Zelboraf

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Zelboraf 240 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 240 mg of vemurafenib (as a co-precipitate of vemurafenib and hypromellose 
acetate succinate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
Pinkish white to orange white, oval, biconvex film-coated tablets of approximately 19 mm, with 
‘VEM’ engraved on one side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Vemurafenib is indicated in monotherapy for the treatment of adult patients with BRAF V600 
mutation-positive unresectable or metastatic melanoma (see section 5.1). 
 
4.2 Posology and method of administration 
 
Treatment with vemurafenib should be initiated and supervised by a qualified physician experienced 
in the use of anticancer medicinal products. 
 
Before taking vemurafenib, patients must have BRAF V600 mutation-positive tumour status 
confirmed by a validated test (see sections 4.4 and 5.1). 
 
Posology 
The recommended dose of vemurafenib is 960 mg (4 tablets of 240 mg) twice daily (equivalent to a 
total daily dose of 1,920 mg). Vemurafenib may be taken with or without food, but consistent intake of 
both daily doses on an empty stomach should be avoided (see section 5.2). 
 
Duration of treatment 
Treatment with vemurafenib should continue until disease progression or the development of 
unacceptable toxicity (see tables 1 and 2 below). 
 
Missed doses 
If a dose is missed, it can be taken up to 4 hours prior to the next dose to maintain the twice daily 
regimen. Both doses should not be taken at the same time. 
 
Vomiting 
In case of vomiting after vemurafenib administration the patient should not take an additional dose of 
the medicinal product but the treatment should be continued as usual. 
 



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Posology adjustments 
Management of adverse drug reactions or QTc prolongation may require dose reduction, temporary 
interruption and/or treatment discontinuation (see tables 1 and 2). Posology adjustments resulting in a 
dose below 480 mg twice daily are not recommended. 
 
In the event the patient develops Cutaneous Squamous Cell Carcinoma (cuSCC), it is recommended to 
continue the treatment without modifying the dose of vemurafenib (see sections 4.4 and 4.8). 
 
Table 1: Dose modification schedule based on the grade of any Adverse Events (AEs)  
 
Grade (CTC-AE) (a) Recommended dose modification 
Grade 1 or Grade 2 (tolerable)  Maintain vemurafenib at a dose of 960 mg twice daily. 
Grade 2 (intolerable) or Grade 3  
1st occurrence of any grade 2 or 3 AE Interrupt treatment until grade 0 – 1. Resume dosing at 

720 mg twice daily (or 480 mg twice daily if the dose 
has already been lowered). 

2nd occurrence of any grade 2 or 3 AE 
or persistence after treatment 
interruption 

Interrupt treatment until grade 0 – 1. Resume dosing at 
480 mg twice daily (or discontinue permanently if the 
dose has already been lowered to 480 mg twice daily). 

3rd occurrence of any grade 2 or 3 AE 
or persistence after 2nd dose reduction 

Discontinue permanently. 

Grade 4  
1st occurrence of any grade 4 AE Discontinue permanently or interrupt vemurafenib 

treatment until grade 0 – 1. 
Resume dosing at 480 mg twice daily (or discontinue 
permanently if the dose has already been lowered to 480 
mg twice daily). 

2nd occurrence of any grade 4 AE or 
persistence of any grade 4 AE after 
1st dose reduction 

Discontinue permanently. 

(a) The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0 
(CTC-AE). 
 
Exposure-dependent QT prolongation was observed in an uncontrolled, open-label phase II study in 
previously treated patients with metastatic melanoma. Management of QTc prolongation may require 
specific monitoring measures (see section 4.4). 
 



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Table 2: Dose modification schedule based on prolongation of the QT interval 
 
QTc value Recommended dose modification 
QTc>500 ms at baseline Treatment not recommended. 
QTc increase meets values of both >500 ms 
and >60 ms change from pre-treatment values 

Discontinue permanently. 

1st occurrence of QTc>500 ms during 
treatment and change from pre-treatment value 
remains <60 ms 

Temporarily interrupt treatment until QTc 
decreases below 500 ms. 
See monitoring measures in section 4.4. 
Resume dosing at 720 mg twice daily (or 
480 mg twice daily if the dose has already 
been lowered). 

2nd occurrence of QTc>500 ms during 
treatment and change from pre-treatment value 
remains <60 ms 

Temporarily interrupt treatment until QTc 
decreases below 500 ms. 
See monitoring measures in section 4.4. 
Resume dosing at 480 mg twice daily (or 
discontinue permanently if the dose has 
already been lowered to 480 mg twice daily). 

3rd occurrence of QTc>500 ms during 
treatment and change from pre-treatment value 
remains <60 ms 

Discontinue permanently. 

 
Special population 
 
Elderly 
No special dose adjustment is required in patients aged > 65 years old. 
 
Renal impairment 
Limited data are available in patients with renal impairment. A risk for increased exposure in patients 
with severe renal impairment cannot be excluded. Patients with severe renal impairment should be 
closely monitored (see sections 4.4 and 5.2). 
 
Hepatic impairment 
Limited data are available in patients with hepatic impairment. As vemurafenib is cleared by the liver, 
patients with moderate to severe hepatic impairment may have increased exposure and should be 
closely monitored (see sections 4.4 and 5.2). 
 
Paediatric population 
The safety and efficacy of vemurafenib in children less than 18 years old have not been established. 
Currently available data are described in sections 4.8, 5.1, and 5.2, but no recommendation on a 
posology can be made.  
 
Non-Caucasian patients 
The safety and efficacy of vemurafenib has not been established in non-Caucasian patients. No data 
are available. 
 
Method of administration 
Vemurafenib is for oral use. The tablets are to be swallowed whole with water. They should not be 
chewed or crushed. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 



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4.4 Special warnings and precautions for use 
 
Before taking vemurafenib, patients must have BRAF V600 mutation-positive tumour status 
confirmed by a validated test. The efficacy and safety of vemurafenib in patients with tumours 
expressing rare BRAF V600 mutations other than V600E and V600K have not been convincingly 
established (see section 5.1). Vemurafenib should not be used in patients with wild type BRAF 
malignant melanoma. 
 
Hypersensitivity reaction 
Serious hypersensitivity reactions, including anaphylaxis have been reported in association with 
vemurafenib (see sections 4.3 and 4.8). Severe hypersensitivity reactions may include 
Stevens-Johnson syndrome, generalised rash, erythema or hypotension. In patients who experience 
severe hypersensitivity reactions, vemurafenib treatment should be permanently discontinued. 
 
Dermatologic reactions 
Severe dermatologic reactions have been reported in patients receiving vemurafenib, including rare 
cases of Stevens-Johnson syndrome and toxic epidermal necrolysis in the pivotal clinical trial. Drug 
reaction with eosinophilia and systemic symptoms (DRESS) has been reported in association with 
vemurafenib in the post-marketing setting (see section 4.8). In patients who experience a severe 
dermatologic reaction, vemurafenib treatment should be permanently discontinued. 
 
Potentiation of radiation toxicity 
Cases of radiation recall and radiation sensitization have been reported in patients treated with 
radiation either prior, during, or subsequent to vemurafenib treatment. Most cases were cutaneous in 
nature but some cases involving visceral organs had fatal outcomes (see sections 4.5 and 4.8). 
Vemurafenib should be used with caution when given concomitantly or sequentially with radiation 
treatment. 
 
QT prolongation 
Exposure-dependent QT prolongation was observed in an uncontrolled, open-label phase II study in 
previously treated patients with metastatic melanoma (see section 4.8). QT prolongation may lead to 
an increased risk of ventricular arrhythmias including Torsade de Pointes. Treatment with 
vemurafenib is not recommended in patients with uncorrectable electrolyte abnormalities (including 
magnesium), long QT syndrome or who are taking medicinal products known to prolong the QT 
interval. 
 
Electrocardiogram (ECG) and electrolytes (including magnesium) must be monitored in all patients 
before treatment with vemurafenib, after one month of treatment and after dose modification. 
Further monitoring is recommended in particular in patients with moderate to severe hepatic 
impairment monthly during the first 3 months of treatment followed by every 3 months thereafter or 
more often as clinically indicated. Initiation of treatment with vemurafenib is not recommended in 
patients with QTc>500 milliseconds (ms). If during treatment the QTc exceeds 500 ms, vemurafenib 
treatment should be temporarily interrupted, electrolyte abnormalities (including magnesium) should 
be corrected, and cardiac risk factors for QT prolongation (e.g. congestive heart failure, 
bradyarrhythmias) should be controlled. Re-initiation of treatment should occur once the QTc 
decreases below 500 ms and at a lower dose as described in table 2. Permanent discontinuation of 
vemurafenib treatment is recommended if the QTc increase meets values of both >500 ms and >60 ms 
change from pre-treatment values. 
 
Ophthalmologic reactions 
Serious ophthalmologic reactions, including uveitis, iritis and retinal vein occlusion, have been 
reported. Monitor patients routinely for ophthalmologic reactions. 
 
