      Document 0189
 DOCN  DRG0189
 UNIQUE IDENTIFIER        DRG-0058
 NAME OF SUBSTANCE        Vidarabine [USAN 1996]
 REGISTRY NUMBER          24356-66-9
 RELATED REGISTRY NUMBER  5536-17-4 (anhydrous)
 STANDARD CHEMICAL NAME   9-beta-D-Arabinofuranosyladenine monohydrate
                          [USAN 1996]
 SYNONYMS                 Adenine arabinoside [Merck Index 1989]
 SYNONYMS                 Adenine, 9-beta-D-arabinofuranosyl-(8CI)
                          [CHEMLINE 1995]
 SYNONYMS                 Ara-A [Merck Index 1989]
 SYNONYMS                 Araadenosine [CHEMLINE]
 SYNONYMS                 Arabinosyladenine [Merck Index 1989]
 SYNONYMS                 beta-D-Arabinosyladenine [CHEMLINE]
 SYNONYMS                 Vidarabin [CHEMLINE]
 SYNONYMS                 Vidarabina [CHEMLINE]
 SYNONYMS                 Spongoadenosine [Merck Index 1989]
 SYNONYMS                 9-Arabinosyladenine [CHEMLINE]
 SYNONYMS                 9-beta-D-Arabinofuranosyladenine [CHEMLINE]
 SYNONYMS                 Vira-A [Merck Index 1989]
 SYNONYMS                 9H-Purin-6-amine, 9-beta-D-arabinofuranosyl-,
                          monohydrate [USAN 1996]
 SYNONYMS                 Arasena-A [Merck Index 1989]
 PROTOCOL ID NUMBERS      NIAID ACTG 095
 SECONDARY SOURCE ID      CI 673 [Merck Index 1989]
 SECONDARY SOURCE ID      AI3-52821 [CHEMLINE]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Following intravenous
                          injection, vidarabine is rapidly deaminated
                          into arabinosylhypoxanthine, its principal
                          metabolite, which is rapidly distributed into
                          the tissues (mean half-life of the metabolite
                          is 3.3 hours). The metabolite penetrates into
                          the cerebrospinal fluid (CSF) to give a
                          CSF:plasma ratio of approximately 1:3;
                          however, in patients with impaired renal
                          function, the metabolite may accumlate in the
                          plasma and reach levels several-fold higher
                          than typical values.  After slow infusion of
                          10 mg/kg of the drug into adults, peak plasma
                          levels of the drug and its metabolite ranged
                          from 0.2-0.4 and 3-6 mcg/ml, respectively;
                          these levels reflect the rate of infusion and
                          show no accumulation across time. The drug is
                          principally excreted via the kidneys, with
                          urinary excretion constant over 24 hours; a
                          total of 41-53 percent of the daily dose is
                          recovered in the urine as the metabolite,
                          with 1-3 percent appearing as the parent
                          compound; there is no evidence of fecal
                          excretion of the drug or its metabolites.
