Cotellic

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 
 
  



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1. NAME OF THE MEDICINAL PRODUCT 
 
Cotellic 20 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains cobimetinib hemifumarate equivalent to 20 mg cobimetinib. 
 
Excipient with known effect 
 
Each film-coated tablet contains 36 mg lactose monohydrate.  
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet.  
 
White, round film-coated tablets of approximately 6.6 mm diameter, with “COB” debossed on one 
side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Cotellic is indicated for use in combination with vemurafenib 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 
 
Treatment with Cotellic in combination with vemurafenib should only be initiated and supervised by a 
qualified physician experienced in the use of anticancer medicinal products.  
 
Before starting this treatment, patients must have BRAF V600 mutation-positive melanoma tumour 
status confirmed by a validated test (see sections 4.4 and 5.1). 
 
Posology 
 
The recommended dose of Cotellic is 60 mg (3 tablets of 20 mg) once daily.  
 
Cotellic is taken on a 28 day cycle. Each dose consists of three 20 mg tablets (60 mg) and should be 
taken once daily for 21 consecutive days (Days 1 to 21-treatment period); followed by a 7-day break 
(Days 22 to 28-treatment break). Each subsequent Cotellic treatment cycle should start after the 7-day 
treatment break has elapsed.  
 
For information on the posology of vemurafenib, please refer to its SmPC. 
 
Duration of treatment 
 
Treatment with Cotellic should continue until the patient no longer derives benefit or until the 
development of unacceptable toxicity (see Table 1 below). 
 



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Missed doses  
 
If a dose is missed, it can be taken up to 12 hours prior to the next dose to maintain the once-daily 
regimen. 
 
Vomiting 
 
In case of vomiting after administration of Cotellic, the patient should not take an additional dose on 
that day and treatment should be continued as prescribed the following day.  
 
General dose modifications 
 
The decision on whether to reduce the dose for either or both treatments should be based on the 
prescriber’s assessment of individual patient safety or tolerability. Dose modification of Cotellic is 
independent of vemurafenib dose modification.  
 
If doses are omitted for toxicity, these doses should not be replaced. Once the dose has been reduced, 
it should not be increased at a later time. 
 
Table 1 below gives general Cotellic dose modification guidance. 
 
Table 1 Recommended Cotellic dose modifications    
 

Grade (CTC-AE)* Recommended Cotellic dose 

Grade 1 or Grade 2 (tolerable)  No dose reduction. Maintain Cotellic at a dose of 
60 mg once daily (3 tablets) 

Grade 2 (intolerable) or Grade 3/4  

1st Appearance Interrupt treatment until Grade ≤ 1, restart treatment 
at 40 mg once daily (2 tablets) 

2nd Appearance Interrupt treatment until Grade ≤ 1, restart treatment 
at 20 mg once daily (1 tablet) 

3rd Appearance Consider permanent discontinuation 
*The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0 
(CTC-AE) 
 
Dose modification advice for haemorrhage 
 
Grade 4 events or cerebral haemorrhage: Cotellic treatment should be interrupted. Cotellic treatment 
should be permanently discontinued for haemorrhage events attributed to Cotellic. 
 
Grade 3 events: Cotellic treatment should be interrupted during evaluation to avoid any potential 
contribution to the event. There is no data on the effectiveness of Cotellic dose modification for 
haemorrhage events. Clinical judgment should be applied when considering restarting Cotellic 
treatment. Vemurafenib dosing can be continued when Cotellic treatment is interrupted, if clinically 
indicated. 
 
Dose modification advice for left ventricular dysfunction 
 
Permanent discontinuation of Cotellic treatment should be considered if cardiac symptoms are 
attributed to Cotellic and do not improve after temporary interruption. 
 



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Table 2 Recommended dose modifications for Cotellic in patients with left ventricular ejection 
fraction (LVEF) decrease from baseline 
 

Patient LVEF value 

Recommended 
Cotellic dose 
modification 

LVEF value 
following 

treatment break 

Recommended Cotellic 
daily dose 

Asymptomatic 

≥ 50%  
(or 40-49% 
and < 10% 

absolute 
decrease 

from 
baseline) 

Continue at 
current dose N/A N/A 

< 40%  
(or 40-49% 
and ≥ 10% 

absolute 
decrease 

from 
baseline)  

Interrupt 
treatment for 

2 weeks 

< 10% absolute 
decrease from 

baseline 

1st occurrence: 40 mg 

2nd occurrence: 20 mg 
3rd occurrence:  
permanent discontinuation 

< 40%  
(or ≥ 10% absolute 

decrease from 
baseline) 

Permanent discontinuation 

Symptomatic N/A 
Interrupt 

treatment for 
4 weeks 

Asymptomatic and 
< 10% absolute 
decrease from 

baseline 

1st occurrence: 40 mg 

2nd occurrence: 20 mg 
3rd occurrence:  
permanent discontinuation 

Asymptomatic and 
< 40%  

(or ≥ 10% absolute 
decrease from 

baseline) 

Permanent discontinuation 

Symptomatic 
regardless of LVEF Permanent discontinuation 

N/A = Not Applicable 
 
Vemurafenib treatment can be continued when Cotellic treatment is modified, if clinically indicated. 
 
Dose modification advice for rhabdomyolysis and creatine phosphokinase (CPK) elevations 
 
Rhabdomyolysis or symptomatic CPK elevations  
 
Cotellic treatment should be interrupted. If rhabdomyolysis or symptomatic CPK elevations do not 
improve within 4 weeks, Cotellic treatment should be permanently discontinued. 
If severity is improved by at least one grade within 4 weeks, Cotellic could be restarted at a dose 
reduced by 20 mg, if clinically indicated.  Patients should be closely monitored. Vemurafenib dosing 
can be continued when Cotellic treatment is modified.  
 
Asymptomatic CPK elevations 
 
Grade 4: Cotellic treatment should be interrupted.  If CPK elevations do not improve to Grade ≤3 
within 4 weeks following dose interruption, Cotellic treatment should be permanently discontinued. 
If CPK improves to Grade ≤3 within 4 weeks, Cotellic could be restarted, if clinically indicated, at a 
dose reduced by 20 mg and the patient should be closely monitored.  Vemurafenib dosing can be 
continued when Cotellic treatment is modified.  
 
Grade ≤3: After rhabdomyolysis has been ruled out, Cotellic dosing does not need to be modified.  
 



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Dose modification advice for Cotellic when used with vemurafenib 
 
Liver laboratory abnormalities 
 
For Grade 1 and 2 liver laboratory abnormalities, Cotellic and vemurafenib should be continued at the 
prescribed dose. 
 
Grade 3: Cotellic should be continued at the prescribed dose. The dose of vemurafenib may be 
reduced as clinically appropriate.  Please refer to the vemurafenib SmPC. 
 
Grade 4: Cotellic treatment and vemurafenib treatment should be interrupted. If liver laboratory 
abnormalities improve to Grade ≤1 within 4 weeks, Cotellic should be restarted at a dose reduced by 
20 mg and vemurafenib at a clinically appropriate dose, per its SmPC.   
 
Cotellic treatment and vemurafenib treatment should be discontinued if liver laboratory abnormalities 
do not resolve to Grade ≤1 within 4 weeks or if Grade 4 liver laboratory abnormalities recur after 
initial improvement. 
 
Photosensitivity 
 
Grade ≤2 (tolerable) photosensitivity should be managed with supportive care.   
 
Grade 2 (intolerable) or Grade ≥3 photosensitivity: Cotellic and vemurafenib should be interrupted 
until resolution to Grade ≤1. Treatment can be restarted with no change in Cotellic dose. Vemurafenib 
dosing should be reduced as clinically appropriate, please refer to its SmPC for further information.  
 
Rash 
 
Rash events may occur with either Cotellic or vemurafenib treatment. The dose of Cotellic and/or 
vemurafenib may be either temporarily interrupted and/or reduced as clinically indicated.   
Additionally, for: 
 
Grade ≤2 (tolerable) rash should be managed with supportive care. Cotellic dosing can be continued 
without modification. 
 
