Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Mektovi: 15 mg
Pharmacology
Mechanism of Action
Binimetinib reversibly inhibits mitogen-activated extracellular kinase (MEK) 1 and 2 activation and kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. Binimetinib inhibits ERK phosphorylation and viability and MEK-dependent phosphorylation of the protein kinase B-raf (BRAF) mutant cell lines. The combination of binimetinib and encorafenib allows for greater antitumor activity in BRAF V600 mutant cell lines; in animal studies, the combination also delayed the emergence of resistance in BRAF V600E mutant cells compared to either drug alone.
Pharmacokinetics/Pharmacodynamics
Distribution
Vd: 92 L
Metabolism
Hepatic; primarily via UGT1A1 glucuronidation; also via N-dealkylation, amide hydrolysis, and loss of side-chain ethane-diol. CYP1A2 and CYP2C19 contribute to the formation of the active metabolite M3.
Excretion
Excretion: Feces (62%; 32% as unchanged drug); urine (31%; 6.5% as unchanged drug)
Time to Peak
1.6 hours
Half-Life Elimination
3.5 hours
Protein Binding
97%; to human plasma proteins
Use in Specific Populations
Special Populations: Hepatic Function Impairment
A 2-fold increase in AUC was observed in subjects with moderate hepatic impairment (total bilirubin >1.5 and ≤3 × ULN and any AST) or severe impairment (total bilirubin levels >3 × ULN and any AST), compared to subjects with normal hepatic function.
Use: Labeled Indications
Melanoma, unresectable or metastatic: Treatment of unresectable or metastatic melanoma with a BRAF V600E or V600K mutation (in combination with encorafenib) as detected by an approved test.
Use: Off Label
Colorectal cancer, metastatic, refractory (RAS wild-type, BRAF V600E-mutant)b
Data from the multicenter, safety lead-in portion of a phase III study suggest that binimetinib (in combination with encorafenib and cetuximab) may be efficacious in the treatment of metastatic RAS wild-type colorectal cancer in patients with BRAF V600E-mutant tumors and disease progression following 1 to 2 prior therapies Van Cutsem 2019.
Contraindications
There are no contraindications listed in the manufacturer's labeling.
Dosage and Administration
Dosing: Adult
Note: Confirm BRAF V600 mutation status prior to treatment initiation.
Colorectal cancer, metastatic, refractory, RAS wild-type, BRAF V600E-mutant (off-label use): Oral: 45 mg twice daily (in combination with encorafenib and cetuximab) until disease progression or unacceptable toxicity (Van Cutsem 2019).
Melanoma, unresectable or metastatic (with BRAF V600E or BRAF V600K mutation): Oral: 45 mg twice daily, ~12 hours apart (in combination with encorafenib) until disease progression or unacceptable toxicity (Dummer 2018).
Missed doses: Do not administer a missed dose if <6 hours until the next dose. Do not take an additional dose if vomiting occurs after binimetinib administration; resume with the next scheduled dose.
Dosing: Geriatric
Refer to adult dosing.
Dosing: Adjustment for Toxicity
Note: If binimetinib is withheld, reduce encorafenib dose; refer to Encorafenib monograph for recommended encorafenib dose reductions. If encorafenib is permanently discontinued, discontinue binimetinib.
When used in combination with encorafenib, binimetinib dosage modification is not recommended for palmar plantar erythrodysesthesia syndrome (PPES), non-cutaneous RAS mutation-positive malignancies, and QTc prolongation.
Recommended binimetinib dose reductions for toxicity:
First dose reduction: 30 mg once twice daily
Subsequent modifications (if unable to tolerate 30 mg twice daily): Permanently discontinue binimetinib.
Cardiotoxicity:
Asymptomatic, absolute LVEF decrease of >10% from baseline and also below lower limit of normal (LLN): Withhold binimetinib for up to 4 weeks, evaluate LVEF every 2 weeks. Resume binimetinib with the dose reduced if LVEF is ≥ LLN and absolute decrease from baseline is ≤10% and patient is asymptomatic. Permanently discontinue binimetinib if the LVEF does not recover within 4 weeks.
