Selective immunosuppressants
Brand names: Leflunomida Cinfa, Arava, Leflunomida Medac, Aubagio (teriflunomide for MS)
Updated · Methodology
Second line
Second-line in rheumatoid arthritis after methotrexate intolerance or inefficacy per 2022 and Spanish SER 2023. Starting loading dose 100 mg once daily for 3 days, then maintenance 10–20 mg once daily. Effect develops over 4–12 weeks. Comparable to methotrexate in efficacy (US301 trial); often used as monotherapy in MTX-intolerant patients or combined. Also suitable for psoriatic arthritis.
Sources
ICD-10: M06.9 · ICD-11: FA20
The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.
Not recommended
Leflunomide is a disease-modifying antirheumatic drug (DMARD), a pyrimidine synthesis inhibitor. It is prescribed for active rheumatoid arthritis and psoriatic arthritis ( 2023 guidelines, AEMPS Ficha Técnica). In alt-anti-aging circles, leflunomide is sometimes promoted as a universal modulator of the autoimmune background in healthy people. In healthy adults, no clinical studies of such use exist. The drug has serious risks: hepatotoxicity up to acute liver failure, severe skin reactions (Stevens-Johnson syndrome), peripheral neuropathy, myelosuppression, and significant teratogenicity (the M1 metabolite persists in the body for up to 2 years, requiring a cholestyramine washout protocol before pregnancy planning). If leflunomide was recommended to a healthy person, seek a second opinion immediately.
Oral selective immunosuppressant, a conventional synthetic disease-modifying antirheumatic drug (csDMARD). Metabolized to the active metabolite teriflunomide, which reversibly inhibits mitochondrial dihydroorotate dehydrogenase (DHODH) – key to pyrimidine synthesis in activated T and B lymphocytes. This block predominantly affects proliferating lymphocytes – selective immunosuppression with less impact on hematopoiesis than methotrexate.
Boxed warning
FDA boxed warning 2010: teratogenicity and severe hepatitis risk. Pregnancy and conception potential without barrier contraception and washout are absolute contraindications.
AEMPS summary of product characteristics (section 4.6): the active metabolite of leflunomide, A771726, is suspected to cause serious birth defects, so leflunomide is contraindicated in pregnancy. Women of childbearing potential must use effective contraception during treatment and for 2 years afterwards (or 11 days if a washout procedure is done); if a period is late, a pregnancy test is done at once, and lowering metabolite levels with a washout at the first delay may reduce the risk to the fetus. In a small prospective study (n = 64) of women who became pregnant on leflunomide, took it for no more than three weeks after conception and then underwent drug elimination, the rate of major structural defects (5.4%) did not differ significantly (p = 0.13) from the comparison groups: 4.2% in disease-matched women and 4.2% in healthy pregnant women. Before a planned pregnancy, A771726 must be below 0.02 mg/L in two tests at least 14 days apart, reached either after a 2-year wait or after washout with cholestyramine (8 g three times daily for 11 days) or activated charcoal (50 g four times daily for 11 days); after washout, a further month and a half must pass from the first result below 0.02 mg/L to fertilisation. Cholestyramine and activated charcoal may alter the absorption of oestrogens and progestogens, so oral contraceptives are replaced with another method during washout.
