Leaflet STIVARGA 40mg film-coated tablets

Stivarga 40 mg film-coated tablets.

Each film-coated tablet contains 40 mg of regorafenib.

Each daily dose of 160 mg contains 2.438 mmol (or 56.06 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.

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.

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

- unresectable or metastatic gastrointestinal stromal tumours (GIST) who progressed on or areintolerant to prior treatment with imatinib and sunitinib

- hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

Stivarga should be prescribed by physicians experienced in the administration of anticancer therapy.

The recommended dose of regorafenib is 160 mg (4 tablets of 40 mg) taken once daily for 3 weeksfollowed 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. Thepatient should not take two doses on the same day to make up for a missed dose. In case of vomitingafter regorafenib administration, the patient should not take additional tablets.

Treatment should continue as long as benefit is observed or until unacceptable toxicity occurs (seesection 4.4).

Patients with performance status (PS) 2 or higher were excluded from clinical studies. There is limiteddata 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 doseis 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 institutesupportive measures for symptomatic relief.

Decrease dose by 40 mg (one tablet) andimmediately institute supportive measures.

If no improvement occurs despite dose reduction,1st occurrence interrupt therapy for a minimum of 7 days, untiltoxicity resolves to Grade 0-1.

A dose re-escalation is permitted at the discretionof the physician.

Interrupt therapy until toxicity resolves to

No improvement Grade 0-1.

Grade 2 within 7 days or When re-starting treatment, decrease dose by2nd occurrence 40 mg (one tablet).

A dose re-escalation is permitted at the discretionof the physician.

Interrupt therapy until toxicity resolves to

Grade 0-1.

3rd occurrence When re-starting treatment, decrease dose by40 mg (one tablet).

A dose re-escalation is permitted at the discretionof the physician.

4th occurrence Discontinue treatment with Stivarga permanently.

Institute supportive measures immediately.

Interrupt therapy for a minimum of 7 days untiltoxicity resolves to Grade 0-1.

1st occurrence When re-starting treatment, decrease dose by40 mg (one tablet).

A dose re-escalation is permitted at the discretion

Grade 3 of the physician.

Institute supportive measures immediately.

Interrupt therapy for a minimum of 7 days until2nd occurrence toxicity resolves to Grade 0-1.

When re-starting treatment, decrease dose by40 mg (one tablet).

3rd occurrence Discontinue treatment with Stivarga permanently.

For recommended measures and dose modifications in case of worsening of liver function testsconsidered related to treatment with Stivarga see Table 2 (see also section 4.4).

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

Observed elevationsof ALT and/or AST Occurrence Recommended measures and dose modification≤5 times upper limit of Continue Stivarga treatment.normal (ULN) Any occurrence Monitor liver function weekly until transaminases(maximum Grade 2) return to <3 times ULN (Grade 1) or baseline.>5 times ULN Interrupt Stivarga treatment.≤20 times ULN Monitor transaminases weekly until return to <3 times(Grade 3) ULN or baseline.

1st occurrence Restart: If the potential benefit outweighs the risk ofhepatotoxicity, re-start Stivarga treatment, reduce doseby 40 mg (one tablet), and monitor liver functionweekly for at least 4 weeks.

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

Discontinue treatment with Stivarga permanently.>3 times ULN Monitor liver function weekly until resolution or return(Grade 2 or higher) to baseline.with concurrent Any occurrence Exception: patients with Gilbert’s syndrome whobilirubin >2 times develop elevated transaminases should be managed as

ULN per the above outlined recommendations for therespective observed elevation of ALT and/or AST.

Regorafenib is eliminated mainly via the hepatic route.

In clinical studies, no relevant differences in exposure, safety or efficacy were observed betweenpatients with mild hepatic impairment (Child-Pugh A) and normal hepatic function. No doseadjustment is required in patients with mild hepatic impairment. Since only limited data are availablefor patients with moderate hepatic impairment (Child Pugh B), no dose recommendation can beprovided. Close monitoring of overall safety is recommended in these patients (see sections 4.4and 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.

Available clinical data indicate similar exposure of regorafenib and its metabolites M-2 and M-5 inpatients with mild, moderate or severe renal impairment compared to patients with normal renalfunction. No dose adjustment is required in patients with mild, moderate or severe renal impairment(see also section 5.2).

In clinical studies, no relevant differences in exposure, safety or efficacy were observed betweenelderly (aged 65 years and above) and younger patients (see also section 5.2).

In clinical studies, no relevant differences in exposure, safety or efficacy were observed between maleand female patients. No dose adjustment is necessary based on gender (see also section 5.2).

