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4.4      Special warnings and precautions for use

[….]

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.

[….]

10.      DATE OF REVISION OF THE TEXT

01/2023

(Re uploaded) BEC15506

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Section 4.8:

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:

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

United Kingdom (Northern Ireland)

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

BEC15506

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Section 4:

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 (see details below). By reporting side effects, you can help provide more information on the safety of this medicine.

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

United Kingdom (Northern Ireland)

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

Section 6:

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

Ireland

Bayer Limited

Tel: +353 1 216 3300

United Kingdom (Northern Ireland)

Bayer AG

Tel: +44-(0) 118 206 3000

Malta

Alfred Gera and Sons Ltd.

Tel: +356‑21 44 62 05

BEC15506

Note:

Text in blue = added text

Section 4.8:

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:

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

United Kingdom (Northern Ireland)

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

BEC19209+15506+17137+20943

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2. What you need to know before you take Stivarga

[….]

Important information about some of the ingredients of Stivarga

This medicine contains 55.856.06 mg sodium (main component of cooking/table salt) in each daily dose (4 tablets).

[….]

6.       Contents of the pack and other information

[….]

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

Ireland

Bayer Limited

Tel: +353 1 216 3300299 93 13

[….]

This leaflet was last revised in 12/2021

BEC19209+15506+17137+20943

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

[….]

Excipients with known effect

Each daily dose of 160 mg contains 2.4272.438mmol (or 55.856.06 mg) of sodium (see section 4.4).

[….]

4.4       Special warnings and precautions for use

[….]

Important information about some of the ingredients

This medicinal product contains 55.856.06 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.

[….]

5.1 Pharmacodynamic properties

[….]

ATC Code: L01XE21 L01EX05

[….]

10 Date of revision of the text

12/2021.

4.       Possible side effects

[..]

The most serious side effects, for which a fatal outcome has been observed, are:

• Severe liver problems (including liver failure), bleeding, gastrointestinal perforation and infection.

[..]

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 (including abdominal pain and back pain)
• constipation
• fever
• weight loss.

Additional text - undelined below

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 hepatic failure and 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).

4.8       Undesirable effects

Constipation added as "very common Gastro-intestinal disorders"; Uncommon Hepatobiliary disorders: Severe liver injury (including hepatic failure)*^#; Very common General disorders and administration site conditions: Asthenia/ fatigue, Pain***, Fever, Mucosal inflammation

***Most frequently reported types of pain (≥10%) are abdominal pain and back pain

10.       DATE OF REVISION OF THE TEXT

08/2021

Addition of (PRAC):

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.

Addition of (PRAC) :

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.

Changes as a result of renewal and removal of black inverted triangle. Change of storage conditions.

Additional changes

Section 4.8 Undesirable effects

The following changes were made to Table 3: Adverse drug reactions (ADRs) reported in clinical trials in patients treated with Stivarga:

·         ‘Infection’ now reads ‘infection*’

·         Headache has been moved from ‘very common’ to ‘common’

·         ‘Dehydration’ has been added as a common side effect under System Organ Class ‘Metabolism and nutrition disorders’

·         ‘Pancreatitis’ has been added as an uncommon side effect under System Organ Class ‘Gastrointestinal disorders’

·         ‘Increase in transaminases’ has been moved from ‘common’ to ‘very common’

·         ‘Alopecia’ has been  moved from ‘very common’ to ‘common’

·         ‘Musculoskeletal stiffness’ has been removed as a side effect under System Organ Class ‘Musculoskeletal and connective tissue disorders’

·         ‘Muscle spasms’ has been added as a common side effect under System Organ Class ‘Musculoskeletal and connective tissue disorders’

In addition, ‘Table 4: Treatment-emergent laboratory test abnormalities reported in placebo-controlled phase III trial in patients with metastatic CRC (CORRECT)’ has been amended to include results from GRID and RESORCE trials, and the heading now reads ‘Table 4: Treatment-emergent laboratory test abnormalities reported in placebo-controlled phase III trial in patients with metastatic CRC (CORRECT), GIST (GRID) and HCC (RESORCE)’.

