Stivarga

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ANNEX I 

 
SUMMARY OF PRODUCT CHARACTERISTICS 

 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Stivarga 40 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 40 mg of regorafenib. 
 
Excipients with known effect 
Each daily dose of 160 mg contains 2.427 mmol (or 55.8 mg) of sodium (see section 4.4). 
Each daily dose of 160 mg contains 1.68 mg of lecithin (derived from soya) (see section 4.4). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Light pink film-coated tablets, oval shaped with a length of 16 mm and a width of 7 mm marked with 
‘BAYER’ on one side and ‘40’ on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Stivarga is indicated as monotherapy for the treatment of adult patients with 
 
- metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered 

candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, an 
anti-VEGF therapy and an anti-EGFR therapy (see section 5.1)  

 
- unresectable or metastatic gastrointestinal stromal tumours (GIST) who progressed on or are 

intolerant to prior treatment with imatinib and sunitinib 
 
- hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. 
 
4.2 Posology and method of administration 
 
Stivarga should be prescribed by physicians experienced in the administration of anticancer therapy. 
 
Posology 
The recommended dose of regorafenib is 160 mg (4 tablets of 40 mg) taken once daily for 3 weeks 
followed by 1 week off therapy. This 4-week period is considered a treatment cycle. 
 
If a dose is missed, then it should be taken on the same day as soon as the patient remembers. The 
patient should not take two doses on the same day to make up for a missed dose. In case of vomiting 
after regorafenib administration, the patient should not take additional tablets. 
 
Treatment should continue as long as benefit is observed or until unacceptable toxicity occurs (see 
section 4.4). 



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Patients with performance status (PS) 2 or higher were excluded from clinical studies. There is limited 
data in patients with PS ≥2. 

 
Posology adjustments 
Dose interruptions and/or dose reductions may be required based on individual safety and tolerability. 
Dose modifications are to be applied in 40 mg (one tablet) steps. The lowest recommended daily dose 
is 80 mg. The maximum daily dose is 160 mg. 
 
For recommended dose modifications and measures in case of hand-foot skin reaction 
(HFSR)/palmar-plantar erythrodysesthesia syndrome see Table 1. 
 
Table 1: Recommended dose modifications and measures for HFSR 

 
Skin toxicity grade Occurrence Recommended dose modification and measures 

Grade 1 Any Maintain dose level and immediately institute supportive measures for symptomatic relief.  

Grade 2 

1st occurrence 

Decrease dose by 40 mg (one tablet) and 
immediately institute supportive measures. 
If no improvement occurs despite dose reduction, 
interrupt therapy for a minimum of 7 days, until 
toxicity resolves to Grade 0-1.  
A dose re-escalation is permitted at the discretion 
of the physician. 

No improvement 
within 7 days or 
2nd occurrence 

Interrupt therapy until toxicity resolves to 
Grade 0-1. 
When re-starting treatment, decrease dose by 
40 mg (one tablet).  
A dose re-escalation is permitted at the discretion 
of the physician. 

3rd occurrence 

Interrupt therapy until toxicity resolves to 
Grade 0-1. 
When re-starting treatment, decrease dose by 
40 mg (one tablet).  
A dose re-escalation is permitted at the discretion 
of the physician. 

4th occurrence Discontinue treatment with Stivarga permanently. 

Grade 3 

1st occurrence 

Institute supportive measures immediately. 
Interrupt therapy for a minimum of 7 days until 
toxicity resolves to Grade 0-1.  
When re-starting treatment, decrease dose by 
40 mg (one tablet).  
A dose re-escalation is permitted at the discretion 
of the physician.  

2nd occurrence 

Institute supportive measures immediately. 
Interrupt therapy for a minimum of 7 days until 
toxicity resolves to Grade 0-1.  
When re-starting treatment, decrease dose by 
40 mg (one tablet). 

3rd occurrence Discontinue treatment with Stivarga permanently. 
 
For recommended measures and dose modifications in case of worsening of liver function tests 
considered related to treatment with Stivarga see Table 2 (see also section 4.4). 



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Table 2: Recommended measures and dose modifications in case of drug-related liver function 
test abnormalities  
 

Observed elevations 
of ALT and/or AST Occurrence Recommended measures and dose modification 

≤5 times upper limit of 
normal (ULN)  
(maximum Grade 2) 

Any occurrence 
Continue Stivarga treatment.  
Monitor liver function weekly until transaminases 
return to <3 times ULN (Grade 1) or baseline. 

>5 times ULN 
≤20 times ULN 
(Grade 3) 

1st occurrence 

Interrupt Stivarga treatment.  
Monitor transaminases weekly until return to <3 times 
ULN or baseline. 

 

Restart: If the potential benefit outweighs the risk of 
hepatotoxicity, re-start Stivarga treatment, reduce dose 
by 40 mg (one tablet), and monitor liver function 
weekly for at least 4 weeks.  

 Re-occurrence Discontinue treatment with Stivarga permanently. 
>20 times ULN  
(Grade 4) Any occurrence Discontinue treatment with Stivarga permanently. 

>3 times ULN 
(Grade 2 or higher) 
with concurrent 
bilirubin >2 times 
ULN 

Any occurrence 

Discontinue treatment with Stivarga permanently.  
Monitor liver function weekly until resolution or return 
to baseline.  
Exception: patients with Gilbert’s syndrome who 
develop elevated transaminases should be managed as 
per the above outlined recommendations for the 
respective observed elevation of ALT and/or AST. 

 
Hepatic impairment 
Regorafenib is eliminated mainly via the hepatic route. 
In clinical studies, no relevant differences in exposure, safety or efficacy were observed between 
patients with mild hepatic impairment (Child-Pugh A) and normal hepatic function. No dose 
adjustment is required in patients with mild hepatic impairment. Since only limited data are available 
for patients with moderate hepatic impairment (Child Pugh B), no dose recommendation can be 
provided. Close monitoring of overall safety is recommended in these patients (see sections 4.4 
and 5.2). 
 
Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) as 
Stivarga has not been studied in this population. 
 
Renal impairment 
Available clinical data indicate similar exposure of regorafenib and its metabolites M-2 and M-5 in 
patients with mild, moderate or severe renal impairment compared to patients with normal renal 
function. No dose adjustment is required in patients with mild, moderate or severe renal impairment 
(see also section 5.2).  
 
Elderly population 
In clinical studies, no relevant differences in exposure, safety or efficacy were observed between 
elderly (aged 65 years and above) and younger patients (see also section 5.2). 
 
Gender 
In clinical studies, no relevant differences in exposure, safety or efficacy were observed between male 
and female patients. No dose adjustment is necessary based on gender (see also section 5.2). 
 



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Ethnic differences 
In clinical studies, no relevant differences in exposure or efficacy were observed between patients of 
different ethnic groups. A higher incidence of hand foot skin reaction (HFSR)/palmar-plantar 
erythrodysesthesia syndrome, severe liver function test abnormalities and hepatic dysfunction was 
observed in Asian (in particular Japanese) patients treated with Stivarga compared with Caucasians. 
The Asian patients treated with Stivarga in clinical studies were primarily from East Asia (~90%). 
There is limited data on regorafenib in the black patient population. 
No dose adjustment is necessary based on ethnicity (see section 5.2). 
 
Paediatric population 
There is no relevant use of Stivarga in the paediatric population in the indication of metastatic 
colorectal cancer.  
The safety and efficacy of regorafenib in patients below 18 years of age in the indication 
gastrointestinal stromal tumours (GIST) have not been established. No data are available. 
There is no relevant use of Stivarga in the paediatric population in the indication of hepatocellular 
carcinoma. 
 
Method of administration 
Stivarga is for oral use. 
 
Stivarga should be taken at the same time each day. The tablets should be swallowed whole with water 
after a light meal that contains less than 30% fat. An example of a light (low-fat) meal would include 
1 portion of cereal (about 30 g), 1 glass of skimmed milk, 1 slice of toast with jam, 1 glass of apple 
juice, and 1 cup of coffee or tea (520 calories, 2 g fat). 
 
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 
 
Hepatic effects 
Abnormalities of liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase 
[AST] and bilirubin) have been frequently observed in patients treated with Stivarga. Severe liver 
function test abnormalities (Grade 3 to 4) and hepatic dysfunction with clinical manifestations 
(including fatal outcomes) have been reported in a small proportion of patients (see section 4.8).  
In clinical trials, a higher incidence of severe liver function test abnormalities and hepatic dysfunction 
was observed in Asian (in particular Japanese) patients treated with Stivarga, compared with 
Caucasians (see section 4.2). 
 
It is recommended to perform liver function tests (ALT, AST and bilirubin) before initiation of 
treatment with Stivarga and monitor closely (at least every two weeks) during the first 2 months of 
treatment. Thereafter, periodic monitoring should be continued at least monthly and as clinically 
indicated.  
 
Regorafenib is a uridine diphosphate glucuronosyl transferase (UGT) 1A1 inhibitor (see section 4.5). 
Mild, indirect (unconjugated) hyperbilirubinaemia may occur in patients with Gilbert’s syndrome. 
 
For patients with observed worsening of liver function tests considered related to treatment with 
Stivarga (i.e. where no alternative cause is evident, such as post-hepatic cholestasis or disease 
progression), the dose modification and monitoring advice in Table 2 should be followed (see 
section 4.2). 
 
Regorafenib is eliminated mainly via the hepatic route.  



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Close monitoring of the overall safety is recommended in patients with mild or moderate hepatic 
impairment (see also sections 4.2 and 5.2). Stivarga is not recommended for use in patients with 
severe hepatic impairment (Child-Pugh C) as Stivarga has not been studied in this population and 
exposure might be increased in these patients. 
 
Infections 
Stivarga has been associated with an increased incidence of infection events, some of which were fatal 
(see section 4.8). 
In cases of worsening infection events, interruption of Stivarga treatment should be considered. 
 
