Class: Protective Agents
ATC Class: V03AF02
VA Class: AN700
Chemical Name: (S)-4,4′-(1-Methyl-1,2-ethanediyl)bis-2,6-piperazinedione
Molecular Formula: C11H16N4O4
CAS Number: 24584-09-6
Uses for Dexrazoxane Hydrochloride
Anthracycline-induced Cardiomyopathy Prophylaxis
Reduction of the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin dose of ≥300 mg/m2 and would benefit from continued doxorubicin therapy (designated an orphan drug by FDA for this use).1 2 3 4 5 6 7 8 9 10 11 16 44 45 47
Dexrazoxane Hydrochloride Dosage and Administration
Consult specialized references for procedures for proper handling and disposal of antineoplastics.1
Handle cautiously; use protective equipment (e.g., latex gloves).1
Administer dexrazoxane ≤30 minutes prior to initiating doxorubicin therapy; administer doxorubicin no later than 30 minutes after the start of dexrazoxane administration.1 2 3 4 5 6 7 8 9 10 11 46 Do not administer doxorubicin prior to dexrazoxane.a
Reconstitute vial containing 250 or 500 mg of dexrazoxane powder with 25 or 50 mL of (1/6) M sodium lactate injection (provided by manufacturer), respectively, to provide a solution containing 10 mg/mL.1
Rate of Administration
Administer in a dosage ratio relative to the IV dose of doxorubicin hydrochloride.1
Prophylaxis of Anthracycline-induced Cardiomyopathy
Prophylaxis of Anthracycline-induced Cardiomyopathy
Maximum 1000 mg/m2 every 3 weeks was administered during clinical trials.a
Reduced doxorubicin dose recommended in patients with hyperbilirubinemia; proportionally reduce dexrazoxane dosage maintaining 10:1 dexrazoxane to doxorubicin ratio.a
Moderate to severe renal impairment (Clcr <40 mL/min): Reduce dosage ratio to 5:1 dexrazoxane to doxorubicin (e.g., 250 mg/m2 dexrazoxane if 50 mg/m2 doxorubicin is administered).a
Not studied in those undergoing dialysis.a
No dosage adjustments except those related to renal impairment.a (See Renal Impairment under Dosage and Administration.)
Cautions for Dexrazoxane Hydrochloride
Use with chemotherapy regimens that do not contain an anthracycline.a
May add to myelosuppression caused by chemotherapeutic agents; perform CBCs frequently.a
Effectiveness of Cytotoxic Regimens
Concurrent use of dexrazoxane with the initiation of fluorouracil, doxorubicin, and cyclophosphamide (FAC) therapy may interfere with the antitumor efficacy of the regimen; such use is not recommended.a (See Prophylaxis of Anthracycline-induced Cardiotoxicity under Uses.)
Use of dexrazoxane does not eliminate potential for anthracycline induced cardiac toxicity; monitor cardiac function carefully.a
Possible increased risk of secondary malignancies; acute myeloid leukemias, lymphomas, and cutaneous carcinomas reported in patients treated chronically with oral razoxane, a racemic mixture of which dexrazoxane is the S(+)-enantiomer.a
Safety and efficacy not established.a
Response in patients >65 years of age does not appear to differ from that in younger adults; however, use with caution due to greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.a
Pharmacokinetics not evaluated; dosage adjustments may be required in patients with hyperbilirubinemia.a (See Hepatic Impairment under Dosage and Administration.)
Decreased clearance; dosage adjustments necessary in patients with moderate to severe renal impairment (Clcr <40 mL/min).a (See Renal Impairment under Dosage and Administration.)
Common Adverse Effects
Alopecia, nausea, vomiting, fatigue/malaise, anorexia, stomatitis, fever, infection, diarrhea, pain on injection, sepsis, neurotoxicity.a
Interactions for Dexrazoxane Hydrochloride
No significant change in pharmacokinetics of doxorubicin and its predominant metabolite reported with concurrent use of dexrazoxane.a
Dexrazoxane Hydrochloride Pharmacokinetics
Distributed primarily in total body water.a
Plasma Protein Binding
Not bound to plasma proteins.a
Metabolized to a diacid-diamide cleavage product and two monoacid-monoamide ring products.a
Excreted principally in urine as unchanged drug (42%), a diacid-diamide cleavage product, and two monoacid-monoamide ring products.a
Reconstituted or diluted solutions are stable for 6 hours at 15–30°C or under refrigeration (2–8°C).1
Discard unused solutions.1
For information on systemic interactions resulting from concomitant use, see Interactions.
