(binimetinib)

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5 WARNINGS AND PRECAUTIONS

5 WARNINGS AND PRECAUTIONS

5.1 New Primary Malignancies

New primary malignancies, cutaneous and non-cutaneous, can occur when MEKTOVI is used in combination with encorafenib.

In PHAROS, cutaneous squamous cell carcinoma and skin papilloma each occurred in 2% of patients who received MEKTOVI in combination with encorafenib.

Monitor patients for new malignancies prior to initiation of treatment, while on treatment, and after discontinuation of treatment [see Dosage and Administration (2.3)].

5.2 Cardiomyopathy

Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients treated with MEKTOVI in combination with encorafenib. In COLUMBUS, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an absolute decrease in LVEF ≥10% below baseline as detected by echocardiography or MUGA) occurred in 7% of patients receiving MEKTOVI plus encorafenib. Grade 3 left ventricular dysfunction occurred in 1.6% of patients. The median time to first occurrence of left ventricular dysfunction (any grade) in patients receiving MEKTOVI in combination with encorafenib was 3.6 months (range 0 to 21 months). Cardiomyopathy resolved in 87% of patients receiving MEKTOVI plus encorafenib.

In PHAROS, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an absolute decrease in LVEF ≥10% below baseline as detected by echocardiography or MUGA) occurred in 11% of patients receiving MEKTOVI in combination with encorafenib. Grade 3 left ventricular dysfunction occurred in 1% of patients. Cardiomyopathy resolved in 82% of patients receiving MEKTOVI plus encorafenib.

Assess ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, one month after initiating treatment, and then every 2 to 3 months during treatment. The safety of MEKTOVI 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). Patients with cardiovascular risk factors should be monitored closely when treated with MEKTOVI.

Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

5.3 Venous Thromboembolism

In COLUMBUS, venous thromboembolism (VTE) occurred in 6% of patients receiving MEKTOVI in combination with encorafenib, including 3.1% of patients who developed pulmonary embolism. In PHAROS, VTE occurred in 7% of patients receiving MEKTOVI in combination with encorafenib, including 1% of patients who developed pulmonary embolism.

Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

5.4 Ocular Toxicities

Serous Retinopathy

In COLUMBUS, serous retinopathy occurred in 20% of patients treated with MEKTOVI in combination with encorafenib; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. No patient discontinued MEKTOVI due to serous retinopathy; 6% of patients required dose interruptions or dose reductions. The median time to onset of the first event of serous retinopathy (all grades) was 1.2 months (range 0 to 17.5 months).

In PHAROS, serous retinopathy (retinal detachment) occurred in 2% of patients with no cases of blindness treated with MEKTOVI in combination with encorafenib. No patient permanently discontinued MEKTOVI due to serous retinopathy; 1% of patients required dose interruptions.

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. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

Retinal Vein Occlusion

RVO is a known class-related adverse reaction of MEK inhibitors and may occur in patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib (n=690), 1 patient experienced RVO (0.1%).

The safety of MEKTOVI 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.

Perform ophthalmologic evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

Uveitis

Uveitis, including iritis and iridocyclitis, has been reported in patients treated with MEKTOVI in combination with encorafenib. In COLUMBUS, the incidence of uveitis among patients treated with MEKTOVI in combination with encorafenib was 4%. In PHAROS, uveitis occurred in 1% of patients receiving MEKTOVI in combination with encorafenib.

Assess for visual symptoms at each visit. Perform an ophthalmologic evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

5.5 Interstitial Lung Disease

In patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib (n=690), 2 patients (0.3%) developed interstitial lung disease (ILD), including pneumonitis. In PHAROS, 1 patient (1%) receiving MEKTOVI with encorafenib developed pneumonitis.

Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

5.6 Hepatotoxicity

Hepatotoxicity can occur when MEKTOVI is administered in combination with encorafenib. In COLUMBUS, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving MEKTOVI in combination with encorafenib was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. No patient experienced Grade 3 or 4 serum bilirubin elevation. In PHAROS, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving MEKTOVI in combination with encorafenib was 10% for AST, 9% for ALT, and 3.2% for alkaline phosphatase.

Monitor liver laboratory tests before initiation of MEKTOVI, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

5.7 Rhabdomyolysis

Rhabdomyolysis can occur when MEKTOVI is administered in combination with encorafenib. In COLUMBUS, elevation of laboratory values of serum CPK occurred in 58% of patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib (n=690), rhabdomyolysis was reported in 1 patient (0.1%). In PHAROS, elevation of laboratory values of serum creatine kinase (CK) occurred in 41% of patients treated with MEKTOVI in combination with encorafenib. No patient experienced rhabdomyolysis.