Grade 2 (intolerable) or Grade ≥3 acneiform rash: General dose modification recommendations in 
Table 1 for Cotellic should be followed. Vemurafenib dosing can be continued when Cotellic 
treatment is modified (if clinically indicated).  
 
Grade 2 (intolerable) or Grade ≥3 non-acneiform or maculopapular rash: Cotellic dosing can be 
continued without modification if clinically indicated. Vemurafenib dosing may be either temporarily 
interrupted and/or reduced, please refer to its SmPC for further information. 
 
QT prolongation 
 
If during treatment the QTc exceeds 500 msec, please refer to the vemurafenib SmPC (section 4.2) for 
dose modifications for vemurafenib. No dose modification of Cotellic is required when taken in 
combination with vemurafenib. 
 
Special populations 
 
Elderly patients 
 
No dose adjustment is required in patients aged ≥65 years old. 
 



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Renal impairment 
 
No dose adjustment is recommended in patients with mild or moderate renal impairment based on 
population pharmacokinetic analysis (see section 5.2). There are minimal data for Cotellic in patients 
with severe renal impairment, therefore an effect cannot be excluded. Cotellic should be used with 
caution in patients with severe renal impairment. 
 
Hepatic impairment 
 
No dose adjustment is recommended in patients with hepatic impairment. Patients with severe hepatic 
impairment may have increased plasma concentrations of unbound cobimetinib compared to patients 
with normal hepatic function (see section 5.2). Liver laboratory abnormalities can occur with Cotellic 
and caution should be used in patients with any degree of hepatic impairment (see section 4.4). 
 
Non-Caucasian patients 
 
The safety and efficacy of Cotellic in non-Caucasian patients have not been established. 
 
Paediatric population 
 
The safety and efficacy of Cotellic in children and adolescents below 18 years of age have not been 
established. No data are available. 
 
Method of administration  
 
Cotellic is for oral use. The tablets should be swallowed whole with water. They can 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 
 
Before taking Cotellic in combination with vemurafenib, patients must have BRAF V600 mutation-
positive tumour status confirmed by a validated test. 
  
Cotellic in combination with vemurafenib in patients who have progressed on a BRAF inhibitor 
 
There are limited data in patients taking the combination of Cotellic with vemurafenib who have 
progressed on a prior BRAF inhibitor. These data show that the efficacy of the combination will be 
lower in these patients (see section 5.1). Therefore other treatment options should be considered before 
treatment with the combination in this prior BRAF inhibitor treated population. The sequencing of 
treatments following progression on a BRAF inhibitor therapy has not been established. 
 
Cotellic in combination with vemurafenib in patients with brain metastases 
 
The safety and efficacy of the combination of Cotellic and vemurafenib have not been evaluated in 
patients with a BRAF V600 mutation-positive melanoma which has metastasised to the brain. The 
intracranial activity of cobimetinib is currently unknown (see sections 5.1 and 5.2). 
 



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Haemorrhage 
 
Haemorrhagic events, including major haemorrhagic events can occur (see section 4.8).  
 
Caution should be used in patients with additional risk factors for bleeding, such as brain metastases, 
and/or in patients that use concomitant medicinal products that increase the risk of bleeding (including 
antiplatelet or anticoagulant therapy). For management of haemorrhage please see section 4.2. 
 
Serous retinopathy  
 
Serous retinopathy (fluid accumulation within the layers of the retina) has been observed in patients 
treated with MEK-inhibitors, including Cotellic (see section 4.8). The majority of events were reported 
as chorioretinopathy or retinal detachment. 
 
Median time to initial onset of serous retinopathy events was 1 month (range 0-9 months). Most events 
observed in clinical studies were resolved, or improved to asymptomatic Grade 1, following dose 
interruption or reduction. 
 
Patients should be assessed at each visit for symptoms of new or worsening visual disturbances. If 
symptoms of new or worsening visual disturbances are identified, an ophthalmologic examination is 
recommended. If serous retinopathy is diagnosed, Cotellic treatment should be withheld until visual 
symptoms improve to Grade ≤1. Serous retinopathy can be managed with treatment interruption, dose 
reduction or with treatment discontinuation (see Table 1 in section 4.2). 
 
Left ventricular dysfunction  
 
Decrease in LVEF from baseline has been reported in patients receiving Cotellic (see section 4.8).  
Median time to initial onset of events was 4 months (1-13 months).   
 
LVEF should be evaluated before initiation of treatment to establish baseline values, then after the first 
month of treatment and at least every 3 months or as clinically indicated until treatment 
discontinuation.  Decrease in LVEF from baseline can be managed using treatment interruption, dose 
reduction or with treatment discontinuation (see section 4.2). 
 
All patients restarting treatment with a dose reduction of Cotellic should have LVEF measurements 
taken after approximately 2 weeks, 4 weeks, 10 weeks and 16 weeks, and then as clinically indicated. 
 
Patients with a baseline LVEF either below institutional lower limit of normal (LLN) or below 50% 
have not been studied. 
 
Liver laboratory abnormalities 
 
Liver laboratory abnormalities can occur when Cotellic is used in combination with vemurafenib and 
with vemurafenib as a single agent (please refer to its SmPC). 
 
Liver laboratory abnormalities, specifically increases in alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), and alkaline phosphatase (ALP), have been observed in patients treated with 
Cotellic plus vemurafenib (see section 4.8).  
 
Liver value abnormalities should be monitored by liver laboratory tests before initiation of 
combination treatment and monthly during treatment, or more frequently as clinically indicated (see 
section 4.2). 
 
Grade 3 liver laboratory abnormalities should be managed with vemurafenib treatment interruption or 
dose reduction. Manage Grade 4 liver laboratory abnormalities with treatment interruption, dose 
reduction or with treatment discontinuation of both Cotellic and vemurafenib (see section 4.2). 
 



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Rhabdomyolysis and CPK elevations 
  
Rhabdomyolysis has been reported in patients receiving Cotellic (see section 4.8).  
 
If rhabdomyolysis is diagnosed, Cotellic treatment should be interrupted and CPK levels and other 
symptoms monitored until resolution. Depending on the severity of rhabdomyolysis, dose reduction or 
treatment discontinuation may be required (see section 4.2).  
 
Grade 3 and 4 CPK elevations, including asymptomatic elevations over baseline, also occurred in 
patients receiving Cotellic with vemurafenib in clinical studies(see section 4.8). The median time to 
first occurrence of Grade 3 or 4 CPK elevations was 16 days (range: 11 days to 10 months); the 
median time to complete resolution was 16 days (range: 2 days to 15 months).   
 
Serum CPK and creatinine levels should be measured before initiation of treatment, to establish 
baseline values, and then monitored monthly during treatment, or as clinically indicated. If serum CPK 
is elevated, check for signs and symptoms of rhabdomyolysis or other causes. Depending on the 
severity of symptoms or CPK elevation; treatment interruption, dose reduction or treatment 
discontinuation may be required (see section 4.2). 
 
Diarrhoea 
 
Cases of Grade ≥3 and serious diarrhoea have been reported in patients treated with Cotellic. 
Diarrhoea should be managed with anti-diarrhoeal agents and supportive care. For Grade ≥3 diarrhoea 
that occurs despite supportive care, Cotellic and vemurafenib should be withheld until diarrhoea has 
improved to Grade ≤1. If Grade ≥3 diarrhoea recurs, the dose of Cotellic and vemurafenib should be 
reduced (see section 4.2).  
 
Drug-drug interactions: CYP3A inhibitors 
 
Concurrent use of strong CYP3A inhibitors during treatment with Cotellic should be avoided. Caution 
should be exercised if a moderate CYP3A inhibitor is co-administered with Cotellic. If concomitant 
use with a strong or moderate CYP3A inhibitor is unavoidable, patients should be carefully monitored 
for safety and dose modifications applied if clinically indicated (see Table 1 in section 4.2).  
 