Ethnic differences

In clinical studies, no relevant differences in exposure or efficacy were observed between patients ofdifferent ethnic groups. A higher incidence of hand foot skin reaction (HFSR)/palmar-plantarerythrodysesthesia syndrome, severe liver function test abnormalities and hepatic dysfunction wasobserved 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).

There is no relevant use of Stivarga in the paediatric population in the indications of metastaticcolorectal cancer, gastrointestinal stromal tumours and hepatocellular carcinoma.

The safety and efficacy of Stivarga in children and adolescents (below 18 years of age) have not beenestablished (see section 5.1).

Stivarga is for oral use.

Stivarga should be taken at the same time each day. The tablets should be swallowed whole with waterafter a light meal that contains less than 30% fat. An example of a light (low-fat) meal would include1 portion of cereal (about 30 g), 1 glass of skimmed milk, 1 slice of toast with jam, 1 glass of applejuice, and 1 cup of coffee or tea (520 calories, 2 g fat).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Abnormalities of liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase[AST] and bilirubin) have been frequently observed in patients treated with Stivarga. Severe liverfunction test abnormalities (Grade 3 to 4) and hepatic dysfunction with clinical manifestations(including hepatic failure and fatal outcomes) have been reported in a small proportion of patients (seesection 4.8).

In clinical trials, a higher incidence of severe liver function test abnormalities and hepatic dysfunctionwas 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 oftreatment with Stivarga and monitor closely (at least every two weeks) during the first 2 months oftreatment. Thereafter, periodic monitoring should be continued at least monthly and as clinicallyindicated.

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 diseaseprogression), the dose modification and monitoring advice in Table 2 should be followed (seesection 4.2).

Regorafenib is eliminated mainly via the hepatic route.

Close monitoring of the overall safety is recommended in patients with mild or moderate hepaticimpairment (see also sections 4.2 and 5.2). Stivarga is not recommended for use in patients withsevere hepatic impairment (Child-Pugh C) as Stivarga has not been studied in this population andexposure might be increased in these patients.

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.

Stivarga has been associated with an increased incidence of haemorrhagic events, some of which werefatal (see section 4.8). Blood counts and coagulation parameters should be monitored in patients withconditions predisposing to bleeding, and in those treated with anticoagulants (e.g. warfarin andphenprocoumon) or other concomitant medicinal products that increase the risk of bleeding. Screeningfor and subsequent treatment of oesophageal varices in patients with liver cirrhosis should beperformed as per standard of care before starting treatment with Stivarga. In the event of severebleeding necessitating urgent medical intervention, permanent discontinuation of Stivarga should beconsidered.

Gastrointestinal perforation and fistula

Gastrointestinal perforation (including fatal outcome) and fistulae have been reported in patientstreated with Stivarga (see section 4.8). These events are also known to be common disease-relatedcomplications in patients with intra-abdominal malignancies. Discontinuation of Stivarga isrecommended in patients developing gastrointestinal perforation or fistula.

Cardiac ischaemia and infarction

Stivarga has been associated with an increased incidence of myocardial ischaemia and infarction (seesection 4.8). Patients with unstable angina or new onset angina (within 3 months of starting Stivargatherapy), recent myocardial infarction (within 6 months of starting Stivarga therapy) and those withcardiac failure New York Heart Association (NYHA) Classification 2 or higher were excluded fromthe clinical studies.

Patients with a history of ischaemic heart disease should be monitored for clinical signs and symptomsof 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 oncareful consideration of the potential benefits and risks of the individual patient. Stivarga should bepermanently discontinued if there is no resolution.

Hyperammonaemic encephalopathy

Hyperammonaemic encephalopathy has been observed with regorafenib, including fatal cases (seesection 4.8). In patients who develop unexplained lethargy or changes in mental status, ammonialevels should be measured and appropriate clinical management should be initiated. Ifhyperammonaemic encephalopathy is confirmed, permanent discontinuation of regorafenib should beconsidered.

Posterior reversible encephalopathy syndrome (PRES)

PRES has been reported in association with Stivarga treatment (see section 4.8). Signs and symptomsof 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 andsupportive 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 tomonitor blood pressure and to treat hypertension in accordance with standard medical practice. Incases of severe or persistent hypertension despite adequate medical management, treatment should betemporarily interrupted and/or the dose reduced at the discretion of the physician (see section 4.2). Incase of hypertensive crisis, Stivarga should be discontinued.

