      Document 0166
 DOCN  DRG0166
 UNIQUE IDENTIFIER        DRG-0081
 NAME OF SUBSTANCE        Etoposide [USAN 1996]
 REGISTRY NUMBER          33419-42-0
 STANDARD CHEMICAL NAME   Furo(3',4':6,7)naphtho(2,3-d)-1,3-dioxol-6(5a-
                          H)-one-, 9-((4,
                          6-0-ethylidene-beta-D-glucopyranosyl)oxy)5,
                          8,8a,9-tetrahydro-
                          5-(4-hydroxy-3,5-dimethoxyphenl,(5R-
                          (5alpha,5abeta,8aalpha, 9beta(R*))))- [USAN
                          1996]
 SYNONYMS                 VePesid [USAN 1996]
 SYNONYMS                 VP-16 [AmFAR Tx Dir 1995;7(4)]
 SYNONYMS                 4'-Demethylepipodophyllotoxin 9-
                          (4,6-0-(R)-ethylidene-beta-D-glucopyranoside)
                          [USAN 1996]
 SYNONYMS                 EPEG [Merck Index 1989]
 SYNONYMS                 VP-16-213 [USAN 1996]
 PROTOCOL ID NUMBERS      NIAID ACTG 110
 PROTOCOL ID NUMBERS      NCI 90 C-34
 PROTOCOL ID NUMBERS      FDA 055A
 PROTOCOL ID NUMBERS      NIAID ACTG 269
 IND NUMBER               34080
 SECONDARY SOURCE ID      NSC-141540 [USAN 1990]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Has been shown to cause
                          metaphase arrest in chick fibroblasts. Its
                          main effect, however, appears to be at the G2
                          portion of the cell cycle in mammalian cells.
                          Two different dose-dependent responses are
                          seen. At high concentrations (10 mcg/ml or
                          more), lysis of cells entering mitosis is
                          observed. At low concentrations (0.3 to 10
                          mcg/ml) cells are inhibited from entering
                          prophase. It does not interfere with
                          microtubule assembly. The predominant
                          macromolecular effect of the drug appears to
                          be DNA synthesis inhibition. On intravenous
                          administration, the disposition of etoposide
                          is best described as a biphasic process with
                          a distribution half-life ranging from 4 to 11
                          hours. Total body clearance values range from
                          33 to 48 ml/min or 16 to 36 ml/min/m2 and,
                          like the terminal elimination half-life, are
                          independent of dose over a range 100-600
                          mg/m2. Over the same dose range, the areas
                          under the plasma concentration versus time
                          curves (AVC) and the maximum plasma
                          concentration (Cmax) values increase linearly
                          with dose. Etoposide does not accumulate in
                          the plasma following daily administration of
                          100 mg/m2 for 4 to 5 days. Etoposide enters
                          the CSF poorly. The exact mechanism of action
                          of etoposide is not known, but the drug
                          appears to produce its cytotoxic effects by
                          damaging DNA and thereby inhibiting or
                          altering DNA synthesis. Etoposide appears to
                          be cell-cycle dependent and cycle-phase
                          specific, inducing G2-phase arrest and
                          preferentially killing cells in the G2 and
                          late S phases. [PDR 1995] [AHFS Drug
                          Information 1995]
 DISEASES STUDIED/TREATED Kaposi's sarcoma [AHFS Drug Information 1995]
 CLASSIFICATION CODE      Antineoplastic [USAN 1996]
 OTHER MAJOR USES         Indicated in combination with other
                          antineoplastics for treatment of refractory
                          testicular tumors in patients who already
                          received appropriate surgical,
                          chemotherapeutic and radiation therapy;
                          indicated treatment of small cell lung
                          carcinoma. [PDR 1995]
 SUBSTANCE INTERACTIONS   Blood dyscrasia causing medications, bone
                          marrow depressants, killed virus vaccines,
                          live virus vaccines, or any combinations
                          containing any of these medications may cause
                          negative reactions with etoposide. Additive
                          bone marrow depression may occur with
                          radiation therapy. Etoposide and cisplatin
                          may be synergistic against some tumors.
                          However, patients previously treated with
                          cisplatin may have impaired elimination of
                          etoposide. [USP DI 1995] [AHFS Drug
                          Information 1995]
 ADVERSE EFFECTS          Myelosuppression is dose related and dose
                          limiting, with granulocyte nadirs occurring 7
                          to 14 days after drug administration. Bone
                          marrow recovery is usually complete by day
                          20, and no cumulative toxicity has been
                          reported. Nausea and vomiting are the major
                          gastrointestinal toxicities. Transient
                          hypotension following rapid intravenous
                          administration has been reported in 1% to 2%
                          of patients. Anaphylactic-like reactions
                          characterized by chills, fever, tachycardia,
                          bronchospasm, dyspnea, and/or hypotension
                          have been reported to occur in 0.7% to 2% of
                          patients receiving the drug intravenously and
                          in less than 1% of the patients treated with
                          oral capsules. Reversible alopecia, sometimes
                          progressing to total baldness, was observed
                          in up to 66% of patients. Other effects
                          include aftertaste, fever, pigmentation,
                          abdominal pain, constipation, dysphagia,
                          transient cortical blindness, and optic
                          neuritis. [PDR 1995]
 CONTRAINDICATIONS        Contraindicated in the presence of chicken
                          pox or existing or recent herpes zoster.
                          Caution should be exercised in the presence
                          of bone marrow depression, hepatic function
                          impairment, general infection, renal function
                          impairment, and in patients who have previous
                          cytotoxic drug therapy and radiation therapy.
