      Document 0145
 DOCN  DRG0145
 UNIQUE IDENTIFIER        DRG-0102
 NAME OF SUBSTANCE        Mitoxantrone hydrochloride [USAN 1996]
 REGISTRY NUMBER          70476-82-3
 RELATED REGISTRY NUMBER  65271-80-9 (base)
 STANDARD CHEMICAL NAME   1,4-dihydroxy-5, 8-bis
                          ((2-((2-hydroxyethyl)amino)-9,10-antracenedio-
                          ne dihydrochloride [PDR 1995]
 SYNONYMS                 Novantrone [USAN 1996]
 SYNONYMS                 Mitozantrone hydrochloride [The Extra
                          Pharmacopoeia 1993]
 SYNONYMS                 DHAQ (base) [Merck Index 1989]
 SYNONYMS                 CL232315 (hydrochloride) [USAN 1996]
 SYNONYMS                 DHAD [Merck Index 1989]
 SYNONYMS                 1,4-Dihydroxy-5,8-bis((2-((2-hydroxyethyl)
                          amino)ethyl)amino)anthraquinone
                          dihydrochloride [USAN 1996]
 PROTOCOL ID NUMBERS      FDA 055A
 PROTOCOL ID NUMBERS      FDA 055B
 SECONDARY SOURCE ID      NSC-279836 [Merck Index 1989]
 SECONDARY SOURCE ID      NSC-301739 [Merck Index 1989]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Although its mode of action
                          is not fully elucidated, mitoxantrone is a
                          DNA reactive agent amd inhibitor of both RNA
                          and DNA synthesis. Mitoxantrone appears to be
                          most active in the late S phase of cell
                          division, but is not cycle-phase-specific.
                          Although the exact mechanism is unknown,
                          evidence seems to indicate involvement of two
                          effects - binding to DNA by intercalation
                          between base pairs, and a nonintercalative
                          electrostatic interaction - resulting in
                          inhibition of DNA and RNA synthesis.
                          Mitoxantrone also has antiviral,
                          antibacterial, antiprotozoal, and
                          immunosuppressant effects. Distribution is
                          rapid and extensive; largest concentrations
                          are in the thyroid, liver, heart, and red
                          blood cells. Protein binding is high (78
                          percent). Biotransformation is hepatic.
                          Apparent mean terminal plasma half-life is
                          5.8 days (range, 2.3-13.0 days). Excretion is
                          via biliary/fecal, up to 25 percent in five
                          days and renal, 6-11 percent (65 percent
                          unchanged). Extensive tissue uptake and
                          binding accounts for most of the dose, which
                          is then thought to be gradually released.
                          Because of extensive tissue binding, it is
                          unlikely to be significantly removed by
                          hemodialysis or peritoneal dialysis. [PDR
                          1995] [USP DI 1995]
 DISEASES STUDIED/TREATED Under investigation for the treatment of
                          Kaposi's sarcoma and lymphoma [AmFAR Tx Dir
                          1995;7(4)]
 CLASSIFICATION CODE      Antineoplastic [USAN 1996]
 OTHER MAJOR USES         Myelogenous, promyelocytic, monocytic and
                          erythroid acute leukemias [PDR 1995]
 SUBSTANCE INTERACTIONS   Possibly interacts with allopurinol,
                          colchicine, probenecid, sulfinpyrazone, blood
                          dyscrasia-causing medications, bone marrow
                          depressants, radiation therapy, daunorubicin,
                          doxorubicin, killed or live virus vaccines,
                          and previously administered antracyclines.
