Page 1017 - Hematology_ Basic Principles and Practice ( PDFDrive )

900 Part VII Hematologic Malignancies

Preparation and Administration: Daunorubicin is supplied powder is reconstituted with either normal saline or sterile water for
with 100 mg of mannitol in 20-mg vials, from which it is reconsti- injection to yield a 2-mg/mL solution. The reconstituted solution
tuted with 4 mL of sterile water for injection. The vial should be must be protected from sunlight. The drug should be injected slowly
protected from sunlight. Daunorubicin is a powerful vesicant that into the tubing of a freely running IV infusion of normal saline or
should be administered into the tubing of a freely flowing IV infusion 5% dextrose in water. Erythematous streaking along the vein is often
of either 5% dextrose in water or normal saline. In the event of an indication that the administration rate is too rapid. The drug is a
extravasation, as much infiltrated drug as possible should be aspirated powerful vesicant, and in case of extravasation, the measures described
from the tissue, and cold compresses should be maintained on the for daunorubicin should be followed.
site for several hours. Despite these measures, skin grafting may be
necessary. Daunorubicin is not physically compatible with heparin, Toxic Effects: The toxic effects are similar to those of daunorubi-
and the two drugs should not be co-administered in the same IV cin. It is important to emphasize that weekly low-dose regimens or
tubing. The patient should be informed that daunorubicin may administration by continuous infusion can decrease the risk of car-
impart a red color to the urine for up to 72 hours after diotoxicity with doxorubicin.
administration.
Potential Drug Interactions: When used in combination with
Toxic Effects: Myelosuppression, predominantly leukopenia, is other drugs as treatment for leukemia or lymphoma, doxorubicin
the dose-limiting toxic effect. Mucositis, nausea and vomiting, and may decrease the oral bioavailability of digoxin. It is not physically
alopecia are common. Facial flushing, conjunctivitis, and lacrimation compatible with heparin or 5-fluorouracil. Barbiturates may increase
may occur in rare cases. Erythematous streaking near the site of the plasma clearance of doxorubicin and decrease its cytotoxic effect.
injection occurs as a benign local allergic reaction and should not be Doxorubicin is compatible with vincristine, and the two drugs can
confused with extravasation. The drug can produce a severe local be administered together in the same IV solution.
reaction (e.g., pneumonitis, esophagitis) in previously irradiated
areas, even when both therapies are not administered concomitantly Therapeutic Indications in Hematology: Doxorubicin is one
(radiation recall). Cardiac toxicity is a unique characteristic of the of the most important drugs in the treatment of hematologic malig-
anthracycline antibiotics and can be acute or chronic. In the acute nancies. It is used in the treatment of Hodgkin lymphoma (ABVD
form, abnormal ECG changes such as ST-T wave elevation and regimen), NHL (CHOP, MACOP-B), and MM (VBAP, VAD).
arrhythmias may be seen. Transient reduction in the ejection fraction
can also occur acutely and is often associated with pericarditis Idarubicin (Idamycin)
(pericarditis-myocarditis syndrome). The chronic form of anthracy-
cline cardiac toxicity is related to the cumulative dose. The dose limit Chemistry and Mechanism of Action: Idarubicin, also called
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of doxorubicin is generally considered to be 450–500 mg/m , where 4′-demethoxydaunorubicin (4-DMDR), is an analog of daunorubicin
the risk of clinical cardiotoxicity is between 1% and 10%. The cor- in which the methoxy group from the aglycone has been replaced
responding cumulative dose limit for daunorubicin is 900–1000 mg/ with hydrogen. Idarubicin is also a topoisomerase II inhibitor and
2
m . The cardiac toxicity is clinically characterized by congestive heart generates free radicals.
failure, usually refractory to medical therapy. Cardiac irradiation or
the administration of cyclophosphamide may increase the risk of Absorption, Fate, and Excretion: The elimination half-life of
cardiotoxicity. The cardiotoxic effects appear to be related to the the parent compound is 11.3 hours and that of the primary metabo-
formation of free radicals and not to the inhibition of DNA topoi- lite, 13-epirubicinol, is 40–60 hours. The major metabolite is as
somerase II. The cardioprotective agent dexrazoxane (Zinecard) is active as idarubicin. The oral bioavailability of this drug is approxi-
now available and recommended to be started at a doxorubicin mately 30%; 80% of the drug is excreted in the urine as 13-epirubicinol.
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cumulative dose greater than 350 mg/m .
Preparation and Administration: Idarubicin is supplied in 5-
Potential Drug Interactions: Daunorubicin is not physically and 10-mg vials from which it is reconstituted with sterile water or
compatible with heparin or dexamethasone. The drug interactions normal saline to obtain a 1-mg/mL solution. The drug should be
described for doxorubicin (description follows) probably occur with infused for 10–15 minutes through the tubing of a freely running IV
daunorubicin as well. infusion. Extravasation precautions should be instituted during
administration. The oral formulation remains investigational.
Therapeutic Indications in Hematology: Daunorubicin is
used in combination with other drugs in the treatment of AML and Toxic Effects: The side effects of idarubicin are similar to those
ALL. of daunorubicin and doxorubicin but are of lesser intensity at equal
myelosuppressive doses.
Doxorubicin (Adriamycin)
Potential Drug Interactions: None reported.
Chemistry and Mechanism of Action: Doxorubicin is also an
anthracycline glycoside antibiotic. It differs from daunorubicin at Therapeutic Indications in Hematology: Idarubicin in com-
C-8, in which a hydroxyacetyl group replaces an acetyl group. Because bination with ara-C is equivalent, if not superior, to combination
of this, doxorubicin is also called hydroxyl daunorubicin. Its mecha- chemotherapy with daunorubicin in the treatment of adult AML and
nisms of action also involve stabilizing DNA–topoisomerase II MDS. Idarubicin has been approved for use in combination therapy
complexes, DNA intercalation, and free radical formation. for adult AML.
Absorption, Fate, and Excretion: Doxorubicin has a triphasic Mitoxantrone (Novantrone)
plasma clearance with a half-life of approximately 30 hours. The drug
is extensively metabolized in the liver to yield an active metabolite Chemistry and Mechanism of Action: Mitoxantrone is a
(doxorubicinol) and a number of inactive metabolites (aglycones). synthetic anthracenedione. Its mechanism of action appears to pri-
Within 7 days, more than 50% of an injected dose is excreted in the marily involve the inhibition of DNA topoisomerase II. Its reduced
bile, but only 5%–10% of the drug is excreted in the urine. Penetra- potential for free radical formation may explain the decreased cardio-
tion into the cerebrospinal fluid is poor. toxicity of this drug.
Preparation and Administration: Doxorubicin is commercially Absorption, Fate, and Excretion: Mitoxantrone is excreted via
available in vials of 10, 20, 50, 150, and 200 mg. The lyophilized the renal and hepatobiliary systems, but the hepatobiliary elimination