachments (RPED)Withhold MEKINIST for up to 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)/pneumonitisPermanently discontinue MEKINIST.Febrile Reactions [see Warnings and Precautions (5.8)]Fever of 100.4F to 104F (or first symptoms in case of recurrence)Withhold MEKINIST until fever resolves, then resume MEKINIST at same or lower dose.Fever higher than 104FFever complicated by rigors, hypotension, dehydration, or renal failureWithhold MEKINIST until febrile reactions resolve for at least 24 hours, then resume MEKINIST at lower dose.OrPermanently discontinue MEKINIST.Skin Toxicities [see Warnings and Precautions (5.9)]Intolerable Grade 2Grade or 4Withhold MEKINIST for up to weeks.If improved, resume MEKINIST at lower dose. If not improved, permanently discontinue. Severe cutaneous adverse reactions (SCARs)Permanently discontinue MEKINIST.Other Adverse Reactionsc Intolerable Grade Any Grade 3Withhold MEKINIST. If improved to Grade 0-1, resume at lower dose. If not improved, permanently discontinue. First occurrence of any Grade 4Withhold MEKINIST until improves to Grade 0-1, then resume at lower dose.OrPermanently discontinue MEKINIST.Recurrent Grade 4Permanently discontinue MEKINIST.Refer to the dabrafenib prescribing information for dose modifications for adverse reactions associated with dabrafenib.. Grade 3. If improved, resume MEKINIST at lower dose.. If not improved, permanently discontinue MEKINIST.. Grade 4. Uncomplicated deep venous thrombosis (DVT) or pulmonary embolism (PE). If improved to Grade 0-1, resume MEKINIST at lower dose.. If not improved, permanently discontinue MEKINIST.. Life threatening PE. 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. 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. Retinal pigment epithelial detachments (RPED). 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). Interstitial lung disease (ILD)/pneumonitis. Fever of 100.4F to 104F (or first symptoms in case of recurrence). Fever higher than 104F. 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.. Permanently discontinue MEKINIST.. Intolerable Grade 2. Grade or 4. If improved, resume MEKINIST at lower dose. If not improved, permanently discontinue.. Severe cutaneous adverse reactions (SCARs). Intolerable Grade . Any Grade 3. If improved to Grade 0-1, resume at lower dose. If not improved, permanently discontinue.. First occurrence of any Grade 4. Withhold MEKINIST until improves to Grade 0-1, then resume at lower dose.. Permanently discontinue MEKINIST.. Recurrent Grade 4.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).New Cutaneous and Non-Cutaneous MalignanciesAdvise patients that MEKINIST administered with dabrafenib can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor 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)].HemorrhageAdvise 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 PerforationAdvise 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 ThrombosisAdvise 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)].CardiomyopathyAdvise 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)].Retinal Pigment Epithelial DetachmentAdvise 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 DiseaseAdvise 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 ReactionsAdvise patients that MEKINIST administered with dabrafenib can cause serious febrile reactions. Instruct patients to contact their healthcare provider if they develop fever while taking MEKINIST with dabrafenib [see Warnings and Precautions (5.8)].Serious Skin ToxicitiesAdvise 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 severe skin reaction [see Warnings and Precautions (5.9)].HypertensionAdvise 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.DiarrheaAdvise 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.Embryo-Fetal ToxicityAdvise pregnant women and males of reproductive potential of the potential risk to fetus [see Warnings and Precautions (5.12), Use in Specific Populations (8.1, 8.3)].Advise females to contact their healthcare provider of known or suspected pregnancy.Advise females of reproductive potential to use effective contraception during treatment with MEKINIST and for months after the last dose.Advise male patients with female partners of reproductive potential to use condoms during treatment with MEKINIST and for at least months after the last dose.LactationAdvise women not to breastfeed during treatment with MEKINIST and for months after the last dose [see Use in Specific Populations (8.2)].InfertilityAdvise females of reproductive potential of the potential risk for impaired fertility [see Use in Specific Populations (8.3)].AdministrationMEKINIST should be taken at least hour before or at least hours after meal [see Dosage and Administration (2.6)].THxID(R) BRAF assay is trademark of bioMerieux.Oncomine(TM) Dx Target Test is trademark of Life Technologies Corporation, part of Thermo Fisher Scientific Inc.Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936(C) NovartisT2022-06. Advise pregnant women and males of reproductive potential of the potential risk to fetus [see Warnings and Precautions (5.12), Use in Specific Populations (8.1, 8.3)].. Advise females to contact their healthcare provider of known or suspected pregnancy.. Advise females of reproductive potential to use effective contraception during treatment with MEKINIST and for months after the last dose.. Advise male patients with female partners of reproductive potential to use condoms during treatment with MEKINIST and for at least months after the last dose.