The following Structured Product Label (SPL) was submitted to the FDA by Array Biopharma Inc. for the product Mektovi (NDC 70255-010). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding 1 indications and usage, 2.1 patient selection, 2.2 recommended dosage, 2.3 dosage modifications for adverse reactions, 2.4 dosage modifications for moderate or severe hepatic impairment, 3 dosage forms and strengths, 4 contraindications, 5.1 cardiomyopathy, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
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)].
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.
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 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. | Dose Modification for MEKTOVI |
|---|---|
| Cardiomyopathy [see Warnings and Precautions (5.1)] | |
| Withhold MEKTOVI for up to 4 weeks, evaluate LVEF every 2 weeks. Resume MEKTOVI at a reduced dose if the following are present:
|
| Permanently discontinue MEKTOVI. |
| Venous Thromboembolism [see Warnings and Precautions (5.2)] | |
| Withhold MEKTOVI.
|
| Permanently discontinue MEKTOVI. |
| Serous Retinopathy [see Warnings and Precautions (5.3)] | |
| Withhold MEKTOVI for up to 10 days.
|
| Retinal Vein Occlusion (RVO) [see Warnings and Precautions (5.3)] | |
| Permanently discontinue MEKTOVI. |
| Uveitis [see Warnings and Precautions (5.3)] | |
| If Grade 1 or 2 does not respond to specific ocular therapy, or for Grade 3 uveitis, withhold MEKTOVI for up to 6 weeks.
|
| Permanently discontinue MEKTOVI. |
| Interstitial Lung Disease [see Warnings and Precautions (5.4)] | |
| Withhold MEKTOVI for up to 4 weeks.
|
| Permanently discontinue MEKTOVI. |
| Hepatotoxicity [see Warnings and Precautions (5.5)] | |
| Maintain MEKTOVI dose.
|
| See Other Adverse Reactions. |
| Rhabdomyolysis or Creatine Phosphokinase (CPK) elevations [see Warnings and Precautions (5.6)] | |
| Withhold MEKTOVI dose for up to 4 weeks.
|
| Dermatologic | |
| 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 (5.7)]) 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. | |
| Withhold MEKTOVI for up to 4 weeks.
|
| Permanently discontinue MEKTOVI, or Withhold MEKTOVI for up to 4 weeks.
|
| Consider permanently discontinuing MEKTOVI. |
| Permanently discontinue MEKTOVI. |
Refer to the encorafenib prescribing information for dose modifications for adverse reactions associated with encorafenib.
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.
None.
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)].
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)].
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).
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%.
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 Summary
Based 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 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).
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 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 Testing
Verify the pregnancy status of females of reproductive potential prior to initiating MEKTOVI [see Use in Specific Populations (8.1)].
Contraception
MEKTOVI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Females
Advise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for at least 30 days after the final dose.
Cardiac Electrophysiology
Following MEKTOVI 45 mg twice daily, no clinically meaningful QT prolongation was observed.
Absorption
After 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 Food
The administration of a single dose of MEKTOVI 45 mg with a high-fat, high-calorie meal (consisting of approximately 150 calories from protein, 350 calories from carbohydrate, and 500 calories from fat) in healthy subjects had no effect on binimetinib exposure.
Distribution
Binimetinib is 97% bound to human plasma proteins and the blood-to-plasma ratio is 0.72. The geometric mean (CV%) of apparent volume of distribution of binimetinib is 92 L (45%).
Elimination
The mean (CV%) terminal half-life (t1/2) of binimetinib is 3.5 hours (28.5%) and apparent clearance (CL/F) is 20.2 L/h (24%).
Metabolism
The primary metabolic pathway is glucuronidation with UGT1A1 contributing up to 61% of the binimetinib metabolism. Other pathways of binimetinib metabolism include N-dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain. The active metabolite M3 produced by CYP1A2 and CYP2C19 represents 8.6% of the binimetinib exposure. Following a single oral dose of 45 mg radiolabeled binimetinib, approximately 60% of the circulating radioactivity AUC in plasma was attributable to binimetinib.
Excretion
Following a single oral dose of 45 mg radiolabeled binimetinib in healthy subjects, 62% (32% unchanged) of the administered dose was recovered in the feces while 31% (6.5% unchanged) was recovered in the urine.
Specific Populations
Age (20 to 94 years), sex, or body weight do not have a clinically important effect on the systemic exposure of binimetinib. The effect of race or ethnicity on the pharmacokinetics of binimetinib is unknown.
Hepatic Impairment: No clinically meaningful changes in binimetinib exposure (AUC and 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).
Cardiomyopathy
Advise patients to report any symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.1)].
Venous Thrombosis
Advise 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 Toxicities
Advise patients to contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.3)].
Interstitial Lung Disease
Advise 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)].
