      Document 0163
 DOCN  DRG0163
 UNIQUE IDENTIFIER        DRG-0084
 NAME OF SUBSTANCE        Atovaquone [USAN 1996]
 REGISTRY NUMBER          95233-18-4
 STANDARD CHEMICAL NAME   1,4-Naphthalenedione,2-[4-(4-chlorophenyl)cyc-
                          lohexyl] -3-hydroxy-,trans- [CHEMLINE]
 SYNONYMS                 Mepron [PDR 1995]
 SYNONYMS                 566 [AmFAR Tx Dir 1995;7(4)]
 SYNONYMS                 1,4-Naphthalenedione,2-[4-(4-chlorophenyl)cyc-
                          lohexyl]-3-hydroxy-,trans- [USAN 1996]
 SYNONYMS                 2-[trans-4-(p-Chlorophenyl)cyclohexyl]-3-hydr-
                          oxy-1,4-naphthoquinone [USAN 1996]
 PROTOCOL ID NUMBERS      NIAID ACTG 167
 PROTOCOL ID NUMBERS      NIAID 90 CC-79
 PROTOCOL ID NUMBERS      NIAID 90 CC-164
 PROTOCOL ID NUMBERS      NIAID 91 CC-54
 PROTOCOL ID NUMBERS      FDA 053B
 PROTOCOL ID NUMBERS      FDA 101A
 PROTOCOL ID NUMBERS      NIAID 91 CC-119
 PROTOCOL ID NUMBERS      NIAID 93 I-36
 PROTOCOL ID NUMBERS      FDA 227B
 PROTOCOL ID NUMBERS      NIAID ACTG 227
 PROTOCOL ID NUMBERS      NIAID ACTG 237
 PROTOCOL ID NUMBERS      NIAID ACTG 277
 PROTOCOL ID NUMBERS      FDA 107A
 SECONDARY SOURCE ID      566C80 [CHEMLINE]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: The exact mechanism of
                          atovaquone's antiprotozoal activity has not
                          been fully elucidated. It may be related
                          principally to the drug's ability to inhibit
                          selectively mitochondrial electron transport
                          with consequent inhibition of de novo
                          pyrimidine synthesis. Unlike mammalian cells,
                          certain protozoa are unable to salvage
                          preformed pyrimidines, thus accounting for
                          the preferential susceptibility (e.g.,
                          relative to human hosts) of the protozoa to
                          the drug. The site of action in the
                          mitochondrial electron transport chain
                          appears to be the cytochrome bc1 complex.
                          Atovaquone is highly lipophilic with low
                          aqueous solubilty. Studies show that the
                          bioavailability of the drug is low, variable
                          and decreases significantly with a single
                          dose above 750 mg. Following a single-dose
                          administration of atovaquone, the plasma
                          concentration - time profile displayed a
                          distinct double peak - the first between 1
                          and 8 hours after dosing, the second between
                          24 to 96 hours post-dose. This suggests that
                          the drug in systemic circulation is excreted
                          into the bile and is subsequently reabsorbed.
                          Bioavailability is increased 3-fold when the
                          drug is administered with meals (especially
                          fatty meals). There is significant difference
                          in bioavailability between normal volunteers,
                          HIV-positive individuals and AIDS patients.
                          Steady-state atovaquone plasma concentrations
                          in the AIDS patients are about one third to
                          one half the levels achieved in the other
                          individuals. [AHFS Drug Information 1995]
                          [PDR 1995]
 DISEASES STUDIED/TREATED FDA approved 11/25/92 for the treatment of
                          mild to moderate PCP in patients intolerant
                          to standard therapies [FDA Talk Paper] [USP
                          DI 1995] [Drug Evaluations Annual 1994]
 DISEASES STUDIED/TREATED Treatment and suppression of T. gondii
                          encephalitis [FDA Talk Paper] [USP DI 1995]
                          [Drug Evaluations Annual 1994]
 DISEASES STUDIED/TREATED Primary prophylaxis of HIV-infected persons
                          at high risk for developing this disease [FDA
                          Talk Paper] [USP DI 1995] [Drug Evaluations
                          Annual 1994]
 DISEASES STUDIED/TREATED Limited studies suggest that atovaquone may
                          also be effective in the treatment of ocular
                          and cerebral toxoplasmosis in AIDS patients
                          [FDA Talk Paper] [USP DI 1995] [Drug
                          Evaluations Annual 1994]
 CLASSIFICATION CODE      Antiprotozoal [AHFS Drug Information 1995]
 CLASSIFICATION CODE      Antifungal [AmFAR Tx Dir 1993;6(3)]
 OTHER MAJOR USES         Potent anti-malarial; good in vitro activity
                          against Toxoplasma gondii [Drug Exp Clin Res
                          1991;17(9)] [USP DI 1995]
 SUBSTANCE INTERACTIONS   Since atovaquone is highly bound to plasma
                          protein, caution should be used when giving
                          the drug concurrently with other highly
                          plasma protein-bound drugs with narrow
                          therapeutic indices, as competition for
                          binding sites may occur. The extent of plasma
                          protein binding of atovaquone is not affected
                          by the presence of therapeutic doses of
                          phenytoin (15 microgram/ml), nor is the
                          binding of phenytoin affected by the presence
                          of atovaquone. [PDR 1995]
 ADVERSE EFFECTS          Although adverse effects associated with
                          atovaquone therapy are common, the drug
                          generally appears to be well tolerated. The
                          most frequent adverse effects include rash,
                          GI effects, fever and headache. Because most
                          HIV-infected patients receiving the drug to
                          date have had serious underlying disease with
                          multiple baseline symptomatology, many
                          reported effects may not be directly
                          attributable to atovaquone.
