      Document 0232
 DOCN  DRG0232
 UNIQUE IDENTIFIER        DRG-0015
 NAME OF SUBSTANCE        Zalcitabine [PDR 1995]
 REGISTRY NUMBER          7481-89-2
 STANDARD CHEMICAL NAME   2',3'-Dideoxycytidine [USAN 1995]
 SYNONYMS                 ddC [Chemline]
 SYNONYMS                 HIVID [PDR 1995]
 SYNONYMS                 CCRIS 692 [CHEMLINE]
 SYNONYMS                 Dideoxycytidine [USAN 1995]
 PROTOCOL ID NUMBERS      NIAID ACTG 011
 PROTOCOL ID NUMBERS      NIAID ACTG 012
 PROTOCOL ID NUMBERS      NIAID ACTG 047
 PROTOCOL ID NUMBERS      NIAID ACTG 050
 PROTOCOL ID NUMBERS      NIAID ACTG 106
 PROTOCOL ID NUMBERS      NIAID ACTG 112
 PROTOCOL ID NUMBERS      NIAID ACTG 114
 PROTOCOL ID NUMBERS      NIAID ACTG 119
 PROTOCOL ID NUMBERS      NIAID ACTG 138
 PROTOCOL ID NUMBERS      NIAID ACTG 155
 PROTOCOL ID NUMBERS      NIAID CPCRA 002
 PROTOCOL ID NUMBERS      NCI 87 C-179B
 PROTOCOL ID NUMBERS      NCI 88 C-47
 PROTOCOL ID NUMBERS      NCI 89 C-89
 PROTOCOL ID NUMBERS      FDA 031C
 PROTOCOL ID NUMBERS      FDA 031B
 PROTOCOL ID NUMBERS      FDA 031D
 PROTOCOL ID NUMBERS      FDA 052B
 PROTOCOL ID NUMBERS      NIAID ACTG 175
 PROTOCOL ID NUMBERS      FDA 031E
 PROTOCOL ID NUMBERS      NIAID CPCRA 007
 PROTOCOL ID NUMBERS      FDA 052C
 PROTOCOL ID NUMBERS      NIAID ACTG 197
 PROTOCOL ID NUMBERS      NIAID ACTG 190
 PROTOCOL ID NUMBERS      NIAID ACTG 193
 PROTOCOL ID NUMBERS      NIAID ACTG 229
 PROTOCOL ID NUMBERS      FDA 015H
 PROTOCOL ID NUMBERS      FDA 031F
 PROTOCOL ID NUMBERS      FDA 229B
 PROTOCOL ID NUMBERS      NCI 93 C-70
 PROTOCOL ID NUMBERS      NIAID ACTG 193A
 PROTOCOL ID NUMBERS      NIAID ACTG 243
 PROTOCOL ID NUMBERS      FDA 129C
 PROTOCOL ID NUMBERS      FDA 220A
 PROTOCOL ID NUMBERS      FDA 229A
 PROTOCOL ID NUMBERS      NIAID 93 CC-113
 PROTOCOL ID NUMBERS      NIAID 93 I-205
 PROTOCOL ID NUMBERS      NIAID 94 I-76
 PROTOCOL ID NUMBERS      NIAID ACTG 163
 PROTOCOL ID NUMBERS      NIAID ACTG 187
 PROTOCOL ID NUMBERS      NIAID ACTG 203P
 PROTOCOL ID NUMBERS      FDA 229C
 IND NUMBER               29,982
 IND NUMBER               31,669
 SECONDARY SOURCE ID      NSC-606170 [USAN 1995]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Inhibits replication and
                          cytopathic effect of HIV more potently than
                          zidovudine (AZT) (in vitro); decreases serum
                          levels of HIV p24 antigen in AIDS patients;
                          infusion of 0.03 and 0.25 mg/kg in humans
                          indicated plasma levels of 0.1-0.3 and 1-2
                          micromolar, respectively (with mean
                          cerebrospinal fluid (CSF) levels about 20
                          percent of plasma levels); plasma half-life:
                          about 1 hour; steady-state volume of
                          distribution: about 0.9 l/kg; total body
                          clearance: 12 ml/min/kg; well absorbed orally
                          in both fasting and non-fasting states; most
                          of the drug is eliminated by renal clearance.
