Braftovi

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions.  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Braftovi 50 mg hard capsules 
Braftovi 75 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Braftovi 50 mg hard capsules 
Each hard capsule contains 50 mg of encorafenib. 
 
Braftovi 75 mg hard capsules 
Each hard capsule contains 75 mg of encorafenib. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule (capsule). 
 
Braftovi 50 mg hard capsules 
Orange opaque cap and flesh opaque body, printed with a stylised “A” on the cap and “LGX 50mg” 
on the body. The length of the capsule is approximately 22 mm.  
 
Braftovi 75 mg hard capsules 
Flesh coloured opaque cap and white opaque body, printed with a stylised “A” on the cap and 
“LGX 75mg” on the body. The length of the capsule is approximately 23 mm. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Encorafenib is indicated: 
 
- in combination with binimetinib for the treatment of adult patients with unresectable or metastatic 
melanoma with a BRAF V600 mutation (see sections 4.4 and 5.1). 
 
- in combination with cetuximab, for the treatment of adult patients with metastatic colorectal cancer 
(CRC) with a BRAF V600E mutation, who have received prior systemic therapy (see sections 4.4 and 
5.1). 
 
4.2 Posology and method of administration 
 
Encorafenib treatment should be initiated and supervised under the responsibility of a physician 
experienced in the use of anticancer medicinal products. 
 



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Posology 
 
Melanoma 
The recommended dose of encorafenib is 450 mg (six 75 mg capsules) once daily, when used in 
combination with binimetinib. 
 
Colorectal cancer  
The recommended dose of encorafenib is 300 mg (four 75 mg capsules) once daily, when used in 
combination with cetuximab.  
 
Dose modification 
 
Melanoma 
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 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 indication 

Dose level Encorafenib dose  when used in combination with binimetinib 
Starting dose 450 mg once daily 
1st dose reduction 300 mg once daily 
2nd dose reduction  200 mg once daily 

Subsequent 
modification 

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 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 at 300 mg once daily during the 
time of binimetinib dose interruption (see section 4.2 of binimetinib Summary of Product 
Characteristics [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. 
 
Colorectal cancer 
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. 
 



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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 300 mg once daily 
1st dose reduction 225 mg once daily 
2nd dose reduction  150 mg once daily 

 
If encorafenib is permanently discontinued, cetuximab should be discontinued. 
If cetuximab is permanently discontinued, encorafenib should be discontinued.  
 
Melanoma and colorectal cancer 
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 reactions 
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.  



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Severity of adverse reactiona Encorafenib 

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 
 



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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. 

 
Duration of treatment 
Treatment should continue until the patient no longer derives benefit or the development of 
unacceptable toxicity. 
 
Missed doses 
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.  
 
Vomiting 
In case of vomiting after administration of encorafenib, the patient should not take an additional dose 
and should take the next scheduled dose. 
 
Special populations 
Elderly patients 
No dose adjustment is required for patients aged 65 years and older (see section 5.2). 
 
Hepatic impairment 
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. 
 
Renal 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).  
 
Paediatric population 
The safety and efficacy of encorafenib have not yet been established in children and adolescents. No 
data are available. 
 



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Method of administration  
 
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)  
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  
 
4.4 Special warnings and precautions for use 
 
Encorafenib is to be given in combination with binimetinib (for patients with BRAF V600 mutant 
unresectable or metastatic melanoma), or in combination with cetuximab (for patients with BRAF 
V600E mutant metastatic colorectal cancer). For additional information on warnings and 
precautions associated with binimetinib or cetuximab treatment, see section 4.4 of binimetinib 
SmPC or cetuximab SmPC. 
 
BRAF mutation testing 
 
Before taking encorafenib, patients must have unresectable or metastatic melanoma with BRAF V600 
mutation or metastatic colorectal cancer with BRAF V600E mutation confirmed by a validated test. 
The efficacy and safety of encorafenib have been established only in patients with melanoma tumours 
expressing BRAF V600E and V600K mutations or colorectal tumours expressing BRAF V600E 
mutation. Encorafenib should not be used in patients with wild type BRAF malignant melanoma or 
wild type BRAF colorectal cancer. 
 
Encorafenib in combination with binimetinib in patients who have progressed on a BRAF inhibitor 
 
There are limited data for the use of the combination of encorafenib with binimetinib in patients who 
have progressed on a prior BRAF inhibitor given for the treatment of unresectable or metastatic 
melanoma with BRAF V600 mutation. These data show that the efficacy of the combination would be 
lower in these patients.  
  
Encorafenib in combination with binimetinib in patients with brain metastases 
 
There are limited efficacy data with the combination of encorafenib and binimetinib in patients with a 
BRAF V600 mutant melanoma which have metastasised to the brain (see section 5.1). 
 
Left ventricular dysfunction (LVD) 
 
LVD defined as symptomatic or asymptomatic decreases in ejection fraction has been reported when 
encorafenib is used in combination with binimetinib. It is recommended that left ventricular ejection 
fraction (LVEF) is assessed by echocardiogram or multi-gated acquisition (MUGA) scan before 
initiation of encorafenib and binimetinib, one month after initiation, and then at approximately 3-
month intervals or more frequently as clinically indicated, while on treatment. If during treatment 
LVD occurs, see section 4.2 of binimetinib SmPC.  
The safety of encorafenib in combination with binimetinib has not been established in patients with a 
baseline LVEF that is either below 50% or below the institutional lower limits of normal. Therefore, in 
these patients, binimetinib should be used with caution and for any symptomatic left ventricular 
dysfunction, Grade 3-4 LVEF decrease or for absolute decrease of LVEF from baseline of ≥ 10%, 
binimetinib and encorafenib should be discontinued and LVEF should be evaluated every 2 weeks 
until recovery.  
 

 



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Haemorrhage 
 
Haemorrhages, including major haemorrhagic events, can occur with encorafenib (see section 4.8). 
The risk of haemorrhage may be increased with concomitant use of anticoagulant and antiplatelet 
therapy. The occurrence of Grade ≥3 haemorrhagic events should be managed with dose interruption 
or treatment discontinuation (see Table 4 in section 4.2) and as clinically indicated. 
 
Ocular toxicities 
 
Ocular toxicities including uveitis, iritis, and iridocyclitis can occur when encorafenib is administered. 
RPED has also been reported in patients treated with encorafenib in combination with binimetinib (see 
section 4.8). 
Patients should be assessed at each visit for symptoms of new or worsening visual disturbance. If 
symptoms of new or worsening visual disturbances including diminished central vision, blurred vision 
or loss of vision are identified, a prompt ophthalmologic examination is recommended.  
If uveitis including iridocyclitis and iritis occurs during treatment, see section 4.2.  
If during treatment patient develops RPED or RVO, see section 4.2 of binimetinib SmPC for guidance. 
 
QT prolongation 
 
QT Prolongation has been observed in patients treated with BRAF-inhibitors. A thorough QT study to 
evaluate the QT prolongation potential of encorafenib has not been conducted.  
Overall, results suggest that single agent encorafenib has the potential to cause mild increases in heart 
rate. Across pooled combination studies of encorafenib and binimetinib at the recommended doses and 
a single-agent encorafenib study, results suggest that encorafenib has the potential to result in small 
increases in QTc interval (see section 5.1). 
There are insufficient data to exclude a clinically significant exposure dependent QT prolongation. 
Due to the potential risk for QT prolongation, it is recommended that serum electrolytes abnormalities, 
including magnesium and potassium, are corrected and risk factors for QT prolongation controlled 
(e.g. congestive heart failure, bradyarrhythmias) before treatment initiation and during treatment. 
It is recommended that an electrocardiogram (ECG) is assessed before initiation of encorafenib, one 
month after initiation, and then at approximately 3-month intervals or more frequently as clinically 
indicated, while on treatment. The occurrence of QTc prolongation can be managed with dose 
reduction, interruption or discontinuation with correction of abnormal electrolytes and control of risk 
factors (see section 4.2). 
 
New primary malignancies 
 
New primary malignancies, cutaneous and non-cutaneous, have been observed in patients treated with 
BRAF inhibitors and can occur when encorafenib is administered (see section 4.8). 
 
Cutaneous malignancies 
Cutaneous malignancies such as cutaneous squamous cell carcinoma (cuSCC) including 
kerathoacanthoma have been observed in patients treated with BRAF-inhibitors including encorafenib. 
New primary melanoma has been observed in patients treated with BRAF inhibitors including 
encorafenib (see section 4.8). 
Dermatologic evaluations should be performed prior to initiation of therapy with encorafenib, every 
2 months while on therapy and for up to 6 months following treatment discontinuation. Suspicious 
skin lesions should be managed with dermatological excision and dermatopathologic evaluation. 
Patients should be instructed to immediately inform their physicians if new skin lesions develop. 
Encorafenib should be continued without any dose modification.  
 
Non-cutaneous malignancies 
Based on its mechanism of action, encorafenib may promote malignancies associated with activation 
of RAS through mutation or other mechanisms. Patients receiving encorafenib should undergo a head 
and neck examination, chest/abdomen computerised tomography (CT) scan, anal and pelvic 
examinations (for women) and complete blood cell counts prior to initiation, during and at the end of 



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treatment as clinically appropriate. It should be considered to permanently discontinue encorafenib in 
patients who develop RAS mutation-positive non-cutaneous malignancies. Benefits and risks should 
be carefully considered before administering encorafenib to patients with a prior or concurrent cancer 
associated with RAS mutation. 
 
Liver laboratory abnormalities 
 
Liver laboratory abnormalities including AST and ALT elevations have been observed with 
encorafenib (see section 4.8). Liver laboratory values should be monitored before initiation of 
encorafenib and monitored at least monthly during the 6 first months of treatment, then as clinically 
indicated. Liver laboratory abnormalities should be managed with dose interruption, reduction or 
treatment discontinuation (see section 4.2). 
 
Hepatic impairment 
 
As encorafenib is primarily metabolised and eliminated via the liver, patients with mild to severe 
hepatic impairment may have increased encorafenib exposure over the range of inter-subject 
variability exposure (see section 5.2).  
In the absence of clinical data, encorafenib is not recommended in patients with moderate or severe 
hepatic impairment.  
Administration of encorafenib should be undertaken with caution at a dose of 300 mg once daily in 
patients with mild hepatic impairment (see section 4.2).  
Closer monitoring of encorafenib related toxicities in patients with mild hepatic impairment is 
recommended, including clinical examination and liver function tests, with assessment of ECGs as 
clinically appropriate during treatment. 
 
Renal impairment 
 
There are no data available in patients with severe renal impairment (see sections 4.2 and 5.2). 
Encorafenib should be used with caution in patients with severe renal impairment. Creatinine 
elevation has been commonly reported with encorafenib as single agent or in combination with 
binimetinib or cetuximab. Observed cases of renal failure including acute kidney injury and renal 
impairment were generally associated with vomiting and dehydration. Other contributing factors 
included diabetes and hypertension. Blood creatinine should be monitored as clinically indicated and 
creatinine elevation managed with dose modification or discontinuation (see Table 4 in section 4.2). 
Patients should ensure adequate fluid intake during treatment. 
 
Effects of other medicinal products on encorafenib. 
 
Concurrent use of strong CYP3A inhibitors during treatment with encorafenib should be avoided. If 
concomitant use with a strong CYP3A inhibitor is necessary, patients should be carefully monitored 
for safety (see section 4.5). 
Caution should be exercised if a moderate CYP3A inhibitor is co-administered with encorafenib. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Effects of other medicinal products on encorafenib 
 
Encorafenib is primarily metabolised by CYP3A4. 
 
