Invokana 100 mg and 300 mg film-coated tablets

Addition of warnings regarding urinary tract and kidney infections.

Addition of warning regarding urinary tract and kidney infections.

Section 1 - Addition of statement 'It also helps to slow down deterioration of kidney function in patients with T2DM by a mechanism beyond blood glucose lowering.'

Section 4 - Addition of warning 'Diabetic ketoacidosis may occur more frequently as the kidney function gets worse.'

Update to local representative details.

Section 2 – Removal of sodium warnings.

Section 4.1 – Addition of cross references to section 4.4, 4.5 and 5.1 in relation to renal events.

Section 4.2 – Addition of posology for the treatment of diabetic kidney disease. Updates to dose adjustment recommendations according to eGFR.

Section 4.4 – Amendment to warnings in relation to eGFR. Addition of warning in relation to risk of diabetic ketoacidosis in patients with decreased renal function. Amendment to warning in relation to lower limb amputation following outcome of the CREDENCE study. Addition of sodium warning in line with the updated Annex to the guideline on ‘Excipients in the labelling and package leaflet of medicinal products for human use’.

Section 4.8 – Amendment to data on patient exposure as a result of the CREDENCE study. Updated data in relation to diabetic ketoacidosis, lower limb amputation, volume depletion, bone fracture and renal impairment following outcome of the CREDENCE study.

Section 5.1 – Addition of further information on the mechanism of action. Addition of section on renal outcomes in the CREDENCE study.

Section 4.8 - Addition of photosensitivity and UTI as potential adverse events.

Addition of photosensitivity and UTI as potential adverse events.

Addition of information on monitoring of patients with diabetic ketoacidosis in section 4.4.

Texts updated following implementation of product class labelling effect regarding the possible side effect  - Fournier’s gangrene

Shelf-life changed form 2 years to 3 years

Removal of the Black Triangle

Update to document including changes to 

4.1       Therapeutic indications

4.4       Special warnings and precautions for use

Lower limb amputations

4.8       Undesirable effects

Summary of the safety profile

Description of selected adverse reactions

5.1       Pharmacodynamic properties

Lower limb amputation

Adverse reactions related to volume depletion

Genital mycotic infections

Bone fracture

Special populations

Renal impairment

Clinical efficacy and safety

Blood pressure

Cardiovascular outcomes

 All‑cause mortality

Heart failure requiring hospitalization

Renal Endpoints

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of latest renewal: 26 July 2018

The black triangle has been removed from the beginning of the SPC.

Section 4.2

‘estimated glomerular filtration rate (   )’ has been added to the first paragraph in section 4.2

‘Special populations’ subheading added to the section.

‘Studies’ replaced ‘trials’ at several places within the section.

‘careful monitoring’ replaces ‘caution’

Section 4.5

‘medicinal product’ replacing ‘drug’ within the second paragraph of section 4.5

‘medicinal product’ replacing ‘drug’ within subheading ‘…/Laboratory test interference’

Section 5.1

‘other’ removed from the first sentence of section 5.1

‘Older patients’ replace ‘elderly’

Section 6.1

‘anhydrous’ removed from ‘lactose anhydrous’ within tablet core excipients

‘Polyvinyl-alcohol’ has become ‘Poly(vinyl alcohol)

Section 8

‘Film-coated’ added to section

Section 9

‘Date of latest renewal: 26 July 2018 ‘  added to section 9

Section 10

Date of revision updated to ’26 July 2018’                      

Section 2

‘Each tablet contains less than 1 mmol sodium (23 mg), and is essentially sodium-free.’ This text has been added to ‘Excipient(s) with known effect’ section for both strengths.

Section 4.4

This text below has be removed from the section:

‘General

Invokana has not been studied in patients with type 1 diabetes and is therefore not recommended for use in these patients

Invokana should not be used for the treatment of diabetic ketoacidosis as it is not effective in this setting.’

The text in bold has been added to the section and the text in strikethrough has been removed from the section:

‘The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product medicine.’

Section 5.1

The text in bold has been added to the section and the text in strikethrough has been removed from the section:

‘A total of 10,285 10,501 patients with type 2 diabetes participated in nine ten double blind, controlled clinical efficacy and safety studies conducted to evaluate the effects of Invokana on glycaemic control. The racial distribution was 72% White, 16% Asian, 4 5% Black, and 8% other groups. 16 17% of patients were Hispanic. Approximately 58% of patients were male. Patients had an overall mean age of 59.6 59.5 years (range 21 years to 96 years), with 3,082 3,135 patients ≥ 65 years of age and 510 513 patients ≥ 75 years of age. 58% of patients had a body mass index (BMI) ≥ 30 kg/m2….’

The text below has been added to section 5.1:

‘Furthermore, canagliflozin was studied as triple therapy with metformin and sitagliptin and dosed with a titration regimen, using a starting dose of 100 mg and titrated to 300 mg as early as week 6 in patients requiring additional glycaemic control who had appropriate eGFR and were tolerating canagliflozin 100 mg (table 2). Canagliflozin dosed with a titration regimen produced clinically and statistically significant (p < 0.001) results relative to placebo in glycaemic control, including HbA1c and change from baseline fasting plasma glucose (FPG), and a statistically significant (p < 0.01) improvement in the percentage of patients achieving HbA1c < 7%. In addition, reductions in body weight and systolic blood pressure relative to placebo were observed.’

Within table 2 there has been this change below:

‘Difference from placebo (adjusted mean)

(97.5 95 % CI) ‘

There has been this addition to table 2

There has been an addition to the footnote of table 2:

‘ e           Canagliflozin 100 mg titrated to 300 mg

 F             p<0.01 compared to placebo

G             90.7% of subjects in the canagliflozin untitrated to 300 mg.’

This text and table below have been added to the section:

 ‘Canagliflozin as initial combination therapy with metformin

Canagliflozin was evaluated in combination with metformin as initial combination therapy in patients with type 2 diabetes failing diet and exercise. Canagliflozin 100 mg and canagliflozin 300 mg in combination with metformin XR resulted in a statistically significant greater improvement in HbA_1C compared to their respective canagliflozin doses (100 mg and 300 mg) alone or metformin XR alone (table 4).

Addition of table 4

Section 10

Date of revision updated to ‘15 March 2018’

Section 5.1

ATC code changed to A10BK02.

Section 4.4: Revision to include class labelling text on diabetic ketoacidosis: “Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been reported in patients treated with SGLT2 inhibitors, including canagliflozin.”

Section 10: Commission Decision of 28 April 2017

Section 4.4: addition of information on lower limb amputations

Section 4.8: addition of “lower limb amputations” as adverse reaction under frequency “uncommon”

Section 10: Commission Decision date of 20 April 2017

Addition of adverse reaction ‘angioedema’ under “not known” frequency. Addition of adverse reactions pyelonephritis and urosepsis for existing adverse reaction ‘Urinary tract infection’