The FDA has alerted the public about interim safety results from an ongoing clinical trial that found an increase in leg and foot amputations, mostly affecting the toes, in patients treated with the diabetes medication canagliflozin (Invokana, Invokamet). The agency has not determined whether canagliflozin increases the risk of leg and foot amputations. It is currently investigating this new safety issue.

Patients taking canaglifozin should notify their health care professionals immediately if they notice new pain or tenderness, sores or ulcers, or infections in their legs or feet.

Health care professionals should follow the recommendations in the canagliflozin labels. Patients should be monitored for the signs and symptoms described above, and they should be advised to seek medical advice if they experience them.

Canagliflozin is a prescription medication used with diet and exercise to lower blood sugar in adults with type-2 diabetes. It belongs to a class of drugs called sodium-glucose cotransporter-2 (SGLT2) inhibitors. Canagliflozin lowers blood sugar by causing the kidneys to remove sugar from the body through the urine. It is available as a single-ingredient product under the brand name Invokana and also in combination with the diabetes drug metformin under the brand name Invokamet. Both products are marketed by Janssen.

In the ongoing Canagliflozin Cardiovascular Assessment Study (CANVAS), the trial’s independent data-monitoring committee (IDMC) identified an increased risk of leg and foot amputations. The amputations occurred about twice as often in patients treated with canagliflozin compared with those receiving placebo. An interim analysis showed that over one year, the risks of amputation for patients in the trial were equivalent to:

  • Seven out of every 1,000 patients treated with 100 mg daily of canagliflozin
  • Five out of every 1,000 patients treated with 300 mg daily of canagliflozin
  • Three out of every 1,000 patients given placebo

Patients in the CANVAS study have been followed for an average of 4.5 years. The IDMC has recommended that the study continue.

The IDMC also reported that a second, similar study evaluating canagliflozin, the CANVAS-R trial, has not shown the same risks of increased leg and foot amputations to date. Patients in that study have been followed for an average of nine months.

Source: FDA; May 18, 2016.


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