Does Folic Acid Reduce the Toxicity of Methotrexate?

Joanna Pangilinan, PharmD, BCOP


February 19, 2009

Should folic acid or folinic acid be given to patients receiving long-term, low-dose methotrexate for rheumatoid arthritis?

Response from Joanna Pangilinan, PharmD, BCOP
Pharmacist, Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor, Michigan

Methotrexate (MTX) inhibits dihydrofolate reductase, resulting in a decreased supply of folates. In high doses, MTX inhibits purine and pyrimidine synthesis, rendering it useful for many malignancies. In low doses (< 20 mg/week), MTX is commonly used as a disease-modifying antirheumatic drug and is indicated for treatment of rheumatoid arthritis (RA).[1] MTX's mechanism of action for this indication is unclear. Efficacy of low-dose MTX may ultimately be the result of anti-inflammatory,[1] immunosuppressant, or immunotoxic effects.[2]

Adverse effects of low-dose MTX in patients with RA are related to folate antagonism and/or folate deficiency. Folate supplementation, in the form of folic acid or folinic acid, is often coadministered with MTX to minimize adverse effects (eg, stomatitis, gastrointestinal intolerance, bone marrow toxicity, and abnormal liver function tests).[1]

Studies have examined the effectiveness of folate supplementation in decreasing adverse effects associated with low-dose MTX. A Cochrane Review evaluated 7 randomized, double-blind, placebo-controlled trials that assessed whether folinic acid or folic acid decreased side effects of MTX in patients with RA. Both folinic acid and folic acid were found to decrease gastrointestinal and mucosal side effects. The use of folinic acid, however, may not be cost-effective unless pharmacoeconomics studies find it to be more clinically effective than the less expensive folic acid.[3]

A recent study by van Ede and colleagues[4] evaluated the effect of folate supplementation on MTX-induced adverse effects in patients with RA. Folic acid was dosed at 1 mg daily and folinic acid was dosed at 2.5 mg weekly; doses were doubled if the MTX dose reached 15 mg weekly. Folate supplementation decreased the incidence of elevated liver enzymes compared with placebo. However, folate supplementation was not shown to decrease gastrointestinal or mucosal side effects. Hoekstra and colleagues[5] found that patients on folate supplementation remained on therapy longer, resulting in "MTX survival" and more durable control of RA symptoms.

While some studies suggest MTX efficacy is not compromised by folate supplementation,[3,4] results of a post hoc analysis[6] advised caution[7] and suggested folic acid supplementation may decrease MTX efficacy. Folic acid supplementation[4] and dietary fortification with folic acid[8] may increase MTX dosage requirements.

Total weekly folic acid doses in the range of 5-27.5 mg have demonstrated efficacy in decreasing MTX adverse effects. Weekly vs daily schedules have not been compared.[1] Whittle and Hughes[1] recommend the "pragmatic" use of folic acid 5 mg once weekly taken the morning after MTX dosing, with a possible dose increase to 10 mg if adverse reactions continue. Others suggest that prophylactic folate supplementation should be reserved for those who have an increased demand for folate, such as during infection or antibiotic treatment.[9] If folic acid is initiated, evidence suggests that it should continue long-term in order to prevent MTX discontinuation due to adverse effects.[10]

A consensus for folic acid or folinic acid dosing or administration does not exist, and the decision to initiate supplementation is physician-dependent. Folate supplementation may reduce low-dose MTX adverse effects and prevent earlier discontinuation of therapy, potentially allowing for a more durable response to MTX. Clinicians should consider that folic acid supplementation may have the additional benefit of cardiovascular protection[11] due to its ability to prevent MTX-induced hyperhomocysteinemia.[2,11]


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