NDC 70255-010 Mektovi

Binimetinib

NDC Product Code 70255-010

NDC 70255-010-02

Package Description: 1 BOTTLE in 1 CARTON > 180 TABLET, FILM COATED in 1 BOTTLE

NDC 70255-010-03

Package Description: 90 TABLET, FILM COATED in 1 BOTTLE

NDC Product Information

Mektovi with NDC 70255-010 is a a human prescription drug product labeled by Array Biopharma Inc.. The generic name of Mektovi is binimetinib. The product's dosage form is tablet, film coated and is administered via oral form. The RxNorm Crosswalk for this NDC code indicates multiple RxCUI concepts are associated to this product: 2049127 and 2049133.

Dosage Form: Tablet, Film Coated - A solid dosage form that contains medicinal substances with or without suitable diluents and is coated with a thin layer of a water-insoluble or water-soluble polymer.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Mektovi Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.


Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
  • CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • POLYVINYL ALCOHOL, UNSPECIFIED (UNII: 532B59J990)
  • POLYETHYLENE GLYCOL 3350 (UNII: G2M7P15E5P)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • TALC (UNII: 7SEV7J4R1U)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)

Administration Route(s)

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  • Oral - Administration to or by way of the mouth.

Product Labeler Information

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Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Array Biopharma Inc.
Labeler Code: 70255
FDA Application Number: NDA210498 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
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Start Marketing Date: 06-27-2018 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2022 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Mektovi Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

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)].

2.1 Patient Selection

Confirm the presence of a BRAF V600E or V600K mutation in tumor specimens prior to initiating MEKTOVI [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.

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 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 (5.1)]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 andAbsolute decrease from baseline is 10% or less andPatient 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 LLNPermanently discontinue MEKTOVI.Venous Thromboembolism [see Warnings and Precautions (5.2)]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 PEPermanently discontinue MEKTOVI. Serous Retinopathy [see Warnings and Precautions (5.3)]Symptomatic serous retinopathy/Retinal pigment epithelial detachmentsWithhold 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 (5.3)]Any Grade Permanently discontinue MEKTOVI.Uveitis [see Warnings and Precautions (5.3)]Grade 1-3If 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 4Permanently discontinue MEKTOVI.Interstitial Lung Disease [see Warnings and Precautions (5.4)]Grade 2Withhold 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 4Permanently discontinue MEKTOVI. Hepatotoxicity [see Warnings and Precautions (5.5)]Grade 2 AST or ALT increasedMaintain 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 increasedSee Other Adverse Reactions.Rhabdomyolysis or Creatine Phosphokinase (CPK) elevations [see Warnings and Precautions (5.6)]Grade 4 asymptomatic CPK elevation or Any Grade CPK elevation with symptoms or with renal impairmentWithhold 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.DermatologicGrade 2If no improvement within 2 weeks, withhold MEKTOVI until Grade 0-1. Resume at same dose if first occurrence or reduce dose if recurrent. Grade 3Withhold MEKTOVI until Grade 0-1. Resume at same dose if first occurrence or reduce dose if recurrent.Grade 4Permanently discontinue MEKTOVI.Other Adverse Reactions (including: Hemorrhage [see Warnings and Precautions (5.7)])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 orFirst occurrence of any Grade 3Withhold 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 4Permanently 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 3Consider permanently discontinuing MEKTOVI. Recurrent Grade 4Permanently 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)].

3 Dosage Forms And Strengths

Tablets: 15 mg, yellow/dark yellow, unscored biconvex oval film-coated tablets debossed with a stylized "A" on one side and "15" on the other side.

4 Contraindications

None.

5.1 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 3 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 0 to 21 months). Cardiomyopathy resolved in 87% 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 2 to 3 months during treatment. The safety of MEKTOVI in combination with encorafenib has not been established in patients with a 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)].

5.2 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. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

Other

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 0 to 17.5 months).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 a 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), 1 patient experienced RVO (0.1%).The safety of MEKTOVI has not been established in patients with a history of RVO or current risk factors for RVO including uncontrolled glaucoma or a 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%.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)].

Risk SummaryBased on findings from animal reproduction studies and its mechanism of action, MEKTOVI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. 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 5 times the human exposure at the clinical dose of 45 mg twice daily (see Data). Advise pregnant women of the potential risk to a fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal 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 5 times the human exposure based on AUC at the recommended clinical dose of 45 mg twice daily). There was a significant increase in fetal ventricular septal defects and pulmonary trunk alterations at 20 mg/kg/day of binimetinib (less than 8 times the human exposure at the recommended clinical dose of 45 mg twice daily).

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 infant, or on milk production. Because of the potential for serious adverse reactions from MEKTOVI in breastfed infants, advise women not to breastfeed during treatment with MEKTOVI and for 3 days after the final dose.

Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating MEKTOVI [see Use in Specific Populations (8.1)].

