      Document 0203
 DOCN  DRG0203
 UNIQUE IDENTIFIER        DRG-0044
 NAME OF SUBSTANCE        Itraconazole [USAN 1996]
 REGISTRY NUMBER          84625-61-6
 STANDARD CHEMICAL NAME   4-(4-(4-(4-((2-(2,4-Dichlorophenyl)-2-((1H-1,-
                          2,4-triazol-
                          1-yl)methyl)-1,3-dioxolan-4-yl)methoxy)phenyl-
                          )-1
                          -piperazinyl)phenyl)-2,4-dihydro-2-(1-methylp-
                          ropyl)-3H -1,2,4-triazol- 3-one [Merck Index
                          1989]
 SYNONYMS                 1-sec-Butyl-4-(p-(4-(p-((2-(2,4-dichloropheny-
                          l)-2-
                          ((1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-
                          -yl) methoxy)-phenyl)-1-piperazinyl)phenyl)-
                          delta-2-1,2,4-triazolin-5-one [USAN 1996]
 SYNONYMS                 Sporanox [USAN 1996]
 SYNONYMS                 Sporanos [Merck Index 1989]
 PROTOCOL ID NUMBERS      NIAID ACTG 084
 PROTOCOL ID NUMBERS      NIAID ACTG 120
 PROTOCOL ID NUMBERS      FDA 235B
 PROTOCOL ID NUMBERS      FDA 236A
 PROTOCOL ID NUMBERS      FDA 236B
 PROTOCOL ID NUMBERS      FDA 236C
 PROTOCOL ID NUMBERS      NIAID ACTG 159
 PROTOCOL ID NUMBERS      FDA 254A
 IND NUMBER               33,047
 SECONDARY SOURCE ID      R 51,211 [USAN 1996]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Interferes with cytochrome
                          P-450 synthesis of ergosterol, a necessary
                          component of fungal cell membranes. Total
                          plasma clearance averaged 381 ml/min and
                          apparent volume of distribution averaged 796
                          liters following intravenous doses. Absolute
                          oral bioavailablility was 55%. Fecal
                          excretion of the parent drug varies between
                          3-18% of the dose. Renal excretion of the
                          parent drug is decreased by 0.03% of the
                          dose. About 40% of the dose is excreted as
                          inactive metabolites in the urine. Renal
                          insufficiency did not affect plasma levels.
                          Plasma protein binding is 99.8%. [PDR 1995]
 DISEASES STUDIED/TREATED FDA approved in both immunocompromised and
                          non-immunocompromised patients for pulmonary
                          and extrapulmonary blastomycosis,
                          aspergillosis and for histoplasmosis [PDR
                          1995]
 CLASSIFICATION CODE      Antifungal [USAN 1996]
 OTHER MAJOR USES         Blastomycosis, pulmonary and extrapulmonary;
                          histoplasmosis, including chronic cavitary
                          pulmonary disease and disseminated,
                          non-meningeal histoplasmosis; aspergillosis,
                          pulmonary and extrapulmonary; and in patients
                          intolerant to amphotericin B therapy [PDR
                          1995]
 SUBSTANCE INTERACTIONS   Itraconazole increases plasma levels of
                          terfenadine, producing cardiac arrhythmias.
                          Possible similar effects with astemizole.
                          Plasma digoxin and cyclosporine levels are
                          increased when administered with
                          itraconazole. Phenytoin, H2 receptor
                          antagonist, and rifampin levels are decreased
                          with concomitant itraconazole. May possibly
                          enhance effects of anticoagulant coumarin
                          derivatives. Azole antifungal plasma levels
                          are decreased when isoniazid is
                          co-administered, therefore itraconazole
                          levels should be monitored. Concomitant azole
                          antifungals have produced severe hypoglycemia
                          in patients receiving oral hypoglycemic
                          agents. [PDR 1995]
 ADVERSE EFFECTS          Gastrointestinal reactions, including nausea
                          and vomiting, diarrhea, abdominal pain and
                          anorexia, are the most common side effects
                          reported. Edema, fever, fatigue, malaise,
                          rash and pruritis occur in more than 1% of
                          patients. Rash has been reported in 8.6% of
                          patients, especially in immunocompromised
                          subjects. Reversible idiosyncratic hepatitis
                          has also occurred in a limited number of
                          patients (3 in 2500). The incidence of
                          hypertriglyceridemia and neuropathy is rare.
