Version May 2024
Dosage guidance:
Safety : Binimetinib is associated with a moderate or high emetic potential; antiemetics may be recommended to prevent nausea and vomiting.
Melanoma, unresectable or metastatic, with BRAF V600E or BRAF V600K mutation: Note: Confirm BRAF V600E or V600K mutation status in tumor specimens prior to initiation.
Oral: 45 mg twice daily (in combination with encorafenib); continue until disease progression or unacceptable toxicity (Ref).
Melanoma, unresectable or metastatic, with NRAS mutation (off-label use): Oral: 45 mg twice daily as a single agent; continue until disease progression or unacceptable toxicity (Ref).
Non-small cell lung cancer, metastatic, with BRAF V600E mutation: Note: Confirm BRAF V600E mutation status in tumor or plasma specimens prior to initiation; if no mutation detected in plasma specimens, then test tumor tissue.
Oral: 45 mg twice daily (in combination with encorafenib); continue until disease progression or unacceptable toxicity (Ref).
Missed doses: Do not administer a missed dose if <6 hours until the next dose. Do not administer an additional dose if vomiting occurs after binimetinib administration; resume with the next scheduled dose.
There are no dosage adjustments provided in the manufacturer's labeling; however, kidney impairment does not have any clinically relevant effect on binimetinib exposure. No dosage adjustment is necessary (Ref).
Hemodialysis: Not likely dialyzed due to extensive protein binding (Ref). No need for dosage adjustment is expected (Ref).
Hepatic impairment prior to treatment initiation:
Mild impairment (total bilirubin >1 to ≤1.5 times ULN and any AST or total bilirubin ≤ ULN and AST > ULN): No dosage adjustment necessary.
Moderate (total bilirubin >1.5 to ≤3 times ULN and any AST) to severe (total bilirubin >3 times ULN and any AST) impairment: 30 mg twice daily.
Acute hepatotoxicity during treatment:
Grade 2 AST or ALT elevations: Maintain binimetinib dose; if no improvement within 2 weeks, withhold binimetinib until improvement to grade 0 or 1 or to pretreatment/baseline levels and then resume at the same dose.
Grade 3 AST or ALT elevation: For the first occurrence of grade 3 AST or ALT elevations, withhold binimetinib for up to 4 weeks; if improves to grade 0 or 1 or to pretreatment/baseline level, resume binimetinib at a reduced dose. If no improvement, permanently discontinue binimetinib. For recurrent grade 3 toxicity, consider permanently discontinuing binimetinib.
Grade 4 AST or ALT elevation: For the first occurrence of grade 4 AST or ALT elevations, permanently discontinue binimetinib or withhold binimetinib therapy for up to 4 weeks; if improves to grade 0 or 1, then resume binimetinib at a reduced dose. If no improvement, permanently discontinue binimetinib. For recurrent grade 4 toxicity, permanently discontinue binimetinib.
Note: If binimetinib is withheld, reduce encorafenib dose until binimetinib is resumed; 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.