ContraceptionMEKTOVI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

FemalesAdvise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for at least 30 days after the final dose.

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

AbsorptionAfter oral administration, at least 50% of the binimetinib dose was absorbed with a median time to maximum concentration (Tmax) of 1.6 hours.

Effect of FoodThe 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.

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 L (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 a single oral dose of 45 mg radiolabeled binimetinib, approximately 60% of the circulating radioactivity AUC in plasma was attributable to binimetinib.

ExcretionFollowing 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 PopulationsAge (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 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). 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 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 a 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 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).

CardiomyopathyAdvise patients to report any symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.1)].

Venous ThrombosisAdvise 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 (5.2)].

Ocular ToxicitiesAdvise patients to contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.3)].

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 (5.4)].

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 (5.5)].

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 (5.6)].

HemorrhageAdvise patients to notify their healthcare provider if they experience symptoms suggestive of hemorrhage, such as unusual bleeding [see Warnings and Precautions (5.7)].

Females and Males of Reproductive Potential

Embryo-Fetal Toxicity: Advise females with reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for 30 days after the final dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with MEKTOVI [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)].

Lactation: Advise women not to breastfeed during treatment with MEKTOVI and for 3 days after the final dose [see Use in Specific Populations (8.2)].

Distributed by: Array BioPharma Inc. 3200 Walnut Street Boulder, CO 80301© 2018 Array BioPharma Inc. All rights reserved. MEKTOVI® is a registered trademark of Array BioPharma Inc. in the United States and various other countries. Patented. See www.arraybiopharma.com/patents

5.4 Interstitial Lung Disease

In patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib (n=690), 2 patients (0.3%) developed interstitial lung disease (ILD), including 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)].

5.5 Hepatotoxicity

Hepatotoxicity can occur when MEKTOVI is administered in combination with encorafenib. In COLUMBUS, the incidence of Grade 3 or 4 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 3 or 4 serum bilirubin elevation.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)].

5.6 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 1 patient (0.1%). 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)].

5.7 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 3 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. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

5.8 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, MEKTOVI can cause fetal harm when administered to a 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 5 times the human exposure at the recommended clinical dose of 45 mg twice daily. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for at least 30 days after the final dose [see Use in Specific Populations (8.1, 8.3)].

5.9 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.

6 Adverse Reactions

  • The following adverse reactions are described elsewhere in the labeling:Cardiomyopathy [see Warnings and Precautions (5.1)]Venous Thromboembolism [see Warnings and Precautions (5.2)]Ocular Toxicities [see Warnings and Precautions (5.3)]Interstitial Lung Disease [see Warnings and Precautions (5.4)]Hepatotoxicity [see Warnings and Precautions (5.5)]Rhabdomyolysis [see Warnings and Precautions (5.6)]Hemorrhage [see Warnings and Precautions (5.7)]

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 [see Warnings and Precautions (5)] 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) or, for rare events, exposure of 690 patients with BRAF V600 mutation-positive melanoma to MEKTOVI (45 mg twice daily) in combination with encorafenib at doses between 300 mg and 600 mg once daily across multiple clinical trials. 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)] 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 COLUMBUSGrades per National Cancer Institute CTCAE v4.03.Adverse ReactionMEKTOVI with encorafenib N=192Vemurafenib N=186All Grades(%)Grades 3 and 4Grade 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  FatigueRepresents a composite of multiple, related preferred terms.433466  Pyrexia184300  Peripheral edema131151Gastrointestinal Disorders  Nausea412342  Diarrhea363342  Vomiting302161  Abdominal pain284161  Constipation22061Skin and Subcutaneous Tissue Disorders  Rash2215313Nervous System Disorders  Dizziness15340Visual Disorders  Visual impairment20040  Serous retinopathy/RPED20320Vascular Disorders  Hemorrhage19392  Hypertension116113Other clinically important adverse reactions occurring in < 10% of patients who received MEKTOVI in combination with encorafenib were:Gastrointestinal disorders: ColitisSkin and subcutaneous tissue disorders: PanniculitisImmune system disorders: Drug hypersensitivityTable 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=192Vemurafenib N=186All Grades(%)Grades 3 and 4 (%)All Grades(%)Grades 3 and 4 (%)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  Hyponatremia 183.6150.5

7 Drug Interactions

No clinically important drug interactions have been observed with MEKTOVI.

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 (45 mg twice daily) in combination with encorafenib at doses between 300 mg and 600 mg once daily across multiple clinical trials, 20% were aged 65 to 74 years and 8% were aged 75 years and older. No overall differences in the safety or effectiveness of MEKTOVI plus encorafenib were observed in elderly patients as compared to younger patients [see Clinical Pharmacology (12.3)].

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)].

10 Overdosage

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

11 Description

Binimetinib is a 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 a 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.

12.1 Mechanism Of Action

Binimetinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (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.

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.

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.

