FDA News

FDA panel: Febuxostat benefits outweigh CV risks, but reduce use

Steven M. Nissen
Steven M. Nissen

A joint panel of the FDA’s Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee 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 (Uloric, Takeda), which was approved by the FDA in 2009, after the CARES postmarket CV outcomes study. The drug’s labeling carries 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.

Mortality risk

As Cardiology Today previously reported, in CARES, presented at the American College of Cardiology Scientific Session in March, although there was no difference in overall major adverse CV event rates between patients assigned febuxostat and patients assigned allopurinol, the febuxostat group had elevated risks for CV death and all-cause death.

“This drug was turned down by the FDA twice because of excess CV events, particularly CV death,” Cardiology Today Editorial Board Member Steven M. Nissen, MD, MACC, a member of the panel who voted that the risks outweigh the benefits, said in an interview. “It was only approved after a small third study showed no excess, and the FDA required a postmarket study, CARES. This study was done very poorly. It had the largest nonretention rate I’ve ever seen, at 45%, and 57% of the febuxostat group was off the drug before the end of the study. Both of those should make the risks go away, but in spite of that, febuxostat had a 34% increased risk for CV death and a 22% increased risk for all-cause mortality.”

However, the majority of panelists said there are patients who cannot tolerate allopurinol because it can cause very serious allergic reactions, and for them, the benefits of febuxostat outweigh the CV risks.

In a press release issued by Takeda, Lawrence Edwards, MD, a rheumatologist at University of Florida Health who is not a member of the panel, said the vote “reflects the continued importance of having treatment options available for patients with gout.”

Nissen, who is chairman of the Robert and Suzanne Tomsich Department of Cardiovascular Medicine at Cleveland Clinic’s Sydell and Arnold Miller Family Heart and Vascular Institute, told Cardiology Today he proposed a risk evaluation and mitigation strategy, but FDA staff were not receptive to the idea.

“It would allow the drug to be dispensed only under certain circumstances,” he said. “It would be kept at a central pharmacy, and only dispensed if the doctor and patient gave informed consent that they are aware of the drug’s risks regarding CV death. The FDA was reluctant to agree to that, so I voted to remove the drug.”

A clear message

However, Nissen said, “the panel sent a clear message that this should be a second-line therapy and there should be black box warnings. The FDA has got to ensure that this is not used as a first-line go-to drug in these patients.”

Takeda stated in the 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 Cardiology Today. “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.”

The FDA is not required to follow the recommendations of its advisory panels, but it usually does. – by Erik Swain

For more information:

Michael A. Carome, MD, can be reached at mcarome@citizen.org.

Steven E. Nissen, MD, MACC, can be reached at nissens@ccf.org.

Disclosures: Carome and Nissen report no relevant financial disclosures.

Steven M. Nissen
Steven M. Nissen

A joint panel of the FDA’s Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee 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 (Uloric, Takeda), which was approved by the FDA in 2009, after the CARES postmarket CV outcomes study. The drug’s labeling carries 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.

Mortality risk

As Cardiology Today previously reported, in CARES, presented at the American College of Cardiology Scientific Session in March, although there was no difference in overall major adverse CV event rates between patients assigned febuxostat and patients assigned allopurinol, the febuxostat group had elevated risks for CV death and all-cause death.

“This drug was turned down by the FDA twice because of excess CV events, particularly CV death,” Cardiology Today Editorial Board Member Steven M. Nissen, MD, MACC, a member of the panel who voted that the risks outweigh the benefits, said in an interview. “It was only approved after a small third study showed no excess, and the FDA required a postmarket study, CARES. This study was done very poorly. It had the largest nonretention rate I’ve ever seen, at 45%, and 57% of the febuxostat group was off the drug before the end of the study. Both of those should make the risks go away, but in spite of that, febuxostat had a 34% increased risk for CV death and a 22% increased risk for all-cause mortality.”

However, the majority of panelists said there are patients who cannot tolerate allopurinol because it can cause very serious allergic reactions, and for them, the benefits of febuxostat outweigh the CV risks.

In a press release issued by Takeda, Lawrence Edwards, MD, a rheumatologist at University of Florida Health who is not a member of the panel, said the vote “reflects the continued importance of having treatment options available for patients with gout.”

Nissen, who is chairman of the Robert and Suzanne Tomsich Department of Cardiovascular Medicine at Cleveland Clinic’s Sydell and Arnold Miller Family Heart and Vascular Institute, told Cardiology Today he proposed a risk evaluation and mitigation strategy, but FDA staff were not receptive to the idea.

PAGE BREAK

“It would allow the drug to be dispensed only under certain circumstances,” he said. “It would be kept at a central pharmacy, and only dispensed if the doctor and patient gave informed consent that they are aware of the drug’s risks regarding CV death. The FDA was reluctant to agree to that, so I voted to remove the drug.”

A clear message

However, Nissen said, “the panel sent a clear message that this should be a second-line therapy and there should be black box warnings. The FDA has got to ensure that this is not used as a first-line go-to drug in these patients.”

Takeda stated in the 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 Cardiology Today. “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.”

The FDA is not required to follow the recommendations of its advisory panels, but it usually does. – by Erik Swain

For more information:

Michael A. Carome, MD, can be reached at mcarome@citizen.org.

Steven E. Nissen, MD, MACC, can be reached at nissens@ccf.org.

Disclosures: Carome and Nissen report no relevant financial disclosures.