CYP3A4 inhibitors  
Co-administration of moderate (diltiazem) and strong (posaconazole) CYP3A4 inhibitors with single 
doses of encorafenib in healthy volunteers resulted in a 2 and 3-fold increase in the area under the 
concentration-time curve (AUC), respectively and in 44.6% and 68.3% increase in maximum 
encorafenib concentration (Cmax) respectively.  
Model based predictions indicate that the effect of posaconazole after repeated administrations could 
be similar for AUC (3-fold increase) and slightly greater for Cmax (2.7-fold increase). Model-based 



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predictions for ketoconazole suggest an increase of approx. 5-fold for encorafenib AUC and 3 to 4-
fold for encorafenib Cmax after administration of encorafenib 450 and 300 mg QD, respectively. 
Therefore, concomitant administration of encorafenib with strong CYP3A4 inhibitors should be 
avoided (due to increased encorafenib exposure and potential increase in toxicity, see section 5.2). 
Examples of strong CYP3A4 inhibitors include, but are not limited to, ritonavir, itraconazole, 
clarithromycin, telithromycin, posaconazole and grapefruit juice. If concomitant use of a strong 
CYP3A inhibitor is unavoidable, patients should be carefully monitored for safety. 
Moderate CYP3A4 inhibitors should be co-administered with caution. Examples of moderate 
CYP3A4 inhibitors include, but are not limited to, amiodarone, erythromycin, fluconazole, diltiazem, 
amprenavir and imatinib. When encorafenib is co-administered with a moderate CYP3A inhibitor, 
patients should be carefully monitored for safety. 
 
CYP3A4 inducers 
Co-administration of encorafenib with a CYP3A4 inducer was not assessed in a clinical study; 
however, a reduction in encorafenib exposure is likely and may result in compromised efficacy. 
Examples of moderate or strong CYP3A4 inducers include, but are not limited to carbamazepine, 
rifampicin, phenytoin and St. John’s Wort. Alternative agents with no or minimal CYP3A induction 
potential should be considered.  
 
Effects of encorafenib on other medicinal products 
 
CYP substrates 
Encorafenib is both an inhibitor and inducer of CYP3A4. Concomitant use with agents that are 
substrates of CYP3A4 (e.g., hormonal contraceptives) may result in increased toxicity or loss of 
efficacy of these agents. Agents that are CYP3A4 substrates should be co-administered with caution.  
Encorafenib is an inhibitor of UGT1A1. Concomitant agents that are substrates of UGT1A1 (e.g. 
raltegravir, atorvastatin, dolutegravir) may have increased exposure and should be therefore 
administered with caution.  
 
Effect of encorafenib on binimetinib 
While encorafenib is a relatively potent reversible inhibitor of UGT1A1, no differences in binimetinib 
exposure have been observed clinically when binimetinib was co-administered with encorafenib. 
 
Transporter substrates 
Encorafenib potentially inhibits a number of transporters. Agents that are substrates of renal 
transporters OAT1, OAT3, OCT2 (such as furosemide, penicillin) or agents that are substrates of the 
hepatic transporters OATP1B1, OATP1B3, OCT1 (such as atorvastatin, bosentan) or substrates of 
BCRP (such as methotrexate, rosuvastatin) or substrates of P-gp (e.g. posaconazole) may have 
increased exposure and should be therefore co-administered with caution. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential / Contraception in females  
 
Women of childbearing potential must use effective contraception during treatment with encorafenib 
and for at least 1 month following the last dose. Encorafenib may decrease the efficacy of hormonal 
contraceptives (see section 4.5). Therefore, female patients using hormonal contraception are advised 
to use an additional or alternative method such as a barrier method (e.g. condom) during treatment 
with encorafenib and for at least 1 month following the last dose. 
 
Pregnancy 
 
There are no data from the use of encorafenib in pregnant women. Studies in animals have shown 
reproductive toxicity (see section 5.3).  
Encorafenib is not recommended during pregnancy and in women of childbearing potential not using 
contraception. If encorafenib is used during pregnancy or if the patient becomes pregnant while taking 
encorafenib, the patient should be informed of the potential hazard to the foetus.  



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Breast-feeding 
 
It is unknown whether encorafenib or its metabolites are excreted in human milk. A risk to the 
newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding 
or to discontinue encorafenib therapy taking into account the benefit of breast-feeding for the child 
and the benefit of therapy for the mother.  
 
Fertility 
 
There are no data on the effects of encorafenib on fertility in humans. Based on findings in animals, 
the use of encorafenib may impact fertility in males of reproductive potential (see section 5.3). As the 
clinical relevance of this is unknown, male patients should be informed of the potential risk for 
impaired spermatogenesis. 
 
4.7 Effects on ability to drive and use machines 
 
Encorafenib has minor influence on the ability to drive or use machines. Visual disturbances have 
been reported in some patients treated with encorafenib during clinical studies. Patients should be 
advised not to drive or use machines if they experience visual disturbances or any other adverse 
reactions that may affect their ability to drive and use machines (see sections 4.4 and 4.8).  
 
4.8 Undesirable effects 
 
Summary of safety profile  
 
The safety of encorafenib (450 mg orally once daily) in combination with binimetinib (45 mg orally 
twice daily) was evaluated in 274 patients with BRAF V600 mutant unresectable or metastatic 
melanoma (hereafter referred to as the pooled Combo 450 population), based on two Phase II studies 
(CMEK162X2110 and CLGX818X2109) and one Phase III study (CMEK162B2301, Part 1).  
At the recommended dose (n = 274) in patients with unresectable or metastatic melanoma, the most 
common adverse reactions (>25%) occurring in patients treated with encorafenib administered with 
binimetinib were fatigue, nausea, diarrhoea, vomiting, retinal detachment, abdominal pain, arthralgia, 
blood CK increased and myalgia.  
 
The safety of encorafenib (300 mg orally once daily) in combination with binimetinib (45 mg orally 
twice daily) was evaluated in 257 patients with BRAF V600 mutant unresectable or metastatic 
melanoma (hereafter referred to as the Combo 300 population), based on the Phase III study 
(CMEK162B2301, Part 2). The most common adverse reactions (>25%) occurring in patients treated 
with encorafenib 300 mg administered with binimetinib were fatigue, nausea and diarrhoea. 
 
The encorafenib single agent (300 mg orally once daily) safety profile is based on data from 
217 patients with unresectable or metastatic BRAF V600-mutant melanoma (hereafter referred to as 
the pooled encorafenib 300 population). The most common adverse drug reactions (ADRs) (>25%) 
reported with encorafenib 300 were hyperkeratosis, alopecia, PPES, fatigue, rash, arthralgia, dry skin, 
nausea, myalgia, headache, vomiting and pruritus. 
 
The safety of encorafenib (300 mg orally once daily) in combination with cetuximab (dosed as per its 
SmPC) was evaluated in 216 patients with BRAF V600E-mutant metastatic colorectal cancer, based 
on the phase III study ARRAY-818-302. The most common ADRs (>25%) reported in this population 
were: fatigue, nausea, diarrhoea, dermatitis acneiform, abdominal pain, arthralgia/musculoskeletal 
pain, decreased appetite, rash and vomiting. 
The rate of all study drug discontinuation due to any adverse reaction was 1.9 % in patients treated 
with encorafenib 300 mg in combination with cetuximab. 
 



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Tabulated list of adverse reactions  
 
Adverse reactions are listed below by MedDRA body system organ class and the following frequency 
convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), 
rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the 
available data). 
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 
 
Table 5: Adverse reactions 

Frequency  Encorafenib single 
agent 300 mg 
(n = 217) 

Encorafenib 450 mg 
in combination with 
binimetinib (n = 274) 

Encorafenib 300 mg in 
combination with cetuximab (n 
= 216) 

Neoplasms benign, malignant and unspecified 

Very common  Skin papilloma
* 

Melanocytic nevus 
 Melanocytic naevus          

Common 
cuSCC a 
New Primary 
Melanoma* 

cuSCCa  
Basal cell carcinoma* 
Skin papilloma*  

cuSCCa 
  Skin papilloma* 
  New Primary Melanoma* 

Uncommon Basal cell carcinoma  Basal cell carcinoma
 

 
Blood and lymphatic system disorders 
Very common  Anaemia  
Immune system disorders  
Common Hypersensitivityb  Hypersensitivityb Hypersensitivityb 
Metabolism and nutrition disorders 
Very common Decreased appetite  Decreased appetite 
Psychiatric disorders 
Very common Insomnia   Insomnia 
Nervous system disorders 

Very common 

Headache*  
Neuropathy peripheral* 
Dysgeusia* 

Neuropathy peripheral* 
Dizziness* 
Headache*  
 

Neuropathy peripheral* 
Headache* 

Common Facial paresisc Dysgeusia* Dizziness* 
Dysgeusia 

Uncommon  Facial paresisc  
Eye disorders 

Very common   Visual impairment
* 

RPED * 
 

Common  Uveitis *  
Uncommon Uveitis*    

Cardiac disorders 
Common Supraventricular 

tachycardiad 
LVDh Supraventricular tachycardiad 

Vascular disorders  

Very common   Haemorrhage
i 

Hypertension * 
Haemorrhagei 

Common  VTEj  



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Gastrointestinal disorders 

Very common 

Nausea  
Vomiting*  
Constipation 

Nausea  
Vomiting*  
Constipation 
Abdominal pain* 
Diarrhoea* 

Nausea 
Vomiting 
Constipation  
Abdominal pain* 
Diarrhoea* 
 

Common  Colitis k  
Uncommon Pancreatitis* Pancreatitis*   Pancreatitis* 

Skin and subcutaneous tissue disorders 

Very common 

PPES 
Hyperkeratosis*  
Rash*  
Dry skin*  
Pruritus*  
Alopecia*  
Erythema e 
Skin 
hyperpigmentation*  

Hyperkeratosis*  
Rash* 
Dry skin* 
Pruritus*  
Alopecia*  

Dermatitis acneiform* 
Rash* 
Dry skin* 
Pruritus* 
 

Common Dermatitis acneiform*  
Skin exfoliationf 
Photosensitivity* 

Dermatitis acneiform* 
PPES 
Erythema* 
Panniculitis* 
Photosensitivity* 

Skin hyperpigmentation 
PPES 
Hyperkeratosis* 
Alopecia  
Erythemae 
 

Uncommon   Skin exfoliationf 

Musculoskeletal and connective tissue disorders 

Very common 

Arthralgia*  
Myalgiag 
Pain in extremity 
Back pain 

Arthralgia*  
Muscular 
disorders/Myalgial 
Pain in extremity 
Back pain 

Arthralgia/Musculoskeletal pain* 
Myopathy/Muscular disorder* 
Pain in extremity 
Back pain 

Common Arthritis *   
Uncommon  Rhabdomyolysis  

Renal and urinary disorders 
Common Renal failure * Renal failure* Renal failure* 

General disorders and administration site conditions 
Very common Fatigue * 

Pyrexia* 
Fatigue*  
Pyrexia* 
Peripheral oedemam 

Fatigue* 
Pyrexia* 
 



14 

Investigations  

Very common 

Gamma-glutamyl 
transferase (GGT) 
increased* 

Blood creatine 
phosphokinase 
increased 
Gamma-glutamyl 
transferase (GGT) 
increased* 
Transaminase 
increased* 

 

Common Transaminase 
increased*  
Blood creatinine 
increased* 
Lipase increased 

Blood alkaline 
phosphatase increased 
Blood creatinine 
increased* 
Amylase increased 
Lipase increased 

Blood creatinine increased* 
Transaminase increased* 

Uncommon Amylase increased  Amylase increased 
Lipase increased 

*composite terms which included more than one preferred term 
a includes, but not limited to, keratoacanthoma and squamous cell carcinoma 
b includes, but not limited to, angioedema, drug hypersensitivity, hypersensitivity, hypersensitivity 
vasculitis, urticaria and anaphylactic reaction 
c includes facial nerve disorder, facial paralysis, facial paresis 
d includes but not limited to extrasystoles and sinus tachycardia  
e includes erythema, generalised erythema, plantar erythema 
f includes dermatitis exfoliative, skin exfoliation, exfoliative rash 
g includes myalgia, muscle fatigue, muscle injury, muscle spasm, muscle weakness 
h includes left ventricular dysfunction, ejection fraction decreased, cardiac failure and ejection fraction 
abnormal 
i includes haemorrhage at various sites including cerebral haemorrhage  
j includes, but not limited to, pulmonary embolism, deep vein thrombosis, embolism, 
thrombophlebitis, thrombophlebitis superficial and thrombosis 
k includes colitis, colitis ulcerative, enterocolitis and proctitis  
l includes myalgia, muscular weakness, muscle spasm, muscle injury, myopathy, myositis  
m includes, but not limited to, fluid retention, peripheral oedema and localised oedema  
 
When encorafenib was used at a dose of 300 mg once daily in combination with binimetinib 45 mg 
twice daily (Combo 300) in study CMEK162B2301-Part 2, the frequency category was lower 
compared to the pooled Combo 450 population for the following adverse reactions: anemia, peripheral 
neuropathy, haemorrhage, hypertension, pruritus (common); and colitis, increased amylase and 
increased lipase (uncommon). 
 
