Methotrexate: Potent Immunosuppression and Disease Control
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Methotrexate is a cornerstone disease-modifying antirheumatic drug (DMARD) and antimetabolite chemotherapeutic agent with a well-established efficacy and safety profile. It functions primarily as a folate antagonist, inhibiting dihydrofolate reductase and thereby disrupting DNA synthesis, cell replication, and modulating inflammatory pathways. This dual mechanism underpins its broad utility across autoimmune, inflammatory, and oncological indications, making it a first-line therapeutic choice in numerous clinical guidelines. Its extensive history of use provides clinicians with a deep reservoir of real-world evidence to support treatment decisions.
Features
- Chemical structure: 4-amino-10-methylfolic acid analog
- Available formulations: oral tablets (2.5 mg, 5 mg, 7.5 mg, 10 mg), subcutaneous injection, intramuscular injection, intravenous solution
- Mechanism: competitive inhibition of dihydrofolate reductase, impairment of thymidylate and purine synthesis, accumulation of adenosine with anti-inflammatory effects
- Onset of action: symptomatic improvement typically observed within 3–6 weeks for rheumatic diseases
- Half-life: approximately 3–10 hours for parent drug; polyglutamated metabolites have prolonged intracellular half-life
- Metabolism: hepatic; primarily via aldehyde oxidase and minor CYP450 pathways
- Excretion: renal (80–90%)
Benefits
- Induces and maintains remission in autoimmune disorders such as rheumatoid arthritis and psoriasis
- Provides steroid-sparing effects, reducing long-term glucocorticoid toxicity
- Offers flexible dosing and administration routes tailored to individual patient needs and response
- Demonstrates cost-effectiveness compared to many biologic agents
- Supported by decades of clinical trial data and real-world outcomes
- Can be used as part of combination therapy regimens for enhanced efficacy
Common use
Methotrexate is indicated for the management of moderate to severe active rheumatoid arthritis in adults and polyarticular juvenile idiopathic arthritis. It is also approved for the treatment of severe, recalcitrant psoriasis and as part of multi-agent chemotherapeutic protocols for various malignancies, including acute lymphoblastic leukemia, non-Hodgkin lymphoma, osteosarcoma, and breast cancer. Off-label uses include Crohn’s disease, ulcerative colitis, systemic lupus erythematosus, dermatomyositis, and vasculitides such as granulomatosis with polyangiitis.
Dosage and direction
Dosage varies significantly by indication. For rheumatoid arthritis and psoriasis, initial oral doses typically range from 7.5 mg to 15 mg once weekly, titrated gradually to a maximum of 20–25 mg weekly based on efficacy and tolerability. Parenteral administration may be utilized for improved bioavailability or gastrointestinal intolerance. For oncological indications, doses are substantially higher (up to 12 g/m² or more) and require leucovorin rescue to mitigate toxicity. Administration should always be weekly, never daily, to reduce adverse effects. Patients must be instructed emphatically regarding the weekly dosing schedule to prevent fatal overdose.
Precautions
Routine monitoring is essential: complete blood count, liver function tests, and serum creatinine should be obtained at baseline, every 2–4 weeks during dose escalation, and every 8–12 weeks during maintenance. Pulmonary function should be assessed if symptoms arise. Patients should avoid alcohol consumption due to heightened hepatotoxicity risk. Live vaccines are contraindicated. Pregnancy must be avoided during and for at least 3 months after treatment cessation in both males and females due to teratogenicity. Sun exposure should be minimized due to photosensitivity risk.
Contraindications
Absolute contraindications include pregnancy, breastfeeding, pre-existing blood dyscrasias, clinically significant immunodeficiency, active infection, hypersensitivity to methotrexate or any component of the formulation, and chronic liver disease (e.g., cirrhosis, hepatitis B or C). Relative contraindications include renal impairment (dose adjustment required for CrCl <60 mL/min), pleural or peritoneal effusions, peptic ulcer disease, and history of alcohol abuse.
Possible side effect
Common adverse reactions include nausea, vomiting, stomatitis, diarrhea, alopecia, elevated transaminases, and fatigue. Myelosuppression (leukopenia, thrombocytopenia, pancytopenia) may occur. Pulmonary toxicity can manifest as interstitial pneumonitis. Hepatotoxicity ranges from transient enzyme elevations to fibrosis and cirrhosis. Renal impairment may occur with high doses. Dermatological reactions include photosensitivity, rash, and ulceration. Rare but serious effects include neurotoxicity, opportunistic infections, and lymphoma.
Drug interaction
Probenecid, NSAIDs, penicillins, and proton pump inhibitors may decrease renal clearance of methotrexate, increasing toxicity. Trimethoprim-sulfamethoxazole and other folate antagonists increase myelosuppression risk. Hepatotoxic agents (e.g., leflunomide, azathioprine) compound liver injury risk. Live vaccines are contraindicated. Protein-bound drugs may be displaced, altering free fractions.
Missed dose
If a weekly dose is missed, it should be taken as soon as remembered unless it is nearly time for the next scheduled dose. Do not double the dose. Contact a healthcare provider for guidance if unsure, particularly if the missed dose is remembered close to the next scheduled administration.
Overdose
Overdose is a medical emergency characterized by severe myelosuppression, mucositis, renal failure, and hepatotoxicity. Leucovorin (folinic acid) rescue must be initiated immediately, ideally within 24 hours, at doses proportional to methotrexate exposure. Hydration and urinary alkalinization are critical to enhance elimination. Supportive care, including granulocyte colony-stimulating factor and blood product transfusions, may be necessary. Serum methotrexate levels should be monitored serially to guide therapy.
Storage
Store at controlled room temperature (20–25°C or 68–77°F). 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; do not flush.
Disclaimer
This information is for educational purposes and does not constitute medical advice. Methotrexate is a prescription medication that must be used under direct supervision of a qualified healthcare professional. Dosage, administration, and monitoring must be individualized based on clinical status, indication, and response. Always consult with a physician for diagnosis, treatment decisions, and management of adverse effects.
Reviews
“Methotrexate remains the anchor drug in my rheumatoid arthritis treatment algorithm. Its efficacy, when dosed and monitored appropriately, is remarkable, and most patients tolerate it well with proactive management of gastrointestinal side effects.” – Rheumatologist, 15 years experience
“In pediatric oncology, high-dose methotrexate with leucovorin rescue is a challenging but critical component of curative protocols. Meticulous monitoring and supportive care are non-negotiable.” – Pediatric Oncologist, 10 years experience
“While biologics have expanded our options, methotrexate’s cost-effectiveness and versatility keep it foundational in dermatology for severe psoriasis. The weekly dosing improves adherence compared to daily regimens.” – Dermatologist, 12 years experience
“The teratogenic potential requires rigorous patient education and contraceptive counseling. We use a structured consent process to ensure understanding before initiation.” – Clinical Pharmacist, 8 years experience