Mektovi ( Braftovi+mektovi) (Binimetinib)

MEKTOVI is a kinase inhibitor indicated:

• •in combination with encorafenib, for the treatment of patients with unresectable or metastatic melanoma with a
  BRAF V600E
  or
  V600K
  mutation, as detected by an FDA-approved test. (
  1.1

  BRAF V600E

  or

  V600K

  Mutation-Positive Unresectable or Metastatic Melanoma

  MEKTOVI is indicated, in combination with encorafenib, for the treatment of patients with unresectable or metastatic melanoma with a

  BRAF V600E

  or

  V600K

  mutation, as detected by an FDA-approved test

  [see Dosage and Administration (2.1)]

  .
  ,
  2.1 Patient Selection

  BRAF V600E

  or

  V600K

  Mutation-Positive Unresectable or Metastatic Melanoma

  Confirm the presence of a

  BRAF V600E

  or

  V600K

  mutation in tumor specimens prior to initiating MEKTOVI

  [see Clinical Studies (14)]

  . Information on FDA-approved tests for the detection of

  BRAF V600E

  and

  V600K

  mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.

  BRAF V600E

  Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)

  Confirm the presence of a

  BRAF V600E

  mutation in tumor or plasma specimens prior to initiating MEKTOVI

  [see Clinical Studies (14.2)]

  . If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA-approved tests for the detection of

  BRAF V600E

  mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.
  )
• •in combination with encorafenib, for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with a
  BRAF V600E
  mutation, as detected by an FDA-approved test. (
  1.2

  BRAF V600E

  Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)

  MEKTOVI is indicated, in combination with encorafenib, for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with a

  BRAF V600E

  mutation, as detected by an FDA-approved test.

  [see Dosage and Administration (2.1)]

  .
  ,
  2.1 Patient Selection

  BRAF V600E

  or

  V600K

  Mutation-Positive Unresectable or Metastatic Melanoma

  Confirm the presence of a

  BRAF V600E

  or

  V600K

  mutation in tumor specimens prior to initiating MEKTOVI

  [see Clinical Studies (14)]

  . Information on FDA-approved tests for the detection of

  BRAF V600E

  and

  V600K

  mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.

  BRAF V600E

  Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)

  Confirm the presence of a

  BRAF V600E

  mutation in tumor or plasma specimens prior to initiating MEKTOVI

  [see Clinical Studies (14.2)]

  . If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA-approved tests for the detection of

  BRAF V600E

  mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.
  )

• •Confirm the presence of
  BRAF V600E
  or
  V600K
  mutation in tumor specimens prior to the initiation of MEKTOVI. (
  2.1 Patient Selection

  BRAF V600E

  or

  V600K

  Mutation-Positive Unresectable or Metastatic Melanoma

  Confirm the presence of a

  BRAF V600E

  or

  V600K

  mutation in tumor specimens prior to initiating MEKTOVI

  [see Clinical Studies (14)]

  . Information on FDA-approved tests for the detection of

  BRAF V600E

  and

  V600K

  mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.

  BRAF V600E

  Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)

  Confirm the presence of a

  BRAF V600E

  mutation in tumor or plasma specimens prior to initiating MEKTOVI

  [see Clinical Studies (14.2)]

  . If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA-approved tests for the detection of

  BRAF V600E

  mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.
  )
• •The recommended dose is 45 mg orally twice daily in combination with encorafenib. Take MEKTOVI with or without food. (
  2.2 Recommended Dosage and Administration

  The recommended dosage of MEKTOVI is 45 mg orally taken twice daily, approximately 12 hours apart, in combination with encorafenib until disease progression or unacceptable toxicity. Refer to the encorafenib prescribing information for recommended encorafenib dosing information.

  MEKTOVI may be taken with or without food

  [see Clinical Pharmacology (12.3)]

  . Do not take a missed dose of MEKTOVI within 6 hours of the next dose of MEKTOVI.