QT prolongation 
 
If during treatment the QTc exceeds 500 msec, please refer to the vemurafenib SmPC sections 4.2 and 
4.4. 
 
Excipients  
 
This medicinal product contains lactose. Patients with rare hereditary problems of galactose 
intolerance, total lactase deficiency or glucosegalactose malabsorption should not take this medicine. 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 
‘sodium-free’.   
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Effects of other medicinal products on cobimetinib 
 
CYP3A inhibitors 
 
Cobimetinib is metabolized by CYP3A and cobimetinib AUC increased approximately 7 fold in the 
presence of a strong CYP3A inhibitor (itraconazole) in healthy subjects. The magnitude of interaction 
could potentially be lower in patients.  
 



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Strong CYP3A inhibitors (see section 4.4.)  
 
Avoid concurrent use of strong CYP3A inhibitors during treatment with cobimetinib. Strong CYP3A 
inhibitors include, but are not limited to ritonavir, cobicistat, telaprevir, lopinavir, itraconazole, 
voriconazole, clarithromycin, telithromycin, posaconazole, nefazodone and grapefruit juice. If 
concomitant use of a strong CYP3A inhibitor is unavoidable, patients should be carefully monitored 
for safety. For strong CYP3A inhibitors used short-term (7 days or less), consider interrupting 
cobimetinib therapy during the duration of inhibitor use. 
 
Moderate CYP3A inhibitors (see section 4.4.)  
 
Caution should be exercised if cobimetinib is co-administered with moderate CYP3A inhibitors. 
Moderate CYP3A inhibitors include, but are not limited to, amiodarone, erythromycin, fluconazole, 
miconazole, diltiazem, verapamil, delavirdine, amprenavir, fosamprenavir, imatinib. When 
cobimetinib is co-administered with a moderate CYP3A inhibitor, patients should be carefully 
monitored for safety.  
 
Mild CYP3A inhibitors  
 
Cobimetinib can be co-administered with mild inhibitors of CYP3A without dose adjustment. 
 
CYP3A inducers 
 
Co-administration of cobimetinib with a strong CYP3A inducer was not assessed in a clinical study, 
however, a reduction in cobimetinib exposure is likely. Therefore, concomitant use of moderate and 
strong CYP3A inducers (e.g. carbamazepine, rifampicin, phenytoin, and St. John’s Wort) should be 
avoided. Alternative agents with no or minimal CYP3A induction should be considered. Given that 
cobimetinib concentrations are likely to be significantly reduced when co-administered with moderate 
to strong CYP3A inducers, patient’s efficacy may be compromised. 
 
P-glycoprotein inhibitors 
 
Cobimetinib is a substrate of P-glycoprotein (P-gp). Concomitant administration of P-gp inhibitors 
such as ciclosporin and verapamil may have the potential to increase plasma concentrations of 
cobimetinib. 
 
Effects of cobimetinib on other medicinal products   
 
CYP3A and CYP2D6 substrates 
 
A clinical drug-drug interaction (DDI) study in cancer patients showed that plasma concentrations of 
midazolam (a sensitive CYP3A substrate) and dextromethorphan (a sensitive CYP2D6 substrate) were 
not altered in the presence of cobimetinib. 
  
CYP1A2 substrates 
 
In vitro, cobimetinib is a potential inducer of CYP1A2 and may therefore reduce the exposure of 
substrates of this enzyme e.g., theophylline. No clinical DDI studies have been conducted to assess the 
clinical relevance of this finding. 
 
BCRP substrates 
 
In vitro, cobimetinib is a moderate inhibitor of BCRP (Breast Cancer Resistance Protein). No clinical 
DDI studies have been conducted to assess this finding, and clinically relevant inhibition of intestinal 
BCRP cannot be ruled out. 
 



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Other anti-cancer agents 
 
Vemurafenib 
 
There is no evidence of any clinically significant drug-drug interaction between cobimetinib and 
vemurafenib in unresectable or metastatic melanoma patients and therefore no dose adjustments is 
recommended. 
 
Effects of cobimetinib on drug transport systems 
 
In vitro studies show that cobimetinib is not a substrate of the liver uptake transporters OATP1B1, 
OATP1B3 and OCT1, however, it weakly inhibits these transporters. The clinical relevance of these 
findings has not been investigated.  
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential / Contraception 
 
Women of childbearing potential should be advised to use two effective contraceptive methods, such 
as a condom or other barrier method (with spermicide, if available) during treatment with Cotellic and 
for at least three months following treatment discontinuation.  
 
Pregnancy 
 
There are no data from the use of Cotellic in pregnant women. Studies in animals have shown 
embryolethality and foetal malformations of the great vessels and skull (see section 5.3). Cotellic 
should not be used during pregnancy unless clearly necessary and after a careful consideration of the 
needs of the mother and the risk to the foetus.   
 
Breast-feeding 
 
It is not known whether cobimetinib is excreted in human breast milk. A risk to the newborns/infants 
cannot be excluded. A decision should be made whether to discontinue breast-feeding or discontinue 
Cotellic therapy, taking into account the benefit of breast-feeding for the child and the benefit of 
therapy for the woman. 
 
Fertility 
 
There are no data in humans for cobimetinib. In animals, no fertility studies have been performed, but 
adverse effects were seen on reproductive organs (see section 5.3). The clinical relevance of this is 
unknown.  
 
4.7 Effects on ability to drive and use machines 
 
Cotellic has minor influence on the ability to drive or use machines. Visual disturbances have been 
reported in some patients treated with cobimetinib during clinical studies (see sections 4.4 and 4.8). 
Patients should be advised not to drive or use machines if they experience visual disturbances or any 
other adverse effects that may affect their ability.  
 



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4.8 Undesirable effects 
 
Summary of the safety profile 
 
The safety of Cotellic in combination with vemurafenib has been evaluated in 247 patients with 
advanced BRAF V600 mutated melanoma in Study GO28141.The median time to onset for the first 
Grade ≥3 adverse events was 0.6 months in the Cotellic plus vemurafenib arm vs 0.8 months in the 
placebo plus vemurafenib arm.  
 
The safety of Cotellic in combination with vemurafenib has also been evaluated in 129 patients with 
advanced BRAF V600 mutated melanoma in Study NO25395.  The safety profile of Study NO25395 
was consistent with that observed in Study GO28141. 
 
In Study GO28141, the most common adverse reactions (>20%) observed with a higher frequency in 
the Cotellic plus vemurafenib arm were diarrhoea, rash, nausea, pyrexia, photosensitivity reaction, 
increased alanine aminotransferase, increased aspartate aminotransferase, increased blood creatine 
phosphokinase, and vomiting. The most common adverse reactions (>20%) observed with a higher 
frequency in the placebo plus vemurafenib arm were arthralgia, alopecia, and hyperkeratosis. Fatigue 
was observed at similar frequencies in both arms. 
 
Please refer to the vemurafenib SmPC for complete descriptions of all undesirable effects associated 
with vemurafenib treatment.  
 
Tabulated list of adverse reactions 
 
Adverse drug reactions (ADRs) are based on results from a multi-centre, randomised, double-blind, 
placebo-controlled, Phase III Study (GO28141) that evaluated the safety and efficacy of Cotellic in 
combination with vemurafenib as compared to vemurafenib alone in previously untreated BRAF V600 
mutation-positive patients with unresectable locally advanced (Stage IIIc) or metastatic melanoma 
(Stage IV). 
 
ADR frequencies are based upon the safety analysis of patients treated with cobimetinib plus 
vemurafenib with a median follow up of 11.2 months (data cut-off date of 19 September 2014). 
 
ADRs which were reported in melanoma patients are listed below by MedDRA body system organ 
class, frequency and grade of severity. The following convention has been used for the classification 
of frequency: 
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 
 
Table 3 lists adverse reactions considered associated with the use of Cotellic. Within each frequency 
grouping, ADRs are presented in order of decreasing severity and were reported according to NCI-
CTCAE v 4.0 (common toxicity criteria) for assessment of toxicity in Study GO28141. 
 



