FDA Orders Stronger Warning About Canagliflozin (Invokana) & Amputation Risk

The U.S. Food and Drug Adminstration is calling attention to the risk of amputation if you're on the drug canagliflozin (Invokana, Invokamet).


It is requiring the drug to carry stronger warnings about the risk. The drug's label will have the so-called ''black box'' warning, designed to call attention to serious or life-threatening risks.1,2

The decision, announced May 16, was not unexpected, says J. Michael Gonzalez-Campoy, MD, PhD, FACE, medical director and CEO of the Minnesota Center for Obesity, Metabolism and Endocrinology and a member of the editorial board for EndocrineWeb.

The recent decision was issued as an update to a 2016 safety alert. "In May, 2016, the FDA called attention to one trial (CANVAS, or CANagliflozin cardioVascular Assessment Study) in which the incidence of amputations was higher among people taking the medication compared to people taking placebo," Dr. Gonzalez-Campoy says.3

The risks were twice as high in those treated with the drug. Over a year's time, the amputation risks were evaluated to be 7 of every 1,000 treated with 100 milligrams of the drug, versus 3 of every 1,000 on placebo.3

A second trial also identified a higher risk of amputation with the drug's use.3,4

"It therefore came as no surprise" when the FDA strengthened the warnings, Dr. Gonzalez-Campoy says.

What the FDA Says

In its statement, the FDA says that ''Based on new data from two large clinical trials, the FDA has concluded that the type 2 diabetes medicine canaglifozin (Invokana, Invokamet, Invokamet XR) causes an increased risk of leg and foot amputations. FDA is requiring new warnings, including the most prominent Boxed Warning, to be added to the canagliflozin drug labels to describe this risk."

The risk is about two-fold, the FDA concludes, and most often affects the toe and middle of the foot.1

More About the Medication

Canagliflozin is a prescription drug, used along with diet and exercise, to lower blood sugar in those with type 2 diabetes. It is in a class known as sodium-glucose cotransporter-2 inhibitor or SGLT2. It works in the kidneys to remove sugar from the body via the urine.

As a single medicine, it is known as Invokana. When it is combined with the diabetes drug metformin, it is Invokamet.

In clinical trials, most on Invokana did reach an A1C of less than 7%, according to Janssen Pharmaceuticals, the drug's maker.5

In 2016, the FDA issued warnings about possible kidney injury linked with the medication, calling for doctors to evaluate kidney health before starting the drug.6

Keeping Risk in Perspective & Explaining It

The risk should be kept in perspective, says Dr. Gonzalez-Campoy. "So far there is an association between canagliflozin use and an increased risk of toe amputations compared to placebo in patients with long-standing diabetes." That does not prove cause and effect, he says.

The people in the studies had long-standing diabetes and were at high risk of heart disease or already had it .4

Experts cannot explain with certainty why the risk is linked with the drug, he says. However, he speculates that because the medicine works via the kidneys, a person on it may get dehydrated, possibly triggering constriction of the blood vessels in the limbs and reduced blood flow there. If blood flow decreases and foot ulcers occur, a serious bacterial infection may take hold, requiring amputation.

Industry Response

In the trials that prompted the stronger labels, the highest number of amputation was found in those who had already had an amputation, says William Foster, a spokesperson for Janssen Pharmaceuticals, Inc., which makes Invokana.

In 2016, after the FDA issued the first safety alert, Janssen shared it with physicians and other health care providers, he says.

The company is working with the FDA now to include the new warnings with the prescription information.

What Patients Should Do

Awareness of problems in the extremities is key. According to the FDA, those on the drug should contact their health care provider immediately if they notice new pain or tenderness, sores, ulcers or infections in the legs or feet. It's important not to stop taking medicines for diabetes (or other conditions) before first talking it over with your doctor.1

Certain people are at higher risk, including anyone with a previous amputation, nerve problems, peripheral vascular disease or foot ulcers.1


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