|
Dosage reduction levels |
Dosage and schedule |
|---|---|
|
Initial (usual) dosage |
45 mg twice daily |
|
First dosage reduction |
30 mg twice daily |
|
Subsequent modification (if unable to tolerate 30 mg twice daily) |
Permanently discontinue binimetinib. |
|
Recommended Binimetinib Dosage Modifications for Adverse Reactions | ||
|---|---|---|
|
a LVEF = left ventricular ejection fraction; DVT = deep vein thrombosis; PE = pulmonary embolism. | ||
|
Adverse reaction |
Severity |
Binimetinib dosage modification |
|
Cardiotoxicity |
Asymptomatic, absolute LVEFa decrease of >10% from baseline and also below LLN |
Withhold binimetinib for up to 4 weeks and evaluate LVEF every 2 weeks. LVEF is ≥ LLN and absolute decrease from baseline is ≤10% and patient is asymptomatic: Resume binimetinib at reduced dose. LVEF does not recover within 4 weeks: Permanently discontinue binimetinib. |
|
Symptomatic heart failure or absolute decrease in LVEF of >20% from baseline and also below LLN |
Permanently discontinue binimetinib. | |
|
Dermatologic toxicity |
Grade 2 |
No improvement within 2 weeks: Withhold binimetinib until improved to grade 0 or 1; resume at same dose (if first occurrence) or reduced dose (if recurrent). |
|
Grade 3 |
Withhold binimetinib until improved to grade 0 or 1; resume at same dose (if first occurrence) or reduced dose (if recurrent). | |
|
Grade 4 |
Permanently discontinue binimetinib. | |
|
Ocular toxicity |
Retinal vein occlusion (any grade) |
Permanently discontinue binimetinib. |
|
Symptomatic serous retinopathy/retinal pigment epithelial detachment |
Withhold binimetinib for up to 10 days. Improvement within 10 days of interruption and asymptomatic: Resume binimetinib at same dose. No improvement within 10 days of interruption: Resume binimetinib at reduced dose or permanently discontinue. | |
|
Uveitis (grade 1 to 2) |
If no response to specific ocular therapy: Withhold binimetinib for up to 6 weeks. Improvement within 6 weeks of interruption: Resume binimetinib at same or reduced dose. No improvement within 6 weeks of interruption: Permanently discontinue binimetinib. | |
|
Uveitis (grade 3) |
Withhold binimetinib for up to 6 weeks. Improvement within 6 weeks of interruption: Resume binimetinib at same or reduced dose. No improvement within 6 weeks of interruption: Permanently discontinue binimetinib. | |
|
Uveitis (grade 4) |
Permanently discontinue binimetinib. | |
|
Pulmonary toxicity |
Interstitial lung disease (grade 2) |
Withhold binimetinib for up to 4 weeks. Improvement to grade 0 or 1 within 4 weeks of interruption: Resume binimetinib at reduced dose. No improvement within 4 weeks of interruption: Permanently discontinue binimetinib. |
|
Interstitial lung disease (grade 3 or 4) |
Permanently discontinue binimetinib. | |
|
Rhabdomyolysis or CPK elevation |
Grade 4 asymptomatic CPK elevation |
Withhold binimetinib for up to 4 weeks. Improvement to grade 0 or 1 within 4 weeks of interruption: Resume binimetinib at reduced dose. No improvement within 4 weeks of interruption: Permanently discontinue binimetinib. |
|
Any grade CPK elevation with symptoms or with kidney impairment |
Withhold binimetinib for up to 4 weeks. Improvement to grade 0 or 1 within 4 weeks of interruption: Resume binimetinib at reduced dose. No improvement within 4 weeks of interruption: Permanently discontinue binimetinib. | |
|
Thromboembolism |
Uncomplicated DVTa or PEa |
Withhold binimetinib. Improvement to grade 0 to 1: Resume binimetinib at reduced dose. No improvement: Permanently discontinue binimetinib. |
|
Life-threatening PE |
Permanently discontinue binimetinib. | |
|
Other treatment-related adverse reaction (including hemorrhage) |
Grade 2 (recurrent) or grade 3 (first occurrence) |
Withhold binimetinib for up to 4 weeks. Improvement to grade 0 or 1 or pretreatment/baseline levels within 4 weeks of interruption: Resume binimetinib at reduced dose. No improvement within 4 weeks of interruption: Permanently discontinue binimetinib. |
|
Grade 4 (first occurrence) |
Permanently discontinue binimetinib or withhold binimetinib for up to 4 weeks. Improvement to grade 0 or 1 or pretreatment/baseline levels within 4 weeks of interruption: Resume binimetinib at reduced dose. No improvement within 4 weeks of interruption: Permanently discontinue binimetinib. | |
|
Grade 3 (recurrent) |
Consider permanently discontinuing binimetinib. | |
|
Grade 4 (recurrent) |
Permanently discontinue binimetinib. | |
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Percentages reported as part of combination chemotherapy regimens in adults.