Haemorrhage 
Stivarga has been associated with an increased incidence of haemorrhagic events, some of which were 
fatal (see section 4.8). Blood counts and coagulation parameters should be monitored in patients with 
conditions predisposing to bleeding, and in those treated with anticoagulants (e.g. warfarin and 
phenprocoumon) or other concomitant medicinal products that increase the risk of bleeding. Screening 
for and subsequent treatment of oesophageal varices in patients with liver cirrhosis should be 
performed as per standard of care before starting treatment with Stivarga. In the event of severe 
bleeding necessitating urgent medical intervention, permanent discontinuation of Stivarga should be 
considered. 
 
Gastrointestinal perforation and fistula 
Gastrointestinal perforation (including fatal outcome) and fistulae have been reported in patients 
treated with Stivarga (see section 4.8). These events are also known to be common disease-related 
complications in patients with intra-abdominal malignancies. Discontinuation of Stivarga is 
recommended in patients developing gastrointestinal perforation or fistula. 
 
Cardiac ischaemia and infarction 
Stivarga has been associated with an increased incidence of myocardial ischaemia and infarction (see 
section 4.8). Patients with unstable angina or new onset angina (within 3 months of starting Stivarga 
therapy), recent myocardial infarction (within 6 months of starting Stivarga therapy) and those with 
cardiac failure New York Heart Association (NYHA) Classification 2 or higher were excluded from 
the clinical studies. 
 
Patients with a history of ischaemic heart disease should be monitored for clinical signs and symptoms 
of myocardial ischaemia. In patients who develop cardiac ischaemia and/or infarction, interruption of 
Stivarga is recommended until resolution. The decision to re-start Stivarga therapy should be based on 
careful consideration of the potential benefits and risks of the individual patient. Stivarga should be 
permanently discontinued if there is no resolution. 
 
Posterior reversible encephalopathy syndrome (PRES) 
PRES has been reported in association with Stivarga treatment (see section 4.8). Signs and symptoms 
of PRES include seizures, headache, altered mental status, visual disturbance or cortical blindness, 
with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging. 
In patients developing PRES, discontinuation of Stivarga, along with control of hypertension and 
supportive medical management of other symptoms is recommended. 
 
Arterial hypertension 
Stivarga has been associated with an increased incidence of arterial hypertension (see section 4.8). 
Blood pressure should be controlled prior to initiation of treatment with Stivarga. It is recommended to 
monitor blood pressure and to treat hypertension in accordance with standard medical practice. In 
cases of severe or persistent hypertension despite adequate medical management, treatment should be 
temporarily interrupted and/or the dose reduced at the discretion of the physician (see section 4.2). In 
case of hypertensive crisis, Stivarga should be discontinued. 
 



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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 Stivarga, this risk should be 
carefully considered in patients with risk factors such as hypertension or history of aneurysm. 
 
Wound healing complications 
As medicinal products with anti-angiogenic properties may suppress or interfere with wound healing, 
temporary interruption of Stivarga is recommended for precautionary reasons in patients undergoing 
major surgical procedures. The decision to resume treatment with Stivarga following major surgical 
intervention should be based on clinical judgment of adequate wound healing. 
 
Dermatological toxicity 
Hand-foot skin reaction (HFSR) or palmar-plantar erythrodysesthesia syndrome and rash represent the 
most frequently observed dermatological adverse reactions with Stivarga (see section 4.8). In clinical 
trials, a higher incidence of HFSR was observed in Asian (in particular Japanese) patients treated with 
Stivarga, compared with Caucasians (see section 4.2). Measures for the prevention of HFSR include 
control of calluses and use of shoe cushions and gloves to prevent pressure stress to soles and palms. 
Management of HFSR may include the use of keratolytic creams (e.g. urea-, salicylic acid-, or alpha 
hydroxyl acid-based creams applied sparingly only on affected areas) and moisturizing creams 
(applied liberally) for symptomatic relief. Dose reduction and/or temporary interruption of Stivarga, or 
in severe or persistent cases, permanent discontinuation of Stivarga should be considered (see 
section 4.2).  
 
Biochemical and metabolic laboratory test abnormalities 
Stivarga has been associated with an increased incidence of electrolyte abnormalities (including 
hypophosphatemia, hypocalcaemia, hyponatraemia and hypokalaemia) and metabolic abnormalities 
(including increases in thyroid stimulating hormone, lipase and amylase). The abnormalities are 
generally of mild to moderate severity, not associated with clinical manifestations, and do not usually 
require dose interruptions or reductions. It is recommended to monitor biochemical and metabolic 
parameters during Stivarga treatment and to institute appropriate replacement therapy according to 
standard clinical practice if required. Dose interruption or reduction, or permanent discontinuation of 
Stivarga should be considered in case of persistent or recurrent significant abnormalities (see 
section 4.2). 
 
Important information about some of the ingredients 
This medicinal product contains 55.8 mg sodium per daily dose of 160 mg, equivalent to 3% of the 
WHO recommended maximum daily intake of 2 g sodium for an adult.Each daily dose of 160 mg 
contains 1.68 mg of lecithin (derived from soya).  
 
Disease-specific precautions – Hepatocellular carcinoma (HCC) 
In the pivotal placebo-controlled phase III study, patients received prior therapy with sorafenib.  
There is insufficient data on patients who discontinued sorafenib therapy due to sorafenib-related 
toxicity or only tolerated a low dose (< 400 mg daily) of sorafenib. The tolerability of Stivarga in these 
patients has not been established. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Inhibitors of CYP3A4 and UGT1A9/inducers of CYP3A4 
In vitro data indicate that regorafenib is metabolized by cytochrome CYP3A4 and uridine diphosphate 
glucuronosyl transferase UGT1A9.  
 
Administration of ketoconazole (400 mg for 18 days), a strong CYP3A4 inhibitor, with a single dose 
of regorafenib (160 mg on day 5) resulted in an increase in mean exposure (AUC) of regorafenib of 
approximately 33%, and a decrease in mean exposure of the active metabolites, M-2 (N-oxide) and 



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M-5 (N-oxide and N-desmethyl), of approximately 90%. It is recommended to avoid concomitant use 
of strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, 
ketoconazole, posaconazole, telithromycin and voriconazole) as their influence on the steady-state 
exposure of regorafenib and its metabolites has not been studied. 
 
Co-administration of a strong UGT1A9 inhibitor (e.g. mefenamic acid, diflunisal, and niflumic acid) 
during regorafenib treatment should be avoided, as their influence on the steady-state exposure of 
regorafenib and its metabolites has not been studied. 
 
Administration of rifampicin (600 mg for 9 days), a strong CYP3A4 inducer, with a single dose of 
regorafenib (160 mg on day 7) resulted in a reduction in AUC of regorafenib of approximately 50%, a 
3- to 4-fold increase in mean exposure of the active metabolite M-5, and no change in exposure of 
active metabolite M-2. Other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital 
and St. John’s wort) may also increase metabolism of regorafenib. Strong inducers of CYP3A4 should 
be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to 
induce CYP3A4 should be considered. 
 
UGT1A1 and UGT1A9 substrates  
In vitro data indicate that regorafenib as well as its active metabolite M-2 inhibit glucuronidation 
mediated by UGT1A1 and UGT1A9 whereas M-5 only inhibits UGT1A1 at concentrations which are 
achieved in vivo at steady state. Administration of regorafenib with a 5-day break prior to 
administration of irinotecan resulted in an increase of approximately 44% in AUC of SN-38, a 
substrate of UGT1A1 and an active metabolite of irinotecan. An increase in AUC of irinotecan of 
approximately 28% was also observed. This indicates that co-administration of regorafenib may 
increase systemic exposure to UGT1A1 and UGT1A9 substrates.  
 
Breast cancer resistance protein (BCRP) and P-glycoprotein substrates 
Administration of regorafenib (160 mg for 14 days) prior to administration of a single dose of 
rosuvastatin (5 mg), a BCRP substrate, resulted in a 3.8-fold increase in mean exposure (AUC) of 
rosuvastatin and a 4.6-fold increase in Cmax. 
 
This indicates that co-administration of regorafenib may increase the plasma concentrations of other 
concomitant BCRP substrates (e.g. methotrexate, fluvastatin, atorvastatin). Therefore, it is 
recommended to monitor patients closely for signs and symptoms of increased exposure to BCRP 
substrates. 
 
Clinical data indicate that regorafenib has no effect on digoxin pharmacokinetics, therefore can be 
given concomitantly with p-glycoprotein substrates, such as digoxin, without a clinically meaningful 
drug interaction. 
 
Inhibitors of P-glycoprotein and BCRP/Inducers of P-glycoprotein and BCRP 
In vitro studies indicate that the active metabolites M-2 and M-5 are substrates for P-glycoprotein and 
BCRP. Inhibitors and inducers of BCRP and P-glycoprotein may interfere with the exposure of M-2 
and M-5. The clinical significance of these findings is unknown (see also section 5.2). 
 
CYP isoform-selective substrates 
In vitro data indicate that regorafenib is a competitive inhibitor of the cytochromes CYP2C8 (Ki value 
of 0.6 micromolar), CYP2C9 (Ki value of 4.7 micromolar), CYP2B6 (Ki value of 5.2 micromolar) at 
concentrations which are achieved in vivo at steady state (peak plasma concentration of 
8.1 micromolar). The in vitro inhibitory potency towards CYP3A4 (Ki value of 11.1 micromolar) and 
CYP2C19 (Ki value of 16.4 micromolar) was less pronounced.  
 



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A clinical probe substrate study was performed to evaluate the effect of 14 days of dosing with 160 mg 
regorafenib on the pharmacokinetics of probe substrates of CYP2C8 (rosiglitazone) CYP2C9 
(S-warfarin), CYP 2C19 (omeprazole) and CYP3A4 (midazolam). 
 
Pharmacokinetic data indicate that regorafenib may be given concomitantly with substrates of 
CYP2C8, CYP2C9, CYP3A4, and CYP2C19 without a clinically meaningful drug interaction (see 
also section 4.4). 
 
