BLACK BOX WARNING
- severe toxic reactions — see prescribing information for complete list
- fetal death or teratogenic effects
- deaths have occurred with concomitant NSAIDs
- renal failure
- bone marrow suppression
- pulmonary toxicity
- hepatotoxicity and liver cirrhosis
- gastrointestinal toxicity (ulceration, bleeding, toxic megacolon)
- serious infections
methotrexate (oncologic)
Brand: Trexall, Otrexup, Rasuvo
⚠ BBW ISMP High Alert TDM Required Prototype Drug
Drug Class: antimetabolite antineoplastic
Drug Family: antineoplastic
Subclass: folate antagonist
Organ Systems: hematology-oncologyimmunologymusculoskeletal
Mechanism of Action
Competitively inhibits DHFR, blocking tetrahydrofolate production; depletes pools of folate cofactors required for purine and thymidylate synthesis; also polyglutamated intracellularly to forms that inhibit thymidylate synthase; S-phase specific.
dihydrofolate reductase (DHFR)thymidylate synthase
Indications
- acute lymphoblastic leukemia (ALL) — cornerstone
- osteosarcoma
- non-Hodgkin lymphoma
- choriocarcinoma
- breast cancer
- CNS prophylaxis (intrathecal)
- rheumatoid arthritis (low dose)
- psoriasis (low dose)
- ectopic pregnancy (intramuscular)
Contraindications
- methotrexate hypersensitivity
- severe renal impairment (high-dose)
- immunodeficiency syndromes (live vaccines)
- pleural effusion or ascites (third-space sequestration)
- pregnancy (teratogenic)
- breastfeeding
Adverse Effects
Common
- mucositis/stomatitis
- nausea/vomiting
- myelosuppression
- hepatotoxicity
Serious
- severe myelosuppression
- mucositis
- nephrotoxicity (at high doses)
- pulmonary toxicity (methotrexate pneumonitis)
- hepatic fibrosis/cirrhosis (chronic low-dose)
- neurotoxicity (intrathecal)
- teratogenicity
Pharmacokinetics (ADME)
| Absorption | 50–90% oral at low doses; IV at high doses for oncology |
| Distribution | widely distributed; 50% protein-bound; intrathecal distribution limited to CSF |
| Metabolism | partial hepatic metabolism; polyglutamation in cells (active, retained intracellularly) |
| Excretion | primarily renal (90% unchanged at high doses); dose adjustment essential in renal impairment |
| Half-life | 3–10 hours (low dose); up to 24 hours (high dose) |
| Onset | hours |
| Peak | 1–4 hours (oral) |
| Duration | varies by indication |
| Protein Binding | 50% |
| Vd | moderate |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| NSAIDs/aspirin | reduce renal tubular secretion of methotrexate; increase levels to toxic; deaths reported — avoid with high-dose MTX | major |
| trimethoprim/sulfonamides | additive folate antagonism; severe myelosuppression | major |
| proton pump inhibitors | reduce renal tubular secretion of MTX at high doses; delay elimination | major |
| leucovorin (folinic acid) | rescues normal cells after high-dose MTX — must be administered on schedule; delays require additional leucovorin rescue | beneficial |
Nursing Considerations
- High-dose methotrexate requires mandatory leucovorin rescue — verify leucovorin is prescribed and the first dose is given at the correct time relative to methotrexate infusion (typically 24 hours after MTX start).
- Maintain urinary pH >7 with sodium bicarbonate during and after high-dose MTX infusion — alkaline urine prevents methotrexate precipitation in renal tubules.
- Monitor methotrexate levels at 24, 48, and 72 hours; if levels are above the nomogram thresholds, increase leucovorin rescue dose.
- NSAIDs (including OTC ibuprofen, naproxen, aspirin) must be held before and during high-dose MTX — these can cause fatal toxicity by blocking renal elimination.
Clinical Pearls
- Leucovorin rescue (folinic acid) after high-dose methotrexate is a clinically elegant strategy: leucovorin bypasses DHFR to restore folate pools in normal cells, while entering cancer cells poorly due to lower affinity for the folate carrier — providing differential rescue.
- Methotrexate polyglutamates are the active intracellular forms with long retention times — this explains the persistent antiproliferative effects of even weekly low-dose MTX for RA and psoriasis, where circulating drug levels are undetectable between doses.
Safety Profile
Pregnancy contraindicated
Lactation avoid
Renal Adjustment Required
Hepatic Adjustment Required
TDM Required
Concordance Terms
Cross-referenced clinical concepts — click any term to see all content where it appears.