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# METHOTREXATE
## Overview
Methotrexate is a folic acid antagonist that inhibits DNA synthesis, repair, and cellular replication. It is used as an antimetabolite in oncology and as an immunosuppressant in rheumatology and dermatology.
## Primary Indications
* **Oncology:** Acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL), osteosarcoma, choriocarcinoma, breast cancer, head and neck cancer, lung cancer.
* **Rheumatology:** Rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis.
* **Dermatology:** Psoriasis.
## Adult Dosing
Dosing is highly variable and depends on the indication, disease stage, and patient-specific factors.
* **Oncology:** Doses range from low-dose (e.g., 40 mg/m² IV weekly for ALL) to high-dose (e.g., 12 g/m² IV over 24 hours for osteosarcoma) with leucovorin rescue.
* **Rheumatoid Arthritis/Psoriatic Arthritis:** Typically 10-25 mg orally or intramuscularly once weekly. Maximum weekly dose usually 30 mg.
* **Psoriasis:** Typically 10-25 mg orally or intramuscularly once weekly. Maximum weekly dose usually 30 mg.
## Pediatric Dosing
Dosing is highly variable and depends on the indication, disease stage, and patient-specific factors.
* **ALL:** Doses range from 1000 mg/m² IV over 24 hours with leucovorin rescue to intrathecal doses of 10-15 mg.
* **Juvenile Idiopathic Arthritis:** Typically 10-15 mg/m² orally or intramuscularly once weekly. Maximum weekly dose usually 20 mg/m².
## Dose Adjustments
* **Renal Impairment:** Dose reduction is crucial. Consult specific guidelines or renal function-based dosing nomograms, especially for high-dose regimens.
* **Hepatic Impairment:** Use with caution. May require dose reduction or discontinuation.
* **Elderly:** Increased risk of toxicity. Initiate at lower doses and monitor closely.
## Contraindications
* Hypersensitivity to methotrexate.
* Severe renal impairment.
* Severe hepatic impairment.
* Pre-existing severe bone marrow suppression.
* Active infection.
* Immunodeficiency syndromes.
* Pregnancy and breastfeeding.
## Adverse Effects
Common adverse effects include stomatitis, nausea, vomiting, diarrhea, alopecia, fatigue, and myelosuppression. Severe adverse effects can include hepatotoxicity, nephrotoxicity, pneumonitis, neurotoxicity (especially with intrathecal administration), and severe mucositis.
## Key Drug Interactions
* **NSAIDs:** Can increase methotrexate levels and toxicity, particularly with high-dose methotrexate. Discontinue NSAIDs before and during high-dose methotrexate therapy. Use with caution in patients on low-dose methotrexate.
* **Sulfonamides (e.g., trimethoprim/sulfamethoxazole):** Can increase methotrexate levels and toxicity.
* **Probenecid:** Can increase methotrexate levels.
* **Live Vaccines:** Avoid concomitant use due to increased risk of disseminated infection.
* **Omeprazole:** May increase methotrexate levels.
## Monitoring
* **Complete Blood Count (CBC) with differential and platelet count:** Weekly for low-dose, more frequently for high-dose.
* **Renal function (BUN, creatinine):** Before and during therapy.
* **Hepatic function tests (AST, ALT, bilirubin):** Before and during therapy.
* **Mucosal examination:** For stomatitis.
* **Pulmonary symptoms:** For pneumonitis.
* **Methotrexate levels:** Crucial for high-dose regimens to guide leucovorin rescue and hydration.
## Clinical Pearls
* **Leucovorin Rescue:** Essential for high-dose methotrexate regimens to "rescue" normal cells from the toxic effects of methotrexate.
* **Hydration and Alkalinization:** Crucial for high-dose methotrexate to prevent precipitation in renal tubules and enhance excretion.
* **Folic Acid Supplementation:** Standard practice for patients on low-dose methotrexate for rheumatologic or dermatologic conditions to reduce toxicity. Do not give folic acid during high-dose therapy without specific protocols.
* **Intrathecal Administration:** Requires preservative-free formulations and specific preparation. Monitor for neurological toxicity.
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**Disclaimer:** This information is for educational purposes only and does not substitute for professional medical advice. Always consult the most current prescribing information and relevant guidelines for specific patient care decisions.
