      Document 0229
 DOCN  DRG0229
 UNIQUE IDENTIFIER        DRG-0018
 NAME OF SUBSTANCE        Ganciclovir [USAN 1995]
 REGISTRY NUMBER          82410-32-0
 RELATED REGISTRY NUMBER  107910-75-8 (sodium salt)
 STANDARD CHEMICAL NAME   6H-Purin-6-one, 2-amino-1,9-dihydro-9-
                          ((2-hydroxy-1-(hydroxymethyl)ethoxy)methyl)-
                          [USAN 1996]
 SYNONYMS                 DHPG [Merck Index 1989]
 SYNONYMS                 2'NDG [Merck Index 1989]
 SYNONYMS                 Cytovene [USAN 1995]
 SYNONYMS                 9-((2-Hydroxy-1-(hydroxymethyl)ethoxy)methyl)-
                          guanine [USAN 1995]
 SYNONYMS                 9-(1,3-Dihydroxy-2-propoxymethyl)guanine [TX
                          303]
 SYNONYMS                 Ganciclovir sodium [USAN 1995]
 SYNONYMS                 Cymevan [Merck Index 1989]
 SYNONYMS                 Cymevene [Merck Index 1989]
 SYNONYMS                 2'-nor-2'deoxyguanosine [Merck Index 1989]
 PROTOCOL ID NUMBERS      NIAID ACTG 004
 PROTOCOL ID NUMBERS      NIAID ACTG 071
 PROTOCOL ID NUMBERS      NIAID ACTG 073
 PROTOCOL ID NUMBERS      NIAID ACTG 085
 PROTOCOL ID NUMBERS      NIAID ACTG 127
 PROTOCOL ID NUMBERS      NIAID ACTG 129
 PROTOCOL ID NUMBERS      NIAID ACTG 151
 PROTOCOL ID NUMBERS      NIAID CC-118
 PROTOCOL ID NUMBERS      NIAID TX 303
 PROTOCOL ID NUMBERS      FDA 005A
 PROTOCOL ID NUMBERS      FDA 017A
 PROTOCOL ID NUMBERS      FDA 029B
 PROTOCOL ID NUMBERS      FDA 029C
 PROTOCOL ID NUMBERS      FDA 029D
 PROTOCOL ID NUMBERS      FDA 029F
 PROTOCOL ID NUMBERS      FDA 029G
 PROTOCOL ID NUMBERS      FDA 059A
 PROTOCOL ID NUMBERS      FDA 059B
 PROTOCOL ID NUMBERS      FDA 079A
 PROTOCOL ID NUMBERS      FDA 059C
 PROTOCOL ID NUMBERS      NIAID ACTG 228
 PROTOCOL ID NUMBERS      FDA 029G
 PROTOCOL ID NUMBERS      FDA 037B
 PROTOCOL ID NUMBERS      FDA 037C
 PROTOCOL ID NUMBERS      FDA 059F
 PROTOCOL ID NUMBERS      NIAID ACTG 226
 PROTOCOL ID NUMBERS      FDA 059D
 PROTOCOL ID NUMBERS      FDA 059E
 PROTOCOL ID NUMBERS      NEI 92 EI-169
 PROTOCOL ID NUMBERS      NIAID 90 CC-118
 PROTOCOL ID NUMBERS      NIAID ACTG 183
 PROTOCOL ID NUMBERS      NIAID CPCRA 023
 PROTOCOL ID NUMBERS      NIAID ACTG 266
 PROTOCOL ID NUMBERS      FDA 251B
 PROTOCOL ID NUMBERS      NIAID ACTG 278
 SECONDARY SOURCE ID      BW 759U [USAN 1995]
 SECONDARY SOURCE ID      RS-21592 [USAN 1995]
 SECONDARY SOURCE ID      BIOLF-62 [Merck Index 1989]
 SECONDARY SOURCE ID      BWB759U [Merck Index 1989]
 PHARMACOLOGICAL ACTION   Ganciclovir is a synthetic nucleoside
                          analogue of 2'-deoxyguanosine that inhibits
                          replication of herpes viruses both in vitro
                          and in vivo. Sensitive human viruses include
                          cytomegaloviruses (CMV), herpes simplex virus
                          -1 and -2 (HSV-1, HSV-2), Epstein-Barr virus
                          (EBV) and varicella zoster virus (VZV).
