Leflunomide (Arava) and pregnancy: the washout protocol

What does the evidence say about leflunomide during pregnancy?

1. The 2024 FDA label contraindicates Arava in pregnancy and directs stopping it and beginning accelerated elimination if pregnancy occurs, because animal data show embryofetal toxicity and controlled human evidence is limited. 1
2. FDA's accelerated elimination options are cholestyramine 8 g three times daily for 11 days or activated charcoal powder 50 g every 12 hours for 11 days, followed by two teriflunomide levels below 0.02 mg/L at least 14 days apart. 1
3. MotherToBaby reports that most leflunomide can leave the body in about 10 weeks on average, but without accelerated elimination it can take up to two years; reported pregnancies are hard to interpret because most stopped early and completed washout. 2
4. A prospective cohort compared 64 first-trimester leflunomide exposures with 108 rheumatoid-arthritis disease controls and 78 healthy controls; major differences were not significantly increased, but 95.3% of exposed participants completed cholestyramine washout. 3
5. A manufacturer pharmacovigilance analysis found no recurring major-malformation pattern among reported leflunomide-exposed pregnancies, but outcomes were known for only 587 of 1,167 reports. Spontaneous reporting and incomplete follow-up cannot establish the safety of continued exposure. 4

Is leflunomide safe in each trimester?

• First trimester. First-trimester exposure requires urgent prescriber and maternal-fetal medicine contact. The FDA plan is drug-specific: stop leflunomide, start accelerated elimination, and verify teriflunomide levels below the target twice at least 14 days apart.
• Second trimester. Later recognition does not make continued exposure acceptable. Human reports are most reassuring when leflunomide was stopped early and washout was completed, so they cannot establish safety for ongoing second-trimester exposure.
• Third trimester. Leflunomide remains contraindicated. Coordinate disease control, washout verification, delivery planning, and the postpartum medication plan with rheumatology and obstetrics rather than waiting for delivery to address the exposure.