Usage
Folic acid is prescribed alongside methotrexate to mitigate methotrexate’s adverse effects, particularly in the treatment of rheumatoid arthritis and other autoimmune diseases. Methotrexate, an antimetabolite and antifolate drug, is used to treat certain cancers, autoimmune conditions (rheumatoid arthritis, psoriasis, lupus), and ectopic pregnancies. Folic acid supplementation does not interfere with methotrexate’s efficacy in treating these conditions. However, in the case of cancer treatment, folic acid may reduce the efficacy of methotrexate, so it’s generally avoided unless specifically prescribed by an oncologist.
Alternate Names
- Folic Acid: Folate, Vitamin B9
- Methotrexate: amethopterin, MTX
- Brand names: Rheumatrex, Trexall, Otrexup, Rasuvo
How It Works
Methotrexate is a folate antimetabolite that inhibits dihydrofolate reductase (DHFR), thereby disrupting DNA, RNA, and protein synthesis. This inhibition primarily affects rapidly dividing cells, such as those involved in immune responses and cancer growth. Its anti-inflammatory effects are partly mediated by increased adenosine release.
Pharmacokinetics: Methotrexate is absorbed variably following oral administration. It undergoes hepatic metabolism and is primarily excreted renally. High doses can exhibit nonlinear pharmacokinetics due to saturable renal clearance. Dose adjustments may be necessary in renal impairment.
Folic acid supplementation counteracts the adverse effects of methotrexate by providing the body with the folate it needs to carry out essential cellular processes unaffected by methotrexate. This reduces the risk of side effects related to folate deficiency. It does not affect the therapeutic effect of methotrexate when used to treat autoimmune conditions, due to different mechanisms.
Dosage
Standard Dosage
Adults:
- Methotrexate: 7.5-25 mg orally or subcutaneously ONCE weekly for rheumatoid arthritis and other autoimmune conditions. For cancers, the dosage and schedule vary based on the specific type and stage of cancer.
- Folic Acid: 5-10mg orally ONCE weekly, taken on a different day than methotrexate, often 2-3 days after the methotrexate dose. Daily doses may be used, usually at a lower dosage (e.g. 1mg daily), starting the day after the weekly methotrexate dose.
Children:
Methotrexate dosing in children is weight-based and should be determined by a specialist. Folic acid supplementation is also recommended.
Special Cases:
- Elderly Patients & Patients with Renal/Hepatic Impairment: Lower starting doses and slower titration are advised. Dose adjustments are crucial in renal impairment.
- Patients with Comorbid Conditions: Individualized dosing is necessary considering the specific comorbidity.
Clinical Use Cases
Methotrexate and folic acid combination is primarily prescribed chronically for autoimmune conditions such as rheumatoid arthritis and psoriasis. Their use in settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations is not routine. Methotrexate is however sometimes used in high doses for cancer treatment, which would also require close monitoring and might necessitate a dose adjustment for folic acid.
Dosage Adjustments
Dose adjustments are required for renal and hepatic impairment, and potentially for other comorbid conditions. Genetic polymorphisms affecting drug metabolism should be considered.
Side Effects
Common Side Effects:
Nausea, vomiting, diarrhea, mouth sores, fatigue, headache, hair loss.
Rare but Serious Side Effects:
Bone marrow suppression, hepatotoxicity, pulmonary toxicity, nephrotoxicity.
Long-Term Effects:
Liver cirrhosis (with prolonged use), increased risk of infections.
Adverse Drug Reactions (ADR):
Severe bone marrow suppression, anaphylaxis, Stevens-Johnson syndrome.
Contraindications
Pregnancy, breastfeeding, alcoholism, severe liver or kidney disease, blood dyscrasias, immunodeficiency.
Drug Interactions
NSAIDs, antibiotics (penicillins, sulfonamides, trimethoprim/sulfamethoxazole), proton pump inhibitors, probenecid, other antifolates, hepatotoxic or nephrotoxic drugs, nitrous oxide, alcohol.
Pregnancy and Breastfeeding
Methotrexate is contraindicated in pregnancy and breastfeeding. Both male and female patients should use effective contraception during and for at least 3 months after methotrexate treatment.
Drug Profile Summary
- Mechanism of Action: Methotrexate: DHFR inhibitor, disrupting DNA/RNA/protein synthesis. Folic acid: Provides folate to mitigate methotrexate’s side effects.
- Side Effects: Nausea, vomiting, mouth sores, fatigue; rarely, bone marrow suppression, hepatotoxicity.
- Contraindications: Pregnancy, breastfeeding, liver/kidney disease, blood dyscrasias.
- Drug Interactions: NSAIDs, antibiotics, proton pump inhibitors.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Methotrexate 7.5-25mg weekly; folic acid 5-10mg weekly (or 1mg daily).
- Monitoring Parameters: CBC, LFTs, renal function.
Popular Combinations
Methotrexate is often combined with other DMARDs, especially biologics, in treating rheumatoid arthritis.
Precautions
Monitor for hepatotoxicity, bone marrow suppression, and pulmonary toxicity. Avoid alcohol. Contraception is crucial during treatment.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Folic Acid + Methotrexate?
A: Methotrexate: 7.5-25 mg weekly; Folic acid: 5-10mg weekly, or 1mg daily, taken on a different day from methotrexate.
Q2: How does folic acid mitigate methotrexate side effects?
A: Folic acid provides the body with folate, bypassing the block caused by methotrexate, thus reducing side effects associated with folate deficiency.
Q3: Can folic acid be taken on the same day as methotrexate?
A: Generally, it’s recommended to take folic acid on a different day to avoid potential interference with GI absorption, although this is debated, with some guidelines allowing daily folic acid dosing and beginning the day after the methotrexate dose.
Q4: What are the contraindications for methotrexate?
A: Pregnancy, breastfeeding, severe liver/kidney disease, blood disorders, immunodeficiency, alcoholism.
Q5: Is methotrexate safe during pregnancy?
A: No, methotrexate is contraindicated in pregnancy due to the risk of serious birth defects.
Q6: What monitoring is required for patients on methotrexate?
A: Regular blood tests (CBC, LFTs, renal function) are essential to monitor for side effects.
Q7: Does folic acid interfere with the efficacy of methotrexate in rheumatoid arthritis?
A: No, folic acid supplementation does not impact methotrexate’s therapeutic effectiveness against RA.
Q8: What should be done if a patient accidentally takes methotrexate daily instead of weekly?
A: Contact a poison control center or seek immediate medical attention, as this can cause serious toxicity.
Q9: Are there any dietary restrictions while taking methotrexate?
A: Excessive alcohol consumption should be avoided. Limiting or avoiding foods rich in milk with Methotrexate might also be advised, especially for cancer patients.
Q10: What are the key drug interactions to be aware of with methotrexate?
A: NSAIDs, certain antibiotics (like trimethoprim/sulfamethoxazole), proton pump inhibitors, and nephrotoxic agents can interact with methotrexate, increasing the risk of adverse effects.
