ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are described elsewhere in the labeling:oNew Primary Malignancies [see Warnings and Precautions (5.1)]oCardiomyopathy [see Warnings and Precautions (5.2)]oVenous Thromboembolism [see Warnings and Precautions (5.3)]oOcular Toxicities [see Warnings and Precautions (5.4)]oInterstitial Lung Disease [see Warnings and Precautions (5.5)]oHepatotoxicity [see Warnings and Precautions (5.6)]oRhabdomyolysis [see Warnings and Precautions (5.7)]oHemorrhage [see Warnings and Precautions (5.8)]oEmbryo-Fetal Toxicity [see Warnings and Precautions (5.9)]oRisks Associated with Combination Treatment [see Warnings and Precautions (5.10)]. oNew Primary Malignancies [see Warnings and Precautions (5.1)]. oCardiomyopathy [see Warnings and Precautions (5.2)]. oVenous Thromboembolism [see Warnings and Precautions (5.3)]. oOcular Toxicities [see Warnings and Precautions (5.4)]. oInterstitial Lung Disease [see Warnings and Precautions (5.5)]. oHepatotoxicity [see Warnings and Precautions (5.6)]. oRhabdomyolysis [see Warnings and Precautions (5.7)]. oHemorrhage [see Warnings and Precautions (5.8)]. oEmbryo-Fetal Toxicity [see Warnings and Precautions (5.9)]. oRisks 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 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 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 MelanomaThe 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 history of Gilberts 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 and Table present adverse drug reactions and laboratory abnormalities, respectively, identified in COLUMBUS. The COLUMBUS trial was not designed to demonstrate 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 COLUMBUSGrades per National Cancer Institute CTCAE v4.03. Adverse ReactionMEKTOVI with encorafenib N=192VemurafenibN=186All Grades(%)Grades and 4Grade 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 and 4(%)General Disorders and Administration Site Conditions FatigueRepresents composite of multiple, related preferred terms. 433466 Pyrexia 184300 Peripheral edema 131151Gastrointestinal Disorders Nausea412342 Diarrhea363342 Vomiting 302161 Abdominal pain 284161 Constipation22061Skin and Subcutaneous Tissue Disorders Rash 2215313Nervous System Disorders Dizziness 15340Visual Disorders Visual impairment 20040 Serous retinopathy/RPED 20320Vascular Disorders Hemorrhage 19392 Hypertension 116113Other 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 COLUMBUSGrades per National Cancer Institute CTCAE v4.03. Laboratory AbnormalityMEKTOVI with encorafenib N=192VemurafenibN=186All Grades(%)Grades and (%)All Grades(%)Grades and (%)Hematology Anemia 363.6342.2 Leukopenia 130100.5 Lymphopenia 132.1307 Neutropenia133.14.80.5Chemistry Increased Creatinine933.6921.1 Increased Creatine Phosphokinase 5853.80 Increased Gamma Glutamyl Transferase 4511344.8 Increased ALT 296272.2 Increased AST 272.6241.6 Increased Alkaline Phosphatase 210.5352.2 Hyponatremia183.6150.5BRAF 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%). 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 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 and Table 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 PHAROSGrades per National Cancer Institute CTCAE v4.03. Adverse ReactionMEKTOVIwith encorafenibN=98AllGrades(%)Grade and 4One Grade adverse reaction of hemorrhage occurred.(%)General Disorders and Administration Site Conditions FatigueFatigue includes fatigue, asthenia. 618 EdemaEdema includes edema peripheral, generalized edema, swelling, localized edema, face edema. 231 Pyrexia220Gastrointestinal Disorders Nausea583.1 DiarrheaDiarrhea includes diarrhea, colitis. 527 Vomiting371 Abdominal painAbdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, epigastric discomfort. 321 Constipation270Eye Disorders Visual impairmentVisual impairment includes vision blurred, visual impairment, vitreous floaters, photophobia, visual acuity reduced, photopsia. 292Musculoskeletal and Connective Tissue Disorders Musculoskeletal painMusculoskeletal pain includes back pain, arthralgia, pain in extremity, myalgia, musculoskeletal chest pain, non-cardiac chest pain, neck pain. 484.1Skin and Subcutaneous Tissue Disorders RashRash includes rash, rash macular, rash maculo-papular, rash papular, rash pustular,dermatitis acneiform, palmar-plantar erythrodysesthesia syndrome, eczema, skin exfoliation. 273.1 PruritisPruritis includes pruritus, pruritus genital. 160 Dry skin130 Alopecia120Respiratory, Thoracic and Mediastinal Disorders DyspneaDyspnea includes dyspnea, dyspnea exertional. 278 CoughCough includes cough, productive cough. 260Nervous System Disorders DizzinessDizziness includes dizziness, balance disorder. 171 Headache110Metabolism and Nutrition Disorders Decreased appetite141Vascular Disorders Hemorrhage Hemorrhage includes anal hemorrhage, hemothorax, gastrointestinal hemorrhage, hematochezia, hematuria, hemoptysis, hemorrhage intracranial, hyphema, small intestinal hemorrhage, upper gastrointestinal hemorrhage, vaginal hemorrhage. 124.1 Hypertension105Cardiac Disorders Left ventricular dysfunction/cardiomyopathyLeft ventricular dysfunction/cardiomyopathy includes ejection fraction decreased, cardiac failure, cardiac failure congestive. 111Investigations Weight increased111Psychiatric Disorders Insomnia100Other 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 PHAROSGrades per National Cancer Institute CTCAE v4.03. Laboratory AbnormalityBased on the number of patients with available baseline and at least one on-treatment laboratory test.MEKTOVI with encorafenibAllGrades(%)Grades3 and 4(%)Hematology Anemia4711 Lymphopenia246 Thrombocytopenia201.1 Leukopenia120 Neutropenia121.1Chemistry Increased creatinine913.2 Hyperglycemia486 Increased creatine kinase413.3 Lipase increased4014 Increased ALT349 Hypoalbuminemia320 Increased AST3110 Increased alkaline phosphatase313.2 Hyperkalemia312.1 Hyponatremia2611 Serum amylase increased221.1 Hypocalcemia122.1.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies with binimetinib have not been conducted. Binimetinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in bone marrow of rats.No dedicated fertility studies have been conducted with binimetinib in animals. In general toxicology studies in rats and monkeys, there were no remarkable findings in male or female reproductive organs.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Binimetinib is reversible inhibitor of mitogen-activated extracellular signal regulated kinase (MEK1) and MEK2 activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. In vitro, binimetinib inhibited extracellular signal-related kinase (ERK) phosphorylation in cell-free assays as well as viability and MEK-dependent phosphorylation of BRAF-mutant human melanoma cell lines. Binimetinib also inhibited in vivo ERK phosphorylation and tumor growth in BRAF-mutant murine xenograft models.Binimetinib and encorafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared to either drug alone, coadministration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of binimetinib and encorafenib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone. In BRAF V600E mutant NSCLC patient-derived xenograft model in mice, coadministration of encorafenib and binimetinib resulted in greater anti-tumor activity compared to binimetinib alone, with respect to tumor growth inhibition. Increased tumor growth delay after dosing cessation was also observed with the coadministration compared to either drug alone.. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyFollowing MEKTOVI 45 mg twice daily, no clinically meaningful QT prolongation was observed.. 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.. AbsorptionAfter oral administration, at least 50% of the binimetinib dose was absorbed with median time to maximum concentration (Tmax) of 1.6 hours. Effect of FoodThe administration of single dose of MEKTOVI 45 mg with 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. DistributionBinimetinib 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 (45%).. EliminationThe mean (CV%) terminal half-life (t1/2) of binimetinib is 3.5 hours (28.5%) and apparent clearance (CL/F) is 20.2 L/h (24%).. MetabolismThe 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 single oral dose of 45 mg radiolabeled binimetinib, approximately 60% of the circulating radioactivity AUC in plasma was attributable to binimetinib.. ExcretionFollowing 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 PopulationsAge (20 to 94 years), sex, or body weight do not have 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 Cmax) 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). 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 m2), 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 clinically important effect on binimetinib exposure. Simulations predict similar Cmax 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 sensitive CYP3A4 substrate (midazolam).. Effect of Acid Reducing Agents on Binimetinib: The extent of binimetinib exposure (AUC) was not altered in the presence of gastric acid reducing agent (rabeprazole). In Vitro Studies. Effect of Binimetinib on CYP Substrates: Binimetinib is not time-dependent inhibitor of CYP1A2, CYP2C9, CYP2D6 or CYP3A.. Effect of Transporters on Binimetinib: Binimetinib is substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Binimetinib is not substrate of organic anion transporting polypeptide (OATP1B1, OATP1B3, OATP2B1) or organic cation transporter (OCT1).

