FDA To Require Prominent Amputation Risk Warning for Canagliflozin SGLT-2 Inhibitors

Post-market clinical trials of the Type 2 medication canagliflozin to assess cardiovascular and renal risks have affirmed a suspected link to leg and toe loss, warranting a step up in FDA’s warning protocol. Action follows similar move by Canada and a lower level 2016 FDA advisory about amputation risk.



The federal Food and Drug Administration has now followed its drug safety announcement in May of last year for certain products in the SGLT-2 (sodium glucose co-transporter) class of oral anti-diabetic drugs to require an elevated type of warning for risk of leg and toe amputation. The decision arises from post-market clinical trials to assess cardiovascular and renal risks associated with Invokana (Janssen / Johnson & Johnson) branded canagliflozin, which achieved FDA clearance in March 2013. In August 2014, FDA cleared Janssen’s Invokamet, a canagliflozin-metformin compound, and last September Invokamet XR, an extended release formula.

The May 16 safety announcement covers all three Janssen formulations. FDA reports that it has confirmed increased amputation risk to users, based upon statistical outcomes among two large patient groups participating in the trials, one focused on cardiovascular outcomes and the other on renal function. Last July, the European Medicines Agency decided to require amputation risk label warnings for canagliflozin and two gliflozin-class products which are also distributed in the U.S.: Farxiga dapagliflozin and Xigduo dapagliflozin with extended release metformin (AstraZeneca), and Jardiance empagliflozin and Glyxambi empagliflozin with an added gliptin, or DPP-4 inhibitor (Boehringer-Ingelheim / Eli Lilly). FDA’s counterpart Health Canada added the canagliflozin amputation risk information to its drug information database last December in the form of a monograph, which is the practical equivalent of a U.S. drug safety warning.

SGLT-2 inhibitors work by re-routing excess blood sugar into the urinary tract before it’s reabsorbed in the kidneys. Janssen reports that its product has become, behind metformin, the most commonly prescribed among primary care doctors treating T2D patients. The company stands by its belief that “canagliflozin is an important treatment option for people with Type 2 diabetes.”

It’s a common practice for FDA to grant market clearance for medications with the condition that post-market trialing be carried out to assess risk of side effects, to assess appropriateness for patients with medical conditions in addition to those for which the drug is to be prescribed, or for interaction with other medications, or for risk of other adverse outcomes. For example, Mannkind’s FDA clearance for its Afrezza inhalable rapid acting insulin committed the manufacturer to conduct a pediatric trial.

FDA has required several package insert changes for canagliflozin and similar gliflozin class medications since their introductions to address reports of bone density loss, urinary tract irritation and infection, dehydration, kidney damage, and ketoacidosis.

Findings from post-market trials, and reports of adverse outcomes filed by doctors, clinics, or patients with the FDA through its Med Watch system, are the main triggers for FDA’s issuance of an advisory, safety warning, a change in prescribing information, or notice of a label change to address a risk to patients, such as will now happen with the Invokana and Invokamet package inserts.

In the industry, the label that Janssen will soon be required to distribute is known colloquially as a “black box” warning. This is nothing covert or sinister, though; it’s just the term that’s emerged to describe the appearance of the label, a box of specified dimensions and typeface around information relating to a significant risk in order to show it prominently. FDA regulations, and published FDA industry guidance on warnings and labeling of prescription drugs and biological products, dictate boxed warnings to alert practitioners and patients to serious adverse effects, up to potentially life threatening ones. In practice the boxed warning is the last stop in the hierarchy of advisories and warnings before the agency considers whether to require more trialing or to withdraw a product from the market.

Once the boxed label language has been settled upon between FDA’s and Janssen’s scientists and compliance specialists, the new package insert will resemble the most recent label revision, but with the addition of the prominently shown warning of amputation risk. At no time has FDA acted to remove canagliflozin from the market; in fact, earlier label changes addressing risks for users of the Jannsen products and other gliflozin products advise users not to discontinue taking the medication except under physician advice, and the soon-to-be label will also carry that information.

At publication time, as shown in FDA’s listing of gliflozin-class safety activities, the agency had not extended the amputation risk boxed label requirement to the Eli Lilly or AstraZeneca SGLT-2 products. Some industry watchers and drug safety writers suggest that may come soon. The two post-market canagliflozin trials showed, over a period of one year, a risk of amputation between 5.9 and 7.5 for every 1,000 patients treated with canagliflozin and 2.8 to 4.2 out of every 1,000 treated with a placebo, enough in FDA’s judgement to cross a risk threshold. Quite likely a move to broaden the boxed label requirement to all drugs in the class would follow completion or interim reporting of post-market trials involving cases of amputation or review of adverse event reports from users or prescribers. FDA does have authority under federal regulation to move ahead more quickly, however, where reasonable evidence correlates use of a drug to one or more adverse health outcomes, even if a direct cause hasn’t yet been definitively established.

The staff at Type 2 Nation will keep an eye out for continued developments regarding these issues and report on updates as soon as we have them.

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Jim Cahill is a senior writer for Insulin Nation and Type 2 Nation. Before turning to writing, he was a lawyer in government and private practice who focused on consumer protection and regulatory law. He can be contacted at jcahill@epscomm.com.