Cutaneous Squamous Cell Carcinoma (cuSCC)  
Cases of cuSCC (which include those classified as keratoacanthoma or mixed keratoacanthoma 
subtype) have been reported in patients treated with vemurafenib (see section 4.8).  



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It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and 
be monitored routinely while on therapy. Any suspicious skin lesions should be excised, sent for 
dermatopathologic evaluation and treated as per local standard of care. The prescriber should examine 
the patient monthly during and up to six months after treatment for cuSCC. In patients who develop 
cuSCC, it is recommended to continue the treatment without dose adjustment. Monitoring should 
continue for 6 months following discontinuation of vemurafenib or until initiation of another 
anti-neoplastic therapy. Patients should be instructed to inform their physicians upon the occurrence of 
any skin changes. 
 
Non-Cutaneous Squamous Cell Carcinoma (non-cuSCC) 
Cases of non-cuSCC have been reported in clinical trials where patients received vemurafenib. 
Patients should undergo a head and neck examination, consisting of at least a visual inspection of oral 
mucosa and lymph node palpation prior to initiation of treatment and every 3 months during treatment. 
In addition, patients should undergo a chest Computerised Tomography (CT) scan, prior to treatment 
and every 6 months during treatment. 
Anal examinations and pelvic examinations (for women) are recommended before and at the end of 
treatment or when considered clinically indicated. 
Following discontinuation of vemurafenib, monitoring for non-cuSCC should continue for up to 
6 months or until initiation of another anti-neoplastic therapy. Abnormal findings should be managed 
according to clinical practices. 
 
New primary melanoma 
New primary melanomas have been reported in clinical trials. Cases were managed with excision and 
patients continued treatment without dose adjustment. Monitoring for skin lesions should occur as 
outlined above for cutaneous squamous cell carcinoma. 
 
Other malignancies 
Based on mechanism of action, vemurafenib may cause progression of cancers associated with RAS 
mutations (see section 4.8). Carefully consider benefits and risks before administering vemurafenib to 
patients with a prior or concurrent cancer associated with RAS mutation. 
 
Pancreatitis 
Pancreatitis has been reported in vemurafenib-treated subjects. Unexplained abdominal pain should be 
promptly investigated (including measurement of serum amylase and lipase). Patients should be 
closely monitored when re-starting vemurafenib after an episode of pancreatitis. 
 
Liver injury 
Liver injury, including cases of severe liver injury, has been reported with vemurafenib (see section 
4.8). Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be measured before 
initiation of treatment and monitored monthly during treatment, or as clinically indicated. Laboratory 
abnormalities should be managed with dose reduction, treatment interruption or with treatment 
discontinuation (see sections 4.2 and 4.8). 
 
Renal toxicity 
Renal toxicity, ranging from serum creatinine elevations to acute interstitial nephritis and acute tubular 
necrosis, has been reported with vemurafenib. Serum creatinine should be measured before initiation 
of treatment and monitored during treatment as clinically indicated (see sections 4.2 and 4.8). 
 
Hepatic impairment 
No adjustment to the starting dose is needed for patients with hepatic impairment. Patients with mild 
hepatic impairment due to liver metastases without hyperbilirubinaemia may be monitored according 
to the general recommendations. There are only very limited data available in patients with moderate 
to severe hepatic impairment. Patients with moderate to severe hepatic impairment may have increased 
exposure (see section 5.2). Thus close monitoring is warranted especially after the first few weeks of 
treatment as accumulation may occur over an extended period of time (several weeks). In addition 
ECG monitoring every month during the first three months is recommended. 
 



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Renal impairment 
No adjustment to the starting dose is needed for patients with mild or moderate renal impairment. 
There are only limited data available in patients with severe renal impairment (see section 5.2). 
Vemurafenib should be used with caution in patients with severe renal impairment and patients should 
be closely monitored. 
 
Photosensitivity 
Mild to severe photosensitivity was reported in patients who received vemurafenib in clinical studies 
(see section 4.8). All patients should be advised to avoid sun exposure while taking vemurafenib. 
While taking the medicinal product, patients should be advised to wear protective clothing and use a 
broad spectrum Ultraviolet A (UVA)/Ultraviolet B (UVB) sunscreen and lip balm (Sun Protection 
Factor ≥ 30) when outdoors to help protect against sunburn. 
For photosensitivity grade 2 (intolerable) or greater, dose modifications are recommended (see section 
4.2). 
 
Dupuytren’s contracture and plantar fascial fibromatosis  
Dupuytren’s contracture and plantar fascial fibromatosis have been reported with vemurafenib. The 
majority of cases were mild to moderate, but severe, disabling cases of Dupuytren’s contracture have 
also been reported (see section 4.8). 
 
Events should be managed with dose reduction with treatment interruption or with treatment 
discontinuation (see section 4.2). 
 
Effects of vemurafenib on other medicinal products 
Vemurafenib may increase the plasma exposure of medicinal products predominantly metabolised by 
CYP1A2 and decrease the plasma exposure of medicines predominantly metabolised by CYP3A4. 
Concomitant use of vemurafenib with agents metabolized by CYP1A2 and CYP3A4 with narrow 
therapeutic windows is not recommended. Dose adjustments for medicinal products predominantly 
metabolised via CYP1A2 or CYP3A4 should be considered based on their therapeutic windows before 
concomitantly treating with vemurafenib (see sections 4.5 and 4.6). 
 
Exercise caution and consider additional INR (International Normalised Ratio) monitoring when 
vemurafenib is used concomitantly with warfarin. 
 
Vemurafenib may increase the plasma exposure of medicinal products that are P-gp substrates. 
Caution should be exercised when dosing vemurafenib concurrently with P-gp substrates. Dose 
reduction and/or additional drug level monitoring for P-gp substrate medicinal products with narrow 
therapeutic index (NTI) (e.g. digoxin, dabigatran etexilate, aliskiren) may be considered if these 
medicinal products are used concomitantly with vemurafenib (see section 4.5). 
  
Effect of other medicinal products on vemurafenib 
 
Concomitant administration of strong inducers of CYP3A4, P-gp and glucuronidation (e.g. rifampicin, 
rifabutin, carbamazepine, phenytoin or St John’s Wort [hypericin]) might lead to decreased exposure 
of vemurafenib and should be avoided when possible (see section 4.5). Alternative treatment with less 
inducing potential should be considered to maintain the efficacy of vemurafenib. Caution should be 
used when administering Vemurafenib with strong CYP3A4/PgP inhibitors. Patients should be 
carefully monitored for safety and dose modifications applied if clinically indicated (see Table 1 in 
section 4.2).  
 
Concurrent administration with ipilimumab 
In a Phase I trial, asymptomatic grade 3 increases in transaminases (ALT/AST >5 x ULN) and 
bilirubin (total bilirubin >3x ULN) were reported with concurrent administration of ipilimumab 
(3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID). Based on these preliminary data, the 
concurrent administration of ipilimumab and vemurafenib is not recommended. 
 



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4.5 Interaction with other medicinal products and other forms of interaction 
 
Effects of vemurafenib on Drug Metabolizing Enzymes 
Results from an in vivo drug-drug interaction study in metastatic melanoma patients demonstrated that 
vemurafenib is a moderate CYP1A2 inhibitor and a CYP3A4 inducer. 
 
Concomitant use of vemurafenib with agents metabolized by CYP1A2  with narrow therapeutic 
windows (e.g. agomelatine, alosetron, duloxetine, melatonin, ramelteon, tacrine, tizanidine, 
theophylline) is not recommended. If co-administration cannot be avoided, exercise caution, as 
vemurafenib may increase plasma exposure of CYP1A2 substrate drugs. Dose reduction of the 
concomitant CYP1A2 substrate drug may be considered, if clinically indicated.  
Co-administration of vemurafenib increased the plasma exposure (AUC) of caffeine (CYP1A2 
substrate) 2.6-fold. In another clinical trial, vemurafenib increased Cmax and AUC of a single 2 mg 
dose of tizanidine (CYP1A2 substrate) approximately 2.2-fold  
and 4.7-fold, respectively.  
 
Concomitant use of vemurafenib with agents metabolized by CYP3A4  with narrow therapeutic 
windows  is not recommended. If co-administration cannot be avoided, it needs to be considered that 
vemurafenib may decrease plasma concentrations of CYP3A4 substrates and thereby their efficacy 
may be impaired. On this basis, the efficacy of contraceptive pills metabolized by CYP3A4 used 
concomitantly with vemurafenib might be decreased. Dose adjustments for CYP3A4 substrates with 
narrow therapeutic window may be considered, if clinically indicated (see sections 4.4 and 4.6). 
In a clinical trial, co-administration of vemurafenib decreased the AUC of midazolam (CYP3A4 
substrate) by an average 39% (maximum decrease up to 80%).   
 
Mild induction of CYP2B6 by vemurafenib was noted in vitro at a vemurafenib concentration of 
10 µM. It is currently unknown whether vemurafenib at a plasma level of 100 µM observed in patients 
at steady state (approximately 50 µg/ml) may decrease plasma concentrations of concomitantly 
administered CYP2B6 substrates, such as bupropion. 
 