  Do not take an additional dose if vomiting occurs after MEKTOVI administration but continue with the next scheduled dose.
  )
• •For patients with moderate or severe hepatic impairment the recommended dose is 30 mg orally twice daily. (
  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)]

  .
  ,
  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)]

  .
  )

• •Confirm the presence of
  BRAF V600E
  mutation in tumor or plasma specimens prior to initiating MEKTOVI. (
  2.1 Patient Selection

  BRAF V600E

  or

  V600K

  Mutation-Positive Unresectable or Metastatic Melanoma

  Confirm the presence of a

  BRAF V600E

  or

  V600K

  mutation in tumor specimens prior to initiating MEKTOVI

  [see Clinical Studies (14)]

  . Information on FDA-approved tests for the detection of

  BRAF V600E

  and

  V600K

  mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.

  BRAF V600E

  Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)

  Confirm the presence of a

  BRAF V600E

  mutation in tumor or plasma specimens prior to initiating MEKTOVI

  [see Clinical Studies (14.2)]

  . If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA-approved tests for the detection of

  BRAF V600E

  mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.
  )
• •The recommended dose is 45 mg orally twice daily in combination with encorafenib. Take MEKTOVI with or without food. (
  2.2 Recommended Dosage and Administration

  The recommended dosage of MEKTOVI is 45 mg orally taken twice daily, approximately 12 hours apart, in combination with encorafenib until disease progression or unacceptable toxicity. Refer to the encorafenib prescribing information for recommended encorafenib dosing information.

  MEKTOVI may be taken with or without food

  [see Clinical Pharmacology (12.3)]

  . Do not take a missed dose of MEKTOVI within 6 hours of the next dose of MEKTOVI.

  Do not take an additional dose if vomiting occurs after MEKTOVI administration but continue with the next scheduled dose.
  )

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.

• •
  New 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 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)]

  .
  )
• •
  Cardiomyopathy:
  Assess left ventricular ejection fraction (LVEF) before initiating treatment, after one month of treatment, then every 2 to 3 months thereafter. The safety of MEKTOVI has not been established in patients with LVEF below 50%. (
  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 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.

  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 3 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 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)]

  .
  )
• •
  Venous Thromboembolism:
  Deep vein thrombosis and pulmonary embolism can occur. (
  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)]

  .
  )
• •
  Ocular 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 Ocular Toxicities

  Serous Retinopathy

  In 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).

  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 Occlusion

  RVO 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)]

  .

  Uveitis

  Uveitis, 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)]

  .
  )
• •
  Interstitial Lung Disease (ILD):
  Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. (
  5.5 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. In PHAROS, 1 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)]

  .
  )
• •
  Hepatotoxicity:
  Monitor liver function tests before and during treatment with MEKTOVI and encorafenib and as clinically indicated. (
  5.6 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. In PHAROS, the incidence of Grade 3 or 4 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)]

  .
  )
• •
  Rhabdomyolysis:
  Monitor creatine phosphokinase and creatinine periodically and as clinically indicated. (
  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 1 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)]

  .
  )
• •
  Hemorrhage:
  Major hemorrhagic events can occur in patients receiving MEKTOVI and encorafenib. (
  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 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.

  In PHAROS, hemorrhage occurred in 12% of patients receiving MEKTOVI in combination with encorafenib including fatal hemorrhage intracranial (1%); Grade 3 or 4 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)]

  .
  )
• •
  Embryo-Fetal Toxicity:
  Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective contraception. (
  5.9 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 pregnant women and females of 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 last dose

  [see Use in Specific Populations (8.1, 8.3)].
  ,
  8.1 Pregnancy

  Risk Summary

  Based on findings from animal reproduction studies and its mechanism of action

  [see Clinical Pharmacology (12.1)]

  , MEKTOVI can cause fetal harm when administered to a 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 5 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 a fetus.

  In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

  Data

  Animal Data

  In reproductive toxicity studies, administration of 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).
  ,
  8.3 Females and Males of Reproductive Potential

  Based on animal data, MEKTOVI can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations (8.1)]

  .

  Pregnancy Testing

  Verify the pregnancy status of females of reproductive potential prior to initiating MEKTOVI

  [see Use in Specific Populations (8.1)].

  Contraception

  Females

  Advise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for 30 days after the last dose.
  )