Nexavar

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Nexavar 200 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 200 mg of sorafenib (as tosylate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
Red, round, biconvex film-coated tablets, debossed with Bayer cross on one side and "200" on the 
other side.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Hepatocellular carcinoma 
 
Nexavar is indicated for the treatment of hepatocellular carcinoma (see section 5.1). 
 
Renal cell carcinoma 
 
Nexavar is indicated for the treatment of patients with advanced renal cell carcinoma who have failed 
prior interferon-alpha or interleukin-2 based therapy or are considered unsuitable for such therapy. 
 
Differentiated thyroid carcinoma 
 
Nexavar is indicated for the treatment of patients with progressive, locally advanced or metastatic, 
differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma, refractory to radioactive iodine. 
 
4.2 Posology and method of administration 
 
Nexavar treatment should be supervised by a physician experienced in the use of anticancer therapies. 
 
Posology 
 
The recommended dose of Nexavar in adults is 400 mg sorafenib (two tablets of 200 mg) twice daily 
(equivalent to a total daily dose of 800 mg).  
 
Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs. 
 
Posology adjustments 
 
Management of suspected adverse drug reactions may require temporary interruption or dose 
reduction of sorafenib therapy.  
 



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When dose reduction is necessary during the treatment of hepatocellular carcinoma (HCC) and 
advanced renal cell carcinoma (RCC), the Nexavar dose should be reduced to two tablets of 200 mg 
sorafenib once daily (see section 4.4). 
 
When dose reduction is necessary during the treatment of differentiated thyroid carcinoma (DTC), the 
Nexavar dose should be reduced to 600 mg sorafenib daily in divided doses (two tablets of 200 mg 
and one tablet of 200 mg twelve hours apart). 
If additional dose reduction is necessary, Nexavar may be reduced to 400 mg sorafenib daily in 
divided doses (two tablets of 200 mg twelve hours apart), and if necessary further reduced to one 
tablet of 200 mg once daily. After improvement of non-haematological adverse reactions, the dose of 
Nexavar may be increased. 
 
Paediatric population 
The safety and efficacy of Nexavar in children and adolescents aged < 18 years have not yet been 
established. No data are available. 
 
Elderly population 
No dose adjustment is required in the elderly (patients above 65 years of age). 
 
Renal impairment 
No dose adjustment is required in patients with mild, moderate or severe renal impairment. No data is 
available in patients requiring dialysis (see section 5.2). 
 
Monitoring of fluid balance and electrolytes in patients at risk of renal dysfunction is advised. 
 
Hepatic impairment 
No dose adjustment is required in patients with Child Pugh A or B (mild to moderate) hepatic 
impairment. No data is available on patients with Child Pugh C (severe) hepatic impairment (see 
sections 4.4 and 5.2). 
 
Method of administration 
 
For oral use. 
It is recommended that sorafenib should be administered without food or with a low or moderate fat 
meal. If the patient intends to have a high-fat meal, sorafenib tablets should be taken at least 1 hour 
before or 2 hours after the meal. The tablets should be swallowed with a glass of water. 
 
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 
 
Dermatological toxicities 
 
Hand foot skin reaction (palmar-plantar erythrodysaesthesia) and rash represent the most common 
adverse drug reactions with sorafenib. Rash and hand foot skin reaction are usually CTC (Common 
Toxicity Criteria) Grade 1 and 2 and generally appear during the first six weeks of treatment with 
sorafenib. Management of dermatological toxicities may include topical therapies for symptomatic 
relief, temporary treatment interruption and/or dose modification of sorafenib, or in severe or 
persistent cases, permanent discontinuation of sorafenib (see section 4.8). 
 



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Hypertension 
 
An increased incidence of arterial hypertension was observed in sorafenib-treated patients. 
Hypertension was usually mild to moderate, occurred early in the course of treatment, and was 
amenable to management with standard antihypertensive therapy. Blood pressure should be monitored 
regularly and treated, if required, in accordance with standard medical practice. In cases of severe or 
persistent hypertension, or hypertensive crisis despite institution of antihypertensive therapy, 
permanent discontinuation of sorafenib should be considered (see section 4.8). 
 
Aneurysms and artery dissections  
 
The use of VEGF pathway inhibitors in patients with or without hypertension may promote the 
formation of aneurysms and/or artery dissections. Before initiating Nexavar, this risk should be 
carefully considered in patients with risk factors such as hypertension or history of aneurysm. 
 
Hypoglycaemia 
 
Decreases in blood glucose, in some cases clinically symptomatic and requiring hospitalization due to 
loss of consciousness, have been reported during sorafenib treatment. In case of symptomatic 
hypoglycaemia, sorafenib should be temporarily interrupted. Blood glucose levels in diabetic patients 
should be checked regularly in order to assess if anti-diabetic medicinal product's dosage needs to be 
adjusted.  
 
Haemorrhage 
 
An increased risk of bleeding may occur following sorafenib administration. If any bleeding event 
necessitates medical intervention it is recommended that permanent discontinuation of sorafenib 
should be considered (see section 4.8).  
 
Cardiac ischaemia and/or infarction 
 
In a randomised, placebo-controlled, double-blind study (study 1, see section 5.1) the incidence of 
treatment-emergent cardiac ischaemia/infarction events was higher in the sorafenib group (4.9 %) 
compared with the placebo group (0.4 %). In study 3 (see section 5.1) the incidence of treatment-
emergent cardiac ischaemia/infarction events was 2.7 % in sorafenib patients compared with 1.3 % in 
the placebo group. Patients with unstable coronary artery disease or recent myocardial infarction were 
excluded from these studies. Temporary or permanent discontinuation of sorafenib should be 
considered in patients who develop cardiac ischaemia and/or infarction (see section 4.8). 
 
QT interval prolongation  
 
Sorafenib has been shown to prolong the QT/QTc interval (see section 5.1), which may lead to an 
increased risk for ventricular arrhythmias. Use sorafenib with caution in patients who have, or may 
develop prolongation of QTc, such as patients with a congenital long QT syndrome, patients treated 
with a high cumulative dose of anthracycline therapy, patients taking certain anti-arrhythmic 
medicines or other medicinal products that lead to QT prolongation, and those with electrolyte 
disturbances such as hypokalaemia, hypocalcaemia, or hypomagnesaemia. When using sorafenib in 
these patients, periodic monitoring with on-treatment electrocardiograms and electrolytes (magnesium, 
potassium, calcium) should be considered. 
 
Gastrointestinal perforation 
 
Gastrointestinal perforation is an uncommon event and has been reported in less than 1% of patients 
taking sorafenib. In some cases this was not associated with apparent intra-abdominal tumour. 
Sorafenib therapy should be discontinued (see section 4.8). 
 



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Hepatic impairment 
 
No data is available on patients with Child Pugh C (severe) hepatic impairment. Since sorafenib is 
mainly eliminated via the hepatic route exposure might be increased in patients with severe hepatic 
impairment (see sections 4.2 and 5.2). 
 
Warfarin co-administration 
 
Infrequent bleeding events or elevations in the International Normalised Ratio (INR) have been 
reported in some patients taking warfarin while on sorafenib therapy. Patients taking concomitant 
warfarin or phenprocoumon should be monitored regularly for changes in prothrombin time, INR or 
clinical bleeding episodes (see sections 4.5 and 4.8). 
 
Wound healing complications 
 
No formal studies of the effect of sorafenib on wound healing have been conducted. Temporary 
interruption of sorafenib therapy is recommended for precautionary reasons in patients undergoing 
major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of 
therapy following major surgical intervention. Therefore, the decision to resume sorafenib therapy 
following a major surgical intervention should be based on clinical judgement of adequate wound 
healing. 
 
Elderly population 
 
Cases of renal failure have been reported. Monitoring of renal function should be considered.  
 