Description of selected adverse reactions 
 
Cutaneous malignancies 
Cutaneous squamous cell carcinoma  
Melanoma 
In the pooled Combo 450 population, cuSCC including keratoacanthomas was observed in 3.3% 
(9/274) of patients. The median time to onset of the first event of cuSCC (all grades) was 6.5 months 
(range 1.0 to 22.8 months).  
 
In the pooled encorafenib 300 population, cuSCC was reported in 7.4% (16/217) patients. For patients 
in the Phase III study (CMEK162B2301) who developed cuSCC, the median time to onset of the first 
event of cuSCC (all grades) was 2.3 months (range 0.3 to 12.0 months).  
 



15 

Colorectal cancer 
In patients treated with encorafenib 300 mg in combination with cetuximab, cuSCC including 
keratoacanthoma was observed in 1.4% (3/216) of patients. The times to first event of cuSCC (all 
grades) were 0.5, 0.6 and 3.6 months for these 3 patients. 
 
New primary melanoma 
Melanoma 
In the pooled encorafenib 300 population, new primary melanoma events occurred in 4.1% of patients 
(9 /217) and was reported as Grade 1 in 1.4% (3/217) of patients, Grade 2 in 2.1% (4/217) of patients, 
Grade 3 in 0.5% (1/217) of patients and Grade 4 in 0.5% (1/217) of patients.  
 
Colorectal cancer 
In patients treated with encorafenib 300 mg in combination with cetuximab, new primary melanoma 
events occurred in 1.9% of patients (4/216) and were reported as Grade 2 in 0.9% (2/216) of patients 
and Grade 3 in 0.9% (2/216) of patients.  
 
Ocular events 
Melanoma 
In the pooled Combo 450 population, uveitis was reported in 4.4% (12/274) of patients, and was 
Grade 1 in 0.4% (1/274), Grade 2 in 3.6% (10/274) and Grade 3 in 0.4% (1/274). Visual impairment, 
including blurred vision and reduced visual acuity, occurred in 21.5% (59/274) of patients. Uveitis and 
visual impairment were generally reversible.  
RPED occurred in 29.6% (81/274) of patients, most of them had Grade 1-2 and 1.8% (5/274) had 
Grade 3 events.  
 
In Study CMEK162B2301-Part 2, in the Combo 300 arm, RPED was observed in 12.5% (32/257) of 
patients with 0.4% (1/257) Grade 4 event. 
 
Left ventricular dysfunction 
LVD was reported when encorafenib is used in combination with binimetinib in melanoma patients 
(see section 4.8 of binimetinib SmPC). 
 
Haemorrhage 
Melanoma 
Haemorrhagic events were observed in 17.9% (49/274) of patients in the pooled Combo 
450 population. Most events were Grade 1 or 2 (14.6%) and 3.3% were Grade 3-4 events. Few 
patients required dose interruptions or dose reductions (0.7% or 2/274). Haemorrhagic events led to 
discontinuation of treatment in 1.1% (3/274) of patients. The most frequent haemorrhagic events were 
haematuria in 3.3% (9/274) of patients, rectal haemorrhage in 2.9% (8/274) and haematochezia in 
2.9% (8/274) of patients. Fatal gastric ulcer haemorrhage, with multiple organ failure as a concurrent 
cause of death, occurred in one patient.  
Cerebral haemorrhage was reported in 1.5% (4/274) of patients, with fatal outcome in 3 patients. All 
events occurred in the setting of new or progressive brain metastases. 
 
In Study CMEK162B2301-Part 2, in the Combo 300 arm, haemorrhagic events were observed in 6.6% 
(17/257) of patients and were Grade 3-4 in 1.6% (4/257) of patients.  
 
Colorectal cancer  
Haemorrhagic events were observed in 21.3% (46/216) of patients treated with encorafenib  
300 mg in combination with cetuximab; 1.4% (3/216) of patients were Grade 3 events and one fatal 
case was reported. Dose interruptions or dose reductions were required in 1.9% (4/216) of patients. 
Haemorrhagic events led to treatment discontinuation in 1 patient (0.5%).  
The most frequent haemorrhagic events were epistaxis in 6.9% (15/216) of patients, haematochezia in 
2.8% (6/216), rectal haemorrhage in 2.8% (6/216) of patients and haematuria in 2.8% (6/216) of 
patients. 
 



16 

Hypertension  
Hypertension was reported when encorafenib was used in combination with binimetinib in melanoma 
patients (see section 4.8 of binimetinib SmPC). 
 
Venous thromboembolism 
VTE was reported when encorafenib is used in combination with binimetinib in melanoma patients 
(see section 4.8 of binimetinib SmPC).  
 
Pancreatitis 
Melanoma 
In the pooled Combo 450 population, pancreatic enzyme elevation, mostly asymptomatic, was 
reported. Amylase and lipase elevations were reported in 3.3% (9/274) and 5.1% (14/274) of patients, 
respectively. Pancreatitis was reported in 0.7% (2/274) of patients. Both patients experienced Grade 3 
events. Pancreatitis led to dose interruption in (0.4 %) 1/274 of patients.  
 
Colorectal cancer 
In the population treated with encorafenib 300 mg in combination with cetuximab, pancreatitis grade 3 
with lipase and amylase increased events were reported in 1 patient (0.5%) and led to dose 
interruption. 
 
Dermatologic reactions 
Rash 
Melanoma 
In the pooled Combo 450 population, rash occurred in 19.7% (54/274) of patients. Most events were 
mild, with Grade 3 or 4 events reported in 0.7% (2/274) of patients. Rash led to discontinuation in 
0.4% (1/274) patients and to dose interruption or dose modification in 1.1% (3/274) of patients. 
 
In the pooled encorafenib 300 population, rash was reported in 43.3% (94/217) of patients. Most 
events were mild, with Grade 3 or 4 events reported in 4.6% (10/217) of patients. Rash led to 
discontinuation in 0.5% (1/217) of patients and to dose interruption or dose modification in 7.4% 
(16/217) of patients. 
 
Colorectal cancer 
In patients treated with encorafenib 300 mg in combination with cetuximab, rash occurred in 30.6% 
(66/216) of patients. Most events were mild, with Grade 3 event reported in 0.5% (1/216) of patients. 
Rash led to dose interruption in 0.5% (1/216) of patients.  
 
Palmar-plantar erythrodysaesthesia syndrome (PPES)  
Melanoma 
PPES was reported in 6.2% (17/274) of patients in the pooled Combo 450 population. All the PPES 
adverse reactions were either Grade 1 (3.3%) or Grade 2 (2.9%). Dose interruption or dose 
modification occurred in 1.1% (3/274) of patients.  
 
In the Combo 300 arm in Part 2 of the pivotal study, PPES was observed in 3.9% (10/257) of patients 
with Grade 3 reported in 0.4% (1/257) of patients. 
  
In the pooled encorafenib 300 population, PPES was reported in 51.6% (112/217) of patients. Most 
events were mild-moderate: Grade 1 in 12.4% (27/217) of patients, Grade 2 in 26.7% (58/217) and 
Grade 3 in 12.4% (27/217) of patients. PPES led to discontinuation in 4.1% (9/217) of patients and to 
dose interruption or dose modification in 23.0% (50/217) of patients. 
 
Colorectal cancer 
In the population treated with encorafenib 300 mg in combination with cetuximab, PPES was reported 
in 5.1% (11/216) of patients. Most of PPES adverse reactions were either Grade 1 in 3.7 % (8/216). 
Grade 2 events were reported in 0.9% (2/216) of patients, and Grade 3 in 0.5% (1/216) of patients. No 
dose interruption, dose modification or treatment discontinuation was required.  
 



17 

Dermatitis acneiform 
Melanoma 
Dermatitis acneiform was reported when encorafenib is used in combination with binimetinib (see 
section 4.8 of binimetinib SmPC). 
 
Colorectal cancer 
In patients treated with encorafenib 300 mg in combination with cetuximab, dermatitis acneiform 
occurred in 33.3% (72/216) of patients and was mostly Grade 1 (25.5% (55 /216) of patients), or 2 
(6.9% (15 /216) of patients). Dose reduction or interruption was reported in 2.3 % (5/216) of patients. 
No treatment discontinuation was reported. Dermatitis acneiform was generally reversible. 
 
Photosensitivity 
Melanoma 
In the pooled Combo 450 population, photosensitivity was observed in 4.0% (11/274) of patients. 
Most events were Grade 1-2, with Grade 3 reported in 0.4% (1/274) of patients and no event led to 
discontinuation. Dose interruption or dose modification was reported in 0.4% (1/274) of patients.  
 
In the pooled encorafenib 300 population, photosensitivity was reported in 4.1% (9/217) of patients. 
All events were Grade 1-2. No event required discontinuation, dose modification or interruption. 
 
Facial paresis 
Melanoma 
In the pooled Combo 450 population, facial paresis occurred in 0.7% (2/274) of patients including 
Grade 3 in 0.4% (1/274) of patients. The events were reversible, and no event led to treatment 
discontinuation. Dose interruption or modification was reported in 0.4% (1/274) of patients. 
 
In the pooled encorafenib 300 population, facial paresis was observed in 7.4% (16/217) of patients. 
Most events were mild-moderate: Grade 1 in 2.3% (5/217); Grade 2 in 3.7% (8/217) and Grade 3 in 
1.4% (3/217) of patients. The median time to onset of the first event of facial paresis was 0.3 months 
(range 0.1 to 12.1 months). Facial paresis was generally reversible and led to treatment discontinuation 
in 0.9% (2/217). Dose interruption or modification was reported in 3.7% (8/217) and symptomatic 
treatment including corticosteroids was reported in 5.1% (11/217) of patients. 
 
CK elevation and rhabdomyolysis 
CK elevation and rhabdomyolysis occurred when encorafenib is used in combination with binimetinib 
in melanoma patients (see section 4.8 of binimetinib SmPC). 
 
Renal dysfunction 
Melanoma 
In the pooled Combo 450 population, mild, mostly Grade 1, asymptomatic blood creatinine elevation 
was noted in 6.2% (17/274) of patients treated with the Combo 450 mg. The incidence of Grade 3 or 4 
elevation was 0.7% (2/274). Renal failure events, including acute kidney injury and renal impairment, 
were reported in 3.3% (9/274) patients treated with encorafenib and binimetinib with Grade 3 or 4 
events in 2.2% (6/274) of patients. Renal failure was generally reversible with dose interruption, 
rehydration and other general supportive measures.  
 
Colorectal cancer 
Blood creatinine elevation was reported in 2.8% (6/216) of patients treated with encorafenib 300 mg in 
combination with cetuximab. All were mild except one event of Grade 4. Renal failure events were 
Grade 3 or 4 and reported as acute kidney injury in 1.9 % (4/216) of patients and renal failure in 0.5% 
(1/216) of patients. 
 
 



18 

Liver laboratory abnormality  
Melanoma 
The incidences of liver laboratory abnormalities reported in the pooled Combo 450 population are 
listed below:  

• Increased transaminases: 15.7% (43/274) overall – Grade 3-4: 5.5% (15/274) 
• Increased GGT: 14.6% (40/274) overall – Grade 3-4: 8.4% (23/274) 

 
In Study CMEK162B2301-Part 2, in the Combo 300 arm, the incidence of liver laboratory 
abnormalities was:  

• Increased transaminases: 13.2% (34/257) overall – Grade 3-4: 5.4% (14/257) 
• Increased GGT: 14.0% (36/257) overall – Grade 3-4: 4.7% (12/257) 

 
Colorectal cancer 
The incidence of increased transaminases in patients treated with encorafenib 300 mg in combination 
with cetuximab was 8.8% (19/216) of patients, with Grade 3 in 1.4% (3/216) of patients. 
 
