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. |
| Molecular Weight | 454.44 |
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 | Contraindicated due to high risk of teratogenicity (methotrexate embryopathy), spontaneous abortion, and fetal death. Use only if benefits outweigh risks for life-threatening conditions. |
| 2nd trimester | Contraindicated due to risk of fetal toxicity, including growth restriction and CNS abnormalities. Avoid use unless no alternative. |
| 3rd trimester | Contraindicated due to risk of neonatal myelosuppression, immunosuppression, and possible neurotoxicity. Avoid use near term. |
Clinical note
NSAIDs and probenecid can decrease renal excretion and increase levels Can cause myelosuppression and hepatotoxicity.
| FDA category | Contraindicated |
| Placental transfer | Extensive placental transfer; fetal concentrations approach maternal levels. Methotrexate is actively transported across the placenta. |
■ 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 |
PregnancyBreastfeedingSevere hepatic impairmentSevere renal impairment (CrCl < 30 mL/min)Alcoholism or alcoholic liver diseasePre-existing severe bone marrow suppression (e.g., WBC < 3000/mm³, platelet count < 100,000/mm³)Active infectious disease (e.g., tuberculosis, hepatitis)Hypersensitivity to methotrexate
| 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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| Breastfeeding |
| Methotrexate is excreted into breast milk in low concentrations but may accumulate in neonates. Risk of immunosuppression, neutropenia, and gastrointestinal toxicity in the nursing infant. Breastfeeding is not recommended during therapy and for at least 1 week after the last dose. |
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | 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. |
| Food/Dietary | Avoid alcohol. High-folate foods (e.g., leafy greens) do not need to be avoided as folic acid is given deliberately. Caffeine may reduce methotrexate absorption; separate by at least 2 hours. Cranberry juice and other acidic beverages may increase methotrexate levels; avoid large amounts. |
| Clinical Pearls | Methotrexate LPF (low-dose) is used for rheumatoid arthritis, psoriasis, and other autoimmune diseases. Always prescribe folic acid 1 mg daily to reduce toxicity. Avoid NSAIDs in patients on high-dose methotrexate; low-dose methotrexate with NSAIDs requires renal monitoring. Monitor liver function, complete blood count, and renal function at baseline and periodically. Administer as a weekly dose; accidental daily dosing can be fatal. Use with caution in patients with liver disease, renal impairment, or ascites. Pulmonary toxicity (cough, fever, dyspnea) requires immediate discontinuation. |
| Patient Advice | Take methotrexate exactly once a week, not daily. Taking it daily can cause severe poisoning. · Always take folic acid as prescribed, usually once daily, to reduce side effects. · Avoid alcohol completely to prevent liver damage. · Report any new cough, fever, or difficulty breathing to your doctor immediately. · Limit sun exposure and use sunscreen; methotrexate can increase sun sensitivity. · Do not take nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen or naproxen without consulting your doctor. · Keep all appointments for blood tests to monitor for side effects. |