Why Methotrexate and Folic Acid Are Given Together
Folic acid supplementation is strongly recommended for all patients on methotrexate therapy to reduce toxicity without compromising treatment efficacy. 1
Mechanism and Rationale
- Methotrexate is a folate antagonist that inhibits folate-dependent purine and pyrimidine synthesis pathways, which is part of its therapeutic mechanism but also the source of many side effects 1
- Folic acid supplementation helps replenish folate stores depleted by methotrexate, reducing adverse effects while maintaining therapeutic efficacy 1, 2
- The supplementation specifically targets the unwanted toxicity without interfering with methotrexate's beneficial anti-inflammatory effects 1, 3
Benefits of Folic Acid Supplementation
Reduction in Side Effects
- Hepatotoxicity: Folic acid significantly reduces the risk of liver enzyme elevations by up to 76.9% (relative risk reduction) 4, 5
- Gastrointestinal side effects: 26% relative risk reduction in nausea, vomiting, and abdominal pain 5
- Stomatitis and mucosal effects: Trend toward reduction in mouth sores, though not always statistically significant 5
- Overall toxicity: Reduces the likelihood of methotrexate discontinuation by 60.8% 5
Maintained Efficacy
- Multiple studies have shown that folic acid supplementation does not significantly reduce methotrexate's therapeutic efficacy in treating psoriasis or rheumatoid arthritis 1, 2, 4
- Daily folic acid supplementation appears safe and does not interfere with methotrexate's clinical benefits 2
Dosing Recommendations
- Dosage: 1-5 mg of folic acid daily is the standard recommendation 1
- Timing: Typically given daily except on the day(s) of methotrexate administration to avoid potential interference with efficacy 1
- Minimum recommendation: At least 5 mg of folic acid per week is strongly recommended by rheumatology guidelines 1
- Alternative: Folinic acid (leucovorin) can also be used but is more expensive with similar efficacy 1, 4
Important Clinical Considerations
- Folic acid is preferred over folinic acid for routine supplementation due to lower cost and similar effectiveness 1, 6
- Folinic acid should be reserved for treating acute methotrexate toxicity rather than routine prevention 1, 3
- Lack of folate supplementation is a major risk factor for methotrexate-induced hematologic toxicity 1
- The FDA drug label for methotrexate acknowledges that vitamin preparations containing folic acid may decrease responses to systemically administered methotrexate, but clinical evidence shows the benefits outweigh this theoretical concern 7, 3
Pitfalls to Avoid
- Timing error: Administering folinic acid too close to methotrexate dosing may reduce methotrexate efficacy, unlike folic acid which can be given more flexibly 2
- Underdosing: Insufficient folate supplementation may fail to prevent toxicity 1
- Discontinuation: Stopping folic acid supplementation during ongoing methotrexate therapy increases risk of adverse effects 6
- Monitoring lapse: Even with folate supplementation, regular monitoring of liver function, blood counts, and renal function remains essential 1
The evidence strongly supports that folic acid supplementation should be a standard practice for all patients receiving methotrexate therapy, as it significantly reduces toxicity without compromising therapeutic efficacy 1, 3, 4.