For information 410.787.4000
Amethopterin; Methotrexate Sodium; MTX; NSC-740
Treatment of trophoblastic neoplasms; leukemias; psoriasis; rheumatoid arthritis (RA), including polyarticular-course juvenile rheumatoid arthritis (JRA); breast, head and neck, and lung carcinomas; osteosarcoma; soft-tissue sarcomas; carcinoma of gastrointestinal tract, esophagus, testes; lymphomas
X (psoriasis, rheumatoid arthritis)
Fetal death or teratogenic effects may occur. Use is contraindicated in pregnant women with psoriasis or rheumatoid arthritis. Use for the treatment of neoplastic diseases only when the potential benefit to the mother outweighs the possible risk to the fetus. Pregnancy should be excluded prior to therapy in women of childbearing potential. Pregnancy should be avoided for 3 months following treatment in male patients and 1 ovulatory cycle in female patients.
Enters breast milk/contraindicated
Hypersensitivity to methotrexate or any component of the formulation; severe renal or hepatic impairment; pre-existing profound bone marrow suppression in patients with psoriasis or rheumatoid arthritis, alcoholic liver disease, AIDS, pre-existing blood dyscrasias; pregnancy (in patients with psoriasis or rheumatoid arthritis); breast-feeding
The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered.
May cause potentially life-threatening pneumonitis (may occur at any time during therapy and at any dosage); monitor closely for pulmonary symptoms, particularly dry, nonproductive cough. Methotrexate may cause photosensitivity and/or severe dermatologic reactions which are not dose-related. Methotrexate has been associated with acute and chronic hepatotoxicity, fibrosis, and cirrhosis. Risk is related to cumulative dose and prolonged exposure. Ethanol abuse, obesity, advanced age, and diabetes may increase the risk of hepatotoxic reactions.
Methotrexate may cause renal failure, gastrointestinal toxicity, or bone marrow depression. Use with caution in patients with renal impairment, peptic ulcer disease, ulcerative colitis, or pre-existing bone marrow suppression. Gastrointestinal toxicity may be severe: diarrhea and ulcerative stomatitis may require interruption of therapy; death from hemorrhagic enteritis or intestinal perforation has been reported. Methotrexate penetrates slowly into 3rd space fluids, such as pleural effusions or ascites, and exits slowly from these compartments (slower than from plasma). The potential for toxicity may be increased under these conditions. Dosage reduction may be necessary in patients with renal or hepatic impairment, ascites, and pleural effusion. Toxicity from methotrexate or any immunosuppressive is increased in the elderly.
Severe bone marrow suppression, aplastic anemia, and GI toxicity have occurred during concomitant administration with NSAIDs. Use caution when used with other hepatotoxic agents (azathioprine, retinoids, sulfasalazine). Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis. Immune suppression may lead to opportunistic infections.
For rheumatoid arthritis and psoriasis, immunosuppressive therapy should only be used when disease is active and less toxic; traditional therapy is ineffective. Discontinue therapy in RA or psoriasis if a significant decrease in hematologic components is noted. Methotrexate formulations and/or diluents containing preservatives should not be used for intrathecal or high-dose therapy. Methotrexate injection may contain benzyl alcohol and should not be used in neonates.
Adverse reactions vary by route and dosage. Hematologic and/or gastrointestinal toxicities may be common at dosages used in chemotherapy; these reactions are much less frequent when used at typical dosages for rheumatic diseases.Note:
Central nervous system (with I.T. administration or very high-dose therapy):
Arachnoiditis: Acute reaction manifested as severe headache, nuchal rigidity, vomiting, and fever; may be alleviated by reducing the dose
Subacute toxicity: 10% of patients treated with 12-15 mg/m2 of I.T. methotrexate may develop this in the second or third week of therapy; consists of motor paralysis of extremities, cranial nerve palsy, seizure, or coma. This has also been seen in pediatric cases receiving very high-dose I.V. methotrexate (when enough methotrexate can get across into the CSF).
