Trametinib

The recommended dosage of MEKINIST in adult patients is 2 mg orally once daily. The recommended dosage for MEKINIST in pediatric patients is based on body weight. ( 2 )

2.1 Patient Selection Melanoma Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with MEKINIST as a single agent or in combination with dabrafenib [see Clinical Studies (14.1, 14.2)] . Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics . NSCLC Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.3)] . Information on FDA-approved tests for the detection of BRAF V600E mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics . ATC Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.4)] . Information on FDA-approved tests for the detection of BRAF V600E mutations in ATC is available at: http://www.fda.gov/CompanionDiagnostics . Solid Tumors Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.6)] . An FDA-approved test for the detection of BRAF V600E mutation in solid tumors other than melanoma and NSCLC is not currently available. Low-Grade Glioma Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.7)] . An FDA-approved test for the detection of BRAF V600E mutation in LGG is not currently available.

2.2 Recommended Dosage MEKINIST Tablets Adult Patients The recommended dosage for MEKINIST tablets in adult patients is 2 mg orally taken once daily [see Dosage and Administration (2.3)] . Pediatric Patients The recommended dosage for MEKINIST tablets in pediatric patients who weigh at least 26 kg is based on body weight (Table 1) [see Dosage and Administration (2.3)] . A recommended dosage of MEKINIST tablets has not been established in patients who weigh less than 26 kg. Table 1. Recommended Dosage for MEKINIST Tablets in Pediatric Patients (Weight-based) Body Weight Recommended Dosage 26 to 37 kg 1 mg orally once daily 38 to 50 kg 1.5 mg orally once daily 51 kg or greater 2 mg orally once daily MEKINIST for Oral Solution Adult and Pediatric Patients The recommended dosage for MEKINIST for oral solution for adult and pediatric patients is based on body weight (Table 2) [see Dosage and Administration (2.3)] . Table 2. Recommended Dosage for MEKINIST for Oral Solution in Adult and Pediatric Patients (Weight-based) Body Weight Recommended Dosage Total Volume of Oral Solution Once Daily (Trametinib Content) 8 kg 0.3 mg (6 mL) 9 kg 0.35 mg (7 mL) 10 kg 0.35 mg (7 mL) 11 kg 0.4 mg (8 mL) 12 to 13 kg 0.45 mg (9 mL) 14 to 17 kg 0.55 mg (11 mL) 18 to 21 kg 0.7 mg (14 mL) 22 to 25 kg 0.85 mg (17 mL) 26 to 29 kg 0.9 mg (18 mL) 30 to 33 kg 1 mg (20 mL) 34 to 37 kg 1.15 mg (23 mL) 38 to 41 kg 1.25 mg (25 mL) 42 to 45 kg 1.4 mg (28 mL) 46 to 50 kg 1.6 mg (32 mL) ≥ 51 kg 2 mg (40 mL) Duration of Treatment The recommended duration of treatment for patients with unresectable or metastatic melanoma or solid tumors, metastatic NSCLC, or locally advanced or metastatic anaplastic thyroid cancer is until disease progression or unacceptable toxicity. The recommended duration of treatment in the adjuvant melanoma setting is until disease recurrence or unacceptable toxicity for up to 1 year. The recommended duration of treatment for pediatric patients with LGG is until disease progression or until unacceptable toxicity. Combination Therapy with Dabrafenib Refer to the dabrafenib prescribing information for recommended dabrafenib dosing information.

2.3 Administration Take MEKINIST at the same time each day, approximately 24 hours apart. Do not take a missed dose of MEKINIST within 12 hours of the next dose of MEKINIST. If vomiting occurs after MEKINIST administration, do not take an additional dose. Take the next dose at its scheduled time. MEKINIST Tablets Take MEKINIST tablets on an empty stomach (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3)] . Do not crush or break MEKINIST tablets. MEKINIST for Oral Solution MEKINIST powder for oral solution must be reconstituted by a pharmacist or other healthcare provider prior to dispensing to the patient. MEKINIST for oral solution is intended for administration by a caregiver. Prior to use of the oral solution, ensure caregivers receive training on proper dosing and administration of MEKINIST for oral solution. When administering MEKINIST for oral solution as a single agent, take the oral solution with a low-fat meal or on an empty stomach [see Clinical Pharmacology (12.3)] . When coadministering with dabrafenib, take the MEKINIST oral solution on an empty stomach (at least 1 hour before or 2 hours after a meal). Breastfeeding and/or baby formula may be given on demand if a pediatric patient is unable to tolerate the fasting conditions [see Clinical Pharmacology (12.3)] . Preparation and Administration To prepare MEKINIST for oral solution, tap the bottle until powder flows freely. Add 90 mL distilled or purified water to the powder in the bottle and invert or gently shake the bottle with re-attached cap for up to 5 minutes until powder is fully dissolved yielding a clear solution. Separate the bottle adapter from the oral syringe. Insert bottle adapter into bottle neck after reconstitution of the solution. Write the discard after date. Once reconstituted, MEKINIST for oral solution can be used for 35 days. The final concentration of the solution is 0.05 mg/mL. Administer MEKINIST for oral solution from an oral syringe or feeding tube (4 French gauge or larger). After reconstitution, store in original bottle below 25°C (77°F) and do not freeze.