The use of VEGF pathway inhibitors in patients with or without hypertension may promote theformation of aneurysms and/or artery dissections. Before initiating Stivarga, this risk should becarefully considered in patients with risk factors such as hypertension or history of aneurysm.

Thrombotic microangiopathy (TMA), including thrombotic thrombocytopaenic purpura (TTP), havebeen associated with the use of regorafenib (see section 4.8). The diagnosis of TMA should beconsidered in patients presenting with haemolytic anaemia, thrombocytopenia, fatigue, fluctuatingneurological manifestation, renal impairment, and fever. Regorafenib therapy should be discontinuedin patients who develop TMA and prompt treatment is required. Reversal of the effects of TMA hasbeen observed after treatment discontinuation.

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 undergoingmajor surgical procedures. The decision to resume treatment with Stivarga following major surgicalintervention 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 themost frequently observed dermatological adverse reactions with Stivarga (see section 4.8). In clinicaltrials, 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 includecontrol 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 alphahydroxyl 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, orin severe or persistent cases, permanent discontinuation of Stivarga should be considered (seesection 4.2).

Biochemical and metabolic laboratory test abnormalities

Stivarga has been associated with an increased incidence of electrolyte abnormalities (includinghypophosphatemia, hypocalcaemia, hyponatraemia and hypokalaemia) and metabolic abnormalities(including increases in thyroid stimulating hormone, lipase and amylase). The abnormalities aregenerally of mild to moderate severity, not associated with clinical manifestations, and do not usuallyrequire dose interruptions or reductions. It is recommended to monitor biochemical and metabolicparameters during Stivarga treatment and to institute appropriate replacement therapy according tostandard clinical practice if required. Dose interruption or reduction, or permanent discontinuation of

Stivarga should be considered in case of persistent or recurrent significant abnormalities (seesection 4.2).

Important information about some of the ingredients

This medicinal product contains 56.06 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 mgcontains 1.68 mg of lecithin (derived from soya).

Inhibitors of CYP3A4 and UGT1A9/inducers of CYP3A4

In vitro data indicate that regorafenib is metabolized by cytochrome CYP3A4 and uridine diphosphateglucuronosyl transferase UGT1A9.

Administration of ketoconazole (400 mg for 18 days), a strong CYP3A4 inhibitor, with a single doseof regorafenib (160 mg on day 5) resulted in an increase in mean exposure (AUC) of regorafenib ofapproximately 33%, and a decrease in mean exposure of the active metabolites, M-2 (N-oxide) and

M-5 (N-oxide and N-desmethyl), of approximately 90%. It is recommended to avoid concomitant useof strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole,ketoconazole, posaconazole, telithromycin and voriconazole) as their influence on the steady-stateexposure 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 ofregorafenib and its metabolites has not been studied.

Administration of rifampicin (600 mg for 9 days), a strong CYP3A4 inducer, with a single dose ofregorafenib (160 mg on day 7) resulted in a reduction in AUC of regorafenib of approximately 50%, a3- to 4-fold increase in mean exposure of the active metabolite M-5, and no change in exposure ofactive metabolite M-2. Other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbitaland St. John’s wort) may also increase metabolism of regorafenib. Strong inducers of CYP3A4 shouldbe avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential toinduce CYP3A4 should be considered.

UGT1A1 and UGT1A9 substrates

In vitro data indicate that regorafenib as well as its active metabolite M-2 inhibit glucuronidationmediated by UGT1A1 and UGT1A9 whereas M-5 only inhibits UGT1A1 at concentrations which areachieved in vivo at steady state. Administration of regorafenib with a 5-day break prior toadministration of irinotecan resulted in an increase of approximately 44% in AUC of SN-38, asubstrate of UGT1A1 and an active metabolite of irinotecan. An increase in AUC of irinotecan ofapproximately 28% was also observed. This indicates that co-administration of regorafenib mayincrease 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 ofrosuvastatin (5 mg), a BCRP substrate, resulted in a 3.8-fold increase in mean exposure (AUC) ofrosuvastatin and a 4.6-fold increase in Cmax.

This indicates that co-administration of regorafenib may increase the plasma concentrations of otherconcomitant BCRP substrates (e.g. methotrexate, fluvastatin, atorvastatin). Therefore, it isrecommended to monitor patients closely for signs and symptoms of increased exposure to BCRPsubstrates.

Clinical data indicate that regorafenib has no effect on digoxin pharmacokinetics, therefore can begiven concomitantly with p-glycoprotein substrates, such as digoxin, without a clinically meaningfuldrug 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-2and 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 valueof 0.6 micromolar), CYP2C9 (Ki value of 4.7 micromolar), CYP2B6 (Ki value of 5.2 micromolar) atconcentrations which are achieved in vivo at steady state (peak plasma concentration of8.1 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.

