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Binimetinib

Class: Antineoplastic Agents
Chemical Name: 5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide
Molecular Formula: C17H15BrF2N4O3
CAS Number: 606143-89-9
Brands: Mektovi

Medically reviewed by Drugs.com on May 17, 2021. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK2.

Uses for Binimetinib

Melanoma

In combination with encorafenib for treatment of unresectable or metastatic melanoma with b-Raf serine-threonine kinase (BRAF) V600E or V600K mutation (designated an orphan drug by FDA for this use).

FDA-approved diagnostic test (e.g., bioMerieux THxID BRAF V600 mutation test) required to confirm presence of BRAF V600E or V600K mutation prior to initiation of therapy.

Binimetinib Dosage and Administration

General

  • Confirm presence of BRAF V600E or V600K mutation prior to initiation of therapy.

Restricted Distribution Program

  • Obtain binimetinib through specialty pharmacies.

  • Contact manufacturer at 844-492-7729 or consult the Braftovi and Mektovi website (https://www.braftovimektovi.com/hcp/).

Administration

Oral Administration

Administer orally twice daily, approximately 12 hours apart, without regard to meals.

Dosage

Adults

Melanoma
Oral

45 mg twice daily; use in combination with encorafenib. Continue therapy until disease progression or unacceptable toxicity occurs.

If encorafenib therapy is permanently discontinued, binimetinib also should be discontinued. Consult manufacturer's labeling for information on dosage modifications of encorafenib.

Dosage Modification for Toxicity
Oral

Some adverse effects require temporary interruption, dosage reduction, and/or discontinuance of therapy.

If dosage reduction from 45 mg twice daily is necessary, reduce dosage to 30 mg twice daily. Dosages <30 mg twice daily not recommended; permanently discontinue drug if 30-mg twice daily dosage is not tolerated.

Cardiovascular Toxicity.
Oral

If asymptomatic absolute decrease in left ventricular ejection fraction (LVEF) from baseline of >10% and to a level below the lower limit of normal (LLN) occurs, interrupt binimetinib therapy for up to 4 weeks and reassess LVEF every 2 weeks; resume therapy at a reduced dosage when an asymptomatic absolute decrease in LVEF from baseline improves to ≤10% and to a level at least the LLN. If toxicity does not improve within 4 weeks of interrupting therapy, permanently discontinue drug. (See Cardiac Effects under Cautions.)

If symptomatic CHF or absolute decrease in LVEF from baseline of >20% and to a level below the LLN occurs, permanently discontinue drug.

If QT-interval prolongation occurs during combination therapy with binimetinib and encorafenib, no dosage adjustment of binimetinib necessary.

Venous Thromboembolism
Oral

If uncomplicated DVT or PE occurs, interrupt binimetinib therapy until toxicity improves to grade 1 or less, and then resume at a reduced dosage. If toxicity does not improve, permanently discontinue drug.

If life-threatening PE occurs, permanently discontinue drug.

Ocular Effects.
Oral

If symptomatic serous retinopathy or retinal pigment epithelial detachment occurs, interrupt binimetinib therapy for up to 10 days until toxicity improves and the patient becomes asymptomatic, and then resume at same dosage. If toxicity does not improve within 10 days of interrupting therapy, resume at a reduced dosage or permanently discontinue drug. (See Ocular Effects under Cautions.)

If grade 1 or 2 uveitis refractory to ocular therapy occurs, interrupt binimetinib therapy for up to 6 weeks until toxicity improves, and then resume at same or reduced dosage. If toxicity does not improve within 6 weeks of interrupting therapy, permanently discontinue drug.

If grade 3 uveitis occurs, interrupt binimetinib therapy for up to 6 weeks until toxicity improves, and then resume at same or reduced dosage. If grade 3 uveitis does not improve within 6 weeks of interrupting therapy, permanently discontinue drug.

If retinal vein occlusion or grade 4 uveitis occurs, permanently discontinue drug.

Pulmonary Effects.
Oral

If grade 2 interstitial lung disease occurs, interrupt binimetinib therapy for up to 4 weeks until toxicity improves to grade 1 or less, and then resume therapy at reduced dosage. If grade 2 interstitial lung disease does not improve within 4 weeks of interrupting therapy, permanently discontinue drug. (See Pulmonary Effects under Cautions.)

If grade 3 or 4 interstitial lung disease occurs, permanently discontinue drug.

