METHOTREXATE SODIUM 
Pronounciation
- (meth-oh-TREKS-ayt SO-dee-um)
Trade Name(s)
- Methotrexate PF, MTX
Baseline studies indicated; see Monitor. Verify pregnancy status; see Contraindications.
Many dose limitations based on patient condition, renal and hepatic function, and concomitant drugs or therapies; see Precautions/Monitor. Doses between 100 and 500 mg/M2 may require leucovorin calcium rescue. Doses over 500 mg/M2 require leucovorin calcium rescue; see leucovorin calcium or levoleucovorin (Fusilev) monograph. Part of numerous protocols that change as new advances in antileukemic therapy and other cancers are developed. Selections from those protocols are included in the following text.
Induction: 3.3 mg/M2 in combination with prednisone 60 mg/M2. Give daily if tolerated, and continue for up to 8 weeks or until satisfactory response (usually 4 to 6 weeks). Usually given PO.
Dose individualized; 15 mg/M2/dose administered 2 times weekly IM or PO (a total weekly dose of 30 mg/M2) or 2.5 mg/kg IV every 14 days has been used.
5 to 50 mg once weekly in the early stages of disease. Adjust dose or discontinue as indicated by patient response and hematologic monitoring. 15 to 37.5 mg twice weekly may be used in patients who respond poorly to weekly therapy. Usually given PO or IM, but combination chemotherapy regimens, including higher doses of IV methotrexate with leucovorin calcium rescue, have been used in advanced stages of the disease.
One regimen administers methotrexate 40 mg/M2 on Days 1 and 8 of each cycle. Given in combination with PO cyclophosphamide 100 mg/M2 on Days 1 through 14 of each cycle and fluorouracil 600 mg/M2 on Days 1 and 8 of each cycle. In patients over 60 years of age, reduce the initial methotrexate dose to 30 mg/M2 and the initial fluorouracil dose to 400 mg/M2. Repeat monthly (allows a 2-week rest period between cycles) for 6 to 12 cycles.
10 to 25 mg once a week until adequate response. Some references suggest an initial test dose of 5 to 10 mg/week before initiating therapy to detect sensitivity to adverse reactions. Sources suggest 30 mg/week as a maximum dose. Use smallest effective dose. Usually given PO or IM. May be used in combination with infliximab; see infliximab monograph.
One regimen recommends 12 Gm/M2 as a single dose given as an infusion over 4 hours. Begin the fourth week after surgery and repeat weekly at Weeks 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, and 45. A peak serum concentration of 1,000 micromolars/L at the end of the infusion is desired. Dose may be increased to 15 Gm/M2 if required. Must be accompanied by leucovorin calcium rescue; see leucovorin calcium or levoleucovorin (Fusilev) monograph. Leucovorin calcium may be given IV or PO; levoleucovorin is IV only. When methotrexate is given in combination with leucovorin rescue, the serum creatinine must be normal, and creatinine clearance must be greater than 60 mL/min before beginning therapy. Osteosarcoma also requires combination chemotherapy. Protocols vary but may include methotrexate in combination with doxorubicin, with cisplatin, and with the combination of bleomycin, cyclophosphamide, and dactinomycin (BCD regimen). These massive doses are highly individualized and require exacting calculations and constant patient monitoring; see Precautions/Monitor.
Safety for use in pediatric patients is limited to chemotherapy and in polyarticular-course juvenile rheumatoid arthritis. May contain benzyl alcohol; not recommended for use in neonates. See Maternal/Child.
Manufacturer does not provide information on dose adjustment in patients with impaired renal or hepatic function. However, various recommendations are available in the literature. In patients with impaired hepatic function, one source recommends administering 75% of dose if bilirubin is between 3.1 and 5 or if transaminases are greater than 3 times the ULN; if bilirubin above 5, omit dose. ■ Reduced doses may be required in patients with impaired renal function. Suggested guidelines are to administer 50% of a dose with a CrCl of 10 to 50 mL/min, and avoid use with a CrCl of less than 10 mL/min in adult patients. In pediatric patients, administer 50% of a dose with a CrCl of 10 to 50 mL/min and 30% of a dose with a CrCl of less than 10 mL/min/1.73M2. ■ Reduced dose may be required in patients with ascites or pleural effusions, in the very young or very elderly, in the debilitated, and in other diseases; see Precautions. ■ Often used with other antineoplastic drugs to achieve tumor remission. ■ See Drug/Lab Interactions.
