Documented changes

Sections of the PIL

Changes/updates

Section 6 Contents of the pack and other information

Lenvatinib (as mesilate) has been changed to lenvatinib (as mesylate)

The following pack sizes have been added:       

The capsules come in blisters of polyamide/aluminium/PVC with a push through aluminium foil lidding in cartons of 30,60 or 90 hard capsules.

Not all pack sizes may be marketed

The date of revision of text has been updated to 10/2019

Documented changes

Sections of the SmPC

Changes/updates

Section 2 Qualitative and quantitative composition

Mesilate has changed to mesylate

Section 6.5 Nature and contents of container

The wording has changed to include the following:

Polyamide/Aluminium/PVC/Aluminium blisters containing 10 capsules. Each carton contains

30 ,60,or 90 hard  capsules.

Not all pack sizes may be marketed.

Section 8 Marketing authorisation number(s)

The wording has changed to include the following:

Lenvima 4mg hard capsules

EU/1/15/1002/001

EU/1/15/1002/003

EU/1/15/1002/004

Lenvima 10 mg hard capsules

EU/1/15/1002/002

EU/1/15/1002/005

EU/1/15/1002/006

Section 10 Date of Revision of the Text

Date of revision of text has been updated to October 2019

Section 4.4

Updated to amend the existing warnings on proteinuria and non-gastro-intestinal fistula

Section 4.8

Pneumothorax and nephrotic syndrome added as new adverse drug reactions (ADRs) with uncommon frequency

Section 10

The date of revision of text has been updated to 10/2018

Documented changes

Sections of the SmPC

Changes/updates

Section 6.3

 Shelf-life has been extended from 3 to 4 years.

Section 10

The Date of revision of text has been updated

Documented changes

Sections of the SmPC

Changes/updates

Section 6.3

 Shelf-life has been extended from 3 to 4 years.

Section 10

The Date of revision of text has been updated

Documented changes

Sections of the SmPC

Changes/updates

Section 4.8

Updated to add the adverse events “cholecystitis” with a frequency of common, and the adverse events “pancreatitis”, “amylase increased” and “lipase increased” with a frequency of uncommon, common and common respectively.

Section 5.2

A correction has been done to ‘Biotransformation’ subsection as below:

“The main metabolic pathways in humans were identified as oxidation by aldehyde oxidase, demethylation via CYP3A4, glutathione conjugation with elimination of the O-aryl group (chlorophenyl moiety), and combinations of these pathways followed by further biotransformations (e.g., glucuronidation, hydrolysis of the glutathione moiety, degradation of the cysteine moiety, and intramolecular rearrangement of the cysteinylglycine and cysteine conjugates with subsequent dimerisation).”  

Section 10

The Date of revision of text has been updated

Documented changes

Sections of the SmPC

Changes/updates

Section 4.8

Updated to add the adverse events “cholecystitis” with a frequency of common, and the adverse events “pancreatitis”, “amylase increased” and “lipase increased” with a frequency of uncommon, common and common respectively.

Section 5.2

A correction has been done to ‘Biotransformation’ subsection as below:

“The main metabolic pathways in humans were identified as oxidation by aldehyde oxidase, demethylation via CYP3A4, glutathione conjugation with elimination of the O-aryl group (chlorophenyl moiety), and combinations of these pathways followed by further biotransformations (e.g., glucuronidation, hydrolysis of the glutathione moiety, degradation of the cysteine moiety, and intramolecular rearrangement of the cysteinylglycine and cysteine conjugates with subsequent dimerisation).”  

Section 10

The Date of revision of text has been updated

Documented changes

Sections of the SPC

Changes/updates

Section 4.2

 For lenvatinib related toxicities, “Adverse reactions requiring dose modification of lenvatinib” has been added as Table 1.

Section 4.4

Section 4.4 has been updated to include special warnings/precautions on non-gastrointestinal fistula and diarrhoea.

