Physicians' Cancer Chemotherapy Drug Manual 2004
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

 

M

Methotrexate


Generic Drug Name
Methotrexate

 

 



 

Trade Names
MTX, Amethopterin
 


 

Classification
Antimetabolite


 

Category
Chemotherapy drug


 

Drug Manufacturer
Lederle Laboratories and Immunex


 

Mechanism of Action
 

  • Cell cycle–specific antifolate analog, active in S-phase of the cell cycle.
  • Enters cells through specific transport systems mediated by the reduced folate carrier and the folate receptor protein.
  • Requires polyglutamation by the enzyme folylpolyglutamate synthase (FPGS) for its cytotoxic activity.
  • Inhibition of dihydrofolate reductase (DHFR) resulting in depletion of critical reduced folates.
  • Inhibition of de novo thymidylate synthesis.
  • Inhibition of de novo purine synthesis.
  • Incorporation of dUTP into DNA resulting in inhibition of DNA synthesis and function.

 


 

Mechanism of Resistance
 

  • Increased expression of the target enzyme DHFR through either gene amplification or increased transcription, translation, and/or post-translational events.
  • Alterations in the binding affinity of DHFR for methotrexate.
  • Decreased carrier-mediated transport of drug into cell through decreased expression and/or activity of reduced folate carrier (RFC) or folate-receptor protein.
  • Decreased formation of cytotoxic MTX polyglutamates through either decreased expression of FPGS or increased expression of gamma-glutamyl hydrolase (GGH).
  • Decreased expression of mismatch repair (MMR) enzymes may contribute to the development of resistance.

 


 

Absorption
Oral bioavailability is saturable and erratic at doses greater than 25 mg/m2. Peak serum levels are achieved within 1–2 hours of oral administration. Methotrexate is completely absorbed from parenteral routes of administration, and peak serum concentrations are reached in 30–60 minutes after IM injection.


 

Distribution
Widely distributed throughout the body. At conventional doses, CSF levels are only about 5%–10% of those in plasma. High-dose MTX yields therapeutic concentrations in the CSF. Distributes into third-space fluid collections such as pleural effusion and ascites. Only about 50% of drug is bound to plasma proteins, mainly to albumin.


 

Metabolism
Extensive metabolism in liver and in cells by FPGS to higher polyglutamate forms. About 10%–20% of parent drug and the 7-hydroxymetabolite are eliminated in bile and then reabsorbed via enterohepatic circulation. Renal excretion is the main route of elimination and is mediated by glomerular filtration and tubular secretion. About 80%–90% of an administered dose is eliminated unchanged in urine within 24 hours. Terminal half-life of drug is on the order of 8–10 hours.


 

Indications
 

  1. Breast cancer.
  2. Head and neck cancer.
  3. Osteogenic sarcoma.
  4. Acute lymphoblastic leukemia.
  5. Non-Hodgkin's lymphoma.
  6. Meningeal leukemia and carcinomatous meningitis.
  7. Bladder cancer.
  8. Colorectal cancer.
  9. Gestational trophoblastic cancer.

 


 

Dosage Range
 

  1. Low dose: 10–50 mg/m2 IV every 3–4 weeks.
  2. Low dose weekly: 25 mg/m2 IV weekly.
  3. Moderate dose: 100–500 mg/m2 IV every 2–3 weeks.
  4. High dose: 1–12 gm/m2 IV over a 3- to 24-hour period every 1–3 weeks.
  5. Intrathecal: 10–15 mg/m2 IT 2 times weekly until CSF is clear, then weekly dose for 2–6 weeks, followed by monthly dose.
  6. Intramuscular: 25 mg/m2 IM every 3 weeks.

 


 

Drug Preparation
 

  • Available in 50, 100, 200, and 1,000 mg single-use reconstituted vials for IV use. Methotrexate can also be given via the oral, IM, and IT routes.
  • May dilute further in 0.9% sodium chloride.
  • Reconstituted solution is stable for 24 hours at room temperature.

 


 

Drug Interaction 1
Aspirin, penicillins, probenecid, nonsteroidal anti-inflammatory agents, cephalosporins, and phenytoin―These drugs inhibit the renal excretion of methotrexate leading to enhanced drug effect and toxicity.


 

Drug Interaction 2
Warfarin―Methotrexate may enhance the anticoagulant effect of warfarin through competitive displacement from plasma proteins.


 

Drug Interaction 3
5-Fluorouracil―Methotrexate enhances the antitumor activity of 5-fluorouracil when given 24 hours before fluoropyrimidine treatment.


 

Drug Interaction 4
Leucovorin―Leucovorin rescues the host toxic effects of methotrexate and may also impair the antitumor activity.


