Last Updated on eMC 11-07-2018 View medicine  | Bayer plc Contact details

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Reasons for adding or updating:

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

Date of revision of text on the SPC:25-06-2018

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



·           Section 4.8 Undesirable effects:

o     Tabulated list of adverse reactions – updated to include new ADR – peripheral neuropathy

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Removal of black triangle

Date of revision of text on the SPC:22-05-2018

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Changes to the SmPC have been made to the following sections:

·          Removal of black triangle

·          Section 4.4 Special warnings and precaution for use - the following section has been amended:

o    Important information about some of the ingredients – update to sodium excipient warning

·                              Section 4.8 Undesirable effects – the following section has been amended:

o    Description of selected adverse reactions - correction of hypertension frequency in GIST

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects - how to report a side effect

Date of revision of text on the SPC:07-08-2017

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



  • In section 4 - how to report a side effect, the address has been modified/added

Reasons for adding or 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

Date of revision of text on the SPC:07-08-2017

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



Changes to the SmPC have been made to the following sections:

·        Section 4.1 Therapeutic indications

o   Addition of HCC

·        Section 4.2 Posology and method of administration – the following section has been amended:

o   Paediatric population

·        Section 4.4 Special warnings and precaution for use - the following sections have been added or amended:

o   Infections

o   Haemorrhage

o   Disease-specific precautions - HCC

·        Section 4.8 Undesirable effects  - the following sections have been  amended

o   Summary of the safety profile

o   Table 3: ADRs reported

o   Description of selected adverse reactions

o   Laboratory test abnormalities

o   Table 4

·        Section 5.1 Pharmacodynamic properties – the following sections have been added or amended:

o   Mechanism of action and pharmacodynamics effects

o   Clinical efficacy and safety

o   Hepatocellular carcinoma (HCC)

o    

·        Section 7 Marketing Authorisation Holder

Reasons for adding or updating:

  • Change to section 10 - Date of revision of the text
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 4.2 - Posology and method of administration
  • 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

Date of revision of text on the SPC:27-01-2017

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



Changes to the SmPC have been made to the following sections:

·        Section 4.2 Posology and method of administration – the following section has been amended and now states:

o   Renal impairment

·        Section 4.5 Interaction with other medicinal products and other forms of interaction

o   Inhibitors of P-glycoprotein and BCRP / Inducers of P-glycoprotein and BCRP – minor change to this section

·        4.8 Undesirable effects

o   Laboratory test abnormalities – minor change to this section

·        5.1 Pharmacodynamic properties – minor change to this section

·        5.2 Pharmacokinetic properties

o   Renal impairment

Reasons for adding or updating:

  • 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 10 - Date of revision of the text

Date of revision of text on the SPC:28-04-2016

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



The key changes to the SmPC are:

 

·        Section 4.5 Interaction with other medicinal products and other forms of interaction – the following section has been amended and now states:

 

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

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

 

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

 

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

 

·        4.8 Undesirable effects

 

Summary of the safety profile – the following statement has been 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

Reasons for adding or updating:

  • 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
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:01-12-2015

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



The key changes are:

4.4 Special warnings and precautions for use-deletion of the statement regarding efficacy in patients with KRAS mutant tumours based on the results of the CONCUR study biomarkers

 

4.5 Interaction with other medicinal products and other forms of interaction-

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.

 

4.8 Undesirable effects-

Description of selected adverse reactions

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

 

5.1 Pharmacodynamic effects

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….. PFS was also significantly longer in patients receiving Stivarga plus BSC (hazard ratio: 0.311, p<0.000001), median PFS 3.2 months with Stivarga vs. 1.7 months with placebo…….

 

Reasons for adding or 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
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:01-05-2015

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



The key changes are:

 

Section 3:

….

Light pink film‑coated tablets, oval shaped with a length of 16 mm and a width of 7 mm marked with ‘BAYER’ on one side and ‘40’ on the other side.

 

Section 4.2:

Ethnic differences

In clinical studies, no relevant differences in exposure or efficacy were observed between patients of different ethnic groups. A higher incidence of hand foot skin reaction (HFSR) / palmar-plantar erythrodysesthesia syndrome, severe liver function test abnormalities and hepatic dysfunction was observed in Asian (in particular Japanese) patients treated with Stivarga compared with Caucasians. The Asian patients treated with Stivarga in clinical studies were primarily from East Asia (~90%). There is limited data on regorafenib in the black patient population.

No dose adjustment is necessary based on ethnicity (see section 5.2).

 

Section 4.4:

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.

……..

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).

……..

 

Section 4.5:

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.

………

 

Section 4.8:

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.

 

Plus new table 4a with details of the laboratory changes from CONCUR

 

Section 5.1:

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.

 

Plus updated efficacy results graphs.

 

Reasons for adding or 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

Date of revision of text on the SPC:23-04-2015

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



The key changes are:

 

Section 5.3 Preclinical safety data - The following statement has been added:

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).

 

Section 6.6 Special precautions for disposal and other handling – This section was amended and now states:

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

Any unused medicinal product or waste material should be disposed of in accordance with local requirements

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects

Date of revision of text on the SPC:01-12-2014

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

hypersensitivity reactions has been added as an uncommon side effect.

Reasons for adding or 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 - 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

Date of revision of text on the SPC:28-07-2014

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



Following the recent approval of a second  indication for Stivarga to treatment patients with “unresectable or metastatic gastrointestinal stromal tumors (GIST) who progressed on or are intolerant to prior treatment with imatinib and sunitinib

Reasons for adding or updating:

  • New SPC for new product

Date of revision of text on the SPC:01-01-0001

Legal Category:POM

Black Triangle (CHM): YES