II. Pathophysiology

  1. Mechanism
    1. Antimetabolite Chemotherapy (Cell Cycle Specific)
      1. S-Phase toxin (DNA synthesis phase)
    2. Folic Acid structural analog
      1. Competitively inhibits at DHF Reductase
    3. Inhibits de novo Pyrimidine synthesis
  2. Effects
    1. Suppresses DNA synthesis (and cell division) in the Gastrointestinal Tract, skin and Bone Marrow

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
    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. Methotrexate Overdose is potentially lethal if not treated
  2. 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 D5
  3. 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
  4. Antidote: Glucarpidase
    1. Glucarpidase is an enzyme that breaks down Methotrexate (as well as Leuocovorin)
    2. Glucarpidase is expensive and not widely available
  5. References
    1. Mason and Vohra (2018) in EM:Rap 18(8): 13

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
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