1. Aschenbrenner, Diane S. MS, RN


* Canagliflozin's labeling no longer carries a boxed warning for an increased risk of amputation with drug use. The risk has been downgraded to the warnings and precautions section of the labeling.



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The Food and Drug Administration (FDA) has removed a boxed warning from the labeling of canagliflozin (Invokana) related to an increased risk of amputation with drug use. Canagliflozin, which is also available in combination with metformin (Invokamet and Invokamet XR), is a sodium-glucose cotransporter-2 inhibitor that lowers blood glucose levels by promoting excretion of glucose in the urine.


Canagliflozin, initially approved in 2013 to control type 2 diabetes in conjunction with diet and exercise, received the boxed warning in 2017. The FDA felt that the risk-benefit ratio of treatment tilted toward risk, as there were other diabetes drugs on the market that did not pose a risk of amputation. Since 2017, other benefits of canagliflozin have been identified and the drug has been approved for several more indications. In 2018 it was approved to reduce the risk of major cardiovascular events in adults with type 2 diabetes and established cardiovascular disease, and in 2019 it was approved to reduce the risk of end-stage kidney disease, doubling of serum creatinine levels, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes and diabetic nephropathy with albuminuria.


The clinical trial data that supported these new indications appear to indicate less risk of amputation than previously believed. Because of the additional identified benefits of canagliflozin, the risk-benefit ratio shifted toward benefit, which led to the FDA's decision to remove the boxed warning. An increased risk of lower limb amputation is, however, still present and is now listed in the warnings and precaution section of the labeling.


The removal of the boxed warning should not change the way nurses and NPs assess patients with diabetes who take canagliflozin. Nurses should still teach patients the importance of foot and leg care and how to assess and monitor for new pain or tenderness, sores, ulcers, and infections of the foot or leg. NPs should consider the patient's risk of lower limb amputation (such as having macrovascular disease, peripheral neuropathy, nephropathy, ischemic diabetic foot, and poor glycemic control) when deciding whether to prescribe canagliflozin.


For complete prescribing information for canagliflozin, see