FDA Issues Boxed Warning for Canagliflozin Due to Amputation Risk

The FDA today issued a new boxed warning for canagliflozin, the type 2 diabetes (T2D) therapy sold as Invokana (and in a combination, Invokamet), due to risk of leg and foot amputation risk.

In a statement, the FDA said the warning is due to the results of 2 trials, CANVAS (Canagliflozin Cardiovascular Assessment Study) and CANVAS-R (A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus), which showed that leg and foot amputations were twice as likely in patients taking canagliflozin as those randomly assigned a placebo.

In the patients studied, amputations of the toe and middle of the foot were most common, but amputations of the leg, both above and below the leg, were also seen. The boxed warning follows a May 18, 2016, safety alert.

Canagliflozin is a sodium glucose co-transporter-2 (SGLT2) inhibitor, which works by targeting the protein that reabsorbs glucose in the renal system and causes excess sugar to be expelled in the urine.

The FDA urges physicians considering prescribing canagliflozin to consider factors that could lead to amputation, such as prior history, peripheral vascular disease, neuropathy, and diabetic foot ulcers.

Janssen, the maker of canagliflozin, issued a statement in response to today's action, which read in part:

"The finding of increased risk of lower-limb amputation—primarily of the toe and forefoot—observed last year in the interim safety analysis of the CANVAS study of patients at high risk for cardiovascular events or with established CV disease, was confirmed in the final analysis of CANVAS and CANVAS-R.

The U.S. FDA shared the initial observation last May in a Drug Safety Communication, and Janssen shared it directly with Heath Care Professionals. While the incidence was low, the highest incidence of amputations across all treatments was seen in patients with prior amputation.

At Janssen, patient safety is our highest priority. We are working with FDA to include this information in the prescribing information for canagliflozin and look forward to the presentation of the full CANVAS Program results at the American Diabetes Association Scientific Sessions in June."