- Ectopic Pregnancy
- Rheumatologic
- Psoriasis
- Dermatomyositis
- Juvenile Idiopathic Arthritis
- Rheumatoid Arthritis (DMARD)
- Early Rheumatoid Arthritis
- Chronic Late Rheumatoid Arthritis
- Seronegative Rheumatoid Arthritis
- Cancer Chemotherapy
- Acute Myelocytic Anemia
- Acute lymphocytic Anemia
- Non-Hodgkin Lymphoma
- Head and Neck Cancer
- Cervical Cancer
- Cutaneous T-Cell Lymphoma
- Breast Cancer
- Lung Cancer
- Meningeal Leukemia
- Testicular Cancer
- Trophoblastic Neoplasia (Hydatidiform Mole)
- Wilms Tumor
- Sarcoma (including Osteosarcoma)
- Absolute
- Renal Insufficiency (Serum Creatinine > 1.5)
- Pleural Effusion
- Ascites
- Active Stomatitis
- Diarrhea
- Infection
- pregnancy
- Liver disease
- Relative (due to hepatotoxicity)
- Alcohol Use
- Pre-existing liver disease
- Diabetes Mellitus
- Obesity
- Age >70 years
- Suppresses DNA synthesis (and cell division) in the Gastrointestinal Tract, skin and Bone Marrow
-
Folic Acid structural analog
- Competitively inhibits at Dihydrofolate Reductase
- Inhibits de novo Pyrimidine synthesis
- Inhibits dihydrofolate reductase (DHFR) which reduces dihydrofolate to Tetrahydrofolate
- Decreases Tetrahydrofolate production which is critical to thymidylate synthesis
-
Antimetabolite Chemotherapy (Cell Cycle Specific)
- S-Phase toxin (DNA synthesis phase)
-
DMARD antiinflammatory drug in Rheumatoid Arthritis (first-line agent)
- Weekly dosing, at lower total doses than for cancer Chemotherapy
- Suppresses immune cell proliferation (via DHFR inhibition)
- Onset of symptomatic relief at 4 to 6 weeks after starting
- Co-administer Folic Acid 1 mg orally daily (or 5-7 mg once weekly)
- Reduces adverse effects (Vomiting, Stomatitis, hepatotoxicity)
- Does not decrease Methotrexate efficacy
-
Rheumatoid Arthritis
- Range: 7.5 - 20 mg/week PO, SQ, IM
- Taken one day per week either in one dose or in a split dose, 12 hours apart
- Split dosing may be better tolerated (fewer gastrointestinal side effects)
- Consider Parenteral dosing if oral dosing is not tolerated
- Have the patient choose a day of the week for the medication to be taken
- Specify that day on the prescription (e.g. Monday)
- Taken one day per week either in one dose or in a split dose, 12 hours apart
- Initial: 7.5 to 10 mg per week (e.g. 5 mg orally twice daily every Monday)
- Lowest effective dose: 7.5 mg orally once daily every Monday AM
- Titrate to target dose of at least 15 mg per week over a 4-6 week period
- Average dose: 20 mg once (or 10 mg orally twice) every Monday (20 mg/week)
- Maximum dose: 25 mg once (or 12.5 mg orally twice) every Monday (25 mg/week)
- If gastrointestinal side effects limit use:
- Divide oral dose into 2 doses, 12 hours apart
- Methotrexate SQ/IM (vial $20/month or autoinjector $600/month)
- Range: 7.5 - 20 mg/week PO, SQ, IM
- Cancer Chemotherapy
- Oral: 2.5 to 5 mg/day
- Intrathecal: 10 mg weekly to biweekly
- Oral Bioavailability: 60%
- Peak blood concentration: 1 to 3 hours
- Half-Life: 8 hours
- Well tolerated dose cutoffs
- Children <20 mg
- Adults <60 mg
- Avoid in Lactation
- Avoid in pregnancy (all trimesters)
- Teratogenic (including fetal death and congenital anomalies)
- Use reliable Contraception
- General
- Oral and Gastrointestinal (most common)
- Hepatic
- Hepatic Fibrosis
- Elevated transaminases
- Cirrhosis
- Pulmonary
- Pulmonary fibrosis or infiltrates
- Hypersensitivity Pneumonitis
- Presents with dry cough, fever, Dyspnea on exertion
- Stop Methotrexate and exclude infection
- Start high dose Corticosteroids
- Consider gallium lung scan
- Hematologic
- Minimal Immunosuppression
- Contrast with Imuran, Cytoxan, Sandimmune
- Myelosuppression (Anemia, Neutropenia)
- Thrombocytopenia
- Minimal Immunosuppression
- Neuropsychiatric
- Dysphoria
- Methotrexate-Induced Leukoencephalopathy (see below)
- Dizziness
- Headache
- Blurred Vision
- Dermatologic
- Alopecia
- Dermatitis
- Photosensitivity
- Methotrexate-Induced Leukoencephalopathy
- Transient, dose-dependent complication of intrathecal Methotrexate in children with Acute Lymphoblastic Leukemia
