Health Canada advises that an increase in the incidence rate of lower limb amputation-primarily of the toe and midfoot, but also of the leg has been seen in the integrated CANagliflozin cardioVascular Assessment Study (CANVAS) Program (0.63 per 100 patient-years in patients treated with canagliflozin versus 0.34 per 100 patient-years in patients treated with placebo). The CANVAS Program was comprised of CANVAS and CANVAS-R, two large, long-term, randomized, placebo-controlled trials evaluating long-term cardiovascular outcomes in 10,142 individuals with type 2 diabetes with established cardiovascular disease (CVD) or at least two risk factors for CVD who were treated with canagliflozin. The products affected are INVOKANA (canagliflozin) Janssen Inc. and INVOKAMET (canagliflozin and metformin) Janssen Inc.
Canagliflozin is a member of a class of drugs called sodium glucose co-transporter type 2 (SGLT2) inhibitors indicated as oral antihyperglycemic agents for the treatment of patients with type 2 diabetes. The increase in the incidence rate of lower limb amputation (mostly affecting the toe and midfoot, but also of the leg) occurred as early as the first 26 weeks of therapy during long-term clinical studies, CANVAS and CANVAS-R, in patients taking INVOKANA. Patients in the CANVAS and CANVAS-R studies were followed for an average of 5.7 and 2.1 years, respectively. This increased risk was independent of predisposing risk factors, although the absolute risk was higher in patients with previous amputations, existing peripheral vascular disease or neuropathy. No dose response was observed. Lower limb infections, diabetic foot ulcers, peripheral arterial disease, and gangrene were the most common medical events associated with the need for an amputation in both treatment groups. A higher incidence of amputation was not observed across 12 other completed Phase 3 or 4 clinical trials which included a general diabetic population of 8,114 patients (the majority of which were without established CVD) with a mean exposure of 0.9 years.
Consumers are advised that canagliflozin is a type of medication used to treat type 2 diabetes. It works by preventing the kidneys from reabsorbing sugar into the blood. Instead, the sugar is excreted in the urine. An increase in surgical amputations of the toe and middle of the foot, was seen in a long-term clinical study, especially in patients at high risk of heart disease. Patients taking INVOKANA or INVOKAMET should be advised to talk to their healthcare professional right away if they have new pain or tenderness or any sores, ulcers, or infections involving the leg or foot. Patients and healthcare professionals should also watch out for signs of poor circulation, such as bluish, cold skin and poor hair and toe nail growth. Proper foot care and adequate hydration are recommended. Consumers should contact their healthcare professional for more information.
Health Canada advised healthcare professionals of the following:
- Consider factors in the patient history that may increase the risk for amputation.
- Carefully monitor patients with risk factors for amputation events, e.g., patients with previous amputations, existing peripheral vascular disease or neuropathy.
- Counsel patients about the importance of routine preventive foot care, good hydration, and the signs and symptoms of volume depletion.
- 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. Use of diuretics may further exacerbate dehydration.
- Advise patients to notify their healthcare provider if they develop sores, ulceration, discoloration, infection, new lower extremity pain or tenderness.
- Initiate early treatment for foot problems for, but not limited to, ulceration, infection, new pain or tenderness.
- Discontinue canagliflozin treatment in patients who develop a significant complication, such as a lower-extremity skin ulcer, infection, osteomyelitis or gangrene
Please refer to the following website in Health Canada for details:
http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/../64366a-eng.php
In Hong Kong, there are two registered pharmaceutical products containing canagliflozin, namely Invokana Tablets 100mg (HK-63499) and 300mg (HK-63500) which are registered by Johnson & Johnson (Hong Kong) Ltd, and 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 17 May 2017. Letters to inform local healthcare professionals on the warnings had been issued on 18 April 2016. According to Johnson & Johnson (Hong Kong) Ltd, the 2 clinical trials CANVAS and CANVAS-R were not conducted in Hong Kong. So far, the Department of Health (DH) has received two cases of adverse drug reaction in connection with canagliflozin, but none of them were related to amputation The matter has been discussed by the Registration Committee on 7 September 2017, and concluded that sales pack labels and/or package inserts should be updated with the risk on lower limb amputation.
Ends/Thursday, September 7, 2017
Issued at HKT 17:00
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