Last reviewed: March 2019
Last updated: February  2019
26 Feb 2019

FDA adds boxed warning to febuxostat after safety trial finds increased risk of death

Febuxostat increases the risk of heart-related and all- cause death compared with allopurinol in patients with gout, according to a large safety trial. Healthcare professionals are advised by the US Food and Drug Administration (FDA) to:

  • Prescribe febuxostat only for patients who have failed treatment with or can not tolerate allopurinol

  • Counsel patients regarding the cardiovascular risk with febuxostat and advise them to seek medical attention immediately if they experience chest pain, shortness of breath, rapid or irregular heartbeat, numbness or weakness on one side of their body, dizziness, trouble speaking, or sudden severe headache.

In 2009, febuxostat was approved by the FDA to treat gout, but with a warning and precaution regarding possible cardiovascular events. The manufacturer was required to conduct a large postmarketinging safety clinical trial.

The double-blind study (CARES) compared cardiovascular outcomes in patients with gout and major cardiovascular disease (n = 6198) who were randomised to febuxostat or to allopurinol. Treatment groups did not differ with respect to a primary composite outcome of cardiovascular events. However, cardiovascular death and all-cause mortality were significantly more common among patients taking febuxostat than allopurinol (4.3% vs. 3.2%, HR 1.34 [95% CI 1.03 to 1.73]; 7.8% vs. 6.4%, HR 1.22 [95% CI 1.01 to 1.47], respectively).

See Management: approach See Management: treatment algorithm

Original source of update



History and exam

Key diagnostic factors

  • presence of risk factors
  • rapid-onset severe pain
  • joint stiffness
  • foot joint distribution
  • few affected joints
  • swelling and joint effusion
  • tenderness
  • tophi

Other diagnostic factors

  • erythema and warmth
  • family history of gout

Risk factors

  • older age
  • male sex
  • menopausal status
  • consumption of meat, seafood, alcohol
  • use of diuretics
  • use of ciclosporin (cyclosporine) or tacrolimus
  • use of pyrazinamide
  • use of aspirin
  • genetic susceptibility
  • high cell turnover state
  • adiposity and insulin resistance
  • hypertension
  • renal insufficiency
  • diabetes mellitus
  • hyperlipidaemia

Diagnostic investigations

1st investigations to order

  • arthrocentesis with synovial fluid analysis
Full details

Investigations to consider

  • uric acid level
  • x-ray of affected joint
  • ultrasound
Full details

Treatment algorithm


Authors VIEW ALL

Fadi Badlissi

Assistant Professor

Harvard Medical School

Attending Physician

Director of the Musculoskeletal Medicine Unit

Department of Orthopedics & Division of Rheumatology

Beth Israel Deaconess Medical Center




FB declares that he has no competing interests.

Peer reviewers VIEW ALL

Professor of Medicine

VA Medical Center




HRS has been a consultant for a number of pharmaceutical companies that produce drugs that can be used for the treatment of gout. Some companies have supplied HRS with funding. HRS is an author of a number of references cited in this monograph.

Associate Director of Teaching and Honorary Senior Lecturer in Rheumatology

Academic Rheumatology Group

Faculty of Medicine

University of Sheffield




AA declares that he has no competing interests.

Professor of Primary Care Research

Warwick Medical School




MU declares that he has no competing interests.

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