FDA Removes Invokana, Invokamet Leg And Foot Amputation Boxed Warnings

Federal regulators indicate that a “black box” warning about the risk of leg and foot amputations will be removed from Invokana, Invokamet and other canagliflozin-based diabetes drugs, following an analysis of additional data from recent clinical trials.

The FDA issued a drug safety communication on August 26, announcing it has decided to remove the black box warning, first placed on Invokana, Invokamet and Invokamet XR about three years ago.

Invokana (canagliflozin) was introduced in March 2013, as the first member of a new generation of diabetes drugs, known as sodium-glucose cotransporter 2 (SGLT2) inhibitors, which works in a unique way by impacting some normal kidney functions. Other members of this class include Invokamet, Jardiance, Farxiga, Xigduo and others, but Invokana has remained the biggest seller, amid aggressive marketing.

In May 2017 the FDA required an Invokana warning update regarding the risk of leg and foot amputation, which manufacturers of other similar diabetes drugs claimed was mostly unique to Invokana, though the results of later studies have varied.

More than three years later, the agency is now announcing the black box warning will be removed, as the agency no longer believes the information is no longer warranted, since new benefits associated with use of Invokana may offset the relatively small risk of leg and foot amputation.

According to the FDA’s findings, the clinical trials linked Invokana to a number of heart and kidney related benefits; including a lower risk of heart attack, stroke and death in type 2 diabetes patients with heart disease, as well as a decreased risk of end-stage kidney disease, worsening kidney function, heart-related deaths, and hospitalization from heart failure.

“Collectively, these newly identified effects of canagliflozin on heart and kidney disease show significantly enhanced benefit of this medicine,” the FDA safety communication states. “Safety information from recent clinical trials also suggests that the risk of amputation, while still increased with canagliflozin, is lower than previously described, particularly when appropriately monitored.”

Even with the black box warning gone, the FDA still recommends health care professionals and patients continue to monitor for signs of leg and foot problems while using Invokana and similar drugs, as well as partake in preventative foot care.

The FDA announcement came just one day after a study was published that confirmed there is a small, but increased, risk of Invokana leg and foot amputations.

In findings published this week in the medical journal The BMJ, Harvard researchers sought to estimate the risk of lower limb amputation among new users of Invokana, indicating that age and cardiovascular disease may play an important factor in the risk.

Researchers conducted a population based cohort study of new Invokana users and matched them with patients prescribed a different class of diabetes drug known as glucagon-like peptide-1 (GLP-1) receptor agonists, like Byetta. They divided the subjects into four categories: patients under 65 with heart disease, those under 65 without heart disease, and those 65 and older with heart disease and 65 and older without heart disease.

According to the findings, while there was a slight increased risk among Invokana patients across the board, the risk of amputation was significantly higher among those patients ages 65 and older, with the highest risk being those 65 and older with heart disease, who faced a 75% increased risk of leg and foot amputation.

Invokana Side Effects

As more and more diabetics have switched to the new drug since it hit the market in 2013, a steady stream of Invokana lawsuits were filed in courts nationwide, and the FDA has required the drug maker to release several warning updates in recent years.

In June 2016, the FDA again required additional warnings about the link between kidney risks and Invokana and other drugs from its class, indicating the medications may increase the risk of acute kidney injury and other severe health problems.

In August 2018, the FDA issued a drug safety communication about the risk of Fournier’s gangrene from Invokana, Invokamet and similar diabetes drugs. Incidents of the serious genital infections, also known as necrotizing fasciitis of the perineum, can result in the disintegration of flesh and can be life-threatening.

Following several years of litigation, Johnson & Johnson and Janssen have reached Invokana settlements to resolve most of the litigation previously filed over earlier failures to adequately warn about the diabetic ketoacidosis risk.