FDA NewsPerspective

FDA adds boxed warning to febuxostat for increased mortality risk

The FDA has added a new boxed warning to febuxostat due an increased risk of cardiovascular and all-cause mortality compared with allopurinol, according to a recent safety announcement.

Clinicians have been advised to reserve febuxostat (Uloric, Takeda) for use among patients with gout who have failed or do not otherwise tolerate maximally titrated allopurinol.

The boxed warning follows a Jan. 11 joint panel of the FDA’s Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee, which voted 19-2 with one abstention that patient populations exist in which the benefits of the gout drug febuxostat outweigh the CV risk. However, most of the panelists stated that the drug should be relegated to a second-line therapy for the treatment of hyperuricemia in patients with gout.

The panel was convened to make recommendations on the market status of febuxostat, which was approved by the FDA in 2009, after the CARES postmarket CV outcomes study. Prior to the boxed warning, the labeling for febuxostat carried a warning and precaution that a higher rate of CV events was observed in clinical trials compared with allopurinol, the only other available xanthine oxidase inhibitor.

In response to the joint panel decision, Takeda stated in a press release that it will continue to work with the FDA to ensure that febuxostat is used as safely as possible.

“Patient safety has always been our first priority at Takeda, and we appreciate that common purpose and the thoughtful discussion … with the Advisory Committee members about CARES,” Tom Harris, senior vice president and head of global regulatory affairs for Takeda, said in the release. “We have studied the safety of Uloric for more than 15 years, and remain confident in Uloric as an important option for the chronic management of hyperuricemia in gout. We look forward to additional discussions with the FDA regarding these CARES data.”

Public Citizen called for the drug’s removal from the market, first in a June petition and then in a statement from Michael A. Carome, MD, director of its health research group, delivered at the panel meeting.

“We disagree with the panel’s vote and urge the FDA to withdraw febuxostat from the market,” Carome told Healio Rheumatology. “If such action is not taken, the agency should require the addition of a black box warning about the increased risk of cardiovascular death and modify the approved indication to limit use of the drug to patients who are not able to use allopurinol.” – by Robert Stott

Disclosure: Carome reports no relevant financial disclosures.

The FDA has added a new boxed warning to febuxostat due an increased risk of cardiovascular and all-cause mortality compared with allopurinol, according to a recent safety announcement.

Clinicians have been advised to reserve febuxostat (Uloric, Takeda) for use among patients with gout who have failed or do not otherwise tolerate maximally titrated allopurinol.

The boxed warning follows a Jan. 11 joint panel of the FDA’s Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee, which voted 19-2 with one abstention that patient populations exist in which the benefits of the gout drug febuxostat outweigh the CV risk. However, most of the panelists stated that the drug should be relegated to a second-line therapy for the treatment of hyperuricemia in patients with gout.

The panel was convened to make recommendations on the market status of febuxostat, which was approved by the FDA in 2009, after the CARES postmarket CV outcomes study. Prior to the boxed warning, the labeling for febuxostat carried a warning and precaution that a higher rate of CV events was observed in clinical trials compared with allopurinol, the only other available xanthine oxidase inhibitor.

In response to the joint panel decision, Takeda stated in a press release that it will continue to work with the FDA to ensure that febuxostat is used as safely as possible.

“Patient safety has always been our first priority at Takeda, and we appreciate that common purpose and the thoughtful discussion … with the Advisory Committee members about CARES,” Tom Harris, senior vice president and head of global regulatory affairs for Takeda, said in the release. “We have studied the safety of Uloric for more than 15 years, and remain confident in Uloric as an important option for the chronic management of hyperuricemia in gout. We look forward to additional discussions with the FDA regarding these CARES data.”

Public Citizen called for the drug’s removal from the market, first in a June petition and then in a statement from Michael A. Carome, MD, director of its health research group, delivered at the panel meeting.

“We disagree with the panel’s vote and urge the FDA to withdraw febuxostat from the market,” Carome told Healio Rheumatology. “If such action is not taken, the agency should require the addition of a black box warning about the increased risk of cardiovascular death and modify the approved indication to limit use of the drug to patients who are not able to use allopurinol.” – by Robert Stott

Disclosure: Carome reports no relevant financial disclosures.

    Perspective
    N. Lawrence Edwards

    N. Lawrence Edwards

    Febuxostat was approved by the FDA in 2009 as a urate-lowering therapy for the treatment of gout. Over its 10 years of utilization, febuxostat has garnered slightly less than 10% of the urate-lowering medication market. Most patients receiving febuxostat have previously taken allopurinol, but for a number of reasons were switched febuxostat. During the phase 3 clinical trials, there was a signal for cardiovascular events for febuxostat that was not statistically significant.

    However, the FDA required a warning in the prescribing information that said, “A higher rate of cardiovascular thromboembolic events was observed in patients treated with Uloric than allopurinol in clinical trials. Monitor for signs and symptoms of MI and stroke.” The FDA also required a post-marketing cardiovascular safety trial that compared febuxostat to allopurinol.