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: December 2021Patient InformationMEKINIST(R) (MEK-in-ist)(trametinib)tabletsImportant information: If your healthcare provider prescribes MEKINIST for you to be taken with dabrafenib, also read the Medication Guide that comes with dabrafenib.What is the most important information should know about MEKINISTMEKINIST may cause serious side effects, including: Risk of new skin cancers. MEKINIST, when used with dabrafenib, may cause skin cancers, called cutaneous squamous cell carcinoma, keratoacanthoma, basal cell carcinoma, or melanoma.Talk to your healthcare provider about your risk for these cancers.Check your skin and tell your healthcare provider right away about any skin changes, including a:new wart skin sore or reddish bump that bleeds or does not heal change in size or color of moleYour healthcare provider should check your skin before treatment with MEKINIST and dabrafenib, every months during treatment with MEKINIST and dabrafenib and for up to months after you stop taking MEKINIST and dabrafenib to look for any new skin cancers.Your healthcare provider should also check for cancers that may not occur on the skin. Tell your healthcare provider about any new symptoms that develop during treatment with MEKINIST with dabrafenib.See What are the possible side effects of MEKINIST for more information about side effects.What is MEKINISTMEKINIST is prescription medicine used: alone or in combination with medicine called dabrafenib to treat type of skin cancer called melanoma: that has spread to other parts of the body or cannot be removed by surgery, and that has certain type of abnormal BRAF gene.in combination with dabrafenib, to help prevent melanoma that has certain type of abnormal BRAF gene from coming back after the cancer has been removed by surgery.MEKINIST should not be used to treat people who already have received BRAF inhibitor for treatment of their melanoma, and it did not work or is no longer working.in combination with dabrafenib to treat type of lung cancer called non-small cell lung cancer (NSCLC) that has spread to other parts of the body, and that has certain type of abnormal BRAF gene.in combination with dabrafenib to treat type of thyroid cancer called anaplastic thyroid cancer (ATC) that has spread to other parts of the body and you have no satisfactory treatment options, and that has certain type of abnormal BRAF gene.Your healthcare provider will perform test to make sure that MEKINIST is right for you.It is not known if MEKINIST alone or MEKINIST with dabrafenib is safe and effective in children.Before you take MEKINIST, tell your healthcare provider about all of your medical conditions, including if you:have had bleeding problems or blood clots have stomach problems have inflammation of the colon have heart problems have eye problems have lung or breathing problems have high blood pressure (hypertension) have liver or kidney problems have diabetes are male (including one who has had vasectomy) with female partner of reproductive potential. Males (including those who have had vasectomy) should use condoms during sexual intercourse during treatment with MEKINIST and for at least months after your last dose of MEKINIST.are pregnant or plan to become pregnant. MEKINIST can harm your unborn baby. Females who are able to become pregnant should use effective birth control (contraception) during treatment with MEKINIST and for months after your last dose of MEKINIST. Talk to your healthcare provider about birth control methods that may be right for you during this time. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with MEKINIST. are breastfeeding or plan to breastfeed. It is not known if MEKINIST passes into your breast milk. Do not breastfeed during treatment and for months after your last dose of MEKINIST. Talk to your healthcare provider about the best way to feed your baby during this time.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How should take MEKINIST Take MEKINIST exactly as your healthcare provider tells you to take it. Do not change your dose or stop MEKINIST unless your healthcare provider tells you. Your healthcare provider may change your dose of MEKINIST, temporarily stop, or completely stop your treatment with MEKINIST if you develop certain side effects. Take MEKINIST one time day, about every 24 hours. Take MEKINIST at least hour before or hours after meal. If you miss dose, take it as soon as you remember. If it is less than 12 hours before your next scheduled dose, skip the missed dose. Just take the next dose at your regular time.What are the possible side effects of MEKINISTMEKINIST may cause serious side effects, including:See What is the most important information should know about MEKINISTbleeding problems. MEKINIST can cause serious bleeding problems, especially in your brain or stomach, that can lead to death. Call your healthcare provider and get medical help right away if you have any signs of bleeding, including: headaches, dizziness, or feeling weak cough up blood or blood clots vomit blood or your vomit looks like coffee grounds red or black stools that look like tar inflammation of the intestines, or tears (perforation) of the stomach or intestines. MEKINIST can cause inflammation of your intestines, or tears in the stomach or intestines that can lead to death. Tell your healthcare provider immediately if you have any of the following symptoms: bleeding. See bleeding problems above. diarrhea (loose stools) or more bowel movements than usual stomach-area (abdomen) pain or tenderness fever nausea blood clots. MEKINIST can cause blood clots in your arms or legs, which can travel to your lungs and can lead to death. Get medical help right away if you have the following symptoms: chest pain sudden shortness of