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma MEKTOVI in combination with encorafenib was evaluated in randomized, active-controlled, open-label, multicenter trial (COLUMBUS; NCT01909453). Eligible patients were required to have BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, as detected using the bioMerieux THxID(TM)BRAF assay. Patients were permitted to have received immunotherapy in the adjuvant setting and one prior line of immunotherapy for unresectable locally advanced or metastatic disease. Prior use of BRAF inhibitors or MEK inhibitors was prohibited. Randomization was stratified by American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c), Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), and prior immunotherapy for unresectable or metastatic disease (yes versus no). Patients were randomized (1:1:1) to receive MEKTOVI 45 mg twice daily in combination with encorafenib 450 mg once daily (MEKTOVI in combination with encorafenib), encorafenib 300 mg once daily, or vemurafenib 960 mg twice daily. Treatment continued until disease progression or unacceptable toxicity. Only the results of the approved dosing (MEKTOVI 45 mg in combination with encorafenib 450 mg) are described below. The major efficacy outcome measure was progression-free survival (PFS), as assessed by blinded independent central review, to compare MEKTOVI in combination with encorafenib with vemurafenib. Additional efficacy measures included overall survival (OS), as well as objective response rate (ORR) and duration of response (DoR) which were assessed by central review.A total of 577 patients were randomized, 192 to the MEKTOVI in combination with encorafenib arm, 194 to the encorafenib arm, and 191 to the vemurafenib arm. Of the 383 patients randomized to either the MEKTOVI in combination with encorafenib or the vemurafenib arms, the median age was 56 years (20 to 89 years), 59% were male, 91% were White, and 72% had baseline ECOG performance status of 0. Ninety-five percent (95%) had metastatic disease, 65% were Stage IVM1c, and 4% received prior CTLA-4, PD-1, or PD-L1 directed antibodies. Twenty-eight percent (28%) had elevated baseline serum lactate dehydrogenase (LDH), 45% had >=3 organs with tumor involvement at baseline, and 3% had brain metastases. Based on centralized testing, 100% of patients tumors tested positive for BRAF mutations; BRAF V600E (88%), BRAF V600K (11%), or both (<1%). MEKTOVI in combination with encorafenib demonstrated statistically significant improvement in PFS compared to vemurafenib. Efficacy results are summarized in Table and Figure 1.Table 7: Efficacy Results for COLUMBUSCI Confidence interval; CR Complete response; DoR Duration of response; HR Hazard ratio; NE Not estimable; ORR Overall response rate; OS Overall survival; PFS Progression-free survival; PR Partial response.MEKTOVIwith encorafenibN=192VemurafenibN=191Progression-Free Survival Number of events (%)98 (51)106 (55) Progressive disease88 (46)104 (54) Death10 (5)2 (1) Median PFS, months (95% CI)14.9 (11.0, 18.5)7.3 (5.6, 8.2) HR (95% CI)Estimated with Cox proportional hazard model adjusted by the following stratification factors: American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c) and Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1). 0.54 (0.41, 0.71) valueLog-rank test adjusted by the same stratification factors. <0.0001Overall SurvivalBased on cutoff date 82.4 months after the date of PFS analysis. Number of events (%)139 (72)147 (77) Median OS, months (95% CI)33.6 (24.4, 39.2)16.9 (14.0, 24.5) HR (95% CI) 0.67 (0.53, 0.84)Overall Response Rate ORR (95% CI)63% (56%, 70%)40% (33%, 48%) CR8%6% PR55%35%Duration of Response Median DoR, months (95% CI)16.6 (12.2, 20.4)12.3 (6.9, 16.9)Figure 1: Kaplan-Meier Curves for Progression-Free Survival in COLUMBUS. Figure 1. 14.2 BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer MEKTOVI in combination with encorafenib was evaluated in an open-label, multicenter, single-arm study in patients with BRAF V600E mutation-positive metastatic non-small cell lung cancer (NSCLC) (PHAROS; NCT03915951). Eligible patients had diagnosis of histologically-confirmed metastatic NSCLC with BRAF V600E mutation that was treatment-naive or had been previously treated with prior line of systemic therapy in the metastatic setting (platinum-based chemotherapy and/or anti-PD-1/PD-L1 therapies), age 18 years or older, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of or 1, and measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Prior use of BRAF inhibitors or MEK inhibitors was not allowed. Patients received MEKTOVI 45 mg orally twice daily and encorafenib 450 mg once daily until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) per RECIST v1.1 and duration of response (DoR) as assessed by independent review committee (IRC).In the efficacy population, BRAF V600E mutation status was determined by prospective local testing using tumor tissue (78%) or blood (22%) specimens. Of the 98 patients with BRAF V600E mutation, patients were enrolled into the trial based on testing of their tumor tissue specimens with the FoundationOne CDx tissue test. Of the remaining 92 patients enrolled based on local testing, 68 patients had their tumor tissue specimens retrospectively confirmed as having BRAF V600E positive status by the FoundationOne CDx tissue test. The remaining patients had either BRAF V600E negative status (n=5) or had unevaluable results (n=19) by the FoundationOne CDx tissue test. In addition, plasma samples from 81 out of 98 patients were retrospectively tested using the FoundationOne Liquid CDx assay. Of the 81 patients, 48 were confirmed positive for BRAF V600E, while 33 patients were BRAF V600E mutation negative by FoundationOne Liquid CDx assay. The remaining 17 samples had unevaluable results with FoundationOne Liquid CDx assay.The efficacy population included 59 treatment-naive patients and 39 previously-treated patients. Among these 98 patients, the median age was 70 years (range: 47 to 86); 53% female; 88% White, 7% Asian, 3% Black or African American, and 1% American Indian or Alaska Native; 99% were not Hispanic or Latino; 13% were current smokers and 57% were former smokers; 73% had ECOG PS of 1; and 97% had adenocarcinoma. All patients had metastatic disease and 8% had brain metastases at baseline.Efficacy results for patients with BRAF V600E mutation-positive metastatic NSCLC are summarized in Table 8.Table 8: Efficacy Results for PHAROSCI Confidence interval; CR Complete response; DoR Duration of response; = Number of patients; NE Not estimable; ORR Objective response rate; PR Partial response.MEKTOVI with encorafenibEfficacy ParameterTreatment naive(N=59)Previously treated(N=39)Objective Response RateAssessed by Independent Central Review (ICR). ORR (95% CI)75% (62, 85)46% (30, 63) CR15%10% PR59%36%Duration of ResponseBased on observed duration of response.N=44N=18 Range in months1.4, 51.6+3.8, 45.8+ with DoR >=12 months64%44% with DoR >=24 months43%22%.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Binimetinib is kinase inhibitor. The chemical name is 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide. The molecular formula is C17H15BrF2N4O3 and the molecular weight is 441.2 daltons. The chemical structure of binimetinib is shown below:Binimetinib is white to slightly yellow powder. In aqueous media, binimetinib is slightly soluble at pH 1, very slightly soluble at pH 2, and practically insoluble at pH 4.5 and higher.MEKTOVI (binimetinib) tablets for oral use contain 15 mg of binimetinib with the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate (vegetable source), and colloidal silicon dioxide. The coating contains polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, ferric oxide yellow, and ferrosoferric oxide.