METHOTREXATE PRESERVATIVE FREE
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 conversion of dihydrofolate to tetrahydrofolate, thereby inhibiting thymidylate and purine synthesis, leading to impaired DNA synthesis, repair, and cellular replication. It also exhibits immunomodulatory and anti-inflammatory effects through adenosine-mediated pathways.
| Metabolism | Methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms. It is primarily eliminated renally via tubular secretion and glomerular filtration. Minor metabolism occurs via hepatic aldehyde oxidase to 7-hydroxymethotrexate. Enterohepatic recirculation occurs. |
| Excretion | Renal excretion (80-90% as unchanged drug via glomerular filtration and active tubular secretion; enterohepatic recirculation occurs; fecal elimination <10%). |
| Half-life | Terminal elimination half-life is 3-10 hours for low doses (≤50 mg/m²) and 8-15 hours for high doses (>1 g/m²); prolonged to 24-48 hours in patients with third-space effusions or renal impairment. |
| Protein binding | 50-60% bound predominantly to albumin; saturable binding at high doses. |
| Volume of Distribution | 0.4-0.8 L/kg (total body water); increased in third-space effusions (pleural, peritoneal) where drug accumulates and slowly redistributes. |
| Bioavailability | Oral: 30-60% (dose-dependent, saturable absorption); IM/SC/IV: 100%. |
| Onset of Action | Oral: 30-60 minutes; IV: minutes; IM: 30-60 minutes; Subcutaneous: 30-60 minutes; Intrathecal: immediate. |
| Duration of Action | Antineoplastic effects: weeks; anti-inflammatory effects: 1-2 weeks; clinical monitoring required for myelosuppression and hepatotoxicity. |
| Molecular Weight | 454.44 |
Rheumatoid arthritis: 7.5 mg orally once weekly. Psoriasis: 10-25 mg orally once weekly. Neoplastic diseases: IV or IM 30-40 mg/m² once weekly, or oral 2.5-5 mg every 12 hours for 3 doses once weekly. Intrathecal: 12 mg/m² (maximum 15 mg) every 2-7 days.
| Dosage form | INJECTABLE |
| Renal impairment | GFR >60 mL/min: No adjustment. GFR 30-59 mL/min: Reduce dose by 50%. GFR <30 mL/min: Contraindicated. Hemodialysis: Not recommended due to minimal removal. |
| Liver impairment | Child-Pugh A (mild): No adjustment. Child-Pugh B (moderate): Reduce dose by 50%. Child-Pugh C (severe): Contraindicated. |
| Pediatric use | Juvenile idiopathic arthritis: 10-15 mg/m² orally once weekly. Acute lymphoblastic leukemia: Induction: 3.3 mg/m²/day IM/IV for 4-6 weeks; Maintenance: 20-40 mg/m² orally/IM/IV once weekly. Intrathecal: <1 year 6 mg, 1-2 years 8 mg, 2-3 years 10 mg, >3 years 12 mg. |
| Geriatric use | Start at lowest adult dose (e.g., 5-7.5 mg orally once weekly for rheumatoid arthritis). Monitor renal function and adjust based on GFR. Increased risk of toxicity due to age-related decline in renal function. |
| 1st trimester | Contraindicated: Known teratogen, causes severe fetal malformations (CNS, skeletal, cardiac). Risk of miscarriage and fetal death. |
| 2nd trimester | Contraindicated: Continued risk of teratogenicity; can cause fetal growth restriction and oligohydramnios. |
| 3rd trimester | Contraindicated: Risk of neonatal myelosuppression, immunosuppression, and folate deficiency; may precipitate preterm labor. |
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 occurs; methotrexate crosses the placenta via active transport and passive diffusion. Fetal concentrations can approach maternal levels, contributing to embryotoxicity and teratogenicity. |
■ FDA Black Box Warning
Methotrexate can cause fetal death or teratogenic effects when administered to pregnant women. It should not be used for severe psoriasis or rheumatoid arthritis in pregnant women. Severe, potentially fatal toxic reactions (e.g., myelosuppression, hepatotoxicity, pulmonary fibrosis, renal failure, gastrointestinal ulcerations, and severe infections) can occur. Methotrexate elimination is reduced in patients with renal impairment, ascites, or pleural effusions. Close monitoring for bone marrow toxicity, liver function, and renal function is required. Intrathecal administration may cause severe neurotoxicity including acute arachnoiditis, subacute myelopathy, and chronic leukoencephalopathy.