Demyelinating encephalopathy: Seen months or years after receiving methotrexate; usually in association with cranial irradiation or other systemic chemotherapy
Dermatologic: Reddening of skin
Endocrine & metabolic: Hyperuricemia, defective oogenesis or spermatogenesis
Gastrointestinal: Ulcerative stomatitis, glossitis, gingivitis, nausea, vomiting, diarrhea, anorexia, intestinal perforation, mucositis (dose dependent; appears in 3-7 days after therapy, resolving within 2 weeks)
<100 mg: Moderately low (10% to 30%)
Hematologic: Leukopenia, thrombocytopenia
Renal: Renal failure, azotemia, nephropathy
1% to 10%:
Central nervous system: Dizziness, malaise, encephalopathy, seizure, fever, chills
Dermatologic: Alopecia, rash, photosensitivity, depigmentation or hyperpigmentation of skin
Endocrine & metabolic: Diabetes
Myelosuppressive: This is the primary dose-limiting factor (along with mucositis) of methotrexate; occurs about 5-7 days after methotrexate therapy, and should resolve within 2 weeks
Onset: 7 days
Nadir: 10 days
Recovery: 21 days
Hepatic: Cirrhosis and portal fibrosis have been associated with chronic methotrexate therapy; acute elevation of liver enzymes are common after high-dose methotrexate, and usually resolve within 10 days.
Neuromuscular & skeletal: Arthralgia
Ocular: Blurred vision
Renal: Renal dysfunction: Manifested by an abrupt rise in serum creatinine and BUN and a fall in urine output; more common with high-dose methotrexate, and may be due to precipitation of the drug. The best treatment is prevention: Aggressively hydrate with 3 L/m2/day starting 12 hours before therapy and continue for 24-36 hours; alkalinize the urine by adding 50 mEq of bicarbonate to each liter of fluid; keep urine flow over 100 mL/hour and urine pH >7.
Respiratory: Pneumonitis: Associated with fever, cough, and interstitial pulmonary infiltrates; treatment is to withhold methotrexate during the acute reaction; interstitial pneumonitis has been reported to occur with an incidence of 1% in patients with RA (dose 7.5-15 mg/week)
<1% (Limited to important or life-threatening): Acute neurologic syndrome (at high dosages - symptoms include confusion, hemiparesis, transient blindness, and coma); anaphylaxis, alveolitis, cognitive dysfunction (has been reported at low dosage), decreased resistance to infection, erythema multiforme, hepatic failure, leukoencephalopathy (especially following craniospinal irradiation or repeated high-dose therapy), lymphoproliferative disorders, osteonecrosis and soft tissue necrosis (with radiotherapy), pericarditis, plaque erosions (psoriasis), seizure (more frequent in pediatric patients with ALL), Stevens-Johnson syndrome, thromboembolism
Symptoms of overdose include nausea, vomiting, alopecia, melena, and renal failure.
Antidote: Leucovorin; administer as soon as toxicity is seen. Administer 10 mg/m2 orally or parenterally. Follow with 10 mg/m2 orally every 6 hours for 72 hours. After 24 hours following methotrexate administration, if the serum creatinine is
Acitretin: May enhance the hepatotoxic effect of methotrexate. Avoid concurrent use.
Cholestyramine: May decrease levels of methotrexate.
Corticosteroids: May decrease uptake of methotrexate into leukemia cells. Administration of these drugs should be separated by 12 hours. Dexamethasone has been reported to not affect methotrexate influx into cells.
Cyclosporine: Concomitant administration with methotrexate may increase levels and toxicity of each.
Cytarabine: Methotrexate, when administered prior to cytarabine, may enhance the efficacy and toxicity of cytarabine. Some combination treatment regimens (eg, hyper-CVAD) have been designed to take advantage of this interaction.
Hepatotoxic agents (azathioprine, retinoids, sulfasalazine) may increase the risk of hepatotoxic reactions
Mercaptopurine: Methotrexate may increase mercaptopurine levels. Dosage adjustment may be required.
NSAIDs: Severe bone marrow suppression, aplastic anemia, and GI toxicity have been reported with concomitant therapy. Should not be used during moderate or high-dose methotrexate due to increased and prolonged methotrexate levels (may increase toxicity); NSAID use during treatment of rheumatoid arthritis has not been fully explored, but continuation of prior regimen has been allowed in some circumstances, with cautious monitoring
Penicillins: May increase methotrexate concentrations (due to a reduction in renal tubular secretion). Primarily a concern with high doses of penicillins and higher dosages of methotrexate.
Probenecid: May increase methotrexate concentrations (due to a reduction in renal tubular secretion). Primarily a concern with higher dosages of methotrexate.
Salicylates: May increase the serum concentration of Methotrexate. Salicylate doses used for prophylaxis of cardiovascular events are not likely to be of concern.
Sulfonamides: May increase methotrexate concentrations (due to a reduction in renal tubular secretion). In addition, sulfonamides may reduce folate levels, increasing the risk/severity of bone marrow suppression. Particularly a concern with higher dosages of methotrexate.
