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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:
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:  high dose: 24-100 mL/min/m2; clearance higher in children than in adults
t½ a  high doses: 8-12 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
• mouth sores (dose related, stomatitis)
• gastrointestinal problems (diarrhea, bleeding, perforation)
• liver problems (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),  CNS problems (acute encephalopathy)
• blood problems (megaloblastosis)
• kidney problems (toxic neuropathy, with high doses)

DELAYED/LATE ONSET (weeks to years)
• liver problems (fibrosis, cirrhosis)
• central nervous system problems


Approved Indications

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

• Breast cancer
• Bladder cancer       
• Chorioadenoma destruens and hydatidiform mole
• Head and neck cancer 
• Lung cancer     
• Meningeal leukemia
• Osteogenic sarcoma
• Sarcoma, adult soft tissue
• Prevention of acute graft-versus host disease


• Intermittent IV (in appropriate volume over 1-8 hours)
• Continuous IV (in appropriate volume over 24 hours)


High-Dose (>1g/m²)
• Hydrate with Normal Saline at 100-125mL/hour, starting 6 to 12 hours before Methotrexate; measure urine output (>60 mL/hour)
• Alkalinize urine, starting 6-12 hours before Methotrexate, with Sodium Bicarbonate 50mmol in alternating litres of IV hydration fluid (or in each litre); maintain urine pH > 7.0 (may also give Sodium Bicarbonate 1000mg/m² PO q6h or Acetazolamide 250 to 500mg PO q6h)
• Admix into 1000mL (5% Dextrose, Normal Saline) and infuse over 4 hours, as an inpatient
• Continue hydration and alkalinization for 24 hours after completion of Methotrexate infusion
• Leucovorin rescue to start 24 hours after Methotrexate dosing finished; continue until serum levels drop below toxic range (<0.05µmol/L)

IV Compatibility

Normal saline, dextrose 5%, lactated Ringer’s.


• q1-3w: 100 mg-30 g/m² followed by leucovorin rescue within 2-24 hours

Leucovorin rescue:
• See leucovorin monograph for dosing guidelines for leucovorin rescue.

• q4w: 300-3000 mg/m²
• q3-4w: 8-12 g/m² IV (top dose 20 g) with hydration of 3 L/m²/day, alkalinization of urine and leucovorin rescue; use only preservative-free methotrexate
• 6 g/m² loading dose, followed by 1.2 g/m²/hour x 23 hours with leucovorin rescue starting 12 hours after end of methotrexate infusion:
• 200 mg/m² loading dose, followed by 12 mg/m² q3h x 6 doses, then q6h until methotrexate levels fall below 0.1µmol; use preservative-free methotrexate

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)

Antiemetic Risk

LOW RISK (Less than 10% of patients)
• No routine antiemetic pre-chemotherapy or post-chemotherapy


• 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 (serum proteins may be added if indicated)]
• Baseline and periodic chest X-ray

Extravasation Hazard


Significant Interactions

Alcohol & other hepatotoxic agents, amiodarone, antibiotics, anticonvulsant agents, asparaginase, co-trimoxazole, cyclosporin, etretinate, leucovorin, nitrous oxide, non-steroidal anti-inflammatory drugs (NSAIDs), non-absorbable oral antibiotics, phenytoin, probenecid, theophylline, thiazide diuretics, thiopurines (azathioprine, mercaptopurine), warfarin other antineoplastic agents.

Product Information

Commercial Product Description

Yellow tablets with 2.5mg Methotrexate. Generic products available Multidose vials with 50mg/2mL, 500mg/20mL, 1000mg/40mL, 5000mg/200mL. Also known as Amethopterin. For intrathecal use: Vials of 20mg for reconstitution,Vials of 20mg/2mL unpreserved solution.

Pharmaceutical Considerations

10 mg/mL solution (preservative-free), and 25 mg/mL solution (preservative-free or preserved with benzyl alcohol). Store at room temperature, protected from light.

Reconstituted solution for injection:
Stable at least 1 week at room temperature protected from light. However, the manufacturers recommend reconstitution immediately before use and that unused portions of vials reconstituted with preservative-free diluents be discarded.

Diluted solution for infusion:
Compatible for 7 days at room temperature in NS, D5W, D10W, dextrose-saline combinations, Ringer’s Injection, lactated Ringer’s, and 5% sodium bicarbonate. Solutions of 0.1 mg/mL are reported to undergo photodegradation (5-8% loss in 10 days, 11-17% in 20 days) on exposure to light. This effect was not noted in the more concentrated solutions.
Immersion of a needle with an aluminum component in methotrexate 25 mg/mL resulted in the formation of orange crystals on the aluminum surface after 36 hours at room temperature, protected from light.
Some mixtures with cytarabine, hydrocortisone sodium succinate, and sodium bicarbonate are compatible (see Stability in Syringes). Compatible with ondansetron. It is recommended that methotrexate not be mixed with other drugs. Incompatible with bleomycin, prednisolone sodium phosphate, ranitidine and some concentrations of heparin and metoclopramide.

Handling Risk Level

FDA Pregnancy Risk Factor D

  • This drug must be handled using precuations outlined in CCNS Policies for Occupational Safety and Administering Cancer Chemotherapy



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

Availability & Funding

Administrative Information (Nova Scotia)

• CCNS Provincial Formulary Status- Injection- Specialized Level (Capital Health Only) for high-dose; • Go to "Additional Information" tab (above) for links to Provincial Formulary of Cancer Drugs • Pharmacare Formulary Status- Formulary • NOTE: It is required to limit ordering of this medication to standard preprinted order forms, for patient safety.