Antibiotics 
The concentration-time profile indicates that regorafenib and its metabolites may undergo 
enterohepatic circulation (see section 5.2). Co-administration with neomycin, a poorly absorbed 
antimicrobial agent used for eradicating the gastrointestinal microflora (which may interfere with the 
enterohepatic circulation of regorafenib) had no effect on the regorafenib exposure, but there was an 
approximately 80% decrease in the exposure of the active metabolites M-2 and M-5 which showed in 
vitro and in vivo comparable pharmacological activity as regorafenib. The clinical significance of this 
neomycin interaction is unknown, but may result in a decreased efficacy of regorafenib. 
Pharmacokinetic interactions of other antibiotics have not been studied. 
 
Bile salt-sequestering agents 
Regorafenib, M-2 and M-5 are likely to undergo enterohepatic circulation (see section 5.2). Bile salt-
sequestering agents such as cholestyramine and cholestagel may interact with regorafenib by forming 
insoluble complexes which may impact absorption (or reabsorption), thus resulting in potentially 
decreased exposure. The clinical significance of these potential interactions is unknown, but may 
result in a decreased efficacy of regorafenib. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/Contraception in males and females 
Women of childbearing potential must be informed that regorafenib may cause foetal harm.  
Women of childbearing potential and men should ensure effective contraception during treatment and 
up to 8 weeks after completion of therapy. 
 
Pregnancy 
There are no data on the use of regorafenib in pregnant women. 
Based on its mechanism of action regorafenib is suspected to cause foetal harm when administered 
during pregnancy. Animal studies have shown reproductive toxicity (see section 5.3). 
Stivarga should not be used during pregnancy unless clearly necessary and after careful consideration 
of the benefits for the mother and the risk to the foetus. 
 
Breast-feeding 
It is unknown whether regorafenib or its metabolites are excreted in human milk. 
In rats, regorafenib or its metabolites are excreted in milk. A risk to the breast-fed child cannot be 
excluded. Regorafenib could harm infant growth and development (see section 5.3). 
Breast-feeding must be discontinued during treatment with Stivarga. 
 
Fertility 
There are no data on the effect of Stivarga on human fertility. Results from animal studies indicate that 
regorafenib can impair male and female fertility (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects of Stivarga on the ability to drive or use machines have been performed. If 
patients experience symptoms affecting their ability to concentrate and react during treatment with 
Stivarga, it is recommended that they do not drive or use machines until the effect subsides. 



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4.8 Undesirable effects 
 
Summary of the safety profile 
The overall safety profile of Stivarga is based on data from more than 4,800 treated patients in clinical 
trials including placebo-controlled phase III data for 636 patients with metastatic colorectal cancer 
(CRC), 132 patients with gastrointestinal stromal tumours (GIST) and 374 patients with hepatocellular 
carcinoma (HCC). 
 
The safety profile of regorafenib in these studies was consistent with the safety results of a phase III B 
study conducted in 2872 patients with metastatic colorectal cancer whose disease had progressed after 
treatment with standard therapies. 
 
The most serious adverse drug reactions in patients receiving Stivarga are severe liver injury, 
haemorrhage, gastrointestinal perforation and infection. 
 
The most frequently observed adverse drug reactions (≥30%) in patients receiving Stivarga are pain, 
hand foot skin reaction, asthenia/fatigue, diarrhoea, decreased appetite and food intake, hypertension 
and infection. 
 
Tabulated list of adverse reactions 
The adverse drug reactions reported in clinical trials in patients treated with Stivarga are shown in 
Table 3. They are classified according to System Organ Class and the most appropriate MedDRA term 
is used to describe a certain reaction and its synonyms and related conditions. 
Adverse drug reactions are grouped according to their frequencies. Frequency groups are defined by 
the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon 
(≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000) and not known (cannot be estimated from the 
available data). 
 
Within each frequency group, undesirable effects are presented in order of decreasing seriousness. 
 
Table 3: Adverse drug reactions (ADRs) reported in clinical trials in patients treated with 
Stivarga 
 

System 
Organ Class 
(MedDRA) 

Very common Common Uncommon Rare Not known 

Infections and 
infestations  

Infection
* 

    

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

   Keratoacan-
thoma/ 
Squamous 
cell 
carcinoma of 
the skin 

 

Blood and 
lymphatic 
system 
disorders 

Thrombo-
cytopenia  
Anaemia 

Leucopenia    

Immune 
system 
disorders 

  Hypersensiti-
vity reaction 

  



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System 
Organ Class 
(MedDRA) 

Very common Common Uncommon Rare Not known 

Endocrine 
disorders 
 

 Hypo-
thyroidism 

   

Metabolism 
and nutrition 
disorders  

Decreased 
appetite and 
food intake 

Hypo-
kalaemia 
Hypophos-
phatemia 
Hypo-
calcaemia 
Hypo-
natraemia 
Hypomag-
nesaemia 
Hyperuri-
caemia 
Dehy-
dration 

   

Nervous 
system 
disorders  

 Headache 
Tremor 
Peripheral 
neuropathy 

 Posterior 
reversible 
encephalo-
pathy 
syndrome 
(PRES) 

 

Cardiac 
disorders 

  Myocardial 
infarction 
Myocardial 
ischaemia 

  

Vascular 
disorders 

Haemorrhage* 
Hypertension 

 Hypertensive 
crisis 

 Aneurysms 
and artery 
dissections 

Respiratory, 
thoracic and 
mediastinal 
disorders 

Dysphonia     

Gastro-
intestinal 
disorders 

Diarrhoea 
Stomatitis 
Vomiting 
Nausea 

Taste 
disorders 
Dry mouth 
Gastro-
oesopha-
geal reflux 
Gastro-
enteritis 

Gastro-
intestinal 
perforation* 
Gastro-
intestinal 
fistula 
Pancreatitis 

  

Hepatobiliary 
disorders 

Hyper-
bilirubinaemia 
Increase in 
transaminases 

 Severe liver 
injury*# 

  



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System 
Organ Class 
(MedDRA) 

Very common Common Uncommon Rare Not known 

Skin and 
subcutaneous 
tissue 
disorders 

Hand-foot skin 
reaction** 
Rash 
 

Alopecia  
Dry skin 
Exfoliative 
rash 

Nail disorder 
Erythema 
multiforme 

Stevens-
Johnson 
syndrome 
Toxic 
epidermal 
necrolysis 

 

Musculo-
skeletal and 
connective 
tissue 
disorders 

 Muscle 
spasms 

   

Renal and 
urinary 
disorders 

 Proteinuria    

General 
disorders and 
administration 
site conditions 

Asthenia/ 
fatigue 
Pain  
Fever 
Mucosal 
inflammation 

    

Investigations Weight loss Increase in 
amylase 
Increase in 
lipase 
Abnormal 
Inter-
national 
normalised 
ratio 

   

*  fatal cases have been reported 
** palmar-plantar erythrodysesthesia syndrome in MedDRA terminology 
# according to drug-induced liver injury (DILI) criteria of the international DILI expert working 

group 
 
Description of selected adverse reactions 
In most cases of severe liver injury, liver dysfunction had an onset within the first 2 months of therapy, 
and was characterized by a hepatocellular pattern of injury with transaminase elevations >20xULN, 
followed by bilirubin increase. In clinical trials, a higher incidence of severe liver injury with fatal 
outcome was observed in Japanese patients (~1.5%) treated with Stivarga, compared with non-
Japanese patients (<0.1%). 

In the placebo-controlled phase III trials, the overall incidence of haemorrhage was 18.2% in patients 
treated with Stivarga and 9.5% in patients receiving placebo. Most cases of bleeding events in patients 
treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 15.2%), most notably 
epistaxis (6.1%). Fatal outcome in patients treated with Stivarga was uncommon (0.7%), and included 
cerebral, respiratory, gastrointestinal and genitourinary events. 

In the placebo-controlled phase III trials, infections were more often observed in patients treated with 
Stivarga, compared to patients receiving placebo (all grades: 31.6% vs. 17.2%). Most infections in 
patients treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 23.0%), and included 
urinary tract infections (5.7%), nasopharyngitis (4.0%), mucocutaneous and systemic fungal infections 
(3.3%) as well as pneumonia (2.6%).  Fatal outcomes associated with infection were observed more 



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often in patients treated with Stivarga (1.0%), compared to patients receiving placebo (0.3%), and 
were mainly respiratory events. 
 
In the placebo-controlled phase III trials, the overall incidence of hand-foot skin reaction was higher in 
patients treated with Stivarga, compared to patients receiving placebo (all grades: 51.4% vs. 6.5% 
CRC, 66.7% vs. 15.2% GIST and 51.6% vs.7.3% HCC). Most cases of hand-foot skin reaction in 
patients treated with Stivarga appeared during the first cycle of treatment and were mild to moderate in 
severity (Grades 1 and 2: 34.3%%, CRC, 44.7%, GIST and 39.3%, HCC). The incidence of Grade 3 
hand-foot skin reaction was 17.1% (CRC), 22.0% (GIST) and 12.3% (HCC). The overall incidence of 
hand-foot skin reaction (74.8%, CRC, 88.2%, GIST and 67.1%, HCC) was higher in Stivarga-treated 
Asian patients, compared to other ethnicities. The incidence of Grade 3 hand-foot skin reaction in 
Asians was 20.5% (CRC), 23.5% (GIST) and 13.5% (HCC) (see sections 4.2 and 4.4).  
 
In the placebo-controlled phase III trials, the overall incidence of hypertension was higher in patients 
treated with Stivarga, compared to patients receiving placebo (29.6% vs. 7.5% CRC, 60.6% vs. 25.8% 
GIST and 31.0% vs. 6.2% HCC). Most cases of hypertension in patients treated with Stivarga 
appeared during the first cycle of treatment and were mild to moderate in severity (Grades 1 and 2: 
20.9%, CRC,  31.8%, GIST and 15.8% HCC). The incidence of Grade 3 hypertension was 8.7% 
(CRC), 28.0% (GIST) and 15.2% (HCC). One case of Grade 4 hypertension was reported in the GIST 
trial. 
 