                          [PDR 1995] [USP DI 1995]
 ADVERSE EFFECTS          Adverse effects include cardiotoxicity
                          including decreased left ventricular ejection
                          fraction, congestive heart failure, cough or
                          shortness of breath (which may be associated
                          with heart failure), ECG changes, arrhythmias
                          such as tachycardia and rarely, myocardial
                          infarction. Other adverse effects may include
                          blood problems, loss of hair,
                          gastrointestinal bleeding, leukopenia or
                          infection, stomatitis or mucositis, stomach
                          pain, conjunctivitis, jaundice, renal
                          failure, seizures, thrombocytopenia, allergic
                          reaction, local irritation, phlebitis,
                          extravasation. Urine may have a blue-green
                          color and whites of eyes may have a blue
                          color during treatment. Mitoxantrone can
                          result in chromosomal aberrations in animals
                          and is mutagenic in bacterial systems. May
                          cause hyperuricemia and transient elevations
                          of AST and ALT. When used in doses indicated
                          for treatment of leukemia, severe
                          myelosuppression will occur. May cause fetal
                          harm when administered to pregnant women.
                          [PDR 1995] [USP DI 1995]
 CONTRAINDICATIONS        Contraindicated in the presence of
                          preexisting myelosuppression, chickenpox
                          (recent or existing), herpes zoster, history
                          of gout or urate renal stones, heart disease,
                          hepatic function impairment, infection,
                          sensitivity to mitoxantrone, pregnancy or
                          breastfeeding. [PDR 1995] [USP DI 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: A synthetic, antineoplastic
                          derivative of anthraquinone [PDR 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C22H28N4O6.2HCl [USAN
                          1996]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 517.41 [USAN 1996]
 CHEMICAL/PHYSICAL DATA   MELTING POINT: 203-205 C (from
                          ethanol/hexane) [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   ELEMENTAL COMPOSITION: C59.45%, H6.35%,
                          N12.60%, O21.60% (base) [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Sparingly soluble in water;
                          slightly soluble in methanol; practically
                          insoluble in acetonitrile, chloroform,
                          acetone [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: Dark blue aqueous
                          solution [PDR 1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Mitoxantrone hydrochloride
                          concentrate is supplied in 10, 12.5, and 15
                          mg vials in sterile aqueous solutions
                          cantaining 2 mg base/ml. [PDR 1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Intravenous. [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Store between 15-25 C (59-77 F). Do
                          not freeze. Opened vials may be stored no
                          longer than 7 days at 15-25 C or 14 days
                          under refrigeration. [PDR 1995]
 MANUFACTURERS            Lederle
 REFERENCES               Harrington WJ, Ucar A, Cabral L, Lai S,
                          Byrnes JJ. Chemotherapy and didanosine (DDI)
                          in AIDS-lymphoma. Int Conf AIDS. 1994 Aug
                          7-12;10(1):178 (abstract no. PB0138).
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                          Am Soc Clin Oncol. 1994;13:A13.
 REFERENCES               Ucar A, Harrington WJ, Cabral L, Hurley J,
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                          etoposide in patients with refractory
                          lymphoma undergoing autologous bone marrow
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 REFERENCES               Romaguera JE, Rodriguez MA. Hagemeister FB,
                          McLaughlin P, Swan F, Moore DF Jr, Sarris AH,
                          Younes A, Hill D, Cabanillas F. A phase II
                          trial of oral etoposide with mitoxantrone and
                          ifosfamide/mesna consolidated with
                          intravenous etoposide, methylprednisolone,
                          high-dose arabinoside, and cisplatin as
                          salvage therapy for relapsing and/or
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                          1994;12(3):217-22.
 REFERENCES               Bezwoda WR, Rastogi RB. A randomized
                          comparative study of cyclophosphamide,
                          vincristine, doxorubicin, and prednisolone
                          and cyclophosphamide, vincristine,
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                          the treatment of intermediate- and high-grade
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 REFERENCES               Wilson WH, Berg SL, Bryant G, Wittes RE,
                          Bates S, Fojo A, Steinberg SM, Goldspiel BR,
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                          in doxorubicin-refractory or
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                          phase I/II trial of 96-hour infusion. J Clin
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                          Huguet F, Muller C, Schlaifer D, Laurent G,
                          Houin G, Bugat R. Plasma and cellular
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                          chemotherapeutic regimen for refractory
                          lymphomas. Cancer Res. 1993 Oct
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                          Orlandi I, Malago D, Lazzarino M. Bernasconi
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 ENTRY MONTH              9102
 LAST REVISION DATE       951213
 

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