Stivarga 40mg film-coated tablets

  • Name:

    Stivarga 40mg film-coated tablets

  • Company:
    info
  • Active Ingredients:

    Regorafenib

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 07/10/19

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Summary of Product Characteristics last updated on medicines.ie: 7/10/2019
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 7 October 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions

Updated on 7 October 2019 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use

Legal category: Product subject to medical prescription which may not be renewed (A)

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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.

Updated on 7 October 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions

Updated on 7 October 2019 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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.

 

Updated on 12 September 2018 PIL

Reasons for updating

  • Change to section 5 - how to store or dispose

Updated on 12 September 2018 SmPC

Reasons for updating

  • Change to section 6.4 - Special precautions for storage
  • Removal of Black Inverted Triangle

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 12 September 2018 SmPC

Reasons for updating

  • Removal of Black Inverted Triangle
  • Change to section 6 - Pharmaceutical particulars

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

Updated on 5 September 2017 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 5 September 2017 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text
  • Correction of spelling/typing errors

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 

Before

After

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 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.

4.1 Therapeutic indications

 

Stivarga is indicated as monotherapy for the treatment of adult patients with

- metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy (see section 5.1).

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

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

4.2 Posology and method of administration

Paediatric population

There is no relevant use of Stivarga in the paediatric population in the indication of metastatic colorectal cancer.

The safety and efficacy of regorafenib in patients below 18 years of age in the indication gastrointestinal stromal tumors (GIST) have not been established. No data are available.

4.2 Posology and method of administration

Paediatric population

There is no relevant use of Stivarga in the paediatric population in the indication of metastatic colorectal cancer.

The safety and efficacy of regorafenib in patients below 18 years of age in the indication gastrointestinal stromal tumors (GIST) have not been established. No data are available.

There is no relevant use of Stivarga in the paediatric population in the indication of hepatocellular carcinoma.

4.4 Special warnings and precautions for use

Haemorrhage

Stivarga has been associated with an increased incidence of haemorrhagic events, some of which were fatal (see section 4.8). Blood counts and coagulation parameters should be monitored in patients with conditions predisposing to bleeding, and in those treated with anticoagulants (e.g. warfarin and phenprocoumon) or other concomitant medicinal products that increase the risk of bleeding. In the event of severe bleeding necessitating urgent medical intervention, permanent discontinuation of Stivarga should be considered.

4.4 Special warnings and precautions for use

Infections

Stivarga has been associated with an increased incidence of infection events, some of which were fatal (see section 4.8).

In cases of worsening infection events, interruption of Stivarga treatment should be considered.

 

Haemorrhage

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

 

[…]

Disease-specific precautions – Hepatocellular carcinoma (HCC)

In the pivotal placebo-controlled phase III study, patients received prior therapy with sorafenib.

There is insufficient data on patients who discontinued sorafenib therapy due to sorafenib-related toxicity or only tolerated a low dose (< 400 mg daily) of sorafenib. The tolerability of Stivarga in these patients has not been established.

4.8 Undesirable effects

Summary of the safety profile

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

 

[…]

The most serious adverse drug reactions in patients receiving Stivarga are severe liver injury, haemorrhage and, gastrointestinal perforation.

 

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

 

 

 

[…]

4.8 Undesirable effects

Summary of the safety profile

The overall safety profile of Stivarga is based on data from more than 4,800 treated patients in clinical trials including placebo-controlled phase III data for 636 patients with metastatic colorectal cancer (CRC), and 132 patients with gastrointestinal stromal tumours (GIST) and 374 patients with hepatocellular carcinoma (HCC).

 

[…]

The most serious adverse drug reactions in patients receiving Stivarga are severe liver injury, haemorrhage and, gastrointestinal perforation and infection.

 

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

 

[…]

 

In the two placebo-controlled phase III trials, the overall incidence of hemorrhage was 19.3% in patients treated with Stivarga. Most cases of bleeding events in patients treated with Stivarga were mild to moderate in severity (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 two placebo-controlled phase III trials, infections were more often observed in patients treated with Stivarga as compared to patients receiving placebo (all grades: 31.0% vs. 14.4%). Most infections in patients treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 22.9%), and included urinary tract infections (6.8%), nasopharyngitis (4.2%) as well as mucocutaneous and systemic fungal infections (2.4%). No difference in fatal outcomes associated with infection between treatment groups was observed (0.6%, Stivarga arm vs. 0.6%, placebo arm)

 

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).

 

In the placebo‑controlled metastatic CRC phase III trial the overall incidence of hypertension was 30.4% in patients treated with Stivarga as compared to 7.9% in patients receiving placebo. In 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 trials are shown in Table 4, Table 4a and Table 5 (see also section 4.4).

 

[…]

 

In the two placebo-controlled phase III trials, the overall incidence of haemorrhage was 19.318.2% in patients treated with Stivarga and 9.5% in patients receiving placebo. Most cases of bleeding events in patients treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 16.915.2%), most notably epistaxis (7.66.1%). Fatal events outcome in patients treated with Stivarga were was uncommon (0.67%), and involved included thecerebral, respiratory, gastrointestinal and genitourinary tractsevents.

 

In the two placebo-controlled phase III trials, infections were more often observed in patients treated with Stivarga, as compared to patients receiving placebo (all grades: 31.60% vs. 14.417.2%). Most infections in patients treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 22.923.0%), and included urinary tract infections (6.85.7%), nasopharyngitis (4.20%) as well as , mucocutaneous and systemic fungal infections (2.43.3%) as well as pneumonia (2.6%). No difference in fatal outcomes associated with infection between treatment groups was observed (0.6%, Stivarga arm vs. 0.6%, placebo arm) Fatal outcomes associated with infection were observed more often in patients treated with Stivarga (1.0%), compared to patients receiving placebo (0.3%), and were mainly respiratory events.

 

In the placebo-controlled metastatic CRC phase III trials, the overall incidence of hand foot skin reaction was 45.2%higher in patients treated with Stivarga as, compared to 7.1% in patients receiving placebo (all grades: 51.4% vs. 6.5% CRC, 66.7% vs. 15.2% GIST and 51.6% vs.7.3% HCC). 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, mMost 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: 28.634.3%, CRC and, 44.7%, GIST and 39.3%, HCC). The incidence of Grade 3 hand-foot skin reaction was 16.617.1% (CRC), and 22.0% (GIST) and 12.3% (HCC). In both trials, tThe overall incidence of hand-foot skin reaction (78.474.8%, CRC and,  88.2%, GIST and 61.7% HCC) was higher in Stivarga-treated Asian patients, compared to other ethnicities. The incidence of Grade 3 hand-foot skin reaction in Asians was 28.420.5% (CRC), and 23.5% (GIST) and 13.5% (HCC) (see sections 4.2 and 4.4).

 

In the placebo controlled metastatic CRC phase III trial the overall incidence of hypertension was 30.4% in patients treated with Stivarga as compared to 7.9% in patients receiving placebo. In 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, mIn the placebo-controlled phase III trials, the overall incidence of hypertension was higher in patients treated with Stivarga, compared to patients receiving placebo (29.6% vs. 7.5% CRC, 60.6% vs. 25.8% GIST and 31.0% vs. 6.2% HCC). Most cases of hypertension in patients treated with Stivarga appeared during the first cycle of treatment and were mild to moderate in severity (Grades 1 and 2: 22.820.9%, CRC, and 31.1%, GIST and 15.8% HCC). The incidence of Grade 3 hypertension was 7.68.7% (CRC), and 27.3% (GIST) and 15.2% (HCC). 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. In the placebo-controlled phase III trials, the overall incidence of treatment emergent proteinuria was 9.1% in patients treated with Stivarga, compared to 1.9% in patients receiving placebo. Of these events, 35.6% in the Stivarga arm and 54.5% in the placebo arm have been reported as not recovered/not resolved.

 

Across all clinical trials, cardiac disorder events (all grades) have been more often (20.513.7% vs. 10.46.5%) reported in Stivarga-treated patients aged 75 years or older (N=78410) as compared to Stivarga-treated patients below 75 years (N=9954108).

