Binimetinib is a MEK inhibitor that inhibits cell growth in BRAF V600 mutation-positive tumors. Using an FDA-approved test, confirm the presence of the BRAF V600 mutation in plasma or tumor specimens prior to initiation of treatment. Binimetinib is indicated in combination with encorafenib for the treatment of BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, and for the treatment of BRAF V600E mutation-positive metastatic non-small cell lung cancer (NSCLC). Cardiomyopathy, venous thromboembolism, interstitial lung disease, and rhabdomyolysis have been reported with binimetinib use.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Binimetinib may be taken with or without food.
-Space doses approximately 12 hours apart.
-If a dose is missed, it may be taken up to 6 hours prior to the next dose. If there is less than 6 hours until the next scheduled dose, skip the dose and take the next dose at the scheduled time.
-If vomiting occurs after a dose, do not take an additional dose; take the next dose at the regularly scheduled time.
Cardiomyopathy (e.g., congestive heart failure, left ventricular dysfunction (LVD), and decreased left ventricular ejection fraction (LVEF)) was reported in 7% to 11% of patients treated with encorafenib and binimetinib in clinical trials; grade 3 LVD occurred in 1% to 1.6% of patients. Evaluate LVEF by echocardiogram or multigated acquisition (MUGA) scan prior to starting binimetinib, at 1 month, and then every 2 to 3 months during therapy. Closely monitor patients with cardiovascular risk factors. Therapy interruption, a dose reduction, or permanent discontinuation of binimetinib may be necessary in patients who develop cardiomyopathy. The median time to LVD was 3.6 months (range, 0 to 21 months); cardiomyopathy resolved in 82% to 87% of patients.
Venous thromboembolism (e.g., deep vein thrombosis) was reported in 6% to 7% of patients treated with encorafenib and binimetinib in clinical trials; 1% to 3.1% of patients had a pulmonary embolism. Therapy interruption, a dose reduction, or permanent discontinuation of binimetinib may be necessary in patients who develop a thromboembolism.
Serious ocular toxicity has been reported in patients who received combination therapy with binimetinib and encorafenib. Monitor patients for signs and symptoms of visual impairment at each clinic visit. Perform an ophthalmologic evaluation regularly and in patients who experience new, worsening, or persistent visual disturbances. Permanently discontinue binimetinib in patients who develop symptoms of retinal vein occlusion (RVO). Therapy interruption, a dose reduction, or permanent discontinuation of binimetinib may be necessary in patients who develop persistent or severe ocular toxicity. RVO was reported in 1 patient (0.1%) who received binimetinib and encorafenib in clinical trials (n = 690). Visual impairment including blurred vision, vitreous floaters, photophobia, reduced visual acuity, and photopsia occurred in 20% to 29% of patients treated with binimetinib and encorafenib in clinical trials (grade 3 or 4, 2% or less). Serous retinopathy/retinal pigment epithelial detachments (RPED) occurred in 20% of melanoma patients who received binimetinib and encorafenib in a randomized clinical trial (grade 3 or 4, 3%), with 8% as symptomatic cases; of the 20%, 8% were retinal detachment and 6% were macular edema. The median time to serous retinopathy was 1.2 months (range, 0 to 17.5 months). Serous retinopathy (retinal detachment) occurred in 2% of NSCLC patients who received the combination in a single-arm, open-label trial. No cases of blindness have been reported. Uveitis including iritis and iridocyclitis was reported in 1% to 4% of patients who received binimetinib and encorafenib.
Interstitial lung disease (ILD) including pneumonitis was reported in 2 patients with advanced melanoma (0.3%) and in 1 NSCLC patient (1%) who received binimetinib and encorafenib in clinical trials. Evaluate new or progressive pulmonary symptoms. Therapy interruption, a dose reduction, or permanent discontinuation of binimetinib may be necessary in patients who develop ILD.