Contraindicated during lactation.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
Verbatim lines from the interaction sections, in the language of the label
«Combinaciones con otros tratamientos: Hasta el momento no se ha estudiado suficientemente en ensayos aleatorizados (a excepción del metotrexato, ver sección 4.5) el empleo de la leflunomida con los…»AEMPS, section 4.4 · Open on CIMA
«Combinaciones con otros tratamientos: Hasta el momento no se ha estudiado suficientemente en ensayos aleatorizados (a excepción del metotrexato, ver sección 4.5) el empleo de la leflunomida con los…»AEMPS, section 4.4 · Open on CIMA
«Dosis repetidas de A771726 aumentaron la C max media y AUC (2,65- y 2,51-veces, respectivamente) de rosuvastatina. Sin embargo, no hubo impacto aparente de este aumento de la exposición en plasma de…»AEMPS, section 4.5 · Open on CIMA
«Dosis repetidas de A771726 aumentaron la C max media y AUC (2,65- y 2,51-veces, respectivamente) de rosuvastatina. Sin embargo, no hubo impacto aparente de este aumento de la exposición en plasma de…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Teriflunomide inhibits the activity of BCRP and OATP1B1/FDA, section 7 · Open on DailyMed
«Warfarina y otros anticoagulantes cumarínicos: Se han notificado casos de aumento del tiempo de protrombina, cuando se administran conjuntamente leflunomida y warfarina. En un estudio farmacológico…»AEMPS, section 4.5 · Open on CIMA
«Dosis repetidas de A771726 aumentaron la C max media y AUC (2,65- y 2,51-veces, respectivamente) de rosuvastatina. Sin embargo, no hubo impacto aparente de este aumento de la exposición en plasma de…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Teriflunomide inhibits the activity of BCRP and OATP1B1/FDA, section 7 · Open on DailyMed
«Dosis repetidas de A771726 aumentaron la C max media y AUC (1,43- y 1,54-veces, respectivamente) de cefaclor, sugiriendo que el A771726 es un inhibidor del OAT3 in vivo. Por tanto, se recomienda…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Teriflunomide inhibits the activity of OAT3 in vivo . In patients taking leflunomide, exposure of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin…»FDA, section 7 · Open on DailyMed
«Dosis repetidas de A771726 disminuyeron la Cmax media y AUC de la cafeina (sustrato CYP1A2) en un 18% y 55%, respectivamente, y sugieren que el A771726 puede ser un débil inductor del CYP1A2 in vivo…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Teriflunomide, the active metabolite of leflunomide, may be a weak inducer of CYP1A2 in vivo . In patients taking leflunomide, exposure of drugs metabolized by CYP1A2 (e.g…»FDA, section 7 · Open on DailyMed
«Dosis repetidas de A771726 aumentaron la C max media y AUC (2,65- y 2,51-veces, respectivamente) de rosuvastatina. Sin embargo, no hubo impacto aparente de este aumento de la exposición en plasma de…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Teriflunomide may increase the systemic exposures of ethinylestradiol and levonorgestrel. Consideration should be given to the type or dose of contraceptives used in combination…»FDA, section 7 · Open on DailyMed
«Dosis repetidas de A771726 aumentaron la C max media y AUC (1,43- y 1,54-veces, respectivamente) de cefaclor, sugiriendo que el A771726 es un inhibidor del OAT3 in vivo. Por tanto, se recomienda…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Teriflunomide inhibits the activity of OAT3 in vivo . In patients taking leflunomide, exposure of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin…»FDA, section 7 · Open on DailyMed
«DRUG INTERACTIONS: Teriflunomide may increase the systemic exposures of ethinylestradiol and levonorgestrel. Consideration should be given to the type or dose of contraceptives used in combination…»FDA, section 7 · Open on DailyMed
«Dosis repetidas de A771726 aumentaron la C max media y AUC (1,43- y 1,54-veces, respectivamente) de cefaclor, sugiriendo que el A771726 es un inhibidor del OAT3 in vivo. Por tanto, se recomienda…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Teriflunomide inhibits the activity of OAT3 in vivo . In patients taking leflunomide, exposure of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin…»FDA, section 7 · Open on DailyMed
«DRUG INTERACTIONS: Teriflunomide may increase the systemic exposures of ethinylestradiol and levonorgestrel. Consideration should be given to the type or dose of contraceptives used in combination…»FDA, section 7 · Open on DailyMed
«DRUG INTERACTIONS: Teriflunomide inhibits the activity of OAT3 in vivo . In patients taking leflunomide, exposure of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin…»FDA, section 7 · Open on DailyMed
«Dosis repetidas de A771726 aumentaron la C max media y la AUC (1,7- y 2,4-veces, respectivamente) de la repaglinida, sugiriendo que el A771726 es un inhibidor de CYP2C8 in vivo. Por tanto, se…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Teriflunomide is an inhibitor of CYP2C8 in vivo . In patients taking leflunomide, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide…»FDA, section 7 · Open on DailyMed