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. MelanomaoConfirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to the initiation of MEKTOVI. (2.1)oThe recommended dose is 45 mg orally twice daily in combination with encorafenib. Take MEKTOVI with or without food. (2.2)oFor patients with moderate or severe hepatic impairment the recommended dose is 30 mg orally twice daily. (2.4, 8.6) NSCLCoConfirm the presence of BRAF V600E mutation in tumor or plasma specimens prior to initiating MEKTOVI. (2.1)oThe recommended dose is 45 mg orally twice daily in combination with encorafenib. Take MEKTOVI with or without food. (2.2). oConfirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to the initiation of MEKTOVI. (2.1). oThe recommended dose is 45 mg orally twice daily in combination with encorafenib. Take MEKTOVI with or without food. (2.2). oFor patients with moderate or severe hepatic impairment the recommended dose is 30 mg orally twice daily. (2.4, 8.6) oConfirm the presence of BRAF V600E mutation in tumor or plasma specimens prior to initiating MEKTOVI. (2.1). oThe 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 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 BRAF V600E mutation in tumor or plasma specimens prior to initiating MEKTOVI [see Clinical Studies (14.2)]. If no mutation is detected in 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 missed dose of MEKTOVI within 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 ReactionsActionRecommended DoseFirst Dose Reduction30 mg orally twice dailySubsequent ModificationPermanently discontinue if unable to tolerate MEKTOVI 30 mg orally twice dailyDosage modifications for adverse reactions associated with MEKTOVI are presented in Table 2.Table 2: Recommended Dosage Modifications for MEKTOVI for Adverse ReactionsSeverity of Adverse ReactionNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.Dose Modification for MEKTOVICardiomyopathy [see Warnings and Precautions (5.2)]oAsymptomatic, absolute decrease in LVEF of greater than 10% from baseline that is also below lower limit of normal (LLN)Withhold MEKTOVI for up to weeks, evaluate LVEF every weeks.Resume MEKTOVI at reduced dose if the following are present:oLVEF is at or above the lower limit of normal andoAbsolute decrease from baseline is 10% or less andoPatient is asymptomatic.If the LVEF does not recover within weeks permanently discontinue MEKTOVI. oSymptomatic congestive heart failure or absolute decrease in LVEF of greater than 20% from baseline that is also below LLNPermanently discontinue MEKTOVI.Venous Thromboembolism [see Warnings and Precautions (5.3)]oUncomplicated deep venous thrombosis (DVT) or pulmonary embolism (PE)Withhold MEKTOVI.oIf improves to Grade 0-1, resume at reduced dose.oIf no improvement, permanently discontinue MEKTOVI.oLife threatening PEPermanently discontinue MEKTOVI.Serous Retinopathy [see Warnings and Precautions (5.4)]oSymptomatic serous retinopathy/Retinal pigment epithelial detachmentsWithhold MEKTOVI for up to 10 days.oIf improves and becomes asymptomatic, resume at same dose.oIf not improved, resume at lower dose level or permanently discontinue MEKTOVI. Retinal Vein Occlusion (RVO) [see Warnings and Precautions (5.4)]oAny Grade Permanently discontinue MEKTOVI.Uveitis [see Warnings and Precautions (5.4)]oGrade 1-3If Grade or does not respond to specific ocular therapy, or for Grade uveitis, withhold MEKTOVI for up to weeks.oIf improved, resume at same or reduced dose. oIf not improved, permanently discontinue MEKTOVI.oGrade 4Permanently discontinue MEKTOVI.Interstitial Lung Disease [see Warnings and Precautions (5.5)]oGrade 2Withhold MEKTOVI for up to weeks.oIf improved to Grade 0-1, resume at reduced dose.oIf not resolved within weeks, permanently discontinue MEKTOVI.oGrade or Grade 4Permanently discontinue MEKTOVI. Hepatotoxicity [see Warnings and Precautions (5.6)]oGrade AST or ALT increasedMaintain MEKTOVI dose. oIf no improvement within weeks, withhold MEKTOVI until improved to Grade 0-1 or to pretreatment/baseline levels and then resume at the same dose.oGrade or AST or ALT increasedSee Other Adverse Reactions. Rhabdomyolysis or Creatine Phosphokinase (CPK) elevations [see Warnings and Precautions (5.7)]oGrade asymptomatic CPK elevation or oAny Grade CPK elevation with symptoms or with renal impairmentWithhold MEKTOVI dose for up to weeks.oIf improved to Grade 0-1 resume at reduced dose.oIf not resolved within weeks, permanently discontinue MEKTOVI.Dermatologic [other than palmar plantar erythrodysesthesia syndrome (PPES)] [see Adverse Reactions (6.1)]oGrade 2If no improvement within weeks, withhold MEKTOVI until Grade 0-1. Resume at same dose if first occurrence or reduce dose if recurrent.oGrade 3Withhold MEKTOVI until Grade 0-1. Resume at same dose if first occurrence or reduce dose if recurrent.oGrade 4Permanently 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.oRecurrent Grade oroFirst occurrence of any Grade 3Withhold MEKTOVI for up to weeks.oIf improves to Grade 0-1 or to pretreatment/baseline levels, resume at reduced dose.oIf no improvement, permanently discontinue MEKTOVI.oFirst occurrence of any Grade 4Permanently discontinue MEKTOVI, orWithhold MEKTOVI for up to weeks.oIf improves to Grade 0-1 or to pretreatment/baseline levels, then resume at reduced dose.oIf no improvement, permanently discontinue MEKTOVI.oRecurrent Grade 3Consider permanently discontinuing MEKTOVI.oRecurrent Grade 4Permanently discontinue MEKTOVI.Refer to the encorafenib prescribing information for dose modifications for adverse reactions associated with encorafenib.. oAsymptomatic, absolute decrease in LVEF of greater than 10% from baseline that is also below lower limit of normal (LLN). oLVEF is at or above the lower limit of normal and. oAbsolute decrease from baseline is 10% or less and. oPatient is asymptomatic.. oSymptomatic congestive heart failure or absolute decrease in LVEF of greater than 20% from baseline that is also below LLN. oUncomplicated deep venous thrombosis (DVT) or pulmonary embolism (PE). oIf improves to Grade 0-1, resume at reduced dose.. oIf no improvement, permanently discontinue MEKTOVI.. oLife threatening PE. oSymptomatic serous retinopathy/Retinal pigment epithelial detachments. oIf improves and becomes asymptomatic, resume at same dose.. oIf not improved, resume at lower dose level or permanently discontinue MEKTOVI. oAny Grade oGrade 1-3. oIf improved, resume at same or reduced dose. oIf not improved, permanently discontinue MEKTOVI.. oGrade 4. oGrade 2. oIf improved to Grade 0-1, resume at reduced dose.. oIf not resolved within weeks, permanently discontinue MEKTOVI.. oGrade or Grade 4. oGrade AST or ALT increased. oIf no improvement within weeks, withhold MEKTOVI until improved to Grade 0-1 or to pretreatment/baseline levels and then resume at the same dose.. oGrade or AST or ALT increased. oGrade asymptomatic CPK elevation or oAny Grade CPK elevation with symptoms or with renal impairment. oIf improved to Grade 0-1 resume at reduced dose.. oIf not resolved within weeks, permanently discontinue MEKTOVI.. oGrade 2. oGrade 3. oGrade 4. oRecurrent Grade or. oFirst occurrence of any Grade 3. oIf improves to Grade 0-1 or to pretreatment/baseline levels, resume at reduced dose.. oIf no improvement, permanently discontinue MEKTOVI.. oFirst occurrence of any Grade 4. oIf improves to Grade 0-1 or to pretreatment/baseline levels, then resume at reduced dose.. oIf no improvement, permanently discontinue MEKTOVI.. oRecurrent Grade 3. oRecurrent Grade 4. 