Tetracyclines: May increase methotrexate toxicity; monitor
Theophylline: Methotrexate may increase theophylline levels.
Vaccines (live virus): Concurrent use with methotrexate may result in vaccinia infections.
Ethanol: Avoid ethanol (may be associated with increased liver injury).
Food: Methotrexate peak serum levels may be decreased if taken with food. Milk-rich foods may decrease methotrexate absorption. Folate may decrease drug response.
Herb/Nutraceutical: Avoid echinacea (has immunostimulant properties).
Store tablets and intact vials at room temperature (15°C to 25°C); protect from light. Dilute powder with D5W or NS to a concentration of 25 mg/mL (20 mg and 50 mg vials) and 50 mg/mL (1 g vial). Intrathecal solutions may be reconstituted to 2.5-5 mg/mL with NS, D5W, lactated Ringer's, or Elliott's B solution. Further dilution in D5W or NS is stable for 24 hours at room temperature (21°C to 25°C). Reconstituted solutions with a preservative may be stored under refrigeration for up to 3 months, and up to 4 weeks at room temperature. Intrathecal dilutions are stable at room temperature for 7 days, but it is generally recommended that they be used within 4-8 hours.
Stable in D5NS, D5W, NS
Y-site administration: Compatible: Allopurinol, amifostine, amphotericin B cholesteryl sulfate complex, asparaginase, aztreonam, bleomycin, cefepime, ceftriaxone, cimetidine, cisplatin, cyclophosphamide, cytarabine, daunorubicin, dexchlorpheniramine, diphenhydramine, doxorubicin, doxorubicin liposome, etoposide, etoposide phosphate, famotidine, filgrastim, fludarabine, fluorouracil, furosemide, ganciclovir, gatifloxacin, granisetron, heparin, hydromorphone, imipenem/cilastatin, leucovorin, linezolid, lorazepam, melphalan, mesna, methylprednisolone sodium succinate, metoclopramide, mitomycin, morphine, ondansetron, oxacillin, paclitaxel, piperacillin/tazobactam, prochlorperazine edisylate, ranitidine, sargramostim, teniposide, thiotepa, vinblastine, vincristine, vindesine, vinorelbine. Incompatible: Chlorpromazine, gemcitabine, idarubicin, ifosfamide, midazolam, nalbuphine, promethazine, propofol. Variable (consult detailed reference): Dexamethasone sodium phosphate, droperidol, vancomycin
Compatibility in syringe: Compatible: Bleomycin, cisplatin, cyclophosphamide, doxapram, doxorubicin, fluorouracil, furosemide, heparin, leucovorin, mitomycin, vinblastine, vincristine. Incompatible: Droperidol. Variable (consult detailed reference): Metoclopramide
Compatibility when admixed: Compatible: Cyclophosphamide, cyclophosphamide with fluorouracil, cytarabine, dacarbazine, fluorouracil, hydrocortisone, hydroxyzine, mercaptopurine, ondansetron, sodium bicarbonate, vincristine. Incompatible: Bleomycin
Methotrexate is a folate antimetabolite that inhibits DNA synthesis. Methotrexate irreversibly binds to dihydrofolate reductase, inhibiting the formation of reduced folates, and thymidylate synthetase, resulting in inhibition of purine and thymidylic acid synthesis. Methotrexate is cell cycle specific for the S phase of the cycle.
The MOA in the treatment of rheumatoid arthritis is unknown, but may affect immune function. In psoriasis, methotrexate is thought to target rapidly proliferating epithelial cells in the skin.
Onset of action: Antirheumatic: 3-6 weeks; additional improvement may continue longer than 12 weeks
Absorption: Oral: Rapid; well absorbed at low doses (<30 mg/m2), incomplete after large doses; I.M.: Complete
Distribution: Penetrates slowly into 3rd space fluids (eg, pleural effusions, ascites), exits slowly from these compartments (slower than from plasma); crosses placenta; small amounts enter breast milk; sustained concentrations retained in kidney and liver
Protein binding: 50%
Metabolism: <10%; degraded by intestinal flora to DAMPA by carboxypeptidase; hepatic aldehyde oxidase converts methotrexate to 7-OH methotrexate; polyglutamates are produced intracellularly and are just as potent as methotrexate; their production is dose- and duration-dependent and they are slowly eliminated by the cell once formed
Half-life elimination: Low dose: 3-10 hours; High dose: 8-12 hours
Time to peak, serum: Oral: 1-2 hours; I.M.: 30-60 minutes
Excretion: Urine (44% to 100%); feces (small amounts)
Refer to individual protocols.
