Folic Acid Supplementation for Methotrexate 2.5mg Weekly
Yes, folic acid supplementation is mandatory for all patients taking methotrexate, regardless of dose—prescribe folic acid 1-5 mg daily on all days except the day methotrexate is taken, ensuring a minimum of 5 mg per week. 1
Standard Dosing Protocol
Folic acid supplementation at a minimum of 5 mg per week is strongly recommended by the American College of Rheumatology and American Academy of Dermatology for all patients receiving methotrexate therapy. 1, 2 This applies even to your patient on the relatively low dose of 2.5 mg weekly.
Practical Dosing Options
You have two equally effective approaches:
- 5 mg once weekly (on a different day than methotrexate) 1, 2
- 1 mg daily (skipping the methotrexate day) 1, 2
Both regimens meet the minimum 5 mg weekly threshold and are endorsed by major dermatology and rheumatology guidelines. 1, 2
Critical Timing Consideration
Never administer folic acid on the same day as methotrexate. 1, 2 Folic acid may theoretically compete with methotrexate for cellular uptake when given simultaneously, potentially reducing therapeutic efficacy. 1 The American Academy of Dermatology explicitly recommends giving folic acid daily except on the day(s) of methotrexate administration to avoid potential interference. 1
Evidence for Toxicity Reduction Without Compromising Efficacy
The rationale for mandatory supplementation is compelling:
Meta-analysis of 788 rheumatoid arthritis patients demonstrated that folic acid supplementation reduces gastrointestinal side effects by 58% (OR 0.42) and hepatotoxicity by 83% (OR 0.17) without reducing methotrexate efficacy. 1
Folic acid at ≤5 mg/week does not reduce methotrexate efficacy in rheumatoid arthritis or psoriasis. 1
Lack of folate supplementation is a major risk factor for methotrexate-induced hematologic toxicity. 1, 3
Even at your patient's low dose of 2.5 mg weekly, the protective effect of folic acid against gastrointestinal and hepatic toxicity is most significant at lower methotrexate doses (<10 mg/week). 1
Why Folic Acid Over Folinic Acid
Use folic acid, not folinic acid (leucovorin), for routine supplementation. 1, 2 Folic acid is preferred due to lower cost and similar effectiveness in preventing side effects. 1, 2 Reserve folinic acid exclusively for methotrexate overdose or severe toxicity as rescue therapy. 2
Critical caveat: 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
Common Pitfalls to Avoid
Do not omit folic acid supplementation in any patient on methotrexate, regardless of dose. 2 Even 2.5 mg weekly requires folate supplementation.
Do not give folic acid on the methotrexate day. 1, 2 This is the single most important timing consideration.
Do not assume folic acid eliminates the need for monitoring. 2 Regular monitoring of CBC, liver function tests, and creatinine remains essential every 3-6 months even with folic acid supplementation. 1, 2
Do not confuse folic acid with folinic acid. 3 Only leucovorin (folinic acid) bypasses methotrexate's metabolic block and serves as an effective antidote for acute toxicity. 3
Monitoring Requirements Despite Supplementation
Even with appropriate folic acid supplementation, your patient requires:
- Complete blood count, liver function tests, and creatinine at least monthly for the first 3 months 3
- After stabilization, CBC and liver function tests every 3-6 months 3, 2
Regular monitoring remains essential because folic acid reduces but does not eliminate the risk of methotrexate toxicity. 1, 2