Drug Profile

Leflunomide (ARAVA) was approved by the Food and Drug Administration (FDA) in September 1998 for the treatment of active rheumatoid arthritis in adults.

Leflunomide is much more toxic to the liver than methotrexate (RHEUMATREX DOSE PACK, TREXALL), an alternative arthritis drug.

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 and hypertension 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.

Leflunomide is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections.[2]

Studies say…

Researchers have not been very impressed with leflunomide’s efficacy compared with existing, less expensive drugs.

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 or sulfasalazine [AZULFIDINE].” Furthermore, Prescrire added, “Leflunomide 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 suflasalazine have fewer adverse effects.”[3] Antimalarial drugs include products such as hydroxychloroquine (PLAQUENIL).

The editors of The Medical Letter on Drugs and Therapeutics concluded their 1998 review of leflunomide by saying it “offers no clear advantage over better established and less expensive drugs such as methotrexate.”[4]

Clinical trials submitted to the FDA by manufacturer Aventis demonstrated that the effectiveness of leflunomide was likely inferior to methotrexate. In one trial, leflunomide and methotrexate were considered equally effective, with 41% of patients on leflunomide, 35% on methotrexate and 19% on placebo responding to treatment.[5] But, in a much larger trial comparing methotrexate with leflunomide, methotrexate was significantly superior, with a 57% response rate compared with a 43 percent rate for those on leflunomide.[6]

Adverse effects

Liver toxicity. Evidence of leflunomide’s liver toxicity appeared during the clinical trials submitted to the FDA, with 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. In the most carefully conducted study comparing leflunomide with methotrexate, 7.1% of patients on leflunomide had abnormal LFTs compared with 3.3% of patients on methotrexate and 1.7% of those on placebo. Patients on leflunomide also were more likely to withdraw from the trial due to adverse events: 22% of patients on leflunomide versus 10% on methotrexate and 9% on placebo.[7]

A new bolded statement about liver toxicity also has been added to the professional product labeling for leflunomide:

High blood pressure. In randomized controlled trials there were more 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.

Additional evidence of leflunomide toxicity comes from a study by FDA scientists after a careful review of a large number of reports of new-onset nerve damage occurring in patients treated with leflunomide (Clinical Pharmacology and Therapeutics, June 2004).[8] In the study, the FDA reviewed 80 patients who developed nerve damage, mostly involving sensation but in some cases involving motor function (weakness) in the arms or legs. Although stopping the drug within 30 days of symptom onset if this cause was suspected was more likely to result in improvement of symptoms, in most patients recovery was not observed.

Lung inflammation. The New Zealand Centre for Adverse Reactions Monitoring reported in its March 2006 newsletter that there is increasing evidence that the arthritis drug leflunomide (ARAVA), taken alone or in combination with the drug methotrexate (TREXALL), can cause serious lung inflammation called pneumonitis.[9]

The Adverse Drug Reactions Advisory Committee of Australia has stated that it has continued to receive reports of severe pulmonary disease in patients on leflunomide therapy. The outcome of the disease was fatal in some patients where the relation of the disease to the drug therapy was not recognized early enough.[10]

Neuropathy. As of October 2006, there were 659 reports in association with leflunomide received by the Adverse Drug Reactions Advisory Committee (ADRAC). Thirty of these described neuropathy (abnormal nerve functioning) or peripheral neuropathy. In 24 of these cases, leflunomide was the sole suspected drug.[11]

The Canadian Adverse Reaction Newsletter published an article stating that Health Canada has received 26 suspected adverse reaction post-marketing reports of peripheral neuropathy associated with leflunomide use. These reports were received up to Oct. 31, 2009, and of the 26 cases, peripheral neuropathy was specified in nine cases and signs and symptoms of peripheral neuropathy were described in 17 cases.[12]

Respiratory problems. By December 2006 ADRAC had received 669 reports associated with leflunomide use, and of those, 142 reports involved respiratory symptoms. Furthermore, there were 22 reports of interstitial lung disease possibly associated with leflunomide.[13]

Public Citizen’s work on leflunomide

On March 28, 2002, Public Citizen’s Health Research Group petitioned the Department of Health and Human Services to immediately remove leflunomide from the market.[14] Through the end of September 2001 leflunomide had been 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.

Regulatory actions surrounding leflunomide

2001: The European Agency for the Evaluation of Medicinal Products (EMEA) issued a warning in March 2001 to patients and physicians concerning the potential link of leflunomide to severe liver injury, including death.[15]

2003: The maker of the arthritis drug leflunomide (ARAVA), Aventis Pharmaceuticals of Bridgewater, NJ, notified health professionals in October 2003 that new safety warnings concerning life-threatening liver toxicity and infections have been required on the professional product labeling or package insert for the drug.

Read more in the October 2010 issue of Worst Pills, Best Pills News.

2004: In November 2004 the FDA changed the Precautions section of the package label adding interstitial lung disease, a potentially fatal adverse effect. Sixteen people in Japan developed interstitial pneumonia after taking the drug. Five of them, aged between 57 and 71, subsequently died, according to the company.

2010: In July 2010 the Food and Drug Administration (FDA) belatedly added information to the boxed warning on the drug label for leflunomide concerning the risk of severe liver injury in patients using leflunomide and how this risk may be reduced. The new information was based on cases of severe and fatal liver injury adverse events reports.[16]

2024: The FDA updated the drug label of leflunomide to warn that there is a risk of skin ulcers in patients using the drug.[17]