Binimetinib

1 INDICATIONS AND USAGE MEKTOVI is a kinase inhibitor indicated: • in combination with encorafenib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test. ( 1.1 , 2.1 ) • in combination with encorafenib, for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-approved test. ( 1.2 , 2.1 ) 1.1 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma MEKTOVI is indicated, in combination with encorafenib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test [see Dosage and Administration (2.1) ] . 1.2 BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC) MEKTOVI is indicated, in combination with encorafenib, for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-approved test. [see Dosage and Administration (2.1) ] .

2 DOSAGE AND ADMINISTRATION Melanoma • Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to the initiation of MEKTOVI. ( 2.1 ) • The recommended dose is 45 mg orally twice daily in combination with encorafenib. Take MEKTOVI with or without food. ( 2.2 ) • For patients with moderate or severe hepatic impairment the recommended dose is 30 mg orally twice daily. ( 2.4 , 8.6 ) NSCLC • Confirm the presence of BRAF V600E mutation in tumor or plasma specimens prior to initiating MEKTOVI. ( 2.1 ) • The recommended dose is 45 mg orally twice daily in combination with encorafenib. Take MEKTOVI with or without food. ( 2.2 ) 2.1 Patient Selection BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma Confirm the presence of a BRAF V600E or V600K mutation in tumor specimens prior to initiating MEKTOVI [see Clinical Studies (14) ] . Information on FDA-approved tests for the detection of BRAF V600E and V600K mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics . BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC) Confirm the presence of a BRAF V600E mutation in tumor or plasma specimens prior to initiating MEKTOVI [see Clinical Studies (14.2) ] . If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA-approved tests for the detection of BRAF V600E mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics . 2.2 Recommended Dosage and Administration The recommended dosage of MEKTOVI is 45 mg orally taken twice daily, approximately 12 hours apart, in combination with encorafenib until disease progression or unacceptable toxicity. Refer to the encorafenib prescribing information for recommended encorafenib dosing information. MEKTOVI may be taken with or without food [see Clinical Pharmacology (12.3) ] . Do not take a missed dose of MEKTOVI within 6 hours of the next dose of MEKTOVI. Do not take an additional dose if vomiting occurs after MEKTOVI administration but continue with the next scheduled dose. 2.3 Dosage Modifications for Adverse Reactions If encorafenib is permanently discontinued, discontinue MEKTOVI. Dose reductions for adverse reactions associated with MEKTOVI are presented in Table 1. Table 1: Recommended Dose Reductions for MEKTOVI for Adverse Reactions Action Recommended Dose First Dose Reduction 30 mg orally twice daily Subsequent Modification Permanently discontinue if unable to tolerate MEKTOVI 30 mg orally twice daily Dosage modifications for adverse reactions associated with MEKTOVI are presented in Table 2. Table 2: Recommended Dosage Modifications for MEKTOVI for Adverse Reactions Severity of Adverse Reaction National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Dose Modification for MEKTOVI Cardiomyopathy [see Warnings and Precautions (5.2) ] • Asymptomatic, absolute decrease in LVEF of greater than 10% from baseline that is also below lower limit of normal (LLN) Withhold MEKTOVI for up to 4 weeks, evaluate LVEF every 2 weeks. Resume MEKTOVI at a reduced dose if the following are present: • LVEF is at or above the lower limit of normal and • Absolute decrease from baseline is 10% or less and • Patient is asymptomatic. If the LVEF does not recover within 4 weeks permanently discontinue MEKTOVI. • Symptomatic congestive heart failure or absolute decrease in