Specific techniques required; see Precautions.
Available in solution or as a lyophilized powder. Reconstitute powder with D5W or NS. The 1-Gm vial should be reconstituted with 19.4 mL to a concentration of 50 mg/mL. When high-dose methotrexate is administered by IV infusion, the total dose is diluted in D5W. 25 mg/mL is the maximum suggested concentration that can be given IV. Reconstitution of each 5 mg with 2 mL of preservative-free D5W or NS is suggested. Each milliliter equals 2.5 mg of methotrexate. Available in preservative-free solution. Do not use formulations or diluents with preservatives (e.g., bacteriostatic) for high-dose therapy or intrathecal injection. 1-Gm vial available for high-dose use with appropriate dilution. Not usually added to IV solutions when given in smaller doses (less than 100 mg). Discard solution if a precipitate forms. May be given through Y-tube or three-way stopcock of a free-flowing IV.
A single dose may be further diluted with D5W or NS immediately before use as an infusion with higher (100 mg or more) methotrexate doses.
No data available from manufacturer. Another source indicates no significant drug loss filtered through a nylon 0.2-micron filter.
Store in unopened container at CRT; protect from light. If prepared without a preservative, use immediately. May be stable up to 24 hours with a preservative.
Compatibility information not available from manufacturer. Other sources suggest specific compatibilities dependent on concentration and manufacturer; consult a pharmacist.
Slow IV push no more than 10 mg/minute.
A single dose equally distributed over 30 minutes to 4 hours or as prescribed by protocol.
An antimetabolite and folic acid antagonist. Inhibits dihydrofolic acid reductase. Cell cycle–specific for the S phase. It interferes with DNA synthesis, repair, and cellular replication. Rapidly proliferating tissues are more sensitive to this effect. Widely distributed and is approximately 50% protein bound. Undergoes some hepatic and intracellular metabolism. Half-life is dose dependent and is 3 to 10 hours in patients receiving low-dose antineoplastic therapy and 8 to 15 hours in patients receiving high-dose methotrexate therapy. 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. Clearance rates decrease with higher doses. Does not cross blood-brain barrier. Secreted in breast milk.
Used for life-threatening neoplastic disease alone or in combination with other anticancer agents in the treatment of acute lymphocytic leukemia, breast cancer, epidermal tumors of the head and neck, small-cell and squamous cell lung cancer, non-Hodgkin lymphoma, advanced mycosis fungoides (cutaneous T-cell lymphoma). ■ Severe, recalcitrant disabling psoriasis or rheumatoid arthritis unresponsive to other treatment. Diagnosis of psoriasis should be established by biopsy and/or dermatology consultation before use. ■ To prolong relapse-free survival in patients with nonmetastatic osteosarcoma who have undergone surgical resection or amputation of the primary tumor. Given as a high-dose regimen with leucovorin rescue in combination with other chemotherapeutic agents. ■ Given PO or IM for early-stage mycosis fungoides, trophoblastic diseases (gestation choriocarcinoma, chorioadenoma destruens, and hydatidiform mole), polyarticular-course juvenile rheumatoid arthritis, rheumatoid arthritis, and other diagnoses, and given intrathecally for treatment and prophylaxis of meningeal leukemia.
Treatment of bladder and testicular cancer. Treatment of soft tissue sarcomas and CNS tumors. Management of Crohn’s disease and ectopic pregnancy and prevention of acute graft-versus-host disease. High-dose regimens for neoplastic diseases other than osteosarcoma are investigational, and therapeutic efficacy is not established.
Hypersensitivity to methotrexate; breast-feeding mothers. Contraindicated in pregnant females with psoriasis or rheumatoid arthritis and should be used during pregnancy for treatment of neoplastic diseases only when the potential benefit outweighs the risk to the fetus. Contraindicated in psoriasis or rheumatoid arthritis patients with immunodeficiency syndromes, pre-existing blood dyscrasias (e.g., bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia), alcoholism, alcoholic liver disease, or other chronic liver disease.
