Overview
Methotrexate is a folate antagonist antimetabolite used as a disease-modifying antirheumatic drug (DMARD) for autoimmune conditions and as chemotherapy for malignancies. It works by inhibiting dihydrofolate reductase, interfering with DNA synthesis and cellular replication. The drug requires careful monitoring due to significant toxicity risks including hepatotoxicity, myelosuppression, and pulmonary toxicity.
Mechanism of Action
Methotrexate competitively inhibits dihydrofolate reductase, the enzyme that converts dihydrofolate to tetrahydrofolate. This depletion of tetrahydrofolate cofactors impairs thymidylate and purine synthesis, thereby inhibiting DNA, RNA, and protein synthesis, particularly in rapidly dividing cells.
Indications
- Rheumatoid arthritis
- Psoriasis
- Polyarticular juvenile idiopathic arthritis
- Certain malignancies including acute lymphoblastic leukemia, non-Hodgkin lymphoma, osteosarcoma, breast cancer, head and neck cancer, lung cancer, and gestational trophoblastic neoplasia
Common Doses
- 2.5 mg tablets
- 5 mg tablets
- 7.5 mg tablets
- 10 mg tablets
- 15 mg tablets
- Injectable: 25 mg/mL
- Powder for injection: 1 g/vial
Dosage
Dosage varies significantly by indication: For rheumatoid arthritis, typical starting dose is 7.5 mg once weekly, which may be increased gradually. For psoriasis, 10-25 mg once weekly. For malignancies, doses range from moderate (30-40 mg/m² weekly) to high (up to 12 g/m²) with leucovorin rescue. Always administered as a single weekly dose, never daily.
Black Box Warning
Black Box Warning: Methotrexate can cause severe, sometimes fatal, toxicities including myelosuppression, hepatotoxicity, pulmonary toxicity, renal toxicity, and gastrointestinal toxicity
Contraindications
- Pregnancy in patients with non-neoplastic diseases
- History of severe hypersensitivity reactions including anaphylaxis to methotrexate
Side Effects
- Myelosuppression (leukopenia, thrombocytopenia, anemia, pancytopenia)
- Gastrointestinal toxicity (nausea, vomiting, diarrhea, stomatitis, mucositis)
- Hepatotoxicity (elevated liver enzymes, cirrhosis)
- Pulmonary toxicity (interstitial pneumonitis, pulmonary fibrosis)
- Dermatologic reactions (rash, photosensitivity, alopecia)
- Renal toxicity
- Neurotoxicity
- Increased risk of infections
Interactions
- NSAIDs, salicylates, and other nephrotoxic drugs may increase methotrexate toxicity
- Probenecid reduces renal clearance of methotrexate
- Trimethoprim-sulfamethoxazole and other folate antagonists may increase toxicity
- Live vaccines are contraindicated
- Alcohol increases risk of hepatotoxicity
Counseling Points
- Take only once weekly as directed - never daily
- Report signs of infection, unusual bleeding, shortness of breath, or severe gastrointestinal symptoms immediately
- Avoid alcohol consumption
- Use effective contraception during treatment and for at least 3 months after discontinuation
- Protect from sun exposure due to photosensitivity risk
- Keep all follow-up appointments for laboratory monitoring