2.4 Dosage Modifications for Adverse Reactions Dose reductions for adverse reactions associated with MEKINIST are presented in Tables 3 and 4. Table 3. Recommended Dosage Reductions for MEKINIST Tablets for Adverse Reactions Recommended Dosage 1 mg orally once daily 1.5 mg orally once daily 2 mg orally once daily First dose reduction 0.5 mg orally once daily 1 mg orally once daily 1.5 mg orally once daily Second dose reduction N/A 0.5 mg orally once daily 1 mg orally once daily Subsequent modification Permanently discontinue MEKINIST tablets if unable to tolerate a maximum of two dose reductions. Table 4. Recommended Dosage Reductions for MEKINIST for Oral Solution for Adverse Reactions Body Weight (Recommended dosage once daily) First Dose Reduction (Administer once daily) Second Dose Reduction (Administer once daily) 8 kg [0.3 mg (6 mL)] 0.25 mg (5 mL) 0.15 mg (3 mL) 9 kg [0.35 mg (7 mL)] 0.25 mg (5 mL) 0.2 mg (4 mL) 10 kg [0.35 mg (7 mL)] 0.25 mg (5 mL) 0.2 mg (4 mL) 11 kg [0.4 mg (8 mL)] 0.3 mg (6 mL) 0.2 mg (4 mL) 12 to 13 kg [0.45 mg (9 mL)] 0.35 mg (7 mL) 0.25 mg (5 mL) 14 to 17 kg [0.55 mg (11 mL)] 0.4 mg (8 mL) 0.3 mg (6 mL) 18 to 21 kg [0.7 mg (14 mL)] 0.55 mg (11 mL) 0.35 mg (7 mL) 22 to 25 kg [0.85 mg (17 mL)] 0.65 mg (13 mL) 0.45 mg (9 mL) 26 to 29 kg [0.9 mg (18 mL)] 0.7 mg (14 mL) 0.45 mg (9 mL) 30 to 33 kg [1 mg (20 mL)] 0.75 mg (15 mL) 0.5 mg (10 mL) 34 to 37 kg [1.15 mg (23 mL)] 0.85 mg (17 mL) 0.6 mg (12 mL) 38 to 41 kg [1.25 mg (25 mL)] 0.95 mg (19 mL) 0.65 mg (13 mL) 42 to 45 kg [1.4 mg (28 mL)] 1.05 mg (21 mL) 0.7 mg (14 mL) 46 to 50 kg [1.6 mg (32 mL)] 1.2 mg (24 mL) 0.8 mg (16 mL) ≥ 51 kg [2 mg (40 mL)] 1.5 mg (30 mL) 1 mg (20 mL) Permanently discontinue MEKINIST for oral solution if unable to tolerate a maximum of two dose reductions. Dosage modifications for adverse reactions associated with MEKINIST are presented in Table 5. Table 5. Recommended Dosage Modifications for MEKINIST for Adverse Reactions a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. b See Tables 3 and 4 for recommended dose reductions of MEKINIST. c Dose modifications are not recommended for MEKINIST when administered with dabrafenib for the following adverse reactions of dabrafenib: non-cutaneous malignancies and uveitis. Dose modification of MEKINIST is not required for new primary cutaneous malignancies. Severity of Adverse Reaction a Dosage Modification for MEKINIST b Hemorrhage [see Warnings and Precautions (5.2)] Grade 3 Withhold MEKINIST. If improved, resume MEKINIST at lower dose. If not improved, permanently discontinue MEKINIST. Grade 4 Permanently discontinue MEKINIST. Venous Thromboembolic Events [see Warnings and Precautions (5.4)] Uncomplicated deep venous thrombosis (DVT) or pulmonary embolism (PE) Withhold MEKINIST for up to 3 weeks. If improved to Grade 0-1, resume MEKINIST at lower dose. If not improved, permanently discontinue MEKINIST. Life-threatening PE Permanently discontinue MEKINIST. Cardiomyopathy [see Warnings and Precautions (5.5)] Asymptomatic, absolute decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline that is below the institutional lower limit of normal (LLN) Withhold MEKINIST for up to 4 weeks. If improved to normal LVEF value, resume MEKINIST at lower dose. If not improved to normal LVEF value, permanently discontinue MEKINIST. Symptomatic cardiomyopathy Absolute decrease in LVEF of greater than 20% from baseline that is below the institutional LLN Permanently discontinue MEKINIST. Ocular Toxicities [see Warnings and Precautions (5.6)] Retinal pigment epithelial detachments (RPED) Withhold MEKINIST for up to 3 weeks. If improved, resume MEKINIST at same or lower dose. If not improved, permanently discontinue MEKINIST or resume MEKINIST at lower dose. Retinal vein occlusion (RVO) Permanently discontinue MEKINIST. Pulmonary [see Warnings and Precautions (5.7)] Interstitial lung disease (ILD)/pneumonitis Permanently discontinue MEKINIST. Febrile Reactions [see Warnings and Precautions (5.8)] Fever of 100.4°F to 104°F (or first symptoms in case of recurrence) Withhold MEKINIST until fever resolves, then resume MEKINIST at same or lower dose. Fever higher than 104°F Fever complicated by rigors, hypotension, dehydration, or renal failure Withhold MEKINIST until febrile reactions resolve for at least 24 hours, then resume MEKINIST at lower dose. Or Permanently discontinue MEKINIST. Skin Toxicities [see Warnings and Precautions (5.9)] Intolerable Grade 2 Grade 3 or 4 Withhold MEKINIST for up to 3 weeks. If improved, resume MEKINIST at lower dose. If not improved, permanently discontinue MEKINIST. Severe cutaneous adverse reactions (SCARs) Permanently discontinue MEKINIST. Other Adverse Reactions c Intolerable Grade 2 Any Grade 3 Withhold MEKINIST. If improved to Grade 0-1, resume MEKINIST at lower dose. If not improved, permanently discontinue MEKINIST. First occurrence of any Grade 4 Withhold MEKINIST until improves to Grade 0-1, then resume MEKINIST at lower dose. Or Permanently discontinue MEKINIST. Recurrent Grade 4 Permanently discontinue MEKINIST. Refer to the dabrafenib prescribing information for dose modifications for adverse reactions associated with dabrafenib.

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

5.1 New Primary Malignancies Cutaneous Malignancies MEKINIST Administered with Dabrafenib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , 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. MEKINIST Administered with Dabrafenib (Pediatric) : In the pooled safety population, new primary melanoma occurred in < 1% of patients. Perform dermatologic evaluations prior to initiation of MEKINIST when used with dabrafenib, every 2 months while on therapy, and for up to 6 months following discontinuation of the combination. Non-Cutaneous Malignancies Based 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. In the pooled safety population 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 hemorrhage defined as symptomatic bleeding in a critical area or organ, can occur with MEKINIST. Fatal cases have been reported. MEKINIST Administered with Dabrafenib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , hemorrhagic events occurred in 17% of patients; gastrointestinal hemorrhage occurred in 3% of patients; intracranial hemorrhage occurred in 0.6% of patients; fatal hemorrhage occurred in 0.5% of patients. The fatal events were cerebral hemorrhage and brainstem hemorrhage. MEKINIST Administered with Dabrafenib (Pediatric) : In the pooled safety population, hemorrhagic events occurred in 25% of patients; the most common type of bleeding was epistaxis (16%). Serious events of bleeding occurred in 3.6% of patients and included gastrointestinal hemorrhage (1.2%), cerebral hemorrhage (0.6%), uterine hemorrhage (0.6%), post-procedural hemorrhage (0.6%), and epistaxis (0.6%). Permanently discontinue MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold MEKINIST for Grade 3 hemorrhagic events; if improved, resume MEKINIST 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 Monotherapy and Administered with Dabrafenib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , colitis occurred in < 1% of patients and gastrointestinal perforation occurred in < 1% of patients. MEKINIST Administered with Dabrafenib (Pediatric) : In the pooled safety population, colitis events occurred in < 1% of patients. Monitor patients closely for colitis and gastrointestinal perforations.

5.4 Venous Thromboembolic Events MEKINIST Administered with Dabrafenib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 2% of patients. MEKINIST Administered with Dabrafenib (Pediatric) : In the pooled safety population, embolism events occurred in < 1% 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 3 weeks; if improved, MEKINIST may be resumed at a lower dose level [see Dosage and Administration (2.4)] .

5.5 Cardiomyopathy Cardiomyopathy, including cardiac failure, can occur with MEKINIST. MEKINIST Administered with Dabrafenib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , cardiomyopathy, defined as a 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. MEKINIST Administered with Dabrafenib (Pediatric) : In the pooled safety population, cardiomyopathy, defined as a decrease in LVEF ≥ 10% from baseline and below the institutional LLN, occurred in 9% of patients. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of MEKINIST as a 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 institutional LLN, withhold MEKINIST for up to 4 weeks. If improved to normal LVEF value, resume MEKINIST at a lower dose. If no improvement to normal LVEF value within 4 weeks, permanently discontinue MEKINIST. For symptomatic cardiomyopathy or an absolute decrease in LVEF of greater than 20% from baseline that is below the institutional LLN, permanently discontinue MEKINIST [see Dosage and Administration (2.4)] .