                          Studies of the mode of action of the drug
                          have shown that it possesses in vitro and in
                          vivo antiviral activity against herpes
                          simplex virus types 1 and 2. While the
                          antiviral mechanism of action of this drug
                          has not yet been established, it is known
                          that it is converted into nucleosides which
                          inhibit viral DNA polymerase. [PDR 1993]
                          Exact mechanism of vidarabine's antiviral
                          activity has not been elucidated; it appears
                          to involve inhibition of viral replication by
                          inhibiting viral DNA polymerase. Vidarabine
                          is only minimally incorporated into viral
                          DNA. It is not immunosuppressive. In the
                          body, vidarabine is rapidly deaminated into
                          ara-HX (arabinosylhypoxanthine) which also
                          possesses antiviral activity but
                          substantially less than vidarabine. Following
                          topical application of vidarabine to the eye
                          in patients with epithelial defect in the
                          cornea, trace amount of the drug and its
                          major metabolite, ara-HX, can be detected in
                          aqueous humor. [AHFS Drug Information 1995]
 DISEASES STUDIED/TREATED IV or topical antiviral drug active against
                          herpes simplex and varicella-zoster (VZV)
                          viruses. Used to treat HSV (herpes simplex
                          virus) encephalitis [AmFAR Tx Dir 1995;7(4)]
 DISEASES STUDIED/TREATED Neonatal encephalitis, infections of the
                          skin, eyes, mouth, disseminated HSV and VZV
                          infections with visceral involvement [AmFAR
                          Tx Dir 1995;7(4)]
 DISEASES STUDIED/TREATED Herpes zoster (shingles) due to reactivated
                          VZV infections in immunosuppressed patients
                          [AmFAR Tx Dir 1995;7(4)]
 CLASSIFICATION CODE      Antiviral [USAN 1996]
 OTHER MAJOR USES         Treatment of Herpes zoster (shingles) and
                          Herpes simplex infections [AHFS Drug
                          Information 1995]
 SUBSTANCE INTERACTIONS   Concurrent topical application of vidarabine
                          and a corticosteriod is contraindicated in
                          superficial herpes simplex keratitis. However
                          such combinations may be of benefit in severe
                          infections. [AHFS Drug Information 1995]
 ADVERSE EFFECTS          Principal adverse reactions in adults involve
                          the gastrointestinal tract (anorexia, nausea,
                          vomiting, diarrhea). Central nervous system
                          disturbances at therapeutic doses include
                          tremor, dizziness, hallucinations, confusion,
                          ataxia, headache, and encephalopathy,
                          especially in patients with impaired hepatic
                          or renal functions. Hematologic clinical
                          changes noted included a decrease in
                          hemoglobin or hematocrit, white blood cell
                          count, and platelet count, and elevations of
                          aspartate aminotransferase; occasional
                          observations included decreases in
                          reticulocyte count and elevated total
                          bilirubin. In newborns with HSV infections,
                          no clear evidence of hematologic, renal, or
                          hepatic toxicity was noted at recommended
                          doses. Other symptoms may include weight
                          loss, malaise, pruritus, rash, hematemesis,
                          and pain at the injection site. Acute massive
                          overdose of the intravenous form has been
                          reported without any serious evidence of
                          adverse effect; it was felt that, because of
                          the low solubility of the drug, acute water
                          overloading would pose a greater threat to
                          the patient than the drug. However, since a
                          dose of over 20 mg/kg/day can produce bone
                          marrow depression with concomitant
                          thrombocytopenia, hematologic, liver, and
                          renal functions should be carefully monitored
                          when a massive overdose of the intravenous
                          form of the drug is used. [PDR 1993] With the
                          ophthalmic preparation, burning, itching and
                          mild irritation are the most common adverse
                          effects. There is some evidence in animals
                          that vidarabine can be mutagenic or
                          tumerigenic. [AHFS Drug Information 1995]
 CONTRAINDICATIONS        Contraindicated in patients with a known or
                          suspected hypersensitivity to the drug. Both
                          topically and parenterally administered
                          vidaradine has been reported to be
                          teratogenic in animals. Additionally, ocular
                          penetration of vidarabine (ophthalmic
                          preparation) is low. The drug should be used
                          in pregnancy only when potential benefits
                          justify possible risk the fetus. It is
                          unlikely that vidarabine is distributed into
                          milk following ophthalmic use. However, the
                          drug has been shown to be tumorigenic (in
                          animals) and a decision should be made
                          whether to discontinue nursing or use the
                          drug. [AHFS Drug Information 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Purine nucleoside
                          derivative obtained from fermentation
                          cultures of Streptomyces antibioticus [AHFS
                          Drug Information 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C10H13N504.H20 Monohydrate
                          [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 285.27 [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   ELEMENTAL COMPOSITION (Monohydrate): C42.1%,
                          H5.30%, N24.55%, O28.04% [Merck 1989]
 CHEMICAL/PHYSICAL DATA   MELTING POINT: 257 C (Monohydrate: 260-270 C)
                          [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY (Monohydrate): 0.45 mg/ml (25 C)
                          [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: White crystalline
                          powder. [AHFS Drug Information 1995]
 CHEMICAL/PHYSICAL DATA   PHYSICAL COMMENT: Molecular formula
                          (Monohydrate: C10H13N504.H20); Molecular
                          weight (Monohydrate: 285.27); Melting point
                          (Monohydrate: 257 C) [Merck Index 1989)
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Vial containing sterile
                          suspension of 1 gram of the drug in 5 ml (for
                          dilution with intravenous infusion solution);
                          3 percent ophthalmic ointment. [PDR 1993]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Intravenous infusion;
                          intraocular. [PDR 1993]
 SUBSTANCE DELIVERY DATA  STORAGE: Dilute just prior to administration
                          and use the diluted solution within 24 hours;
                          do not refrigerate the dilution solution.
