      Document 0219
 DOCN  DRG0219
 UNIQUE IDENTIFIER        DRG-0028
 NAME OF SUBSTANCE        Ribavirin [USAN 1995]
 REGISTRY NUMBER          36791-04-5
 STANDARD CHEMICAL NAME   1-beta-D-Ribofuranosyl-1H-1,2,4-triazole-3-ca-
                          rboxamide [Merck Index 1989]
 SYNONYMS                 Tribavirin [USAN 1995]
 SYNONYMS                 Virazole [USAN 1995]
 SYNONYMS                 Viramid [Merck Index 1989]
 SYNONYMS                 RTCA [Merck Index 1989]
 SYNONYMS                 Vilona [USP DI 1989]
 SYNONYMS                 Virazid [USP DI 1989]
 PROTOCOL ID NUMBERS      NIAID ACTG 034
 PROTOCOL ID NUMBERS      NIAID ACTG 035
 PROTOCOL ID NUMBERS      FDA 013A
 PROTOCOL ID NUMBERS      NIAID ACTG 231
 PROTOCOL ID NUMBERS      NIAID NS 403
 PROTOCOL ID NUMBERS      NIAID ACTG 274
 IND NUMBER               31,103
 SECONDARY SOURCE ID      ICN-1229 [AHFS Drug Information 1995]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Virustatic; reversal of its
                          antiviral action by guanosine and xanthosine
                          suggests that ribavirin may act as a
                          competitive inhibitor of cellular enzymes
                          that act on these metabolites. The drug is
                          rapidly transported into cells and acts
                          within virus-infected cells. It is readily
                          phosphorylated intracellularly by adenosine
                          kinase to mono-, di-, and tri-phosphate
                          metabolites, the latter being a potent
                          competitive inhibitor of inosine
                          monophosphate dehydrogenase, influenza virus
                          RNA polymerase, and messenger RNA
                          guanylyltransferase - these diverse effects
                          result in marked reduction of intracellular
                          guanosine triphosphate pools and impaired
                          viral RNA and protein synthesis, with viral
                          replication and spreading to other cells
                          being prevented or greatly inhibited.
                          Ribavirin is rapidly absorbed following oral
                          ingestion or oral inhalation, and is
                          distributed to plasma, respiratory tract
                          secretions, and red blood cells. Ribavirin is
                          also metabolized to 1,2,4-triazole
                          carboxamide metabolite and subsequently via
                          amide hydrolysis to tricarboxylic acid,
                          deribosylation, and breakdown to the triazole
                          ring. Its elimination half-life following
                          inhalation and oral and intravenous routes,
                          and from erythrocytes is 9.5 hours, 24 hours,
                          and 40 days, respectively. Elimination routes
                          (as the 1,2,4-triazole carboxamide
                          metabolite) are renal (about 30-55 percent
                          excreted in urine within 72-80 hours) and
                          fecal (about 15 percent eliminated within 72
                          hours), with the remainder sequestered in
                          erythrocytes for several weeks. Time to peak
                          serum concentration following oral
                          administration is 1-1.5 hours. Inhalation of
                          ribavirin aerosol for 2.5 hours/day for 3
                          days produced plasma concentrations of
                          0.44-1.55 micromolar (mean, 0.76 micromolar);
                          plasma half-life, 9.5 hours; inhalation for
                          20 hours/day for 5 days gave plasma levels of
                          1.5-14.3 micromolar (mean 6.8 micromolar);
                          ribavirin and/or its metabolites accumulate
                          in red blood cells, reaching steady-state
                          levels in about 4 days and gradually
                          declining with an apparent half-life of 40
                          days. [USP DI 1995]
 DISEASES STUDIED/TREATED Primary HIV infection [AHFS Drug Information
                          1995]
 CLASSIFICATION CODE      Antiviral [USAN 1995]
 CLASSIFICATION CODE      Antiretroviral [AHFS Drug Information 1995]
 OTHER MAJOR USES         Treatment of selected hospitalized infants
                          and young children with severe lower
                          respiratory tract infections due to
                          respiratory syncytial virus (RSV) [PDR 1995]
 SUBSTANCE INTERACTIONS   Potentiates antiretrovial activity of
                          didanosine and antagonizes antiviral activity
                          of zidovudine and zalcitabine. [AHFS Drug
                          Information 1995]
 ADVERSE EFFECTS          Most studies indicate that ribavirin
                          inhalation solutions produce few adverse
                          effects. Anemia following oral or intravenous
                          therapy is the most frequent reaction.
