Current Recommended Folic Acid Dosing for Methotrexate Therapy
For adults with seronegative arthritis taking methotrexate, prescribe at least 5 mg of folic acid per week, given on a day separate from methotrexate administration. 1
Standard Dosing Regimens
The evidence supports two equivalent approaches for folic acid supplementation:
- 5 mg once weekly - taken the day after methotrexate administration 2, 3
- 1 mg daily - taken every day except the day(s) methotrexate is administered 2, 3
Both regimens provide equivalent protection against methotrexate toxicity without compromising therapeutic efficacy. 2
Critical Timing Consideration
Never administer folic acid on the same day as methotrexate. 2 Folic acid may theoretically compete for cellular uptake of methotrexate when given simultaneously, potentially reducing therapeutic efficacy. 2 This timing restriction is based on the mechanistic understanding that both compounds compete for the same cellular transport mechanisms. 2
Dose Escalation for Higher Methotrexate Doses
For patients requiring methotrexate doses >15 mg/week, consider increasing folic acid supplementation to 7-10 mg weekly. 2 The protective effect of standard-dose folic acid is most significant at lower methotrexate doses (<10 mg/week), and higher methotrexate doses may benefit from proportionally increased folate supplementation. 2
Evidence Supporting This Recommendation
The multinational evidence-based guidelines provide Level 1a evidence (Grade A recommendation) that "prescription of at least 5 mg folic acid per week with methotrexate therapy is strongly recommended." 1 This recommendation achieved high expert agreement (mean 7.5, SD 2.7). 1
Meta-analysis of 788 RA patients demonstrated that folic acid supplementation reduces:
- Gastrointestinal side effects by 58% (OR 0.42) 2
- Hepatotoxicity by 83% (OR 0.17) 2
- Patient withdrawal from methotrexate by 61% (OR 0.39) 1
Importantly, folic acid at doses ≤5 mg/week does not reduce methotrexate efficacy in treating inflammatory arthritis. 2, 4
Why Folic Acid (Not Folinic Acid)
Use folic acid for routine supplementation, not folinic acid (leucovorin). 2, 5 Folic acid is preferred because it provides equivalent protection against methotrexate toxicity at significantly lower cost. 2, 5 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 methotrexate efficacy at higher doses. 2
Reserve leucovorin (folinic acid) exclusively for methotrexate overdose or severe toxicity, where it serves as the life-saving antidote. 2, 6
Common Pitfall to Avoid
Do not confuse routine folic acid supplementation (for prevention) with leucovorin rescue therapy (for treatment of acute toxicity). 2 Only leucovorin bypasses methotrexate's metabolic block and serves as an effective antidote in overdose situations. 6
Monitoring Remains Essential
Even with appropriate folic acid supplementation, continue regular monitoring of liver function tests (ALT/AST), complete blood count, and creatinine every 1-1.5 months initially, then every 1-3 months once stable. 1, 2 Folic acid reduces but does not eliminate the risk of methotrexate toxicity. 2