3) What are the reproductive risks for men who father a child when receiving leflunomide therapy? In particular what is the risk of fathering a child with congenital malformations or other harmful effects on the fetus due to exposure to leflunomide, its active metabolite or 4-trifluoromethylaniline (TFMA)(Brent 1994, 1999)?
The review of the reproductive effects of mutagenic agents consistently indicates the low risk of these agents for reproductive effects in the F1 generation. Leflunomide and its main metabolic product interfere with pyrimidine synthesis but do not have the mutagenic potential that has been demonstrated for proven mutagenic agents. The reproductive risks for men taking leflunomide are related to the properties of the drug, which are primarily related to the interference with DNA synthesis. Even with the potential reduction in DNA synthesis the risks of infertility are remote, unless the individual already has an infertility problem before starting the medication. Since leflunomide does not have mutagenic potential and the minor metabolite, TFMA is in such low concentration, there should be no measurable increase in the risk of genetic disease in the offspring. TFMA, a minor metabolite of leflunomide, accounts for less than 5% of the metabolic products. In a large series of patients receiving leflunomide in therapeutic doses, 25% of the patients had undetectable levels of TFMA. In the remaining 202 patients, plasma concentrations were very low (8.1 +/- 3.0 ng/ml). While TFMA at high concentrations was mutagenic in the Ames test, the HGPRT and cytogenetics tests, it was not positive in an in vivo cytogenetics test, unscheduled DNA synthesis, and the mouse micronucleus test. Thus, the mutagenicity testing of leflunomide and the phamacokinetics would indicate that preconception exposures would represent no measurable genetic risk in exposed populations and a theoretical risk of reducing gonadal cell populations, but not to the extent of affecting fertility at therapeutic exposure levels in humans.
IV. Clinical Evaluations and Recommendations: