Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: PIERRE FABRE MEDICAMENT, Les Cauquillous, 81500 Lavaur, France
Encorafenib in combination with binimetinib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.
Encorafenib in combination with cetuximab is indicated for the treatment of adult patients with metastatic colorectal cancer with a BRAF V600E mutation, who have received prior systemic therapy.
Encorafenib in combination with binimetinib is indicated for the treatment of adult patients with advanced non-small cell lung cancer with a BRAF V600E mutation.
Encorafenib treatment should be initiated and supervised under the responsibility of a physician experienced in the use of anticancer medicinal products.
Before taking encorafenib, patients must have confirmation of BRAF V600E mutation assessed by a CE-marked in vitro diagnostic (IVD) medical device with the corresponding intended purpose. If the CE-marked IVD is not available, an alternative validated test should be used.
The efficacy and safety of encorafenib have been established only in patients with melanoma tumours expressing BRAF V600E and V600K mutations, colorectal tumours expressing a BRAF V600E mutation or NSCLC expressing a BRAF V600E mutation. Encorafenib should not be used in patients with wild type BRAF malignant melanoma, wild type BRAF colorectal cancer or wild-type BRAF NSCLC.
The recommended dose of encorafenib is 450 mg (six 75 mg capsules) once daily, when used in combination with binimetinib.
The recommended dose of encorafenib is 300 mg (four 75 mg capsules) once daily, when used in combination with cetuximab.
The management of adverse reactions may require dose reduction, temporary interruption or treatment discontinuation of encorafenib (see Tables 1, 3 and 4). For information on the posology and recommended dose modifications of binimetinib, see section 4.2 of binimetinib Summary of Product Characteristics (SmPC).
Dose reduction recommendations for encorafenib are presented in Table 1.
Table 1. Recommended dose modifications for encorafenib when used in combination with binimetinib in melanoma or NSCLC indications:
| Dose level | Encorafenib dose when used in combination with binimetinib |
|---|---|
| Starting dose | Six 75 mg (450 mg) capsules once daily |
| 1st dose reduction | Four 75 mg (300 mg) capsules once daily |
| 2nd dose reduction | Three 75 mg (225 mg) capsules once daily |
| Subsequent modification | For melanoma indication: There are limited data for dose reduction to 100 mg once daily. Encorafenib should be permanently discontinued if patient is unable to tolerate 100 mg (two 50 mg capsules) once daily. For NSCLC indication: Encorafenib should be permanently discontinued if patient is unable to tolerate 225 mg (three 75 mg capsules) once daily. |
Administration of encorafenib at a dose of 450 mg once daily as a single agent is not recommended. If binimetinib is temporarily interrupted, encorafenib should be reduced to 300 mg once daily during the time of binimetinib dose interruption (see section 4.2 of binimetinib SmPC) as encorafenib is not well-tolerated at the dose of 450 mg as a single agent. If binimetinib is permanently discontinued, encorafenib should be discontinued.
If encorafenib is temporarily interrupted (see Tables 3 and 4), binimetinib should be interrupted. If encorafenib is permanently discontinued, then binimetinib should be discontinued
If treatment-related toxicities occur, then encorafenib and binimetinib should be dose reduced, interrupted or discontinued. Dose modifications are necessary for binimetinib only (adverse reactions primarily related to binimetinib) for the following: retinal pigment epithelial detachment (RPED), retinal vein occlusion (RVO), interstitial lung disease/pneumonitis, cardiac dysfunction, creatine phosphokinase (CK) elevation and rhabdomyolysis, and venous thromboembolism (VTE).
If one of these toxicities occurs, see section 4.2 of binimetinib SmPC for dose modification instructions for binimetinib.
The management of adverse reactions may require dose reduction, temporary interruption or treatment discontinuation of encorafenib (see Tables 2, 3 and 4). For information on the posology and recommended dose modifications of cetuximab, see section 4.2 of cetuximab SmPC.
Dose reduction recommendations for encorafenib are presented in Table 2.
