Dosing & Uses
Dosage Forms & Strengths
capsule
- 75mg
Melanoma
Indicated in combination with binimetinib for unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation, as detected by an FDA-approved test
450 mg PO qDay in combination with binimetinib
Continue until disease progression or unacceptable toxicity
See binimetinib drug monograph for recommended dosing information
Metastatic Colorectal Cancer
Indicated in combination with cetuximab for metastatic colorectal cancer (CRC) in patients with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy
300 mg PO qDay in combination with cetuximab
Continue until disease progression or unacceptable toxicity
See cetuximab drug monograph for recommended dosing information
Dosage Modifications
If binimetinib is withheld, reduce encorafenib to a maximum dose of 300 mg/day until binimetinib is resumed
Recommended dose reductions for encorafenib for adverse reactions
-
Melanoma
- If binimetinib is withheld, reduce encorafenib to a maximum dose of 300 mg/day until binimetinib is resumed
- First dose reduction: 300 mg PO qDay
- Second dose reduction: 225 mg PO qDay
- Subsequent modifications: Permanently discontinue if unable to tolerate 225 mg/day
-
Metastatic colorectal cancer
- If cetuximab is discontinued, discontinue encorafenib
- First dose reduction: 225 mg PO qDay
- Second dose reduction: 150 mg PO qDay
- Subsequent modifications: Permanently discontinue if unable to tolerate 150 mg/day
New primary malignancies
- Noncutaneous RAS mutation-positive malignancies: Permanently discontinue
Uveitis
- Grade 1 or 2 (no response to specific ocular therapy), or Grade 3 uveitis: Withhold for up to 6 weeks; if uveitis resolves, resume at same or reduced dose; permanently discontinue if uveitis does not improve
- Grade 4: Permanently discontinue
QT prolongation
- QTcF >500 ms and ≤60 ms increase from baseline: Withhold until QTcF ≤500 ms, then resume at reduced dose; if >1 recurrence, permanently discontinue
- QTcF >500 ms and >60 ms increase from baseline: Permanently discontinue
Hepatotoxicity
Grade 2 AST or ALT increased: Maintain dose; if no improvement within 4 weeks, withhold until improves to Grade <1 or baseline and then resume at same dose
-
Grade 3 or 4 AST or ALT increased
- First occurrence Grade 3: Withhold for up to 4 weeks; if improves to Grade <1 or baseline, resume at reduced dose; if no improvement, permanently discontinue
- First occurrence Grade 4: Permanently discontinue or withhold for up to 4 weeks; if improves to Grade <1 or to baseline, resume at reduced dose; if no improvement, permanently discontinue
- Recurrent Grade 3: Consider permanently discontinuing
- Recurrent Grade 4: Permanently discontinue
Dermatologic
- Grade 2: If no improvement within 2 weeks, withhold until Grade 0-1; resume at same dose
- Grade 3: Withhold until Grade <1; resume at same dose if first occurrence or reduce dose if recurrent
- Grade 4: Permanently discontinue
Other adverse reactions, including hemorrhage
- Recurrent Grade 2 or first occurrence of any Grade 3: Withhold for up to 4 weeks; if improves to Grade <1 or baseline, 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 <1 or baseline, resume at reduced dose; if no improvement, permanently discontinue
- Recurrent Grade 3: Consider permanently discontinuing
- Recurrent Grade 4: Permanently discontinue
Coadministered strong or moderate CYP3A4 inhibitors
- Avoid concurrent use of strong or moderate CYP3A4 inhibitors during treatment
- Planned dose is based on the recommendations for dose reductions for adverse effects
- After discontinuing the inhibitor for 3-5 elimination half-lives, resume previous encorafenib dose
-
Moderate CYP3A4 inhibitors
- Planned dose (encorafenib 450 mg/day): Reduce to 225 mg/day
- Planned dose (encorafenib 300 mg/day): Reduce to 150 mg/day
- Planned dose (encorafenib 150 mg or 225 mg/day): Reduce to 75 mg/day
-
Strong CYP3A4 inhibitors
- Planned dose (encorafenib 450 mg/day): Reduce to 150 mg/day
- Planned dose (encorafenib 150, 225, or 300 mg/day): Reduce to 75 mg/day
Hepatic impairment
- Mild (Child-Pugh A): No dose adjustment required
- Moderate-to-severe (Child-Pugh B or C): No recommended dose established
Renal impairment
- Mild-to-moderate (CrCl 30 to <90 mL/min): No dose adjustment required
- Severe (CrCl <30 mL/min): A recommended dose has not been established
