      Document 0223
 DOCN  DRG0223
 UNIQUE IDENTIFIER        DRG-0024
 NAME OF SUBSTANCE        Methotrexate [USAN 1995]
 REGISTRY NUMBER          59-05-2
 STANDARD CHEMICAL NAME   N-(4-(((2,4-Diamino-6-pteridinyl)methyl)
                          methylamino) benzoyl)-L-glutamic acid [USAN
                          1995]
 SYNONYMS                 4-Amino-N10-methylpteroylglutamic acid [Merck
                          Index 1989]
 SYNONYMS                 4-Amino-10-methylfolic acid [Merck Index
                          1989]
 SYNONYMS                 Methylaminopterin [Merck Index 1989]
 SYNONYMS                 Amethopterin [USAN 1995]
 SYNONYMS                 MTX [Merck Index 1989]
 SYNONYMS                 Emtexate [Merck Index 1989]
 SYNONYMS                 A-Methopterin [Merck Index 1989]
 SYNONYMS                 Mexate (disodium salt of Methotrexate) [USAN
                          1995]
 SYNONYMS                 Rheumatrex [USAN 1995]
 SYNONYMS                 Folex [USAN 1995]
 PROTOCOL ID NUMBERS      NIAID ACTG 008
 PROTOCOL ID NUMBERS      NIAID ACTG 009
 PROTOCOL ID NUMBERS      NIAID ACTG 074
 PROTOCOL ID NUMBERS      NIAID ACTG 142
 PROTOCOL ID NUMBERS      NCI 90 C-34
 PROTOCOL ID NUMBERS      NCI 93 C-207
 SECONDARY SOURCE ID      Cl-14377 [Merck Index 1989]
 SECONDARY SOURCE ID      NSC-740 [USAN 1995]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Competitive inhibition of
                          dihydrofolic acid reductase, thereby
                          inhibiting the reduction of folic acid to
                          tetrahydrofolic acid in the process of DNA
                          synthesis and cellular replication.
                          Methotrexate binds almost irreversibly to
                          this enzyme and inhibits the formation of
                          tetrahydrofolates needed for the metabolic
                          transfer of one-carbon units in various
                          intracellular biochemical processes
                          (conversion of deoxyuridylate to the
                          thymidylate (required for DNA synthesis);
                          purine, RNA, amino acid, and protein
                          synthesis), thus disrupting several basic
                          processes involved in cell growth.  In
                          adults, oral absorption appears to be dose
                          dependent, reaching peak serum levels in 1-2
                          hours; following parenteral dosing, peak
                          serum levels are reached in about 0.5-1
                          hours; about half the drug is reversibly
                          bound to serum protein, but exchanges easily
                          with body fluids, diffusing into body tissue
                          cells; 55-88 percent of the drug is excreted
                          through the kidneys within 24 hours. Liver
                          cells retain some of the drug for prolonged
                          periods, but the drug does not penetrate the
                          blood cerebrospinal fluid barrier in
                          therapeutic amounts when given parenterally.
                          [PDR 1995]
 DISEASES STUDIED/TREATED Use in mixed drug therapy of patients with
                          AIDS-associated lymphoma [NIAID-ACTG 074]
 CLASSIFICATION CODE      Antineoplastic [USAN 1995]
 CLASSIFICATION CODE      Folic acid antagonist [Merck Index 1989]
 CLASSIFICATION CODE      Anti-inflammatory [Merck Index 1989]
 OTHER MAJOR USES         Methotrexate is clinically effective in
                          treating gestational choriocarcinoma,
                          chorioadenoma destruens, and hydatidiform
                          mole; it also is used for treating acute
                          lymphocytic leukemia, meningeal leukemia,
                          advanced malignant lymphoma, severe,
                          recalcitrant, disabling psoriasis and
                          rheumatoid arthritis. High dose methotrexate
                          with leucovorin rescue is used for
                          nonmetastatic osteosarcoma [PDR 1995]
 SUBSTANCE INTERACTIONS   Leucovorin (citrovorum factor) neutralizes
                          immediate toxic effects of methotrexate on
                          the hematopoietic system; concomitant
                          administration of leucovorin may reduce the
                          therapeutic effect of intrathecally
                          administered methotrexate. Methotrexate is
                          partially bound to serum albumin after
                          absorption and may be displaced by the
                          coadministration of certain drugs, e.g.,
                          salicylates, sulfonamides, phenytoin,
                          phenylbutazone, and some antibacterials,
                          e.g., tetracycline, chloramphenicol, and
                          para-aminobenzoic acid (PABA). Vitamin
                          preparations containing folic acid or its
                          derivatives may alter responses to
                          methotrexate - these drugs, especially
                          salicylates, phenylbutazone, and
                          sulfonamides, should not be given
                          concurrently with methotrexate. Neurotoxicity
                          may result from the concurrent administration
                          of intrathecal methotrexate and acyclovir.
                          [PDR 1995] [USP DI 1995]
 ADVERSE EFFECTS          Due to the possibility of fatal/serious toxic
                          reactions, the drug should be used only by
                          physicians experienced in antimetabolite
                          chemotherapy; may cause marked depression of
                          bone marrow, anemia, leukopenia,
                          thrombocytopenia, bleeding, hepatotoxicity,
                          liver atrophy, necrosis, cirrhosis,
                          periportal fibrosis, fetal death and/or
                          congenital anomalies, diarrhea, ulcerative
                          stomatitis, hemorrhagic enteritis, and
                          intestinal perforation.  The most common
                          adverse reactions include ulcerative
                          stomatitis, leukopenia, nausea, and abdominal
                          distress. Other adverse reactions include:
                          anaphylaxis, malaise, undue fatigue, chills
                          and fever, dizziness, decreased resistance to
                          infection. Adverse reactions have been
                          reported for various body systems (skin and
                          alimentary, urogenital, pulmonary, central
                          nervous systems).  Use with extreme caution
                          in the presence of infection, peptic ulcer,
                          ulcerative colitis, debility, and in extreme
                          youth and old age.  The high potential
                          toxicity of this drug is usually
                          dose-related. Large doses may cause
                          convulsions. [PDR 1995]
 CONTRAINDICATIONS        Should not be used by pregnant psoriatic
                          patients, psoriatic or rheumatoid arthritis
                          patients with severe renal/hepatic disorders,
                          or preexisting blood dyscrasias (bone marrow
                          hypoplasia, leukopenia, thrombocytopenia, or
                          anemia). [PDR 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Folic acid derivative [USP
                          DI [1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C20H22N8O5 (free acid)
                          [USAN 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 454.44 [USAN 1995]
 CHEMICAL/PHYSICAL DATA   PERCENT ELEMENTAL COMPOSITION: C52.86%;
                          H4.88%; N24.66%; O17.60% [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Soluble in alkaline solutions
                          with decomposition [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: Orange-brown or yellow
                          crystalline powder [USP DI 1989]
 CHEMICAL/PHYSICAL DATA   STABILITY: A diluted solution of methotrexate
                          sodium injection maintains 90% of its labeled
                          potency if stored for 24 hours at 21 C to 25
                          C [USP DI 1995]
 CHEMICAL/PHYSICAL DATA   STABILITY: Preservative solutions should be
                          diluted immediately prior to use, any unused
                          portions should be discarded [USP DI 1995]
 CHEMICAL/PHYSICAL DATA   PHYSICAL COMMENT: C20H20N8Na2O5 (disodium
                          salt) [Merck Index 1989]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Tablets (2.5 mg of
                          methotrexate); vials containing 20 mg to 1 gm
                          of freeze-dried methotrexate sodium; vials
                          containing methotrexate sodium parenteral
                          isotonic solution (25mg/ml). [PDR 199
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Vials containing Methotrexate
                          Sodium parenteral isotonic
                          preservative-protected solution (2.5 mg/ml
                          and 25 mg/ml). [PDR 1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY:  Oral. Intravenous,
                          intramuscular, intra-arterial, or intrathecal
                          administration. [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Store all preparations below 40 C,
                          preferable between 15 C and 30 C, unless
                          otherwise specified by the manufacturer. [USP
                          DI 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Store tablets in a well closed
                          container and protect injections from light.