Elevated hepatic enzymes have been reported in patients who received combination therapy with binimetinib and encorafenib. Monitor liver function tests prior to starting binimetinib therapy, monthly during therapy, and as clinically indicated. Therapy interruption, a dose reduction, or permanent discontinuation of binimetinib may be necessary in patients who develop elevated transaminase levels. Elevated hepatic enzymes including increased ALT (29% to 34%; grade 3 or 4, 6% to 9%), AST (27% to 31%; grade 3 or 4, 2.6% to 10%), alkaline phosphatase (21% to 31%; grade 3 or 4, 0.5% to 3.2%), and gamma glutamyl transferase (45% or less; grade 3 or 4, 11% or less) levels were reported in patients who received binimetinib and encorafenib in clinical trials.
Rhabdomyolysis was reported in 1 patient (0.3%) who received binimetinib and encorafenib in clinical trials (n = 690). Monitor creatine phosphokinase (CPK) and serum creatinine levels prior to starting binimetinib therapy, periodically during therapy, and as clinically indicated. Therapy interruption, a dose reduction, or permanent discontinuation of binimetinib may be necessary in patients who develop rhabdomyolysis. Increased creatine phosphokinase (CPK) level was reported in 58% of patients with advanced melanoma who received binimetinib and encorafenib in a randomized trial (grade 3 or 4, 5%); increased creatine kinase (CK) occurred in 41% (grade 3 or 4, 3.3%) of NSCLC patients treated with binimetinib plus encorafenib in a single-arm, open-label trial.
Bleeding was reported in 12% to 19% of patients who received binimetinib and encorafenib in clinical trials (grade 3 or higher, 3.2% to 4.1%), including anal hemorrhage, hemothorax, GI bleeding, hematochezia, hematuria, hemoptysis, intracranial bleeding, hyphema, and vaginal bleeding. Therapy interruption, a dose reduction, or permanent discontinuation of therapy may be necessary in patients who develop bleeding. Fatal intracranial bleeding occurred in 1.6% of advanced melanoma patients who also had new or progressive brain metastases. GI bleeding (e.g., rectal bleeding (2% to 4.2%), hematochezia (3.1% or less), and hemorrhoid bleeding (1% or less)) was the most frequently reported bleeding event; hemothorax occurred in 2% or fewer patients.
Fatigue including asthenia was reported in 43% to 61% (grade 3 or 4, 3% to 8%) of patients who received binimetinib and encorafenib in clinical trials.
Infection has also occurred, with serious cases of pneumonia (3.1%) and device-related infections (2%) reported in patients treated with binimetinib plus encorafenib in an open-label, single-arm clinical trial. Fever occurred in 18% to 22% (grade 3 or 4, 4% or less) of patients treated with binimetinib plus encorafenib.
Peripheral edema was reported in 13% of patients with advanced melanoma who received binimetinib and encorafenib in a randomized trial; grade 3 peripheral edema occurred in 1% of patients. Edema occurred in 23% (grade 3 or 4, 1%) of NSCLC patients treated with binimetinib and encorafenib in an open-label, single-arm clinical trial, including peripheral edema, generalized edema, swelling, localized edema, and facial edema.
Gastrointestinal adverse events including nausea (41% to 58%; grade 3, 2% to 3.1%), diarrhea (36% to 52%; grade 3 or 4, 3% to 7%), vomiting (30% to 36%; grade 3, 1% to 2%), abdominal pain (28% to 32%; grade 3, 1% to 4%), and constipation (22% to 27%) were reported in patients who received binimetinib and encorafenib in clinical trials; the term diarrhea included colitis in the open-label, single-arm trial, and was reported in less than 10% of patients in the randomized controlled trial.
Rash (22% to 27%; grade 3, 1% to 3.1%) and hypersensitivity (less than 10%) were reported in patients who received binimetinib and encorafenib in clinical trials; the term rash included maculopapular rash, pustular rash, acneiform rash, palmar-plantar erythrodysesthesia (hand and foot syndrome), eczema, and exfoliative dermatitis. Panniculitis was reported in fewer than 10% of patients treated with binimetinib and encorafenib in a randomized controlled trial. Pruritus (16%), xerosis (13%), hyperkeratosis (less than 10%), and erythema (less than 10%) were reported in an open-label, single-arm trial.
