Mektovi

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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 
 
Mektovi 15 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 15 mg of binimetinib. 
 
Excipient with known effect 
Each film-coated tablet contains 133.5 mg of lactose monohydrate. 
 
For the full list of excipients, see section 6.1 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
Yellow to dark yellow, unscored biconvex, ovaloid film-coated tablets approximately 12 mm in length 
and 5 mm in width, with the “A” logo debossed on one side of the tablet and “15” on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Binimetinib in combination with encorafenib is indicated for the treatment of adult patients with 
unresectable or metastatic melanoma with a BRAF V600 mutation (see sections 4.4 and 5.1). 
 
4.2 Posology and method of administration 
 
Binimetinib treatment in combination with encorafenib should be initiated and supervised under the 
responsibility of a physician experienced in the use of anticancer medicinal products. 
 
Posology 
 
The recommended dose of binimetinib is 45 mg (three 15 mg tablets) twice daily, corresponding to a 
total daily dose of 90 mg approximately 12 hours apart. 
 
Dose modification 
The management of adverse reactions may require dose reduction, temporary interruption or treatment 
discontinuation (see below, Table 1 and Table 2).  
 
For patients receiving 45 mg binimetinib twice daily, the recommended reduced dose of binimetinib is 
30 mg twice daily. Dose reduction below 30 mg twice daily is not recommended. Therapy should be 
discontinued if the patient is not able to tolerate 30 mg orally twice daily. 
 
If the adverse reaction that resulted in a dose reduction is under effective management, dose 
re-escalation to 45 mg twice daily may be considered. Dose re-escalation to 45 mg twice daily is not 
recommended if the dose reduction is due to left ventricular dysfunction (LVD) or any Grade 4 toxicity. 
 



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Dose modifications recommendations in case of adverse reactions are presented below and in 
Tables 1 and 2.  
 
If treatment-related toxicities occur when binimetinib is used in combination with encorafenib, then 
both treatments should be simultaneously dose reduced, interrupted or discontinued. Exceptions where 
dose reductions are necessary for encorafenib only (adverse reactions primarily related to encorafenib) 
are: palmar-plantar erythrodysaesthesia syndrome (PPES), uveitis including iritis and iridocyclitis and 
QTc prolongation. 
 
If one of these toxicities occurs, see section 4.2. of encorafenib Summary of Product Characteristics 
(SmPC) for dose modification instructions for encorafenib. 
 
If binimetinib is temporarily interrupted, encorafenib should be reduced to 300 mg once daily during 
the time of binimetinib dose interruption (see Tables 1 and 2) 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 section 4.2 of encorafenib SmPC), binimetinib should be 
interrupted. If encorafenib is permanently discontinued, then binimetinib should be discontinued.  
For information on the posology and recommended dose modifications of encorafenib, see section 4.2 
of encorafenib SmPC. 
 
Table 1: Recommended dose modifications for binimetinib (used in combination with 

encorafenib) for selected adverse reaction 

Severity of adverse reactiona Binimetinib 

Cutaneous reactions 

• Grade2 Binimetinib should be maintained.  
If rash worsens or does not improve within 2 weeks with 
treatment, binimetinib should be withheld until improved to 
Grade 0 or 1 and then resumed at the same dose if first 
occurrence or resumed at a reduced dose if recurrent Grade2. 

• Grade 3 
 

Binimetinib 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 Binimetinib should be permanently discontinued. 

Ocular events 

• Symptomatic retinal pigment 
epithelial detachments (RPED) 
(Grade 2 or 3) 

Binimetinib should be withheld for up to 2 weeks and 
ophthalmic monitoring should be repeated including visual 
acuity assessment. 
• If improved to Grade 0 or 1, binimetinib should be 

resumed at same dose. 
• If improved to Grade 2, binimetinib should be resumed at 

a lower dose. 
• If not improved to Grade 2, binimetinib should be 

permanently discontinued. 

• Symptomatic RPED (Grade 4) 
associated with reduced visual 
acuity (Grade 4) 

Binimetinib should be permanently discontinued. 

• Retinal vein occlusion (RVO) Binimetinib should be permanently discontinued. 



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Severity of adverse reactiona Binimetinib 

Cardiac events 

• Grade 2 Left ventricular 
ejection fraction (LVEF) 
decrease or asymptomatic, 
absolute decrease in LVEF of 
greater than 10 % from baseline 
that is below lower limit of 
normal (LLN) 

LVEF should be evaluated every 2 weeks.  
• If asymptomatic: 

Binimetinib should be withheld for up to 4 weeks. 
Binimetinib should be resumed at a reduced dose if all of 
the following are present within 4 weeks: 
o LVEF is at or above the LLN  
o Absolute decrease from baseline is 10 % or less. 

• If the LVEF does not recover within 4 weeks, binimetinib 
should be permanently discontinued. 

• Grade 3 or 4 LVEF decrease or 
symptomatic left ventricular 
dysfunction (LVD) 

Binimetinib should be permanently discontinued. 
LVEF should be evaluated every 2 weeks until recovery. 

Rhabdomyolysis/Creatine phosphokinase (CK) elevation 

• Grade 3 (CK > 5 – 10x upper 
limit of normal (ULN)) 
asymptomatic 

Binimetinib dose should be maintained and it should be 
ensured that patient is adequately hydrated. 

• Grade 4 (CK > 10x ULN) 
asymptomatic 

Binimetinib should be withheld until improved to 
Grade 0 or 1. It should be ensured that patient has adequate 
hydration. 

• Grade 3 or grade 4 (CK > 5x 
ULN) with muscle symptoms or 
renal impairment 

Binimetinib should be withheld until improved to 
Grade 0 or 1. 
• If resolved within 4 weeks, binimetinib should be resumed 

at a reduced dose, or 
• Binimetinib should be permanently discontinued. 

Venous thromboembolism (VTE) 

• Uncomplicated deep vein 
thrombosis (DVT) or 
pulmonary embolism (PE) ≤ 
Grade 3 

Binimetinib should be withheld. 
• If improved to Grade 0 or 1, binimetinib should be 

resumed at a reduced dose, or 
• If not improved, binimetinib should be permanently 

discontinued. 

• Grade 4 PE Binimetinib should be permanently discontinued.  
 



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Severity of adverse reactiona Binimetinib 

Liver laboratory abnormalities 

• Grade 2 aspartate 
aminotransferase (AST) or 
alanine aminotransferase 
(ALT) > 3x – ≤ 5x upper limit 
of normal (ULN)  

Binimetinib dose should be maintained. 
If no improvement within 2 weeks, binimetinib should be 
withheld until improved to Grade 0 or 1 or to baseline levels, 
and then resumed at the same dose. 