Dosing Considerations
Confirm the presence of a BRAF V600E or V600K mutation in tumor specimens prior to initiating
Limitations of use
- Not indicated for melanoma in patients with wild-type BRAF melanoma or wild-type BRAF CRC
Safety and efficacy not established
Interactions
Interaction Checker
No Results

Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor

Adverse Effects
>10% (Melanoma)
All grades
- Fatigue (43%)
- Nausea (41%)
- Vomiting (30%)
- Abdominal pain (28%)
- Arthralgia (26%)
- Myopathy (23%)
- Hyperkeratosis (23%)
- Constipation (22%)
- Rash (22%)
- Headache (22%)
- Hemorrhage (19%)
- Pyrexia (18%)
- Dry skin (16%)
- Dizziness (15%)
- Alopecia (14%)
- Pruritus (13%)
- Peripheral neuropathy (12%)
- Pain in extremity (11%)
>10% (mCRC)
All grades
- Fatigue (51%)
- Anemia (34%)
- Nausea (34%)
- Diarrhea (33%)
- Dermatitis acneiform (32%)
- Abdominal pain (30%)
- Decreased appetite (27%)
- Arthralgia (27%)
- Rash (26%)
- Lymphopenia (24%)
- Vomiting (21%)
- Headache (20%)
- Hypomagnesemia (19%)
- Hemorrhage (19%)
- Peripheral neuropathy (19%)
- Increased alkaline phosphatase (18%)
- Pyrexia (17%)
- Increased AST/ALT (15-17%)
- Constipation (15%)
- Myopathy (15%)
- Melanocytic nevus (14%)
- Pruritus (14%)
- Increased aPTT (13%)
- Insomnia (13%)
- Dry skin (13%)
- Hypokalemia (12%)
- Hyponatremia (11%)
1-10% (Melanoma)
All grades
- Facial paresis (<10%)
- Pancreatitis (<10%)
- Panniculitis (<10%)
- Drug hypersensitivity (<10%)
Grade 3 or 4
- Abdominal pain (4%)
- Pyrexia (4%)
- Fatigue (3%)
- Hemorrhage (3%)
- Dizziness (3%)
- Vomiting (2%)
- Nausea (2%)
- Headache (2%)
- Pruritus (1%)
- Rash (1%)
- Hyperkeratosis (1%)
- Peripheral neuropathy (1%)
- Pain in extremity (1%)
- Arthralgia (1%)
1-10% (mCRC)
All grades
- Pancreatitis (<10%)
- Pain in extremity (10%)
Grade 3 or 4
- Fatigue (7%)
- Increased alkaline phosphatase (4%)
- Abdominal pain (4%)
- Hypokalemia (3%)
- Diarrhea (2%)
- Hyponatremia (2%)
- Hemorrhage (2%)
- Peripheral neuropathy (1%)
- Increased AST (1%)
- Dermatitis acneiform (1%)
- Arthralgia (1%)
- Myopathy (1%)
- Decreased appetite (1%)
- Vomiting (1%)
- Nausea (1%)
- Pyrexia (1%)
Warnings
Contraindications
None
Cautions
Confirm evidence of BRAF V600E or V600K mutation prior to initiating treatment; 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; not indicated for wild-type BRAF melanoma
Hemorrhage can occur; hemorrhagic events include GI, hemorrhoidal, rectal, and intracranial hemorrhage and hematochezia
Uveitis (eg, iritis, iridocyclitis) reported; assess for visual symptoms at each visit; perform an ophthalmologic evaluation regularly and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings
Dose-dependent QTc interval prolongation reported; monitor patients who already have or who are at significant risk of developing QTc prolongation (eg, patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure, those taking medications associated with QT prolongation); correct hypokalemia and hypomagnesemia prior to and during administration
Based on its mechanism of action, fetal harm may occur when administered to a pregnant woman
Grade 3 or 4 dermatologic reactions occurred in 21% of patients treated with encorafenib as a single agent compared with 2% of patients treated with encorafenib in combination with binimetinib
Refer to the binimetinib or cetuximab prescribing information for additional risk information that applies to combination use treatment
New primary malignancies
- New primary malignancies, cutaneous and noncutaneous, observed
-
Cutaneous squamous cell carcinoma
- In the COLUMBUS trial, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA) and basal cell carcinoma occurred in patients who received encorafenib in combination with binimetinib
- Perform dermatologic evaluations before initiating treatment, q2months 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, encorafenib may promote malignancies associated with activation of RAS through mutation or other mechanisms
- Monitor for signs and symptoms of noncutaneous malignancies
- Discontinue treatment for RAS mutation-positive noncutaneous malignancies
Drug interaction overview
- Encorafenib is a reversible inhibitor of UGT1A1, CYP1A2, CYP2B6, CYP2C8/9, CYP2D6, and CYP3A, and a time-dependent inhibitor of CYP3A4 at clinically relevant plasma concentrations