 

Laboratory test abnormalities

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

 

[…]

 

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.

In the two placebo-controlled phase III trials, tests on thyroid stimulating hormone (TSH) showed post baseline >ULN in 26.134.6% of patients treated with Stivarga and in 15.117.2% of patients receiving placebo. TSH post baseline >4 times ULN was reported in 6.96.5% of patients treated with Stivarga and in 0.71.3% of patients receiving placebo. Concentration of free triiodothyronine (FT3) post baseline below lower limit of normal (<LLN) was reported in 25.629.2% of patients treated with Stivarga and in 20.920.4% of patients receiving placebo. Concentration of free thyroxin (FT4) post baseline <LLN was reported in 8.08.1% of patients treated with Stivarga and 6.65.6% of patients receiving placebo. Overall approximately 74.6% of patients treated with Stivarga developed hypothyroidism requiring hormonal replacement treatment.

[See below for additional changes to tables in section 4.8]

[See below for additional changes to tables in section 4.8]

5.1 Pharmacodynamic properties

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 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 in in vitro and in vivo models.

5.1 Pharmacodynamic properties

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 microenvironmentmetastasis (VEGFR3, PDGFR, FGFR) and tumour immunity (CSF1R). In particular, regorafenib inhibits mutated KIT, a major oncogenic driver in gastrointestinal stromal tumours, and thereby blocks tumour cell proliferation. In preclinical studies regorafenib has demonstrated potent antitumour activity in a broad spectrum of tumour models including colorectal, and gastrointestinal stromal and hepatocellular tumour models which is likely mediated by its anti-angiogenic and anti-proliferative effects. In addition, regorafenib reduced the levels of tumour associated macrophages and has shown anti-metastatic effects in vivo. Major human metabolites (M-2 and M-5) exhibited similar efficacies, compared to regorafenib in in vitro and in vivo models.

 

[…]

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 5 and Figure 1). PFS was significantly longer in patients receiving Stivarga plus BSC (hazard ratio: 0.494, p<0.000001, see Table 5). The response rate (complete response or partial response) was 1% and 0.4% for Stivarga and placebo treated patients, respectively (p=0.188432, 1-sided). The 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).

 

[…]

The addition of Stivarga to BSC resulted in significantly longer survival, as 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] (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 56 and Figure 1). PFS was significantly longer in patients receiving Stivarga plus BSC (hazard ratio: 0.494, p<0.000001, see Table 56). 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).

 

[…]

 

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).

[…]

 

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Stivarga in all subsets of the paediatric population in the treatment of adenocarcinoma of the colon and rectum (see section 4.2 for information on paediatric use).

The European Medicines Agency has deferred the obligation to submit the results of studies with Stivarga in one or more subsets of the paediatric population in the treatment of solid malignant tumours (see section 4.2 for information on paediatric use).

The European Medicines Agency has waived the obligation to submit the results of studies with Stivarga in all subsets of the paediatric population in the treatment of hepatocellular carcinoma (see section 4.2 for information on paediatric use).

[See below for additional changes to section 5.1]

[See below for additional changes to section 5.1]

7. MARKETING AUTHORISATION HOLDER

Bayer Pharma AG

13342 Berlin

Germany

7. MARKETING AUTHORISATION HOLDER

Bayer Pharma AG

13342 Berlin

Germany

 

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

 

Efficacy parameter

Hazard Ratio* (95% CI)

P‑value

(one‑sided)

Median (95% CI)

Stivarga plus BSC§

(N=379)

Placebo plus BSC§

(N=194)

Overall Survival

 

0.624

(0.498,0.782)

0.000017

10.6 months

(9.1, 12.1)

7.8 months

(6.3, 8.8)

Progression-Free Survival **

0.453

(0.369, 0.555)

<0.000001

3.1 months

(2.8, 4.2)

1.5 months

(1.4, 1.6)

Time To Progression **

0.439 (0.355,0.542)

<0.000001

3.2 months

(2.9, 4.2)

1.5 months

(1.4, 1.6)

 

 

 

Percentages

 

Objective Response Rate**#

NA

0.003650

11%

4%

Disease Control Rate**#

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),  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)

 

 

 

Updated on 22 August 2017 PIL

Reasons for updating

  • New PIL for new product

Updated on 22 August 2017 PIL

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  • Change to section 1 - what the product is used for
  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 2 - use in children and adolescents
  • Change to section 4 - possible side effects
  • Change to section 6 - marketing authorisation holder
  • Change to section 6 - date of revision

Updated on 27 February 2017 SmPC

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Additional text in italics:

Section 4.2
[..]

