      Document 0040
 DOCN  DRG0040
 UNIQUE IDENTIFIER        DRG-0207
 NAME OF SUBSTANCE        Ifosfamide [USAN 1996]
 REGISTRY NUMBER          3778-73-2
 STANDARD CHEMICAL NAME   2H-1,3,2-Oxazaphosphorin-2-amine,
                          N,3-bis(2-chloroethyl)tetrahydro-, 2-oxide
                          [USAN 1996]
 SYNONYMS                 Ifex [USAN 1996]
 SYNONYMS                 Iphosphamid(e) [Merck Index 1989]
 SYNONYMS                 Isoendoxan [Merck Index 1989]
 SYNONYMS                 Isophosphamide [Merck Index 1989]
 SYNONYMS                 Cyfos [Merck Index 1989]
 SYNONYMS                 Holoxan [Merck Index 1989]
 SYNONYMS                 Mitoxana [Merck Index 1989]
 SYNONYMS                 Naxamide [Merck Index 1989]
 PROTOCOL ID NUMBERS      NCI 93 C-207
 SECONDARY SOURCE ID      MJF-9325 [USAN 1996]
 SECONDARY SOURCE ID      Z-4942 [USAN 1996]
 SECONDARY SOURCE ID      NSC-109724 [USAN 1996]
 SECONDARY SOURCE ID      A4942 [Merck Index 1989]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Ifosfamide exhibits
                          dose-dependent pharmacokinetics in humans. At
                          single doses of 3.8-5.0 g/m2, the plasma
                          concentrations decay biphasically and the
                          mean terminal elimination half-life is about
                          15 hours. At doses of 1.6-2.4 g/m2/day, the
                          plasma decay is monoexponential and the
                          terminal elimination half-life is about 7
                          hours. Ifosfamide is extensively metabolized
                          in humans and the metabolic pathways appear
                          to be saturated at high doses. After
                          administration of doses of 5 g/m2 of
                          14C-labeled ifosfamide, from 70% to 86% of
                          the dosed radioactivity was recovered in the
                          urine, with about 61% of the dose excreted as
                          parent compound. At doses of 1.6-2.4 g/m2
                          only 12% to 18% of the dose was excreted in
                          the urine as unchanged drug within 72 hours.
                          Two different dechloroethylated derivatives
                          of ifosfamide, 4-carboxyifosfamide,
                          thiodiacetic acid and cysteine conjugates of
                          chloroacetic acid have been identified as the
                          major urinary metabolites of ifosfamide in
                          humans and only small amounts of
                          4-hydroxyifosfamide and acrolein are present.
                          Small quantities (nmole/ml) of ifosfamide
                          mustard and 4-hydroxyifosfamide are
                          detectable in human plasma. Metabolism of
                          ifosfamide is required for the generation of
                          the biologically active species and while
                          metabolism is extensive, it is also quite
                          variable among patients. Enzymatic oxidation
                          of the chloroethyl side chains and subsequent
                          dealkylation produces the major urinary
                          metabolites, dechloroethyl ifosfamide and
                          dechloroethyl cyclophosphamide. The alkylated
                          metabolites of ifosfamide have been shown to
                          interact with DNA. [PDR 1995]
 DISEASES STUDIED/TREATED Treatment of AIDS-related non-Hodgkin's
                          lymphoma [NCI 93 C-207]
 CLASSIFICATION CODE      Antineoplastic [USAN 1996]
 OTHER MAJOR USES         Germ cell testicular cancer [PDR 1995]
 SUBSTANCE INTERACTIONS   Precautions should be observed if
                          coadministered with bone marrow depressants,
                          live virus vaccines or radiation therapy.
                          [USP DI 1995]
 ADVERSE EFFECTS          In patients receiving ifosfamide as a single
                          agent, the dose-limiting toxicities are
                          myleosuppression and urotoxicity. Alopecia
                          occurred in many of the patients treated.
                          Nausea and vomiting also was a common
                          occurrence in patients receiving ifosfamide.