Symptomatic heart failure or absolute decrease in LVEF of >20% from baseline and also below LLN: Permanently discontinue binimetinib.
Dermatologic toxicity:
Grade 2: If no improvement within 2 weeks, withhold binimetinib until improved to grade 0 or 1, then resume at the same dose (if first occurrence) or a reduced dose (if recurrent).
Grade 3: Withhold binimetinib until improved to grade 0 or 1, then resume at the same dose (if first occurrence) or a reduced dose (if recurrent).
Grade 4: Permanently discontinue binimetinib.
Ocular toxicity:
Symptomatic serous retinopathy/retinal pigment epithelial detachment: Withhold binimetinib for up to 10 days. If improves and become asymptomatic, resume therapy at the same dose. If not improved, resume therapy at a lower dose level or permanently discontinue binimetinib.
Retinal vein occlusion (any grade): Permanently discontinue binimetinib.
Uveitis (grades 1 to 3): If grade 1 or 2 uveitis does not respond to specific ocular therapy (or for grade 3 uveitis), interrupt binimetinib therapy for up to 6 weeks. If improves within 6 weeks following therapy interruption, resume at the same dose or a lower dose. If does not improve, permanently discontinue binimetinib.
Uveitis (grade 4): Permanently discontinue binimetinib.
Pulmonary toxicity:
Interstitial lung disease (grade 2): Withhold binimetinib for up to 4 weeks. If improves to grade 0 or 1, resume therapy at a reduced dose. If not resolved within 4 weeks, permanently discontinue binimetinib.
Interstitial lung disease (grade 3 or 4): Permanently discontinue binimetinib.
Rhabdomyolysis or creatine kinase elevations:
Grade 4 asymptomatic CPK elevation or any grade CPK elevation with symptoms or with renal impairment: Withhold binimetinib for up to 4 weeks. If improves to grade 0 or 1, resume therapy at a reduced dose. If not resolved within 4 weeks, permanently discontinue binimetinib.
Thromboembolism:
Uncomplicated DVT or PE: Withhold binimetinib. If improves to grade 0 or 1, resume therapy at a reduced dose. If no improvement, permanently discontinue binimetinib.
Life threatening PE: Permanently discontinue binimetinib.
Other toxicities (including hemorrhage):
Recurrent grade 2 or first occurrence of any grade 3 toxicity: Interrupt binimetinib therapy for up to 4 weeks; if improves to grade 0 or 1 or to pretreatment/baseline level, resume at a reduced dose. If no improvement, permanently discontinue binimetinib.
Grade 3 toxicity (recurrent): Consider permanently discontinuing binimetinib.
Grade 4 toxicity (first occurrence): Permanently discontinue binimetinib or withhold binimetinib therapy for up to 4 weeks until improvement to grade 0 or 1 or to pretreatment/baseline level, then resume at a reduced dose (permanently discontinue if no improvement).
Grade 4 toxicity (recurrent): Permanently discontinue binimetinib.
Administration
Oral: Administer twice a day (~12 hours apart) with or without food.
Storage
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).
Drug Interactions
There are no known significant interactions.
Adverse Reactions
Incidences of adverse reactions were defined during combination therapy with encorafenib.