Drug-drug interactions 
 
Caution is recommended when administering sorafenib with compounds that are 
metabolised/eliminated predominantly by the UGT1A1 (e.g. irinotecan) or UGT1A9 pathways (see 
section 4.5). 
 
Caution is recommended when sorafenib is co-administered with docetaxel (see section 4.5). 
 
Co-administration of neomycin or other antibiotics that cause major ecological disturbances of the 
gastrointestinal microflora may lead to a decrease in sorafenib bioavailability (see section 4.5). The 
risk of reduced plasma concentrations of sorafenib should be considered before starting a treatment 
course with antibiotics. 
 
Higher mortality has been reported in patients with squamous cell carcinoma of the lung treated with 
sorafenib in combination with platinum-based chemotherapies. In two randomised trials investigating 
patients with Non-Small Cell Lung Cancer in the subgroup of patients with squamous cell carcinoma 
treated with sorafenib as add-on to paclitaxel/carboplatin, the HR for overall survival was found to be 
1.81 (95% CI 1.19; 2.74) and as add-on to gemcitabine/cisplatin 1.22 (95% CI 0.82; 1.80). No single 
cause of death dominated, but higher incidence of respiratory failure, hemorrhages and infectious 
adverse events were observed in patients treated with sorafenib as add-on to platinum-based 
chemotherapies. 
 
Disease specific warnings 
 
Differentiated thyroid cancer (DTC) 
 
Before initiating treatment, physicians are recommended to carefully evaluate the prognosis in the 
individual patient considering maximum lesion size (see section 5.1), symptoms related to the disease 
(see section 5.1) and progression rate. 
 



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Management of suspected adverse drug reactions may require temporary interruption or dose 
reduction of sorafenib therapy. In study 5 (see section 5.1), 37% of subjects had dose interruption and 
35% had dose reduction already in cycle 1 of sorafenib treatment. 
 
Dose reductions were only partially successful in alleviating adverse reactions. Therefore repeat 
evaluations of benefit and risk is recommended taking anti-tumour activity and tolerability into 
account. 
 
Haemorrhage in DTC 
Due to the potential risk of bleeding, tracheal, bronchial, and oesophageal infiltration should be treated 
with localized therapy prior to administering sorafenib in patients with DTC. 
 
Hypocalcaemia in DTC  
When using sorafenib in patients with DTC, close monitoring of blood calcium level is recommended. 
In clinical trials, hypocalcaemia was more frequent and more severe in patients with DTC, especially 
with a history of hypoparathyroidism, compared to patients with renal cell or hepatocellular 
carcinoma. Hypocalcaemia grade 3 and 4 occurred in 6.8% and 3.4% of sorafenib-treated patients with 
DTC (see section 4.8). Severe hypocalcaemia should be corrected to prevent complications such as 
QT-prolongation or torsade de pointes (see section QT prolongation).   
 
TSH suppression in DTC 
In study 5 (see section 5.1), increases in TSH levels above 0.5mU/L were observed in sorafenib 
treated patients. When using sorafenib in DTC patients, close monitoring of TSH level is 
recommended. 
 
Renal cell carcinoma 
 
High Risk Patients, according to MSKCC (Memorial Sloan Kettering Cancer Center) prognostic 
group, were not included in the phase III clinical study in renal cell carcinoma (see study 1 in section 
5.1), and benefit-risk in these patients has not been evaluated. 
 
Information about excipients 
 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium 
free”. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Inducers of metabolic enzymes 
 
Administration of rifampicin for 5 days before administration of a single dose of sorafenib resulted in 
an average 37 % reduction of sorafenib AUC. Other inducers of CYP3A4 activity and/or 
glucuronidation (e.g. Hypericum perforatum also known as St. John’s wort, phenytoin, 
carbamazepine, phenobarbital, and dexamethasone) may also increase metabolism of sorafenib and 
thus decrease sorafenib concentrations. 
 
CYP3A4 inhibitors 
 
Ketoconazole, a potent inhibitor of CYP3A4, administered once daily for 7 days to healthy male 
volunteers did not alter the mean AUC of a single 50 mg dose of sorafenib. These data suggest that 
clinical pharmacokinetic interactions of sorafenib with CYP3A4 inhibitors are unlikely. 
 
CYP2B6, CYP2C8 and CYP2C9 substrates 
 
Sorafenib inhibited CYP2B6, CYP2C8 and CYP2C9 in vitro with similar potency. However, in 
clinical pharmacokinetic studies, concomitant administration of sorafenib 400 mg twice daily with 
cyclophosphamide, a CYP2B6 substrate, or paclitaxel, a CYP2C8 substrate, did not result in a 



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clinically meaningful inhibition. These data suggest that sorafenib at the recommended dose of 
400 mg twice daily may not be an in vivo inhibitor of CYP2B6 or CYP2C8.  
Additionally, concomitant treatment with sorafenib and warfarin, a CYP2C9 substrate, did not result 
in changes in mean PT-INR compared to placebo. Thus, also the risk for a clinically relevant in vivo 
inhibition of CYP2C9 by sorafenib may be expected to be low. However, patients taking warfarin or 
phenprocoumon should have their INR checked regularly (see section 4.4). 
 
CYP3A4, CYP2D6 and CYP2C19 substrates 
 
Concomitant administration of sorafenib and midazolam, dextromethorphan or omeprazole, which are 
substrates for cytochromes CYP3A4, CYP2D6 and CYP2C19 respectively, did not alter the exposure 
of these agents. This indicates that sorafenib is neither an inhibitor nor an inducer of these cytochrome 
P450 isoenzymes. Therefore, clinical pharmacokinetic interactions of sorafenib with substrates of 
these enzymes are unlikely.  
 
UGT1A1 and UGT1A9 substrates 
 
In vitro, sorafenib inhibited glucuronidation via UGT1A1 and UGT1A9. The clinical relevance of this 
finding is unknown (see below and section 4.4).  
 
In vitro studies of CYP enzyme induction 
 
CYP1A2 and CYP3A4 activities were not altered after treatment of cultured human hepatocytes with 
sorafenib, indicating that sorafenib is unlikely to be an inducer of CYP1A2 and CYP3A4. 
 
P-gp-substrates 
 
In vitro, sorafenib has been shown to inhibit the transport protein p-glycoprotein (P-gp). Increased 
plasma concentrations of P-gp substrates such as digoxin cannot be excluded with concomitant 
treatment with sorafenib. 
 
Combination with other anti-neoplastic agents 
 
In clinical studies sorafenib has been administered with a variety of other anti-neoplastic agents at 
their commonly used dosing regimens including gemcitabine, cisplatin, oxaliplatin, paclitaxel, 
carboplatin, capecitabine, doxorubicin, irinotecan, docetaxel and cyclophosphamide. Sorafenib had no 
clinically relevant effect on the pharmacokinetics of gemcitabine, cisplatin, carboplatin, oxaliplatin or 
cyclophosphamide. 
 
Paclitaxel/carboplatin 
 
o Administration of paclitaxel (225 mg/m2) and carboplatin (AUC = 6) with sorafenib (≤ 400 mg 

twice daily), administered with a 3-day break in sorafenib dosing (two days prior to and on the 
day of paclitaxel/carboplatin administration), resulted in no significant effect on the 
pharmacokinetics of paclitaxel.  

 
o Co-administration of paclitaxel (225 mg/m2, once every 3 weeks) and carboplatin (AUC=6) 

with sorafenib (400 mg twice daily, without a break in sorafenib dosing) resulted in a 47% 
increase in sorafenib exposure, a 29% increase in paclitaxel exposure and a 50% increase in 6-
OH paclitaxel exposure. The pharmacokinetics of carboplatin were unaffected.  

