U.S. FDA Adds Boxed Warning on Invokana Label Over Increased Risk of Foot/Leg Amputations

IHS Global Insight

May 18, 2017

The U.S. Food and Drug Administration (FDA) has announced that it will be imposing new warnings, including a Boxed Warning, on canagliflozin products including Invokana, Invokamet, Invokamet XR (all marketed by Johnson & Johnson, J&J; U.S.) in light of new safety concerns observed in two large clinical trials (CANVAS and CANVAS-R). The prescription drugs are indicated for the treatment of type 2 diabetes, and were found to double the chances of leg and foot amputations in patients’ treatment with canagliflozin relative to control, according to the FDA. CANVAS-R demonstrated that over the span of a year, the risk of amputation was 7.5 out of a 1,000 for canagliflozin versus 4.2 out of 1,000 patients treated with placebo. The most common amputations were the toe and middle of the foot, although there were amputations involving the leg above the knee. The agency is encouraging healthcare professionals to consider factors that may predispose patients to amputations, such as peripheral vascular disease, neuropathy and diabetic foot ulcers, before starting treatment with canagliflozin.

The warnings will likely serve as a major setback for J&J, as they single out one of its top-selling products among several other sodium-glucose cotransporter-2 (SGLT2) inhibitors on the market that lower the levels of blood sugar by facilitating glucose removal via the kidneys. Notably, the European Medicines Agency issued a warning in February 2017 informing patients and doctors of the increased risk of lower limb amputation associated with “SGLT2 inhibitors” including canagliflozin, Forxiga (dapagliflozin; AstraZeneca, UK), and Jardiance (empagliflozin; Eli Lilly, U.S./Boehringer Ingelheim, Germany). The European regulator also cited data from the CANVAS and CANVAS-R trials, which prompted a “review of SGLT2 inhibitors,” and has noted that although there have been no similar studies carried out with the other medicines in the same class, the data is limited and the “risk may also apply to these other medicines.” Additional data is anticipated from ongoing studies, according to the EMA. J&J generated USD1.4 billion in global sales for Invokana/Invokamet in 2016, up 7.6% year on year.

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