                          Clinical studies have been limited to
                          assessment of efficacy in patients with CMV
                          infection. Available evidence indicates that
                          upon entry into host cells, cytomegaloviruses
                          induce one or more cellular kinases that
                          phosphorylate ganciclovir to its
                          triphosphate. In vitro ganciclovir
                          triphosphate is catabolized slowly, with 60%
                          to 70% of the original level remaining in the
                          infected cells 18 hours after removal of
                          ganciclovir from the extracellular medium.
                          The antiviral activity of ganciclovir
                          triphosphate is believed to be the result of
                          inhibition of viral DNA synthesis by two
                          known modes: (1) competitive inhibition of
                          viral DNA polymerases (2) direct
                          incorporation into viral DNA, resulting in
                          the eventual termination of viral DNA
                          elongation. The cellular DNA polymerase alpha
                          is also inhibited, but at a higher
                          concentration than required for viral DNA
                          polymerase. Median effective inhibitory dose
                          (ED50) of ganciclovir for human CMV isolates
                          ranged from 0.2-3 mcg/ml. Plasma level at the
                          end of the first 1 hour infusion was 8.3+/-4
                          mcg/ml. Plasma half-life was 2.9+/-1.3 hours
                          and the systemic clearance was 3.64+/-1.86
                          ml/kg/min. In patients with normal, renal
                          function, more than 90% of administered drug
                          was recovered unmetabolized in the urine.
                          [PDR 1995]
 DISEASES STUDIED/TREATED Indicated in the treatment of CMV
                          (cytomegalovirus) retinitis in
                          immunocompromised individuals [PDR 1995]
 DISEASES STUDIED/TREATED FDA approved 6/26/89 for CMV retinitis [PDR
                          1995]
 DISEASES STUDIED/TREATED FDA approved oral ganciclovir for marketing
                          1/5/95 [FDA Personal Communication]
 CLASSIFICATION CODE      Antiviral [USAN 1995]
 OTHER MAJOR USES         Also used transplant patients at risk for CMV
                          disease. [PDR 1995]
 SUBSTANCE INTERACTIONS   Possible interaction with probenecid and
                          other drugs inhibiting renal tubular
                          secretion. Also possible that drugs that
                          inhibit replication of rapidly dividing cell
                          populations (e.g., dapsone, pentamidine,
                          flucytosine, vincristine, adriamycin,
                          amphotericin B, trimethoprim/sulfamethoxazole
                          combination) may have additional toxicity
                          when administered with ganciclovir. Since
                          both zidovudine and ganciclovir have the
                          potential to cause granulocytopenia
                          (neutropenia) many patients will not tolerate
                          combination therapy with these two drugs at
                          full strength. [PDR 1995]
 ADVERSE EFFECTS          In clinical trials, Cytovene (Syntex brand of
                          ganciclovir sodium) was withdrawn in approx.
                          32% of patients because of toxicity. The most
                          frequent adverse events seen in treated
                          patients include granulocytopenia and
                          thrombocytopenia/neutropenia; the former was
                          generally reversible by drug withdrawal.
                          Other possible adverse effects included:
                          renal toxicity (increased serum creatinine
                          levels); CNS toxicity (seizures, dizziness,
                          headaches); retinal detachment (observed in
                          CMV retinitis patients before and after
                          Cytovene therapy); effects on the digestive
                          system (nausea, vomiting, anorexia, diarrhea,
                          hemorrhage); the urogenital system
                          (hematuria, increased blood urea nitrogen);
                          and respiratory system (dyspnea). [PDR 1995]
 CONTRAINDICATIONS        Should not be administered if the absolute
                          neutrophil count is less than 500 cells/cubic
                          millimeter or the platelet count is less than
                          25,000 cells/cubic millimeter. Because of the
                          mutagenic potential of ganciclovir, male and
                          female patients should use effective
                          contraception during treatment. Concomitant
                          treatment with zidovudine may not be
                          tolerated by many patients and may result in
                          severe granulocytopenia (neutropenia). [PDR
                          1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Synthetic purine nucleoside
                          analog of guanine. [AHFS Drug Information
                          1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C9H13N5O4 (Ganciclovir
                          Sodium: C9H12N5NaO4) [USAN 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 255.23 (Ganciclovir sodium:
                          277.22) [USAN 1995]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: White lyophilized
                          powder [PDR 1995]
 CHEMICAL/PHYSICAL DATA   MELTING POINT: 250 C [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   PERCENT ELEMENTAL COMPOSITION: C42.35%,
                          H5.13%, N27.44%, O25.07% [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Soluble in water [Merck Index
                          1989]
 CHEMICAL/PHYSICAL DATA   PHYSICAL COMMENT: Molecular formula
                          (Ganciclovir sodium C9H12N5NaO4); Molecular
                          weight (Ganciclovir ssodium 277.22). [USAN
                          1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Vials (10 ml) containing 500 mg
                          ganciclovir as ganciclovir sodium
                          reconstituted with 10 ml of sterile water for
                          injection. [PDR 1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: (yielding a drug solution
                          concentration of 50 mg/ml, which should be
                          added to an acceptable infusion fluid). [PDR
                          1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Ganciclovir sodium is
                          administered by slow IV infusion. Should not
                          be given by rapid IV infusion or direct IV
                          injection.
