Febuxostat (Uloric) and its problem with cardiovascular mortality

Despite drug safety problems of cardiovascular mortality with Febuxostat (Uloric), the benefits might still be seen to outweigh risks for selected gout patients. This notion may become more and more disputed, however.

Febuxostat (Uloric) was approved by the American Food and Drug Administration (FDA) in 2009 for the chronic management of hyperuricemia in patients with gout. One condition of the approval of Febuxostat (Uloric) in 2009 was that a postmarketing safety study be conducted by Takeda Pharmaceuticals America, Inc. The postmarketing safety trial required by the FDA was called Cardiovascular Safety of Febuxostat (Uloric) and Allopurinol in Patients with Gout and Cardiovascular Comorbidities (CARES).

In March 2018 it was announced that this CARES trial found that Febuxostat (Uloric) was inexplicably linked to more cardiac deaths than was Allopurinol, the mainstay drug for patients with gout and cardiovascular disease. As a consequence, on January 10, 2019, the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee panelists discussed the potential biological mechanisms behind cardiovascular (CV) events associated with the use of Febuxostat (Uloric) and its seemingly heightened risk for unwanted cardiovascular events.

The panelists came to the conclusion that for the general population with gout, the benefits of Febuxostat (Uloric) would not outweigh the risks (particularly cardiovascular events) when compared to Allopurinol, one of the standard treatments in patients with gout. In contrast, they proposed that the benefits of urate-lowering Febuxostat (Uloric) outweigh its risks for selected gout patients, though only for unrestricted access only as a second-line therapy, mostly for individuals who have had a serious skin reaction to or otherwise "absolutely don't tolerate" Allopurinol, the mainstay xanthine oxidase inhibitor for uric acid reduction.

The panelists came to the conclusion that for the general population with gout, the benefits of Febuxostat (Uloric) would not outweigh the risks (particularly cardiovascular events) when compared to Allopurinol, one of the standard treatments in patients with gout. In contrast, they proposed that the benefits of urate-lowering Febuxostat (Uloric) outweigh its risks for selected gout patients, though only for unrestricted access only as a second-line therapy, mostly for individuals who have had a serious skin reaction to or otherwise "absolutely don't tolerate" Allopurinol, the mainstay xanthine oxidase inhibitor for uric acid reduction.In this context, it is noteworthy that Febuxostat (Uloric)'s label already warns of increased risk of gout flares with initiation of therapy, cardiovascular events, hepatic toxicity, and serious skin reactions. Panelists further recommended several regulatory actions such as an additional black box warning and a change in the indication to label Febuxostat (Uloric) as a second-line therapy after Allopurinol only. They kept it open, if even a recall of Febuxostat (Uloric) could be considered.

Further to the status at the time of this writing, the FDA has now added a "Boxed Warning" to the drug label of Febuxostat (Uloric) due to the obvious increased risk of death for patients under Febuxostat (Uloric) and introduce a new, strengthened patient Medication Guide. FDA also limits the approved use of Uloric to certain patients who are not treated effectively or experience severe side effects with Allopurinol. See here the according safety communication by the FDA as of February 02, 2019.