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Leflunomide (ARAVA) was approved by the Food and Drug Administration (FDA) in September 1998 for the treatment of active rheumatoid arthritis in adults. On March 28, 2002, we petitioned Health and Human Services Secretary Tommy Thompson to remove leflunomide from the market immediately. In the two years ending September 30, 2001, leflunomide was associated with at least 130 severe liver reactions including 56 hospitalizations and 22 deaths. Two of these reactions were in patients in their...
Leflunomide (ARAVA) was approved by the Food and Drug Administration (FDA) in September 1998 for the treatment of active rheumatoid arthritis in adults. On March 28, 2002, we petitioned Health and Human Services Secretary Tommy Thompson to remove leflunomide from the market immediately. In the two years ending September 30, 2001, leflunomide was associated with at least 130 severe liver reactions including 56 hospitalizations and 22 deaths. Two of these reactions were in patients in their 20s. In 12 of these deaths, leflunomide-induced liver toxicity appears to be the most plausible explanation.
Leflunomide is produced by Aventis Pharmaceutical based in Bridgewater, New Jersey and is much more toxic to the liver than methotrexate, another arthritis drug. The petition can be found on the web at www.citizen.org/documents/1614.pdf or by writing to us at the Health Research Group, 1600 20th Street NW, Washington, DC 20009.
The European Agency for the Evaluation of Medicinal Products (EMEA) issued a warning in March 2001 to patients and physicians concerning the potential causal link of leflunomide to severe liver injury, including death. The highly regarded French source of independent drug information, Prescrire International, reviewed leflunomide and other drugs for rheumatoid arthritis and concluded “...leflunomide appears to be less effective than methotrexate; and it has been associated with more severe adverse events than methotrexate... .” Furthermore, “[l]eflunomide provides no clinically tangible advantage in the management of patients with rheumatoid arthritis who require treatment with a disease-modifying drug. When long term treatment with such a drug is warranted, methotrexate remains the first choice option if maximal efficacy is sought, while antimalarials and oral sulfasalazine [AZULFIDINE] have fewer adverse effects.” Antimalarial drugs include products such as hydroxychloroquine (PLAQUENIL).
The U.S. perspective on the therapeutic value of leflunomide echoes that of the Europeans. The editors of The Medical Letter on Drugs and Therapeutics, a U.S. source of high quality prescription drug information, concluded their 1998 review of leflunomide by saying it “...offers no clear advantage over better established and less expensive drugs such as methotrexate.”
Clinical trials submitted to the FDA by Aventis demonstrated that the effectiveness of leflunomide was likely inferior to methotrexate. In one trial, leflunomide and methotrexate were considered equally effective with 41 percent of patients on leflunomide, 35 percent on methotrexate, and 19 percent on placebo responding to treatment. In a much larger trial comparing methotrexate to leflunomide, methotrexate was significantly superior with a 57 percent response rate in those on methotrexate compared to 43 percent of those on leflunomide.
Evidence of leflunomide’s liver toxicity appeared during the clinical trials submitted to the FDA before the drug was approved. There were four cases of extremely elevated abnormal liver function test (LFT) enzymes and two patients requiring liver biopsies. Elevated LFTs of greater than three times the upper limit of what is considered normal is an early indicator of possible liver toxicity. One patient in these trials had elevations of 39 times and another 80 times the upper limit of normal for their LFTs. In the most carefully conducted study that compared leflunomide with methotrexate, 7.1 percent of patients on leflunomide had abnormal LFTs compared to 3.3 percent of patients on methotrexate and 1.7 percent of those on placebo. Patients on leflunomide were also more likely to withdraw from the trial due to adverse events: 22 percent of patients on leflunomide versus 10 percent on methotrexate and 9 percent on placebo.
In randomized controlled trials, there were greater than three times as many cases of hypertension caused by leflunomide than by methotrexate. Since the drug came on the market, there have been 38 reports of hypertension with leflunomide but only one with methotrexate even though there were more than five times as many prescriptions filled for methotrexate than for leflunomide.
Leflunomide is another example of allowing drugs that are less effective and more dangerous than existing treatments on the market. The FDA had the authority to keep leflunomide off the market, but failed to act in the public’s interest.
The solution to the problem of new drugs that are less safe and effective than available products is in the hands of Congress. First, there must be rigorous oversight hearings about the FDA’s drug approval process. This is something that Congress has neglected since the mid-1980s. Second, the legal “bar” for approving new drugs must be raised. The present standard is outmoded and every time that Congress has raised the standard over the last 100 years, drugs have become safer and more effective.
Leflunomide offers no therapeutic advantage to patients over other drugs approved for rheumatoid arthritis. It poses an increased likelihood of serious adverse reactions such as liver toxicity when compared to methotrexate, the current “gold standard.” With a variety of better drug treatments available, there is no reason to subject patients to an accumulating list of added risks; leflunomide should be promptly removed from the market.
What You Can Do
If you are now using leflunomide you should discuss with your physician the possibility of taking one of the safer and more effective drugs already available for treating rheumatoid arthritis.