 
These data indicate no need for dose adjustments when paclitaxel and carboplatin are co-administered 
with sorafenib with a 3-day break in sorafenib dosing (two days prior to and on the day of 
paclitaxel/carboplatin administration). The clinical significance of the increases in sorafenib and 
paclitaxel exposure, upon co-administration of sorafenib without a break in dosing, is unknown. 
 



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Capecitabine 
 
Co-administration of capecitabine (750-1050 mg/m2 twice daily, Days 1-14 every 21 days) and 
sorafenib (200 or 400 mg twice daily, continuous uninterrupted administration) resulted in no 
significant change in sorafenib exposure, but a 15-50% increase in capecitabine exposure and a 0-52% 
increase in 5-FU exposure. The clinical significance of these small to modest increases in capecitabine 
and 5-FU exposure when co-administered with sorafenib is unknown. 
 
Doxorubicin/Irinotecan 
 
Concomitant treatment with sorafenib resulted in a 21 % increase in the AUC of doxorubicin. When 
administered with irinotecan, whose active metabolite SN-38 is further metabolised by the UGT1A1 
pathway, there was a 67 - 120 % increase in the AUC of SN-38 and a 26 - 42 % increase in the AUC 
of irinotecan. The clinical significance of these findings is unknown (see section 4.4). 
 
Docetaxel 
 
Docetaxel (75 or 100 mg/m2 administered once every 21 days) when co-administered with sorafenib 
(200 mg twice daily or 400 mg twice daily administered on Days 2 through 19 of a 21-day cycle with 
a 3-day break in dosing around administration of docetaxel) resulted in a 36-80 % increase in 
docetaxel AUC and a 16-32 % increase in docetaxel Cmax. Caution is recommended when sorafenib is 
co-administered with docetaxel (see section 4.4). 
 
Combination with other agents 
 
Neomycin 
Co-administration of neomycin, a non-systemic antimicrobial agent used to eradicate gastrointestinal 
flora, interferes with the enterohepatic recycling of sorafenib (see section 5.2, Metabolism and 
Elimination), resulting in decreased sorafenib exposure. In healthy volunteers treated with a 5-day 
regimen of neomycin the average exposure to sorafenib decreased by 54%. Effects of other antibiotics 
have not been studied, but will likely depend on their ability to interfere with microorganisms with 
glucuronidase activity. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no data on the use of sorafenib in pregnant women. Studies in animals have shown 
reproductive toxicity including malformations (see section 5.3). In rats, sorafenib and its metabolites 
were demonstrated to cross the placenta and sorafenib is anticipated to cause harmful effects on the 
foetus. Sorafenib should not be used during pregnancy unless clearly necessary, after careful 
consideration of the needs of the mother and the risk to the foetus. 
Women of childbearing potential must use effective contraception during treatment.  
 
Lactation 
 
It is not known whether sorafenib is excreted in human milk. In animals, sorafenib and/or its 
metabolites were excreted in milk. Because sorafenib could harm infant growth and development (see 
section 5.3), women must not breast-feed during sorafenib treatment. 
 
Fertility 
 
Results from animal studies further indicate that sorafenib can impair male and female fertility (see 
section 5.3). 
 



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4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed. There is no 
evidence that sorafenib affects the ability to drive or to operate machinery. 
 
4.8 Undesirable effects 
 
The most important serious adverse reactions were myocardial infarction/ischaemia, gastrointestinal 
perforation, drug induced hepatitis, haemorrhage, and hypertension/hypertensive crisis. 
 
The most common adverse reactions were diarrhoea, fatigue, alopecia, infection, hand foot skin 
reaction (corresponds to palmar plantar erythrodysaesthesia syndrome in MedDRA) and rash. 
 
Adverse reactions reported in multiple clinical trials or through post-marketing use are listed below in 
table 1, by system organ class (in MedDRA) and frequency. Frequencies are defined as: 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), 
not known (cannot be estimated from the available data).  
 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 
 
Table 1: All adverse reactions reported in patients in multiple clinical trials or through post-
marketing use 
 
System 
organ class 

Very common 
 

Common 
 

Uncommon 
 

Rare 
 

Not known 

Infections 
and 
infestations 

infection folliculitis    

Blood and 
lymphatic 
system 
disorders 

lymphopenia leucopenia 

neutropenia 

anaemia 

thrombocytope-
nia 

   

Immune 
system 
disorders 

  hypersensitivity 
reactions 
(including skin 
reactions and 
urticaria) 

anaphylactic 
reaction 

angioedema   

Endocrine 
disorders 

 hypothyroidism hyperthyroidism   

Metabolism 
and nutrition 
disorders 

anorexia 

hypo-
phosphataemia 

hypocalcaemia 

hypokalaemia 

hyponatraemia 

hypoglycaemia 

dehydration   

Psychiatric 
disorders 

 depression    



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System 
organ class 

Very common 
 

Common 
 

Uncommon 
 

Rare 
 

Not known 

Nervous 
system 
disorders 

 peripheral 
sensory 
neuropathy 

dysgeusia  

 

reversible 
posterior 
leukoencephalo-
pathy* 
 

 encephalo-
pathy° 

Ear and 
labyrinth 
disorders 

 tinnitus    

Cardiac 
disorders 

 congestive heart 
failure* 

myocardial 
ischaemia and 
infarction* 

 QT 
prolongation 

 

Vascular 
disorders 

haemorrhage 
(inc. 
gastrointestinal*, 
respiratory tract* 
and cerebral 
haemorrhage*) 

hypertension 

flushing hypertensive 
crisis* 

 aneurysms and 
artery 
dissections 

Respiratory, 
thoracic and 
mediastinal 
disorders 

 rhinorrhoea 

dysphonia 

interstitial lung 
disease-like 
events* 
(pneumonitis, 
radiation 
pneumonitis, 
acute 
respiratory 
distress, etc. ) 

  

Gastro-
intestinal 
disorders 

diarrhoea 

nausea 

vomiting 

constipation 

stomatitis 
(including dry 
mouth and 
glossodynia) 

dyspepsia 

dysphagia 

gastro 
oesophageal 
reflux disease 

pancreatitis 

gastritis 

gastrointestinal 
perforations* 

  

Hepatobi-
liary 
disorders 

  increase in 
bilirubin and 
jaundice, 
cholecystitis, 
cholangitis 

drug induced 
hepatitis* 

 



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System 
organ class 

Very common 
 

Common 
 

Uncommon 
 

Rare 
 

Not known 

Skin and 
subcutaneous 
tissue 
disorders 

dry skin 

rash 

alopecia 

hand foot skin 
reaction** 

erythema  

pruritus 

keratoacan-
thoma/ 
squamous cell 
cancer of the 
skin 

dermatitis 
exfoliative 

acne 

skin 
desquamation 

hyperkeratosis 

eczema 

erythema 
multiforme  

radiation recall 
dermatitis 
Stevens-
Johnson 
syndrome 
leucocyto-
clastic 
vasculitis 
toxic epidermal 
necrolysis* 

 

Musculo-
skeletal and 
connective 
tissue 
disorders 

arthralgia myalgia 

muscle spasms 

 rhabdomyolysis  

Renal and 
urinary 
disorders 

 renal failure 

proteinuria 

 nephrotic 
syndrome 

 

Reproductive 
system and 
breast 
disorders 

 erectile 
dysfunction 

gynaecomastia   

General 
disorders and 
adminis-
tration site 
conditions 

fatigue 

pain (including 
mouth, 
abdominal, 
bone, tumour 
pain and 
headache) 

fever 

asthenia 

influenza like 
illness 

mucosal 
inflammation 

   

Investiga-
tions 

weight 
decreased 

increased 
amylase  

increased lipase  

transient 
increase in 
transaminases  

transient 
increase in 
blood alkaline 
phosphatase 

INR abnormal, 
prothrombin 
level abnormal 

  

*  The adverse reactions may have a life-threatening or fatal outcome. Such events are either 
uncommon or less frequent than uncommon. 

