      Document 0174
 DOCN  DRG0174
 UNIQUE IDENTIFIER        DRG-0073
 NAME OF SUBSTANCE        Ketoconazole [USAN 1996]
 REGISTRY NUMBER          65277-42-1
 STANDARD CHEMICAL NAME   Piperazine,1-acetyl-4-(4-((2-(2,4-dichlorophe-
                          nyl)-
                          2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl)-
                          methoxy) phenyl)-, cis- [CHEMLINE]
 SYNONYMS                 Nizoral [PDR 1995]
 SYNONYMS                 Fungarest [Merck Index 1989]
 SYNONYMS                 Fungoral [Merck Index 1989]
 SYNONYMS                 Ketoderm [Merck Index 1989]
 SYNONYMS                 Ketoisdin [Merck Index 1989]
 SYNONYMS                 Orifungal M [Merck Index 1989]
 SYNONYMS                 Panfungol [Merck Index 1989]
 PROTOCOL ID NUMBERS      FDA 012B
 PROTOCOL ID NUMBERS      FDA 042A
 SECONDARY SOURCE ID      R 41400 [USAN 1996]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Inhibits biosynthesis of
                          ergosterol and other steroids, damaging and
                          altering the permeability of the fungal cell
                          membrane; inhibits fungal triglyceride and
                          phospholipid biosynthesis; inhibits oxidative
                          and peroxidative enzyme activity, causing
                          fungal intracellular buildup of toxic
                          hydrogen peroxide levels. Postprandial mean
                          peak plasma levels of about 3.5 mcg/ml are
                          reached in 1-2 hours after oral 200 mg dose
                          taken with a meal; subsequent plasma
                          elimination is biphasic (half-life of 2 hours
                          during first 10 hours, and 8 hours
                          thereafter). Following gastrointestinal
                          uptake, major metabolic pathways are
                          oxidation and degradation of the imidazole
                          and piperazine rings, oxidative
                          O-dealkylation and aromatic hydroxylation to
                          several inactive metabolites. About 13
                          percent of the dose is excreted in the urine,
                          of which 2-4 percent is unchanged drug. The
                          major excretion route is through the bile
                          into the intestinal tract. Administration of
                          this drug has been shown to lower serum
                          testosterone. [PDR 1995] [USP DI 1995]
 DISEASES STUDIED/TREATED Systemic or topical antifungal treatment
                          [AHFS Drug Information 1995]
 CLASSIFICATION CODE      Antifungal [PDR 1995]
 CLASSIFICATION CODE      Antineoplastic [USP DI 1995]
 CLASSIFICATION CODE      Antiadrenal [USP DI 1995]
 OTHER MAJOR USES         Blastomycosis, candidiasis (chronic
                          mucocutaneous, oropharyngeal, vulvovaginal,
                          prostatic cancer), candiduria, chromomycosis,
                          coccidioidomycosis [PDR 1995] [AHFS Drug
                          Information 1995]
 SUBSTANCE INTERACTIONS   Ketoconazole interacts with coumarin-like
                          drugs to possibly enhance their anticoagulant
                          effect. Concomitant administration with
                          rifampin reduces blood levels of
                          ketoconazole. INH (isoniazid) is also
                          reported to affect ketoconazole
                          concentrations adversely. These drugs should
                          not be given concomitantly. Ketoconazole
                          increases the blood level of cyclosporine and
                          methylprednisolone. Concomitant use with
                          phenytoin may alter metabolism of one or both
                          of the drugs. Severe hypoglycemia has been
                          reported in patients concomitantly receiving
                          oral miconazole (an imidazole) and oral
                          hypoglycemia agents, such a potential
                          interaction cannot be ruled out. Ketoconazole
                          tablets inhibit metabolism of terfenadine and
                          astermizole, thus increasing their plasma
                          levels. [PDR 1993]
 ADVERSE EFFECTS          Several cases of hypersensitivity reactions
                          including urticaria have also been reported.