Co-administration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 
substrate).  Exercise caution and consider additional INR (international normalized ratio) monitoring 
when vemurafenib is used concomitantly with warfarin (see section 4.4).  
 
Vemurafenib moderately inhibited CYP2C8 in vitro. The in vivo relevance of this finding is unknown, 
but a risk for a clinically relevant effect on concomitantly administered CYP2C8 substrates cannot be 
excluded. Concomitant administration of CYP2C8 substrates with a narrow therapeutic window 
should be made with caution since vemurafenib may increase their concentrations. 
 
Due to the long half-life of vemurafenib, the full inhibitory effect of vemurafenib on a concomitant 
medicinal product might not be observed before 8 days of vemurafenib treatment. 
After cessation of vemurafenib treatment, a washout of 8 days might be necessary to avoid an 
interaction with a subsequent treatment. 
 
Radiation treatment 
Potentiation of radiation treatment toxicity has been reported in patients receiving vemurafenib (see 
sections 4.4 and 4.8).  In the majority of cases, patients received radiotherapy regimens greater than or 
equal to 2 Gy/day (hypofractionated regimens). 
 
Effects of vemurafenib on drug transport systems 
In vitro studies have demonstrated that vemurafenib is an inhibitor of the efflux transporters 
P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). 
 
A clinical drug interaction study demonstrated that multiple oral doses of vemurafenib (960 mg twice 
daily) increased the exposure of a single oral dose of the P-gp substrate digoxin, approximately 1.8 
and 1.5 fold for digoxin AUClast and Cmax, respectively.  



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Caution should be exercised when dosing vemurafenib concurrently with P-gp substrates (e.g. 
aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, lapatinib, 
maraviroc, nilotinib, posaconazole, ranolazine, sirolimus, sitagliptin, talinolol, topotecan) and dose 
reduction of the concomitant medicinal product may be considered, if clinically indicated. Consider 
additional drug level monitoring for P-gp substrate medicinal products with a narrow therapeutic index 
(NTI) (e.g. digoxin, dabigatran etexilate, aliskiren) (see section 4.4). 
 
The effects of vemurafenib on medicinal products that are substrates of BCRP are unknown.  It cannot 
be excluded that vemurafenib may increase the exposure of medicines transported by  BCRP (e.g. 
methotrexate, mitoxantrone, rosuvastatin). 
Many anticancer medicinal products  are substrates of BCRP and therefore there is a theoretical risk 
for an interaction with vemurafenib. 
 
The possible effect of vemurafenib on other transporters is currently unknown. 
 
Effects of concomitant medicines on vemurafenib 
In vitro studies suggest that CYP3A4 metabolism and glucuronidation are responsible for the 
metabolism of vemurafenib. Biliary excretion appears to be another important elimination pathway. In 
vitro studies have demonstrated that vemurafenib is a substrate of the efflux transporters P-gp and 
BCRP. It is currently unknown whether vemurafenib is a substrate also to other transport proteins. 
Concomitant administration of strong CYP3A4 inhibitors or inducers or inhibitors/inducer of transport 
protein activity may alter vemurafenib concentrations.  
 
Co-administration of itraconazole, a strong CYP3A4/Pgp inhibitor, increased steady state vemurafenib 
AUC by approximately 40%. Vemurafenib should be used with caution in combination with strong 
inhibitors of CYP3A4, glucuronidation and/or transport proteins (e.g. ritonavir, saquinavir, 
telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone, atazanavir). 
Patients co-treated with such agents should be carefully monitored for safety and dose modifications 
applied if clinically indicated (see Table 1 in section 4.2). 
 
In a clinical study, co-administration of a single dose 960 mg of vemurafenib with rifampicin, 
significantly decreased the plasma exposure of vemurafenib by approximately 40%. 
Concomitant administration of strong inducers of P-gp, glucuronidation, and/or CYP3A4 (e.g. 
rifampicin, rifabutin, carbamazepine, phenytoin or St John’s Wort [Hypericum perforatum]) may lead 
to suboptimal exposure to vemurafenib and should be avoided. 
 
The effects of P-gp and BCRP inhibitors that are not also strong CYP3A4 inhibitors are unknown. It 
cannot be excluded that vemurafenib pharmacokinetics could be affected by such medicines through 
influence on P-gp (e.g. verapamil, cyclosporine, quinidine) or BCRP (e.g. cyclosporine, gefitinib). 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential / Contraception in females 
Women of childbearing potential have to use effective contraception during treatment and for at least 
6 months after treatment. 
Vemurafenib might decrease the efficacy of hormonal contraceptives (see section 4.5). 
 
Pregnancy 
There are no data regarding the use of vemurafenib in pregnant women. 
Vemurafenib revealed no evidence of teratogenicity in rat or rabbit embryo/foetuses (see section 5.3). 
In animal studies, vemurafenib was found to cross the placenta. Based on its mechanism of action, 
vemurafenib could cause fetal harm when administered to a pregnant woman. Vemurafenib should not 
be administered to pregnant women unless the possible benefit to the mother outweighs the possible 
risk to the foetus. 
 



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Breast-feeding 
It is not known whether vemurafenib is 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 
vemurafenib therapy taking into account the benefit of breast-feeding for the child and the benefit of 
therapy for the woman. 
 
Fertility 
No specific studies with vemurafenib have been conducted in animals to evaluate the effect on 
fertility. However, in repeat-dose toxicity studies in rats and dogs, no histopathological findings were 
noted in reproductive organs in males and females (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Vemurafenib has minor influence on the ability to drive and use machines. Patients should be made 
aware of the potential fatigue or eye problems that could be a reason for not driving. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The most common adverse drug reactions (ADR) of any grade (> 30%) reported with vemurafenib 
include arthralgia, fatigue, rash, photosensitivity reaction, alopecia, nausea diarrhea, headache, 
pruritus, vomiting, skin papilloma and hyperkeratosis. The most common (≥ 5%) Grade 3 ADRs were 
cuSCC, keratoacanthoma, rash, arthralgia and gamma-glutamyltransferase (GGT) increased. CuSCC 
was most commonly treated by local excision. 
 
Tabulated summary of adverse reactions 
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 
 
In this section, ADRs are based on results in 468 patients from a phase III randomised open label 
study in adult patients with BRAF V600 mutation-positive unresectable or stage IV melanoma, as well 
as a phase II single-arm study in patients with BRAF V600 mutation-positive stage IV melanoma who 
had previously failed at least one prior systemic therapy (see section 5.1). In addition ADRs 
originating from safety reports across all clinical trials and post-marketing sources are reported. All 
terms included are based on the highest percentage observed among phase II and phase III clinical 
trials. Within each frequency grouping, ADRs are presented in order of decreasing severity and were 
reported using NCI-CTCAE v 4.0 (common toxicity criteria) for assessment of toxicity. 
 



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Table 3: ADRs occurring in patients treated with vemurafenib in the phase II or phase III study 
and events originating from safety reports across all trials(1) and post-marketing sources(2). 
 

System organ class Very Common 
 

Common 
 

Uncommon 
 

Rare 

Infections and 
infestations 

 Folliculitis   

Neoplasms benign, 
malignant and 
unspecified 
(including cysts and 
polyps) 

SCC of the skin (d), 
keratoacanthoma, 
seborrhoeic keratosis, 
skin papilloma 

Basal cell carcinoma, 
new primary 
melanoma(3) 

Non-cuSCC(1)(3) Chronic 
myelomonocytic 
leukaemia(2)(4), 
pancreatic 
adenocarcinoma(5) 

Blood and lymphatic 
system disorders 

 Neutropenia   

Immune System 
Disorders 

   Sarcoidosis (1)(2)(j) 

Metabolism and 
nutrition disorders  

Decreased appetite    

Nervous system 
disorders  

Headache, dysgeusia, 
dizziness 

7th nerve paralysis, 
neuropathy 
peripheral 

  

Eye disorders  Uveitis,  Retinal vein 
occlusion, iridocyclitis 

 

Vascular disorders  Vasculitis   

Respiratory, thoracic 
and mediastinal 
disorders  

Cough    

Gastrointestinal 
disorders  

Diarrhoea, vomiting, 
nausea, constipation 

 Pancreatitis(2)  

Hepatobiliary 
disorders 

  Liver injury(1)(2) (g)  

Skin and 
subcutaneous tissue 
disorders  

Photosensitivity 
reaction, actinic 
keratosis, rash, rash 
maculo-papular, 
pruritus, 
hyperkeratosis, 
erythema, palmar-
plantar 
erythrodysaesthesia 
syndrome, alopecia, 
dry skin, sunburn 

Rash papular, 
panniculitis 
(including erythema 
nodosum), keratosis 
pilaris 

Toxic epidermal 
necrolysis (e), Stevens-
Johnson syndrome (f)  
 

Drug reaction with 
eosinophilia and 
systemic 
symptoms(1)(2) 

Musculoskeletal and 
connective tissue 
disorders  

Arthralgia, myalgia, 
pain in extremity, 
musculoskeletal pain, 
back pain 

Arthritis,  Plantar fascial 
fibromatosis(1)(2) 
Dupuytren’s 
contracture(1)(2) 
 

 



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System organ class Very Common 
 

Common 
 

Uncommon 
 

Rare 

Renal and urinary 
disorders 

   Acute interstitial 
nephritis(1)(2) (h), 
acute tubular 
necrosis(1)(2) (h) 

General disorders 
and administration 
site conditions  

Fatigue, pyrexia, 
oedema peripheral, 
asthenia 

   

Investigations  ,  ALT increased (c), 
alkaline phosphatase 
increased (c), AST 
increased (c),bilirubin 
increased (c) GGT 
increased (c, weight 
decreased, 
electrocardiogram 
QT prolonged, blood 
creatinine 
increased(1)(2) (h) 

  

Injury, Poisoning, 
and Procedural 
Complications 

 Potentiation of 
Radiation toxicity (1) 
(2) (i) 

  

(1) Events originating from safety reports across all trials 
(2) Events originating from post-marketing sources. 
(3) A causal relationship between the medicinal product and the adverse event is at least a reasonable possibility. 
(4) Progression of pre-existing chronic myelomonocytic leukaemia with NRAS mutation. 
(5) Progression of pre-existing pancreatic adenocarcinoma with KRAS mutation. 
 
