encorafenib

en-koe-RAF-e-nib

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

High Alert

Metastatic or unresectable melanoma in patients with a BRAF V600E or V600K mutation (in combination with binimetinib).
Metastatic colorectal cancer in patients with a BRAF V600E mutation (in combination with cetuximab).
Metastatic non-small cell lung cancer (NSCLC) in patients with a BRAF V600E mutation (in combination with binimetinib).

Kinase inhibitor that targets BRAF V600E, a mutated enzyme that promotes tumor cell proliferation.

Therapeutic effects:

Improvement in progression-free survival and overall survival in patients with melanoma and colorectal cancer.
Decreased progression of NSCLC.

Absorption: Well absorbed (86%) following oral administration.

Distribution: Extensively distributed to tissues.

Metabolism/Excretion: Primarily metabolized by the liver via the CYP3A4 and CYP2C19 isoenzymes. Primarily excreted as metabolites in feces (42%) and urine (45%).

Half-Life: 3.5 hr

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	2 hr	24 hr

Contraindicated in:

Wild-type BRAF melanoma (may ↑ proliferation);
Long QT syndrome, bradyarrhythmias, severe or decompensated HF, hypokalemia, or hypomagnesemia (↑ risk of QT interval prolongation);
Concurrent use of QT-interval prolonging medications;
Baseline QTc interval >500 msec;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Left ventricular ejection fraction (LVEF) <50%;
Moderate or severe hepatic impairment;
Severe renal impairment;
Rep: Women of reproductive potential;
Pedi: Safety and effectiveness not established in children.

CV: cardiomyopathy, QT interval prolongation

Derm: alopecia, dry skin, hyperkeratosis, pruritus, rash, BASAL CELL CARCINOMA, CUTANEOUS SQUAMOUS CELL CARCINOMA, nodule formation, photosensitivity

EENT: uveitis

Endo: hyperglycemia

F and E: hypermagnesemia, hyponatremia

GI: ↑liver enzymes, abdominal pain, constipation, nausea, vomiting, GI HEMORRHAGE, PANCREATITIS

GU: ↑serum creatinine, ↓fertility (men)

Hemat: anemia, bleeding, leukopenia, lymphopenia, neutropenia

MS: arthralgia, myalgia

Neuro: dizziness, fatigue, headache, peripheral neuropathy, facial paralysis, INTRACRANIAL HEMORRHAGE

Misc: fever, HYPERSENSITIVITY REACTIONS, MALIGNANCY

Drug-drug:

QT interval prolonging drugs may ↑ the risk of QT interval prolongation and torsades de pointes; avoid concurrent use.
Strong or moderate CYP3A4 inhibitors, including diltiazem and posaconazole, may ↑ levels and risk of toxicity; avoid concurrent use. If concurrent use unavoidable, ↓ encorafenib dose.
Strong CYP3A4 inducers may ↓ levels and effectiveness; avoid concurrent use.
May ↓ effectiveness of hormonal contraceptives; avoid concurrent use.
May ↑ levels and risk of toxicity of OATP1B1 substrates, OATP1B3 substrates, or BCRP substrates.

Drug-Natural Products:

St. John's wort may ↓ levels and effectiveness; avoid concurrent use.

Drug-Food:

Grapefruit juice may ↑ levels and risk of toxicity; avoid concurrent use.

BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma and BRAF V600E Mutation-Positive Metastatic NSCLC

PO (Adults ): 450 mg once daily until disease progression or unacceptable toxicity. Concurrent use of moderate CYP3A4 inhibitor: 225 mg once daily (if planned dose 450 mg once daily); 150 mg once daily (if planned dose 300 mg once daily); 75 mg once daily (if planned dose 225 mg once daily); Concurrent use of strong CYP3A4 inhibitor: 150 mg once daily (if planned dose 450 mg once daily); 75 mg once daily (if planned dose 300 mg once daily or 225 mg once daily).