Dizziness was reported in 15% to 17% (grade 3 or 4, 1% to 3%) of patients who received binimetinib and encorafenib in clinical trials; headache was reported in 11% of patients in an open-label, single-arm clinical trial.
Hypertension was reported in 10% to 11% of patients who received binimetinib and encorafenib in 2 clinical trials (grade 3 or 4, 5% to 6%).
Hematologic adverse events including anemia (36% to 47%; grade 3 or 4, 3.6% to 11%), lymphopenia (13% to 24%; grade 3 or 4, 2.1% to 6%), leukopenia (12% to 13%), and neutropenia (12% to 13%; grade 3 or 4, 1.1% to 3.1%) were reported in patients who received binimetinib and encorafenib in clinical trials. Thrombocytopenia occurred in 20% (grade 3 or 4, 1.1%) of patients treated with binimetinib plus encorafenib in an open-label, single-arm trial.
Nephrotoxicity, specifically increased serum creatinine level, was reported in 91% to 93% of patients who received binimetinib and encorafenib in clinical trials; grade 3 or 4 increases in serum creatinine occurred in 3.2% to 3.6% of patients.
Hyponatremia was reported in 18% to 26% of patients who received binimetinib and encorafenib in clinical trials (grade 3 or 4, 3.6% to 11%). Hyperkalemia (31%; grade 3 or 4, 2.1%) and hypocalcemia (12%; grade 3 or 4, 2.1%) were also reported with binimetinib plus encorafenib treatment in an open-label, single-arm trial.
A new primary malignancy, including both cutaneous and noncutaneous malignancies, can occur when binimetinib is used in combination with encorafenib. Cutaneous squamous cell carcinoma and skin papilloma each occurred in 2% of NSCLC patients treated with binimetinib plus encorafenib in a noncomparative, open-label clinical trial. Monitor patients for new malignancies at baseline, while on treatment, and after discontinuation of therapy.
Alopecia occurred in 12% of patients with advanced NSCLC treated with binimetinib plus encorafenib in an open-label, single-arm trial.
Pancreatitis occurred in fewer than 10% of patients treated with binimetinib plus encorafenib in an open-label, single-arm clinical trial; additionally, hyperamylasemia (22%; grade 3 or 4, 1.1%) and increased lipase levels (40%; grade 3 or 4, 14%) were reported in these patients.
Hyperglycemia occurred in 48% of patients treated with binimetinib plus encorafenib in an open-label, single-arm clinical trial (grade 3 or 4, 6%).
Hypoalbuminemia occurred in 32% of patients treated with binimetinib plus encorafenib in an open-label, single-arm clinical trial.
Peripheral neuropathy, dysgeusia, and facial paresis each occurred in fewer than 10% of patients treated with binimetinib plus encorafenib in an open-label, single-arm clinical trial.
Insomnia was reported in 10% of patients treated with binimetinib plus encorafenib in an open-label, single-arm clinical trial.
Dyspnea (27%; grade 3 or 4, 8%) and cough (26%) were reported in patients treated with binimetinib plus encorafenib in an open-label, single-arm clinical trial.
Musculoskeletal pain including back pain, arthralgia, extremity pain, myalgia, non-cardiac chest pain, and neck pain was reported in 48% (grade 3 or 4, 4.1%) of patients treated with binimetinib plus encorafenib in an open-label, single-arm clinical trial.
Decreased appetite/anorexia was reported in 14% (grade 3 or 4, 1%) of patients treated with binimetinib plus encorafenib in an open-label, single-arm clinical trial.
Weight gain was reported in 11% (grade 3 or 4, 1%) of patients treated with binimetinib plus encorafenib in an open-label, single-arm clinical trial.
Serious cases of arrhythmia exacerbation and myocardial infarction were each reported in 2% of patients treated with binimetinib plus encorafenib in an open-label, single-arm clinical trial.
Pleural effusion was reported in 2% of patients treated with binimetinib plus encorafenib in an open-label, single-arm clinical trial.
