Why is folic acid given with methotrexate (MTX)?

Folic Acid Supplementation with Methotrexate: Reducing Side Effects While Maintaining Efficacy

Folic acid is given with methotrexate to decrease the rate of adverse effects associated with methotrexate therapy, including gastrointestinal side effects, hepatotoxicity, and mucocutaneous reactions, without compromising treatment efficacy. 1

Mechanism and Rationale

Methotrexate is a folate antagonist that inhibits dihydrofolate reductase, disrupting folate metabolism and DNA synthesis. This mechanism is responsible for both its therapeutic effects and adverse reactions. Supplementation with folic acid helps to:

• Reduce gastrointestinal toxicity (nausea, vomiting, abdominal pain)
• Decrease hepatotoxicity (abnormal liver function tests)
• Potentially reduce mucocutaneous side effects (stomatitis, mouth sores)
• Allow patients to continue methotrexate therapy with fewer interruptions

Evidence for Benefit

The British Association of Dermatologists' guidelines (2016) strongly recommend folic acid supplementation (strength of recommendation A; level of evidence 1++) based on multiple randomized controlled trials showing significant reduction in side effects 1. A systematic review demonstrated that folic acid supplementation reduces:

• Hepatic side effects by 76.9% relative risk reduction 2
• Gastrointestinal side effects by 26% relative risk reduction 2
• Patient withdrawal from methotrexate for any reason by 60.8% 2

Dosing Recommendations

• Folic acid is typically given daily, except for the days when methotrexate is administered, to avoid influencing efficacy 1
• The American Academy of Dermatology recommends at least 5 mg/week of folic acid 1
• British guidelines suggest dosing can range from 5 mg weekly to 5 mg daily 1

Important Clinical Considerations

1. Timing matters: Folic acid should be avoided on the same day as methotrexate administration to prevent interference with efficacy 1

2. Folic acid vs. folinic acid:

   • Both are effective in reducing side effects
   • Folic acid is more cost-effective and generally preferred 1
   • No significant difference in efficacy between the two 1

3. Effect on methotrexate efficacy:

   • Studies have shown that folic acid supplementation does not significantly reduce the therapeutic efficacy of methotrexate 3
   • Daily folic acid appears safe without compromising treatment outcomes 3

Common Pitfalls to Avoid

1. Omitting folic acid supplementation: This significantly increases risk of side effects and treatment discontinuation

2. Administering folic acid on the same day as methotrexate: May theoretically reduce methotrexate efficacy by competing for cellular uptake 1

3. Confusing folic acid with folinic acid (leucovorin):

   • Folinic acid is primarily used for methotrexate toxicity rescue, not routine supplementation 3
   • Folinic acid given close to methotrexate administration may reduce efficacy more than folic acid 3

4. Inadequate monitoring: Despite folic acid supplementation, regular monitoring of complete blood count, liver function, and renal function remains essential 1

By implementing appropriate folic acid supplementation with methotrexate therapy, clinicians can significantly improve treatment tolerability and adherence, ultimately leading to better patient outcomes and quality of life.