Table 2. Recommended dose modifications for encorafenib when used in combination with cetuximab in CRC indication:
| Dose level | Encorafenib dose when used in combination with cetuximab |
|---|---|
| Starting dose | Four 75 mg (300 mg) capsules once daily |
| 1st dose reduction | Three 75 mg (225 mg) capsules once daily |
| 2nd dose reduction | Two 75 mg (150 mg) capsules once daily |
If encorafenib is permanently discontinued, cetuximab should be discontinued.
If cetuximab is permanently discontinued, encorafenib should be discontinued.
Dose modifications in case of adverse reactions are provided below and in Tables 3 and 4.
For new primary cutaneous malignancies: No dose modifications are required for encorafenib.
For new primary non-cutaneous RAS mutation-positive malignancies: it should be considered to discontinue encorafenib permanently.
Table 3. Recommended dose modifications for encorafenib when used in combination with binimetinib or in combination with cetuximab for selected adverse reaction:
| Severity of adverse reactiona | Encorafenib |
|---|---|
| Cutaneous reactions | |
| • Grade 2 | Encorafenib should be maintained. If rash worsens or does not improve within 2 weeks with treatment, encorafenib should be withheld until Grade 0 or 1 and then resumed at the same dose. |
| • Grade 3 | Encorafenib should be withheld until improved to Grade 0 or 1 and resumed at the same dose if first occurrence, or resumed at a reduced dose if recurrent Grade 3. |
| • Grade 4 | Encorafenib should be permanently discontinued. |
| Palmar-plantar erythrodysaesthesia syndrome (PPES) | |
| • Grade 2 | Encorafenib should be maintained and supportive measures such as topical therapy should be instituted. If not improved despite supportive therapy within 2 weeks, encorafenib should be withheld until improved to Grade 0 or 1 and treatment should be resumed at same dose level or at a reduced dose. |
| • Grade 3 | Encorafenib should be withheld, supportive measures such as topical therapy should be instituted, and the patient should be reassessed weekly. Encorafenib should be resumed at same dose level or at a reduced dose level when improved to Grade 0 or 1. |
| Uveitis including iritis and iridocyclitis | |
| • Grade 1-3 | If Grade 1 or 2 uveitis does not respond to specific (e.g. topical) ocular therapy or for Grade 3 uveitis, encorafenib should be withheld and ophthalmic monitoring should be repeated within 2 weeks. If uveitis is Grade 1 and it improves to Grade 0, then treatment should be resumed at the same dose. If uveitis is Grade 2 or 3 and it improves to Grade 0 or 1, then treatment should be resumed at a reduced dose. If not improved within 6 weeks, ophthalmic monitoring should be repeated and encorafenib should be permanently discontinued. |
| • Grade 4 | Encorafenib should be permanently discontinued and a follow up with ophthalmologic monitoring should be performed. |
| QTc Prolongation | |
| • QTcF > 500 ms and change ≤ 60 ms from pre-treatment value | Encorafenib should be withheld (see monitoring in section 4.4). Encorafenib should be resumed at a reduced dose when QTcF ≤500 ms. Encorafenib should be discontinued if more than one recurrence. |
| • QTcF>500 ms and increased by >60 ms from pre-treatment values | Encorafenib should be permanently discontinued (see monitoring in section 4.4). |
| Liver laboratory abnormalities | |
| • Grade 2 (aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3x ≤5x upper limit of normal (ULN)) | Encorafenib should be maintained. If no improvement within 4 weeks, encorafenib should be withheld until improved to Grade 0 or 1 or to pre- treatment/baseline levels and then resumed at the same dose. |
| • First occurrence of Grade 3 (AST or ALT >5x ULN and blood bilirubin >2x ULN) | Encorafenib should be withheld for up to 4 weeks. • If improved to Grade 0 or 1 or to baseline levels, it should be resumed at a reduced dose. • If not improved, encorafenib should be permanently discontinued |
| • First occurrence of Grade 4 (AST or ALT >20 ULN) | Encorafenib should be withheld for up to 4 weeks • If improved to Grade 0 or 1 or to baseline levels, then it should be resumed at a reduced dose level. • If not improved, encorafenib should be permanently discontinued. Or, encorafenib should be permanently discontinued. |