Cardiomyopathy (e.g., congestive heart failure, left ventricular dysfunction, and decreased left ventricular ejection fraction (LVEF)) has been reported in patients who received combination therapy with binimetinib and encorafenib. Safety has not been established in patients with a LVEF below 50% or below the institutional lower limits of normal. Evaluate LVEF by echocardiogram or multigated acquisition (MUGA) scan prior to starting binimetinib, at 1 month, and then every 2 to 3 months during therapy. Closely monitor patients with cardiovascular risk factors. Therapy interruption, a dose reduction, or permanent discontinuation of binimetinib may be necessary in patients who develop cardiomyopathy.
Serious ocular toxicity including retinal pigment epithelial detachments, retinal detachment, retinal vein occlusion (RVO), uveitis, iritis, and iridocyclitis has been reported in patients who received combination therapy with binimetinib and encorafenib. Monitor patients for signs and symptoms of visual impairment at each clinic visit. Perform an ophthalmologic evaluation regularly and in patients who experience a new, worsening, or persistent visual disturbance. Permanently discontinue binimetinib in patients who develop RVO. Therapy interruption, a dose reduction, or permanent discontinuation of binimetinib may be necessary in patients who develop persistent or severe ocular toxicity.
Hepatotoxicity has been reported in patients who received combination therapy with binimetinib and encorafenib. Monitor liver function tests prior to starting binimetinib therapy, monthly during therapy, and as clinically indicated. No dosage adjustment is necessary in patients with mild hepatic disease/impairment; however, reduce the binimetinib dosage to 30 mg PO twice daily in patients with moderate (total bilirubin level greater than 1.5- to 3-times the upper limit of normal (ULN) and any AST level) or severe (total bilirubin level greater than 3-times the ULN and any AST level) hepatic impairment. Therapy interruption, a dose reduction, or permanent discontinuation of binimetinib may be necessary in patients who develop elevated hepatic enzymes.
Rhabdomyolysis has been reported in patients who received combination therapy with binimetinib and encorafenib. Monitor creatine phosphokinase (CPK) and serum creatinine levels prior to starting binimetinib therapy, periodically during therapy, and as clinically indicated. Therapy interruption, a dose reduction, or permanent discontinuation of binimetinib may be necessary in patients who develop rhabdomyolysis.
Binimetinib may cause fetal harm when administered to a pregnant woman, based on its mechanism of action and data from animal studies. Advise females of reproductive potential to avoid pregnancy while taking binimetinib. Discuss the potential hazard to the fetus if binimetinib is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicities including decreased fetal weights and an increased rate of pregnancy loss and malformations were observed in the offspring of pregnant rabbits who received binimetinib doses that resulted in drug exposures that were about 5-times the recommended human exposure.
A new primary malignancy, including both cutaneous and noncutaneous malignancies, can occur when binimetinib is used in combination with encorafenib. Monitor patients for new malignancies at baseline, while on treatment, and after discontinuation of therapy.
Counsel patients about the reproductive risk and contraception requirements during binimetinib therapy. Pregnancy testing prior to starting binimetinib therapy is recommended for females of reproductive potential. These patients should use effective contraceptive methods during and for at least 30 days after the last binimetinib dose. Advise women to contact their healthcare provider if pregnancy is suspected or confirmed. Women who become pregnant while receiving binimetinib should be apprised of the potential hazard to the fetus.
It is not known if binimetinib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during binimetinib therapy and for 3 days after the last dose.
For the treatment of malignant melanoma:
NOTE: Confirm the BRAF V600E or V600K mutation prior to starting therapy. Information on FDA-approved tests for the detection of BRAF V600 mutations is available at http://www.fda.gov/CompanionDiagnostics.
-for the treatment of unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutations, in combination with encorafenib:
NOTE: The FDA has designated binimetinib in combination with encorafenib as an orphan drug for the treatment of stage IIB to IV melanoma.
