Cabometyx Tablets

• Addition of the missing frequency of the side effects “Swelling, or shortness of breath” in the section 4 of the Patient Information Leaflet in line with the approved SmPC.
• To amend the section 6 with updated information for local representative for Croatia

• Addition of pneumonia as an Adverse Drug Reaction (ADR) in section 4.8 of the SmPC of CABOMETYX.

• Addition of a missing ADR – ‘Embolism arterial’ in the section 4.8 of the SmPC and PIL accordingly.
• Addition of an ADR and warning for ‘Vanishing Bile Duct Syndrome (VBDS)’ to be in-line with the CCSI V9 update in the section 4.4, 4.8 of the SmPC and PIL accordingly.
• Minor changes to the PIL which aims to have a better clarity for the patient by simplifying and formatting the leaflet in Section 4 of the Leaflet.
• "Decreased amount of protein albumin in blood (which carries substances such as hormones, medicines, and enzymes throughout your body)" was repeated twice in section 4 of the PIL. It only appears once in the attached PI.
• "Increased blood levels of calcium, magnesium, or sodium" was written in the common side effects combination section in the PIL. This ADR has been moved to the “very common” section.
• Minor change made in the PIL - contact details of local representative in Croatia.

Section 4.2, 4.8, 5.1, and 5.2 of the SmPC have been updated with information on pediatrics data.

• Addition of a missing ADR – ‘Embolism arterial’ in the section 4.8 of the SmPC and PIL accordingly.
• Addition of an ADR and warning for ‘Vanishing Bile Duct Syndrome (VBDS)’ to be in-line with the company core safety information update in the section 4.4, 4.8 of the SmPC and PIL accordingly.

• "Decreased amount of protein albumin in blood (which carries substances such as hormones, medicines, and enzymes throughout your body)" was repeated twice in section 4 of the PIL. 
• "Increased blood levels of calcium, magnesium, or sodium" was written in the common side effects combination section in the PIL. This ADR has been moved to the “very common” section.
• Minor changes to the PIL which aims to have a better clarity for the patient by simplifying and formatting the leaflet in Section 4 of the Leaflet. 
• Addition of a missing ADR – ‘Embolism arterial’ in the section 4.8 of the SmPC and PIL accordingly.
• Addition of an ADR and warning for ‘Vanishing Bile Duct Syndrome (VBDS)’ to be in-line with the company core safety information update in the section 4.4, 4.8 of the SmPC and PIL accordingly.

• Addition of a missing ADR – ‘Embolism arterial’ in the section 4.8 of the SmPC and PIL accordingly. 
• Addition of an ADR and warning for ‘Vanishing Bile Duct Syndrome (VBDS)’ to be in-line with the company core safety information update in the section 4.4, 4.8 of the SmPC.

SmPC:

4.4 Special warnings and precautions for use

Clinical trials data for dose reductions on DTC have been updated.

4.8 Undesirable side effects

The summary of safety profile for cabozantinib as monotherapy has been updated with additional AEs as well as clinical study date figures has been amended.

2. What you need to know before you take CABOMETYX

Warnings and precautions has been updated.

4 Possible side effects

Section 4 has been updated: to include information on possible side effects to let your doctor know; side effects of Cabometyx alone; Cabometyx in combination with nivolumab side effects; changes in test results.

6 Contents of the pack and other information.

Update to the appearance description of the packaging of Cabometyx.

Section 4 has been updated with pneumothorax for in the ‘Uncommon’ side effects and addition of cutaneous vasculitis in the ‘Not Known’ side effects for both Cabometyx alone and Cabometyx in combination with nivolumab.

SmPC:

4.4 Special warnings and precautions for use

Amendment of wording on hypertension warning.

4.8 Undesirable side effects

Section 4.8 has been updated with addition of pneumothorax in ‘Uncommon’ for “Respiratory, thoracic and mediastinal disorders” and cutaneous vasculitis in ‘Not known’ for “Skin and subcutaneous tissue disorders’ in the ADR section.

The following sections were updated in the SmPC:

4.1 Therapeutic Indications

Section 4.1 has been updated to include indication of Cabometyx as monotherapy for the treatment of adult patients with locally advanced or metastatic differentiated thyroid carcinoma (DTC), refractory or not eligible to radioactive iodine (RAI) who have progressed during or after prior systemic therapy.

