Last reviewed: May 2019
Last updated: September  2018
27 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 postmarketing 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

  • acute, severe flank pain

Other diagnostic factors

  • previous episodes of nephrolithiasis
  • nausea and vomiting
  • urinary frequency/urgency
  • haematuria
  • testicular pain
  • obesity
  • family history
  • precipitant medications
  • groin pain
  • fever
  • tachycardia
  • hypotension
  • costovertebral angle and ipsilateral flank tenderness

Risk factors

  • high protein intake
  • high salt intake
  • white ancestry
  • male sex
  • dehydration
  • obesity
  • crystalluria
  • occupational exposure to dehydration
  • warm climate
  • family history
  • precipitant medications

Diagnostic investigations

1st investigations to order

  • urinalysis
  • FBC and differential
  • serum electrolytes, urea, and creatinine
  • urine pregnancy test
  • non-contrast helical CT scan
  • stone analysis
Full details

Investigations to consider

  • plain abdominal radiograph (KUB)
  • renal ultrasound
  • intravenous pyelogram (IVP)
  • 24-hour urine monitoring
  • spot urine for cystine
Full details

Treatment algorithm


Authors VIEW ALL

Assistant Professor

Department of Urology

University of Texas Southwestern Medical Center




JA is a member of the Scientific Advisory Board for Boston Scientific. JA has received a research grant from the US National Institutes of Health to study strategies to reduce recurrence of nephrolithiasis and reduce stent-associated pain.

Associate Program Director

Associate Professor

University of Texas Southwestern Medical Center




NM has received a research grant from the US National Institutes of Health to study strategies to reduce recurrence of nephrolithiasis and reduce stent-associated pain.

Dr Jodi Antonelli and Dr Naim Maalouf would like to gratefully acknowledge Dr Brian Eisner, Dr Michael E. Lipkin, Dr Muhammad Iqbal, Dr Keith Xavier, and Dr Mantu Gupta, previous contributors to this monograph. BE has received fees for consulting from Boston Scientific, Olympus/Gyrus ACMI, PercSys, and The Ravine Group. MEL declares that he is a consultant for Boston Scientific Corporation. MI, KX, and MG declare that they have no competing interests.

Peer reviewers VIEW ALL

Associate Professor

Department of Family Medicine

University of Texas Health Science Center




RT declares that he has no competing interests.

Associate Professor of Medicine

Division of Nephrology

University of California at San Francisco



LF declares that she has no competing interests.

Assistant Professor

Chicago Medical School

Rosalind Franklin University




IM declares that he has no competing interests.

Consultant Urological Surgeon

Spire Manchester Hospital




NR declares no competing interests.

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