Methotrexate

See Also

Indications

Ectopic Pregnancy
Rheumatologic
1. Psoriasis
2. Dermatomyositis
3. Juvenile Idiopathic Arthritis
4. Rheumatoid Arthritis (DMARD)
  1. Early Rheumatoid Arthritis
  2. Chronic Late Rheumatoid Arthritis
  3. Seronegative Rheumatoid Arthritis
Cancer Chemotherapy
1. Acute Myelocytic Anemia
2. Acute lymphocytic Anemia
3. Non-Hodgkin Lymphoma
4. Head and Neck Cancer
5. Cervical Cancer
6. Cutaneous T-Cell Lymphoma
7. Breast Cancer
8. Lung Cancer
9. Meningeal Leukemia
10. Testicular Cancer
11. Trophoblastic Neoplasia (Hydatidiform Mole)
12. Wilms Tumor
13. Sarcoma (including Osteosarcoma)

Contraindications
Absolute

Renal Insufficiency (Serum Creatinine > 1.5)
Pleural Effusion
Ascites
Active Stomatitis
Diarrhea
Infection

Contraindications
Relative (due to hepatotoxicity)

Alcohol Use
Pre-existing liver disease
Diabetes Mellitus
Obesity
Age >70 years

Mechanism

Suppresses DNA synthesis (and cell division) in the Gastrointestinal Tract, skin and Bone Marrow
Folic Acid structural analog
1. Competitively inhibits at Dihydrofolate Reductase
Inhibits de novo Pyrimidine synthesis
1. Inhibits dihydrofolate reductase (DHFR) which reduces dihydrofolate to Tetrahydrofolate
2. Decreases Tetrahydrofolate production which is critical to thymidylate synthesis
Antimetabolite Chemotherapy (Cell Cycle Specific)
1. S-Phase toxin (DNA synthesis phase)
DMARD antiinflammatory drug in Rheumatoid Arthritis (first-line agent)
1. Weekly dosing, at lower total doses than for cancer Chemotherapy
2. Suppresses immune cell proliferation (via DHFR inhibition)
3. Onset of symptomatic relief at 4 to 6 weeks after starting

Dosing

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
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)
Cancer Chemotherapy
1. Oral: 2.5 to 5 mg/day
2. Intrathecal: 10 mg weekly to biweekly

Pharmacokinetics

Oral Bioavailability: 60%
Peak blood concentration: 1 to 3 hours
Half-Life: 8 hours
Well tolerated dose cutoffs
1. Children <20 mg
2. Adults <60 mg

Safety

Avoid in Lactation
Avoid in pregnancy (all trimesters)
1. Teratogenic (including fetal death and congenital anomalies)
2. Use reliable Contraception

Adverse Effects
General

Oral and Gastrointestinal (most common)
1. Nausea or Vomiting
2. Oral Ulcers
3. Stomatitis
4. Diarrhea
Hepatic
1. Hepatic Fibrosis
2. Elevated transaminases
3. Cirrhosis
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
Hematologic
1. Minimal Immunosuppression
  1. Contrast with Imuran, Cytoxan, Sandimmune
2. Myelosuppression
3. Thrombocytopenia
Neuropsychiatric
1. Dysphoria
2. Methotrexate-Induced Leukoencephalopathy (see below)

Adverse Effects
Methotrexate-Induced Leukoencephalopathy

Transient, dose-dependent complication of intrathecal Methotrexate in children with Acute Lymphoblastic Leukemia
1. 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
1. Presents with 2 weeks of Methotrexate, with Headaches, lethargy, confusion, Seizures and stroke symptoms
2. Symptoms typically resolve within 1 week, after which Methotrexate may be restarted (with leucovorin)
Leukoencephalopathy is a diagnosis of exclusion
1. Evaluate for other emergent causes of acute neurologic changes (CVA, TIA, CNS bleed, PRES, acute Delirium)
2. Obtain emergent CNS imaging and other testing (including CT/CTA if stroke-like symptoms)
References
1. Waldner and Beamon (2024) Crit Dec Emerg Med 38(6): 16-7

Efficacy

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

Monitoring

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
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
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

Management
Toxicity or Overdose

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
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
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
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
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
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
Other measures
1. Hemodialysis may be indicated in significant Acute Kidney Injury
Disposition
1. Observe and treat symptomatic exposures until Methotrexate level <0.01 umol/L
2. Asymptomatic exposures should be observed 6 hours before discharge
References
1. Mason and Vohra (2018) in EM:Rap 18(8): 13
2. Tomaszewski (2022) Crit Dec Emerg Med 36(7): 32

Drug Interactions
Agents that increase Methotrexate levels

Antibiotics (hold Methotrexate dose until Antibiotic course completed)
1. Sulfa Antibiotics (e.g. Trimethoprim Sulfamethoxazole)
2. Cephalosporins
3. Penicillins
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

Resources

Methotrexate Tablet (DailyMed)
1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=dd39255b-81d1-4c08-aecf-acc4f2cdc04a

References