Dexrazoxane, a cyclic derivative of edetic acid (EDTA), is a cardioprotective agent used to prevent or decrease cardiomyopathy associated with anthracycline derivatives.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 16, 44, 45
Prophylaxis in Patients Receiving Anthracyclines
Dexrazoxane is used to prevent or reduce the incidence and severity of anthracycline-induced cardiomyopathy1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 16, 44, 45 and is designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition.47 The drug currently is labeled by FDA for such use in women with metastatic breast cancer who have received a cumulative doxorubicin hydrochloride dose of 300 mg/m2 and who, in the clinician's opinion, would benefit from continued doxorubicin therapy. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 16
Dexrazoxane has been shown to prevent or reduce the incidence and severity of anthracycline-induced cardiotoxicity,1, 3, 16, 17, 44, 45 although limited evidence from one study suggests that dexrazoxane also may interfere with the antineoplastic efficacy of certain chemotherapeutic regimens (e.g., when initiated concurrently with cyclophosphamide, doxorubicin, and fluorouracil therapy).1, 2, 4, 5, 16, 18, 35, 39, 46 This potentially detrimental effect was not observed when dexrazoxane therapy was withheld until several initial courses of chemotherapy could be administered,1, 3, 6, 7, 16, 39 and results from most clinical studies have failed to demonstrate interference by dexrazoxane with the antineoplastic efficacy of chemotherapeutic regimens.1, 3, 6, 7, 16, 39, 45, 46 In the study suggesting interference, patients with advanced breast cancer receiving dexrazoxane with the initial and subsequent cycles of fluorouracil, doxorubicin, and cyclophosphamide had a lower response rate (48 vs 63%) and a shorter time to tumor progression than those receiving this chemotherapy regimen initially with placebo; however, the survival of patients who did or did not receive dexrazoxane was similar.1, 2, 4, 5, 16 To minimize the risk of such potential interference with antineoplastic efficacy, the manufacturer currently warns that cardioprotectant therapy with the drug not be initiated at the same time as doxorubicin-containing chemotherapy, but instead be delayed until patients have received a cumulative doxorubicin hydrochloride dose of 300 mg/m2.1 Although patients receiving dexrazoxane generally can tolerate higher cumulative doses of doxorubicin before experiencing cardiotoxicity, the cardioprotectant will not eliminate the risk of cardiotoxicity in patients who have already received cumulative doxorubicin hydrochloride doses of 300 mg/m2.1 Therefore, cardiac function should be monitored carefully even when dexrazoxane is used.1
The ability of dexrazoxane to reduce the incidence and severity of doxorubicin-induced cardiomyopathy has been demonstrated in placebo-controlled and open-label studies of patients receiving doxorubicin-containing combination chemotherapy (e.g., IV doxorubicin hydrochloride 50 mg/m2, fluorouracil 500 mg/m2, and cyclophosphamide 500 mg/m2).1, 4, 6, 7, 8, 9, 10, 11, 16, 44, 45 In a study in women receiving doxorubicin concomitantly with cyclophosphamide and fluorouracil for advanced breast cancer, patients receiving concomitant cardioprotection with dexrazoxane (administered prior to each dose of doxorubicin) tolerated higher cumulative doxorubicin hydrochloride doses (median: 500 mg/m2) than those who did not receive the cardioprotectant (median: 441 mg/m2), and one-third of cardioprotected patients were able to tolerate cumulative doxorubicin hydrochloride doses of at least 700 mg/m2 (about 40% of whom received cumulative doses of 1 g/m2 or more) whereas only 4% of unprotected patients could tolerate such doses.2, 3, 8, 9, 16 Results of this and several other studies in women with breast cancer who received doxorubicin-containing chemotherapy indicate that patients who received dexrazoxane had substantially smaller declines (relative to baseline values) in left-ventricular ejection fraction (LVEF), as determined by multigated radionuclide angiography (MUGA scans), and lower incidences of congestive heart failure than those receiving placebo.1, 4, 6, 7, 8, 9, 10, 11, 16 Differences in decline in LVEF were evident at cumulative doxorubicin hydrochloride doses of 150 mg/m2 and were statistically significant at cumulative doses of 400 mg/m2 or more.1 In 2 of these studies in which the study design was amended after initiation to permit women who had received placebo initially to subsequently receive dexrazoxane once they had received a cumulative doxorubicin hydrochloride dose of 300 mg/m2, retrospective historical analyses within the same studies revealed a 13-fold smaller risk of developing congestive heart failure in women who subsequently received dexrazoxane compared with those who did not receive such delayed cardioprotectant therapy (i.e., those who continued to receive placebo).1, 44 In these studies, the incidence of congestive heart failure was 3% in patients receiving doxorubicin-containing chemotherapy with delayed dexrazoxane therapy and 22% in those receiving doxorubicin-containing chemotherapy without the cardioprotectant.1, 4, 5
Because of the cardioprotective effect of dexrazoxane, addition of the drug to a doxorubicin-containing regimen permitted a greater percentage of patients to be treated with higher cumulative doses of the anthracycline.1, 2, 3, 4, 5, 23, 24, 39 Although time to tumor progression was similar both in those who did or did not receive dexrazoxane and survival was at least as long in those who received dexrazoxane after a cumulative doxorubicin hydrochloride dose of 300 mg/m2, these data should be interpreted with caution since they were based on comparisons of groups entered sequentially into the studies and not on comparisons of prospectively randomized patients.1, 3, 5