                          However, the most frequent adverse reactions
                          were nausea and/or vomiting, abdominal pain,
                          and pruritis. Less common (in less than 1% of
                          all patients) was headache, dizziness,
                          somnolence, fever and chills, photophobia,
                          diarrhea, gynecomastia, impotence,
                          thrombocytopenia, leukopenia, hemolytic
                          anemia, and bulging fontanelles. Oligospermia
                          has been reported in investigational studies
                          with the drug at dosages above those
                          currently approved. Neuropsychiatric
                          disturbances, including suicidal tendencies
                          and severe depression have occurred rarely in
                          patients using ketoconazole. Ventricular
                          dysrhythmias have occurred with concomitant
                          use of terfenadine. [PDR 1995]
 CONTRAINDICATIONS        Contraindicated in patients who have shown
                          hypersensitivity to this drug and in patients
                          receiving terfenadine or astemizole. [PDR
                          1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Imidazole derivative [USP
                          DI 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C26H28C12N4O4 [USAN 1996]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 531.44 [USAN 1996]
 CHEMICAL/PHYSICAL DATA   MELTING POINT: 146 C [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Soluble in acids [PDR 1996]
 CHEMICAL/PHYSICAL DATA   ELEMENTAL COMPOSITION: C58.76%, H5.31%,
                          C113.34%, N10.54%, O12.04% [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: White-beige odorless
                          powder [PDR 1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Tablets (200 mg), topical cream
                          (2%) and shampoo (2%). [PDR 1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral; topical. [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Store tablets below 40 C (104 F),
                          preferably between 15-30 C (59-86 F) in a
                          well-closed container unless otherwise
                          specified by manufacturer, and protect from
                          freezing. [USP DI 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Store cream below 30 C in a
                          well-closed container. Store shampoo at a
                          temperature not greater than 25 C and protect
                          from light. [PDR 1995]
 MANUFACTURERS            Janssen Pharmaceutical
 REFERENCES               Hernandes-Sampelayo T. Fluconazole versus
                          ketoconazole in the treatment of
                          oropharyngeal candidiasis in HIV-infected
                          children. Eur J Clin Microbiol Infect Dis.
                          1994 Apr;13(4):340-4.
 REFERENCES               Parente F, Ardizzone S, Cernuschi M, Antinori
                          S, Esposito R, Moroni M, Lazzarin A, Porro
                          GB. Prevention of symptomatic recurrences of
                          esophageal candidiasis in AIDS patients after
                          the first episode: a prospective open study.
                          Am J Gastroenterol. 1994 Mar;89(3):416-20.
 REFERENCES               Knupp CA, Brater DC, Relue J, Barbhaiya RH.
                          Pharmacokinetics of didanosine and
                          ketoconazole after coadministration to
                          patients seropositive for the human
                          immunodeficiency virus. J Clin Pharmacol.
                          1993 Oct;33(10):912-7.
 REFERENCES               Barchiesi F, Giacometti A, Arzeni D,
                          Branchesi P, Crescenzi G, Ancarani F, Scalise
                          G. Fluconazole and ketoconazole in the
                          treatment of oral and esophageal candidiasis
                          in AIDS patients. J Chemother. 1992
                          Dec;4(6):381-6.
 REFERENCES               Laine L, Dretler RH, Conteas CN, Tuazon C,
                          Koster FM, Sattler F, Squires K, Islam MZ.
                          Fluconazole compared with ketoconazole for
                          the treatment of Candida esophagitis in AIDS.
                          A randomized trial. Ann Intern Med. 1992 Oct
                          15;117(8):655-60.
 REFERENCES               Nyst MJ, Perriens JH, Kimputu L, Lumbila M,
                          Nelson AM, Piot P. Gentian violet,
                          ketoconazole and nystatin in oropharyngeal
                          and esophageal candidiasis in Zairian AIDS
                          patients. Ann Soc Belg Med Trop. 1992
                          Mar;72(1):45-52.
 REFERENCES               Korting HC, Blecher P, Froschl M, Braun-Falco
                          O. Quantitative assessment of the efficacy of
                          oral ketoconazole for oral candidosis in
                          HIV-infected patients. Mycoses. 1992
                          Jul-Aug;35(7-8):173-6.
 REFERENCES               Sprinz E, Matias K. Cryptococcal meningitis
                          prophylaxis with ketoconazole in patients
                          with AIDS. Int Conf AIDS. 1992 Jul
                          19-24;8(2):B130 (abstract no. PoB 3261).
 REFERENCES               Kronfeld M, Sprinz E, Zimmer P. Ketoconazole
                          as a prophylactic agent against cryptococcal
                          meningitis. Int Conf AIDS. 1991 Jun
                          16-21;7(2):258 (abstract no. W.B.2307).
 REFERENCES               Smith DE, Midgley J, Allan M, Connelly GM,
                          Gazzard BG. Itraconazole vs ketoconazole in
                          the treatment of oral and oesophageal
                          candidosis in patients infected with HIV.
                          AIDS. 1991 Nov;5 (11):1367-71.
 ENTRY MONTH              8911
 LAST REVISION DATE       951031
 

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