• First occurrence of Grade 3 
(AST or ALT > 5x ULN and 
blood bilirubin > 2x ULN)  

Binimetinib should be withheld for up to 4 weeks. 
• If improved to Grade 0 or 1 or baseline level, binimetinib 

should be resumed at reduced dose, or 
• If not improved, binimetinib should be permanently 

discontinued. 

• First occurrence of Grade 4 
(AST or ALT > 20 ULN)  

Binimetinib should be withheld for up to 4 weeks. 
• If improved to Grade 0 or 1 or baseline levels, binimetinib 

should be resumed at a reduced dose level, or 
• If not improved, binimetinib should be permanently 

discontinued. 
 
Or, binimetinib should be permanently discontinued. 

• Recurrent Grade 3 (AST or 
ALT > 5x ULN and blood 
bilirubin > 2x ULN)  

It should be considered to permanently discontinue 
binimetinib. 
 

• Recurrent Grade 4 (AST or 
ALT > 20 ULN)   
 

Binimetinib should be permanently discontinued. 

Interstitial lung disease (ILD)/pneumonitis 

• Grade 2 Binimetinib should be withheld for up to 4 weeks. 
• If improved to Grade 0 or 1, binimetinib should be 

resumed at reduced dose, or 
• If not resolved within 4 weeks, binimetinib should be 

permanently discontinued. 

• Grade 3 or Grade 4 Binimetinib should be permanently discontinued. 
a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
version 4.03 
 



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Table 2: Recommended dose modifications for binimetinib (used in combination with 
encorafenib) for other adverse reactions 

Severity of adverse reaction Binimetinib 

• Recurrent or intolerable Grade 2 
adverse reactions 

• First occurrence of Grade 3 
adverse reactions 

 

Binimetinib should be withheld for up to 4 weeks.  
• If improved to Grade 0 or 1 or baseline level, binimetinib 

should be resumed at reduced dose, or 
• If not improved, binimetinib should be permanently 

discontinued. 

• First occurrence of Grade 4 
adverse reactions 

Binimetinib should be withheld for up to 4 weeks. 
• If improved to Grade 0 or 1 or baseline levels, 

binimetinib should be resumed at a reduced dose level, 
or 

• If not improved, binimetinib should be permanently 
discontinued. 

 
Or, binimetinib should be permanently discontinued 
binimetinib. 

• Recurrent Grade 3 adverse 
reactions 

It should be considered to permanently discontinue 
binimetinib.  

• Recurrent Grade 4 adverse 
reactions 

Binimetinib 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 binimetinib is missed, it should not be taken if it is less than 6 hours until the next dose is 
due. 
 
Vomiting 
In case of vomiting after administration of binimetinib, the patient should not re-take the 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 
No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh A).  
 
As encorafenib is not recommended in patients with moderate (Child Pugh B) or severe hepatic 
impairment (Child-Pugh C), administration of binimetinib is not recommended in these patients. (see 
section 4.2 of encorafenib SmPC).  
 
Renal impairment 
No dose adjustment is recommended for patients with renal impairment (see section 5.2). 
 
Paediatric population 
The safety and efficacy of binimetinib in children and adolescents have not yet been established. No 
data are available. 
 



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Method of administration  
 
Mektovi is for oral use. 
The tablets are to be swallowed whole with water. They may be taken with or without food. 
 
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 
 
Binimetinib is to be given in combination with encorafenib. For additional information on warnings 
and precautions associated with encorafenib treatment, see section 4.4 of encorafenib SmPC. 
 
BRAF mutation testing 
 
Before taking binimetinib in combination with encorafenib, patients must have BRAF V600 mutation 
confirmed by validated test. The efficacy and safety of binimetinib in combination with encorafenib 
have been established only in patients with tumours expressing BRAF V600E and V600K mutations. 
Binimetinib in combination with encorafenib should not be used in patients with wild type BRAF 
malignant melanoma. 
 
Binimetinib in combination with encorafenib in patients who have progressed on a BRAF inhibitor 
 
There are limited data for use of the combination of binimetinib with encorafenib 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. 
 
Binimetinib in combination with encorafenib in patients with brain metastases 
 
There are limited efficacy data with the combination of binimetinib and encorafenib 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 can occur when 
binimetinib is administered.  
It is recommended that LVEF is assessed by echocardiogram or multi-gated acquisition (MUGA) scan 
before initiation of binimetinib, 1 month after initiation, and then at approximately 3-month intervals 
or more frequently as clinically indicated, while on treatment. The occurrence of LVEF decrease can 
be managed with treatment interruption, dose reduction or with treatment discontinuation (see 
section 4.2).  
 
The safety of binimetinib in combination with encorafenib has not been established in patients with a 
baseline LVEF that is either below 50 % or below the institutional LLN. Therefore, in these patients, 
binimetinib should be used with caution and for any symptomatic left ventricular dysfunction, 
Grade 3-4 LVEF, or absolute decrease of LVEF from baseline of ≥ 10 %, binimetinib should be 
discontinued and LVEF should be evaluated every 2 weeks until recovery. 
 
Haemorrhage 
 
Haemorrhages, including major haemorrhagic events, can occur when binimetinib is administered (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 

. 



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interruption, reduction or treatment discontinuation (see Table 2 in section 4.2) and as clinically 
indicated. 
 
Ocular toxicities 
 
Ocular toxicities including RPED and RVO can occur when binimetinib is administered. Uveitis 
including iridocyclitis and iritis have been reported in patients treated with binimetinib in combination 
with encorafenib (see section 4.8). 
 
Binimetinib is not recommended in patients with a history of RVO. The safety of binimetinib has not 
been established in patients with predisposing factors for RVO including uncontrolled glaucoma, 
ocular hypertension, uncontrolled diabetes mellitus or a history of hyperviscosity or 
hypercoagulability syndromes. Therefore, binimetinib should be used with caution in these patients.  
 
Patients should be assessed at each visit for symptoms of new or worsening visual disturbances. 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.  
The occurrence of symptomatic RPED can be managed with treatment interruption, dose reduction or 
with treatment discontinuation (see Table 1 in section 4.2). 
Binimetinib should be permanently discontinued with the occurrence of RVO (see Table 1 in 
section 4.2). 
 
If during treatment patient develops uveitis, see section 4.2 of encorafenib SmPC for guidance.  
 
