Invokana Review Launched in Europe Over Lower-Limb Amputations

Published on April 19, 2016 by Sandy Liebhard

Drug safety regulators are trying to determine if Invokana (canagliflozin) might be linked to lower-limb amputations. In a statement issued on April 15^th, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) said it has requested more information from Johnson & Johnson, and is working to determine whether or not changes should be made in the way the Type 2 diabetes medication is currently used.

According to the statement, the PRAC review was launched after a large ongoing clinical trial showed an increase in toe amputations among patients taking Invokana. That study, known as CANVAS (Canagliflozin Cardiovascular Assessment Study), is following 4,000 Type 2 diabetics treated with either a 100 mg or 300 mg daily dose of Invokana or a placebo. Lower limb amputations occurred at a rate of 7 in 1,000 patient-years among those taking 100 mg Invokana, while patients on the higher dose required amputations at a rate of 5 in 1,000 patient-years.  The rate in the placebo group was 3 in 1,000 patient-years.

In another ongoing trial called CANVAS-R,  the rate of lower limb amputation was 7 in 1,000 patient-years among Invokana patients, and 5 in 1,000 patient-years with placebo. The difference is not considered statistically significant.

The PRAC statement indicated that the regulator will also seek amputation data on other Type 2 diabetes medicines in the SGLT2 class, which includes Farxiga and Jardiance.

It should be noted that Type 2 diabetics already face a risk of lower-limb amputation. The PRAC is reminding doctors about the importance of routine foot care to avoid cuts or sores of the feet. Any such occurrence should be treated promptly in order to prevent infection and ulceration.

FDA Reviews Invokana, Other SGLT2 Inhibitors

Nearly a year ago, the U.S. Food & Drug Administration (FDA) began investigating a possible link between SGLT2 inhibitors, including Invokana, and diabetic ketoacidosis. This dangerous condition occurs when toxic acids called ketones accumulate in the bloodstream. Untreated, ketoacidosis can lead to diabetic coma and death.

This past December, the FDA ordered the drugs’ manufacturers to add new warnings to their product labels regarding diabetic ketoacidosis, as well as serious urinary tact infections. At the time, the agency revealed that least 73 cases of ketoacidosis had been reported to its adverse event database from March 2013 to May 2015. The database also received 19 reports of life-threatening blood infections (urosepsis) and kidney infections (pyelonephritis) that started as urinary tract infections inSGLT2 inhibitor patients from March 2013 through October 2014. All of these patients required hospitalization, and a few required admission to an intensive care unit or dialysis in order to treat kidney failure.