The US Food and Drug Administration (FDA) has issued a new safety alert that the diabetes drug canagliflozin (Invokana, Invokamet, Janssen) has been associated with an approximately twofold risk for leg and foot amputations compared with placebo in an ongoing clinical trial. The FDA has not yet determined whether the sodium-glucose cotransporter 2 (SGLT2) inhibitor actually increases the risk for amputations and is investigating further. In the meantime, healthcare professionals are advised to follow the recommendations in the canagliflozin drug label and monitor patients for signs and symptoms of foot problems.
The FDA move follows a 4.5-year interim analysis by the independent monitoring committee for the Canagliflozin Cardiovascular Assessment Study (CANVAS). The panel found that the rate of amputations, mostly of the toes per every 1000 patients was equivalent to seven for 100 mg/day and five for 300 mg/day of canagliflozin compared with three per 1000 patients taking placebo. However, the same amputation risk has not been seen in 9 months of follow-up in a second, similar canagliflozin trial, CANVAS-R. Based on an overall data assessment, the monitoring committee has recommended that CANVAS continue.
This issue was flagged in April by the European Medicines Agency (EMA), which has begun a review based on the same data. The EMA’s Pharmacovigilance Risk Assessment Committee requested more information from the company to assess whether canagliflozin causes an increase in lower-limb amputations and whether any changes are needed in the way the drug is used in the European Union.
The CANVAS trial is scheduled to complete in 2017. Patients in the CANVAS trial have been followed for an average of 4.5 years to date. The IDMC has recommended, based on an overall assessment that the CANVAS trial continue. The IDMC has also reported that a second, similar trial evaluating canagliflozin, the CANVAS-R trial, has not shown the same risks of increased leg and foot amputations to date. Patients in the CANVAS-R trial have been followed for an average of 9 months.
Readers of this blog are highly encouraged to read the links provided below to read complete details of the findings and FDA actions related to this matter. In addition, healthcare professionals are encouraged to review additional medical and scientific information readily available in the public domain on this important issue.