Methotrexate Treatment : Dose of Folic Acid

Availability in Hospital Keningau:

• T. Methotrexate 2.5mg 
• T. Folic Acid 5mg
• T. Obimin (Contain 1mg FA)
• T. Zincofer (Contain 1mg FA)

Need of Folate Supplementation

• Methotrexate is a first line disease-modifying-anti-rheumatic-drug (DMARD) for rheumatoid arthritis
• Administered in low doses, methotrexate inhibits a number of folate dependent metabolic steps, including a very potent inhibition of dihydrofolate reductase which reduces folic acid to dihydrofolic acid and to tetrahydrofolate thus causes a depleted pool of reduced folates and produces a state of effective folate deficiency.
• The British Society for Rheumatology states that regular folic acid supplements are thought to reduce toxicity of methotrexate
• But there has been much controversy regarding the dose of supplementation and whether it has benefit on toxicity without being detrimental to methotrexate efficacy

Dose Selection

• Meta-analysis shown that concurrently supplementation of low dose folic acid (<5mg/week) in low dose methotrexate (<20mg/week) achieved a 79% reduction of mucosal and gastrointestinal side-effects (p < 0.0001). 
• There were no major differences between low and high doses of folic acid (p = 0.17).
• Other studies have not found any significant difference in efficacy of methotrexate whether given with or without folate supplements.
• The potential of folic acid interfering with the gastro-intestinal absorption of methotrexate is a matter of controversy, but this possibility may be overcome by administration of folic acid 24 hours prior to the weekly methotrexate dose.
• The British Society for Rheumatology guidelines for disease modifying anti-rheumatic drug therapy recommends a typical folic acid dose of 5mg once weekly, preferably the day after the methotrexate.

Recommendation:

• Based on the evidence, 5mg of folic acid weekly is sufficient enough to benefit on reducing methotrexate toxicity.
• Preferably not to consume on methotrexate day which may reduce the effectiveness and efficacy of methotrexate.
• In other hand, prescribing with 5mg folic acid weekly may reduce the cost of medication and improve the compliancy.

References:

1. Ortiz Z, Shea B, Suarez-Almazor ME, Moher D, Wells GA, Tugwell P.  Folic Acid and Folinic Acid for Reducing Side-Effects in Patients Receiving Methotrexate for Rheumatoid Arthritis (Review).  Cochrane Review 2009
2. Ortiz Z, Shea B, Suarez-Almazor M E et al.  The Efficacy of Folic Acid and Folinic Acid in Reducing Methotrexate Gastrointestinal Toxicity in Rheumatoid Arthritis.  A Meta-analysis of Randomized Controlled Trials.  J Rheum 1998; 25 (1): 36 – 43
3. https://www.sps.nhs.uk/articles/what-is-the-dose-of-folic-acid-to-use-with-methotrexate-therapy-for-rheumatoid-arthritis/
4. https://academic.oup.com/rheumatology/article/43/3/267/1774685