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Table 3 Adverse drug reactions in patients treated with Cotellic in combination with 
vemurafenib in Study GO28141^ 
 
System organ class Very Common  

 
Common Uncommon 

Neoplasms benign, 
malignant and 
unspecified (incl. cysts 
and polyps) 

 Basal cell carcinoma,  
Cutaneous squamous 
cell  carcinoma**, 
Keratoacanthoma** 

 

Blood and lymphatic 
system disorders 

Anaemia   

Metabolism and 
nutrition disorders 

 Dehydration, 
Hypophosphataemia, 
Hyponatremia, 
Hyperglycaemia 
 

 

Eye disorders Serous retinopathya, 
Blurred vision 
 

Visual impairment 
 

 

Vascular disorders Hypertension, 
Haemorrhage* 
 

  

Respiratory, thoracic 
and mediastinal 
disorders  

 Pneumonitis 
 

 

Gastrointestinal 
disorders 
 

Diarrhoea, Nausea, 
Vomiting 
 

  

Skin and subcutaneous 
tissue disorders 

Photosensitivityb, Rash, 
Rash maculo-papular, 
Dermatitis acneiform, 
Hyperkeratosis** 
 

  

Musculoskeletal and 
connective tissue 
disorders 

  Rhabdomyolysis*** 

General disorders and 
administration site 
conditions 

Pyrexia, Chills 
 

  

Investigations  Blood CPK increased, 
ALT increased, AST 
increased, Gamma-
Glutamyltransferase 
(GGT) increased, Blood 
ALP  increased 

Ejection fraction 
decreased, Blood 
bilirubin increased 
 

 

^ Data cut-off date of 19 September 2014 
* Please refer to the paragraph Haemorrhage in the “Description of selected adverse reactions” section 
** Please refer to the paragraph Cutaneous squamous cell carcinoma, keratoacanthoma and hyperkeratosis in 
the “Description of selected adverse reactions” section. 
*** Please refer to the paragraph Rhabdomyolysis  in the “Description of selected adverse reactions” section. 
a Includes both chorioretinopathy and retinal detachment events indicative of serous retinopathy (see section 4.4) 
b Combined figure includes reports of photosensitivity reaction, sunburn, solar dermatitis, actinic elastosis 



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Description of selected adverse reactions 
 
Haemorrhage 
 
Bleeding events have been reported more frequently in the Cotellic plus vemurafenib arm than in the 
placebo plus vemurafenib arm (all types and Grades: 13% vs 7%).  The median time to first onset was 
6.1 months in the Cotellic plus vemurafenib arm. 
 
The majority of events were Grade 1 or 2 and non-serious. Most events resolved with no change in 
Cotellic dose. Major haemorrhagic events (including intracranial and gastrointestinal tract 
haemorrhage) were reported in the post-marketing setting. The risk of haemorrhage may be increased 
with concomitant use of antiplatelet or anticoagulant therapy. If haemorrhage occurs, treat as clinically 
indicated (see section 4.2 and 4.4).  
 
Rhabdomyolysis  
 
Rhabdomyolysis has been reported in the post-marketing setting.  Signs or symptoms of 
rhabdomyolysis warrant an appropriate clinical evaluation and treatment as indicated, along with 
Cotellic dose modification or discontinuation according to the severity of the adverse reaction (see 
section 4.2 and 4.4). 
 
Photosensitivity 
 
Photosensitivity has been observed with a higher frequency in the Cotellic plus vemurafenib arm vs 
placebo plus vemurafenib arm (47% vs 35%).  The majority of events were Grades 1 or 2, with 
Grade ≥3 events occurring in 4% of patients in the Cotellic plus vemurafenib arm vs 0% in the placebo 
plus vemurafenib arm.  
 
There were no apparent trends in the time of onset of Grade ≥3 events. Grade ≥3 photosensitivity 
events in the Cotellic plus vemurafenib arm were treated with primary topical medicinal products in 
conjunction with dose interruptions of both cobimetinib and vemurafenib (see section 4.2). 
 
No evidence of phototoxicity was observed with Cotellic as a single agent. 
 
Cutaneous squamous cell carcinoma, keratoacanthoma and hyperkeratosis 
 
Cutaneous squamous cell carcinoma has been reported with a lower frequency in the Cotellic plus 
vemurafenib arm vs placebo plus vemurafenib arm (all Grade: 3% vs 13%).  Keratoacanthoma has 
been reported with a lower frequency in the Cotellic plus vemurafenib arm vs placebo plus 
vemurafenib arm (all Grade: 2% vs 9%). Hyperkeratosis has been reported with a lower frequency in 
the Cotellic plus vemurafenib vs placebo plus vemurafenib arm (all Grade: 11% vs 30%). 
 
Serous retinopathy  
 
Cases of serous retinopathy have been reported in patients treated with Cotellic (see section 4.4.) For 
patients reporting new or worsening visual disturbances, an ophthalmologic examination is 
recommended. Serous retinopathy can be managed with treatment interruption, dose reduction or with 
treatment discontinuation (see Table 1 in section 4.2). 
 
Left ventricular dysfunction  
 
Decrease in LVEF from baseline has been reported in patients receiving Cotellic (see section 4.4). 
LVEF should be evaluated before initiation of treatment to establish baseline values, then after the first 
month of treatment and at least every 3 months or as clinically indicated until treatment 
discontinuation.  Decrease in LVEF from baseline can be managed using treatment interruption, dose 
reduction or with treatment discontinuation (see section 4.2). 



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Laboratory abnormalities 
 
Liver laboratory abnormalities 
Liver laboratory abnormalities, specifically ALT, AST, and ALP have been observed in patients 
treated with Cotellic in combination with vemurafenib (see section 4.4).   
Liver laboratory tests should be monitored before initiation of combination treatment and monthly 
during treatment, or more frequently if clinically indicated (see section 4.2). 
 
Blood creatine phosphokinase increase 
Asymptomatic increases in blood CPK levels were observed with a higher frequency in the Cotellic 
plus vemurafenib arm vs placebo plus vemurafenib arm in Study GO28141 (see section 4.2 and 4.4). 
One event of rhabdomyolysis was observed in each treatment arm of the study with concurrent 
increases in blood CPK.  
 
Table 4 provides the frequency of measured liver laboratory abnormalities and elevated creatine 
phosphokinase for all Grades and Grades 3-4. 
 
Table 4 Liver function and other laboratory tests observed in the Phase III Study GO28141 
 

Changes in reported 
laboratory data 

Cobimetinib plus 
vemurafenib 

(n = 247) 
 (%) 

Placebo plus vemurafenib 
(n = 246) 

(%) 

 All Grades Grades 3-4 All Grades Grades 3-4 
Liver function test 
Increased ALP 69 7 55 3 
Increased ALT 67 11 54 5 
Increased AST 71 7 43 2 
Increased GGT 62 20 59 17 
Increased blood bilirubin 33 2 43 1 
Other laboratory abnormalities 
Increased blood CPK 70 12 14 <1 
 
Special populations 
 
Elderly patients 
 
In the Phase III study with Cotellic in combination with vemurafenib in patients with unresectable or 
metastatic melanoma (n=247), 183 patients (74%) were <65 years of age, and 44 patients (18%) were 
65-74 years of age, 16 (6%) were 75-84 years of age, and 4 patients (2%) were aged ≥85 years. The 
proportion of patients experiencing adverse events (AE) was similar in the patients aged <65 years and 
those aged ≥65 years. Patients ≥65 years were more likely to experience serious adverse events 
(SAEs) and experience AEs leading to discontinuation of cobimetinib than those <65 years. 
 
Renal impairment 
 
No pharmacokinetic trial in subjects with renal impairment has been conducted. Dose adjustment is 
not recommended for mild to moderate renal impairment based on the results of the population 
pharmacokinetic analysis. There are minimal data for Cotellic in patients with severe renal impairment. 
Cotellic should be used with caution in patients with severe renal impairment.  
 
Hepatic impairment 
 
No dose adjustment is recommended in patients with hepatic impairment (see section 5.2). 
 



