Drug Safety Alerts

Canagliflozin Black Box Warning

5/16/2017

On May 16, 2017, the United States Food and Drug Administration (FDA) issued a MedWatch to announce that, based on new data from two large clinical trials, the type 2 diabetes medicine canagliflozin (Invokana^®, Invokamet^®, Invokamet XR) causes an increased risk of leg and foot amputations. The FDA is requiring new warnings, including a Boxed Warning, to be added to the canagliflozin drug labels to describe this risk. A complete list of the affected products is provided at the end of this document.

Patients taking canagliflozin should notify your health care professionals right away if you develop new pain or tenderness, sores or ulcers, or infections in your legs or feet. Talk to your health care professional if you have questions or concerns. Do not stop taking your diabetes medicine without first talking to your health care professional.

Health care professionals should, before starting canagliflozin, consider factors that may predispose patients to the need for amputations. These factors include a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Monitor patients receiving canagliflozin for the signs and symptoms described above and discontinue canagliflozin if these complications occur.

Final results from two clinical trials – the CANVAS (Canagliflozin Cardiovascular Assessment Study) and CANVAS-R (A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus) – showed that leg and foot amputations occurred about twice as often in patients treated with canagliflozin compared to patients treated with placebo, which is an inactive treatment. The CANVAS trial showed that over a year’s time, the risk of amputation for patients in the trial were equivalent to:

• 5.9 out of every 1,000 patients treated with canagliflozin

• 2.8 out of every 1,000 patients treated with placebo

The CANVAS-R trial showed that over a year’s time, the risk of amputation for patients in the trial were equivalent to:

• 7.5 out of every 1,000 patients treated with canagliflozin

• 4.2 out of every 1,000 patients treated with placebo

Amputations of the toe and middle of the foot were the most common; however, amputations involving the leg, below and above the knee, also occurred. Some patients had more than one amputation, some involving both limbs.

The FDA has provided the following information for health care providers:

• The type 2 diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR) causes an increased risk of lower limb amputations.

• Before initiating canagliflozin, consider factors in the patient’s history that may predispose them to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.

• Monitor patients receiving canagliflozin for signs and symptoms of infection, new pain or tenderness, sores, or ulcers involving the lower limbs, and discontinue canagliflozin if these complications occur.

• Inform patients that canagliflozin is associated with an increased risk of amputations. Instruct patients to monitor for the signs and symptoms described above and to seek medical advice immediately if they develop.

• In the clinical trials, amputations of the toe and mid-foot occurred most frequently; however, amputations involving the leg, below and above the knee, also occurred.

• Lower limb infections, gangrene, diabetic foot ulcers, and ischemia were the most common precipitating medical events leading to the need for an amputation.

• Encourage patients to read the Medication Guide they receive with their canagliflozin prescriptions.

• Report adverse events involving canagliflozin or other medicines to the FDA MedWatch program.

A complete list of the products affected by this issue is provided here:

CVS Caremark Response: Please note: There have been no recalls issued on this product because of this action. CVS Caremark Mail Service Pharmacy will continue to dispense canagliflozin.

For more information, health care providers may contact the FDA consumer inquiry line at 1‑888‑INFO‑FDA (1‑888‑463‑6332) or visit https://www.fda.gov.