- Encorafenib induces CYP2B6, CYP2C9, and CYP3A4 at clinically relevant plasma concentrations
- Encorafenib is a CYP3A4 and P-glycoprotein (P-gp) substrate
-
Strong or moderate CYP3A4 inhibitors
- Coadministration with a strong or moderate CYP3A4 inhibitor increased encorafenib plasma concentrations and may increase encorafenib adverse reactions
- Avoid use with strong or moderate CYP3A4 inhibitors (eg, grapefruit juice)
- If coadministration of strong or moderate CYP3A4 inhibitors is unavoidable, modify dose as recommended
-
Strong or moderate CYP3A4 inducers
- Coadministration with a strong or moderate CYP3A4 inducer may decrease encorafenib plasma concentrations and may decrease encorafenib efficacy
- Avoid use with strong or moderate CYP3A4 inducers
-
Sensitive CYP3A4 substrates
- Coadministration with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents
- Concomitant use of encorafenib with hormonal contraceptives (CYP3A4 substrates) can result in decreased concentrations and loss of hormonal contraceptive efficacy; avoid hormonal contraceptives
-
Drugs that prolong the QT interval
- Encorafenib is associated with dose-dependent QTc interval prolongation
- Avoid use with drugs known to prolong QT/QTc
Pregnancy
Pregnancy
Based on its mechanism of action, fetal harm may occur when administered to pregnant women
There are no available clinical data on the use of encorafenib during pregnancy
Advise pregnant women of the potential risk to a fetus
Animal data
- In animal reproduction studies, 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 ~26 (in the rat) and 178 (in the rabbit) times the human exposure at the clinical dose of 450 mg, with no clear findings at lower doses
Contraception
- Verify the pregnancy status of females of reproductive potential prior to initiating treatment
- Advise females of reproductive potential to use effective contraception during treatment and for 2 weeks 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 (see Drug Interactions)
Infertility
- Based on findings in male rats at doses ~13 times the human exposure at the 450-mg clinical dose, use of encorafenib may impact fertility in males
Lactation
The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for the drug and any potential adverse effects on the breastfed child or from the underlying maternal condition
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.Pharmacology
Mechanism of Action
Kinase inhibitor that targets BRAF V600E
This pathway regulates several key cellular activities, including proliferation, differentiation, survival, and angiogenesis; inappropriate activation of proteins in this pathway has been shown to occur in many cancers, including melanoma
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 anti-tumor 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 to either drug alone
Absorption
Peak plasma time: 2 hr
At least 86% of the dose is absorbed
Effect of Food
- Administration of a single dose of encorafenib 100 mg (0.2 times the recommended dose) with a high-fat, high-calorie meal (composed of ~150 calories from protein, 350 calories from carbohydrates, and 500 calories from fat) decreased the mean peak plasma concentration by 36% with no effect on AUC
Distribution
Protein bound: 86%
Vd: 164 L
Metabolism
Primary metabolic pathway is N-dealkylation, with CYP3A4 as the main contributor (83%) to total oxidative clearance of encorafenib in human liver microsomes, followed by CYP2C19 (16%) and CYP2D6 (1%)
Elimination
Half-life: 3.5 hr
Clearance: 14 L/hr (day 1); 32 L/hr (steady-state)
Excretion, single 100-mg dose: Feces 47% (5% unchanged); urine 47% (2% unchanged)
Administration
Oral Administration
May take with or without food
Missed dose: Do not take a missed dose within 12 hr of the next scheduled dose
Vomiting: Do not take an additional dose if vomiting occurs following administration, but continue with the next scheduled dose
Storage
Store at 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)
Dispense in original bottle and protect from moisture
Capsules are moisture sensitive; advise patients to store encorafenib in the original bottle with desiccant and to keep the cap of the bottle tightly closed
Do not remove the desiccants from the bottle
Images
Patient Handout
Formulary
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