SYNONYM(S):

ICRF-187

COMMON TRADE NAME(S): ZINECARD(r), CARDIOXANE(r)

CLASSIFICATION:

Cytoprotectant, cytotoxic

Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION:

Dexrazoxane is a cyclic derivative of edetic acid (EDTA) that readily penetrates cell membranes. Dexrazoxane is converted intracellularly to a ring-opened chelating agent. The hydrolysis products of dexrazoxane are thought to exert their effects by chelating free or bound intracellular iron in the myocardium, thus preventing the formation of the anthracycline-iron complex and resultant free radical generation.1,2 The hydrolysis products are believed to be responsible for most of the activity of dexrazoxane.3

PHARMACOKINETICS:

Adapted from standard references3,4 unless specified otherwise.

SPECIAL PRECAUTIONS:

Contraindications: Should not be used as a chemotherapeutic agent1 or with chemotherapy regimens that do not contain doxorubicin.6

Carcinogenicity:

Secondary malignancies (acute myeloid leukemia, T-cell lymphoma, B-cell lymphoma, cutaneous basal cell or squamous cell carcinoma) have been reported in patients treated chronically with oral razoxane, a racemic mixture containing dexrazoxane as the S(+)-enantiomer.

6,7

Mutagenicity: Not mutagenic in Ames test. Dexrazoxane is clastogenic in mammalian in vitro and in vivo chromosome tests.

6,7

Fertility: 7

Animal studies have shown impaired fertility at maturity in both males and females at a dose of 8 mg/kg.

Pregnancy: FDA Pregnancy Category C.7 Animal studies have shown fetal risks and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.

Breastfeeding

is not recommended due to the potential secretion into breast milk.

1,7

INTERACTIONS:

SUPPLY AND STORAGE:

For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.

Injection:

Supplied as a sterile, lyophilized powder containing 250 mg (supplied with 25 mL M/6 Sodium Lactate Injection, USP), or 500 mg (supplied with 50 mL M/6 Sodium Lactate Injection, USP) of dexrazoxane in single dose vials; store unopened vials at room temperature.

1,6

SOLUTION PREPARATION AND COMPATIBILITY:

Reconstitute lyophilized powder with the M/6 Sodium Lactate Injection (USP) provided to give a concentration of 10 mg/mL; reconstituted solution stable for 6 hours at room temperature9 or under refrigeration. Discard unused solutions.1,6 Reconstituted solution for injection: Reconstituted solution should be given by slow IV push or rapid-drip IV infusion from an empty VIAFLEX(r) bag. No further dilution required.1 Diluted solution for infusion: Reconstituted solution may be further diluted with either NS or D5W to a concentration ranging from 1.3 to 5.0 mg/mL.7,9 Resultant solutions are stable for 6 hours when stored at room temperature or refrigerated.7 However, there is data indicating < 10% loss in 24 hours at room temperature when exposed to or protected from light, when diluted with NS or D5W.9 Refrigeration resulted in precipitation after one day.9 Discard unused solutions.7

Bacterial challenge:

No information found.

Compatibility:

consult detailed reference

PARENTERAL ADMINISTRATION:

DOSAGE GUIDELINES:

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.

Adults: Cycle Length: BCCA usual dose noted in bold, italics

Intravenous:

with each dose of doxorubicin

500 mg/m2 IV for one dose on day 11,6

Concurrent radiation:

no information found

Dosage in myelosuppression:

modify according to protocol by which patient is being treated; if no guidelines

available, refer to Appendix 6 "Dosage Modification for Myelosuppression"

Dosage in renal failure: 10

reduce dose by 50% in patients with creatinine clearance < 40 mL/min

Dosage in hepatic failure:

proportionate to doxorubicin dose reduction (10:1 ratio of

dexrazoxane:doxorubicin is recommended)

1,6

Dosage in dialysis

possibly dialyzable

1,6

Children:

Intravenous: 5

10:1 ratio of dexrazoxane:doxorubicin IV prior to each dose of doxorubicin (COG AOST0121 for osteosarcoma)

REFERENCES:

1. Repchinsky C editor. Compendium of Pharmaceuticals and Specialties. Ottawa, Ontario: Canadian Pharmacists Association; 2004.

2. McEvoy G. 2005 AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2005.

3. Wiseman LR, Spencer CM. Dexrazoxane. A review of its use as a cardioprotective agent in patients receiving anthracycline- based chemotherapy. Drugs 1998; 56(3):385-403.

4. Cvetkovic RS, Scott LJ. Dexrazoxane : a review of its use for cardioprotection during anthracycline chemotherapy. Drugs 2005; 65(7):1005-24.

5. Roberta Esau. Personal Communication. Pharmacist BC Children's Hospital & Sunny Hill Health Centre for Children; 4 July 2005.

6. Pfizer Canada Inc. Zinecard product monograph. Kirkland, Quebec; 8 October 2003.

7. Pharmacia & Upjohn Company. ZINECARD(r) product monograph. Kalamazoo, Michigan; August 1998.

8. Karen Gelmon MD. Personal Communication. BC Cancer Agency Breast Tumor Group; 25 July 2005.

9. Trissel LA editor. Handbook on Injectable Drugs (13th Edition). Bethesda, Maryland: American Society of Health-System Pharmacists; 2005.

10. Pfizer Inc. ZINECARD(r) product monograph. New York, New York; December 2005.