Follow guidelines for handling cytotoxic agents. See Appendix A. ■ Administered by or under the direction of the physician specialist.■ Methotrexate should be used only in life-threatening neoplastic diseases or in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease that is not responsive to other forms of therapy.■ Deaths have been reported with methotrexate use in the treatment of malignancy, psoriasis, and rheumatoid arthritis.■ Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Careful monitoring, dose reduction and, in some cases, discontinuation of therapy are required; consider evacuating excess fluid from ascites and pleural effusions before treatment if possible. ■ Methotrexate can suppress hematopoiesis, causing anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. ■ Serious and sometimes fatal bone marrow suppression, aplastic anemia, and GI toxicity have been reported with concomitant use of methotrexate (usually high doses) and some NSAIDs; see Drug/Lab Interactions.■ Leukoencephalopathy has been reported in patients who have received both IV methotrexate and craniospinal irradiation. ■ A transient stroke-like encephalopathy has been reported with high-dose methotrexate therapy. Symptoms may include confusion, hemiparesis, transient blindness, seizures, and coma. ■ Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, may occur at any time, may occur even with low doses, and has been fatal. Patients may present with fever, dry cough, dyspnea, hypoxemia, and an infiltrate on chest x-ray. May require interruption of therapy and is not always fully reversible. ■ Severe skin reactions can occur at any time and have been fatal.■ Transient elevations in liver enzymes may occur early during treatment. Chronic hepatotoxicity (fibrosis and cirrhosis) occurs more frequently with prolonged use and a total dose of at least 1.5 Gm. Persistent abnormalities in liver function tests and/or depression of serum albumin may be indicators of serious liver toxicity. Has resulted in deaths; see Monitor. ■ Use with extreme caution in patients with ascites, bone marrow suppression, folate deficiency, GI obstruction, impaired renal or liver function, infection, peptic ulcer, pleural effusion, or ulcerative colitis; in debilitated patients; and in the very young or very elderly. ■ Diarrhea and ulcerative stomatitis will require interrupting therapy; otherwise hemorrhagic enteritis and death from intestinal perforation may occur.■ Tumor lysis syndrome may occur, and S/S include hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, metabolic acidosis, urate crystalluria, and renal failure. Prevent or alleviate tumor lysis syndrome with appropriate supportive and pharmacologic measures; see Monitor. ■ Potentially fatal opportunistic infections, especially Pneumocystis jiroveci pneumonia, may occur.■ Risk of soft tissue necrosis and osteonecrosis may be increased with concomitant use of methotrexate and radiotherapy.■ May cause renal damage that may lead to acute renal failure. Nonreversible oliguric renal failure is likely to develop in patients who experience delayed early methotrexate elimination. ■ Malignant lymphomas have been reported. May occur in patients receiving low-dose methotrexate and may not require cytotoxic treatment; discontinue methotrexate first and initiate appropriate treatment if the lymphoma does not regress.■ Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitors. ■ Use caution when administering methotrexate after a recent history of nitrous oxide administration. ■ Lesions of psoriasis may be aggravated by concomitant exposure to UV radiation. ■ Radiation dermatitis and sunburn may be “recalled” by methotrexate use. ■ See Drug Interactions.
CBC with differential and platelet counts, chest x-ray, and renal and liver function tests before, during, and after therapy are essential to comprehensive treatment. ■ Close patient observation is mandatory. Course of therapy is not repeated until all signs of toxicity from the previous course subside. ■ Monitor closely for bone marrow, liver, lung, kidney, and skin toxicities.■ Nadir of leukocyte and platelet count usually occurs after 7 to 10 days, with recovery 7 days later. ■ Liver biopsy, pulmonary studies, and bone marrow studies may be indicated in high-dose or long-term therapy.■ Monitor renal function closely; verify by measurement of serum methotrexate and CrCl levels; see Precautions. Maintain continuing adequate hydration and urine alkalinization. ■ Prevention and treatment of hyperuricemia due to tumor lysis syndrome may be accomplished with adequate hydration and, if necessary, uric acid–lowering drugs (e.g., allopurinol).■ Monitor serum methotrexate levels. ■ Use prophylactic antiemetics to reduce nausea and vomiting and increase patient comfort. ■ Observe closely for signs of infection. Prophylactic antibiotics may be indicated pending results of C/S in a febrile neutropenic patient. ■ Profound granulocytopenia and fever should be evaluated immediately and usually requires parenteral broad-spectrum antibiotic therapy. ■ Monitor for thrombocytopenia (platelet count less than 50,000/mm3). Initiate precautions to prevent excessive bleeding (e.g., inspect IV sites, skin, and mucous membranes; use extreme care during invasive procedures; test urine, emesis, stool, and secretions for occult blood). ■ Administration of high-dose methotrexate requires the following: a WBC count greater than 1,500/mm3, neutrophil count greater than 200/mm3, platelet count greater than 75,000/mm3, serum bilirubin less than 1.2 mg/dL, alanine aminotransferase (ALT) level less than 450 units, healing of any mucositis, ascites or pleural effusion must be drained dry, normal SCr, CrCl greater than 60 mL/min, 1 L/M2 of IV fluid over 6 hours before dosing and 3 L/M2/day on day of infusion and for 2 days after, alkalinization of urine with sodium bicarbonate to maintain pH above 7, and repeat serum methotrexate and SCr levels at least daily until methotrexate level is below 0.05 micromolar. ■ See Drug/Lab Interactions.