breath or trouble breathing pain in your legs with or without swelling swelling in your arms or legs cool pale arm or leg heart problems, including heart failure. Your healthcare provider should check your heart function before and during treatment with MEKINIST. Call your healthcare provider right away if you have any of the following signs and symptoms of heart problem: feeling like your heart is pounding or racing shortness of breath swelling of your ankles and feet feeling lightheaded eye problems. MEKINIST can cause severe eye problems that might lead to blindness. Call your healthcare provider right away if you get these symptoms of eye problems: blurred vision, loss of vision, or other vision changes see color dots halo (seeing blurred outline around objects) eye pain, swelling, or redness lung or breathing problems. MEKINIST can cause lung or breathing problems. Tell your healthcare provider if you have any new or worsening symptoms of lung or breathing problems, including: shortness of breath cough fever. Fever is common during treatment with MEKINIST and dabrafenib, but it may also be serious. When taking MEKINIST with dabrafenib, fever may happen more often or may be more severe. In some cases, chills or shaking chills, too much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems may happen with the fever. Call your healthcare provider right away if you get fever during treatment with MEKINIST. Your healthcare provider may temporarily or permanently stop your treatment, or change your dose of MEKINIST with dabrafenib if you have fevers. Your healthcare provider will treat you as needed for your fever and any signs and symptoms of infection, and should check your kidney function during and after you have had severe fever.serious skin reactions. Skin rash is common side effect of MEKINIST. MEKINIST can also cause other skin reactions. In some cases these rashes and other skin reactions can be severe or serious, and may need to be treated in hospital or lead to death.Tell your healthcare provider if you get skin rash or acne that bothers you or worsens. Tell your healthcare provider right away if you develop any of the following signs or symptoms of severe skin reaction, including: blisters or peeling of your skin mouth sores blisters on your lips, or around your mouth or eyes high fever or flu-like symptoms enlarged lymph nodesincreased blood sugar (hyperglycemia). Some people may develop high blood sugar or worsening diabetes during treatment with MEKINIST and dabrafenib. If you are diabetic, your healthcare provider should check your blood sugar levels closely during treatment with MEKINIST and dabrafenib. Your diabetes medicine may need to be changed. Tell your healthcare provider if you have any of the following symptoms of severe high blood sugar: increased thirst urinating more often than normal or urinating an increased amount of urine The most common side effects of MEKINIST when taken alone include:rashdiarrhea. Call your healthcare provider if you get severe diarrhea.swelling of the face, arms, or legsThe most common side effects of MEKINIST when taken with dabrafenib in people with melanoma that has spread to other parts of the body or cannot be removed by surgery include:o fevero diarrheao rasho vomitingo nauseao high blood pressure (hypertension)o chillso swelling of the face, arms, or legsThe most common side effects of MEKINIST when taken with dabrafenib to help prevent melanoma from coming back after the cancer has been removed by surgery include:o fevero chillso fatigueo diarrheao nauseao vomitingo headacheo joint acheso rasho muscle achesThe most common side effects of MEKINIST when taken with dabrafenib in people with NSCLC include:o fevero rasho fatigueo swelling of face, arms, and legso nauseao chillso vomitingo bleedingo diarrheao cougho dry skino shortness of breatho decreased appetiteMEKINIST can cause new or worsening high blood pressure (hypertension). Your healthcare provider should check your blood pressure during treatment with MEKINIST. Call your healthcare provider right away if you develop high blood pressure, your blood pressure worsens, or you have severe headache, lightheadedness, blurry vision, or dizziness.MEKINIST may cause fertility problems in females. This could affect your ability to become pregnant. Talk to your healthcare provider if this is concern for you.These are not all the possible side effects of MEKINIST.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.You may also report side effects to Novartis Pharmaceuticals Corporation at 1-888-669-6682.How should store MEKINIST Store MEKINIST in the refrigerator between 36F to 46F (2C to 8C). Keep MEKINIST dry and away from moisture and light. The bottle of MEKINIST contains desiccant packet to help keep your medicine dry. Do not throw away the desiccant packet. Keep MEKINIST in its original bottle. Do not place tablets in pill box. Safely throw away MEKINIST that is out of date or no longer needed.Keep MEKINIST and all medicine out of the reach of children.General information about the safe and effective use of MEKINIST.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use MEKINIST for condition for which it was not prescribed. Do not give MEKINIST to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about MEKINIST that is written for health professionals.What are the ingredients in MEKINISTActive ingredient: trametinibInactive ingredients:Tablet Core: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate (vegetable source), mannitol, microcrystalline cellulose, sodium lauryl sulfate.Tablet Coating: hypromellose, iron oxide red (2 mg tablets), iron oxide yellow (0.5 mg tablets), polyethylene glycol, polysorbate 80 (2 mg tablets), titanium dioxide.Distributed by:Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936For more information, go to www.MEKINIST.com or call 1-888-669-6682.