Federal regulators are again putting doctors and patients on notice about the risk of severe liver damage connected with the use of the rheumatoid arthritis drug leflunomide (Arava).

The U.S. Food and Drug Administration (FDA) first ordered that a bolded warning about the risk of liver injury be added to leflunomide's label in 2003.

That caution came after at least 130 cases of severe liver damage, including 56 hospitalizations and 12 deaths, were connected to its use, according to FDA data reported by Public Citizen, a non-profit, consumer watchdog organization.

But after continued reports of hospitalizations and deaths, the agency updated that review and identified 49 more cases of severe liver injury associated with the medication, which led to hospitalization in 36 cases and 14 deaths between August 2002 and May 2009.

As a result, regulators have ordered that the liver injury warning be boxed and placed more prominently at the top of the label; and they have issued new alerts for doctors and patients, warning that leflunomide is not safe for people who have preexisting liver disease like hepatitis, those who have elevated levels of liver enzymes or a history of alcohol abuse.  

Also, people who take other drugs associated with liver injury like acetaminophen (Tylenol), non-steroidal anti-inflammatory drugs (NSAIDs) – including ibuprofen (Motrin, Advil) and naproxen (Alleve), hydroxychloroquine and statins should use leflunomide with caution.

The FDA says patients taking leflunomide need to have blood tests to check their liver enzyme levels every month for the first three months of use and every three months thereafter.

Doctors prescribe leflunomide, a disease-modifying anti-rheumatic drug that has been on the market since 1998, to help stop rheumatoid arthritis, a disease caused by an autoimmune attack on the joints and organs.

And many rheumatologists say that though this enhanced caution is an important reminder, they have long known that leflunomide is not a drug to use when liver injury is a concern.

“With proper monitoring, Arava is an effective drug which I do not hesitate to use,” says Robert Shaw, MD, a rheumatologist at the Carroll County Arthritis and Osteoporosis Center in Baltimore, Md., and member of Arthritis Today’s Medical Advisory Board.

Others, however, think the drug is too risky.

In 2002, Public Citizen petitioned the FDA to remove the drug from the market, noting that in the three-year period after the drug’s approval, there were six times as many cases of fatal liver toxicity and 13 times more reports of hypertension linked to the use of leflunomide as were connected to a similar medication, methotrexate, though there were 6.8 million more prescriptions filled for methotrexate than leflunomide during that time.