From the Guidelines
Folic acid supplementation is strongly recommended for patients taking methotrexate for rheumatoid arthritis, with a standard recommendation of at least 5 mg/week, as it significantly reduces methotrexate-related adverse effects without compromising therapeutic efficacy. The most recent and highest quality study, published in 2021 1, found that concurrent supplementation with folic acid or folinic acid significantly reduces many adverse effects associated with methotrexate use, including gastrointestinal, hepatotoxic, mucocutaneous, and hematological effects. This study also highlighted that folic acid supplementation may reduce the incidence of gastrointestinal side effects, protect against elevated liver function tests, and reduce the likelihood of drug discontinuation.
Key points to consider when implementing folic acid supplementation include:
- Starting folic acid supplementation when beginning methotrexate therapy and continuing it for the duration of methotrexate treatment
- Taking folic acid at a dose of at least 5 mg/week, with some studies suggesting that higher doses may be more effective in reducing adverse effects
- Avoiding taking folic acid on the same day as methotrexate to minimize potential interactions and maintain therapeutic efficacy
- Monitoring patients for potential adverse effects and adjusting the folic acid dose as needed to minimize toxicity
Overall, the evidence supports the use of folic acid supplementation as a safe and effective strategy to reduce methotrexate-related adverse effects in patients with rheumatoid arthritis, and healthcare providers should prioritize this recommendation to improve patient outcomes and quality of life.
From the FDA Drug Label
Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate
- Folic acid supplementation may decrease the effectiveness of methotrexate in patients with rheumatoid arthritis.
- It is recommended to exercise caution when using folic acid supplements with methotrexate, as it may reduce the drug's efficacy 2.
From the Research
Folic Acid Supplementation with Methotrexate in Rheumatoid Arthritis
- Folic acid supplementation has been shown to reduce the incidence of gastrointestinal side effects, hepatic dysfunction, and patient withdrawal from methotrexate treatment in patients with rheumatoid arthritis 3, 4, 5.
- The evidence suggests that folic acid supplementation can reduce the risk of gastrointestinal side effects by 26% and hepatic dysfunction by 76.9% 3, 4.
- Folic acid supplementation has also been shown to reduce patient withdrawal from methotrexate treatment by 60.8% 3, 4.
- There is no significant difference in the efficacy of methotrexate treatment between patients receiving folic acid supplementation and those receiving placebo 3, 4, 5.
- The optimal dosage of folic acid supplementation is not established, but a daily dosage of 1.25 mg has been shown to be effective in reducing methotrexate toxicity without affecting its efficacy 6.
- Clinical practice guidelines recommend routine folic acid supplementation for patients treated with methotrexate for rheumatoid arthritis, with a minimal dosage of 5 mg of folic acid once a week 7.
Benefits of Folic Acid Supplementation
- Reduction in gastrointestinal side effects such as nausea, vomiting, and abdominal pain
- Reduction in hepatic dysfunction as measured by elevated serum transaminase levels
- Reduction in patient withdrawal from methotrexate treatment
- Potential reduction in mouth sores, although the evidence is not statistically significant
Dosage and Administration
- Daily dosage of 1.25 mg of folic acid has been shown to be effective in reducing methotrexate toxicity without affecting its efficacy
- Weekly dosage of 5 mg of folic acid is recommended as a minimal dosage for routine supplementation
- Folic acid supplementation should be taken at a distance from the methotrexate dose to minimize interactions.