DMARD (pyrimidine synthesis inhibitor)
Leflunomide is a disease-modifying medicine used to treat active rheumatoid arthritis in adults. It relieves symptoms and slows disease progression. It affects the liver and bone marrow and can harm the fetus, so regular monitoring and effective contraception in women of childbearing age are required.
Also known as: Arava, leflunomida, leflunomide
Leflunomide + methotrexate: increased risk of hepatotoxicity and marrow suppression.
The leflunomide label states that "for patients at high risk for leflunomide-associated hepatotoxicity (e.g., those taking concomitant methotrexate)" or myelosuppression "the recommended leflunomide dosage is 20 mg once daily without a loading dose" and that, if given together, "follow the American College of Rheumatology (ACR) guidelines for monitoring methotrexate liver toxicity with ALT, AST, and serum albumin testing". Both drugs are immunomodulators used in rheumatoid arthritis, often in combination, and both have hepatotoxic and myelotoxic potential. Monitor ALT, AST and albumin monthly during the first 6 months, then quarterly; complete blood count with differential monthly; discontinue if ALT > 3× ULN or signs of myelosuppression. Leflunomide should not be started with a loading dose (100 mg × 3 days) when used with methotrexate; start at 20 mg/day from the beginning.
Leflunomide + methotrexate: additive hepatic and bone marrow toxicity in rheumatoid arthritis. Monitor ALT, AST and blood counts; use without leflunomide loading dose.
Additive toxic effects on the liver and bone marrow.
Transaminases and full blood count monthly; renal function.
Jaundice, fever, infections, oral ulcers.
Combination only in specialist settings, with tight monitoring of transaminases and full blood count.
DailyMed (FDA) — approved Leflunomide label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fc044417-cd9a-42f6-8a3d-a14e7c2f81a2 ; approved Methotrexate label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=757d6cef-6696-7a1c-8074-01258aaa8bdd — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Leflunomida + anticoagulant: possible increased anticoagulant effect.
Leflunomide (and its active metabolite teriflunomide) has been associated with INR elevation in warfarin-anticoagulated patients, with reports of severe bleeding. The mechanism is not fully established but probably involves interference with warfarin metabolism. The effect can appear weeks after starting leflunomide. The INR should be monitored frequently when starting leflunomide and after dose changes, and bleeding signs watched for; if rapid discontinuation is needed, consider the cholestyramine washout procedure described in the label.
Leflunomide can raise the INR in warfarin patients. Monitor the INR when starting and adjust the dose; cases of severe bleeding described.
Leflunomide may inhibit warfarin metabolism, raising INR.
Periodic INR during the combination.
Bleeding, spontaneous ecchymosis.
Monitor INR after starting or changing leflunomide dose.
DailyMed (FDA) — approved Leflunomide label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fc044417-cd9a-42f6-8a3d-a14e7c2f81a2 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Alcohol increases the risk of liver injury.
Avoid alcohol during treatment.
EMC-UK (MHRA) — approved Leflunomide SmPC: https://www.medicines.org.uk/emc/product/4944/smpc
Reduced elimination may increase exposure and toxicity.
Use with caution and monitor renal function.
EMC-UK (MHRA) — approved Leflunomide SmPC: https://www.medicines.org.uk/emc/product/4944/smpc
Immunosuppression from leflunomide may worsen infections.
Assess and treat infections before starting; watch for signs of infection.
EMC-UK (MHRA) — approved Leflunomide SmPC: https://www.medicines.org.uk/emc/product/4944/smpc
Leflunomide may cause severe liver injury, especially with pre-existing liver disease.
Contraindicated; monitor transaminases monthly on therapy.
EMC-UK (MHRA) — approved Leflunomide SmPC: https://www.medicines.org.uk/emc/product/4944/smpc
Leflunomide is teratogenic; contraindicated in pregnancy.
Contraindicated; mandatory effective contraception and washout procedure (cholestyramine) before conception.
Contraindicated during breastfeeding.
Effective contraception mandatory; cholestyramine washout before pregnancy.
EMC-UK (MHRA) — approved Leflunomide SmPC: https://www.medicines.org.uk/emc/product/4944/smpc
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Immunomodulator (isoxazole derivative) with anti-inflammatory and antiproliferative activity, indicated for the treatment of active rheumatoid arthritis in adults (and psoriatic arthritis). The active metabolite, teriflunomide, is responsible for essentially all of the in vivo activity. Because of the very long half-life (18-19 days), a loading dose of 100 mg/day for 3 days is used to reach steady state rapidly.
Inhibits dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity; several in vivo and in vitro experimental models demonstrate an anti-inflammatory effect. The active metabolite teriflunomide is responsible for essentially all of the in vivo activity.
After oral administration, peak teriflunomide concentrations occur between 6-12 hours after dosing. Because of the very long half-life (18-19 days), a loading dose of 100 mg/day for 3 days is used; without a loading dose, steady state would take about two months. Concentrations are dose proportional. Extensively bound to plasma proteins (>99%), distributed mainly in plasma; volume of distribution 11 L. Food does not significantly affect concentrations.
Leflunomide is metabolised to the active metabolite teriflunomide and many minor metabolites (in vitro, CYP1A2, CYP2C19 and CYP3A4 are involved in leflunomide metabolism; teriflunomide is not metabolised by CYP450). Teriflunomide is eliminated by direct biliary excretion of unchanged drug and renal excretion of metabolites: over 21 days, 60.1% of the dose is excreted in faeces (37.5%) and urine (22.6%). Cholestyramine accelerates elimination.
Median half-life of 18-19 days in healthy volunteers (teriflunomide). Without an accelerated elimination procedure, it may take up to 2 years to reach plasma teriflunomide concentrations below 0.02 mg/L. Cholestyramine or activated charcoal accelerate elimination.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