>10%:
Cardiovascular: Cardiomyopathy (absolute decreased left ventricular ejection fraction ≥10% below baseline: 7% to 11%), edema (23%), hypertension (10% to 11%), peripheral edema (13%)
Dermatologic: Alopecia (12%), pruritus (16%), skin rash (22% to 27%), xeroderma (13%)
Endocrine & metabolic: Hyperglycemia (48%), hyperkalemia (31%), hypoalbuminemia (32%), hypocalcemia (12%), hyponatremia (18% to 26%), weight gain (11%)
Gastrointestinal: Abdominal pain (28% to 32%), constipation (22% to 27%), decreased appetite (14%), diarrhea (36% to 52%; grades 3/4: 3% to 7%), increased serum amylase (22%), increased serum lipase (40%), nausea (41% to 58%; grades 3/4: 2% to 3%), vomiting (30% to 37%; grades 3/4: 1% to 2%)
Hematologic & oncologic: Anemia (36% to 47%; grades 3/4: 4% to 11%), hemorrhage (12% to 19%; grades 3/4: 3% to 4%), leukopenia (12% to 13%), lymphocytopenia (13% to 24%; grades 3/4: 2% to 6%), neutropenia (12% to 13%; grades 3/4: 1% to 3%), thrombocytopenia (20%; grades 3/4: 1%)
Hepatic: Increased gamma-glutamyl transferase (45%), increased serum alanine aminotransferase (29% to 34%), increased serum alkaline phosphatase (21% to 31%), increased serum aspartate aminotransferase (27% to 31%)
Nervous system: Dizziness (15% to 17%), fatigue (43% to 61%), headache (11%)
Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (41% to 58%), musculoskeletal pain (48%)
Ophthalmic: Retinopathy (serous: 20%, including macular edema [6%], retinal detachment [2% to 8%]), visual impairment (20% to 29%)
Renal: Increased serum creatinine (91% to 93%)
Respiratory: Cough (26%), dyspnea (27%)
Miscellaneous: Fever (18% to 22%)
1% to 10%:
Cardiovascular: Pulmonary embolism (1% to 3%), venous thromboembolism (6% to 7%)
Dermatologic: Cutaneous papilloma (2%), erythema of skin, hyperkeratosis, squamous cell carcinoma of skin (2%)
Gastrointestinal: Anal hemorrhage (2%), colitis, dysgeusia, hematochezia (3%), hemorrhoidal bleeding (1%), pancreatitis, rectal hemorrhage (4%)
Hypersensitivity: Hypersensitivity reaction
Nervous system: Facial paresis, insomnia (10%), peripheral neuropathy
Neuromuscular & skeletal: Panniculitis
Ophthalmic: Uveitis (1% to 4%, including iridocyclitis, iritis)
Respiratory: Hemothorax (2%), pneumonitis (1%)
<1%: Ophthalmic: Retinal vein occlusion
Frequency not defined:
Nervous system: Intracranial hemorrhage
Renal: Acute kidney injury
There are no contraindications listed in the manufacturer's labeling.
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 left ventricular ejection fraction (LVEF) below the institutional 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. Safety has not been established in patients with a baseline ejection fraction that is either <50% or below the institutional LLN.
• 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/anal hemorrhage, hematochezia, hemorrhoidal hemorrhage, and hemothorax. Fatal intracranial hemorrhage (may occur in the setting of new or progressive brain metastases) was also reported.
• 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.
• Malignancy: New primary malignancies (cutaneous and noncutaneous) may occur. Cutaneous squamous cell carcinoma and skin papilloma have been observed in a small percentage of patients who received the combination of binimetinib and encorafenib.
• 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 clinical studies, 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.
• Pulmonary toxicity: Cases of interstitial lung disease, including pneumonitis, developed in patients receiving the combination of binimetinib and encorafenib.
• Rhabdomyolysis: Rhabdomyolysis may occur with the combination of binimetinib and encorafenib; CPK elevations may commonly occur.
• Thromboembolism: Venous thromboembolism, including pulmonary embolism, has occurred in patients receiving binimetinib in combination with encorafenib.
Concurrent drug therapy issues:
• Combination therapy with encorafenib: Additional toxicities may occur when used in combination with encorafenib (BRAF inhibitor).
