INFO - Medscape: Folic acid or folinic acid with methotrexate

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Medscape.com

Posted: 19 Feb 2009

Question

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 [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.

http://www.medscape.com/viewarticle/588229

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