24 October 2019

Febuxostat warning strengthened by the TGA

Clinical Gout

Patients with gout who have pre-existing cardiovascular disease (CVD) should not be prescribed febuxostat, the TGA has warned.

The safety alert, published on the TGA’s website in October, was prompted by a randomised study showing that febuxostat (Adenuric) was 34% more likely to be associated with CVD death than allopurinol in patients with gout and CVD.

The CARES study, which was published in the New England Journal of Medicine in March 2018, tracked around 6,000 patients over 32 months.

It had taken over a year to respond to the study findings because the TGA had been interpreting the study, analysing Australian case reports, liaising with international regulatory counterparts and negotiating with the drug sponsor, Menarini, to include a warning on the product information sheets, a TGA spokesperson told Rheumatology Republic.

Menarini also sent letters to prescribers to advise them of the issue, the TGA spokesperson said.

“The product information for febuxostat previously included a warning that it was not recommended for patients with ischaemic heart disease or congestive heart failure,” the TGA safety advisory states.

“In response to the CARES study, this has been strengthened to include all patients with pre-existing major cardiovascular disease.

“Please consider patients’ cardiovascular risk factors before initiating febuxostat.”

Dr Neil McGill, a rheumatologist at Royal Prince Alfred Hospital and an associate professor at The University of Sydney, said febuxostat “should not be, and should never have been, a first-choice option for urate-lowering drug therapy”.

“I think the adverse cardiac data in comparison to allopurinol will keep (or move) febuxostat into the sensible place as a reasonable choice for people with proven gout who are allergic to allopurinol,” he said.

“We know that gout poses an increased risk of cardiac events. For the patient with definite allopurinol allergy and ischaemic cardiac disease, the decision to use febuxostat versus a uricosuric versus no urate-lowering therapy currently needs to be made without guidance from good quality trial data.”

The FDA also updated its guidance on febuxostat, but it did not take the same approach as the TGA, Dr William White, a cardiologist at the University of Connecticut and the lead author of the CARES study, said.

“The recommendations by the TGA regarding febuxostat are different from the US FDA label,” he said in an email.

“Aside from the black box warning based on the CARES trial, the drug has been made more or less into a second line agent after allopurinol. However, there is no language that recommends febuxostat not be used in patients with pre-existing CV disease.”

The FDA prescribing information states that febuxostat “should only be used in patients who have an inadequate response to a maximally titrated dose of allopurinol, who are intolerant to allopurinol, or for whom treatment with allopurinol is not advisable”.