FDA Issues Safety Alert for Canagliflozin


The new warning is based on recent data from 2 clinical trials.

The FDA has issued a drug safety communication warning concerning Janssen’s type 2 diabetes drug, canagliflozin (Invokana, Invokamet, Invokamet XR) due to increased risk of leg and foot amputations. A boxed warning will be added to canagliflozin drug labels to describe the risk.

The new warning is based on recent data from 2 clinical trials, CANVAS (Canagliflozin Cardiovascular Assessment Study) and CANVAS-R, that demonstrated an increased risk of leg and foot amputation, mostly affecting toes. The results indicated that leg and foot amputations occurred about twice as often in patients treated with the drug than those treated with a placebo.

Results from the CANVAS trial over a 1-year period showed that the risk was equivalent to:

  • 5.9 out of every 1000 patients treated with canagliflozin
  • 2.9 out of every 1000 patients treated with placebo

Results from the CANVAS-R trial over a 1-year period showed that the risk was equivalent to:

  • 7.5 out of every 1000 patients treated with canagliflozin
  • 4.2 out of every 1000 patients treated with placebo

The most common amputations that occurred were of the toe and middle of the foot. However, amputations of the leg, below and above the knee, also occurred, and some patients had more than 1 amputation.

According to Janssen's statement, "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 US 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."

FDA officials urge patients taking canagliflozin to notify their health care providers immediately if new pain or tenderness, sores or ulcers, or infections in the legs or feet occur. Health care professionals should identify factors that may predispose patients to the need for amputations before starting the therapy. History of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers are all factors that may put patients at an increased risk.

Health care professionals should inform patients of the risk and instruct patients to recognize the signs and symptoms of precipitating medical events that can lead to the need for amputation.

Canagliflozin is used with diet and exercise to lower blood sugar in adults with type 2 diabetes.


FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR) [news release]. FDA’s website. https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery. Accessed May 16, 2017.

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