The risk for leg and foot amputation is now listed under Warnings and Precautions instead of box warning for the SGLT2 inhibitor canagliflozin.
Canagliflozin, the generic drug for Invokana, is a sodium-glucose cotransporter-2 (SGLT2) inhibitor used in patients with type 2 diabetes as an adjunct to diet and exercise to lower blood sugar. This medication lowers blood sugar by removing sugar from the body through the urine with help from the kidneys.
On May 16, 2017, The Food and Drug Administration (FDA) announced an increased risk of leg and foot amputations in people with diabetes taking canagliflozin. The FDA made this decision after reviewing data from two large trials. These two trials were the CANVAS and CANVAS-R. CANVAS trial was the Canagliflozin Cardiovascular Assessment Study, and CANVAS-R was “A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus”. These studies showed a significantly higher incidence of leg and foot amputations in patients treated with canagliflozin than in patients treated with a placebo. The results were twice as high in patients treated with canagliflozin. The CANVAS trial showed that 5.9 out of every 1,000 patients treated with canagliflozin and 2.8 out of every 1,000 patients treated with placebo were at risk for amputations. Amputations of the toe and middle of the foot were the most common in these trials. Lower limb infections, gangrene, and diabetic foot ulcers were the most common conditions that led to amputations. The risk of amputation was highest in patients with a baseline history of prior amputation and neuropathy. In July of 2017, product labeling was modified to include these warnings.
As of August 2020, this is no longer the case for the use of canagliflozin. The Food and Drug Administration decided to remove the black boxed warning for the risk of leg and foot amputations. This decision was made after reviewing data from three clinical trials. These clinical trials revealed that canagliflozin reduced the risk of heart attack, stroke, or death and the risk of end-stage kidney disease in patients with type 2 diabetes. The heart and kidney benefit of this medication contributed to different uses. Findings also showed that the risk of amputation is lower than previously described when appropriately monitored. While the risk for amputations remains, it has been removed as a Box Warning and listed under the Warnings and Precautions section. Under the Warnings and Precautions section, it states to monitor patients for infection or ulcers of the lower limb and discontinue in these scenarios.
As stated, even though leg and foot amputations are no longer a boxed warning, it is still listed as a warning and precaution for this drug. According to the CDC, about 73,000 non-traumatic lower-limb amputations were performed in adults aged 20 years or older with diagnosed diabetes in 2010. The rate of amputations rose 50% between 2009 and 2015, with African American patients losing limbs three times more than other races. The American Diabetes Association found a 17% decrease in the risk of amputation for patients that resided in states with Medicaid expansions.
In conclusion, the amputation risk is no longer a boxed warning, but it is still relevant to patients taking canagliflozin. While taking canagliflozin, patients should inform their physician if there is new pain or tenderness, any sores, ulcers, or infections in the leg or foot. The physician should also be notified if the patient has a history of amputation with heart disease or if they are at risk for heart disease; if they have had blocked or narrowed blood vessels, damage to the nerves (neuropathy) in the leg, or diabetic foot ulcers or sores. All of these precautions are in place to reduce the patient’s risk of amputations.
- The Food and Drug Administration decided to remove black boxed warning for the risk of leg and foot amputations for the diabetes medicine canagliflozin.
- Canagliflozin’s risk for amputations remains and is still described in the Warnings and Precautions section of its prescribing information.
- While taking canagliflozin, patients should inform their physician if there is new pain or tenderness, any sores, ulcers, or infections in the leg or foot.
U.S. Food and Drug Administration. (2020, August 26). FDA removes Boxed Warning about risk of leg and foot amputations for the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR) Retrieved from https://www.fda.gov/drugs/drug-safety-and-availability/fda-removes-boxed-warning-about-risk-leg-and-foot-amputations-diabetes-medicine-canagliflozin
U.S. Food and Drug Administration. (2017, May 16). FDA confirms the risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). Drug Safety Communications. Retrieved from https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-confirms-increased-risk-leg-and-foot-amputations-diabetes-medicine
American Diabetes Association. (2016, February 5). Foot Complications. Retrieved from http://www.diabetes.org/living-with-diabetes/complications/foot-complications/
Destiny Funchess, PharmD Candidate, Tougaloo College, South College School of Pharmacy