BRAF V600E Mutation-Positive Metastatic Colorectal Cancer

PO (Adults ): 300 mg once daily until disease progression or unacceptable toxicity. Concurrent use of moderate CYP3A4 inhibitor: 150 mg once daily (if planned dose 300 mg once daily); 75 mg once daily (if planned dose 225 mg once daily or 150 mg once daily); Concurrent use of strong CYP3A4 inhibitor: 75 mg once daily (if planned dose 300 mg once daily, 225 mg once daily, or 150 mg once daily).

Capsules: 75 mg

Assess for signs and symptoms of HF (dyspnea, cough, paroxysmal nocturnal dyspnea, peripheral edema, S₃ gallop, rales) prior to and frequently during therapy. Assess LVEF by echocardiogram or MUGA scan before starting therapy, 1 mo after starting therapy, and then every 2–3 mo throughout treatment. If symptomatic HF or absolute ↓ in LVEF of >20% from baseline that is also below the lower limit of normal develops, ↓ dose by one level. If LVEF improves to at least institutional lower limit of normal and absolute ↓ is ≤10% compared to baseline, continue encorafenib at the reduced dose. If no improvement in LVEF after dose ↓, hold encorafenib until LVEF improves to at least institutional lower limit of normal and absolute ↓ is ≤10% compared to baseline, and then resume at the reduced dose or reduce dose an additional dose level.
Assess skin for lesions prior to starting, every 2 mo during, and for up to 6 mo following discontinuation of therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. For Grade 2 reaction, if no improvement in 2 wk, hold encorafenib until Grade 0–1; then resume at same dose. For Grade 3 reaction, hold encorafenib until Grade 0–1. Resume at same dose if 1st occurrence or ↓ dose if recurrent. For Grade 4 reaction, discontinue encorafenib permanently.
Monitor for noncutaneous RAS mutation-positive malignancies. Permanently discontinue encorafenib if these malignancies occur.
Monitor for signs and symptoms of hemorrhage (bleeding GI, rectal, anal, hemorrhoidal) periodically during therapy. If Grade 2 or 1st occurrence of Grade 3 hemorrhagic event: Hold encorafenib up to 4 wk. If improves to Grade 0–1 or to pretreatment level, resume at ↓ dose. If no improvement, permanently discontinue encorafenib. If 1st occurrence of Grade 4 hemorrhagic event: Permanently discontinue encorafenib or hold up to 4 wk. If improves to Grade 0–1 or to pretreatment level, resume at ↓ dose. If no improvement, permanently discontinue encorafenib. If recurrent Grade 3 hemorrhagic event: Consider permanently discontinuing encorafenib. If recurrent Grade 4 hemorrhagic event: Permanently discontinue encorafenib.
Monitor ECG in patients who already have or are at risk of QTc interval prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled HF, and those taking other medications leading to QT interval prolongation. If QTcF interval >500 msec and ≤60 msec ↑ from baseline, hold encorafenib until QTcF interval ≤500 msec. Resume at ↓ dose. If occurs more than once, permanently discontinue encorafenib. If QTcF interval >500 msec and >60 msec ↑ from baseline, permanently discontinue encorafenib.
Assess for signs and symptoms of uveitis (visual changes, eye pain) during therapy. Perform ophthalmologic exam regularly and for new or worsening visual disturbances; follow new or persistent ophthalmologic findings. If Grade 1 or 2 does not respond to ocular therapy, or for Grade 3 uveitis, hold encorafenib for up to 6 wk. If improved, resume at same or ↓ dose. If not improved, permanently discontinue encorafenib. If Grade 4 uveitis occurs, permanently discontinue encorafenib.

Lab Test Considerations:

Verify a negative pregnancy test before starting therapy.
- Confirm presence of a BRAF V600E or V600K mutation in tumor specimens before starting therapy for melanoma and of BRAF V600E mutation before starting therapy for colorectal cancer or NSCLC. Information on FDA-approved tests for the detection of BRAF V600E and V600K mutations is available at http://www.fda.gov/CompanionDiagnostics.
- Monitor serum electrolytes periodically during therapy. Correct hypokalemia and hypomagnesemia before and during therapy. May also cause hyponatremia and hyperglycemia.
- May cause anemia, leukopenia, lymphopenia, and neutropenia.
- Monitor liver function periodically during therapy. May ↑ GGT, AST, ALT, and alkaline phosphatase. If Grade 2 AST or ALT ↑: Continue dose. If no improvement within 4 wk, hold encorafenib until Grade 0–1 or to baseline levels; then resume at same dose. If no improvement, permanently discontinue encorafenib. If Grade 3 AST or ALT ↑: Consider permanently discontinuing encorafenib. If Grade 4 AST or ALT ↑: Permanently discontinue encorafenib.

Melanoma and NSCLC reduced-dose recommendations: If binimetinib is held, ↓ encorafenib dose to maximum dose of 300 mg once daily until binimetinib is resumed. First dose reduction: 300 mg (four 75-mg capsules) orally once daily. Second dose reduction: 225 mg (three 75-mg capsules) orally once daily. Subsequent modification: Permanently discontinue if unable to tolerate encorafenib 225 mg (three 75-mg capsules) once daily.
- Colorectal cancer reduced-dose recommendationsIf cetuximab is discontinued, discontinue encorafenib. First dose reduction: 225 mg (three 75-mg capsules) orally once daily. Second dose reduction: 150 mg (two 75-mg capsules) orally once daily. Subsequent modification: Permanently discontinue if unable to tolerate encorafenib 150 mg (two 75-mg capsules) once daily.
PO: Administer once daily without regard to food. Store in original bottle, tightly capped, at room temperature; do not remove desiccant; protect from moisture.

Explain purpose and side effects of medication to patient. Advise patient to read Patient Information before starting therapy. Instruct patient to take as directed. Take missed dose within 12 hr of missed dose; do not take dose within 12 hr of next dose. If vomiting occurs, skip dose; continue with next scheduled dose.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially St. John's wort.
Inform patient to avoid grapefruit and grapefruit juice during therapy.
Instruct patient to notify health care professional promptly if new onset or worsening shortness of breath; cough; swelling of the ankles, legs, or face; palpitations; or weight gain of >5 pounds in 24 hr occur.
Inform patient of the ↑ risk of developing new cutaneous malignancies. Notify health care professional immediately if new lesions (wart, skin sore or reddish bump that bleeds or does not heal) or changes in size or color of existing moles or lesions occur.
Advise patient to notify health care professional immediately if signs and symptoms of bleeding (headaches, dizziness, weakness, coughing up blood or blood clots, vomiting blood or vomit looks like coffee grounds, red or black tarry stools); liver dysfunction (yellow skin or whites of eyes, feeling tired, dark or brown urine, nausea or vomiting, loss of appetite, pain on right side of stomach), changes in heart rhythm (feeling faint, light-headed, or dizzy; heart beating irregularly or fast); or eye problems (blurred vision, loss of vision, other vision changes, seeing colored dots, seeing halos or blurred outline around objects, eye pain, swelling, redness) occur.
Inform patient that regular assessments of skin and assessments for signs and symptoms of other malignancies must be done every 2 mo during and for up to 6 mo after therapy. Advise patient to notify health care professional immediately if any changes in skin occur.
Rep: May cause fetal harm, and may ↓ effectiveness of hormonal contraceptives. Advise women to use a highly effective nonhormonal form of contraception during and for 2 wk after last dose. Advise patient to notify health care professional if pregnancy is suspected and to avoid breastfeeding during therapy and for >2 wk after last dose. May impair fertility in men.

Improvement in progression-free survival and overall survival in patients with melanoma and colorectal cancer.
Decreased progression of NSCLC.

Braftovi

NDC Code

70255- Array BioPharma Inc.
- 70255-025- BRAFTOVI
  - 70255-025-01- 2 BOTTLE in 1 CARTON (70255-025-01) > 90 CAPSULE in 1 BOTTLE (70255-025-02)

70255- Array BioPharma Inc.
- 70255-025- BRAFTOVI
  - 70255-025-03- 2 BOTTLE in 1 CARTON (70255-025-03) > 60 CAPSULE in 1 BOTTLE (70255-025-04)

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