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Zinecard

Generic Name: Dexrazoxane Hydrochloride
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

Introduction

Cardioprotective agent; a cyclic derivative of edetic acid (EDTA).1 2 3 4 5 6 7 8 9 10 11 13 16 44 45

Uses for Zinecard

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

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Not recommended for use with initiation of doxorubicin therapy.1 2 4 5 16 18 35 39 46 (See Effectiveness of Cytotoxic Regimens under Cautions.)

Zinecard Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

Administration

IV Administration

Administer by slow IV injection or by rapid IV infusion.1 2 3 4 6 7 8 9 13

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

Reconstitution

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

Dilution

May be further diluted with 0.9% sodium chloride injection or 5% dextrose injection to a concentration of 1.3–5 mg/mL.a 1

Rate of Administration

Administer by slow IV push or rapid IV infusion over 5–15 minutes.a 1 2 3 4 6 7 8 9 13

Dosage

Available as dexrazoxane hydrochloride; dosage expressed in terms of dexrazoxane.a 1

Administer in a dosage ratio relative to the IV dose of doxorubicin hydrochloride.1

Adults

Prophylaxis of Anthracycline-induced Cardiomyopathy
IV

Recommended dosage ratio of dexrazoxane to doxorubicin is 10:1 (e.g., 500 mg/m2 dexrazoxane should be administered with 50 mg/m2 doxorubicin).1 2 4 5 8 9 13 44

Prescribing Limits

Adults

Prophylaxis of Anthracycline-induced Cardiomyopathy
IV

Maximum 1000 mg/m2 every 3 weeks was administered during clinical trials.a

Special Populations

Hepatic Impairment

Reduced doxorubicin dose recommended in patients with hyperbilirubinemia; proportionally reduce dexrazoxane dosage maintaining 10:1 dexrazoxane to doxorubicin ratio.a

Renal Impairment

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

Geriatric Patients

No dosage adjustments except those related to renal impairment.a (See Renal Impairment under Dosage and Administration.)

Cautions for Zinecard

Contraindications

Use with chemotherapy regimens that do not contain an anthracycline.a

Warnings/Precautions

Warnings

Hematologic Effects

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.)

Cardiotoxicity

Use of dexrazoxane does not eliminate potential for anthracycline induced cardiac toxicity; monitor cardiac function carefully.a

Secondary Malignancies

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

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether dexrazoxane is distributed into milk.a Discontinue nursing because of potential risk to nursing infants.a

Pediatric Use

Safety and efficacy not established.a

Geriatric Use

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

Hepatic Impairment

Pharmacokinetics not evaluated; dosage adjustments may be required in patients with hyperbilirubinemia.a (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

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 Zinecard

Antineoplastic Agents

No significant change in pharmacokinetics of doxorubicin and its predominant metabolite reported with concurrent use of dexrazoxane.a

Zinecard Pharmacokinetics

Distribution

Extent

Distributed primarily in total body water.a

Plasma Protein Binding

Not bound to plasma proteins.a

Elimination

Metabolism

Metabolized to a diacid-diamide cleavage product and two monoacid-monoamide ring products.a

Elimination Route

Excreted principally in urine as unchanged drug (42%), a diacid-diamide cleavage product, and two monoacid-monoamide ring products.a

Half-life

2.1–2.5 hours.a

Stability

Storage

Parenteral

Injection

25°C (may be exposed to 15–30°C).a 1

Reconstituted or diluted solutions are stable for 6 hours at 15–30°C or under refrigeration (2–8°C).1

Discard unused solutions.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Dextrose 5% in water

Sodium chloride 0.9%

Drug CompatibilityHID
Y-Site Compatibility

Compatible

Gemcitabine HCl

Pemetrexed disodium

Actions

  • 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)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Dexrazoxane Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use

250 mg (of dexrazoxane)

Zinecard (with 25 mL sodium lactate injection 0.167 Molar [M/6] diluent)

Pfizer

500 mg (of dexrazoxane)

Zinecard (with 50 mL sodium lactate injection 0.167 Molar [M/6] diluent)

Pfizer

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

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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]

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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.

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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.

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46. Pharmacia & Upjohn, Kalamazoo, MI: Personal communication.

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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.

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