Gastrointestinal disorders   
Melanoma 
In the pooled Combo 450 population, diarrhoea was observed in 38% (104/274) of patients and was 
Grade 3-4 in 3.3% (9/274) patients. Diarrhoea led to treatment discontinuation in 0.4% of patients and 
to dose interruption or dose modification in 4.4% of patients.   
Constipation occurred in 24.1% (66/274) of patients and was Grade 1 or 2. Abdominal pain was 
reported in 27.4% (75/274) of patients and was Grade 3 in 2.6% (7/274) patients. Nausea occurred in 
41.6% (114/274) with Grade 3 or 4 observed in 2.6% (7/274) of patients. Vomiting occurred in 28.1% 
(77/274) of patients with Grade 3 or 4 reported in 2.2% (6/274) of patients. 
 
In Study CMEK162B2301-Part 2, in the Combo 300 arm, nausea was observed in 27.2% (70/257) of 
patients and was Grade 3 in 1.6% (4/257) of patients. Vomiting occurred in 15.2% (39/257) of patients 
with Grade 3 reported in 0.4% (1/257) of patients. Diarrhoea occurred in 28.4% (73/257) of patients 
with Grade 3 reported in 1.6% (4/257) of patients. 
 
Colorectal cancer 
In patients treated with encorafenib 300 mg in combination with cetuximab, diarrhoea was observed in 
38.4% (83/216) of patients and was Grade 3 in 2.8% (6/216) of patients. Diarrhoea led to treatment 
discontinuation in 0.5% (1/216) of patients and to dose interruption or dose modification in 3.7% 
(8/216) of patients.   
 
Abdominal pain was reported in 36.6% (79/216) of patients and was Grade 3 in 5.1% (11/216) of 
patients. Nausea occurred in 38.0% (82/216) of patients with Grade 3 observed in 0.5% (1/216) of 
patients. Vomiting occurred in 27.3% (59/216) of patients with Grade 3 reported in 1.4 % (3/216) of 
patients. Constipation occurred in 18.1% (39/216) of patients and was Grade 1 or 2. 
 
Gastrointestinal disorders were typically managed with standard therapy. 
 
Anaemia 
Melanoma 
In the pooled Combo 450 population, anaemia was reported in 19.7% (54/274) of patients; 4.7% 
(13/274) patients had a Grade 3 or 4. No patients discontinued treatment due to anaemia, 1.5% (4/274) 
required dose interruption or dose modification. 
 
In Study CMEK162B2301-Part 2, in the Combo 300 arm, anaemia was observed in 9.7% (25/257) of 
patients with Grade 3-4 reported in 2.7% (7/257) patients.  
 
Headache 
Melanoma 
In the pooled Combo 450 population, headache occurred in 21.5% (59/274) of patients, including 
Grade 3 in 1.5% (4/274) of patients.  



19 

 
In Study CMEK162B2301-Part 2, in the Combo 300 arm, headache was reported in 12.1% (31/257) of 
patients and was Grade 3 in 0.4% (1/257) of patients. 
 
Colorectal cancer 
In patients treated with encorafenib 300 mg in combination with cetuximab, headache occurred in 
20.4% (44/216) of patients and was Grade 1 or 2. 
 
Fatigue 
Melanoma 
In the pooled Combo 450 population, fatigue occurred in 43.8% (120/274) of patients including Grade 
3 in 2.9% (8/274) of patients.  
 
In Study CMEK162B2301-Part 2, in the Combo 300 arm, fatigue was observed in 33.5% (86/257) of 
patients with 1.6% (4/257) Grade 3-4 events. 
 
Colorectal cancer 
In patients treated with encorafenib 300 mg in combination with cetuximab, fatigue was reported in 
56.9% (123/216) of patients including Grade 3 in 7.9% (17/216) of patients. 
 
Special populations 
 
Elderly 
Melanoma 
In patients treated with Combo 450 (n = 274), 194 patients (70.8%) were <65 years old, 65 patients 
(23.7%) were 65 -74 years old and 15 patients (5.5%) were aged > 75. No overall differences in safety 
or efficacy were observed between elderly patients (≥ 65) and younger patients. The proportions of 
patients experiencing adverse events (AE) and serious adverse events (SAE) were similar in patients 
aged <65 years and those aged ≥65 years. The most common AEs reported with a higher incidence in 
patients aged ≥ 65 years compared to patients aged < 65 years included diarrhoea, pruritus, GGT and 
blood phosphatase alkaline elevation.  
 
Colorectal cancer 
In patients treated with encorafenib 300 mg in combination with cetuximab (n=216), 134 patients (62 
%) were < 65 years old, 62 patients (28.7%) were 65-74 years old and 20 patients (9.3%) were aged  
≥ 75. The most common AEs reported with a higher incidence in patients aged ≥ 65 years compared to 
patients aged < 65 years included, anaemia, asthenia, decreased appetite and dyspnoea.  
 
In both melanoma and colorectal cancer populations, due to a very small number of patients treated in 
the age subgroup of patients aged ≥ 75 years, differences in the incidence of AEs compared to patients 
aged < 75 years could not be assessed. 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Symptoms 
 
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 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


20 

1200 mg). Adverse reactions reported by this patient were Grade 1 events of nausea, vomiting and 
blurred vision; all subsequently resolved. 
 
Management 
 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: antineoplastic agent, protein kinase inhibitor, ATC code: L01XE46 
 
Mechanism of action 
 
Encorafenib is a potent and highly selective ATP-competitive small molecule RAF kinase inhibitor. 
The half maximal inhibitory concentration (IC50) of encorafenib against BRAF V600E, BRAF and 
CRAF enzymes was determined to be 0.35, 0.47 and 0.30 nM, respectively. The encorafenib 
dissociation half-life was >30 hours and resulted in prolonged pERK inhibition. Encorafenib 
suppresses the RAF/MEK/ERK pathway in tumour cells expressing several mutated forms of BRAF 
kinase (V600E, D and K). Specifically, encorafenib inhibits in vitro and in vivo BRAF V600E, D and 
K mutant melanoma cell growth and BRAF V600E mutant colorectal cancer cell growth. Encorafenib 
does not inhibit RAF/MEK/ERK signalling in cells expressing wild-type BRAF. 
 
Combination with binimetinib  
Encorafenib and binimetinib (a MEK inhibitor, see section 5.1 of binimetinib SmPC) both inhibit the 
MAPK pathway, resulting in higher anti-tumour activity. 
Additionally, the combination of encorafenib and binimetinib prevented the emergence of resistance in 
BRAF V600E mutant human melanoma xenografts in vivo.  
 
Combination with cetuximab 
One of the main mechanisms of resistance of BRAF-mutant CRC to RAF inhibitors has been 
identified as the re-activation of EGFR with bypassing signal transduction via BRAF. Combinations of 
a BRAF inhibitor, e.g.encorafenib and agents targeting EGFR, e.g. cetuximab have shown to improve 
anti-tumour efficacy in non-clinical models.   
 
Clinical efficacy and safety 
 
BRAF V600 Mutant Unresectable or Metastatic Melanoma 
The safety and efficacy of encorafenib in combination with binimetinib were evaluated in a 2-part 
Phase III, randomised (1:1:1) active-controlled, open-label, multicentre study in patients with 
unresectable or metastatic BRAF V600 E or K mutant melanoma (Study CMEK162B2301), as 
detected using a BRAF assay. Patients had histologically confirmed cutaneous or unknown primary 
melanoma but those with uveal or mucosal melanoma were excluded. Patients were permitted to 
receive prior adjuvant therapy and one prior line of immunotherapy for unresectable locally advanced 
or metastatic disease. Prior treatment with BRAF/ MEK inhibitors was not allowed.  
 
Study CMEK162B2301, Part 1 
In Part 1, patients in the study were randomised to receive encorafenib 450 mg orally daily and 
binimetinib 45 mg orally twice daily (Combo 450, n = 192), encorafenib 300 mg orally daily 
(Enco 300, n = 194), or vemurafenib 960 mg orally twice daily (hereafter referred to as Vem, n = 191). 
Treatment continued until disease progression or unacceptable toxicity. Randomisation was stratified 



21 

by American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, vs IVM1c) and 
Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1) and prior immunotherapy 
for unresectable or metastatic disease (yes vs no).  
 
The primary efficacy outcome measure was progression-free survival (PFS) of Combo 450 compared 
with vemurafenib as assessed by a blinded independent review committee (BIRC). PFS as assessed by 
investigators (investigator assessment) was a supportive analysis. An additional secondary endpoint 
included PFS of Combo 450 compared with Enco 300. Other secondary efficacy comparisons between 
Combo 450 and either vemurafenib or Enco 300 included overall survival (OS), objective response 
rate (ORR), duration of response (DoR) and disease control rate (DCR) as assessed by BIRC and by 
investigator assessment. 
 
The median age of patients was 56 years (range 20-89), 58% were male, 90% were Caucasian, and 
72% of patients had baseline ECOG performance status of 0. Most patients had metastatic disease 
(95%) and were Stage IVM1c (64%); 27% of patients had elevated baseline serum lactate 
dehydrogenase (LDH), and 45% of patients had at least 3 organs with tumour involvement at baseline 
and 3.5% had brain metastases. 27 patients (5%) had received prior checkpoint inhibitors (anti-
PD1/PDL1 or ipilimumab) (8 patients in Combo 450 arm (4%); 7 patients in vemurafenib arm (4%); 
12 patients in Enco 300 arm (6%) including 22 patients in the metastatic setting (6 patients in Combo 
450 arm; 5 patients in vemurafenib arm; 11 patients in Enco 300 arm) and 5 patients in the adjuvant 
setting (2 patients in Combo 450 arm; 2 patients in vemurafenib arm; 1 patient in Enco 300 arm). 
 
The median duration of exposure was 11.7 months in patients treated with Combo 450, 7.1 months in 
patients treated with Enco 300 and 6.2 months in patients treated with vemurafenib. The median 
relative dose intensity (RDI) for Combo 450 was 100% for encorafenib and 99.6% for binimetinib; the 
median RDI was 86.2% for Enco 300 and 94.5% for vemurafenib. 
 
Part 1 of Study CMEK162B2301 demonstrated a statistically significant improvement in PFS in the 
patients treated with Combo 450 compared with patients treated with vemurafenib. Table 6 and 
Figure 1 summarise the PFS and other efficacy results based on central review of the data by a blinded 
independent radiology committee.  
 
The efficacy results based on investigator assessment were consistent with the independent central 
assessment. Unstratified subgroup analyses demonstrated point estimates in favour of Combo 450, 
including LDH at baseline, ECOG performance status and AJCC stage.  
 