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 x ULN and any AST) or severe (total bilirubin levels greater than x 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)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Tablets: 15 mg, yellow/dark yellow, unscored biconvex oval film-coated tablets debossed with stylized A on one side and 15 on the other side.. Tablets: 15 mg. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. No clinically important drug interactions have been observed with MEKTOVI.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Based on animal data, MEKTOVI can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating MEKTOVI [see Use in Specific Populations (8.1)]. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for 30 days after the last dose.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 690 patients with BRAF mutation-positive melanoma who received MEKTOVI in combination with encorafenib across multiple clinical trials, 20% were aged 65 to 74 years and 8% were aged 75 years and older [see Clinical Pharmacology (12.3)].Of the 98 patients with BRAF V600E mutation-positive metastatic NSCLC who received MEKTOVI in combination with encorafenib, 62 (63.2%) were 65 years of age and over and 20 (20.4%) were 75 years and over [see Clinical Studies (14.2)].No overall differences in the safety or effectiveness of MEKTOVI plus encorafenib were observed in older patients as compared to younger patients.

HEPATIC IMPAIRMENT SUBSECTION.

8.6 Hepatic Impairment. Binimetinib concentrations may increase in patients with moderate or severe hepatic impairment. Dose adjustment for MEKTOVI is not recommended in patients with mild hepatic impairment (total bilirubin >1 and <=1.5 ULN and any AST or total bilirubin <= ULN and AST ULN). Reduce the dose of MEKTOVI for patients 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), Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. MEKTOVI (binimetinib) is supplied as 15 mg yellow/dark yellow, unscored biconvex oval film-coated tablets debossed with stylized A on one side and 15 on the other side, available in bottles of 180 tablets (NDC 70255-010-02).. Store at 20C to 25C (68F to 77F); excursions permitted between 15C and 30C (59F and 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. MEKTOVI is kinase inhibitor indicated:oin combination with encorafenib, for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation, as detected by an FDA-approved test. (1.1, 2.1)oin combination with encorafenib, for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation, as detected by an FDA-approved test. (1.2, 2.1). oin combination with encorafenib, for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation, as detected by an FDA-approved test. (1.1, 2.1). oin combination with encorafenib, for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with 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 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 BRAF V600E mutation, as detected by an FDA-approved test. [see Dosage and Administration (2.1)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).Inform patients of the following:. New Primary MalignanciesAdvise patients that MEKTOVI administered with encorafenib 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)].CardiomyopathyAdvise patients to report any symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.2) ]. Venous ThromboembolismAdvise patients to contact their healthcare provider if they experience symptoms of venous thrombosis or pulmonary embolism. Advise patients to seek medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.3) ].. Ocular ToxicitiesAdvise patients to contact their healthcare provider as soon as possible if they experience any changes in their vision [see Warnings and Precautions (5.4) ].. Interstitial Lung DiseaseAdvise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including cough or dyspnea [see Warnings and Precautions (5.5) ].. HepatotoxicityAdvise patients that serial testing of serum liver tests (ALT, AST, bilirubin) is recommended during treatment with MEKTOVI. Instruct patients to report symptoms of liver dysfunction including jaundice, dark urine, nausea, vomiting, loss of appetite, fatigue, bruising, or bleeding [see Warnings and Precautions (5.6) ].. RhabdomyolysisAdvise patients to contact their healthcare provider as soon as possible if they experience unusual or new onset weakness, myalgia, or darkened urine [see Warnings and Precautions (5.7) ].. HemorrhageAdvise patients to notify their healthcare provider if they experience symptoms suggestive of hemorrhage, such as unusual bleeding [see Warnings and Precautions (5.8) ].. Females and Males of Reproductive Potential. Embryo-Fetal Toxicity: Advise females with reproductive potential of the potential risk to fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with MEKTOVI [see Warnings and Precautions (5.9), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for 30 days after the last dose.. Lactation: Advise women not to breastfeed during treatment with MEKTOVI and for days after the last dose [see Use in Specific Populations (8.2)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of binimetinib or its active metabolite in human milk, or the effects of binimetinib on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed child, advise women not to breastfeed during treatment with MEKTOVI and for days after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Binimetinib is reversible inhibitor of mitogen-activated extracellular signal regulated kinase (MEK1) and MEK2 activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. In vitro, binimetinib inhibited extracellular signal-related kinase (ERK) phosphorylation in cell-free assays as well as viability and MEK-dependent phosphorylation of BRAF-mutant human melanoma cell lines. Binimetinib also inhibited in vivo ERK phosphorylation and tumor growth in BRAF-mutant murine xenograft models.Binimetinib and encorafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared to either drug alone, coadministration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of binimetinib and encorafenib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone. In BRAF V600E mutant NSCLC patient-derived xenograft model in mice, coadministration of encorafenib and binimetinib resulted in greater anti-tumor activity compared to binimetinib alone, with respect to tumor growth inhibition. Increased tumor growth delay after dosing cessation was also observed with the coadministration compared to either drug alone.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies with binimetinib have not been conducted. Binimetinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in bone marrow of rats.No dedicated fertility studies have been conducted with binimetinib in animals. In general toxicology studies in rats and monkeys, there were no remarkable findings in male or female reproductive organs.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Since binimetinib is 97% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKTOVI.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 15 mg Tablet Bottle Label. NDC 70255-010-02MEKTOVI(R) (binimetinib) tablets15 mgRx only180 Tablets. PRINCIPAL DISPLAY PANEL 15 mg Tablet Bottle Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of MEKTOVI have not been established in pediatric patients.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyFollowing MEKTOVI 45 mg twice daily, no clinically meaningful QT prolongation was observed.