Description of selected adverse reactions 
 
Hepatic enzyme increase (c) 
Liver enzyme abnormalities reported in the phase III clinical study are expressed below as the 
proportion of patients who experienced a shift from baseline to a grade 3 or 4 liver enzyme 
abnormalities: 

• Very common: GGT  
• Common: ALT, alkaline phosphatase, bilirubin 
• Uncommon: AST 
 

There were no increases to Grade 4 ALT, alkaline phosphatase or bilirubin. 
 
Liver injury (g) 
Based on the criteria for drug induced liver injury developed by an international expert working group 
of clinicians and scientists, liver injury was defined as any one of the following laboratory 
abnormalities: 

• ≥ 5x ULN ALT 
• ≥ 2x ULN ALP (without other cause for ALP elevation) 
• ≥ 3x ULN ALT with simultaneous elevation of bilirubin concentration > 2x ULN 

 
Cutaneous squamous cell carcinoma (d) (cuSCC) 
Cases of cuSCC have been reported in patients treated with vemurafenib. The incidence of cuSCC in 
vemurafenib-treated patients across studies was approximately 20%. The majority of the excised 
lesions reviewed by an independent central dermatopathology laboratory were classified as SCC-
keratoacanthoma subtype or with mixed-keratoacanthoma features (52%). Most lesions classified as 
“other” (43%) were benign skin lesions (e.g. verruca vulgaris, actinic keratosis, benign keratosis, 
cyst/benign cyst). CuSCC usually occurred early in the course of treatment with a median time to the 



13 

first appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approximately 33% 
experienced > 1 occurrence with median time between occurrences of 6 weeks. Cases of cuSCC were 
typically managed with simple excision, and patients generally continued on treatment without dose 
modification (see sections 4.2 and 4.4). 
 
Non-cutaneous squamous cell carcinoma (non-cuSCC) 
Cases of non-cuSCC have been reported in patients receiving vemurafenib while enrolled in clinical 
trials. Surveillance for non-cuSCC should occur as outlined in section 4.4. 
 
New primary melanoma 
New primary melanomas have been reported in clinical trials. These cases were managed with 
excision, and patients continued treatment without dose adjustment. Monitoring for skin lesions should 
occur as outlined in section 4.4. 
 
Potentiation of radiation toxicity(i) 
Cases reported include recall phenomenon, radiation skin injury, radiation pneumonitis, radiation 
esophagitis, radiation proctitis, radiation hepatitis, cystitis radiation, and radiation necrosis. 
 
In a phase III clinical trial (MO25515, N= 3219), a higher incidence of potentiation of radiation 
toxicity was reported when vemurafenib patients received radiation prior to and during vemurafenib 
therapy (9.1%) compared to those patients who received radiation and vemurafenib concomitantly (5.2 
%) or to those whose radiation treatment was prior to vemurafenib (1.5%). 
 
Hypersensitivity reactions (e) 
Serious hypersensitivity reactions, including anaphylaxis have been reported in association with 
vemurafenib. Severe hypersensitivity reactions may include Stevens-Johnson syndrome, generalised 
rash, erythema or hypotension. In patients who experience severe hypersensitivity reactions, 
vemurafenib treatment should be permanently discontinued (see section 4.4). 
 
Dermatologic reactions (f) 
Severe dermatologic reactions have been reported in patients receiving vemurafenib, including rare 
cases of Stevens-Johnson syndrome and toxic epidermal necrolysis in the pivotal clinical trial. In 
patients who experience a severe dermatologic reaction, vemurafenib treatment should be permanently 
discontinued. 
 
QT prolongation 
Analysis of centralised ECG data from an open-label uncontrolled phase II QT sub-study in 132 
patients dosed with vemurafenib 960 mg twice daily (NP22657) showed an exposure-dependent QTc 
prolongation. The mean QTc effect remained stable between 12-15 ms beyond the first month of 
treatment, with the largest mean QTc prolongation (15.1 ms; upper 95% CI: 17.7 ms) observed within 
the first 6 months (n=90 patients). Two patients (1.5%) developed treatment-emergent absolute QTc 
values >500 ms (CTC Grade 3), and only one patient (0.8%) exhibited a QTc change from baseline of 
>60 ms (see section 4.4). 
 
Acute kidney injury (h) 
Cases of renal toxicity have been reported with vemurafenib ranging from creatinine elevations to 
acute interstitial nephritis and acute tubular necrosis, some observed in the setting of dehydration 
events. Serum creatinine elevations were  mostly mild (>1-1.5x ULN) to moderate (>1.5-3x ULN) and 
observed to be reversible in nature (see table 4). 
 
Table 4: Creatinine changes from baseline in the phase III study 
 
 Vemurafenib (%) Dacarbazine (%) 
Change ≥ 1 grade from baseline to any grade 27.9 6.1 
Change ≥ 1 grade from baseline to grade 3 or higher 1.2 1.1 

• To grade 3 0.3 0.4 
• To grade 4 0.9 0.8 



14 

 
Table 5: Acute kidney injury cases in the phase III study 
 
 Vemurafenib (%) Dacarbazine (%) 
Acute kidney injury cases* 10.0 1.4 
Acute kidney injury cases associated with 
dehydration events 5.5 1.0 

Dose modified for acute kidney injury 2.1 0 
All percentages are expressed as cases out of total patients exposed to each medicinal product. 
*  Includes acute kidney injury, renal impairment, and laboratory changes consistent with acute kidney injury. 
 
Sarcoidosis (j) 
Cases of sarcoidosis have been reported in patients treated with vemurafenib, mostly involving the 
skin, lung and eye. In majority of the cases, vemurafenib was maintained and the event of sarcoidosis 
either resolved or persisted.  
 
Special populations 
 
Elderly 
In the phase III study, ninety-four (28%) of 336 patients with unresectable or metastatic melanoma 
treated with vemurafenib were ≥ 65 years. Older patients (≥ 65 years) may be more likely to 
experience adverse reactions, including cuSCC, decreased appetite, and cardiac disorders. 
 
Gender 
During clinical trials with vemurafenib, grade 3 adverse reactions reported more frequently in females 
than males were rash, arthralgia and photosensitivity. 
 
Paediatric population 
The safety of vemurafenib  in children and adolescents has not been established. No new safety signals 
were observed in a clinical study with six adolescent patients. 
 
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 specific antidote for overdose of vemurafenib. Patients who develop adverse reactions 
should receive appropriate symptomatic treatment. No cases of overdose have been observed with 
vemurafenib in clinical trials. In case of suspected overdose, vemurafenib should be withheld and 
supportive care initiated.  
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor, ATC code: L01XE15 
 
Mechanism of action and pharmacodynamic effects 
Vemurafenib is an inhibitor of BRAF serine-threonine kinase. Mutations in the BRAF gene result in 
constitutive activation of BRAF proteins, which can cause cell proliferation without associated growth 
factors. 
Preclinical data generated in biochemical assays demonstrated that vemurafenib can potently inhibit 
BRAF kinases with activating codon 600 mutations (table 6). 

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


15 

 
Table 6: Kinase inhibitory activity of vemurafenib against different BRAF kinases  
 

Kinase Anticipated frequency in V600 
mutation-positive melanoma (t) 

Inhibitory Concentration 50 
(nM) 

BRAFV600E 87.3% 10 
BRAFV600K 7.9% 7 
BRAFV600R 1% 9 
BRAFV600D <0.2% 7 
BRAFV600G <0.1% 8 
BRAFV600M <0.1% 7 
BRAFV600A <0.1% 14 
BRAFWT N/A 39 

(t) Estimated from 16,403 melanomas with annotated BRAF codon 600 mutations in the public COSMIC 
database, release 71 (November 2014).  
 
This inhibitory effect was confirmed in the ERK phosphorylation and cellular anti-proliferation assays 
in available melanoma cell lines expressing V600-mutant BRAF. In cellular anti-proliferation assays 
the inhibitory concentration 50 (IC50) against V600 mutated cell lines (V600E, V600R, V600D and 
V600K mutated cell lines) ranged from 0.016 to 1.131 µM whereas the IC50 against BRAF wild type 
cell lines were 12.06 and 14.32 µM, respectively. 
 
Determination of BRAF mutation status 
Before taking vemurafenib, patients must have BRAF V600 mutation-positive tumour status 
confirmed by a validated test. In the phase II and phase III clinical trials, eligible patients were 
identified using a real-time polymerase chain reaction assay (the cobas 4800 BRAF V600 Mutation 
Test). This test has CE marking and is used to assess the BRAF mutation status of DNA isolated from 
formalin-fixed, paraffin-embedded (FFPE) tumour tissue. It was designed to detect the predominant 
BRAF V600E mutation with high sensitivity (down to 5% V600E sequence in a background of wild 
type sequence from FFPE-derived DNA). Non-clinical and clinical studies with retrospective 
sequencing analyses have shown that the test also detects the less common BRAF V600D mutations 
and V600K mutations with lower sensitivity. Of the specimens available from the non-clinical and 
clinical studies (n=920), that were mutation-positive by the cobas test and additionally analyzed by 
sequencing, no specimen was identified as being wild type by both Sanger and 454 sequencing. 
 
Clinical efficacy and safety 
 
The efficacy of vemurafenib has been evaluated in 336 patients from a phase III clinical trial 
(NO25026) and 278 patients from two phase II clinical trials (NP22657 and MO25743). All patients 
were required to have advanced melanoma with BRAF V600 mutations according to the cobas 4800 
BRAF V600 Mutation Test. 
 
Results from the Phase III study (NO25026) in previously untreated patients 
An open-label, multicentre, international, randomised phase III study supports the use of vemurafenib 
in previously untreated patients with BRAF V600E mutation-positive unresectable or metastatic 
melanoma. Patients were randomised to treatment with vemurafenib (960 mg twice daily) or 
dacarbazine (1000 mg/m2 on day 1 every 3 weeks). 
 
A total of 675 patients were randomised to vemurafenib (n=337) or dacarbazine (n=338). Most 
patients were male (56%) and Caucasian (99%), the median age was 54 years (24% were ≥ 65 years), 
all patients had ECOG performance status of 0 or 1, and the majority of patients had stage M1c 
disease (65%). The co-primary efficacy endpoints of the study were overall survival (OS) and 
progression-free survival (PFS). 
 
At the pre-specified interim analysis with a December 30, 2010 data cut-off, significant improvements 
in the co-primary endpoints of OS (p<0.0001) and PFS (p<0.0001) (unstratified log-rank test) were 



16 

observed. Upon Data Safety Monitoring Board (DSMB) recommendation, those results were released 
in January 2011 and the study was modified to permit dacarbazine patients to cross over to receive 
vemurafenib. Post-hoc survival analyses were undertaken thereafter as described in table 7. 
 
Table 7: Overall survival in previously untreated patients with BRAF V600 mutation-positive 
melanoma by study cut-off date (N=338 dacarbazine, N=337 vemurafenib) 
 
Cut-off dates Treatment Number of deaths 

(%) 
Hazard Ratio  
(95% CI) 

Number of cross-
over patients (%) 

December 30, 
2010 

dacarbazine 75 (22) 0.37 (0.26, 0.55) 
 

0 (not applicable) 
vemurafenib 43 (13) 

March 31, 
2011 

dacarbazine 122 (36) 0.44 (0.33, 0.59) (w) 
 

50 (15%) 
vemurafenib 78 (23) 

October 3, 
2011 

dacarbazine 175 (52) 0.62 (0.49, 0.77) (w) 81 (24%) 
vemurafenib 159 (47) 

February 1, 
2012 

dacarbazine 200 (59) 0.70 (0.57, 0.87) (w) 83 (25%) 
vemurafenib 199 (59) 

December 20, 
2012 

dacarbazine 236 (70) 0.78 (0.64, 0.94) (w) 84 (25%) 
vemurafenib 242 (72) 

(w) Censored results at time of cross-over 
Non-censored results at time of cross-over: March 31 2011: HR (95% CI) = 0.47 (0.35, 0.62); October 3 2011: 
HR (95% CI) = 0.67 (0.54, 0.84); February 1 2012: HR (95% CI) = 0.76 (0.63, 0.93); December 20 2012: 
HR (95% CI) = 0.79 (0.66, 0.95) 
 
Figure 1: Kaplan-Meier curves of overall survival – previously untreated patients (December 20, 
2012 cut-off)  

 
Table 8 shows the treatment effect for all pre-specified stratification variables which are established as 
prognostic factors. 
 



17 

Table 8: Overall survival in previously untreated patients with BRAF V600 mutation-positive 
melanoma by LDH, tumour stage and ECOG status (post hoc analysis, December 20, 2012 cut-
off, censored results at time of cross over) 
 

Stratification variable N Hazard Ratio 95% Confidence Interval 
LDH normal 391 0.88 0.67; 1.16 
LDH >ULN 284 0.57 0.44; 0.76 
Stage IIIc/M1A/M1B 234 1.05 0.73; 1.52 
Stage MIC 441 0.64 0.51; 0.81 
ECOG PS=0 459 0.86 0.67; 1.10 
ECOG PS=1 216 0.58 0.42; 0.9 

LDH: Lactate Dehydrogenase, ECOG PS: Eastern Cooperative Oncology Group Performance Status 
 
Table 9 shows the overall response rate and progression-free survival in previously untreated patients 
with BRAF V600 mutation-positive melanoma. 
 
Table 9: Overall response rate and progression-free survival in previously untreated patients 
with BRAF V600 mutation-positive melanoma  
 

 vemurafenib dacarbazine p-value (x) 
December 30, 2010 data cut-off date (y) 
Overall Response Rate 
(95% CI) 

48.4% 
(41.6%, 55.2%) 

5.5% 
(2.8%, 9.3%) <0.0001 

Progression-free survival 
Hazard Ratio 
(95% CI) 

0.26 
(0.20, 0.33) <0.0001 

Number of events (%) 104 (38%) 182 (66%)  
Median PFS (months) 
(95% CI) 

5.32 
(4.86, 6.57) 

1.61 
(1.58, 1.74)  

February 01, 2012 data cut-off date (z) 
Progression-free survival 
Hazard Ratio 
(95% CI) 

0.38 
(0.32, 0.46) <0.0001 

Number of events (%) 277 (82%) 273 (81%)  
Median PFS (months) 
(95% CI) 

6.87 
(6.14, 6.97) 

1.64 
(1.58, 2.07)  

(x) Unstratified log-rank test for PFS and Chi-squared test for Overall Response Rate. 
(y) As of December 30, 2010, a total of 549 patients were evaluable for PFS and 439 patients were evaluable for 
overall response rate. 
(z) As of February 01, 2012, a total of 675 patients were evaluable for the post-hoc analysis update of PFS. 
 
A total of 57 patients out of 673 whose tumours were analysed retrospectively by sequencing were 
reported to have BRAF V600K mutation-positive melanoma in NO25026. Although limited by the 
low number of patients, efficacy analyses among these patients with V600K-positive tumours 
suggested similar treatment benefit of vemurafenib in terms of OS, PFS and confirmed best overall 
response. No data are available in patients with melanoma harbouring rare BRAF V600 mutations 
other than V600E and V600K. 
 
Results from the phase II study (NP22657) in patients who failed at least one prior therapy 
 
A phase II single-arm, multi-centre, multinational study was conducted in 132 patients who had BRAF 
V600E mutation-positive metastatic melanoma according to the cobas 4800 BRAF V600 Mutation 
Test and had received at least one prior therapy. The median age was 52 years with 19% of patients 
being older than 65 years. The majority of patients was male (61%), Caucasian (99%), and had stage 
M1c disease (61%). Forty-nine percent of patients failed ≥ 2 prior therapies.  



18 

With a median follow-up of 12.9 months (range, 0.6 to 20.1), the primary endpoint of confirmed best 
overall response rate (CR + PR) as assessed by an independent review committee (IRC) was 53% 
(95% CI: 44%, 62%). Median overall survival was 15.9 months (95% CI: 11.6, 18.3). The overall 
survival rate at 6 months was 77% (95% CI: 70%, 85%) and at 12 months was 58% (95% CI: 49%, 
67%).  
Nine of the 132 patients enrolled into NP22657 had V600K mutation-positive tumours according to 
retrospective Sanger sequencing. Amongst these patients, 3 had a PR, 3 had SD, 2 had PD and one 
was not evaluable. 
 
Results from the phase II study (MO25743) in  patients with brain metastases 
 
A single-arm, multicentre study (N = 146) of vemurafenib was conducted in adult patients with 
histologically confirmed metastatic melanoma harbouring the BRAF V600 mutation (according to the 
cobas 4800 BRAF V600 Mutation Test) and with brain metastases. The study included two 
simultaneously enrolling cohorts: 
 
- Cohort 1 with previously untreated patients (N = 90): Patients who had not received previous 

treatment for brain metastases; prior systemic therapy for metastatic melanoma was allowed, 
excluding BRAF inhibitors and MEK inhibitors. 

