II. Pharmacology

  1. Mechanism
    1. Antimetabolite Chemotherapy (Cell Cycle Specific)
      1. S-Phase toxin (DNA synthesis phase)
    2. Folic Acid structural analog
      1. Competitively inhibits at Dihydrofolate Reductase
    3. Inhibits de novo Pyrimidine synthesis
      1. Decreases Tetrahydrofolate production
  2. Effects
    1. Suppresses DNA synthesis (and cell division) in the Gastrointestinal Tract, skin and Bone Marrow
  3. Pharmacokinetics
    1. Oral bioavailability: 60%
    2. Peak blood concentration: 1 to 3 hours
    3. Half-Life: 8 hours
    4. Well tolerated dose cutoffs
      1. Children <20 mg
      2. Adults <60 mg

IV. Dosing

  1. Co-administer Folic Acid 1 mg orally daily (or 5-7 mg once weekly)
    1. Reduces adverse effects (Vomiting, Stomatitis, hepatotoxicity)
    2. Does not decrease Methotrexate efficacy
  2. Rheumatoid Arthritis
    1. Range: 7.5 - 20 mg/week PO, SQ, IM
      1. Taken one day per week either in one dose or in a split dose, 12 hours apart
        1. Split dosing may be better tolerated (fewer gastrointestinal side effects)
        2. Consider parenteral dosing if oral dosing is not tolerated
      2. Have the patient choose a day of the week for the medication to be taken
        1. Specify that day on the prescription (e.g. Monday)
    2. Initial: 7.5 to 10 mg per week (e.g. 5 mg orally twice daily every Monday)
      1. Lowest effective dose: 7.5 mg orally once daily every Monday AM
    3. Titrate to target dose of at least 15 mg per week over a 4-6 week period
      1. Average dose: 10 mg orally twice daily every Monday (20 mg/week)
      2. Maximum dose: 12.5 mg orally twice daily every Monday (25 mg/week)
  3. Cancer Chemotherapy
    1. Oral: 2.5 to 5 mg/day
    2. Intrathecal: 10 mg weekly to biweekly

V. Efficacy

  1. Rheumatoid Arthritis
    1. Very effective (>85% initially)
    2. Response in 4-6 weeks (faster than other DMARDs)
  2. Curative in Choriocarcinoma

VI. Adverse Effects

  1. Oral and Gastrointestinal (most common)
    1. Nausea or Vomiting
    2. Oral Ulcers
    3. Stomatitis
    4. Diarrhea
  2. Hepatic
    1. Hepatic fibrosis
    2. Elevated transaminases
    3. Cirrhosis
  3. Pulmonary
    1. Pulmonary fibrosis or infiltrates
    2. Hypersensitivity Pneumonitis
      1. Presents with dry cough, fever, Dyspnea on exertion
      2. Stop Methotrexate and exclude infection
      3. Start high dose Corticosteroids
      4. Consider gallium lung scan
  4. Neuropsychiatric
    1. Dysphoria
  5. Hematologic
    1. Minimal Immunosuppression
      1. Contrast with Imuran, Cytoxan, Sandimmune
    2. Myelosuppression
    3. Thrombocytopenia

VII. Cost

  1. Very expensive (>$1000 per year)

VIII. Monitoring

  1. Baseline screening
    1. Complete Blood Count with Platelet Count
    2. Recent Chest XRay
    3. Liver Function Tests
      1. Aspartate Aminotransferase (AST)
      2. Alanine Aminotransferase (ALT)
      3. Alkaline Phosphatase
      4. Albumin
      5. Consider Hepatitis B and Hepatitis C serologies
    4. Renal Function Tests
      1. Creatinine
  2. Follow-up Monitoring: (monthly x3, then every 8 weeks)
    1. Complete Blood Count with Platelet Count
    2. Liver Function Tests
      1. Aspartate Aminotransferase (AST)
      2. Alkaline Phosphatase
    3. Renal Function Tests
      1. Creatinine
  3. Liver Biopsy Indications
    1. Cumulative Methotrexate dose >8 gram
    2. Prior heavy Alcohol use
    3. Persistently elevated AST (SGOT) 2-3x normal
    4. Psoriatic Arthritis

IX. Contraindications: Absolute

X. Contraindications: Relative (due to hepatotoxicity)

  1. Alcohol Use
  2. Pre-existing liver disease
  3. Diabetes Mellitus
  4. Obesity
  5. Age >70 years

XI. Management: Toxicity or Overdose

  1. Consider Activated Charcoal if presents within first hours of ingestion and patient controlling airway
    1. May require multiple doses of Activated Charcoal if Renal Failure is present
  2. Background
    1. Methotrexate Overdose is potentially lethal if not treated
    2. Most common antineoplastic Overdose
    3. Toxicity occurs with repeated high doses, massive oral ingestions (>1000 mg) or Renal Failure
      1. Single large dose typically saturates absorption and is less likely to cause toxicity
  3. Labs
    1. See Unknown Ingestion
      1. General approach including other toxicology studies (e.g. Acetaminophen level)
    2. Serum Methotrexate level (repeat as needed when administering antidotes)
    3. Comprehensive Panel and Complete Blood Count daily in massive ingestion
  4. Optimize Urine Output
    1. Administer Intravenous Fluids
    2. Alkalinize the urine (IV bicarbonate) to prevent Methotrexate precipitation in renal tubules
      1. Place 150 meq bicarbonate in each liter of fluid
  5. Administer folinic acid or Leucovorin (Citrovorum factor, Leucovorin rescue)
    1. Bypasses the Methotrexate induced blockade of dihydrofolate reductase
    2. Dihydrofolate reductase is an enzyme that typically activate Folate
    3. Indicated if Methotrexate ingestion >1000 mg or Renal Failure
      1. Start with Leucovorin 40 mg orally, then
      2. Leucovorin 10 mg/m2 IV over 15 min every 3 hours until Methotrexate level <0.01 umol/L
  6. Glucarpidase
    1. Glucarpidase is an enzyme that breaks down Methotrexate (as well as Leuocovorin)
    2. Glucarpidase is expensive and not widely available
    3. Indicated in intrathecal or massive intravenous dose
  7. Other measures
    1. Hemodialysis may be indicated in significant Acute Kidney Injury
  8. Disposition
    1. Observe and treat symptomatic exposures until Methotrexate level <0.01 umol/L
    2. Asymptomatic exposures should be observed 6 hours before discharge
  9. References
    1. Mason and Vohra (2018) in EM:Rap 18(8): 13
    2. Tomaszewski (2022) Crit Dec Emerg Med 36(7): 32