Hepatotoxicity
Advise 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)].
Rhabdomyolysis
Advise 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)].
Hemorrhage
Advise 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
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)].
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)].
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)].
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)].
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)].
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.
The following adverse reactions are described elsewhere in the labeling:
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.
| Adverse Reaction | MEKTOVI with encorafenib N=192 | Vemurafenib N=186 | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3 and 4 Grade 4 adverse reactions limited to diarrhea (n=1) and hemorrhage (n=3) in the MEKTOVI with encorafenib arm and constipation (n=1) in the vemurafenib arm. (%) | All Grades (%) | Grades 3 and 4 (%) | |
| General Disorders and Administration Site Conditions | ||||
| Fatigue Represents a composite of multiple, related preferred terms. | 43 | 3 | 46 | 6 |
| Pyrexia | 18 | 4 | 30 | 0 |
| Peripheral edema | 13 | 1 | 15 | 1 |
| Gastrointestinal Disorders | ||||
| Nausea | 41 | 2 | 34 | 2 |
| Diarrhea | 36 | 3 | 34 | 2 |
| Vomiting | 30 | 2 | 16 | 1 |
| Abdominal pain | 28 | 4 | 16 | 1 |
| Constipation | 22 | 0 | 6 | 1 |
| Skin and Subcutaneous Tissue Disorders | ||||
| Rash | 22 | 1 | 53 | 13 |
| Nervous System Disorders | ||||
| Dizziness | 15 | 3 | 4 | 0 |
| Visual Disorders | ||||
| Visual impairment | 20 | 0 | 4 | 0 |
| Serous retinopathy/RPED | 20 | 3 | 2 | 0 |
| Vascular Disorders | ||||
| Hemorrhage | 19 | 3 | 9 | 2 |
| Hypertension | 11 | 6 | 11 | 3 |
Other clinically important adverse reactions occurring in < 10% of patients who received MEKTOVI in combination with encorafenib were:
Gastrointestinal disorders: Colitis
Skin and subcutaneous tissue disorders: Panniculitis
Immune system disorders: Drug hypersensitivity
| Laboratory Abnormality | MEKTOVI with encorafenib N=192 | Vemurafenib N=186 | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3 and 4 (%) | All Grades (%) | Grades 3 and 4 (%) | |
| Hematology | ||||
| Anemia | 36 | 3.6 | 34 | 2.2 |
| Leukopenia | 13 | 0 | 10 | 0.5 |
| Lymphopenia | 13 | 2.1 | 30 | 7 |
| Neutropenia | 13 | 3.1 | 4.8 | 0.5 |
| Chemistry | ||||
| Increased Creatinine | 93 | 3.6 | 92 | 1.1 |
| Increased Creatine Phosphokinase | 58 | 5 | 3.8 | 0 |
| Increased Gamma Glutamyl Transferase | 45 | 11 | 34 | 4.8 |
| Increased ALT | 29 | 6 | 27 | 2.2 |
| Increased AST | 27 | 2.6 | 24 | 1.6 |
| Increased Alkaline Phosphatase | 21 | 0.5 | 35 | 2.2 |
| Hyponatremia | 18 | 3.6 | 15 | 0.5 |
No clinically important drug interactions have been observed with MEKTOVI.
The safety and effectiveness of MEKTOVI have not been established in pediatric patients.
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)].
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)].
Since binimetinib is 97% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKTOVI.
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:
Chemical Structure (Mektovi 01)
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.
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.
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.
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.
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.
| MEKTOVI with encorafenib N=192 | Vemurafenib N=191 | |
|---|---|---|
| CI = 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 disease | 88 (46) | 104 (54) |
| Death | 10 (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 value Log-rank test adjusted by the same stratification factors. | < 0.0001 | |
| Overall Response Rate | ||
| ORR (95% CI) | 63% (56%, 70%) | 40% (33%, 48%) |
| CR | 8% | 6% |
| PR | 55% | 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 (Mektovi 02)
OS was not mature at the time of analysis of PFS.
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).
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].
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Inform patients of the following:
| This Patient Information has been approved by the U.S. Food and Drug Administration. | Issued: June 2018 |
| PATIENT INFORMATION MEKTOVI® (mek-TOE-vee) (binimetinib) tablets | |
| Important 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:
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:
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?
| |
| What are the possible side effects of MEKTOVI? MEKTOVI may cause serious side effects, including:
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?
| |
| 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: binimetinib Inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate (vegetable source), and colloidal silicon dioxide Tablet coating: polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, ferric oxide yellow, ferrosoferric oxide Distributed 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. | |
NDC 70255-010-02
MEKTOVI®
(binimetinib) tablets
15 mg
Rx only
180 Tablets
Principal Display Panel (15 mg Tablet Bottle Carton)
* Please review the disclaimer below.
