Nerve Damage: Another Serious Adverse Effect of Leflunomide (ARAVA)

Worst Pills, Best Pills readers know (Worst Pills, Best Pills News, June, 2002) that we petitioned the FDA to ban this widely-prescribed arthritis drug in March, 2002 because of its liver toxicity, occurring more often than with any other arthritis drug. At the time of our petition, 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 the 22 deaths, leflunomide-induced liver toxicity appears to be the most plausible explanation. 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.”

Warnings have also been subsequently added to leflunomide’s labeling concerning infections that have resulted in deaths (Worst Pills, Best Pills News, January, 2004). Drugs like leflunomide which suppress the immune system are called immunosuppressants and have the potential to cause patients to be more susceptible to infections.

Leflunomide can also cause the failure of the bone marrow to produce certain types of blood cells important in fighting infections. Bone marrow suppression has been reported most often in patients who also received treatment with methotrexate or other immunosuppressant drugs, or who had recently discontinued these drugs; in some cases, patients had a prior history of significant bone marrow problems.

In Japan (Worst Pills, Best Pills News, March, 2004) sixteen people developed interstitial pneumonia, a debilitating lung condition, after taking the drug. Five of them, aged between 57 and 71, subsequently died, according to the company. The company has warned doctors not to prescribe the drug to patients with respiratory problems, a history of interstitial pneumonia or lung problems. It further advised that X-rays be conducted on any patient who is to receive the drug for the first time.

The newest evidence of toxicity from leflunomide comes from a study just published 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). Drs. Bonnell and Graham, both from FDA’s Office of Drug Safety, 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.

The onset of symptoms of nerve damage usually occurred beginning about 6 months after treatment with the drug had started. “The median time to improvement or recovery was 135 days among patients stopping leflunomide within 30 days compared to more than two years in those who did not stop within the 30-day time frame.” The authors concluded that the mechanism of this nerve damage was probably a direct toxic effect of leflunomide on the nerves.

What You Can Do

If you are now taking leflunomide you should discuss with your doctor recommendations for liver testing and strongly consider switching to a less dangerous drug. If you experience unusual tiredness, abdominal pain, or yellow discoloration of the eyes or skin (jaundice) while taking leflunomide contact your doctor immediately. These symptoms may indicate the development of liver toxicity. If you experience the onset of abnormal or diminished sensation or weakness in your arms or legs, contact your physician to report this and inform them about the study on nerve damage discussed above. We repeat to readers our warning not to use this drug, first expressed in the December, 2001 issue of Worst Pills, Best Pills News.