Rationale for using folic acid supplements
Between 7 and 30% of people discontinue methotrexate in the first year due to adverse effects. The 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.
The 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.
The dose should be high enough to prevent folate deficiency. The dose can be increased to 10mg if the person experiences any adverse effects to the methotrexate.
No evidence was identified to support increasing the dose beyond 10mg.
Use of folic acid to reduce adverse effects is off-label.
Administration relative to methotrexate
Methotrexate is a folate antagonist and there has been concern that folic acid could reduce its efficacy. It 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.
Continue folic acid supplements for as long as methotrexate therapy is continued.
The risk of adverse effects with methotrexate is slightly higher in the first 6 months. The risk of any adverse effects remains throughout treatment. Long-term monitoring is therefore required.
National guidance dose recommendations
Several sources of national guidance advocate use of a 5mg weekly dosing schedule. The recommendations are based on limited clinical evidence.
BNF and NICE CKS
British National Formulary (BNF) and National Institute for Health and Care Excellence Clinical Knowledge Summary (NICE CKS) for monitoring of DMARDS recommend folic acid 5mg once weekly, taken on a different day to the methotrexate, is routinely co-prescribed with methotrexate to reduce adverse effects and toxicity.
British Society for Rheumatology
British Society for Rheumatology (BSR) guideline for non-biologic disease-modifying anti-rheumatic drug therapy recommends a minimum folic acid dose of 5mg once weekly but does not specify when it should be taken in relation to methotrexate.
Several national and international guidelines on the management of rheumatoid arthritis e.g., National Institute for Health and Care Excellence (NICE), Scottish Intercollegiate Guidelines Network (SIGN), European League Against Rheumatism and the American College of Rheumatology advise on methotrexate’s place in therapy but do not discuss folic acid supplementation.
Alternative dosing schedules
Large randomised controlled trials are not available to inform the optimal dosing of folic acid to prevent side effects from methotrexate. Doses other than 5mg weekly have been investigated in small clinical studies. There may be situations when patients or clinicians wish to use folic acid dosing which deviates from standard dosing schedules, for example, continuing side effects, patient choice and preference.
Doses used in clinical studies
The best clinical study data has been presented below which can be used to guide clinical decisions on alternative dosing schedules.
Folic acid 10mg or 30mg weekly
A double-blind, randomized, controlled trial of 100 patients for 24 weeks assessed incidence of toxicity and change in disease activity and found there was no additional benefit or harm from using the higher dose.
Folic acid 30mg weekly
A multicentre, cross-sectional, observational study included 240 patients who received either folic acid 5mg or 30mg weekly. Disease activity was statistically significantly lower for the 5mg group but there was no significant difference in adverse effects or tolerability between the groups.
Folic acid 5mg twice weekly or folic acid 1mg daily
A non-inferiority study of patients that compared folic acid 5mg twice weekly or weekly with folic acid 1mg daily found no statistically significant difference in effects on liver enzymes, but weekly dosing resulted in reduced protection against gastrointestinal adverse effects.
Folic acid 1mg daily
A 48 week, randomized, placebo-controlled, multi-centre trial of 434 patients found folic acid 1mg reduced the incidence of elevated liver enzyme levels.
Folic acid 1mg or 5.5mg daily for 5 days avoiding methotrexate day
A randomized, double-blind placebo-controlled trial of 79 patients found a statistically significantly higher toxicity scores (duration, intensity and severity) for the placebo group compared with the low and high dose folic acid groups. Both folic acid regimens decreased methotrexate toxicity without compromising efficacy.
Folic acid 5mg daily long term (1 year)
A prospective, randomized, double-blind, placebo-controlled study of 75 patients found folic acid 5mg daily long-term use (1 year) reduced discontinuation of methotrexate due to mouth ulcers, nausea, vomiting and low neutrophil counts.
Licence and supply
Folic acid is not licensed to prevent adverse effects from methotrexate. Use for this indication is off-label.
Folic acid should be supplied on prescription. It is often found in multivitamins sold by pharmacies and supermarkets but these are unlikely to contain an adequate amount of folic acid to prevent side effects caused by methotrexate.
Information for patients
Refer patients to the following NHS information leaflets for further information:
Bramley D. What dose of folic acid to use with methotrexate in rheumatoid arthritis? Drug and Therapeutics Bulletin. July 2021; 59 (7): p103-106.