Folic Acid Supplementation with Methotrexate
All patients on methotrexate therapy must receive folic acid supplementation at a minimum of 5 mg per week, given daily except on the day(s) of methotrexate administration, to reduce gastrointestinal, hepatic, and hematologic toxicity without compromising therapeutic efficacy. 1
Dosing Protocol
Prescribe folic acid 1-5 mg daily, instructing patients to skip the dose on the day they take methotrexate (and the day after if using split-dose methotrexate regimens). 1
The standard recommendation is at least 5 mg of folic acid per week, which can be administered as 1 mg daily for 5-6 days (avoiding the methotrexate day) or as a single 5 mg weekly dose. 2, 1
For patients on higher methotrexate doses (>15 mg/week), consider increasing folic acid supplementation to 7-10 mg weekly, as the protective effect is most significant at lower methotrexate doses (<10 mg/week). 1
Rationale for Timing
Folic acid should not be given on the same day as methotrexate because it may theoretically compete for cellular uptake of methotrexate, potentially reducing its therapeutic efficacy. 1
This timing recommendation is based on the concern that simultaneous administration could diminish methotrexate's ability to enter cells and exert its therapeutic effect. 1
Studies have demonstrated that folic acid supplementation at ≤5 mg/week does not reduce methotrexate efficacy in rheumatoid arthritis or psoriasis when dosed appropriately with this timing strategy. 1
Evidence for Toxicity Reduction
Folic acid supplementation reduces gastrointestinal side effects by 26% (relative risk reduction), including nausea, vomiting, and abdominal pain. 3
Hepatotoxicity is reduced by 77% (relative risk reduction), with significant protection against elevated liver transaminases. 2, 3
Meta-analysis of 788 rheumatoid arthritis patients demonstrated that folic acid reduces gastrointestinal side effects (OR 0.42) and hepatotoxicity (OR 0.17) without reducing methotrexate efficacy. 1
Patient withdrawal from methotrexate for any reason is reduced by 61% (relative risk reduction) with folic acid supplementation. 3
Critical Distinction: Folic Acid vs. Folinic Acid
Use folic acid, not folinic acid (leucovorin), for routine supplementation. 1
Folic acid is preferred due to lower cost and similar effectiveness in preventing side effects. 1, 4
Folinic acid at doses >5 mg/week was associated with increased tender and swollen joints (OR 6.27 and 5.3 respectively), suggesting potential interference with efficacy at higher doses. 1
Reserve folinic acid (leucovorin) exclusively for methotrexate overdose or severe toxicity, where it should be administered immediately regardless of timing concerns. 1
Common Pitfalls to Avoid
Do not allow patients to take folic acid on the same day as methotrexate, as this is the most common error that may compromise therapeutic effect. 1
Do not confuse routine folic acid supplementation with leucovorin rescue therapy—these are entirely different clinical scenarios. 1
Lack of folate supplementation is a major risk factor for methotrexate-induced hematologic toxicity, which accounts for the majority of methotrexate-associated fatalities. 1, 5
Monitoring Requirements
Regular monitoring of complete blood counts, liver function tests, and renal function remains essential every 1-3 months even with folic acid supplementation. 1
Continue monitoring for signs of folate deficiency, including macrocytic anemia, which can present with progressive fatigue and shortness of breath. 5
Baseline chest x-ray should be obtained for all patients starting methotrexate to monitor for pulmonary toxicity. 5