Renal impairment

Available clinical data indicate similar exposure of regorafenib and its metabolites M-2 and M-5 in patients with mild, moderate or severe renal impairment compared to patients with normal renal function. In clinical studies, no relevant differences in exposure, safety or efficacy were observed between patients with mild renal impairment (estimated Glomerular Filtration Rate [eGFR] 60‑89 mL/min/1.73m2) and patients with normal renal function. Limited pharmacokinetic data indicate no difference in exposure in patients with moderate renal impairment (eGFR 30‑59 mL/min/1.73m2). No dose adjustment is required in patients with mild or moderate renal impairment (see also section 5.2). No clinical data are available in patients with severe renal impairment (eGFR <30 mL/min/1.73m2).


Section 5.2:
[..]

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

Updated on 24 February 2017 PIL

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  • Change to section 3 - how to take/use
  • Change to section 6 - date of revision

Updated on 20 July 2016 SmPC

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Section 4.8:

The following text was added:

The safety profile of regorafenib in these studies was consistent with the safety results of a phase III B study conducted in 2872 patients with metastatic colorectal cancer whose disease had progressed after treatment with standard therapies.

Updated on 20 July 2016 PIL

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  • Change to warnings or special precautions for use
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  • Change to MA holder contact details

Updated on 12 May 2016 PIL

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  • Change to drug interactions
  • Change to date of revision

Updated on 12 May 2016 SmPC

Reasons for updating

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In section 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". -was removed

and- "Administration of regorafenib (160 mg for 14 days) prior to administration of a single dose of rosuvastatin (5 mg), a BCRP substrate, resulted in a 3.8-fold increase in mean exposure (AUC) of rosuvastatin and a 4.6-fold increase in Cmax.  

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

Clinical data indicate that regorafenib has no effect on digoxin pharmacokinetics, therefore can be given concomitantly with p-glycoprotein substrates, such as digoxin, without a clinically meaningful drug interaction." -was added.

In section 10 - Date of Revision of the Text:

December 2015 -was removed and 03/2016 -was added.

Updated on 4 January 2016 SmPC

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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.

Updated on 2 December 2015 SmPC

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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.

Updated on 23 June 2015 PIL

Reasons for updating

  • Change to date of revision
  • Change to improve clarity and readability

Updated on 23 June 2015 SmPC

Reasons for updating

  • Change to section 3 - Pharmaceutical form
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
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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)

Laboratory parameter,
(in % of samples investigated)

Stivarga plus BSC§

(N=136)

Placebo plus BSC§

(N=68)

 

All Grades*

 

Grade 3*

Grade 4*

All Grades*

Grade 3*

Grade 4*

Bilirubin increased

66.7

7.4

4.4

32.8

4.5

0.0

AST increased

69.6

10.4

0.7

47.8

3.0

0.0

ALT increased

54.1

8.9

0.0

29.9

1.5

0.0

 

§ Best Supportive Care

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

 

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

Laboratory parameter,
(in % of samples investigated)

Stivarga plus BSC§

(N=132)

Placebo plus BSC§

(N=66)

 

All Grades*

 

Grade 3*

Grade 4*

All Grades*

Grade 3*

Grade 4*

Blood and

lymphatic system

disorders 

 

 

 

 

 

 

Haemoglobin decreased

75.0

3.0

0

72.7

1.5

0

Platelet count decreased

12.9

0.8

0

1.5

0

1.5

Neutrophil count decreased

15.9

2.3

0

12.1

3.0

0

Lymphocyte count decreased

29.5

7.6

0

24.2

3.0

0

Metabolism and nutrition disorders

 

 

