Safety advisory - potential increased risk of lower limb amputation
Consumers and health professionals are advised that an ongoing clinical study involving canagliflozin has identified a potential increased risk of requiring lower limb amputations, primarily of the toes.
Canagliflozin, which is also known as Invokana in Australia, is a medicine used to lower blood glucose in adult patients with type 2 diabetes.
A two-fold higher incidence of lower limb amputations, primarily of the toes, has been seen in the ongoing CANagliflozin cardioVascular Assessment Study (CANVAS). The reasons for this increase are not currently known, however dehydration and volume depletion may play a role.
It should be noted that CANVAS involves patients at high risk of problems with the heart and blood vessels, and that lower limb amputations occurred in both the canagliflozin and placebo groups in the study.
Patients with diabetes (especially those with poorly controlled diabetes and pre-existing problems with the heart and blood vessels) are at increased risk of infection and ulceration that can lead to requiring lower limb amputations.
Information for consumers
If you or someone you care for is taking canagliflozin, you should be aware of this issue but not alarmed.
The increased risk of requiring lower limb amputation is not high and the benefits of taking your medicine likely still outweigh the risks. You should not stop taking your medicine without first consulting a doctor.
All patients with diabetes have a risk of foot complications. It is very important that you undertake routine preventative foot care and immediately notify your doctor if you experience ulceration, discolouration or new pain or tenderness in your foot or toes. It is also important to remain well hydrated and to be aware of the signs and symptoms of dehydration and volume depletion.
If you have any questions or concerns about this issue, speak to your diabetes nurse educator or other health professional.
Information for health professionals
If you are treating patients who are taking canagliflozin advise them of this issue, but reassure them that the increased risk of requiring lower limb amputation is not high and the benefits of taking their medicine likely still outweighs the risks.
No increase in lower limb amputations was seen in 12 other completed clinical trials with canagliflozin. You are reminded to follow established diabetes care practice guidelines in patients treated with canagliflozin, including:
- established diabetes guidelines emphasise routine preventive foot care
- patients with risk factors for amputation events, such as patients with previous amputations, existing peripheral vascular disease or neuropathy, should be carefully monitored
- early treatment for foot problems should be initiated for, but not limited to, ulceration, infection, new pain or tenderness
- as a precautionary measure, consideration should be given to stop canagliflozin treatment in patients who develop a significant complication, such as a lower-extremity skin ulcer, osteomyelitis or gangrene, at least until the condition has resolved
- monitor patients for signs and symptoms of volume depletion and ensure that hydration is sufficient to prevent volume depletion in line with recommendations in the product information; note that use of diuretics may further exacerbate dehydration.
Please refer to the Product Information for canagliflozin for complete prescribing information.
CANVAS is a long-term study to look at whether canagliflozin reduces cardiovascular disease. It compares the effects of canagliflozin and placebo, together with standard care in diabetes patients at high risk of heart problems.
CANVAS enrolled around 4300 patients. The incidence of lower limb amputation in the study is currently 7 in 1000 patient-years with canagliflozin 100 mg daily and 5 in 1000 patient-years with canagliflozin 300 mg daily, compared with 3 in 1000 patient-years with placebo.
CANVAS-R is an ongoing study with a similar population to CANVAS. In this trial, the incidence of lower limb amputation is 7 in 1000 patient-years with canagliflozin and 5 in 1000 patient-years with placebo. This difference is not statistically significant.
The Independent Data Monitoring Committee for CANVAS and CANVAS-R has recommended that both trials should continue.
Consumers and health professionals are encouraged to report problems with medicines or vaccines. Your report will contribute to the TGA's monitoring of these products.
The TGA cannot give advice about an individual's medical condition. You are strongly encouraged to talk with a health professional if you are concerned about a possible adverse event associated with a medicine or vaccine.