4.2 Posology and method of administration

Section 4.2 has been updated to include information on the posology of Cabometyx in DTC.

4.4 Special warnings and precautions for use

Section 4.4 has been updated to expand on special warnings and precautions of hypertension on the use of Cabometyx.

4.8 Undesirable side effects

Section 4.8 has been updated to differentiate between adverse events occurring with Cabometyx use in DTC.

5.1 Pharmacodynamic properties

Section 5.1 has been updated to include information on clinical trials involving treatment with Cabometyx in DTC.

5.2 Pharmacokinetic properties

Section 5.2 has been updated to include information involving treatment with Cabometyx in DTC for paediatrics.

5.3 Preclinical safety data

Section 5.3 has been updated with additional wording regarding preclinical trial on male rates.

The following changes were made to the PIL:

1 What Cabometyx is and what it is used for

Information on the use of Cabometyx in locally advanced or metastatic differentiated thyroid carcinoma (DTC).

2. What you need to know before you take CABOMETYX

‘Cabometyx’ has been replaced with the wording ‘This medicine’ where mentioned throughout section 2.

3. How to take CABOMETYX

‘Cabometyx’ has been replaced with the wording ‘This medicine’ where mentioned throughout section 3.

4 Possible side effects

Section 4 has been updated to include information on possible side effects as a result of Cabometyx treatment.

Section 4.8 

Addition of Epistaxis as footnote in section 4.8 of SmPC.

5.1 Pharmacodynamic properties

The ATC code was updated from L01XE26 to L01EX07. 

The shelf-life has been changed to 4 years.

Section 4: In section 4 of the PIL, to remove “Increase blood levels of magnesium”, added twice.

Section 6: To make some formatting changes.

The following sections were changed in the PIL:

The black triangle warning has been removed

1. What CABOMETYX is and what it is used for

Clarification regarding the wording of the indication liver cancer in line with SmPC

2. What you need to know before you take CABOMETYX

Addition of sodium warning

6. Contents of the pack and other information

An update is being made to the list of the local representatives.

The following sections are being changed in the PIL:

The black triangle warning has been removed.

1. What CABOMETYX is and what it is used for

Clarification regarding the wording of the indication liver cancer in line with SmPC

2. What you need to know before you take CABOMETYX

Addition of sodium warning

6. Contents of the pack and other information

An update is being made to the list of the local representatives.

The following changes are being made in the SmPC:

The black triangle warning has been removed

4.1 Therapeutic indications

The authorised indication in renal cell carcinoma has been further clarified and reworded in the section 4.1 in line with the SmPC guidelines and the EMA assessors guide for the wording of therapeutic indication

4.2 Posology and method of administration

Minor re-wording of the following sentence ‘’CABOMETYX tablets and cabozantinib capsules are not bioequivalent and should not be used interchangeably (see section 5.2)’’ and other minor editorial changes.

4.4 Special warnings and precautions for use

Addition of sodium warning as below.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.

Minor re-wording of lactose warning

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose‑galactose malabsorption should not take this medicinal product.

4.5      Interaction with other medicinal products and other forms of interaction

Minor re-wording relating to the fact that the effect of cabozantinib on the pharmacokinetics of warfarin has not been investigated.

4.8 Undesirable effects

Section 4.8 has been updated to add “erythema” in the tabulated list of adverse drug reactions.   Also deletion and addition of footnotes at the end of Table 2.

5.1 Pharmacodynamic properties

Section 5.1 is being updated so that baseline and demographics data of hepatocellular carcinoma patients randomized in the CELESTIAL study is being rephrased to harmonize with other studies data.

5.2 Pharmacokinetic properties

Additional information relating to Pharmacokinetics in special patient populations (Renal Impairment) relating to unbound plasma cabozantinib

6.5 Nature and contents of container

Minor correction are being made to section 6.5 of the SmPC (to add “polyester coil”).

The following sections were changed in the PIL:

1 What Cabometyx is and what it is used for

Information on the use of Cabometyx in combination with nivolumab has been added to section 1.

2 What you need to know before you take CABOMETYX

Warnings and precautions section has been updated with precaution wording to inform doctor or pharmacist in the case of thyroid problems.

3 How to take Cabometyx

Information on the use and dosage recommended for Cabometyx when used in combination with nivolumab has been added to section 3.