Hepatotoxicity
Oral

If grade 2 serum ALT or AST elevations occur, continue therapy at same dosage for up to 2 weeks. If toxicity persists, interrupt binimetinib therapy until toxicity improves to grade 1 or less or to baseline, and then resume therapy at same dosage. (See Hepatic Toxicity under Cautions.)

For first occurrence of grade 3 serum ALT or AST elevations, interrupt binimetinib therapy for up to 4 weeks until toxicity improves to grade 1 or less or to baseline, and then resume therapy at a reduced dosage. If toxicity does not improve to grade 1 or less or to baseline within 4 weeks of interrupting therapy, permanently discontinue drug. If grade 3 serum ALT or AST elevations recur, consider permanent discontinuance of drug.

For first occurrence of grade 4 serum ALT or AST elevations, interrupt binimetinib therapy or permanently discontinue drug. If binimetinib therapy is temporarily interrupted, withhold therapy for up to 4 weeks until toxicity improves to grade 1 or less or to baseline, and then resume therapy at a reduced dosage. If toxicity does not improve to grade 1 or less or to baseline within 4 weeks of interrupting therapy, permanently discontinue drug. If grade 4 serum ALT or AST elevations recur, permanently discontinue drug.

Musculoskeletal Effects
Oral

In patients with asymptomatic grade 4 elevations in CK concentration or any grade of CK elevation with symptoms or concomitant renal impairment, interrupt binimetinib therapy for up to 4 weeks until toxicity improves to grade 1 or less, and then resume therapy at a reduced dosage. If toxicity does not improve within 4 weeks of interrupting therapy, permanently discontinue drug. (See Musculoskeletal Effects under Cautions.)

Dermatologic Effects
Oral

For first occurrence of grade 2 dermatologic reactions, continue therapy at same dosage. If toxicity does not improve within 2 weeks, interrupt binimetinib therapy until toxicity improves to grade 1 or less, and then resume therapy at same dosage. If grade 2 dermatologic reactions recur and do not improve within 2 weeks, interrupt binimetinib therapy until toxicity improves to grade 1 or less, and then resume therapy at a reduced dosage.

For the first occurrence of grade 3 dermatologic reactions, interrupt binimetinib therapy until toxicity improves to grade 1 or less, and then resume therapy at same dosage. If grade 3 dermatologic reactions recur, interrupt binimetinib therapy until toxicity improves to grade 1 or less, and then resume therapy at a reduced dosage.

If grade 4 dermatologic reactions occur, permanently discontinue drug.

If palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome) occurs during combination therapy with binimetinib and encorafenib, no dosage adjustment of binimetinib necessary.

Development of New Primary Malignancies
Oral

No dosage adjustment of binimetinib necessary if new primary RAS mutation-positive, noncutaneous malignancies develop during combination therapy with binimetinib and encorafenib. (See Development of New Primary Malignancies under Cautions.)

Other Toxicities
Oral

For recurrent grade 2 adverse reaction, interrupt binimetinib therapy for up to 4 weeks until toxicity improves to grade 1 or less or to baseline, and then resume therapy at a reduced dosage. If toxicity does not improve within 4 weeks of interrupting therapy, permanently discontinue drug.

For first occurrence of any grade 3 adverse reaction, interrupt binimetinib therapy for up to 4 weeks until toxicity improves to grade 1 or less or to baseline, and then resume therapy at a reduced dosage. If toxicity does not improve within 4 weeks of interrupting therapy, permanently discontinue drug. If grade 3 adverse reaction recurs, consider permanent discontinuance of drug.

For first occurrence of any grade 4 adverse reaction, temporarily interrupt binimetinib therapy or permanently discontinue drug. If binimetinib therapy is temporarily interrupted, withhold therapy for up to 4 weeks until toxicity improves to grade 1 or less or to baseline, and then resume therapy at a reduced dosage. If grade 4 adverse reaction does not improve within 4 weeks of interrupting therapy, permanently discontinue drug. If grade 4 adverse reaction recurs, permanently discontinue drug.

Prescribing Limits

Adults

Melanoma
Oral

Dosages <30 twice daily not recommended.

Special Populations

Hepatic Impairment

Moderate (total bilirubin concentration >1.5 times the ULN, but ≤3 times the ULN, with any AST concentration) or severe (total bilirubin concentration >3 times the ULN, with any AST concentration) hepatic impairment: Reduce dosage to 30 mg twice daily. (See Hepatic Impairment under Cautions.)