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Because of the high pH of
                          the solution, IM or subcutaneous injection of
                          the drug should be avoided since severe
                          tissue irritation may result. [AHFS Drug
                          Information 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Store below 40 C (104 F); solutions
                          of ganciclovir should be reconstituted in
                          sterile water. Do not use bacteriostatic
                          water containing parabens. [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Reconstituted solutions should be
                          used within 12 hours and should not be
                          refrigerated. [PDR 1995]
 MANUFACTURERS            Roche Global Development - Palo Alto
 REFERENCES               Combination foscarnet and ganciclovir therapy
                          vs monotherapy for the treatment of relapsed
                          cytomegalovirus retinitis in patients with
                          AIDS. The Cytomegalovirus Retreatment Trial.
                          The Studies of Ocular Complications of AIDS
                          Research Group in Collaboration with the AIDS
                          Clinical Trials Group. Arch Ophthalmol 1996
                          Jan;114(1):23-33.
 REFERENCES               Wolf DG, Lee DJ, Spector SA. Detection of
                          human cytomegalovirus mutations associated
                          with gancicolvir resistance in cerebrospinal
                          fluid of AIDS patients with central nervous
                          system disease. Antimicrob Agents Chemother.
                          1995 Nov;39(11):2552-4.
 REFERENCES               Anderson RD, Griffy KG, Jung D, Dorr A, Hulse
                          JD, Smith RB. Ganciclovir absolute
                          bioavailability and steady-state
                          pharmacokinetics after oral administration of
                          two 3000-mg/d dosing regimens in human
                          immunodeficiency virus-and
                          cytomegalovirus-seropositive patients. Clin
                          Ther 1995 May-Jun;17(3):425-32.
 REFERENCES               Hanson MN, Preheim LC, Chou S, Talarico CL,
                          Biron KK, Erice A. Novel mutation in the UL97
                          gene of a clinical cytomegalvirus strain
                          conferring resistance to ganciclovir.
                          Antimicrob Agents Chemother. 1995
                          May;39(5):1204-5.
 REFERENCES               Drew WL, Anderson R, Lang W, Miner RC, Davis
                          G, Lalezari J. Failure of high-dose oral
                          acyclovir to suppress CMV viruria or induce
                          ganciclovir-resistant CMV in HIV antibody
                          positive patients. J Acquir Immune Defic
                          Syndr Hum Retrovirol. 1995 Mar 1;8(3):289-91.
 REFERENCES               Baldanti F, Silini E, Sarasini A, Talarico
                          CL, Stanat SC, Biron KK, Furione M, Bono F,
                          Palu G, Gerna G. A three-nucleotide deletion
                          in the UL97 open reading frame is responsible
                          for the ganciclovir resistance of human
                          cytomegalovirus clinical isolate. J Virol.
                          1995 Feb;69(2):796-800.
 REFERENCES               Wilcox CM, Straub RF, Schwartz DA.
                          Cytomegalovirus esophagitis in AIDS: a
                          prospective evaluation of clinical response
                          to ganciclovir therapy, relapse rate, and
                          long-term outcome. Am J Med. 1995
                          Feb;98(2):169-76.
 REFERENCES               Morbidity and toxic effects associated with
                          ganciclovir or foscarnet therapy in a
                          randomized cytomegalovirus retinitis trial.
                          Arch Intern Med. 1995 Jan 9;155(1):65-74.
 REFERENCES               Wolf DG, Smith IL, Lee DJ, Freeman WR,
                          Flores-Aguilar M, Spector SA. Mutations in
                          human cytomegalovirus UL97 gene confer
                          clinical resistance to ganciclovir and can be
                          detected directly in patient plasma. J Clin
                          Invest. 1995 Jan;95(1):257-63.
 REFERENCES               Markham A, Faulds D. Ganciclovir. An update
                          of its therapeutic use in cytomegalovirus
                          infection. Drugs. 1994 Sep;48(3):455-84.
 ENTRY MONTH              8906
 LAST REVISION DATE       960514
 

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