                          [PDR 1995]
 CONTRAINDICATIONS        Coadministration of astemizole or terfenadine
                          is contraindicated, as is administration to
                          patients who have shown sensitivity to the
                          itraconazole or other antifungal azoles.
                          Itraconazole should not be given to nursing
                          mothers and use in pregnant women should be
                          determined by evaluating the risk-benefits of
                          therapy. [PDR 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: A synthetic triazole
                          antifungal drug [PDR 1995]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: White to slightly
                          yellowish powder [PDR 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C35H38Cl2N8O4 [USAN 1996]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 705.65 [USAN 1996]
 CHEMICAL/PHYSICAL DATA   MELTING POINT: 166.2 C [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   ELEMENTAL COMPOSITION: C59.57%, H5.43%,
                          Cl10.05%, N15.88%, O9.07% [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Insoluble in water, freely
                          soluble in alcohols [PDR 1995]
 CHEMICAL/PHYSICAL DATA   PHYSICAL COMMENT: pKa 3.70 [PDR 1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM:  Capsules (100 mg). [PDR 1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY:  Oral. [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Store at room temperature, 15 C to
                          30 C, protect from light and moisture. [PDR
                          1995]
 MANUFACTURERS            Janssen
 REFERENCES               Wheat J, Hafner R, Korzun AH, Limjoco MT,
                          Spencer P, Larsen RA, Hecht FM, Powderly W.
                          Itraconazole treatment of disseminated
                          histoplasmosis in patients with the acquired
                          immunodeficiency syndrome. Am J Med. 1995
                          Apr;98(4):336-42.
 REFERENCES               Denning DW, Lee JY, Hostetler JS, Pappas P,
                          Kauffman CA, Dewsnup DH, Galgiani JN,
                          Graybill JR, Sugar AM, Catanzaro A, et al.
                          NIAID Mycoses Study Group Multicenter Trial
                          of Oral Itraconazole Therapy for Invasive
                          Aspergillosis. Am J Med. 1994
                          Aug;97(2):135-44.
 REFERENCES               Smith D, Gazzard B, Kenny DW. Itraconazole as
                          secondary prophylaxis against
                          oral/oesophageal candidosis in patients with
                          AIDS or ARC. Int Conf AIDS. 1994 Aug
                          7-12;10(1):190 (abstract no. PB0188).
 REFERENCES               Supparatpinyo K, Nelson K, Khamwan C,
                          Sirisanthana T. Treatment of penicilliosis
                          marneffei in HIV infected patients. Int Conf
                          AIDS. 1994 Aug 7-12;10(2):148 (abstract no.
                          PB0606).
 REFERENCES               Mahmood W, Hamann-Trou D, Phillips P, Zemcov
                          SJ, Montaner JS, Clarke AM. Itraconazole
                          solution for fluconazole-refractory
                          oropharyngeal candidiasis in AIDS:
                          correlation of clinical response with in
                          vitro susceptibility. Int Conf AIDS. 1994 Aug
                          7-12;10(2):23 (abstract no. 386B).
 REFERENCES               Wheat J, Hafner R, Wulfsohn M, Spencer P,
                          Squires K, Powderly W, Wong B, Rinaldi M,
                          Saag M, Hamill R, et al. Prevention of
                          relapse of histoplasmosis with itraconazole
                          in patients with the acquired
                          immunodeficiency syndrome. Ann Intern Med.
                          1993 Apr 15;118(8):610-6.
 REFERENCES               Taelman H, Boogaerts J, Kagame A,
                          Batungwanayo J, et al. Randomized trial
                          comparing itraconazole with amphotericin B in
                          the primary therapy of AIDS associated
                          cryptococcal meningitis. Int Conf AIDS. 1993
                          Jun 6-11;9(1):55 (abstract no. WS-B12-3).
 REFERENCES               Jennings TS, Hardin TC. Treatment of
                          aspergillosis with itraconazole. Ann
                          Pharmacother. 1993 Oct;27(10):1206-11.
 REFERENCES               Cauwenbergh G. Cryptococcal meningitis: the
                          place of itraconazole. Mycoses. 1993
                          Jul-Aug;36(7-8):221-8.
 REFERENCES               de Gans J, Portegies P, Tiessens G, Eeftinck
                          Schattenkerk JK, van Boxtel CJ, van Ketel RJ,
                          Stam J. Itraconazole compared with
                          amphotericin B plus flucytosine in AIDS
                          patients with cryptococcal meningitis. AIDS
                          1992 Feb;6(3):185-90.
 ENTRY MONTH              8909
 LAST REVISION DATE       951128
 

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