      Document 0204
 DOCN  DRG0204
 UNIQUE IDENTIFIER        DRG-0043
 NAME OF SUBSTANCE        Stavudine [USAN 1996]
 REGISTRY NUMBER          3056-17-5
 STANDARD CHEMICAL NAME   2'3'-didehydro-3'-deoxythymidine [USAN 1996]
 SYNONYMS                 d4T [AmFAR Tx Dir 1995;7(4)]
 SYNONYMS                 1-(2,3-Dideoxy-beta-D-glycero-pent-2-enofuran-
                          osyl)thymine [CHEMLINE]
 SYNONYMS                 BMY-27857 [USAN 1996]
 SYNONYMS                 ZERIT [USAN 1996]
 PROTOCOL ID NUMBERS      NIAID ACTG 089
 PROTOCOL ID NUMBERS      NIAID ACTG 111
 PROTOCOL ID NUMBERS      FDA 116A
 PROTOCOL ID NUMBERS      FDA 166B
 PROTOCOL ID NUMBERS      FDA 015H
 PROTOCOL ID NUMBERS      NIAID ACTG 240
 PROTOCOL ID NUMBERS      NIAID 95 CC-102
 PROTOCOL ID NUMBERS      FDA 244A
 PROTOCOL ID NUMBERS      NIAID ACTG 290
 PROTOCOL ID NUMBERS      NIAID ACTG 298
 PROTOCOL ID NUMBERS      FDA 246D
 PROTOCOL ID NUMBERS      NIAID ACTG 302
 PROTOCOL ID NUMBERS      NIAID ACTG 306
 PROTOCOL ID NUMBERS      NIAID ACTG 320
 SECONDARY SOURCE ID      CO51248 [CHEMLINE]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Phosphorylated stavudine
                          inhibits retrovirus replication by inhibiting
                          HIV reverse transcriptase and by inhibiting
                          viral DNA synthesis by causing DNA chain
                          termination. The antiviral activity is
                          dependent on the conversion of stavudine to
                          the triphospate. Plasma clearance and
                          terminal elimination were independent of dose
                          over an IV dosing range of 0.0625 to 1 mg/kg
                          and an oral dosing range of 0.03 to 4 mg/kg.
                          Following 1 hour infusions drug levels
                          decreased in a biphasic manner with a mean
                          terminal elimination half-life of 1.15 hour.
                          After single oral doses the mean terminal
                          elimination half-life was 1.44 hours. Renal
                          elimination accounted for 40% of the overall
                          clearance regardless of the route of
                          administration. In children stavudine is
                          rapidly absorbed following oral doses with a
                          mean absolute bioavailability of 78.5% and
                          69.2% for capsules and solution dosage forms,
                          respectively. No accumulation was observed.
                          Renal insufficiency decreased clearance and
                          the terminal elimination half-life was
                          increased up to 8 hours. [PDR 1995]
 DISEASES STUDIED/TREATED Treatment of advanced AIDS/ARC patients in
                          adults intolerant to zidovudine or other
                          antiviral drugs [AHFS Drug Information 1995]
 DISEASES STUDIED/TREATED Approved by FDA for expanded access use in
                          HIV treatment on 10/5/92 [HHS Press Release]
 DISEASES STUDIED/TREATED FDA approved 6/27/94 for treatment of HIV
                          infection and AIDS [HHS Press Release]
 CLASSIFICATION CODE      Antiretroviral [AmFAR Tx Dir 1995;7(4)]
 ADVERSE EFFECTS          Dose related peripheral neuropathy is the
                          major clinical toxicity occurring in 15% to
                          21% of patients. Neuropathy is characterized
                          by numbness, tingling or pain in the hands or
                          feet. Symptoms may resolve if the drug is
                          discontinued. [PDR 1995]
 CONTRAINDICATIONS        Should only be used in pregnant women if
                          clearly needed. There are no adequate or well
                          controlled studies in pregnant women. It is
                          not know whether stavudine is excreted in
                          human milk. Mothers should discontinue
                          nursing if receiving this drug. [PDR 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: d4T is dideoxynucleoside
                          pyrimidine analogue [AmFAR Tx Dir 1995;7(4)]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C10H12N2O4 [USAN 1996]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 222.22 [USAN 1996]
