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FDA Approves Expanded Indication In Rheumatoid Arthritis For Arava (Leflunomide) Tablets

STRASBOURG, FRANCE -- June 16, 2003 -- Aventis announced that the U.S. Food and Drug Administration (FDA) approved an expanded indication for the rheumatoid arthritis treatment AravaŽ (leflunomide) Tablets for improvement in physical function. The FDA based this approval on a supplemental new drug application (sNDA) submitted by Aventis in December 2002.

"We believe the new physical function indication will reinforce for physicians the clinically meaningful benefits of Arava treatment," said Francois Nader, M.D., Senior Vice President, Medical Affairs, Aventis North America. "Rheumatoid arthritis can have devastating effects on a person's ability to carry out daily activities like buttoning a shirt, opening a door and even walking. For people with rheumatoid arthritis, demonstrating an improvement in the ability to perform daily activities is an important indicator of treatment success."

Arava (leflunomide), an oral disease-modifying antirheumatic drug (DMARD), is a first-line therapy to reduce signs and symptoms, inhibit structural damage as evidenced by X-ray erosions and joint space narrowing, and improve physical function 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 FDA also approved revisions and additions to the Arava safety information, which include revised liver function and hematology monitoring recommendations. When used as directed, Arava is a safe and effective drug among the very limited therapies available to treat RA.

The FDA approval was based on 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. 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 efficacy was 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.

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: Rare cases of severe liver injury, including cases with fatal outcome, have been reported during treatment with leflunomide. Most cases of severe liver injury occur within 6 months of therapy and in a setting of multiple risk factors for hepatotoxicity (liver disease, other hepatotoxins).

Arava 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.

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 reductions or discontinuation of treatment, marked elevations (greater than three times the upper limit of normal) occurred as well. Therefore, at minimum, ALT levels must be measured at the beginning of therapy (baseline) and monitored initially at monthly intervals during the first six months, then, if stable, every 6 to 8 weeks thereafter.

Arava is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. Rarely, severe infections including sepsis, which may be fatal, have been reported. Rare cases of pancytopenia, agranulocytosis, thrombocytopenia, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported in post-marketing experience. At minimum, patients taking Arava should have platelet, white blood cell count and hemoglobin or hematocrit monitored at baseline and monthly for six months following initiation of therapy and every 6 to 8 weeks thereafter.

Adverse reactions associated with the use of Arava in clinical trials include diarrhea, elevated liver enzymes (ALT and AST), alopecia, and rash.

Prescribing information is available by visiting http://www.arava.com.


SOURCE: Aventis

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