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FDA Alerts
Experience of Supervising Clinician
Administer only under supervision of qualified clinicians experienced in use of antimetabolite therapy.
Serious Toxic Reactions (Sometimes Fatal) Possible
Deaths reported with use in treatment of malignancy, psoriasis, and rheumatoid arthritis.
Use only for treatment of life-threatening neoplastic diseases or severe, recalcitrant, disabling psoriasis or rheumatoid arthritis in patients who have not responded adequately to other forms of therapy.
Closely monitor patients for bone marrow, hepatic, pulmonary, or renal toxicities. (See Major Toxicities under Cautions.)
Inform patients of risks involved with therapy and importance of remaining under care of clinician throughout therapy.
High-Dose Regimens
Use of high-dose regimens recommended for treatment of osteosarcoma requires meticulous care. (See High-Dose Methotrexate Therapy with Leucovorin Rescue and also Osteosarcoma, under Dosage and Administration.)
Use of high-dose regimens for other neoplastic diseases is investigational; therapeutic advantage not established.
Formulations or Diluents Containing Preservatives
Do not use formulations or diluents containing preservatives for intrathecal administration or high-dose therapy.
Fetal/Neonatal Morbidity and Mortality
Fetal death and/or congenital anomalies reported. Not recommended for use in women of childbearing potential unless potential benefit clearly outweighs risks; do not use in pregnant women with psoriasis or rheumatoid arthritis. (See Contraindications and also Fetal/Neonatal Morbidity and Mortality, under Cautions.)
Reduced Elimination
Elimination reduced in patients with renal impairment, ascites, or pleural effusions. Carefully monitor for toxicity in such patients; dosage reduction or discontinuance may be required.
Concomitant Therapy with NSAIAs
Unexpectedly severe, sometimes fatal, myelosuppression, aplastic anemia, and GI toxicity reported with concomitant use of methotrexate (usually at high dosages) and some NSAIAs. (See Specific Drugs under Interactions.)
Hepatotoxicity
Possible hepatotoxicity, fibrosis, and cirrhosis, generally only after prolonged use. (See Hepatic Effects under Cautions.)
Acute liver enzyme elevations frequently observed; usually transient and asymptomatic and do not appear predictive of subsequent hepatic disease.
Liver biopsy after sustained use often shows histologic changes. Fibrosis and cirrhosis may not be preceded by symptoms or abnormal liver function tests in patients with psoriasis; periodic liver biopsies usually recommended in such patients undergoing long-term therapy.
Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in patients with rheumatoid arthritis.
Pulmonary Toxicity
Potentially dangerous pulmonary lesions, not always reversible, may occur acutely at any time during therapy and have been reported at dosages as low as 7.5 mg weekly. Pulmonary symptoms (especially dry, nonproductive cough) may require therapy interruption and careful evaluation.
GI Toxicity
Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.
Malignant Lymphomas
Malignant lymphomas (e.g., non-Hodgkin’s lymphoma) may occur in patients receiving low-dose oral therapy; such lymphomas may regress following methotrexate discontinuance and may not require cytotoxic therapy. If the lymphoma does not regress following discontinuance, institute appropriate therapy.
Tumor Lysis Syndrome
May induce tumor lysis syndrome in patients with rapidly growing tumors; appropriate pharmacologic and supportive treatment may prevent or alleviate syndrome.
Dermatologic Reactions
Severe, occasionally fatal skin reactions reported following single or multiple doses; reactions occurred within days of oral, IM, IV, or intrathecal administration. Recovery reported with discontinuance of therapy. (See Dermatologic and Sensitivity Reactions under Cautions.)
Treatment (alone or, more commonly, in combination chemotherapy) of breast cancer.
First-line adjuvant chemotherapy in combination with other drugs (i.e., cyclophosphamide and fluorouracil, with or without hormonal therapy). An anthracycline-containing regimen is preferred in patients with node-positive disease.
Some studies suggest a slight advantage for anthracycline-containing regimens in relapse-free and survival rates in both premenopausal and postmenopausal patients.
Combination therapy with cisplatin, methotrexate, bleomycin, and vincristine has been used for recurrent or metastatic squamous cell carcinoma of the head and neck.
Further study needed to establish comparative benefit of methotrexate-containing regimens.
Leukemias
Component of various chemotherapy regimens in palliative treatment of acute leukemias.
Intrathecally for prophylaxis and treatment of meningeal leukemia.
First-line therapy in combination with mercaptopurine for maintenance of drug-induced remissions of acute lymphoblastic leukemia (ALL).
Has been used in high doses as a component of some alternative combination chemotherapy regimens for remission induction in ALL, but not generally considered a drug of choice for remission induction.
Rarely effective alone for treatment of acute myeloblastic leukemia (AML); has been used as an additional component in some chemotherapy regimens for induction or post-induction therapy of AML.
Lung Cancer
Has been used in second-line therapy of recurrent small cell lung cancer.
Although labeled for use in squamous cell type of non-small cell lung cancer, other agents are preferred.
Lymphomas
Component of combination chemotherapeutic regimens as first-line palliative therapy for high-grade Burkitt’s lymphoma or maintenance therapy for high-grade lymphoblastic non-Hodgkin’s lymphoma.
Component of alternative combination chemotherapy regimens for treatment of intermediate-grade non-Hodgkin’s lymphomas (diffuse large cell, diffuse small cell, diffuse mixed, follicular large cell).
Has been used intrathecally in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone with or without rituximab for first-line therapy of intermediate-grade non-Hodgkin’s lymphomas.
Although radiation or topical therapy is generally used for treatment of localized histiocytic lymphoma, lymphosarcoma, and mycosis fungoides, chemotherapy may be useful in generalized stages of these diseases.
Also has been used as a component of adjunctive combination chemotherapy regimens in patients with metastatic osteosarcoma.
Psoriasis
Symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy in carefully selected patients; not curative.
Use only after diagnosis definitely established (e.g., biopsy, after dermatologic consultation).
Rheumatoid Arthritis
Management of rheumatoid arthritis in adults whose symptoms progress despite an adequate regimen of NSAIAs.
Management of active polyarticular-course juvenile rheumatoid arthritis in children who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy (i.e., full-dose NSAIAs). (See Pediatric Use under Cautions.)
One of several disease-modifying antirheumatic drugs (DMARDs) that can be used when DMARD therapy is appropriate.
Substantially greater long-term efficacy than other DMARDs; used as the initial or anchor DMARD in many patients with rheumatoid arthritis. Also has been used in combination with other DMARDs.
Use only as part of a comprehensive treatment program, including nondrug therapies (e.g., rest, physical therapy).
No substantial evidence that methotrexate permanently arrests or reverses the underlying disease process, although disease progression is slowed in some patients.
Trophoblastic Neoplasms
Treatment (with or without leucovorin) of trophoblastic neoplasms (choriocarcinoma, chorioadenoma destruens, hydatidiform mole) in women (except those with impaired renal or hepatic function or who have failed to respond to previous methotrexate therapy, in which case dactinomycin is used).
Most effective in patients who have had disease for only a short period prior to initiation of chemotherapy, who have low initial gonadotropin concentrations, and who do not have metastases.
First-line therapy with or without leucovorin in patients with nonmetastatic or good-prognosis metastatic gestational trophoblastic neoplasms.
Component of combination chemotherapy regimen with dactinomycin and chlorambucil in patients with good-prognosis metastatic gestational trophoblastic neoplasms with refractory disease.
In patients with poor-prognosis metastatic trophoblastic neoplasms, methotrexate in combination with etoposide, dactinomycin, vincristine, and cyclophosphamide (EMA-CO) is a standard treatment option. A dose-intensive regimen, EMA-CE, in which etoposide and cisplatin are substituted for vincristine and cyclophosphamide of the EMA-CO regimen, may offer additional benefits.
Has been used prophylactically against malignant trophoblastic disease in patients with hydatidiform mole.
Testicular choriocarcinomas are usually resistant to methotrexate alone; has been used as component of combination therapy in patients with metastatic tumors of the testes.
Bladder Cancer
Used in combination regimens with vinblastine and cisplatin, with or without doxorubicin, as first- or second-line therapy for invasive and advanced bladder cancer†.
Use of leucovorin rescue or deletion of methotrexate is advised if methotrexate-containing regimens are being considered for the treatment of advanced or metastatic bladder cancer in patients with renal dysfunction, edema, pleural fluid collections, or ascites.
Crohn’s Disease
Management of chronically active Crohn’s disease†.
Ectopic Pregnancy
Used as an alternative to surgical management of ectopic pregnancy† in selected patients with small, unruptured tubal pregnancies.
Multiple Sclerosis
Low-dose oral therapy has been used in patients with chronic progressive multiple sclerosis†.
Psoriatic Arthritis
Has been used for its immunosuppressive and/or anti-inflammatory effects in treatment of psoriatic arthritis†.
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