Table 6: Study CMEK162B2301, Part 1: Progression-free survival and confirmed overall 

response results (independent central review) 
 Encorafenib + 

binimetinib  
N=192 
(Combo 450) 

Encorafenib 
N=194 
(Enco300) 

Vemurafenib 
N=191 
(Vem) 

Cut-off date: 19 May 2016 

PFS (primary analysis) 

Number of events (progressive 
disease (PD)) (%) 98 (51.0) 96 (49.5) 106 (55.5) 

Median, months 
(95% CI) 

14.9 
(11.0, 18.5) 

9.6 
(7.5,14.8) 

7.3 
(5.6, 8.2) 

HRa (95% CI) (vs Vem) 
p-value (stratified log-rank)b 

0.54 (0.41, 0.71) 
<0.001 

  

HRa (95% CI) (vs Vem) 
Nominal p-value 

 0.68 (0.52, 0.90) 
0.007 

 



22 

HRa (95% CI) (vs Enco 300) 
p-value (stratified log-rank)b 

0.75 (0.56,1.00) 
0.051 

  

Confirmed overall responses  

Overall response rate, n (%) 121 (63.0) 98 (50.5) 77 (40.3) 

(95% CI) (55.8, 69.9) (43.3, 57.8) (33.3, 47.6) 

CR, n (%) 15 (7.8) 10 (5.2) 11 (5.8) 

PR, n (%) 106 (55.2) 88 (45.4) 66 (34.6) 

SD, n (%) 46 (24.0) 53 (27.3) 73 (38.2) 

DCR, n (%) 177 (92.2) 163 (84.0) 156 (81.7) 

(95% CI) (87.4, 95.6) (78.1, 88.9) (75.4, 86.9) 
Duration of response  
Median, months 
(95% CI) 

16.6 
(12.2, 20.4) 

14.9 
(11.1, NE) 

12.3 
(6.9, 16.9) 

Updated analysis, cut-off date: 07 November 2017 

PFS 

Number of events (progressive 
disease) (%) 

113 (58.9) 112 (57.7) 118 (61.8) 

Median, months 
(95% CI) 

14.9 
(11.0, 20.2) 

9.6 
(7.4,14.8) 

7.3 
(5.6, 7.9) 

HRa (95% CI) (vs Vem) 
Nominal p-value 

0.51 (0.39, 0.67) 
<0.001 

  

HRa (95% CI) (vs Vem) 
Nominal p-value 

 0.68 (0.52, 0.88) 
0.0038 

 

HRa (95% CI) (vs Enco 300) 
Nominal p-value 

0.77 (0.59,1.00) 
0.0498 

  

CI=Confidence interval; CR=Complete Response; DCR=Disease Control Rate (CR+PR+SD+Non-CR/Non-PD; 
Non-CR/Non-PD applies only to patients without a target lesion who did not achieve CR or have PD); 
HR=hazard ratio; NE=Not estimable; PFS=progression-free survival; PR=Partial response; SD=stable disease. 
Vem=vemurafenib. 
a Hazard ratio based on a stratified Cox proportional hazard model 
b Log-rank p-value (2-sided) 
 



23 

Figure 1 Study CMEK162B2301, Part 1: Kaplan-Meier plot of progression-free survival by 
independent central review (cut-off date: 19 May 2016) 

 
 
An interim OS analysis of Study CMEK162B2301 Part 1, (cut-off date 07 November 2017) 
demonstrated a statistically significant improvement in OS for Combo 450 compared with 
vemurafenib (see Table 7 and Figure 2).  
A similar proportion of patients in each treatment arm received subsequent treatment with checkpoint 
inhibitors, mainly pembrolizumab, nivolumab and ipilimumab (34.4% Combo 450 arm, 36.1% 
encorafenib arm, 39.8% vemurafenib arm). 
 

Patients at risk
-----------
COMBO 450
ENCO 300
Vemurafenib

192 171 151 128 107 92 87 70 57 41 28 14 4 0
194 162 125 99 84 71 68 55 41 28 17 10 1 0
191 149 101 75 56 45 36 32 23 18 13 10 4 3 0

Pr
ob

ab
ili

ty
 o

f P
ro

gr
es

sio
n 

Fr
ee

 S
ur

vi
va

l(%
)

0

10

20

30

40

50

60

70

80

90

100

Time (months)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Treatment
Median PFS (months)

COMBO 450
14.9

ENCO 300
9.6

Vemurafenib
7.3



24 

Table 7:  Study CMEK162B2301, Part 1: Overall survival interim results (cut-off date: 
7 November 2017) 

 Encorafenib + 
binimetinib N=192 
(Combo 450) 

Encorafenib 
N=194 
(Enco 300) 

Vemurafenib 
N=191 
(Vem) 

OS 
Number of events (%) 105 (54.7) 106 (54.6) 127 (66.5) 

Median, months 
(95% CI) 

33.6 
(24.4, 39.2) 

23.5 
(19.6, 33.6) 

16.9 
(14.0, 24.5) 

Survival at 12 months 
(95% CI) 

75.5%  
(68.8, 81.0) 

74.6% 
(67.6, 80.3)  

63.1%  
(55.7, 69.6) 

Survival at 24 months 
(95% CI) 

57.6%  
(50.3, 64.3) 

49.1%  
(41.5, 56.2) 

43.2%  
(35.9, 50.2) 

HR (95% CI) (vs Vem) 
p-value (stratified log-rank) 

0.61 (0.47, 0.79) 
<0.0001 

   

HR (95% CI) (vs Enco 300) 
p-value (stratified log-rank) 

0.81 (0.61,1.06) 
0.061 

  

 
Figure 2 Study CMEK162B2301, Part 1: Kaplan-Meier plot of interim overall survival 
(cut-off date: 7 November 2017) 

 
 

Patients at risk-----------
COMBO 450
ENCO 300
Vemurafenib

192 185 172 144 129 117 108 100 89 57 23 2 0
194 178 151 133 115 98 86 82 67 40 16 0
191 176 155 115 94 84 77 68 59 30 14 2 0

Pr
ob

ab
ili

ty
 o

f O
ve

ra
ll 

Su
rv

iv
al

 (%
)

0

10

20

30

40

50

60

70

80

90

100

Time (months)
0 4 8 12 16 20 24 28 32 36 40 44 48

Treatment
Median OS (months)

COMBO 450
33.6

ENCO 300
23.5

Vemurafenib
16.9



25 

Quality of Life (QoL) (cut-off date: 19 May 2016) 
The Functional Assessment of Cancer Therapy-Melanoma (FACT-M), the European Organisation for 
Research and Treatment of Cancer’s core quality of life questionnaire (EORTC QLQ-C30) and the 
EuroQoL-5 Dimension-5 Level examination (EQ-5D-5L) were used to explore patient-reported 
outcomes (PRO) measures of health-related Quality of Life, functioning, melanoma symptoms, and 
treatment-related adverse reactions. A definitive 10% deterioration in FACT-M and in EORTC QLQ-
C30 was significantly delayed in patients treated with Combo 450 relative to other treatments. The 
median time to definitive 10% deterioration in the FACT-M score was not reached in the Combo 450 
arm and was 22.1 months (95% CI: 15.2, NE) in the vemurafenib arm with a HR for the difference of 
0.46 (95% CI: 0.29, 0.72). An analysis of time to definitive 10% deterioration in EORTC QLQ-C30 
score provided with similar results. 
Patients receiving Combo 450 reported no change or a slight improvement in the mean change from 
baseline EQ-5D-5L index score at all visits, whilst patients receiving vemurafenib or encorafenib 
reported decreases at all visits (with statistical significant differences). An evaluation of change over 
time in score yielded the same trend for EORTC QLQ-C30 and at all visit for FACT-M.  
 
Study CMEK162B2301, Part 2: 
Part 2 of Study CMEK162B2301 was designed to assess the contribution of binimetinib to the 
encorafenib and binimetinib combination. 
The PFS for encorafenib 300 mg orally daily used in combination with binimetinib 45 mg orally twice 
daily (Combo 300, n = 258) was compared to the PFS for Enco 300 (n = 280, including 194 patients 
from Part 1 and 86 patients from Part 2). Enrolment in Part 2 started after all Part 1 patients were 
randomised.  
 
Preliminary Part 2 data, at a cut-off date of 9 November 2016, demonstrated the contribution of 
binimetinib with an improved median PFS estimate of 12.9 months (95% CI: 10.1, 14.0) for 
Combo 300 compared to 9.2 months (95% CI: 7.4, 11.0) for Enco 300 (Parts 1 and 2) per independent 
central review (BIRC). Similar results were observed per Investigator assessment.  
The confirmed ORR per BIRC was 65.9% (95% CI: 59.8, 71.7) for Combo 300 and 50.4% (95% CI: 
44.3, 56.4) for Enco 300 (Parts 1 and 2). Median DOR for confirmed responses per BIRC was 
12.7 months [95% CI: 9.3, 15.1] for Combo 300 and 12.9 months [95% CI: 8.9, 15.5] for Enco 300. 
The median duration of treatment was longer for Combo 300 vs Enco 300, 52.1 weeks vs 31.5 weeks. 
 
Cardiac Electrophysiology 
In the safety analysis of pooled studies, the incidence of new QTcF prolongation >500 ms was 
0.7% (2/268) in the encorafenib 450 mg plus binimetinib group, and 2.5% (5/203) in the encorafenib 
single agent group. QTcF prolongation of >60 ms compared to pre-treatment values was observed in 
4.9% (13/268) patients in the encorafenib plus binimetinib group, and in 3.4% (7/204) in the 
encorafenib single agent group (see Sections 4.2 and 4.4). 
 
BRAF V600E Mutant Metastatic Colorectal Cancer - Study ARRAY-818-302 
Encorafenib in combination with cetuximab was evaluated in a randomised, active-controlled, open-
label, multicentre trial (ARRAY 818-302 BEACON CRC). Eligible patients were required to have 
BRAF V600E mutant metastatic colorectal cancer that had progressed after 1 or 2 prior regimens. 
Enrolled patients were eligible to receive cetuximab per locally approved label with regards to tumour 
RAS status. Prior use of RAF inhibitors, MEK inhibitors or EGFR inhibitors was prohibited. 
Randomisation was stratified by Eastern Cooperative Oncology Group (ECOG) performance status, 
prior use of irinotecan and cetuximab source.  
 
A total of 665 patients were randomised (1:1:1) to receive encorafenib 300 mg orally daily in 
combination with cetuximab dosed as per its approved SmPC (n=220), or encorafenib 300 mg orally 
daily in combination with binimetinib 45 mg orally twice daily and cetuximab dosed as per its 
approved SmPC (n=224) or Control (irinotecan with cetuximab or irinotecan/5-fluorouracil/folinic 
acid (FOLFIRI) with cetuximab, n= 221). Treatment continued until disease progression or 
unacceptable toxicity. 
 



26 

The efficacy outcome measures were overall survival (OS) and overall response rate (ORR) as 
assessed by a blinded independent central review committee (BIRC), comparing encorafenib 300 mg 
in combination with cetuximab versus Control. Other efficacy measures are summarised in Table 8 
below. 
 
The median age of patients was 61 years (range 26-91), 47 % were male and 83% were white. 51% of 
patients had baseline ECOG performance status of 0, and 51% received prior irinotecan. 46.8% of 
patients had at least 3 organs with tumour involvement at baseline.  
The median duration of exposure was 3.2 months in patients treated with encorafenib 300 mg in 
combination with cetuximab, and 1.4 months in patients treated with irinotecan/cetuximab or 
FOLFIRI/cetuximab (Control arm).  In patients treated with the combination of encorafenib 300 mg 
and cetuximab, the median relative dose intensity (RDI) was 98% for encorafenib and 93.5% for 
cetuximab. In the control arm, the median RDI was 85.4% for cetuximab, 75.7% for irinotecan and in 
the subset of patients who received Folinic acid and 5-FU, the median RDI was 75.2% and 75% 
respectively.  
 
Encorafenib 300 mg in combination with cetuximab demonstrated a statistically significant 
improvement in OS, ORR and PFS compared to Control. Efficacy results are summarised in Table 8 
and Figures 3 and 4. 
 
The efficacy results based on investigator assessment were consistent with the independent central 
assessment. 
 
