using folic acid with methotrexate in rheumatoid arthritis

Last edited 02/2023 and last reviewed 03/2023

Using folic acid with methotrexate in rheumatoid arthritis

Folate (folic acid, pteroylglutamic acid) is a water soluble vitamin that is a component of enzyme systems synthesising purines and pyrimidines.

• is essential for the normal production of white and red blood cells
  
  
• folate is synthesised by bacteria of the gastrointestinal tract
  
  
• other sources include green leafy vegetables and liver
  
  
• absorption occurs in the duodenum and jejunum
  
  
• are sufficient body stores for four months supply

• between 7 and 30% of people discontinue methotrexate in the first year due to adverse effects (1)
• incidence of adverse events is associated with reduced adherence to methotrexate
  • some of the adverse effects of methotrexate are likely to be due to folate antagonism
  • common adverse effects associated with methotrexate can be divided into:
    • minor effects (e.g. mouth ulcers and gastrointestinal disturbance such as nausea and vomiting)
    • major effects (e.g. bone marrow toxicity and liver function test abnormalities).

Methotrexate adverse effects may be prevented with folic acid supplements

• folic acid supplementation reduces the number of people who discontinue methotrexate treatment due to side effects

Folic acid regimens

Dose

• folic acid 5mg weekly, on a different day to the methotrexate dose, is the most commonly recommended regimen from clinical studies and national guidance
  • this dose should be high enough to prevent folate deficiency
  • dose can be increased to 10mg if the person experiences any adverse effects to the methotrexate

Administration relative to methotrexate

• methotrexate is a folate antagonist and there has been concern that folic acid could reduce its efficacy
• has also been suggested that folic acid may interfere with the gastrointestinal absorption of methotrexate
• folic acid supplements are usually avoided on the day of oral or subcutaneous methotrexate
• taking folic acid 48 hours prior to the methotrexate dose may give added protection against gastrointestinal adverse effects (1)

Duration

• continue folic acid supplements for as long as methotrexate therapy is continued
• risk of adverse effects with methotrexate is slightly higher in the first 6 months
• risk of any adverse effects remains throughout treatment
• long-term monitoring is therefore required (1)

Reference:

• NHS Specialist Pharmacy Service (February 2023). Using folic acid with methotrexate in rheumatoid arthritis