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FDA: Boxed Warning: Amputation Risk for Canagliflozin

Post-marketing trial data show doubled rates compared to placebo.

Based on new data from two large clinical trials, the FDA has concluded that the type 2 diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR) causes an increased risk of leg and foot amputations. FDA is requiring new warnings, including the most prominent Boxed Warning, to be added to the canagliflozin drug labels to describe this risk.

Final results from two clinical trials – the 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) – showed that leg and foot amputations occurred about twice as often in patients treated with canagliflozin compared to patients treated with placebo, which is an inactive treatment. Amputations of the toe and middle of the foot were the most common; however, amputations involving the leg, and below and above the knee also occurred. Some patients had more than one amputation, some involving both limbs.

The CANVAS trial showed that over a year’s time, the risk of amputation for patients in the trial were equivalent to:

  • 5.9 out of every 1,000 patients treated with canagliflozin
  • 2.8 out of every 1,000 patients treated with placebo

The CANVAS-R trial showed that over a year’s time, the risk of amputation for patients in the trial were equivalent to:

  • 7.5 out of every 1,000 patients treated with canagliflozin
  • 4.2 out of every 1,000 patients treated with placebo

The differences were statistically significant. CANVAS was the FDA-required study investigating cardiovascular outcomes; CANVAS-R assessed renal endpoints.

Lower-limb infections, gangrene, diabetic foot ulcers, and ischemia were the most common precipitating factors for amputations in the studies, the FDA said. Patients with previous amputations were more likely than others to need additional ones during the trial. Notably, patients in the two trials were included only if they had cardiovascular disease or risk factors for it other than type 2 diabetes. However, the new warning applies to all patients regardless of cardiovascular risk.

This information is an update to the May 18, 2016 MedWatch safety alert. Canagliflozin is a prescription medicine 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 medicine metformin under the brand name Invokamet.

Patients taking canagliflozin should notify your health care professionals right away if you develop new pain or tenderness, sores or ulcers, or infections in your legs or feet. Talk to your health care professional if you have questions or concerns. Do not stop taking your diabetes medicine without first talking to your health care professional.

Health care professionals should, before starting canagliflozin, consider factors that may predispose patients to the need for amputations. These factors include a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Monitor patients receiving canagliflozin for the signs and symptoms described above and discontinue canagliflozin if these complications occur.

 

See the FDA Drug Safety Communication for additional information, including a data summary.