CK elevation and rhabdomyolysis 
 
Asymptomatic CK elevations are seen in patients treated with binimetinib (see section 4.8), and, 
rhabdomyolysis was uncommonly reported. Special attention should be paid to patients with 
neuromuscular conditions associated with CK elevation and rhabdomyolysis. 
 
CK and creatinine levels should be monitored monthly during the first 6 months of treatment and as 
clinically indicated. The patient should be advised to maintain an adequate fluid intake during 
treatment. Depending on the severity of symptoms, degree of CK elevation or creatinine elevation, 
dose reduction, dose interruption or permanent discontinuation of binimetinib may be required (see 
Table 1 in section 4.2). 
 
Hypertension 
 
Hypertension, or worsening of pre-existing hypertension, can occur with the use of binimetinib. Blood 
pressure should be measured at baseline and monitored during treatment, with control of hypertension 
by standard therapy as appropriate. In case of severe hypertension, temporary interruption of 
binimetinib is recommended until hypertension is controlled (see Table 2 in section 4.2). 
 
Venous thromboembolism (VTE) 
 
VTE can occur when binimetinib is administered (see section 4.8). Binimetinib should be used with 
caution in patients who are at risk for, or who have a history of VTE.  
If during treatment patient develops VTE or pulmonary embolism, it should be managed with dose 
interruption, reduction or treatment discontinuation (see Table 1 in section 4.2). 
 
Pneumonitis/Interstitial lung disease 
 
Pneumonitis/ILD can occur with binimetinib. Treatment with binimetinib should be withheld in 
patients with suspected pneumonitis or ILD, including patients presenting new or progressive 
pulmonary symptoms or findings such as cough, dyspnoea, hypoxia, reticular opacities or pulmonary 



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infiltrates (see Table 1 in section 4.2). Binimetinib should be permanently discontinued in patients 
diagnosed with treatment related pneumonitis or ILD.  
 
New primary malignancies 
 
New primary malignancies, cutaneous and non-cutaneous, have been observed in patients treated with 
BRAF inhibitors and can occur when binimetinib is administered in combination with encorafenib 
(see section 4.8). 
 
Cutaneous malignancies 
Cutaneous malignancies such as cutaneous squamous cell carcinoma (cuSCC) including 
kerathoacanthoma has been observed in patients treated with binimetinib when used in combination 
with encorafenib. 
Dermatologic evaluations should be performed prior to initiation of therapy with binimetinib in 
combination with encorafenib, every 2 months while on therapy and for up to 6 months following 
discontinuation of the combination. 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. Binimetinib and encorafenib should be continued without any 
dose modifications.  
 
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 binimetinib in combination with 
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 treatment as clinically appropriate. 
Permanent discontinuation of binimetinib and encorafenib should be considered in patients who 
develops RAS mutation-positive non-cutaneous malignancies. Benefits and risks should be carefully 
considered before administering binimetinib in combination with encorafenib to patients with a prior 
or concurrent cancer associated with RAS mutation. 
 
Liver laboratory abnormalities 
 
Liver laboratory abnormalities including AST and ALT elevations can occur with binimetinib (see 
section 4.8). Liver laboratory values should be monitored before initiation of binimetinib and 
encorafenib and at least monthly during the 6 first months of treatment, and then as clinically 
indicated. Liver laboratory abnormalities should be managed with dose interruption, reduction or 
treatment discontinuation (see Table 1 in section 4.2). 
 
Hepatic impairment 
 
Liver metabolism mainly via glucuronidation is the primary route of elimination of binimetinib (see 
section 5.2). As encorafenib is not recommended in patients with moderate (Child Pugh B) and severe 
hepatic impairment (Child Pugh C), administration of binimetinib is not recommended in these 
patients (see sections 4.2 and 5.2). 
 
Lactose intolerance 
 
Mektovi contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase 
deficiency or glucose-galactose malabsorption should not take this medicinal product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Effects of other medicinal products on binimetinib 
 
Binimetinib is primarily metabolised through UGT1A1 mediated glucuronidation. The extent of drug 
interactions mediated by UGT1A1 is unlikely to be clinically relevant (see section 5.2); however, as 



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this has not been evaluated in a formal clinical study, UGT1A1 inducers (such as rifampicin and 
phenobarbital) and inhibitors (such as indinavir, atazanavir, sorafenib) should be co-administered with 
caution. 
 
While encorafenib is a relatively potent reversible inhibitor of UGT1A1, no differences in binimetinib 
exposure have been observed clinically when binimetinib is co-administered with encorafenib (see 
section 5.2). 
 
Inducers of CYP1A2 enzymes (such as carbamazepine and rifampicin) and inducers of Pgp transport 
(such as Saint John's wort or phenytoin) may decrease binimetinib exposure, which could result in a 
decrease of efficacy. 
 
Effects of binimetinib on other medicinal products 
 
Binimetinib is a potential inducer of CYP1A2, and caution should be taken when it is used with 
sensitive substrates (such as duloxetine or theophylline). 
 
Binimetinib is a weak inhibitor of OAT3, and caution should be taken when it is used with sensitive 
substrates (such as pravastatin or ciprofloxacin). 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/Contraception in females 
 
Women of childbearing potential must use effective contraception during treatment with binimetinib 
and for at least 1 month following the last dose. 
 
Pregnancy 
 
There are no data from the use of binimetinb in pregnant women. Studies in animals have shown 
reproductive toxicity (see section 5.3). Binimetinib is not recommended during pregnancy and in 
women of childbearing potential not using contraception. If binimetinib is used during pregnancy, or if 
the patient becomes pregnant while taking binimetinib, the patient should be informed of the potential 
hazard to the foetus. 
 
Breast-feeding 
 
It is unknown whether binimetinib or its metabolite 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 Mektovi 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 effect on fertility in humans for binimetinib. 
 
4.7 Effects on ability to drive and use machines 
 
Binimetinib has minor influence on the ability to drive or use machines. Visual disturbances have been 
reported in patients treated with binimetinib during clinical studies. Patients should be advised not to 
drive or use machines if they experience visual disturbances or any other adverse reaction that may 
affect their ability to drive and use machines (see sections 4.4 and 4.8). 
 



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4.8 Undesirable effects 
 
Summary of safety profile 
 
The safety of binimetinib (45 mg orally twice daily) in combination with encorafenib (450 mg orally 
once daily) (hereafter referred to as Combo 450) was evaluated in 274 patients with BRAF V600 
mutant unresectable or metastatic melanoma, based on two Phase II studies (CMEK162X2110 and 
CLGX818X2109) and one Phase III study (CMEK162B2301, Part 1) (hereafter referred to as the 
pooled Combo 450 population). At the recommended dose (n = 274) in patients with unresectable or 
metastatic melanoma, the most common adverse reactions (> 25 %) occurring in patients treated with 
binimetinib administered with encorafenib 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. 
 
