FDA Removes Canagliflozin's Boxed Warning for Amputations

A Boxed Warning on increased risk of leg and foot amputations has been removed from the label of canagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor.

Canagliflozin was originally indicated for patients with type 2 diabetes (T2D) and is marketed by Johnson & Johnson’s Janssen unit.

In 2017, the FDA confirmed increased risk of leg and foot amputations with the medication, commercially marketed as Invokana, Invokamet, and Invokamet XR. At that time, results from 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 who took canagliflozin compared with those who received a placebo.

The warning’s removal comes after the FDA reviewed new data from 3 clinical trials. “Safety information from recent clinical trials…suggests that the risk of amputation, while still increased with canagliflozin, is lower than previously described, particularly when appropriately monitored,” the administration’s statement reads.

A boxed warning is the FDA’s most prominent and is included within the package insert of a drug. Canagliflozin’s amputation risk remains and is still described in the Warnings and Precautions section of the drug’s prescribing information.

Canagliflozin has since been approved for multiple other conditions including reducing the risk of major heart-related events such as stroke in 2018. In 2019, canagliflozin was also approved by the FDA to prevent kidney failure and hospitalization for heart failure.

According to the FDA, “these newly identified effects of canagliflozin on heart and kidney disease show significantly enhanced benefit of this medicine.”

Providers and patients should continue to monitor for new pain, tenderness, sores, ulcers and infection in both the legs and feet when taking canagliflozin. Side effects involving the treatment and other medicines should also be reported to the FDA’s MedWatch program.

Amputations continue to be a serious outcome among patients with diabetes living in the United States. Even though progress in diabetes treatments and technology has been made, the rate of amputations rose 50% between 2009 and 2015, while African American patients lose limbs at triple the rate of other groups.