>10%:
Cardiovascular: Peripheral edema (13%), hypertension (11%)
Central nervous system: Fatigue (43%), dizziness (15%)
Dermatologic: Skin rash (22%)
Endocrine & metabolic: Increased gamma-glutamyl transferase (45%), hyponatremia (18%)
Gastrointestinal: Nausea (41%), diarrhea (36%), vomiting (30%), abdominal pain (28%), constipation (22%)
Hematologic & oncologic: Anemia (36%, grades 3/4: 4%), hemorrhage (19%; grades 3/4:3%), leukopenia (13%), lymphocytopenia (13%, grades 3/4: 2%), neutropenia (13%, grades 3/4: 3%)
Hepatic: Increased serum alanine aminotransferase (29%), increased serum aspartate aminotransferase (27%), increased serum alkaline phosphatase (21%)
Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (58%)
Ophthalmic: Visual impairment (20%), retinal pigment changes (≤20%, retinal pigment epithelial dystrophy), retinopathy (≤20%, serous including 8% retinal detachment and 6% macular edema)
Renal: Increased serum creatinine (93%)
Miscellaneous: Fever (18%)
1% to 10%:
Cardiovascular: Decreased left ventricular ejection fraction (7%), venous thromboembolism (6%), pulmonary embolism (3%)
Gastrointestinal: Colitis (<10%), hematochezia (3%), hemorrhoidal bleeding (1%)
Hematologic & oncologic: Rectal hemorrhage (4%)
Hypersensitivity: Hypersensitivity (<10%)
Neuromuscular & skeletal: Panniculitis (<10%)
Ophthalmic: Uveitis (4%)
Frequency not defined:
Cardiovascular: Left ventricular dysfunction
Central nervous system: Headache
<1%, postmarketing, and/or case reports: Interstitial pulmonary disease, pneumonitis, retinal vein occlusion, rhabdomyolysis
Warnings/Precautions
Concerns related to adverse effects:
- Cardiotoxicity: Cardiomyopathy (manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic ejection fraction decreases) has been reported in patients who received the combination of binimetinib and encorafenib. A decrease in LVEF below the institutional lower limit of normal (LLN) with an absolute decrease in LVEF ≥10% below baseline (detected by echocardiography or MUGA) has occurred. Grade 3 left ventricular dysfunction has been reported. The median time to first occurrence of any grade left ventricular dysfunction was 3.6 months (range: up to 21 months). Cardiomyopathy resolved in a majority of patients. Assess ejection fraction (by echocardiogram or MUGA scan) prior to treatment initiation, one month after initiation, and then every 2 to 3 months during treatment. Safety has not been established in patients with a baseline ejection fraction that is either <50% or below the institutional LLN. Monitor closely in patients with cardiovascular risk factors receiving binimetinib. Based on the severity, cardiomyopathy may require treatment interruption, dose reduction and/or permanent discontinuation.
- Hemorrhage: Hemorrhage may occur with the combination of binimetinib and encorafenib, including ≥ grade 3 hemorrhage. The most frequent hemorrhagic events were gastrointestinal in nature, including rectal hemorrhage, hematochezia, and hemorrhoidal hemorrhage. Fatal intracranial hemorrhage (in the setting of new or progressive brain metastases) was also reported. May require treatment interruption, dosage reduction, and/or permanent discontinuation based on the severity of the hemorrhage.
- Hepatotoxicity: Hepatotoxicity may occur with the combination of binimetinib and encorafenib; grade 3 or 4 elevations in ALT, AST, and/or alkaline phosphatase have been reported, although grade 3 or 4 total bilirubin elevations were not reported. Monitor liver function tests prior to treatment initiation, monthly during treatment, and as clinically indicated. May require treatment interruption, dose reduction, and/or permanent discontinuation, depending on the severity. Dosage reduction is recommended in patients with moderate or severe hepatic impairment at baseline.
