New Warnings About Fatal Liver Toxicity And Infections For The Arthritis Drug Leflunomide (ARAVA)

The maker of the arthritis drug leflunomide (ARAVA), Aventis Pharmaceuticals of Bridgewater, NJ, notified health professionals in October 2003 that new safety warnings concerning life-threatening liver toxicity and infections have been required on the professional product labeling or package insert for the drug.

We first warned readers in the December 2001 Worst Pills, Best Pills News that leflunomide was a Do Not Use drug because it causes life-threatening liver toxicity. In June 2002, we petitioned the Food and Drug Administration (FDA) asking that leflunomide immediately be removed from the market because of this liver toxicity (see Worst Pills, Best Pills News June 2002). In our petition we noted that from when the drug was first marketed in the U.S.in late September 1998 through September 2001, leflunomide had been associated with at least 130 severe liver adverse reactions including 56 hospitalizations and 22 deaths, two of whom were patients in their twenties. For 12 of these deaths, leflunomide-induced liver toxicity appears to be the most plausible explanation.

This petition can be found on our web site at www.citizen.org/documents/1614.pdf or by writing to us at the Health Research Group, 1600 20th Street NW, Washington, DC 20009.

The Aventis notification to health professionals related the results of a six-month study of 263 patients with persistent active rheumatoid arthritis despite treatment with the older drug methotrexate (RHEUMATREX). These patients had normal liver function tests at the beginning of the study. Leflunomide treatment was added to a group of 133 patients starting at a dose of 10 milligrams per day and increased to 20 milligrams if needed. There was an increase in a liver enzyme that was three times the upper limit of normal, an early signal of liver toxicity, in 3.8 percent of these patients. In 130 patients continued on methotrexate and given a placebo rather than leflunomide, only 0.8 percent of patients exhibited an elevation of the liver enzyme that was three times the upper limit of normal.

This is an almost five-fold increase in the number of patients showing potential liver toxicity with leflunomide compared with placebo.

There are also new requirements in leflunomide’s professional product labeling for monitoring for liver toxicity. A blood test to check liver enzymes must be performed before treatment is started with leflunomide and at monthly intervals during the first six months of therapy. If no problem is detected, then the liver enzymes must be checked every six to eight weeks thereafter. Also, if leflunomide is given together with methotrexate, additional blood testing is required every month.

Additional new requirements apply if the liver enzymes are elevated between two and three times the upper limit of normal. In this case, the dose of leflunomide must be reduced. If the liver enzymes remain elevated between two and three times the upper limit of normal despite a reduction in the dose of the drug, or if the liver enzymes are greater than three times the upper limit of normal, leflunomide must be stopped and cholestryramine (QUESTRAN) or charcoal should be started to speed the elimination of the drug from the body.

The above new requirements for liver toxicity testing are almost exactly the same as the requirements for leflunomide in the European Union that we wrote about almost two years ago in the December 2001 newsletter.

A new bolded statement about liver toxicity has also been added to the professional product labeling for leflunomide. It reads:

If you experience the symptoms of liver toxicity, unusual tiredness, abdominal pain, or yellow discoloration of the eyes or skin (jaundice) while taking leflunomide contact your doctor immediately.

Warnings have also been added to leflunomide’s labeling concerning infections that have resulted in deaths. Drugs like leflunomide which suppress the immune system are called immunosuppressants and have the potential to cause patients to be more susceptible to infections.

Leflunomide can also cause the failure of the bone marrow to produce certain types of blood cells important in fighting infections. Bone marrow suppression has been reported most often in patients who also received treatment with methotrexate or other immunosuppressant drugs, or who had recently discontinued these drugs; in some cases, patients had a prior history of significant bone marrow problems.

Patients taking leflunomide should have blood tests to monitor bone marrow function when beginning treatment with the drug and monthly for six months following initiation of treatment, and every six to eight weeks thereafter. If leflunomide is being used with methotrexate and/or other potential immunosuppressant drugs, blood tests should be conducted monthly.

Leflunomide was the subject of a controversial meeting of the FDA’s Arthritis Drugs Advisory Committee held March 5, 2003. Despite a strong recommendation from FDA drug safety experts that leflunomide should be withdrawn from the market, senior FDA managers overruled this conclusion and backed the continued marketing of the drug. FDA management did not allow its own drug safety experts to present their work before the advisory committee. The safety experts concluded that a lack of proven risk management strategies that would prevent harm left no alternative other than to withdraw leflunomide from the market. However, this recommendation was dismissed by the Director of the FDA’s Office of Drug Safety, who has since left the agency to take a position in the pharmaceutical industry.

Leflunomide offers no therapeutic advantage to patients over other drugs approved for rheumatoid arthritis. It poses an increased likelihood of serious adverse reactions such as liver toxicity when compared to methotrexate, the current gold standard. With a variety of better drug treatments available, there is no reason to subject patients to an accumulating list of added risks. Leflunomide should be promptly removed from the market.

What You Can Do

If you are now using leflunomide, you should discuss with your physician the possibility of taking one of the safer and more effective drugs already available for treating rheumatoid arthritis.