The Food and Drug Administration (FDA) has issued a drug safety communication announcing the removal of the Boxed Warning about amputation risk from the labeling for canagliflozin.

Canagliflozin is a sodium-glucose contransporter-2 (SGLT2) inhibitor that was initially approved for the treatment of type 2 diabetes (T2D). In 2017, the Agency had required that a Boxed Warning be added to the labeling for canagliflozin based on data from the CANVAS and CANVAS-R trials, which showed that the incidence of leg and foot amputations occurred about twice as often with the drug compared with placebo.

“We required the Boxed Warning in 2017 based on our assessment that the risk of amputations was very serious in relation to the potential benefit of canagliflozin,” the FDA explained in their communication.

Since its initial approval, canagliflozin has gained additional indications including use in adults with T2D and established cardiovascular disease to reduce the risk of major cardiovascular events, and in adults with T2D and diabetic nephropathy with albuminuria to reduce the risk of end stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure. According to the Agency, the clinical trial data supporting these approvals not only demonstrated the additional benefits of the medication but also provided more information about the risk of amputation.

As such, the FDA concluded “the risk no longer meets the standard for a Boxed Warning given the current benefit-risk profile of the treatment and more recent indications.” However, the risk of lower limb amputation remains in the Warnings and Precautions section.

Prior to initiating treatment, healthcare professionals should consider factors that may predispose patients to the need for amputation (ie, prior amputation, peripheral vascular disease, neuropathy, diabetic foot ulcers). The risk of lower limb amputations was observed at both the 100mg and 300mg once daily dosage regimens.

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Canagliflozin is marketed under the brand name Invokana and is also a component of the combination therapies Invokamet and Invokamet XR.

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  1. FDA removes Boxed Warning about risk of leg and foot amputations for the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). Accessed August 26, 2020.
  2. Important changes to the INVOKANA® (canagliflozin) US prescribing information. Accessed August 26, 2020.