A clinical probe substrate study was performed to evaluate the effect of 14 days of dosing with 160 mgregorafenib 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 (seealso section 4.4).

Antibiotics

The concentration-time profile indicates that regorafenib and its metabolites may undergoenterohepatic circulation (see section 5.2). Co-administration with neomycin, a poorly absorbedantimicrobial agent used for eradicating the gastrointestinal microflora (which may interfere with theenterohepatic circulation of regorafenib) had no effect on the regorafenib exposure, but there was anapproximately 80% decrease in the exposure of the active metabolites M-2 and M-5 which showed invitro and in vivo comparable pharmacological activity as regorafenib. The clinical significance of thisneomycin 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 forminginsoluble complexes which may impact absorption (or reabsorption), thus resulting in potentiallydecreased exposure. The clinical significance of these potential interactions is unknown, but mayresult in a decreased efficacy of regorafenib.

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 andup to 8 weeks after completion of therapy.

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 administeredduring pregnancy. Animal studies have shown reproductive toxicity (see section 5.3).

Stivarga should not be used during pregnancy unless clearly necessary and after careful considerationof the benefits for the mother and the risk to the foetus.

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 beexcluded. Regorafenib could harm infant growth and development (see section 5.3).

Breast-feeding must be discontinued during treatment with Stivarga.

There are no data on the effect of Stivarga on human fertility. Results from animal studies indicate thatregorafenib can impair male and female fertility (see section 5.3).

No studies on the effects of Stivarga on the ability to drive or use machines have been performed. Ifpatients 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.

The overall safety profile of Stivarga is based on data from more than 4,800 treated patients in clinicaltrials 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 hepatocellularcarcinoma (HCC).

The safety profile of regorafenib in these studies was consistent with the safety results of a phase III Bstudy conducted in 2872 patients with metastatic colorectal cancer whose disease had progressed aftertreatment 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, hypertensionand infection.

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 termis 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 bythe 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 theavailable data).

Within each frequency group, undesirable effects are presented in order of decreasing seriousness.

Table 3: Adverse drug reactions (ADRs) reported in clinical trials and postmarketing in patientstreated with Stivarga

System

Organ Class Very common Common Uncommon Rare Not known(MedDRA)

Infections and Infectioninfestations *

Neoplasms Keratoacan-benign, thoma/malignant and Squamousunspecified cell(including carcinoma ofcysts and the skinpolyps)

Blood and Thrombo- Leucopenia Thromboticlymphatic cytopenia microangiopsystem Anaemia athydisorders

Immune Hypersensiti-system vity reactiondisorders

Endocrine Hypo-disorders thyroidism

System

Organ Class Very common Common Uncommon Rare Not known(MedDRA)

Metabolism Decreased Hypo-and nutrition appetite and kalaemiadisorders food intake Hypophos-phatemia

Hypo-calcaemia

Hypo-natraemia

Hypomag-nesaemia

Hyperuri-caemia

Dehy-dration

Nervous Headache Posterior Hyperammonsystem Tremor reversible aemicdisorders Peripheral encephalo- encephalopatneuropathy pathy hysyndrome(PRES)

Cardiac Myocardialdisorders infarction

Myocardialischaemia

Vascular Haemorrhage* Hypertensive Aneurysmsdisorders Hypertension crisis and arterydissections

Respiratory, Dysphoniathoracic andmediastinaldisorders

Gastro- Diarrhoea Taste Gastro-intestinal Stomatitis disorders intestinaldisorders Vomiting Dry mouth perforation*

Nausea Gastro- Gastro-

Constipation oesopha- intestinalgeal reflux fistula

Gastro- Pancreatitisenteritis

Hepatobiliary Hyper- Severe liverdisorders bilirubinaemia injury

Increase in (includingtransaminases hepaticfailure)*#

Skin and Hand-foot Alopecia Nail disorder Stevens-subcutaneous skin Dry skin Erythema Johnsontissue reaction** Exfoliative multiforme syndromedisorders Rash rash Toxicepidermalnecrolysis

System

Organ Class Very common Common Uncommon Rare Not known(MedDRA)

Musculo- Muscleskeletal and spasmsconnectivetissuedisorders

Renal and Proteinuriaurinarydisorders

General Asthenia/disorders and fatigueadministration Pain***site Feverconditions Mucosalinflammation

