EMA Probes Link With Diabetes Drug Canagliflozin, Toe Amputation

April 15, 2016

The European Medicines Agency (EMA) has begun a review of the sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (Invokana, Janssen), used to treat type 2 diabetes, after an increase in amputations, mostly of the toe, was observed in a large ongoing clinical trial of the drug.

Cases of lower-limb amputation occurred in both the active drug and placebo groups in the Canagliflozin Cardiovascular Assessment Study (CANVAS), which is the cardiovascular-outcomes trial for this agent and is randomizing just over 4000 type 2 diabetes patients to canagliflozin 100 mg or 300 mg daily or to placebo, slated for completion in 2017.

The EMA Pharmacovigilance Risk Assessment Committee (PRAC) has requested more information from the company to assess whether canagliflozin causes an increase in lower-limb amputations and whether any changes are needed in the way this medicine is used in the European Union.

The EMA notes that patients with diabetes (and especially those with poorly controlled diabetes and preexisting vascular problems) are at increased risk of infection and ulceration, which can result in lower-limb amputations. No increase in such amputations was seen in 12 other completed clinical trials with canagliflozin, it adds, although a small, statistically nonsignificant increase in the number of amputations occurred in another ongoing study called CANVAS-R.

Both CANVAS and CANVAS-R involve patients at high cardiovascular risk.

The PRAC will also ask for data on other medicines in the SGLT2 inhibitor class, which include dapagliflozin (Farxiga, Forxiga, AstraZeneca) and empagliflozin (Jardiance, Lilly/Boehringer Ingelheim).

"Based on this, the PRAC may decide to extend the scope of the review to cover these medicines," the EMA notes.

Combination products containing SGLT2 inhibitors with metformin are also available in the European Union.

While the review on canagliflozin is ongoing, healthcare professionals will receive a letter reminding them about the importance of routine foot care among diabetic patients to avoid cuts or sores of the feet and to treat them promptly should they occur to prevent infection and ulceration.

Patients at increased risk of amputation (such as those who have had a previous amputation) should be carefully monitored. As a precautionary measure, doctors may consider stopping treatment with canagliflozin in patients who develop significant foot complications.

"Patients who have any questions should speak to their doctor or pharmacist. It is important that patients with diabetes continue to take their prescribed treatment and not stop treatment without first consulting a healthcare professional," the EMA notes.

Details of Amputations Occurring in CANVAS, CANVAS-R

The incidence of lower-limb amputation in CANVAS is currently seven in 1000 patient-years with canagliflozin 100 mg daily and five in 1000 patient-years with canagliflozin 300 mg daily, compared with three in 1000 patient-years with placebo, EMA indicates.

Patients in the study have so far been followed up for an average of 4.5 years.

In CANVAS-R, a study on the effects of canagliflozin on renal end points in adults with type 2 diabetes, the incidence of lower-limb amputation is seven in 1000 patient-years with canagliflozin and five in 1000 patient-years with placebo. This difference is not statistically significant. Patients in this study have so far been followed up for an average of 0.75 years.

The independent data monitoring committee for CANVAS and CANVAS-R has recommended that the trials should continue.


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