Trial Compares Titrated Treatment With Two Gout Drugs: Allopurinol and Febuxostat

Gout is a chronic condition that affects approximately 4% of American adults.[1] It is a painful type of inflammatory arthritis characterized by excessive amounts of uric acid in the blood (hyperuricemia), which can cause sudden gout flares (attacks) due to needle-like deposits of uric-acid crystals in the joints causing redness, swelling and pain.

Two main uric-acid–lowering medications are available. The first is allopurinol (LOPURIN, ZYLOPRIM), which has been the first-line medication for preventing gout attacks since the Food and Drug Administration (FDA) approved it in 1966.[2] Allopurinol is particularly effective in reducing uric acid in patients with kidney disease.[3] The second is febuxostat (ULORIC), which the FDA approved in 2009 and is almost 20 times more expensive than allopurinol.[4],[5]

Public Citizen’s Health Research Group has long recommended the use of allopurinol for most patients with gout and designated febuxostat as a Do Not Use drug.[6],[7]

A weakness of the earlier major clinical trials supporting the approval of febuxostat is that they compared subjects who received fixed doses of febuxostat with those who received a maximal dose of allopurinol, rather than comparing titrated doses of these drugs as necessary to achieve adequate reduction of blood uric- acid levels, which should be done in the management of gout patients. A new randomized clinical trial that addressed this limitation and hypothesized that allopurinol is inferior to febuxostat showed that allopurinol actually did better than febuxostat in controlling gout flares, including in patients with moderate chronic kidney disease.

Funded by the Department of Veterans Affairs, the new trial was initiated before the FDA warned about the risks of febuxostat and limited its use (see next section). The findings of the trial were published in the March 2022 issue of the New England Journal of Medicine (NEJM) Evidence, a new online journal.

Grounds for our position regarding febuxostat

We based our Do Not Use designation of febuxostat on evidence from the clinical trials that supported its approval, which showed that even though the drug lowered blood uric-acid levels more than allopurinol, it was not more effective than allopurinol in preventing gout attacks, which is the main goal of treatment.[8] Additionally, there was early troubling evidence suggesting that febuxostat increased the risk of serious cardiovascular adverse effects and related mortality.

In June 2018, we petitioned the FDA to ban febuxostat[9] following the release of findings from a postmarketing safety trial (called CARES) that was required by the agency. These findings provided stronger evidence that febuxostat increases cardiovascular and all-cause mortality compared with allopurinol.[10]

In February 2019, the FDA mandated the addition of a black-box warning, the agency’s most prominent warning, to febuxostat’s labeling indicating that patients with established cardiovascular disease who were treated with the drug had an increased risk of death compared with similar patients treated with allopurinol.[11],[12] The agency also limited the approved use of febuxostat to certain patients who have an inadequate response to a maximally titrated dose of allopurinol, who cannot tolerate allopurinol or for whom treatment with allopurinol is not recommended.

The new clinical trial[13]

Trial researchers enrolled 940 subjects with gout and hyperuricemia. As designed by the researchers, one-third of these subjects had moderate chronic kidney disease in order to approximate the prevalence of this condition among gout patients in the real world. The trial subjects were randomized to receive either allopurinol or febuxostat for 72 weeks.

The trial had three phases: weeks 0 to 24 (during which allopurinol and febuxostat dosages were titrated gradually for each subject to achieve adequate reduction of blood uric-acid levels), weeks 25 to 48 (during which further dosage adjustments of both drugs was permitted until week 33) and weeks 49 to 72 (during which no dosage adjustments of the drugs were permitted).

Subjects received first doses of either 100 milligram (mg) of allopurinol, which were maximally titrated to 800 mg, or 40 mg of febuxostat, which were maximally titrated to 120 mg initially and to 80 mg later at the request of the FDA. All subjects also received anti-inflammatory treatment (mostly with colchicine [COLCRYS, GLOPERBA, MITIGARE]) in the first two phases of the trial, which is recommended as prophylaxis for gout attacks during initial treatment with allopurinol or febuxostat.

In the third phase, the researchers found that 37% of the subjects in the allopurinol-treated group had one or more gout flares (the primary efficacy outcome of the trial), compared with 44% of those in the febuxostat-treated group. This finding negated the hypothesis that allopurinol is inferior to febuxostat. However, 80% of the subjects in both groups reached their target uric-acid levels in the blood.

