BRAFTOVI® Dosage and Administration

(encorafenib)

2 DOSAGE AND ADMINISTRATION

2.1 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 tumor specimens prior to initiating BRAFTOVI [see Warnings and Precautions (5.2), Clinical Studies (14.2)]. 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 (14.3)]. 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 NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 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.

2.3 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 cetuximab until disease progression or unacceptable toxicity. Refer to the cetuximab prescribing information for recommended cetuximab dosing information.

2.4 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.

2.5 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

ActionRecommended 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.

Table 2: Recommended Dose Reductions for BRAFTOVI for Adverse Reactions – CRC
ActionRecommended 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.

Table 3: Recommended Dosage Modifications for BRAFTOVI for Adverse Reactions
Severity of Adverse Reaction*Dose Modification for BRAFTOVI
*
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
Dose modification of BRAFTOVI when administered with binimetinib or with cetuximab is not recommended for new primary cutaneous malignancies; ocular events other than uveitis, iritis, and iridocyclitis; interstitial lung disease/pneumonitis; creatine phosphokinase (CPK) elevation; rhabdomyolysis; and venous thromboembolism.

New Primary Malignancies [see Warnings and Precautions (5.1)]

Non-Cutaneous RAS Mutation-positive Malignancies

Permanently discontinue BRAFTOVI.

Cardiomyopathy [see Warnings and Precautions (5.3)]

Symptomatic congestive heart failure or absolute decrease in LVEF of greater than 20% from baseline that is also below LLN

Reduce BRAFTOVI by one dose level [see Dosage and Administration (2.3)].

If LVEF improves to at least institutional LLN and absolute decrease to less than or equal to 10% compared to baseline, continue BRAFTOVI at the reduced dose [see Dosage and Administration (2.3)].
If no improvement, withhold BRAFTOVI until improves to at least institutional LLN and absolute decrease to less than or equal to 10% compared to baseline and then resume at the reduced dose or reduce dose an additional dose level.

Hepatotoxicity [see Warnings and Precautions (5.4)]

Grade 2 AST or ALT increased

Maintain BRAFTOVI dose.

If no improvement within 4 weeks, withhold BRAFTOVI 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

See Other Adverse Reactions.

Uveitis [see Warnings and Precautions (5.6)]

Grade 1–3

If Grade 1 or 2 does not respond to specific ocular therapy, or for Grade 3 uveitis, withhold BRAFTOVI for up to 6 weeks.

If improved, resume at same or reduced dose.
If not improved, permanently discontinue BRAFTOVI.
Grade 4

Permanently discontinue BRAFTOVI.

QTc Prolongation [see Warnings and Precautions (5.7)]

QTcF greater than 500 ms and less than or equal to 60 ms increase from baseline

Withhold BRAFTOVI until QTcF less than or equal to 500 ms. Resume at reduced dose.

If more than one recurrence, permanently discontinue BRAFTOVI.
QTcF greater than 500 ms and greater than 60 ms increase from baseline

Permanently discontinue BRAFTOVI.

Dermatologic [other than Hand-foot Skin Reaction (HFSR)] [see Adverse Reactions (6.1)]

Grade 2

If no improvement within 2 weeks, withhold BRAFTOVI until Grade 0–1. Resume at same dose.

Grade 3

Withhold BRAFTOVI until Grade 0–1. Resume at same dose if first occurrence or reduce dose if recurrent.

Grade 4

Permanently discontinue BRAFTOVI.

Other Adverse Reactions (including Hemorrhage) [see Warnings and Precautions (5)] and HFSR [see Adverse Reactions (6.1)]

Recurrent Grade 2 or
First occurrence of any Grade 3

Withhold BRAFTOVI 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 BRAFTOVI.
First occurrence of any Grade 4

Permanently discontinue BRAFTOVI or
Withhold BRAFTOVI for up to 4 weeks.

If improves to Grade 0–1 or to pretreatment/baseline level, then resume at reduced dose.
If no improvement, permanently discontinue BRAFTOVI.
Recurrent Grade 3

Consider permanently discontinuing BRAFTOVI.

Recurrent Grade 4

Permanently discontinue BRAFTOVI.

Refer to the binimetinib or cetuximab prescribing information for dose modifications for adverse reactions associated with each product, as appropriate.

2.6 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)].

Table 4: Recommended Dose Reductions for BRAFTOVI for Coadministration With Strong or Moderate CYP3A4 Inhibitors
Current Daily Dose*Dose for Coadministration with Moderate CYP3A4 InhibitorDose for Coadministration with Strong CYP3A4 Inhibitor
*
Current daily dose refers to recommended dose of BRAFTOVI based on indication or reductions for adverse reactions based on dosing recommendations in Table 1 (Melanoma) and Table 2 (CRC).
Encorafenib exposure at the 75 mg QD BRAFTOVI dosage when coadministered with a strong CYP3A4 inhibitor is expected to be higher than at the 150 mg QD dosage in the absence of a CYP3A4 inhibitor and similar to exposure at the 225 mg QD dosage in the absence of a CYP3A4 inhibitor. Monitor patients closely for adverse reactions and use clinical judgement when using BRAFTOVI with strong CYP3A4 inhibitors at the 150 mg dose level.

