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Dexrazoxane (dexrazoxane HCl)

Chemoprotectives - Cardioprotective Intracellular Chelators Intravenous Vial (Ea)

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Last reviewed · Source: First Databank (FDB) drug data

Overview

Dexrazoxane, a cyclic derivative of edetic acid (EDTA), is a cardioprotective agent used to prevent or decrease cardiomyopathy associated with anthracycline derivatives.

Dexrazoxane, a cyclic derivative of edetic acid (ethylenediaminetetraacetic acid, EDTA), is a cardioprotective agent used to prevent or decrease cardiomyopathy associated with anthracycline derivatives (e.g., doxorubicin).

Three types of cardiotoxicity may occur in patients receiving anthracycline-derivative antineoplastic agents (e.g., doxorubicin): an acute transient type; a chronic, subacute type, which is related to cumulative dose and has a later, more indolent onset; and a late-onset type cardiotoxicity that manifests years after anthracycline therapy and occurs mainly in patients exposed to the drugs as children.

Acute anthracycline-induced cardiotoxicity is uncommon. It occurs immediately after a single dose or a single course of anthracycline therapy and may involve abnormal ECG findings including ST-T wave changes (e.g., T-wave flattening and ST-segment depression), prolongation of the QT interval, and arrhythmias (e.g., sinus tachycardia; ventricular, supraventricular, and junctional tachycardia). Conduction disturbances (including atrioventricular (AV) and bundle-branch block) have been reported rarely in acute anthracycline-induced cardiotoxicity; such disturbances usually are associated more with late-onset anthracycline-induced cardiotoxicity.

Although acute cardiotoxicity generally is transient, rarely, pericarditis-myocarditis syndrome (e.g., pericardial effusion and/or decreased myocardial contractility) and possible cardiac failure may occur.

Time of onset of chronic cardiotoxicity may vary but usually is manifested within 1 year of anthracycline therapy. In one study, onset of congestive heart failure developed 0-231 days after discontinuance of anthracycline therapy. Chronic cardiotoxicity reflects a progressive injury and loss of cardiac myocyte, with increasing cumulative anthracycline doses resulting in thinning of ventricular walls and decreased systolic performance.

Initially, there is functional compensation by the remaining myocytes allowing overall cardiac function to appear normal despite histologic damage, which can be demonstrated by endomyocardial biopsy. However, as cumulative doses of anthracycline increase, there is a decrease in systolic performance, as measured by a decrease in fractional shortening (FS) and left-ventricular ejection fraction (LVEF) with eventual progression to symptomatic congestive heart failure, if cardiac reserve is exhausted, and cardiorespiratory decompensation. Symptoms of the described rapidly progressing syndrome may include tachycardia, tachypnea, dilation of the heart, exercise intolerance, pulmonary and venous congestion, poor perfusion, and pleural effusion; these manifestations may respond to cardiac supportive therapy and be self-limiting, or, alternatively, may be irreversible and unresponsive to therapy and fatal.

Late-onset anthracycline induced cardiotoxicity, which may include late-onset ventricular dysfunction, heart failure, conduction disturbances, and arrhythmias (e.g., nonsustained ventricular tachycardia), which may be life-threatening, occurs several years or even decades after discontinuance of anthracycline therapy, and it may develop after a prolonged asymptomatic interval. In one study, in patients with solid tumors or leukemia who were followed for 4 to less than 10 or 10-20 years after discontinuance of anthracycline therapy had an 18 or 38% incidence, respectively, of abnormal fractional shortening (FS) in echocardiograms. It has been suggested that myocyte damage and ventricular dysfunction progress after the initial myocardial insult and may lead to late-onset cardiac decompensation.

Some clinicians state that late-onset cardiotoxicity can clinically manifest in response to stressful situations (e.g., surgery, pregnancy), exercise (e.g., weight lifting), and acute viral infection. (See Cautions: Cardiac Effects, in Doxorubicin 10:00.)

The exact mechanism of anthracycline-induced cardiotoxicity is not known. Anthracyclines exert a variety of actions that may contribute to the development of cardiotoxicity. In animals, anthracyclines cause a selective inhibition of cardiac muscle gene expression for alpha-actin, troponin, myosin light-chain 2, and the M isoform of creatine kinase, which may result in myofibrillar loss associated with anthracycline-induced cardiotoxicity.