Among gout subjects with moderate chronic kidney disease, 32% and 45% of allopurinol- and febuxostat-treated subjects, respectively, experienced one or more gout flares during phase three of the trial. Subjects with moderate chronic kidney disease in both drug groups were similarly successful in achieving their target uric- acid levels in the blood.

For all subjects and for the subgroup of subjects with moderate chronic kidney disease, there were no differences between the two drug groups in the frequency of serious adverse effects, including cardiovascular events. However, unlike the CARES trial, the current trial was not large enough to evaluate cardiovascular safety. Therefore, its safety findings do not override those of the CARES trial.

What You Can Do

You should avoid starting febuxostat if you are not currently taking it. If you are already taking febuxostat, consult with your doctor about switching to the older and safer gout drug, allopurinol. If allopurinol fails to adequately prevent gout attacks, talk to your doctor about adding probenecid (PROBALAN). It is important not to stop taking febuxostat without first talking to your doctor because doing so can exacerbate your condition.[14] Seek emergency medical attention right away if you experience chest pain, dizziness, numbness or weakness on one side of your body, rapid or irregular heartbeat, shortness of breath, sudden severe headache and trouble with your speech while taking febuxostat.

You also should discuss with your doctor lifestyle modifications that can reduce your risk of acute gout attacks, including losing weight, avoiding or reducing alcohol intake and making changes to your diet to lower blood uric acid levels.
 

References

[1] Chen-Xu M, Yokose C, Rai SK, et al. Contemporary prevalence of gout and hyperuricemia in the United States and decadal trends: The National Health and Nutrition Examination Survey, 2007-2016. Arthritis Rheumatol. 2019;71(6):991-999.

[2] FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology guideline for the management of gout. Arthritis Care Res. 2020;72(6):744-760.

[3] Casper Pharma LLC. Label: allopurinol (ZYLOPRIM). December 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016084s044lbl.pdf. Accessed June 1, 2022.

[4] Takeda Pharmaceuticals. Label: febuxostat (ULORIC). February 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021856s013lbl.pdf. Accessed June 1, 2022.

[5] O’Dell JR, Brophy MT, Pillinger MH, et al. Comparative effectiveness of allopurinol and febuxostat in gout management. NEJM Evid. 2022;1(3):10.1056/evidoa2100028.

[6] Gout drug febuxostat (ULORIC): Risks outweigh benefits. Worst Pills, Best Pills News. May 2018. https://www.worstpills.org/newsletters/view/1195. Accessed June 1, 2022.

[7] New gout drug febuxostat (ULORIC) has important drug interactions: Do Not Use until 2016. Worst Pills, Best Pills News. November 2009. https://www.worstpills.org/newsletters/view/667. Accessed June 1, 2022.

[8] Public Citizen’s Health Research Group. Testimony before the FDA’s Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee regarding febuxostat. January 11, 2019. https://www.citizen.org/sites/default/files/2464.pdf. Accessed June 1, 2022.

[9] Public Citizen’s Health Research Group. Petition to ban febuxostat (ULORIC). June 21, 2018. https://www.citizen.org/sites/default/files/2434.pdf. Accessed June 1, 2022.

[10] White WB, Saag KG, Becker MA, et al. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med. 2018;378(13):1200-1210.

[11] Food and Drug Administration. FDA adds boxed warning for increased risk of death with gout medicine Uloric (febuxostat). February 21, 2019. https://www.fda.gov/media/120418/download. Accessed June 1, 2022.

[12] Takeda Pharmaceuticals. Label: febuxostat (ULORIC). February 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021856s013lbl.pdf. Accessed June 1, 2022.

[13] O’Dell JR, Brophy MT, Pillinger MH, et al. Comparative effectiveness of allopurinol and febuxostat in gout management. NEJM Evid. 2022;1(3):10.1056/evidoa2100028.

[14] Food and Drug Administration. Food and Drug Administration. FDA adds boxed warning for increased risk of death with gout medicine uloric (febuxostat). February 21, 2019. https://www.fda.gov/media/120418/download. Accessed June 1, 2022.