FDA advisors overwhelmingly voted that the benefits of urate-lowering febuxostat (Uloric) outweigh its risks for selected gout patients, though most advocated broad unrestricted access only as a second-line therapy.
Members voted 19 to 2 (with one abstention) that a patient population exists for whom febuxostat’s benefit-to-risk profile is favorable in its current indication as first-line treatment for hyperuricemia in gout, despite a known link to cardiac deaths.
This includes 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, suggested Steven Nissen, MD, of the Cleveland Clinic and a panelist at the meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee.
“For everybody else, for the general population with gout, I would say that in those people the benefits do not outweigh the risk,” he cautioned.
Fellow panelists largely agreed with that sentiment, given that febuxostat isn’t proven to be more effective than allopurinol and was in fact linked to a higher risk of cardiovascular mortality in the CARES trial (HR 1.34, 95% CI 1.03-1.73).
The FDA is not required to follow the advice of its advisory committees, but it usually does.
Febuxostat’s label already warns of increased risk of gout flares with initiation of therapy, cardiovascular events, hepatic toxicity, and serious skin reactions.
Faced with the problem of cardiovascular mortality, panelists recommended several regulatory actions such as an additional black box warning and a change in the indication to make febuxostat a second-line therapy after allopurinol.
However, these types of actions rarely make a real dent in utilization, according to Nissen. He suggested a more drastic Risk Evaluation and Mitigation Strategy (REMS) action keeping the drug at a centralized pharmacy — available only if both the physician and the patient give informed consent recognizing the increased risk of cardiovascular mortality.
This restriction strategy, notably used in the case of certain opioids, would allow patients who need the drug to still get it while keeping them part of the shared decision-making process, he said.
Fellow panelist Steven Meisel, PharmD, of Fairview Health Services/Healtheast Care System in Minneapolis, agreed that black box warnings have “minimal impact.” Nevertheless, he favored a less restrictive REMS that could be administered at the doctor’s office.
During the discussion, however, FDA staff signaled that the Office of Surveillance and Epidemiology is unlikely to construct a REMS in this case.
“If a REMS can’t be developed, I would favor withdrawal,” Nissen responded. Other panelists called for boxed warnings but stopped short of calling for febuxostat to be withdrawn because of cardiovascular mortality, the mechanism for which remains unclear.
“Biological plausibility’s a red herring. Just because you can’t explain something doesn’t mean it’s not real. All sorts of things are only explained after years and years of research,” Meisel commented, adding that if the CARES data had been available in 2008, it wouldn’t have been approved.
Takeda started the postmarketing trial as one condition to get febuxostat on the market in 2009.
Notably, 57% of the 6,198 enrolled patients left the trial prematurely, often when they encountered gout flares or thought they weren’t being taken good care of, explained lead investigator William White, MD, of UConn Health in Farmingdale, Connecticut, at the meeting. He noted that withdrawal occurred at the same rate in the febuxostat and allopurinol groups.
The CARES population not uncommonly had difficult problems like alcoholism and obesity and would commonly drop out when they felt like it, White said. “They’re ornery. They’re in pain all the time from the disease.”
Such a large drop-out rate would have biased results to the null, which makes the observed cardiovascular mortality risk even more striking, according to panelist Bruce Psaty, MD, of the University of Washington in Seattle.
The trouble with allopurinol for most people is it’s difficult to titrate the right dose to achieve target serum urate, such that there’s been a pattern of underdosing in patients with renal impairment.
Febuxostat, on the other hand, tends to get more patients to target serum urate because of its dosing simplicity, according to a Takeda representative.
“Just because clinicians don’t know how to use allopurinol properly doesn’t make this drug more desirable,” Meisel argued. “That’s not an argument for this as the preferential agent.”
Takeda plans to continue postmarket monitoring with its ongoing FAST trial of febuxostat versus allopurinol in Europe.