PHARMACOKINETICS SECTION.

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.. AbsorptionAfter oral administration, at least 50% of the binimetinib dose was absorbed with median time to maximum concentration (Tmax) of 1.6 hours. Effect of FoodThe administration of single dose of MEKTOVI 45 mg with 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. DistributionBinimetinib 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 (45%).. EliminationThe mean (CV%) terminal half-life (t1/2) of binimetinib is 3.5 hours (28.5%) and apparent clearance (CL/F) is 20.2 L/h (24%).. MetabolismThe 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 single oral dose of 45 mg radiolabeled binimetinib, approximately 60% of the circulating radioactivity AUC in plasma was attributable to binimetinib.. ExcretionFollowing 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 PopulationsAge (20 to 94 years), sex, or body weight do not have 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 Cmax) 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). 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 m2), 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 clinically important effect on binimetinib exposure. Simulations predict similar Cmax 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 sensitive CYP3A4 substrate (midazolam).. Effect of Acid Reducing Agents on Binimetinib: The extent of binimetinib exposure (AUC) was not altered in the presence of gastric acid reducing agent (rabeprazole). In Vitro Studies. Effect of Binimetinib on CYP Substrates: Binimetinib is not time-dependent inhibitor of CYP1A2, CYP2C9, CYP2D6 or CYP3A.. Effect of Transporters on Binimetinib: Binimetinib is substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Binimetinib is not substrate of organic anion transporting polypeptide (OATP1B1, OATP1B3, OATP2B1) or organic cation transporter (OCT1).

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings from animal reproduction studies and its mechanism of action [see Clinical Pharmacology (12.1)], MEKTOVI can cause fetal harm when administered to pregnant woman. There are no available clinical data on the use of MEKTOVI during pregnancy. In animal reproduction studies, oral administration of binimetinib during the period of organogenesis was embryotoxic and an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately times the human exposure at the clinical dose of 45 mg twice daily (see Data). Advise pregnant women and females of reproductive potential of the potential risk to 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 DataIn reproductive toxicity studies, administration of binimetinib to rats during the period of organogenesis resulted in maternal toxicity, decreased fetal weights and increased variations in ossification at doses >=30 mg/kg/day (approximately 37 times the human exposure based on AUC at the recommended clinical dose of 45 mg twice daily). In pregnant rabbits, administration of binimetinib during the period of organogenesis resulted in maternal toxicity, decreased fetal body weights, an increase in malformations, and increased post-implantation loss, including total loss of pregnancy at doses >=10 mg/kg/day (approximately times the human exposure based on AUC at the recommended clinical dose of 45 mg twice daily). There was significant increase in fetal ventricular septal defects and pulmonary trunk alterations at 20 mg/kg/day of binimetinib (less than times the human exposure at the recommended clinical dose of 45 mg twice daily).

SPL MEDGUIDE SECTION.

MEDICATION GUIDEMEKTOVI(R) (mek-TOE-vee)(binimetinib)tabletsImportant Information: If your healthcare provider prescribes MEKTOVI with encorafenib, please read the Medication Guide that comes with encorafenib.What is the most important information should know about MEKTOVI when taken in combination with encorafenibMEKTOVI when taken in combination with encorafenib may cause serious side effects, including:oRisk of new skin cancers. MEKTOVI, when used with encorafenib, may cause skin cancers called cutaneous squamous cell carcinoma or basal cell carcinoma. Talk to your healthcare provider about your risk for these cancers. Check your skin and tell your healthcare provider right away about any skin changes, including a:onew wartoskin sore or reddish bump that bleeds or does not healochange in size or color of mole Your healthcare provider should check your skin before treatment with MEKTOVI, when taken in combination with encorafenib, every months during treatment, and for up to months after you stop treatment to look for any new skin cancers. Your healthcare provider should also check for cancers that may not occur on the skin. Tell your healthcare provider about any new symptoms that develop during treatment with MEKTOVI when taken in combination with encorafenib.See What are the possible side effects of MEKTOVI for more information about side effects.What is MEKTOVI MEKTOVI is prescription medicine used:oin combination with medicine called encorafenib to treat people with type of skin cancer called melanoma: othat has spread to other parts of the body or cannot be removed by surgery, and othat has certain type of abnormal BRAF gene oin combination with medicine called encorafenib to treat adults with type of lung cancer called non-small cell lung cancer (NSCLC): othat has spread to other parts of the body, andothat has certain type of abnormal BRAF geneYour healthcare provider will perform test to make sure that MEKTOVI is right for you.It is not known if MEKTOVI is safe and effective in children.Before taking MEKTOVI, tell your healthcare provider about all of your medical conditions, including if you:ohave heart problems ohave had blood clotsohave eye problemsohave lung or breathing problemsohave liver or kidney problemsohave any muscle problemsohave bleeding problemsohave high blood pressure (hypertension)oare pregnant or plan to become pregnant. MEKTOVI can harm your unborn baby.oFemales who are able to become pregnant should use effective birth control (contraception) during treatment with MEKTOVI and for at least 30 days after the last dose of MEKTOVI. oTalk to your healthcare provider about birth control methods that may be right for you during this time. oYour healthcare provider will do pregnancy test before you start taking MEKTOVI. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with MEKTOVI.oare breastfeeding or plan to breastfeed. It is not known if MEKTOVI passes into your breast milk. Do not breastfeed during treatment with MEKTOVI and for days after the last dose of MEKTOVI. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How should take MEKTOVI oTake MEKTOVI exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking MEKTOVI unless your healthcare provider tells you to. oTake MEKTOVI in combination with encorafenib by mouth times day, about 12 hours apart. oMEKTOVI may be taken with or without food.oIf you miss dose of MEKTOVI, take it as soon as you remember. If it is within hours of your next scheduled dose, take your next dose at your regular time. Do not make up for the missed dose.oDo not take an extra dose if you vomit after taking your scheduled dose. Take your next dose at your regular time.oIf you stop treatment with encorafenib, talk to your healthcare provider about whether your MEKTOVI treatment may need to be stopped. What are the possible side effects of MEKTOVI MEKTOVI may cause serious side effects, including: oHeart problems, including heart failure. MEKTOVI, when taken with encorafenib, can cause heart problems. Your healthcare provider should check your heart function before and during treatment with MEKTOVI. Call your healthcare provider right away if you have any of the following signs and symptoms of heart problem:ofeeling like your heart is pounding or racing oshortness of breathoswelling of your ankles and feet ofeeling lightheaded oBlood clots. MEKTOVI, when taken with encorafenib, can cause blood clots in your arms or legs, which can travel to your lungs and can lead to death. Get medical help right away if you have the following symptoms:ochest painosudden shortness of breath or trouble breathingopain in your legs with or without swellingoswelling in your arms and legsoa cool pale arm or leg oEye problems. MEKTOVI, when taken with encorafenib, can cause eye problems. Your healthcare provider