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Dexrazoxane - Zinecard ®

The authors make no claims of the accuracy of the information contained herein; and these suggested doses and/or guidelines are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this document shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material.    PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.

Usual Diluents

LR

Dilution Data

IMPORTANT NOTE: Generic dexrazoxane (Bedford labs) and Totect® are reconstituted with sodium lactate. Zinecard® must be reconstituted with sterile water. Totect® dilution data can be found here.....

PREPARATION: ZINECARD®

ZINECARD is available in 250 mg and 500 mg single use only vials. ZINECARD must be reconstituted with Sterile Water for Injection, USP. Each 250 mg vial contains dexrazoxane hydrochloride equivalent to 250 mg dexrazoxane. Hydrochloric Acid, NF is added for pH adjustment. When reconstituted as directed with 25 mL of Sterile Water for Injection, USP, each mL contains: 10 mg dexrazoxane. The pH of the resultant solution is 1.0 to 3.0. Each 500 mg vial contains dexrazoxane hydrochloride equivalent to 500 mg dexrazoxane. Hydrochloric Acid, NF is added for pH adjustment. When reconstituted as directed with 50 mL of Sterile Water for Injection, USP, each mL contains: 10 mg dexrazoxane. The pH of the resultant solution is 1.0 to 3.0. The reconstituted ZINECARD solutions prepared from Sterile Water for Injection, USP, is intended for further dilution with Lactated Ringer's Injection, USP, for rapid intravenous drip infusion. DO NOT ADMINISTER VIA IV PUSH

Stability / Miscellaneous

HOW SUPPLIED CLINICAL PHARMACOLOGY INDICATIONS
CONTRAINDICATIONS DOSAGE AND ADMINISTRATION RECONSTITUTION / DILUTION
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DESCRIPTION
Dexrazoxane, a potent intracellular chelating agent is a derivative of EDTA. Dexrazoxane is a whitish crystalline powder that melts at 191° to 197°C. It is sparingly soluble in water and 0.1 N HCl, slightly soluble in ethanol and methanol, and practically insoluble in nonpolar organic solvents. The pKa is 2.1. Dexrazoxane has an octanol/water partition coefficient of 0.025 and degrades rapidly above a pH of 7.0.

ZINECARD is available in 250 mg and 500 mg single use only vials. ZINECARD must be reconstituted with Sterile Water for Injection, USP.

Each 250 mg vial contains dexrazoxane hydrochloride equivalent to 250 mg dexrazoxane. Hydrochloric Acid, NF is added for pH adjustment. When reconstituted as directed with 25 mL of Sterile Water for Injection, USP, each mL contains: 10 mg dexrazoxane. The pH of the resultant solution is 1.0 to 3.0.

Each 500 mg vial contains dexrazoxane hydrochloride equivalent to 500 mg dexrazoxane. Hydrochloric Acid, NF is added for pH adjustment. When reconstituted as directed with 50 mL of Sterile Water for Injection, USP, each mL contains: 10 mg dexrazoxane. The pH of the resultant solution is 1.0 to 3.0.

The reconstituted ZINECARD solutions prepared from Sterile Water for Injection, USP, is intended for further dilution with Lactated Ringer's Injection, USP, for rapid intravenous drip infusion. DO NOT ADMINISTER VIA IV PUSH

CLINICAL PHARMACOLOGY

Mechanism of Action
The mechanism by which ZINECARD exerts its cardioprotective activity is not fully understood. Dexrazoxane is a cyclic derivative of EDTA that readily penetrates cell membranes. Results of laboratory studies suggest that dexrazoxane is converted intracellularly to a ring-opened chelating agent that interferes with iron-mediated free radical generation thought to be responsible, in part, for anthracycline induced cardiomyopathy.

Pharmacokinetics
The pharmacokinetics of dexrazoxane have been studied in advanced cancer patients with normal renal and hepatic function. Generally, the pharmacokinetics of dexrazoxane can be adequately described by a two-compartment open model with first-order elimination. Dexrazoxane has been administered as a 15 minute infusion over a dose range of 60 to 900 mg/m2 with 60 mg/m2 of doxorubicin, and at a fixed dose of 500 mg/m2 with 50 mg/m2 doxorubicin. The disposition kinetics of dexrazoxane are dose-independent, as shown by linear relationship between the area under plasma concentration-time curves and administered doses ranging from 60 to 900 mg/m2. The mean peak plasma concentration of dexrazoxane was 36.5 µg/mL at the end of the 15 minute infusion of a 500 mg/m2 dose of ZINECARD administered 15 to 30 minutes prior to the 50 mg/m2 doxorubicin dose.

INDICATIONS AND USAGE
ZINECARD is indicated for reducing 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 who will continue to receive doxorubicin therapy to maintain tumor control. It is not recommended for use with the initiation of doxorubicin therapy

CONTRAINDICATIONS
ZINECARD should not be used with chemotherapy regimens that do not contain an anthracycline.

WARNINGS
ZINECARD may add to the myelosuppression caused by chemotherapeutic agents.

There is some evidence that the use of dexrazoxane concurrently with the initiation of fluorouracil, doxorubicin, and cyclophosphamide (FAC) therapy interferes with the antitumor efficacy of the regimen, and this use is not recommended. In the largest of three breast cancer trials, patients who received dexrazoxane starting with their first cycle of FAC therapy had a lower response rate (48% vs. 63%; p=0.007) and shorter time to progression than patients who did not receive dexrazoxane (see Clinical Studies section of CLINICAL PHARMACOLOGY). Therefore, ZINECARD should only be used in those patients who have received a cumulative doxorubicin dose of 300 mg/m2 and are continuing with doxorubicin therapy.