Monitor CPK and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

5.8 Hemorrhage

Hemorrhage can occur when MEKTOVI is administered in combination with encorafenib. In COLUMBUS, hemorrhage occurred in 19% of patients receiving MEKTOVI in combination with encorafenib. Grade 3 or greater hemorrhage occurred in 3.2% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%). Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients.

In PHAROS, hemorrhage occurred in 12% of patients receiving MEKTOVI in combination with encorafenib including fatal hemorrhage intracranial (1%); Grade 3 or 4 hemorrhage occurred in 4.1% of patients. The most frequent hemorrhagic events were anal hemorrhage and hemothorax (2% each).

Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

5.9 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, MEKTOVI can cause fetal harm when administered to a pregnant woman. Binimetinib was embryotoxic and abortifacient when administered to rabbits during the period of organogenesis at doses greater than or equal to those resulting in exposures approximately 5 times the human exposure at the recommended clinical dose of 45 mg twice daily.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for 30 days after the last dose [see Use in Specific Populations (8.1, 8.3)].

5.10 Risks Associated with Combination Treatment

MEKTOVI is indicated for use in combination with encorafenib. Refer to the encorafenib prescribing information for additional risk information that applies to combination use treatment.

Medication Guide

MEDICATION GUIDE

     

MEDICATION GUIDE

MEKTOVI® (mek-TOE-vee)

(binimetinib)

tablets

Important Information: If your healthcare provider prescribes MEKTOVI with encorafenib, please read the Medication Guide that comes with encorafenib.

What is the most important information I should know about MEKTOVI when taken in combination with encorafenib?

MEKTOVI when taken in combination with encorafenib may cause serious side effects, including:

•
Risk of new skin cancers. MEKTOVI, when used with encorafenib, may cause skin cancers called cutaneous squamous cell carcinoma or basal cell carcinoma.
 
Talk to your healthcare provider about your risk for these cancers.
 
Check your skin and tell your healthcare provider right away about any skin changes, including a:
o
new wart
o
skin sore or reddish bump that bleeds or does not heal
o
change in size or color of a mole
 
Your healthcare provider should check your skin before treatment with MEKTOVI, when taken in combination with encorafenib, every 2 months during treatment, and for up to 6 months after you stop treatment to look for any new skin cancers.
 
Your healthcare provider should also check for cancers that may not occur on the skin. Tell your healthcare provider about any new symptoms that develop during treatment with MEKTOVI when taken in combination with encorafenib.

See "What are the possible side effects of MEKTOVI?" for more information about side effects.

What is MEKTOVI?

MEKTOVI is a prescription medicine used:

•
in combination with a medicine called encorafenib to treat people with a type of skin cancer called melanoma:
o
that has spread to other parts of the body or cannot be removed by surgery, and
o
that has a certain type of abnormal “BRAF” gene
•
in combination with a medicine called encorafenib to treat adults with a type of lung cancer called non-small cell lung cancer (NSCLC):
o
that has spread to other parts of the body, and
o
that has a certain type of abnormal “BRAF” gene

Your healthcare provider will perform a test to make sure that MEKTOVI is right for you.

It is not known if MEKTOVI is safe and effective in children.

Before taking MEKTOVI, tell your healthcare provider about all of your medical conditions, including if you:

•
have heart problems
•
have had blood clots
•
have eye problems
•
have lung or breathing problems
•
have liver or kidney problems
•
have any muscle problems
•
have bleeding problems
•
have high blood pressure (hypertension)
•
are pregnant or plan to become pregnant. MEKTOVI can harm your unborn baby.
o
Females who are able to become pregnant should use effective birth control (contraception) during treatment with MEKTOVI and for at least 30 days after the last dose of MEKTOVI.
o
Talk to your healthcare provider about birth control methods that may be right for you during this time.
o
Your healthcare provider will do a pregnancy test before you start taking MEKTOVI. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with MEKTOVI.
•
are breastfeeding or plan to breastfeed. It is not known if MEKTOVI passes into your breast milk. Do not breastfeed during treatment with MEKTOVI and for 3 days after the last dose of MEKTOVI. Talk to your healthcare provider about the best way to feed your baby during this time.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I take MEKTOVI?

•
Take MEKTOVI exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking MEKTOVI unless your healthcare provider tells you to.
•
Take MEKTOVI in combination with encorafenib by mouth 2 times a day, about 12 hours apart.
•
MEKTOVI may be taken with or without food.
•
If you miss a dose of MEKTOVI, take it as soon as you remember. If it is within 6 hours of your next scheduled dose, take your next dose at your regular time. Do not make up for the missed dose.
•
Do not take an extra dose if you vomit after taking your scheduled dose. Take your next dose at your regular time.
•
If you stop treatment with encorafenib, talk to your healthcare provider about whether your MEKTOVI treatment may need to be stopped.