Other warnings/precautions:
• Appropriate use: Prior to initiating therapy, confirm BRAF V600E or BRAF V600K mutation status with an approved test. Test tumor specimens for melanoma and tumor or plasma specimens for non-small cell lung cancer (NSCLC); if no mutation detected in plasma specimens, then test tumor tissue (NSCLC only). Information on approved tests for detection of BRAF V600 mutations is available at http://www.fda.gov/companiondiagnostics.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Mektovi: 15 mg
No
Tablets (Mektovi Oral)
15 mg (per each): $104.05
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Mektovi: 15 mg
Binimetinib is available through specialty pharmacies and various specialty institutions or accounts. Examples from the manufacturer may be found at https://www.braftovimektovi.com/hcp.
Oral: Administer twice a day (~12 hours apart) with or without food. Binimetinib is associated with a moderate or high emetic potential; antiemetics may be recommended to prevent nausea and vomiting.
Mekoovi: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/210498s009lbl.pdf#page=20
Melanoma, unresectable or metastatic, with BRAF V600E or BRAF V600K mutation: Treatment of unresectable or metastatic melanoma with a BRAF V600E or V600K mutation (in combination with encorafenib). Select patients for therapy based on the presence of a BRAF V600E or BRAF V600K mutation in tumor specimens as detected by an approved test.
Non-small cell lung cancer, metastatic, with BRAF V600E mutation: Treatment of metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation (in combination with encorafenib) in adults. Select patients for therapy based on the presence of a BRAF V600E mutation in tumor or plasma specimens as detected by an approved test.
Melanoma, unresectable or metastatic, with NRAS mutation
Binimetinib may be confused with alectinib, bosutinib, brigatinib, cobimetinib, encorafenib, neratinib, selumetinib, trametinib.
Mektovi may be confused with Mekinist.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Substrate of BCRP/ABCG2, CYP1A2 (minor), CYP2C19 (minor), P-glycoprotein/ABCB1 (minor), UGT1A1; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Mitapivat: May decrease the serum concentration of UGT1A1 Substrates. Risk C: Monitor therapy
Verify pregnancy status prior to initiating binimetinib therapy in patients who could become pregnant. Patients who could become pregnant should use a highly effective contraceptive during therapy and for 30 days after the last binimetinib dose.
Based on its mechanism of action and on findings in animal reproduction studies, in utero exposure to binimetinib may cause fetal harm.
It is not known if binimetinib is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during treatment and for 3 days after the last binimetinib dose.
BRAF mutation status: BRAF V600K or V600E mutation status in tumor specimens prior to treatment in melanoma. BRAF V600E mutation status in tumor or plasma specimens prior to treatment for non-small cell lung cancer (NSCLC); if no mutation detected in plasma specimens, then test tumor tissue.
Monitor LFTs 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 prior to treatment initiation in patients who could become pregnant. 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), new cutaneous or noncutaneous malignancy (prior to initiation of treatment, during treatment, and after discontinuation), ocular toxicity, rhabdomyolysis, and thromboembolism. Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Cardiovascular monitoring specifics: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017]). Assess BP at baseline and each clinical visit (as well as outpatient monitoring weekly for initial 3 months, then monthly thereafter), obtain a baseline echocardiography in high- and very-high risk patients scheduled to receive BRAF-MEK inhibitor combination therapy (consider repeating every 4 months during the first year); consider echocardiography in low- and moderate-risk patients scheduled to receive BRAF-MEK inhibitor combination therapy (ESC [Lyon 2022]).
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. In animal models, the combination also delayed the emergence of resistance in BRAF V600E mutant melanoma cells compared to either drug alone. In BRAF mutant non-small cell lung cancer animal models, after dosing cessation, increased tumor growth delays were also observed with the combination (compared to either drug alone).
Distribution: Vd: 92 L.
Protein binding: 97%; to human plasma proteins.
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.
Bioavailability: ≥50%.
Half-life elimination: 3.5 hours.
Time to peak: 1.6 hours.
Excretion: Feces (62%; 32% as unchanged drug); urine (31%; 6.5% as unchanged drug).
Clearance: 20.2 L/hour.
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.
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