Table 8: Study ARRAY-818-302: Efficacy Results 

 
Encorafenib with cetuximab  Irinotecan with cetuximab or 

FOLFIRI with cetuximab (Control) 

Cut-off date: 11 February 2019 (Primary analysis) 

OS 

Number of patientsa 220 221 
Number of events (%) 93 (42.3) 114 (51.6) 

Median, months (95% 
CI) 

8.4 (7.5-11.0) 5.4 (4.8, 6.6) 

HR (95% CI)b,c  (vs 
Control) 
p-valueb,c 

0.60 (0.41-0.88) 
 
0.0002 

 

Median duration of 
follow-up, months 
  (95% CI) 

7.6  
 
(6.4, 9.20) 

7.2  
 
(6.1, 8.1) 

ORR (per BIRC) 

Number of patientse 113 107 
ORR n (%) 
(95% CI)f 

23 (20.4) 
(13.4, 29.0) 

2 (1.9) 
(0.2, 6.6) 

P-valueb,d,g <0.0001  

CR, n (%) 6 (5.3) 0 
PR, n (%) 17 (15.0) 2 (1.9) 
SD, n (%) 57 (50.4) 26 (24.3) 
DCR, n (%) 
(95% CI)f 

84 (74.3) 
(65.3, 82.1) 

33 (30.8) 
(22.3, 40.5) 



27 

PFS (per BIRC) 

Number of patientsa 220 221 
Number of events (%) 133 (60.5) 128 (57.9) 
Median PFS, months 
(95% CI) 

4.2 (3.7, 5.4) 1.5 (1.5, 1.7) 

HR (95% CI)b,c 
P-valueb,d 

0.40 (0.30, 0.55 
< 0.0001   

 

Updated analysis, cut-off date: 15 August 2019 
OS 

Number of patientsa 220 221 

Number of events (%) 128 (58.2) 157 (71.0) 

Median, months (95% 
CI) 

9.3 (8.0, 11.3) 5.9 (5.1, 7.1) 

HR (95% CI)b  (vs 
Control) 
p-valueb,d,h 

0.61 (0.48, 0.77) 
 
< 0.0001 

 

Median duration of 
follow-up, months  
(95% CI) 

12.3 
 
(11.1, 14.1) 

12.9  
 
(10.9, 14.6) 

ORR (per BIRC) 

Number of patientsa 220 221 
ORR n (%) 
(95% CI)f 

43 (19.5) 
(14.5, 25.4) 

4 (1.8) 
(0.5, 4.6) 

p-valueb,d,g,h <0.0001  
CR, n (%) 7 (3.2) 0 
PR, n (%) 36 (16.4) 4 (1.8) 
SD, n (%) 117 (53.2) 59 (26.7) 
DCR, n (%) 
(95% CI)f 

167 (75.9) 
(69.7, 81.4) 

69 (31.2) 
(25.2, 37.8) 

PFS (per BIRC) 

Number of patientsa 220 221 
Number of events (%) 167 (75.9) 147 (66.5) 
Median PFS, months 
(95% CI) 

4.3 
 (4.1, 5.5) 

1.5 
(1.5, 1.9) 

HR (95% CI)b 
P-valueb,d, h 

0.44 (0.35, 0.55) 
< 0.0001 

 

CI = Confidence interval; CR = Complete response; HR = Hazard ratio; ORR = Overall response rate; OS = 
Overall survival; PR = Partial response; SD = Stable disease, DCR: Disease control rate (CR+PR+SD+Non-
CR/Non-PD; Non-CR/Non-PD applies only to patients with a non-measurable disease who did not achieve CR 
or have PD) 
a Randomised Phase 3, Full Analysis Set 
b Stratified by ECOG PS, source of cetuximab, and prior irinotecan use at randomization 
c Repeated CI derived using Lan DeMets O’Brien-Fleming boundaries associated with the observed 

information fraction at the interim analysis 
d 1-sided 
e Among the first 331 randomised patients 
f Clopper-Pearson’s method 
g Cochran Mantel-Haenszel test 
h Nominal p-value 

 



28 

Figure 3: Study ARRAY-818-302: Kaplan-Meier plot of Overall Survival (cut-off 
date: 11 February 2019) 

 
Figure 4: Study ARRAY-818-302: Kaplan-Meier plot of Overall Survival (cut-off 

date: 15 August 2019) 

 
 



29 

Cardiac Electrophysiology 
In the safety analysis of the Phase 3 (ARRAY-818-302) safety set in colorectal indication, the 
incidence of new QTcF prolongation >500 ms was 3.2% (7/216) and QTcF prolongation of >60 ms 
compared to pre-treatment values was observed in 8.8% (19/216) of patients of the encorafenib + 
cetuximab arm (see Sections 4.2 and 4.4). 
 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
encorafenib in one or more subsets of the paediatric population in melanoma (see section 4.2 for 
information on paediatric use). 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
encorafenib in all subsets of the paediatric population in colorectal carcinoma (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of encorafenib were studied in healthy subjects and patients with solid tumours, 
including advanced and unresectable or metastatic cutaneous melanoma harbouring a BRAF-V600E or 
K mutation, and in adult patients with metastatic colorectal cancer with a BRAF V600E mutation. The 
pharmacokinetics of encorafenib have been shown to be approximatively dose linear after single and 
multiples doses. After repeat once-daily dosing, steady-state conditions were reached within 15 days. 
The accumulation ratio of approximately 0.5 is likely due to auto-induction of CYP3A4. The 
inter-subject variability (CV%) of AUC is ranged from 12.3% to 68.9%.  
 
Absorption 
 
After oral administration, encorafenib is rapidly absorbed with a median Tmax of 1.5 to 2 hours. 
Following a single oral dose of 100 mg [14C] encorafenib in healthy subjects, at least 86% of the 
encorafenib dose was absorbed. Administration of a single 100 mg dose of encorafenib with a high-
fat, high-calorie meal decreased the Cmax by 36%, while the AUC was unchanged. A drug interaction 
study in healthy subjects indicated the extent of encorafenib exposure was not altered in the presence 
of a gastric pH-altering agent (rabeprazole). 
 
Distribution 
 
Encorafenib is moderately (86.1%) bound to human plasma proteins in vitro. Following a single oral 
dose of 100 mg [14C] encorafenib in healthy subjects, the mean (SD) blood-to-plasma concentration 
ratio is 0.58 (0.02) and the mean (CV%) apparent volume of distribution (Vz/F) of encorafenib is 
226 L (32.7%). 
 
Biotransformation 
 
Following a single oral dose of 100 mg [14C] encorafenib in healthy subjects, metabolism was found to 
be the major clearance pathway for encorafenib (approximately 88% of the recovered radioactive 
dose). The predominant biotransformation reaction of encorafenib was N-dealkylation. Other major 
metabolic pathways involved hydroxylation, carbamate hydrolysis, indirect glucuronidation and 
glucose conjugate formation.  
 
Elimination 
 
Following a single oral dose of 100 mg [14C] encorafenib in healthy subjects, radioactivity was 
eliminated equally in both the faeces and urine (mean of 47.2%). In urine, 1.8% of the radioactivity 
was excreted as encorafenib. The mean (CV%) apparent clearance (CL/F) of encorafenib was 27.9 L/h 
(9.15%). The median (range) encorafenib terminal half-life (T1/2) was 6.32 h (3.74 to 8.09 h). 
 



30 

Medicinal product interactions 
 
No drug drug interaction was evidenced between encorafenib and cetuximab. 
 
Effect of CYP enzymes on encorafenib  
Encorafenib is metabolised by CYP3A4, CYP2C19 and CYP2D6. In vitro, CYP3A4 was predicted to 
be the major enzyme contributing to total oxidative clearance of encorafenib in human liver 
microsomes (~83.3%), followed by CYP2C19 and CYP2D6 (~16.0% and 0.71%, respectively).  
 
Effect of encorafenib on CYP substrates 
In vitro experiments indicate encorafenib is a relatively potent reversible inhibitor of UGT1A1, 
CYP2B6, CYP2C9 and CYP3A4/5, as well as a time-dependent inhibitor of CYP3A4. Encorafenib 
induced CYP1A2, CYP2B6, CYP2C9 and CYP3A4 in human primary hepatocytes. Simulations of 
450 mg encorafenib co-administered with probe substrates for CYP2B6, CYP1A2, CYP2C9, 
CYP2C19 and CYP2D6 on Day 1 and Day 15 all indicated no clinically relevant interactions are 
expected. For co-administration with CYP3A4 and UGT1A1 substrates that undergo gut extraction, a 
minor to moderate interaction is expected. While binimetinib is a UGT1A1 substrate, it does not 
undergo gut extraction and therefore no DDI with encorafenib is expected. Additionally, no 
differences in exposure have been observed clinically when binimetinib is co-administered with 
encorafenib. 
 
Effect of transporters on encorafenib  
Encorafenib was found to be a substrate of the P-glycoprotein (P-gp) transporters. Inhibition of P-gp is 
unlikely to result in a clinically important increase in encorafenib concentrations as encorafenib 
exhibits high intrinsic permeability. The involvement of several uptake transporter families (OCT1, 
OATP1B1, OATP1B3 and OATPB1) was investigated in vitro using relevant transporter inhibitors. 
The data suggest that hepatic uptake transporters are not involved in encorafenib distribution into 
primary human hepatocytes. 
 
Effect of encorafenib on transporters  
In vitro, encorafenib inhibited the hepatic transporter OCT1, but is unlikely to be an effective inhibitor 
clinically. Based on in vitro studies, there is potential for encorafenib to inhibit renal transporters 
OCT2, OAT1, OAT3 and hepatic transporters OATP1B1 and OATP1B3 at clinical concentrations. In 
addition, encorafenib may inhibit P-gp in the gut and BCRP at the expected clinical concentrations. 
 
Special populations 
 
Age  
Based on a population pharmacokinetic analysis, age was found to be a significant covariate on 
encorafenib volume of distribution, but with high variability. Given the small magnitude of these 
changes and high variability, these are unlikely to be clinically meaningful, and no dose adjustments 
are needed for elderly patients. 
 
Gender 
Based on a population pharmacokinetic analysis gender was not found to be a significant model 
covariate on clearance or volume of distribution. As a result, no major changes in encorafenib 
exposure are expected based upon gender. 
 
Body weight 
Based on a population pharmacokinetic analysis, body weight was found to be a significant model 
covariate on clearance and volume of distribution. However, given the small magnitude of change in 
clearance and the high variability in the predicted volume of distribution in the model, weight is 
unlikely to have a clinically relevant influence on the exposition of encorafenib.  
 



31 

Race  
There are no clinically relevant differences in encorafenib PK between Asians and non Asians . There 
are insufficient data to evaluate potential differences in the exposure of encorafenib in other races or 
ethnicity.  
 
Hepatic impairment 
Results from a dedicated clinical study indicate a 25% higher total encorafenib exposures in patients 
with mild hepatic impairment (Child-Pugh Class A) compared with subjects with normal liver 
function. This translates into a 55% increase of the unbound encorafenib exposure.  
The pharmacokinetics of encorafenib has not been evaluated clinically in patients with moderate 
(Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. As encorafenib is primarily 
metabolised and eliminated via the liver, based on PBPK modelling, patients with moderate to severe 
hepatic impairment may have greater increases in exposure than patients with mild hepatic 
impairment. No dosing recommendation can be made in patients with moderate or severe hepatic 
impairment (see sections 4.2 and 4.4).  
 
Renal impairment 
Encorafenib undergoes minimal renal elimination. No formal clinical study has been conducted to 
evaluate the effect of renal impairment on the pharmacokinetics of encorafenib. 
In a population pharmacokinetic analysis, no clear trend in encorafenib CL/F was observed in patients 
with mild (eGFR 60 to 90 mL/min/1.73 m2) or moderate (eGFR 30 to 59 mL/min/1.73 m2) renal 
impairment compared with subjects with normal renal function (eGFR ≥90 mL/min/1.73 m2). A small 
decrease in CL/F (≤5%) was predicted for patients with mild and moderate renal impairment, which is 
unlikely to be clinically relevant. The pharmacokinetics of encorafenib have not been studied in 
patients with severe renal impairment. 
 
5.3 Preclinical safety data 
 
In the 4-week and 13-week rat toxicity studies, clinical signs, reduced body weight reduced 
epididymides and prostate weights and microscopic findings in testes, epididymides, stomach and skin 
were noted. Partial reversibility of these findings was noted after a 4-week recovery period. 
Additionally, in the 13-week rat toxicity study, reversible clinical pathology changes were noted at 
doses ≥ 100 mg/kg/d. No NOAEL could be established for the 4-week study. The NOAEL determined 
in the 13-week study was more than 10-times human therapeutic exposures. 
 
In the 4-week and 13-week monkey toxicity study, isolated/sporadic episodes of emesis and diarrhoea 
as well as ophthalmic lesions were observed at slightly above human therapeutic exposures. 
Ophthalmic lesions were partially reversible and consisted of a separation or detachment in the retina 
between the outer rods and cones layer and retinal pigmented epithelium at the central macula at the 
fovea. This observation was similar to that described in humans as central serous-like 
chorioretinopathy or central serous retinopathy. 
 
Encorafenib was not genotoxic. 
Fertility studies were not conducted with encorafenib. In the 13-week rat toxicology studies, 
encorafenib treatment at 6 mg/kg/d (dose level more than 5 times the human exposure at the 
therapeutic dose) resulted in decreased testes and epididymis weights with tubular degeneration and 
oligospermia. In the 13-week study, partial reversibility was noted at the highest dose level 
(60 mg/kg/d).  
 