(C) NovartisT2021-172. new wart skin sore or reddish bump that bleeds or does not heal change in size or color of mole. alone or in combination with medicine called dabrafenib to treat type of skin cancer called melanoma: that has spread to other parts of the body or cannot be removed by surgery, and that has certain type of abnormal BRAF gene.. in combination with dabrafenib, to help prevent melanoma that has certain type of abnormal BRAF gene from coming back after the cancer has been removed by surgery.. in combination with dabrafenib to treat type of lung cancer called non-small cell lung cancer (NSCLC) that has spread to other parts of the body, and that has certain type of abnormal BRAF gene.. in combination with dabrafenib to treat type of thyroid cancer called anaplastic thyroid cancer (ATC) that has spread to other parts of the body and you have no satisfactory treatment options, and that has certain type of abnormal BRAF gene.. have had bleeding problems or blood clots have stomach problems have inflammation of the colon have heart problems have eye problems have lung or breathing problems have high blood pressure (hypertension) have liver or kidney problems have diabetes are male (including one who has had vasectomy) with female partner of reproductive potential. Males (including those who have had vasectomy) should use condoms during sexual intercourse during treatment with MEKINIST and for at least months after your last dose of MEKINIST.. are pregnant or plan to become pregnant. MEKINIST can harm your unborn baby. Females who are able to become pregnant should use effective birth control (contraception) during treatment with MEKINIST and for months after your last dose of MEKINIST. Talk to your healthcare provider about birth control methods that may be right for you during this time. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with MEKINIST. are breastfeeding or plan to breastfeed. It is not known if MEKINIST passes into your breast milk. Do not breastfeed during treatment and for months after your last dose of MEKINIST. Talk to your healthcare provider about the best way to feed your baby during this time.. Take MEKINIST exactly as your healthcare provider tells you to take it. Do not change your dose or stop MEKINIST unless your healthcare provider tells you. Your healthcare provider may change your dose of MEKINIST, temporarily stop, or completely stop your treatment with MEKINIST if you develop certain side effects. Take MEKINIST one time day, about every 24 hours. Take MEKINIST at least hour before or hours after meal. If you miss dose, take it as soon as you remember. If it is less than 12 hours before your next scheduled dose, skip the missed dose. Just take the next dose at your regular time.. See What is the most important information should know about MEKINIST. bleeding problems. MEKINIST can cause serious bleeding problems, especially in your brain or stomach, that can lead to death. Call your healthcare provider and get medical help right away if you have any signs of bleeding, including: headaches, dizziness, or feeling weak cough up blood or blood clots vomit blood or your vomit looks like coffee grounds red or black stools that look like tar inflammation of the intestines, or tears (perforation) of the stomach or intestines. MEKINIST can cause inflammation of your intestines, or tears in the stomach or intestines that can lead to death. Tell your healthcare provider immediately if you have any of the following symptoms: bleeding. See bleeding problems above. diarrhea (loose stools) or more bowel movements than usual stomach-area (abdomen) pain or tenderness fever nausea blood clots. MEKINIST can cause blood clots in your arms or legs, which can travel to your lungs and can lead to death. Get medical help right away if you have the following symptoms: chest pain sudden shortness of breath or trouble breathing pain in your legs with or without swelling swelling in your arms or legs cool pale arm or leg heart problems, including heart failure. Your healthcare provider should check your heart function before and during treatment with MEKINIST. Call your healthcare provider right away if you have any of the following signs and symptoms of heart problem: feeling like your heart is pounding or racing shortness of breath swelling of your ankles and feet feeling lightheaded eye problems. MEKINIST can cause severe eye problems that might lead to blindness. Call your healthcare provider right away if you get these symptoms of eye problems: blurred vision, loss of vision, or other vision changes see color dots halo (seeing blurred outline around objects) eye pain, swelling, or redness lung or breathing problems. MEKINIST can cause lung or breathing problems. Tell your healthcare provider if you have any new or worsening symptoms of lung or breathing problems, including: shortness of breath cough fever. Fever is common during treatment with MEKINIST and dabrafenib, but it may also be serious. When taking MEKINIST with dabrafenib, fever may happen more often or may be more severe. In some cases, chills or shaking chills, too much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems may happen with the fever. Call your healthcare provider right away if you get fever during treatment with MEKINIST. Your healthcare provider may temporarily or permanently stop your treatment, or change your dose of MEKINIST with dabrafenib if you have fevers. Your healthcare provider will treat you