In the placebo-controlled phase III trials, the overall incidence of treatment emergent proteinuria was 
9.1% in patients treated with Stivarga, compared to 1.9% in patients receiving placebo. Of these 
events, 35.6% in the Stivarga arm and 54.5% in the placebo arm have been reported as not 
recovered/not resolved. 
Across all clinical trials, cardiac disorder events (all grades) have been more often (13.7% vs. 6.5%) 
reported in Stivarga-treated patients aged 75 years or older (N=410), compared to Stivarga-treated 
patients below 75 years (N=4108). 
 
Laboratory test abnormalities 
Treatment-emergent laboratory abnormalities observed in the placebo-controlled phase III trials are 
shown in Table 4 and Table 4a (see also section 4.4). 
 



14 

Table 4: Treatment-emergent laboratory test abnormalities reported in placebo-controlled phase III trials in patients with metastatic CRC 
(CORRECT), GIST (GRID) and HCC (RESORCE) 
 

 mCRC (CORRECT) GIST (GRID) HCC (RESORCE) 

Laboratory 
Parameter 

(in % of samples 
investigated) 

Stivarga 
plus  
BSC  

(n= 500) 

Placebo 
plus BSC 
(n=253) 

Stivarga 
plus BSC 
(n= 500) 

Placebo 
plus BSC 
(n=253) 

Stivarga 
plus  
BSC  

(n= 132) 

Placebo 
plus 
BSC 

(n= 66) 

Stivarga 
plus BSC 
(n=132) 

Placebo 
plus 
BSC 

(n= 66) 

Stivarga 
plus BSC  
(n= 374) 

Placebo 
plus BSC 
(n=193) 

Stivarga 
plus BSC 
(n= 374) 

Placebo 
plus 
BSC 

(n=193) 
Grade a Grade b Grade b 

All Grades % Grade 3/4 % All Grades % Grade 3/4 % All Grades % Grade 3/4 % 
Blood and lymphatic 
system disorders 
Haemoglobin 
decreased 
Thrombocytopenia 
Neutropenia 
Lymphopenia 

 
 

78.5 
 

40.5 
2.8 

54.1 

 
 

66.3 
 

16.8 
0 

34.8 

 
 

5.3 
 

2.8 
0.6 
9.3 

 
 

2.8 
 

0.4 
0 

4.0 

 
 

75.0 
 

12.9 
15.9 
29.9 

 
 

72.7 
 

1.5 
12.1 
24.2 

 
 

3.0 
 

0.8 
3.1 
7.6 

 
 

1.5 
 

1.5 
3.0 
3.0 

 
 

72.5 
 

63.1 
13.6 
67.8 

 
 

71.3 
 

50.0 
14.9 
58.5 

 
 

6.0 
 

5.4 
3.0 

17.4 

 
 

4.8 
 

0 
1.0 

11.7 
Metabolism and 
nutrition disorders 
Hypocalcaemia 
Hypokalemia 
Hypophosphatemia 

 
 

59.3 
25.7 
57.4 

 
 

18.3 
8.3 

11.1 

 
 

1.2 
4.3 

31.1 

 
 

1.2 
0.4 
3.6 

 
 

16.7 
20.5 
54.5 

 
 

4.5 
3.0 
3.1 

 
 

1.5 
3.0 

21.2 

 
 

0 
0 

1.5 

 
 

23.4 
30.7 
70.4 

 
 

10.1 
9.0 

31.4 

 
 

0.3 
4.3 

33.9 

 
 

0 
2.1 
6.9 

Hepatobiliary 
disorders 
Hyperbilirubinemia 
Increased AST 
Increased ALT 

 
 

44.6 
65.0 
45.2 

 
 

17.1 
45.6 
29.8 

 
 

12.2 
5.9 
5.5 

 
 

8.4 
5.2 
3.2 

 
 

33.3 
58.3 
39.4 

 
 

12.1 
47.0 
39.4 

 
 

3.8 
3.8 
4.6 

 
 

1.5 
3.0 
1.5 

 
 

78.2 
92.7 
70.4 

 
 

54.5 
84.3 
58.6 

 
 

15.9 
17.8 
6.2 

 
 

15.7 
19.9 
4.7 

Renal and urinary 
disorders 
Proteinuria 

 
 

83.6 

 
 

61.0 

 
 

1.8 

 
 

0.8 

 
 

59.2 

 
 

52.5 

 
 

3.1 

 
 

3.4 

 
 

51.0 

 
 

36.5 

 
 

16.7 

 
 

3.1 
Investigations 
Increased INR* 
Increased Lipase 
Increased Amylase 

 
23.7 
46.0 
25.5 

 
16.6 
18.7 
16.7 

 
4.2 

11.4 
2.6 

 
1.6 
4.4 
2.4 

 
9.3 

14.4 
- 

 
12.5 
4.6 
- 

 
1.6 
0.8 
- 

 
4.7 
0 
- 

 
44.4 
40.5 
23.0 

 
35.4 
27.0 
19.0 

 
0.7 

14.2 
2.8 

 
2.1 
8.7 
2.7 

a Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 
b Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0  
* International normalized ratio 
BSC = Best Supportive Care 
 



15 

 
Compared to the global phase III CRC trial (CORRECT) with predominantly (~80%) Caucasian 
patients enrolled, a higher incidence of liver enzyme increases was observed in Stivarga-treated 
patients in the Asian phase III CRC trial (CONCUR) with predominantly (> 90%) East Asian patients 
enrolled. 

 

Table 4a: Treatment emergent liver enzyme test abnormalities reported in placebo-controlled 
phase III trial in Asian patients with metastatic CRC (CONCUR) 

Laboratory parameter,  
(in % of samples 

investigated) 

Stivarga plus BSC§ 
(N=136) 

Placebo plus BSC§ 
(N=68) 

 
All 

Grades* 
 

Grade 
3* 

Grade 
4* 

All 
Grades* 

Grade 
3* 

Grade 
4* 

Bilirubin increased  66.7 7.4 4.4 32.8 4.5 0.0 
AST increased 69.6 10.4 0.7 47.8 3.0 0.0 
ALT increased 54.1 8.9 0.0 29.9 1.5 0.0 
§ Best Supportive Care 
* Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 
 
In the placebo-controlled phase III trials, tests on thyroid stimulating hormone (TSH) showed post 
baseline >ULN in 34.6% of patients treated with Stivarga and in 17.2% of patients receiving placebo. 
TSH post baseline >4 times ULN was reported in 6.5% of patients treated with Stivarga and in 1.3% 
of patients receiving placebo. Concentration of free triiodothyronine (FT3) post baseline below lower 
limit of normal (<LLN) was reported in 29.2% of patients treated with Stivarga and in 20.4% of 
patients receiving placebo. Concentration of free thyroxin (FT4) post baseline <LLN was reported in 
8.1% of patients treated with Stivarga and 5.6% of patients receiving placebo. Overall approximately 
4.6% of patients treated with Stivarga developed hypothyroidism requiring hormonal replacement 
treatment. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
The highest dose of Stivarga studied clinically was 220 mg per day. The most frequently observed 
adverse drug reactions at this dose were dermatological events, dysphonia, diarrhoea, mucosal 
inflammation, dry mouth, decreased appetite, hypertension, and fatigue.  
 
There is no specific antidote for Stivarga overdose. In the event of suspected overdose, Stivarga 
should be discontinued immediately, with best supportive care initiated by a medical professional, and 
the patient should be observed until clinical stabilisation. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor; ATC Code: L01XE21 
 

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


16 

Mechanism of action and pharmacodynamic effects 
Regorafenib is an oral tumour deactivation agent that potently blocks multiple protein kinases, 
including kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, 
RAF-1, BRAF, BRAFV600E), metastasis (VEGFR3, PDGFR, FGFR) and tumour immunity (CSF1R). 
In particular, regorafenib inhibits mutated KIT, a major oncogenic driver in gastrointestinal stromal 
tumours, and thereby blocks tumour cell proliferation. In preclinical studies regorafenib has 
demonstrated potent antitumour activity in a broad spectrum of tumour models including colorectal, 
gastrointestinal stromal and hepatocellular tumour models which is likely mediated by its 
anti-angiogenic and anti-proliferative effects. In addition, regorafenib reduced the levels of tumour 
associated macrophages and has shown anti-metastatic effects in vivo. Major human metabolites (M-2 
and M-5) exhibited similar efficacies, compared to regorafenib in in vitro and in vivo models. 
 
Clinical efficacy and safety 

Metastatic colorectal cancer (CRC) 

The clinical efficacy and safety of Stivarga have been evaluated in an international, multi-centre, 
randomised, double-blind, placebo-controlled phase III study (CORRECT) in patients with metastatic 
colorectal cancer who have progressed after failure of standard therapy. 
 
The primary efficacy endpoint was Overall Survival (OS). Secondary endpoints were Progression-Free 
Survival (PFS), Objective Tumour Response Rate (ORR) and Disease Control Rate (DCR).  
 
In total, 760 patients were randomised 2:1 to receive 160 mg regorafenib (4 tablets Stivarga each 
containing 40 mg regorafenib) orally once daily (N=505) plus Best Supportive Care (BSC or matching 
placebo (N=255) plus BSC for 3 weeks on therapy followed by 1 week off therapy. The mean daily 
regorafenib dose received was 147 mg. 
 
Patients continued therapy until disease progression or unacceptable toxicity. A pre-planned interim 
analysis for efficacy was performed when 432 deaths had occurred. The study was un-blinded after 
this planned interim analysis of OS had crossed the pre-specified efficacy boundary.  
 
Of the 760 randomised patients, the median age was 61 years, 61% were male, 78% were Caucasian, 
and all patients had baseline ECOG Performance Status (PS of 0 or 1. PS ≥2 was reported during 
Stivarga treatment in 11.4% of patients. The median treatment duration and daily dose, as well as the 
rate of dose modification and dose reduction were similar to those observed in patients with a reported 
PS ≥ 2 receiving placebo (8.3%). The majority of patients with PS ≥2 discontinued treatment for 
progressive disease. The primary site of disease was colon (65%), rectum (29%), or both (6%). A 
KRAS mutation was reported in 57% of patients at study entry. 
 