The embryo-foetal development study in rats indicated that encorafenib induced foetal toxicity with 
lower foetal weights and delays in skeletal development.  
The embryo-foetal development study in rabbits indicated that encorafenib induced foetal toxicity with 
lower foetal weights and transitory changes in skeletal development. Dilatation of the aortic arc was 
observed in some foetuses.  
 



32 

Encorafenib was phototoxic in an in vitro 3T3 Neutral Red Uptake Test. Encorafenib was not a 
sensitiser in the in vivo mouse sensitization assay. Collectively, these data indicate that encorafenib 
has a risk of phototoxic potential and minimal risk for sensitization at therapeutic doses in patients. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsule content 
 
Copovidone (E1208) 
Poloxamer 188 
Cellulose microcrystalline (E460i) 
Succinic acid (E363) 
Crospovidone (E1202) 
Silica colloidal anhydrous (E551) 
Magnesium stearate (E470b) 
 
Capsule shell 
 
Gelatin (E441) 
Titanium dioxide (E171) 
Iron oxide red (E172) 
Iron oxide yellow (E172) 
Iron oxide black (E172) 
 
Printing ink 
 
Shellac (E904) 
Iron oxide black (E172) 
Propylene glycol (E1520) 
 
6.2 Incompatibilities 
 
Not applicable.  
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Store below 30°C. 
Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container  
 
Braftovi 50 mg hard capsules 
 
Polyamide/aluminum/PVC/aluminum blister containing 4 capsules.   
Each pack contains either 28 or 112 hard capsules. 
Not all pack sizes may be marketed. 
 



33 

Braftovi 75 mg hard capsules 
 
Polyamide/aluminum/PVC/aluminum blister containing 6 capsules.  
Each pack contains either 42 or 168 hard capsules. 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.  
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Pierre Fabre Médicament 
45, place Abel Gance 
92100 Boulogne-Billancourt  
France 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
Braftovi 50 mg hard capsules 
 
EU/1/18/1314/001 28 hard capsules 
EU/1/18/1314/003 112 hard capsules 
 
Braftovi 75 mg hard capsules 
 
EU/1/18/1314/002 42 hard capsules 
EU/1/18/1314/004 168 hard capsules 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 20 September 2018 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

  

http://www.ema.europa.eu/


34 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 

 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE  

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

 



35 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Pierre Fabre Médicament Production 
Aquitaine Pharm International 1 
Avenue du Béarn 
64320 Idron 
France 
 
PIERRE FABRE MEDICAMENT PRODUCTION 
Site Progipharm, rue du Lycée  
45500 GIEN  
France 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of 
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and 
any subsequent updates published on the European medicines web-portal. 
 
The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 
months following authorisation.  
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 
authorisation and any agreed subsequent updates of the RMP. 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.  

 
  



36 

 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



37 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



38 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Braftovi 50 mg hard capsules 
encorafenib  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 50 mg encorafenib. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 hard capsules 
112 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C. Store in the original package in order to protect from moisture.  
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 



39 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pierre Fabre Médicament 
45, place Abel Gance 
92100 Boulogne-Billancourt  
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1314/001 28 hard capsules 
EU/1/18/1314/003 112 hard capsules 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
braftovi 50 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 
 
  



40 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Braftovi 50 mg capsules 
encorafenib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pierre Fabre Médicament 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
  



41 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Braftovi 75 mg hard capsules 
encorafenib  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 75 mg encorafenib. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
42 hard capsules 
168 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C. Store in the original package in order to protect from moisture.  
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 



42 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pierre Fabre Médicament 
45, place Abel Gance 
92100 Boulogne-Billancourt  
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1314/002 42 hard capsules 
EU/1/18/1314/004 168 hard capsules 
  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
braftovi 75 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 
 
  



43 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Braftovi 75 mg capsules 
encorafenib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pierre Fabre Médicament 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
  



44 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



45 

Package leaflet: Information for the patient 
 

Braftovi 50 mg hard capsules 
Braftovi 75 mg hard capsules 

encorafenib 
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Braftovi is and what it is used for  
2. What you need to know before you take Braftovi  
3. How to take Braftovi  
4. Possible side effects  
5. How to store Braftovi  
6. Contents of the pack and other information 
 
 
1. What Braftovi is and what it is used for 
 
Braftovi is an anti-cancer medicine that contains the active substance encorafenib. Changes 
(mutations) in the BRAF gene can produce proteins that cause the cancer to grow. Braftovi targets 
proteins made from this changed BRAF gene. 
 
It is used in combination with another medicine containing binimetinib to treat adult patients with a 
type of skin cancer called melanoma when it has 
- a particular change (mutation) in a gene responsible for producing a protein called BRAF, and 
- spread to other parts of the body, or cannot be removed by surgery 
When Braftovi is used in combination with binimetinib, which targets another protein that stimulates 
cancer cell growth, the combination slows down or stops the growth of your cancer. 
 
Braftovi is also used in combination with another medicine cetuximab, to treat adult patients with a 
type of large intestine cancer when it has 
- a particular change (mutation) in a gene responsible for producing a protein called BRAF, and 
- spread to other parts of the body of patients who have been previously treated with other 

anticancer medicines 
When Braftovi is used in combination with cetuximab (which binds to the epidermal growth factor 
receptor (EGFR)), a protein on the surface of certain cancer cells), the combination slows down or 
stops the growth of your cancer. 
 
 
2. What you need to know before you take Braftovi  
 
Before starting treatment your doctor will check for the BRAF mutation. 
 



46 

As Braftovi is to be used in combination with binimetinib to treat melanoma, read the binimetinib 
leaflet carefully as well as this leaflet.   
 
As Braftovi is to be used in combination with cetuximab to treat large intestine cancer, read the 
cetuximab leaflet carefully as well as this leaflet.   
 
Do not take Braftovi  
-  if you are allergic to encorafenib or any of the other ingredients of this medicine (listed in 

section 6). 
 
Warnings and precautions  
Talk to your doctor, pharmacist or nurse before taking Braftovi, about all of your medical conditions, 
particularly if you have any of the following: 
- heart problems including alteration of the electrical activity of your heart (QT interval 

prolongation) 
- bleeding problems or if you are taking medicines that may cause bleeding 
- eye problems  
- liver or kidney problems 
 
Tell your doctor if you have had a different type of cancer than melanoma or large intestine cancer, 
as Braftovi may worsen certain other types of cancers. 
 
Tell your doctor, pharmacist or nurse immediately if you get the following while you are taking this 
medicine: 
- Heart problems: Braftovi when taken with binimetinib can make your heart work less well, alter 

the electrical activity of your heart called “QT interval prolongation” or make existing heart 
problems worse. Your doctor will check that your heart is working properly before and during 
your treatment with these medicines. Talk to your doctor immediately if you have any 
symptoms of heart problems such as feeling dizzy, tired, lightheaded, if you have shortness of 
breath, if you feel like your heart is pounding, racing, beating irregularly, or if you have 
swelling in the legs. 
 

- Bleeding problems: Braftovi may cause serious bleeding problems. Talk to your doctor 
immediately if you have any symptoms of bleeding problems such as coughing up of blood, 
blood clots, vomit containing blood or that looks like “coffee grounds”, red or black stools that 
look like tar, passing blood in the urine, stomach (abdominal) pain, unusual vaginal bleeding. 
Also tell your doctor if you have headache, dizziness or weakness. 
 

- Eye problems: Braftovi, when taken with binimetinib , can cause serious eye problems. Talk to 
your doctor immediately if you get blurred vision, loss of vision, or other vision changes (e.g. 
coloured dots in your vision), halo (seeing blurred outline around objects). Your doctor will 
examine your eyes for any problems with your sight while you are taking Braftovi. 
 

- Skin changes: Braftovi may cause other types of skin cancer such as cutaneous squamous cell 
carcinoma. New melanomas may also occur while taking Braftovi. Your doctor will check your 
skin for any new skin cancers before treatment, every 2 months during treatment, and for up to 6 
months after you stop taking Braftovi. Tell your doctor immediately if you detect skin changes 
during and after treatment including: new wart, skin sore or reddish bump that bleeds or does 
not heal, or a change in size or colour of a mole. Additionally, your doctor needs to check for 
squamous cell carcinoma on your head, neck, mouth and lymph glands, and you will have CT 
scans regularly. This is a precaution in case a squamous cell carcinoma develops inside your 
body. Genital examinations (for women) and anal examinations are also recommended before 
and at the end of your treatment. 
 

- Liver problems: Braftovi can cause abnormal blood tests related to how your liver works (raised 
levels of liver enzymes). Your doctor will run blood tests to check your liver before and during 
treatment. 



47 

 
- Kidney problems: Braftovi can alter your kidney activity (often abnormal blood tests, more 

rarely dehydration and vomiting). Your doctor will run blood tests to monitor your kidneys 
before and during treatment. Drink plenty of fluids during treatment. Tell your doctor 
immediately if you vomit and become dehydrated. 

 
Children and adolescents 
Braftovi is not recommended for children and adolescents under 18 years of age. This medicine has 
not been studied in this age group. 
 
Other medicines and Braftovi 
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines.  
Some medicines may affect how Braftovi works or make it more likely that you will have side effects. 
In particular, tell your doctor if you are taking anything in this list or any other medicines: 
- some medicines to treat fungal infections (such as itraconazole, posaconazole, fluconazole)  
- some medicines to treat bacterial infections (such as rifampicin, clarithromycin, telithromycin, 

erythromycin, penicillin) 
- medicines typically used to treat epilepsy (seizures) (such as phenytoin, carbamazepine)  
- medicines typically used to treat cancer (such as methotrexate, imatinib) 
- medicines typically used to treat high cholesterol (such as rosuvastatin, atorvastatin) 
- an herbal treatment for depression: St. John’s wort  
- some medicines for HIV treatment such as ritonavir, amprenavir, raltegravir, dolutegravir 
- birth control medicines containing hormones  
- medicines typically used to treat high blood pressure (such as diltiazem, bosentan, furosemide)  
- a medicine used to treat an uneven heartbeat: amiodarone. 
 
Braftovi with food and drink  
Do not have grapefruit juice during your treatment with Braftovi. This is because it could increase 
Braftovi side effects. 
 
Pregnancy, breast-feeding and fertility 
Pregnancy 
Braftovi is not recommended during pregnancy. It may cause harm or birth defects to an unborn baby. 
If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for 
advice before taking this medicine. 
If you are a woman who could become pregnant, you must use reliable contraception while you are 
taking Braftovi, and you must continue to use reliable contraception for at least 1 month after taking 
your last dose. Birth control medicines containing hormones (such as pills, injections, patches, 
implants and certain intrauterine devices (IUDs) that release hormones) may not work as well as 
expected while you are taking Braftovi. You should use another reliable method of birth control such 
as a barrier method (e.g. condom) so you do not become pregnant while you are taking this medicine. 
Ask your doctor, pharmacist or nurse for advice. 
Contact your doctor straightaway if you become pregnant while taking Braftovi.  
 
Breast-feeding 
Braftovi is not recommended while breast-feeding. It is not known if Braftovi passes into breast milk. 
If you are breast-feeding, or planning to breast-feed, ask your doctor for advice before taking this 
medicine.  
 
Fertility 
Braftovi may reduce sperm count in males. This could affect the ability to father a child. Talk to your 
doctor if this is a concern for you.  
 
Driving and using machines 
Braftovi can affect your ability to drive or use machines. Avoid driving or using machines if you have 
any problems with your vision, or have any other side effects that can affect your ability to drive or 



48 

use machines (see section 4), while taking Braftovi. Talk to your doctor if you are not sure you can 
drive. 
 
 
3. How to take Braftovi 
 
How much to take  
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure.  
 
For melanoma treatment 
The recommended dose of Braftovi to treat melanoma is 6 capsules of 75 mg once daily 
(corresponding to a daily dose of 450 mg). You will also receive treatment with another medicine, 
binimetinib. 
 
For large intestine cancer treatment 
The recommended dose of Braftovi to treat large intestine cancer is 4 capsules of 75 mg once daily 
(corresponding to a daily dose of 300 mg). You will also receive treatment with another medicine 
cetuximab. 
 
