Systemic Therapy Program

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Disease Group

Cancer Type

Document Type

Drug Monographs
Treatment Regimens

Scientific Name:
Brand Name(s):
Amethopterin, Methotrexate

Drug Monograph


Mechanism of Action

Methotrexate is a folate antimetabolite that inhibits DNA synthesis. Methotrexate irreversibly binds to dihydrofolate reductase, inhibiting the formation of reduced folates, and thymidylate synthase, resulting in inhibition of purine and thymidylic acid synthesis. It is cell cycle specific for the S phase of the cycle.


Oral Absorption
well absorbed <30 mg/m2, 20% >80 mg/m2, bioavailability decreased by food and milk
highest levels kidney, gallbladder, spleen, liver and skin, retained in liver for prolonged periods, crosses placenta, found in breast milk and malignant effusions
cross blood brain barrier? poorly
Vd:  0.4-0.8 L/kg, 16.4 L/m2 
PPB: 50%
<10% of dose is metabolized, converted to 4-deoxy-4-amino-N10-methyl pteroic acid (DAMPA) by carboxypeptidase (GI-tract), to 7-hydroxymethotrexate by aldehyde oxidase (liver) and polyglutamated intracellularly
metabolite(s): active- yes inactive- yes
excreted principally by the kidney (80%) via both glomerular filtration and active transport, biliary excretion <10%, significant inter- and intrapatient variability; small amounts are excreted in the feces
Urine: 44%-100% excreted unchanged
Cl:  low dose: 36-138 mL/min/m2; clearance higher in children than in adults
t½ a  low doses: 3-10 hours
t½ b 8-15 hours

Side Effects

IMMEDIATE ONSET (hours to days)
* anaphylaxis (rare)
   nausea and vomiting (dose related, 40% with high dose)
   allergic (fever and chills, rare) radiation recall reaction (rare)
   chemical meningitis (intrathecal use)
   lung problems (pulmonary edema, pleuritic chest pain)
EARLY ONSET  (days to weeks)
* low WBC, RBC, platelets (myelosuppression, nadir 7-14 days, recovery 14-21 days)
   mouth sores (dose related, stomatitis), diarrhea
* gastrointestinal bleeding, perforation
   dizziness, drowsiness, dysphagia
   elevated liver function tests
   skin problems (pigmentation changes, photosensitivity, rash)
   loss of appetite (anorexia),  hair loss (alopecia, usually mild)
* lung problems (interstitial pneumonitis)
   eye problems (conjunctivitis)
* kidney problems (toxic nephropathy, with high doses)
* cardiovascular problems (hypotension, pericardial effusion, thrombosis)
DELAYED/LATE ONSET (weeks to years)
* hepatotoxicity (fibrosis, cirrhosis)
   central nervous system problems  (acute encephalopathy, paresthesia)


Approved Indications

• Acute lymphocytic leukemia
• Choriocarcinoma
• Graft versus host disease (prophylaxis)
• Mycosis fungoides
• Non-Hodgkin’s lymphoma


• oral (well absorbed <30 mg/m2)


• daily: 0.625-2.5 mg/kg
• q1-2w: 15-30 mg x 5 days (or IM)
• biw (twice a week): 10-15 mg/m²/dose (or IM)
• q2w: 2.5 mg/kg
• daily: 3.3 mg/m² x 4-6 weeks

Dose Adjustment Criteria

Hepatic dysfunction
Reduce to 75% dose if Bili = 50-85µmol/L or AST> 180IU/L;
Omit if Bili > 85µmol/L
Renal failure
Reduce to 50% dose if CrCl = 0.2-0.8mL/sec or Serum Creatinine= 100-180µmol/L;
Omit if CrCl < 0.2mL/sec or Serum Creatinine >180µmol/L (Suggested action)


pregnancy and breast feeding low WBC, RBC, platelets (myelosuppression) effusions severe renal failure


Clinical Monitoring

Complete blood count including differential, platelets and hemoglobin (CBC) before each cycle of treatment
Clinical assessment of stomatitis; oral examination upon patient complaint of a sore mouth
• Baseline renal function tests (if failure suspected) [serum creatinine, electrolytes & BUN]
• Baseline and periodic liver function tests [serum alkaline phosphatase, GGT, ALT, AST & Bilirubin levels]
• Baseline and periodic chest X-ray

