binimetinib (Rx)

Brand and Other Names:Mektovi
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 15mg

Melanoma

Indicated in combination with encorafenib for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test

45 mg PO BID in combination with encorafenib until disease progression or unacceptable toxicity

See encorafenib drug monograph for recommended dosing information

Also see Administration

Dosage Modifications

If encorafenib is permanently discontinued, discontinue binimetinib

Recommended dose reductions for binimetinib for adverse reactions

  • First dose reduction: 30 mg PO BID
  • Subsequent modifications: Permanently discontinue if unable to tolerate 30 mg/day

Cardiomyopathy

  • Asymptomatic, absolute decrease in left ventricular ejection fraction (LVEF) of >10% from baseline that is also below lower limit of normal (LLN): Withhold for up to 4 weeks, evaluate LVEF q2Weeks
  • Resume at a reduced dose if the following are present
    • LVEF is at or above the LLN and
    • Absolute decrease from baseline is ≤10% and
    • Patient is asymptomatic
    • If the LVEF does not recover within 4 weeks permanently discontinue
  • Symptomatic congestive heart failure or absolute decrease in LVEF of greater than >20% from baseline that is also below LLN: Permanently discontinue

Venous thromboembolism

  • Uncomplicated DVT or PE
    • Withhold drug; if improves to Grade 0-1, resume at a reduced dose
    • If no improvement, permanently discontinue
  • Life-threatening PE: Permanently discontinue

Serous retinopathy

  • Symptomatic serous retinopathy/retinal pigment epithelial detachments
  • Withhold drug for up to 10 days
    • If improves and becomes asymptomatic, resume at same dose
    • If not improved, resume at a lower dose or permanently discontinue

Retinal vein occlusion

  • Any grade: Permanently discontinue

Uveitis

  • Grades 1-3
    • If Grade 1 or 2 does not respond to specific ocular therapy, or for Grade 3 uveitis, withhold for up to 6 weeks; if improved, resume at same or reduced dose
    • If not improved, permanently discontinue
  • Grade 4: Permanently discontinue

Interstitial lung disease

  • Grade 2
    • Withhold for up to 4 weeks; if improved to Grade 0-1, resume at a reduced dose
    • If not resolved within 4 weeks, permanently discontinue
  • Grades 3 or 4: Permanently discontinue

Hepatotoxicity

  • Grade 2 AST/ALT increased
    • Maintain binimetinib dose; if no improvement within 2 weeks, withhold dose until improved to Grade 0-1 or to pretreatment/baseline levels and then resume at the same dose
  • Recurrent Grade 2 or first occurrence of any Grade 3 AST/ALT increased
    • Withhold for up to 4 weeks; if improves to Grade 0-1 or to pretreatment/baseline level, resume at reduced dose
    • If no improvement, permanently discontinue
  • First occurrence of any Grade 4 AST/ALT increased
    • Permanently discontinue OR
    • Withhold for up to 4 weeks; if improves to Grade 0-1 or to pretreatment/baseline level, resume at reduced dose; if no improvement, permanently discontinue
  • Recurrent Grade 3 AST/ALT increased
    • Consider permanently discontinuing
  • Recurrent Grade 4 AST/ALT increased
    • Permanently discontinue

Rhabdomyolysis or CPK elevations

  • Grade 4 asymptomatic CPK elevation OR any Grade CPK elevation with symptoms or with renal impairment
  • Withhold dose for up to 4 weeks; if improved to Grade 0-1 resume at a reduced dose
  • If not resolved within 4 weeks, permanently discontinue

Dermatologic

  • Grade 2: If no improvement within 2 weeks, withhold drug until Grade 0-1; resume at same dose if first occurrence or reduce dose if recurrent
  • Grade 3: Withhold until Grade 0-1; resume at same dose if first occurrence or reduce dose if recurrent
  • Grade 4: Permanently discontinue

Other adverse reactions, including hemorrhage

  • Dose modification when administered with encorafenib is NOT recommended for palmarplantar erythrodysesthesia syndrome (PPES), noncutaneous RAS mutation-positive malignancies, and QTc prolongation
  • Recurrent Grade 2 or first occurrence of any Grade 3
    • Withhold for up to 4 weeks; if improves to Grade 0-1 or to pretreatment/baseline level, resume at reduced dose
    • If no improvement, permanently discontinue
  • First occurrence of any Grade 4
    • Permanently discontinue OR
    • Withhold for up to 4 weeks; if improves to Grade 0-1 or to pretreatment/baseline level, resume at reduced dose; if no improvement, permanently discontinue
  • Recurrent Grade 3
    • Consider permanently discontinuing
  • Recurrent Grade 4
    • Permanently discontinue

