FDA Data Reinforces Warning for Canagliflozin Amputation Link

The FDA's FAERS analysis of canagliflozin has confirmed that its use "might be associated with an increased risk of amputations."

Analysis of the US Food and Drug Administration’s adverse event reporting system (FAERS)’s data has reaffirmed current warnings about amputations for canagliflozin (Invokana, Janssen).

Canagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, was found to be involved with 86% of 66 total reports of SGLT2-inhibitor-associated amputations. More concerning, two-thirds of the 57 amputations associated with the drug involved patients with no apparent amputation risk factors.

Diabetes is a major risk factor for amputations, making the FAERS analysis notable. The study authors, Gian Paolo Fadini, MD, PhD, and Angelo Avogaro, MD, PhD, of the division of metabolic diseases, department of medicine, University of Padova, Italy, noted that “the frequency of amputation reports for canagliflozin in this analysis was still significantly higher than for non-SGLT2 inhibitor drugs, with a PRR of 1·59 (95% CI 1·12—2·30; p=0·009).”

The most common amputation was the toe, but 13 above-ankle leg or limbs amputations took place, as well as 2 multiple amputations, 1 hand amputation, and 3 fatal cases. The frequency of amputation was 3.4 per 1,000.

The patients had an average age of around 60 years, and average treatment duration was 1.5 years, with 11% of the patients having diabetic-foot syndrome. The study considered concomitant adverse events like necrosis, gangrene, ischemia, and wounds, but the portion of patients with an evident risk of amputation was 36%, whereas the other 64% had no predictors.

Earlier this year, after the results of the Canagliflozin Cardiovascular Assessment Study (CANVAS) and A Study of the Effects of Canagliflozin on Renal Endpoints (CANVAS-R) trials, the FDA issued a boxed warning to the drug’s label.

The trials showed an estimated doubled risk for amputations of the lower extremities when compared to the placebo. This risk has not yet been seen in empagliflozin and dapagliflozin, other SGLT2 inhibitors on the market.

"At Janssen, patient safety is our highest priority," Jessica Castles Smith, spokesperson, Janssen Pharmaceuticals, Inc., told MD Magazine. "We continuously evaluate the safety and effectiveness of canagliflozin through ongoing clinical trials and post-marketing analyses to ensure prescribing information reflects the latest data. Based on findings from the CANVAS Program, we worked with the U.S. FDA to update the product labels for canagliflozin to include the risk of lower-limb amputation—primarily of the toe or part of the foot—which was communicated previously to healthcare professionals by Janssen and by the FDA."

The study noted that “this pharmacovigilance analysis confirms that use of canagliflozin, but not dapagliflozin or empagliflozin, might be associated with an increased risk of amputations."

But, Fadini and Avogaro stated that there are still “important limitations” of FAERS data, writing that "deciphering predisposing factors and mechanisms of this rare adverse event will be crucial to maximize the benefits of SGLT2 inhibitors in clinical practice.”

"We remain confident, based on all evidence available, that canagliflozin is an important treatment option for people with type 2 diabetes," Castles Smith told MD Magazine. "Healthcare professionals should continue to follow the most recent prescribing recommendations in the canagliflozin product labels."

FAERS analysis of the safety signal reports was published online in Lancet Diabetes and Endocrinology.

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