«Dosis repetidas de A771726 aumentaron la C max media y AUC (2,65- y 2,51-veces, respectivamente) de rosuvastatina. Sin embargo, no hubo impacto aparente de este aumento de la exposición en plasma de…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Teriflunomide inhibits the activity of BCRP and OATP1B1/FDA, section 7 · Open on DailyMed
«Dosis repetidas de A771726 aumentaron la C max media y la AUC (1,7- y 2,4-veces, respectivamente) de la repaglinida, sugiriendo que el A771726 es un inhibidor de CYP2C8 in vivo. Por tanto, se…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Teriflunomide is an inhibitor of CYP2C8 in vivo . In patients taking leflunomide, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide…»FDA, section 7 · Open on DailyMed
«Dosis repetidas de A771726 aumentaron la C max media y AUC (2,65- y 2,51-veces, respectivamente) de rosuvastatina. Sin embargo, no hubo impacto aparente de este aumento de la exposición en plasma de…»AEMPS, section 4.5 · Open on CIMA
«Dosis repetidas de A771726 aumentaron la C max media y AUC (2,65- y 2,51-veces, respectivamente) de rosuvastatina. Sin embargo, no hubo impacto aparente de este aumento de la exposición en plasma de…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Teriflunomide inhibits the activity of BCRP and OATP1B1/FDA, section 7 · Open on DailyMed
«Dosis repetidas de A771726 disminuyeron la Cmax media y AUC de la cafeina (sustrato CYP1A2) en un 18% y 55%, respectivamente, y sugieren que el A771726 puede ser un débil inductor del CYP1A2 in vivo…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Teriflunomide, the active metabolite of leflunomide, may be a weak inducer of CYP1A2 in vivo . In patients taking leflunomide, exposure of drugs metabolized by CYP1A2 (e.g…»FDA, section 7 · Open on DailyMed
«Warfarina y otros anticoagulantes cumarínicos: Se han notificado casos de aumento del tiempo de protrombina, cuando se administran conjuntamente leflunomida y warfarina. En un estudio farmacológico…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Coadministration of leflunomide with warfarin requires close monitoring of the international normalized ratio (INR) because teriflunomide, the active metabolite of leflunomide, may…»FDA, section 7 · Open on DailyMed
«AINEs/AEMPS, section 4.5 · Open on CIMA
«AINEs/AEMPS, section 4.5 · Open on CIMA
«Anticonceptivos orales: En un estudio con voluntarias sanas en el que se administró leflunomida junto con un anticonceptivo oral trifásico que contenía 30 μ g de etinilestradiol, no se produjo…»AEMPS, section 4.5 · Open on CIMA
«Anticonceptivos orales: Efecto en anticonceptivos orales (0,03 mg etinilestradiol y 0,15 mg levonorgestrel)»AEMPS, section 4.5 · Open on CIMA
«Alcohol, medicamentos hepatotóxicos y medicamentos hematotóxicos: La probabilidad de que el metotrexato produzca un efecto hepatotóxico aumenta con el consumo regular de alcohol y con la…»AEMPS, section 4.5 · Open on CIMA
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Leflunomide is evaluated for the following indications with varying evidence strength: Rheumatoid arthritis (evidence tier A), Anti-aging and longevity (evidence tier F). See the full indication matrix with dosing and citations above on this page.
Common side effects of Leflunomide (≥ 1 in 100): Diarrhea, Nausea, Alopecia, Skin rash, ALT/AST elevation, Hypertension. See the Safety section for uncommon and serious reactions.
AEMPS summary of product characteristics (section 4.6): the active metabolite of leflunomide, A771726, is suspected to cause serious birth defects, so leflunomide is contraindicated in pregnancy. Women of childbearing potential must use effective contraception during treatment and for 2 years afterwards (or 11 days if a washout procedure is done); if a period is late, a pregnancy test is done at once, and lowering metabolite levels with a washout at the first delay may reduce the risk to the fetus. In a small prospective study (n = 64) of women who became pregnant on leflunomide, took it for no more than three weeks after conception and then underwent drug elimination, the rate of major structural defects (5.4%) did not differ significantly (p = 0.13) from the comparison groups: 4.2% in disease-matched women and 4.2% in healthy pregnant women. Before a planned pregnancy, A771726 must be below 0.02 mg/L in two tests at least 14 days apart, reached either after a 2-year wait or after washout with cholestyramine (8 g three times daily for 11 days) or activated charcoal (50 g four times daily for 11 days); after washout, a further month and a half must pass from the first result below 0.02 mg/L to fertilisation. Cholestyramine and activated charcoal may alter the absorption of oestrogens and progestogens, so oral contraceptives are replaced with another method during washout.
Contraindicated during lactation.
Leflunomide is contraindicated in: Hypersensitivity; Severe hepatic impairment; Severe immunodeficiency; Severe hypoproteinemia (nephrotic syndrome); Pregnancy or conception potential without separate washout. Full list in the Safety section.
FDA boxed warning 2010: teratogenicity and severe hepatitis risk. Pregnancy and conception potential without barrier contraception and washout are absolute contraindications.
Direct links to regulator labels. Open in a new tab.
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