Mild hepatic impairment (total bilirubin concentration at or below ULN with AST concentration exceeding ULN or total bilirubin concentration exceeding ULN, but not >1.5 times the ULN, with any AST concentration): No dosage adjustment required.

Renal Impairment

No specific dosage recommendations. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations. (See Geriatric Use under Cautions.)

Cautions for Binimetinib

Contraindications

  • Manufacturer states none known.

Warnings/Precautions

Combination Therapy

When used in combination with encorafenib, consider cautions, precautions, and contraindications of encorafenib.

Cardiac Effects

Cardiomyopathy (i.e., symptomatic or asymptomatic decrease in LVEF), sometimes requiring temporary interruption or dosage reduction, reported in patients receiving binimetinib in combination with encorafenib. Median time to first onset of left ventricular dysfunction was 3.6 months in patients receiving combination therapy with binimetinib and encorafenib in the COLUMBUS study. Cardiomyopathy resolved in 87% of patients receiving combination therapy with binimetinib and encorafenib.

Safety of combination therapy with binimetinib and encorafenib not established in patients with baseline LVEF below the LLN or <50%.

Closely monitor patients with preexisting cardiovascular risk factors.

Assess LVEF by echocardiogram or multigated radionuclide angiography (MUGA) prior to and 1 month after initiation of therapy, then every 2–3 months during therapy. If left ventricular dysfunction occurs, therapy interruption followed by dosage reduction or discontinuance of therapy may be necessary. (See Cardiovascular Toxicity under Dosage and Administration.)

Venous Thromboembolism

Venous thromboembolism (VTE) reported in patients receiving binimetinib in combination with encorafenib.

If DVT or PE occurs, therapy interruption followed by dosage reduction or discontinuance of therapy may be necessary. (See Venous Thromboembolism under Dosage and Administration.)

Ocular Effects

Ocular toxicities, including serous retinopathy, retinal vein occlusion, retinal pigment epithelial detachment, and macular edema, reported in patients receiving binimetinib in combination with encorafenib. Median time to initial onset of serous retinopathy was 1.2 months. Uveitis, including iritis and iridocyclitis, also reported in patients receiving binimetinib in combination with encorafenib.

Perform ophthalmologic examinations regularly and as clinically indicated (i.e., if new or worsening visual disturbances occur; to follow new or persistent ophthalmologic findings) during therapy; if visual disturbances occur, perform ophthalmologic examinations urgently (within 24 hours). Monitor patients for visual symptoms at each visit. If ocular toxicities occur, interrupt therapy, reduce dosage, or permanently discontinue drug. (See Ocular Effects under Dosage and Administration.)

Safety not established in patients with a history of or predisposition to retinal vein occlusion, including those with uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes.

Pulmonary Effects

Interstitial lung disease or pneumonitis reported in patients receiving binimetinib in combination with encorafenib.

Evaluate patients with manifestations of interstitial lung disease (e.g., new or progressive pulmonary symptoms).

If interstitial lung disease confirmed, therapy interruption followed by dosage reduction or discontinuance of therapy may be necessary. (See Pulmonary Effects under Dosage and Administration.)

Hepatic Toxicity

Liver function test abnormalities (i.e., elevations in ALT, AST, or alkaline phosphatase) reported in patients receiving binimetinib in combination with encorafenib.

Perform liver function tests prior to initiation of therapy and then monthly, or more frequently as clinically indicated. If liver function test abnormalities occur, interrupt therapy, reduce dosage, or permanently discontinue drug. (See Hepatotoxicity under Dosage and Administration.)

Musculoskeletal Effects

Rhabdomyolysis reported in patients receiving binimetinib in combination with encorafenib.

Evaluate serum CK and Scr concentrations at baseline, periodically during therapy, and as clinically indicated. If elevated CK concentrations occur, therapy interruption followed by dosage reduction or discontinuance of drug may be necessary. (See Musculoskeletal Effects under Dosage and Administration.)

Hemorrhage

Hemorrhage reported in patients receiving binimetinib in combination with encorafenib. Most common hemorrhagic events include GI hemorrhage (e.g., rectal hemorrhage, hematochezia, hemorrhoidal hemorrhage) in patients receiving binimetinib in combination with encorafenib in the COLUMBUS study. Fatal intracranial hemorrhage also reported.

