Arava: the 'sixth drug' that may soon be under fire
At a recent hearing into the Vioxx affair, the FDA's Dr David Graham named five drugs that he considers too dangerous to be on the market. However, in his testimony, Dr Graham also cited Sanofi-Aventis' Arava as a drug he has recommended be withdrawn. Unlike the other five drugs, Arava has largely escaped the media spotlight, but there may yet be some tough questions asked about its safety.

Arava (leflunomide) is marketed by Aventis, part of Sanofi-Aventis, and recorded sales of $288 million in 2003. It is an oral disease modifying treatment for rheumatoid arthritis (RA), and may be next in the firing line for increased regulatory scrutiny, in the wake of the withdrawal of Vioxx (rofecoxib).

Dr Graham, the Associate Director for Science and Medicine in the FDA's Office of Drug Safety, cited the now familiar list of five drugs that he considers should be removed from the market, in response to open questioning from the Senate Finance committee. Much media attention has been given to these five drugs, which include Crestor (rosuvastatin), Serevent (salmeterol xinafoate), Accutane (isotretinoin), Meridia (sibutramine hydrochloride monohydrate) and Bextra (valdecoxib). Some of the companies involved immediately countered Dr Graham's statement, reassuring the public of the safety of these treatments, but the mention of Arava appears to have gone largely unnoticed.

Regulatory approval

In his prepared testimony to the committee Dr Graham related his past record from 20 years at the FDA, where he has recommended a total of 12 drugs for withdrawal from the market, only two of which remain on the market today. One of these is Accutane, mentioned in the list above, and the other was Arava. Dr Graham stated that he and another, unnamed, FDA colleague believe that it "causes an unacceptably high risk of acute liver failure and death".

On November 23, 2004 the FDA announced the strengthening of the risk minimization action plan (RiskMAP) for Accutane to reduce the risk of birth defects associated with fetal exposure to it. Steps to monitor the use of other drugs on Dr Graham's list, including Arava, which is targeted at a similar market to Vioxx, may be required by the FDA.

Arava was approved in the US in 1998, 2000 in the EU and more recently in April 2003 in Japan. However in February 2004 Sanofi-Aventis reported that the deaths of five Japanese RA patients may be linked to Arava and it recommended Arava not be used on patients with respiratory problems. Arava had previously been linked to at least 12 other deaths due to liver failures.

Safety concerns

However, the FDA cleared Arava over liver side effects in April 2004 when it denied a Public Citizen petition. This petition was backed by Dr David Yocum, director of the University of Arizona Arthritis Center, who previously served on the FDA's arthritis drugs advisory committee and was its chairman for two years until late 2001. The FDA concluded that the benefit to risk ratio for Arava was acceptable, but the disagreement with this fact by such an experienced and prominent researcher as Dr Graham indicates a certain conflict within the organization on this issue.

Arava is marketed as an alternative option to methotrexate, an established treatment used in severe RA, which has some serious side effects. The option appears to have been a dangerous one as reports have emerged that Arava patients may have a higher death rate than methotrexate patients. The parallel with Vioxx, marketed as a less dangerous alternative to traditional NSAIDs, is clear.

If this information is reassessed in light of the Vioxx inquiries currently taking place, Sanofi-Aventis may find itself in a similar position to its fellow pharma giant Merck & Co, not to mention the likes of Pfizer and GSK, which are also looking on anxiously as concern mounts over the safety of products such as Bextra and Serevent. Legal action is already underway against Arava in the US, with lawyers advertising for clients to engage in class action lawsuits. Despite passing almost unnoticed in the wider media reporting of Dr Graham's 'hit list', there seems to be little doubt that Sanofi-Aventis will shortly be forced to defend the safety of Arava: in the present post-Vioxx climate, it appears that this drug may not survive the scrutiny.

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