 
- Cohort 2 with previously treated patients (N = 56): Patients who had been previously treated for 

their brain metastases and had progressed following this treatment.  For patients treated with 
stereotactic radiotherapy (SRT) or surgery, a new RECIST-assessable brain lesion must have 
developed following this prior therapy.  

 
A total of 146 patients were enrolled. The majority of patients were male (61.6%), and Caucasian 
(92.5%), and the median age was 54 years (range 26 to 83 years), similarly distributed between the 
two cohorts. The median number of brain target lesions at baseline was 2 (range 1 to 5), in both 
cohorts. 
The primary efficacy objective of the study was best overall response rate (BORR) in the brain of 
metastatic melanoma patients with previously untreated brain metastases, as assessed by an 
independent review committee (IRC).   
Secondary objectives included an evaluation of the efficacy of vemurafenib using BORR in the brain 
of previously treated patients, duration of response (DOR), progression-free survival (PFS) and overall 
survival (OS) in patients with melanoma metastatic to the brain (see table 10). 
 



19 

Table 10:  Efficacy of vemurafenib in patients with brain metastases 
 

 Cohort 1 
No previous 

treatment 
n = 90 

Cohort 2 
Previously 

treated 
n = 56 

Total 
 
 

n =  146 
BORRa in brain 
Responders n (%) 
(95% CI)b 

 
16 (17.8%) 
(10.5, 27.3) 

 
10 (17.9%) 
(8.9, 30.4) 

 
26 (17.8%) 
(12.0, 25.0) 

DORc in brain (n) 
Median (months) 
(95% CI)d 

(n = 16) 
4.6 

(2.9, 6.2) 

(n = 10) 
6.6 

(2.8, 10.7) 

(n = 26) 
5.0 

(3.7, 6.6) 
BORR extra-
cranial n (%)a 26 (32.9%) 9 (22.5%) 35 (29.4%) 
PFS - overall  
Median (months)e 
(95% CI)d 

 
3.7 

(3.6, 3.7) 

 
3.7 

(3.6, 5.5) 

 
3.7 

(3.6, 3.7) 
PFS - brain only  
Median (months)e   
(95% CI)d 

 
3.7 

(3.6, 4.0) 

 
4.0 

(3.6, 5.5) 

 
3.7 

(3.6, 4.2) 
OS 
Median (months) 
(95% CI)d 

 
8.9 

(6.1, 11.5) 

 
9.6 

(6.4, 13.9) 

 
9.6 

 (6.9, 11.5) 
a Best overall confirmed response rate as assessed by independent review committee, number of responders 

n (%) 
b Two-sided 95% Clopper-Pearson Confidence Interval (CI) 
c Duration of response as assessed by an Independent Review Committee 
d Kaplan-Meier estimate 
e Assessed by investigator 
 
Paediatric population 
 
Results from the phase I study (NO25390) in  paediatric patients 
 
A phase I dose-escalation study evaluating the use of vemurafenib in six adolescent patients with stage 
IIIC or IV BRAF V600 mutation positive melanoma was conducted. All patients treated were at least 
15 years of age and weighed at least 45 kg. Three patients were treated with vemurafenib 720 mg 
twice daily, and three patients were treated with vemurafenib 960 mg twice daily. The maximum 
tolerated dose could not be determined. Although transient tumour regressions were seen, the best 
overall response rate (BORR) was 0% (95% CI: 0%, 46%) based on confirmed responses. The study 
was terminated due to low enrollment. See section 4.2 for information on paediatric use.  
 
5.2 Pharmacokinetic properties 
 
Vemurafenib is a Class IV substance (low solubility and permeability), using the criteria described in 
the Biopharmaceutics Classification System. The pharmacokinetic parameters for vemurafenib were 
determined using non-compartmental analysis in a phase I and phase III studies (20 patients after 15 
days of dosing at 960 mg twice daily, and 204 patients in steady state day 22) as well as by population 
PK analysis using pooled data from 458 patients. Among these patients, 457 were Caucasians.  
 
Absorption 
The bioavailability at steady state ranged between 32 and 115% (mean 64%) relative to an intravenous 
microdose, in a phase I study with uncontrolled food conditions in 4 patients with BRAF V600 
positive malignancies. 
 



20 

Vemurafenib is absorbed with a median Tmax of approximately 4 hours following a single 960 mg 
dose (four 240 mg tablets). Vemurafenib exhibits high inter-patient variability. In the phase II study, 
AUC0-8h and Cmax at day 1 were 22.1 ± 12.7 µg⋅h/mL and 4.1 ± 2.3 µg/mL. Accumulation occurs upon 
multiple twice daily dosing of vemurafenib. In the non-compartmental analysis, after dosing with 
960 mg vemurafenib twice daily the Day 15 / Day 1 ratio ranged from 15- to 17-fold for AUC, and 13- 
to 14-fold for Cmax, yielding AUC0-8h and Cmax of 380.2 ± 143.6 µg⋅h/mL and 56.7 ± 21.8 µg/mL, 
respectively, under steady-state conditions. 
Food (high fat meal) increases the relative bioavailability of a single 960 mg dose of vemurafenib. The 
geometric mean ratios between the fed and fasted states for Cmax and AUC were 2.5 and 4.6 to 5.1 
fold, respectively. The median Tmax was increased from 4 to 7.5 hours when a single vemurafenib dose 
was taken with food.  
The effect of food on steady state vemurafenib exposure is currently unknown. Consistent intake of 
vemurafenib on an empty stomach may lead to significantly lower steady state exposure than 
consistent intake of vemurafenib with or a short time after a meal. Occasional intake of vemurafenib 
on an empty stomach is expected to have limited influence on steady state exposure due to the high 
accumulation of vemurafenib at steady state. Safety and efficacy data from pivotal studies were 
collected from patients taking vemurafenib with or without food. 
Variability in exposure may also occur due to differences in gastro-intestinal fluid content, volumes, 
pH, motility and transition time and bile composition. 
At steady state, the mean vemurafenib exposure in plasma is stable during the 24-hour interval as 
indicated by the mean ratio of 1.13 between the plasma concentrations before and 2-4 hours after the 
morning dose. Following oral dosing, the absorption rate constant for the population of metastatic 
melanoma patients is estimated to be 0.19 hr-1 (with 101% between patient variability). 
 
Distribution 
The population apparent volume of distribution for vemurafenib in metastatic melanoma patients is 
estimated to be 91 L (with 64.8% between patient variability). It is highly bound to human plasma 
proteins in vitro (>99%).  
 
Biotransformation 
The relative proportions of vemurafenib and its metabolites were characterised in a human mass 
balance study with a single dose of 14C-labeled vemurafenib administered orally. CYP3A4 is the 
primary enzyme responsible for the metabolism of vemurafenib in vitro. Conjugation metabolites 
(glucuronidation and glycosylation) were also identified in humans. However, the parent compound 
was the predominant component (95%) in plasma. Although metabolism does not appear to result in a 
relevant amount of metabolites in plasma, the importance of metabolism for excretion cannot be 
excluded.  
 
Elimination 
The population apparent clearance of vemurafenib in patients with metastatic melanoma is estimated 
to be 29.3 L/day (with 31.9% between patient variability). The population elimination half-life 
estimated by the population PK analysis for vemurafenib is 51.6 hours (the 5th and 95th percentile 
range of the individual half-life estimates is 29.8 - 119.5 hours). 
 
In the human mass balance study with vemurafenib administered orally, on average 95% of the dose 
was recovered within 18 days. The majority of vemurafenib-related material (94%) was recovered in 
faeces, and <1% in urine. Renal elimination does not appear to be of importance for vemurafenib 
elimiation, whereas biliary excretion of unchanged compound may be an important route of 
elimination.. Vemurafenib is a substrate and inhibitor of P-gp in vitro. 
 
Special populations 
 
Elderly 
Based on the population PK analysis, age has no statistically significant effect on vemurafenib 
pharmacokinetics. 
 



21 

Gender 
The population pharmacokinetic analysis indicated a 17% greater apparent clearance (CL/F) and a 
48% greater apparent volume of distribution (V/F) in males than in females. It is unclear whether this 
is a gender or a body size effect. However, the differences in exposure are not large enough to warrant 
dose adjustment based on body size or gender. 
 
Renal impairment 
In the population pharmacokinetic analysis using data from clinical trials in patients with metastatic 
melanoma, mild and moderate renal impairment did not influence the apparent clearance of 
vemurafenib (creatinine clearance >40 ml/min). There are no data in patients with severe renal 
impairment (see sections 4.2 and 4.4). 
 