**  Hand foot skin reaction corresponds to palmar plantar erythrodysaesthesia syndrome in 
MedDRA. 

°  Cases have been reported in the post marketing setting. 
  



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Further information on selected adverse drug reactions 
 
Congestive heart failure 
In company sponsored clinical trials congestive heart failure was reported as an adverse event in 1.9% 
of patients treated with sorafenib (N= 2276). In study 11213 (RCC) adverse events consistent with 
congestive heart failure were reported in 1.7% of patients treated with sorafenib and 0.7% receiving 
placebo. In study 100554 (HCC), 0.99% of those treated with sorafenib and 1.1% receiving placebo 
were reported with these events. 
 
Additional information on special populations 
In clinical trials, certain adverse drug reactions such as hand foot skin reaction, diarrhoea, alopecia, 
weight decrease, hypertension, hypocalcaemia, and keratoacanthoma/squamous cell carcinoma of skin 
occurred at a substantially higher frequency in patients with differentiated thyroid compared to 
patients in the renal cell or hepatocellular carcinoma studies. 
 
Laboratory test abnormalities in HCC (study 3) and RCC (study 1) patients 
 
Increased lipase and amylase were very commonly reported. CTCAE Grade 3 or 4 lipase elevations 
occurred in 11 % and 9 % of patients in the sorafenib group in study 1 (RCC) and study 3 (HCC), 
respectively, compared to 7 % and 9 % of patients in the placebo group. CTCAE Grade 3 or 4 amylase 
elevations were reported in 1 % and 2 % of patients in the sorafenib group in study 1 and study 3, 
respectively, compared to 3 % of patients in each placebo group. Clinical pancreatitis was reported in 
2 of 451 sorafenib treated patients (CTCAE Grade 4) in study 1, 1 of 297 sorafenib treated patients in 
study 3 (CTCAE Grade 2), and 1 of 451 patients (CTCAE Grade 2) in the placebo group in study 1. 
 
Hypophosphataemia was a very common laboratory finding, observed in 45 % and 35 % of sorafenib 
treated patients compared to 12 % and 11 % of placebo patients in study 1 and study 3, respectively. 
CTCAE Grade 3 hypophosphataemia (1 – 2 mg/dl) in study 1 occurred in 13 % of sorafenib treated 
patients and 3 % of patients in the placebo group, in study 3 in 11 % of sorafenib treated patients and 
2 % of patients in the placebo group. There were no cases of CTCAE Grade 4 hypophosphataemia 
(< 1 mg/dl) reported in either sorafenib or placebo patients in study 1, and 1 case in the placebo group 
in study 3. The aetiology of hypophosphataemia associated with sorafenib is not known. 
 
CTCAE Grade 3 or 4 laboratory abnormalities occurring in ≥ 5 % of sorafenib treated patients 
included lymphopenia and neutropenia. 
 
Hypocalcaemia was reported in 12% and 26.5% of sorafenib treated patients compared to 7.5% and 
14.8% of placebo patients in study 1 and study 3, respectively. Most reports of hypocalcaemia were 
low grade (CTCAE Grade 1 and 2). CTCAE grade 3 hypocalcaemia (6.0 – 7.0 mg /dL) occurred in 
1.1% and 1.8% of sorafenib treated patients and 0.2% and 1.1% of patients in the placebo group, and 
CTCAE grade 4 hypocalcaemia (< 6.0 mg/dL) occurred in 1.1% and 0.4% of sorafenib treated patients 
and 0.5% and 0% of patients in the placebo group in study 1 and 3, respectively. The aetiology of 
hypocalcaemia associated with sorafenib is not known. 
 
In studies 1 and 3 decreased potassium was observed in 5.4% and 9.5% of sorafenib-treated patients 
compared to 0.7% and 5.9% of placebo patients, respectively. Most reports of hypokalaemia were low 
grade (CTCAE Grade 1). In these studies CTCAE Grade 3 hypokalaemia occurred in 1.1% and 0.4% 
of sorafenib treated patients and 0.2% and 0.7% of patients in the placebo group. There were no 
reports of hypokalaemia CTCAE grade 4. 
 
Laboratory test abnormalities in DTC patients (study 5) 
 
Hypocalcaemia was reported in 35.7% of sorafenib treated patients compared to 11.0% of placebo 
patients. Most reports of hypocalcaemia were low grade. CTCAE grade 3 hypocalcaemia occurred in 
6.8% of sorafenib treated patients and 1.9% of patients in the placebo group, and CTCAE grade 4 
hypocalcaemia occurred in 3.4% of sorafenib treated patients and 1.0% of patients in the placebo 
group. 



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Other clinically relevant laboratory abnormalities observed in the study 5 are shown in table 2. 
 
Table 2: Treatment-emergent laboratory test abnormalities reported in DTC  patient (study 5) 
double blind period 
 

Laboratory parameter,  
(in % of samples 

investigated) 

Sorafenib N=207 Placebo N=209 
All 

Grades* 
Grade 

3* 
Grade 

4* 
All 

Grades* 
Grade 

3* 
Grade 

4* 

Blood and lymphatic system disorders 
Anemia 30.9 0.5 0 23.4 0.5 0 
Thrombocytopenia 18.4 0 0 9.6 0 0 
Neutropenia  19.8 0.5 0.5 12 0 0 
Lymphopenia  42 9.7 0.5 25.8 5.3 0 

Metabolism and nutrition disorders 

Hypokalemia 17.9 1.9 0 2.4 0 0 

Hypophosphatemia** 19.3 12.6 0 2.4 1.4 0 
Hepatobiliary disorders 
Bilirubin increased  8.7 0 0 4.8 0 0 
ALT increased 58.9 3.4 1.0 24.4 0 0 
AST increased 53.6 1.0 1.0 14.8 0 0 
Investigations  
Amylase increased 12.6 2.4 1.4 6.2 0 1.0 
Lipase increased 11.1 2.4 0 2.9 0.5 0 
* Common Terminology Criteria for Adverse Events (CTCAE), version 3.0  
** The aetiology of hypophosphatemia associated with sorafenib is not known. 
 
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 treatment for sorafenib overdose. The highest dose of sorafenib studied clinically 
is 800 mg twice daily. The adverse events observed at this dose were primarily diarrhoea and 
dermatological events. In the event of suspected overdose sorafenib should be withheld and supportive 
care instituted where necessary. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE05 
 
Sorafenib is a multikinase inhibitor which has demonstrated both anti-proliferative and anti-
angiogenic properties in vitro and in vivo. 
 



14 

Mechanism of action and pharmacodynamic effects 
 
Sorafenib is a multikinase inhibitor that decreases tumour cell proliferation in vitro. Sorafenib inhibits 
tumour growth of a broad spectrum of human tumour xenografts in athymic mice accompanied by a 
reduction of tumour angiogenesis. Sorafenib inhibits the activity of targets present in the tumour cell 
(CRAF, BRAF, V600E BRAF, c-KIT, and FLT-3) and in the tumour vasculature (CRAF, VEGFR-2, 
VEGFR-3, and PDGFR-ß). RAF kinases are serine/threonine kinases, whereas  
c-KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-ß are receptor tyrosine kinases.  
 
Clinical efficacy 
 
The clinical safety and efficacy of sorafenib have been studied in patients with hepatocellular 
carcinoma (HCC), in patients with advanced renal cell carcinoma (RCC) and in patients with 
differentiated thyroid carcinoma (DTC). 
 