Most patients (52%) received 3 or fewer previous lines of treatment for metastatic disease. Therapies 
included treatment with fluoropyrimidine-based chemotherapy, an anti-VEGF therapy, and, if the 
patient was KRAS wild type, an anti-EGFR therapy. 
 
The addition of Stivarga to BSC resulted in significantly longer survival, compared to placebo plus 
BSC with a p value of 0.005178 from stratified log rank test, a hazard ratio of 0.774 [95% CI 0.636, 
0.942] ) and a median OS of 6.4 months vs. 5.0 months (see Table 5 and Figure 1). PFS was 
significantly longer in patients receiving Stivarga plus BSC (hazard ratio: 0.494, p<0.000001, see 
Table 5). The response rate (complete response or partial response) was 1% and 0.4% for Stivarga and 
placebo treated patients, respectively (p=0.188432, 1-sided). The DCR (complete response or partial 
response or stable disease) was significantly higher in patients treated with Stivarga (41.0% vs. 14.9%, 
p<0.000001, 1 sided). 
 
 
 



17 

Table 5: Efficacy results from the CORRECT study 

Efficacy 
parameter 

Hazard ratio* 
(95% CI) 

P-value 
(one-sided) 

Median (95% CI) 

Stivarga plus BSC§ 
(N=505) 

Placebo plus BSC§ 
(N=255) 

OS  
  

0.774  
(0.636, 0.942) 

0.005178 6.4 months 
(5.9, 7.3) 

5.0 months 
(4.4, 5.8) 

PFS** 0.494  
(0.419, 0.582) 

<0.000001 1.9 months 
(1.9, 2.1) 

1.7 months 
(1.7, 1.7) 

§ BSC Supportive Care 
* Hazard ratio < 1 favours Stivarga 
** based on investigator’s assessment of tumour response 
 
Figure 1: Kaplan-Meier curve of OS  

 
 
Subgroup analyses for OS and PFS according to age (<65; ≥65), gender, ECOG PS, primary site of 
disease, time from first diagnosis of metastatic disease, prior anticancer treatment, prior treatment lines 
for metastatic disease, and KRAS mutation status showed a treatment effect favouring the regorafenib 
regimen over the placebo regimen. 
 
Subgroup analysis results by historical KRAS mutational status showed a treatment effect for OS in 
favour of regorafenib over placebo for patients with KRAS wild-type tumours whereas a numerically 
lower effect was reported in patients with KRAS mutant tumours; the treatment effect for PFS 
favouring regorafenib was observed regardless of KRAS mutational status. The hazard ratio (95% CI) 
of OS was 0.653 (0.476 to 0.895) for patients with KRAS wild-type tumours and 0.867 (0.670 to 
1.123) for patients with KRAS mutant tumours, with no evidence of heterogeneity in treatment effect 
(non-significant interaction test). The hazard ratio (95% CI) of PFS was 0.475 (0.362 to 0.623) for 
patients with KRAS wild-type tumours and 0.525 (0.425 to 0.649) for patients with KRAS mutant 
tumours. 
 
A second phase III, international, multi-centre, randomised, double blind, placebo-controlled study 
(CONCUR) evaluated the efficacy and safety of Stivarga in 204 pre-treated Asian patients (> 90% 
East Asian) with metastatic colorectal cancer who have progressed after failure of fluoropyrimidine-
based chemotherapy. Only 59.5 % of patients enrolled in the CONCUR study were also previously 



18 

treated with VEGF- or EGFR-targeted agents. The primary efficacy endpoint was OS. The addition of 
Stivarga to BSC resulted in a significantly longer survival, compared to placebo plus BSC with a 
hazard ratio of 0.550 (p = 0.000159 stratified log rank test) and a median OS of 8.8 months vs. 6.3 
months [95% CI 0.395, 0.765]. PFS was also significantly longer in patients receiving Stivarga plus 
BSC (hazard ratio: 0.311, p<0.000001), median PFS 3.2 months with Stivarga vs. 1.7 months with 
placebo. The safety profile of Stivarga plus BSC in the CONCUR study was consistent with the safety 
profile observed in the CORRECT study.  
 
Gastrointestinal stromal tumours (GIST) 

The clinical efficacy and safety of Stivarga have been evaluated in an international, multi-centre, 
randomised, double-blind, placebo-controlled phase III study (GRID) in patients with gastrointestinal 
stromal tumours (GIST) previously treated with 2 tyrosine kinase inhibitors (imatinib and sunitinib).  

The analysis of the primary efficacy endpoint Progression-Free Survival (PFS) was conducted after 
144 PFS events (central blinded assessment). Secondary endpoints including Time To Progression 
(TTP) and Overall Survival (OS (interim analysis) were also assessed.  

In total, 199 patients with GIST were randomised 2:1 to receive either 160 mg regorafenib plus Best 
Supportive Care (BSC) (N=133) orally once daily or matching placebo plus BSC (N=66) for 3 weeks 
on therapy followed by 1 week off therapy. The mean daily regorafenib dose received was 140 mg.  

Patients continued therapy until disease progression or unacceptable toxicity. Patients receiving 
placebo who experienced disease progression were offered open-label regorafenib (cross-over option). 
Patients receiving regorafenib who experienced disease progression and for whom in the investigator’s 
opinion, treatment with regorafenib was providing clinical benefit, were offered the opportunity to 
continue open-label regorafenib. 

Of the 199 randomised patients, the mean age was 58 years, 64% were male, 68% were Caucasian, 
and all patients had baseline ECOG Performance Status (PS of 0 or 1. The overall median time since 
most recent progression or relapse to randomisation was 6 weeks.  

Regorafenib plus BSC resulted in significantly longer PFS, compared to placebo plus BSC with a 
hazard ratio of 0.268 [95% CI 0.185, 0.388] and a median PFS of 4.8 months vs. 0.9 months (p < 
0.000001). The relative risk of disease progression or death was reduced by approximately 73.2% in 
regorafenib-treated patients, compared to placebo treated patients (see Table 6, Figure 2).The increase 
in PFS was consistent independent of age, sex, geographic region, prior lines of treatment, ECOG PS.  

TTP was significantly longer in patients receiving regorafenib plus BSC than in patients receiving 
placebo plus BSC with a hazard ratio of 0.248 [95% CI 0.170, 0.364], and median TTP of 5.4 months 
vs. 0.9 months (p<0.000001) (see Table 6). 
 
The HR for OS was 0.772 (95% CI, 0.423, 1.408; p = 0.199; median OS not reached in either arm); 
85% of patients initially randomised to the placebo arm received post-progression treatment with 
regorafenib (see Table 6, Figure 3). 



19 

 
Table 6: Efficacy results from the GRID study 

Efficacy 
parameter 

Hazard ratio* 
(95% CI) 

P-value 
(one-sided) 

Median (95% CI) 

Stivarga plus 
BSC§ 

(N=133) 

Placebo plus 
BSC§ 

(N=66) 
PFS  0.268  

(0.185, 0.388)  
<0.000001 4.8 months 

(4.0, 5.7) 
0.9  months 
(0.9, 1.1) 

TTP 0.248 
(0.170,0.364) 

<0.000001 5.4 months 
(4.1, 5.7) 

0.9  months 
(0.9, 1.1) 

OS 0.772  
(0.423, 1.408) 

0.199 NR** NR** 

§ Best Supportive Care 
* Hazard ratio < 1 favours Stivarga 
** NR: not reached 
 
 
Figure 2: Kaplan-Meier curves of PFS 

 
 



20 

 

Figure 3: Kaplan-Meier curves of OS 

 

 
 
In addition, 56 placebo plus BSC patients received open-label Stivarga after cross-over following 
disease progression and a total of 41 Stivarga plus BSC patients continued Stivarga treatment after 
disease progression. The median secondary PFS (as measured by the investigator’s assessment) were 
5.0 and 4.5 months, respectively. 
 
Hepatocellular carcinoma (HCC) 

The clinical efficacy and safety of Stivarga have been evaluated in an international, multi-centre, 
randomised, double-blind, placebo-controlled phase III study (RESORCE) in patients with 
hepatocellular carcinoma who have been previously treated with sorafenib. 
 
The primary efficacy endpoint was Overall Survival (OS). Secondary endpoints were Progression-Free 
Survival (PFS), Time To Progression (TTP), Objective Tumour Response Rate (ORR) and Disease 
Control Rate (DCR). 
 
In total, 573 patients with HCC were randomised 2:1 to receive either 160 mg regorafenib orally once 
daily (n=379) plus Best Supportive Care (BSC) or matching placebo (n=194) plus BSC for 3 weeks on 
therapy followed by 1 week off therapy. The mean daily regorafenib dose received was 144 mg. 
Patients were eligible to participate in the study if they experienced radiological disease progression 
during treatment with sorafenib and if they had a liver function status of Child-Pugh class A. Patients 
who permanently discontinued sorafenib therapy due to sorafenib-related toxicity or who tolerated less 
than 400 mg sorafenib once daily prior to withdrawal were excluded from the study. Randomisation 
was performed within 10 weeks after the last treatment with sorafenib. Patients continued therapy with 
Stivarga until clinical or radiological disease progression or unacceptable toxicity. However, patients 
could continue Stivarga therapy past progression at the discretion of the investigator. 
 