LVEF of greater than 20% from baseline that is also below LLN Permanently discontinue MEKTOVI. Venous Thromboembolism [see Warnings and Precautions (5.3) ] • Uncomplicated deep venous thrombosis (DVT) or pulmonary embolism (PE) Withhold MEKTOVI. • If improves to Grade 0-1, resume at a reduced dose. • If no improvement, permanently discontinue MEKTOVI. • Life threatening PE Permanently discontinue MEKTOVI. Serous Retinopathy [see Warnings and Precautions (5.4) ] • Symptomatic serous retinopathy/Retinal pigment epithelial detachments Withhold MEKTOVI for up to 10 days. • If improves and becomes asymptomatic, resume at same dose. • If not improved, resume at a lower dose level or permanently discontinue MEKTOVI. Retinal Vein Occlusion (RVO) [see Warnings and Precautions (5.4) ] • Any Grade Permanently discontinue MEKTOVI. Uveitis [see Warnings and Precautions (5.4) ] • Grade 1-3 If Grade 1 or 2 does not respond to specific ocular therapy, or for Grade 3 uveitis, withhold MEKTOVI for up to 6 weeks. • If improved, resume at same or reduced dose. • If not improved, permanently discontinue MEKTOVI. • Grade 4 Permanently discontinue MEKTOVI. Interstitial Lung Disease [see Warnings and Precautions (5.5) ] • Grade 2 Withhold MEKTOVI for up to 4 weeks. • If improved to Grade 0-1, resume at a reduced dose. • If not resolved within 4 weeks, permanently discontinue MEKTOVI. • Grade 3 or Grade 4 Permanently discontinue MEKTOVI. Hepatotoxicity [see Warnings and Precautions (5.6) ] • Grade 2 AST or ALT increased Maintain MEKTOVI dose. • If no improvement within 2 weeks, withhold MEKTOVI until improved to Grade 0-1 or to pretreatment/baseline levels and then resume at the same dose. • Grade 3 or 4 AST or ALT increased See Other Adverse Reactions . Rhabdomyolysis or Creatine Phosphokinase (CPK) elevations [see Warnings and Precautions (5.7) ] • Grade 4 asymptomatic CPK elevation or • Any Grade CPK elevation with symptoms or with renal impairment Withhold MEKTOVI dose for up to 4 weeks. • If improved to Grade 0-1 resume at a reduced dose. • If not resolved within 4 weeks, permanently discontinue MEKTOVI. Dermatologic [other than palmar plantar erythrodysesthesia syndrome (PPES)] [see Adverse Reactions (6.1) ] • Grade 2 If no improvement within 2 weeks, withhold MEKTOVI until Grade 0-1. Resume at same dose if first occurrence or reduce dose if recurrent. • Grade 3 Withhold MEKTOVI until Grade 0-1. Resume at same dose if first occurrence or reduce dose if recurrent. • Grade 4 Permanently discontinue MEKTOVI. Other Adverse Reactions (including Hemorrhage) [see Warnings and Precautions (5.8) , Adverse Reactions (6.1) ] Dose modification of MEKTOVI when administered with encorafenib is not recommended for the following adverse reactions: palmar-plantar erythrodysesthesia syndrome (PPES), non-cutaneous RAS mutation-positive malignancies, and QTc prolongation. • Recurrent Grade 2 or • First occurrence of any Grade 3 Withhold MEKTOVI for up to 4 weeks. • If improves to Grade 0-1 or to pretreatment/baseline levels, resume at reduced dose. • If no improvement, permanently discontinue MEKTOVI. • First occurrence of any Grade 4 Permanently discontinue MEKTOVI, or Withhold MEKTOVI for up to 4 weeks. • If improves to Grade 0-1 or to pretreatment/baseline levels, then resume at a reduced dose. • If no improvement, permanently discontinue MEKTOVI. • Recurrent Grade 3 Consider permanently discontinuing MEKTOVI. • Recurrent Grade 4 Permanently discontinue MEKTOVI. Refer to the encorafenib prescribing information for dose modifications for adverse reactions associated with encorafenib. 2.4 Dosage Modifications for Moderate or Severe Hepatic Impairment For patients with moderate (total bilirubin greater than 1.5 and less than or equal to 3 × ULN and any AST) or severe (total bilirubin levels greater than 3 × ULN and any AST) hepatic impairment, the recommended dosage is 30 mg orally taken twice daily [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] .

