How to administer folic acid to a patient taking methotrexate?

How to Administer Folic Acid with Methotrexate

Prescribe folic acid 1-5 mg daily, instructing patients to take it every day EXCEPT on the day(s) they take methotrexate. 1, 2

Standard Dosing Protocol

• Give folic acid 1-5 mg daily on all days except methotrexate administration day(s) to reduce gastrointestinal and hepatic toxicity without compromising therapeutic efficacy 1, 2

• The minimum recommended dose is at least 5 mg per week total, which can be administered as 1 mg daily for 5-6 days (skipping methotrexate day) or as a single 5 mg dose once weekly 1, 2

• For patients on higher methotrexate doses (>15 mg/week), consider increasing folic acid to 7-10 mg weekly 2

Critical Timing Consideration

• Never give folic acid on the same day as methotrexate because folic acid may theoretically compete for cellular uptake of methotrexate when both are present simultaneously, potentially reducing therapeutic efficacy 1, 2

• This timing restriction applies specifically to folic acid, not folinic acid (leucovorin), which is reserved for methotrexate overdose or severe toxicity 2, 3

Rationale and Evidence

• Folic acid supplementation reduces gastrointestinal side effects by 58% (OR 0.42) and hepatotoxicity by 83% (OR 0.17) without reducing methotrexate efficacy when dosed at ≤5 mg/week 2

• Lack of folate supplementation is a major risk factor for methotrexate-induced hematologic toxicity and hepatotoxicity 1, 2, 4

• Daily folic acid supplementation (excluding methotrexate day) decreases both GI intolerance and hepatic adverse effects compared to weekly-only folic acid dosing 1

Practical Implementation

• Use folic acid, NOT folinic acid (leucovorin) for routine supplementation—folic acid is less expensive with similar effectiveness 1, 2

• Folinic acid should only be used for methotrexate overdose or severe toxicity, where it must be administered immediately regardless of timing concerns 2, 3

• For pediatric patients, the same principle applies: 1 mg daily (or 6 days per week, sparing the methotrexate administration day) 1

Common Pitfall to Avoid

• Do not confuse routine folic acid supplementation with leucovorin rescue therapy—leucovorin is the antidote for methotrexate overdose and requires immediate administration in emergency situations 2, 3

• Some clinicians mistakenly give folic acid on the same day as methotrexate, which may compromise therapeutic effect 2

Monitoring Requirements

• Continue regular monitoring of liver function tests, complete blood count, and renal function every 3-6 months even with folic acid supplementation, as folate does not eliminate all toxicity risk 2, 4

• Folic acid supplementation does not replace the need for vigilant laboratory monitoring 2, 4