Methotrexate

Methotrexate is a cornerstone disease-modifying antirheumatic drug (DMARD) and antimetabolite chemotherapeutic agent with established efficacy across multiple clinical domains. As a folate antagonist, it exerts its therapeutic effects through competitive inhibition of dihydrofolate reductase, thereby impeding DNA synthesis and cellular replication. This mechanism underpins its utility in managing proliferative and inflammatory disorders, offering a balance of potency and manageability under appropriate medical supervision. Its longstanding use is supported by extensive clinical evidence and well-characterized safety protocols.

Features

• Chemical structure: 4-amino-10-methylfolic acid analog
• Available formulations: oral tablets, subcutaneous injections, intravenous solutions
• Mechanism: competitive dihydrofolate reductase inhibition
• Bioavailability: dose-dependent, approximately 60% for lower oral doses
• Half-life: 3–10 hours (dose-dependent), with prolonged tissue retention
• Metabolism: hepatic, via aldehyde oxidase and cytochrome P450 system
• Excretion: primarily renal (80–90%)

Benefits

• Induces remission and suppresses disease activity in rheumatoid arthritis and psoriasis
• Reduces dependency on corticosteroids and associated adverse effects
• Provides flexible dosing regimens adaptable to individual patient tolerance and indication
• Cost-effective compared to many biologic agents
• Demonstrated efficacy in maintaining long-term disease control
• May be used as part of combination therapy in oncology protocols

Common use

Methotrexate is indicated for the management of moderate to severe rheumatoid arthritis, juvenile idiopathic arthritis, and severe, recalcitrant psoriasis. It is also employed in the treatment of certain neoplastic conditions, including acute lymphoblastic leukemia, non-Hodgkin lymphoma, and osteosarcoma. Off-label uses include Crohn’s disease, systemic lupus erythematosus, and ectopic pregnancy management. Selection of methotrexate therapy should be guided by comprehensive diagnostic evaluation and risk-benefit assessment.

Dosage and direction

Dosage varies significantly by indication. For autoimmune conditions: initial oral doses typically range from 7.5–15 mg weekly, titrated gradually to a maximum of 20–25 mg weekly based on clinical response and tolerability. For oncological use: doses range from 10–12,000 mg/m², administered intravenously or intramuscularly under strict clinical supervision. Administration should occur on the same day each week. Folic acid supplementation (1–5 mg daily, excluding methotrexate day) is strongly recommended to mitigate toxicity.

Precautions

Regular monitoring of complete blood count, renal function, and liver enzymes is mandatory. Avoid use in patients with significant renal impairment (CrCl <60 mL/min). Exercise caution in patients with hepatic dysfunction, pleural effusions, or ascites. Patients should be advised to avoid alcohol consumption and NSAIDs during therapy. Vaccination with live vaccines is contraindicated. Pregnancy must be excluded before initiation, and effective contraception is required during and after treatment.

Contraindications

Absolute contraindications include pregnancy, breastfeeding, pre-existing blood dyscrasias, clinically significant immunodeficiency, active infection, and hypersensitivity to methotrexate or any component of the formulation. Relative contraindications include peptic ulcer disease, ulcerative colitis, and pre-existing hepatic or renal disease. Concurrent use with other hepatotoxic or myelosuppressive agents requires extreme caution.

Possible side effect

Common adverse effects include nausea, vomiting, stomatitis, fatigue, and alopecia. Myelosuppression (leukopenia, thrombocytopenia, anemia) may occur and is dose-dependent. Hepatotoxicity ranges from transient transaminase elevations to fibrosis and cirrhosis. Pulmonary toxicity includes pneumonitis and fibrosis. Renal impairment, dermatological reactions, and neurological symptoms (e.g., headache, dizziness) have been reported. Long-term use may increase infection risk and rarely cause lymphoproliferative disorders.

Drug interaction

Methotrexate interacts significantly with probenecid, NSAIDs, salicylates, and sulfonamides, which may reduce renal clearance and increase toxicity. Penicillins and proton pump inhibitors may similarly elevate methotrexate levels. Concurrent use with other myelosuppressive or hepatotoxic agents (e.g., leflunomide, azathioprine) requires careful monitoring. Trimethoprim-sulfamethoxazole increases the risk of bone marrow suppression.

Missed dose

If a weekly dose is missed, administer as soon as remembered unless the next scheduled dose is within 2 days. Do not double the dose. Consult the prescribing physician for specific guidance, particularly for high-dose regimens. Maintaining a consistent dosing schedule is critical for efficacy and safety.

Overdose

Overdose may manifest as myelosuppression, mucositis, renal failure, or neurotoxicity. Leucovorin (folinic acid) rescue is the cornerstone of management and should be initiated as soon as possible—typically within 24–36 hours of methotrexate administration. Dosing is based on methotrexate levels and clinical status. Supportive care, hydration, and alkalinization of urine may be necessary. Immediate medical attention is required.

Storage

Store at controlled room temperature (20–25°C). Protect from light and moisture. Keep oral and injectable forms in their original packaging. Do not freeze. Keep out of reach of children and pets. Dispose of unused or expired medication via take-back programs or following local guidelines—do not flush.

Disclaimer

This information is intended for educational purposes and does not replace professional medical advice, diagnosis, or treatment. Always consult a qualified healthcare provider for personalized recommendations. Dosage, administration, and monitoring must be supervised by a clinician experienced in methotrexate use. Individual patient factors may necessitate adjustments to therapy.

Reviews

Clinical studies and meta-analyses consistently demonstrate methotrexate’s efficacy in reducing disease activity and structural progression in rheumatoid arthritis, with ACR50 response rates of 60–70% at 6–12 months. In psoriasis, PASI75 achievement is reported in approximately 40–50% of patients. Oncology protocols show significant remission rates in ALL and lymphoma. Long-term safety data support its use with appropriate monitoring, though adherence to guidelines is critical for minimizing risks.