      Document 0003
 DOCN  DRG0003
 UNIQUE IDENTIFIER        DRG-0244
 NAME OF SUBSTANCE        Ritonavir [Abbott Laboratories Package Insert
                          March 1996]
 STANDARD CHEMICAL NAME   10-Hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-
                          -methylethyl)-
                          4-thiazoly]-3,6-dioxo-8,11-bis(phenylmethyl)--
                          2,4,7,12-tetra azatridecan-13-oic
                          acid,5-thiazolylmethyl ester,[5S-(5R*,8R*,
                          10R*,11R*)] [Abbott Laboratories Package
                          Insert March 1996]
 SYNONYMS                 Norvir [Abbott Laboratories Package Insert
                          March 1996]
 SECONDARY SOURCE ID      ABT 538 [AmFAR Tx Dir 1996;8(1)]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Peptidomimetic inhibitor of
                          both the HIV-1 and HIV-2 proteases.
                          Inhibition of HIV protease renders the enzyme
                          incapable of processing the gag-pol
                          polyprotein precursor which leads to
                          production of noninfectious immature HIV
                          particles. In vitro, the EC50 of ritonavir
                          was 3.8-1.53 nM depending on viral isolate
                          and type of cells used. Absolute
                          bioavailability of the drug has not been
                          determined. After a 600 mg dose of oral
                          solution, peak concentrations of ritonavir
                          occurred at approximately 2 and 4 h after
                          dosing under fasting and non-fasting
                          conditions, respectively. Ritonavir is
                          metabolized primarily by the liver;
                          cytochrome P450 3A is the major isoform
                          involved in ritonavir metabolism. Ritonavir
                          is a potent inhibitor of the liver's
                          cytochrome p450 metabolic pathway. [Abbott
                          Laboratories Package Insert March 1996]
                          [AmFAR Tx Dir 1996;8(1)].
 DISEASES STUDIED/TREATED HIV infection [Abbott Laboratories Package
                          Insert March 1996]
 DISEASES STUDIED/TREATED FDA approved 3/1/96 as monotherapy or in
                          combination with nucleoside analogues for HIV
                          disease [HHS Press Release]
 CLASSIFICATION CODE      Protease inhibitor [Abbott Laboratories
                          Package Insert March 1996]
 CLASSIFICATION CODE      Antiretroviral [Abbott Laboratories Package
                          Insert March 1996]
 SUBSTANCE INTERACTIONS   Interacts with drugs that are metabolized by
                          the liver's cytochrome p450 enzyme pathway.
                          [AmFAR Tx Dir 1996;8(1)].
 ADVERSE EFFECTS          Adverse effects most frequently reported
                          include asthenia, nausea, diarrhea, vomiting,
                          anorexia, abdominal pain, taste perversion,
                          and circumoral and peripheral paresthesias.
                          Less common adverse effects include fever,
                          headache, malaise, vasodilation,
                          constipation, dyspepsia, flatulence, local
                          throat irritation, increase in creatine
                          phosphokinase, hyperlipidemia, myalgia,
                          dizziness, insomnia, somnolence, abnormal
                          thinking, pharyngitis, rash, and sweating.
                          [Abbott Laboratories Package Insert March
                          1996].
 CONTRAINDICATIONS        CAUTION: Strongly contraindicated in patients
                          receiving nonsedating antihistamines,
                          sedative hypnotics, or antiarrhythmics.
                          Should not be coadministered with meperidine,
                          piroxicam, propoxyphene, amiodarone,
                          encainide, flecainide, propafenone,
                          quinidine, rifabutin, bepridil, astemizole,
                          terfenadine, cisapride, bupropion, clozapine,
                          alprazolam, clorazepate, diazepam, estazolam,
                          flurazepam, midazolam, triazolam, or
                          zolpidem. [Abbott Laboratories Package Insert
                          March 1996].
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Peptide-based protease
                          inhibitor. [AmFAR Tx Dir 1996;8(1)]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C37H48N6O5S2 [Abbott
                          Laboratories Package Insert March 1996]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 720.95 [Abbott Laboratories
                          Package Insert March 1996]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Freely soluble in methanol and
                          ethanol; soluble in isopropanol; practically
                          insoluble in water. [Abbott Laboratories
                          Package Insert March 1996]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: White to light tan
                          powder with bitter metallic taste. [Abbott
                          Laboratories Package Insert March 1996]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: 100 mg capsules and 80 mg/ml
                          oral solution. [Abbott Laboratories Package
                          Insert March 1996]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [Abbott Laboratories
                          Package Insert March 1996].
 SUBSTANCE DELIVERY DATA  STORAGE INSTRUCTIONS: Store capsules at 2-8 C
                          (36-46); protect from light. Store oral
                          solution at 2-8 C (36-46 F); avoid exposure
                          to excessive heat. [Abbott Laboratories
                          Package Insert March 1996].
 MANUFACTURERS            Abbott Laboratories
 REFERENCES               Kelleher AD, Carr A, Zaunders J, Cooper DA.
                          Alterations in the immune response of human
                          immunodeficiency virus (HIV)-infected
                          subjects treated with an HIV-specific
                          protease inhibitor, ritonavir. J Infect Dis.
                          1996 Feb; 173(2):321-9.
 REFERENCES               Markowitz M, Saag M, Powderly WG, Hurley AM,
                          Hsu A, Valdes JM, Henry D, Sattler F, La
                          Marca A, Leonard JM, et al. A preliminary
                          study of ritonavir, an inhibitor of HIV-1
                          protease, to treat HIV-1 infection. N Eng J
                          Med. 1995 Dec 7;333(23):1543-9.
 REFERENCES               Danner SA, Carr A, Leonard JM, Lehman LM,
                          Gudiol F, Gonzales J, Raventos A, Rubio R,
                          Bouza E, Pintado V, et al. A short-term study
                          of the safety, pharmacokinetics, and efficacy
                          of ritonavir, an inhibitor of HIV-1 protease.
                          European-Australian Collaborative Ritonavir
                          Study Group. N Engl J Med 1995 Dec
                          7;333(23):1528-33.
 REFERENCES               Kempf DJ, Marsh KC, Denissen JF, McDonald E,
                          Vasavanonda S, Flentge CA, Green BE, Fino L,
                          Park CH, Kong XP, et al. ABT-538 is a potent
                          inhibitor of human immunodeficiency virus
                          protease and has high oral bioavailability in
                          humans. Proc Natl Acad Sci U S A. 1995 Mar
                          28;92(7):2484-8.
 ENTRY MONTH              9604
 LAST REVISION DATE       960405
 

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