                          Hematuria occurred in 6% to 92% of patients
                          treated. CNS side effects most commonly seen
                          were somnolence, confusion, depressive
                          psychosis, and hallucinations. Other adverse
                          reactions observed in less than 1% of
                          patients include stomatitis, salivation,
                          pulmonary symptoms, polyneuropathy, malaise,
                          hypotension, hypertension, fatigue, diarrhea,
                          dermatitis, constipation, coagulopathy,
                          cardiotoxicity, anorexia, allergic reaction,
                          fever, phlebitis, liver dysfunction and
                          infections. [PDR 1995]
 CONTRAINDICATIONS        Continued use of ifosfamide is
                          contraindicated in patients with severely
                          depressed bone marrow function and in
                          patients who have demonstrated a previous
                          hypersensitivity to it. [PDR 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Alkylating agent that is
                          chemically related to the nitrogen mustards
                          and is a synthetic analog of cyclophosphamide
                          [PDR 1995] [USP DI 1995]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: White crystalline
                          powder [PDR 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C7H15Cl2N2O2P [USAN 1996]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 261.09 [USAN 1996]
 CHEMICAL/PHYSICAL DATA   ELEMENTAL COMPOSITION: C32.20%, H5.79%,
                          Cl27.16%, N10.73%, P11.86% [Merck 1989]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Soluble in water [PDR 1995]
 CHEMICAL/PHYSICAL DATA   STABILITY: Reconstituted solutions are
                          chemically and physically stable for one week
                          at 30 C or three weeks at 5 C [PDR 1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: 1 and 3 g single dose vials;
                          available in combination packages with the
                          uroprotective agent mesna. [PDR 1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Intravenous. [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: The dry powder may be stored at room
                          temperature preferably between 15-30 C.
                          Storage above 40 C should be avoided. [PDR
                          1995] [USP DI 1995]
 MANUFACTURERS            Bristol-Myers Squibb Company
 REFERENCES               Dincol D, Icli F, Karaoguz H, Cay F, Arican
                          A, Demirkazik A, Akbulut H. Mesna/ifosfamide,
                          mitoxantrone, etoposide, bleomycin,
                          vincristine, prednisone (MINE-BOP)
                          combination chemotherapy in the treatment of
                          refractory and relapsed non-Hodgkin's
                          lymphoma. Acta Oncol;VOL 34,ISS
                          7,1995,P937-40.
 REFERENCES               De Lena M, Ditonno P, Lorusso V, Brandi M,
                          Timurian A, Marzullo F, Ventrella V,
                          Pellecchia A. CEOP-B alternated with VIMB in
                          intermediate-grade and high-grade
                          non-Hodgkin's lymphoma: a pilot study. J Clin
                          Oncol;VOL 13, ISS 4,1995,P953-60.
 REFERENCES               Quezado ZM, Wilson WH, Cunnion RE, Parker MM,
                          Reda D, Bryant G, Ognibene FP. High-dose
                          ifosfamide is associated with severe,
                          reversible cardiac dysfunction. Ann Intern
                          Med. 1993 Jan 1;118(1):31-6.
 REFERENCES               Gisselbrecht C, Lepage E, Tirelli U,
                          Oksenhendler E, Gabarre J, Farcet JP,
                          Gastaldi R, Coiffier B, Thyss A, Rapahel M,
                          et al. Human immunodeficiency virus-related
                          lymphoma treatment with intensive combination
                          chemotherapy (Meeting abstract). Proc Annu
                          Meet Am Soc Clin Oncol. 1993;12:A1227.
 REFERENCES               Cabanillas F. Non-Hodgkin's lymphomas: a
                          review of the M.D. Anderson experience. Semin
                          Oncol. 1992 Feb;19(1 Suppl 1):11-3.
 REFERENCES               Goss PE. New perspectives in the treatment of
                          non-Hodgkin's lymphoma. Semin Oncol. 1992
                          Dec;19(6 Suppl 12):23-9.
 REFERENCES               Northfelt DW, Kahn JO, Volberding PA, Kaplan
                          LD. Ifosfamide/etoposide for AIDS-related
                          non-Hodgkin's lymphoma (AIDS-NHL). Int Conf
                          AIDS. 1991 Jun 16-21;7(2):274 (abstract no.
                          W.B.2370).
 REFERENCES               Cabanillas F. Malignant lymphomas.
                          Hematology. 1991;14:299-334.
 ENTRY MONTH              9404
 LAST REVISION DATE       960411
 

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