5.6 Ocular Toxicities Retinal Vein Occlusion In the pooled safety population [see Adverse Reactions (6.1)] of MEKINIST monotherapy, the incidence of retinal vein occlusion (RVO) was 0.6%. In the pooled safety population [see Adverse Reactions (6.1)] 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 (2.4)] . Retinal Pigment Epithelial Detachment Retinal 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. MEKINIST Administered with Dabrafenib (Adult) : In a clinical trial of 131 patients treated with MEKINIST in combination with dabrafenib that included ophthalmological monitoring with optical coherence tomography (OCT), RPED occurred in 5% of patients, including 1 patient with visual field defect symptoms. MEKINIST Administered with Dabrafenib (Pediatric) : In the pooled safety population, RPED events occurred in < 1% of patients. Perform ophthalmological evaluation periodically and at any time a patient reports visual disturbances. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at same or reduced dose. If no improvement after 3 weeks, resume MEKINIST at reduced dose or permanently discontinue MEKINIST [see Dosage and Administration (2.4)] .

5.7 Interstitial Lung Disease/Pneumonitis In the pooled safety population [see Adverse Reactions (6.1)] of MEKINIST monotherapy, interstitial lung disease or pneumonitis occurred in 2% of patients. In the pooled safety population [see Adverse Reactions (6.1)] 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 (2.4)] .

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. MEKINIST Administered with Dabrafenib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , 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. MEKINIST Administered with Dabrafenib (Pediatric) : In the pooled safety population [see Adverse Reactions (6.1)] , pyrexia occurred in 66% of patients. Withhold MEKINIST when used as monotherapy, and both MEKINIST and dabrafenib when used in combination, if the patient’s temperature is ≥ 100.4°F. 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 (2.4)] . Administer antipyretics as secondary prophylaxis when resuming MEKINIST if patient had a prior episode of severe febrile reaction or fever associated with complications. Administer corticosteroids (e.g., prednisone 10 mg daily) for at least 5 days for second or subsequent pyrexia if temperature does not return to baseline within 3 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)] . MEKINIST Administered with Dabrafenib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , other serious skin toxicity occurred in < 1% of patients. MEKINIST Administered with Dabrafenib (Pediatric) : In the pooled safety population, serious adverse events of skin and subcutaneous tissue disorders occurred in 1.8% of patients. Monitor for new or worsening serious skin reactions. Permanently discontinue MEKINIST for SCARs [see Dosage and Administration (2.4)] . For other skin toxicities, withhold MEKINIST for intolerable or severe skin toxicity. Resume MEKINIST at a lower dose in patients with improvement or recovery from skin toxicity within 3 weeks. Permanently discontinue MEKINIST if skin toxicity has not improved in 3 weeks [see Dosage and Administration (2.4)] .

5.10 Hyperglycemia MEKINIST Administered with Dabrafenib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , 15% of patients with a history of diabetes who had received MEKINIST with dabrafenib required more intensive hypoglycemic therapy. Grade 3 and Grade 4 hyperglycemia occurred in 2% of patients. MEKINIST Administered with Dabrafenib (Pediatric) : In the pooled safety population, Grade 3 and Grade 4 hyperglycemia events occurred in < 1% 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 Hemophagocytic Lymphohistiocytosis Hemophagocytic lymphohistiocytosis (HLH) has been observed in the post-marketing setting when MEKINIST was administered with dabrafenib. If HLH is suspected, interrupt treatment. If HLH is confirmed, discontinue treatment and initiate appropriate management of HLH.

5.13 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, MEKINIST can cause fetal harm when administered to a 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 adult clinical dose. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with MEKINIST and for 4 months after treatment [see Use in Specific Populations (8.1, 8.3)] .

