Stronger Liver Toxicity Warning for the Arthritis Drug Leflunomide (ARAVA)

On July 13, 2010, the Food and Drug Administration (FDA) announced that the black-box warning for the arthritis drug leflunomide (ARAVA) will be updated to highlight the risk of severe liver injury with the use of this drug and to explain how this risk may be reduced.

Leflunomide was approved by the FDA in September 1998 for the treatment of active rheumatoid arthritis in adults. At the time, the agency required a black-box warning for leflunomide, which was limited to saying the drug should not be used by pregnant women or women of childbearing age who do not use a reliable form of contraception.

The FDA said that its decision to add new information about severe liver injury to leflunomide’s black-box warning was based on a review of the adverse event reports submitted to the agency regarding the drug. The review identified 49 cases of severe liver injury, including 14 cases of fatal liver failure, between August 2002 and May 2009. In its review, the FDA found that the greatest risk for liver injury was seen in patients taking other drugs known to cause liver injury and in patients with pre-existing liver problems.

Recognizing liver toxicity

Consumers using leflunomide who experience itching, yellow eyes or skin, dark urine, loss of appetite, or light-colored stools should contact a health care professional immediately. These may be signs of severe liver injury.

Leflunomide and Public Citizen: our 2002 alert about liver toxicity

On March 28, 2002, Public Citizen petitioned the government to immediately remove leflunomide from the market because of the risk of liver toxicity. In the petition, we said that in the two years ending on September 30, 2001, leflunomide was associated with at least 130 severe liver reactions, including 56 hospitalizations and 22 deaths. Two of these reactions were in patients in their 20s. In 12 of these deaths, leflunomide-induced liver toxicity appeared to be the most plausible explanation.

Our petition also noted that the studies submitted to the FDA by the manufacturer of leflunomide demonstrated that the drug’s effectiveness was likely inferior to that of an older drug, methotrexate (TREXALL). In one trial, leflunomide and methotrexate were considered equally effective, with 41 percent of patients on leflunomide, 35 percent on methotrexate and 19 percent on a placebo responding to treatment. But in a much larger trial comparing methotrexate to leflunomide, methotrexate was significantly superior — with a 57-percent response rate in those on methotrexate compared to 43 percent for those on leflunomide.

What You Can Do

Leflunomide is listed as a Do Not Use drug in Worst Pills, Best Pills News and on WorstPills.org. If you are using leflunomide, you should discuss with your physician the possibility of taking one of the safer and more effective drugs available for treating rheumatoid arthritis.

According to the highly respected Medical Letter, in the May 2009 issue of its “Treatment Guidelines,” recommended treatment of rheumatoid arthritis is as follows:

When the diagnosis of rheumatoid arthritis has been established, most Medical Letter consultants start a disease-modifying anti-rheumatic drug (DMARD) and use a nonsteroidal anti-inflammatory drug (NSAID) with or without a corticosteroid to control symptoms. Methotrexate is generally the DMARD of choice; somewhat safer drugs such as hydroxychloroquine (PLAQUENIL) or sulfasalazine (AZULFIDINE) may be appropriate in the mildest cases.

Tumor necrosis factor (TNF) inhibitors (etanercept [ENBREL], infliximab [REMICADE], or adalimumab [HUMIRA]) as monotherapy may be more effective than methotrexate and other nonbiologic DMARDs in limiting joint destruction and act more quickly in relieving symptoms, but their long-term safety remains unclear.

In patients with features that suggest a poor prognosis and those who do not respond adequately to methotrexate or other single agents, combination therapies are often effective, especially methotrexate plus a TNF inhibitor. Use of a TNF inhibitor concurrently with methotrexate is more effective than either one alone.

Injecting one or two joints with a corticosteroid can control rheumatoid arthritis in some patients who do not have generalized disease.

In addition to drug treatment, however, non-drug remedies such as heat and joint range-of-motion exercises can help to relieve the joint stiffness that limits activities in many patients with rheumatoid arthritis.