Hepatocellular carcinoma 
 
Study 3 (study 100554) was a Phase III, international, multi-centre, randomised, double blind, 
placebo-controlled study in 602 patients with hepatocellular carcinoma. Demographics and baseline 
disease characteristics were comparable between the sorafenib and the placebo group with regard to 
ECOG status (status 0: 54 % vs. 54 %; status 1: 38 % vs. 39 %; status 2: 8 % vs. 7 %), TNM stage 
(stage I: <1 % vs. <1 %; stage II: 10.4 % vs. 8.3 %; stage III: 37.8 % vs. 43.6 %; stage IV: 50.8 % 
vs. 46.9 %), and BCLC stage (stage B: 18.1 % vs. 16.8 %; stage C: 81.6 % vs. 83.2 %; stage D: < 1 % 
vs. 0 %). 
 
The study was stopped after a planned interim analysis of OS had crossed the prespecified efficacy 
boundary. This OS analysis showed a statistically significant advantage for sorafenib over placebo for 
OS (HR: 0.69, p = 0.00058, see table 3).  
 
There are limited data from this study in patients with Child Pugh B liver impairment and only one 
patient with Child Pugh C had been included. 
 
Table 3: Efficacy results from study 3 (study 100554) in hepatocellular carcinoma 
 
Efficacy Parameter Sorafenib 

(N=299) 
Placebo 
(N=303) 

P-value HR 
(95% CI) 

Overall Survival (OS) 
[median, weeks (95% 
CI)] 

46.3 
(40.9, 57.9) 

34.4 
(29.4, 39.4) 

0.00058* 
 

0.69 
(0.55, 0.87) 

Time to Progression 
(TTP) [median, weeks 
(95% CI)]** 

24.0 
(18.0, 30.0) 

12.3 
(11.7, 17.1) 

0.000007 0.58 
(0.45, 0.74) 

CI=Confidence interval, HR=Hazard ratio (sorafenib over placebo) 
* statistically significant as the p-value was below the prespecified O’Brien Fleming stopping 

boundary of 0.0077 
** independent radiological review 
 
A second Phase III, international, multi-centre, randomised, double blind, placebo-controlled study 
(Study 4, 11849) evaluated the clinical benefit of sorafenib in 226 patients with advanced 
hepatocellular carcinoma. This study, conducted in China, Korea and Taiwan confirmed the findings 
of Study 3 with respect to the favourable benefit-risk profile of sorafenib (HR (OS): 0.68, 
p = 0.01414). 
 
In the pre-specified stratification factors (ECOG status, presence or absence of macroscopic vascular 
invasion and/or extrahepatic tumour spread) of both Study 3 and 4, the HR consistently favoured 
sorafenib over placebo. Exploratory subgroup analyses suggested that patients with distant metastases 
at baseline derived a less pronounced treatment effect. 



15 

 
Renal cell carcinoma 
 
The safety and efficacy of sorafenib in the treatment of advanced renal cell carcinoma (RCC) were 
investigated in two clinical studies: 
 
Study 1 (study 11213) was a Phase III, multi-centre, randomised, double blind, placebo-controlled 
study in 903 patients. Only patients with clear cell renal carcinoma and low and intermediate risk 
MSKCC (Memorial Sloan Kettering Cancer Center) were included. The primary endpoints were 
overall survival and progression-free survival (PFS).  
Approximately half of the patients had an ECOG performance status of 0, and half of the patients were 
in the low risk MSKCC prognostic group.  
PFS was evaluated by blinded independent radiological review using RECIST criteria. The PFS 
analysis was conducted at 342 events in 769 patients. The median PFS was 167 days for patients 
randomised to sorafenib compared to 84 days for placebo patients (HR = 0.44; 95 % CI: 0.35 - 0.55; 
p < 0.000001). Age, MSKCC prognostic group, ECOG PS and prior therapy did not affect the 
treatment effect size.  
 
An interim analysis (second interim analysis) for overall survival was conducted at 367 deaths in 903 
patients. The nominal alpha value for this analysis was 0.0094. The median survival was 19.3 months 
for patients randomised to sorafenib compared to 15.9 months for placebo patients (HR = 0.77; 95 % 
CI:  0.63 - 0.95; p = 0.015). At the time of this analysis, about 200 patients had crossed-over to 
sorafenib from the placebo group.  
 
Study 2 was a Phase II, discontinuation study in patients with metastatic malignancies, including RCC. 
Patients with stable disease on therapy with sorafenib were randomised to placebo or continued 
sorafenib therapy. Progression-free survival in patients with RCC was significantly longer in the 
sorafenib group (163 days) than in the placebo group (41 days) (p = 0.0001, HR = 0.29). 
 
Differentiated thyroid carcinoma (DTC) 
 
Study 5 (study 14295) was a Phase III, international, multi-centre, randomised, double blind, placebo-
controlled trial in 417 patients with locally advanced or metastatic DTC refractory to radioactive 
iodine. Progression-free survival (PFS) as evaluated by a blinded independent radiological review 
using RECIST criteria was the primary endpoint of the study. Secondary endpoints included overall 
survival (OS), tumour response rate and duration of response. Following progression, patients were 
allowed to receive open label sorafenib.  
Patients were included in the study if they experienced progression within 14 months of enrollment 
and had DTC refractory to radioactive iodine (RAI). DTC refractory to RAI was defined as having a 
lesion without iodine uptake on a RAI scan, or receiving cumulative RAI ≥ 22.2  GBq, or experiencing 
a progression after a RAI treatment within 16 months of enrollment or after two RAI treatments within 
16 months of each other.  
 
Baseline demographics and patient characteristics were well balanced for both treatment groups. 
Metastases were present in the lungs in 86%, lymph node in 51% and bone in 27% of the patients. The 
median delivered cumulative radioactive iodine activity before enrollment was approximately 14.8  
GBq. Majority of patients had papillary carcinoma (56.8%), followed by follicular (25.4%) and poorly 
differentiated carcinoma (9.6%). 
 
Median PFS time was 10.8 months in the sorafenib group compared to 5.8 months in the placebo 
group (HR=0.587; 95% Confidence Interval (CI): 0.454, 0.758; one-sided p <0.0001).  
The effect of sorafenib on PFS was consistent independent of geographic region, age above or below 
60 years, gender, histological subtype, and presence or absence of bone metastasis.  
 
In an overall survival analysis conducted 9 months after the data cut-off for the final PFS analysis 
there was no statically significant difference in overall survival between the treatment groups 
(HR=0.884; 95% CI: 0.633, 1.236, one-sided p value of 0.236). The median OS was not reached in 



16 

the sorafenib arm and was 36.5 months in the placebo arm. One hundred fifty seven (75%) patients 
randomised to placebo and 61 (30%) patients randomised to sorafenib received open-label sorafenib. 
 
The median duration of therapy in the double-blind period was 46 weeks (range 0.3-135) for patients 
receiving sorafenib and 28 weeks (range 1.7–132) for patients receiving placebo. 
 
No complete response (CR) according to RECIST was observed. The overall response rate (CR + 
partial response (PR) per independent radiological assessment was higher in the sorafenib group (24 
patients, 12.2%) than in the placebo group (1 patient, 0.5%), one-sided p<0.0001. The median duration 
of response was 309 days (95% CI: 226,505 days) in sorafenib treated patients who experienced a PR. 
 
A post-hoc subgroup analysis by maximum tumour size showed a treatment effect for PFS in favour of 
sorafenib over placebo for patients with maximum tumour size of 1.5 cm or larger (HR 0.54  (95% CI: 
0.41 - 0.71)) whereas a numerically lower effect was reported in patients with a maximum tumour size 
of less than 1.5 cm (HR 0.87 (95% CI: 0.40 - 1.89). 
 
A post-hoc subgroup analysis by thyroid carcinoma symptoms at baseline showed a treatment effect 
for PFS in favour of sorafenib over placebo for both symptomatic and asymptomatic patients. The HR 
of progression free survival was 0.39 (95% CI: 0.21 - 0.72) for patients with symptoms at baseline and 
0.60 (95% CI: 0.45 - 0.81) for patients without symptoms at baseline. 
 