                          Central nervous system effects such as
                          fatigue, headache and insomnia may occur with
                          higher doses. Skin irritation has occurred in
                          patients and in health care workers handling
                          the drug. [USP DI 1995]
 CONTRAINDICATIONS        Contraindicated in patients hypersensitive to
                          the drug and in women who are or may become
                          pregnant. [PDR 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: A synthetic nucleoside,
                          structurally related to inosine, guanosine,
                          and xanthosine [USP DI 1989]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C8H12N4O5 [USAN 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 244.21 [USAN 1995]
 CHEMICAL/PHYSICAL DATA   PERCENT ELEMENTAL COMPOSITION: C39.34%;
                          H4.95%; N22.94%; O32.76% [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   MELTING POINT (2 polymorphic forms): 166-168
                          C (aqueous ethanol); 174-176 C (ethanol)
                          [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: 142 mg/ml (in water at 25 C (77
                          F); slightly soluble in ethanol [PDR 1995]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: Stable, white
                          crystalline compound [PDR 1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Vials containing 6 grams of
                          sterile, lyophilized powder to be
                          reconstituted in sterile water for aerosol
                          administration. [USP DI 1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Oral solutions and intravenous
                          preparations must be compounded since these
                          dosage forms are not commercially available.
                          [USP DI 1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Inhalation; injection, oral
                          solutions. [USP DI 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Vials containing lyophilized powder
                          should be stored in a dry location at 15-25 C
                          (59-78 F) [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Reconstituted solutions should be
                          stored under sterile conditions at room
                          temperature (20-30 C; 68-86 F) for 24 hours.
                          [PDR 1995]
 MANUFACTURERS            Viratek ICN Pharmaceuticals
 REFERENCES               Connor E, Morrison S, Lane J, Oleske J, Sonke
                          RL, Connor J. Safety, tolerance, and
                          pharmacokinetics of systemic ribavirin in
                          children with human immunodeficiency virus
                          infection. Antimicrob Agents Chemother. 1993
                          Mar;37(3):532-9.
 REFERENCES               Multicenter clinical trial of oral ribavirin
                          in symptomatic HIV-infected patients. The
                          Ribavirin ARC Study Group. J Acquir Immune
                          Defic Syndr. 1993 Jan;6(1):32-41.
 REFERENCES               Japour A, Chatis P, Kim S, Crumpacker C.
                          HIV-1 ddI-resistance overcome with
                          combination ddI/ribavirin. Int Conf AIDS.
                          1993 Jun 6-11;9(1):241 (abstract no.
                          PO-A26-0640).
 REFERENCES               Gorbea M, Perez G, Paquentin J, Torres F,
                          Morales E, Fortuno V. Ribavarin vs zidovudine
                          in children with advanced human
                          immunodeficiency virus disease: Mexican
                          experience in 18 months of follow-up. Int
                          Conf AIDS. 1992 Jul 19-24;8(2):B197 (abstract
                          no. PoB 3640).
 REFERENCES               Snell N, Pocock SJ. A meta-analysis of
                          placebo-controlled clinical trials of
                          ribavirin in patients with HIV infection. Int
                          Conf AIDS. 1992 Jul 19-24;8(3):136 (abstract
                          no. PuB 7523).
 REFERENCES               Bergeron MG, Tsoukas CM, Roberts R, Gent M,
                          Aoki F, Conly J, Falutz J, Fanning M, Fong
                          IW, Garber G, et al. Tolerance of ribavirine
                          in early HIV disease. Int Conf AIDS. 1991 Jun
                          16-21;7(2):201 (abstract no. M.B.2353).
 REFERENCES               Senay H, Trottier S, Morissette M, Gareau L,
                          Belles-Isles M, Jutras M, Bergeron MG.
                          Ribavirin therapy in patients in early stages
                          of HIV infections. Int Conf AIDS. 1991 Jun
                          16-21;7(2):201 (abstract no. W.B.2105).
 REFERENCES               Lertora J, Rege A, Lacour J, Ferencz N,
                          George W, Agrawal K, VanDyke R, Hyslop N.
                          Ribavirin pharmacokinetics and tolerance in
                          HIV-infected patients. Int Conf AIDS. 1991
                          Jun 16-21;7(2):201 (abstract no. W.B.2077).
 REFERENCES               Crumpacker C, Pearlstein G, van der Horst C,
                          Valentine F, Spector S, Mills J. A phase one
                          increasing dose trial of oral ribavirin (RBV)
                          in patients with AIDS and ARC. Int Conf AIDS.
                          1990 Jun 20-23;6(3):203 (abstract no.
                          S.B.468).
 REFERENCES               Roberts RB, Hollinger FB, Parks WP, Rasheed
                          S, Laurence J, Heseltine PN, Makuch RW,
                          Lubina JA, Johnson KM. A multicenter clinical
                          trial of oral ribavirin in HIV-infected
                          people with lymphadenopathy: virologic
                          observations. AIDS. 1990 Jan;4(1):67-72.
 ENTRY MONTH              8906
 LAST REVISION DATE       960310
 

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