The FDA’s Arthritis Advisory Committee (AAC) and Drug Safety and Risk Management (DSaRM) Advisory Committee held a joint meeting on January 11, 2019, to discuss the “Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES)” trial results and the benefit-risk assessment of febuxostat. Members of the committees voted 19 to 2, with 1 abstention, that based on available data, there are patient populations in which the benefit-risk profile for febuxostat is favourable for the treatment of hyperuricemia in patients with gout. The committees held a widely varied discussion about the appropriate patient populations and potential regulatory actions.
The outcome of the FDA joint committee review was announced by Takeda, makers of Uloric® (brand of febuxostat). Febuxostat is available in Nigeria under the brand name Febo-G®, marketed by Getz Pharma Ltd
“Many believe that gout is a condition that comes and goes for patients, but it is a chronic disease that can be severe and potentially debilitating, and many patients require pharmacologic treatment options to manage their disease,” said Lawrence Edwards, MD, rheumatologist, University of Florida Health. “Today’s vote from the Advisory Committees reflects the continued importance of having treatment options available for patients with gout.”
Laurel A. Habel, MPH, PhD (voted yes), an epidemiologist, said that at the very least febuxostat’s label should “include the CARES results, even though they’re not definitive.” This might come in the form of a BLACK-BOX WARNING or some other phrasing to “result in more restrictive use and encourage it as second-line therapy,” she commented. Further, professional societies should also frame febuxostat as second-line therapy, Habel asserted, though there shouldn’t be barriers that make the drug hard to obtain for patients who really need it to treat debilitating gout.
Martin Kulldorff, PhD voted against febuxostat having a favourable risk-benefit balance. He cited the argument that “there is evidence that the drug causes death in some people.” Moreover, it isn’t known whether patients who are unable to take allopurinol would, in fact, do well on febuxostat, he said. “I think we basically don’t know. I think the future of this drug for the moment is to withdraw it from the market and encourage prospective clinical trials to study the drug among those who do not tolerate allopurinol.”
In the CARES trial, febuxostat met the primary endpoint, demonstrating that the rate of major adverse CV events (MACE: CV death, non-fatal myocardial infarction (MI), non-fatal stroke, and unstable angina with urgent coronary revascularization) in patients treated with febuxostat was non-inferior to that of allopurinol. When analyzing the individual components of MACE as secondary endpoints, the individual rates for MI, stroke, and unstable angina with urgent coronary revascularization were similar with febuxostat compared to allopurinol. However, the rate of CV death was higher among patients assigned to febuxostat compared to allopurinol, which also contributed to a higher rate of death from all causes. Based on analyses conducted to date, a reason for this finding has not been identified. There were no significant differences in rates of other serious CV events such as hospitalization for heart failure or arrhythmias.
Febuxostat was approved in 2009 and allopurinol in 1966. The two drugs are the only xanthine oxidase inhibitors (XOIs) on the market for the treatment of gout. Since approval, the Prescribing Information for febuxostat has included a warning and precaution that a higher rate of adverse CV events was observed in patients treated with febuxostat when compared with allopurinol in clinical trials.
Febuxostat is the only first-line alternative for patients who cannot take allopurinol, due to being genetically predisposed to a hypersensitivity reaction, having chronic kidney disease, or developing a skin reaction or other side effects on the drug.
The outcome of the Advisory Committee meeting is non-binding and will be taken into consideration by the FDA.
Uses of Febuxostat:
Febuxostat is a prescription medicine used to lower blood uric acid levels in adults with gout. Febuxostat is not for the treatment of high uric acid without a history of gout.
Important Safety Information:
Do not take febuxostat if you are taking azathioprine or mercaptopurine.
Febuxostat may cause serious side effects, including:
Gout Flares: Gout flares can happen when you first start taking febuxostat. Your healthcare provider may give you other medicines to help prevent your gout flares.
Heart Problems: People who take febuxostat can have serious heart problems including heart attacks, strokes and heart-related deaths. It is not known that febuxostat caused these problems. Call your healthcare provider right away or get emergency medical help if you have any of the following symptoms: chest pain, shortness of breath, dizziness, numbness or weakness on one side of your body, trouble talking or a headache.
Liver Problems: Liver problems can happen in people who take febuxostat. Your healthcare provider may do blood tests to check how well your liver is working before and during your treatment with febuxostat.
Severe Skin and Allergic Reactions: Serious skin and allergic reactions that may affect different parts of the body such as your liver, kidneys, heart or lungs, can happen in people who take febuxostat. Call your healthcare provider right away or get emergency medical help if you have any of the following symptoms: rash, red and painful skin, severe skin blisters, peeling skin, sores around the lips, eyes or mouth, swollen face, lips, mouth, tongue or throat, or flu-like symptoms.
The most common side effects of febuxostat include liver problems, nausea, gout flares, joint pain, and rash. Tell your healthcare provider if you have any side effect that bothers you, or that does not go away.
About Gouty Arthritis:
Gout is caused by a buildup of uric acid in the body. Uric acid forms crystals in the joints, which can lead to the inflammation and pain of a gout attack. As the uric acid level rises, so does the chance for gout and gout attacks. Over time, these attacks, or flares, can involve more joints, last longer, and happen more often.
An estimated 8.3 million Americans have gout, which may be increasing. Half of the gout patients have three or more attacks per year; a typical gout attack can last at least 4 days.
References:
- Takeda Announces Outcome of Uloric FDA Advisory Committee Meeting [Internet]. [cited 2019 Jan 16]. Available from: https://www.takeda.com/en-us/newsroom/news-releases/2019/takeda-announces-outcome-of-uloric-fda-advisory-committee-meeting/
- Febuxostat Emerges Relatively Unscathed After FDA Advisory Committee Review [Internet]. TCTMD.com. [cited 2019 Jan 16]. Available from: https://www.tctmd.com/news/febuxostat-emerges-relatively-unscathed-after-fda-advisory-committee-review
- FDA Advisers Back Febuxostat for Gout Despite Possible CV Risk [Internet]. Medscape. [cited 2019 Jan 16]. Available from: http://www.medscape.com/viewarticle/907633