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: • New Primary Malignancies [see Warnings and Precautions (5.1) ] • Cardiomyopathy [see Warnings and Precautions (5.2) ] • Venous Thromboembolism [see Warnings and Precautions (5.3) ] • Ocular Toxicities [see Warnings and Precautions (5.4) ] • Interstitial Lung Disease [see Warnings and Precautions (5.5) ] • Hepatotoxicity [see Warnings and Precautions (5.6) ] • Rhabdomyolysis [see Warnings and Precautions (5.7) ] • Hemorrhage [see Warnings and Precautions (5.8) ] • Embryo-Fetal Toxicity [see Warnings and Precautions (5.9) ] • Risks Associated with Combination Treatment [see Warnings and Precautions (5.10) ] Melanoma: Most common adverse reactions (≥25%) for MEKTOVI, in combination with encorafenib, are fatigue, nausea, diarrhea, vomiting, and abdominal pain. ( 6.1 ) NSCLC: Most common adverse reactions (≥25%) for MEKTOVI, in combination with encorafenib, are fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, and cough. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in WARNINGS AND PRECAUTIONS reflect exposure of 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma to MEKTOVI 45 mg twice daily in combination with encorafenib 450 mg once daily in a randomized open-label, active-controlled trial (COLUMBUS) [see Clinical Studies (14.1) ] or, for rare events, exposure of 690 patients with BRAF V600 mutation-positive melanoma to MEKTOVI 45 mg twice daily in combination with encorafenib once daily across multiple clinical trials (NCT03915951, NCT01909453). The pooled safety population described in the WARNINGS AND PRECAUTIONS also reflect exposure of 98 patients with BRAF V600E mutation-positive metastatic non-small cell lung cancer to MEKTOVI 45 mg twice daily and encorafenib 450 mg once daily until disease progression or unacceptable toxicity in PHAROS [see Clinical Studies (14.2) ] . BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma The data described below reflect exposure of 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma to MEKTOVI (45 mg twice daily) in combination with encorafenib (450 mg once daily) in COLUMBUS. The COLUMBUS trial [see Clinical Studies (14.1) ] excluded patients with a history of Gilbert's syndrome, abnormal left ventricular ejection fraction, prolonged QTc (>480 msec), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 11.8 months for patients treated with MEKTOVI in combination with encorafenib and 6.2 months for patients treated with vemurafenib. The most common (≥25%) adverse reactions in patients receiving MEKTOVI in combination with encorafenib were fatigue, nausea, diarrhea, vomiting, and abdominal pain. Adverse reactions leading to dose interruptions of MEKTOVI occurred in 33% of patients receiving MEKTOVI in combination with encorafenib; the most common were left ventricular dysfunction (6%) and serous retinopathy (5%). Adverse reactions leading to dose reductions of MEKTOVI occurred in 19% of patients receiving MEKTOVI in combination with encorafenib; the most common were left ventricular dysfunction (3%), serous retinopathy (3%), and colitis (2%). Five percent (5%) of patients receiving MEKTOVI in combination with encorafenib experienced an adverse reaction that resulted in permanent discontinuation of MEKTOVI. The most common adverse reactions resulting in permanent discontinuation of MEKTOVI were hemorrhage in 2% and headache in 1% of patients. Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities, respectively, identified in COLUMBUS. The COLUMBUS trial was not designed to demonstrate a statistically significant difference in adverse reaction rates for MEKTOVI in combination with encorafenib, as compared to vemurafenib, for any specific adverse reaction listed in Table 3. Table 3: Adverse Reactions Occurring in ≥10% of Patients Receiving MEKTOVI in Combination with Encorafenib in COLUMBUS Grades per National Cancer Institute CTCAE v4.03. Adverse Reaction MEKTOVI with encorafenib N=192 Vemurafenib N=186 All Grades (%) Grades 3 and 4 Grade 4 adverse reactions limited to diarrhea (n=1) and hemorrhage (n=3) in the MEKTOVI with encorafenib arm and constipation (n=1) in the vemurafenib arm. (%) All Grades (%) Grades 3 and 4 (%) General Disorders and Administration Site Conditions Fatigue Represents a composite of multiple, related preferred terms. 43 3 46 6 Pyrexia 18 4 30 0 Peripheral edema 13 1 15 1 Gastrointestinal Disorders Nausea 41 2 34 2 Diarrhea 36 3 34 2 Vomiting 30 2 16 1 Abdominal pain 28 4 16 1 Constipation 22 0 6 1 Skin and Subcutaneous Tissue Disorders Rash 22 1 53 13 Nervous System Disorders Dizziness 15 3 4 0 Visual Disorders Visual impairment 20 0 4 0 Serous retinopathy/RPED 20 3 2 0 Vascular Disorders Hemorrhage 19 3 9 2 Hypertension 11 6 11 3 Other clinically important adverse reactions occurring in <10% of patients who received MEKTOVI in combination with encorafenib were: Gastrointestinal disorders: Colitis Skin and subcutaneous tissue disorders: Panniculitis, Photosensitivity Immune system disorders: Drug hypersensitivity Table 4: Laboratory Abnormalities Occurring in ≥10% (All grades) of Patients Receiving MEKTOVI in Combination with Encorafenib in COLUMBUS Grades per National Cancer Institute CTCAE v4.03. Laboratory Abnormality MEKTOVI with encorafenib N=192 Vemurafenib N=186 All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) Hematology Anemia 36 3.6 34 2.2 Leukopenia 13 0 10 0.5 Lymphopenia 13 2.1 30 7 Neutropenia 13 3.1 4.8 0.5 Chemistry Increased Creatinine 93 3.6 92 1.1 Increased Creatine Phosphokinase 58 5 3.8 0 Increased Gamma Glutamyl Transferase 45 11 34 4.8 Increased ALT 29 6 27 2.2 Increased AST 27 2.6 24 1.6 Increased Alkaline Phosphatase 21 0.5 35 2.2 Hyponatremia 18 3.6 15 0.5 BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC) The safety of MEKTOVI in combination with encorafenib is described in 98 patients with BRAF V600E mutation-positive metastatic NSCLC who received MEKTOVI (45 mg twice daily) in combination with encorafenib (450 mg once daily) in an open-label, single-arm trial (PHAROS). The PHAROS trial [see Clinical Studies (14.2) ] excluded patients with abnormal LVEF, prolonged QTc (>480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of treatment for MEKTOVI and encorafenib was 8.4 and 9.2 months respectively. The most common (≥25%) adverse reactions in patients receiving MEKTOVI were fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, and cough. Adverse reactions leading to dose interruptions of MEKTOVI occurred in 62% of patients receiving MEKTOVI; the most common (≥5%) were diarrhea (17%); nausea (15%); fatigue (9%); AST increased (7%); ALT increased, anemia, musculoskeletal pain, vomiting (6% each); and acute kidney injury, hemorrhage, and LV dysfunction/cardiomyopathy (5% each). Adverse reactions leading to dose reductions of MEKTOVI occurred in 33% of patients receiving MEKTOVI; the most common (≥5%) were diarrhea (8%), nausea (6%), and AST increased (5%). A total of 17% of patients receiving MEKTOVI experienced an adverse reaction that resulted in permanent discontinuation of MEKTOVI; the most common (≥2%) were diarrhea (3.1%); musculoskeletal pain, LV dysfunction/cardiomyopathy, fatigue, nausea, rash, visual impairment, and vomiting (2% each). None of the other adverse reactions leading to permanent discontinuation of MEKTOVI occurred in more than 1 patient. Serious adverse reactions occurred in 38% of patients who received MEKTOVI in combination with encorafenib. Serious adverse reactions in ≥2% of patients included hemorrhage (6%); diarrhea (4.1%); anemia, dyspnea, pneumonia (3.1% each); arrhythmia, device related infection, edema, myocardial infarction, and pleural effusion (2% each). Fatal adverse reactions occurred in 2% of patients who received MEKTOVI (45 mg twice-daily) in combination with encorafenib, including intracranial hemorrhage and myocardial infarction (1% each). Table 5 and Table 6 present adverse drug reactions and laboratory abnormalities, respectively, identified in PHAROS. Table 5: Adverse Reactions Occurring in ≥10% of Patients Receiving MEKTOVI in Combination with Encorafenib in PHAROS Grades per National Cancer Institute CTCAE v4.03. Adverse Reaction MEKTOVI with encorafenib N=98 All Grades (%) Grade 3 and 4 One Grade 5 adverse reaction of hemorrhage occurred. (%) General Disorders and Administration Site Conditions Fatigue Fatigue includes fatigue, asthenia. 61 8 Edema Edema includes edema peripheral, generalized edema, swelling, localized edema, face edema. 23 1 Pyrexia 22 0 Gastrointestinal Disorders Nausea 58 3.1 Diarrhea Diarrhea includes diarrhea, colitis. 52 7 Vomiting 37 1 Abdominal pain Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, epigastric discomfort. 32 1 Constipation 27 0 Eye Disorders Visual impairment Visual impairment includes vision blurred, visual impairment, vitreous floaters, photophobia, visual acuity reduced, photopsia. 29 2 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Musculoskeletal pain includes back pain, arthralgia, pain in extremity, myalgia, musculoskeletal chest pain, non-cardiac chest pain, neck pain. 48 4.1 Skin and Subcutaneous Tissue Disorders Rash Rash includes rash, rash macular, rash maculo-papular, rash papular, rash pustular,dermatitis acneiform, palmar-plantar erythrodysesthesia syndrome, eczema, skin exfoliation. 27 3.1 Pruritis Pruritis includes pruritus, pruritus genital. 16 0 Dry skin 13 0 Alopecia 12 0 Respiratory, Thoracic and Mediastinal Disorders Dyspnea Dyspnea includes dyspnea, dyspnea exertional. 27 8 Cough Cough includes cough, productive cough. 26 0 Nervous System Disorders Dizziness Dizziness includes dizziness, balance disorder. 17 1 Headache 11 0 Metabolism and Nutrition Disorders Decreased appetite 14 1 Vascular Disorders Hemorrhage Hemorrhage includes anal hemorrhage, hemothorax, gastrointestinal hemorrhage, hematochezia, hematuria, hemoptysis, hemorrhage intracranial, hyphema, small intestinal hemorrhage, upper gastrointestinal hemorrhage, vaginal hemorrhage. 12 4.1 Hypertension 10 5 Cardiac Disorders Left ventricular dysfunction/cardiomyopathy Left ventricular dysfunction/cardiomyopathy includes ejection fraction decreased, cardiac failure, cardiac failure congestive. 11 1 Investigations Weight increased 11 1 Psychiatric Disorders Insomnia 10 0 Other clinically important adverse reactions occurring in <10% of patients who received MEKTOVI in combination with encorafenib were: Nervous system disorders: Peripheral neuropathy, Dysgeusia, Facial paresis Gastrointestinal disorders: Pancreatitis Skin and subcutaneous tissue disorders: Hyperkeratosis, Erythema, Photosensitivity Immune system disorders: Drug hypersensitivity Table 6: Laboratory Abnormalities Occurring in ≥10% (All Grades) of Patients Receiving MEKTOVI with Encorafenib in PHAROS Grades per National Cancer Institute CTCAE v4.03. Laboratory Abnormality Based on the number of patients with available baseline and at least one on-treatment laboratory test. MEKTOVI with encorafenib All Grades (%) Grades 3 and 4 (%) Hematology Anemia 47 11 Lymphopenia 24 6 Thrombocytopenia 20 1.1 Leukopenia 12 0 Neutropenia 12 1.1 Chemistry Increased creatinine 91 3.2 Hyperglycemia 48 6 Increased creatine kinase 41 3.3 Lipase increased 40 14 Increased ALT 34 9 Hypoalbuminemia 32 0 Increased AST 31 10 Increased alkaline phosphatase 31 3.2 Hyperkalemia 31 2.1 Hyponatremia 26 11 Serum amylase increased 22 1.1 Hypocalcemia 12 2.1