Investigations Weight loss Increase inamylase

Increase inlipase

Abnormal

Inter-nationalnormalisedratio

* fatal cases have been reported

** palmar-plantar erythrodysesthesia syndrome in MedDRA terminology

***Most frequently reported types of pain (≥10%) are abdominal pain and back pain# according to drug-induced liver injury (DILI) criteria of the international DILI expert workinggroup

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 fataloutcome 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 patientstreated with Stivarga and 9.5% in patients receiving placebo. Most cases of bleeding events in patientstreated with Stivarga were mild to moderate in severity (Grades 1 and 2: 15.2%), most notablyepistaxis (6.1%). Fatal outcome in patients treated with Stivarga was uncommon (0.7%), and includedcerebral, 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 inpatients treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 23.0%), and includedurinary 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 moreoften in patients treated with Stivarga (1.0%), compared to patients receiving placebo (0.3%), andwere mainly respiratory events.

In the placebo-controlled phase III trials, the overall incidence of hand-foot skin reaction was higher inpatients 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 inpatients treated with Stivarga appeared during the first cycle of treatment and were mild to moderate inseverity (Grades 1 and 2: 34.3%%, CRC, 44.7%, GIST and 39.3%, HCC). The incidence of Grade 3hand-foot skin reaction was 17.1% (CRC), 22.0% (GIST) and 12.3% (HCC). The overall incidence ofhand-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 patientstreated 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 Stivargaappeared 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 GISTtrial.

In the placebo-controlled phase III trials, the overall incidence of treatment emergent proteinuria was9.1% in patients treated with Stivarga, compared to 1.9% in patients receiving placebo. Of theseevents, 35.6% in the Stivarga arm and 54.5% in the placebo arm have been reported as notrecovered/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-treatedpatients below 75 years (N=4108).

Laboratory test abnormalities

Treatment-emergent laboratory abnormalities observed in the placebo-controlled phase III trials areshown in Table 4 and Table 4a (see also section 4.4).

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)

Stivarga Placebo Stivarga Placebo Stivarga Placebo Stivarga Placebo Stivarga Placebo Stivarga Placebo

Laboratory plus plus plus BSC plus plus plus plus BSC plus plus BSC plus BSC plus plus

Parameter BSC BSC (n= 500) BSC BSC BSC (n=132) BSC (n= 374) (n=193) BSC BSC(in % of samples (n= 500) (n=253) (n=253) (n= 132) (n= 66) (n= 66) (n= 374) (n=193)investigated) Grade a Grade b Grade b

All Grades % Grade 3/4 % All Grades % Grade 3/4 % All Grades % Grade 3/4 %

Blood and lymphaticsystem disorders

Haemoglobin 78.5 66.3 5.3 2.8 75.0 72.7 3.0 1.5 72.5 71.3 6.0 4.8decreased

Thrombocytopenia 40.5 16.8 2.8 0.4 12.9 1.5 0.8 1.5 63.1 50.0 5.4 0

Neutropenia 2.8 0 0.6 0 15.9 12.1 3.1 3.0 13.6 14.9 3.0 1.0

Lymphopenia 54.1 34.8 9.3 4.0 29.9 24.2 7.6 3.0 67.8 58.5 17.4 11.7

Metabolism andnutrition disorders

Hypocalcaemia 59.3 18.3 1.2 1.2 16.7 4.5 1.5 0 23.4 10.1 0.3 0

Hypokalemia 25.7 8.3 4.3 0.4 20.5 3.0 3.0 0 30.7 9.0 4.3 2.1

Hypophosphatemia 57.4 11.1 31.1 3.6 54.5 3.1 21.2 1.5 70.4 31.4 33.9 6.9

Hepatobiliarydisorders

Hyperbilirubinemia 44.6 17.1 12.2 8.4 33.3 12.1 3.8 1.5 78.2 54.5 15.9 15.7

Increased AST 65.0 45.6 5.9 5.2 58.3 47.0 3.8 3.0 92.7 84.3 17.8 19.9

Increased ALT 45.2 29.8 5.5 3.2 39.4 39.4 4.6 1.5 70.4 58.6 6.2 4.7

Renal and urinarydisorders

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

Increased INR* 23.7 16.6 4.2 1.6 9.3 12.5 1.6 4.7 44.4 35.4 0.7 2.1

Increased Lipase 46.0 18.7 11.4 4.4 14.4 4.6 0.8 0 40.5 27.0 14.2 8.7

Increased Amylase 25.5 16.7 2.6 2.4 - - - - 23.0 19.0 2.8 2.7a Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0b Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0