Hepatic impairment 
Based on preclinical data and the human mass balance study, major part of vemurafenib is eliminated 
via the liver. In the population pharmacokinetic analysis using data from clinical trials in patients with 
metastatic melanoma, increases in AST and ALT up to three times the upper limit of normal did not 
influence the apparent clearance of vemurafenib. Data are insufficient to determine the effect of 
metabolic or excretory hepatic impairment on vemurafenib pharmacokinetics (see sections 4.2 and 
4.4). 
 
Paediatric population 
Limited pharmacokinetic data from six adolescent patients aged between 15 and 17 years with stage 
IIIC or IV BRAF V600 mutation positive melanoma suggest that vemurafenib pharmacokinetic 
characteristics in adolescents are generally similar to those in adults. See section 4.2 for information 
on paediatric use.   
 
5.3 Preclinical safety data 
 
The preclinical safety profile of vemurafenib was assessed in rats, dogs, and rabbits. 
 
Repeat-dose toxicology studies identified the liver and bone marrow as target organs in the dog. 
Reversible toxic effects (hepatocellular necrosis and degeneration) in the liver at exposures below the 
anticipated clinical exposure (based on AUC comparisons) were noted in the 13-week dog study. 
Focal bone marrow necrosis was noted in one dog in a prematurely terminated 39-week BID dog study 
at exposures similar to the anticipated clinical exposure (based on AUC comparisons). In an in vitro 
bone marrow cytotoxicity study, slight cytotoxicity was observed in some lympho-haematopoietic cell 
populations of rat, dog and human at clinically relevant concentrations. 
 
Vemurafenib was shown to be phototoxic, in vitro, on cultured murine fibroblasts after UVA 
irradiation, but not in vivo in a rat study at doses up to 450 mg/kg/day (at exposures below the 
anticipated clinical exposure (based on AUC comparison). No specific studies with vemurafenib have 
been conducted in animals to evaluate the effect on fertility. However, in repeat-dose toxicity studies, 
no histopathological findings were noted on reproductive organs in males and females in rats and dogs 
at doses up to 450 mg/kg/day (at exposures below the anticipated clinical exposure based on AUC 
comparison). No teratogenicity was observed in embryofoetal development studies in rats and rabbits 
at doses up to respectively 250 mg/kg/day and 450 mg/kg/day leading to exposures below the 
anticipated clinical exposure (based on AUC comparison). However, exposures in the embryofoetal 
development studies were below the clinical exposure based on AUC comparison, it is therefore 
difficult to define to what extent these results can be extrapolated to humans. Therefore an effect of 
vemurafenib on the foetus cannot be excluded. No studies were performed regarding pre- and 
postnatal development. 
 
No signs of genotoxicity were identified in in vitro assays (bacterial mutation [AMES Assay], human 
lymphocyte chromosome aberration) nor in the in vivo rat bone marrow micronucleus test conducted 
with vemurafenib.  
 
Carcinogenicity studies have not been conducted with vemurafenib. 



22 

 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Croscarmellose sodium 
Colloidal anhydrous silica 
Magnesium stearate 
Hydroxypropylcellulose 
 
Film-coating 
Polyvinyl alcohol 
Titanium dioxide (E171) 
Macrogol 3350 
Talc 
Iron oxide red (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container  
 
Aluminium/Aluminium perforated unit dose blisters. 
Pack-size: 56 x 1 film-coated tablets (7 blisters of 8 x 1 tablet) 
 
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/1/12/751/001 
 
 



23 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 17 February 2012 
Date of latest renewal: 22 September 2016 
 
 
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/


24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 

 



25 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Roche Pharma AG 
Emil-Barell-Strasse 1 
D-79639 Grenzach-Wyhlen 
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 

 
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.  
 
 
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. 

 



26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 



28 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zelboraf 240 mg film-coated tablets 
vemurafenib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 240 mg of vemurafenib (as a co-precipitate of vemurafenib and 
hypromellose acetate succinate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 x 1 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 
 
Store in the original package in order to protect from moisture 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 



29 

 
 
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/1/12/751/001 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
zelboraf 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 



30 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
UNIT DOSE PERFORATED BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zelboraf 240 mg tablets 
vemurafenib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 

 



31 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



32 

Package leaflet: Information for the user 
 

Zelboraf 240 mg film-coated tablets 
vemurafenib 

 
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. 
● 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. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Zelboraf is and what it is used for 
2. What you need to know before you take Zelboraf 
3. How to take Zelboraf 
4. Possible side effects 
5. How to store Zelboraf 
6. Contents of the pack and other information 
 
 
1. What Zelboraf is and what it is used for 
 
Zelboraf is an anticancer medicine that contains the active substance vemurafenib. It is used to treat 
adult patients with melanoma that has spread to other parts of the body or cannot be removed by 
surgery. 
 
It can only be used in patients whose cancer has a change (mutation) in the “BRAF” gene. This change 
may have led to the development of melanoma. 
 
Zelboraf targets proteins made from this modified gene and slows down or stops the development of 
your cancer. 
 
 
2. What you need to know before you take Zelboraf 
 
Do not take Zelboraf: 
● If you are allergic to vemurafenib or any of the other ingredients of this medicine (listed in 

section 6 of this leaflet). Symptoms of allergic reactions may include swelling of the face, lips 
or tongue, difficulty breathing, rash, or fainting sensation. 

 
Warnings and precautions 
Talk to your doctor before taking Zelboraf. 
 
Allergic reactions 
● Allergic reactions can happen while taking Zelboraf and may be severe. Stop taking 

Zelboraf and get medical help immediately if you have any symptoms of an allergic reaction 
such as swelling of the face, lips or tongue, difficulty breathing, rash, or fainting sensation. 

 
Severe skin reactions 
● Severe skin reactions can happen while taking Zelboraf. Stop taking Zelboraf and talk to 

your doctor immediately if you get a skin rash with any of the following symptoms: blisters on 
your skin, blisters or sores in your mouth, peeling of your skin, fever, redness or swelling of 
your face, hands, or soles of your feet. 



33 

 
Previous history of cancer 
● Tell your doctor if you have had a different type of cancer than melanoma, as Zelboraf may 

cause progression of certain types of cancers. 
 
Radiation therapy reactions 
● Tell your doctor if you have had, or are going to have radiotherapy, as Zelboraf may worsen 
radiation treatment side effects.  
 
Heart disorder 
● Tell your doctor if you have a heart disorder, such as an alteration of the electrical activity 

of your heart called “QT prolongation”. Your doctor will run tests to check that your heart is 
working properly before and during your treatment with Zelboraf. If necessary, your doctor may 
decide to interrupt your treatment temporarily or stop it altogether. 

 
Eye problems 
● You should have your eyes examined by your doctor while you are taking Zelboraf. Tell 

your doctor immediately if you get eye pain, swelling, redness, blurred vision or other vision 
changes during your treatment. 

 
Musculoskeletal/Connective Tissue disorder  
● Tell your doctor if you observe any unusual thickening of the palms of your hands 

accompanied by tightening of the fingers inward or any unusual thickening of the soles of your 
feet which may be painful. 

 
Checks of your skin before, during and after treatment  
● If you notice any changes in your skin while taking this medicine, please talk to your 

doctor as soon as possible. 
● Regularly during your treatment and up to 6 months after your treatment, your doctor needs to 

check your skin for a type of cancer called “cutaneous squamous cell carcinoma”.  
● Usually, this lesion appears on sun-damaged skin, remains local and can be cured by surgical 

removal.  
● If your doctor finds this type of skin cancer, he or she will treat it or send you to another doctor 

for treatment.  
● Additionally, your doctor needs to inspect your head, your neck, your mouth, your lymph 

glands and you will undergo CT scans regularly. This is a precautionary measure in case a 
squamous cell carcinoma lesion would develop inside your body. Genital examinations (for 
women) and anal examinations are also recommended before and at the end of your treatment.   

● You may develop new melanoma lesions while taking Zelboraf. These lesions are usually 
removed by surgery and patients continue their treatment. Monitoring of these lesions occurs as 
outlined above for cutaneous squamous cell carcinoma.  

 
Kidney or liver problems 
● Tell your doctor if you have kidney or liver problems. This may affect the activity of 

Zelboraf. Your doctor will also do some blood tests to check your liver and kidney functions 
before you start taking Zelboraf and during treatment. 

 
Sun protection 
● If you are taking Zelboraf, you may become more sensitive to sunlight and get sunburns that can 

be severe. During treatment, avoid exposing your skin to direct sunlight. 
● If you do plan to go into the sun: 

● wear clothing which protects your skin, including your head and face, arms and legs; 
● use a lip balm and a broad spectrum sunscreen (minimum of Sun Protection Factor (SPF) 30, 

re-applied every 2 to 3 hours). 
● This will help to protect you against sunburn.  
 



34 

Children and adolescents 
Zelboraf is not recommended for children and adolescents. The effects of Zelboraf in people younger 
than 18 years old are not known.  
 
Other medicines and Zelboraf 
Before starting treatment, tell your doctor if you are taking, have recently taken or might use 
any other medicines (including those you have bought for yourself from a pharmacy, supermarket or 
health store). This is very important, as using more than one medicine at the same time can strengthen 
or weaken the effect of medicines.  
 
