Posology : מינונים

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 (13.1)].
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 (13.2))]
2.2 Recommended Dosage for BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic
Melanoma
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 (11.3)]. 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 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 (5.7)].
Dose reductions for adverse reactions associated with BRAFTOVI are presented in Table 1.
Table 1:   Recommended Dose Reductions for BRAFTOVI for Adverse Reactions – Melanoma 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.
Table 2:   Recommended Dose Reductions for BRAFTOVI for Adverse Reactions – CRC 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 and BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)
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 Reactiona                        Dose Modification for BRAFTOVI New Primary Malignancies [see Warnings and Precautions (5.1)]
Non-Cutaneous RAS Mutation-positive Permanently discontinue BRAFTOVI.
Malignancies
Hepatotoxicity
• Grade 2 AST or ALT             Maintain BRAFTOVI dose.
increased                        • 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        See Other  Adverse Reactions.
increased


Severity of Adverse Reactiona                           Dose Modification for BRAFTOVI Uveitis [see Warnings and Precautions (5.4)]
• 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 (5.5)]
•      QTcF greater than 500 ms and Withhold BRAFTOVI until QTcF less than or equal to 500 ms. Resume at less than or equal to 60 ms     reduced dose.
increase from baseline              • If more than one recurrence, permanently discontinue BRAFTOVI.
•      QTcF greater than 500 ms and Permanently discontinue BRAFTOVI.
greater than 60 ms increase from baseline
Dermatologic (other than Hand-foot Skin Reaction [HFSR])
• 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 (5.3)] and HFSRb • Recurrent Grade 2 or             Withhold BRAFTOVI for up to 4 weeks.
• First occurrence of any Grade 3      • 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.
a    National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
b    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; cardiac dysfunction; creatine phosphokinase (CPK) elevation; rhabdomyolysis; and venous thromboembolism.

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 (11.3)].
Table 4:         Recommended Dose Reductions for BRAFTOVI for Coadministration With Strong or Moderate CYP3A4 Inhibitors
Current Daily Dosea            Dose for Coadministration with Moderate                      Dose for Coadministration with Strong CYP3A4 Inhibitor                                            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 mgb a   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).
b   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.