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FDA Advisory Committee Recommends Arava (Leflunomide) For Improvement In Physical Function In Rheumatoid Arthritis

Committee Also Confirms the Safety Profile of Arava

STRASBOURG, FRANCE -- March 6, 2003 -- Aventis announced that the Arthritis Advisory Committee of the U.S. Food and Drug Administration (FDA) voted to recommend approval of an expanded indication for AravaŽ (leflunomide) Tablets for improvement in physical function in patients with rheumatoid arthritis (RA). The committee's recommendation, although not binding, may be considered by the FDA in its review of the supplemental new drug application (sNDA), which Aventis submitted in December 2002.

"Rheumatoid arthritis can severely hinder a person's ability to carry out daily activities such as eating, dressing and walking. The committee's recommendation is promising because, if approved by the FDA, the new indication will reinforce for physicians the benefit of Arava in improving physical function for patients," said Francois Nader, M.D., Senior Vice President, Medical Affairs, Aventis North America. "We are pleased by the committee's decision and will continue to work closely with the FDA to quickly update the Arava labeling if the indication is approved."

The Advisory Committee also reviewed the safety profile of Arava, including data from clinical trials and post-marketing experience, as well as an analysis provided by the FDA. The committee unanimously agreed that Arava has a positive benefit-risk profile for its current indications. When used as directed, Arava is a safe and effective drug among the very limited therapies available to treat RA.

Arava (leflunomide), an oral disease-modifying antirheumatic drug (DMARD), is a first-line therapy to reduce signs and symptoms and retard structural damage as evidenced by X-ray erosions and joint space narrowing in active rheumatoid arthritis in adults. Rheumatoid arthritis is one of the most common forms of arthritis, a potentially crippling autoimmune disease that affects more than two million Americans, 70 percent of whom are women.

The committee's recommendation was supported by data from three long-term, Phase III pivotal trials. Improvement in physical function was assessed through a series of validated and widely accepted tools measuring patients' ability to conduct daily activities (e.g., walking, eating, dressing and washing), their function in daily life, and their sense of well-being. The committee agreed that a marked, clinically meaningful improvement in physical function was demonstrated in the same three studies that previously had demonstrated improvement in signs and symptoms of rheumatoid arthritis and retardation of structural damage evidenced by X-ray erosions and joint space narrowing. The data showed that these effects were sustained for two years in patients continuing treatment in the three multinational, multicenter, double-blind, parallel group studies.

Safety Information Pregnancy contraindication: Pregnancy must be excluded before the start of treatment with Arava. Arava is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Before starting treatment with Arava, patients must be fully counseled on the potential for serious risks to the fetus. Pregnancy must be avoided during Arava treatment or prior to the completion of a drug elimination procedure with cholestyramine after Arava treatment. It is recommended that all women of childbearing potential undergo this elimination procedure upon discontinuing Arava as the drug may increase the risk of fetal death or teratogenic effects when administered to a pregnant woman. If this drug is used during pregnancy or if the patient becomes pregnant when taking this drug, the patient should be apprised of potential hazard to the fetus. In addition, men wishing to father a child should consider discontinuing use of Arava and taking cholestyramine eight grams three times daily for 11 days to minimize any possible risk to the fetus.

Important hepatic information: Arava was associated with elevations in liver enzymes, primarily ALT and AST, in a significant number of patients in clinical trials. Although these effects were generally reversible with dose reduction or discontinuation of treatment, marked elevations (greater than three times the upper limit of normal) occurred as well. Therefore, at minimum, ALT levels should be measured at the beginning of therapy (baseline) and monitored initially at monthly intervals, then, if stable, at intervals determined by the individual clinical situation.

Arava (leflunomide) is not recommended in patients with significant hepatic impairment or evidence of infection with hepatitis B or C viruses given the risk of increased hepatotoxicity.

Increased side effects may occur when Arava is given concomitantly with hepatotoxic substances. Arava is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. Rare cases of pancytopenia, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported in post-marketing experience. Adverse reactions associated with the use of Arava include diarrhea, elevated liver enzymes (ALT and AST), alopecia, and rash. Prescribing information is available by visiting http://www.arava.com.

About Aventis
Aventis is dedicated to treating and preventing disease by discovering and developing innovative prescription drugs and human vaccines. In 2002, Aventis generated sales of 17.6 billion euros, invested 3.1 billion euros in research and development and employed approximately 71,000 people in its core business. Aventis corporate headquarters are in Strasbourg, France. For more information, please visit: http://www.aventis.com.

Statements in this news release other than historical information are forward-looking statements subject to risks and uncertainties. Actual results could differ materially depending on factors such as the availability of resources, the timing and effects of regulatory actions, the strength of competition, the outcome of litigation, and the effectiveness of patent protection. Additional information regarding risks and uncertainties is set forth in the current Annual Report on Form 20-F of Aventis on file with the Securities and Exchange Commission.


SOURCE: Aventis

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