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) and not known (cannot be estimated from the available 
data).  
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 
  

Table 3: Adverse reactions occurring in patients receiving binimetinib in combination with 
encorafenib at the recommended dose (n = 274) 

System Organ Class Adverse reaction  Frequency (All grades) 

Neoplasms benign, 
malignant and unspecified 

Cutaneous squamous cell carcinomaa Common 
Basal cell carcinoma* Common 
Skin papilloma*  Common 

Blood and lymphatic 
system disorders 

Anaemia Very common 

Immune system disorders Hypersensitivityb Common 

Nervous system disorders 

Neuropathy peripheral*  Very common 
Dizziness* Very common 
Headache*  Very common 
Dysgeusia  Common 
Facial paresisc Uncommon 

Eye disorders 
Visual impairment* Very common 
RPED* Very common 
Uveitis* Common 

Cardiac disorders Left ventricular dysfunctiond Common 

Vascular disorders 
Haemorrhagee  Very common 
Hypertension* Very common 
Venous thromboembolismf  Common 



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Gastrointestinal disorders 

Abdominal pain* Very common 
Diarrhoea* Very common 
Vomiting*  Very common 
Nausea Very common 
Constipation Very common 
Colitisg  Common 
Pancreatitis*   Uncommon 

Skin and subcutaneous 
tissue disorders 

Hyperkeratosis * Very common 
Rash * Very common 
Dry skin*  Very common 
Pruritus*  Very common 
Alopecia*  Very common 
Photosensitivity* Common 
Dermatitis acneiform* Common 
Palmar-plantar erythrodysaesthesia 
syndrome (PPES) 

Common 

Erythema* Common 
Panniculitis* Common 

Musculoskeletal and 
connective tissue disorders 

Arthralgia*  Very common 
Muscular disorders/Myalgiah Very common 
Back pain  Very common 
Pain in extremity Very common 
Rhabdomyolysis Uncommon 

Renal and urinary 
disorders 

Renal failure* Common 

General disorders and 
administration site 
conditions 

Pyrexia*   Very common 
Peripheral oedema i Very common 
Fatigue*  Very common 

Investigations 

Blood creatine phosphokinase 
increased 

Very Common 

Transaminase increased* Very Common 
Gamma-glutamyl transferase 
increased* 

Very Common 

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

*composite terms which included more than one preferred term 
a includes keratoacanthoma, squamous cell carcinoma, lip squamous cell carcinoma and squamous cell 
carcinoma of skin  
b includes angioedema, drug hypersensitivity, hypersensitivity, hypersensitivity vasculitis and urticaria 
c includes facial nerve disorder, facial paralysis, facial paresis 
d includes left ventricular dysfunction, ejection fraction decreased, cardiac failure and ejection fraction 
abnormal 
e includes haemorrhage at various sites including cerebral haemorrhage 
f includes pulmonary embolism, deep vein thrombosis, embolism, thrombophlebitis, thrombophlebitis 
superficial and thrombosis 
g includes colitis, colitis ulcerative, enterocolitis and proctitis 
h includes myalgia, muscular weakness, muscle spasm, muscle injury, myopathy, myositis 
i includes fluid retention, peripheral oedema, 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 



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neuropathy, haemorrhage, hypertension, pruritus (common) and colitis, increased amylase and 
increased lipase (uncommon). 
 
Description of selected adverse reactions 
 
Cutaneous malignancies 
CuSCC was reported when binimetinib was used in combination with encorafenib (see section 4.8 of 
encorafenib SmPC). 
 
Ocular events 
In the pooled Combo 450 population, RPED was reported in 29.6 % (81/274) of patients. RPED was 
Grade 1 (asymptomatic) in 21.2 % (58/274) of patients, Grade 2 in 6.6 % (18/274) of patients and 
Grade 3 in 1.8 % (5/274) of patients. Most events were reported as retinopathy, retinal detachment, 
subretinal fluid, macular oedema, and chorioretinopathy and led to dose interruptions or dose 
modifications in 4.7 % (13/274) of patients. The median time to onset of the first event of RPED (all 
grades) was 1.5 month (range 0.03 to 17.5 months).  
Visual impairment, including vision blurred and reduced visual acuity, occurred in 21.5 % (59/274) of 
patients. Visual impairment was generally reversible. 
Uveitis was also reported when binimetinib was used in combination with encorafenib (see section 4.8 
of encorafenib SmPC). 
 
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 
In the pooled Combo 450 population, LVD was reported in 8.4 % (23/274) of patients. Grade 3 events 
occurred in 1.1 % (3/274) of patients. LVD led to treatment discontinuation in 0.4% (1/274) of 
patients and led to dose interruptions or dose reductions in 6.6 % (18/274) of patients.  
The median time to first occurrence of LVD (any grade) was 4.4 months (range 0.03 to 21.3 months) 
in patients who developed an LVEF below 50 %. The mean LVEF value dropped by 5.9 % in the 
pooled Combo 450 population, from a mean of 63.9 % at baseline to 58.1 %. LVD was generally 
reversible following dose reduction or dose interruption. 
 
Haemorrhage 
Haemorrhagic events were observed in 17.9 % (49/274) of patients in the pooled Combo 450 
population. Most of these cases were Grade 1 or 2 (14.6 %) and 3.3 % were Grade 3 or 4 events. Few 
patients requiring 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 occurred 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.  
 
Hypertension  
New onset elevated blood pressure or worsening of pre-existing hypertension were reported in 11.7 % 
(32/274) of patients treated with the Combo 450. Hypertension events were reported as Grade 3 in 
5.5 % (15/274) of patients, including hypertensive crisis (0.4 % (1/274)). Hypertension led to dose 
interruption or adjustment in 2.9 % of patients. Hypertensive adverse reactions required additional 
therapy in 8.0 % (22/274) of patients.  
 



14 

Venous thromboembolism 
In patients treated with Combo 450, VTE occurred in 4.7 % (13/274) of patients, including 2.2 % 
(6/274) of patients who developed pulmonary embolism. In the pooled Combo 450 population, VTE 
was reported as Grade 1 or 2 in 3.6 % (10/274) of patients and Grade 3 or 4 in 1.1 % (3/274) of 
patients. VTE led to dose interruptions or dose modifications in 1.1 % (3/274) patients and to 
additional therapy in 4.7 % (13/274) of patients. 
 