What are the possible side effects of MEKTOVI?

MEKTOVI may cause serious side effects, including:

•
Heart problems, including heart failure. MEKTOVI, when taken with encorafenib, can cause heart problems. Your healthcare provider should check your heart function before and during treatment with MEKTOVI. Call your healthcare provider right away if you have any of the following signs and symptoms of a heart problem:
o
feeling like your heart is pounding or racing
o
shortness of breath
o
swelling of your ankles and feet
o
feeling lightheaded
•
Blood clots. MEKTOVI, when taken with encorafenib, can cause blood clots in your arms or legs, which can travel to your lungs and can lead to death. Get medical help right away if you have the following symptoms:
o
chest pain
o
sudden shortness of breath or trouble breathing
o
pain in your legs with or without swelling
o
swelling in your arms and legs
o
a cool pale arm or leg
•
Eye problems. MEKTOVI, when taken with encorafenib, can cause eye problems. Your healthcare provider should perform an eye exam regularly during treatment with MEKTOVI. Tell your healthcare provider right away if you develop any new or worsening symptoms of eye problems, including:
o
blurred vision, loss of vision, or other vision changes
o
see colored dots
o
see halos (blurred outline around objects)
o
eye pain, swelling, or redness
•
Lung or breathing problems. MEKTOVI, when taken with encorafenib, can cause lung or breathing problems. Tell your healthcare provider if you have any new or worsening symptoms of lung or breathing problems, including:
o
shortness of breath
o
cough
•
Liver problems. MEKTOVI, when taken with encorafenib, can cause liver problems. Your healthcare provider should perform blood tests to check your liver function before and during treatment with MEKTOVI. Tell your healthcare provider if you have any of the following signs and symptoms of a liver problem:
o
yellowing of your skin or your eyes
o
dark or brown (tea-colored) urine
o
nausea or vomiting
o
loss of appetite
o
tiredness
o
bruising
o
bleeding
•
Muscle problems (rhabdomyolysis). MEKTOVI, when taken with encorafenib, can cause muscle problems that can be severe. Treatment with MEKTOVI may increase the level of an enzyme in your blood called creatine phosphokinase (CPK) and can be a sign of muscle damage. Your healthcare provider should perform a blood test to check your levels of CPK before and during treatment. Tell your healthcare provider right away if you develop any of these symptoms:
o
weakness
o
muscle aches or pain
o
dark, reddish urine
•
Bleeding problems. MEKTOVI, when taken with encorafenib, can cause serious bleeding problems, including in your brain or stomach, that can lead to death. Tell your healthcare provider and get medical help right away if you develop any signs of bleeding, including:
o
headaches, dizziness, or feeling weak
o
cough up blood or blood clots
o
vomit blood or your vomit looks like “coffee grounds”
o
red or black stool that look like tar

Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with MEKTOVI if you have certain side effects.

The most common side effects of MEKTOVI when taken with encorafenib for melanoma include:

•
fatigue
•
nausea
•
diarrhea
•
vomiting
•
stomach-area (abdominal) pain

The most common side effects of MEKTOVI when taken with encorafenib for NSCLC include:

•
fatigue
•
nausea
•
diarrhea
•
muscle or joint pain
•
vomiting
•
stomach-area (abdominal) pain
•
blurred vision, loss of vision, or other vision changes
•
constipation
•
shortness of breath
•
rash
•
cough

These are not all of the possible side effects of MEKTOVI.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

You may also report side effects to Pfizer Inc. at 1-800-438-1985.

How should I store MEKTOVI?

•
Store MEKTOVI at room temperature between 68°F to 77°F (20°C to 25°C).

Keep MEKTOVI and all medicines out of the reach of children.

General information about the safe and effective use of MEKTOVI.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use MEKTOVI for a condition for which it was not prescribed. Do not give MEKTOVI to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about MEKTOVI that is written for health professionals.

What are the ingredients in MEKTOVI?

Active ingredient: binimetinib

Inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate (vegetable source), and colloidal silicon dioxide

Tablet coating: polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, ferric oxide yellow, ferrosoferric oxide

Distributed by: Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc., Boulder, Colorado 80301.

MEKTOVI® is a registered trademark of Array BioPharma Inc. in the United States and various other countries.

For more information, go to www.BRAFTOVIMEKTOVI.com or call 1-844-792-7729.

©2020 Array BioPharma Inc. All rights reserved.

LAB-1427-2.0

This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: 10/2023

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