21 

Demographics and baseline disease characteristics were comparable between the Stivarga- and 
placebo-treated groups and are shown below for all 573 randomised patients: 
• Median age: 63 years 
• Male: 88% 
• Caucasian: 36%, Asian: 41% 
• ECOG Performance Status (PS) of 0: 66% or ECOG PS of 1: 34% 
• Child-Pugh A: 98%, Child-Pugh B: 2% 
• Aetiology included Hepatitis B (38%), Hepatitis C (21%), Non-Alcoholic Steato Hepatitis 

(NASH, 7%) 
• Absence of both macroscopic vascular invasion and extra-hepatic tumour spread: 19%  
• Barcelona Clinic Liver Cancer (BCLC) stage B: 13%; BCLC stage C: 87% 
• Loco-regional transarterial embolisation or chemoinfusion procedures: 61% 
• Radiotherapy prior to regorafenib treatment: 15% 
• Median duration of sorafenib treatment: 7.8 months  
 
The addition of Stivarga to BSC resulted in a statistically significant improvement in OS compared to 
placebo plus BSC with a hazard ratio of 0.624 [95% CI 0.498, 0.782], p=0.000017 stratified log rank 
test, and a median OS of 10.6 months vs. 7.8 months (see Table 7 and Figure 4). 
 
 
Table 7: Efficacy results from the RESORCE study 
 

Efficacy 
parameter 

Hazard ratio* 
(95% CI) 

P-value 
(one-sided) 

Median (95% CI) 

Stivarga plus BSC§ 
(N=379) 

Placebo plus BSC§ 
(N=194) 

OS  
 

0.624 
(0.498,0.782) 

0.000017 10.6 months 
(9.1, 12.1) 

7.8 months 
(6.3, 8.8) 

PFS** 0.453  
(0.369, 0.555) 

<0.000001 3.1 months 
(2.8, 4.2) 

1.5 months 
(1.4, 1.6) 

TTP** 0.439 
(0.355,0.542) 

<0.000001 3.2 months 
(2.9, 4.2) 

1.5 months 
(1.4, 1.6) 

   Percentages 
 

ORR**# NA 0.003650 11% 4% 
DCR **# NA <0.000001 65% 36% 
§   Best Supportive Care 
*   Hazard ratio < 1 favours Stivarga  
**  based on investigator’s assessment of tumour response by modified RECIST 
# Response rate (complete or partial response), DCR  (complete response,  partial response and 
stable disease maintained for 6 weeks) 



22 

 
Figure 4: Kaplan-Meier curve of OS  

 

 
 
 



23 

Figure 5: Kaplan-Meier curve of PFS (mRECIST) 
 

 
 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Stivarga in all subsets of the paediatric population in the treatment of adenocarcinoma of the colon and 
rectum (see section 4.2 for information on paediatric use). 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Stivarga in one or more subsets of the paediatric population in the treatment of solid malignant 
tumours (see section 4.2 for information on paediatric use). 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Stivarga in all subsets of the paediatric population in the treatment of hepatocellular carcinoma (see 
section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption  
Regorafenib reaches mean peak plasma levels of about 2.5 mg/l at about 3 to 4 hours after a single oral 
dose of 160 mg given as 4 tablets each containing 40 mg. Following single doses of 60 mg or 100 mg, 
the average relative bioavailability of tablets compared to an oral solution was 69% and 83%, 
respectively. 
 
The concentrations of regorafenib and its major pharmacologically active metabolites (M-2 and M-5) 
were highest when given after a low-fat (light) breakfast, compared to either a high-fat breakfast or 
fasting condition. The exposure for regorafenib was increased by 48% when administered with a 
high-fat breakfast, and 36% when administered with a low fat breakfast, compared to fasting. The 
exposure of metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) is higher when 
regorafenib is given with a low fat breakfast, compared to fasting condition and lower when given 
with a high fat meal, compared to fasting condition. 
 



24 

Distribution 
Plasma concentration-time profiles for regorafenib as well as for the major circulating metabolites 
showed multiple peaks across the 24-hour dosing interval, which are attributed to enterohepatic 
circulation. In vitro protein binding of regorafenib to human plasma proteins is high (99.5%). In vitro 
protein binding of M-2 and M-5 is higher (99.8% and 99.95%, respectively) than that of regorafenib. 
Metabolites M-2 and M-5 are weak substrates of P-gp. Metabolite M-5 is a weak BCRP-substrate. 
 
Biotransformation 
Regorafenib is metabolized primarily in the liver by oxidative metabolism mediated by CYP3A4, as 
well as by glucuronidation mediated by UGT1A9. Two major and six minor metabolites of 
regorafenib have been identified in plasma. The main circulating metabolites of regorafenib in human 
plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), which are pharmacologically active 
and have similar concentrations as regorafenib at steady state. M-2 is further metabolised by oxidative 
metabolism mediated by CYP3A4, as well as by glucuronidation mediated by UGT1A9. 
 
Metabolites may be reduced or hydrolysed in the gastrointestinal tract by microbial flora, allowing 
reabsorption of the unconjugated active substance and metabolites (enterohepatic circulation). 
 
Elimination 
Following oral administration, mean elimination half-life for regorafenib and its metabolite M-2 in 
plasma ranges from 20 to 30 hours in different studies. The mean elimination half-life for the 
metabolite M-5 is approximately 60 hours (range from 40 to 100 hours).  
Approximately 90% of the radioactive dose was recovered within 12 days after administration, with 
about 71% of the dose excreted in faeces (47% as parent compound, 24% as metabolites), and about 
19% of the dose excreted in urine as glucuronides. Urinary excretion of glucuronides decreased below 
10% under steady-state conditions. Parent compound found in faeces could be derived from intestinal 
degradation of glucuronides or reduction of metabolite M-2 (N-oxide), as well as unabsorbed 
regorafenib. 
M-5 may be reduced to M-4 in the gastrointestinal tract by microbial flora, allowing reabsorption of 
M-4 (enterohepatic circulation). M-5 is finally excreted via M-4 as M-6 (carboxylic acid) in faeces. 
 
Linearity/non-linearity 
Systemic exposure of regorafenib at steady-state increases dose proportionally up to 60 mg and less 
than proportionally at doses greater than 60 mg. Accumulation of regorafenib at steady state results in 
about a 2-fold increase in plasma concentrations, which is consistent with the elimination half-life and 
dosing frequency. At steady state, regorafenib reaches mean peak plasma levels of about 3.9 mg/L 
(8.1 micromolar) after oral administration of 160 mg regorafenib and the peak-to-trough ratio of mean 
plasma concentrations is less than 2. 
Both metabolites, M-2 and M-5, exhibit non-linear accumulation, which might be caused by entero-
hepatic recycling or saturation of the UGT1A9 pathway. Whereas plasma concentrations of M-2 and 
M-5 after a single dose of regorafenib are much lower than those of parent compound, steady-state 
plasma concentrations of M-2 and M-5 are comparable to those of regorafenib. 
 
Hepatic impairment 
The exposure of regorafenib and its metabolites M-2 and M-5 is comparable in patients with mild 
hepatic impairment (Child-Pugh A) and patients with normal hepatic function. 
Limited data in patients with moderate hepatic impairment (Child-Pugh B) indicate similar exposure, 
compared to patients with normal hepatic function after a single 100 mg dose of regorafenib. There are 
no data for patients with Child-Pugh C (severe) hepatic impairment. Regorafenib is mainly eliminated 
via the liver, and exposure might be increased in this patient population. 
 
Renal impairment 
Available clinical data and physiology-based pharmacokinetic modelling indicate similar steady-state 
exposure of regorafenib and its metabolites M-2 and M-5 in patients with mild or moderate renal 



25 

impairment, compared to patients with normal renal function. In patients with severe renal impairment 
compared to patients with normal renal function, regorafenib exposure was similar while exposure to 
M-2 and M-5 was decreased by about 30% under steady-state conditions, which is not considered 
clinically relevant. 
The pharmacokinetics of regorafenib has not been studied in patients with end-stage renal disease. 
However, physiology-based pharmacokinetic modelling does not predict any relevant change in 
exposure in these patients. 
 
Elderly 
Age did not affect the regorafenib pharmacokinetics over the studied age range (29 – 85 years). 
 
Gender 
The pharmacokinetics of regorafenib is not influenced by gender. 
 
Ethnic differences 
The exposure of regorafenib in various Asian populations (Chinese, Japanese, Korean) is within the 
same range as seen in Caucasians. 
 
Cardiac electrophysiology/QT prolongation 
No QTc prolonging effects were observed after administration of 160 mg regorafenib at steady state in 
a dedicated QT study in male and female cancer patients. 
 
5.3 Preclinical safety data 
 
Systemic toxicity 
After repeated dosing to mice, rats and dogs, adverse effects were observed in a number of organs, 
primarily in the kidneys, liver, digestive tract, thyroid gland, lympho-/haematopoietic system, 
endocrine system, reproductive system and skin. A slightly increased incidence of thickening of the 
atrioventricular valves of the heart was seen in the 26 week repeat-dose toxicity study in rats. This 
may be due to acceleration of an age-related physiological process. These effects occurred at systemic 
exposures in the range of or below the anticipated human exposure (based on AUC comparison).  
Alterations of teeth and bones and adverse effects in the reproductive system were more pronounced in 
young and growing animals as well as in juvenile rats and indicate a potential risk for children and 
adolescents. 
 
Reproductive and developmental toxicity 
Specific studies on fertility have not been performed. However, a potential of regorafenib to adversely 
affect male and female reproduction has to be considered based on morphological changes in the 
testes, ovaries, and the uterus observed after repeated dosing in rats and dogs at exposures below the 
anticipated human exposure (based on AUC comparison). The observed changes were only partially 
reversible. 
 
An effect of regorafenib on intrauterine development was shown in rabbits at exposures below the 
anticipated human exposure (based on AUC comparison). Main findings consisted of malformations 
of the urinary system, the heart and major vessels, and the skeleton. 
 
Genotoxicity and carcinogenicity 
There was no indication for a genotoxic potential of regorafenib tested in standard assays in vitro and 
in vivo in mice. 
 
Studies on the carcinogenic potential of regorafenib have not been performed. 
 



26 

Environmental risk assessment (ERA) 
Environmental risk assessment studies have shown that regorafenib has the potential to be persistent, 
bioaccumulative and toxic to the environment and may pose a risk to the surface water and to the 
sediment compartment (see section 6.6). 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Cellulose microcrystalline  
Croscarmellose sodium  
Magnesium stearate  
Povidone (K-25) 
Silica, colloidal anhydrous 
 
Film coat 
Iron oxide red (E172) 
Iron oxide yellow (E172) 
Lecithin (derived from soya) 
Macrogol 3350 
Polyvinyl alcohol, partially hydrolysed 
Talc 
Titanium dioxide (E171) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
Once the bottle is opened the medicinal product has shown to be stable for 7 weeks. Thereafter, the 
medicinal product is to be discarded. 
 
