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Teratogen Update: Reproductive Risks of Leflunomide (Arava™); a Pyrimidine Synthesis - page 14 / 21

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A.  Planning a pregnancy

For men or women who are taking Arava™  (leflunomide) for the treatment of RA who are planning a pregnancy, they can eliminate the drug to safe levels with an 11-day regimen of cholestyramine.  Cholesytramine, 8 g, three times daily reduces the active metabolite half-life to approximately one day.  After 11 days of the washout, the blood level would be 100 fold lower than the no-effect level of 3 g/ml.   Without cholestyramine, half-lives of up to 96 days have been found (population kinetics analysis). Thus, eleven half-lives are approximately two years in the worst case situation.  Therefore, common sense would dictate that men or women planning a pregnancy should initiate the 11-day cholestyramine washout.  

While the reproductive risks of preconception exposure to leflunomide are minuscule, the most conservative approach would be to have a women wait for three menstrual cycles following the washout before conceiving and a man  should wait for at least one spermatogenesis cycle following the washout before considering  impregnating his wife.  This recommendation  for men is described in the package insert (Although available information does not suggest that AravaTM would be associated with an increase in male-mediated  fetal toxicity , to minimize any possible risk, men wishing to father a child should consider  discontinuing  the use of AravaTM and take  cholestyramine 8 g, three time  daily for eleven days.

B.  Unplanned pregnancy by Mothers and Fathers taking Leflunomide

Women who become pregnant while taking leflunomide are at risk for reproductive effects, based on the theoretical extrapolation of the reproductive studies in rats and rabbits.  Even if the women informs her physician that she has missed her menstrual period and the pregnancy test is positive, it would be unlikely that a cholestyramine washout could be completed before organogenesis begins.  Even with the most conscientious patient and doctor,

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