| Common Effects | certain cancers |
| Serious Effects |
Pregnancy or planned pregnancyBreastfeedingSevere renal impairment (CrCl < 30 mL/min)Severe hepatic impairment or active liver diseasePre-existing blood dyscrasias (severe anemia, leukopenia, thrombocytopenia)Active infection (including tuberculosis, hepatitis B/C, HIV)Hypersensitivity to methotrexate or any componentConcurrent use of live vaccinesAlcoholism or alcoholic liver diseaseImmunodeficiency syndromesUncontrolled peptic ulcer disease
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| Breastfeeding |
| Methotrexate is excreted into breast milk in low levels, but due to its potential for accumulation and serious adverse effects (bone marrow suppression, gastrointestinal toxicity, immunosuppression) in the nursing infant, breastfeeding is contraindicated during methotrexate therapy. The American Academy of Pediatrics recommends avoiding breastfeeding while on methotrexate. |
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | Pregnancy category X. First trimester: High risk of spontaneous abortion, central nervous system (anencephaly, hydrocephaly, myelomeningocele), craniofacial (cleft palate, hypertelorism), cardiovascular, and skeletal anomalies. Second and third trimesters: Continued risk of growth restriction, neurodevelopmental delay, and potential for methotrexate-induced fetopathy with prolonged exposure. Contraindicated in all trimesters. |
| Fetal Monitoring | Maternal: Complete blood count with differential, liver function tests (AST, ALT, bilirubin), renal function (serum creatinine, BUN), and methotrexate trough levels (if applicable) at baseline and monthly during therapy. Fetal: Ultrasound for structural anomalies (detailed anatomy scan at 18-20 weeks) if inadvertent exposure occurs; consider amniocentesis for methotrexate levels in cases of high-dose exposure. No drug is safe; termination may be discussed. |
| Fertility Effects | Reversible or irreversible ovarian failure with oligomenorrhea or amenorrhea, increased risk of premature ovarian insufficiency; may cause oligospermia or azoospermia in males, reversible upon drug discontinuation. Conception should be avoided for at least 3 months after treatment in both sexes due to potential gamete toxicity. |
| Precautions |
| Hepatotoxicity (including cirrhosis, fibrosis), pulmonary toxicity (pneumonitis, pulmonary fibrosis), severe myelosuppression (anemia, leukopenia, thrombocytopenia), renal toxicity (increased creatinine, acute renal failure), gastrointestinal toxicity (stomatitis, ulcerative colitis, diarrhea), neurotoxicity (especially with intrathecal use), serious infections (including opportunistic infections), lymphoproliferative disorders, tumor lysis syndrome, hypersensitivity reactions, and increased risk of photosensitivity. Monitor CBC, LFTs, renal function, and chest imaging. Avoid concomitant NSAIDs (increase methotrexate toxicity) and live vaccines. |
| Food/Dietary | Avoid alcohol. Limit caffeine intake? Not clinically significant. No specific food restrictions beyond general healthy diet. Caution with folic acid-rich foods? Folic acid supplements may reduce efficacy; natural dietary folate not restricted. |
| Clinical Pearls | Administer as a single IM dose (50 mg/m2) for ectopic pregnancy; monitor hCG levels. In high-dose protocols, leucovorin rescue is mandatory 24 hours after start. Contraindicated in pregnancy (Category X). Use preservative-free formulation for intrathecal or high-dose IV use to avoid neurotoxicity. Monitor for pulmonary toxicity, hepatotoxicity, and myelosuppression. Check renal function before dosing; adjust in CKD. NSAIDs reduce methotrexate clearance; avoid concurrent use. |
| Patient Advice | Avoid alcohol completely to reduce risk of hepatotoxicity. · Do not take NSAIDs (ibuprofen, naproxen) or aspirin without consulting your doctor. · Report symptoms of infection, unexplained bleeding, bruising, or shortness of breath immediately. · Use effective contraception during treatment and for at least 3 months after last dose. · Take folic acid as prescribed to reduce side effects. · Avoid live vaccines during therapy. |