Aventis is in discussions with FDA regarding labeling changes for Arava (leflunomide) to reflect reports of hepatic injury associated with use of the rheumatoid arthritis therapy.

The discussions with FDA follow revised European labeling and a public statement issued March 12 by the European Agency for the Evaluation of Medicinal Products on liver injuries associated with Arava.

Aventis Pharmaceuticals CEO Richard Markham indicated during a March 2 analyst meeting that European labeling changes regarding the drug's effects on the liver were possible (¹ Also see "Arava labeling change" - Pink Sheet, 12 March, 2001.).

Revised European labeling calls for monitoring of liver alanine transaminase levels before initiation and at monthly or more frequent intervals during the first six months of treatment and every eight weeks thereafter. Previous labeling did not provide a detailed timeframe for monitoring.

U.S. labeling suggests ALT monitoring at baseline and "initially at monthly intervals then, if stable, at intervals determined by the individual clinical situation."

During Arava's advisory committee review prior to approval in 1998, the company, then Hoechst Marion Roussel, and the committee recommended monthly monitoring during the first three months of therapy, with testing every four-to-eight weeks thereafter.

Dosage reduction from 20 mg to 10 mg and weekly monitoring should occur when ALT elevations are between two and three times the upper limit of normal, European labeling states.

Leflunomide must be discontinued and a washout period initiated if elevations of more than two times the upper limit of normal persist or if ALT increases to more than three times the upper limit of normal.

U.S. labeling recommends a liver biopsy if ALT elevations are greater than two but less than or equal to three-fold the upper limit. Discontinuation and washout with cholestyramine should occur if elevations greater than three-fold the upper limit persist.

The revised European labeling adds that a complete blood cell count should be performed at the start of treatment, and every two weeks for the first six months of treatment, and then every eight weeks.

"Most of the cases [of severe liver injury] occurred within six months of treatment," European labeling states.

Under the undesirable effects section of European labeling, "hepatitis, jaundice/cholestasis and very rarely, severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal" were added as rare gastrointestinal and liver effects.

From a database of 104,000 patient years of exposure since Arava's U.S. approval in September 1998, 296 cases of hepatic reactions have been reported worldwide. Of 129 cases considered serious, two cases of liver cirrhosis and 15 cases of liver failure, nine of which were fatal, were recorded.

Of the serious reports, concomitant treatment with hepatotoxic medications occurred in 101 patients (78%). Fifty-eight percent of patients with elevated liver function tests were also being treated with methotrexate and/or NSAIDs.

"Monitoring of liver function tests and washout procedures might not have been fully adhered to," EMEA recommends based on preliminary prescribing data. "Although confounding factors were present in many cases, a causal relationship to leflunomide cannot be excluded."

"Arava should only be prescribed by specialists experienced in the treatment of rheumatoid arthritis," the statement adds.

European information for patients on Arava advises patients to report unusual tiredness, abdominal pain and jaundice to physicians immediately.

A washout must be performed if switching from leflunomide to another disease-modifying antirheumatic drug, when serious undesirable effects occur, in the case of pregnancy and when the active metabolite needs to be cleared from the body. Both U.S. and European labeling suggest a washout period of 11 days in which eight grams of cholestyramine is administered three times daily. An alternative is to use 50 g of activated powdered charcoal administered four times daily, European labeling notes.

Aventis Discussing Arava Label Changes With FDA; EU Revises Monitoring

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