Pancreatitis 
Pancreatitis was reported when binimetinib was used in combination with encorafenib (see section 4.8 
of encorafenib SmPC). 
 
Dermatologic reactions 
Dermatologic reactions may occur when binimetinib is used in combination with encorafenib. 
 
Rash 
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 treatment 
discontinuation in 0.4 % (1/274) of patients and to dose interruption or dose modification in 1.1 % 
(3/274) of patients. 
 
Dermatitis acneiform 
In patients treated with Combo 450, dermatitis acneiform occurred in 4.4 % (12/274) of patients, was 
Grade 1 and 2 and no event led to treatment discontinuation. Dose modification was reported in 0.7 % 
(2/274) of patients.  
 
Palmar-plantar erythrodysaesthesia syndrome 
PPES can occur when binimetinib is used in combination with encorafenib (see section 4.8 of 
encorafenib SmPC). 
 
Photosensitivity 
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.  
 
Facial paresis 
Facial paresis was reported when binimetinib was used in combination with encorafenib (see 
section 4.8 of encorafenib SmPC). 
 
CK elevation/rhabdomyolysis 
In the pooled Combo 450 population, mostly mild asymptomatic blood CK elevation was reported in 
27.0 % (74/274) of patients. The incidence of Grade 3 or 4 adverse reactions was 5.8 % (16/274). The 
median time to onset of the first event was 2.7 months (range: 0.5 to 17.5 months). 
 
Rhabdomyolysis was reported in 0.4 % (1/274) of patients treated with encorafenib in combination 
with binimetinib. In this patient, rhabdomyolysis was observed with concomitant symptomatic 
Grade 4 CK elevation. 
 
Renal dysfunction 
Blood creatinine elevation and renal failure occurred when binimetinib was used in combination with 
encorafenib (see section 4.8 of encorafenib SmPC). 
 
Liver laboratory abnormalities 
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) 



15 

 
In Study CMEK162B2301-Part 2, in the Combo 300 arm, the incidences of liver laboratory 
abnormalities are listed below:  

• 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) 

 
Gastrointestinal disorders   
In the pooled Combo 450 population, diarrhoea was observed in 38 % (104/274) of patients and was 
Grade 3 or 4 in 3.3 % (9/274) of patients. Diarrhoea led to dose 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.  
 
Gastrointestinal disorders were typically managed with standard therapy. 
 
Anaemia 
In the pooled Combo 450 population, anaemia was reported in 19.7 % (54/274) of patients; 4.7 % 
(13/274) of patients had 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 
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.  
 
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. 
 
Fatigue 
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. 
 



16 

Special populations 
 
Elderly 
 
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 proportion 
of patients experiencing adverse events and serious adverse events were similar in patients aged <65 
years and those aged > 65 years. The most common adverse events 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. In the small group of patients aged ≥ 75 years (n=15), patients 
were more likely to experience serious adverse events and adverse events leading to discontinuation of 
treatment.  
 
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 
 
The highest dose of binimetinib evaluated as single agent in clinical studies was 80 mg administered 
orally twice daily and was associated with ocular (chorioretinopathy) and skin toxicities (dermatitis 
acneiform).  
 
There is no specific treatment of overdose. If overdose occurs, the patient should be treated 
supportively with appropriate monitoring as necessary.  
Since binimetinib is highly bound to plasma proteins, haemodialysis is likely to be ineffective in the 
treatment of overdose with binimetinib.  
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: antineoplastic agent, protein kinase inhibitor, ATC code: L01XE41 
 
Mechanism of action 
 
Binimetinib is an ATP-uncompetitive, reversible inhibitor of the kinase activity of mitogen-activated 
extracellular signal regulated kinase 1 (MEK1) and MEK2. In cell free system, binimetinib inhibits 
MEK1 and MEK2 with the half maximal inhibitory concentration (IC50)’s in the 12-46 nM. MEK 
proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which 
promotes cellular proliferation. In melanoma and other cancers, this pathway is often activated by 
mutated forms of BRAF which activates MEK. Binimetinib inhibits activation of MEK by BRAF and 
inhibits MEK kinase activity. Binimetinib inhibits growth of BRAF V600 mutant melanoma cell lines 
and demonstrates anti-tumour effects in BRAF V600 mutant melanoma animal models.  
 
Combination with encorafenib 
 
Binimetinib and encorafenib (a BRAF inhibitor, see section 5.1 of encorafenib SmPC) both inhibit the 
MAPK pathway resulting in higher anti-tumour activity.   
Additionally, the combination of encorafenib and binimetinib prevented the emergence of treatment 
resistance in BRAF V600E mutant human melanoma xenografts in vivo. 
 



17 

Clinical efficacy and safety 
 
BRAF V600 mutant unresectable or metastatic melanoma 
The safety and efficacy of binimetinib in combination with encorafenib were evaluated in a 2-part 
Phase III, randomised (1:1:1) active-controlled, open-label, multicenter 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 binimetinib 45 mg orally twice daily plus 
encorafenib 450 mg orally daily (Combo 450, n = 192), encorafenib 300 mg orally daily (hereafter 
referred to as 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 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 encorafenib 300 mg and 6.2 months in patients treated with vemurafenib. The 
median relative dose intensity (RDI) for Combo 450 was 99.6 % for binimetinib and 100 % for 
encorafenib 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 4 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.  
 



18 

Table 4: Study CMEK162B2301, Part 1: Progression-free survival and confirmed overall 
response results (independent central review) 
 Encorafenib + 

binimetinib  
n = 192 
(Combo 450) 

Encorafenib 
 
n = 194 
(Enco 300) 

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 

 

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 (%) 
(95 % CI) 

121 (63.0) 
(55.8, 69.9) 

98 (50.5) 
(43.3, 57.8) 

77 (40.3) 
(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 (%) 
(95 % CI) 

177 (92.2) 
(87.4, 95.6) 

163 (84.0) 
(78.1, 88.9) 

156 (81.7) 
(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) 
 



19 

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

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

 
 
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 5 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). 
 