12.3 Pharmacokinetics The pharmacokinetics of binimetinib was studied in healthy subjects and patients with solid tumors. After twice-daily dosing, the accumulation is 1.5-fold and the coefficient of variation (CV%) of the area under the concentration-time curve (AUC) is <40% at steady state. The systemic exposure of binimetinib is approximately dose proportional. Absorption After oral administration, at least 50% of the binimetinib dose was absorbed with a median time to maximum concentration (T max ) of 1.6 hours. Effect of Food The administration of a single dose of MEKTOVI 45 mg with a high-fat, high-calorie meal (consisting of approximately 150 calories from protein, 350 calories from carbohydrate, and 500 calories from fat) in healthy subjects had no effect on binimetinib exposure. Distribution Binimetinib is 97% bound to human plasma proteins and the blood-to-plasma ratio is 0.72. The geometric mean (CV%) of apparent volume of distribution of binimetinib is 92 L (45%). Elimination The mean (CV%) terminal half-life (t 1/2 ) of binimetinib is 3.5 hours (28.5%) and apparent clearance (CL/F) is 20.2 L/h (24%). Metabolism The primary metabolic pathway is glucuronidation with UGT1A1 contributing up to 61% of the binimetinib metabolism. Other pathways of binimetinib metabolism include N-dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain. The active metabolite M3 produced by CYP1A2 and CYP2C19 represents 8.6% of the binimetinib exposure. Following a single oral dose of 45 mg radiolabeled binimetinib, approximately 60% of the circulating radioactivity AUC in plasma was attributable to binimetinib. Excretion Following a single oral dose of 45 mg radiolabeled binimetinib in healthy subjects, 62% (32% unchanged) of the administered dose was recovered in the feces while 31% (6.5% unchanged) was recovered in the urine. Specific Populations Age (20 to 94 years), sex, or body weight do not have a clinically important effect on the systemic exposure of binimetinib. The effect of race or ethnicity on the pharmacokinetics of binimetinib is unknown. Hepatic Impairment: No clinically meaningful changes in binimetinib exposure (AUC and C max ) were observed in subjects with mild hepatic impairment (total bilirubin >1 and ≤1.5 × ULN and any AST or total bilirubin ≤ ULN and AST > ULN) as compared to subjects with normal liver function (total bilirubin ≤ ULN and AST ≤ ULN). A 2-fold increase in AUC was observed in subjects with moderate (total bilirubin >1.5 and ≤3 × ULN and any AST) or severe (total bilirubin levels >3 × ULN and any AST) hepatic impairment [see Dosage and Administration (2.4) ] . Renal Impairment: In subjects with severe renal impairment (eGFR ≤29 mL/min/1.73 m 2 ), no clinically important changes in binimetinib exposure were observed as compared to subjects with normal renal function. Drug Interaction Studies Clinical Studies Effect of UGT1A1 Inducers or Inhibitors on Binimetinib : UGT1A1 genotype and smoking (UGT1A1 inducer) do not have a clinically important effect on binimetinib exposure. Simulations predict similar C max of binimetinib 45 mg in the presence or absence of atazanavir 400 mg (UGT1A1 inhibitor). No differences in binimetinib exposure have been observed when MEKTOVI is coadministered with encorafenib. Effect of Binimetinib on CYP Substrates : Binimetinib did not alter the exposure of a sensitive CYP3A4 substrate (midazolam). Effect of Acid Reducing Agents on Binimetinib : The extent of binimetinib exposure (AUC) was not altered in the presence of a gastric acid reducing agent (rabeprazole). In Vitro Studies Effect of Binimetinib on CYP Substrates: Binimetinib is not a time-dependent inhibitor of CYP1A2, CYP2C9, CYP2D6 or CYP3A. Effect of Transporters on Binimetinib: Binimetinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Binimetinib is not a substrate of organic anion transporting polypeptide (OATP1B1, OATP1B3, OATP2B1) or organic cation transporter 1 (OCT1).