as needed for your fever and any signs and symptoms of infection, and should check your kidney function during and after you have had severe fever.. serious skin reactions. Skin rash is common side effect of MEKINIST. MEKINIST can also cause other skin reactions. In some cases these rashes and other skin reactions can be severe or serious, and may need to be treated in hospital or lead to death.Tell your healthcare provider if you get skin rash or acne that bothers you or worsens. Tell your healthcare provider right away if you develop any of the following signs or symptoms of severe skin reaction, including: increased blood sugar (hyperglycemia). Some people may develop high blood sugar or worsening diabetes during treatment with MEKINIST and dabrafenib. If you are diabetic, your healthcare provider should check your blood sugar levels closely during treatment with MEKINIST and dabrafenib. Your diabetes medicine may need to be changed. Tell your healthcare provider if you have any of the following symptoms of severe high blood sugar: increased thirst urinating more often than normal or urinating an increased amount of urine rash. diarrhea. Call your healthcare provider if you get severe diarrhea.. swelling of the face, arms, or legs. Store MEKINIST in the refrigerator between 36F to 46F (2C to 8C). Keep MEKINIST dry and away from moisture and light. The bottle of MEKINIST contains desiccant packet to help keep your medicine dry. Do not throw away the desiccant packet. Keep MEKINIST in its original bottle. Do not place tablets in pill box. Safely throw away MEKINIST that is out of date or no longer needed.

USE IN SPECIFIC POPULATIONS SECTION.

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). 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 SummaryBased on its mechanism of action [see Clinical Pharmacology (12.1)] and findings from animal reproduction studies, MEKINIST can cause fetal harm when administered to 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 clinical dose (see Data). Advise pregnant women 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% to 4% and 15% to 20%, respectively.DataAnimal DataIn 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 dose based on area under the curve (AUC)]. In rats, at 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 SummaryThere 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, advise women not to breastfeed during treatment with MEKINIST and for months following the last dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating MEKINIST.ContraceptionBased 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 )]. FemalesAdvise female patients of reproductive potential to use effective contraception during treatment with MEKINIST and for months after the last dose.MalesTo 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 at least months after the last dose.InfertilityFemalesAdvise 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 single agent or in combination with dabrafenib have not been established in pediatric patients.Juvenile Animal Toxicity DataIn 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, 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 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, patients who received starting dose of 1.5 mg orally once daily and two patients who received starting dose of mg orally once daily did not experience dose limiting toxicities (DLTs) during the first cycle of therapy.In patients with severe hepatic impairment, patients who received starting dose of mg orally once daily did not experience DLTs during the first cycle; one patient who received starting dose of 1.5 mg orally once daily experienced DLT (grade 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. New Primary Malignancies, Cutaneous, and Non-Cutaneous, can occur when MEKINIST is used with dabrafenib. Monitor patients for new malignancies prior to initiation of therapy, while on therapy, and following discontinuation of treatment. (5.1)Hemorrhage: Major hemorrhagic events can occur. Monitor for signs and symptoms of bleeding. (5.2)Colitis and Gastrointestinal Perforation: Colitis and gastrointestinal perforation can occur in patients receiving MEKINIST. (5.3)Venous Thromboembolism: Deep vein thrombosis (DVT) and pulmonary embolism (PE) can occur in patients receiving MEKINIST. (5.4, 2.7)Cardiomyopathy: Assess left ventricular ejection fraction (LVEF) before treatment, after one month of treatment, then every to months thereafter. (5.5, 2.7)Ocular Toxicities: Perform ophthalmologic evaluation for any visual disturbances. For Retinal Vein Occlusion (RVO), permanently discontinue MEKINIST. (5.6, 2.7)Interstitial Lung Disease (ILD): Withhold MEKINIST for new or progressive unexplained pulmonary symptoms. Permanently discontinue MEKINIST for treatment-related ILD or pneumonitis. (5.7, 2.7)Serious Febrile Reactions can occur when MEKINIST is used with dabrafenib. (5.8, 2.7)Serious Skin Toxicities: Monitor for skin toxicities and for secondary infections. Permanently discontinue MEKINIST for intolerable Grade 2, or Grade or rash not improving within weeks despite interruption of MEKINIST. Permanently discontinue for severe cutaneous adverse reactions (SCARs). (5.9, 2.7)Hyperglycemia: Monitor serum glucose levels in patients with preexisting diabetes or hyperglycemia. (5.10)Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to fetus and to use effective contraception. (5.12, 8.1, 8.3). New Primary Malignancies, Cutaneous, and Non-Cutaneous, can occur when MEKINIST is used with dabrafenib. Monitor patients for new malignancies prior to initiation of therapy, while on therapy, and following discontinuation