The following clinically significant adverse reactions are described elsewhere in the labeling: New Primary Malignancies [see Warnings and Precautions ( 5.1)] Hemorrhage [see Warnings and Precautions (5.2)] Colitis and Gastrointestinal Perforation [see Warnings and Precautions (5.3)] Venous Thromboembolic Events [see Warnings and Precautions (5. 4 )] Cardiomyopathy [see Warnings and Precautions (5. 5 )] Ocular Toxicities [see Warnings and Precautions (5. 6 )] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5. 7 )] Serious Febrile Reactions [see Warnings and Precautions (5. 8 )] Serious Skin Toxicities [see Warnings and Precautions (5. 9 )] Hyperglycemia [see Warnings and Precautions (5. 10 )] Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions (5. 12 )] There are additional adverse reactions associated with dabrafenib. Refer to the dabrafenib prescribing information for additional information. Most common adverse reactions (≥ 20%) for MEKINIST as a single agent include rash, diarrhea, and lymphedema. ( 6.1 ) Most common adverse reactions (≥ 20%) for MEKINIST in combination with dabrafenib include: Unresectable or metastatic melanoma: pyrexia, nausea, rash, chills, diarrhea, vomiting, hypertension, and peripheral edema. ( 6.1 ) Adjuvant treatment of melanoma: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia. ( 6.1 ) NSCLC: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea. ( 6.1 ) Adult patients with solid tumors: pyrexia, fatigue, nausea, rash, chills, headache, hemorrhage, cough, vomiting, constipation, diarrhea, myalgia, arthralgia, and edema. ( 6.1 ) Pediatric patients with solid tumors: pyrexia, rash, vomiting, fatigue, dry skin, cough, diarrhea, dermatitis acneiform, headache, abdominal pain, nausea, hemorrhage, constipation, and paronychia. ( 6.1 ) Pediatric patients with LGG: pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, and dermatitis acneiform. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Safety Pools The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to MEKINIST 2 mg orally, once daily as a single agent in 329 patients with various solid tumors enrolled in METRIC, MEK113583, and MEK111054. Among these 329 patients who received MEKINIST as a single agent, 33% were exposed for 6 months or longer and 9% were exposed for greater than one year. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to MEKINIST 2 mg orally, once daily, administered in combination with dabrafenib 150 mg orally, twice daily, in 1087 patients enrolled in COMBI-d, COMBI-v, COMBI-AD, and BRF113928 with unresectable or metastatic melanoma, adjuvant melanoma, or NSCLC. Among these 1087 patients who received MEKINIST administered with dabrafenib, 70% were exposed for 6 months or longer and 21% were exposed for greater than one year. Pediatric Safety Pool The pediatric pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to weight-based MEKINIST orally, once daily administered in combination with dabrafenib in 166 pediatric patients across two trials: a multi-center, open-label, multi-cohort study in pediatric patients with BRAF V600E mutation-positive glioma requiring systemic therapy (Study G2201; n = 123) and a multi-center, open-label, multi-cohort study in pediatric patients with refractory or recurrent solid tumors with MAPK pathway activation (Study X2101; n = 43) [see Clinical Studies (14.6, 14.7)] . Among 166 patients who received MEKINIST administered with dabrafenib, 85% were exposed for 6 months and 69% were exposed for greater than one year. The most common (> 20%) adverse reactions were pyrexia (66%), rash (54%), headache (40%), vomiting (38%), musculoskeletal pain (36%), fatigue (31%), dry skin (31%), diarrhea (30%), nausea (26%), epistaxis and other bleeding events (25%), abdominal pain (24%), and dermatitis acneiform (23%). The most common (> 2%) Grade 3 or 4 laboratory abnormalities were decreased neutrophil count (20%), increased alanine aminotransferase (3.1%), and increased aspartate aminotransferase (3.1%). Unresectable or Metastatic BRAF V600E or V600K Mutation-Positive Melanoma MEKINIST as a Single Agent The safety of MEKINIST was evaluated in the METRIC study, a randomized, open-label trial of patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma who received MEKINIST (N = 211) 2 mg orally once daily or chemotherapy (N = 99) (either dacarbazine 1000 mg/m 2 every 3 weeks or paclitaxel 175 mg/m 2 every 3 weeks) [see Clinical Studies (14.1)] . Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, or current evidence of Class II or greater congestive heart failure (New York Heart Association) were excluded. The median duration of treatment with MEKINIST was 4.3 months. In this study, 9% of patients who received MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication. The most frequent adverse reactions resulting in permanent discontinuation of MEKINIST were decreased LVEF, pneumonitis, renal failure, diarrhea, and rash. Adverse reactions led to dose reductions in 27% of patients treated with MEKINIST. Rash and decreased LVEF were the most frequent reasons cited for dose reductions of MEKINIST. Table 6 and Table 7 present adverse reactions and laboratory abnormalities, respectively, of MEKINIST as a single agent in the METRIC study. Table 6. Select Adverse Reactions Occurring in ≥ 10% of Patients Who Received MEKINIST and at a Higher Incidence (≥ 5%) Than in the Chemotherapy Arm or ≥ 2% (Grades 3 or 4) Adverse Reactions in the METRIC Study a NCI CTCAE version 4.0. b Grade 4 adverse reactions limited to rash (n = 1) in trametinib arm and diarrhea (n = 1) in chemotherapy arm. c Includes stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation. d Includes abdominal pain, lower abdominal pain, upper abdominal pain, and abdominal tenderness. e Includes lymphedema, edema, and peripheral edema. f Includes epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, melena, vaginal hemorrhage, hemorrhoidal hemorrhage, hematuria, and conjunctival hemorrhage. Adverse Reactions MEKINIST Chemotherapy N = 211 N = 99 All Grades a (%) Grades 3 and 4 b (%) All Grades a (%) Grades 3 and 4 b (%) Skin and subcutaneous tissue Rash 57 8 10 0 Acneiform dermatitis 19 < 1 1 0 Dry skin 11 0 0 0 Pruritus 10 2 1 0 Paronychia 10 0 1 0 Gastrointestinal Diarrhea 43 0 16 2 Stomatitis c 15 2 2 0 Abdominal pain d 13 1 5 1 Vascular Lymphedema e 32 1 4 0 Hypertension 15 12 7 3 Hemorrhage f 13 < 1 0 0 Table 7. Laboratory Abnormalities Occurring at a Higher Incidence in Patients Who Received MEKINIST in the METRIC Study [Between-Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3 or 4) a ] Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Only Grade 3 adverse reactions were reported in either treatment arm. Laboratory Abnormality MEKINIST Chemotherapy N = 211 N = 99 All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) Increased AST 60 2 16 1 Hypoalbuminemia 42 2 23 1 Increased ALT 39 3 20 3 Anemia 38 2 26 3 Increased alkaline phosphatase 24 2 18 3 Other clinically important adverse reactions for MEKINIST in a pool of MEKINIST monotherapy clinical studies observed in less than 10% of patients who received MEKINIST were: Cardiac: Bradycardia, atrioventricular block, bundle branch block Gastrointestinal: Dry mouth Infections and Infestations: Folliculitis, rash pustular, cellulitis Musculoskeletal and Connective Tissue: Rhabdomyolysis Nervous System: Dizziness, dysgeusia, peripheral neuropathy Ocular: Blurred vision, dry eye MEKINIST with Dabrafenib The safety of MEKINIST when administered with dabrafenib was evaluated in 559 patients with previously untreated, unresectable or metastatic, BRAF V600 mutation-positive melanoma who received MEKINIST in two trials, the COMBI-d study (n = 209), a multi-center, double-blind, randomized (1:1), active-controlled trial and the COMBI-v study (n = 350), a multi-center, open-label, randomized (1:1), active-controlled trial. In both trials, patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. Both trials excluded patients with abnormal LVEF, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), history of RVO or RPED, QTcB interval ≥ 480 msec, uncontrolled hypertension, uncontrolled arrhythmias, active brain metastases, or known history of glucose-6-phosphate dehydrogenase deficiency [see Clinical Studies (14.1)] . Among these 559 patients, 197 (35%) were exposed to MEKINIST for > 6 months to 12 months while 185 (33%) were exposed to MEKINIST for > 1 year. The median age was 55 years (range: 18 to 91), 57% were male, and 98% were White, 72% had baseline ECOG performance status of 0 and 28% had ECOG performance status of 1, 64% had M1c disease, 35% had elevated lactate dehydrogenase (LDH) at baseline, and 0.5% had a history of brain metastases. The most common adverse reactions (≥ 20%) for MEKINIST in patients who received MEKINIST plus dabrafenib in the COMBI-d and COMBI-v studies were: pyrexia, nausea, rash, chills, diarrhea, vomiting, hypertension, and peripheral edema. The demographics and baseline tumor characteristics of patients enrolled in the COMBI-d study are summarized in Clinical Studies [see Clinical Studies (14.1)] . Patients who received MEKINIST plus dabrafenib had a median duration of exposure of 11 months (range: 3 days to 30 months) to MEKINIST. Among the 209 patients who received MEKINIST plus dabrafenib, 26% were exposed