In particular, tell your doctor if you are taking: 
● Medicines that are known to affect the way your heart beats:  

● medicines for heart rhythm problems (e.g. quinidine, amiodarone) 
● medicines for depression (e.g. amitriptyline, imipramine) 
● medicines for bacterial infections (e.g. azithromycin, clarithromycin) 
● medicines for nausea and vomiting (e.g. ondansetron, domperidone). 

● Medicines that are mainly eliminated by metabolising proteins called CYP1A2 (e.g caffeine, 
olanzapine, theophylline), CYP3A4 (e.g. some oral contraceptives) or called CYP2C8. 

● Medicines that influence a protein called P-gp or BCRP (e.g. verapamil, cyclosporine, ritonavir, 
quinidine, itraconazole, gefitinib). 

● Medicines that could be influenced by a protein called P-gp (e.g. aliskiren, colchicine, digoxin, 
everolimus, fexofenadine) or a protein called BCRP (e.g. methotrexate, mitoxantrone, 
rosuvastatin). 

● Medicines that stimulate the metabolising proteins called CYP3A4 or a metabolising process 
called glucuronidation (e.g. rifampicin, rifabutin, carbamazepine, phenytoin or St John’s Wort) 

● Medicines that strongly inhibit the metabolising protein called CYP3A4  (e.g. ritonavir, 
saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone, 
atazanavir) 

● A medicine used to prevent blood clots called warfarin 
● A medicine called ipilimumab, another medicine for the treatment of melanoma. The 

combination of this medicine with Zelboraf is not recommended due to increased toxicity to the 
liver. 

 
If you are taking any of these medicines (or if you are not sure), please talk to your doctor before 
taking Zelboraf. 
 
Pregnancy and breast-feeding 
● Use an appropriate method of contraception during your treatment and for at least 

6 months after the end of your treatment. Zelboraf may decrease the efficacy of some oral 
contraceptives. Please tell your doctor if you are taking an oral contraceptive. 

● Zelboraf is not recommended for use during pregnancy unless your doctor considers that the 
benefit for the mother outweighs the risk for the baby. There is no information about the safety 
of Zelboraf in pregnant women. Tell your doctor if you are pregnant or planning to become 
pregnant.  

● It is not known whether the ingredients in Zelboraf pass into human milk. Breast-feeding is not 
recommended during treatment with Zelboraf. 

 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine. 
 
Driving and using machines 
Zelboraf has side effects that can affect your ability to drive or to operate machines. Beware of fatigue 
or eye problems that could be a reason for not driving. 
 
Important information about some of the ingredients of Zelboraf 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-
free’.   



35 

 
 
3. How to take Zelboraf 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. 
 
How many tablets should you take 
● The recommended dose is 4 tablets twice a day (a total of 8 tablets).  
● Take 4 tablets in the morning. Then take 4 tablets in the evening.  
● If you experience side effects, your doctor may decide to carry on your treatment but lower your 

dose. Always take Zelboraf exactly as your doctor has told you. 
● In case of vomiting, continue to take Zelboraf as usual and do not take an additional dose.  
 
Taking your tablets 
● Do not take Zelboraf regularly on an empty stomach. 
● Swallow the tablets whole with a glass of water. Do not chew or crush the tablets. 
 
If you take more Zelboraf than you should 
If you take more Zelboraf than you should, talk to your doctor immediately. Taking too much Zelboraf 
may increase the likelihood and severity of side effects. No cases of overdose have been observed with 
Zelboraf.  
 
If you forget to take Zelboraf 
● If you forget a dose and it is more than 4 hours before your next dose, just take your dose as 

soon as you remember it. Take the next dose at the usual time. 
● If it is less than 4 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 forgotten dose.  
 
If you stop taking Zelboraf 
It is important to keep taking Zelboraf for as long as your doctor prescribes it for you. If you have any 
further questions on the use of this medicine, ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines, Zelboraf can cause side effects, although not everybody gets them. 
 
Serious allergic reactions 
If you get any of these: 
● Swelling of the face, lips or tongue 
● Difficulty breathing 
● Rash 
● Fainting sensation. 
Call a doctor immediately. Do not use any more Zelboraf until you have spoken to a doctor. 
 
Worsening of radiation treatment side effects can occur in patients who are treated with radiation 
before, during, or after Zelboraf treatment. This can occur on the area that was treated with radiation, 
such as the skin, esophagus, bladder, liver, rectum, and lungs.  
Tell your doctor immediately if you experience any of the following symptoms: 
● Skin rash, blistering, peeling or discoloration of the skin 
● Shortness of breath, which may be accompanied by a cough, fever or chills (pneumonitis) 
● Difficulty or pain when swallowing, chest pain, heartburn or acid reflux (esophagitis). 
 



36 

Please talk to your doctor as soon as possible if you notice any changes in your skin.  
 
Side effects are listed below by frequency: 
 
Very common (may affect more than 1 in 10 people): 
● Rash, itching, dry or scaly skin 
● Skin problems including warts 
● A type of skin cancer (cutaneous squamous cell carcinoma) 
● Palmar plantar syndrome (i.e. redness, skin peeling or blisters on hands and feet) 
● Sunburn, being more sensitive to sunlight 
● Loss of appetite 
● Headache 
● Changes in the way things taste 
● Diarrhoea 
● Constipation 
● Feeling sick (nausea), vomiting 
● Hair loss 
● Joint or muscle pain, musculoskeletal pain 
● Pain in the extremities 
● Back pain 
● Feeling tired (fatigue) 
● Dizziness 
● Fever 
● Swelling usually in the legs (peripheral oedema) 
● Cough. 
 
Common (may affect up to 1 in 10 people): 
● Types of skin cancers (basal cell carcinoma, new primary melanoma) 
● Thickening of tissues underneath the palm of the hand which may cause tightening of the 

fingers inward; it can be disabling if severe 
● Inflammation of the eye (uveitis) 
● Bell's palsy (a form of facial paralysis that is often reversible) 
● Tingling or burning feelings in hands and feet 
● Inflammation of joints 
● Inflammation of hair’s roots 
● Weight loss 
● Inflammation of blood vessels 
• Problem with the nerves that can produce pain, loss of sensation and/or muscle weakness 

(neuropathy peripheral) 
● Change in liver tests results (ALT, alkaline phosphatase and bilirubin increase) 
● Changes in electrical activity of the heart (QT prolongation) 
● Inflammation of the fatty tissue under the skin 
● Abnormal kidney blood test results (creatinine increased). 
● Change in liver tests results (GGT increase) 
● Decreased white blood cells (neutropenia). 
 
Uncommon (may affect up to 1 in 100 people):  
● Allergic reactions that may include swelling of the face and difficulty breathing 
● Blockage of blood flow to part of the eye (retinal vein occlusion) 
 
● Inflammation of the pancreas 
● Change in liver laboratory tests results or liver injury, including severe liver injury where liver 

is injured to the extent that it is not able to fully perform its function 
● A type of cancer (non-cutaneous squamous cell carcinoma) 
● Thickening of deep tissues underneath the sole of the feet that may be disabling if severe 
 



37 

Rare (may affect up to 1 in 1,000 people) 
● Progression of a type of pre-existing cancers with RAS mutations (Chronic Myelomonocytic 

Leukaemia, Pancreatic adenocarcinoma) 
● A type of severe skin reaction characterised by rash accompanied by fever and inflammation of 

internal organs such as liver and kidney 
● Inflammatory disease mainly affecting the skin, lung and eye (sarcoidosis) 
● Types of kidney injury characterized by inflammation (acute interstitial nephritis) or damage to 

the tubules of the kidney (acute tubular necrosis). 
 
Reporting of side effects 
If you get any side effects, talk to your doctor. 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 Zelboraf  
 
Keep this medicine out of the sight and reach of children. 
 
Do not use Zelboraf after the expiry date which is stated on the carton and the blister after EXP. The 
expiry date refers to the last day of that month.  
 
Store in the original package in order to protect from moisture. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 
 
 
6.  Contents of the pack and other information 
 
What Zelboraf contains 
● The active substance is vemurafenib. Each film-coated tablet contains 240 milligrams (mg) of 

vemurafenib (as a co-precipitate of vemurafenib and hypromellose acetate succinate). 
● The other ingredients are: 

● Tablet core: colloidal anhydrous silica, croscarmellose sodium, hydroxypropyl cellulose and 
magnesium stearate 

● Film-coating: iron oxide red, macrogol 3350, polyvinyl alcohol, talc and titanium dioxide. 
 
What Zelboraf looks like and contents of the pack 
Zelboraf 240 mg film-coated tablets are pinkish white to orange white. They are oval with “VEM” 
engraved on one side. 
They are available in aluminium perforated unit dose blisters in packs of 56 x 1 tablets. 
 
Marketing Authorisation Holder  
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
Manufacturer 
Roche Pharma AG  
Emil-Barell-Strasse 1 
D-79639  
Grenzach-Wyhlen  
Germany 
 

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


38 

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 
 

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 
 



39 

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. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  
	A. LABELLING
	B. PACKAGE LEAFLET