                          [PDR 1993]
 MANUFACTURERS            Warner-Lambert Parke-Davis
 REFERENCES               Balfour HH Jr, Benson C, Braun J, Cassens B,
                          Erice A, Friedman-Kien A, Klein T, Polsky B,
                          Safrin S. Management of acyclovir-resistant
                          herpes simplex and varicella-zoster virus
                          infections. J Acquir Immune Defic Syndr. 1994
                          Mar;7(3):254-60.
 REFERENCES               McGrath BJ, Newman CL. Genital herpes simplex
                          infections in patients with the acquired
                          immunodeficiency syndrome. Pharmacotherapy.
                          1994 Sep-Oct;14(5):529-42.
 REFERENCES               Washio M, Hamada T, Goda H, Yoshimitsu T,
                          Kajioka T, Koga H, Shogakuchi Y, Fujishma M,
                          Okayama M. Acyclovir-resistant herpes zoster
                          encephalitis successfully treated with
                          vidarabine: a case report. Fukuoka Igaku
                          Zasshi. 1993 Oct;84(10):436-9.
 REFERENCES               Sasadeusz JJ, Sacks SL. Systemic antivirals
                          in herpesvirus infections. Dermatol Clin.
                          1993 Jan;11(1):171-85.
 REFERENCES               Whitley RJ, Gnann JW Jr, Hinthorn D, Liu C,
                          Pollard RB, Hayden F, Mertz GJ, Oxman M,
                          Soong SJ. Disseminated herpes zoster in the
                          immunocompromised host: a comparative trial
                          of acyclovir and vidarabine. J Infect Dis.
                          1992 Mar;165(3):450-5.
 REFERENCES               Teich SA, Cheung TW, Friedman AH. Systemic
                          antiviral drugs used in ophthalmology. Surv
                          Ophthalmol. 1992 Jul-Aug;37(1):19-53.
 REFERENCES               Safrin S, Crumpacker C, Chatis P, Davis R,
                          Hafner R, Rush J, Kessler HA, Landry B, Mills
                          J. A controlled trial comparing foscarnet
                          with vidarabine for acyclovir-resistant
                          mucocutaneous herpes simplex in the acquired
                          immunodeficiency syndrome. N Engl J Med. 1991
                          Aug 22;325(8):551-5.
 REFERENCES               Shepp DH, Farber BF. Ineffectiveness of
                          vidarabine in mucocutaneous herpes simplex
                          virus infection [letter]. Lancet. 1990 Jun
                          2;335(8701):1344.
 REFERENCES               Gizzi M, Rudolph S, Perakis A. Ocular flutter
                          in vidaribine toxicity. Am J Ophthalmol. 1990
                          Jan 15;109(1):105.
 REFERENCES               Kunitomi T, Akazai A, Ikeda M, Oda M, Kodani
                          N. Comparison of acyclovir and vidarabine in
                          immunocompromised children with
                          varicella-zoster virus infection. Acta
                          Paediatr Jpn. 1989 Dec;31(6):702-5.
 ENTRY MONTH              8911
 LAST REVISION DATE       950907
 

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