test). A minor metabolite of leflunomide, 4-trifluoromethylaniline (TFMA), has been detected sporadically in low levels in patients receiving leflunomide. In 268 of 491 patients, plasma concentrations of TFMA were determined. In 66 patients (25%) the TFMA concentrations were low (8.1 3.0 ng/ml). TFMA concentrations did not increase over time, indicating that it did not accumulate. TFMA was mutagenic in the Ames test, the HGPRT and in vitro cytogenetics tests. It was not mutagenic in the unscheduled DNA synthesis test in hepatocytes, the mouse micronucleus test and in the in vivo cytogenetics tests in Chinese Hamster Ovaries (CHO). It is not believed that treatment of patients with leflunomide will cause unacceptable risks due to the very low amounts of TFMA formed in humans at the selected daily dose of 20 mg.
III. Evaluation of Reproductive Effects of Leflunomide:
The following questions that pertain to the reproductive risks of leflunomide are addressed.
1) Are there teratogenic risks to pregnant women taking leflunomide during pregnancy? What would be a reasonable safety factor, based on the fact that we have pharmacokinetic data for the no-effect level for teratogenicity in an animal model (Brent 1986, 1987, 1999, Brent et al 1986, Beckman and Brent 1999, Brent and Beckman 1999).
No epidemiological studies have been completed with regard to the teratogenicity of leflunomide, since the drug was introduced in 1998. Of the few women who have been exposed during pregnancy, most have decided to interrupt their pregnancies. The pharmacokinetic level of the active metabolite of leflunomide reached clinically in humans is in the range of exposure that results in teratogenesis in the rat and rabbit. It is evident that leflunomide effects vary with species and it appears that the rat and rabbit are more sensitive to leflunomide’s inhibition of pyrimidine synthesis. But it is difficult to translate that metabolic difference into differences in