                          Etoposide is teratogenic and embryotoxic in
                          mice and rats at doses of 1-3% of the
                          recommended clinical dose based on body
                          surface; therefore, although human studies
                          have not been done, its use in pregnancy is
                          contraindicated. Breastfeeding is not
                          recommended while etoposide is being
                          administered. Dental work during etoposide
                          therapy is discouraged due to the bone marrow
                          depressant effects which may result in an
                          increased incidence of microbial infection,
                          delayed healing, and gingival bleeding. [USP
                          DI 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Etoposide is a
                          semisynthetic derivative of podophyllin [PDR
                          1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C29H32O13 [Merck Index
                          1989]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 588.56 [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Very soluble in methanol and in
                          chloroform; slightly soluble in ethanol;
                          sparingly soluble in water and in ether; made
                          more miscible with water by means of organic
                          solvents [PDR 1995]
 CHEMICAL/PHYSICAL DATA   STABILITY: Unopened vials of VePesid
                          Injection are stable for 24 months at room
                          temperature (25 C) [PDR 1995]
 CHEMICAL/PHYSICAL DATA   STABILITY: Vials diluted to a concentration
                          of 0.2 or 0.4 mg/ml are stable for 96 and 48
                          hours, at room temperature under normal room
                          fluorescent light in both glass and plastic
                          containers [PDR 1995]
 CHEMICAL/PHYSICAL DATA   MELTING POINT: 236-251 C [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   ELEMENTAL COMPOSITION: C59.18%, H5.48%,
                          O35.34% [Merck Index 1989]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: 50 mg capsules; 5 ml vials
                          containing 100 mg for injection. [AHFS Drug
                          Information 1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral; intravenous. [AHFS
                          Drug Information 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: VePesid capsules must be stored
                          under refrigeration 2-8 C. [PDR 1995]
 MANUFACTURERS            Bristol-Myers Squibb
 REFERENCES               Paredes J, Kahn HO, Tong WP, Feldstein ML,
                          Lin S, Bennett JM, Metroka CE, Ratner L,
                          Krown SE. Weekly oral etoposide in patients
                          with Kaposi's sarcoma associated with human
                          immunodeficiency virus infection: a phase I
                          multicenter trial of the AIDS Clinical Triald
                          Group. J Acquir Immune Defic Syndr Hum
                          Retrovirol. 1995 Jun 1;9(2):138-44.
 REFERENCES               Mans D, Sprinz E, Sander I, Kalakun F, Jung
                          G, Prolla G, Schwarstmann G. A phase II study
                          of oral etoposide (VP-16) in AIDS-related
                          Kaposi's sarcoma (KS). Int Conf AIDS. 1994
                          Aug 7-12;10(1):173 (abstract no. PB0118).
 REFERENCES               Belani CP, Doyle LA, Aisner J. Etoposide:
                          current status and future perspectives in the
                          management of malignant neoplasms. Cancer
                          Chemother Pharmacol. 1994;34 Suppl:S118-26.
 REFERENCES               Sparano JA, Wiernek PH, Dutcher JP, Sarta C,
                          Leaf A, Hu XP. A pilot trial of infusional
                          cyclophosphamide, doxorubicin and etoposide
                          (CDE) plus didanosine (DDI) in HIV-related
                          non-Hodgkin's lymphoma (NHL). Proc Annu Meet
                          Am Soc Clin Oncol. 1994;13:A7.
 REFERENCES               Sparano JA, Wiernik PH, Strack M, Leaf A,
                          Becker NH, Sarta C, Carney D, Elkind R, Shah
                          M, Valentine ES, et al. Infusional
                          cyclophosphamide, doxorubicin and etoposide
                          in HIV-related non-Hodgkin's lymphoma: a
                          follow-up report of a highly active regimen.
                          Leuk Lymhoma. 1994 Jul14(3-4):263-71.
 REFERENCES               Schmilovich A, Perez H, Gil Deza E, Cahn P,
                          Casiro A, Grinberg N. Low-dose oral etoposide
                          (E) + DDI in patients (pts) with AIDS-related
                          neoplasias (Meeting abstract). Proc Annu Meet
                          Am Soc Clin oncol. 1994;13:A12.
 REFERENCES               Brambilla L, Labianca R, Boneschi V, Fossati
                          S, Dallavalle G, Finzi AF, Luporini G.
                          Mediterranean Kaposi's sarcoma in the
                          elderly. A randomized study of oral etopside
                          versus vinblastine. Cancer. 1994 Nov
                          15;74(10):2873-8.
 REFERENCES               Sander E, Zampese M, Prolla G, Marques A,
                          Jung F, Venegas LF, Sprinz E, Kronfeld M,
                          Kalakun L, Mans DA, et al. Phase II trial of
                          low-dose oral etoposide in AIDS-related
                          Kaposi's sarcoma (KS) (Meeting abstract).
                          Proc Annu Meet Am Soc Clin Oncol.
                          1993;12:A19.
 REFERENCES               Sparano JA, Wiernik PH, Strack M, Leaf A,
                          Becker N, Valentine ES. Infusional
                          cyclophosphamide, doxorubicin, and etoposide
                          in human immunodeficiency virus- and human
                          T-cell leukemia virus type I-related
                          non-Hodgkin's lymphoma: a highly active
                          regimen. Blood. 1993 May 15;81(10):2810-5.
 REFERENCES               Bufill JA, Grace WR, Astrow AB. PHASE II
                          TRIAL OF PROLONGED, LOW-DOSE, ORAL VP-16 IN
                          AIDS-RELATED KAPOSI'S SARCOMA (KS) (MEETING
                          ABSTRACT). Proc Annu Meet Am Soc Clin Oncol.
                          1992;11:A13.
 ENTRY MONTH              9006
 LAST REVISION DATE       951128
 

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