Severe liver reactions -- some with fatal outcomes -- have occurred in patients treated with Aventis' novel rheumatoid arthritis drug Arava (leflunomide), according to the European Medicines Evaluation Agency (EMEA).

In a public statement on its Web site, the agency said a total of 296 liver reactions had been reported.

"Of these, 129 cases were considered as serious, including two cases of liver cirrhosis and 15 cases of liver failure, nine with a fatal outcome." The statement warns that "although confounding factors were present in many cases, a causal relationship to leflunomide cannot be excluded."

Arava, a so-called "disease-modifying antirheumatic drug," is the first new treatment for rheumatoid arthritis in more than 10 years. Rheumatoid arthritis is an autoimmune disease in which progressive damage to the joints leads to increasing disability.

The EMEA's statement, dated March 12, reports that most side effects occurred within 6 months of starting therapy.

The agency said that, in view of the seriousness of the reactions, it wished to point out that the drug is contraindicated in patients with impaired liver function. It added that combining drugs such as leflunomide and methotrexate or other medications that can be toxic to the liver is associated with an increased risk of serious liver reactions and is not advisable.

A spokesman for Aventis told Reuters Health that the firm is sending out a "Dear Doctor" letter and reinforcing the drug's labeling about liver injury in the EU. In the United States, talks are underway with the Food and Drug Administration to determine whether similar steps are necessary, he added.

The spokesman said that 200,000 patients have used the drug since it was launched in the US in September 1998 and in the EU in September 1999.

The new labeling states that liver enzyme function must be checked before therapy is started, at least monthly during the first 6 months of treatment, and then every 8 weeks thereafter.

If liver enzymes are between two and three times the normal upper limit, the drug dose can be reduced from 20 milligrams to 10 milligrams and monitoring should be performed weekly. If elevations of more than twice the normal upper limit persist, or if they increase to more than three times the normal upper limit, leflunomide must be stopped and "wash-out" procedures implemented to reduce drug levels in the body.

The EMEA statement makes clear that 78% of the patients experiencing serious reactions were also taking other medications known to be toxic to the liver. "In addition, in 33 of these serious cases (27%) other risk factors were reported, including a history of alcohol abuse and liver function disturbance," the statement reports.

"Preliminary data on the prescribing profile of leflunomide suggest that monitoring of liver function tests and washout procedures might not have been fully adhered to," the EMEA added.

LONDON, March 14, 2001 Reuters News Service