should perform an eye exam regularly during treatment with MEKTOVI. Tell your healthcare provider right away if you develop any new or worsening symptoms of eye problems, including: oblurred vision, loss of vision, or other vision changes osee colored dotsosee halos (blurred outline around objects)oeye pain, swelling, or redness oLung or breathing problems. MEKTOVI, when taken with encorafenib, can cause lung or breathing problems. Tell your healthcare provider if you have any new or worsening symptoms of lung or breathing problems, including: oshortness of breathocough oLiver problems. MEKTOVI, when taken with encorafenib, can cause liver problems. Your healthcare provider should perform blood tests to check your liver function before and during treatment with MEKTOVI. Tell your healthcare provider if you have any of the following signs and symptoms of liver problem:oyellowing of your skin or your eyesodark or brown (tea-colored) urine onausea or vomitingoloss of appetiteotirednessobruising obleedingoMuscle problems (rhabdomyolysis). MEKTOVI, when taken with encorafenib, can cause muscle problems that can be severe. Treatment with MEKTOVI may increase the level of an enzyme in your blood called creatine phosphokinase (CPK) and can be sign of muscle damage. Your healthcare provider should perform blood test to check your levels of CPK before and during treatment. Tell your healthcare provider right away if you develop any of these symptoms:oweaknessomuscle aches or painodark, reddish urineoBleeding problems. MEKTOVI, when taken with encorafenib, can cause serious bleeding problems, including in your brain or stomach, that can lead to death. Tell your healthcare provider and get medical help right away if you develop any signs of bleeding, including:oheadaches, dizziness, or feeling weakocough up blood or blood clotsovomit blood or your vomit looks like coffee groundsored or black stool that look like tar Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with MEKTOVI if you have certain side effects. The most common side effects of MEKTOVI when taken with encorafenib for melanoma include:ofatigueonauseaodiarrheaovomitingostomach-area (abdominal) painThe most common side effects of MEKTOVI when taken with encorafenib for NSCLC include:ofatigueonauseaodiarrheaomuscle or joint painovomitingostomach-area (abdominal) painoblurred vision, loss of vision, or other vision changesoconstipationoshortness of breathorashocoughThese are not all of the possible side effects of MEKTOVI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Pfizer Inc. at 1-800-438-1985.How should store MEKTOVI oStore MEKTOVI at room temperature between 68F to 77F (20C to 25C). Keep MEKTOVI and all medicines out of the reach of children.General information about the safe and effective use of MEKTOVI. Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use MEKTOVI for condition for which it was not prescribed. Do not give MEKTOVI to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about MEKTOVI that is written for health professionals.What are the ingredients in MEKTOVI Active ingredient: binimetinib Inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate (vegetable source), and colloidal silicon dioxideTablet coating: polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, ferric oxide yellow, ferrosoferric oxideDistributed by: Array BioPharma Inc., wholly owned subsidiary of Pfizer Inc., Boulder, Colorado 80301.MEKTOVI(R) is registered trademark of Array BioPharma Inc. in the United States and various other countries.For more information, go to www.BRAFTOVIMEKTOVI.com or call 1-844-792-7729.(C)2020 Array BioPharma Inc. All rights reserved.LAB-1427-2.0This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 10/2023. oRisk of new skin cancers. MEKTOVI, when used with encorafenib, may cause skin cancers called cutaneous squamous cell carcinoma or basal cell carcinoma.. Talk to your healthcare provider about your risk for these cancers.. Check your skin and tell your healthcare provider right away about any skin changes, including a:onew wartoskin sore or reddish bump that bleeds or does not healochange in size or color of mole. onew wart. oskin sore or reddish bump that bleeds or does not heal. ochange in size or color of mole. Your healthcare provider should check your skin before treatment with MEKTOVI, when taken in combination with encorafenib, every months during treatment, and for up to months after you stop treatment to look for any new skin cancers.. Your healthcare provider should also check for cancers that may not occur on the skin. Tell your healthcare provider about any new symptoms that develop during treatment with MEKTOVI when taken in combination with encorafenib.. oin combination with medicine called encorafenib to treat people with type of skin cancer called melanoma: othat has spread to other parts of the body or cannot be removed by surgery, and othat has certain type of abnormal BRAF gene othat has spread to other parts of the body or cannot be removed by surgery, and othat has certain type of abnormal BRAF gene oin combination with medicine called encorafenib to treat adults with type of lung cancer called non-small cell lung cancer (NSCLC): othat has spread to other parts of the body, andothat has certain type of abnormal BRAF gene. othat has spread to other parts of the body, and. othat has certain type of abnormal BRAF gene. ohave heart problems ohave had blood clots. ohave eye problems. ohave lung or breathing problems. ohave liver or kidney problems. ohave any muscle problems. ohave bleeding problems. ohave high blood pressure (hypertension). oare pregnant or plan to become pregnant. MEKTOVI can harm your unborn baby.oFemales who are able to become pregnant should use effective birth control (contraception) during treatment with MEKTOVI and for at least 30 days after the last dose of MEKTOVI. oTalk to your healthcare provider about birth control methods that may be right for you during this time. oYour healthcare provider will do pregnancy test before you start taking MEKTOVI. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with MEKTOVI.. oFemales who are able to become pregnant should use effective birth control (contraception) during treatment with MEKTOVI and for at least 30 days after the last dose of MEKTOVI. oTalk to your healthcare provider about birth control methods that may be right for you during this time. oYour healthcare provider will do pregnancy test before you start taking MEKTOVI. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with MEKTOVI.. oare breastfeeding or plan to breastfeed. It is not known if MEKTOVI passes into your breast milk. Do not breastfeed during treatment with MEKTOVI and for days after the last dose of MEKTOVI. Talk to your healthcare provider about the best way to feed your baby during this time. oTake MEKTOVI exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking MEKTOVI unless your healthcare provider tells you to. oTake MEKTOVI in combination with encorafenib by mouth times day, about 12 hours apart. oMEKTOVI may be taken with or without food.. oIf you miss dose of MEKTOVI, take it as soon as you remember. If it is within hours of your next scheduled dose, take your next dose at your regular time. Do not make up for the missed dose.. oDo not take an extra dose if you vomit after taking your scheduled dose. Take your next dose at your regular time.. oIf you stop treatment with encorafenib, talk to your healthcare provider about whether your MEKTOVI treatment may need to be stopped. oHeart problems, including heart failure. MEKTOVI, when taken with encorafenib, can cause heart problems. Your healthcare provider should check your heart function before and during treatment with MEKTOVI. Call your healthcare provider right away if you have any of the following signs and symptoms of heart problem:ofeeling like your heart is pounding or racing oshortness of breathoswelling of your ankles and feet ofeeling lightheaded ofeeling like your heart is pounding or racing oshortness of breath. oswelling of your ankles and feet ofeeling lightheaded oBlood clots. MEKTOVI, when taken with encorafenib, can cause blood clots in your arms or legs, which can travel to your lungs and can lead to death. Get medical help right away if you have the following symptoms:ochest painosudden shortness of breath or trouble