Significant Interactions

* Drinking alcohol while taking Methotrexate increases hepatotoxicity and should be avoided. • Acitretin: may increase hepatotoxicity of Methotrexate (avoid combination) • Alitretinoin (systemic): may increase hepatotoxicity of Methotrexate • BCG: Methotrexate may decrease therapeutic effect of BCG (avoid combination) • Bile acid sequestrants: may decrease absorption of Methotrexate • Ciprofloxacin (systemic): may increase the serum concentration of Methotrexate • CloZAPine: Methotrexate may enhance the toxicity of CloZAPine, especially agranulocytosis. (avoid combination) • Cyclosporine (systemic): may increase the serum concentration of Methotrexate. This may cause vomiting, oral ulcers, hepatotoxicity and/or nephrotoxicity. Methotrexate may increase the serum concentration of Cyclosporine. This may result in nephrotoxicity. (consider therapy modification) • Denosumab: may enhance the toxicity of Methotrexate, especially the risk for serious infections • Digoxin: Methotrexate may decrease absorption of Digoxin. • Echinacea: may diminish the therapeutic effect of Methotrexate, because Echinacea may stimulate the immune system. Do not take Echinacea. • Eltrombopag: may increase the serum concentration of OATP1B1/SLCO1B1 substrates. Consideration of a preventative dose reduction may be warranted. (Consider therapy modification) • Leflunomide: Methotrexate may increase the toxicity of Leflunomide, especially the risk of pancytopenia and/or hepatotoxicity • Loop diuretics (e.g. furosemide): Methotrexate may diminish the therapeutic effect of loop diuretics. Methotrexate may increase the serum concentration of these drugs. Loop diuretics may also increase the serum concentration of Methotrexate. Monitor for increased Methotrexate and/or loop diuretic levels/toxicity and monitor for decrease therapeutic effect of loop diuretic. Dose reductions may be needed. • NSAIDs: may increase the serum concentration of Methotrexate (Consider therapy modification) • Penicillins: may increase the serum concentration of Methotrexate • P-glycoprotein/ABCB1 Inducers: may decrease the serum concentration of P-glycoprotein substrates, and may also limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large quantities (brain, T cells, testes, etc.) • P-glycoprotein/ABCB1 Inhibitors: may increase the serum concentration of P-glycoprotein/ABCB1 substrates. P-glycoprotein inhibitors may also increase the distribution of p-glycoprotein substrates to specific cells, tissues, or organs where p-glycoprotein is found in large amounts. • Phenytoin, Fosphenytoin: Methotrexate may decrease the serum concentration of Fosphenytoin-Phenytoin • Probenecid: may increase serum concentration of Methotrexate (Avoid combination if possible, and consider lower Methotrexate doses/monitor for toxicity if used concomitantly.) • Proton Pump Inhibitors: may increase serum concentration of Methotrexate • Roflumilast: may increase immunosuppressive effect of Methotrexate (Consider therapy modification) • Salicylates: may increase serum concentration of Methotrexate. Doses used for prophylaxos of cardiovascular events are not likely of concern. • Sapropterin: Methotrexate may decrease serum concentration of Sapropterin (may decrease tissue concentrations of tetrahydrobiopterin. • SulfaSALAzine: may increase hepatotoxicity of Methotrexate • Sulfonamide antibiotics: may increase the toxicity of Methotrexate. Consider avoiding concomitant use of Methotrexate and either sulfamethoxazole or trimethoprim. If used together, monitor for Methotrexate toxicity (e.g. bone marrow suppression). • Tacrolimus (topical): may increase toxicity of Methotrexate (avoid combination) • Theophylline derivatives: Methotrexate may increase serum concentration of these drugs • Trastuzumab: may increase the neutropenic effect of Methotrexate • Vaccines (inactivated): Methotrexate may diminish the effect of vaccines • Vaccines (live): Methotrexate may increase the toxicity of live vaccinations • Vitamin supplements containing folic acid: may decrease Methotrexate levels (avoid combination) • Vitamin K Antagonists (e.g. Warfarin): Methotrexate may increase/decrease the anticoagulant effect of these drugs.

Product Information

Commercial Product Description

Brand Name: Methotrexate Yellow tablets with 2.5mg Methotrexate Generic products available

Pharmaceutical Considerations

Tablets:   2.5 mg. The Lederle brand also contains cornstarch, magnesium stearate and lactose but is dye- and tartrazine-free. The David Bull Laboratories product contains no preservatives or colouring agents. Store at room temperature.



FDA Pregnancy Risk Factor D
• This drug must be handled using precautions outlined in CCNS Policies for Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy and the CCNS Standard for Oral Systemic Therapy for Cancer
• Go to "Additional Information" tab (above) for links to CCNS Policies

Availability & Funding

Administrative Information (Nova Scotia)

CCNS Provincial Formulary Status- Injection- Basic Level for low dose • Go to "Additional Information" tab (above) for links to Provincial Formulary of Cancer Drugs Pharmacare Formulary Status- Formulary NOTE: It is recommended to limit ordering of this medication to standard preprinted order forms, for patient safety

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