QT interval prolongation 
 
In a clinical pharmacology study, QT/QTc measurements were recorded in 31 patients at baseline 
(pre-treatment) and post-treatment. After one 28-day treatment cycle, at the time of maximum 
concentration of sorafenib, QTcB was prolonged by 4 ±19 msec and QTcF by 9 ±18 msec, as 
compared to placebo treatment at baseline. No subject showed a QTcB or QTcF >500 msec during the 
post-treatment ECG monitoring (see section 4.4). 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies, in all 
subsets of the paediatric population, in kidney and renal pelvis carcinoma (excluding nephroblastoma, 
nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary carcinoma and 
rhabdoid tumour of the kidney) and liver and intrahepatic bile duct carcinoma (excluding 
hepatoblastoma) and differentiated thyroid carcinoma (see section 4.2 for information on paediatric 
use). 
 
5.2 Pharmacokinetic properties 
 
Absorption and distribution 
 
After administration of sorafenib tablets the mean relative bioavailability is 38 - 49 % when compared 
to an oral solution. The absolute bioavailability is not known. Following oral administration sorafenib 
reaches peak plasma concentrations in approximately 3 hours. When given with a high-fat meal 
sorafenib absorption was reduced by 30 % compared to administration in the fasted state.  
Mean Cmax and AUC increased less than proportionally beyond doses of 400 mg administered twice 
daily. In vitro binding of sorafenib to human plasma proteins is 99.5 %. 
Multiple dosing of sorafenib for 7 days resulted in a 2.5- to 7-fold accumulation compared to single 
dose administration. Steady state plasma sorafenib concentrations are achieved within 7 days, with a 
peak to trough ratio of mean concentrations of less than 2. 
 
The steady-state concentrations of sorafenib administered at 400 mg twice daily were evaluated in 
DTC, RCC and HCC patients. The highest mean concentration was observed in DTC patients 
(approximately twice that observed in patients with RCC and HCC), though variability was high for 
all tumour types. The reason for the increased concentration in DTC patients is unknown. 
 



17 

Biotransformation and elimination 
 
The elimination half-life of sorafenib is approximately 25 - 48 hours. Sorafenib is metabolised 
primarily in the liver and undergoes oxidative metabolism, mediated by CYP 3A4, as well as 
glucuronidation mediated by UGT1A9. Sorafenib conjugates may be cleaved in the gastrointestinal 
tract by bacterial glucuronidase activity, allowing reabsorption of unconjugated active substance. Co-
administration of neomycin has been shown to interfere with this process, decreasing the mean 
bioavailability of sorafenib by 54%. 
 
Sorafenib accounts for approximately 70 - 85 % of the circulating analytes in plasma at steady state. 
Eight metabolites of sorafenib have been identified, of which five have been detected in plasma. The 
main circulating metabolite of sorafenib in plasma, the pyridine N-oxide, shows in vitro potency 
similar to that of sorafenib. This metabolite comprises approximately 9 - 16 % of circulating analytes 
at steady state. 
 
Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96 % of the 
dose was recovered within 14 days, with 77 % of the dose excreted in faeces, and 19 % of the dose 
excreted in urine as glucuronidated metabolites. Unchanged sorafenib, accounting for 51 % of the 
dose, was found in faeces but not in urine, indicating that biliary excretion of unchanged active 
substance might contribute to the elimination of sorafenib. 
 
Pharmacokinetics in special populations 
 
Analyses of demographic data suggest that there is no relationship between pharmacokinetics and age 
(up to 65 years), gender or body weight. 
 
Paediatric population 
 
No studies have been conducted to investigate the pharmacokinetics of sorafenib in paediatric patients.  
 
Race 
 
There are no clinically relevant differences in pharmacokinetics between Caucasian and Asian 
subjects. 
 
Renal impairment 
 
In four Phase I clinical trials, steady state exposure to sorafenib was similar in patients with mild or 
moderate renal impairment compared to the exposures in patients with normal renal function. In a 
clinical pharmacology study (single dose of 400 mg sorafenib), no relationship was observed between 
sorafenib exposure and renal function in subjects with normal renal function, mild, moderate or severe 
renal impairment. No data is available in patients requiring dialysis. 
 
Hepatic impairment 
 
In hepatocellular carcinoma (HCC) patients with Child-Pugh A or B (mild to moderate) hepatic 
impairment, exposure values were comparable and within the range observed in patients without 
hepatic impairment. The pharmacokinetics (PK) of sorafenib in Child-Pugh A and B non-HCC 
patients were similar to the PK in healthy volunteers. There are no data for patients with Child-Pugh C 
(severe) hepatic impairment. Sorafenib is mainly eliminated via the liver, and exposure might be 
increased in this patient population. 
 
5.3 Preclinical safety data 
 
The preclinical safety profile of sorafenib was assessed in mice, rats, dogs and rabbits. 
Repeat-dose toxicity studies revealed changes (degenerations and regenerations) in various organs at 
exposures below the anticipated clinical exposure (based on AUC comparisons). 



18 

After repeated dosing to young and growing dogs effects on bone and teeth were observed at 
exposures below the clinical exposure. Changes consisted in irregular thickening of the femoral 
growth plate, hypocellularity of the bone marrow next to the altered growth plate and alterations of the 
dentin composition. Similar effects were not induced in adult dogs. 
 
The standard program of genotoxicity studies was conducted and positive results were obtained as an 
increase in structural chromosomal aberrations in an in vitro mammalian cell assay (Chinese hamster 
ovary) for clastogenicity in the presence of metabolic activation was seen. Sorafenib was not 
genotoxic in the Ames test or in the in vivo mouse micronucleus assay. One intermediate in the 
manufacturing process, which is also present in the final active substance (< 0.15 %), was positive for 
mutagenesis in an in vitro bacterial cell assay (Ames test). Furthermore, the sorafenib batch tested in 
the standard genotoxicity battery included 0.34 % PAPE. 
Carcinogenicity studies have not been conducted with sorafenib. 
 
No specific studies with sorafenib have been conducted in animals to evaluate the effect on fertility. 
An adverse effect on male and female fertility can however be expected because repeat-dose studies in 
animals have shown changes in male and female reproductive organs at exposures below the 
anticipated clinical exposure (based on AUC). Typical changes consisted of signs of degeneration and 
retardation in testes, epididymides, prostate, and seminal vesicles of rats. Female rats showed central 
necrosis of the corpora lutea and arrested follicular development in the ovaries. Dogs showed tubular 
degeneration in the testes and oligospermia. 
 
Sorafenib has been shown to be embryotoxic and teratogenic when administered to rats and rabbits at 
exposures below the clinical exposure. Observed effects included decreases in maternal and foetal 
body weights, an increased number of foetal resorptions and an increased number of external and 
visceral malformations.  
 
Environmental Risk assessment studies have shown that sorafenib tosylate has the potential to be 
persistent, bioaccumulative and toxic to the environment. Environmental Risk Assessment information 
is available in the EPAR of this medicine (see section 6.6). 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
Croscarmellose sodium 
Microcrystalline cellulose 
Hypromellose 
Sodium laurilsulfate 
Magnesium stearate  
 
Tablet coating: 
Hypromellose 
Macrogol (3350) 
Titanium dioxide (E 171) 
Ferric oxide red (E 172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years  
 



19 

6.4 Special precautions for storage 
 
Do not store above 25°C. 
 
6.5 Nature and contents of container 
 
112 film-coated tablets (4 x 28) in transparent (PP/Aluminium) blister packs. 
 
6.6 Special precautions for disposal 
 
This medicinal product could have potential risk for the environment. Any unused medicinal product 
or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER 
 
EU/1/06/342/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 July 2006 
Date of latest renewal: 21 July 2011 
 
 
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/
http://www.ema.europa.eu/


20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITION OR RESTRICTIONS WITH REGARD TO THE SAFE 

AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

 



21 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Bayer AG 
Kaiser-Wilhelm-Allee 
51368 Leverkusen 
Germany 
 
Bayer HealthCare Manufacturing Srl. 
Via delle Groane, 126 
20024 Garbagnate Milanese 
Italy 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
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. 



