(encorafenib)

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5 WARNINGS AND PRECAUTIONS

5 WARNINGS AND PRECAUTIONS

5.1 New Primary Malignancies

New primary malignancies, cutaneous and noncutaneous, have been observed in patients treated with BRAF inhibitors and can occur with BRAFTOVI.

Cutaneous Malignancies

In COLUMBUS, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6%, and basal cell carcinoma occurred in 1.6% of patients who received BRAFTOVI in combination with binimetinib. Median time to first occurrence of cuSCC/KA was 5.8 months (range 1 to 9 months) [see Adverse Reactions (6.1)].

For patients who received BRAFTOVI as a single agent, cuSCC/KA was reported in 8%, basal cell carcinoma in 1%, and a new primary melanoma in 5% of patients.

In BEACON CRC, cuSCC/KA occurred in 1.4% of patients with CRC, and a new primary melanoma occurred in 1.4% of patients who received BRAFTOVI in combination with cetuximab.

In PHAROS, cuSCC and skin papilloma, each occurred in 2% of patients who received BRAFTOVI in combination with binimetinib.

In BREAKWATER, the following cutaneous malignancies occurred in patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6: melanocytic nevus in 5.6%, skin papilloma in 3%, basal cell carcinoma in 1.3%, squamous cell carcinoma of skin in 0.9%, keratoacanthoma in 0.4% and malignant melanoma in situ in 0.4%. In patients who received BRAFTOVI in combination with cetuximab and FOLFIRI, skin papilloma occurred in 2.8% and keratoacanthoma in 1.4% of patients.

Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies.

Noncutaneous Malignancies

Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. Monitor patients receiving BRAFTOVI for signs and symptoms of noncutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive noncutaneous malignancies [see Dosage and Administration (2.5)].

5.2 Tumor Promotion in BRAF Wild-Type Tumors

In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells, which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation prior to initiating BRAFTOVI [see Indications and Usage (1), Dosage and Administration (2.1)].

5.3 Cardiomyopathy

Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients treated with BRAFTOVI in combination with binimetinib. In COLUMBUS, evidence of cardiomyopathy (decreased in LVEF below the institutional LLN with an absolute decreased in LVEF ≥10% below baseline as detected by echocardiography or MUGA) occurred in 7% of patients receiving BRAFTOVI plus binimetinib. 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 BRAFTOVI in combination with binimetinib was 3.6 months (range 0 to 21 months). Cardiomyopathy resolved in 87% of patients receiving BRAFTOVI plus binimetinib.

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 BRAFTOVI in combination with binimetinib. Grade 3 left ventricular dysfunction occurred in 1% of patients. Cardiomyopathy resolved in 82% of patients receiving BRAFTOVI plus binimetinib.

Assess ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, one month after initiating treatment, and every 2 to 3 months during treatment. The safety of BRAFTOVI in combination with binimetinib has not been established in patients with 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 BRAFTOVI.

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

5.4 Hepatotoxicity

Hepatotoxicity can occur when BRAFTOVI is administered in combination with binimetinib. In COLUMBUS, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving BRAFTOVI in combination with binimetinib was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. In PHAROS, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving BRAFTOVI in combination with binimetinib was 10% for AST, 9% for ALT, and 3.2% for alkaline phosphatase.

In BREAKWATER, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6 was 2.6% for alkaline phosphatase, and 1.3% each for ALT and AST. In patients receiving BRAFTOVI in combination with cetuximab and FOLFIRI, the incidence of Grade 3 or 4 increases in liver function laboratory tests was 1.5% each for ALT and AST.

Monitor liver laboratory tests before initiation of BRAFTOVI, 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)].

5.5 Hemorrhage

In COLUMBUS, hemorrhage occurred in 19% of patients receiving BRAFTOVI in combination with binimetinib; 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 BEACON CRC, hemorrhage occurred in 19% of patients receiving BRAFTOVI in combination with cetuximab; Grade 3 or higher hemorrhage occurred in 1.9% of patients, including fatal gastrointestinal hemorrhage in 0.5% of patients. The most frequent hemorrhagic events were epistaxis (6.9%), hematochezia (2.3%), and rectal hemorrhage (2.3%).

In PHAROS, hemorrhage occurred in 12% of patients receiving BRAFTOVI in combination with binimetinib 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).

In BREAKWATER, hemorrhage occurred in 34% of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6; Grade 3 or 4 hemorrhage occurred in 3% of patients. In patients receiving BRAFTOVI in combination with cetuximab and FOLFIRI, hemorrhage occurred in 21% of patients.

Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.5), Adverse Reactions (6.1)].

5.6 Uveitis

Uveitis, including iritis and iridocyclitis, has been reported in patients treated with BRAFTOVI in combination with binimetinib. In COLUMBUS, the incidence of uveitis among patients treated with BRAFTOVI in combination with binimetinib was 4%. In PHAROS, the incidence of uveitis among patients treated with BRAFTOVI in combination with binimetinib was 1%. In BREAKWATER, the incidence of uveitis among patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6 was 0.4%.