* International normalized ratio

BSC = Best Supportive Care

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

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

Stivarga plus BSC§ Placebo plus BSC§

Laboratory parameter, (N=136) (N=68)(in % of samplesinvestigated) All Grade Grade All Grade Grade

Grades* 3* 4* Grades* 3* 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 postbaseline >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 lowerlimit of normal (<LLN) was reported in 29.2% of patients treated with Stivarga and in 20.4% ofpatients receiving placebo. Concentration of free thyroxin (FT4) post baseline <LLN was reported in8.1% of patients treated with Stivarga and 5.6% of patients receiving placebo. Overall approximately4.6% of patients treated with Stivarga developed hypothyroidism requiring hormonal replacementtreatment.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The highest dose of Stivarga studied clinically was 220 mg per day. The most frequently observedadverse drug reactions at this dose were dermatological events, dysphonia, diarrhoea, mucosalinflammation, dry mouth, decreased appetite, hypertension, and fatigue.

There is no specific antidote for Stivarga overdose. In the event of suspected overdose, Stivargashould be discontinued immediately, with best supportive care initiated by a medical professional, andthe patient should be observed until clinical stabilisation.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor; ATC Code: L01EX05

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 stromaltumours, and thereby blocks tumour cell proliferation. In preclinical studies regorafenib hasdemonstrated potent antitumour activity in a broad spectrum of tumour models including colorectal,gastrointestinal stromal and hepatocellular tumour models which is likely mediated by itsanti-angiogenic and anti-proliferative effects. In addition, regorafenib reduced the levels of tumourassociated macrophages and has shown anti-metastatic effects in vivo. Major human metabolites (M-2and M-5) exhibited similar efficacies, compared to regorafenib in in vitro and in vivo models.

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 metastaticcolorectal 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 eachcontaining 40 mg regorafenib) orally once daily (N=505) plus Best Supportive Care (BSC or matchingplacebo (N=255) plus BSC for 3 weeks on therapy followed by 1 week off therapy. The mean dailyregorafenib dose received was 147 mg.

Patients continued therapy until disease progression or unacceptable toxicity. A pre-planned interimanalysis for efficacy was performed when 432 deaths had occurred. The study was un-blinded afterthis 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 therate 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 forprogressive 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. Therapiesincluded treatment with fluoropyrimidine-based chemotherapy, an anti-VEGF therapy, and, if thepatient 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 wassignificantly 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 andplacebo treated patients, respectively (p=0.188432, 1-sided). The DCR (complete response or partialresponse or stable disease) was significantly higher in patients treated with Stivarga (41.0% vs. 14.9%,p<0.000001, 1 sided).

Table 5: Efficacy results from the CORRECT study

Efficacy Hazard ratio* P-value Median (95% CI)parameter (95% CI) (one-sided) Stivarga plus BSC§ Placebo plus BSC§(N=505) (N=255)

OS 0.774 0.005178 6.4 months 5.0 months(0.636, 0.942) (5.9, 7.3) (4.4, 5.8)

PFS** 0.494 <0.000001 1.9 months 1.7 months(0.419, 0.582) (1.9, 2.1) (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 ofdisease, time from first diagnosis of metastatic disease, prior anticancer treatment, prior treatment linesfor metastatic disease, and KRAS mutation status showed a treatment effect favouring the regorafenibregimen over the placebo regimen.

Subgroup analysis results by historical KRAS mutational status showed a treatment effect for OS infavour of regorafenib over placebo for patients with KRAS wild-type tumours whereas a numericallylower effect was reported in patients with KRAS mutant tumours; the treatment effect for PFSfavouring 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 to1.123) 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) forpatients with KRAS wild-type tumours and 0.525 (0.425 to 0.649) for patients with KRAS mutanttumours.

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 previouslytreated 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 ahazard ratio of 0.550 (p = 0.000159 stratified log rank test) and a median OS of 8.8 months vs. 6.3months [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 withplacebo. The safety profile of Stivarga plus BSC in the CONCUR study was consistent with the safetyprofile 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 gastrointestinalstromal 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 after144 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 weekson 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 receivingplacebo 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’sopinion, treatment with regorafenib was providing clinical benefit, were offered the opportunity tocontinue 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 sincemost recent progression or relapse to randomisation was 6 weeks.

