dm+d

703681008

Medicine Compliance Aid Stability

InvokanaJanssen-Cilag Ltd

Janssen-Cilag Ltd
Invokana
Tablets f/c 100mg, 300mg
A2 · Amber 2No stability data is available, the manufacturer does not, or cannot recommend use in CAs but there are no theoretical concerns with the product.
No special precautions for storage
No special precautions for storage
23 January 2015

New Medicines

InvokanaDiabetic kidney disease (nephropathy) in adults with type 2 diabetes

Information

Invokana
Licence extension / variation
Janssen-Cilag
Scios

Development and Regulatory status

Launched
Launched
Launched
June 2020
Aug 20Final EMA conclusions were "A separate indication or separate indent for treatment of Diabetic Kidney Disease in SmPC 4.1 is not approvable. Invokana in addition to standard of care for the treatment of diabetic kidney disease is covered by the current indication “Treatment of adults with insufficiently controlled type 2 diabetes mellitus”. Minor update to SmPC 4.1 and addition of relevant information to other SmPC sections (mainly 4.2, 4.4, 4.8 and 5.1) were agreed." [28]
Jun 20Licence change approved in EU [27].
May 20EU positive opinion for a change to an existing indication to include effects on renal events. The revised wording states: Invokana is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise: as monotherapy when metformin is considered inappropriate due to intolerance or contraindications or in addition to other medicinal products for the treatment of diabetes. For study results with respect to combination of therapies, effects on glycaemic control, and cardiovascular and renal events, and the populations studied, see sections 4.4, 4.5 and 5.1 [26].
Sep 19Approved in US [24].
Aug 19Filed in EU [23].
May 19Granted priority review status in the US shortening the review period from 10 to 6 months [20].
Mar 19Janssen submit sNDA to US FDA seeking a new indication for canagliflozin to reduce risk of end-stage kidney disease (ESKD), doubling of serum creatinine (a key predictor of ESKD) and renal or cardiovascular (CV) death in adults with T2D and CKD [18].
Jan 19Filings in EU & US planned for 2019 [15].
Feb 18EU filing will be using the centralised procedure [13].
Oct 15PIII development ongoing in US & EU [7].
May 15FDA safety warning after over 20 cases of diabetic ketoacidosis (DKA), requiring hospitalisation, were seen in pts treated with SGLT2 inhibitors to date. The FDA warned that pts taking SGLT2 inhibitors should monitor themselves for any signs of ketoacidosis, such as difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue or sleepiness [4].
Apr 14PIII in the US & EU [1]

Category

Selective sodium glucose co-transporter type 2 (SGLT2) inhibitor
Currently 3.8 million people in the UK are diagnosed with diabetes (90% type 2), and it is estimated that a further 1 million people with type 2 diabetes have not yet been diagnosed [16]. Chronic painful neuropathy is estimated to affect up to 26% of people with diabetes [17].
Diabetic kidney disease (nephropathy) in adults with type 2 diabetes
Oral

Further information

Yes

Trial or other data

Nov 19Data from a new secondary analysis of the CREDENCE trial shows consistent renal and cardiovascular benefit when treated with canagliflozin including when pts had moderate to severe renal deficiency. Of the 4,401 pts, 30% had eGFR 30 to <45 mL/min/1.73 m2, 29% had eGFR 45 to <60 mL/min/1.73 m2 and 41% had eGFR 60 to 0.11) [25].
Jul 19Subgroup analysis from the PIII CREDENCE trial published in Circulation; it reports that canagliflozin significantly reduced major CV events (HR 0.80; 95% CI; 0.67-0.95; p=0.01) overall, as well as kidney failure, in patients with type 2 diabetes and CKD including in participants who did not have prior CVD [22].
Jun 19Positive results of a new subgroup analysis from the PIII CREDENCE study presented at the American Diabetes Association´s 79th scientific sessions showed canagliflozin could produce benefits across diabetic chronic kidney disease (CKD) patients with or without known cardiovascular disease. One of the study investigators reported that this was "the first time a type 2 diabetes medicine has shown a cardiovascular benefit in patients who did not have pre-existing CV disease. This is an important, clinically meaningful finding as it uncovers the potential of canagliflozin to offer a protective effect in this patient population" [21].
Apr 19PIII CREDENCE RCT (n=4401) is published in the NEJM; the authors reported that the relative risk of renal failure and cardiovascular events was 30% lower with canagliflozin vs placebo at median follow-up of 2.62 years (event rates of 43.2 and 61.2 per 1000 patient-years, respectively; P=0.00001) [19]. A related editorial estimates that “among 1000 patients treated for 2.5 years, 22 would need to be treated with canagliflozin to prevent the composite primary outcome of end-stage kidney disease, doubling of the serum creatinine level, or renal or cardiovascular death. In addition, among the same number of patients, canagliflozin treatment would prevent 22 hospitalizations for heart failure and 25 composite events of cardiovascular death, myocardial infarction, or stroke.”
Jul 18PIII CREDENCE trial canagliflozin vs.placebo (n~4400; eGFR≥30-<90 mL/min; albuminuria, on max dose ACEI/ARB) is stopped early on achievement of pre-specified criteria for primary composite efficacy endpoint [14].
Dec 17NCT02065791 (CREDENCE) ongoing but not recruiting. Estimated primary completion date now Jun 19 [12].
Jan 17CREDENCE trial is currently recruiting patients. Estimated primary completion date remains Feb 19 [11].
Apr 16EMA start review of canagliflozin after noting an increase in amputations, mostly affecting the toes seen in the CANVAS trial [10].
Feb 16The EMA has confirmed recommendations to minimise the risk of diabetic ketoacidosis in patients taking SGLT2 inhibitors (a class of type 2 diabetes medicines)[9].
Oct 15PRAC recommendation based on safety review of SGLT2 inhibitors expected in Feb 16 [6].
Jun 15The PRAC of the EMA has started a review of the SGLT2 inhibitors with the aim of evaluating their risk of diabetic ketoacidosis. It is estimated that the review will compete in Oct 15 [5].
Jan 15NCT02065791 (CREDENCE) ongoing and recruiting participants The goal of this study is to assess whether cancliflozin has a renal and vascular protective effect in the progression of renal impairment relative to placebo in patients with T2DM, stage 2/3 CKS and macroalbuminuria , who are receiving SOC including a maximum tolerated daily dose of an ACEi or ARB. The study is estimated to complete in Jan 2020 with final data collection for primary outcome in Feb 19 [8].
Jun 14PIII (NCT02065791) study is currently recruiting pts. It was initiated in Feb 14 to assess whether canagliflozin has a renal and vascular protective effect in reducing the progression of renal impairment relative to placebo in participants with type 2 diabetes mellitus (T2DM), Stage 2 or 3 chronic kidney disease (CKD) and macroalbuminuria, who are receiving standard of care including a maximum tolerated labeled daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). The primary outcome is time to first occurrence of an event in the primary composite endpoint which includes end-stage kidney disease (ESKD), doubling of serum creatinine, renal or cardiovascular (CV) death. Pts are being recruited in the US & Canada. The study is expected to complete in Feb 19 [2].

Evidence based evaluations

InvokanaHeart failure - any type, regardless of diabetes status

Information

Invokana
Janssen-Cilag
Janssen

Development and Regulatory status

None
None
Phase III Clinical Trials

Category

SGLT2-inhibitor
Nearly 500,000 people in England have heart failure. Both the prevalence and incidence of heart failure increase with age. About 20% of people diagnosed with heart failure die within the first year, with a 5-year mortality rate of about 50% [1].
Heart failure - any type, regardless of diabetes status
Oral