Methotrexate is a cornerstone medication in both rheumatology and oncology, offering targeted therapeutic action with a well-established safety profile when used appropriately. As a disease-modifying antirheumatic drug (DMARD) and chemotherapeutic agent, it works by inhibiting dihydrofolate reductase, thereby impeding DNA synthesis and cellular proliferation. This dual mechanism makes it invaluable for managing inflammatory autoimmune diseases and certain malignancies. Proper dosing, monitoring, and patient education are essential to maximize efficacy and minimize risks.

Features

• Chemical name: (2S)-2-[(4-{(2,4-diaminopteridin-6-yl)methylamino}benzoyl)amino]pentanedioic acid
• Available formulations: oral tablets (2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg), subcutaneous injection, intramuscular injection, intravenous solution
• Mechanism of action: competitive inhibitor of dihydrofolate reductase, leading to impaired synthesis of thymidine and purines
• Half-life: approximately 3–10 hours for low doses; up to 27 hours for high-dose regimens
• Bioavailability: dose-dependent, with oral absorption decreasing at doses above 15 mg/m²
• Metabolism: hepatic, partially intracellular to polyglutamated forms which prolong action
• Excretion: primarily renal (80–90%), with some biliary elimination

Benefits

• Provides significant reduction in disease activity and symptom burden in rheumatoid arthritis, psoriatic arthritis, and psoriasis
• Slows radiographic progression of joint damage in inflammatory arthritides, preserving long-term function
• Induces and maintains remission in certain hematologic and solid tumor malignancies
• Offers flexible administration routes, including convenient weekly oral dosing for chronic conditions
• Cost-effective compared to many biologic therapies, improving accessibility
• Well-studied in combination regimens, enhancing therapeutic options

Common use

Methotrexate is indicated for the management of moderate to severe rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, and severe psoriasis. In oncology, it is used for treatment of acute lymphoblastic leukemia, lymphomas, breast cancer, lung cancer, osteosarcoma, and head and neck cancers. It is also employed off-label for conditions such as Crohn’s disease, systemic lupus erythematosus, and ectopic pregnancy.

Dosage and direction

Dosage varies significantly based on indication. For autoimmune diseases: initial dose is typically 7.5 mg once weekly, titrated gradually to 15–25 mg weekly based on response and tolerance. Administer orally, subcutaneously, or intramuscularly. For oncologic use: doses range from 30–40 mg/m² weekly up to high-dose regimens of 1–12 g/m² with leucovorin rescue. Always take exactly as prescribed; weekly dosing is critical to avoid toxicity. Take with food if gastrointestinal upset occurs. Avoid concomitant folic acid antagonists unless specifically directed.

Precautions

Regular monitoring of complete blood count, liver enzymes, renal function, and serum albumin is mandatory. Use with caution in patients with impaired renal function, pre-existing liver disease, or pleural or peritoneal effusions. Avoid in patients with active infection or immunodeficiency. Vaccination with live vaccines is contraindicated. Pregnancy must be avoided during and for at least 3 months after treatment cessation in both males and females due to teratogenic risk. Sun exposure should be limited due to photosensitivity risk.

Contraindications

Hypersensitivity to methotrexate or any component of the formulation; pregnancy or breastfeeding; pre-existing blood dyscrasias; clinically significant immunodeficiency; active infectious disease; severe hepatic impairment; severe renal impairment (CrCl <30 mL/min); alcoholism or chronic liver disease; peptic ulcer disease; ulcerative stomatitis.

Possible side effect

Common: nausea, vomiting, stomatitis, diarrhea, alopecia, elevated liver enzymes, leukopenia, thrombocytopenia, rash, fatigue. Serious: myelosuppression, hepatotoxicity (fibrosis or cirrhosis), pneumonitis, severe mucositis, renal failure, opportunistic infections, neurotoxicity (with intrathecal administration), Stevens-Johnson syndrome. Long-term use may increase risk of lymphoma.

Drug interaction

NSAIDs, salicylates, proton pump inhibitors: may increase methotrexate levels and toxicity. Penicillins, sulfonamides: may enhance myelosuppression. Probenecid: decreases renal clearance of methotrexate. Retinoids, trimethoprim/sulfamethoxazole: increase risk of hepatotoxicity. Live vaccines: contraindicated due to immunosuppression. Folic acid supplements may reduce efficacy but are often co-administered to mitigate toxicity.

Missed dose

If a weekly dose is missed, take it as soon as remembered unless it is nearly time for the next dose. Do not double the dose. Contact your healthcare provider for guidance, particularly if high-dose regimens are used. Consistent timing helps maintain stable therapeutic levels.

Overdose

Overdose may cause severe myelosuppression, mucositis, renal failure, and hepatotoxicity. Leucovorin (folinic acid) rescue is imperative and should be initiated as soon as possible, ideally within 24–36 hours. Dosing of leucovorin is based on methotrexate levels and continued until levels are nontoxic. Supportive care, hydration, alkalinization of urine, and possibly dialysis may be required.

Storage

Store at room temperature (20–25°C). Protect from light and moisture. Keep in original container. Do not freeze. Keep out of reach of children and pets. Dispose of unused medication via take-back programs or according to local regulations.

Disclaimer

This information is for educational purposes and does not replace professional medical advice. Always consult a qualified healthcare provider for diagnosis, treatment decisions, and individualized dosing. Use strictly as prescribed. Report any adverse effects promptly.

Reviews

“Methotrexate has been transformative for my rheumatoid arthritis. After 6 months, my joint swelling and pain reduced dramatically. Blood monitoring is essential, but the benefits outweigh the routine checks.” – Patient, 54

“As an oncologist, I rely on high-dose methotrexate with leucovorin rescue for osteosarcoma protocols. It demands meticulous monitoring but achieves remarkable remission rates when managed correctly.” – Physician, oncology

“Initially experienced nausea, but splitting the dose and taking with food helped. My psoriasis cleared significantly within 12 weeks. Folic acid supplementation reduced side effects noticeably.” – Patient, 38