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FDA is strengthening warnings in the febuxostat (Uloric) product labeling and has added a Medication Guide requirement because of an increased risk of cardiovascular death and all-cause mortality. In November 2017, FDA issued a safety alert about these risks based on initial results of the Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) trial. FDA’s review of the trial has been completed, leading to the new requirements.
Febuxostat was associated with an increased risk of cardiovascular death and all-cause mortality in the CARES trial. In this double-blind trial, 6,190 patients over the age of 50 years with gout and a history of either cardiovascular or cerebrovascular disease were randomized to feboxustat or allopurinol once daily. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and unstable angina requiring urgent coronary revascularization. Patients were followed for a median of 32 months. There was no significant difference between febuxostat and allopurinol for the primary endpoint. However, cardiovascular death was significantly more common with febuxostat (4.3%) than allopurinol (3.2%; P = 0.03). All-cause mortality was also more common with febuxostat (7.8%) than allopurinol (6.4%; P = 0.04).
Febuxostat is manufactured by Takeda Pharmaceuticals and is FDA-approved to treat gout. Febuxostat labeling already had a Warning and Precaution about cardiovascular events. In the clinical trials that led to FDA-approval, febuxostat demonstrated an increased risk of cardiovascular events when compared to allopurinol. For this reason, the FDA requested that Takeda Pharmaceuticals conduct the CARES trial to evaluate cardiovascular safety.
The febuxostat labeling has been revised to include a boxed warning. In addition, a Medication Guide must be provided to patients taking febuxostat. Avoid prescribing febuxostat to patients with a history of stroke or heart disease. Reserve febuxostat for use in patients who experience severe side effects or lack of efficacy with other gout medicines. Educate patients treated with febuxostat to seek immediate medical attention if they experience chest pain, dizziness, one-sided numbness or weakness rapid or irregular heartbeat, shortness of breath, sudden severe headache, or trouble talking. Report adverse effects involving febuxostat to the FDA MedWatch program.
FDA requires the distribution of Medication Guides for drugs determined to be a serious and significant public health concern. Distribution requirements and exceptions (eg, certain inpatient care situations) for Medication Guides are addressed in an FDA Guidance Document: www.fda.gov/Drugs/DrugSafety/ucm085729.htm. Medication Guide distribution requirements are stricter for medications with a Risk Evaluation and Mitigation Strategy (REMS) that includes Elements To Assure Safe Use (ETASU) with specific requirements for providing and reviewing the Medication Guide: www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/.
A complete list of drugs that require a Medication Guide as part of the FDA-regulated product labeling is available online at: www.fda.gov/Drugs/DrugSafety/ucm085729.htm.
More information is available at the following links:
- Febuxostat product labeling – February 2019
https://general.takedapharm.com/ULORICPI - FDA Medwatch Alerts
- February 21, 2019
www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM631824 - November 15, 2017
www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm585281.htm
- February 21, 2019
- CARES trial – White et al. N Engl J Med. 2018;378(13):1200-10.
www.nejm.org/doi/10.1056/NEJMoa1710895 - FDA Drug Safety Communication – February 21, 2019
www.fda.gov/Drugs/DrugSafety/ucm631182.htm - FDA Safety Alert – November 15, 2017
www.fda.gov/Drugs/DrugSafety/ucm584702.htm