    The Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) trial enrolled nearly 6,200 patients with gout who were at high risk for cardiovascular disease into a long-term, randomized, double-blind study with a 1:1 randomization to either febuxostat (40-80 mg daily) or allopurinol (200-600 mg daily).

    Both groups had an initial 3-month period when therapy was up-titrated to achieve a target serum uric acid of < 6.0 mg/dL. Patients were followed for up to 85 months with a median follow-up of 32 months. The primary end-point of the trial was the occurrence of a major adverse cardiovascular event (MACE) in either treatment group.

    The secondary end-points were the individual MACE components, including CV death, nonfatal MI, nonfatal stroke and unstable angina requiring urgent revascularization. All-cause mortality was also analyzed.

    The primary end-point of the trial was not significantly different between febuxostat (10.8%) and allopurinol (10.4%). However, within the secondary end-points, CV death did show a significant difference between febuxostat (4.3%) and allopurinol (3.2%). This, in turn, resulted in a higher all-cause mortality for the febuxostat group.

    These results were published in the New England Journal of Medicine in March 2018 and presented to the FDA Arthritis Advisory Committee in January 2019. The result of that hearing was a new FDA-approved black box warning in the Febuxostat package insert. That warning states: “Gout patients with established cardiovascular (CV) disease treated with Uloric had a higher rate of CV death compared to those treated with allopurinol in a CV outcome study.”

    The warning went on to recommend: (1) to consider the risk/benefit of Uloric when prescribing or continuing patients on Uloric, (2) to only use Uloric in patients with an inadequate response or intolerance to allopurinol, or (3) to use in patients for whom allopurinol is not advisable.

    Many questions remain about the meaning of the CARES study. This is the first cardiovascular safety trial for any type of medication where an increase in CV death was not paralleled by an uptick in one or more of the other MACE components. Mechanisms for the observed increased death rate were extensively investigated by the sponsoring company and the cardiologist who adjudicated this trial. To date, no physiologic mechanism has been detected.

    Similarly, there was no subset within the treatment cohort of gout patients with existing CV disease that seem to be a particular risk for this outcome. The other unusual aspect of this trial is that most subjects who experienced CV death were not on medication (either febuxostat or allopurinol) when death occurred.

    The CARES trial had flaws in both its design and execution. The lack of a placebo-controlled arm in this study, while probably being the correct ethical approach, leaves us wondering if CARES demonstrated true cardiotoxicity for febuxostat or whether febuxostat is simply not as cardioprotective as allopurinol. The study was also flawed in its execution by the very high rate of premature treatment discontinuation and discontinued follow-up for both arms of the trial.

    The new FDA-approved warning for febuxostat is a prudent reflection of our current knowledge about CV risk when using this drug. The recommendation for the use of febuxostat only after an earnest trial of allopurinol is in keeping with how febuxostat is already being used in this country. Perhaps the results of another large, on-going, perspective trial comparing allopurinol and febuxostat will help clarify the real meaning of the CARES study findings.

    • N. Lawrence Edwards, MD, MACP, MACR
    • Vice Chairman, Department of Medicine
      Program director, Medicine Residency Training Program
      University of Florida
      Member, Medical Policy Committee
      United Rheumatology

    Disclosures: Edwards reports a consultant/advisory role with Ardea Biosciences, Inc, Novartis Pharmaceuticals Corporation, Savient Pharmaceuticals, Inc and Takeda Pharmaceuticals North America, Inc.

    Perspective
    Vickie L. Sayles

    Vickie L. Sayles

    Approved by the FDA in 2009 to treat gout in adults, febuxostat lowers the uric acid in the blood and reduces sudden attacks of this inflammatory arthritis. Recently, following an in-depth cardiovascular safety study, the FDA added a new boxed warning indicating that there is an increased risk of heart-related death and death from all causes with febuxostat. As a result, patients should only be prescribed this medication if they are unresponsive to or unable to tolerate the maximum dosage of allopurinol.

    Patients considering febuxostat as a gout treatment should inform their health care provider if they have a history of heart problems or stroke and discuss the risks/benefits of using this drug compared with other gout medications.

    Additionally, providers should advise patients of the increased cardiovascular risk associated with febuxostat and counsel them to seek emergency treatment if they experience any of these symptoms: Chest pain; severe skin reactions including rash; red and painful skin; skin blisters; sores around the mouth, eyes or mouth; shortness of breath/trouble breathing; rapid or irregular heart beat; numbness or weakness on one side of the body; dizziness; slurring of speech; sudden severe headache; and vision changes.

    • Vickie L. Sayles, BSN, CRNI, RN-BC
    • Treasurer, Rheumatology Nurses Society
      Clinical nurse manager
      Department of Rheumatic and Immunologic Diseases
      The Cleveland Clinic Foundation

    Disclosures: Sayles reports speaking fees from Kevzara and Sanofi Genzyme.