Regorafenib plus BSC resulted in significantly longer PFS, compared to placebo plus BSC with ahazard 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% inregorafenib-treated patients, compared to placebo treated patients (see Table 6, Figure 2).The increasein 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 receivingplacebo plus BSC with a hazard ratio of 0.248 [95% CI 0.170, 0.364], and median TTP of 5.4 monthsvs. 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 withregorafenib (see Table 6, Figure 3).

Table 6: Efficacy results from the GRID study

Median (95% CI)

Efficacy Hazard ratio* P-valueparameter (95% CI) (one-sided) Stivarga plus Placebo plus

BSC§ BSC§(N=133) (N=66)

PFS 0.268 <0.000001 4.8 months 0.9 months(0.185, 0.388) (4.0, 5.7) (0.9, 1.1)

TTP 0.248 <0.000001 5.4 months 0.9 months(0.170,0.364) (4.1, 5.7) (0.9, 1.1)

OS 0.772 0.199 NR** NR**(0.423, 1.408)§ Best Supportive Care

* Hazard ratio < 1 favours Stivarga

** NR: not reached

Figure 2: Kaplan-Meier curves of PFS

Figure 3: Kaplan-Meier curves of OS

In addition, 56 placebo plus BSC patients received open-label Stivarga after cross-over followingdisease progression and a total of 41 Stivarga plus BSC patients continued Stivarga treatment afterdisease progression. The median secondary PFS (as measured by the investigator’s assessment) were5.0 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 withhepatocellular 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 oncedaily (n=379) plus Best Supportive Care (BSC) or matching placebo (n=194) plus BSC for 3 weeks ontherapy 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 progressionduring treatment with sorafenib and if they had a liver function status of Child-Pugh class A. Patientswho permanently discontinued sorafenib therapy due to sorafenib-related toxicity or who tolerated lessthan 400 mg sorafenib once daily prior to withdrawal were excluded from the study. Randomisationwas 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, patientscould continue Stivarga therapy past progression at the discretion of the investigator.

Demographics and baseline disease characteristics were comparable between the Stivarga- andplacebo-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 toplacebo plus BSC with a hazard ratio of 0.624 [95% CI 0.498, 0.782], p=0.000017 stratified log ranktest, 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 Hazard ratio* P-value Median (95% CI)parameter (95% CI) (one-sided) Stivarga plus BSC§ Placebo plus BSC§(N=379) (N=194)

OS 0.624 0.000017 10.6 months 7.8 months(0.498,0.782) (9.1, 12.1) (6.3, 8.8)

PFS** 0.453 <0.000001 3.1 months 1.5 months(0.369, 0.555) (2.8, 4.2) (1.4, 1.6)

TTP** 0.439 <0.000001 3.2 months 1.5 months(0.355,0.542) (2.9, 4.2) (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 andstable disease maintained for 6 weeks)

Figure 4: Kaplan-Meier curve of OS

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

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 andrectum, gastrointestinal stromal tumours and hepatocellular carcinoma (see section 4.2 for informationon paediatric use).

A multicentre, randomised, controlled, open-label study (CT3 portion of the FaR-RMS study)evaluated the safety and efficacy of regorafenib in combination with vincristine and irinotecan (VIRR)compared to standard therapy vincristine, irinotecan, and temozolomide (VIRT) in patients with a firstor subsequent relapses of rhabdomyosarcoma.

Upon data review of 103 patients, including 84 paediatric patients from 6 months to less than 18 yearsold, at the first interim futility analysis, the recruitment of the study was terminated without formalevaluation of the primary endpoint of 1-year event-free survival (EFS). The futility boundary was met(EFS HR >1), indicating a low probability that VIRR would achieve the protocol-defined 15%superiority over VIRT.

Regorafenib reaches mean peak plasma levels of about 2.5 mg/l at about 3 to 4 hours after a single oraldose 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 orfasting condition. The exposure for regorafenib was increased by 48% when administered with ahigh-fat breakfast, and 36% when administered with a low fat breakfast, compared to fasting. Theexposure of metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) is higher whenregorafenib is given with a low fat breakfast, compared to fasting condition and lower when givenwith a high fat meal, compared to fasting condition.

Plasma concentration-time profiles for regorafenib as well as for the major circulating metabolitesshowed multiple peaks across the 24-hour dosing interval, which are attributed to enterohepaticcirculation. In vitro protein binding of regorafenib to human plasma proteins is high (99.5%). In vitroprotein 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.

Regorafenib is metabolized primarily in the liver by oxidative metabolism mediated by CYP3A4, aswell as by glucuronidation mediated by UGT1A9. Two major and six minor metabolites ofregorafenib have been identified in plasma. The main circulating metabolites of regorafenib in humanplasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), which are pharmacologically activeand have similar concentrations as regorafenib at steady state. M-2 is further metabolised by oxidativemetabolism mediated by CYP3A4, as well as by glucuronidation mediated by UGT1A9.