15 

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 
 
There is no experience with overdose in human clinical studies. In case of suspected overdose, 
cobimetinib should be withheld and supportive care instituted. There is no specific antidote for 
overdosage with cobimetinib. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE38 
 
Mechanism of action 
 
Cobimetinib is a reversible, selective, allosteric, oral inhibitor that blocks the mitogen-activated 
protein kinase (MAPK) pathway by targeting the mitogen-activated extracellular signal-regulated 
kinase (MEK) 1 and MEK 2 which results in inhibition of phosphorylation of the extracellular signal-
regulated kinase (ERK) 1 and ERK 2. Therefore, cobimetinib blocks the cell proliferation induced by 
the MAPK pathway through inhibition of the MEK1/2 signalling node. 
 
In the preclinical models, the combination of cobimetinib and vemurafenib showed that by 
simultaneously targeting mutated BRAF V600 proteins and MEK proteins in melanoma cells, the 
combination of the two products inhibits MAPK pathway reactivation through MEK1/2, resulting in a 
stronger inhibition of intracellular signalling and decreased tumour cell proliferation  
 
Clinical efficacy and safety 
 
There are no data on the safety or efficacy of Cotellic in combination with vemurafenib in patients 
with central nervous system metastasis or in patients with non-cutaneous malignant melanoma. 
 
Study GO28141 (coBRIM) 
 
Study GO28141 is a multi-centre, randomised, double-blind, placebo-controlled, Phase III study to 
evaluate the safety and efficacy of Cotellic in combination with vemurafenib as compared to 
vemurafenib plus placebo, in previously untreated patients with BRAF V600 mutation-positive 
unresectable locally advanced (Stage IIIc) or metastatic melanoma (Stage IV).  
 
Only patients with ECOG performance status 0 and 1 were enrolled in Study GO28141. Patients with 
ECOG performance status 2 or higher were excluded from the study. 
 
Following confirmation of a BRAF V600 mutation, using the cobas® 4800 BRAF V600 mutation test, 
495 previously untreated patients with unresectable locally advanced or metastatic melanoma were 
randomised to receive either: 

∑ Placebo once daily on Days 1-21 of each 28-day treatment cycle and 960 mg vemurafenib 
twice daily on Days 1-28, or 

∑ Cotellic 60 mg once daily on Days 1-21 of each 28-day treatment cycle and 960 mg 
vemurafenib twice daily on Days 1-28 

 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


16 

Progression-free survival (PFS) as assessed by the investigator (INV) was the primary endpoint.  
Secondary efficacy endpoints included overall survival (OS), objective response rate, duration of 
response (DoR) as assessed by INV and PFS as assessed by an independent review facility (IRF). 
 
Key baseline characteristics included: 58% of patients were male, median age was 55 years (range 23 
to 88 years), 60% had metastatic melanoma stage M1c and the proportion of patients with elevated 
LDH was 46.3% in the cobimetinib plus vemurafenib arm and 43.0% in the placebo plus vemurafenib 
arm.  
 
In Study GO28141, there were 89 patients (18.1%) aged 65-74, 38 patients (7.7%) aged 75-84 and 
5 patients (1.0%) aged 85 years and older. 
  
Efficacy results are summarized in Table 5. 
 
Table 5 Efficacy results from Study GO28141 (coBRIM)  
 

 Cotellic + vemurafenib                                                                  N=247     
Placebo + vemurafenib 

N=248                                       

  

Primary Endpointa, f  

Progression-Free Survival (PFS) 
Median (months) 
(95 % CI) 

12.3     
(9.5, 13.4)      

7.2   
(5.6, 7.5)                               

Hazard ratio (95% CI) b 0.58 (0.46; 0.72) 

Key Secondary Endpointsa, f,  

Overall Survival (OS)g 
Median (months) 
(95 % CI) 

22.3  
(20.3, NE) 

17.4  
(15.0, 19.8) 

Hazard ratio (95% CI)b 
0.70 (95% CI: 0.55, 0.90) 

(p-value = 0.0050e) 

Objective response rate 
(ORR) 172 (69.6%) 124 (50.0%) 

(95% CI) for ORRc (63.5%, 75.3%) (43.6%, 56.4%) 
Difference in ORR % (95% CI) d 19.6 (11.0, 28.3) 
Best Overall Response (BOR) 
Complete Response 39 (15.8%) 26 (10.5%) 
Partial Response 133 (53.8%) 98 (39.5%) 
Stable disease 44 (17.8%) 92 (37.1%) 
Duration of Response (DoR) 
Median DoR (months) 
(95% CI) for median 

13 
(11.1, 16.6) 

9.2 
(7.5, 12.8) 

NE = Not evaluable 
a Assessed and confirmed by the investigator (INV) using RECIST v1.1 
b Stratified analysis by geographic region and metastasis classification (disease stage) 
c Using Clopper-Pearson method 
d Using Hauck-Anderson method 
e The OS p-value (0.0050) crossed the pre-specified boundary (p value <0.0499) 
f The data cut-off date for this updated PFS analysis and the secondary endpoints of ORR, BOR and DoR is 
16 January 2015. The median follow up was 14.2 months. 
g The data cut-off date for the final OS analysis is 28 August 2015 and median follow-up was 18.5 months. 
 



17 

The primary analysis for Study GO28141 was conducted with a data cut-off date of 09 May 2014. 
Significant improvement in the primary endpoint, investigator-assessed PFS, was observed in patients 
assigned to the Cotellic plus vemurafenib arm compared to the placebo plus vemurafenib arm (HR 
0.51 (0.39; 0.68); p-value < 0.0001). The median estimate for investigator-assessed PFS was 9.9 
months for the Cotellic plus vemurafenib arm vs. 6.2 months for the placebo plus vemurafenib arm. 
The median estimate for independent review of PFS was 11.3 months for the Cotellic plus 
vemurafenib arm vs. 6.0 months for the placebo plus vemurafenib arm (HR 0.60 (0.45; 0.79); p-value 
= 0.0003). The objective response rate (ORR) in the Cotellic plus vemurafenib arm was 67.6% vs 
44.8% in the placebo plus vemurafenib arm. The difference in ORR was 22.9 % (p-value<0.0001). 
 
The final OS analysis for Study GO28141 was conducted with a data-cut off date of 28 August 2015.  
Significant improvement in OS was observed in patients assigned to the Cotellic plus vemurafenib arm 
compared to the placebo plus vemurafenib arm (Figure 1). The 1-year (75 %) and 2-year (48 %) OS 
estimates for the Cotellic plus vemurafenib arm were greater than those for placebo plus vemurafenib 
arm (64 % and 38 % respectively). 
 
Figure 1 Kaplan-Meier curves of final overall survival – Intent to treat population (cut-off date: 
28 August 2015) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



18 

 
Figure 2: Forest plot for hazard ratios of final overall survival subgroup analyses – Intent to 
treat population (cut-off date: 28 August 2015) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Global health status / health-related quality of life by patient-report were measured using the EORTC 
Quality of Life Questionnaire – Core 30 (QLQ-C30). Scores for all functioning domains and most 
symptoms (appetite loss, constipation, nausea and vomiting, dyspnoea, pain, fatigue) showed that the 
mean change from baseline was similar between the two treatment arms and did not demonstrate a 
clinically meaningful change (all scores were ≤ 10 point change from baseline). 
 
Study NO25395 (BRIM7) 
 
The efficacy of Cotellic was evaluated in Phase Ib Study, NO25395, which was designed to assess the 
safety, tolerability, pharmacokinetics and efficacy of Cotellic when added to vemurafenib for the 
treatment of patients with BRAFV600 mutation-positive (as detected by the cobas® 4800 BRAF V600 
Mutation Test), unresectable or metastatic melanoma.  
This study treated 129 patients with Cotellic and vemurafenib: 63 were BRAF inhibitor (BRAFi) 
therapy naïve and 66 patients had previously progressed on prior vemurafenib therapy. Among the 63 
BRAFi naïve patients, 20 patients had received prior systemic therapy for advanced melanoma with 
the majority (80%) being immunotherapy.  
 