 

Drug Interaction 5
Thymidine―Thymidine rescues the host toxic effects of methotrexate and may also impair the antitumor activity.


 

Drug Interaction 6
Folic acid supplements―Folic acid supplements may counteract the antitumor effects of methotrexate and should be discontinued while on therapy.


 

Drug Interaction 7
Omeprazole―Omeprazole increases serum methotrexate levels, leading to enhanced antitumor activity and host toxicity.


 

Drug Interaction 8
L-Asparaginase―L-Asparaginase antagonizes the antitumor activity of methotrexate.


 

 

 



 

Special Considerations
 

  1. Use with caution in patients with abnormal renal function. Dose should be reduced in proportion to the creatinine clearance. Important to obtain baseline creatinine clearance and to monitor renal status during therapy.
  2. Instruct patients to stop folic acid supplements during therapy as they may counteract the effects of methotrexate.
  3. Monitor complete blood counts on a weekly basis and more frequently with high-dose therapy.
  4. Use with caution in patients with third-space fluid collections such as pleural effusion and ascites, as the half-life of methotrexate is prolonged, leading to enhanced clinical toxicity. Fluid collections should be drained before methotrexate therapy.
  5. Use with caution in patients with bladder cancer status post cystectomy and ileal conduit diversion as they are at increased risk for delayed elimination of methotrexate and subsequent toxicity.
  6. With high-dose therapy, methotrexate doses > 1 gm/m2, important to vigorously hydrate the patient with 2.5–3.5 liters/m2/day of IV 0.9% sodium chloride starting 12 hours before and for 24–48 hours after methotrexate infusion. Sodium bicarbonate (1–2 amps/L solution) should be included in the IV fluid to ensure that the urine pH is greater than 7.0 at the time of drug infusion and ideally for up to 48–72 hours after drug is given.
  7. Methotrexate blood levels should be monitored in patients receiving high-dose therapy, patients with renal dysfunction (creatinine clearance < 60 mL/min) regardless of dose, and patients who have experienced excessive toxicity with prior treatment with methotrexate.
  8. With high-dose therapy, methotrexate blood levels should be monitored every 24 hours starting at 24 hours after methotrexate infusion. Leucovorin rescue should begin at 24 hours after drug infusion and should continue until the methotrexate drug level is < 50 nM.
  9. Patients should be instructed to lie on their side for at least 1 hour after intrathecal administration of methotrexate. This will ensure adequate delivery of drug throughout the CSF.
  10. Intrathecal administration of methotrexate may lead to myelosuppression and/or mucositis as therapeutic blood levels can be achieved.
  11. Methotrexate overdose can be treated with leucovorin and/or thymidine.
  12. Instruct patients to avoid sun exposure for at least 1 month after therapy.
  13. Pregnancy category D.

 


 

Toxicity 1
Myelosuppression. Dose-limiting toxicity with leukocyte nadir at days 4–7 and recovery usually by day 14.
 


 

Toxicity 2
Mucositis. Can be dose-limiting. Typical onset is 3–7 days after methotrexate therapy and precedes the decrease in leukocyte and platelet count. Nausea and vomiting are dose-dependent.
 


 

Toxicity 3
Acute renal failure, azotemia, urinary retention, and uric acid nephropathy. Renal toxicity results from the intratubular precipitation of methotrexate and its metabolites. Methotrexate itself may exert a direct toxic effect on the renal tubules.
 


 

Toxicity 4
Transient elevation in serum transaminases and bilirubin are often observed with high-dose therapy. May occur within the first 12–24 hours after start of infusion and returns to normal within 10 days.
 


 

Toxicity 5
Poorly defined pneumonitis characterized by fever, cough, and interstitial pulmonary infiltrates.
 


 

Toxicity 6
Acute chemical arachnoiditis with severe headaches, nuchal rigidity, seizures, vomiting, fever, and an inflammatory cell infiltrate in the CSF is observed immediately after intrathecal administration. Chronic, demyelinating encephalopathy observed in children months to years after intrathecal methotrexate and presents as dementia, limb spasticity, and in advanced cases, coma.
 


 

Toxicity 7
Acute cerebral dysfunction with paresis, aphasia, behavioral abnormalities, and seizures observed in 5%–15% of patients receiving high-dose methotrexate. Usually occurs within 6 days of treatment and resolves within 48–72 hours. A chronic form of neurotoxicity manifested as an encephalopathy with dementia and motor paresis can develop 2–4 months after treatment.
 


 

Toxicity 8
Erythematous skin rash, pruritus, urticaria, photosensitivity, and hyperpigmentation. Radiation recall skin reaction is also observed.
 


 

Toxicity 9
Menstrual irregularities, abortion, and fetal deaths in women. Reversible oligospermia with testicular failure reported in men with high-dose therapy.