of treatment. (5.1). Hemorrhage: Major hemorrhagic events can occur. Monitor for signs and symptoms of bleeding. (5.2). Colitis and Gastrointestinal Perforation: Colitis and gastrointestinal perforation can occur in patients receiving MEKINIST. (5.3). Venous Thromboembolism: Deep vein thrombosis (DVT) and pulmonary embolism (PE) can occur in patients receiving MEKINIST. (5.4, 2.7). Cardiomyopathy: Assess left ventricular ejection fraction (LVEF) before treatment, after one month of treatment, then every to months thereafter. (5.5, 2.7). Ocular Toxicities: Perform ophthalmologic evaluation for any visual disturbances. For Retinal Vein Occlusion (RVO), permanently discontinue MEKINIST. (5.6, 2.7). Interstitial Lung Disease (ILD): Withhold MEKINIST for new or progressive unexplained pulmonary symptoms. Permanently discontinue MEKINIST for treatment-related ILD or pneumonitis. (5.7, 2.7). Serious Febrile Reactions can occur when MEKINIST is used with dabrafenib. (5.8, 2.7). Serious Skin Toxicities: Monitor for skin toxicities and for secondary infections. Permanently discontinue MEKINIST for intolerable Grade 2, or Grade or rash not improving within weeks despite interruption of MEKINIST. Permanently discontinue for severe cutaneous adverse reactions (SCARs). (5.9, 2.7). Hyperglycemia: Monitor serum glucose levels in patients with preexisting diabetes or hyperglycemia. (5.10). Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to fetus and to use effective contraception. (5.12, 8.1, 8.3). 5.1 New Primary Malignancies. Cutaneous MalignanciesAcross clinical trials of MEKINIST administered with dabrafenib, cutaneous squamous cell carcinomas (cuSCCs) and keratoacanthomas occurred in 2% of patients. Basal cell carcinoma and new primary melanoma occurred in 3% and 1% of patients, respectively.Perform dermatologic evaluations prior to initiation of MEKINIST when used with dabrafenib, every months while on therapy, and for up to months following discontinuation of the combination.Non-Cutaneous MalignanciesBased on its mechanism of action, dabrafenib may promote growth and development of malignancies with activation of RAS through mutation or other mechanisms; refer to the prescribing information for dabrafenib. Across clinical trials of MEKINIST administered with dabrafenib, non-cutaneous malignancies occurred in 1% of patients.Monitor patients receiving MEKINIST and dabrafenib closely for signs or symptoms of non-cutaneous malignancies. No dose modification is required for MEKINIST in patients who develop non-cutaneous malignancies.. 5.2 Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in critical area or organ, can occur with MEKINIST. Fatal cases have been reported.Across clinical trials of MEKINIST administered with dabrafenib, hemorrhagic events occurred in 17% of patients. Gastrointestinal hemorrhage occurred in 3% of patients who received MEKINIST administered with dabrafenib. Intracranial hemorrhage occurred in 0.6% of patients who received MEKINIST administered with dabrafenib. Fatal hemorrhage occurred in 0.5% of patients who received MEKINIST administered with dabrafenib. The fatal events were cerebral hemorrhage and brainstem hemorrhage.Permanently discontinue MEKINIST for all Grade hemorrhagic events and for any Grade hemorrhagic events that do not improve. Withhold MEKINIST for Grade hemorrhagic events; if improved, resume at the next lower dose level.. 5.3 Colitis and Gastrointestinal Perforation. Colitis and gastrointestinal perforation, including fatal outcomes, have been reported in patients taking MEKINIST as single agent and when administered with dabrafenib. Across clinical trials of MEKINIST, colitis occurred in 1% of patients and gastrointestinal perforation occurred in 1% of patients. Across clinical trials of MEKINIST administered with dabrafenib, colitis occurred in 1% of patients and gastrointestinal perforation occurred in 1% of patients.Monitor patients closely for colitis and gastrointestinal perforations.. 5.4 Venous Thromboembolic Events. Across clinical trials of MEKINIST administered with dabrafenib, deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 2% of patients.Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue MEKINIST for life-threatening PE. Withhold MEKINIST for uncomplicated DVT and PE for up to weeks; if improved, MEKINIST may be resumed at lower dose level [see Dosage and Administration (2.7)].. 5.5 Cardiomyopathy. Cardiomyopathy, including cardiac failure, can occur with MEKINIST.Across clinical trials of MEKINIST administered with dabrafenib, cardiomyopathy, defined as decrease in left ventricular ejection fraction (LVEF) >= 10% from baseline and below the institutional lower limit of normal (LLN), occurred in 6% of patients. Development of cardiomyopathy resulted in dose interruption or discontinuation of MEKINIST in 3% and 1% of patients, respectively. Cardiomyopathy resolved in 45 of 50 patients who received MEKINIST administered with dabrafenib.Assess LVEF by echocardiogram or multi-gated acquisition (MUGA) scan before initiation of MEKINIST as single agent or with dabrafenib, one month after initiation, and then at 2- to 3-month intervals while on treatment. For an asymptomatic absolute decrease in LVEF of 10% or greater from baseline that is below the LLN, withhold MEKINIST for up to weeks. If improved to normal LVEF value, resume at lower dose. If no improvement to normal LVEF value within weeks, permanently discontinue MEKINIST. For symptomatic cardiomyopathy or an absolute decrease in LVEF of greater than 20% from baseline that is below LLN, permanently discontinue MEKINIST [see Dosage and Administration (2.7)].. 