Dextrose 5% in water
Sodium chloride 0.9%
Cardioprotective agent that readily penetrates cell membranes; however, exact mechanism of cardioprotective effect not clearly established.a
Converts intracellularly to a ring-opened bidentate chelating agent that may 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.a 1 2 3 4 5 7 11 13 16 38 40 42
Advice to Patients
Importance of recognizing and reporting signs and symptoms of CHF.a
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.a
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.a
Importance of informing patients of other important precautionary information. (See Cautions)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
For injection, for IV use
250 mg (of dexrazoxane)
Zinecard (with 25 mL sodium lactate injection 0.167 Molar [M/6] diluent)
500 mg (of dexrazoxane)
Zinecard (with 50 mL sodium lactate injection 0.167 Molar [M/6] diluent)
AHFS DI Essentials. © Copyright, 2004-2016, Selected Revisions September 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
1. Pharmacia Inc. Zinecard (dexrazoxane) for injection prescribing information. Columbus, OH; 1995 May.
2. Anon. Dexrazoxane. Phase III Drug Profiles. 1993; 3:20-7.
3. Speyer JL, Green MD, Zeleniuch-Jacquotte A et al. ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J Clin Oncol. 1992; 10:117-27. [PubMed 1727913]
4. Hochster H, Wasserheit C, Speyer J. Cardiotoxicity and cardioprotection during chemotherapy. Curr Opin Oncol. 1995; 7:304-9. [PubMed 7578376]
5. Seifert CF, Nesser ME, Thompson DF. Dexrazoxane in the prevention of doxorubicin-induced cardiotoxicity. Ann Pharmacother. 1994; 28:1063-72. [IDIS 335811] [PubMed 7803884]
6. Speyer JL, Green MD, Kramer E et al. Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer. N Engl J Med. 1988; 319:745-52. [IDIS 246005] [PubMed 3137469]
7. Koning J, Palmer P, Franks CR et al. Cardioxane—ICRF-187: towards anticancer drug specificity through selective toxicity reduction. Cancer Treat Rev. 1991; 18:1-19. [PubMed 1933909]
8. Mailliard JA, Speyer JL, Hanson K et al. Prevention of chronic adriamycin cardiotoxicity with the bisdioxopiperazine dexrazoxane (ICRF-187, ADR-529, Zinecard) in patients with advanced or metastatic breast cancer. Proc ASCO. 1992; 11:A191.
9. Weisberg SR, Rosenfeld CS, York RM et al. Dexrazoxane, (ADR-529, ICRF-187, Zinecard) protects against doxorubicin-induced chronic cardiotoxicity. Proc ASCO. 1992; 11:A190.
10. Feldmann JE, Jones SE, Weisberg SR et al. Advanced small cell lung cancer treated with CAV (cyclophosphamide + adriamycin + vincristine) chemotherapy and the cardioprotective agent dexrazoxane (ADR-529, ICRF-187, Zinecard). Proc ASCO. 1992; 11:A993.
11. Rosenfeld CS, Weisberg SR, York RM et al. Prevention of adriamycin cardiomyopathy with dexrazoxane (ADR-529, ICRF-187). Proc ASCO. 1992; 11:A74.
12. Halliwell B, Bomford A. ICRF-187 and doxorubicin-induced cardiac toxicity. N Engl J Med. 1989; 320:399-400.
13. Hochster H, Liebes L, Wadler S et al. Pharmacokinetics of the cardioprotector ADR-529 (ICRF-187) in escalating doses combined with fixed-dose doxorubicin. J Natl Cancer Inst. 1992; 84:1725-30. [PubMed 1433357]
14. Beijnen JH, Van Gijn R. Chemical stability of the cardioprotective agent ICRF-187 in infusion fluids. J Parenter Sci Technol. 1993; 47:166-71. [IDIS 318887] [PubMed 8410562]
15. Pharmacia Inc. Product information form for American hospital formulary service: Zinecard (dexrazoxane for injection). Columbus, OH; 1995 Jul.
16. Lewis C. A review of the use of chemoprotectants in cancer chemotherapy. Drug Saf. 1994; 11:153-62. [PubMed 7811398]
17. The United States pharmacopeia, 23rd rev, and The national formulary, 18th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1995:11.
18. ten Bokkel-Huinink WW, Schreuder JE, Dubbleman R et al. ICRF-187 protects against doxorubicin induced cardiomyopathy. Ann Oncol. 1992; 1(Suppl 3):A221.