XII. Drug Interactions: Agents that increase Methotrexate levels

  1. Antibiotics (hold Methotrexate dose until antibiotic course completed)
    1. Sulfa antibiotics (e.g. Trimethoprim Sulfamethoxazole)
    2. Cephalosporins
    3. Penicillins
  2. Proton Pump Inhibitors
    1. May decrease Methotrexate (and metabolite) renal clearance and result in toxic levels
    2. Hold Proton Pump Inhibitors for a few days before and after high dose Methotrexate infusions
    3. Consider use of an H2 Blocker in place of a Proton Pump Inhibitor
    4. Exercise caution in chronic lower dose Methotrexate with Proton Pump Inhibitors
      1. Risk of toxicity increases with concurrent NSAIDs and Aspirin (also decrease Methotrexate renal clearance)
      2. Decrease Methotrexate dose if mild toxicity signs occur
      3. Stop Methotrexate for severe toxicity (e.g. Bone Marrow toxicity)
    5. References
      1. (2012) Presc Lett 19(12): 72

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Cost: Medications

methotrexate (on 5/17/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
METHOTREXATE 2.5 MG TABLET Generic $1.08 each
METHOTREXATE 25 MG/ML VIAL Generic $1.45 per ml
METHOTREXATE 250 MG/10 ML VIAL Generic $0.81 per ml
METHOTREXATE 50 MG/2 ML VIAL Generic $1.45 per ml

Ontology: Methotrexate (C0025677)

Definition (CHV) cancer treatment drug
Definition (CHV) cancer treatment drug
Definition (CHV) cancer treatment drug
Definition (NCI_NCI-GLOSS) A drug used to treat some types of cancer, rheumatoid arthritis, and severe skin conditions, such as psoriasis. Amethopterin stops cells from making DNA and may kill cancer cells. It is a type of antimetabolite.
Definition (NCI) An antimetabolite and antifolate agent with antineoplastic and immunosuppressant activities. Methotrexate binds to and inhibits the enzyme dihydrofolate reductase, resulting in inhibition of purine nucleotide and thymidylate synthesis and, subsequently, inhibition of DNA and RNA syntheses. Methotrexate also exhibits potent immunosuppressant activity although the mechanism(s) of actions is unclear.
Definition (MSH) An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of TETRAHYDROFOLATE DEHYDROGENASE and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA.
Definition (CSP) folic acid antagonist that acts by inhibiting the synthesis of nucleic acids, thymidylate, and protein; used as an antineoplastic in a wide variety of malignancies, and as an antipsoriatic and antirheumatic.
Definition (PDQ) An antimetabolite with antineoplastic and immunomodulating properties. Methotrxate binds to and inhibits the enzyme dihydrofolate reductase, resulting in inhibition of purine nucleotide and thymidylate synthesis and, subsequently, inhibition of DNA and RNA syntheses. Methotrexate also exhibits potent immunosuppressant properties. Check for "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=41719&idtype=1" active clinical trials or "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=41719&idtype=1&closed=1" closed clinical trials using this agent. ("http://nciterms.nci.nih.gov:80/NCIBrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C642" NCI Thesaurus)
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH D008727
SnomedCT 387381009, 68887009
LNC LP16198-1, MTHU005020, LA14339-8
English Amethopterin, Methotrexate, L-Glutamic acid, N-(4-(((2,4-diamino-6-pteridinyl)methyl)methylamino)benzoyl)-, 4-Amino-10-methylfolic Acid, 4-Amino-4-deoxy-10-methylpteroyl-L-glutamic Acid, N-[4-[[(2,4-Diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic Acid, methotrexate, Methotrexatum, Metotrexato, Alpha-Methopterin, methotrexate (medication), METHOTREXATE, Methotrexate [Chemical/Ingredient], mtx, MTX, MTX - Methotrexate, Methotrexate (product), Methotrexate (substance), amethopterin, methotrexate methylaminopterin, Methotrexate Methylaminopterin
Swedish Metotrexat
Czech methotrexát, metotrexát
Spanish MTX, ametopterina, metotrexato (producto), metotrexato (sustancia), metotrexato, Ametopterina, Metotrexato
Finnish Metotreksaatti
Russian METOTREKSAT, AMETOPTERIN, METILAMINOPTERIN, АМЕТОПТЕРИН, МЕТИЛАМИНОПТЕРИН, МЕТОТРЕКСАТ
Croatian METOTREKSAT
Polish Metotreksat, Metopteryna
Japanese アメトプテリン, メチルアミノプテリン, メトトレキサート, メトトレキセート, リウマトレックス, メソトレキサート, メソトレキセート
French Améthoptérine, Méthotrexate, Méthylaminoptérine
German Amethopterin, Methotrexat
Italian Metotressato
Portuguese Ametopterina, Metotrexato