- Of the <4% of ALL patients with neurotoxicity, 20% demonstrate leukoencephalopathy on MRI
- White matter edema mediated by direct toxicity as well as IL-6 mediated inflammation
- Leukoencephalopathy is a diagnosis of exclusion
- References
- Waldner and Beamon (2024) Crit Dec Emerg Med 38(6): 16-7
- Curative in Choriocarcinoma
-
Rheumatoid Arthritis
- Very effective (>85% initially)
- Response in 4-6 weeks (faster than other DMARDs)
- Baseline screening
- Complete Blood Count with Platelet Count
- Recent Chest XRay
- Liver Function Tests
- Aspartate Aminotransferase (AST)
- Alanine Aminotransferase (ALT)
- Alkaline Phosphatase
- Albumin
- Consider Hepatitis B and Hepatitis C serologies
- Renal Function Tests
- Follow-up Monitoring: (monthly x3, then every 8 weeks)
-
Liver Biopsy Indications
- Cumulative Methotrexate dose >8 gram
- Prior heavy Alcohol use
- Persistently elevated AST (SGOT) 2-3x normal
- Psoriatic Arthritis
- Toxicity or Overdose
- Consider Activated Charcoal if presents within first hours of ingestion and patient controlling airway
- May require multiple doses of Activated Charcoal if Renal Failure is present
- Background
- Methotrexate Overdose is potentially lethal if not treated
- Most common antineoplastic Overdose
- Toxicity occurs with repeated high doses, massive oral ingestions (>1000 mg) or Renal Failure
- Single large dose typically saturates absorption and is less likely to cause toxicity
- Labs
- See Unknown Ingestion
- General approach including other toxicology studies (e.g. Acetaminophen level)
- Serum Methotrexate level (repeat as needed when administering antidotes)
- Comprehensive Panel and Complete Blood Count daily in massive ingestion
- See Unknown Ingestion
- Optimize Urine Output
- Administer Intravenous Fluids
- Alkalinize the urine (IV bicarbonate) to prevent Methotrexate precipitation in renal tubules
- Place 150 meq bicarbonate in each liter of fluid
- Administer folinic acid or Leucovorin (Citrovorum factor, Leucovorin rescue)
- Bypasses the Methotrexate induced blockade of dihydrofolate reductase
- Dihydrofolate reductase is an enzyme that typically activate Folate
- Indicated if Methotrexate ingestion >1000 mg or Renal Failure
- Start with Leucovorin 40 mg orally, then
- Leucovorin 10 mg/m2 IV over 15 min every 3 hours until Methotrexate level <0.01 umol/L
- Glucarpidase
- Glucarpidase is an enzyme that breaks down Methotrexate (as well as Leuocovorin)
- Glucarpidase is expensive and not widely available
- Indicated in intrathecal or massive intravenous dose
- Other measures
- Hemodialysis may be indicated in significant Acute Kidney Injury
- Disposition
- Observe and treat symptomatic exposures until Methotrexate level <0.01 umol/L
- Asymptomatic exposures should be observed 6 hours before discharge
- References
- Mason and Vohra (2018) in EM:Rap 18(8): 13
- Tomaszewski (2022) Crit Dec Emerg Med 36(7): 32
- Agents that increase Methotrexate levels
- Antibiotics (hold Methotrexate dose until Antibiotic course completed)
-
Proton Pump Inhibitors
- May decrease Methotrexate (and metabolite) Renal Clearance and result in toxic levels
- Hold Proton Pump Inhibitors for a few days before and after high dose Methotrexate infusions
- Consider use of an H2 Blocker in place of a Proton Pump Inhibitor
- Exercise caution in chronic lower dose Methotrexate with Proton Pump Inhibitors
- Risk of toxicity increases with concurrent NSAIDs and Aspirin (also decrease methotrexate Renal Clearance)
- Decrease Methotrexate dose if mild toxicity signs occur
- Stop Methotrexate for severe toxicity (e.g. Bone Marrow toxicity)
- References
- (2012) Presc Lett 19(12): 72
-
Vaccines
- Hold Methotrexate for 4 weeks before and 4 weeks after Live Vaccines
- Hold Methotrexate for 2 weeks after Influenza Vaccine (non-live attenuated)
- Methotrexate Tablet (DailyMed)
- (2014) Presc Lett 21(10): 56
- Furst (1997) Br J Rheumatol 36:1196-204 [PubMed]
- Jones (2000) Am Fam Physician 62(7):1607-14 [PubMed]
- Matterson (2000) Mayo Clin Proc 75:669-74 [PubMed]
- Peterson (2024) Am Fam Physician 110(5): 515-26 [PubMed]
- Pincus (1999) Clin Rheumatol 17(6 Suppl 18): S2-S124 [PubMed]