According to an announcement made by the U.S. Food and Drug Administration (FDA), an Invokana black box warning was added to type-2 diabetes medications, Invokana, Invokamet, and Invokamet XR.

These labels were added to medications that contain canagliflozin because of increased risks of leg and foot amputation, discovered by data from two randomized, placebo controlled trials (CANVAS and CANVAS-R).

The data from the clinical trials illustrated that irrespective of dosage amounts, rates of lower-extremity amputations doubled with those actively taking the medications.

Overview: Invokana Black Box Warning

Invokana (canagliflozin) is a type-2 diabetes medication prescribed to lower patients’ blood sugar levels. It reduces blood glucose levels by having sugar become excreted and eliminated through the urine. It is prescribed in combination of diet and exercise and became approved by the FDA on March 29, 2013. Invokana belongs to a class of medications termed sodium-glucose contransporter-2 (SGLT2) inhibitors.

However, there have been several adverse effects associated with Invokana, including a severe complication linked to the drug that was announced by the FDA. According to the May 2017 announcement, “based on new data from two large clinical trials, the U.S. Food and Drug Administration (FDA) has concluded that the type-2 diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR) causes an increased risk of leg and foot amputations.”

“We are requiring new warnings, including our most prominent Boxed Warning, to be added to the canagliflozin drug labels to describe this risk.” the FDA said.

The warning came after the FDA reviewed data from the two clinical trials, which included nearly 6,000 patients taking canagliflozin. According to the trials, rates of amputations were 5.8 and 7.5 per 1,000 patient-years. This was reportedly in comparison to the placebo groups that reported amputation rates of 2.8 and 4.2 per 1,000 patient-years. According to reports, this data showed major statistical differences.

According to the FDA announcement, although patients that were included in the trial were only included if they possessed cardiovascular disease or risk factors for the disease, in addition to type-2 diabetes, the warning does apply to all patients regardless of whether they do possess that risk.

Moreover, while the CANVAS study was an FDA-required clinical trial looking in to cardiovascular outcomes, CANVAS-R was conducted as an assessment for renal endpoints.

Common factors for amputations, nonetheless, were ischemia, gangrene, diabetic foot ulcers, and lower-limb infections. Additionally, patients with prior amputations had a much greater likelihood to have to undergo a second procedure.

According to the FDA’s announcement, they urged medical practitioners to evaluate a patients’ overall risk of amputation before prescribing Invokana. Patients taking Invokana should also be closely monitored for adverse side effects such as foot ulcers and infections that may lead a patient to have to undergo an amputation procedure.

While the FDA has not stated that other SGLT-2 inhibitors may cause the same effect and increased risk for amputation, the European Agency, in February, made an announcement indicating that this may be a class effect. Other inhibitors a part of the class also include empagliflozin (Jardiance) and dapagliflozin (Farxiga).