New FDA Warning on Canagliflozin

The FDA has issued a warning about canagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor used to treat type 2 diabetes. The drug is made by Johnson & Johnson and is sold under the brand name Invokana, and combined with metformin as Invokamet, and Invokamet XR.

Two large clinical trials, (CANVAS and CANVAS-R) have found that leg and foot amputations occurred about twice as often in patients treated with canagliflozin as those who were treated with placebo. The most common amputations were of the toe and middle of the foot, but amputations of the leg-below and above the knee-also occurred. Some patients had more than one amputation; in some cases involving both legs. CANVAS is the Canagliflozin Cardiovascular Assessment Study and CANVAS-R is A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants with Type 2 Diabetes Mellitus.

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According to the FDA, The CANVAS trial showed that the risk of amputation in patients treated with Invokana was equivalent to 5.9 out of 1,000 over the course of a year, compared with 2.8 out of 1,000 for patients given placebo. The CANVAS-R trial showed the risk of amputation was equivalent to 7.5 out of every 1,000 patients treated with Invokana compared with 4.2 out of every 1,000 patients given a placebo.

The FDA is requiring new warnings on the labeling for canagliflozin, including a boxed warning. Interim results of the two studies had prompted FDA to issue a release about the link between the drug and amputations in May 2016.

Before prescribing canagliflozin, health-care professionals should consider factors that might predispose a patient to amputations. These include a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Patients who are prescribed canagliflozin should be advised to look for new pain or tenderness, sores or ulcers, or infections in the legs or feet. 

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"While the incidence was low, the highest incidence of amputations across all treatments was seen in patients with prior amputation," said Sarah Freeman, a spokesperson for Jannsen, the subsidiary of Johnson & Johnson that markets Invokana and invokamet. "At Janssen, patient safety is our highest priority. We are working with FDA to include this information in the prescribing information for canagliflozin and look forward to the presentation of the full CANVAS Program results at the American Diabetes Association Scientific Sessions in June."

Health-care professionals and patients are being encouraged to report any adverse events or side effects related to canagliflozin to the FDA's MedWatch Safety Information and Adverse Event Reporting Program at www.fda.gov/MedWatch/report.

Whether other SGLT2 drugs will have similar problems is not known. Others in the class include empagliflozin (Jardiance) and dapagliflozin (Farxiga).

(This article was edited to add a statement from Janssen.)