Dosing & Uses
Dosage Forms & Strengths
capsule
- 50mg
- 75mg
Melanoma
Indicated in combination with binimetinib for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test
450 mg PO qDay in combination with binimetinib until disease progression or unacceptable toxicity
See binimetinib drug monograph for recommended dosing information
Also see Administration
Dosage Modifications
If binimetinib is withheld owing to adverse effects, reduce encorafenib to a maximum dose of 300 mg/day until binimetinib is resumed
Recommended dose reductions for encorafenib for adverse reactions
- First dose reduction: 300 mg PO qDay
- Second dose reduction: 200 mg PO qDay
- Subsequent modifications: Permanently discontinue if unable to tolerate 200 mg/day
New primary malignancies
- Non-cutaneous RAS mutation-positive malignancies: 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
QT prolongation
- QTcF >500 ms and ≤60 ms increase from base line: Withhold until QTcF ≤500 ms, then resume at reduced dose; if >1 recurrence, permanently discontinue
- QTcF >500 ms and >60 ms increase from base line: Permanently discontinue
Hepatotoxicity
- Grade 2 AST or ALT increased
- Maintain dose
- If no improvement within 4 weeks, withhold until improves to Grade 0-1 or to pretreatment/baseline levels 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 0-1 or to pretreatment/baseline level, 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 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
Dermatologic
- Grade 2: If no improvement within 2 weeks, withhold until Grade 0-1; resume at same dose
- 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
- 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
Coadministered strong or moderate CYP3A4 inhibitors
- Avoid concurrent use of strong or moderate CYP3A4 inhibitors during treatment
- If concomitant use of a strong CYP3A4 inhibitor is unavoidable, reduce encorafenib dose to one third of the dose before use of strong CYP3A4 inhibitors
- If concomitant use of a moderate CYP3A4 inhibitor is unavoidable, reduce encorafenib dose to one half of the dose before use of strong CYP3A4 inhibitors
- After discontinuing the inhibitor for 3-5 elimination half-lives, resume previous encorafenib dose
Hepatic impairment
- Mild (Child-Pugh A): No dose adjustment required
- Moderate-to-severe (Child-Pugh B or C): A recommended dose has not been 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 patient with wild-type BRAF melanoma
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
All grades of severity are listed unless otherwise indicated
>10%
Increased creatinine (93%)
Increased gamma glutamyl transferase (GGT) (45%)
Fatigue (43%)
Nausea (41%)
Anemia (36%)
Vomiting (30%)
Increased AST/ALT (27-29%)
Hyperglycemia (28%)
Abdominal pain (28%)
Arthralgia (26%)
Hyperkeratosis (23%)
Myopathy (23%)
Headache (22%)
Rash (22%)
Constipation (22%)
Increased alkaline phosphatase (21%)
Hemorrhage (19%)
Hyponatremia (18%)
Pyrexia (18%)
Dry skin (16%)
Dizziness (15%)
Alopecia (14%)
Pruritus (13%)
Leukopenia (13%)
Lymphopenia (13%)
Neutropenia (13%)
Peripheral neuropathy (12%)
Pain in extremity (11%)
Increased GGT, Grades 3 and 4 (11%)
1-10%
Hypermagnesemia (10%)
Facial paresis (<10%)
Pancreatitis (<10%)
Panniculitis (<10%)
Drug hypersensitivity (<10%)
Increased ALT/AST, Grades 3 and 4 (2.6-6%)
Hyperglycemia, Grades 3 and 4 (5%)
Pyrexia, Grades 3 and 4 (4%)
Abdominal pain, Grades 3 and 4 (4%)
Anemia, Grades 3 and 4 (3.6%)
Increased creatinine, Grades 3 or 4 (3.6%)
Hyponatremia, Grades 3 or 4 (3.6%)
Neutropenia, Grades 3 and 4 (3.1%)
Fatigue, Grades 3 and 4 (3%)
Dizziness, Grades 3 and 4 (3%)
Hemorrhage, Grades 3 and 4 (3%)
Lymphopenia, Grades 3 and 4 (2.1%)
Nausea, Grades 3 and 4 (2%)
Vomiting, Grades 3 and 4 (2%)
Headache, Grades 3 and 4 (2%)
Hypomagnesemia, Grades 3 and 4 (1%)
Arthralgia, Grades 3 and 4 (1%)
Pain, Grades 3 and 4 (1%)
Hyperkeratosis, Grades 3 and 4 (1%)
Peripheral neuropathy, Grades 3 and 4 (1%)
Rash, Grades 3 and 4 (1%)
Pruritus, Grades 3 and 4 (1%)
<1%
Increased alkaline phosphatase
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 (see Dosing Considerations)
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)
Uveitis (eg, iritis, iridocyclitis) reported in patients treated with encorafenib in combination with binimetinib; 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 (see Dosage Modifications)
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 (see Dosage Modifications)
Based on its mechanism of action, fetal harm may occur when administered to a pregnant woman (see Pregnancy)
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 (see Dosage Modifications)
Refer to the binimetinib prescribing information for additional risk information that applies to combination use treatment
New primary malignancies
- New primary malignancies, cutaneous and noncutaneous, observed in patients treated with BRAF inhibitors and may occur with encorafenib
- Cutaneous squamous cell carcinoma
- In the COLUMBUS trial, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6%, and basal cell carcinoma occurred in 1.6% of patients who received encorafenib in combination with binimetinib; median time to first occurrence of cuSCC/KA was 5.8 months
- Perform dermatologic evaluations prior to 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
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.
- Manage and view all your plans together – even plans in different states.
- Compare formulary status to other drugs in the same class.
- Access your plan list on any device – mobile or desktop.