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 (2.5), Adverse Reactions (6.1)].

5.7 QT Prolongation

BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients [see Clinical Pharmacology (12.2)]. In COLUMBUS, an increase in QTcF to >500 ms was measured in 0.5% (1/192) of patients who received BRAFTOVI in combination with binimetinib. In PHAROS, an increase in QTcF to >500 ms was measured in 2.1% (2/95) of patients who received BRAFTOVI in combination with binimetinib.

In BREAKWATER, an increase of QTcF >500 ms was measured in 4% (9/226) of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6. In patients receiving BRAFTOVI in combination with cetuximab and FOLFIRI, an increase of QTcF >500 ms was measured in 1.5% (1/65) of patients.

Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc >500 ms [see Dosage and Administration (2.5), Adverse Reactions (6.1)].

5.8 Embryo-Fetal Toxicity

Based on its mechanism of action, BRAFTOVI can cause fetal harm when administered to a pregnant woman. Encorafenib produced embryo-fetal developmental changes in rats and rabbits and was an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 26 (in the rat) and 178 (in the rabbit) times the human exposure at the recommended dose of 450 mg, with no clear findings at lower doses.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use an effective, nonhormonal method of contraception since BRAFTOVI can render hormonal contraceptives ineffective, during treatment and for 2 weeks after the last dose of BRAFTOVI [see Use in Specific Populations (8.1, 8.3)].

5.9 Risks Associated with BRAFTOVI as a Single Agent

BRAFTOVI when used as a single agent is associated with an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with binimetinib. In COLUMBUS, Grades 3 or 4 dermatologic reactions occurred in 21% of patients treated with BRAFTOVI single agent compared to 2% of patients treated with BRAFTOVI in combination with binimetinib [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].

If binimetinib is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended [see Dosage and Administration (2.5)].

5.10 Risks Associated with Combination Treatment

BRAFTOVI is indicated for use as part of a regimen in combination with binimetinib, in combination with cetuximab, in combination with cetuximab and mFOLFOX6 or FOLFIRI. Refer to the prescribing information for binimetinib, cetuximab and individual product components of mFOLFOX6 and FOLFIRI for additional risk information.

Medication Guide

MEDICATION GUIDE

MEDICATION GUIDE
BRAFTOVI® (braf-TOE-vee)
(encorafenib)
capsules

Important information: BRAFTOVI is used in combination with other medicines, including binimetinib, cetuximab, or cetuximab and fluorouracil-based chemotherapy. Read the Medication Guide that comes with binimetinib if BRAFTOVI is used with binimetinib. Talk to your healthcare provider about cetuximab, or cetuximab and mFOLFOX6 or FOLFIRI if used with BRAFTOVI.

What is the most important information I should know about BRAFTOVI?
BRAFTOVI can cause serious side effects, including:

Risk of new skin cancers. BRAFTOVI can 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:

•
new wart
•
skin sore or reddish bump that bleeds or does not heal
•
change in size or color of a mole

Your healthcare provider should check your skin before treatment with BRAFTOVI, every 2 months during treatment, and for up to 6 months after you stop treatment with BRAFTOVI 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 BRAFTOVI.

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

What is BRAFTOVI?
BRAFTOVI is a prescription medicine used:

•
in combination with a medicine called binimetinib 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 medicines called cetuximab and mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) or cetuximab and FOLFIRI (fluorouracil, leucovorin, and irinotecan) to treat adults with cancer of the colon or rectum (colorectal cancer):
o
that has spread to other parts of the body, and
o
that has a certain type of abnormal "BRAF" gene
•
in combination with a medicine called cetuximab to treat adults with cancer of the colon or rectum (colorectal cancer) after past treatment:
o
that has spread to other parts of the body, and
o
that has a certain type of abnormal "BRAF" gene
•
in combination with a medicine called binimetinib 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

BRAFTOVI should not be used to treat people with wild-type‑BRAF melanoma, wild-type‑BRAF colorectal cancer, or wild-type‑BRAF NSCLC.

Your healthcare provider will perform a test to make sure that BRAFTOVI is right for you.
It is not known if BRAFTOVI is safe and effective in children.

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

•
have had bleeding problems
•
have eye problems
•
have heart problems, including a condition called long QT syndrome
•
have been told that you have low blood levels of potassium, calcium, or magnesium
•
have liver or kidney problems
•
are pregnant or plan to become pregnant. BRAFTOVI can harm your unborn baby.

Females who are able to become pregnant:

 
o
Use effective nonhormonal birth control (contraception) during treatment with BRAFTOVI and for 2 weeks after the last dose of BRAFTOVI. Birth control methods that contain hormones (such as birth control pills, injections or transdermal systems) may not work as well during treatment with BRAFTOVI.
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 BRAFTOVI. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with BRAFTOVI.
•
are breastfeeding or plan to breastfeed. It is not known if BRAFTOVI passes into your breast milk. Do not breastfeed during treatment with BRAFTOVI and for 2 weeks after the last dose of BRAFTOVI. 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.
BRAFTOVI and certain other medicines can affect each other, causing side effects or affecting how BRAFTOVI or the other medicines work.
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 BRAFTOVI?