- Ocular toxicity: Serous retinopathy (including retinal detachment and macular edema) has occurred with the combination of binimetinib and encorafenib, Symptomatic serous retinopathy has been reported, although blindness did not occur. In the clinical study, some patients required treatment interruption or dose reduction due to serous retinopathy, although discontinuation was not required. The median time to onset of the first serous retinopathy event (all grades) was 1.2 months (range: up to 17.5 months). Retinal vein occlusion (RVO) is a known (class-related) adverse reaction of MEK inhibitors, and may occur with the combination of binimetinib and encorafenib. The safety of binimetinib 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. Uveitis, including iritis and iridocyclitis, has been reported in patients treated with the combination of binimetinib and encorafenib. Assess visual symptoms at each visit; perform an ophthalmologic examination at regular intervals and for new or worsening visual disturbances (and to follow new or persistent ophthalmologic findings). Perform ophthalmologic evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Based on the severity, ocular toxicity may require treatment interruption, dose reduction and/or permanent discontinuation. Permanently discontinue binimetinib in patients with documented RVO.
- Pulmonary toxicity: Cases of interstitial lung disease (ILD), including pneumonitis, developed in patients with BRAF mutation-positive melanoma receiving the combination of binimetinib and encorafenib. Evaluate new or progressive unexplained pulmonary symptoms/findings for possible ILD. Based on the severity, may require treatment interruption, dose reduction or permanent discontinuation.
- Rhabdomyolysis: Rhabdomyolysis may occur with the combination of binimetinib and encorafenib; CPK elevations may commonly occur. Monitor CPK and creatinine levels prior to treatment initiation, periodically during treatment, and as clinically indicated. Based on severity, may require treatment interruption, dosage reduction and/or permanent discontinuation.
- Thromboembolism: VTE, including PE, has occurred in patients receiving binimetinib in combination with encorafenib. Based on the severity, thromboembolism may require treatment interruption, dose reduction, and/or permanent discontinuation.
Concurrent drug therapy issues:
- Combination therapy with encorafenib: Additional toxicities may occur when used in combination with encorafenib (BRAF inhibitor). Refer to the encorafenib monograph for further information on warnings/precautions or encorafenib dosage modifications. If encorafenib is permanently discontinued, discontinue binimetinib.
Other warnings/precautions:
- Appropriate use: Prior to initiating therapy, confirm BRAF V600E or BRAF V600K mutation status with an approved test. Information on approved tests for detection of BRAF V600 mutations is available at http://www.fda.gov/companiondiagnostics.
Monitoring Parameters
BRAFV600K or V600E mutation status (prior to treatment); monitor liver function tests prior to treatment initiation, monthly during treatment, and as clinically indicated; monitor CPK and creatinine levels prior to treatment initiation, periodically during treatment, and as clinically indicated. Verify pregnancy status in females of reproductive potential prior to treatment initiation. Assess ejection fraction (by echocardiogram or MUGA scan) prior to treatment initiation, one month after initiation, and then every 2 to 3 months during treatment; monitor closely in patients with cardiovascular risk factors. Evaluate visual symptoms at each visit; perform an ophthalmologic examination at regular intervals and for new or worsening visual disturbances (and to follow new or persistent ophthalmologic findings); perform ophthalmologic evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Monitor for signs/symptoms of dermatologic toxicity, hemorrhage, interstitial lung disease (including new or progressive unexplained pulmonary symptoms/findings), ocular toxicity, rhabdomyolysis, and thromboembolism. Monitor adherence.
Pregnancy
Pregnancy Considerations
Based on its mechanism of action and on findings in animal reproduction studies, binimetinib may cause fetal harm if administered during pregnancy.
Verify pregnancy status in females of reproductive potential prior to initiating binimetinib therapy. Females of reproductive potential should use a highly effective contraceptive during therapy and for at least 30 days after the final binimetinib dose.
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience nausea, vomiting, diarrhea, abdominal pain, and constipation. Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of blood clots (numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood), signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin), signs of low sodium (headache, difficulty focusing, trouble with memory, confusion, weakness, seizures, or change in balance), severe headache, dizziness, passing out, vision changes, blurred vision, seeing colored dots, seeing halos or bright colors around lights, blindness, chills, severe loss of strength and energy, muscle pain, muscle weakness, dark urine, eye pain, eye edema, eye redness, and signs of heart problems (cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out) (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