Oral dosage:
Adults: 45 mg orally twice daily in combination with encorafenib 450 mg orally once daily until disease progression. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. At a median follow-up time of 40.8 months, combination therapy with encorafenib plus binimetinib resulted in a significantly longer median progression-free survival (PFS) time (primary endpoint) compared with single-agent vemurafenib (14.9 months vs. 7.3 months; hazard ratio (HR) = 0.51; 95% CI, 0.4 to 0.67) in patients with locally advanced stage IIIB, IIIC, or IV melanoma, unresectable or metastatic cutaneous melanoma, or unknown primary melanoma and BRAF V600E and/or V600K mutations in a multinational, randomized, 3-arm, phase 3 study (n = 577; the COLUMBUS study). Additionally, the median overall survival (OS) time was significantly improved in the combination therapy arm compared with vemurafenib (33.6 months vs. 16.9 months; HR = 0.65; 95% CI, 0.5 to 0.81) at a median follow-up time of 70.4 months. The median PFS (14.9 months vs. 9.6 months; HR = 0.79; 95% CI, 0.61 to 1.02) and OS (33.6 months vs. 23.5 months; HR = 0.93; 95% CI, 0.72 to 1.19) times were not significantly longer in the combination therapy arm compared with single-agent encorafenib. The 5-year PFS rates were 23%, 10%, and 19% in the encorafenib plus binimetinib, single-agent vemurafenib, and single-agent encorafenib arms, respectively; the 5-year OS rates were 35%, 21%, and 35%, respectively. Most patients in this study had extensive disease (stage IV M1c disease, 64%; 3 or more organs involved, 45%); 30% of patients had progressed on or after immunotherapy.
For the treatment of non-small cell lung cancer (NSCLC):
-for the treatment of metastatic non-small cell lung cancer (NSCLC) in patients with a BRAF V600E mutation, in combination with encorafenib:
NOTE: Confirm the presence of a BRAF V600E mutation in plasma specimens prior to starting therapy; if no BRAF V600E mutation is present in a plasma specimen, test tumor tissue. Information on FDA-approved tests for the detection of BRAF V600 mutations is available at www.fda.gov/CompanionDiagnostics.
Oral dosage:
Adults: 45 mg PO twice daily in combination with encorafenib (450 mg PO once daily) until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with binimetinib plus encorafenib resulted in an objective response rate (ORR) of 75% (complete response [CR], 15%) for a median duration that was not estimable in treatment-naive patients with BRAF V600E metastatic NSCLC (n = 59) in a multicenter, open-label, noncomparative phase 2 trial (PHAROS); the ORR was 46% (CR, 10%) for a median duration of 16.7 months in patients with previously treated disease (n = 39). Prior use of BRAF inhibitors or MEK inhibitors was not allowed. Seventy-five percent (75%) of patients with treatment-naive disease and 67% of patients with previously treated disease had a duration of response of at least 6 months. The duration of response was 12 months or longer in 59% and 33% of patients, respectively.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Recommended Dose Reductions
Dose reduction: 30 mg PO twice daily; permanently discontinue therapy in patients unable to tolerate 30 mg PO twice daily.
NOTE: Discontinue binimetinib therapy if encorafenib is permanently discontinued.
Cardiac Toxicity
Asymptomatic cardiac toxicity, an absolute decrease in left ventricular ejection fraction (LVEF) of greater than 10% from baseline, and the LVEF is below institutional lower limits of normal (LLN): Hold binimetinib for up to 4 weeks. Therapy may be resumed at a reduced dose when the LVEF is at the LLN or above, the absolute decrease in LVEF is 10% or less from baseline, and the patient is asymptomatic. If the LVEF does not recover within 4 weeks, permanently discontinue binimetinib.
Symptomatic congestive heart failure OR an absolute decrease in LVEF of greater than 20% from baseline and the LVEF is below institutional LLN: Permanently discontinue binimetinib.
Malignancy
RAS-positive non-cutaneous malignancy: Dose adjustment not required.
Ocular Toxicity
Symptomatic and serious retinopathy/retinal pigment epithelial detachment (RPED): Hold binimetinib for up to 10 days. If the toxicity improves and becomes asymptomatic, resume therapy at the same dose. If the RPED does not improve within 10 days, consider permanently discontinuing binimetinib or resume binimetinib at a lower dose.
Retinal vein occlusion: Permanently discontinue binimetinib.
Grade 1 or 2 uveitis that does not respond to specific ocular therapy or grade 3 uveitis: Hold binimetinib for up to 6 weeks; resume binimetinib at same dose or at a reduced dose when uveitis improves. Permanently discontinue binimetinib if toxicity does not improve after 6 weeks.
