For clinicians
Leflunomide
Arava, teriflunomide (active metabolite)
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Bottom lineBottom line: discontinue before conception with cholestyramine washout and confirm plasma levels below threshold, given the long half-life of the active metabolite. Registry data (OTIS) where washout was performed are more reassuring than the label warning implies, which is the source of divergence.
By reproductive phase
| Phase | Position | Detail | Evidence |
|---|---|---|---|
| Pre-conception | Stop pre-conception | EULAR 2024: discontinue ~5 half-lives (approx 3.5 months) before pregnancy, or use accelerated elimination (cholestyramine) with confirmatory teriflunomide level below threshold.[1, 2, 3] | ●●●○moderate evidencestrong |
| 1st trimester | Avoid | Avoid; if inadvertent exposure occurs, perform washout and counsel using registry data.[1] | ●●●○moderate evidenceconditional |
| 2nd/3rd trimester | Avoid | Avoid.[1] | ●●●○moderate evidenceconditional |
| Breastfeeding | Avoid | Avoid in lactation; limited data.[3] | ●●○○low evidenceconditional |
| Paternal | Continue | Paternal use considered compatible; limited data.[2, 3] | ●●○○low evidenceconditional |
Guideline comparison
| Guideline | Position | Strength |
|---|---|---|
| ACR 2020 | Strongly recommend against before and during pregnancy: perform a cholestyramine washout if levels are detectable pre-conception, and stop with cholestyramine washout during pregnancy. Breastfeeding: strongly recommend against. Paternal: conditionally recommend continuing.[1] | Strong against (maternal); conditional continue (paternal) |
| EULAR 2024 | Insufficient pregnancy data; discontinue 5 half-lives (~3.5 months) before pregnancy, or use accelerated elimination e.g. cholestyramine (2b/B). Avoid in lactation (5/D). Continuable in men (2c/C).[2] | Oxford LoE/GoR as shown |
| BSR 2022/23 | Not compatible peri-conception without cholestyramine washout; not compatible in either trimester or with breastfeeding. Compatible with paternal exposure.[3] | Verified against BSR Table 1 |
=Guideline divergence. VERIFIED DIVERGENCE (washout detail). EULAR 2024 lists leflunomide under insufficient pregnancy data and specifies discontinuing 5 half-lives (about 3.5 months) before pregnancy OR using accelerated elimination such as cholestyramine (2b/B). BSR 2023 requires cholestyramine washout at peri-conception. Both consider paternal exposure compatible and both avoid it in lactation.
Key points
| Point | Evidence |
|---|---|
| Cholestyramine washout with confirmatory teriflunomide level is the standard pre-conception step.[1] | ●●●○moderate evidencestrong |
Monitoring
- Cholestyramine washout and confirmatory drug level before conception.
- Effective contraception until cleared.
References
- Sammaritano LR, et al. 2020 ACR Guideline for the Management of Reproductive Health in RMD. Arthritis Rheumatol. 2020;72(3):529-556. https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/art.41191
- Ruegg L, et al. EULAR recommendations for antirheumatic drugs in reproduction, pregnancy, and lactation: 2024 update. Ann Rheum Dis. 2025;84(6):910-926. https://ard.eular.org/article/S0003-4967(25)00818-0/fulltext
- Russell MD, et al. BSR guideline on prescribing drugs in pregnancy and breastfeeding: immunomodulatory drugs and corticosteroids. Rheumatology (Oxford). 2023;62(4):e48-e88. https://academic.oup.com/rheumatology/article/62/4/e48/6783012