      Document 0199
 DOCN  DRG0199
 UNIQUE IDENTIFIER        DRG-0048
 NAME OF SUBSTANCE        Cyclophosphamide [USAN 1996]
 REGISTRY NUMBER          6055-19-2
 STANDARD CHEMICAL NAME   2H-1,3,2-oxazaphosphorin- 2-amine
                          N,N-bis(2-chloroethyl)tetrahydro-2-oxide
                          monohydrate [Merck Index 1989]
 SYNONYMS                 Cytoxan [USAN 1996]
 SYNONYMS                 Neosar [USAN 1996]
 SYNONYMS                 Procytox [Merck Index 1989]
 SYNONYMS                 Sendoxan [Merck Index 1989]
 SYNONYMS                 Cyclophosphane [Merck Index 1989]
 SYNONYMS                 bis(2-Chloroethyl)phosphamide cyclic
                          propanolamide ester [Merck Index 1989]
 SYNONYMS                 bis(2-Chloroethyl)phosphoramide cyclic
                          propanolamide ester [Merck Index 1989]
 SYNONYMS                 N,N-bis(beta-Chloroethyl)-N',O-propylenephosp-
                          horic acid ester diamide [Merck Index 1989]
 SYNONYMS                 N-bis(beta-Chloroethyl)-N'O,trimethylenephosp-
                          horic acid ester diamide [Merck Index 1989]
 SYNONYMS                 Endoxan [Merck Index 1989]
 SYNONYMS                 1-bis(2-Chloroethyl)amino-1-oxo-2-aza-5-oxaph-
                          osphoridin [Merck Index 1989]
 SYNONYMS                 Cytophosphane [Merck Index 1989]
 SYNONYMS                 2-(bis(2-Chloroethyl)-amino)tetrahydro-2H-1,3-
                          ,2-oxazaphosphorine 2-oxide [Merck Index
                          1989]
 SYNONYMS                 Cycloblastin [Merck Index 1989]
 SYNONYMS                 Cyclostin [Merck Index 1989]
 PROTOCOL ID NUMBERS      NIAID ACTG 008
 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
 PROTOCOL ID NUMBERS      NIAID ACTG 252
 SECONDARY SOURCE ID      B-518 [Merck Index 1989]
 SECONDARY SOURCE ID      NSC-26271 [USAN 1996]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Interferes with the growth of
                          susceptible neoplasms and, to some extent,
                          certain tissues; the mechanism of action of
                          the active metabolites is alkylation,
                          principally of DNA; cyclophosphamide is first
                          hydroxylated by hepatic mixed function
                          oxidases to the intermediate metabolites, the
                          4-hydroxy derivative and aldophosphamide,
                          which are then oxidized to several inactive
                          metabolites and to the active antineoplastic
                          alkylating compounds nor-nitrogen mustard and
                           phosphoramide mustard. Cyclophosphamide is
                          absorbed from the gastrointestinal tract and
                          parenteral sites; the drug and its
                          metabolites are distributed throughout the
                          body; intravenously administered, it has a
                          half-life of about 4 hours, but is found in
                          plasma after as long as 72 hours; elimination
                          of the drug and its metabolites is via the
                          kidneys. Its cytotoxic action is primarily
                          due to cross-linking of strands of DNA and
                          RNA, as well as inhibition of protein
                          synthesis. It is a potent immunosuppressant.
                          It is almost completely absorbed from the
                          gastrointestinal tract, crosses the
                          blood-brain barrier to a limited extent,
                          exhibits very low protein binding (active
                          metabolites, about 50 percent), exhibits a
                          mean half-life in adults and children of 6.5
                          and 4.1 hours, undergoes hepatic
                          biotransformation, is dialyzable, and
                          eliminated via the renal route (less than 25
                          percent unchanged). [PDR 1995; USP DI 1995]
 DISEASES STUDIED/TREATED Under investigation for HIV-related cancer
                          [NIAID ACTG 252]
 CLASSIFICATION CODE      Antineoplastic [USAN 1996]
 CLASSIFICATION CODE      Immunosuppressant [USAN 1996]
 OTHER MAJOR USES         Used in treatment of various acute and
                          chronic leukemias, carcinomas, lymphomas,
                          mycosis fungoides, neuroblastoma and
                          retinoblastoma. An approved anti-cancer drug
                          with activity, alone or in combinaton,
                          against a wide spectrum of tumors [PDR 1995;
                          USP DI 1995]
 SUBSTANCE INTERACTIONS   Has been reported to potentiate
                          doxorubicin-induced cardiotoxicity;
                          interactions have been reported with
                          allopurinol, colchicine, probenecid,
                          sulfinpyrazone, oral anticoagulants, blood
                          dyscrasia-causing medications, other bone
                          marrow depressants, cytarabine, daunorubicin,
                          doxorubicin, hepatic enzyme inducers, other
                          immunosuppressants (e.g.: glucocorticoid
                          adrenocorticoids, azathioprine, chlorambucil,
                          cyclosporine, mercaptopurine, muromonab-CD3),
                          lovastatin, succinylcholine, killed and live
                          virus vaccines, and with radiation therapy.
                          [PDR 1995] [USP DI 1995]
 ADVERSE EFFECTS          May cause the following adverse reactions:
                          Digestive system: nausea, vomiting, anorexia,
                          diarrhea, abdominal pain, hemorrhagic
                          colitis, oral mucosal ulceration and
                          jaundice. Skin: Skin rash, pigmentation of
                          skin and changes in nails, alopecia.
                          Hematopoietic system: Leukopenia,
                          thrombocytopenia, and anemia. Urinary system:
                          Hemorrhagic ureteritis, renal tubular
                          necrosis, fibrosis of the urinary bladder.
                          Respiratory system: Interstitial pulmonary
                          fibrosis. Reproductive system: Ovarian
                          fibrosis, amenorrhea, secondary sexual
                          characteristics, impairment of sexual potency
                          and libido in males, testicular atrophy. It
                          may cause sterility in both sexes.
                          Carcinogenesis: Secondary malignancy has
                          developed in some patients, most frequently
                          they have been urinary bladder,
                          myeloproliferative or lymphoproliferative.
                          Pregnancy: Cyclophosphamide can cause fetal
                          harm (abnormalities like ectodactylia).
                          Cardiac: Cardiotoxicity. [PDR 1995]
 CONTRAINDICATIONS        Contraindicated in patients who have
                          demonstrated a previous hypersensitivity to
                          it. Continued use of cyclophosphamide is
                          contraindicated in patients with severely
                          depressed bone marrow function. Should not be
                          used by pregnant or lactating women (may be
                          teratogenic or cause fetal resorption and it
                          is excreted in breast milk) or by persons
                          with heart conditions (cardiotoxicity). [PDR
                          1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Cyclophosphamide is a
                          nitrogen mustard derivative which is a
                          polyfunctional alkylating agent [AHFS Drug
                          Information 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C7H15Cl2N2O2P.H2O [USAN
                          1996]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 279.10 [USAN 1996]
 CHEMICAL/PHYSICAL DATA   PERCENT ELEMENTAL COMPOSITION: C32.20%,
                          H5.79%, Cl27.16%, N10.73%, O12.26%, P11.86%
                          [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   MELTING POINT: 41-45 C [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: 40 g/l in water; slightly soluble
                          in alcohol, benzene, ethylene glycol, carbon
                          tetrachloride, dioxane; sparingly soluble in
                          ether and acetone [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: White crystalline
                          powder [AHFS Drug Information 1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Tablets (25 and 50 mg), oral
                          solution, and solution for injection (100 mg
                          to 2 grams). [PDR 1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral, intravenous,
                          intramuscular, intraperitoneal, or
                          intrapleural injection. [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Store at or below 77 F (25 C);
                          protect from temperatures above 86 F (30 C).
                          [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Extemporaneous oral solutions
                          prepared from injectable dosage forms are
                          stable for 14 days under refrigeration. [PDR
                          1995]
 MANUFACTURERS            Bristol-Myers
 MANUFACTURERS            Adria Laboratories
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                          cisplatin and cyclophosphamide on human
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                          and etoposide in human immunodeficiency
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 REFERENCES               Schurmann D, Weiss R, Jautzke G, Pohle HD,
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                          CG, Eastman AY, Wagner H, Portuese E, Wighton
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                          combination chemotherapy in the treatment of
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 REFERENCES               Nagatani T, Miyazawa M, Matsuzaki T, Iemoto
                          G, Kim S, Baba N, Miyakawa K, Miyamoto H,
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                          trial. JAMA. 1991 Jul 3;266(1):84-8.
 ENTRY MONTH              8906
 LAST REVISION DATE       960604
 

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