EMA, MHRA, Janssen Warn of Increased Risk of Toe Amputation With Type 2 Diabetes Drug

Regulatory NewsRegulatory News | 11 May 2016 |  By 

A two-fold higher incidence of lower limb amputation, primarily of the toe, has been seen in a clinical trial with canagliflozin, Janssen, the European Medicines Agency (EMA) and UK’s Medicines and Healthcare products Regulatory Agency (MHRA) said in a letter to health professionals.

“The risk in the canagliflozin groups was 6 per 1000 patient years, compared with 3 per 1000 patient years with placebo,” the regulators and Janssen UK and Ireland’s medical director Rozlyn Bekker wrote in a letter to health professionals dated 29 April. “This increased risk was observed 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.”

The issue is currently under investigation by both regulators, which have said the cause of the increase in safety events is not yet known though “dehydration and volume depletion might play a role in the development.”

The US Food and Drug Administration (FDA) and EMA both approved Invokana in 2013 as a treatment for type 2 diabetes. Vokanamet (canagliflozin/metformin), which is known as Invokamet in the US, was also approved as a type 2 diabetes treatment by both regulators in 2014.

Clinical Trials

The increase in amputations were discovered in the CANVAS trial (CANagliflozin cardioVascular Assessment Study), which is an ongoing randomized, double-blind, placebo-controlled, three-arm, parallel-group, multi-center study to evaluate the safety, tolerability and cardiovascular (CV) risk with canagliflozin plus standard of care, compared with placebo plus standard of care, in subjects with type 2 diabetes mellitus who have either a prior history or high risk of CV disease, the letter says.

4,330 subjects were randomly assigned to treatment with one of two doses of canagliflozin (100 mg or 300 mg) or matching placebo in a 1:1:1 ratio.

“Serious adverse event monitoring in this study has observed an approximately two-fold higher incidence of lower limb amputation (primarily of the toe) in the canagliflozin 100 mg (7/1000 patient-years) and 300 mg (5/1000 patient-years) treatment groups versus placebo (3/1000 patient-years) across all baseline risk factors for amputations,” Janssen said.

However, the CANVAS-R study, an ongoing outcome study with a similar population to CANVAS, showed 16 amputation events in the canagliflozin group and 12 events in the placebo group. The estimated annual incidence of amputations is 7 events per 1000 patient-year exposure in the canagliflozin and 5 events per 1000 patient-year exposure in the placebo group, with no statistically significant difference, the letter noted.

“A higher incidence of amputation was not observed across 12 other completed Phase 3/4 clinical trials with a mean follow-up of 0.9 years (0.6/1000 patient-years in canagliflozin and 2/1000 patient-years in control groups),” Janssen added.

Other Letters

In addition to the letter on canagliflozin, EMA and MHRA also recently worked with Celgene on ensuring hepatitis B virus status is established before initiating treatment with pomalidomide due to cases of hepatitis B reactivation.

And the regulators, alongside Novartis, Bristol-Myers Squibb, Pfizer and Ariad, also raised similar concerns about patients receiving BCR-ABL tyrosine kinase inhibitors (TKIs) last month.

GlaxoSmithKline, meanwhile, sent a letter to healthcare professionals with regard to acquired vitelliform maculopathy (AVM) as it was diagnosed in some patients taking Trobalt (retigabine), which was approved in 2011 and is used in combination with other anti-epileptic medicines to treat adults with drug-resistant partial-onset seizures.

MHRA also offered interim measures with regard to the signal of serious infection and deaths related to infection found in clinical trials of Gilead’s Zydelig (idelalisib) for relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed chronic lymphocytic leukemia (CLL).

MHRA Drug Safety Update for May


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