Switching from Arava (Leflunomide) to Methotrexate
When switching from leflunomide to methotrexate, you must perform a drug elimination procedure with cholestyramine or activated charcoal to rapidly clear leflunomide before starting methotrexate, due to the significant risk of additive bone marrow suppression and hepatotoxicity when these agents overlap. 1
Drug Elimination Protocol (Critical First Step)
Before initiating methotrexate, eliminate leflunomide using one of these protocols:
- Cholestyramine 8 grams three times daily for 11 days (days do not need to be consecutive unless rapid elimination is needed) 1
- Activated charcoal 50 grams four times daily for 11 days (alternative if cholestyramine unavailable) 1
- Verify elimination with plasma level testing: obtain two separate tests at least 14 days apart to confirm leflunomide active metabolite levels are <0.02 mg/L 1
Critical warning: Without drug elimination, there will be systemic overlap of both compounds, creating a "prudent" need to monitor for severe hematologic toxicity including pancytopenia, agranulocytosis, and thrombocytopenia 1. The FDA label explicitly states this risk is highest when switching between agents with hematologic suppression potential 1.
Rationale for the Switch
The 2021 American College of Rheumatology guidelines establish methotrexate as preferred over leflunomide due to greater dosing flexibility and lower cost 2. This preference applies across disease activity levels and makes switching from leflunomide to methotrexate clinically appropriate when leflunomide fails or causes intolerance 2.
Initiating Methotrexate After Elimination
Start with oral methotrexate at 10-15 mg weekly, titrating to at least 15 mg within 4-6 weeks:
- Begin with oral administration due to ease of use and similar bioavailability at typical starting doses 2
- Escalate dose by 2.5-5 mg increments every 4-6 weeks if inadequate response, up to 20-25 mg weekly 3, 4
- The ACR conditionally recommends reaching at least 15 mg weekly within 4-6 weeks for optimal efficacy 2
Mandatory baseline testing before methotrexate:
- Complete blood count, liver transaminases, serum creatinine with creatinine clearance calculation, chest radiograph 4
- Hepatitis B and C serologies, serum albumin (recommended) 4
Monitoring During Transition
Intensive monitoring is required due to overlapping toxicity risks:
- Monthly complete blood counts, liver enzymes, and creatinine for the first 6 months 1, 4
- Then every 6-8 weeks if stable 2, 1
- Watch specifically for bone marrow suppression (the FDA warns this occurs most frequently when patients recently discontinued other immunosuppressive agents like leflunomide) 1
Folic Acid Supplementation
Prescribe folic acid 5 mg once weekly at a different day than methotrexate to reduce mucosal and gastrointestinal toxicity 4. This is particularly important given that studies without folate supplementation (like MN302) showed significantly higher liver enzyme elevations with methotrexate 5, 6.
If Methotrexate Proves Inadequate
Consider subcutaneous administration before abandoning methotrexate:
- Switch to subcutaneous route if oral methotrexate at adequate doses (15-25 mg) fails to achieve target 2
- Subcutaneous administration may provide superior efficacy and fewer gastrointestinal side effects 2, 3
Common Pitfalls to Avoid
- Never start methotrexate without eliminating leflunomide first - the FDA explicitly warns about hematologic toxicity from overlapping exposure 1
- Do not skip the verification plasma levels if rapid disease control is needed, as leflunomide has a very long half-life 1
- Avoid starting methotrexate at doses <10 mg weekly - this is inadequately effective per multiple guidelines 3, 4
- Do not forget folate supplementation - the comparative trials show dramatically different safety profiles with versus without folate 5, 6