The Medicines and Healthcare products Regulatory Agency (MHRA) advised that canagliflozin may increase the risk of lower-limb amputation (mainly toes) in patients with type 2 diabetes. Evidence does not show an increased risk for dapagliflozin and empagliflozin, but the risk may be a class effect. Preventive foot care is important for all patients with diabetes.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors are indicated in adults with type 2 diabetes mellitus to improve glycaemic control when diet and exercise alone are inadequate for control.
SGLT2 inhibitors are given alone in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications. SGLT2 inhibitors can also be given with other glucose-lowering drugs, including insulin, when these drugs do not provide adequate glycaemic control.
The SGLT2 inhibitor-containing medicines marketed in the UK are Invokana▼ (canagliflozin), Vokanamet▼ (canagliflozin and metformin), Forxiga▼ (dapagliflozin), Xigduo▼ (dapagliflozin and metformin), Jardiance▼ (empagliflozin), and Synjardy▼ (empagliflozin and metformin).
In June 2016, the MHRA published a Drug Safety Update article about an increase in cases of lower-extremity amputation with canagliflozin, compared with placebo, in two clinical trials. A Direct Healthcare Professional Communication was also sent.
The trials, CANVAS and CANVAS-R, are ongoing and involve patients at high risk of cardiovascular disease. 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. The study enrolled around 4,300 patients.
A European review of the risk of lower-limb amputation with all approved SGLT2 inhibitors noted that 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 ulcers (sores), which can lead to amputation. The mechanism by which canagliflozin may increase the risk of amputation is still unclear.
An increased risk of amputation was not seen in studies of dapagliflozin and empagliflozin. However, data are limited and the risk could also apply to these other medicines. Further data are expected from ongoing trials with the approved SGLT2 inhibitors.
In the UK, the product information for canagliflozin, dapagliflozin, and empagliflozin is being revised to include a warning on the potential increased risk of lower-limb amputation, mostly affecting the toes. For canagliflozin, the prescribing information will also list lower-limb amputation as an uncommon side effect (occurring in fewer than 10 patients in 1,000).
The MHRA advised healthcare professionals of the following:
• carefully monitor patients receiving canagliflozin who have risk factors for amputation, such as poor control of diabetes and problems with the heart and blood vessels
• consider stopping canagliflozin if patients develop foot complications such as infection, skin ulcers, osteomyelitis, or gangrene
• advise patients receiving any sodium-glucose co-transporter 2 (SGLT2) inhibitor about the importance of routine preventive foot care and adequate hydration
• continue to follow standard treatment guidelines for routine preventive foot care for people with diabetes
Please refer to the following website in MHRA for details:
http://www.gov.uk/drug-safety-update/sglt2-inhibitors-updated-advice-on-increased-risk-of-lower-limb-amputation-mainly-toes
In Hong Kong, there are 12 registered pharmaceutical products containing SGLT2 inhibitors, including 2 canagliflozin products, namely Invokana Tablets 100mg (HK-63499) and 300mg (HK-63500) registered by Johnson & Johnson (HK) Ltd; 2 dapagliflozin products, namely Forxiga Tablet 10mg (HK-63302) and Forxiga Tablet 5mg (HK-63301) registered by Astrazeneca HK Ltd; and 8 empagliflozin products, namely Jardiance Tablets 10mg (HK-64095) and 25mg (HK-64096), Jardiance Duo Tablets 12.5mg/850mg (HK-64240), 5mg/850mg (HK-64241), 12.5mg/1000mg (HK-64242), 5mg/1000mg (HK-64243), 12.5mg/500mg (HK-65019) and 5mg/500mg (HK-65020) registered by Boehringer Ingelheim (HK) Ltd. All these products are prescription only medicines.
Related news was previously issued by various overseas drug regulatory authorities, and was posted on the Drug Office website since 18 April 2016, with the latest update posted on 25 February 2017. Letters to inform local healthcare professionals on the warnings had been issued on 18 April 2016. According to Johnson & Johnson (HK) Ltd, the 2 clinical trials CANVAS and CANVAS-R mentioned in the MHRA announcement were not conducted in Hong Kong.
So far, the Department of Health (DH) has received four cases of adverse drug reactions related to SGLT2 inhibitors, but none of them was related to amputation. As previously reported, the matter will be discussed by the Registration Committee of the Pharmacy and Poisons Board (the Registration Committee). The information in the above MHRA announcement will also be forwarded to the Registration Committee for consideration.
Ends/ Thursday, March 23, 2017
Issued at HKT 14:00
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