20 

Table 5: 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) 

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

0.61 (0.47, 0.79) 
< 0.0001 

   

HRa (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

 



21 

 
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 reaction. 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 of encorafenib 450 mg once daily in combination with 45 mg 
binimetinib twice daily (Combo 450), the incidence of new QTc 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. QTc 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 section 5.1 of encorafenib SmPC). 
 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
binimetinib in one or more subsets of the paediatric population in melanoma (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of binimetinib were studied in healthy subjects and patients with solid tumours 
and advanced and unresectable or metastatic cutaneous melanoma. After repeat twice-daily dosing 
concomitantly with encorafenib, steady-state conditions for binimetinib were reached within 15 days 
with no major accumulation. The mean (CV %) Cmax,ss was 654 ng/mL (34.7 %) and mean AUCss was 
2.35 ug.h/mL (28.0 %) in combination with encorafenib as estimated by population PK modelling. 
Binimetinib pharmacokinetics have been shown to be approximately dose-linear. 



22 

 
Absorption 
 
After oral administration, binimetinib is rapidly absorbed with a median Tmax of 1.5 hours. Following a 
single oral dose of 45 mg [14C] binimetinib in healthy subjects, at least 50 % of the binimetinib dose 
was absorbed. Administration of a single 45 mg dose of binimetinib with a high-fat, high-calorie meal 
decreased the maximum binimetinib concentration (Cmax) by 17 %, while the area under the 
concentration-time curve (AUC) was unchanged. A drug interaction study in healthy subjects 
indicated that the extent of binimetinib exposure is not altered in the presence of a gastric pH-altering 
agent (rabeprazole). 
 
Distribution 
 
Binimetinib is 97.2 % bound to human plasma proteins in vitro. Binimetinib is more distributed in 
plasma than blood. In humans, the blood-to-plasma ratio is 0.718. Following a single oral dose of 
45 mg [14C] binimetinib in healthy subjects, the apparent volume of distribution (Vz/F) of binimetinib 
is 374 L. 
 
Biotransformation 
 
Following a single oral dose of 45 mg [14C] binimetinib in healthy subjects, the primary 
biotransformation pathways of binimetinib observed in humans include glucuronidation, N-
dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain. The maximum 
contribution of direct glucuronidation to the clearance of binimetinib was estimated to have been 
61.2 %. Following a single oral dose of 45 mg [14C] binimetinib in healthy subjects, approximately 
60 % of the circulating radioactivity AUC in plasma was attributable to binimetinib. In vitro, CYP1A2 
and CYP2C19 catalyse the formation of the active metabolite, which represents less than 20 % of the 
binimetinib exposure clinically. 
 
Elimination 
 
Following a single oral dose of 45 mg [14C] binimetinib in healthy subjects, a mean of 62.3 % of the 
radioactivity was eliminated in the feces while 31.4 % was eliminated in the urine. In urine, 6.5 % of 
the radioactivity was excreted as binimetinib. The mean (CV %) apparent clearance (CL/F) of 
binimetinib was 28.2 L/h (17.5 %). The median (range) binimetinib terminal half-life (T1/2) was 8.66 h 
(8.10 to 13.6 h). 
 
Medicinal product interactions 
 
Effect of UGT1A1 inducers or inhibitors on binimetinib 
Binimetinib is primarily metabolised through UGT1A1 mediated glucuronidation. In clinical study 
sub-analysis, however, there was no apparent relationship observed between binimetinib exposure and 
UGT1A1 mutation status. In addition, simulations to investigate the effect of 400 mg atazanavir 
(UGT1A1 inhibitor) on the exposure of 45 mg binimetinib predicted similar binimetinib Cmax in the 
presence or absence of atazanavir. Therefore, the extent of drug interactions mediated by UGT1A1 is 
minimal, and unlikely clinically relevant; however, as this has not been evaluated in a formal clinical 
study, UGT1A1 inducers or inhibitors should be administered with caution.  
 
Effect of CYP enzymes on binimetinib 
In vitro, CYP1A2 and CYP2C19 catalyse the formation of the active metabolite, AR00426032 (M3) 
by oxidative N-desmethylation.  
 
Effect of binimetinib on CYP substrates 
Binimetinib is a weak reversible inhibitor of CYP1A2 and CYP2C9. 
 



23 

Effect of transporters on binimetinib 
In vitro experiments indicate that binimetinib is a substrate of P-glycoprotein (P-gp) and breast cancer 
resistance protein (BCRP). Inhibition of P-gp or BCRP is unlikely to result in a clinically important 
increase in binimetinib concentrations as binimetinib exhibits moderate to high passive permeability.  
 
Effect of binimetinib on transporters 
Binimetinib is a weak inhibitor of OAT3. No clinicallly significant drug-drug interactions caused by 
binimetinib on other transporters is expected. 
 
Binimetinib is metabolised by UGTs and CYP1A2 and is a substrate for Pgp. Specific inducers of 
these enzymes have not been studied and may result in a loss of efficacy. 
 
Special populations 
 
Age, body weight 
Based on a population pharmacokinetic analysis, age or body weight do not have a clinically important 
effect on the systemic exposure of binimetinib. 
 
Gender 
Based on a population pharmacokinetic (PK) analysis, the PK of binimetinib were similar in males as 
compared with females. 
 
Race 
There are insufficient data to evaluate potential differences in the exposure of binimetinib by race or 
ethnicity. 
 
Hepatic impairment 
As binimetinib is primarily metabolised and eliminated via the liver, patients with moderate to severe 
hepatic impairment may have increased exposure. Results from a dedicated clinical study with 
binimetinib only indicate similar exposures in patients with mild impairment (Child-Pugh Class A) 
and subjects with normal liver function. A two-fold increase in total binimetinib exposure (AUC) was 
observed in patients with moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic 
impairment (see section 4.2). This increase expends to three fold in both moderate and severe hepatic 
impairment when considering unbound binimetinib exposure (see section 4.2). 
 
Gilbert’s syndrome 
Binimetinib has not been evaluated in patients with Gilbert’s disease. The main route of hepatic 
transformation of binimetinib being glucoronidation, the decision for treatement should be made by 
the treating physician taking into account the individual benefit-risk. 
 
Renal impairment 
Binimetinib undergoes minimal renal elimination. Results from a dedicated clinical study showed that 
patients with severe renal impairment (eGFR ≤ 29 mL/min/1.73 m2), had a 29 % increase in exposure 
(AUCinf), a 21 % increase in Cmax, and a 22 % decrease in CL/F compared to matching healthy 
subjects. These differences were within the variability observed for these parameters in both cohorts of 
this study (25 % - 49 %) and the variability previously observed in patient clinical studies, hence these 
differences are unlikely to be clinically relevant. 
 
The effects of renal impairment on the pharmacokinetics of binimetinib in combination with 
encorafenib have not been evaluated clinically.  
 