If hemorrhagic events occur, therapy interruption followed by dosage reduction or discontinuance of therapy may be necessary. (See Other Toxicities under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Embryotoxicity, fetotoxicity, and teratogenicity demonstrated in animals.

Confirm pregnancy status prior to initiating therapy. Avoid pregnancy during therapy. Women of childbearing potential should use effective contraception while receiving binimetinib and for ≥30 days after the last dose.

Apprise patients of potential fetal hazard.

Development of New Primary Malignancies

New primary cutaneous and noncutaneous malignancies are a known class effect of BRAF inhibitors (i.e., dabrafenib, encorafenib, vemurafenib). Cutaneous squamous cell carcinoma (including keratoacanthoma), basal cell carcinoma, and noncutaneous malignancies reported in patients receiving binimetinib in combination with encorafenib in the COLUMBUS study.

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether binimetinib or its metabolites are distributed into human milk. Effects on nursing infants and milk production also unknown. Discontinue nursing during therapy and for 3 days after the last dose.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in safety and efficacy of binimetinib in combination with encorafenib relative to younger adults.

Hepatic Impairment

Mild hepatic impairment did not substantially affect systemic exposure of binimetinib; dosage adjustment not necessary.

Increased systemic exposure in patients with moderate or severe hepatic impairment; dosage reduction recommended. (See Hepatic Impairment under Dosage and Administration and also see Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

Severe renal impairment did not substantially affect systemic exposure of binimetinib. (See Absorption: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Combination therapy with encorafenib in patients with unresectable or metastatic melanoma: Fatigue, nausea, diarrhea, vomiting, abdominal pain, constipation, arthralgia, hyperkeratosis, myopathy, headache, rash, asthenia, visual impairment, serous retinopathy/retinal pigment epithelial detachment (RPED), pyrexia, elevated Scr concentrations, elevated CK concentrations, elevated γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP) concentrations, anemia, elevated AST or ALT concentrations, elevated alkaline phosphatase concentrations.

Interactions for Binimetinib

Metabolized principally by uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and to a lesser extent by CYP1A2 and CYP2C19 to form minor active metabolite (M3).

Does not cause time-dependent inhibition of CYP isoenzymes 1A2, 2C9, 2D6, and 3A and shows little to no induction of CYP2C9.

In vitro, weak inhibitor of UGT1A and organic cation transporter (OCT) 2, but is not an inhibitor of OCT1.

Substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but is not a substrate for OCT1 or organic anion transport protein (OATP) 1B1, OATP1B3, and OATP2B1.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4: Pharmacokinetic interaction not observed to date.

Drug Affecting Uridine Diphosphate-glucuronosyltransferase

Inhibitors of UGT1A1: Clinically important pharmacokinetic interactions not expected.

Inducers of UGT1A1: Clinically important pharmacokinetic interactions not expected.

Drugs Transported by Organic Cation Transporters

Substrates of OCT1 or OCT2: Clinically important pharmacokinetic interactions not expected.

Specific Drugs

Drug

Interaction

Atazanavir

Pharmacokinetic simulations suggest no substantial effect on peak plasma concentrations of binimetinib

Cigarette smoking

No substantial effect on systemic exposure of binimetinib

Encorafenib

No substantial effect on systemic exposure of binimetinib

Midazolam

No substantial effect on systemic exposure of midazolam

Rabeprazole

No substantial effect on pharmacokinetics of binimetinib and M3

Binimetinib Pharmacokinetics

Absorption

Bioavailability

≥50%.

Following oral administration, peak plasma concentrations achieved in 1.6 hours.

Systemic exposure and peak plasma concentrations are dose proportional following single or repeated administration of binimetinib 5–80 mg or 5–60 mg once daily, respectively.

Food

Administration with high-fat, high-calorie meal does not affect exposure.

Special Populations

Mild hepatic impairment (total bilirubin concentration at or below ULN with AST concentration exceeding ULN or total bilirubin concentration exceeding ULN, but not >1.5 times the ULN, with any AST concentration): Systemic exposure similar to that in individuals with normal hepatic function.

Moderate hepatic impairment (total bilirubin concentration >1.5 times the ULN, but ≤3 times the ULN, with any AST concentration): Systemic exposure 80% higher than that in individuals with normal hepatic function.

Severe hepatic impairment (total bilirubin concentration >3 times the ULN, with any AST concentration): Systemic exposure 110% higher than that in individuals with normal hepatic function.

Severe renal impairment (estimated GFR ≤29 mL/minute per 1.73 m2): Systemic exposure similar to that in individuals with normal renal function.

Age (20–94 years), gender, body weight, and UGT1A1 genotype do not have clinically important effects on binimetinib pharmacokinetics.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

97%.

Elimination

Metabolism

Metabolized mainly by UGT1A1 and to lesser extent by CYP1A2 and CYP2C19.

Elimination Route

Eliminated in feces (62%) and urine (31%), mainly as metabolites.

Half-life

3.5 hours.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).

Actions

  • Reversible inhibitor of MEK 1 and 2 activation.

  • MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation.

  • Approximately 40–60% of cutaneous melanomas carry a BRAF mutation. Substitution of glutamic acid for valine at codon 600 in exon 15 (BRAF V600E) is the most common BRAF mutation; substitution of lysine for valine at codon 600 in exon 15 (BRAF V600K) occurs less frequently.

  • BRAF V600 mutations result in activation of BRAF pathway that includes MEK 1 and 2.

  • Mutation of BRAF V600E activates the mitogen-activated protein kinase (MAPK) and ERK signal transduction pathway, which enhances cell proliferation and tumor progression (e.g., metastasis).

  • Combination therapy with a BRAF inhibitor (i.e., dabrafenib, encorafenib, vemurafenib) and an MEK inhibitor (i.e., binimetinib, cobimetinib, trametinib) results in complete inhibition of the MAPK/ERK pathway.

  • Combination therapy with binimetinib and encorafenib resulted in increased antiproliferative activity in cell lines testing positive for BRAF V600 mutation compared with either drug alone.

  • Combination therapy with binimetinib and encorafenib increased inhibition of tumor growth and delayed emergence of resistance compared with either drug alone in xenograft models of melanoma harboring BRAF V600E mutation in mice.

Advice to Patients

  • Importance of reading the manufacturer's patient information.

  • If a dose of binimetinib is missed by >6 hours or vomited, importance of administering the next dose at the regularly scheduled time. A replacement dose should not be administered.

  • Risk of hemorrhage. Importance of contacting a clinician promptly and seeking immediate medical attention if signs and/or symptoms of unusual bleeding (e.g., headache, dizziness, weakness, blood in stool, coughing up blood, vomiting blood) occur.

  • Risk of VTE. Importance of contacting a clinician promptly and seeking immediate medical attention if sudden onset of breathing difficulty, chest pain, leg pain, or swelling occurs.

  • Risk of cardiomyopathy. Importance of contacting a clinician promptly if manifestations of heart failure (e.g., tachycardia, shortness of breath, peripheral edema, feeling lightheaded) occur.

  • Risk of serous retinopathy or retinal vein occlusion. Importance of contacting a clinician promptly if ocular pain, swelling, redness, changes in vision, or blurred vision occurs.

  • Risk of interstitial lung disease. Importance of contacting a clinician if new or progressive pulmonary symptoms (e.g., cough, dyspnea) occur.

  • Risk of hepatotoxicity. Importance of liver function test monitoring before and during binimetinib therapy. Importance of reporting any possible manifestations of hepatotoxicity (e.g., jaundice, dark or tea-colored urine, nausea, vomiting, fatigue, loss of appetite, bruising, bleeding).

  • Risk of rhabdomyolysis. Importance of monitoring CK concentrations before and during binimetinib therapy. Importance of immediately reporting any possible manifestations of rhabdomyolysis (e.g., dark or red urine, muscle pain, unusual or new-onset weakness).

  • Risk of fetal harm. Necessity of advising women of childbearing potential that they should use an effective method of contraception while receiving the drug and for ≥30 days after the last dose. Importance of women informing clinicians if they are or plan to become pregnant. Apprise patient of potential fetal hazard if used during pregnancy.

  • Importance of advising women to avoid breast-feeding while receiving binimetinib and for 3 days after the last dose.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of binimetinib is restricted. (See Restricted Distribution Program under Dosage and Administration.)

Binimetinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

15 mg

Mektovi

Array BioPharma

AHFS DI Essentials™. © Copyright 2021, Selected Revisions May 27, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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