Grade 4 uveitis: Permanently discontinue binimetinib.
Pulmonary Toxicity
Grade 2 interstitial lung disease (ILD): Hold binimetinib for up to 4 weeks. If the toxicity improves to grade 1 or less, resume binimetinib at a reduced dose. If the toxicity does not resolve within 4 weeks, permanently discontinue binimetinib.
Grade 3 or 4 ILD: Permanently discontinue binimetinib.
Rhabdomyolysis or Elevated Creatine Phosphokinase (CPK) levels
Grade 4 asymptomatic elevated CPK level or any grade elevated CPK level with symptoms or renal impairment: Hold binimetinib for up to 4 weeks. If the toxicity improves to grade 1 or less, resume binimetinib at a reduced dose. If the toxicity does not resolve within 4 weeks, permanently discontinue binimetinib.
Skin Toxicity (excluding palmar-plantar erythrodysesthesia/hand and foot syndrome)
Grade 2 toxicity with no improvement within 2 weeks: Hold binimetinib until toxicity improves to grade 1 or less. Resume binimetinib therapy at the same dose for the first occurrence and at a reduced dose for recurrent toxicity.
Grade 3 toxicity: Hold binimetinib until toxicity improves to grade 1 or less. Resume binimetinib therapy at the same dose for the first occurrence and at a reduced dose for recurrent toxicity.
Grade 4 toxicity: Permanently discontinue binimetinib.
Thromboembolism
Uncomplicated deep vein thrombosis or pulmonary embolism (PE): Hold binimetinib. If the toxicity improves to grade 1 or less, resume binimetinib at a reduced dose. If the toxicity does not improve to grade 1 or less, permanently discontinue binimetinib.
Life threatening PE: Permanently discontinue binimetinib.
Other Adverse Reactions (including bleeding)
Recurrent grade 2 toxicity or first occurrence of grade 3 toxicity: Hold binimetinib for up to 4 weeks. If toxicity improves to grade 1 or less or to baseline level, resume binimetinib at a reduced dose. If the toxicity does not improve within 4 weeks, permanently discontinue binimetinib.
Recurrent grade 3 toxicity: Consider permanently discontinuing binimetinib.
Grade 4 toxicity: Consider permanently discontinuing binimetinib or hold binimetinib for up to 4 weeks. If toxicity improves to grade 1 or less or to baseline level, resume binimetinib at a reduced dose. Permanently discontinue binimetinib if the toxicity does not improve within 4 weeks or for recurrent grade 4 toxicity.
Maximum Dosage Limits:
-Adults
90 mg/day PO.
-Geriatric
90 mg/day PO.
-Adolescents
Safety and efficacy not established.
-Children
Safety and efficacy not established.
-Infants
Safety and efficacy not established.
Patients with Hepatic Impairment Dosing
Mild hepatic impairment (total bilirubin greater than 1 and 1.5-times the upper limit of normal (ULN) and any AST level OR total bilirubin level at the ULN or less and AST level greater than the ULN) at baseline: No dosage adjustment is necessary.
Moderate (total bilirubin level greater than 1.5- to and 3-times the ULN and any AST level) or severe (total bilirubin level greater than 3-times the ULN and any AST level) hepatic impairment at baseline: 30 mg PO twice daily.
Treatment-Related Toxicity
Grade 2 elevated hepatic enzymes (AST or ALT levels): Continue current binimetinib dose. If the toxicity does not improve within 4 weeks, hold therapy until toxicity improves to grade 1 or less or to baseline levels. Therapy may be resumed at the same dose.
Recurrent grade 2 toxicity or first occurrence of grade 3 toxicity: Hold binimetinib for up to 4 weeks. If toxicity improves to grade 1 or less or to baseline level, resume binimetinib at a reduced dose. If the toxicity does not improve within 4 weeks, permanently discontinue binimetinib.
Recurrent grade 3 toxicity: Consider permanently discontinuing binimetinib.
