FDA Removes Black Box Warning for Canagliflozin's Amputation Risk

Author: Shilin-Acorn

On August 26, the U.S. FDA announced the removal of the boxed warning regarding amputation risk from the prescribing information for Johnson & Johnson’s diabetes treatment canagliflozin. The affected products include Invokana, as well as canagliflozin-based combination products Invokamet (canagliflozin/metformin hydrochloride) and Invokamet XR (canagliflozin/extended-release metformin hydrochloride). The FDA’s decision to remove the boxed warning was based on a review of new data from three clinical trials.

Canagliflozin is a novel oral hypoglycemic agent belonging to the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, which lowers blood glucose by facilitating the excretion of glucose from the body into the urine via the kidneys. In 2017, based on its evaluation that canagliflozin posed a serious risk of amputation, the FDA required the addition of a boxed warning to the product labeling.

Canagliflozin was initially approved in 2013, in conjunction with diet and exercise, to lower blood glucose in adult patients with type 2 diabetes. The FDA subsequently reviewed new clinical trial data for the drug, which demonstrated additional cardiovascular and renal benefits, leading to expanded approved indications. These include the 2018 approval for reducing the risk of major adverse cardiovascular events (such as heart attack, stroke, or death) from cardiovascular causes in adults with type 2 diabetes and established cardiovascular disease; and the 2019 approval for reducing the risk of end-stage kidney disease, worsening kidney function, cardiovascular death, and hospitalization for heart failure in certain patients with type 2 diabetes and diabetic nephropathy. In the Chinese market, canagliflozin was approved in September 2017 under the brand name Invokana (Yike’an) and was officially launched in July 2018.

The FDA stated, “Overall, these newly identified effects of canagliflozin on cardiac and renal diseases indicate a substantial enhancement in the drug’s benefits. Safety information from recent clinical trials also indicates that although the use of canagliflozin continues to increase the risk of amputation, this risk is lower than previously described, particularly when appropriate monitoring is implemented.” Based on these considerations, the FDA concluded that the Boxed Warning should be removed. The risk of amputation associated with canagliflozin persists and is described in the “Warnings and Precautions” section of the prescribing information.

The FDA stated that healthcare professionals and patients should continue to recognize the importance of preventive foot care and monitor for new pain, tenderness, ulcers, and infections in the legs and feet. When selecting diabetes treatments, risk factors that may predispose patients to amputation should be considered.