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

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Dosage and Administration

2 DOSAGE AND ADMINISTRATION

2.1 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 tumor specimens prior to initiating BRAFTOVI [see Warnings and Precautions (5.2), Clinical Studies (14.2)]. 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 (14.3)]. 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 NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 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.

2.3 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 cetuximab until disease progression or unacceptable toxicity. Refer to the cetuximab prescribing information for recommended cetuximab dosing information.

2.4 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.

2.5 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

ActionRecommended 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.

Table 2: Recommended Dose Reductions for BRAFTOVI for Adverse Reactions – CRC
ActionRecommended 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.

Table 3: Recommended Dosage Modifications for BRAFTOVI for Adverse Reactions
Severity of Adverse Reaction*Dose Modification for BRAFTOVI
*
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
Dose modification of BRAFTOVI when administered with binimetinib or with cetuximab is not recommended for new primary cutaneous malignancies; ocular events other than uveitis, iritis, and iridocyclitis; interstitial lung disease/pneumonitis; creatine phosphokinase (CPK) elevation; rhabdomyolysis; and venous thromboembolism.

New Primary Malignancies [see Warnings and Precautions (5.1)]

Non-Cutaneous RAS Mutation-positive Malignancies

Permanently discontinue BRAFTOVI.

Cardiomyopathy [see Warnings and Precautions (5.3)]

Symptomatic congestive heart failure or absolute decrease in LVEF of greater than 20% from baseline that is also below LLN

Reduce BRAFTOVI by one dose level [see Dosage and Administration (2.3)].

If LVEF improves to at least institutional LLN and absolute decrease to less than or equal to 10% compared to baseline, continue BRAFTOVI at the reduced dose [see Dosage and Administration (2.3)].
If no improvement, withhold BRAFTOVI until improves to at least institutional LLN and absolute decrease to less than or equal to 10% compared to baseline and then resume at the reduced dose or reduce dose an additional dose level.

Hepatotoxicity [see Warnings and Precautions (5.4)]

Grade 2 AST or ALT increased

Maintain BRAFTOVI dose.

If no improvement within 4 weeks, withhold BRAFTOVI 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

See Other Adverse Reactions.

Uveitis [see Warnings and Precautions (5.6)]

Grade 1–3

If Grade 1 or 2 does not respond to specific ocular therapy, or for Grade 3 uveitis, withhold BRAFTOVI for up to 6 weeks.

If improved, resume at same or reduced dose.
If not improved, permanently discontinue BRAFTOVI.
Grade 4

Permanently discontinue BRAFTOVI.

QTc Prolongation [see Warnings and Precautions (5.7)]

QTcF greater than 500 ms and less than or equal to 60 ms increase from baseline

Withhold BRAFTOVI until QTcF less than or equal to 500 ms. Resume at reduced dose.

If more than one recurrence, permanently discontinue BRAFTOVI.
QTcF greater than 500 ms and greater than 60 ms increase from baseline

Permanently discontinue BRAFTOVI.

Dermatologic [other than Hand-foot Skin Reaction (HFSR)] [see Adverse Reactions (6.1)]

Grade 2

If no improvement within 2 weeks, withhold BRAFTOVI until Grade 0–1. Resume at same dose.

Grade 3

Withhold BRAFTOVI until Grade 0–1. Resume at same dose if first occurrence or reduce dose if recurrent.

Grade 4

Permanently discontinue BRAFTOVI.

Other Adverse Reactions (including Hemorrhage) [see Warnings and Precautions (5)] and HFSR [see Adverse Reactions (6.1)]

Recurrent Grade 2 or
First occurrence of any Grade 3

Withhold BRAFTOVI 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 BRAFTOVI.
First occurrence of any Grade 4

Permanently discontinue BRAFTOVI or
Withhold BRAFTOVI for up to 4 weeks.

If improves to Grade 0–1 or to pretreatment/baseline level, then resume at reduced dose.
If no improvement, permanently discontinue BRAFTOVI.
Recurrent Grade 3

Consider permanently discontinuing BRAFTOVI.

Recurrent Grade 4

Permanently discontinue BRAFTOVI.

Refer to the binimetinib or cetuximab prescribing information for dose modifications for adverse reactions associated with each product, as appropriate.

2.6 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)].

Table 4: Recommended Dose Reductions for BRAFTOVI for Coadministration With Strong or Moderate CYP3A4 Inhibitors
Current Daily Dose*Dose for Coadministration with Moderate CYP3A4 InhibitorDose for Coadministration with Strong CYP3A4 Inhibitor
*
Current daily dose refers to recommended dose of BRAFTOVI based on indication or reductions for adverse reactions based on dosing recommendations in Table 1 (Melanoma) and Table 2 (CRC).
Encorafenib exposure at the 75 mg QD BRAFTOVI dosage when coadministered with a strong CYP3A4 inhibitor is expected to be higher than at the 150 mg QD dosage in the absence of a CYP3A4 inhibitor and similar to exposure at the 225 mg QD dosage in the absence of a CYP3A4 inhibitor. Monitor patients closely for adverse reactions and use clinical judgement when using BRAFTOVI with strong CYP3A4 inhibitors at the 150 mg dose level.

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

Medication Guide

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