5.3 Preclinical safety data 
 
Repeated oral administration of binimetinib in rats for up to 6 months was associated with soft tissue 
mineralisation, gastric mucosal lesions and reversible minimal to mild clinical pathology changes at 7 
to 12.5 times human therapeutic exposures. In a gastric irritation study in rats, an increased incidence 
of superficial mucosal lesions and of hemorrhagic ulcers were observed. In cynomolgus monkeys, oral 



24 

administration of binimetinib was associated with gastro-intestinal intolerance, moderate clinical 
pathology changes, bone marrow hypercellularity and microscopic findings of gastrointestinal 
inflammation, reversible at the lowest doses which were below human therapeutic exposures. 
 
Carcinogenic potential of binimetinib was not evaluated. Standard genotixicity studies with 
binimetinib were negative. 
 
The potential embryo-foetal effects of binimetinib were evaluated in rats and rabbits. In rats, lower 
gestational body weight gain and fetal body weights and a decreased number of ossified fetal 
sternebrae were noted. No effects were noted at 14-times the human therapeutic exposure .  
In rabbits, mortality, maternal physical signs of toxicity, lower gestational body weight and abortion 
were noted. The number of viable foetuses and foetal body weights were reduced and 
post-implantation loss and resorptions were increased. An increased litter incidence of foetal 
ventricular septal defects and pulmonary trunk alterations was noted at the highest doses. No effects 
were observed at 3times the human therapeutic exposure.   
 
Fertility studies were not conducted with binimetinib. In repeat-dose toxicity studies, no concern in 
terms of fertility was raised from pathological examination of reproductive organs in rats and 
monkeys. 
 
Binimetinib has phototoxic potential in vitro.  
A minimal risk for photosensitisation was shown in vivo at an oral dose providing 3.8-fold higher 
exposure than that achieved with the recommended dose in humans. These data indicate that there is 
minimal risk for phototoxicity with binimetinib at therapeutic doses in patients. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core  
Lactose monohydrate  
Cellulose microcrystalline (E460i) 
Silica colloidal anhydrous (E551) 
Croscarmellose sodium (E468) 
Magnesium stearate  (E470b) 
 
Film-coating  
Polyvinyl alcohol (E1203) 
Macrogol 3350 (E1521) 
Titanium dioxide (E171) 
Talc (E533b) 
Iron oxide yellow (E172) 
Iron oxide black (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions.  
 



25 

6.5 Nature and contents of container  
 
PVC/PVDC/Alu blister containing 12 tablets. Each pack contains either 84 or 168 tablets. 
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)  
 
EU/1/18/1315/001 84 film-coated tablets 
EU/1/18/1315/002 168 film-coated tablets 
 
 
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. 



26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 
 

 



27 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer 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  
 
The requirements for submission of periodic safety update reports 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 shall submit the first periodic safety update report 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 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.  

 
 



28 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



29 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



30 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Mektovi 15 mg film-coated tablets 
binimetinib  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 15 mg binimetinib. 
 
 
3. LIST OF EXCIPIENTS 
 
The tablets also contain lactose. See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
84 film-coated tablets 
168 film-coated tablets 
 
 
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 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 



31 

 
 
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/1/18/1315/001 84 film-coated tablets 
EU/1/18/1315/002 168 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE  
 
 
16. INFORMATION IN BRAILLE 
 
mektovi 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN: 
NN: 
 



32 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Mektovi 15 mg tablets 
binimetinib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pierre Fabre Médicament 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



33 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



34 

Package leaflet: Information for the patient 
 

Mektovi 15 mg film-coated tablets 
binimetinib 

 
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 Mektovi is and what it is used for  
2. What you need to know before you take Mektovi  
3. How to take Mektovi  
4. Possible side effects  
5. How to store Mektovi  
6. Contents of the pack and other information 
 
 
1. What Mektovi is and what it is used for 
 
Mektovi is an anti-cancer medicine that contains the active substance binimetinib. It is used in adults 
in combination with another medicine containing encorafenib to treat 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. 

 
Mutations in the BRAF gene can produce proteins that cause the melanoma to grow. Mektovi targets 
another protein called “MEK” that stimulates cancer cell growth. When Mektovi is used in 
combination with encorafenib (which targets the changed “BRAF” protein), the combination slows 
down or stops the growth of your cancer. 
 
 
2. What you need to know before you take Mektovi  
 
Before starting treatment your doctor will check for BRAF mutation.  
 
As Mektovi is to be used in combination with encorafenib, read the encorafenib leaflet carefully as 
well as this leaflet.   
 
Do not take Mektovi  
-  if you are allergic to binimetinib or any of the other ingredients of this medicine (listed in 

section 6). 
 



35 

Warnings and precautions  
Talk to your doctor, pharmacist or nurse before taking Mektovi about all of your medical conditions, 
particularly if you have any of the following:   

• heart problems 
• bleeding problems or if you are taking medicines that may cause bleeding  
• eye problems including glaucoma or increased pressure in your eyes 
• muscle problems 
• high blood pressure 
• blood clots 
• lung or breathing problems 
• liver problems  

 
Tell your doctor if you have ever had blockage in the vein carrying blood away from the eye (retinal 
vein occlusion), as Mektovi is not recommended in such cases. 
 
Tell your doctor if you have had a different type of cancer than melanoma, as binimetinib when taken 
with encorafenib 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: Mektovi can make your heart work less well, or make existing heart problems 
worse. Your doctor will check that your heart is working properly before and during your 
treatment with this medicine. 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: Mektovi 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: Mektovi can cause serious eye problems. Talk to your doctor immediately if 

you get blurred vision, loss of vision or other vision changes (such as 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 Mektovi.  
 

• Muscle problems: Mektovi can cause breakdown of muscle (rhabdomyolysis). Your doctor 
will run blood tests to check for muscle problems before and during treatment. As a 
precaution, drink plenty of fluids during treatment. Talk to your doctor immediately if you get 
muscle pain, cramps, stiffness, spasm, dark urine. 
 

• High blood pressure: Mektovi can raise blood pressure. Your doctor or nurse will check your 
blood pressure before and during treatment with Mektovi. Talk to your doctor immediately if 
you get severe headache, feel dizzy, lightheaded or if your blood pressure measured on a home 
blood pressure device is much higher than usual. 
 

• Blood clots: Mektovi can cause blood clots in your arms or legs, and if a clot travels to your 
lungs it could lead to death. Talk to your doctor immediately if you get chest pain, sudden 
shortness of breath, trouble breathing, pain in your legs with or without swelling, swelling in 
your arms and legs, or a cool, pale arm or leg. If necessary, your doctor may interrupt your 
treatment or stop it altogether. 