Although clinical studies have shown that patients receiving FAC with ZINECARD may receive a higher cumulative dose of doxorubicin before experiencing cardiac toxicity than patients receiving FAC without ZINECARD, the use of ZINECARD in patients who have already received a cumulative dose of doxorubicin of 300 mg/m2 without ZINECARD, does not eliminate the potential for anthracycline induced cardiac toxicity. Therefore, cardiac function should be carefully monitored.

Secondary malignancies (primarily acute myeloid leukemia) have been reported in patients treated chronically with oral razoxane. Razoxane is the racemic mixture, of which dexrazoxane is the S(+)-enantiomer. In these patients, the total cumulative dose of razoxane ranged from 26 to 480 grams and the duration of treatment was from 42 to 319 weeks. One case of T-cell lymphoma, one case of B-cell lymphoma, and six to eight cases of cutaneous basal cell or squamous cell carcinoma have also been reported in patients treated with razoxane.

DOSAGE AND ADMINISTRATION
The recommended dosage ratio of ZINECARD:doxorubicin is 10:1 (e.g., 500 mg/m2 ZINECARD:50 mg/m2 doxorubicin). In patients with moderate to severe renal dysfunction (creatinine clearance values < 40 mL/min), the recommended dosage ratio of ZINECARD:doxorubicin is 5:1 (e.g., 250 mg/m2 ZINECARD:50 mg/m2 doxorubicin). Creatinine clearance can be determined from a 24-hour urinary creatinine collection or estimated using the Crockroft-Gault equation (assuming stable renal function):

CLCR=[140-age (years)] x weight (kg) {x 0.85 for female patients}
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72 x serum creatinine (mg/dL)

Since a doxorubicin dose reduction is recommended in the presence of hyperbilirubinemia, the ZINECARD dosage should be proportionately reduced (maintaining the 10:1 ratio) in patients with hepatic impairment.

PREPARATION:

ZINECARD must be reconstituted with Sterile Water for Injection, USP. For ZINECARD 250 mg vials, reconstitute with 25 mL. For ZINECARD 500 mg vials, reconstitute with 50 mL. The resultant reconstituted solutions will have a concentration of 10 mg dexrazoxane for each mL of solution. Further dilution with Lactated Ringer's Injection, USP, is necessary prior to administration.

Following reconstitution with Sterile Water for Injection, USP, ZINECARD is stable for 30 minutes at room temperature or if storage is necessary, up to 3 hours from the time of reconstitution when stored under refrigeration, 2° to 8°C (36° to 46°F). The pH of the resultant solution is 1.0 to 3.0. DISCARD UNUSED SOLUTIONS. The reconstituted ZINECARD solution is intended for further dilution with Lactated Ringer's Injection, USP, to a concentration range of 1.3 to 3.0 mg/mL in intravenous infusion bags for rapid drip infusion. DO NOT ADMINISTER VIA IV PUSH. The infusion solutions have a pH of 3.5 to 5.5. The infusion solutions are stable for one hour at room temperature or if storage is necessary, up to 4 hours when stored under refrigeration, 2° to 8°C (36° to 46°F). DISCARD UNUSED SOLUTIONS.

After completing the infusion of ZINECARD, and prior to a total elapsed time of 30 minutes (from the beginning of the ZINECARD infusion), the intravenous injection of doxorubicin should be given.

Incompatibility

ZINECARD should not be mixed with other drugs.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Handling and Disposal

Caution in the handling and preparation of the reconstituted solution must be exercised and the use of gloves is recommended. If ZINECARD powder or solutions contact the skin or mucosae, immediately wash thoroughly with soap and water.

Procedures normally used for proper handling and disposal of anticancer drugs should be considered for use with ZINECARD. Several guidelines on this subject have been published.1–8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

HOW SUPPLIED

ZINECARD (dexrazoxane for injection) is available in the following strengths as sterile, pyrogen-free lyophilizates.

NDC 0013-8717-62

250 mg single dose vial with a red flip-top seal, packaged in single vial packs.

NDC 0013-8727-89

500 mg single dose vial with a blue flip-top seal, packaged in single vial packs.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Reference(s)

PRIMARY: 1) [PACKAGE INSERT DATA] : ZINECARD (dexrazoxane) kit [Pharmacia and Upjohn Company] . New York, NY 10017. Revised: August 2011. Handling and Disposal:

  1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh,PA; Oncology Nursing Society; 1999:32-41.
  2. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402.
  3. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics JAMA. 1985 March 15.
  4. National Study Commission on Cytotoxic Exposure-Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.
  5. Clinical Oncological Society of Australia. Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia. 1983; 1:426-428.
  6. Jones RB. et al. Safe handling of Chemotherapeutic Agents: A report from the Mount Sinai Medical Center. CA - A Cancer Journal for Clinicians. 1983; (Sept/Oct) 258-263.
  7. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990; 47:1033-1049.
  8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA WORK-PRACTICE GUIDELINES). Am J Health-Syst Pharm 1996; 53:1669-1685.

Disclaimer

The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user’s use of or reliance upon this material.PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER. Read the disclaimer