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Teratogen Update: Reproductive Risks of Leflunomide (Arava™); a Pyrimidine Synthesis - page 16 / 21





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exposure might be insignificant.  Without the pharmacokinetic data it would not be advisable for a mother to breast feed while taking leflunomide.

D. Counseling

There have been approximately 30 women  who have become pregnant on leflunomide that have been brought to my attention by referrals from rheumatologists and counselors at Hoechst-Marion-Roussell.  In spite of the efforts to initiate the cholestyramine washout as soon as pregnancy was diagnosed, in all but one instance, there was exposure to therapeutic levels of leflunomide during early organogenesis.  It is theoretically possible to diagnose pregnancy at the time of the first missed menstrual period and have two to three days of cholostyramine washout before organogenesis begins.  Therefore, the predominant risk during this period would be pregnancy loss.  Malformations are at a much lower risk with teratogenic exposures during the period before organogenesis begins (the “All or None Period”)(Wilson and Brent 1953)  After discussions with the physicians and patients, all but three of the pregnant women have elected to interrupt their pregnancies.  

The three women who have elected to maintain their pregnancies have been advised about their risks.  They have been advised to be followed by a perinatologist, with level 2 ultrasounds and serum alpha fetoproteins.  Amniocentesis will be offered because of the patient’s age or recommendations of the perinatologist.  An increase risk of chromosome abnormalities is not to be expected because of leflunomide exposure.  It is possible that these three pregnancies are not at an increased risk for congenital malformations and therefore it is possible that the offspring may be unaffected.  This suggestion is derived from the animal data which indicates that the rodent is more sensitive than the human to some of the effects of leflunomide, which may indicate that leflunomide has less of a teratogenic risk in the human at serum concentrations

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