| • Recurrent Grade 3 (AST or ALT > 5x ULN and blood bilirubin > 2x ULN) | It should be considered to permanently discontinue encorafenib. |
| • Recurrent Grade 4 (AST or ALT > 20 ULN) | Encorafenib should be permanently discontinued. |
a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03
Table 4. Recommended dose modifications for encorafenib when used in combination with binimetinib or in combination with cetuximab for other adverse reactions:
| Severity of adverse reaction | Encorafenib |
|---|---|
| • Recurrent or intolerable Grade 2 adverse reactions • First occurrence of Grade 3 adverse reactions | Encorafenib should be withheld for up to 4 weeks. • If improved to Grade 0 or 1 or to baseline levels, It should be resumed at a reduced dose. • If not improved, encorafenib should be permanently discontinued |
| • First occurrence of any Grade 4 adverse reaction | Encorafenib should be withheld for up to 4 weeks • If improved to Grade 0 or 1 or to baseline levels, then it should be resumed at a reduced dose level. • If not improved, encorafenib should be permanently discontinued. Or, encorafenib should be permanently discontinued. |
| • Recurrent Grade 3 adverse reactions | Permanent discontinuation of encorafenib should be considered. |
| • Recurrent Grade 4 adverse reactions | Encorafenib should be permanently discontinued. |
Treatment should continue until the patient no longer derives benefit or the development of unacceptable toxicity.
If a dose of encorafenib is missed, the patient should only take the missed dose if it is more than 12 hours until the next scheduled dose.
In case of vomiting after administration of encorafenib, the patient should not take an additional dose and should take the next scheduled dose.
No dose adjustment is required for patients aged 65 years and older (see section 5.2).
Patients with mild to severe hepatic impairment may have increased encorafenib exposure (see section 5.2).
Administration of encorafenib should be undertaken with caution at a dose of 300 mg once daily in patients with mild hepatic impairment (Child-Pugh Class A).
No dosing recommendation can be made in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment.
No dose adjustment is required for patients with mild or moderate renal impairment based on a population pharmacokinetics (PK) analysis. There are no clinical data with encorafenib in patients with severe renal impairment. Therefore, the potential need for dose adjustment cannot be determined. Encorafenib should be used with caution in patients with severe renal impairment (see sections 4.4 and 5.2).
The safety and efficacy of encorafenib have not yet been established in children and adolescents. No data are available.
Braftovi is for oral use. The capsules are to be swallowed whole with water. They may be taken with or without food. The concomitant administration of encorafenib with grapefruit juice should be avoided (see sections 4.4 and 4.5)
At doses of encorafenib between 600 to 800 mg once daily, renal dysfunction (Grade 3 hypercreatinaemia) was observed in 3 out of 14 patients. The highest administered dose occurred as a dosing error in one patient who took encorafenib at a dose of 600 mg twice daily for 1 day (total dose 1200 mg). Adverse reactions reported by this patient were Grade 1 events of nausea, vomiting and blurred vision; all subsequently resolved.
There is no specific treatment for overdose. Since encorafenib is moderately bound to plasma proteins, haemodialysis is likely to be ineffective in the treatment of overdose with encorafenib. There is no known antidote for encorafenib. In the event of an overdose, encorafenib treatment should be interrupted and renal function must be monitored as well as adverse reactions. Symptomatic treatment and supportive care should be provided as needed.
3 years.
Store below 30°C.
Store in the original package in order to protect from moisture.
Braftovi 50 mg hard capsules:
Each pack contains either 28x1 or 112x1 hard capsules in polyamide/aluminium/PVC/aluminium/PET/paper perforated unit dose blisters.
Not all pack sizes may be marketed.
Braftovi 75 mg hard capsules:
Each pack contains either 42x1 or 168x1 hard capsules in polyamide/aluminium/PVC/aluminium/PET/paper perforated unit dose blisters.
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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