to MEKINIST for > 6 months to 12 months while 46% were exposed to MEKINIST for > 1 year. In the COMBI-d study, adverse reactions leading to discontinuation of MEKINIST occurred in 11% of patients who received MEKINIST plus dabrafenib; the most frequent were pyrexia (1.4%) and decreased ejection fraction (1.4%). Adverse reactions leading to dose reductions of MEKINIST occurred in 18% of patients who received MEKINIST plus dabrafenib; the most frequent were pyrexia (2.9%), neutropenia (1.9%), decreased ejection fraction (1.9%), and rash (1.9%). Adverse reactions leading to dose interruptions of MEKINIST occurred in 46% of patients who received MEKINIST plus dabrafenib; the most frequent were pyrexia (18%), chills (7%), vomiting (6%), and decreased ejection fraction (4.8%). Table 8 and Table 9 present selected adverse reactions and laboratory abnormalities, respectively, of MEKINIST observed in the COMBI-d study. Table 8. Adverse Reactions Occurring in ≥ 10% (All Grades) of Patients Who Received MEKINIST with Dabrafenib and at a Higher Incidence* Than in Patients Who Received Single-Agent Dabrafenib in COMBI-d a * ≥ 5% for All Grades or ≥ 2% for Grades 3–4 incidence in patients who received MEKINIST with dabrafenib compared with patients who received dabrafenib as a single agent. a NCI CTCAE version 4.0. b Includes peripheral edema, edema, lymphedema, localized edema, and generalized edema. c Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal discomfort. d Includes rash, generalized rash, pruritic rash, erythematous rash, papular rash, vesicular rash, macular rash, maculo-papular rash, and follicular rash. e Most common events (≥ 1%) include epistaxis, hematochezia, decreased hemoglobin, purpura, and rectal hemorrhage. Grade 4 events were limited to hepatic hematoma and duodenal ulcer hemorrhage (each n = 1 in the pooled combination arm). Adverse Reactions Pooled MEKINIST plus Dabrafenib N = 559 COMBI-d Study MEKINIST plus Dabrafenib N = 209 Dabrafenib N = 211 All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) General Pyrexia 54 5 57 7 33 1.9 Chills 31 0.5 31 0 17 0.5 Peripheral edema b 21 0.7 25 1.4 11 0.5 Gastrointestinal Nausea 35 0.4 34 0.5 27 1.4 Diarrhea 31 1.3 30 1.4 16 0.9 Vomiting 27 1.1 25 1.0 14 0.5 Abdominal pain c 18 0.9 26 1.0 14 2.4 Skin and subcutaneous tissue Rash d 32 1.1 42 0 27 1.4 Vascular Hypertension 26 11 25 6 16 6 Hemorrhage e 18 2.0 19 1.9 15 1.9 Nervous system Dizziness 11 0.2 14 0 7 0 Other clinically important adverse reactions for MEKINIST across the COMBI-d and COMBI-v studies (N = 559) observed in less than 10% of patients who received MEKINIST in combination with dabrafenib were: Cardiac: Bradycardia, atrioventricular block, bundle branch block Immune System: Sarcoidosis Musculoskeletal and Connective Tissue: Rhabdomyolysis Nervous System: Peripheral neuropathy, Guillain-Barré syndrome Skin and Subcutaneous Tissue: Photosensitivity Table 9. Laboratory Abnormalities Worsening from Baseline Occurring at ≥ 10% (All Grades) of Patients Who Received MEKINIST with Dabrafenib and at a Higher Incidence* Than in Patients Who Received Single-Agent Dabrafenib in COMBI-d Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. * ≥ 5% for All Grades or ≥ 2% for Grades 3–4 incidence in patients who received MEKINIST with dabrafenib compared with patients who received dabrafenib as a single agent. a For these laboratory tests, the denominator is 556. b For these laboratory tests, the denominator is 208 for the combination arm, 207-209 for the dabrafenib arm. c Grade 4 adverse reactions limited to lymphopenia and hyperglycemia (each n = 4), increased ALT and increased AST (each n = 3), neutropenia (n = 2), and hyponatremia (n = 1) in the pooled combination arm; neutropenia, lymphopenia, increased ALT, increased AST, and hyperglycemia (each n = 1) in the COMBI-d study combination arm; neutropenia, thrombocytopenia, increased ALT, and increased AST (each n = 1) in the dabrafenib arm. Laboratory Abnormality Pooled MEKINIST plus Dabrafenib N = 559 a COMBI-d Study MEKINIST plus Dabrafenib N = 209 b Dabrafenib N = 211 b All Grades (%) Grades 3 and 4 c (%) All Grades (%) Grades 3 and 4 c (%) All Grades (%) Grades 3 and 4 c (%) Chemistry Hyperglycemia 60 4.7 65 6 57 4.3 Hypoalbuminemia 48 1.1 53 1.4 27 0 Hyponatremia 25 8 24 6 14 2.9 Hepatic Increased AST 59 4.1 60 4.3 21 1.0 Increased blood alkaline phosphatase 49 2.7 50 1.0 25 0.5 Increased ALT 48 4.5 44 3.8 28 1.0 Hematology Neutropenia 46 7 50 6 16 1.9 Anemia 43 2.3 43 2.4 38 4.3 Lymphopenia 32 8 38 9 28 7 Thrombocytopenia 21 0.7 19 0.5 10 0.5 Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma The safety of MEKINIST when administered with dabrafenib was evaluated in 435 patients with Stage III melanoma with BRAF V600E or V600K mutations following complete resection who received at least one dose of study therapy in the COMBI-AD study [see Clinical Studies (14.2)] . Patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily for 12 months. The trial excluded patients with abnormal LVEF; history of acute coronary syndromes, coronary angioplasty, or stenting within 6 months; Class II or greater congestive heart failure (New York Heart Association); QTc interval ≥ 480 msec; treatment refractory hypertension; uncontrolled arrhythmias; or history of RVO. Patients who received MEKINIST in combination with dabrafenib had a median duration of exposure of 11 months (range: 0 to 12) to MEKINIST. Among the 435 patients who received MEKINIST in combination with dabrafenib, 72% were exposed to MEKINIST for > 6 months. The median age of patients who received MEKINIST in combination with dabrafenib was 50 years (range: 18 to 89), 56% were male, 99% were White, 92% had baseline ECOG performance status of 0, and 8% had baseline ECOG performance status of 1. The most common adverse reactions (≥ 20%) in patients who received MEKINIST in combination with dabrafenib were: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia. Adverse reactions resulting in discontinuation and dose interruptions of MEKINIST occurred in 24% and 54% of patients, respectively; the most frequent for each were pyrexia and chills. Adverse reactions leading to dose reductions of MEKINIST occurred in 23% of patients; the most frequent were pyrexia and decreased ejection fraction. Table 10 summarizes the adverse reactions that occurred in at least 20% of the patients who received MEKINIST in combination with dabrafenib. Table 10. Adverse Reactions Occurring in ≥ 20% of Patients in the COMBI-AD Study a a NCI CTCAE version 4.0. b Includes pyrexia and hyperpyrexia. c Includes fatigue, asthenia, and malaise. d Includes headache and tension headache. e Includes rash, rash maculo-papular, rash macular, rash generalized, rash erythematous, rash papular, rash pruritic, nodular rash, rash vesicular, and rash pustular. f Includes myalgia, musculoskeletal pain, and musculoskeletal chest pain. Adverse Reactions MEKINIST plus Dabrafenib N = 435 Placebo N = 432 All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) General Pyrexia b 63 5 11 < 1 Fatigue c 59 5 37 < 1 Chills 37 1 4 0 Gastrointestinal Nausea 40 < 1 20 0 Diarrhea 33 < 1 15 < 1 Vomiting 28 < 1 10 0 Nervous system Headache d 39 1 24 0 Skin and subcutaneous tissue Rash e 37 < 1 16 < 1 Musculoskeletal and connective tissue Arthralgia 28 < 1 14 0 Myalgia f 20 < 1 14 0 Other clinically important adverse reactions for MEKINIST in the COMBI-AD study observed in less than 20% of patients who received MEKINIST in combination with dabrafenib were: blurred vision (6%), decreased ejection fraction (5%), peripheral neuropathy (2.5%), rhabdomyolysis (< 1%), atrioventricular block (< 1%), Guillain-Barré syndrome (< 1%), and sarcoidosis (< 1%). The laboratory abnormalities are summarized in Table 11. Table 11. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients in the COMBI-AD Study Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a The incidence is based on the number of patients who had both a baseline and at least one on-study laboratory measurement: MEKINIST plus Dabrafenib (range: 429 to 431) and Placebo arm (range: 426 to 428). Laboratory Abnormality MEKINIST plus Dabrafenib a N = 435 Placebo a N = 432 All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) Chemistry Hyperglycemia 63 3 47 2 Hypophosphatemia 42 7 10 < 1 Hypoalbuminemia 25 < 1 < 1 0 Hepatic Increased AST 57 6 11 < 1 Increased ALT 48 5 18 < 1 Increased blood alkaline phosphatase 38 1 6 < 1 Hematology Neutropenia 47 6 12 < 1 Lymphopenia 26 5 6 < 1 Anemia 25 < 1 6 < 1 Trial COMBI-APlus (Pyrexia Management Study) COMBI-APlus evaluated the impact of pyrexia-related outcomes of a revised pyrexia management algorithm in patients who received dabrafenib administered with trametinib in the adjuvant treatment of BRAF V600 mutation-positive melanoma after complete resection. The pyrexia management algorithm interrupted both dabrafenib and trametinib when patient’s temperature is ≥ 100.4°F. Grade 3-4 pyrexia occurred in 4.3% of patients, hospitalizations due to pyrexia occurred in 5.1% of patients, pyrexia with complications (dehydration, hypotension, renal dysfunction, syncope, severe chills) occurred in 2.2% of patients, and treatment discontinuation due to pyrexia occurred in 2.5% of patients. Metastatic, BRAF V600E Mutation-Positive Non-Small Cell Lung Cancer The