The European Medicines Agency (EMA) on Friday noted the potential increased risk of lower limb amputation (mostly affecting the toes) in patients taking the SGLT2 inhibitors canagliflozin, dapagliflozin and empagliflozin for type 2 diabetes.
“Patients taking these medicines are reminded to check their feet regularly and follow their doctor’s advice on routine preventative foot care. They should also tell their doctor if they notice any wounds or discoloration, or if their feet are tender or painful,” EMA said in a statement.
The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) recommendations have now been endorsed by the Committee for Medicinal Products for Human Use (CHMP), and will be sent to the European Commission for a final legally binding decision valid throughout the EU.
Canagliflozin, dapagliflozin and empagliflozin are type 2 diabetes mellitus medicines of the class sodium-glucose co-transporter-2 (SGLT2) inhibitors. According to EMA, the medicines block a protein in the kidneys called SGLT2, which absorbs glucose back from the urine into the bloodstream as the blood is filtered in the kidneys. By blocking the action of SGLT2, these medicines cause more glucose to be lost in the urine, thereby reducing the levels of glucose in the blood.
The review of canagliflozin, initiated at the request of the European Commission on 15 April 2016, under Article 20 of Regulation (EC) No 726/2004, was extended to include the other medicines in the same class, dapagliflozin and empagliflozin, on 7 July 2016.
The review covers: AstraZeneca’s Ebymect (dapagliflozin /metformin), Edistride (dapagliflozin), Xigduo (dapagliflozin/metformin) and Forxiga (dapagliflozin), Janssen Pharmaceuticals’ Invokana (canagliflozin) and Vokanamet (canagliflozin /metformin), Eli Lilly and Boehringer Ingelheim’s Jardiance (empagliflozin) and Boehringer’s Synjardy (empagliflozin /metformin).
Prompted by an increase in lower limb amputations (mostly affecting the toes) in patients taking canagliflozin in two clinical trials, CANVAS and CANVAS-R, the studies, which are still ongoing, involved patients at high risk of heart problems and compared canagliflozin with placebo.
“An increase in lower limb amputations has not been seen in studies with other medicines in the same class, dapagliflozin and empagliflozin. However, data available to date are limited and the risk may also apply to these other medicines,” EMA said.
In addition to the EMA warnings, the US Food and Drug Administration (FDA) in June 2016 strengthened the existing warning about the risk of acute kidney injury for the type 2 diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR).
Potential Increased Risk
A warning of the potential increased risk of toe amputation will be included in the prescribing information for these medicines in the EU. For canagliflozin, the prescribing information will also list lower limb amputation as an uncommon side effect (occurring in between 1 and 10 patients in 1,000). Doctors may consider stopping treatment with canagliflozin if patients develop significant foot complications such as infection or skin ulcers, EMA said.
As of September 2016, the incidence of lower limb amputation (mostly affecting the toes) in the CANVAS study was 7 in 1,000 patient-years with canagliflozin 100 mg daily and 5 in 1,000 patient-years with canagliflozin 300 mg daily, compared with 3 in 1,000 patient-years with placebo. (One patient-year is equivalent to 1 patient taking the medicine for 1 year.) The study enrolled around 4,300 patients.
For the CANVAS-R study, an ongoing study with a similar population to CANVAS, as of September 2016, the incidence of lower limb amputation was 8 in 1,000 patient-years with canagliflozin and 4 in 1,000 patient-years with placebo. The study enrolled over 5,800 patients.
“The incidences of lower limb amputation given above for both CANVAS and CANVAS-R are based on interim data, and final incidence rates will depend on analysis of the final study datasets,” EMA said.