19. Legha S, Wang YM, Mackay B et al. Clinical and pharmacological investigation of the effects of alpha-tocopherol on adriamycin cardiotoxicity. Ann NY Acad Sci. 1982; 393:411-8. [PubMed 6959564]
20. Myers CE, Monow R, Palmeri S et al. A randomised controlled trial assessing the prevention of doxorubicin cardiomyopathy by N-acetylcysteine. Semin Oncol. 1983; 1(Suppl 10):53-5.
21. Myers CE, Gianna L, Zweier J et al. Role of iron in adriamycin biochemistry. Fed Proc. 1986; 45:2792-7. [PubMed 3533644]
22. Sugioka KA, Nakano M. Mechanism of phospholipid peroxidation induced by ferric ion-ADP-adriamycin-co-ordination complex. Biochem Biophys Acta. 1982; 713: 333-43. [PubMed 6295497]
23. Breast cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1995 Dec 12.
24. Anon. A drug for prevention of anthracycline-induced cardiac toxicity. Med Lett Drugs Ther. 1991; 33:85-6. [PubMed 1908544]
25. Von Hoff DD, Layard MW, Basa P et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979; 91:710-7. [PubMed 496103]
26. Adria Laboratories, Inc. Adriamycin™ (doxorubicin hydrochloride for injection) for intravenous use only prescribing information. Wilmington, DE; 1974 Jul.
27. Blum RH, Carter SK. Adriamycin: a new anticancer drug with significant clinical activity. Ann Intern Med. 1974; 80:249-59. [IDIS 41143] [PubMed 4590654]
28. Bachur NR. Current status of studies with adriamycin (NSC-123127). Cancer Chemother Rep Part 3. 1973; 4:47-50.
29. Cortes EP, Holland JF, Wang JJ et al. Doxorubicin in disseminated osteosarcoma. JAMA. 1972; 221:1132-8. [IDIS 27992] [PubMed 4512088]
30. O’Bryan RM, Luce JK, Talley RW et al. Phase II evaluation of adriamycin in human neoplasia. Cancer. 1973; 32:1-8. [PubMed 4716773]
31. Haskell CM, Sullivan A. Comparative survival in tissue culture of normal and neoplastic human cells exposed to adriamycin. Cancer Res. 1974; 34:2991-4. [PubMed 4417828]
32. Benjamin RS, Riggs CE Jr, Bachur NR. Pharmacokinetics and metabolism of adriamycin in man. Clin Pharmacol Ther. 1973; 14:592-600. [IDIS 35937] [PubMed 4723268]
33. Gamble JF. Drug therapy of Hodgkin’s disease. Drug Ther. 1973; 3:35-52.
34. Gottlieb JA, Hill CS. Chemotherapy of thyroid cancer with adriamycin: experience with 30 patients. N Engl J Med. 1974; 290:193-7. [IDIS 39790] [PubMed 4808917]
35. Pharmacia. Adriamycin RDF (doxorubicin hydrochloride for injection, USP) and Adriamycin PFS (doxorubicin hydrochloride injection, USP) for intravenous use only prescribing information dated 1994 Dec 1. In: Physician’s desk reference. 50th ed. Medical Economics Company Inc; 1996; 1947-9.
36. Chiron Therapeutics. Cerubidine (daunorubicin hcl) for injection prescribing information (dated 1995 Jan). In: Physicians’ desk reference. 50th ed. Montvale, NJ: Medical Economics Company Inc; 1996:795-6.
37. Hale JP, Lewis IJ. Anthracyclines: cardiotoxicity and its prevention. Arch Dis Child. 1994; 71:457-62. [IDIS 339358] [PubMed 7826122]
38. Jelic S, Radulovic S, Neskovic-Konstantinovic Z et al. Cardioprotection with ICRF- 187 (Cardioxane) in patients with advanced breast cancer having cardiac risk factors for doxorubicin cardiotoxicity, treated with the FDC regimen. Support Care Cancer. 1995; 3:176-82. [PubMed 7655778]
39. Hellmann K, Franks CR. Reduction of doxorubicin-induced cardiotoxicity by dexrazoxane. In: Zeller WJ, Eisenbrand G, Hellmann K, eds. Reduction of anticancer drug toxicity: pharmacologic, biologic, immunologic and gene therapeutic approaches. Contrib Oncol, Vol 48. Basel, Switzerland: Karger; 1995:40-7.
40. Hasinoff BB. NADPH-cytochrome-P450 reductase promotes hydroxyl radical production by the iron complex of ADR-925, the hydrolysis product of ICRF-187 (dexrazoxane). Free Radical Res. 1995; 22:319-25.