safety of MEKINIST when administered with dabrafenib was evaluated in 93 patients with previously untreated (n = 36) and previously treated (n = 57) metastatic BRAF V600E mutation-positive NSCLC in a multi-center, multi-cohort, non-randomized, open-label trial (Study BRF113928). Patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. The trial excluded patients with abnormal LVEF, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), QTc interval ≥ 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, history of ILD or pneumonitis, or history or current RVO [see Clinical Studies (14.3)]. Among these 93 patients, 53 (57%) were exposed to MEKINIST and dabrafenib for > 6 months and 27 (29%) were exposed to MEKINIST and dabrafenib for ≥ 1 year. The median age was 65 years (range: 41 to 91), 46% were male, 85% were White; 32% had baseline ECOG performance status of 0 and 61% had ECOG performance status of 1; 98% had non-squamous histology; and 12% were current smokers, 60% were former smokers, and 28% had never smoked. The most common adverse reactions (≥ 20%) in these 93 patients were: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea. Adverse reactions leading to discontinuation of MEKINIST occurred in 19% of patients; the most frequent were pyrexia (2.2%), decreased ejection fraction (2.2%), and respiratory distress (2.2%). Adverse reactions leading to dose reductions of MEKINIST occurred in 30% of patients; 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; the most frequent were pyrexia (16%), vomiting (10%), neutropenia (8%), nausea (5%), and decreased ejection fraction (5%). Table 12 and Table 13 present adverse reactions and laboratory abnormalities, respectively, of MEKINIST in combination with dabrafenib in Study BRF113928. Table 12. Adverse Reactions Occurring in ≥ 20% (All Grades) of Patients Treated with MEKINIST plus Dabrafenib in Study BRF113928 a a NCI CTCAE version 4.0. b Includes fatigue, malaise, and asthenia. c Includes peripheral edema, edema, and generalized edema. d Includes rash, rash generalized, rash papular, rash macular, rash maculo-papular, and rash pustular. e Includes hemoptysis, hematoma, epistaxis, purpura, hematuria, subarachnoid hemorrhage, gastric hemorrhage, urinary bladder hemorrhage, contusion, hematochezia, injection site hemorrhage, pulmonary hemorrhage, and retroperitoneal hemorrhage. Adverse Reactions MEKINIST plus Dabrafenib N = 93 All Grades (%) Grades 3 and 4 (%) General Pyrexia 55 5 Fatigue b 51 5 Edema c 28 0 Chills 23 1.1 Gastrointestinal Nausea 45 0 Vomiting 33 3.2 Diarrhea 32 2.2 Decreased appetite 29 0 Skin and subcutaneous tissue Dry skin 31 1.1 Rash d 28 3.2 Vascular Hemorrhage e 23 3.2 Respiratory system Cough 22 0 Dyspnea 20 5 Other clinically important adverse reactions for MEKINIST in Study BRF113928 observed in less than 20% of patients who received MEKINIST administered with dabrafenib were: Cardiac: Atrioventricular block Nervous System: Peripheral neuropathy Table 13. Treatment-Emergent Laboratory Abnormalities Occurring in ≥ 20% (All Grades) of Patients Who Received MEKINIST plus Dabrafenib in Study BRF113928 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a For these laboratory tests, the denominator is 90. b For these laboratory tests, the denominator is 91. Laboratory Abnormality MEKINIST plus Dabrafenib N = 93 All Grades (%) Grades 3 and 4 (%) Chemistry a Hyperglycemia 71 9 Hyponatremia 57 17 Hypophosphatemia 36 7 Increased creatinine 21 1.1 Hepatic a Increased blood alkaline phosphatase 64 0 Increased AST 61 4.4 Increased ALT 32 6 Hematology b Leukopenia 48 8 Anemia 46 10 Neutropenia 44 8 Lymphopenia 42 14 Advanced BRAF V600E Mutation-Positive Tumors Study BRF117019 The safety of MEKINIST when administered with dabrafenib was evaluated in a multi-cohort, multi-center, non-randomized, open-label study in adult patients with cancers with the BRAF V600E mutation (Study BRF117019). A total of 206 patients were enrolled in the trial, 36 of whom were enrolled in the ATC cohort, 105 were enrolled in specific solid tumor cohorts, and 65 in other malignancies [see Clinical Studies (14.4, 14.6)] . Patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. Among these 206 patients, 101 (49%) were exposed to MEKINIST for ≥ 1 year and 103 (50%) were exposed to dabrafenib for ≥ 1 year. The median age was 60 years (range: 18 to 89); 56% were male; 79% were White; and 34% had baseline ECOG performance status of 0 and 60% had ECOG performance status of 1. Serious adverse reactions occurred in 45% of patients who received MEKINIST in combination with dabrafenib. Serious adverse reactions in > 5% of patients included pyrexia (11%) and pneumonia (6%). Fatal adverse reactions occurred in 3.9% of patients who received MEKINIST in combination with dabrafenib. Fatal adverse reactions that occurred in > 1% of patients included sepsis (1.9%). Permanent treatment discontinuation due to an adverse reaction occurred in 13% of patients. Adverse reactions which resulted in permanent treatment discontinuation in > 1% of patients included nausea (1.5%). Dosage interruptions due to an adverse reaction occurred in 55% of patients. Adverse reactions which required dosage interruption in > 5% of patients included pyrexia (22%), chills (9%), fatigue (6%), neutropenia (6%), and nausea (5%). Dose reductions due to an adverse reaction occurred in 44% of patients. Adverse reactions which required dose reductions in > 5% of patients included pyrexia (18%), chills (8%), and fatigue (6%). The most common (≥ 20%) adverse reactions, including laboratory abnormalities, are listed in Table 14 and Table 15. Table 14 summarizes the adverse reactions in Study BRF117019. Table 14. Adverse Reactions (≥ 20%) in Adult Patients Treated with MEKINIST Plus Dabrafenib in Study BRF117019 a NCI CTCAE version 4.0. b Includes fatigue, asthenia, and malaise. c Includes peripheral edema and peripheral swelling. d Includes rash, rash maculo-papular, rash erythematous, rash pustular, and rash papular. e Includes epistaxis, hematuria, contusion, hematoma, hemoptysis, conjunctival hemorrhage, hematochezia, rectal hemorrhage, hemorrhoidal hemorrhage, melaena, purpura, eye contusion, eye hemorrhage, gastric hemorrhage, gingival bleeding, hematemesis, hemorrhage intracranial, hemorrhagic stroke, hemothorax, increased tendency to bruise, large intestinal hemorrhage, mouth hemorrhage, petechiae, pharyngeal hemorrhage, prothrombin time prolonged, pulmonary hematoma, retinal hemorrhage, vaginal hemorrhage, and vitreous hemorrhage. f Includes cough and productive cough. g Includes myalgia, musculoskeletal chest pain, and musculoskeletal pain. Adverse Reactions MEKINIST plus Dabrafenib a (N = 206) All Grades (%) Grade 3 or 4 (%) General Pyrexia 55 4.95 Fatigue b 50 5 Chills 30 0.5 Peripheral edema c 22 0 Gastrointestinal Nausea 40 1.5 Constipation 27 0 Vomiting 27 1.5 Diarrhea 26 2.93 Skin and subcutaneous tissue Rash d 40 2.4 Nervous system Headache 30 1.5 Vascular Hemorrhage e 29 4.4 Respiratory system Cough f 29 0 Musculoskeletal and connective tissue Myalgia g 24 0.5 Arthralgia 23 0.5 Clinically relevant adverse reactions for MEKINIST in Study BRF117019 observed in less than 20% of patients who received MEKINIST in combination with dabrafenib were: peripheral neuropathy (9%), decreased ejection fraction (8%), atrioventricular block (2.9%), uveitis (1.9%), hypersensitivity (1.9%), Guillain-Barré syndrome (< 1%), and sarcoidosis (< 1%). Table 15 summarizes the laboratory abnormalities in Study BRF117019. Table 15. Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Adult Patients Treated with MEKINIST Plus Dabrafenib in Study BRF117019 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a The denominator used to calculate the rate varied from 199 to 202 based on the number of patients with a baseline value and at least one post-treatment value. Laboratory Abnormality MEKINIST plus Dabrafenib a All Grades (%) Grade 3 or 4 (%) Chemistry Hyperglycemia 61 8 Decreased sodium 35 10 Decreased magnesium 24 0 Increased creatinine 21 1.5 Hepatic Increased alkaline phosphatase 51 5 Increased AST 51 4.6 Increased ALT 39 3 Hematology Decreased hemoglobin 44 9 BRAF V600E Mutation-Positive Solid Tumors in Pediatric Patients Study CTMT212X2101 (X2101) The safety of MEKINIST when administered with dabrafenib was evaluated in Study X2101, a multi-center, open-label, multi-cohort study in pediatric patients (n = 48) with refractory or recurrent solid tumors activation [see Clinical Studies (14.6)] . The median duration of exposure to MEKINIST in Parts C (dose escalation) and D (cohort expansion) was 20.8 and 24.4 months, respectively. The median duration of exposure to dabrafenib in Parts C and D was 20.8 and 24.9 months, respectively. The median age of pediatric patients who received MEKINIST with dabrafenib was 9 years (range: 1 to 17). Serious adverse reactions occurred in 46% of patients who received MEKINIST in combination with dabrafenib. Serious adverse reactions in > 5% of patients included pyrexia (25%) and decreased ejection fraction (6%). Permanent treatment discontinuation due to an adverse reaction occurred in 21% of patients. Adverse reactions which resulted in permanent treatment discontinuation in > 3% of patients included increased ALT (6%), increased AST (4.2%) and decreased ejection fraction …

