New clinical trial data compelled FDA to remove the boxed warning on canagliflozin products regarding the risk of amputation. The FDA originally warned of a potential risk for lower limb amputations with canagliflozin on May 18, 2016 based on interim data from two trials: Canagliflozin Cardiovascular Assessment Study (CANVAS) and A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus (CANVAS-R). The boxed warning was added in May of 2017. Data from these 2 trials suggested that patients using canagliflozin had double the risk of leg and foot amputations compared with similar patients not using canagliflozin. FDA states there is still an increased risk of amputation associated with canagliflozin, but it is lower than previously described, especially when patients are appropriately monitored. Since the boxed warning was originally added in 2017, canagliflozin has had additional FDA-approved indications added. Reduction in the risk of major heart-related events was added in 2018, and reduction in the risk of end-stage kidney disease, worsening kidney function, heart-related death, and hospitalization for heart failure was added in 2019. These new benefits in combination with the lower than previously estimated risk of amputation led to the removal of the boxed warning. The amputation risk is still discussed in the warnings and precautions section of the labeling.
Canagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor used to treat adults with type 2 diabetes. It is available as a single agent (Invokana) and in combination with metformin (Invokamet and Invokamet XR). Health care professionals should follow the current prescribing information for canagliflozin and monitor patients for new sores, ulcers, or infections on their lower limbs. History of amputation, neuropathy, and peripheral vascular disease predispose patients to developing amputations with canagliflozin. Patients should not stop taking canagliflozin without discussing the decision with their health care professional because uncontrolled blood sugar levels can cause serious health problems. Advise patients to contact their health care professional if they experience new pain or tenderness in their lower limbs or notice sores or ulcers on their legs or feet.
More information is available at the following links:
- FDA MedWatch Updated Alert 2020
www.fda.gov/safety/medical-product-safety-information/invokana-invokamet-invokamet-xr-canagliflozin-medwatch-safety-alert-boxed-warning-about-risk-leg-and - FDA Drug Safety Communication 2020
www.fda.gov/drugs/drug-safety-and-availability/fda-removes-boxed-warning-about-risk-leg-and-foot-amputations-diabetes-medicine-canagliflozin - FDA MedWatch Updated Alert 2017
www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm558605.htm - FDA Drug Safety Communication 2017
www.fda.gov/downloads/Drugs/DrugSafety/UCM558427.pdf - FDA MedWatch Alert 2016
www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm501565.htm