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



24 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nexavar 200 mg film-coated tablets 
sorafenib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
Each tablet contains 200 mg of sorafenib (as tosylate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
112 film-coated tablets 
 
 
5. METHOD AND ROUTE OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before 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 
 
Do not store above 25 °C. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



25 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER 
 
EU/1/06/342/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Nexavar 200 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



26 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nexavar 200 mg tablets 
sorafenib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer (Logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
MON 
TUE 
WED 
THU 
FRI 
SAT 
SUN 
 
 



27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



28 

 
Package Leaflet: Information for the user 

Nexavar 200 mg film-coated tablets 
sorafenib 

 
 

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 or pharmacist. 
- 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 or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Nexavar is and what it is used for 
2. What you need to know before you take Nexavar 
3. How to take Nexavar 
4. Possible side effects 
5. How to store Nexavar 
6. Contents of the pack and other information 
 
 
1. What Nexavar is and what it is used for 
 
Nexavar is used to treat liver cancer (hepatocellular carcinoma). 
Nexavar is also used to treat kidney cancer (advanced renal cell carcinoma) at an advanced stage 
when standard therapy has not helped to stop your disease or is considered unsuitable. 
Nexavar is used to treat thyroid cancer (differentiated thyroid carcinoma). 
 
Nexavar is a so-called multikinase inhibitor. It works by slowing down the rate of growth of cancer 
cells and cutting off the blood supply that keeps cancer cells growing.  
 
 
2. What do you need to know before you take Nexavar 
 
Do not take Nexavar  
- If you are allergic to sorafenib or any of the other ingredients of this medicine (listed in section 

6). 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Nexavar. 
 
Take special care with Nexavar 
- If you experience skin problems. Nexavar can cause rashes and skin reactions, especially on the 

hands and feet. These can usually be treated by your doctor. If not, your doctor may interrupt 
treatment or stop it altogether.  

- If you have high blood pressure. Nexavar can raise blood pressure, and your doctor will usually 
monitor your blood pressure and may give you a medicine to treat your high blood pressure.  

- If you have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a 
tear in a blood vessel wall. 

- If you have diabetes. Blood sugar levels in diabetic patients should be checked regularly in order 
to assess if anti-diabetic medicine’s dosage needs to be adjusted to minimize the risk of low blood 
sugar. 



29 

- If you get any bleeding problems, or are taking warfarin or phenprocoumon. Treatment with 
Nexavar may lead to a higher risk of bleeding. If you are taking warfarin or phenprocoumon, 
medicines which thin the blood to prevent blood clots, there may be a greater risk of bleeding.  

- If you get chest pain or heart problems. Your doctor may decide to interrupt treatment or stop it 
altogether. 

- If you have a heart disorder, such as an abnormal electrical signal called "prolongation of the 
QT interval". 

- If you are going to have surgery, or if you had an operation recently. Nexavar might affect the 
way your wounds heal. You will usually be taken off Nexavar if you are having an operation. 
Your doctor will decide when to start with Nexavar again. 

- If you are taking irinotecan or are given docetaxel, which are also medicines for cancer. 
Nexavar may increase the effects and, in particular, the side effects of these medicines. 

- If you are taking Neomycin or other antibiotics. The effect of Nexavar may be decreased. 
- If you have severe liver impairment. You may experience more severe side effects when taking 

this medicine. 
- If you have poor kidney function. Your doctor will monitor your fluid and electrolyte balance. 
- Fertility. Nexavar may reduce fertility in both men and women. If you are concerned, talk to a 

doctor.  
- Holes in the gut wall (gastrointestinal perforation) may occur during treatment (see section 4: 

Possible Side Effects). In this case your doctor will interrupt the treatment. 
- If you have thyroid cancer. Your doctor will monitor blood calcium and thyroid hormone levels. 
 
Tell your doctor if any of these affect you. You may need treatment for them, or your doctor may 
decide to change your dose of Nexavar, or stop treatment altogether (see also section 4: Possible side 
effects). 
 
Children and adolescents 
Children and adolescents have not yet been tested with Nexavar.  
 
Other medicines and Nexavar 
Some medicines may affect Nexavar, or be affected by it. Tell your doctor or pharmacist if you are 
taking, have recently taken or might take anything in this list or any other medicines, including 
medicines obtained without a prescription: 
- Rifampicin, Neomycin or other medicines used to treat infections (antibiotics) 
- St John’s wort, a herbal treatment for depression 
- Phenytoin, carbamazepine or phenobarbital, treatments for epilepsy and other conditions 
- Dexamethasone, a corticosteroid used for various conditions 
- Warfarin or phenprocoumon, anticoagulants used to prevent blood clots 
- Doxorubicin, capecitabine, docetaxel, paclitaxel and irinotecan, which are cancer treatments 
- Digoxin, a treatment for mild to moderate heart failure 
 
Pregnancy and breast-feeding 
Avoid becoming pregnant while being treated with Nexavar. If you could become pregnant use 
adequate contraception during treatment. If you become pregnant while being treated with Nexavar, 
immediately tell your doctor who will decide if the treatment should be continued. 
 
You must not breast-feed your baby during Nexavar treatment, as this medicine may interfere 
with the growth and development of your baby. 
 
Driving and using machines 
There is no evidence that Nexavar will affect the ability to drive or to operate machines. 
 
Nexavar contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium 
free”. 
 
 



30 

3. How to take Nexavar 
 
The recommended dose of Nexavar in adults is 2 x 200 mg tablets, twice daily.  
This is equivalent to a daily dose of 800 mg or four tablets a day.  
 
Swallow Nexavar tablets with a glass of water, either without food or with a low-fat or moderate fat 
meal. Do not take this medicine with high fat meals, as this may make Nexavar less effective. If you 
intend to have a high fat meal, take the tablets at least 1 hour before or 2 hours after the meal. 
Always take this medicine exactly as your doctor has told you to. Check with your doctor or 
pharmacist if you are not sure. 
 
It is important to take this medicine at about the same times each day, so that there is a steady amount 
in the bloodstream. 
 
You will usually carry on taking this medicine as long as you are getting clinical benefits, and not 
suffering unacceptable side effects. 
 
If you take more Nexavar than you should 
Tell your doctor straight away if you (or anyone else) have taken more than your prescribed dose. 
Taking too much Nexavar makes side effects more likely or more severe, especially diarrhoea and skin 
reactions. Your doctor may tell you to stop taking this medicine. 
 
If you forget to take Nexavar 
If you have missed a dose, take it as soon as you remember. If it is nearly time for the next dose, forget 
about the missed one and carry on as normal. Do not take a double dose to make up for forgotten 
individual doses. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects although not everybody gets them. This 
medicine may also affect the results of some blood tests. 
 