Lactation : Do not breastfeed. ( 8.2 ) Females and Males of Reproductive Potential : May impair fertility. Counsel patients on pregnancy planning and prevention. ( 8.3 )

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

8.2 Lactation Risk Summary There are no data on the presence of trametinib in human milk, or the effects of trametinib on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with MEKINIST and for 4 months following the last dose.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating MEKINIST. Contraception Based on data from animal studies and its mechanism of action, MEKINIST can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1 )]. Females Advise female patients of reproductive potential to use effective contraception during treatment with MEKINIST and for 4 months after the last dose. Males To avoid potential drug exposure to pregnant partners and female partners of reproductive potential, advise male patients (including those who have had vasectomies) with female partners of reproductive potential to use condoms during treatment with MEKINIST and for 4 months after the last dose. Infertility Females Advise female patients of reproductive potential that MEKINIST may impair fertility. Increased follicular cysts and decreased corpora lutea were observed in female rats at dose exposures equivalent to 0.3 times the human exposure at the recommended adult dose [see Nonclinical Toxicology (13.1)] .

8.4 Pediatric Use BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors and LGG The safety and effectiveness of MEKINIST in combination with dabrafenib have been established in pediatric patients 1 year of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options; or with LGG with BRAF V600E mutation who require systemic therapy. Use of MEKINIST in combination with dabrafenib for these indications is supported by evidence from studies X2101 and G2201 that enrolled 171 patients (1 to < 18 years of age) with BRAF V600 mutation-positive advanced solid tumors, of which 4 (2.3%) patients were 1 to < 2 years of age, 39 (23%) patients were 2 to < 6 years of age, 54 (32%) patients were 6 to < 12 years of age, and 74 (43%) patients were 12 to < 18 years of age [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.6, 14.7)] . The safety and effectiveness of MEKINIST in combination with dabrafenib have not been established for these indications in pediatric patients less than 1 year old. The safety and effectiveness of MEKINIST as a single agent in pediatric patients have not been established. Juvenile Animal Toxicity Data In a repeat-dose toxicity study in juvenile rats, decreased bone length and corneal dystrophy were observed at doses resulting in exposures as low as 0.3 times the human exposure at the recommended adult dose based on AUC. Additionally, a delay in sexual maturation was noted at doses resulting in exposures as low as 1.6 times the human exposure at the recommended adult dose based on AUC.

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

8.6 Hepatic Impairment No dose adjustment is recommended in patients with mild (bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or bilirubin > 1x to 1.5x ULN and any AST) hepatic impairment. A recommended dosage of MEKINIST has not been established for patients with moderate (bilirubin > 1.5x to 3x ULN and any AST) or severe (bilirubin > 3x to 10x ULN and any AST) hepatic impairment. Consider the risk-benefit profile of MEKINIST related to dosing prior to determining whether to administer MEKINIST to patients with moderate or severe hepatic impairment. In patients with moderate hepatic impairment, 3 patients who received a starting dose of 1.5 mg orally once daily and two patients who received a starting dose of 2 mg orally once daily did not experience dose limiting toxicities (DLTs) during the first cycle of therapy. In patients with severe hepatic impairment, 3 patients who received a starting dose of 1 mg orally once daily did not experience DLTs during the first cycle; one patient who received a starting dose of 1.5 mg orally once daily experienced a DLT (grade 3 acneiform rash). Compared to patients with normal hepatic function, there was no increase in exposure of trametinib in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3)] .