                          [USP DI 1995]
 MANUFACTURERS            Lederle
 MANUFACTURERS            Adria
 MANUFACTURERS            Bristol-Myers
 REFERENCES               Jost LM, Jacky E, Dommann-Scherrer C,
                          Honegger HP, Maurer R, Sauter C, Stahel RA.
                          Short-term weekly chemotherapy followed by
                          high-dose therapy with autologous bone marrow
                          transplantation for lymphoblastic and
                          Burkitt's lymphomas in adult patients. Ann
                          Oncol. 1995 May;6(5):445-51.
 REFERENCES               Greenberg AL, Droller DG. Successful
                          treatment of a patient with seropositive
                          human immunodeficiency virus with high risk
                          Burkitt's leukemia. Cancer. 1994 Aug
                          15;74(4):1261-4.
 REFERENCES               Maurer TA, Zackheim HS, Tuffanelli L, Berger
                          TG. The use of methotrexate for treatment of
                          psoriasis in patients with HIV infection. J
                          Am Acad Dermatol. 1994 Aug;31(2 Pt 2):372-5.
 REFERENCES               Walsh C, Wernz JC, Levine A, Rarick M,
                          Willson E, Melendez D, Bonnem E, Thompson J,
                          Shelton B. Phase I trial of m-BACOD and
                          granulocyte macrophage colony stimulating
                          factor in HIV-associated non-Hodgkin's
                          lymphoma. J Acquir Immune Defic Syndr. 1993
                          Mar;6(3):265-71.
 REFERENCES               Chamberlain MC, Dirr L. Involved-field
                          radiotherapy and intra-Ommaya
                          methotrexate/cytarabine in patients with
                          AIDS-related lymphomatous meningitis. J Clin
                          Oncol. 1993 Oct;11(10):1978-84.
 REFERENCES               Schurmann D, Weiss R, Jautzke G, Pohle HD,
                          Ruf B. Intensive treatment of AIDS-related
                          non-Hodgkin's lymphomas with the MACOP-B
                          protocol. Int Conf AIDS. 1993 Jun
                          6-11;9(1):404 (abstract no. PO-B13-1616).
 REFERENCES               Taillan B, Pesce A, Garnier G, Vinti H,
                          Fuzibet JG, Cassuto JP, Dujardin P. AIDS
                          related malignant lymphoma: results of MACOP
                          B chemotherapy. Int Conf AIDS. 1992 Jul
                          19-24;8(2):B108 (abstract no. PoB 3127).
 REFERENCES               Sawka CA, Shepherd FA, Brandwein J, Burkes
                          RL, Sutton DM, Warner E. Treatment of
                          AIDS-related non-Hodgkin's lymphoma with a
                          twelve week chemotherapy program. Leuk
                          Lymphoma. 1992 Oct;8(3):213-20.
 REFERENCES               Levin M, Merrick S, Root J. Diagnosis,
                          treatment and complete remission of primary
                          leptomeningeal lymphoma in a patient with
                          AIDS. Int Conf AIDS. 1992 Jul 19-24;8(3):100
                          (abstract no. PuB 7308).
 REFERENCES               Levine AM, Wernz JC, Kaplan L, Rodman N,
                          Cohen P, Metroka C, Bennett JM, Rarick MU,
                          Walsh C, Kahn J, et al. Low-dose chemotherapy
                          with central nervous system prophylaxis and
                          zidovudine maintenance in AIDS-related
                          lymphoma. A prospective multi-institutional
                          trial. JAMA. 1991 Jul 3;266(1):84-8.
 ENTRY MONTH              8906
 LAST REVISION DATE       960422
 

SOURCE: National Library of Medicine, Bethesda, MD.  Distributed by AEGIS.