If you have liver or kidney problems, your doctor may start you on a lower dose.  
If you get serious side effects (such as heart, eye or bleeding problems) your doctor may lower the 
dose or stop treatment temporarily or permanently. 
  
How to take Braftovi 
Swallow the capsules whole with water. Braftovi can be taken with food or between meals. 
 
If you are sick  
If you vomit at any time after taking Braftovi, do not take an additional dose. Take the next dose as 
scheduled. 
 
If you take more Braftovi than you should 
If you take more capsules than you should, contact your doctor, pharmacist or nurse straightaway. Side 
effects of Braftovi such as nausea, vomiting, dehydration and blurred vision may appear or worsen. If 
possible, show them this leaflet and the medicine package. 
 
If you forget to take Braftovi 
If you miss a dose of Braftovi, take it as soon as you remember. However if the missed dose is more 
than 12 hours late, skip that dose and take your next dose at the usual time. Then continue taking your 
capsules at regular times as usual. 
Do not take a double dose to make up for a forgotten dose. 
 
If you stop taking Braftovi 
It is important to take Braftovi for as long as your doctor prescribes it. Do not stop taking this 
medicine unless your doctor tells you to. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 



49 

Serious side effects 
 
Braftovi may cause serious side effects. Tell your doctor immediately if you have any of the 
following serious side effects, either for the first time or if they get worse (see also section 2):  
 
Heart problems: Braftovi when taken with binimetinib can affect how well your heart works (left 
ventricular ejection fraction decrease); signs and symptoms can include:  
- feeling dizzy, tired or lightheaded 
- shortness of breath 
- feeling like your heart is pounding, racing or beating irregularly 
- swelling in the legs 
 
Eye problems: Braftovi, when taken with binimetinib can cause serious eye problems such as fluid to 
leak under the retina in the eye, leading to detachment of different layers in the eye (retinal epithelial 
pigmental detachment). Call your doctor right away if you get these symptoms of eye problems: 
- blurred vision, loss of vision, or other vision changes (such as coloured dots in your vision) 
- halo (seeing blurred outline around objects) 
- eye pain, swellling or redness  
 
Bleeding problems: Braftovi can cause serious bleeding problems. Tell your doctor right away if you 
have any unusual signs of bleeding, including: 
- headaches, dizziness or weakness 
- coughing up of blood or blood clots 
- vomit containing blood or that looks like “coffee grounds” 
- red or black stools that look like tar 
- passing blood in the urine 
- stomach (abdominal) pain 
- unusual vaginal bleeding 
 
Muscle problems: Braftovi, when taken with binimetinib can cause breakdown of muscles 
(rhabdomyolysis) which can lead to kidney damage and can be fatal; signs and symptoms can include: 
- muscle pain, cramps, stiffness or spasm 
- dark urine  
 

 Other skin cancers: Treatment with Braftovi may result in a type of skin cancer such as cutaneous 
squamous cell carcinoma. Usually, these skin changes (see also section 2) are confined to a small area 
and can be removed with surgery and treatment with Braftovi can continue without interruption. Some 
people taking Braftovi may also notice new melanomas. These melanomas are usually removed by 
surgery and treatment with Braftovi can continue without interruption. 
 
Other side effects 
Besides the serious side effects mentioned above, people taking Braftovi may also get other side 
effects.  
 
Side effects when Braftovi and binimetinib are taken together for treatment of melanoma 
 
Very common (may affect more than 1 in 10 people): 
- reduced red blood cell count (anaemia) 
- problem with the nerves resulting in pain, loss of sensation or tingling in hands and feet  
- headache 
- dizziness 
- bleeding at various sites in the body 
- high blood pressure 
- problems with your vision (visual impairment) 
- stomach pain 
- diarrhoea 
- being sick (vomiting) 



50 

- feeling sick (nausea) 
- constipation 
- itching  
- dry skin 
- hair loss or thinning (alopecia) 
- skin rash of various types 
- thickening of the outer layers of the skin 
- joint pain (arthralgia) 
- muscle pain, weakness or spasm 
- back pain 
- pain in the extremities  
- fever 
- swelling of the hands or feet (peripheral oedema), localised swelling 
- fatigue 
- abnormal blood test results for liver function 
- abnormal blood test results related to blood creatine kinase (an enzyme found in the blood that 

may indicate muscle inflammation or damage) 
 
Common (may affect up to 1 in 10 people) 
- some types of skin tumours such as skin papilloma and basal cell carcinoma 
- allergic reaction that may include swelling of the face and difficulty breathing  
- changes in the way things taste 
- inflammation of the eye (uveitis) 
- blood clots 
- inflammation of the colon (colitis) 
- redness, chapping or cracking of the skin 
- inflammation of the fatty layer under the skin, symptoms include tender skin nodules  
- skin rash with a flat discoloured area or raised bumps like acne (dermatitis acneiform) 
- redness, skin peeling or blisters on hand and feet (palmar-plantar erythrodysesthesia or hand and  

foot syndrome) 
- kidney failure 
- abnormal kidney test results (creatinine elevations) 
- abnormal blood test results for liver function (blood alkaline phosphatase) 
- abnormal blood test results for pancreas function (amylase, lipase) 
- increased skin sensitivity to sunlight 
 
Uncommon (may affect up to 1 in 100 people) 
- weakness and paralysis of face muscles  
- inflammation of the pancreas (pancreatitis) causing severe abdominal pain 
 
Side effects when Braftovi was used on its own in clinical trials conducted in patients with 
melanoma 
 
If you continue Braftovi on its own while the other medicine (binimetinib) is temporarily stopped 
based on your doctor’s decision, you may get some of the side effects given in the lists above, 
although the frequency may change (increase or decrease). 
 
Very common (may affect more than 1 in 10 people) 
- fatigue 
- feeling sick (nausea) 
- being sick (vomiting) 
- constipation 
- skin rash of various types  
- redness, skin peeling or blisters on hand and feet (called palmar-plantar erythrodysesthesia or 

hand and foot syndrome) 
- thickening of the outer layers of the skin (hyperkeratosis) 
- dry skin 



51 

- itching  
- abnormal hair loss or thinning (alopecia) 
- redness, chapping or cracking of the skin  
- skin darkening 
- lost of appetite 
- difficulty sleeping  (insomnia) 
- headache 
- problem with the nerves that can produce pain, loss of sensation or tingling in hands and feet 
- changes in the way things taste 
- joint pain (arthralgia) 
- muscle pain, spasm or weakness 
- pain in the extremities 
- back pain 
- fever 
- some types of benign skin tumour such as melanocytic naevus and skin papilloma 
- abnormal blood tests results related to the liver 
 
Common (may affect up to 1 in 10 people) 
- allergic reaction that may include swelling of the face and difficulty in breathing  
- weakness and paralysis of face muscles  
- fast heart beat 
- skin rash with a flat discoloured area or raised bumps like acne (dermatitis acneiform) 
- peeling or scaly skin 
- inflammation of joints (arthritis) 
- kidney failure 
- abnormal kidney test results (creatinine elevations) 
- increased skin sensitivity to sunlight 
- abnormal blood test result for pancreas function (lipase) 
 
Uncommon (may affect up to 1 in 100 people) 
- type of skin cancer such as basal cell carcinoma 
- inflammation of the eye (uveitis)  
- inflammation of the pancreas (pancreatitis) causing severe abdominal pain 
- abnormal blood test result for pancreas function (amylase) 
 
Side effects when Braftovi is taken together with cetuximab for treatment of large intestine 
cancer 
Besides the serious side effects mentioned above, people taking Braftovi together with cetuximab may 
also get the following side effects.  
 
Very common (may affect more than 1 in 10 people) 
- new moles called “melanocytic naevus” 
- lost of appetite 
- difficulty sleeping  (insomnia) 
- problem with the nerves resulting in pain, loss of sensation or tingling in hands and feet  
- headache 
- bleeding at various sites in the body 
- diarrhoea 
- stomach pain 
- feeling sick (nausea) 
- being sick (vomiting) 
- constipation 
- skin rash with a flat discoloured area or raised bumps like acne (dermatitis acneiform) 
- skin rash of various types 
- dry skin 
- itching  
- joint pain (arthralgia) and muscle and/or bone pain (musculosketal pain)  



52 

- muscle pain, weakness or spasm 
- pain in the extremities 
- back pain 
- fatigue 
- fever 
 
Common (may affect up to 1 in 10 people) 
- some types of skin tumours such as skin papilloma. 
- allergic reaction that may include swelling of the face and difficulty breathing 
- dizziness 
- changes in the way things taste 
- fast heart beat 
- skin darkening 
- redness, skin peeling or blisters on hand and feet (palmar plantar erythrodysesthesia or hand and 

foot syndrome) 
- thickening of the outer layers of the skin (hyperkeratosis) 
- redness, chapping or cracking of the skin 
- hair loss or thinning (alopecia) 
- kidney failure 
- abnormal kidney test results (creatinine elevations) 
- abnormal blood test results for liver function 
 
Uncommon (may affect up to 1 in 100 people) 
- some types of skin tumours such as basal cell carcinoma 
- inflammation of the pancreas (pancreatitis) causing severe abdominal pain 
- skin peeling 
- abnormal blood test results for pancreas function (amylase, lipase) 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Braftovi 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and the blister after EXP. 
The expiry date refers to the last day of that month. 
 
Store below 30°C. Store in the original package in order to protect from moisture. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


53 

6. Contents of the pack and other information 
 
What Braftovi contains  
- The active substance is encorafenib.  

Braftovi 50 mg: Each hard capsule contains 50 mg encorafenib. 
Braftovi 75 mg: Each hard capsule contains 75 mg encorafenib. 

- The other ingredients are: 
• Capsule contents: copovidone (E1208), poloxamer 188, cellulose microcrystalline (E460i), 

succinic acid (E363), crospovidone (E1202), silica colloidal anhydrous (E551), magnesium 
stearate (E470b) 

• Capsule shell: gelatin (E441), titanium dioxide (E171), iron oxide red (E172), iron oxide yellow 
(E172), iron oxide black (E172) 

• Printing ink: shellac (E904), iron oxide black (E172), propylene glycol (E1520) 
 
What Braftovi looks like and contents of the pack 
Braftovi 50 mg hard capsules  
The hard capsule (capsule) has an orange opaque cap and flesh opaque body, with a stylised “A” 
printed on the cap and “LGX 50mg” printed on the body.  
Braftovi 50 mg is available in packs of 28 capsules (7 blisters of 4 capsules each) or 112 capsules (28 
blisters of 4 capsules each). Not all pack sizes may be marketed. 
 
Braftovi 75 mg hard capsules  
The hard capsule (capsule) has a flesh coloured opaque cap and white opaque body, with a stylised 
“A” printed on the cap and “LGX 75mg” printed on the body. 
Braftovi 75 mg is available in packs of 42 capsules (7 blisters of 6 capsules each) or 168 capsules (28 
blisters of 6 capsules each). Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Pierre Fabre Médicament 
45, place Abel Gance 
92100 Boulogne-Billancourt 
France 
 
Manufacturer 
Pierre Fabre Médicament Production 
Aquitaine Pharm International 1 
Avenue du Béarn 
64320 Idron 
France 
 
or 
 
PIERRE FABRE MEDICAMENT PRODUCTION 
Site Progipharm, Rue du Lycée  
45500 GIEN  
France 
 
This leaflet was last revised in. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  
  



54 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX IV 

CONCLUSIONS ON THE REQUEST FOR ONE-YEAR MARKETING PROTECTION 
PRESENTED BY THE EUROPEAN MEDICINES AGENCY 

 
  
 



55 

Conclusions presented by the European Medicines Agency on: 

• one-year marketing protection 

 The CHMP reviewed the data submitted by the Marketing Authorisation Holder, taking into account 
the provisions of Article 14(11) of Regulation (EC) No 726/2004, and considers that the new 
therapeutic indication brings significant clinical benefit in comparison with existing therapies as 
further explained in the European Public Assessment Report.  

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	CONCLUSIONS ON THE REQUEST FOR ONE-YEAR MARKETING PROTECTION PRESENTED BY THE EUROPEAN MEDICINES AGENCY