14 Clinical Studies

MEKTOVI in combination with encorafenib was evaluated in a 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™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) of MEKTOVI in combination with encorafenib compared with vemurafenib as assessed by a blinded independent central review. PFS was defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause, whichever occurred first. Other outcome measures included overall survival (OS), objective response rate (ORR), and duration of response (DoR) as 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 a statistically significant improvement in PFS compared to vemurafenib. Efficacy results are summarized in Table 5 and Figure 1.Table 5: Efficacy Results for COLUMBUSMEKTOVI with encorafenib N=192VemurafenibN=191CI = Confidence interval; CR = Complete response; DoR = Duration of response; HR = Hazard ratio; NE = Not estimable; ORR = Overall response rate; PFS = Progression-free survival; PR = Partial response.Progression-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, 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)  P valueLog-rank test adjusted by the same stratification factors.< 0.0001Overall 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 COLUMBUSOS was not mature at the time of analysis of PFS.

16 How Supplied/Storage And Handling

MEKTOVI (binimetinib) is supplied as 15 mg yellow/dark yellow, unscored biconvex oval film-coated tablets debossed with a stylized "A" on one side and "15" on the other side, available in bottles of 180 tablets (NDC 70255-010-02).

Storage And Handling

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

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).Inform patients of the following:

Spl Patient Package Insert

  • This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: June 2018PATIENT INFORMATIONMEKTOVI® (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 MEKTOVI? MEKTOVI is a prescription medicine used in combination with a medicine called encorafenib to treat people with a type of skin cancer called melanoma: that has spread to other parts of the body or cannot be removed by surgery, andthat has a certain type of abnormal "BRAF" gene Your healthcare provider will perform a 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:have heart problems have had blood clotshave eye problemshave lung or breathing problemshave liver or kidney problemshave any muscle problemshave bleeding problemshave high blood pressure (hypertension)are pregnant or plan to become pregnant. MEKTOVI can harm your unborn baby.Females who are able to become pregnant should use effective birth control (contraception) during treatment with MEKTOVI and for at least 30 days after the final dose of MEKTOVI. Talk to your healthcare provider about birth control methods that may be right for you during this time. Your healthcare provider will do a 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.are 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 3 days after the final 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 a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take MEKTOVI?Take 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. Your healthcare provider may change your dose of MEKTOVI, temporarily stop, or completely stop your treatment with MEKTOVI if you develop certain side effects.Take MEKTOVI in combination with encorafenib by mouth 2 times a day, about 12 hours apart. MEKTOVI may be taken with or without food.If you miss a dose of MEKTOVI, take it as soon as you remember. If it is within 6 hours of your next scheduled dose, take your next dose at your regular time. Do not make up for the missed dose.Do not take an extra dose if you vomit after taking your scheduled dose. Take your next dose at your regular time.If 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:Heart problems, including heart failure. 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 a heart problem: feeling like your heart is pounding or racing shortness of breathswelling of your ankles and feet feeling lightheaded Blood clots. MEKTOVI can cause blood clots in your arms or legs, which can travel to your lungs and can lead to death. Get medical help right away if you have the following symptoms: chest painsudden shortness of breath or trouble breathingpain in your legs with or without swellingswelling in your arms and legsa cool pale arm or legEye problems. MEKTOVI can cause serious eye problems that might lead to blindness. Call your healthcare provider right away if you develop any of these symptoms of eye problems: blurred vision, loss of vision, or other vision changes see colored dotssee halos (blurred outline around objects)eye pain, swelling, or redness Lung or breathing problems. MEKTOVI can cause lung or breathing problems. Tell your healthcare provider if you have any new or worsening symptoms of lung or breathing problems, including: shortness of breathcoughLiver 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 a liver problem: yellowing of your skin or the white part of your eyes (jaundice)dark or brown (tea-colored) urinenausea or vomitingloss of appetiteMuscle problems (rhabdomyolysis). MEKTOVI 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 a sign of muscle damage. Your healthcare provider should perform a 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: weaknessmuscle aches or paindark, reddish urineBleeding problems. MEKTOVI, when taken with encorafenib, can cause serious bleeding problems, including in your brain or stomach, that can lead to death. Call your healthcare provider and get medical help right away if you have any signs of bleeding, including: headaches, dizziness, or feeling weakcough up blood or blood clotsvomit blood or your vomit looks like "coffee grounds"red or black stool that look like tarThe most common side effects of MEKTOVI when taken with encorafenib, include:fatiguenauseadiarrheavomitingabdominal painThese are not all 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 Array BioPharma Inc. at 1-844-792-7729. How should I store MEKTOVI?Store MEKTOVI at room temperature between 68°F to 77°F (20°C to 25°C).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 a Patient Information leaflet. Do not use MEKTOVI for a 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: binimetinibInactive 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. Boulder, Colorado 80301.MEKTOVI® is a 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.©2018 Array BioPharma Inc. All rights reserved.

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