•
Take BRAFTOVI exactly as your healthcare provider tells you. Do not change your dose or stop taking BRAFTOVI unless your healthcare provider tells you to.
•
Take BRAFTOVI by mouth 1 time each day.
•
BRAFTOVI may be taken with or without food.
•
Avoid grapefruit and grapefruit juice during treatment with BRAFTOVI. Grapefruit products may increase the amount of BRAFTOVI in your body.
•
If you miss a dose of BRAFTOVI, take it as soon as you remember. If it is within 12 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 binimetinib or cetuximab, talk to your healthcare provider about your BRAFTOVI treatment. Your BRAFTOVI dose may need to be changed or stopped.

What are the possible side effects of BRAFTOVI?
BRAFTOVI can cause serious side effects, including:

•
See "What is the most important information I should know about BRAFTOVI?"
•
Heart problems, including heart failure. BRAFTOVI can cause heart problems. Your healthcare provider will check your heart function before and during treatment with BRAFTOVI. Tell your healthcare provider right away if you get 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 in your hands, ankles legs or feet
o
feeling faint or lightheaded
•
Liver problems. BRAFTOVI can cause liver problems. Your healthcare provider will perform blood tests to check your liver function before and during treatment with BRAFTOVI. Tell your healthcare provider if you get 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
•
Bleeding problems. BRAFTOVI can cause serious bleeding problems, including in your stomach or brain, 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 stools that look like tar
o
nose bleeds
•
Eye problems. BRAFTOVI can cause eye problems. Your healthcare provider should perform an eye exam regularly. 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
•
Changes in the electrical activity of your heart called QT prolongation. QT prolongation can cause irregular heartbeats that can be life threatening. Your healthcare provider should do tests before you start treatment with BRAFTOVI during your treatment to check your body salts (electrolytes). Tell your healthcare provider right away if you feel faint, lightheaded, dizzy or if you feel your heart beating irregularly or fast during treatment with BRAFTOVI. These symptoms may be related to QT prolongation.

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

The most common side effects of BRAFTOVI when taken in combination with binimetinib for melanoma include:

•
fatigue
•
nausea
•
vomiting
•
abdominal pain
•
pain or swelling of your joints (arthralgia)

The most common side effects of BRAFTOVI when taken in combination with cetuximab and mFOLFOX6 for colorectal cancer include:

•
numbness, tingling or burning in your hands or feet (peripheral neuropathy)
•
nausea
•
fatigue
•
diarrhea
•
decreased appetite
•
rash
•
vomiting
•
bleeding (hemorrhage)
•
stomach-area (abdominal) pain
•
pain or swelling of your joints (arthralgia)
•
fever
•
constipation

The most common side effects of BRAFTOVI when taken in combination with cetuximab and FOLFIRI for colorectal cancer include:

•
nausea
•
diarrhea
•
fatigue
•
vomiting
•
hair loss (alopecia)
•
constipation
•
stomach-area (abdominal) pain
•
decreased appetite
•
rash

The most common side effects of BRAFTOVI when taken in combination with cetuximab for colorectal cancer include:

•
fatigue
•
nausea
•
diarrhea
•
acne-like rash (dermatitis acneiform)
•
stomach-area (abdominal) pain
•
decreased appetite
•
pain or swelling of your joints (arthralgia)
•
rash

The most common side effects of BRAFTOVI when taken in combination with binimetinib 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

BRAFTOVI may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if this is a concern for you.

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

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 BRAFTOVI?

•
Store BRAFTOVI at room temperature between 68°F to 77°F (20°C to 25°C).
•
Store BRAFTOVI in the original bottle.
•
Keep the BRAFTOVI bottle tightly closed and protect it from moisture.
•
BRAFTOVI comes with a desiccant packet in the bottle to help protect your medicine from moisture. Do not remove the desiccant packet from the bottle.

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

General information about the safe and effective use of BRAFTOVI.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use BRAFTOVI for a condition for which it was not prescribed. Do not give BRAFTOVI 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 BRAFTOVI that is written for health professionals.

What are the ingredients in BRAFTOVI?
Active ingredient: encorafenib
Inactive ingredients: copovidone, poloxamer 188, microcrystalline cellulose, succinic acid, crospovidone, colloidal silicon dioxide, and magnesium stearate of vegetable origin
Capsule shell: gelatin, titanium dioxide, iron oxide red, iron oxide yellow, ferrosoferric oxide, monogramming ink (pharmaceutical glaze, ferrosoferric oxide, propylene glycol)
Distributed by: Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc. Boulder, Colorado 80301.
BRAFTOVI® is a registered trademark of Array BioPharma Inc. in the United States and various other countries.
LAB-1429-5.0
For more information, go to www.braftovi.com or call 1-844-792-7729.
© 2024 Array BioPharma Inc. All rights reserved.

This Medication Guide has been approved by the U.S. Food and Drug Administration.       Revised: 02/2026

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