                          Treatment-limiting adverse effects were
                          substantially less common with atovaquone
                          than with co-trimoxazole or pentamidine.
                          [AHFS Drug Information 1995]
 CONTRAINDICATIONS        Patients should be advised regarding
                          pulmonary manifestations of possibly
                          concurrent bacterial, viral, fungal or
                          mycobacterial infections associated with HIV
                          infection. Atovaquone is presently not
                          recommended for severe P. carinii pneumonia
                          nor in the prevention of P. carinii
                          pneumonia. Efficacy of the drug in children
                          has not been established. The drug should be
                          used with caution in geriatric patients. The
                          drug should be used during pregnancy only if
                          potential benefits justify the possible risks
                          to the fetus. It is not known whether
                          atovaquone is distributed in human milk; the
                          drug should be used with caution in nursing
                          women. [AHFS Drug Information 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Synthetic
                          hydroxynaphthoquinone-derivative
                          antiprotozoal agent [AHFS Drug Information
                          1995]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: Yellow crystalline
                          solid [PDR 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C22H19ClO3 [PDR 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 366.84 [PDR 1995]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Practically insoluble in water
                          [PDR 1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: 250 mg tablets; 150 mg/ml
                          micronized suspension in 120 ml amber
                          bottles. Suspension formulation FDA approved
                          2/8/95. [PDR 1995] [NIAID ACTG 227]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Store tablets and micronized
                          suspension at 15-25 C (59-77 F); protect
                          micronized suspension from light. [PDR 1995]
                          [NIAID ACTG 227]
 MANUFACTURERS            Glaxo Wellcome
 REFERENCES               Hughes WT. The role of atovaquone tablets in
                          treating Pneumocystis carinii pneumonia. J
                          Acquir Immune Defic Syndr Hum Retrovirol.
                          1995 Mar 1;8(3):247-52.
 REFERENCES               Dohn MN, Weinberg WG, Torres RA, Follansbee
                          SE, Caldwell PT, Scott JD, Gathe JC Jr,
                          Haghighat DP, Sampson JH, Spotkov J, et al.
                          Oral atovaquone compared with intravenous
                          pentamidine for Pneumocystis carinii
                          pneumonia in patients with AIDS. Ann Intern
                          Med. 1994 Aug 1;121(3):174-80.
 REFERENCES               Iribarren JA, Goenaga M, Arrizabalaga J,
                          Rodriguez F, Von Wichmann MA, Huarte I, Garde
                          C. Atovaquone in cerebral toxoplasmosis:
                          preliminary experience. Int Conf AIDS. 1994
                          Aug 7-12;10(2):153 (abstract no. PB0626).
 REFERENCES               Epstein LJ, Mohsenifar Z, Daar ES, Yeh V,
                          Meyer RD. Clinical experience with
                          atovaquone: a new drug for treating
                          Pneumocystis carinii pneumonia. Am J Med Sci.
                          1994 Jul;408(1):5-8.
 REFERENCES               Lafeuillade A, Pellegrino P, Quilichini R.
                          Atovaquone for resistant cerebral
                          toxoplasmosis in AIDS. Int Conf AIDS. 1993
                          Jun 6-11;9(1):377 (abstract no. PO-B10-1449).
 REFERENCES               Torres R, Weinberg W, Stansell J, Leoung G,
                          Kovacs J, Rogers M. Multicenter clinical
                          trial of atovaquone (ATQ) for salvage
                          treatment and suppression of toxoplasmic
                          encephalitis (TE). Int Conf AIDS. 1993 Jun
                          6-11;9(1):377 (abstract no. PO-B10-1453).
 REFERENCES               Raise E, Rosini G, Ferlini D, Guerra L,
                          Mazzetti M, Gritti F. Salvage treatment of
                          cerebral toxoplasmosis/PCP in AIDS with
                          atovaquone. Int Conf AIDS. 1993 Jun
                          6-11;9(1):382 (abstract no. PO-B10-1481).
 REFERENCES               LaFon S, Masur H, Sattler F, Frame P, Clumeck
                          N, Hughes W. The relationship of
                          treatment-limiting adverse events (TLAE) to
                          time on therapy and plasma drug
                          comcentrations in a randomized trial of
                          trimethoprim/sulfamthoxazole (T/S) vs.
                          atovaquone (AATQ) for the threapy of AIDS
                          related Pneumocystis pneumonia (PCP). Int
                          Conf AIDS. 1993 Jun 6-11;9(1):377 (abstract
                          no. PO-B10-1454).
 REFERENCES               White A, Rogers M, Andrews E, Brown N,
                          Nusinoff-Lehrman S, Tilson H. Results of a
                          treatment IND for Mepron (atovaquone) therapy
                          in patients with acute PCP. Int Conf AIDS.
                          1993 Jun 6-11;9(1):57 (abstract no.
                          WS-B14-1).
 REFERENCES               Pagano G, Kennedy W, Weller S, McKinney R,
                          Brown N, Hughes W. The safety and
                          pharmacokinetics of atovaquone in
                          immunocompromised children. Int Conf AIDS
                          1993 Jun 6-11;9(1):378 (abstract no.
                          PO-B10-1455).
 ENTRY MONTH              9003
 LAST REVISION DATE       960612
 

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