• Manoj Swaminathan

How can Pharmacovigilance Help? ----A Real-World Example

The primary objective of Pharmacovigilance is to ensure that safe and effective medicines are available for Public Health. In August 2020, the FDA removed the Boxed Warning about amputation risk from the diabetes medicine canagliflozin, based on the review of new data from three clinical trials. This boxed warning was imposed in May 2017. Thanks to the effective Pharmacovigilance measures, that the warning could be revoked in less than 40 months.

Canagliflozin belongs to a class of medicines called sodium-glucose cotransporter-2 (SGLT2) inhibitors. It lowers blood sugar by causing the kidneys to remove sugar from the body through the urine. In 2013, Canagliflozin was approved by the FDA and EMA, for glycemic control in adults with type 2 diabetes mellitus.

However, in less than four years, the U.S. Food and Drug Administration (FDA), based on new data from two large clinical trials, concluded that canagliflozin causes an increased risk of leg and foot amputations.

Source: https://www.fda.gov/media/104870/download

This resulted in FDA requiring new warnings, including a Boxed Warning, to be added to the canagliflozin drug labels to describe this risk. Based on ongoing studies (CANVAS), in October 2018, the FDA approved canagliflozin to reduce the risk of Heart Attack, Stroke or Cardiovascular Death in Adults with Type 2 Diabetes and Established Cardiovascular Disease.  This resulted in canagliflozin becoming the only oral type 2 diabetes treatment indicated to reduce the risk of heart attack, stroke or cardiovascular death. This was followed by the CREDENCE trial leading in FDA approval for canagliflozin reducing the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria. Finally, in August 2020, the FDA concluded that collectively, these newly identified effects of canagliflozin on heart and kidney disease show significantly enhanced benefit of this medicine. 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.

Source: https://www.fda.gov/media/141533/download

Based on these considerations, FDA concluded that the Boxed Warning should be removed. However, the amputation risk with canagliflozin continues to remain in the Warnings and Precautions section of the prescribing information. Effective Pharmacovigilance is indeed beneficial!