Results of the BRAFi naïve population from Study NO25395 were generally consistent with those 
from Study GO28141. The BRAFi-naïve patients (n=63) attained an 87% objective response rate, 
including a complete response in 16% of patients. The median duration of response was 14.3 months. 
The median PFS for BRAFi-naïve patients was 13.8 months, with median follow-up time of 
20.6 months.  
 
Among patients who had progressed on vemurafenib (n=66), the objective response rate was 15%. The 
median duration of response was 6.8 months. The median PFS for patients who had progressed on 
vemurafenib was 2.8 months, with median follow-up time of 8.1 months. 
 



19 

In patients who were naive to BRAF inhibitor therapy, the median overall survival was 28.5 months 
(95% CI 23.3-34.6). In patients who had progressed on BRAF inhibitor therapy, the median overall 
survival was 8.4 months (95% CI 6.7-11.1).  
 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Cotellic in one or more subsets of the paediatric population in malignant solid tumours (see section 4.2 
for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
Following oral dosing of 60 mg in cancer patients, cobimetinib showed a moderate rate of absorption 
with a median Tmax of 2.4 hours. The mean steady-state Cmax and AUC0-24 were 273 ng/mL and 
4340 ng.h/mL respectively. The mean accumulation ratio at steady state was approximately 2.4-fold. 
Cobimetinib has linear pharmacokinetics in the dose range of ~3.5 mg to 100 mg. 
 
The absolute bioavailability of cobimetinib was 45.9% (90% CI: 39.7%, 53.1%) in healthy subjects. 
A human mass balance study was conducted in healthy subjects, and showed that cobimetinib was 
extensively metabolised and eliminated in faeces. The fraction absorbed was ~88% indicating high 
absorption and first pass metabolism.  
 
The pharmacokinetics of cobimetinib are not altered when administered in the fed state (high-fat meal) 
compared with the fasted state in healthy subjects. Since food does not alter the pharmacokinetics of 
cobimetinib, it can be administered with or without food.   
 
Distribution 
 
Cobimetinib is 94.8% bound to human plasma proteins in vitro. No preferential binding to human red 
blood cells was observed (blood to plasma ratio 0.93).  
 
The volume of distribution was 1050 L in healthy subjects given an intravenous dose of 2 mg. The 
apparent volume of distribution was 806 L in cancer patients based on population pharmacokinetic 
analysis. 
 
Cobimetinib is a substrate of P-gp in vitro. The transport across the blood brain barrier is unknown. 
 
Biotransformation 
  
Oxidation by CYP3A and glucuronidation by UGT2B7 appear to be the major pathways of 
cobimetinib metabolism. Cobimetinib is the predominant moiety in plasma. No oxidative metabolites 
greater than 10% of total circulating radioactivity or human specific metabolites were observed in 
plasma. Unchanged medicinal product in faeces and urine accounted for 6.6% and 1.6% of the 
administered dose, respectively, indicating that cobimetinib is primarily metabolised with minimal 
renal elimination. In vitro data indicate cobimetinib is not an inhibitor of OAT1, OAT3 or OCT2. 
 
Elimination 
 
Cobimetinib and its metabolites were characterised in a mass balance study in healthy subjects. On 
average, 94% of the dose was recovered within 17 days. Cobimetinib was extensively metabolised and 
eliminated in faeces. 
 
Following intravenous administration of a 2 mg dose of cobimetinib, the mean plasma clearance (CL) 
was 10.7 L/hr. The mean apparent CL following oral dosing of 60 mg in cancer patients was 13.8 L/hr. 



20 

The mean elimination half-life following oral dosing of cobimetinib was 43.6 hours (range: 23.1 to 
69.6 hours). Therefore, it may take up to 2 weeks following treatment cessation for cobimetinib to be 
completely removed from systemic circulation.    
 
Special populations 
 
Based on a population pharmacokinetic analysis, gender, race, ethnicity, baseline ECOG, mild and 
moderate renal impairment did not affect the pharmacokinetic of cobimetinib. Baseline age and 
baseline body weight were identified as statistically significant covariates on cobimetinib clearance 
and volume of distribution respectively. However, sensitivity analysis suggests neither of these 
covariates had clinically significant impact on steady state exposure. 
 
Gender 
 
Gender does not have an effect on the exposure of cobimetinib, based on a population 
pharmacokinetic analysis including 210 women and 277 men. 
 
Elderly 
 
Age does not have an effect on the exposure of cobimetinib, based on a population pharmacokinetic 
analysis including 133 patients ≥ 65 years of age. 
 
Renal impairment 
 
Based on preclinical data and the human mass balance study, cobimetinib is mainly metabolised, with 
minimal renal elimination. No formal pharmacokinetic study has been conducted in patients with renal 
impairment.  
 
A population pharmacokinetic analysis using data from 151 patients with mild renal impairment 
(creatinine clearance (CRCL) 60 to less than 90 mL/min), 48 patients with moderate renal impairment 
(CRCL 30 to less than 60 mL/min), and 286 patients with normal renal function (CRCL greater than 
or equal to 90 mL/min), showed that CRCL had no meaningful influence on exposure of cobimetinib. 
Mild to moderate renal impairment does not influence cobimetinib exposure based on the population 
pharmacokinetic analysis.  There are minimal data for Cotellic in patients with severe renal 
impairment.  
 
Hepatic impairment 
 
The pharmacokinetics of cobimetinib were evaluated in 6 subjects with mild hepatic impairment 
(Child Pugh A), 6 subjects with moderate hepatic impairment (Child Pugh B), 6 subjects with severe 
hepatic impairment (Child Pugh C) and 10 healthy subjects. Systemic total cobimetinib exposures 
after a single dose were similar in subjects with mild or moderate hepatic impairment compared to 
healthy subjects, while subjects with severe hepatic impairment had lower total cobimetinib exposures 
(AUC0-∞ geometric mean ratio of 0.69 compared to healthy subjects) which is not considered to be 
clinically significant. Unbound cobimetinib exposures were similar between subjects with mild and 
moderate hepatic impairment compared to subjects with normal hepatic function while subjects with 
severe hepatic impairment had approximately 2-fold higher exposures (see section 4.2). 
 
Paediatric population 
 
No studies have been conducted to investigate the pharmacokinetics of cobimetinib in paediatric 
patients. 
 
5.3 Preclinical safety data 
 
Carcinogenicity studies have not been conducted with cobimetinib. Standard genotoxicity studies with 
cobimetinib were negative. 



21 

 
No dedicated fertility studies in animals have been performed with cobimetinib. In  toxicology studies, 
degenerative changes were observed in reproductive tissues including increased apoptosis/necrosis of 
corpora lutea and seminal vesicle, epididymal and vaginal epithelial cells in rats, and epididymal 
epithelial cells in dogs. The clinical relevance of this is unknown.  
 
When administered to pregnant rats, cobimetinib caused embryolethality and foetal malformations of 
the great vessels and skull at systemic exposures similar to human exposure at recommended dose.  
 
Cardiovascular safety of cobimetinib in combination with vemurafenib has not been evaluated in vivo. 
In vitro, cobimetinib produced moderate hERG ion channel inhibition (IC50= 0.5 µM [266 ng/mL]), 
which is approximately 18 fold higher than peak plasma concentrations (Cmax) at the 60 mg to be 
marketed dose (unbound Cmax=14 ng/mL [0.03 µM]).  
 
Toxicity studies in rats and dogs identified generally reversible degenerative changes in the bone 
marrow, gastrointestinal tract, skin, thymus, adrenal gland, liver, spleen, lymph node, kidney, heart, 
ovary, and vagina at plasma exposures below clinical efficacious levels.  Dose limiting toxicities 
included skin ulcerations, surface exudates, and acanthosis in the rat and chronic active inflammation 
and degeneration of the oesophagus associated with varying degrees of gastroenteropathy in dogs. 
 