Very common: 
may affect more than 1 in 10 people 
- diarrhoea 
- feeling sick (nausea) 
- feeling weak or tired (fatigue) 
- pain (including mouth pain, abdominal pain, headache, bone pain, tumour pain) 
- hair loss (alopecia) 
- flushed or painful palms or soles (hand foot skin reaction) 
- itching or rash 
- throwing up (vomiting) 
- bleeding (including bleeding in the brain, gut wall and respiratory tract; haemorrhage) 
- high blood pressure, or increases in blood pressure (hypertension) 
- infections 
- loss of appetite (anorexia) 
- constipation 
- joint pain (arthralgia) 
- fever 
- weight loss 
- dry skin 
 



31 

Common: 
may affect up to 1 in 10 people 
- flu-like illness 
- indigestion (dyspepsia) 
- difficulty swallowing (dysphagia) 
- inflamed or dry mouth, tongue pain (stomatitis and mucosal inflammation) 
- low calcium levels in the blood (hypocalcaemia) 
- low potassium levels in the blood (hypokalaemia) 
- low blood sugar level (hypoglycaemia) 
- muscle pain (myalgia) 
- disturbed sensations in fingers and toes, including tingling or numbness (peripheral sensory 

neuropathy) 
- depression 
- erection problems (impotence) 
- altered voice (dysphonia) 
- acne 
- inflamed, dry or scaly skin that sheds (dermatitis, skin desquamation) 
- heart failure 
- heart attack (myocardial infarction) or chest pain 
- tinnitus (ringing sound in the ear) 
- kidney failure 
- abnormally high levels of protein in the urine (proteinuria) 
- general weakness or loss of strength (asthenia) 
- decrease in the number of white blood cells (leucopenia and neutropenia) 
- decrease in the number of red blood cells (anaemia) 
- low number of platelets in the blood (thrombocytopenia) 
- inflammation of hair follicles (folliculitis) 
- underactive thyroid gland (hypothyroidism) 
- low sodium levels in the blood (hyponatraemia) 
- distortion of the sense of taste (dysgeusia) 
- red in the face and often other areas of the skin (flushing) 
- runny nose (rhinorrhoea) 
- heartburn (gastro oesophageal reflux disease) 
- skin cancer (keratoacanthomas/squamous cell cancer of the skin) 
- a thickening  of the outer layer of the skin (hyperkeratosis) 
- a sudden, involuntary contraction of a muscle (muscle spasms) 
 
Uncommon: 
may affect up to 1 in 100 people 
- inflamed stomach lining (gastritis) 
- pain in the tummy (abdomen) caused by pancreatitis, inflammation of the gall bladder and/or bile 

ducts 
- yellow skin or eyes (jaundice) caused by high levels of bile pigments (hyperbilirubinaemia) 
- allergic like reactions (including skin reactions and hives) 
- dehydration 
- enlarged breasts (gynaecomastia) 
- breathing difficulty (lung disease) 
- eczema 
- overactive thyroid gland (hyperthyroidism) 
- multiple skin eruptions (erythema multiforme) 
- abnormally high blood pressure 
- holes in the gut wall (gastrointestinal perforation) 
- reversible swelling in the rear part of the brain that can be associated with headache, altered 

consciousness, fits and visual symptoms including visual loss (reversible posterior 
leukoencephalopathy) 

- a sudden, severe allergic reaction (anaphylactic reaction) 
 

http://www.webmd.com/allergies/tc/allergic-reaction-topic-overview
http://www.webmd.com/allergies/tc/allergic-reaction-topic-overview


32 

Rare: may affect up to 1 in 1,000 people 
- allergic reaction with swelling of the skin (e. g. face, tongue) that may cause difficulty in breathing 

or swallowing (angioedema) 
- abnormal heart rhythm (QT prolongation) 
- inflammation of the liver, which may lead to nausea, vomiting, abdominal pain, and jaundice 

(drug induced hepatitis) 
- a sunburn-like rash that may occur on skin that has previously been exposed to radiotherapy and 

can be severe (radiation recall dermatitis) 
- serious reactions of the skin and/or mucous membranes which may include painful blisters and 

fever, including extensive detachment of the skin (Stevens-Johnson syndrome and toxic epidermal 
necrolysis) 

- abnormal muscle breakdown which can lead to kidney problems (rhabdomyolysis) 
- damage of the kidney causing them to leak large amounts of protein (nephrotic syndrome) 
- inflammation of the vessels in the skin which may result in rash (leucocytoclastic vasculitis) 
 
Not known: frequency cannot be estimated from the available data 
- impaired brain function that can be associated with e.g. drowsiness, behavioural changes, or 

confusion (encephalopathy) 
- an enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms 

and artery dissections). 
 
 
Reporting of side effects  
If you get any side effects, talk to your doctor or pharmacist. 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 Nexavar 
 
Keep this medicine out of the sight and reach of children.  
 
Do not use this medicine after the expiry date which is stated on the carton and on each blister after 
EXP. The expiry date refers to the last day of that month. 
 
Do not store this medicine above 25°C. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Nexavar contains 
 
- The active substance is sorafenib. Each film-coated tablet contains 200 mg sorafenib (as 

tosylate). 
- The other ingredients are: 

Tablet core: croscarmellose sodium, microcrystalline cellulose, hypromellose, sodium 
laurilsulfate, magnesium stearate. 
Tablet coating: hypromellose, macrogol, titanium dioxide (E 171), ferric oxide red (E 172). 

 

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


33 

What Nexavar looks like and contents of the pack 
 
Nexavar 200 mg film-coated tablets are red and round with the Bayer cross on one side and “200” on 
the other side. They come in calendar packs of 112 tablets: four transparent blister packs of 28 tablets 
each. 
 
Marketing Authorisation Holder 
Bayer AG 
51368 Leverkusen 
Germany 
 
Manufacturer 
Bayer AG 
Kaiser-Wilhelm-Allee 
51368 Leverkusen 
Germany 
 
Bayer HealthCare Manufacturing Srl. 
Via delle Groane, 126 
20024 Garbagnate Milanese 
Italy 
 
 



34 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder . 
 
België / Belgique / Belgien 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 

Lietuva 
UAB Bayer 
Tel. +37 05 23 36 868 

България 
Байер България ЕООД 
Тел.: +359 02-424 72 80 

Luxembourg / Luxemburg 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 

Česká republika 
Bayer s.r.o. 
Tel: +420 266 101 111 

Magyarország 
Bayer Hungária KFT 
Tel.:+36 14 87-41 00 

Danmark 
Bayer A/S 
Tlf: +45-45 23 50 00 

Malta 
Alfred Gera and Sons Ltd. 
Tel: +35 621 44 62 05 

Deutschland 
Bayer Vital GmbH 
Tel: +49 (0)214-30 513 48 

Nederland 
Bayer B.V. 
Tel: +31-(0)297-28 06 66 

Eesti 
Bayer OÜ 
Tel: +372 655 8565 

Norge 
Bayer AS 
Tlf. +47 24 11 18 00 

Ελλάδα 
Bayer Ελλάς ΑΒΕΕ 
Τηλ: +30 210 61 87 500 

Österreich 
Bayer Austria Ges. m. b. H. 
Tel: +43-(0)1-711 46-0 

España 
Bayer Hispania S.L. 
Tel: +34-93-495 65 00 

Polska 
Bayer Sp. z o.o. 
Tel.: +48 22 572 35 00 

France 
Bayer HealthCare 
Tél(N° vert): +33-(0)800 87 54 54 

Portugal 
Bayer Portugal, Lda. 
Tel: +351 21 416 42 00 

Hrvatska 
Bayer d.o.o. 
Tel: + 385-(0)1-6599 900 

România 
SC Bayer SRL 
Tel: +40 21 529 59 00 

Ireland 
Bayer Limited 
Tel: +353 1 2999313 

Slovenija 
Bayer d. o. o. 
Tel.: +386 (0)1 58 14 400 

Ísland 
Icepharma hf. 
Sími: +354 540 8000 

Slovenská republika 
Bayer, spol. s r.o. 
Tel: +421 2 59 21 31 11 

Italia 
Bayer S.p.A. 
Tel: +39 02 397 81 

Suomi/Finland 
Bayer Oy 
Puh/Tel: +358 20 785 21 

Κύπρος 
NOVAGEM Limited 
Τηλ: +357 22 48 38 58 

Sverige 
Bayer AB 
Tel: +46 (0) 8 580 223 00 

Latvija 
SIA Bayer 
Tel: +371 67 84 55 63 

United Kingdom 
Bayer plc 
Tel: +44 (0) 118 206 3000 

 
This booklet was last revised in {month 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/
http://www.ema.europa.eu/

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