New Gout Drug Febuxostat (ULORIC) Has Important Drug Interactions: Do Not Use Until 2016

Febuxostat (ULORIC), the first new gout drug to enter the U.S. market in decades, can interact with immunosuppressant drugs to suppress bone marrow production of blood cells. This can result in severe and sometimes fatal infections because of a deficiency in these infection-fighting blood cells.

Although the drug is more effective in lowering blood uric acid levels than the main drug used in preventing gout attacks — allopurinol (ZYLOPRIM) — it was no more effective in preventing gout attacks in clinical trials and, in the first two months, it was less effective than allopurinol in preventing such attacks.

Gout, a condition that occurs when a person’s blood levels of uric acid rise to the point that the uric acid crystallizes in joints and surrounding tissues, results in painful inflammation.

Febuxostat works by inhibiting xanthine oxidase, an enzyme involved in the production of uric acid in the body. Febuxostat has the same mechanism of action as an old drug used for gout called allopurinol.

Febuxostat was first made available to American consumers on Feb. 13, 2009.

In general, people should wait at least seven years from the date of FDA approval to take any new drug unless it is one of those rare "breakthrough" drugs that offers a documented therapeutic advantage over older, proven drugs.

In the case of febuxostat, we agree with the assessment of the French drug review bulletin, Prescrire that this drug represents "nothing new."

New drugs are tested in a relatively small number of people before being released, and serious side effects or life-threatening drug interactions may not be detected until the new drug has been taken by hundreds of thousands of people.

We call this our "Seven Year Rule," and it is based on a study we co-authored in the May 1, 2002, Journal of the American Medical Association. This study found that one-half of all drug safety withdrawals and major relabelings occurred within seven years of drug approval — thus the Seven Year Rule.

What are the critical interactions?

The most dangerous interactions with febuxostat occur when it is combined with either of the immunosuppressants azathioprine (IMURAN) or mercaptopurine (PURINETHOL).

Azathioprine is used to prevent organ rejection in people with kidney transplants and as an immunosuppressant in patients with diseases such as rheumatoid arthritis and Crohn’s disease. Mercaptopurine is used in chemotherapy, mainly for acute lymphocytic leukemia, but it is sometimes used for inflammatory bowel disease — as is azathioprine.

Xanthine oxidase, the enzyme that is inhibited by febuxostat, is also the enzyme that the body uses to process azathioprine and mercaptopurine. Thus, taking febuxostat with either of these drugs is likely to substantially increase the blood levels of these two immunosuppressants.

At high blood levels, both azathioprine and mercaptopurine suppress bone marrow formation of blood cells, resulting in severe or fatal infections and bleeding.

Are there any interactions with other drugs?

The asthma drug theophylline is also partially metabolized by xanthine oxidase. Adding febuxostat to theophylline therapy is likely to increase theophylline blood levels, and in some patients may produce theophylline toxicity.

Some of the early symptoms of theophylline toxicity are gastrointestinal (nausea, vomiting, diarrhea), but can also include symptoms such as restlessness and insomnia. Severe theophylline toxicity can be life-threatening with cardiac arrhythmias or seizures.

Are other gout drugs safer?

Cases of severe or fatal azathioprine or mercaptopurine toxicity due to interactions between those drugs and allopurinol, the older gout drug that also works as a xanthine oxidase inhibitor, began to appear 40 years ago, and these reactions continue to occur. Now that another xanthine oxidase inhibitor, febuxostat, is on the market, there is the potential for these severe reactions to increase.

Many of the severe interactions that have occurred when allopurinol was given with azathioprine or mercaptopurine have occurred when patients were prescribed medications from more than one medical professional. In this case, although both doctors might know about the potential for such an interaction, one prescriber might not be aware of the other drugs you have been given.

What You Can Do

Avoid taking febuxostat with drugs that are metabolized by xanthine oxidase: azathioprine, mercaptopurine and theophylline.

Make sure every one of your prescribers is aware of every medication you take, including nonprescription and herbal medications. Even those physicians who are aware of this drug interaction cannot prevent interactions if you do not keep them informed about all of your medications.

If possible, get all of your prescriptions filled at one pharmacy or an affiliated group of pharmacies that will check all of your medications for drug interactions. While it is true that pharmacy-based computerized drug interaction detection systems are not perfect, they cannot effectively detect drug interactions if they do not have a record of all of the medications you are taking.