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

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

12.3 Pharmacokinetics The pharmacokinetics of trametinib were characterized following a single dose and multiple doses in patients with solid tumors and BRAF V600 mutation-positive metastatic melanoma. Following administration of MEKINIST tablets 0.125 mg (0.0625 times the approved recommended adult dosage) to 4 mg (2 times the approved recommended adult dosage) daily, both C max and AUC increase proportionally with dose. Intersubject variability in AUC and C max at steady state is 22% and 28%, respectively. Absorption The median time to achieve peak plasma concentrations (T max ) is 1.5 hours post-dose. The mean absolute bioavailability of MEKINIST tablets is 72% and MEKINIST for oral solution is 81%. Effect of Food Following administration of MEKINIST tablets, a high-fat, high-calorie meal (approximately 1000 calories) decreased trametinib AUC by 24%, C max by 70%, and delayed T max by approximately 4 hours as compared with fasted conditions. Administration of a single 2 mg dose of MEKINIST for oral solution with a low-fat, low-calorie meal (approximately 500 calories, 14 grams fat, 80 grams carbohydrates, and 12 grams protein) showed no clinically significant changes on both AUC and C max of trametinib as compared with fasted conditions. Distribution Trametinib is 97.4% bound to human plasma proteins. The apparent volume of distribution (V c /F) is 214 L. Elimination The estimated elimination half-life is 3.9 to 4.8 days. The apparent clearance is 4.9 L/h. Metabolism Trametinib is metabolized predominantly via deacetylation alone or with mono-oxygenation or in combination with glucuronidation biotransformation pathways in vitro. Deacetylation is mediated by carboxylesterases (i.e., carboxylesterase 1b/c and 2) and may also be mediated by other hydrolytic enzymes. Following a single dose of [ 14 C]-trametinib, approximately 50% of circulating radioactivity is represented as the parent compound; however, ≥ 75% of drug-related material in plasma is the parent compound based on metabolite profiling after repeat dosing of trametinib. Excretion Following oral administration of [ 14 C]-trametinib, greater than 80% of excreted radioactivity was recovered in the feces while less than 20% of excreted radioactivity was recovered in the urine with less than 0.1% of the excreted dose as parent. Specific Populations Age (18 to 93 years), sex, body weight (36 to 170 kg), and renal impairment (eGFR 15 to 89 mL/min/1.73 m 2 ) have no clinically significant effect on the exposure of trametinib. There are insufficient data to evaluate potential differences in the exposure of trametinib by race or ethnicity. Pediatric Patients: The pharmacokinetics of trametinib in glioma and other solid tumors were evaluated in 244 patients aged 1 to < 18 years following a single dose or multiple doses. Pharmacokinetic parameters in patients aged 1 to < 18 years are within range of values previously observed in adults given the same dose based on weight. Weight (6 to 156 kg) was found to have a statistically significant effect on trametinib oral clearance in this population. Patients with Hepatic Impairment: Hepatic impairment (defined by bilirubin and AST levels) had no significant effect in trametinib exposure or apparent drug clearance compared with patients with normal hepatic function. Drug Interaction Studies Effect of Dabrafenib on Trametinib : Coadministration of MEKINIST tablets 2 mg daily with dabrafenib resulted in no change in AUC of trametinib. Effect of Trametinib on CYP Substrates: Coadministration of MEKINIST tablets 2 mg once daily with a sensitive CYP3A4 substrate had no clinically relevant effect on the AUC and C max of the sensitive CYP3A4 substrate. Based on in vitro studies, trametinib is an inhibitor of CYP2C8, but is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at a clinically relevant systemic concentration. Effect of Transporters on Trametinib: Trametinib is a substrate of P-glycoprotein (P-gp) and BSEP. Inhibition of P-gp is unlikely to result in a clinically important increase in trametinib concentrations as trametinib exhibits high passive permeability and bioavailability. Trametinib is not a substrate of BCRP, OATP1B1, OATP1B3, OATP2B1, OCT1, MRP2, or MATE1 in vitro. Effect of Trametinib on Transporters: Based on in vitro studies, trametinib is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, BSEP, MRP2, or MATE1 at a clinically relevant systemic concentration.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). New Primary Cutaneous and Non-cutaneous Malignancies Advise patients that MEKINIST administered with dabrafenib can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their healthcare provider immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)] . Hemorrhage Advise patients that MEKINIST administered with dabrafenib increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.2)] . Colitis and Gastrointestinal Perforation Advise patients that MEKINIST can cause colitis and gastrointestinal perforation and to contact their healthcare provider for signs or symptoms of colitis or gastrointestinal perforation [see Warnings and Precautions (5.3)] . Venous Thromboembolic Events Advise patients that MEKINIST administered with dabrafenib increases the risks of PE and DVT. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)] . Cardiomyopathy Advise patients that MEKINIST can cause cardiomyopathy and to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)] . Ocular Toxicities Advise patients that MEKINIST can cause severe visual disturbances that can lead to blindness and to contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)] . Interstitial Lung Disease/Pneumonitis Advise patients that MEKINIST can cause ILD (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs, such as cough or dyspnea [see Warnings and Precautions (5.7)] . Serious Febrile Reactions Advise patients that MEKINIST administered with dabrafenib can cause serious febrile reactions. Instruct patients to contact their healthcare provider if they develop a fever while taking MEKINIST with dabrafenib [see Warnings and Precautions (5.8)] . Serious Skin Toxicities Advise patients that MEKINIST can cause serious skin toxicities, which may require hospitalization, and to contact their healthcare provider for progressive or intolerable rash. Advise patients to contact their healthcare provider immediately if they develop signs and symptoms of a severe skin reaction [see Warnings and Precautions (5.9)] . Hypertension Advise patients that MEKINIST can cause hypertension and that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension, such as severe headache, blurry vision, or dizziness [see Adverse Reactions (6.1)] . Diarrhea Advise patients that MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment [see Adverse Reactions (6.1)] . Embryo-Fetal Toxicity Advise pregnant women and males of reproductive potential of the potential risk to a fetus [see Warnings and Precautions (5.13), Use in Specific Populations (8.1, 8.3)] . Advise females to contact their healthcare provider of a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with MEKINIST and for 4 months after the last dose. Advise male patients with female partners of reproductive potential to use condoms during treatment with MEKINIST and for 4 months after the last dose. Lactation Advise women not to breastfeed during treatment with MEKINIST and for 4 months after the last dose [see Use in Specific Populations (8.2)] . Infertility Advise females of reproductive potential of the potential risk for impaired fertility [see Use in Specific Populations (8.3)] . Administration Instruct patients to take MEKINIST tablets on an empty stomach (at least 1 hour before or 2 hours after a meal) [see Dosage and Administration (2.3)] . When administering MEKINIST for oral solution as a single agent, instruct patients to take the oral solution with a low-fat meal or on an empty stomach [see Dosage and Administration (2.3)] . When coadministering with dabrafenib, instruct patients to take the MEKINIST oral solution on an empty stomach (at least 1 hour before or 2 hours after a meal). Breastfeeding and/or baby formula may be given on demand if a pediatric patient is unable to tolerate the fasting conditions [see Dosage and Administration (2.3)] . THxID ® BRAF assay is a trademark of bioMérieux. Oncomine ™ Dx Target Test is a trademark of Life Technologies Corporation, a part of Thermo Fisher Scientific Inc. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2026-14