Metabolites may be reduced or hydrolysed in the gastrointestinal tract by microbial flora, allowingreabsorption of the unconjugated active substance and metabolites (enterohepatic circulation).

Following oral administration, mean elimination half-life for regorafenib and its metabolite M-2 inplasma ranges from 20 to 30 hours in different studies. The mean elimination half-life for themetabolite 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, withabout 71% of the dose excreted in faeces (47% as parent compound, 24% as metabolites), and about19% of the dose excreted in urine as glucuronides. Urinary excretion of glucuronides decreased below10% under steady-state conditions. Parent compound found in faeces could be derived from intestinaldegradation of glucuronides or reduction of metabolite M-2 (N-oxide), as well as unabsorbedregorafenib.

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.

Systemic exposure of regorafenib at steady-state increases dose proportionally up to 60 mg and lessthan proportionally at doses greater than 60 mg. Accumulation of regorafenib at steady state results inabout a 2-fold increase in plasma concentrations, which is consistent with the elimination half-life anddosing 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 meanplasma 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-stateplasma concentrations of M-2 and M-5 are comparable to those of regorafenib.

The exposure of regorafenib and its metabolites M-2 and M-5 is comparable in patients with mildhepatic 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 areno data for patients with Child-Pugh C (severe) hepatic impairment. Regorafenib is mainly eliminatedvia the liver, and exposure might be increased in this patient population.

Available clinical data and physiology-based pharmacokinetic modelling indicate similar steady-stateexposure of regorafenib and its metabolites M-2 and M-5 in patients with mild or moderate renalimpairment, compared to patients with normal renal function. In patients with severe renal impairmentcompared 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 consideredclinically 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 inexposure in these patients.

Age did not affect the regorafenib pharmacokinetics over the studied age range (29 - 85 years).

The pharmacokinetics of regorafenib is not influenced by gender.

Ethnic differences

The exposure of regorafenib in various Asian populations (Chinese, Japanese, Korean) is within thesame range as seen in Caucasians.

Cardiac electrophysiology/QT prolongation

No QTc prolonging effects were observed after administration of 160 mg regorafenib at steady state ina dedicated QT study in male and female cancer patients.

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 theatrioventricular valves of the heart was seen in the 26 week repeat-dose toxicity study in rats. Thismay be due to acceleration of an age-related physiological process. These effects occurred at systemicexposures 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 pronouncedin young and growing animals as well as in juvenile rats and indicate a potential risk for children andadolescents.

Specific studies on fertility have not been performed. However, a potential of regorafenib to adverselyaffect male and female reproduction has to be considered based on morphological changes in thetestes, ovaries, and the uterus observed after repeated dosing in rats and dogs at exposures below theanticipated human exposure (based on AUC comparison). The observed changes were only partiallyreversible.

An effect of regorafenib on intrauterine development was shown in rabbits at exposures below theanticipated human exposure (based on AUC comparison). Main findings consisted of malformationsof the urinary system, the heart and major vessels, and the skeleton.

There was no indication for a genotoxic potential of regorafenib tested in standard assays in vitro andin vivo in mice.

Studies on the carcinogenic potential of regorafenib have not been performed.

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 thesediment compartment (see section 6.6).

Cellulose microcrystalline

Croscarmellose sodium

Magnesium stearate

Povidone (K-25)

Silica, colloidal anhydrous

Iron oxide red (E172)

Iron oxide yellow (E172)

Lecithin (derived from soya)

Macrogol 3350

Polyvinyl alcohol, partially hydrolysed

Talc

Titanium dioxide (E171)

Not applicable.

3 years.

Once the bottle is opened the medicinal product has shown to be stable for 7 weeks. Thereafter, themedicinal product is to be discarded.

Store in the original package in order to protect from moisture.

Keep the bottle tightly closed.

White opaque HDPE bottle closed with a PP/PP (polypropylene) screw cap with sealing insert and amolecular sieve desiccant.

Each bottle contains 28 film-coated tablets.

Pack of 28 film-coated tablets.

Pack of 84 (3 bottles of 28) film-coated tablets.

Not all pack sizes may be marketed.

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 localrequirements.

Bayer AG51368 Leverkusen

Germany

EU/1/13/858/001

EU/1/13/858/002

Date of first authorisation: 26 August 2013

Date of latest renewal: 22 May 2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu