METHOTREXATE LPF
Clinical safety rating: avoid
NSAIDs and probenecid can decrease renal excretion and increase levels Can cause myelosuppression and hepatotoxicity.
Methotrexate is a folate analog that inhibits dihydrofolate reductase (DHFR), blocking the synthesis of tetrahydrofolate and subsequently thymidylate and purine synthesis. This inhibits DNA synthesis, repair, and cellular replication. In low-dose regimens, it has anti-inflammatory and immunomodulatory effects through adenosine release and inhibition of cytokine production.
| Metabolism | Hepatic metabolism via aldehyde oxidase and xanthine oxidase to 7-hydroxymethotrexate; undergoes polyglutamation intracellularly; partially metabolized by hepatic CYP450 enzymes (minor). |
| Excretion | Primarily renal (80-90% unchanged via glomerular filtration and active tubular secretion); small amount biliary/fecal (<10%). |
| Half-life | Terminal half-life 3-10 hours for low doses, 8-15 hours for high doses; prolonged to 12-24 hours in renal impairment due to delayed clearance. |
| Protein binding | Approximately 50% bound, primarily to albumin. |
| Volume of Distribution | 0.4-0.8 L/kg, indicating distribution into total body water; higher (1-2 L/kg) with high-dose therapy due to tissue accumulation. |
| Bioavailability | Oral: 30-60% (dose-dependent, saturable absorption); IM/SC: ~100%. |
| Onset of Action | Oral: 30-60 minutes; IM/SC: 30-60 minutes; IV: rapid (within minutes). Clinical antirheumatic effect may take 3-6 weeks. |
| Duration of Action | Dosing interval typically weekly; antimetabolite effect persists for days; in rheumatoid arthritis, dosing every 7 days maintains effect. |
7.5 to 25 mg orally once weekly for rheumatoid arthritis; for psoriasis, 10 to 25 mg orally once weekly. Intravenous dosing varies by indication; for high-dose methotrexate (e.g., osteosarcoma), 8 to 12 g/m² IV over 4 hours.
| Dosage form | INJECTABLE |
| Renal impairment | CrCl >80 mL/min: no adjustment; CrCl 50-80 mL/min: reduce dose by 50%; CrCl 10-50 mL/min: reduce dose by 75%; CrCl <10 mL/min: avoid use. |
| Liver impairment | Child-Pugh Class A (5-6): caution, monitor; Class B (7-9): reduce dose by 50%; Class C (10-15): contraindicated. |
| Pediatric use | For juvenile idiopathic arthritis: 10 to 15 mg/m² orally once weekly. For acute lymphoblastic leukemia: high-dose regimens, e.g., 1 to 5 g/m² IV over 24-36 hours with leucovorin rescue. |
| Geriatric use | Use lower initial doses (e.g., 5 mg orally once weekly) due to decreased renal function and increased risk of toxicity; monitor renal function and adjust accordingly. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
NSAIDs and probenecid can decrease renal excretion and increase levels Can cause myelosuppression and hepatotoxicity.
| FDA category | Contraindicated |
| Breastfeeding | Methotrexate is excreted into breast milk at low concentrations. The M/P ratio is approximately 0.08:1. Due to potential for accumulation in the nursing infant, especially with high doses, breastfeeding is not recommended during therapy. A washout period of at least 1 week after the last dose is advised. |
| Teratogenic Risk |
■ FDA Black Box Warning
Methotrexate should be used only by physicians experienced in antimetabolite therapy. Because of the possibility of serious toxic reactions (which can be fatal), patients should be fully informed of the risks and monitored closely. High-dose regimens for neoplastic diseases require specialized facilities and supportive care. Deaths have been reported with the use of methotrexate in the treatment of psoriasis and rheumatoid arthritis. Patients should be closely monitored for bone marrow suppression, hepatotoxicity, pulmonary fibrosis, and renal toxicity.
| Common Effects | certain cancers |
| Serious Effects |
["Pregnancy (category X)","Breastfeeding","Severe renal impairment (CrCl < 30 mL/min)","Severe hepatic impairment (Child-Pugh class C)","Pre-existing blood dyscrasias (significant bone marrow failure)","Alcoholism or alcoholic liver disease","Immunodeficiency syndromes","Hypersensitivity to methotrexate or any component of the formulation"]
| Precautions | ["Hepatotoxicity: risk increased with cumulative dose, alcohol use, obesity, diabetes, and concomitant hepatotoxic drugs; monitor liver function tests and consider liver biopsy if persistent elevations.","Pulmonary toxicity: acute or chronic interstitial pneumonitis and fibrosis; discontinue if suspected.","Bone marrow suppression: leukopenia, thrombocytopenia, anemia; monitor complete blood counts regularly.","Renal toxicity: increased risk with high-dose therapy; ensure adequate hydration and urine alkalinization; monitor renal function.","Gastrointestinal toxicity: stomatitis, mucositis, diarrhea, ulcerative colitis; can be severe.","Infections: increased risk due to immunosuppression; avoid live vaccines.","Fetal toxicity: pregnancy category X; teratogenic and embryotoxic; use effective contraception during therapy and for at least 3 months after in males and females.","Tumor lysis syndrome: risk in high-dose therapy for rapidly growing tumors.","Neurotoxicity: leukoencephalopathy, seizures, dizziness; with high-dose regimens."] |
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| Methotrexate is contraindicated in pregnancy. First trimester exposure is associated with a high risk of spontaneous abortion, major congenital malformations (craniofacial, limb, neural tube defects). Second and third trimester exposure can cause fetal growth restriction, oligohydramnios, and neurodevelopmental abnormalities. It is a potent abortifacient. |
| Fetal Monitoring | Complete blood count (CBC) with differential, liver function tests (LFTs), renal function tests (serum creatinine, BUN), and chest X-ray at baseline. During therapy: weekly CBC and LFTs for the first month, then monthly; monitor renal function periodically. Folate levels should be monitored and supplementation given. For pregnant patients (if exposure occurs), ultrasound for fetal anatomy and growth. |
| Fertility Effects | Methotrexate can cause reversible oligospermia in men and menstrual dysfunction in women. In females, it may delay or inhibit ovulation. Fertility may be impaired during therapy but typically returns after discontinuation. Use effective contraception during and for at least 3 months after treatment in both sexes. |