This December 2016 Label Change Mandated By Health Canada, However, Does Not Apply To Jardiance, Farxiga, And The Rest Of SGLT2 Inhibitors Class Of Drugs
UPDATE: Invokana "Black-Box Warning" For Leg And Foot Amputations
[5-16-2017] Based on new data from two large clinical trials, the U.S. Food and Drug Administration (FDA) has concluded that the type 2 diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR) causes an increased risk of leg and foot amputations. We are requiring new warnings, including our most prominent Boxed Warning, to be added to the canagliflozin drug labels to describe this risk.
See also: "Risk of Lower Limb Amputations Doubled with Invokana and Invokamet Use" from our Drug Safety Developments blog.
From the Health Product InfoWatch newsletter -- formerly The Canadian Adverse Reaction Newsletter (CARN) -- put out by Health Canada in December 2016, under the "Product monograph updates" heading, we get this drug safety development:
The risk of lower limb amputation, primarily of the toe, has been added to the Adverse Reactions section of the Canadian product monographs for Invokana (canagliflozin) and Invokamet (canagliflozin and metformin hydrochloride).
Key messages for healthcare professionals:
- In an ongoing cardiovascular study† of 4 327 patients with type 2 diabetes, with known or at high risk for cardiovascular disease, the incidence rates of lower limb amputation, primarily of the toe, were 7.3, 5.4 and 3.0 per 1 000 patient years of exposure to canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively, with the imbalance occurring as early as the first 26 weeks of therapy.
- In other type 2 diabetes studies with canagliflozin, which enrolled a general diabetes population of 8 111 patients, no difference in lower limb amputation risk was observed relative to control.
† Study details available at https://clinicaltrials.gov/ct2/show/NCT01032629.
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As background, from this July 2016 Medscape Medical News report, "EMA Extends Amputation Investigation to All SGLT2 Inhibitors" (free registration required to access article):
The European Medicines Agency (EMA)'s Pharmacovigilance Risk Assessment Committee (PRAC) has extended the scope of its investigation into the possible link between the sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (Invokana, Vokanamet, Janssen) and amputations to include other drugs of the same class.
Now, the PRAC's review will include the other SGLT2 inhibitor medicines dapagliflozin (Farxiga, Xigduo XR, AstraZeneca), and empagliflozin (Jardiance, Boehringer Ingelheim), based on the determination that the potential risk may be relevant for them as well.
In April 2016, PRAC launched a safety review of canagliflozin based on an increase in amputations — mostly of the toes — seen in the ongoing long-term Canagliflozin Cardiovascular Assessment Study (CANVAS).
A 4.5-year interim analysis by the independent monitoring committee for the trial found that the rate of amputations per every 1000 patients was equivalent to seven for 100 mg/day and five for 300 mg/day of canagliflozin compared with three per 1000 patients taking placebo.
And back in mid-May 2016 there was this item, "FDA Drug Safety Communication: Interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet); FDA to investigate".
From the Safety Announcement section of that document we get this information:
The U.S. Food and Drug Administration (FDA) is alerting the public about interim safety results from an ongoing clinical trial that found an increase in leg and foot amputations, mostly affecting the toes, in patients treated with the diabetes medicine canagliflozin (Invokana, Invokamet). We have not determined whether canagliflozin increases the risk of leg and foot amputations. We are currently investigating this new safety issue and will update the public when we have more information.
Since then, we have not heard again from the FDA about the results of this investigation regarding leg, foot, and toe amputations possibly caused by the use of Invokana and Invokamet.
We will continue to monitor the drug safety regulators as well as the medical literature concerning the possible link between an increased risk of these amputations and the use of SGLT2 inhibitors such as Invokana, Invokamet, Farxiga, Xigduo XR, and Jardiance.
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