6.4 Special precautions for storage 
 
Store in the original package in order to protect from moisture. 
Keep the bottle tightly closed. 
 
6.5 Nature and contents of container  
 
White opaque HDPE bottle closed with a PP/PP (polypropylene) screw cap with sealing insert and a 
molecular sieve desiccant. 
 
Each bottle contains 28 film-coated tablets.  
 
Pack sizes 
Pack of 28 film-coated tablets. 
Pack of 84 (3 bottles of 28) film-coated tablets. 
 
Not all pack sizes may be marketed. 



27 

 
6.6 Special precautions for disposal and other handling 
 
Keep the desiccant in the bottle. 
 
This medicinal product may pose a risk to the environment (see section 5.3).  
 
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(S) 
 
EU/1/13/858/001 
EU/1/13/858/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 26 August 2013 
Date of latest renewal: 22 May 2018 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 
. 
 

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


28 

 

 

 

 

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. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 



29 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Bayer AG 
Kaiser-Wilhelm-Allee 
51368 Leverkusen 
Germany 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal products 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.  



30 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 



31 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
A. LABELLING 

 



32 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Stivarga 40 mg film-coated tablets 
regorafenib  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 40 mg of regorafenib. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains sodium and lecithin (derived from soya), see leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 film-coated tablets 
84 (3 x 28) film-coated tablets 
 
 
5. METHOD AND ROUTE(S) 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 
 
Keep the desiccant in the bottle. 
 
  
8. EXPIRY DATE 
 
EXP 
 
 



33 

9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture. Keep the bottle tightly closed. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/858/001 
EU/1/13/858/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
stivarga 40 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



34 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Stivarga 40 mg film-coated tablets 
regorafenib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 40 mg of regorafenib. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains sodium and lecithin (derived from soya). 
Read the package leaflet before use. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) 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 
 
Keep the desiccant in the bottle.  
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture. Keep the bottle tightly closed.  



35 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/858/001 
EU/1/13/858/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 



36 

 
 
 
 
 
 

 

 
 
 
 
 

 

 
 
 
 
 

 

 
B. PACKAGE LEAFLET 

 



37 

Package Leaflet: Information for the user 
 

Stivarga 40 mg film-coated tablets 
regorafenib 

 
 
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 Stivarga is and what it is used for 
2. What you need to know before you take Stivarga 
3. How to take Stivarga 
4. Possible side effects 
5. How to store Stivarga 
6. Contents of the pack and other information 
 
 
1. What Stivarga is and what it is used for 
 
Stivarga contains the active substance regorafenib. It is a medicine used to treat cancer by slowing 
down the growth and spread of cancer cells and cutting off the blood supply that keeps cancer cells 
growing. 
 

Stivarga is used to treat:  
- colon or rectal cancer that has spread to other parts of the body in adult patients who have received 

other treatments or cannot be treated with other medicines (fluoropyrimidine-based chemotherapy, 
an anti-VEGF therapy and an anti-EGFR therapy) 

- gastrointestinal stromal tumours (GIST), a type of cancer of the stomach and bowel, that has 
spread to other parts of the body or is not amenable to surgery, in adult patients who have been 
previously treated with other anticancer medicines (imatinib and sunitinib) 

- liver cancer in adult patients who have been previously treated with another anticancer medicine 
(sorafenib). 
 

If you have any questions about how Stivarga works or why this medicine has been prescribed for you, 
please ask your doctor. 
 
 
2. What you need to know before you take Stivarga 
 
Do not take Stivarga  
- if you are allergic to regorafenib or any of the other ingredients of this medicine (listed in 

section 6). 
 



38 

Warnings and precautions 
 
Talk to your doctor or pharmacist before taking Stivarga. 
 
Take special care with Stivarga  

- if you have any liver problems including Gilbert’s syndrome with signs such as: yellowish 
discolouration of the skin and the whites of the eyes, dark urine and confusion and/or 
disorientation. Treatment with Stivarga may lead to a higher risk of liver problems. Prior to 
and during treatment with Stivarga, your doctor will do blood tests to monitor your liver 
function. If your liver function is severely impaired, you should not be treated with Stivarga, 
as there are no data on the use of Stivarga in patients with a severely impaired liver function. 
 

- if you get an infection with signs such as high fever, severe cough with or without an increase 
in mucus (sputum) production, severe sore throat, shortness of breath, burning/pain when 
urinating, unusual vaginal discharge or irritation, redness, swelling and/or pain in any part of 
the body. Your doctor may temporarily stop your treatment. 
 

- if you had or have any bleeding problems and if you are taking warfarin, phenprocoumon or 
another medicine that thins the blood to prevent blood clots. Treatment with Stivarga may lead 
to a higher risk of bleeding. Before you start taking Stivarga your doctor may decide to do 
blood tests. Stivarga can cause severe bleeding in the digestive system such as stomach, throat, 
rectum or intestine, or in the lungs, kidneys, mouth, vagina and/or brain. Get medical help 
immediately, if you get the following symptoms: passing blood in the stools or passing black 
stools, passing blood in the urine, stomach pain, coughing/vomiting up blood. 
 

- if you get severe stomach and bowel problems (gastrointestinal perforation or fistula), your 
doctor should decide to discontinue treatment with Stivarga. Get medical help immediately, if 
you get the following symptoms: severe stomach pain or stomach pain that does not go away, 
vomiting blood, red or black stools. 
 

- if you get chest pain or have any heart problems. Before you start taking Stivarga and 
during treatment your doctor will check how well your heart is working. Get medical help 
immediately if you get the following symptoms, as they may be signs of a heart attack or 
decreased blood flow to the heart: chest discomfort or pain which may spread beyond your 
chest to your shoulders, arms, back, neck, teeth, jaw or stomach and may come and go; 
shortness of breath; sudden outbreak into a sweat with cold, clammy skin, feeling dizzy or 
fainting. 
 

- if you develop a severe and persistent headache, visual disturbances, seizures or altered 
mental status (such as confusion, memory loss or loss of orientation) please contact your 
doctor immediately. 
 

- if you have high blood pressure Stivarga can raise your blood pressure. Your doctor will 
monitor your blood pressure prior to and during treatment and may give you a medicine to 
treat 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 recently had, or are going to have, a surgical procedure Stivarga might affect the 
way your wounds heal and treatment may need to be stopped until your wound have healed. 
 

- if you experience skin problems Stivarga can cause redness, pain, swelling, or blisters on the 
palms of your hands or soles of your feet. If you notice any changes contact your doctor. To 



39 

manage your symptoms, your doctor may recommend the use of creams and/or the use of shoe 
cushions and gloves. If you get this side effect, your doctor may change your dose or stop your 
treatment until your condition improves. 

 
Before you take Stivarga tell your doctor if any of these conditions apply to you. You may need 
treatment for them and extra tests may be done (see also section 4 ‘Possible side effects’). 
 
Children and adolescents 
There is no relevant use of Stivarga in children and adolescents in the indication of colon or rectal 
cancer that has spread to other parts of the body. 
The safety and efficacy of Stivarga in children and adolescents in the indication of gastrointestinal 
stromal tumours (GIST) have not been established. No data are available. 
There is no relevant use of Stivarga in children and adolescents in the indication of liver cancer. 
 
Other medicines and Stivarga 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This includes medicines obtained without a prescription or even over-the-counter 
medicines, such as vitamins, dietary supplements or herbal medicines. Some medicines may affect the 
way Stivarga works or Stivarga may affect how other medicines work and cause serious side effects. 
In particular, tell your doctor if you are taking anything in this list or any other medicines: 
- some medicines to treat fungal infections (e.g. ketoconazole, itraconazole, posaconazole and 

voriconazole) 
- some medicines to treat pain (e.g. mefenamic acid, diflunisal, and niflumic acid) 
- some medicines to treat bacterial infections (e.g. rifampicin, clarithromycin, telithromycin) 
- medicines typically used to treat epilepsy (seizures) (e.g. phenytoin, carbamazepine or 

phenobarbital) 
- methotrexate, a medicine typically used to treat cancer 
- rosuvastatin, fluvastatin, atorvastatin, medicines typically used to treat high cholesterol  
- warfarin or phenprocoumon, medicines typically used to thin your blood 
- St. John’s wort (medicine obtained also without a prescription), a herbal treatment for depression.  
 
Ask your doctor or pharmacist for advice before taking any medicine. 
 
Taking Stivarga with food and drink 
Avoid drinking grapefruit juice while taking Stivarga. This can affect the way Stivarga works. 
 
Pregnancy, breast-feeding and fertility 
Tell your doctor if you think you are pregnant, may be pregnant or plan on becoming pregnant 
as Stivarga should not be used during pregnancy unless clearly necessary. Your doctor will discuss 
with you the potential risks of taking Stivarga during pregnancy. 
 
Avoid becoming pregnant while being treated with Stivarga, as this medicine may harm your 
unborn baby. 
 
Both women of childbearing potential and men should use effective contraception during treatment 
and for at least eight weeks after completion of treatment. 
 
You must not breast-feed your baby during Stivarga treatment, as this medicine may interfere 
with the growth and development of your baby. Tell your doctor if you are breast-feeding or 
planning to breast-feed. 
 
Stivarga may reduce fertility in both men and women. Ask your doctor for advice before taking 
Stivarga. 



40 

 
Driving and using machines 
It is not known whether Stivarga alters the ability to drive or use machines. Do not drive or use any 
tools or machines if you experience treatment-related symptoms that affect your ability to concentrate 
and react. 
 
Important information about some of the ingredients of Stivarga 
This medicine contains 55.8 mg sodium (main component of cooking/table salt) in each daily dose 
(4 tablets). This is equivalent to 3% of the recommended maximum daily dietary intake of sodium for 
an adult. 
 