Reconstitution and Administration
Dexrazoxane hydrochloride is administered IV by slow direct injection or by continuous infusion over 5-15 minutes.1, 2, 3, 4, 6, 7, 8, 9, 13
Dexrazoxane hydrochloride powder for injection should be reconstituted by adding 25 or 50 mL of (1/6) M sodium lactate injection (provided by the manufacturer) to a vial labeled as containing 250 or 500 mg of dexrazoxane, respectively; the resultant solutions contain 10 mg of dexrazoxane per mL.1 For IV infusion, the reconstituted solution of the drug may be further diluted to the desired concentration (usually 1.3-5 mg/mL) in a compatible IV solution such as 0.9% sodium chloride or 5% dextrose injection.1 These solutions are stable for 6 hours when stored at a controlled room temperature of 15-30°C or when refrigerated at 2-8°C; any unused portion should be discarded. 1 The manufacturer recommends that dexrazoxane hydrochloride not be admixed with other parenteral drugs.1 Dexrazoxane hydrochloride solutions should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.1
After completing IV administration of dexrazoxane hydrochloride, but no later than 30 minutes after the start of this administration, doxorubicin hydrochloride should be given. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 46
The usual precautions of handling antineoplastic agents should be observed with dexrazoxane hydrochloride.1 The manufacturer recommends that protective gloves be used during the handling and preparation of dexrazoxane hydrochloride injection.1 If contact with the skin or mucous membranes occurs, the affected area should be washed immediately and thoroughly with soap and water.1
Dosage of dexrazoxane hydrochloride is expressed in terms of dexrazoxane.1
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.1, 2, 4, 5, 8, 9, 13, 44 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).1 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.1
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/m2.1
For further information on the handling of antineoplastic agents, see the guidelines at the end of Antineoplastic Agents 10:00.
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).1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 16, 44, 45
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.48, 49, 52
Acute anthracycline-induced cardiotoxicity is uncommon.49, 52 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).49, 52 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.49, 52 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.49, 50, 52
Time of onset of chronic cardiotoxicity may vary but usually is manifested within 1 year of anthracycline therapy.52 In one study, onset of congestive heart failure developed 0-231 days after discontinuance of anthracycline therapy.25, 52 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.49 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.49 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.49 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.49
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.48, 51, 52, 53, 54, 55, 56, 57 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.51, 52 It has been suggested that myocyte damage and ventricular dysfunction progress after the initial myocardial insult and may lead to late-onset cardiac decompensation.49, 51, 52 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.49, 51, 52 (See Cautions: Cardiac Effects, in Doxorubicin 10:00.)
The exact mechanism of anthracycline-induced cardiotoxicity is not known.2, 5 Anthracyclines exert a variety of actions that may contribute to the development of cardiotoxicity.1, 2, 5, 16, 19, 20, 21, 22 In animals, anthracyclines cause a selective inhibition of cardiac muscle gene expression for α-actin, troponin, myosin light-chain 2, and the M isoform of creatine kinase, which may result in myofibrillar loss associated with anthracycline-induced cardiotoxicity.52, 59, 60, 61 Other potential causes of anthracycline-induced cardiotoxicity include myocyte damage from calcium overload, altered myocardial adrenergic function, release of vasoactive amines, and proinflammatory cytokines.52, 62, 63, 64 Limited data indicate that calcium-channel blocking agents (e.g., prenylamine [not commercially available in the US]) or β-adrenergic blocking agents may prevent calcium overload; however, the cardioprotective effects of β-adrenergic blocking agents have not been studied.52 It has been suggested that the principal cause of anthracycline-induced cardiotoxicity is associated with free-radical damage to DNA.52 The drugs intercalate DNA, chelate metal ions to produce drug-metal complexes, and generate superoxide radicals via oxidation-reduction reactions.1, 2, 3, 13, 16, 19, 20, 21, 22, 38, 40, 42 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.2, 16, 19 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.2, 3, 4, 5, 6, 12, 13, 16, 21, 22, 38, 40 This reaction is not blocked by free-radical scavengers, and may be the principal mechanism of anthracycline-induced cardiotoxicity.2, 16 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.2, 5, 13, 38 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.1, 2, 3, 4, 5, 7, 11, 13, 16, 38, 40, 42
Additional Information
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.
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Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions May 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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