 CHEMICAL/PHYSICAL DATA   STABILITY: d4T solids are stable to heat,
                          light, high moisture, and are hygroscopic;
                          d4T is stable in acidic solution, and thus
                          does not require enteric coating [NIAID ACTG
                          089]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Solubility in water is about 83
                          mg/ml. [PDR 1995]
 CHEMICAL/PHYSICAL DATA   COMPOSITION: The ratio of the phosphorylated
                          form of d4T in cells is relatively constant,
                          being about 1:1:3 for the mono, di, and
                          triphosphates, respectively [NIAID ACTG 089]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: White to off-white
                          crystalline powder. [PDR 1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Capsules, 15 mg, 20 mg, 30 mg
                          and 40 mg. [PDR 1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Store capsules in tightly closed
                          container at 15 C to 30 C. [PDR 1995]
 MANUFACTURERS            Bristol-Myers
 REFERENCES               Murray HW, Squires KE, Weiss W, Sledz S,
                          Sacks HS, Hassett J, Cross A, Anderson RE,
                          Dunkle LM. Stavudine in patients with AIDS
                          and AIDS-related complex: AIDS clinical
                          trials group 089. J Infect Dis. 1995 Mar;171
                          Suppl 2:S123-30.
 REFERENCES               Petersen EA, Ramirez-Ronda CH, Hardy WD,
                          Schwartz R, Sacks HS, Follansbee S, Petersen
                          DM, Cross A, Anderson RE, Dunkle LM.
                          Dose-related activity of stavudine in
                          patients infected with human immunodeficiency
                          virus. J Infect Dis. 1995 Mar;171 Suppl
                          2:S131-9.
 REFERENCES               Skowron G. Biologic effects and safety of
                          stavudine: overview of phase I and II
                          clinical trials. J Infect Dis. 1995 Mar;171
                          Suppl 2:S113-7.
 REFERENCES               Friedland G. FDA approves d4T as alternative
                          to AZT, ddI, or ddC. AIDS Clin Care. 1995
                          Jan;7(1):4, 10.
 REFERENCES               Dudley MN. Clinical pharmacokinetics of
                          nucleoside antiretroviral agents. J Infect
                          Dis. 1995 Mar;171 Suppl 2:S99-112.
 REFERENCES               Pottage J Jr, Benson C, Sha B. Experience
                          with stavudine (d4T) therapy of patients with
                          advanced AIDS and < 50 CD4 cells. Int Conf
                          AIDS. 1994 Aug 7-12;10(2):194 (abstract no.
                          PB0790).
 REFERENCES               Conant M, Okabe M, Slaton A, Cafaro V,
                          Illeman M, Sanford G, English L, King C. d4T
                          (stavudine) therapy: one large clinic's
                          experience. Int Conf AIDS. 1994 Aug
                          7-12;10(1):7 (abstract no. 003B).
 REFERENCES               Seifert RD, Stewart MB, Sramek JJ, Conrad J,
                          Kaul S, Cutler NR. Pharmacokinetics of
                          co-administerd didanosine and stavudine in
                          HIV-seropositive male patients. Br J Clin
                          Pharmacol. 1994 Nov;38(5):405-10.
 REFERENCES               Lutz B, Mogabgab W, Santos M, Combs K.
                          Delayed PML diagnosis and d4T treatment. Int
                          Conf AIDS. 1994 Aug 7-12;10(1): 201 (abstract
                          no. PB0234).
 REFERENCES               Browne MJ, Mayer KH, Chafee SB, Dudley MN,
                          Posner MR, Steinberg SM, Graham KK, Geletko
                          SM, Zinner SH, Deman SL, et al.
                          2',3'-didehydro-3'-deoxythymidine (d4T) in
                          patients with AIDS or AIDS-related complex: a
                          phase I trial. J Infect Dis. 1993
                          Jan;167(1):21-9.
 ENTRY MONTH              8906
 LAST REVISION DATE       960514
 

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