                          (FDA approved 6/22/92 for combination
                          treatment with zidovudine in adult HIV
                          infection). [AHFS Drug Information 1995] [PDR
                          1995]
 DISEASES STUDIED/TREATED FDA approved 6/19/92 in combination with
                          zidovudine (AZT) for advanced HIV infection
                          [AHFS Drug Information 1995] [FDA Press
                          Release]
 DISEASES STUDIED/TREATED FDA approved 8/8/94 as monotherapy in adults
                          and chidren 13 years or older with advanced
                          HIV who are intolerant to or have disease
                          progression on AZT [AHFS Drug Information
                          1995] [FDA Press Release]
 CLASSIFICATION CODE      Antiretroviral [AmFAR TX Dir 1995;7(4)]
 SUBSTANCE INTERACTIONS   Should not be used with other drugs with
                          pancreatic toxicity (e.g., parenteral
                          pentamidine), peripheral neuropathy (e.g.,
                          chloramphenicol, cisplatin, dapsone,
                          didanosine, disulfiram, isoniazid,
                          nitrofurantoin, phenytoin, ribavarin,
                          vincristine), and drugs that may decrease
                          renal clearance of zalcitabine (e.g.
                          aminoglycosides, amphotericin B, foscarnet,
                          probenecid). Bioavailability of zalcitabine
                          may be decreased 25% by antacids containing
                          Mg or Ca. Concomitant use of zalcitabine and
                          zidovudine against HIV appears to be
                          synergistic. [AHFS Drug Information 1995]
 ADVERSE EFFECTS          Major dose-limiting zalcitabine toxicity is
                          peripheral neuropathy. Several other
                          dose-related adverse effects are rashes and
                          oral ulcers. Zalcitabine, at currently
                          recommended dosages, appears generally to be
                          well tolerated. Pharyngitis (in 5% of
                          patients) and coughing, dyspnea, cyanosis,
                          fever and flu-like manifestations (less than
                          1% of patients) have been reported. Rare
                          occurrences of lactic acidosis in the absence
                          of hypoxemia and severe hepatomegaly with
                          steatosis have been reported and are
                          potentially fatal. Rare cases of hepatic
                          failure and death considered possibly related
                          to underlying hepatitis B also have been
                          reported. [PDR 1995; AHFS Drug Information
                          1995]
 CONTRAINDICATIONS        Discontinue on signs of numbness, tingling,
                          burning or pain of extremities; use with
                          caution in patients with history of
                          pancreatitis, elevated serum amylase
                          concentration, renal impairment, baseline
                          cardiomyopathy or congestive heart failure.
                          Should be used during pregnancy only when the
                          potential benefits justify possible risks to
                          the fetus. [AHFS Drug Information 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Zalcitabine is a synthetic
                          nucleoside analog of the naturally occurring
                          nucleoside 2'-deoxycytidine in which the
                          3'-hydroxyl group has been replaced by
                          hydrogen. [PDR 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Within cells, it is
                          converted to the 5'-triphosphate (ddCTP)
                          which inhibits replication of HIV-1 by
                          inhibition of viral DNA synthesis. [PDR 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Because ddCTP lacks the
                          3'-hydroxyl group required for chain
                          elongation, its incorporation into a growing
                          DNA chain leads to premature chain
                          termination. [PDR 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C9H13N3O3 [USAN 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 211.22 [USAN 1995]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: White to off-white
                          crystalline powder [PDR 1995]
 CHEMICAL/PHYSICAL DATA   MELTING POINT: 215-217 C [MERCK Index 1989]
 CHEMICAL/PHYSICAL DATA   ELEMENTAL COMPOSITION: C51.18%, H6.20%,
                          N19.89%, 022.72% [MERCK Index 1989]
 CHEMICAL/PHYSICAL DATA   STABILITY: Zalcitabine tablets should be
                          stored in tight containers at 15-30 C. [AHFS
                          Drug Information 1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Oral tablets, 0.375 mg and 0.75
                          mg, film-coated (HIVID Roche's zalcitabine).