In addition, hypertension, haemorrhage, QT interval prolongation and Impairment of thyroid stimulating hormone suppression/Thyroid dysfunction subheading have been updated with new information.

Following wording regarding hypertension has been removed from the SmPC: “For patients with hypertension and proteinuria, treatment with an angiotensin-converting enzyme inhibitor or angiotensin-II receptor antagonist is preferred.”

Section 4.8

“Arterial thromboembolism (3.9%)” has been added to the most important serious adverse reactions.

New adverse reaction frequency has been added to the SmPC as “Not known (cannot be estimated from available data)”.

The table of adverse reactions has been updated to include      “Non-Gastrointestinal fistula^k ” as a general disorder and administration site AE under “Not known” frequency.

k:  Non-gastrointestinal fistula includes cases of fistula occurring outside of the stomach and intestines such as tracheal, tracheo-oesophageal, oesophageal, female genital tract fistula, and cutaneous fistula.

New adverse reaction descriptions have been added for:

·        Gastrointestinal perforation and fistula formation

·        Non-Gastrointestinal fistulae

·        QT interval prolongation

·        Diarrhoea

Description of following adverse reactions have been updated:

·        Renal failure and impairment

·        Cardiac dysfunction

·        Posterior reversible encephalopathy syndrome (PRES) / Reversible posterior leucoencephalopathy syndrome (RPLS)

·        Hepatotoxicity

·        Arterial thromboembolisms

·        Haemorrhage

Section 5.2

Change of wording from severe hepatic impairment to severe renal impairment (see below):

Lenvatinib exposure, based on AUC0-inf data, was 101%, 90%, and 122% of normal for subjects with mild, moderate, and severe renal impairment, respectively.  It is unknown whether there is a change in the plasma protein binding in renally impaired subjects.  See section 4.2 for dosing recommendation.

Section 10

The Date of revision of text has been updated

Documented changes

Sections of the SPC

Changes/updates

Section 4.2

 For lenvatinib related toxicities, “Adverse reactions requiring dose modification of lenvatinib” has been added as Table 1.

Section 4.4

Section 4.4 has been updated to include special warnings/precautions on non-gastrointestinal fistula and diarrhoea.

In addition, hypertension, haemorrhage, QT interval prolongation and Impairment of thyroid stimulating hormone suppression/Thyroid dysfunction subheading have been updated with new information.

Following wording regarding hypertension has been removed from the SmPC: “For patients with hypertension and proteinuria, treatment with an angiotensin-converting enzyme inhibitor or angiotensin-II receptor antagonist is preferred.”

Section 4.8

“Arterial thromboembolism (3.9%)” has been added to the most important serious adverse reactions.

New adverse reaction frequency has been added to the SmPC as “Not known (cannot be estimated from available data)”.

The table of adverse reactions has been updated to include      “Non-Gastrointestinal fistula^k ” as a general disorder and administration site AE under “Not known” frequency.

k:  Non-gastrointestinal fistula includes cases of fistula occurring outside of the stomach and intestines such as tracheal, tracheo-oesophageal, oesophageal, female genital tract fistula, and cutaneous fistula.

New adverse reaction descriptions have been added for:

·        Gastrointestinal perforation and fistula formation

·        Non-Gastrointestinal fistulae

·        QT interval prolongation

·        Diarrhoea

Description of following adverse reactions have been updated:

·        Renal failure and impairment

·        Cardiac dysfunction

·        Posterior reversible encephalopathy syndrome (PRES) / Reversible posterior leucoencephalopathy syndrome (RPLS)

·        Hepatotoxicity

·        Arterial thromboembolisms

·        Haemorrhage

Section 5.2

Change of wording from severe hepatic impairment to severe renal impairment (see below):

Lenvatinib exposure, based on AUC0-inf data, was 101%, 90%, and 122% of normal for subjects with mild, moderate, and severe renal impairment, respectively.  It is unknown whether there is a change in the plasma protein binding in renally impaired subjects.  See section 4.2 for dosing recommendation.

Section 10

The Date of revision of text has been updated