‘Table 5: Treatment-emergent laboratory test abnormalities reported in placebo-controlled phase III trial (double-blind phase) in patients with GIST (GRID)’ has been removed.

Section 5.1 Pharmacodynamic properties

The below text (in red) and figures have been added:

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.

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 of 0: 66% or ECOG Performance Status of 1: 34%

•       Child-Pugh A: 98%, Child-Pugh B: 2%

•       Etiology 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

^§           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),  Disease Control Rate (complete response,           partial response and stable disease maintained for 6 weeks)

Figure 4: Kaplan-Meier curve of Overall survival

Figure 5: Kaplan-Meier curve of Progression Free survival (mRECIST)

Renal impairment

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 and or moderate renal 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 relevant.

Date of revision January 2017

Breast cancer resistance protein (BCRP) and P‑glycoprotein substrates

The Interactions section has changed to include the following:

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.

In Section 4.4 Special warnings and precautions for use, the following section has been deleted:

Patients with KRAS mutant tumours

In patients with KRAS mutant tumours, a significant improvement in PFS was observed and a numerically lower effect on OS was documented (refer to section 5.1). In view of the substantial toxicity related to treatment, physicians are recommended to carefully evaluate benefits and risks when prescribing regorafenib in patients with KRAS mutant tumours.

Stivarga – EU/1/13/858/002
www.medicines.ie

(Inserted Text; Deleted Text)

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 embossedmarked with ‘BAYER’ on one side and ‘40’ on the other side.

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).

4              Clinical Particulars

...

4.2          Posology and method of administration

…

Ethnic differences

In clinical studies, no relevant differences in exposure, safety or efficacy were observed between patients of different ethnic groups. No dose adjustment is necessary based on ethnicity (see section 5.2). 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).

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 as compared with Caucasians (see section 4.2).

…

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.  

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, treatmentStivarga should be discontinued.

…

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 as 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).

4.5          Interaction with other medicinal products and other forms of interaction

…

Breast cancer resistance protein (BCRP) and P glycoprotein substrates

In vitro data indicate that regorafenib, M-2 and M-5 are inhibitors of BCRP (IC₅₀ values about 40 to 70 nanomolar [regorafenib], 390 nanomolar [M-2 metabolite] and 150 nanomolar [M-5 metabolite]) and that regorafenib and M-2 are inhibitors of P-glycoprotein (IC₅₀ value of about 2 micromolar [regorafenib] and 1.5 micromolar [M-2 metabolite]) at concentrations which are achieved in vivo at steady state. Co-administration of regorafenib may increase the plasma concentrations of concomitant BCRP substrates, such as methotrexate, or P-glycoprotein substrates, such as digoxin.

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.

4.8          Undesirable effects

…

Description of selected adverse reactions

Severe drug induced liver injury (DILI) with fatal outcome occurred in 3 patients out of more than 1,200 Stivarga treated patients across all clinical trials (0.25%). Two of the patients had liver metastases. Liver dysfunction in these patients had an onset within the first 2 months of therapy, and was characterised by a hepatocellular pattern of injury with transaminase elevations >20xULN, followed by bilirubin increase. Liver biopsies in 2 patients revealed hepatocellular necrosis with inflammatory cell infiltration.

In the two placebo-controlled phase III trials, the overall incidence of hemorrhage/bleeding events was 19.3% in patients treated with Stivarga. Most cases of bleeding events in patients treated with Stivarga were mild to moderate in intensity (Grades 1 and 2: 16.9%), most notably epistaxis (7.6%). Fatal events in patients treated with Stivarga were uncommon (0.6%), and involved the respiratory, gastrointestinal and genitourinary tracts.