In a repeat dose toxicity study in juvenile rats, cobimetinib systemic exposures were 2 to11 fold higher 
on post natal day 10 than on post natal day 38 when exposures were similar to those in adult rats. In 
juvenile rats, cobimetinib administration resulted in similar changes as seen in the pivotal toxicity 
studies in adults, including reversible degenerative changes in the thymus and liver, decreased spleen 
and thyroid/parathyroid weights, increased phosphorus, bilirubin and red blood cell mass and 
decreased triglycerides. Mortality occurred in juvenile animals at a dose (3 mg/kg) which did not lead 
to mortalities in adult animals. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Lactose monohydrate 
Microcrystalline cellulose (E460) 
Croscarmellose sodium (E468) 
Magnesium stearate (E470b) 
 
Film coating 
Polyvinyl alcohol 
Titanium dioxide (E171) 
Macrogol 3350 
Talc (E553b) 
 
6.2 Incompatibilities 
 
Not applicable.  
 
6.3 Shelf life 
 
5 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 



22 

6.5 Nature and contents of container  
 
Transparent PVC/PVDC blister containing 21 tablets. Each pack contains 63 tablets. 
 
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 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1048/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 20 November 2015 
Date of latest renewal:  
 
 
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/


23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 

 

 



24 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Roche Pharma AG 
Emil-Barell-Strasse 1 
79639 Grenzach-Whylen 
Germany 
 

 
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. 

 
 

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.  

  



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 

A. LABELLING 
  



27 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Cotellic 20 mg film-coated tablets  
cobimetinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains cobimetinib hemifumarate equivalent to 20 mg cobimetinib 
 
 
3. LIST OF EXCIPIENTS 
 
The tablets also contain lactose. See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
63 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 

 
 



28 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1048/001  
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
cotellic 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN  
  



29 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Cotellic 20 mg film-coated tablets 
cobimetinib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot  
 
 
5. OTHER 
 
 

 
  



30 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



31 

Package leaflet: Information for the patient 
 

Cotellic 20 mg film-coated tablets 
cobimetinib 

 
 
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 Cotellic is and what it is used for 
2. What you need to know before you take Cotellic 
3. How to take Cotellic 
4. Possible side effects 
5. How to store Cotellic 
6. Contents of the pack and other information 
 
 
1. What Cotellic is and what it is used for 
 
What Cotellic is 
Cotellic is an anti-cancer medicine that contains the active substance cobimetinib.  
 
What Cotellic is used for 
Cotellic is used to treat adult patients with a type of skin cancer called melanoma, that has spread to 
other parts of the body or cannot be removed by surgery. 
∑ It is used in combination with another anti-cancer medicine called vemurafenib.  
∑ It can only be used in patients whose cancer has a change (mutation) in a protein called “BRAF”. 

Before starting treatment, your doctor will test for this mutation. This change may have led to the 
development of melanoma.  

 
How Cotellic works 
Cotellic targets a protein called “MEK” that is important in controlling cancer cell growth. When 
Cotellic is used in combination with vemurafenib (which targets the changed “BRAF” protein), it 
further slows down or stops the growth of your cancer. 
 
 
2. What you need to know before you take Cotellic 
 
Do not take Cotellic: 
∑ if you are allergic to cobimetinib or any of the other ingredients of this medicine (listed in 

section 6). 
If you are not sure, talk to your doctor, pharmacist or nurse before taking Cotellic. 
 
Warnings and precautions 
Talk to your doctor, pharmacist or nurse before taking Cotellic if you have: 
 
∑ Bleeding 
Cotellic can cause severe bleeding, especially in your brain or stomach (see also “Severe bleeding” in 
Section 4). Tell your doctor straight away if you have any unusual bleeding or any of these 
symptoms: headaches, dizziness, feeling weak, blood in the stools or black stools and vomiting blood.   



32 

 
∑ Eye problems 
Cotellic can cause eye problems (see also “Eye (vision) problems” in Section 4). Tell your doctor 
straight away if you get the following symptoms: blurred vision, distorted vision, partly missing vision, 
or any other changes to your sight during treatment. Your doctor should examine your eyes if you 
have any new or worsening problems with your sight while you are taking Cotellic. 

 
∑ Heart problems 
Cotellic can lower the amount of blood pumped by your heart (see also “Heart problems” in 
Section 4). Your doctor should do tests before and during your treatment with Cotellic to check how 
well your heart can pump blood. Tell your doctor straight away if it feels like your heart is pounding, 
racing or beating unevenly, or if you experience dizziness, lightheadedness, shortness of breath, 
tiredness, or swelling in the legs.  
 
∑ Liver problems 
Cotellic can increase the amount of some liver enzymes in your blood during treatment. Your doctor 
will do blood tests to check these amounts and monitor how well your liver is working.   

 
∑ Muscle problems 
Cotellic can cause increased levels of creatine phosphokinase, an enzyme that is found mainly in the 
muscle, heart, and brain. This can be a sign of muscle damage (rhabdomyolysis) (see also “Muscle 
problems” in Section 4). Your doctor will do blood tests to monitor for this. Tell your doctor straight 
away if you get any of these symptoms: muscle aches, muscle spasms, weakness, or dark- or red-
coloured urine.  

 
∑ Diarrhoea 
Tell your doctor straight away if you get diarrhoea. Severe diarrhoea can cause loss of body fluid 
(dehydration). Follow your doctor’s instructions for what to do to help prevent or treat diarrhoea. 
 
Children and adolescents 
Cotellic is not recommended for children and adolescents. The effects of Cotellic in people younger 
than 18 years old are not known. 
 
Other medicines and Cotellic 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. 
This is because Cotellic can affect the way some other medicines work. Also, some other medicines 
can affect the way Cotellic works. 
 
Talk to your doctor before taking Cotellic if you are taking: 
 

Medicine  Purpose of the medicine 
itraconazole, clarithromycin, erythromycin, 
telithromycin, voriconazole, rifampicin, 
posaconazole, fluconazole, miconazole 

for some fungal and bacterial infections 

ritonavir, cobicistat, lopinavir, delavirdine, 
amprenavir, fosamprenavir  

for HIV infection 

telaprevir for hepatitis C 
nefadozone for depression 
amiodarone for an uneven heartbeat 
diltiazem, verapamil for high blood pressure  
imatinib for cancer 
carbamazepine, phenytoin for fits (seizures) 
St John’s Wort a herbal medicine, used to treat depression. 

This is available without prescription. 



33 

 
Cotellic with food and drink 
Avoid taking Cotellic with grapefruit juice. This is because it could increase the amount of Cotellic in 
your blood. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you might be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
∑ Cotellic is not recommended during pregnancy - although the effects of Cotellic have not been 

studied in pregnant women, it may cause permanent harm or birth defects to an unborn baby.  
∑ If you become pregnant during treatment with Cotellic or in the 3 months after your last dose, tell 

your doctor straight away.   
∑ It is not known if Cotellic passes into breast milk. Your doctor will discuss with you the benefits 

and risks of taking Cotellic, if you are breast-feeding.  
 
Contraception 
Women of childbearing potential should use two effective methods of contraception, such as a 
condom or other barrier method (with spermicide, if available) during treatment and for at least 
3 months after treatment has finished. Ask your doctor about the best contraception for you. 
 
Driving and using machines 
Cotellic can affect your ability to drive or use machines. Avoid driving or using machines if you have 
problems with your vision or other problems that might affect your ability e.g. if you feel dizzy or 
tired. Talk to your doctor if you are not sure.  
 
Cotellic contains lactose and sodium 
The tablets contain lactose (a type of sugar). If you have been told by your doctor that you have an 
intolerance to some sugars, talk to your doctor before taking this medicine. 
 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-
free’.   
 
 
3. How to take Cotellic 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure.  
 
How much to take 
The recommended dose is 3 tablets (a total of 60 mg) once a day.  
∑ Take the tablets every day for 21 days (called a “treatment period”).  
∑ After the 21 days, do not take any Cotellic tablets for 7 days. During this 7 day break in Cotellic 

treatment, you should keep taking vemurafenib as told by your doctor. 
∑ Start your next Cotellic 21 day treatment period after the 7 day break. 
∑ If you get side effects, your doctor may decide to lower your dose, stop treatment temporarily or 

permanently. Always take Cotellic exactly as your doctor or pharmacist has told you. 
 
Taking the medicine 
∑ Swallow the tablets whole with water. 
∑ Cotellic can be taken with or without food.  
 
If you are sick 
If you are sick (vomit) after taking Cotellic, do not take an extra dose of Cotellic on that day. Continue 
to take Cotellic as normal, the next day.   
 
If you take more Cotellic than you should 
If you take more Cotellic than you should, talk to a doctor straight away. Take the medicine package 



34 

and this leaflet with you.  
 
If you forget to take Cotellic 
∑ If it is more than 12 hours before your next dose, take the missed dose as soon as you remember.  
∑ If it is less than 12 hours before your next dose, skip the missed dose. Then take the next dose at 

the usual time. 
∑ Do not take a double dose to make up for a missed dose. 
 
If you stop taking Cotellic 
It is important to keep taking Cotellic for as long as your doctor prescribes it.  
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. If you get 
side effects your doctor may decide to lower your dose, stop treatment temporarily or permanently. 
 
Please also refer to the Package Leaflet for vemurafenib, which is used in combination with Cotellic. 
 
Serious side effects 
Tell your doctor straight away if you notice any of the side effects listed below or if these get worse 
during treatment. 
 

Severe bleeding (common: may affect up to 1 in 10 people) 
Cotellic can cause severe bleeding, especially in your brain or stomach. Depending on the area 
of the bleeding, symptoms may include: 
∑ headaches, dizziness, or weakness 
∑ vomiting blood 
∑ abdominal pain 
∑ red or black coloured stools. 
 
Eye (vision) problems (very common: may affect more than 1 in 10 people) 
Cotellic can cause eye problems. Some of these eye problems may be a result of “serous 
retinopathy” (a build-up of fluid under the retina in the eye). Symptoms of serous retinopathy 
include:  
∑ blurred vision 
∑ distorted vision 
∑ partly missing vision 
∑ any other changes to your sight. 
 
Heart problems (common: may affect up to 1 in 10 people) 
Cotellic can lower the amount of blood pumped by your heart. Symptoms may include:  
∑ feeling dizzy 
∑ feeling light-headed 
∑ feeling short of breath  
∑ feeling tired 
∑ feeling like your heart is pounding, racing or beating unevenly 
∑ swelling in the legs. 

 
Muscle problems (uncommon: may affect up to 1 in 100 people) 
Cotellic can result in the breakdown of muscle (rhabdomyolysis), symptoms may include: 
∑ muscle aches 
∑ muscle spasms and weakness 
∑ dark- or red-coloured urine. 

 



35 

Diarrhoea (very common: may affect more than 1 in 10 people) 
Tell your doctor straight away if you get diarrhoea and follow your doctor’s instructions for 
what to do to help prevent or treat diarrhoea. 
 

Other side effects 
Tell your doctor, pharmacist or nurse if you notice any of the following side effects: 

Very common (may affect more than 1 in 10 people) 
∑ increased skin sensitivity to sunlight 
∑ skin rash  
∑ feeling sick (nausea) 
∑ fever 
∑ chills 
∑ increased liver enzymes (shown in blood tests)   
∑ abnormal blood test results related to creatine phosphokinase, an enzyme found mainly in 

heart, brain and skeletal muscle 
∑ vomiting 
∑ skin rash with a flat discoloured area or raised bump like acne 
∑ high blood pressure 
∑ anaemia (a low level of red blood cells) 
∑ bleeding 
∑ abnormal thickening of the skin. 
   
Common (may affect up to 1 in 10 people) 
∑ some types of skin cancer such as basal cell carcinoma, cutaneous squamous cell carcinoma 

and keratoacanthoma 
∑ dehydration, when your body does not have enough fluid 
∑ decreased levels of phosphate or sodium (shown in blood tests) 
∑ increased sugar level (shown in blood tests) 
∑ increased liver pigment (called “bilirubin”) in the blood. Signs include yellowing of the skin 

or eyes 
∑ inflammation of the lungs that may cause difficulty breathing, and can be life-threatening 

(called “pneumonitis”). 
 
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 Cotellic 
 
∑ Keep this medicine out of the sight and reach of children. 
∑ Do not take 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 to protect the 
environment. 

 
 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


36 

6. Contents of the pack and other information 
 
What Cotellic contains 
∑ The active substance is cobimetinib. Each film-coated tablet contains cobimetinib hemifumarate 

equivalent to 20 mg cobimetinib. 
∑ The other ingredients are (see Section 2 “Cotellic contains lactose and sodium”):  

∑ lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium 
stearate in the tablet core; and 

∑ polyvinyl alcohol, titanium dioxide, macrogol and talc in the film-coating.  
 

What Cotellic looks like and contents of the pack 
Cotellic film-coated tablets are white, round with “COB” debossed on one side. One pack size is 
available: 63 tablets (3 blisters of 21 tablets). 
  
Marketing Authorisation Holder 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 

 
 

Manufacturer 
Roche Pharma AG 
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 

 

 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 

België/Belgique/Belgien  
N.V. Roche S.A.  
Tél/Tel: +32 (0) 2 525 82 11  

Lietuva  
UAB “Roche Lietuva”  
Tel: +370 5 2546799  

България  
Рош България ЕООД  
Тел: +359 2 818 44 44  

Luxembourg/Luxemburg  
(Voir/siehe Belgique/Belgien)  

Česká republika  
Roche s. r. o.  
Tel: +420 - 2 20382111  

Magyarország  
Roche (Magyarország) Kft.  
Tel: +36 - 23 446 800  

Danmark  
Roche a/s  
Tlf: +45 - 36 39 99 99  

Malta  
(see Ireland)  

Deutschland  
Roche Pharma AG  
Tel: +49 (0) 7624 140  

Nederland  
Roche Nederland B.V.  
Tel: +31 (0) 348 438050  

Eesti  
Roche Eesti OÜ  
Tel: + 372 - 6 177 380  

Norge  
Roche Norge AS  
Tlf: +47 - 22 78 90 00  

Ελλάδα  
Roche (Hellas) A.E.  
Τηλ: +30 210 61 66 100  

Österreich  
Roche Austria GmbH  
Tel: +43 (0) 1 27739  

España  
Roche Farma S.A.  
Tel: +34 - 91 324 81 00  

Polska  
Roche Polska Sp.z o.o.  
Tel: +48 - 22 345 18 88  



37 

France  
Roche  
Tél: +33 (0) 1 47 61 40 00  

Portugal  
Roche Farmacêutica Química, Lda  
Tel: +351 - 21 425 70 00  

Hrvatska  
Roche d.o.o.  
Tel: +385 1 4722 333  

România  
Roche România S.R.L.  
Tel: +40 21 206 47 01  

Ireland  
Roche Products (Ireland) Ltd.  
Tel: +353 (0) 1 469 0700  

Slovenija  
Roche farmacevtska družba d.o.o.  
Tel: +386 - 1 360 26 00  

Ísland  
Roche a/s  
c/o Icepharma hf  
Sími: +354 540 8000  

Slovenská republika  
Roche Slovensko, s.r.o.  
Tel: +421 - 2 52638201  

Italia  
Roche S.p.A.  
Tel: +39 - 039 2471  

Suomi/Finland  
Roche Oy  
Puh/Tel: +358 (0) 10 554 500  

Kύπρος  
Γ.Α.Σταμάτης & Σια Λτδ.  
Τηλ: +357 - 22 76 62 76  

Sverige  
Roche AB  
Tel: +46 (0) 8 726 1200  

Latvija  
Roche Latvija SIA  
Tel: +371 - 6 7039831  

United Kingdom  
Roche Products Ltd.  
Tel: +44 (0) 1707 366000  

 
This leaflet was last revised in {MM/YYYY} 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  

 
 
 

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

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS 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