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# METHOTREXATE
## Overview
Methotrexate is a folic acid antagonist that inhibits DNA synthesis, repair, and cellular replication. It is used in various inflammatory conditions and malignancies.
## Primary Indications
* **Oncology:** Acute lymphoblastic leukemia, osteosarcoma, non-Hodgkin lymphoma, breast cancer, head and neck cancer, lung cancer, gestational trophoblastic neoplasia.
* **Rheumatology:** Rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, psoriasis.
## Adult Dosing
Dosing is highly variable and depends on the indication, route of administration, and specific protocol.
* **Rheumatology:** Typically 7.5 mg to 25 mg orally or intramuscularly once weekly. Some protocols may use subcutaneous administration.
* **Oncology:** Doses range from low-dose (e.g., 40 mg/m² IV) to high-dose (e.g., 12 g/m² IV over 24 hours) with leucovorin rescue. Specific protocols must be followed.
## Pediatric Dosing
Dosing is highly variable and depends on the indication, route of administration, and specific protocol.
* **Juvenile Idiopathic Arthritis:** Typically 10 mg/m² orally or intramuscularly once weekly.
* **Oncology:** Dosing varies significantly based on the specific malignancy and protocol.
## Dose Adjustments
* **Renal Impairment:** Dose reduction is necessary based on creatinine clearance (CrCl). Specific guidelines should be consulted as high-dose methotrexate can accumulate with impaired renal function.
* **Hepatic Impairment:** Use with caution. Dose reduction may be necessary.
* **Myelosuppression:** Dosing may need to be delayed or reduced based on blood counts.
## Contraindications
* Hypersensitivity to methotrexate.
* Severe renal impairment.
* Severe hepatic impairment.
* Pre-existing severe pulmonary disease.
* Severe immunodeficiency.
* Alcoholism.
* Significant pre-existing blood dyscrasias.
## Adverse Effects
* **Common:** Nausea, vomiting, stomatitis, diarrhea, abdominal pain, alopecia, fatigue, headache.
* **Serious:** Myelosuppression (leukopenia, thrombocytopenia, anemia), hepatotoxicity, nephrotoxicity, pulmonary toxicity (pneumonitis), mucositis, neurotoxicity (especially with high-dose or intrathecal administration), skin reactions, opportunistic infections.
## Key Drug Interactions
* **NSAIDs:** Increased methotrexate toxicity, especially with high-dose methotrexate. Avoid concurrent use, particularly around high-dose methotrexate.
* **Penicillins:** Can decrease renal clearance of methotrexate, leading to increased levels and toxicity.
* **Probenecid:** Can decrease renal clearance of methotrexate.
* **Trimethoprim/Sulfamethoxazole:** Can increase methotrexate levels and toxicity.
* **Folic Acid:** Concurrent administration can decrease efficacy in certain oncologic indications but is required for rescue in high-dose protocols.
* **Live Vaccines:** Contraindicated due to immunosuppression.
## Monitoring
* **Complete Blood Count (CBC) with differential and platelets:** Prior to each dose and as indicated.
* **Renal function (BUN, creatinine):** Prior to each dose and as indicated.
* **Liver function tests (AST, ALT, bilirubin):** Baseline and periodically.
* **Methotrexate levels:** Crucial with high-dose therapy and in patients with impaired renal function.
* **Pulmonary symptoms:** Monitor for cough, shortness of breath.
* **Oral mucosa:** Monitor for stomatitis.
## Clinical Pearls
* Always verify the route of administration (oral, IV, IM, SC, intrathecal) as toxicity varies greatly.
* Strict adherence to dosing schedules (e.g., once weekly for rheumatologic conditions) is critical to minimize toxicity.
* Leucovorin rescue is essential for high-dose methotrexate protocols to prevent severe toxicity.
* Patient education on recognizing and reporting early signs of toxicity (e.g., mouth sores, unusual bleeding or bruising, fever, shortness of breath) is vital.
* Hydration is important, especially with high-dose therapy, to promote renal excretion.
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*This information is intended for clinical professionals and does not replace a comprehensive review of current prescribing information, product monographs, or established clinical guidelines. Always verify current drug information before making clinical decisions.*