…

In the placebo controlled metastatic CRC phase III trial, the overall incidence of hand foot skin reaction was 45.2% in patients treated with Stivarga as compared to 7.1% in patients receiving placebo. In the placebo-controlled GIST phase III trial, the overall incidence of hand-foot skin reaction was 66.7% in patients treated with Stivarga as compared to 15.2% in patients receiving placebo. In both trials, 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: 28.6%, CRC and 44.7%, GIST). The incidence of Grade 3 hand-foot skin reaction was 16.6% (CRC) and 22.0% (GIST). In both trials, the overall incidence of hand-foot skin reaction (78.4%, CRC and 88.2%, GIST) was higher in Stivarga-treated Asian patients compared to other ethnicities. The incidence of Grade 3 hand-foot skin reaction in Asians was 28.4% (CRC) and 23.5% (GIST) (see sections 4.2 and 4.4).

…

Laboratory test abnormalities

Treatment-emergent laboratory abnormalities observed in the placebo-controlled phase III trials are shown in Table 4, 4a and Table 5 (see also section 4.4).

…

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)

^§ Best Supportive Care

* Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0

Table 5: Treatment-emergent laboratory test abnormalities reported in placebo-controlled phase III trial (double-blind phase) in patients with GIST (GRID)

^§ Best Supportive Care

*    Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0

**           International normalized ratio

-              No Grade 4 denoted in Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0

5.            PHARMACOLOGICAL PROPERTIES

5.1          Pharmacodynamic properties

…

Clinical Efficacy and Safety

Metastatic colorectal cancer (CRC)

…

The addition of Stivarga to BSC resulted in significantly longer survival as compared to placebo plus BSC with a hazard ratio of 0.774 (p=0.005178 stratified log rank test) and a median OS of 6.4 months vs. 5.0 months [95% CI 0.636, 0.942] (see Table 6 and Figure 1). PFS was significantly longer in patients receiving Stivarga plus BSC (hazard ratio: 0.494, p<0.000001, see Table 6). 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 disease control rate (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).

Table 6: Efficacy results from the CORRECT study

^§ Best Supportive Care

* Hazard ratio < 1 favours Stivarga

** based on investigator’s assessment of tumour response

Figure 1: Kaplan Meier curve of overall survival

<Updated image>

…

A second phase III, international, multi-center, randomized, 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 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, as 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. 1.9 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-center, randomized, double-blind, placebo-controlled phase III study (GRID) in patients with gastrointestinal stromal tumors (GIST) previously treated with 2 tyrosine kinase inhibitors (imatinib and sunitinib).

…

Table 7: Efficacy Results from the GRID study

^§ Best Supportive Care

* Hazard ratio < 1 favors Stivarga

** NR: not reached

Figure 2: Kaplan-Meier curves of Progression-Free Survival

<Updated image>

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

10.          DATE OF REVISION OF THE TEXT

April 2015 May 2015

Stivarga – EU/1/13/858/002
www.medicines.ie

(Inserted Text; Deleted Text)

5.3          Preclinical safety data

…

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).

6.6          Special precautions for disposal and other handling

...

The use of the compound regorafenib may result in a risk to the surface water and to the sediment compartment.

This medicinal product may pose a risk to the environment (see section 5.3).

Therefore Stivarga should not be disposed of via wastewater or household waste. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

This leaflet was last revised in 12/2014April 2015.

4.1              Therapeutic indications

Stivarga is indicated 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 and an anti-EGFR therapy (see section 5.1);

- 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 tumors (GIST) who progressed on or are intolerant to prior treatment with imatinib and sunitinib.

4.2

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)and since regorafenib has not been studied in patients with severe hepatic impairment (Child Pugh C, no dose recommendation can be provided. Close monitoring of overall safety is recommended in these patients (see sections 4.4 and 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. There is only limited information for patientsolder than 75 years(see also section 5.2).

Ethnic differences

In clinical studies, no relevant differences in exposure, safety or efficacy were observed between patients of different ethnic groups. No dose adjustment is necessary based on ethnicity (see section 5.2). There is limited data on regorafenib in the black patient of black race population.

Breast cancer resistance protein (BCRP) and P‑glycoprotein substrates

In vitro data indicate that regorafenib, M-2 and M-5 are inhibitors of BCRP (IC₅₀ values about 40 to 70 nanomolar [regorafenib], 390 nanomolar [M-2 metabolite] and 150 nanomolar [M-5 metabolite]) and P‑glycoprotein (IC₅₀ value of about 2 micromolar [regorafenib] and 1.5 micromolar [M-2 metabolite]). Co‑administration of regorafenib may increase the plasma concentrations of concomitant BCRP substrates, such as methotrexate, or P‑glycoprotein substrates, such as digoxin.

