How should methotrexate be administered with folic acid in an adult with rheumatoid arthritis?

How to Administer Methotrexate with Folic Acid in Rheumatoid Arthritis

All patients with rheumatoid arthritis taking methotrexate must receive at least 5 mg of folic acid weekly, administered on all days except the day(s) methotrexate is taken, to reduce gastrointestinal and hepatic toxicity without compromising therapeutic efficacy. 1, 2

Standard Dosing Protocol

Methotrexate Administration

• Administer methotrexate once weekly only—never daily—as daily dosing causes significantly more liver enzyme elevations and reduced efficacy 3
• The typical starting dose ranges from 7.5-15 mg weekly, taken as a single dose or divided over 24 hours on one day per week 1

Folic Acid Supplementation Regimen

• Prescribe folic acid at a minimum of 5 mg weekly for all patients on methotrexate 1, 2
• The most practical dosing schedule is 1 mg folic acid daily (providing 7 mg/week total), skipping only the day methotrexate is taken 1, 2
• Alternative acceptable regimen: 5 mg folic acid once weekly, given 24 hours after the methotrexate dose 4
• For patients on higher methotrexate doses (>15 mg/week), consider increasing folic acid to 7-10 mg weekly 1, 2

Rationale for Timing

The critical rule is to avoid giving folic acid on the same day as methotrexate because folic acid may theoretically compete for cellular uptake of methotrexate, potentially reducing its therapeutic effect. 1

• This timing recommendation is based on the mechanism that both compounds compete for the same cellular transport systems 1
• Studies confirm that folic acid supplementation at ≤5 mg/week does not reduce methotrexate efficacy when properly timed 1, 5

Evidence for Toxicity Reduction

Gastrointestinal Protection

• Folic acid reduces GI side effects (nausea, vomiting, abdominal pain) by 26% relative risk (9% absolute risk reduction) 5
• This protection occurs without compromising disease control as measured by joint counts and disease activity scores 5, 6

Hepatic Protection

• Folic acid supplementation reduces abnormal liver enzyme elevation by 77% relative risk (16% absolute risk reduction) 5
• Daily 1 mg folic acid provides significant hepatoprotection regardless of methotrexate dose 2

Treatment Continuation

• Folic acid reduces patient withdrawal from methotrexate for any reason by 61% relative risk (15% absolute risk reduction) 5
• Continuation rates at 1-4 years reach 74-87% with folic acid supplementation, at the upper end of reported ranges 7

Important Clinical Caveats

What NOT to Do

• Never use folinic acid (leucovorin) for routine supplementation—it is more expensive and doses >5 mg/week may paradoxically reduce methotrexate efficacy (increasing tender and swollen joints) 1, 2
• Never prescribe less than 5 mg folic acid weekly—lower doses have insufficient evidence for toxicity reduction 2
• Never give folic acid on the same day as methotrexate—this may interfere with therapeutic efficacy 1

When to Increase Folic Acid Dose

• Consider increasing above 5 mg/week (up to 10-30 mg/week) if persistent GI symptoms occur despite adequate methotrexate dosing 2
• Patients on methotrexate 20-30 mg/week may benefit from proportionally higher folate supplementation 2

Monitoring Requirements

Despite folic acid supplementation, regular monitoring remains mandatory:

• First 3 months: Complete blood count, liver function tests, and creatinine at least monthly 3
• After stabilization: Complete blood count and liver function tests every 3-6 months 3
• Lack of folate supplementation is a major risk factor for hematologic toxicity, making adherence critical 1, 3

Managing Persistent Side Effects

If GI intolerance persists despite folic acid:

• Split the weekly methotrexate dose into 2-3 administrations over 24 hours (still only one day per week) 3
• Administer methotrexate with food or at bedtime 3
• Consider switching from oral to subcutaneous/intramuscular methotrexate 3
• Increase folic acid dose to 7-10 mg weekly 2

Common Pitfall to Avoid

Do not confuse routine folic acid supplementation (for prevention) with leucovorin rescue therapy (for methotrexate overdose or severe toxicity)—leucovorin is the antidote for acute toxicity and must be given immediately in overdose situations, regardless of timing concerns. 1, 3