FDA Adds Information on Severe Liver Injury to Leflunomide's Boxed Warning

Agency Acts in Wake of Dozens of Case Reports, 14 Deaths

July 14, 2010 02:00 pm News Staff

The FDA has identified 49 cases of severe liver injury -- 14 of which proved fatal -- in patients taking the rheumatoid arthritis drug leflunomide, which is marketed as Arava. The agency said in a July 13 safety announcement(www.fda.gov) that it has responded by adding information about severe liver injury to the boxed warning of the product's package label.

The FDA previously had required a boxed warning stating that the medication was contraindicated in pregnant women or women of childbearing potential who were not using reliable contraception.

The following information about liver injury was added to the boxed warning:

  • patients with elevated liver enzymes (i.e., alanine transaminase, or ALT, levels greater than two times the upper limit of normal) and those with pre-existing liver disease should not receive leflunomide;
  • liver enzymes should be monitored at least monthly for three months after starting leflunomide and at least quarterly thereafter;
  • if ALT levels rise to greater than two times the upper limit of normal while a patient is on leflunomide, the medication should be stopped, a cholestyramine washout should be performed to speed removal of the drug from the body, and follow-up liver function tests should be conducted at least weekly until the ALT value is within normal range; and
  • caution should be used in patients who are taking other drugs that can cause liver injury.

The FDA's review of adverse events reported from August 2002 to May 2009 indicate that 46 of the 49 patients who had severe liver injury were taking other medications that have been associated with liver injury, including methotrexate, which is marketed as Rheumatrex and Trexall; tumor necrosis factor blockers; hydroxychloroquine, which is marketed as Plaquenil; acetaminophen; nonsteroidal anti-inflammatory drugs; and statins.

In addition, 14 patients had pre-existing liver disease, such as acute or chronic infection with hepatitis B or hepatitis C virus, and/or a history of alcohol abuse.

Although many patients were taking other drugs or had pre-existing liver disease, the FDA concluded that the use of leflunomide was associated with the development of severe liver injury in the affected patients.

The agency advised physicians that only patients for whom the anticipated therapeutic benefit is expected to outweigh the risk of severe liver injury should be considered for leflunomide treatment.

Patients who experience signs or symptoms of severe liver injury -- itching, yellow eyes or skin, dark urine, loss of appetite, or light-colored stools -- should contact their physicians right away, according to the FDA.

Side effects associated with leflunomide use should be reported to the FDA's MedWatch program(www.accessdata.fda.gov).