41. Von Hoff DD, Layard MW, Basa P et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979; 91:710-7. [PubMed 496103]
42. Steinherz LJ, Yahalom J. Cardiac complications of cancer therapy. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia, PA: J. B. Lippincott; 1993:2370-4.
43. Von Hoff DD, Rozencweig M, Layard M et al. Daunomycin-induced cardiotoxicity in children and adults: a review of 110 cases. Am J Med. 1977; 62:200-8. [IDIS 82336] [PubMed 835599]
44. Wexler LH, Audrich MP, Venzon D et al. Randomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin. J Clin Oncol. 1996; 14:362-72. [IDIS 362031] [PubMed 8636745]
45. Swain SM, Whaley FS, Gerber MC et al. Congestive heart failure (CHF) after doxorubicin-containing therapy in advanced breast cancer patients treated with or without dexrazoxane (ICRF-187, ADR-529). Proc Am Soc Clin Oncol. 1996:15:A1739. Abstract.
46. Pharmacia & Upjohn, Kalamazoo, MI: Personal communication.
47. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD; 1996 Jul.
48. Steinherz LJ, Yahalom J. Cardiac complications of cancer therapy. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia, PA: J. B. Lippincott; 1993:2370-85.
49. Reviewers’ comments (personal observations) on doxorubicin hydrochloride. 1996 Dec.
50. Bu Lock FA, Mott MG, Oakhill A et al. Early identification of anthracycline cardiomyopathy: possibilites and implications. Arch Dis Child. 1996; 75:416-22. [IDIS 379000] [PubMed 8957955]
51. Steinherz LJ, Steinherz PG, Tan CTC et al. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA. 1991; 266:1672-7. [IDIS 285848] [PubMed 1886191]
52. Shan K, Lincoff M, Young JB et al. Anthracycline-induced cardiotoxicity. Ann Intern Med. 1996; 125:47-58. [IDIS 367329] [PubMed 8644988]
53. Gottlieb SL, Edmiston WA Jr, Haywood LJ. Late, late doxorubicin cardiotoxicity. Chest. 1980; 78:880-2. [IDIS 129724] [PubMed 7449470]
54. Freter CE, Lee TC, Billingham ME et al. doxorubicin cardiac toxicity manifesting seven years after tretament: case report and review. Am J Med. 1986; 80:483-5. [IDIS 213735] [PubMed 3513562]
55. Davis LE, Brown CEL. Peripartum heart failure in a patient treted previously with doxorubicin. Obstet Gynecol. 1988; 71:506-8. [IDIS 241012] [PubMed 3162299]
56. Wood WC, Budman DR, Korzun AH et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med. 1994;330:1253-9.
57. Steinherz LJ, Steinherz PG, Tan C. Cardiac failure and dysrhythmias 6–19 years after anthracycline therapy: a series of 15 patients. Med Pediatr Oncol. 1995; 24:352-61. [PubMed 7715541]
58. Wyeth Laboratories Inc. Cerubidine (daunorubicin hydrochloride) for injection prescribing information. Philadelphia, PA; 1992 May 14.
59. Ferrans VJ. Overview of cardiac pathology in relation to anthracycline cardiotoxicity. Cancer Treat Rep. 1978; 62:955-61. [IDIS 107253] [PubMed 352510]
60. Ito H, Miller SC, Billingham ME et al. Doxorubicin selectively inhibits muscle gene expression in cardiac muscle in vivo and in vitro. Proc Natl Acad Sci. 1990; 87:4275-9. [PubMed 2349236]
61. Billingham ME, Bristow MR, Glatstein E et al. Adriamycin cardiotoxicity: endomyocardial biopsy evidence of enhancement by irradiation. Am J Surg Pathol. 1977; 1:17-23. [PubMed 602969]
62. Mann DL, Young JB. Basic mechanisms in congestive heart failure: recognizing the role of proinflammatory cytokines. Chest. 1994; 897-904.
63. Matsumori A, Yamada T, Suzuki H et al. Increased circulating cytokines in patients with myocarditis and cardiomyopathy. Br Heart J. 1994; 72:561-6. [PubMed 7857740]
64. Kusuoka H, Futaki S, Koretsune Y et al. Alterations of intracellular calcium homeostasis and myocardial energetics in acute adriamycin-induced heart failure. J Cardiovasc Pharmacol. 1991; 18:437-4. [PubMed 1720844]
a. Pharmacia & Upjohn Co. Div. of Pfizer, Inc. Zinecard (dexrazoxane) for injection prescribing information. New York, NY; 2004 Oct.
HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:496.