The European Medicines Agency (EMA) has extended the scope of its investigation into the risk of lower limb amputations with the type 2 diabetes drugs Invokana and Invokamet to include other drugs in the class.
Invokana and Invokamet contain the active ingredient canagliflozin, which is in a class called sodium glucose cotransporter 2 (SGLT2) inhibitors. The EMA’s investigation will now also focus on other SGLT2 inhibitors such as dapagliflozin (which includes the brand names Farxiga and Xigduo XR) and empagliflozin (which includes the brand name Jardiance).
The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) launched a safety review on canagliflozin in April 2016 based on trial data that showed an increased risk of lower limb amputations – in particular toe amputations – in patients taking Invokana or Invokamet. The clinical trial had shown that amputations occurred in seven out of 1,000 patients taking 100 mg/day of canagliflozin, and five out of 1,000 patients taking 300 mg/day of canagliflozin. The rate was three out of 1,000 patients for patients given a placebo.
The increase in amputations was not seen in 12 other completed clinical trials, though a small, statistically nonsignificant increase in the number of amputations occurred in another ongoing study involving patients at high cardiovascular risk.
In May, the U.S. Food and Drug Administration (FDA) issued a safety alert for canagliflozin based on the same data and launched its own investigation. The agency said it is also investigating whether other SGLT2 drugs pose the same amputation risk and will communicate its findings when its investigation is completed.
Invokana was the first SGLT2 inhibitor to be approved by the FDA and EMA. Since then, the agencies have added new warnings to the safety labels to include warnings for increased risk of bone fractures and bone density decreases, severe urinary tract infection, acute kidney injury, and ketoacidosis, a condition in which too much acid builds up in the blood.