                          Parental dosage form currently is not
                          availble in US. [AHFS Drug Information 1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Tablets should be stored in tightly
                          closed bottles at 59 86 F. [PDR 1995]
 MANUFACTURERS            Hoffmann-La Roche
 REFERENCES               Goldman AI, Carlin BP, Crane LR, Launer C,
                          Korvick JA, Deyton L, Abrams DI. Response of
                          CD4 lymphocytes and clinical consequences of
                          treatment using ddI or ddC in patients with
                          advanced HIV infection. J Acquir Immune Defic
                          Syndr Hum Retrovirol. 1996 Feb 1;11(2):161-9.
 REFERENCES               Chadwick EG, Nazareno LA, Nieuwenhuis TJ,
                          Massarella JW, de Dennis SR, Williams K,
                          Yogev R. Phase I evalution of zalcitabine
                          administered to human immunodeficiency
                          virus-infected children. J Infect Dis. 1995
                          Dec;172(6):1475-9.
 REFERENCES               Torres RA, Barr MR, McIntyre KI, Thornton JR,
                          Shay WM, Feldman RD, George NJ, Britton DJ. A
                          comparison of zidovudine, didanosine,
                          zalcitabine and no antiretroviral therapy in
                          patients with advanced HIV disease. Int J STD
                          AIDS. 1995 Jan-Feb;6(1):19-26.
 REFERENCES               Fischl MA, Stanley K, Collier AC, Arduino JM,
                          Stein DS, Feinberg JE, Allan JD, Goldsmith
                          JC, Powderly WG. Combination and monotherapy
                          with zidovudine and zalcitabine in patients
                          with advanced HIV disease. Ann Intern Med.
                          1995 Jan 1;122(1):24-32.
 REFERENCES               Bozzette SA, Kanouse DE, Berry S, Duan N.
                          Health status and function with zidovudine or
                          zalcitabine as initial therapy for AIDS.
                          JAMA. 1995 Jan 25;273(4):295-301.
 REFERENCES               Liu M, Fahey JL, Aziz N, Cumberland WG,
                          Skowron G, Merigan T. Zidovudine And
                          dideoxycytidine differ in their effects on
                          human immunodeficiency virus-induced
                          pathologic activation of the immune system.
                          AIDS Clinical Trial Research Group 047. J
                          Infect Dis. 1994 Nov;170(5):1165-71.
 REFERENCES               Barr M, Torres RA. Retrospective study of
                          zidovudine (ZDV) or didanosine (ddI)
                          monotherapy or zalcitabine plus zidovudine
                          (ddC + ZDV) combination therapy in patients
                          with early AIDS. Int Conf AIDS. 1994 Aug
                          7-12;10(1):209 (abstract no. PBO266).
 REFERENCES               Abrams DI, Goldman AI, Launer C, Korvick JA,
                          Neaton JD, Crane LR, Grodesky M, Wakefield S,
                          Muth K, Kornegay S, et al. A comparative
                          trial of didanosine or zalcitabine after
                          treatment with zidovudine in patients with
                          human immunodeficiency virus infection. N
                          Engl J Med. 1994 Mar 10;330(10):657-62.
 REFERENCES               Richman DD, Meng TC, Spector SA, Fischl MA,
                          Resnick L, Lai S. Resistance to AZT and ddC
                          during long-term combination therapy in
                          patients with advanced infection with human
                          immunodeficiency virus. J Acquir Immune Defic
                          Syndr. 1994 Feb;7(2):135-8.
 REFERENCES               Fischl MA, Olson RM, Follansbee SE, Lalezari
                          JP, Henry DH, Frame PT, Remick SC, Salgo MP,
                          Lin AH, Nauss-Karol C, et al. Zalcitabine
                          compared with zidovudine in patients with
                          advanced HIV-1 infection who received
                          previous zidovudine therapy [see comments].
                          Ann Intern Med. 1993 May 15;118(10):762-9.
 ENTRY MONTH              8906
 LAST REVISION DATE       960501
 

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