This article is part of the Arthritis Archives.
Dateline: March 15, 2001
EMEA Issues Public Statement
The EMEA (European Medicines Evaluation Agency) issued a public statement on March 12, 2001 regarding Arava (generic name leflunomide) and serious hepatic reactions.
When the FDA (U.S. Food and Drug Administration) approved Arava in September 1998, it was heralded as the first new treatment for rheumatoid arthritis in 10 years. The European Union followed with its approval of the drug in September 1999. Approximately 200,000 people have used Arava since it became available.
The statement from the EMEA revealed a total of 296 adverse reports of hepatic (liver) reactions, of which 129 were considered serious. Included were 2 cases of liver cirrhosis and 15 cases of liver failure, of which 9 were fatal. The reported hepatic reactions occurred within six months of when treatment had been started. The EMEA report emphasizes that "confounding factors" existed in many of the cases. Of the reported adverse reactions:
- 78% (101 patients) were treated with other hepatotoxic medications (medications potentially toxic to the liver) along with Arava
- 58% of patients with elevated liver function tests were simultaneously treated with methotrexate and/or NSAIDs (nonsteroidal anti-inflammatory drugs)
- 27% (33 patients) had other risk factors such as:
- history of alcohol abuse
- liver function disturbance
- acute heart failure
- severe pulmonary disease
- pancreatic carcinoma
The EMEA statement points out that in these cases, liver function tests may not have been properly monitored and washout procedures (procedures to clear the drug from the body) may not have been followed.
Due to the serious nature of these adverse reports, the EMEA offered the following recommendations:
- Arava is contraindicated in patients with impaired liver function.
- Although confounding circumstances were a factor in many cases, a causal relationship to Arava cannot be overlooked or disregarded.
- Concomitant use of Arava with methotrexate or other hepatotoxic medications is not recommended and increases the risk of serious hepatic reactions.
- ALT (SGPT) must be checked prior to treatment with Arava, followed by monthly checks during the first 6 months, and then at 8 week intervals.
- If ALT (SGPT) test results are 2-3 times the upper limit of normal, the dose of Arava should be reduced from 20 mg. to 10 mg. and monitoring should be increased to weekly.
- If ALT (SGPT) test results of more than twice the upper limit of normal continue or if ALT increases to more than 3 times the upper limit of normal, Arava must be stopped and washout procedures begun.
- If any other severe side effect of Arava is experienced, or for any reason the active metabolite of Arava needs to be rid from the body, washout and monitoring procedures must be followed.
- If a change in treatment from Arava to another hepatotoxic DMARD is prescribed, washout and monitoring procedures must be followed.
The washout procedure consists of 8 g. cholestyramine (3 times daily) or 50 g. activated powdered charcoal (4 times daily). Usually a complete washout takes 11 days.
The EMEA has also added information to the Arava package insert which advises patients to inform their doctor immediately of symptoms which may be indicative of a developing liver disorder, including:
The FDA, upon review of the adverse reports, will decide if any action is necessary in the United States.
Sources: EMEA Public Statement on Leflunomide, March 12, 2001,<www.emea.eu.int/pdfs/human/press/pus/561101en.pdf> Liver Problems Linked To Arthritis Drug, Richard Woodman, ReutersHealth, March 14, 2001
First published: 3/15/2001