Grade 4 toxicity: Consider permanently discontinuing binimetinib or hold binimetinib for up to 4 weeks. If toxicity improves to grade 1 or less or to baseline level, resume binimetinib at a reduced dose. Permanently discontinue binimetinib if the toxicity does not improve within 4 weeks or for recurrent grade 4 toxicity.
Patients with Renal Impairment Dosing
No binimetinib dosage adjustment is recommended for renal impairment. Binimetinib exposure was similar in subjects with severe renal impairment (defined as an estimated glomerular filtration rate 29 mL/min/1.73 m2 or less) compared with subjects who had normal renal function.
*non-FDA-approved indication
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Binimetinib is a reversible protein kinase inhibitor that targets mitogen-activated extracellular signal-related kinase (MEK)-1 and MEK-2. MEK kinases are upstream regulators of the extracellular signal-related kinase (ERK) pathway; activation of this pathway stimulates tumor cell growth. In vitro, binimetinib inhibits MEK-dependent phosphorylation of BRAF-mutant human melanoma cells. In animal studies in mice implanted with BRAF-mutant expressing tumors, binimetinib inhibited ERK phosphorylation and tumor growth. Additionally, combination therapy with binimetinib and encorafenib, a BRAF inhibitor, led to greater anti-tumor activity and delayed resistance in BRAF V600-mutant human melanoma xenografts in mice compared with either drug alone.
Binimetinib is administered orally. It is 97% bound to plasma proteins, has a blood-to-plasma ratio of 0.72, and has an apparent volume of distribution of 92 L (coefficient of variation (CV), 45%). Binimetinib is metabolized mostly by glucuronidation via UGT1A1 (61%) but also by N-dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain. The active metabolite M3 is produced via CYP1A2 and CYP2C19 and represents 8.6% of binimetinib exposure. The mean terminal half-life is 3.5 hours (CV, 28.5%) and the apparent clearance is 20.2 L/hour (CV, 24%). Following a radioactive binimetinib 45-mg dose, 62% of the dose was recovered in the feces and 31% of the total reactivity was recovered in the urine; unchanged drug excretion was 32% and 6.5%, respectively.
Affected cytochrome P450 isoenzymes and drug transporters: none
Binimetinib has no clinically important drug interactions. In vitro, binimetinib is a substrate of P-glycoprotein (P-gp) and the breast cancer resistance protein (BCRP).
-Route-Specific Pharmacokinetics
Oral Route
Following oral administration, 50% or more of the dose is absorbed and the median time to peak plasma concentration (Tmax) is 1.6 hours. Binimetinib exhibits approximately dose proportional exposure. The accumulation was 1.5-fold at steady-state following twice-daily dosing in healthy subjects and patients with solid tumors. The AUC inter-subject variability (CV%) was less than 40%.
Effects of Food: Administering a single-dose of binimetinib 45 mg orally with a high-fat (500 calories from fat), high-calorie (150 calories from protein; 350 calories from carbohydrates) meal had no effect on the AUC when compared to the fasted state. Binimetinib may be taken with or without food.
-Special Populations
Hepatic Impairment
Mild hepatic impairment (total bilirubin greater than 1 and 1.5-times the upper limit of normal (ULN) and any AST level OR total bilirubin level at the ULN or less and AST level greater than the ULN) had no significant impact on the AUC or Cmax values of binimetinib in a population pharmacokinetic analysis. However, AUC values increased by 2-fold in subjects with moderate (total bilirubin level greater than 1.5- to and 3-times the ULN and any AST level) or severe (total bilirubin level greater than 3-times the ULN and any AST level) hepatic impairment.
Renal Impairment
Severe renal impairment (creatinine clearance less than 30 mL/min) had no significant impact on the AUC or Cmax values of binimetinib in a population pharmacokinetic analysis.
Geriatric
Age (range, 20 to 94 years) had no significant impact on the AUC or Cmax values of binimetinib in a population pharmacokinetic analysis.
Gender Differences
Gender had no significant impact on the AUC or Cmax values of binimetinib in a population pharmacokinetic analysis.
Obesity
Body weight had no significant impact on the AUC or Cmax values of binimetinib in a population pharmacokinetic analysis.