The European Medicines Agency (EMA) is informing about a potential increased risk of lower limb amputation (mostly affecting the toes) in patients taking the SGLT2 inhibitors canagliflozin, dapagliflozin and empagliflozin used 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.
Canagliflozin, dapagliflozin and empagliflozin are type 2 diabetes mellitus medicines of the class sodium-glucose co-transporter-2 (SGLT2) inhibitors. They 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 SGLT2 inhibitors was 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 (a dummy treatment). Further information about the studies can be found at the EMA website.
All patients with diabetes (especially those with poorly controlled diabetes and problems with the heart and blood vessels) are at higher risk of infection and ulcers (sores) which can lead to amputations. The mechanism by which canagliflozin may increase the risk of amputation is still unclear. 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. Further data are expected from ongoing studies with canagliflozin, dapagliflozin and empagliflozin.
A warning of the potential increased risk of toe amputation will be included in the prescribing information for these medicines. 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.
The review of SGLT2 inhibitors was carried out by EMA’s Pharmacovigilance Risk Assessment Committee (PRAC). The 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.
Healthcare professionals are advised of the followings:
• An increase in lower limb amputation (mostly affecting the toes) has been observed in two long-term clinical trials, CANVAS and CANVAS-R, in patients taking canagliflozin compared with those taking placebo. The studies, which are still ongoing, involved patients at high cardiovascular risk.
• Although an increase in amputations has not been seen in studies with other SGLT2 inhibitors, dapagliflozin and empagliflozin, data available to date are limited and the risk may also apply to these other medicines.
• The underlying mechanism by which canagliflozin may increase the risk of amputation has not been established and no risk factors apart from general risk factors for amputation have been identified.
• As a precaution, patients taking an SGLT2-inhibitor should be counselled about the importance of routine preventative foot care.
• For canagliflozin, consideration should also be given to carefully monitoring patients at higher risk of amputation and counselling them about the importance of maintaining adequate hydration.
• Consideration may be given to stopping treatment with canagliflozin in patients who develop events preceding amputation such as lower-extremity skin ulcer, infection, osteomyelitis or gangrene.
Please refer to the following website in EMA for details:
http://www.ema.europa.eu/../news_detail_002699.jsp&mid=WC0b01ac058004d5c1
In Hong Kong, there are 10 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 6 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) and 5mg/1000mg (HK-64243) registered by Boehringer Ingelheim (HK) Ltd. All these 10 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 11 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 EMA 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 were related to amputation. In light of the EMA announcement, the matter will be discussed by the Registration Committee of the Pharmacy and Poisons Board. DH will continue to remain vigilant on further safety updates on SGLT2 inhibitors issued by other drug regulatory authorities.
Ends/ Saturday, February 25, 2017
Issued at HKT 12:00
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