Inhibitors of P-glycoprotein and BCRP / Inducers of P-glycoprotein and BCRP

In vitro studies indicate that 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.

4.8 Undesirable effects

Summary of the safety profile

The overall safety profile of Stivarga is based on data from more than 1000 cancer 1,200 treated patients(all types of cancer)  in clinical trials including placebo-controlled phase IIItrial data for 500 patients with metastatic colorectal cancer (CRC) and 132 patients with gastrointestinal stromal tumours (GIST).

The most frequently observed adverse drug reactions (≥30%) in patients receiving Stivarga are asthenia/fatigue,decreased appetite and food intake hand foot skin reaction, diarrhoea, decreased appetite and food intake,  hypertension, dysphonia and infection.

Description of selected adverse reactions

Severe drug‑induced liver injury (DILI) with fatal outcome occurred in 3 patients out of more than 1,100200 Stivarga‑treated patients across all clinical trials (0.325%). Two of the patients had liver metastases. Liver dysfunction in these patients had an onset within the first 2 months of therapy, and was characterised by a hepatocellular pattern of injury with transaminase elevations >20xULN, followed by bilirubin increase. Liver biopsies in 2 patients revealed hepatocellular necrosis with inflammatory cell infiltration.

In the two placebo‑-controlled phase III trial in patients with metastatic CRCtrials, the overall incidence of haemorrhagehemorrhage/bleeding events was 21.419.3% in patients treated with Stivarga as compared to 7.5% in patients receiving placebo. Most cases of bleeding events in patients treated with Stivarga were mild to moderate in severity (Grades  1 and  2: 19.216.9%), most notably epistaxis (8.87.6%). Fatal events in patients treated with Stivarga were uncommon (0.86%), and involved the respiratory, gastrointestinal and genitourinary tracts.

In the two placebo‑-controlled phase III trial in patients with metastatic CRCtrials, infections were more often observed in patients treated with Stivarga as compared to patients receiving placebo (all grades: 30.831.0% vs. 17.014.4%). Most infections in patients treated with Stivarga were mild to moderate in severity (Grades  1 and  2: 22.09%), and included urinary tract infections (76.8%), nasopharyngitis (4.2%) as well as mucocutaneous and systemic fungal infections (6.62.4%). No difference in fatal outcomes associated with infection between treatment groups was observed (0.6%, Stivarga arm vs. 0.86%, placebo arm).)

In the placebo‑controlled phase III trial in patients with metastatic CRC phase III trial, the overall incidence of hand‑foot skin reactionsreaction was 45.2% in patients treated with Stivarga as compared to 7.1% in patients receiving placebo. Most In the placebo-controlled GIST phase III trial, the overall incidence of hand-foot skin reaction was 66.7% in patients treated with Stivarga as compared to 15.2% in patients receiving placebo. In both trials, most cases of hand foot skin reactions-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: 28.6%) and most appeared during the first cycle of treatment with Stivarga.%, CRC and 44.7%, GIST). The incidence of Grade 3 hand-foot skin reaction was 16.6% (CRC) and 22.0% (GIST). In both trials, the overall incidence of hand-foot skin reaction (78.4%, CRC and 88.2%, GIST) was higher in Stivarga-treated Asian patients compared to other ethnicities. The incidence of Grade 3 hand-foot skin reaction in Asians was 28.4% (CRC) and 23.5% (GIST).

In the placebo‑controlled metastatic CRC phase III trial the overall incidence of hypertension was 30.4% in patients treated with Stivarga andas compared to 7.9% in patients receiving placebo. MostIn the placebo-controlled GIST phase III trial, the overall incidence of hypertension was 59.1% in patients treated with Stivarga as compared to 27.3% in patients receiving placebo. In both trials, 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: 22.8%).%, CRC and 31.1%, GIST). The incidence of Grade 3 hypertension was 7.6%.% (CRC) and 27.3% (GIST). One case of Grade 4 hypertension was reported in the GIST trial.

