Braftovi
(encorafenib)Dosage & Administration
Melanoma
CRC
NSCLC
Take BRAFTOVI with or without food.
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Braftovi Prescribing Information
BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma
BRAFTOVI is indicated, in combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test [see Dosage and Administration (2.1)].
BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (mCRC)
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- BRAFTOVI is indicated, in combination with cetuximab and mFOLFOX6, for the treatment of patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA-approved test [see Dosage and Administration (2.1)].
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- This indication is approved under accelerated approval based on response rate and durability of response [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
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- BRAFTOVI is indicated, in combination with cetuximab, for the treatment of adult patients with mCRC with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy [see Dosage and Administration (2.1)].
BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)
BRAFTOVI is indicated, in combination with binimetinib, for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-approved test [see Dosage and Administration (2.1)].
Limitations of Use
BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma, wild-type BRAF CRC, or wild-type BRAF NSCLC [see Warnings and Precautions (5.2)].
Patient Selection
BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma
Confirm the presence of a BRAF V600E or V600K mutation in tumor specimens prior to initiating BRAFTOVI [see Warnings and Precautions (5.2), Clinical Studies (14.1)]. Information on FDA-approved tests for the detection of BRAF V600E and V600K mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.
BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)
Confirm the presence of a BRAF V600E mutation in plasma or tumor tissue prior to initiating BRAFTOVI [see Warnings and Precautions (5.2), Clinical Studies (14.2, 14.3)]. If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA-approved tests for the detection of BRAF V600E mutations in CRC is available at: http://www.fda.gov/CompanionDiagnostics.
BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)
Confirm the presence of a BRAF V600E mutation in tumor or plasma specimens prior to initiating BRAFTOVI [see Warnings and Precautions (5.2), Clinical Studies (14.4)]. If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA-approved tests for the detection of BRAF V600E mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.
Recommended Dosage for BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma and for BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)
The recommended dosage of BRAFTOVI is 450 mg (six 75 mg capsules) orally once daily in combination with binimetinib until disease progression or unacceptable toxicity. Refer to the binimetinib prescribing information for recommended binimetinib dosing information.
Recommended Dosage for BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)
The recommended dosage of BRAFTOVI is 300 mg (four 75 mg capsules) orally once daily in combination with biweekly cetuximab and mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) [see Clinical Studies (14.2)] or in combination with weekly cetuximab [see Clinical Studies (14.3)] until disease progression or unacceptable toxicity.
Administration
BRAFTOVI may be taken with or without food [see Clinical Pharmacology (12.3)]. Do not take a missed dose of BRAFTOVI within 12 hours of the next dose of BRAFTOVI.
Do not take an additional dose if vomiting occurs after BRAFTOVI administration but continue with the next scheduled dose.
Dosage Modifications for Adverse Reactions
BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma or BRAF V600E Mutation-Positive Metastatic NSCLC
If binimetinib is withheld, reduce BRAFTOVI to a maximum dose of 300 mg (four 75 mg capsules) once daily until binimetinib is resumed [see Warnings and Precautions (5.9)].
Dose reductions for adverse reactions associated with BRAFTOVI are presented in Table 1.
Table 1: Recommended Dose Reductions for BRAFTOVI for Adverse Reactions – Melanoma or NSCLC
Action | Recommended Dose |
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 BRAFTOVI 225 mg (three 75 mg capsules) once daily |
BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)
If cetuximab is discontinued, discontinue BRAFTOVI.
Dose reductions for adverse reactions associated with BRAFTOVI are presented in Table 2.
Action | Recommended Dose |
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 BRAFTOVI 150 mg (two 75 mg capsules) once daily |
BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma, BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC), or BRAF V600E Mutation-Positive NSCLC
Dosage modifications for adverse reactions associated with BRAFTOVI are presented in Table 3.
| Severity of Adverse Reaction * | Dose Modification for BRAFTOVI |
|---|---|
| |
New Primary Malignancies [see Warnings and Precautions (5.1)] | |
Noncutaneous RAS Mutation-positive Malignancies | Permanently discontinue BRAFTOVI. |
Cardiomyopathy [see Warnings and Precautions (5.3)] | |
| Reduce BRAFTOVI by one dose level [see Dosage and Administration (2.3)].
|
Hepatotoxicity [see Warnings and Precautions (5.4)] | |
| Maintain BRAFTOVI dose.
|
| See Other Adverse Reactions. |
Uveitis [see Warnings and Precautions (5.6)] | |
| If Grade 1 or 2 does not respond to specific ocular therapy, or for Grade 3 uveitis, withhold BRAFTOVI for up to 6 weeks.
|
| Permanently discontinue BRAFTOVI. |
QTc Prolongation [see Warnings and Precautions (5.7)] | |
| Withhold BRAFTOVI until QTcF less than or equal to 500 ms. Resume at reduced dose.
|
| Permanently discontinue BRAFTOVI. |
Dermatologic [other than Hand-foot Skin Reaction (HFSR)] [see Adverse Reactions (6.1)] | |
| If no improvement within 2 weeks, withhold BRAFTOVI until Grade 0–1. Resume at same dose. |
| Withhold BRAFTOVI until Grade 0–1. Resume at same dose if first occurrence or reduce dose if recurrent. |
| Permanently discontinue BRAFTOVI. |
Other Adverse Reactions (including Hemorrhage) [see Warnings and Precautions (5)] and HFSR [see Adverse Reactions (6.1)] † | |
| Withhold BRAFTOVI for up to 4 weeks.
|
| Permanently discontinue BRAFTOVI or
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| Consider permanently discontinuing BRAFTOVI. |
| Permanently discontinue BRAFTOVI. |
Refer to the binimetinib or cetuximab prescribing information for dose modifications for adverse reactions associated with each product, as appropriate.
Dose Modifications for Coadministration with Strong or Moderate CYP3A4 Inhibitors
Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors. If coadministration is unavoidable, reduce the BRAFTOVI dose according to the recommendations in Table 4. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the BRAFTOVI dose that was taken prior to initiating the CYP3A4 inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].
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Current Daily Dose * | Dose for Coadministration with Moderate CYP3A4 Inhibitor | Dose for Coadministration with Strong CYP3A4 Inhibitor |
450 mg | 225 mg (three 75 mg capsules) | 150 mg (two 75 mg capsules) |
300 mg | 150 mg (two 75 mg capsules) | 75 mg |
225 mg | 75 mg | 75 mg |
150 mg | 75 mg | 75 mg † |
Capsules: 75 mg, hard gelatin, stylized "A" on beige cap and "LGX 75mg" on white body.
Pregnancy
Risk Summary
Based on its mechanism of action, BRAFTOVI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available clinical data on the use of BRAFTOVI during pregnancy. 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 approximately 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 (see Data). Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
In reproductive toxicity studies, administration of encorafenib to rats during the period of organogenesis resulted in maternal toxicity, decreased fetal weights, and increased incidence of total skeletal variations at a dose of 20 mg/kg/day (approximately 26 times the human exposure based on area under the concentration-time curve [AUC] at the recommended clinical dose of 450 mg once daily). In pregnant rabbits, administration of encorafenib during the period of organogenesis resulted in maternal toxicity, decreased fetal body weights, increased incidence of total skeletal variations and increased post-implantation loss, including total loss of pregnancy at a dose of 75 mg/kg/day (approximately 178 times the human exposure based on AUC at the recommended clinical dose of 450 mg once daily). While formal placental transfer studies have not been performed, encorafenib exposure in the fetal plasma of both rats and rabbits was up to 1.7% and 0.8%, respectively, of maternal exposure.
Lactation
Risk Summary
There are no data on the presence of encorafenib or its metabolites in human milk or the effects of encorafenib on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child from BRAFTOVI, advise women not to breastfeed during treatment with BRAFTOVI and for 2 weeks after the last dose.
Females and Males of Reproductive Potential
BRAFTOVI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating BRAFTOVI [see Use in Specific Populations (8.1)].
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with BRAFTOVI and for 2 weeks after the last dose. Counsel patients to use a nonhormonal method of contraception since BRAFTOVI has the potential to render hormonal contraceptives ineffective [see Drug Interactions (7.2)].
Infertility
Males
Based on findings in male rats at doses approximately 13 times the human exposure at the 450 mg clinical dose, use of BRAFTOVI may impact fertility in males [see Nonclinical Toxicology (13.1)].
Pediatric Use
The safety and effectiveness of BRAFTOVI have not been established in pediatric patients.
Geriatric Use
Of the 690 patients with BRAF mutation-positive melanoma who received BRAFTOVI in combination with binimetinib across multiple clinical trials, 20% were aged 65 to 74 years and 8% were aged 75 years and older [see Clinical Studies (14.1)].
Of the 231 patients with BRAF V600E mutation-positive metastatic CRC who received BRAFTOVI in combination with cetuximab and mFOLFOX6, 83 (36%) were 65 years of age and over and 16 (7%) were 75 years of age and over [see Clinical Studies (14.2)].
Of the 216 patients with BRAF V600E mutation-positive metastatic CRC who received BRAFTOVI in combination with cetuximab, 62 (29%) were 65 years of age to up to 75 years of age, while 20 (9%) were 75 years of age and over [see Clinical Studies (14.3)].
Of the 98 patients with BRAF V600E mutation-positive metastatic NSCLC who received BRAFTOVI with binimetinib, 62 (63%) were 65 years of age and over and 20 (20%) were 75 years and over [see Clinical Studies (14.4)].
No overall differences in the safety or effectiveness of BRAFTOVI plus binimetinib, BRAFTOVI plus cetuximab, or BRAFTOVI plus cetuximab and mFOLFOX6 were observed in older patients as compared to younger patients.
Hepatic Impairment
No BRAFTOVI dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh Class A) [see Clinical Pharmacology (12.3)]. A recommended dosage has not been established in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment.
Renal Impairment
No BRAFTOVI dosage adjustment is recommended in patients with mild to moderate renal impairment (CLcr 30 to <90 mL/min) [see Clinical Pharmacology (12.3)]. A recommended dosage has not been established in patients with severe renal impairment (CLcr <30 mL/min).
None.
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, skin papilloma was reported in 2.6%, 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% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6.
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)].
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)].
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)].
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 2.2% for alkaline phosphatase, 1.3% for ALT, and 0.9% for 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)].
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 30% of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6; Grade 3 or 4 hemorrhage occurred in 3% of patients.
Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.5), Adverse Reactions (6.1)].
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%.
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)].
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 3.6% (8/222) of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6.
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)].
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)].
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)].
Risks Associated with Combination Treatment
BRAFTOVI is indicated for use as part of a regimen in combination with binimetinib, in combination with cetuximab, or in combination with cetuximab and mFOLFOX6. Refer to the prescribing information for binimetinib, cetuximab and individual product components of mFOLFOX6 for additional risk information.