Note: Doses between 100-500 mg/m2may require leucovorin rescue. Doses >500 mg/m2require leucovorin rescue.
Dermatomyositis: Oral: 15-20 mg/m2/week as a single dose once weekly or 0.3-1 mg/kg/dose once weekly
Juvenile rheumatoid arthritis: Oral, I.M.: 10 mg/m2 once weekly, then 5-15 mg/m2/week as a single dose or as 3 divided doses given 12 hours apart
Antineoplastic dosage range:
Oral, I.M.: 7.5-30 mg/m2/week or every 2 weeks
I.V.: 10-18,000 mg/m2 bolus dosing or continuous infusion over 6-42 hours
For dosing schedules, see table:
|Conventional|| || |
|15-20 mg/m2||P.O.||Twice weekly|
|30-50 mg/m2||P.O., I.V.||Weekly|
|15 mg/day for 5 days||P.O., I.M.||Every 2-3 weeks|
|Intermediate|| || |
|50-150 mg/m2*||I.V. push||Every 2-3 weeks|
|240 mg/m2*||I.V. infusion||Every 4-7 days|
|0.5-1 g/m2**||I.V. infusion||Every 2-3 weeks|
|High|| || |
|1-25 g/m2*||I.V. infusion||Every 1-3 weeks|
|*Doses between 100-500 mg/m2 may require leucovorin rescue in some patients.|
|**Followed with leucovorin rescue - refer to Leucovorin monograph for details.|
Pediatric solid tumors (high-dose): I.V.:
<12 years: 12-25 g/m2
Acute lymphocytic leukemia (intermediate-dose): I.V.: Loading: 100 mg/m2 bolus dose, followed by 900 mg/m2/day infusion over 23-41 hours.
Meningeal leukemia: I.T.: 10-15 mg/m2 (maximum dose: 15 mg) or an age-based dosing regimen; one possible system is:
4-11 months: 6 mg/dose
1 year: 8 mg/dose
2 years: 10 mg/dose
Adults: I.V.: Range is wide from 30-40 mg/m2/week to 100-12,000 mg/m2 with leucovorin rescue
Oral, I.M.: 15-30 mg/day for 5 days; repeat in 7 days for 3-5 courses
I.V.: 11 mg/m2 days 1 through 5 every 3 weeks
Head and neck cancer: Oral, I.M., I.V.: 25-50 mg/m2 once weekly
Mycosis fungoides (cutaneous T-cell lymphoma): Oral, I.M.: Initial (early stages):
5-50 mg once weekly or
15-37.5 mg twice weekly
Bladder cancer: I.V.:
30 mg/m2 day 1 and 8 every 3 weeks or
30 mg/m2 day 1, 15, and 22 every 4 weeks
Breast cancer: I.V.: 30-60 mg/m2 days 1 and 8 every 3-4 weeks
Gastric cancer: I.V.:1500 mg/m2 every 4 weeks
Lymphoma, non-Hodgkin's: I.V.:
30 mg/m2 days 3 and 10 every 3 weeks or
120 mg/m2 day 8 and 15 every 3-4 weeks or
200 mg/m2 day 8 and 15 every 3 weeks or
400 mg/m2 every 4 weeks for 3 cycles or
1 g/m2 every 3 weeks or
1.5 g/m2 every 4 weeks
Sarcoma: I.V.: 8-12 g/m2 weekly for 2-4 weeks
Rheumatoid arthritis: Oral: 7.5 mg once weekly or 2.5 mg every 12 hours for 3 doses/week, not to exceed 20 mg/week
Oral: 2.5-5 mg/dose every 12 hours for 3 doses given weekly or
Oral, I.M.: 10-25 mg/dose given once weekly
Ectopic pregnancy: I.M., I.V.: 50 mg/m2 as a single dose
Elderly: Rheumatoid arthritis/psoriasis: Oral: Initial: 5-7.5 mg/week, not to exceed 20 mg/week
Dosing adjustment in renal impairment:
Clcr 61-80 mL/minute: Reduce dose to 75% of usual dose
Clcr 51-60 mL/minute: Reduce dose to 70% of usual dose
Clcr 10-50 mL/minute: Reduce dose to 30% to 50% of usual dose
Clcr<10 mL/minute: Avoid use
Hemodialysis: Not dialyzable (0% to 5%); supplemental dose is not necessary
Peritoneal dialysis: Supplemental dose is not necessary
Dosage adjustment in hepatic impairment:
Bilirubin 3.1-5 mg/dL or AST >180 units: Administer 75% of usual dose
Bilirubin >5 mg/dL: Do not use
Methotrexate may be administered I.M., I.V., or I.T.; I.V. administration may be as slow push, short bolus infusion, or 24- to 42-hour continuous infusion
Specific dosing schemes vary, but high dose should be followed by leucovorin calcium to prevent toxicity; refer to Leucovorin monograph
For prolonged use (especially rheumatoid arthritis, psoriasis) a baseline liver biopsy, repeated at each 1-1.5 g cumulative dose interval, should be performed; WBC and platelet counts every 4 weeks; CBC and creatinine, LFTs every 3-4 months; chest x-ray
Therapeutic levels: Variable; Toxic concentration: Variable; therapeutic range is dependent upon therapeutic approach.
High-dose regimens produce drug levels that are between 10-6 Molar and 10-7 Molar 24-72 hours after drug infusion
10-6Molar unit = 1 microMolar unit
Toxic: Low-dose therapy: >9.1 ng/mL; high-dose therapy: >454 ng/mL
Sodium content of 100 mg injection: 20 mg (0.86 mEq)
Sodium content of 100 mg (low sodium) injection: 15 mg (0.65 mEq)
Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Report immediately any redness, swelling, pain, or burning at infusion/injection site. It is very important to maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake, and nutrition (small, frequent meals may help). Avoid alcohol to prevent serious side effects. You will be more susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations without consulting prescriber). May cause sensitivity to sunlight (use sunscreen, wear protective clothing, and eyewear); nausea or vomiting (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help - if unresolved, contact prescriber); drowsiness, dizziness, numbness, or blurred vision (use caution when driving or engaging in tasks that require alertness until response to drug is known); loss of hair (may be reversible); color change of skin; permanent sterility; or mouth sores (frequent mouth care with soft toothbrush or cotton swabs and frequent rinses may help). Report immediately any rash, excessive or unusual fatigue, or respiratory difficulty. Report rapid heartbeat or palpitations, black or tarry stools, fever, chills, unusual bleeding or bruising, shortness of breath, persistent GI disturbances, diarrhea, constipation, pain on urination or change in urinary patterns, or any other persistent adverse effects. Do not get pregnant while taking this medication. Consult prescriber for appropriate contraceptive measures. This drug may cause birth defects. Do not breast-feed.Infusion/injection:Pregnancy/breast-feeding precautions:
50 mg/2 mL, 100 mg/4 mL, and 250 mg/10 mL vials with and without preservatives by ImmunexLatex-free products:
Key adverse event(s) related to dental treatment: Ulcerative stomatitis, gingivitis, glossitis, and mucositis (dose dependent; appears 3-7 days post-therapy and resolves within 2 weeks).
No information available to require special precautions
May cause drowsiness or dizziness
Leukopenia is common; avoid clozapine and carbamazepine
Very low (<10%):
Low (10% to 30%):
Moderate (30% to 60%):
High (60% to 90%): >1000 mg/m2
Injection, powder for reconstitution [preservative free]: 20 mg, 1 g
Injection, solution, as sodium: 25 mg/mL (2 mL, 10 mL) [contains benzyl alcohol]
Injection, solution, as sodium [preservative free]: 25 mg/mL (2 mL, 4 mL, 8 mL, 10 mL)
Tablet, as sodium: 2.5 mg
Rheumatrex®: 2.5 mg
Trexall™: 5 mg, 7.5 mg, 10 mg, 15 mg
Tablet, as sodium [dose pack] (Rheumatrex® Dose Pack): 2.5 mg (4 cards with 2, 3, 4, 5, or 6 tablets each)
Evans WE, Pratt CB, Taylor RH, et al, "Pharmacokinetic Monitoring of High-Dose Methotrexate: Early Recognition of High-Risk Patients,"Cancer Chemother Pharmacol, 1979, 3:161-6.
Furst DE, "Methotrexate: New Mechanisms and Old Toxicities,"Agents Actions Suppl, 1993, 44:131-7.
Grem JL, King SA, Wittes RE, et al, "The Role of Methotrexate in Osteosarcoma,"J Natl Cancer Inst, 1988, 80(9):626-55.
Jolivet J, Cowan KH, Curt GA, et al, "The Pharmacology and Clinical Use of Methotrexate,"N Engl J Med, 1983, 309(18):1094-104.
Treon SP and Chabner BA, "Concepts in Use of High-Dose Methotrexate Therapy,"Clin Chem, 1996, 42(8 Pt 2):1322-9.
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