In the placebo-controlled phase III trial in patients with metastatic CRC, the overall incidence of treatment emergent proteinuria was 7.4%  in patients treated with Stivarga as compared to 2.4% in patients receiving placebo . Of these events, 40.5% in the Stivarga arm and 66.7%  in the placebo arm have been reported as not recovered / not resolved. In the placebo-controlled GIST phase III trial, the overall incidence of proteinuria was 6.8% in patients treated with Stivarga compared to 1.5% in patients receiving placebo.

Across all clinical trials, cardiac disorder events (all grades) have been more often (20.5% vs. 10.4%) reported in Stivarga-treated patients aged 75 years or older (N=78) as compared to Stivarga-treated patients below 75 years (N=995).

Laboratory test abnormalities

Treatment‑emergent laboratory abnormalities observed in the placebo‑controlled phase III trial in patients with metastatic CRCtrials are shown in Table 4 and Table 5 (see also section 4.4).

Overall, tests on thyroid stimulating hormone (TSH) showed post baseline >ULN in 23.1% in the regorafenib and 13.3% in the placebo arm. TSH post baseline >4 times ULN was reported in 4.0% in the regorafenib arm and in no patients in the placebo arm. Concentration of free triiodothyronine (FT3) post baseline below lower limit of normal (< LLN) was reported in 20.8% in the regorafenib arm and 15.7% in the placebo arm. Concentration of free thyroxin (FT4) post baseline <LLN was reported in 8.5% in regorafenib arm and 7.2% in the placebo arm.

Table 5: Treatment-emergent laboratory test abnormalities reported in placebo-controlled phase III trial (double-blind phase) in patients with GIST (GRID)

*   Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0

**        International normalized ratio

-    No Grade 4 denoted in Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0

In the two placebo-controlled phase III trials, tests on thyroid stimulating hormone (TSH) showed post baseline >ULN in 26.1% of patients treated with Stivarga and in 15.1% of patients receiving placebo. TSH post baseline >4 times ULN was reported in 6.9% of patients treated with Stivarga and in 0.7% of patients receiving placebo. Concentration of free triiodothyronine (FT3) post baseline below lower limit of normal (<LLN) was reported in 25.6% of patients treated with Stivarga and in 20.9% of patients receiving placebo. Concentration of free thyroxin (FT4) post baseline <LLN was reported in 8.0% of patients treated with Stivarga and 6.6% of patients receiving placebo. Overall approximately 7% 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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL-DUblin 2; Tel +353 1 6764971; Fax; +353 1 6762517. Website; www.hpra.ie email: medsafety@hpra.ie

5.         PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor;

ATC Code: L01XE21

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, BRAF^V600E), and the tumour microenvironment (PDGFR, FGFR). In particular, regorafenib inhibits mutated KIT, a major oncogenic driver in gastrointestinal stromal tumors, and thereby blocks tumor cell proliferation. In preclinical studies regorafenib has demonstrated potent antitumour activity in a broad spectrum of tumour models including colorectal and gastrointestinal stromal tumour models which is mediated both by its anti‑angiogenic and anti‑proliferative effects. In addition, regorafenib has shown anti‑metastatic effects in vivo. Major human metabolites (M‑2 and M‑5) exhibited similar efficacies compared to regorafenib bothin in vitro and in vivo models.

Clinical efficacy and safety

Metastatic colorectal cancer (CRC)

* Hazard ratio < 1 favors Stivarga

** NR: not reached

Figure 2: Kaplan-Meier curves of Progression-Free Survival

Figure 3: Kaplan-Meier curves of Overall Survival

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

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).

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 observedmore pronounced in young and growing animals as well as in juvenile rats and indicate a potential risk for children and adolescents

Date of revision of the text:
07/2014

Healthcare professionals are asked to report any suspected adverse reactions preferably through the online reporting option accessible from the IMB homepage. A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’, in addition to the traditional post-paid ‘yellow card’ option.

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie