From the Guidelines
Folic acid supplementation is strongly recommended for patients taking methotrexate to reduce side effects, and it should be taken daily, except for the days when methotrexate is given, to avoid influencing efficacy. The typical recommendation is 1-5 mg of folic acid daily, with many rheumatologists prescribing 1 mg daily or 5 mg once weekly (typically taken 24-48 hours after the methotrexate dose) 1. Folic acid supplementation helps prevent common methotrexate side effects such as nausea, mouth sores, hair thinning, fatigue, and liver enzyme elevations by replenishing folate stores that methotrexate depletes. Methotrexate works by inhibiting dihydrofolate reductase, an enzyme involved in folate metabolism, which can lead to folate deficiency.
Some key points to consider when prescribing folic acid supplementation with methotrexate include:
- Folic acid or folinic acid has been reported to decrease hepatic laboratory abnormalities and GI adverse effects in patients with rheumatoid arthritis 1
- There is no difference in efficacy between folinic acid and folic acid, but folic acid is less expensive 1
- The routine use of liver biopsy for monitoring MTX hepatotoxicity is not recommended, instead, monitoring of LFTs and PIIINP at least every 3 months is recommended 1
- Reduction in MTX dosage should be considered in those with suboptimal renal function < 20 mL min1 1
Without folic acid supplementation, patients are more likely to discontinue methotrexate due to intolerable side effects, potentially missing out on an effective treatment for their condition. The most recent and highest quality study recommends folic acid supplementation to decrease the rate of adverse effects associated with methotrexate therapy 1.
From the FDA Drug Label
Leucovorin calcium is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent over dosages of folic acid antagonists.
The use of methotrexate without folic acid supplementation is not recommended, as folic acid deficiency can occur. However, in cases where methotrexate is taken without folic acid, leucovorin calcium can be used to counteract the effects of impaired methotrexate elimination and diminish toxicity 2.
- Key points:
- Leucovorin calcium can be used to rescue after high dose methotrexate therapy.
- Leucovorin calcium is indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination.
From the Research
Folic Acid Supplementation with Methotrexate
- Methotrexate is often prescribed with folic acid supplementation to reduce side effects and toxicity, as seen in studies 3, 4, 5, 6, 7.
- The use of folic acid supplementation during methotrexate therapy reduces both toxicity and side effects without compromising efficacy, according to research 5, 7.
- Folic acid should be used daily with methotrexate to ameliorate side effects, whereas folinic acid should only be used for methotrexate toxicity, as suggested by a study 3.
Recommendations for Folic Acid Supplementation
- Folate supplementation should be routinely prescribed to every patient taking low-dose methotrexate, as recommended by a review 4.
- Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during long-term, low-dose methotrexate therapy for rheumatoid arthritis, as found in a trial 6.
- Supplementation with folic acid is an effective measure to reduce hepatic adverse effects associated with methotrexate treatment, with no difference between folinic acid and folic acid, but the lower cost of the latter promotes its use, according to a systematic review 7.
Cases Where Methotrexate is Taken Without Folic Acid
- There are cases where methotrexate is taken without folic acid, but this is not recommended due to the increased risk of side effects and toxicity, as seen in studies 4, 6.
- Without folic acid supplementation, methotrexate therapy can lead to deficient blood folate levels and hyperhomocysteinemia, which can increase the risk of cardiovascular disease, as found in a trial 6.