Do Not Use. Europeans Strengthen Liver Toxicity Warnings on the Arthritis Drug Leflunomide (ARAVA)

Leflunomide (ARAVA) was approved by the Food and Drug Administration (FDA) on September 10, 1998 to reduce signs and symptoms of active rheumatoid arthritis in adults and to retard structural damage as evidenced by X-ray erosion and joint space narrowing. The drug is sold by Aventis Pharmaceuticals Inc. of Kansas City, Missouri.

The drug’s potential to cause liver toxicity was known before its approval. In clinical trials, leflunomide treatment was associated with elevation of liver enzymes, an early indicator of possible liver damage. The FDA-approved professional product labeling (or “package insert”) for the drug instructs physicians that at a minimum, liver enzymes should be tested before treatment is started and monitored initially at monthly intervals and then, if stable, at intervals determined by the prescribing physician.

The European Agency for the Evaluation of Medicinal Products, in a statement issued March 12, 2001, reported that 296 cases of liver adverse reactions had been associated with leflunomide. Of these, 129 cases were considered serious, including two cases of cirrhosis and 15 cases of liver failure, nine of which resulted in death. Liver reactions appeared within six months of starting treatment. Other factors may have contributed to this. Of the 129 serious reports, 101 patients (78 percent) were taking other drugs that could cause liver toxicity, and 58 percent were taking methotrexate, also used to treat rheumatoid arthritis, or a nonsteroidal anti-inflammatory drug (NSAID) or both. In addition, in 33 of the serious cases (26 percent) other risk factors were present for liver toxicity, such as a history of alcohol abuse, acute heart failure, severe lung disease, or pancreatic cancer.

The Europeans now require the following liver enzyme monitoring for users of leflunomide:

Routine Testing

1. A baseline test before treatment is started.
2. Testing at monthly or more frequent intervals during the first six months of treatment.
3. After the first six months, testing at eight-week intervals thereafter.

Liver Enzymes Elevated Between 2 and 3 Times the Upper Limit of Normal

1. A dose reduction may permit the continued administration of leflunomide.
2. Testing must then be performed weekly.

Liver Enzymes Elevated Above 3 Times the Upper Limit of Normal, or a Persistent Elevation of Liver Enzymes of More than 2 Times the Upper Limit of Normal

1. Leflunomide must be discontinued.
2. A washout procedure should be started using cholestyramine (QUESTRAN). Leflunomide remains in the body an exceptionally long time, up to three months. The cholesterol-lowering drug cholestyramine binds to leflunomide and will cause a more rapid elimination of leflunomide from the body.

What You Can Do

If you are now taking leflunomide you should discuss with your doctor the European recommendations for liver testing and strongly consider switching to a less dangerous drug.

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

Adverse drug reactions should be reported to the FDA MedWatch Program.