Other potential causes of anthracycline-induced cardiotoxicity include myocyte damage from calcium overload, altered myocardial adrenergic function, release of vasoactive amines, and proinflammatory cytokines. Limited data indicate that calcium-channel blocking agents (e.g., prenylamine (not commercially available in the US)) or beta-adrenergic blocking agents may prevent calcium overload; however, the cardioprotective effects of beta-adrenergic blocking agents have not been studied. It has been suggested that the principal cause of anthracycline-induced cardiotoxicity is associated with free-radical damage to DNA.

The drugs intercalate DNA, chelate metal ions to produce drug-metal complexes, and generate superoxide radicals via oxidation-reduction reactions. Anthracyclines contain a quinone structure that may undergo reduction via NADPH-dependent reactions to produce a semiquinone free radical that initiates a cascade of superoxide and hydroxide radical generation. Chelation of metal ions, particularly iron, by anthracyclines results in an anthracycline-metal complex that catalyzes the generation of reactive oxygen free radicals, and the complex is a powerful oxidant that can initiate lipid peroxidation in the absence of oxygen free radicals.

This reaction is not blocked by free-radical scavengers, and may be the principal mechanism of anthracycline-induced cardiotoxicity. In addition, the toxic potential of anthracyclines is exacerbated in cardiac cells since these cells do not possess sufficient amounts of certain enzymes (e.g., superoxide dismutase, catalase, glutathione peroxidase) involved in detoxifying free radicals and protecting the cells from subsequent damage. While the precise mechanism of the cardioprotective effect of dexrazoxane has not been clearly established, administration of dexrazoxane, which is converted intracellularly to a ring-opened bidentate chelating agent, is thought to prevent anthracycline-induced cardiotoxicity, at least in part, by chelating free iron and thus preventing the formation of the anthracycline-iron complex and resultant free radical generation.

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information.

The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

USES: Dexrazoxane is used to reduce the risk and severity of heart damage caused by doxorubicin treatment and similar cancer chemotherapy medications. Heart damage limits the length of time you can be treated with doxorubicin. Dexrazoxane allows you to continue doxorubicin treatment for longer.

When used for this purpose, dexrazoxane treatment is usually started after you have received several doses of doxorubicin. It is usually not given with the first doses of doxorubicin since doing so may reduce the effectiveness of doxorubicin.

Generic name: dexrazoxane HCl
Pronunciation: (DEX-ra-ZOX-ane)
Drug class: Chemoprotectives - Cardioprotective Intracellular Chelators
Therapeutic class: Antineoplastics

Reference product & biosimilars

No reference, biosimilar or interchangeable associated with this drug.

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Indications

The following indications are listed for Dexrazoxane:

  • Doxorubicin-Induced Cardiomyopathy

Also known as: Doxorubicin Induced Cardiomyopathy.

Dosing

Dosage of dexrazoxane hydrochloride is expressed in terms of dexrazoxane.

The manufacturer recommends that dexrazoxane be administered IV in a dose ratio of 10:1 relative to the IV dose of doxorubicin hydrochloride (e.g., 500 mg/m2 of dexrazoxane should be administered with 50 mg/m2 of doxorubicin hydrochloride) in patients with a creatinine clearance of at least 40 mL/minute. In patients with moderate to severe renal impairment (i.e., creatinine clearance of less than 40 mL/minute measured by 24-hour urinary creatinine collection or estimated using the Cockroft-Gault equation), the manufacturer recommends that dexrazoxane be administered IV in a dose ratio of 5:1 relative to the IV dose of doxorubicin hydrochloride (e.g., 250 mg/m2 of dexrazoxane should be administered with 50 mg/m2 of doxorubicin hydrochloride). Because the doxorubicin dose is reduced in patients with hyperbilirubinemia, the dexrazoxane dose is reduced in patients with hepatic impairment; the dose ratio of 10:1 is used in patients with hepatic impairment.

To minimize the risk of potential interference with antineoplastic efficacy (see Uses), the manufacturer warns that cardioprotectant therapy with dexrazoxane not be initiated at the time doxorubicin-containing chemotherapy is initiated but instead be delayed until patients have received a cumulative doxorubicin hydrochloride dose of 300 mg/m2.

For further information on the handling of antineoplastic agents, see the guidelines at the end of Antineoplastic Agents 10:00.

Drug interactions

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Contraindications

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Adverse reactions

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Precautions

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ICD codes

CodeTypeDescription
Doxorubicin-induced cardiomyopathy
I42.7ICD10CMCardiomyopathy due to drug and external agent

ICD code information from First Databank (FDB).

Formulary status

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Last reviewed · Source: First Databank (FDB) drug data