breathingopain in your legs with or without swellingoswelling in your arms and legsoa cool pale arm or leg ochest pain. osudden shortness of breath or trouble breathing. opain in your legs with or without swelling. oswelling in your arms and legs. oa cool pale arm or leg. oEye problems. MEKTOVI, when taken with encorafenib, can cause eye problems. Your healthcare provider should perform an eye exam regularly during treatment with MEKTOVI. Tell your healthcare provider right away if you develop any new or worsening symptoms of eye problems, including: oblurred vision, loss of vision, or other vision changes osee colored dotsosee halos (blurred outline around objects)oeye pain, swelling, or redness oblurred vision, loss of vision, or other vision changes osee colored dots. osee halos (blurred outline around objects). oeye pain, swelling, or redness oLung or breathing problems. MEKTOVI, when taken with encorafenib, can cause lung or breathing problems. Tell your healthcare provider if you have any new or worsening symptoms of lung or breathing problems, including: oshortness of breathocough oshortness of breath. ocough. oLiver problems. MEKTOVI, when taken with encorafenib, can cause liver problems. Your healthcare provider should perform blood tests to check your liver function before and during treatment with MEKTOVI. Tell your healthcare provider if you have any of the following signs and symptoms of liver problem:. oyellowing of your skin or your eyes. odark or brown (tea-colored) urine onausea or vomiting. oloss of appetite. otiredness. obruising obleeding. oMuscle problems (rhabdomyolysis). MEKTOVI, when taken with encorafenib, can cause muscle problems that can be severe. Treatment with MEKTOVI may increase the level of an enzyme in your blood called creatine phosphokinase (CPK) and can be sign of muscle damage. Your healthcare provider should perform blood test to check your levels of CPK before and during treatment. Tell your healthcare provider right away if you develop any of these symptoms:oweaknessomuscle aches or painodark, reddish urine. oweakness. omuscle aches or pain. odark, reddish urine. oBleeding problems. MEKTOVI, when taken with encorafenib, can cause serious bleeding problems, including in your brain or stomach, that can lead to death. Tell your healthcare provider and get medical help right away if you develop any signs of bleeding, including:oheadaches, dizziness, or feeling weakocough up blood or blood clotsovomit blood or your vomit looks like coffee groundsored or black stool that look like tar oheadaches, dizziness, or feeling weak. ocough up blood or blood clots. ovomit blood or your vomit looks like coffee grounds. ored or black stool that look like tar. ofatigue. onausea. odiarrhea. ovomiting. ostomach-area (abdominal) pain. ofatigue. onausea. odiarrhea. omuscle or joint pain. ovomiting. ostomach-area (abdominal) pain. oblurred vision, loss of vision, or other vision changes. oconstipation. oshortness of breath. orash. ocough. oStore MEKTOVI at room temperature between 68F to 77F (20C to 25C).

SPL UNCLASSIFIED SECTION.

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 BRAF V600E or V600K mutation, as detected by an FDA-approved test [see Dosage and Administration (2.1)].

STORAGE AND HANDLING SECTION.

Store at 20C to 25C (68F to 77F); excursions permitted between 15C and 30C (59F and 86F) [see USP Controlled Room Temperature].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2) 8.1 Pregnancy. Risk SummaryBased on findings from animal reproduction studies and its mechanism of action [see Clinical Pharmacology (12.1)], MEKTOVI can cause fetal harm when administered to pregnant woman. There are no available clinical data on the use of MEKTOVI during pregnancy. In animal reproduction studies, oral administration of binimetinib during the period of organogenesis was embryotoxic and an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately times the human exposure at the clinical dose of 45 mg twice daily (see Data). Advise pregnant women and females of reproductive potential of the potential risk to 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 DataIn reproductive toxicity studies, administration of binimetinib to rats during the period of organogenesis resulted in maternal toxicity, decreased fetal weights and increased variations in ossification at doses >=30 mg/kg/day (approximately 37 times the human exposure based on AUC at the recommended clinical dose of 45 mg twice daily). In pregnant rabbits, administration of binimetinib during the period of organogenesis resulted in maternal toxicity, decreased fetal body weights, an increase in malformations, and increased post-implantation loss, including total loss of pregnancy at doses >=10 mg/kg/day (approximately times the human exposure based on AUC at the recommended clinical dose of 45 mg twice daily). There was significant increase in fetal ventricular septal defects and pulmonary trunk alterations at 20 mg/kg/day of binimetinib (less than times the human exposure at the recommended clinical dose of 45 mg twice daily).. 8.2 Lactation. Risk SummaryThere are no data on the presence of binimetinib or its active metabolite in human milk, or the effects of binimetinib on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed child, advise women not to breastfeed during treatment with MEKTOVI and for days after the last dose.. 8.3 Females and Males of Reproductive Potential. Based on animal data, MEKTOVI can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating MEKTOVI [see Use in Specific Populations (8.1)]. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for 30 days after the last dose.. 8.4 Pediatric Use. The safety and effectiveness of MEKTOVI have not been established in pediatric patients.. 8.5 Geriatric Use. Of the 690 patients with BRAF mutation-positive melanoma who received MEKTOVI in combination with encorafenib across multiple clinical trials, 20% were aged 65 to 74 years and 8% were aged 75 years and older [see Clinical Pharmacology (12.3)].Of the 98 patients with BRAF V600E mutation-positive metastatic NSCLC who received MEKTOVI in combination with encorafenib, 62 (63.2%) were 65 years of age and over and 20 (20.4%) were 75 years and over [see Clinical Studies (14.2)].No overall differences in the safety or effectiveness of MEKTOVI plus encorafenib were observed in older patients as compared to younger patients.. 8.6 Hepatic Impairment. Binimetinib concentrations may increase in patients with moderate or severe hepatic impairment. Dose adjustment for MEKTOVI is not recommended in patients with mild hepatic impairment (total bilirubin >1 and <=1.5 ULN and any AST or total bilirubin <= ULN and AST ULN). Reduce the dose of MEKTOVI for patients 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), Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oNew Primary Malignancies, Cutaneous and Non-cutaneous: Can occur when MEKTOVI is used in combination with encorafenib. Monitor patients for new malignancies prior to initiation of treatment, during treatment, and after discontinuation of treatment. (5.1)oCardiomyopathy: Assess left ventricular ejection fraction (LVEF) before initiating treatment, after one month of treatment, then every to months thereafter. The safety of MEKTOVI has not been established in patients with LVEF below 50%. (5.2)oVenous Thromboembolism: Deep vein thrombosis and pulmonary embolism can occur. (5.3)oOcular Toxicities: Serous retinopathy, retinal vein occlusion (RVO) and uveitis have occurred. Perform an ophthalmologic evaluation at regular intervals and for any visual disturbances. (5.4)oInterstitial Lung Disease (ILD): Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. (5.5)oHepatotoxicity: Monitor liver function tests before and during treatment with MEKTOVI and encorafenib and as clinically indicated. (5.6)oRhabdomyolysis: Monitor creatine phosphokinase and creatinine periodically and as clinically indicated. (5.7)oHemorrhage: Major hemorrhagic events can occur in patients receiving MEKTOVI and encorafenib. (5.8)oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective contraception. (5.9, 8.1, 8.3). oNew Primary Malignancies, Cutaneous and Non-cutaneous: Can occur when MEKTOVI is used in combination with encorafenib. Monitor patients for new malignancies prior to initiation of treatment, during treatment, and after discontinuation of treatment. (5.1). oCardiomyopathy: Assess left ventricular ejection fraction (LVEF) before initiating treatment, after one month of treatment, then every to months thereafter. The safety of MEKTOVI has not been established in patients with LVEF below 50%. (5.2). oVenous Thromboembolism: Deep vein thrombosis and pulmonary embolism can occur. (5.3). oOcular Toxicities: Serous retinopathy, retinal vein occlusion (RVO) and uveitis have occurred. Perform an ophthalmologic evaluation at regular intervals and for any visual disturbances. (5.4). oInterstitial Lung Disease (ILD): Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. (5.5). oHepatotoxicity: Monitor liver function tests before and during treatment with MEKTOVI and encorafenib and as clinically indicated. (5.6). oRhabdomyolysis: Monitor creatine phosphokinase and creatinine periodically and as clinically indicated. (5.7). oHemorrhage: Major hemorrhagic events can occur in patients receiving MEKTOVI and encorafenib. (5.8). oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective contraception. (5.9, 8.1, 8.3). 