      Document 0162
 DOCN  DRG0162
 UNIQUE IDENTIFIER        DRG-0085
 NAME OF SUBSTANCE        Rifabutin [USAN 1996]
 REGISTRY NUMBER          72559-06-9
 RELATED REGISTRY NUMBER  76609-88-6
 STANDARD CHEMICAL NAME   1',4-didehydro-1-deoxy-1,4-dihydro-5'-
                          (2-methylpropyl)-1-oxorifamycin XIV- [PDR
                          1995]
 SYNONYMS                 Antibiotic LM 427 [CHEMLINE]
 SYNONYMS                 LM 427 [CHEMLINE]
 SYNONYMS                 Rifabutine [PDR 1995]
 SYNONYMS                 Mycobutin [USAN 1996]
 SYNONYMS                 Ansamycin [CHEMLINE]
 PROTOCOL ID NUMBERS      FDA 048A
 PROTOCOL ID NUMBERS      FDA 048B
 PROTOCOL ID NUMBERS      FDA 048C
 PROTOCOL ID NUMBERS      FDA 109A
 PROTOCOL ID NUMBERS      NIAID DATRI 001
 PROTOCOL ID NUMBERS      FDA 048D
 PROTOCOL ID NUMBERS      FDA 048E
 PROTOCOL ID NUMBERS      FDA 226A
 PROTOCOL ID NUMBERS      NCI 93 C-70
 PROTOCOL ID NUMBERS      NIAID ACTG 223
 PROTOCOL ID NUMBERS      NIAID CPCRA 027
 PROTOCOL ID NUMBERS      NIAID ACTG 196
 PROTOCOL ID NUMBERS      NIAID 95 CC-102
 PROTOCOL ID NUMBERS      NIAID ACTG 283
 SECONDARY SOURCE ID      DRG
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Like rifampin, rifabutin is
                          believed to exert its primary bactericidal
                          effect by inhibiting DNA-dependent RNA
                          polymerase and is active against a wide
                          variety of gram-positive and gram-negative
                          bacteria in vitro. The drug is also active in
                          vitro against a variety of mycobacteria,
                          including both M. tuberculosis and atypical
                          species. It is not known whether this
                          activity is dependent on inhibition of
                          DNA-dependent RNA polymerase. Rifabutin is
                          readily absorbed from the GI tract. Plasma
                          concentrations declined in an apparent
                          biphasic manner. Due to its high
                          lipophilicity, rifabutin demonstrates a high
                          propensity for distribution and intracellular
                          tissue uptake. Substantially higher
                          intracellular tissue levels than those seen
                          in plasma have been observed in both rat and
                          man. The lung to plasma concentration ratio,
                          obtained at 12 hours, was found to be
                          approximately 6.5 in four surgical patients
                          administered oral doses. About 85% of the
                          drug is bound in a concentration-independent
                          manner to plasma proteins. Binding does not
                          seem to be influenced by renal or hepatic
                          dysfunction. Renal and biliary clearance of
                          unchanged drug each contribute about 5% to
                          the mean systemic clearance. About 30% of the
                          dose is excreted in the feces. About 53% of
                          the oral dose (in one mass-balance study in
                          healthy volunteers) was excreted in the
                          urine, primarily as metabolites. Of the 5
                          metabolites that have been identified,
                          25-O-desacetyl and 31-hydroxy predominate.
                          The former has an activity equal to the
                          parent drug and contributes up to 10% of the
                          total antimicrobial activity. Absolute
                          bioavailability assessed in 5 HIV-positive
                          patients who received both oral and IV doses,
                          averaged 20%. At least 53% of orally
                          administered rifabutin is absorbed from the
                          GI tract. High-fat meals slow the rate
                          without influencing the extent of absorption
                          (capsule dosage form). Rifabutin steady-state
                          kinetics in early symptomatic HIV-positive
                          patients are similar to healthy volunteers.
                          [Drug Evaluations Annual 1994] [PDR 1995]
 DISEASES STUDIED/TREATED FDA approved 12/23/92 for prevention of
                          Mycobacterium avium Complex (MAC) bacteremia
                          and disseminated infections in patients with
                          advanced HIV infection [AHFS Drug Information
                          1995]
 DISEASES STUDIED/TREATED Designated by the FDA as an orphan drug for
                          this use [AHFS Drug Information 1995]
 CLASSIFICATION CODE      Antimycobacterial [AmFAR Tx Dir 1995;7(4)]
 CLASSIFICATION CODE      Antibacterial [USAN 1996]
 OTHER MAJOR USES         Most strains of M. tuberculosis are inhibited
                          by rifabutin; however, it remains to be
                          established whether rifabutin is effective
                          for the prevention of M. tuberculosis
                          infection [AHFS Drug Information 1995]
 SUBSTANCE INTERACTIONS   May act synergistically with ethambutol,
                          ciprofloxacin, or erythromycin against
                          strains of Mycobacterium avium complex
                          isolated from AIDS patients. Rifampin, which
                          is structurally related to rifabutin, is
                          known to reduce the activity of many drugs
                          due to its hepatic enzyme-inducing
                          properties. Drug interaction data for
                          rifabutin itself are not available but
                          patients taking rifabutin concurrently with
                          these drugs should be monitored. Steady-state
                          plasma concentrations of zidovudine (AZT)
                          were decreased after repeated rifabutin
                          dosing (healthy volunteers and HIV-positive
                          patients). However, population
                          pharmacokinetic analysis of zidovudine
                          concentration vs. time data showed a
                          nonsignificant trend for rifabutin to
                          increase the apparent renal clearance of
                          zidovudine. In vitro studies show that
                          rifabutin does not affect the inhibition of
                          HIV by zidovudine. [Am Rev Respir Dis
                          1988;173(3)] [USP DI 1995] Antimicrob Agents
                          Chemother 1988 Sep;32(9)]
 ADVERSE EFFECTS          Rifabutin is generally well tolerated. The
                          most common adverse effects are rash, GI
                          intolerance, and neutropenia. In patients
                          with severe HIV infection, adverse effects
                          serious enough to discontinue treatment
                          occurred in 16% of patients receiving
                          rifabutin and 8% of patients on placebo.
                          [AHFS Drug Information 1995]
 CONTRAINDICATIONS        Contraindicated in patients who have
                          clinically important hypersensitivity to this
                          drug or any other rifamycin (e.g., rifampin).
                          Preventive therapy with rifabutin should not
                          be initiated in patients with active M.
                          tuberculosis since use of the drug as sole
                          antimycobacterial therapy in such patients
                          would likely lead to development of
                          tuberculosis that is resistant to both
                          rifabutin and rifampin. Because uveitis may
                          occur in patients receiving rifabutin, the
                          drug should be discontinued temporarily on
                          appearance of inflammatory ocular conditions.
                          [AHFS Drug Information 1995]
 CHEMICAL/PHYSICAL DATA   DESCRIPTION: Semisynthetic ansamycin
                          antibiotic that is derived from rifamycin S
                          [Drug Evaluations Annual 1994]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 847.02 [USAN 1993]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C46H62N4O11 [USAN 1993]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [PDR 1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Hard gelatin capsules. [PDR
                          1995]
 SUBSTANCE DELIVERY DATA  STORAGE INSTRUCTIONS: Store at room
                          temperature (15-30 C) (59-86 F). [PDR 1995]
 MANUFACTURERS            Adria
 REFERENCES               Skinner MH, Blaschke TF. Clinical
                          pharmacokinetics of rifabutin. Clin
                          Pharmacokinet. 1995 Feb;28(2):115-25.
 REFERENCES               Mandigo K, Hogg RS, Le R, Phillips P,
                          Montaner JS, O'Shaughnessy MV. Effectiveness
                          of rifabutin in preventing MAC in persons
                          with HIV-disease. Int Conf AIDS. 1994 Aug
                          7-12;10(2):176 (abstract no. PB0718).
 REFERENCES               Oualls J, Salvato P, Thompson C. MAIC
                          prevention: clarithromycin vs. rifabutin. Int
                          Conf AIDS. 1994 Aug 7-12;10(2):178 (abstract
                          no. PB0726).
 REFERENCES               Sullam PM, Gordin FM, Wynne BA. Efficacy of
                          rifabutin in the treatment of disseminated
                          infection due to Mycobacterium avium complex.
                          Clin Infect Dis. 1994 Jul;19(1):84-6.
 REFERENCES               Jacobs DS, Piliero PH, Kuperwaser MG, Smith
                          JA, Harris SD, Flanigan TP, Goldberg JH, Ives
                          DV. Acute uveitis associated with rifabutin
                          use in patients with human immunodeficiency
                          virus infection [see comments]. Am J
                          Ophthalmol. 1994 Dec 15;118(6):716-22.
 REFERENCES               Saran BR, Maguire AM, Nichols C, Frank I,
                          Hertle RW, Brucker AJ, Goldman S, Brown M,
                          Van Uitert B. Hypopyon uveitis in patients
                          with acquired immunodeficiency syndrome
                          treated for systemic Mycobacyterium avium
                          complex infection with rifabutin. Arch
                          Ophthalmol. 1994 Sep;112(9):1159-65.
 REFERENCES               Gordin FM, Sullam PM, Smith BR, Schoenfelder
                          J, Depietro N, Wynne B. Rifabutin MAC
                          prophylaxis treatment IND. Int Conf AIDS.
                          1994 Aug 7-12;10(2):70 (abstract no. 557B).
 REFERENCES               Brogden RN, Fitton A. Rifabutin. A review of
                          its antimicrobial activity, pharmacokinetic
                          properties and therapuetic efficacy. Drugs.
                          1994 Jun;47(6):983-1009.
 REFERENCES               Maddix DS, Talliam KB, Mead PS. Rifabutin: a
                          review with emphasis on its role in the
                          prevention of disseminated Mycobacterium
                          avium complex infection. Ann Pharmcother.
                          1994 Nov;28(11):1250-4.
 REFERENCES               Gordin F, Masur H. Prophylaxis of
                          Mycobacterium avium complex bacteremia in
                          patients with AIDS. Clin Infect Dis. 1994
                          Apr;18 Suppl 3:S223-6.
 ENTRY MONTH              9003
 LAST REVISION DATE       951128
 

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