5.6 Ocular Toxicities. Retinal Vein OcclusionAcross clinical trials with MEKINIST monotherapy, the incidence of retinal vein occlusion (RVO) was 0.6%. Across clinical trials of MEKINIST administered with dabrafenib, there were no cases of RVO. RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO [see Dosage and Administration (2.7)].Retinal Pigment Epithelial DetachmentRetinal pigment epithelial detachment (RPED) can occur with MEKINIST. Retinal detachments may be bilateral and multifocal, occurring in the central macular region of the retina or elsewhere in the retina. In melanoma and NSCLC trials, routine monitoring of patients to detect asymptomatic RPED was not conducted; therefore, the true incidence of this finding is unknown.Perform ophthalmological evaluation periodically and at any time patient reports visual disturbances. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within weeks, resume MEKINIST at same or reduced dose. If no improvement after weeks, resume at reduced dose or permanently discontinue MEKINIST [see Dosage and Administration (2.7)].. 5.7 Interstitial Lung Disease/Pneumonitis. Across clinical trials of MEKINIST monotherapy, interstitial lung disease or pneumonitis occurred in 2% of patients. Across clinical trials of MEKINIST administered with dabrafenib, ILD or pneumonitis occurred in 1% of patients.Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings, including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis [see Dosage and Administration (2.7)].. 5.8 Serious Febrile Reactions. Serious febrile reactions and fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure, can occur when MEKINIST is administered with dabrafenib.Across clinical trials of MEKINIST administered with dabrafenib, fever occurred in 58% of patients. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration or renal failure occurred in 5% of patients. Fever was complicated by hypotension in 4%, dehydration in 3%, syncope in 2%, renal failure in 1%, and severe chills/rigors in 1% of patients.Withhold MEKINIST when used as monotherapy, and both MEKINIST and dabrafenib when used in combination, if the patients temperature is >= 100.4F. In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia [see Adverse Reactions (6.1)]. Fever may be complicated by hypotension, rigors or chills, dehydration, or renal failure. Evaluate for signs and symptoms of infection, and monitor serum creatinine and other evidence of renal function during and following severe pyrexia. If appropriate, MEKINIST, or both MEKINIST and dabrafenib when used in combination, may be restarted if the patient has recovered from the febrile reaction for at least 24 hours, either at same or lower dose [see Dosage and Administration (2.7)]. Administer antipyretics as secondary prophylaxis when resuming MEKINIST if patient had prior episode of severe febrile reaction or fever associated with complications. Administer corticosteroids (e.g., prednisone 10 mg daily) for at least days for second or subsequent pyrexia if temperature does not return to baseline within days of onset of pyrexia, or for pyrexia associated with complications, such as dehydration, hypotension, renal failure, or severe chills/rigors, and there is no evidence of active infection.. 5.9 Serious Skin Toxicities. Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with MEKINIST administered with dabrafenib [see Adverse Reactions (6.2)].Across clinical trials of MEKINIST administered with dabrafenib, other serious skin toxicity occurred in 1% of patients.Monitor for new or worsening serious skin reactions. Permanently discontinue MEKINIST for SCARs [see Dosage and Administration (2.7)]. For other skin toxicities, withhold MEKINIST for intolerable or severe skin toxicity. Resume MEKINIST at lower dose in patients with improvement or recovery from skin toxicity within weeks. Permanently discontinue MEKINIST if skin toxicity has not improved in weeks [see Dosage and Administration (2.7)].. 5.10 Hyperglycemia. Across clinical trials of MEKINIST administered with dabrafenib, 15% of patients with history of diabetes who had received MEKINIST with dabrafenib required more intensive hypoglycemic therapy. Grade and Grade hyperglycemia occurred in 2% of patients.Monitor serum glucose levels upon initiation and as clinically appropriate when MEKINIST is administered with dabrafenib in patients with preexisting diabetes or hyperglycemia. Initiate or optimize anti-hyperglycemic medications as clinically indicated.. 5.11 Risks Associated With Combination Treatment. MEKINIST is indicated for use in combination with dabrafenib. Review the prescribing information for dabrafenib for information on the serious risks of dabrafenib prior to initiation of MEKINIST with dabrafenib.. 5.12 Embryo-Fetal Toxicity. Based on findings from animal studies and its mechanism of action, MEKINIST can cause fetal harm when administered to pregnant woman. 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. Advise pregnant women of the potential risk to fetus. Advise female patients of reproductive potential to use effective contraception during treatment with MEKINIST and for months after treatment [see Use in Specific Populations (8.1, 8.3)].