4 Possible side effects

Section 4 has been updated to include information on possible side effects as a result of Cabometyx use as monotherapy and, possible side effects as a result of Cabometyx use in combination with nivolumab.

The following sections were changed in the SmPC:

4.1 Therapeutic indications

Information on the use of Cabometyx in combination with nivolumab for the treatment of advanced renal cell carcinoma in adults has been added to section 4.1.

4.2 Posology and method of administration

Section 4.2 has been updated to include information on the posology of Cabometyx as monotherapy and in combination with nivolumab in first line advanced RCC.

4.4 Special warnings and precautions for use

Section 4.4 has been updated to include special warnings and precautions on the use of Cabometyx in combination with nivolumab.

Warnings on Hepatotoxicity have also been updated in relation to the use of Cabometyx as combination therapy.

4.8 Undesirable side effects

Section 4.8 has been updated to differentiate between adverse events occurring with Cabometyx use as monotherapy or in combination with nivolumab.

5.1 Pharmacodynamic properties

Section 5.1 has been updated to include information on clinical trials involving treatment with Cabometyx in combination with nivolumab.

The following PIL section has been updated:

-Section 6: Addition of manufacturer Rottendorf Pharma GmbH

Changes have been made to the following sections of the PIL:

• Section 5, to remove details of blister packaging
• Section 6, to remove details of blister packaging

The following changes have been made to the SmPC:

• Update of section 6.5 to remove details of blister packaging.
• Update to section 8 to remove Marketing Authorisation Numbers associated with blister packaging

• In section 2 Warnings and Precautions, a sentence was added regarding oral healthcare
• In section 2 Interactions with other medicines, was updated to include medicines for the treatment of angina pectoris
• In section 4 Possible side effects, a sentence was added regarding side effects related to osteonecrosis and additionally;
• • to remove Anaemia, Oral pain and Dry mouth from the list of adverse reactions (ADRs),
  • to add Dysphagia and Hyperkeratosis to the existing ADR, 
  • to replace Peripheral sensory neuropathy by Peripheral neuropathy in order to reflect the broader medical concept and to add DVT (Deep vein thrombosis) to the existing ADR venous thrombosis in order to alert prescribers to the most frequently reported type of venous thrombosis.
• In section 6, update to name  and addresses of local affiliates 

• Update of section 4.2 to remove sentence regarding switching from capsule to tablet 
• Update of section 4.4 of the SmPC to include the addition of the risk of Osteonecrosis.
• Update of Section 4.8 of the SmPC based on the new version of the Company Core Safety Information (CCSI v4):
  • to remove Anaemia, Oral pain and Dry mouth from the list of adverse reactions (ADRs),
  • to add Dysphagia and Hyperkeratosis to the existing ADR, 
  • to replace Peripheral sensory neuropathy by Peripheral neuropathy in order to reflect the broader medical concept and to add DVT (Deep vein thrombosis) to the existing ADR venous thrombosis in order to alert prescribers to the most frequently reported type of venous thrombosis.
• Changes to the frequency categorisation of some ADRs are also proposed based on new pooled data.
• Update to section 5.1 to update Clinical efficacy and safety 

Correction to table in section 4.8 to reinstate AEs.

Type IAin variation to update sections 4.4 and 4.8 of the SmPC and sections 2 and 4 of the PIL to implement the recommendation of the PRAC further to artery dissections and aneurysms signal on Vascular Endothelial Growth Factor (VEGF) inhibitors for systemic administration

Type IAin variation to update sections 4.4 and 4.8 of the SmPC and sections 2 and 4 of the PIL to implement the recommendation of the PRAC further to artery dissections and aneurysms signal on Vascular Endothelial Growth Factor (VEGF) inhibitors for systemic administration

Update to sections 4.1, 4.2, 4.4, 4.8, 5.1, 5.2 and 10 due to additon of new indication for the treatment of hepatocellular carcinoma

Update to section 4.8 to include additional adverse events after review of PSUR for cabozantinib.

Update to SmPC to include indication for treatment for 1st line RCC patients.

Update to Sections 4.5, 5.1 and 5.3:

Section 4.5: addition of interaction between warfarin and cabozantanib

Sections 5.1 and 5.3: additional data on OS for patients