Avoid pregnancy. Effective contraception recommended for both females and males. Continue for at least 3 months after treatment is complete in male patients and for at least one ovulatory cycle after therapy is complete for female patients. ■ Avoid alcohol and take only prescribed medications. Reactions can be lethal. ■ Side effects such as dizziness and fatigue may interfere with ability to drive or operate machinery. ■ Review early signs and symptoms of toxicity with health care provider. ■ Close follow-up with physician is imperative.■ See Appendix D.
Category X: avoid pregnancy. Has caused fetal death and congenital anomalies; effective contraception recommended.■ Discontinue breast-feeding. ■ Safety for use in pediatric patients established for cancer chemotherapy and polyarticular-course juvenile rheumatoid arthritis. ■ Serious neurotoxicity (e.g., general or focal seizures) has been reported in patients with acute lymphoblastic leukemia who have been treated with intermediate-dose methotrexate. ■ Administration of formulations containing the preservative benzyl alcohol has been associated with fatal gasping syndrome in neonates. Use preservative-free formulation of methotrexate in neonates.
See Dose Adjustments. Dose selection should be cautious and based on the potential for decreased organ function, decreased folate stores, and concomitant disease or drug therapy. ■ Consider monitoring CrCl and methotrexate levels. ■ Monitor for early signs of hepatic, renal, or bone marrow toxicity. ■ In chronic administration, certain toxicities may be decreased by folate supplementation. ■ Post-marketing experience suggests that the occurrence of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age.
The following drugs may enhance methotrexate toxicity when administered concomitantly: cyclosporine, any hepatotoxic drug (e.g., azathioprine, retinoids, sulfasalazine), NSAIDs (e.g., ibuprofen, ketoprofen, naproxen), penicillins (e.g., amoxicillin, nafcillin), probenecid, salicylates, sulfonamides, phenylbutazone, phenytoin, pyrimethamine, trimethoprim (component of sulfamethoxazole/trimethoprim), and vancomycin (given up to 10 days prior to methotrexate); interactions may be life threatening. Monitoring serum levels and/or reduced doses of methotrexate may be indicated or a longer duration of leucovorin calcium rescue may be required. One source suggests delaying administration of aspirin, NSAIDs, and probenecid for 48 hours after larger doses of methotrexate; see Precautions. ■ NSAIDs are used in the treatment of rheumatoid arthritis in combination with low doses of methotrexate (e.g., 7.5 to 15 mg/week). Do not administer NSAIDs before or concomitantly with high doses of methotrexate (e.g., treatment of osteosarcoma); deaths from severe hematologic and GI toxicity have been reported.■ Use caution if high-dose methotrexate is administered in combination with nephrotoxic chemotherapy agents (e.g., cisplatin). ■ Concurrent use of methotrexate (primarily at high dose) with some proton pump inhibitors such as esomeprazole, omeprazole, and pantoprazole may cause prolonged elevation of serum levels of methotrexate and its metabolite, hydroxymethotrexate, leading to toxicity. Discontinue several days before methotrexate administration. Consider an H2 antagonist. ■ Doxycycline may increase toxicity of methotrexate in high-dose regimens. ■ Vitamins with folic acid or its derivatives may inhibit the antifolate effects of methotrexate, decreasing effectiveness. ■ Use of nitrous oxide anesthesia results in the potential for increased toxicity such as myelosuppression, neurotoxicity, and stomatitis. Avoid concomitant administration with methotrexate. ■ May increase serum levels of mercaptopurine; dose adjustment may be required. ■ Do not administer live virus vaccines to patients receiving antineoplastic drugs. ■ Procarbazine may increase nephrotoxicity of methotrexate. Allow 72 hours between last dose of procarbazine and first dose of methotrexate. ■ Monitor for signs of increased bone marrow suppression with sulfonamides (e.g., sulfisoxazole, SMZ-TMP), bone marrow–suppressing agents (e.g., antineoplastics), and radiation therapy. May also cause SMZ-TMP-induced megaloblastic anemia. ■ May decrease theophylline clearance and increase serum levels; monitor theophylline serum levels with concurrent use. ■ Urinary alkalinizers increase renal excretion and may reduce effectiveness.
Toxicity usually dose related. Death can occur from average doses, high doses, drug interactions (e.g., NSAIDs), bone marrow toxicity, GI toxicity, hepatic toxicity, pulmonary toxicity, and/or severe skin reactions. Abdominal distress, chills, decreased resistance to infection, dizziness, fatigue, fever, leukopenia, malaise, nausea, and ulcerative stomatitis occur most frequently. Other side effects reported include abortion (spontaneous), acne, acute hepatitis, agranulocytosis, alopecia, alveolitis, anaphylaxis, anemia, anorexia, aplastic anemia, azotemia, blurred vision, chronic fibrosis and cirrhosis, convulsions, COPD, cystitis, decreased serum albumin, defective oogenesis or spermatogenesis, diabetes, diarrhea, drowsiness, ecchymosis, enteritis, eosinophilia, erythema multiforme, erythematous rashes, exfoliative dermatitis, fetal defects or death, furunculosis, GI ulceration and bleeding, gingivitis, gynecomastia, headache, hematemesis, hematuria, hemiparesis, hepatic failure, hepatotoxicity, hypotension, infertility, interstitial pneumonitis, liver enzyme elevations, lymphadenopathy and lymphoproliferative disorders, melena (passage of dark, tarry stools), menstrual dysfunction, nephropathy (severe), neutropenia, oligospermia (transient), opportunistic infections (e.g., cryptococcosis, cytomegalovirus infection, disseminated H. simplex, herpes zoster, histoplasmosis, H. simplex hepatitis, nocardiosis, Pneumocystis jiroveci pneumonia, pneumonia, sepsis [including fatal]), pancreatitis, pancytopenia, paresis, pericardial effusion, pericarditis, pharyngitis, photosensitivity, pigmentary changes, proteinuria, pruritus, pseudomembranous colitis, renal failure, respiratory failure, respiratory fibrosis, serious visual changes of unknown etiology, skin necrosis, skin ulceration, speech impairment (aphasia, dysarthria), Stevens-Johnson syndrome, stomatitis, stress fracture, suppressed hematopoiesis (blood cell formation), telangiectasia, thrombocytopenia, thromboembolic events (e.g., arterial thrombosis, cerebral thrombosis, deep vein thrombosis, pulmonary embolus, retinal vein thrombosis, thrombophlebitis), sudden death, toxic epidermal necrolysis, transient blindness, tumor lysis syndrome, urticaria, vaginal discharge, vomiting. Many other rarer side effects, including anaphylactoid reactions, have been reported.
Discontinue methotrexate and notify the physician of any side effects.Leucovorin calcium (citrovorum factor, folinic acid) may be given PO, IM, or IV promptly to counteract inadvertent overdose. Leucovorin calcium is also indicated as a planned rescue mechanism for large doses of methotrexate required to treat some malignancies. Doses equal to dose of methotrexate are frequently required. Should be given within 1 hour in overdose, 24 hours in rescue. See specific process for overdose and for rescue for high-dose MTX in leucovorin calcium monograph. Doses up to 150 mg or 100 mg/M2 every 3 hours may be required if SCr is 50% or greater than baseline measurement before methotrexate administration. Serum methotrexate must come down to below 0.05 micromolar. Continuing hydration and urinary alkalinization are mandatory to prevent precipitation in renal tubules. Monitor fluid and electrolyte status until serum methotrexate has fallen to less than 0.05 micromolar and renal failure has resolved. Glucarpidase (Voraxaze), an antidote indicated for the treatment of toxic methotrexate concentration in patients with delayed methotrexate clearance due to impaired renal function, may also be used. If glucarpidase is used, do not administer leucovorin within 2 hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase; see glucarpidase monograph. Administration of whole blood products (e.g., packed RBCs, platelets, leukocytes) and/or blood modifiers (e.g., darbepoetin alfa, epoetin alfa, filgrastim, pegfilgrastim, sargramostim) may be indicated to treat bone marrow toxicity. Death may occur from the progression of most of these side effects. Symptomatic and supportive therapy is indicated. Charcoal hemoperfusion may be helpful, and/or acute intermittent hemodialysis with a high-flux dialyzer may be used to counteract toxicity or inadvertent overdose.