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Using folic acid with methotrexate in rheumatoid arthritis

Last reviewed dd mmm yyyy. Last edited dd mmm yyyy

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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

Rationale for using folic acid supplements

  • 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


  • 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)


  • 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)


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The content herein is provided for informational purposes and does not replace the need to apply professional clinical judgement when diagnosing or treating any medical condition. A licensed medical practitioner should be consulted for diagnosis and treatment of any and all medical conditions.


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