 
• Lung or breathing problems: This medicine may cause lung or breathing problems including 

inflammation of the lungs (pneumonitis or interstitial lung disease); signs and symptoms can 



36 

include: cough, shortness of breath or fatigue. If necessary, your doctor may interrupt your 
treatment or stop it altogether.  
 

• Skin changes: Mektovi, when taken with encorafenib, may cause other types of skin cancer 
such as cutaneous squamous cell carcinoma. Your doctor will check your skin before initiation 
of treatment, every 2 months during treatment, and for up to 6 months after you stop taking 
these medicines to look for any new skin cancer. Tell your doctor immediately if you detect 
any skin changes during and after the 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 the initiation and at the end of your treatment. 

 
• Liver problems: Mektovi can cause abnormal blood tests related to your liver (raised levels of 

liver enzymes). Your doctor will run blood tests to check your liver before and during 
treatment.  

 
Children and adolescents 
Mektovi 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 Mektovi 
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines.  
Some medicines may affect how Mektovi 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 bacterial infections such as rifampicin, ciprofloxacin 
• some medicines typically used to treat epilepsy such as phenobarbital, phenytoin, 

carbamazepine 
• some medicines to treat HIV such as indinavir, atazanavir 
• a medicine for carcinoma treatment called sorafenib 
• an herbal treatment for depression: St. John’s wort  
• medicine used to treat depression such as duloxetine 
• medicine typically used to treat high cholesterol such as pravastatin 
• a medicine used to treat breathing problems, theophylline.  

 
Pregnancy and breast-feeding  
Pregnancy 
Mektovi is not recommended during pregnancy. It may cause permanent 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 Mektovi, and you must continue to use reliable contraception at least 1 month after taking your 
last dose. Contact your doctor straightaway if you become pregnant while taking Mektovi.  
 
Breast-feeding 
Mektovi is not recommended while breast-feeding. It is not known if Mektovi passes into breast milk. 
If you are breast-feeding, or planning to breast-feed, ask your doctor for advice before taking this 
medicine.  
 
Driving and using machines 
Mektovi 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 use 
machines (see section 4), while taking Mektovi. Talk to your doctor if you are not sure you can drive. 



37 

 
Mektovi contains lactose 
If you have been told by your doctor that you have an intolerance to some sugars, talk to your doctor 
before taking this medicine. 
 
 
3. How to take Mektovi 
 
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.  
 
The recommended dose of Mektovi is 45 mg (3 tablets of 15 mg) twice daily, taken about 12 hours 
apart (corresponding to a daily dose of 90 mg). You will also receive treatment with another medicine, 
encorafenib. 
 
If you get serious side effects (such as heart, eye or skin problems) your doctor may lower the dose or 
stop treatment temporarily or permanently.  
 
How to take Mektovi 
Swallow the tablets whole with water. Mektovi can be taken with food or between meals. 
 
If you are sick  
If you vomit at any time after taking Mektovi, do not take an additional dose. Take the next dose as 
scheduled. 
 
If you take more Mektovi than you should 
If you take more tablets than you should, contact your doctor, pharmacist or nurse straightaway. If 
possible, show them this leaflet and the medicine package. 
 
If you forget to take Mektovi 
If you miss a dose of Mektovi, take it as soon as you remember. However, if the missed dose is more 
than 6 hours late, skip that dose and take your next dose at the usual time. Then continue taking your 
tablets at regular times as usual. 
Do not take a double dose to make up for a forgotten dose. 
 
If you stop taking Mektovi 
It is important to take Mektovi 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. 
 
Serious side effects 
 
Mektovi 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: Mektovi 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 



38 

• swelling in the legs 
 
High blood pressure: Mektovi can increase blood pressure. Tell your doctor immediately if you get 
severe headache, feel dizzy or lightheaded or if your blood pressure measured on a home blood 
pressure device is much higher than usual. 
 
Blood clots: Mektovi may cause blood clots (venous thromboembolism including pulmonary 
embolism); signs and symptoms can include: 

• chest pain 
• sudden shortness of breath or trouble breathing 
• pain in your legs with or without swelling 
• swelling in your arms and legs 
• a cool, pale arm or leg 

 
Eye problems: Mektovi can cause fluid to leak under the retina in the eye, leading to detachment of 
different layers in the eye (retinal pigment epithelial detachment) which could lead to: 

• blurred vision, loss of vision, or other vision changes (such as coloured dots in your vision) 
• halo (seeing blurred outline around objects) 
• eye pain, swelling or redness  

 
Muscle problems: Mektovi 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 

 
Bleeding problems: Mektovi can cause serious bleeding problems. Tell your doctor right away if you 
have any unusual bleeding or 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 

 
Other skin cancers: When Mektovi is taken with encorafenib, the patient may develop different 
types of skin cancer such as cutaneous squamous cell carcinoma. Usually, these skin cancers (see 
also section 2) are confined to a small area and can be removed with surgery and treatment with 
Mektovi (and encorafenib) can continue without interruption.  
 
Other side effects when Mektovi and encorafenib are taken together: 
Besides the serious side effects mentioned above, people taking Mektovi and encorafenib together 
may also get the following side effects.  
 
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 
- problems with your vision (visual impairment) 
- stomach pain 
- diarrhoea 
- being sick (vomiting) 
- feeling sick (nausea)  
- constipation 



39 

- 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 result related to blood creatine kinase, indicating damage to heart and muscle  
 
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) 
- 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 
 
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 Mektovi 
 
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 blister and the carton after EXP. 
The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
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. 
 
 



40 

6. Contents of the pack and other information 
 
What Mektovi contains  
- The active substance is binimetinib. Each film-coated tablet contains 15 mg of binimetinib.  
- The other ingredients are: 

•  Tablet core: lactose monohydrate, cellulose microcrystalline (E460i), silica colloidal 
anhydrous (E551), croscarmellose sodium (E468) and magnesium stearate (E470b). See 
section 2 “Mektovi contains lactose”. 

•  Tablet film-coat: polyvinyl alcohol (E1203), macrogol 3350 (E1521), titanium dioxide 
(E171), talc (E533b), iron oxide yellow (E172) and iron oxide black (E172). 

 
What Mektovi looks like and contents of the pack 
Mektovi film-coated tablets are yellow/dark yellow, unscored biconvex, oval film-coated tablets 
debossed with “A” on one side and “15” on the other side.  
 
Mektovi is available in packs of 84 tablets (7 blisters of 12 tablets each) or 168 tablets (14 blisters of 
12 tablets 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. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER 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