INSTRUCTIONS FOR USE SECTION.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.Revised: May 2023INSTRUCTIONS FOR USEMEKINIST(R) (MEK-in-ist)(trametinib)for oral solutionThis Instructions for Use contains information on how to give MEKINIST.Important information you need to know before giving MEKINIST oral solutionMEKINIST for oral solution should only be given by caregiver.Read this Instructions for Use carefully before you start giving MEKINIST for the first time and each time you get 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 childs 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 dose of MEKINIST correctly. Always give MEKINIST exactly as the healthcare provider tells you to.If you have any questions about how to give 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 powder, contact the healthcare provider or pharmacist.If at any time MEKINIST oral solution gets on your or your childs skin, wash the area well with soap and water.If at any time MEKINIST oral solution gets in your or your childs 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 solutionStore the bottle of oral solution at room temperature below 25C (77F).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 syringeStore the oral syringe with the MEKINIST oral solution.Keep oral syringes out of the reach of children.Section A. Measuring and giving dose of MEKINIST oral solutionGather your supplies:To give dose of MEKINIST oral solution, you will need: bottle adapter (already inserted into the bottle neck)1 amber bottle containing oral solution1 reusable oral syringeCall the healthcare provider or pharmacist if you do not have one or more of these texts.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 dose of MEKINIST oral solution.Step 2. Place your supplies on 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 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 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 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 dose of MEKINIST oral solution by mouth, move to step 12.If you are giving dose of MEKINIST oral solution through feeding tube, go to Section B.Step 12. Important: If giving dose of MEKINIST oral solution to 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 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 Cleaning the reusable oral syringe.SECTION B. Giving dose of MEKINIST through feeding tubeThis section is for use only if you are going to give dose of MEKINIST oral solution through feeding tube.Before giving dose of MEKINIST oral solution through feeding tube, carefully read the following information, then move to step 1. MEKINIST oral solution may be given through feeding tube, as directed by the healthcare provider.Only use nasogastric (NG) or gastric (G-tube) feeding tube with minimum size of French 4. Always use the 20mL oral syringe provided in this pack to give 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 manufacturers instructions right away before giving dose of MEKINIST oral solution.Step 2. Follow steps through 11 in Section A, then move to step 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 through 5.Step 6. Flush the tube again according to the manufacturers instructions.Step 7. Go to Section for instructions on Cleaning the reusable oral syringe.SECTION C. Cleaning the reusable oral syringeNote: Keep the oral syringe separate from other kitchen texts.Step 1. Fill 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 to 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 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 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 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 sealable plastic bag, such as food storage bag.4. Wipe all surfaces exposed to the solution with alcohol wipes or pour rubbing alcohol onto 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 CorporationEast Hanover, New Jersey 07936 (C) Novartis T2023-31. MEKINIST for oral solution should only be given by caregiver.. Read this Instructions for Use carefully before you start giving MEKINIST for the first time and each time you get 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 childs 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 dose of MEKINIST correctly. Always give MEKINIST exactly as the healthcare provider tells you to.. If you have any questions about how to give 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 powder, contact the healthcare provider or pharmacist.. If at any time MEKINIST oral solution gets on your or your childs skin, wash the area well with soap and water.. If at any time MEKINIST oral solution gets in your or your childs 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. Store the bottle of oral solution at room temperature below 25C (77F).. 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.. Store the oral syringe with the MEKINIST oral solution.. Keep oral syringes out of the reach of children.. Gather your supplies:. bottle adapter (already inserted into the bottle neck). amber bottle containing oral solution. reusable oral syringe. 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.. If you have powder, do not give MEKINIST and contact your pharmacist or healthcare provider.. If you have solution, continue to step below.. Your pharmacist prepared the solution to an exact concentration. Do not add any more water to the solution you received from the pharmacy.. 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.. If foam appears, put the amber bottle on flat surface and let it sit there until the foam disappears.. MEKINIST oral solution may be given through feeding tube, as directed by the healthcare provider.. Only use nasogastric (NG) or gastric (G-tube) feeding tube with minimum size of French 4. Always use the 20mL oral syringe provided in this pack to give 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.. Store the oral syringe with the MEKINIST oral solution.. Keep oral syringes out of the reach of children.. 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 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.. 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.