5.1 New Primary Malignancies. New primary malignancies, cutaneous and non-cutaneous, can occur when MEKTOVI is used in combination with encorafenib.In PHAROS, cutaneous squamous cell carcinoma and skin papilloma each occurred in 2% of patients who received MEKTOVI in combination with encorafenib.Monitor patients for new malignancies prior to initiation of treatment, while on treatment, and after discontinuation of treatment [see Dosage and Administration (2.3)].. 5.2 Cardiomyopathy Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients treated with MEKTOVI in combination with encorafenib. In COLUMBUS, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an absolute decrease in LVEF >=10% below baseline as detected by echocardiography or MUGA) occurred in 7% of patients receiving MEKTOVI plus encorafenib. Grade left ventricular dysfunction occurred in 1.6% of patients. The median time to first occurrence of left ventricular dysfunction (any grade) in patients receiving MEKTOVI in combination with encorafenib was 3.6 months (range to 21 months). Cardiomyopathy resolved in 87% of patients receiving MEKTOVI plus encorafenib.In PHAROS, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an absolute decrease in LVEF >=10% below baseline as detected by echocardiography or MUGA) occurred in 11% of patients receiving MEKTOVI in combination with encorafenib. Grade left ventricular dysfunction occurred in 1% of patients. Cardiomyopathy resolved in 82% of patients receiving MEKTOVI plus encorafenib.Assess ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, one month after initiating treatment, and then every to months during treatment. The safety of MEKTOVI in combination with encorafenib has not been established in patients with baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely when treated with MEKTOVI.Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].. 5.3 Venous Thromboembolism. In COLUMBUS, venous thromboembolism (VTE) occurred in 6% of patients receiving MEKTOVI in combination with encorafenib, including 3.1% of patients who developed pulmonary embolism. In PHAROS, VTE occurred in 7% of patients receiving MEKTOVI in combination with encorafenib, including 1% of patients who developed pulmonary embolism.Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)]. 5.4 Ocular Toxicities. Serous RetinopathyIn COLUMBUS, serous retinopathy occurred in 20% of patients treated with MEKTOVI in combination with encorafenib; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. No patient discontinued MEKTOVI due to serous retinopathy; 6% of patients required dose interruptions or dose reductions. The median time to onset of the first event of serous retinopathy (all grades) was 1.2 months (range to 17.5 months).In PHAROS, serous retinopathy (retinal detachment) occurred in 2% of patients with no cases of blindness treated with MEKTOVI in combination with encorafenib. No patient permanently discontinued MEKTOVI due to serous retinopathy; 1% of patients required dose interruptions.Assess for visual symptoms at each visit. Perform an ophthalmologic examination at regular intervals, for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].. Retinal Vein OcclusionRVO is known class-related adverse reaction of MEK inhibitors and may occur in patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib (n=690), patient experienced RVO (0.1%).The safety of MEKTOVI has not been established in patients with history of RVO or current risk factors for RVO including uncontrolled glaucoma or history of hyperviscosity or hypercoagulability syndromes. Perform ophthalmologic evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO [see Dosage and Administration (2.3), Adverse Reactions (6.1)].. UveitisUveitis, including iritis and iridocyclitis, has been reported in patients treated with MEKTOVI in combination with encorafenib. In COLUMBUS, the incidence of uveitis among patients treated with MEKTOVI in combination with encorafenib was 4%. In PHAROS, uveitis occurred in 1% of patients receiving MEKTOVI in combination with encorafenib.Assess for visual symptoms at each visit. Perform an ophthalmologic evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].. 5.5 Interstitial Lung Disease. In patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib (n=690), patients (0.3%) developed interstitial lung disease (ILD), including pneumonitis. In PHAROS, patient (1%) receiving MEKTOVI with encorafenib developed pneumonitis.Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].. 5.6 Hepatotoxicity. Hepatotoxicity can occur when MEKTOVI is administered in combination with encorafenib. In COLUMBUS, the incidence of Grade or increases in liver function laboratory tests in patients receiving MEKTOVI in combination with encorafenib was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. No patient experienced Grade or serum bilirubin elevation. In PHAROS, the incidence of Grade or increases in liver function laboratory tests in patients receiving MEKTOVI in combination with encorafenib was 10% for AST, 9% for ALT, and 3.2% for alkaline phosphatase.Monitor liver laboratory tests before initiation of MEKTOVI, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].. 5.7 Rhabdomyolysis. Rhabdomyolysis can occur when MEKTOVI is administered in combination with encorafenib. In COLUMBUS, elevation of laboratory values of serum CPK occurred in 58% of patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib (n=690), rhabdomyolysis was reported in patient (0.1%). In PHAROS, elevation of laboratory values of serum creatine kinase (CK) occurred in 41% of patients treated with MEKTOVI in combination with encorafenib. No patient experienced rhabdomyolysis. Monitor CPK and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].. 5.8 Hemorrhage. Hemorrhage can occur when MEKTOVI is administered in combination with encorafenib. In COLUMBUS, hemorrhage occurred in 19% of patients receiving MEKTOVI in combination with encorafenib. Grade or greater hemorrhage occurred in 3.2% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%). Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients. In PHAROS, hemorrhage occurred in 12% of patients receiving MEKTOVI in combination with encorafenib including fatal hemorrhage intracranial (1%); Grade or hemorrhage occurred in 4.1% of patients. The most frequent hemorrhagic events were anal hemorrhage and hemothorax (2% each).Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].. 5.9 Embryo-Fetal Toxicity. Based on findings from animal studies and its mechanism of action, MEKTOVI can cause fetal harm when administered to pregnant woman. Binimetinib was embryotoxic and abortifacient when administered to rabbits during the period of organogenesis at doses greater than or equal to those resulting in exposures approximately times the human exposure at the recommended clinical dose of 45 mg twice daily. Advise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for 30 days after the last dose [see Use in Specific Populations (8.1, 8.3)]. 5.10 Risks Associated with Combination Treatment. MEKTOVI is indicated for use in combination with encorafenib. Refer to the encorafenib prescribing information for additional risk information that applies to combination use treatment.