This medicine contains 1.68 mg of lecithin (derived from soya) per daily dose (4 tablets). 
 
 
3. How to take Stivarga 
 
Always take this medicine exactly as your doctor has told you to. Check with your doctor or 
pharmacist if you are not sure. 
 
The recommended daily dose in adults is 4 tablets of Stivarga 40 mg (160 mg regorafenib). Your 
doctor may change your dose. Take the dose of Stivarga that your doctor prescribes for you. 
Your doctor will usually ask you to take Stivarga for 3 weeks and then to stop for 1 week. This is 
1 cycle of treatment.  
 
Take Stivarga at the same time each day after a light (low-fat) meal. Swallow the tablet whole with 
water after a light meal that contains less than 30% fat. An example of a light (low-fat) meal would 
include 1 portion of cereal (about 30 g), 1 glass of skimmed milk, 1 slice of toast with jam, 1 glass of 
apple juice, and 1 cup of coffee or tea (520 calories, 2 g fat). You should not take Stivarga together 
with grapefruit juice (see also section ‘Taking Stivarga with food and drink’). 
 
In case of vomiting after regorafenib administration, you should not take additional tablets and you 
should inform your doctor. 
 
Your doctor may need to reduce your dose or may decide to interrupt or discontinue the treatment 
permanently if necessary. You will usually take Stivarga as long as you are benefiting and not 
suffering unacceptable side effects. 
 
No dosage adjustment is necessary if you have a mildly impaired liver function. If you have a mildly 
or moderately impaired liver function while you are being treated with Stivarga, your doctor should 
monitor you closely. If your liver function is severely impaired, you should not be treated with 
Stivarga, as there are no data on the use of Stivarga in patients with a severely impaired liver function. 
 
No dosage adjustment is necessary if you have a mildly, moderately or severely impaired kidney 
function.  
 
If you take more Stivarga than you should 
Tell your doctor immediately if you have taken more than your prescribed dose. You may require 
medical attention and your doctor may tell you to stop taking Stivarga. 
 
Taking too much Stivarga may make some side effects more likely or more severe, especially: 
- skin reactions (rash, blisters, redness, pain, swelling, itching or peeling of your skin) 
- voice changes or hoarseness (dysphonia) 
- frequent or loose bowel movements (diarrhoea) 
- mouth sores (mucosal inflammation) 



41 

- dry mouth 
- decreased appetite 
- high blood pressure (hypertension) 
- excessive tiredness (fatigue). 
 
If you forget to take Stivarga 
If you miss a dose, take it as soon as you remember on that day. Do not take two doses of Stivarga on 
the same day to make up for a missed dose from the previous day. Tell your doctor about any missed 
dose. 
 
 
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.  
 
The most serious side effects, for which a fatal outcome has been observed, are: 
- Severe liver problems, bleeding, gastrointestinal perforation and infection. 
 
Tell your doctor immediately if you have any of the following symptoms: 
 
Liver problems 
Treatment with Stivarga may lead to a higher risk of severe liver problems. Get medical help 
immediately if you get the following symptoms: 
- yellowish discolouration of the skin and the whites of the eyes 
- dark urine 
- confusion and/or disorientation. 
These may be signs of severe liver injury. 
 
Bleeding 
Stivarga can cause severe bleeding in the digestive system such as stomach, throat, rectum or intestine, 
or in the lungs, kidneys, mouth, vagina and/or brain. Get medical help immediately, if you get the 
following symptoms: 
- passing blood in the stools or passing black stools 
- passing blood in the urine 
- stomach pain 
- coughing/vomiting up blood. 
These may be signs of bleeding. 
 
Severe stomach and bowel problems (gastrointestinal perforation or fistula) 
Get medical help immediately, if you get the following symptoms:  
- severe stomach (abdominal) pain or stomach pain that does not go away  
- vomiting blood  
- red or black stools. 
These may be signs of severe stomach or bowel problems. 
 
Infection 
Treatment with Stivarga may lead to a higher risk of infections, especially of the urinary tract, nose, 
throat and lung. Treatment with Stivarga may also lead to a higher risk of fungal infections of the 
mucous membrane, skin or the body. Get medical help immediately if you get the following 
symptoms:  
- high fever 
- severe cough with or without an increase in mucus (sputum) production  
- severe sore throat 



42 

- shortness of breath 
- burning/pain when urinating 
- unusual vaginal discharge or irritation  
- redness, swelling and/or pain in any part of the body. 
These may be signs of an infection. 
Other side effects with Stivarga listed by frequency: 

 
Very common side effects (may affect more than 1 in 10 users) 
 

- reduction in the number of blood platelets, characterised by easy bruising or bleeding 
(thrombocytopenia) 

- reduction in the number of red blood cells (anaemia) 
- decreased appetite and food intake 
- high blood pressure (hypertension) 
- voice changes or hoarseness (dysphonia) 
- frequent or loose bowel movements (diarrhoea) 
- painful or dry mouth, painful tongue, mouth sores (stomatitis and/or mucosal inflammation) 
- feeling sick (nausea) 
- vomiting 
- high blood levels of bilirubin, a substance produced by the liver (hyperbilirubinaemia)  
- changes in enzymes produced by the liver, which may indicate that something is wrong with 

the liver (increase in transaminases) 
- redness, pain, blisters and swelling of the palms of the hands or soles of the feet (hand-foot 

skin reaction) 
- rash 
- weakness, lack of strength and energy, excessive tiredness and unusual sleepiness 

(asthenia/fatigue) 
- pain 
- fever 
- weight loss. 

 
Common side effects (may affect up to 1 in 10 users)  
 

- reduction in the number of white blood cells (leucopenia) 
- decreased activity of the thyroid gland (hypothyroidism) 
- low levels of potassium, phosphate, calcium, sodium or magnesium in your blood 

(hypokalaemia, hypophosphatemia, hypocalcaemia, hyponatraemia and hypomagnesaemia) 
- high level of uric acid in the blood (hyperuricaemia)  
- loss of body fluids (dehydration)  
- headache 
- shaking (tremor)  
- disorder of the nerves which can cause a change in sensation, such as numbness, tingling, 

weakness or pain (peripheral neuropathy) 
- taste disorders 
- dry mouth 
- heartburn (gastro-oesophageal reflux) 
- infection or irritation of the stomach and intestines (gastroenteritis)  
- hair loss (alopecia) 
- dry skin 
- rash with flaking or peeling of skin (exfoliative rash) 
- a sudden, involuntary contraction of a muscle (muscle spasms) 
- protein in the urine (proteinuria)  
- high levels of certain enzymes involved in digestion (increase in amylase and lipase) 
- abnormal blood clotting condition (abnormal International Normalized Ratio). 



43 

 
Uncommon side effects (may affect up to 1 in 100 users)  
 

- signs/symptoms of an allergic reaction which may include widespread severe rash, feeling 
sick, fever, breathlessness, jaundice, changes in chemicals produced by the liver 
(hypersensitivity reaction) 

- heart attack, chest pain (myocardial infarction and ischaemia) 
- severely elevated blood pressure causing headache, confusion, blurry vision, nausea, vomiting, 

and fits (hypertensive crisis) 
- inflammation of the pancreas characterized by pain in the area of the stomach, nausea, 

vomiting, and fever (pancreatitis) 
- nail disorder (changes to the nail such as ridges and/or splitting) 
- multiple skin eruptions (erythema multiforme). 

 
Rare side effects (may affect up to 1 in 1,000 users)  
 

- certain skin cancers (keratoacanthoma/squamous cell carcinoma of the skin) 
- headache, confusion, seizures and visual loss associated with or without high blood pressure 

(posterior reversible encephalopathy syndrome/PRES) 
- 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). 

  
Not known (frequency cannot be estimated from the available data) 
 

- 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 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 Stivarga 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and the bottle label after 
EXP. The expiry date refers to the last day of that month. 
 
Store in the original package in order to protect from moisture. 
 
Keep the bottle tightly closed. 
 
Once the bottle is opened the medicine is to be discarded after 7 weeks. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 

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


44 

6. Contents of the pack and other information 
 
What Stivarga contains 
- The active substance is regorafenib. Each film-coated tablet contains 40 mg regorafenib. 
- The other ingredients are: cellulose microcrystalline, croscarmellose sodium, magnesium 

stearate, povidone (K-25) and silica colloidal anhydrous, iron oxide red (E172), iron oxide yellow 
(E172), lecithin (derived from soya), macrogol 3350, polyvinyl alcohol (partially hydrolysed), 
talc and titanium dioxide (E171) (see also section ‘Important information about some of the 
ingredients of Stivarga’).  

 
What Stivarga looks like and contents of the pack 
Stivarga 40 mg tablets are light pink and oval, marked with “BAYER” on one side and “40” on the 
other side. 
 
Each bottle contains 28 film-coated tablets. 
 
Stivarga 40 mg tablets are available in packs containing one bottle or three bottles. 
 
Not all pack sizes may be marketed. 
 
Keep the desiccant in the bottle. The desiccant is a moisture absorbing material filled in a small 
container to protect the tablets from moisture. 
 
Marketing Authorisation Holder  
Bayer AG 
51368 Leverkusen 
Germany 
 
Manufacturer 
Bayer AG 
Kaiser-Wilhelm-Allee 
51368 Leverkusen 
Germany 
 



45 

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. +370 5 23 36 868 

България 
Байер България ЕООД 
Тел. +359-(0)2-424 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: +356-21 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 85 65 

Norge 
Bayer AS 
Tlf. +47 23 13 05 00 

Ελλάδα 
Bayer Ελλάς ΑΒΕΕ 
Τηλ:+30 210 618 75 00 

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: +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 21 528 59 00 

Ireland 
Bayer Limited 
Tel: +353 1 299 93 13 

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

Ísland 
Icepharma hf. 
Sími: +354 540 80 00 

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 leaflet was last revised in 
 



46 

Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency (EMA) 
website: 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