Mektovi ( Braftovi+mektovi)
(binimetinib)Dosage & Administration
Melanoma
NSCLC
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Mektovi ( Braftovi+Mektovi) Prescribing Information
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)].
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)].
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.
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.
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.
| Action | Recommended Dose |
|---|---|
First Dose Reduction | 30 mg orally twice daily |
Subsequent Modification | Permanently discontinue if unable to tolerate MEKTOVI 30 mg orally twice daily |
Dosage modifications for adverse reactions associated with MEKTOVI are presented in Table 2.
| Severity of Adverse Reaction * | Dose Modification for MEKTOVI |
|---|---|
| |
Cardiomyopathy [see Warnings and Precautions (5.2)] | |
| Withhold MEKTOVI for up to 4 weeks, evaluate LVEF every 2 weeks.
If the LVEF does not recover within 4 weeks permanently discontinue MEKTOVI. |
| Permanently discontinue MEKTOVI. |
Venous Thromboembolism [see Warnings and Precautions (5.3)] | |
| Withhold MEKTOVI.
|
| Permanently discontinue MEKTOVI. |
Serous Retinopathy [see Warnings and Precautions (5.4)] | |
| Withhold MEKTOVI for up to 10 days.
|
Retinal Vein Occlusion (RVO) [see Warnings and Precautions (5.4)] | |
| Permanently discontinue MEKTOVI. |
Uveitis [see Warnings and Precautions (5.4)] | |
| If Grade 1 or 2 does not respond to specific ocular therapy, or for Grade 3 uveitis, withhold MEKTOVI for up to 6 weeks.
|
| Permanently discontinue MEKTOVI. |
Interstitial Lung Disease [see Warnings and Precautions (5.5)] | |
| Withhold MEKTOVI for up to 4 weeks.
|
| Permanently discontinue MEKTOVI. |
Hepatotoxicity [see Warnings and Precautions (5.6)] | |
| Maintain MEKTOVI dose.
|
| See Other Adverse Reactions. |
Rhabdomyolysis or Creatine Phosphokinase (CPK) elevations [see Warnings and Precautions (5.7)] | |
| Withhold MEKTOVI dose for up to 4 weeks.
|
Dermatologic [other than palmar plantar erythrodysesthesia syndrome (PPES)] [see Adverse Reactions (6.1)] | |
| If no improvement within 2 weeks, withhold MEKTOVI until Grade 0-1. Resume at same dose if first occurrence or reduce dose if recurrent. |
| Withhold MEKTOVI until Grade 0-1. Resume at same dose if first occurrence or reduce dose if recurrent. |
| Permanently discontinue MEKTOVI. |
Other Adverse Reactions (including Hemorrhage) [see Warnings and Precautions (5.8), Adverse Reactions (6.1)] † | |
| Withhold MEKTOVI for up to 4 weeks.
|
| Permanently discontinue MEKTOVI, or
|
| Consider permanently discontinuing MEKTOVI. |
| Permanently discontinue MEKTOVI. |
Refer to the encorafenib prescribing information for dose modifications for adverse reactions associated with encorafenib.
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)].
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.
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).
Lactation
Risk Summary
There 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 a breastfed child, advise women not to breastfeed during treatment with MEKTOVI and for 3 days after the last dose.
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.
Pediatric Use
The safety and effectiveness of MEKTOVI have not been established in pediatric patients.
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
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)].
None.
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
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
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
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
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
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
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
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
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)].
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.