Why Folic Acid is Not Given on the Same Day as Methotrexate
Folic acid should be given daily except on the day(s) of methotrexate administration because, in theory, folic acid may compete for cellular uptake of methotrexate when given on the same day, potentially reducing its therapeutic efficacy. 1
Mechanistic Rationale
The concern about same-day administration stems from the pharmacological interaction at the cellular level:
Methotrexate functions as a folate antagonist that inhibits dihydrofolic acid reductase, thereby interfering with DNA synthesis, repair, and cellular replication—this is its primary therapeutic mechanism. 2
Folic acid may theoretically compete with methotrexate for cellular uptake when both are present simultaneously, potentially diminishing methotrexate's ability to enter cells and exert its therapeutic effect. 1
This theoretical concern is based on the understanding that both compounds utilize similar cellular transport mechanisms, and concurrent administration could result in competitive inhibition at the cellular level. 3
Evidence-Based Dosing Schedule
The standard recommendation across multiple high-quality guidelines is consistent:
Folic acid supplementation at 1-5 mg daily is strongly recommended, with administration on all days except the day(s) when methotrexate is taken. 1, 3
The British Association of Dermatologists (2016) explicitly states that folic acid may compete for cellular uptake of methotrexate when given on the same day, providing the theoretical basis for this practice. 1
The American Academy of Dermatology guidelines (2020) recommend folate supplementation daily except for the days in which methotrexate is given to avoid influencing efficacy. 1
Clinical Evidence on Efficacy
The evidence regarding whether same-day administration actually reduces efficacy is nuanced:
Studies have shown that folic acid supplementation does not affect methotrexate efficacy when dosed appropriately (≤5 mg/week), with most evidence derived from rheumatoid arthritis patients. 1
Daily folic acid supplementation does not appear to reduce methotrexate efficacy in clinical practice, though the theoretical concern remains. 4
Research demonstrates that folic acid supplementation at 1 mg daily significantly reduces toxicity without altering efficacy during the first 6 months of treatment. 5
Important Clinical Caveats
Distinction Between Folic Acid and Folinic Acid
Folic acid is preferred over folinic acid (leucovorin) for routine supplementation due to lower cost and similar effectiveness in preventing side effects. 1, 3
Folinic acid at doses >5 mg/week was associated with increased tender and swollen joints in rheumatoid arthritis patients, suggesting potential interference with efficacy at higher doses. 3
Folinic acid should be reserved for methotrexate toxicity or overdose, not routine supplementation, and its timing relative to methotrexate administration is more critical. 4
Practical Implementation
The recommended approach is straightforward:
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, 3
For patients on methotrexate >15 mg/week, consider increasing folic acid to 7-10 mg weekly total. 3
At least 5 mg of folic acid per week is strongly recommended by rheumatology guidelines to reduce gastrointestinal and hepatic toxicity. 3
Benefits of Folic Acid Supplementation
Despite the theoretical concern about same-day administration, folic acid supplementation provides substantial benefits:
Reduces gastrointestinal side effects (nausea, stomatitis) and hepatotoxicity without compromising therapeutic efficacy. 1, 3
Prevents folate deficiency and hyperhomocysteinemia, which may reduce cardiovascular disease risk in patients on long-term methotrexate therapy. 6
Low baseline folate levels are an independent risk factor for methotrexate toxicity, making supplementation particularly important. 7, 5
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. 3
Common Pitfall to Avoid
Do not confuse routine folic acid supplementation with leucovorin rescue therapy. Leucovorin (folinic acid) is the antidote for methotrexate overdose or severe toxicity and should be administered immediately in those situations, regardless of timing concerns. 1, 8 For routine supplementation to prevent side effects, use folic acid daily except on methotrexate day(s).