 

 

 

 

Calcium decreased

16.7

1.5

0

4.5

0

0

Potassium decreased

Phosphate decreased

20.5

54.5

3.0

19.7

0

1.5

3.0

3.1

0

1.5

0

0

Hepatobiliary disorders

 

 

 

 

 

 

Bilirubin increased

33.3

3.0

0.8

12.1

1.5

0

AST increased

58.3

3.0

0.8

47.0

3.0

0

ALT increased

39.4

3.8

0.8

39.4

1.5

0

Renal and urinary disorders

 

 

 

 

 

 

Proteinuria

38.5

1.5

-

39.0

1.7

-

Investigations

 

 

 

 

 

 

INR increased**

9.3

1.6

-

12.5

4.7

-

Lipase increased

14.4

0

0.8

4.6

0

0

§ 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

Efficacy parameter

Hazard ratio* (95% CI)

P‑value

(one‑sided)

Median (95% CI)

Stivarga plus BSC§

(N=505)

Placebo plus BSC§

(N=255)

Median Overall Survival

 

0.774

(0.636, 0.942)

0.005178

6.4 months

(5.9, 7.3)

5.0 months

(4.4, 5.8)

Median Progression Free Survival**

0.494

(0.419, 0.582)

<0.000001

1.9 months

(1.9, 2.1)

1.7 months

(1.7, 1.7)

§ 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

Efficacy parameter

Hazard Ratio* (95% CI)

P-value

(one-sided)

Median (95% CI)

Stivarga plus BSC§

(N=133)

Placebo plus BSC§

(N=66)

Median Progression-Free Survival

0.268

(0.185, 0.388)

<0.000001

4.8 months

(4.0, 5.7)

0.9  months

(0.9, 1.1)

Median Time To Progression

0.248

(0.170,0.364)

<0.000001

5.4 months

(4.1, 5.7)

0.9  months

(0.9, 1.1)

Median Overall

Survival

0.772

(0.423, 1.408)

0.199

NR**

NR**

§ 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

 

 

Updated on 11 May 2015 SmPC

Reasons for updating

  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

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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.

Updated on 28 January 2015 PIL

Reasons for updating

  • Change to side-effects

Updated on 21 January 2015 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

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In section 4.8, "Hypersensitivity reaction" is included as an Uncommon side effect under the new System order class "Immune system disorders"

Updated on 16 September 2014 PIL

Reasons for updating

  • Improved electronic presentation

Updated on 2 September 2014 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text

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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.

Gastrointestinal disorders

Diarrhoea

Stomatitis

Vomiting

Nausea

Taste disorders

Dry mouth

Gastro‑oesophageal reflux

Gastroenteritis

Gastrointestinal perforation*

Gastrointestinal fistula

 

Hepatobiliary disorders

Hyperbilirubin-aemia

Increase in transaminases

Severe liver injury*#

 

Skin and subcutaneous tissue disorders

Hand‑foot skin reaction**

Rash

Alopecia

Dry skin

Alopecia
Nail Disorder
 

 

Exfoliative rash

Nail disorder

Erythema multiforme

Stevens‑Johnson syndrome

Toxic epidermal necrolysis


 

  

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)

Laboratory parameter,
(in % of samples investigated)

Stivarga plus BSC

(N=132)

Placebo plus BSC

(N=66)

 

All Grades*

 

Grade 3*

Grade 4*

All Grades*

Grade 3*

Grade 4*

Blood and

lymphatic system

disorders 

 

 

 

 

 

 

Haemoglobin decreased

75.0

3.0

0

72.7

1.5

0

Platelet count decreased

12.9

0.8

0

1.5

0

1.5

Neutrophil count decreased

15.9

2.3

0

12.1

3.0

0

Lymphocyte count decreased

29.5

7.6

0

24.2

3.0

0

Metabolism and nutrition disorders

 

 

 

 

 

 

Calcium decreased

16.7

1.5

0

4.5

0

0

Potassium decreased

Phosphate decreased

20.5

54.5

3.0

19.7

0

1.5

3.0

3.1

0

1.5

0

0

Hepatobiliary disorders