Hepatic impairment

  • Moderate (total bilirubin >1.5 to ≤3 x ULN and any AST): 30 mg PO BID
  • Severe (total bilirubin >3 x ULN and any AST): 30 mg PO BID

Renal impairment

  • No clinically important changes in binimetinib exposure were observed with severe renal impairment as compared with patients with normal renal function

Dosing Considerations

Confirm the presence of a BRAF V600E or V600K mutation in tumor specimens prior to initiating

Limitations of use: Not indicated for patient with wild-type BRAF melanoma

Safety and efficacy not established

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Adverse Effects

All grades of severity are listed unless otherwise indicated

>10%

Increased creatinine (93%)

Increased creatine phosphokinase (58%)

Increased gamma glutamyl transferase (GGT) (45%)

Fatigue (43%)

Nausea (41%)

Diarrhea (36%)

Anemia (36%)

Vomiting (30%)

Increased AST/ALT (27-29%)

Abdominal pain (28%)

Constipation (22%)

Rash (22%)

Increased alkaline phosphatase (21%)

Visual impairment (20%)

Serous retinopathy/retinal pigment epithelial dystrophy (RPED) (20%)

Hemorrhage (19%)

Hyponatremia (18%)

Pyrexia (18%)

Dizziness (15%)

Leukopenia (13%)

Lymphopenia (13%)

Neutropenia (13%)

Peripheral edema (13%)

Increased GGT, Grades 3 and 4 (11%)

Hypertension (11%)

1-10%

Colitis (<10%)

Panniculitis (<10%)

Drug hypersensitivity (<10%)

Hypertension, Grades 3 and 4 (6%)

Increased AST/ALT (2.6-6%)

Increased creatine phosphokinase, Grades 3 and 4 (5%)

Pyrexia, Grades 3 and 4 (4%)

Anemia, Grades 3 and 4 (3.6%)

Increased creatinine, Grades 3 and 4 (3.6%)

Hyponatremia, Grades 3 and 4 (3.6%)

Neutropenia, Grades 3 or 4 (3.1%)

Fatigue, Grades 3 and 4 (3%)

Dizziness, Grades 3 and 4 (3%)

Peripheral edema, Grades 3 and 4 (3%)

Hemorrhage, Grades 3 and 4 (3%)

Diarrhea, Grades 3 and 4 (3%)

Serous retinopathy/RPED, Grades 3 and 4 (3%)

Lymphopenia, Grades 3 or 4 (2.1%)

Nausea, Grades 3 and 4 (2%)

Vomiting, Grades 3 and 4 (2%)

Abdominal pain, Grades 3 and 4 (2%)

Rash, Grades 3 and 4 (1%)

<1%

Increased alkaline phosphatase

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Warnings

Contraindications

None

Cautions

Also see Dosage Modifications

In the COLUMBUS trial, venous thromboembolism (VTE) occurred in 6% of patients receiving binimetinib in combination with encorafenib, including 3.1% of patients who developed pulmonary embolism

In patients with BRAF mutation-positive melanoma receiving binimetinib with encorafenib (n=690), 2 patients (0.3%) developed interstitial lung disease (ILD), including pneumonitis; assess new or progressive unexplained pulmonary symptoms or findings for possible ILD

Hepatotoxicity can occur when binimetinib concomitantly used with encorafenib; monitor liver laboratory tests before initiating, monthly during treatment, and as clinically indicated

Rhabdomyolysis can occur when binimetinib is administered in combination with encorafenib; monitor CPK and creatinine levels prior to initiating treatment, periodically during treatment, and as clinically indicated; withhold, reduce dose, or permanently discontinue based on severity of adverse reaction

Hemorrhage can occur when encorafenib is administered in combination with binimetinib; hemorrhagic events include GI, hemorrhoidal, rectal, and intracranial hemorrhage, and hematochezia; withhold, reduce dose, or discontinue drug (see Dosage Modifications)

Based on findings from animal studies and its mechanism of action, fetal harm may occur when administered to a pregnant woman (see Pregnancy)

Risks associated with combination treatment; refer to the encorafenib prescribing information for additional risk information

Ocular toxicities

  • Serous retinopathy
    • In the COLUMBUS trial, serous retinopathy occurred in 20% of patients, including retinal detachment (8%) and macular edema (6%)
    • Assess for visual symptoms at each visit
    • Perform an ophthalmologic examination at regular intervals for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings
  • Retinal vein occlusion
    • Retinal vein occlusion (RVO) is a known class-related adverse reaction of MEK inhibitors and may occur
    • Perform ophthalmologic evaluation for patient-reported acute vision loss or other visual disturbance within 24 hr
  • Uveitis
    • Uveitis (eg, iritis and iridocyclitis) reported in patients treated with binimetinib in combination with encorafenib
    • Perform an ophthalmologic evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings

Cardiomyopathy

  • Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, reported in patients treated with binimetinib in combination with encorafenib
  • Assess ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, one month after initiating treatment, and then every 2-3 months during treatment
  • Safety of binimetinib in combination with encorafenib has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN)
  • Closely monitor patients with cardiovascular risk factors
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Pregnancy

Pregnancy

Based on animal reproduction studies and its mechanism of action, fetal harm may occur when binimetinib is administered to a pregnant woman

There are no available clinical data on the use of binimetinib during pregnancy

Advise pregnant women of the potential risk to a fetus

Animal data

  • In animal reproduction studies, oral administration of binimetinib during the period of organogenesis was embryotoxic and an abortifacient in rabbits at doses greater than or equal to those resulting in exposures ~5 times the human exposure at the clinical dose of 45 mg PO BID

Contraception

  • Verify pregnancy status of females of reproductive potential prior to initiating treatment Advise females of reproductive potential to use effective contraception during treatment with binimetinib and for at least 30 days after the final dose
  • Nonhormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking encorafenib and binimetinib

Lactation

There are no data on the presence of binimetinib or its active metabolite in human milk, the effects of binimetinib on the breastfed infant, or on milk production

Because of the potential for serous adverse reactions from binimetinib in breastfed infants, advise women not to breastfeed during treatment with binimetinib and for 3 days after the final dose

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

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Pharmacology

Mechanism of Action

Inhibits mitogen-activated extracellular signal regulated kinase (MEK) 1 and MEK 2

MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK)-related phosphorylation and MEK-dependent phosphorylation of BRAF-mutant human melanoma cell lines

Encorafenib and binimetinib target 2 different kinases in the RAS/RAF/MEK/ERK pathway; compared with either drug alone, coadministration resulted in greater antiproliferative activity in vitro in BRAF mutation-positive cell lines and greater antitumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice

Additionally, the combination of encorafenib and binimetinib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared with either drug alone

Absorption

Peak plasma time: 1.6 hr

Effect of food

  • Administration of a single 45-mg dose with a high-fat, high-calorie meal (consisting of ~150 calories from protein, 350 calories from carbohydrate, and 500 calories from fat) in healthy subjects had no effect on binimetinib exposure

Distribution

Protein bound: 97%

Vd: 92 L

Metabolism

Primary metabolic pathway is glucuronidation with UGT1A1 contributing up to 61% of the binimetinib metabolism

Other pathways of binimetinib metabolism include N-dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain

The active metabolite M3 produced by CYP1A2 and CYP2C19 represents 8.6% of the binimetinib exposure

Elimination

Half-life: 3.5 hr

Clearance: 20.2 L/hr

Excretion: Feces 62% (32% unchanged); urine 31% (6.5% unchanged)

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Administration

Oral Administration

Administer doses twice daily, ~12 hr apart

May take with or without food

Missed dose: Do not take a missed dose within 6 hr of the next scheduled dose

Vomited dose: Do not take an additional dose if vomiting occurs following administration, but continue with the next scheduled dose

Storage

Store tablets at 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)

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Formulary

FormularyPatient Discounts

Adding plans allows you to compare formulary status to other drugs in the same class.

To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

Adding plans allows you to:

  • View the formulary and any restrictions for each plan.
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  • Compare formulary status to other drugs in the same class.
  • Access your plan list on any device – mobile or desktop.

The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

Tier Description
1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
NC NOT COVERED – Drugs that are not covered by the plan.
Code Definition
PA Prior Authorization
Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
QL Quantity Limits
Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
ST Step Therapy
Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
OR Other Restrictions
Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.