Dexrazoxane – Totect®, Zinecard®

Dexrazoxane - Totect®

Usual Diluents

Dilution Data

 Zinecard® dilution data can be found here.....
 

PREPARATION:   Generic dexrazoxane (Bedford labs) and Totect®

Dexrazoxane must be reconstituted with 0.167 Molar (M/6) Sodium Lactate Injection USP to give a concentration of 10 mg dexrazoxane for each mL of sodium lactate. The reconstituted solution should be given by slow I.V. push (5-15 minutes) or rapid drip intravenous infusion from a bag. After completing the infusion of dexrazoxane, and prior to a total elapsed time of 30 minutes (from the beginning of the dexrazoxane infusion), the intravenous injection of doxorubicin should be given.1

Reconstituted dexrazoxane, when transferred to an empty infusion bag, is stable for 6 hours from the time of reconstitution when stored at 20° to 25°C (68° to 77°F), see USP controlled room temperature, or under refrigeration, 2° to 8°C (36° to 46°F). DISCARD UNUSED SOLUTIONS.1

The reconstituted dexrazoxane solution may be diluted with either 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration range of 1.3 to 5 mg/mL in intravenous infusion bags. The resultant solutions are stable for 6 hours when stored at 20° to 25°C (68° to 77°F), see USP controlled room temperature, or under refrigeration, 2° to 8°C (36° to 46°F). DISCARD UNUSED SOLUTIONS.1

HOW SUPPLIED
Dexrazoxane for Injection is available as a sterile, pyrogen-free Iyophilizate.

NDC 55390-014-02 250 mg single dose vial of Dexrazoxane for Injection packaged in a dual carton with one 25 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP.

NDC 55390-060-02 500 mg single dose vial of Dexrazoxane for Injection packaged in a dual carton with one 50 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP.

Totect®: treatment of extravasation resulting from intravenous anthracycline chemotherapy:
Preparation of Totect®
Step 1. Each vial of Totect® (dexrazoxane for injection) (500 mg) must first be mixed with 50 mL of the enclosed diluent. The resultant solution contains 10 mg/mL. This resultant solution should be used immediately (within 2 hours) after preparation. It contains no antibacterial preservative.

Step 2. Withdraw the recommended dose from the solution containing 10 mg/mL as prepared in Step 1 and further dilute into an infusion bag containing 1000 mL 0.9% Sodium Chloride. In order to obtain the required dose more than one vial may be needed. Totect® must not be mixed with any other drugs.

The infusion bag should be used immediately after preparation. The product is stable for 4 hours from the time of preparation when stored below 25ºC (77ºF).

The solution of Totect® is slightly yellow.

Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit. Solutions containing a precipitate should be discarded. Vials are for single use only. Unused solution should be discarded.

Administration:
Totect® should not be mixed or administered with any other drug during the infusion. Administer as an intravenous infusion over 1 to 2 hours at room temperature and normal light conditions in a large caliber vein in an extremity/area other than the one affected by the extravasation. Cooling procedures such as ice packs, if used, should be removed from the extravasation area at least 15 minutes before Totect® administration in order to allow sufficient blood flow to the area of extravasation. Treatment on Day 2 and Day 3 should start at the same hour (+/- 3 hours) as on the first day.

HOW SUPPLIED
Totect® is available as an urgent treatment kit for single patient use. Each kit contains 10 vials of Totect® (dexrazoxane for injection) 500 mg and 10 vials of 50 mL diluent, which provides a complete three day treatment.

DESCRIPTION
Dexrazoxane for Injection is a sterile, pyrogen-free lyophilizate intended for intravenous administration. It is a cardioprotective agent for use in conjunction with doxorubicin.

Dexrazoxane, a potent intracellular chelating agent is a derivative of EDTA. Dexrazoxane is a whitish crystalline powder which melts at 191° to 197°C. It is sparingly soluble in water and 0.1 N HCI, 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.

Each 250 mg vial contains dexrazoxane hydrochloride equivalent to 250 mg dexrazoxane. Hydrochloric acid is added for pH adjustment. When reconstituted as directed with the 25 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection USP diluent provided, each mL contains: 10 mg dexrazoxane. The pH of the resultant solution is 3.5 to 5.5.

Each 500 mg vial contains dexrazoxane hydrochloride equivalent to 500 mg dexrazoxane. Hydrochloric acid is added for pH adjustment. When reconstituted as directed with the 50 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection USP diluent provided, each mL contains: 10 mg dexrazoxane. The pH of the resultant solution is 3.5 to 5.5.

CLINICAL PHARMACOLOGY

Mechanism of Action
The mechanism by which dexrazoxane 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 mcg/mL at the end of the 15 minute infusion of a 500 mg/m2 dose of dexrazoxane administered 15 to 30 minutes prior to the 50 mg/m2 doxorubicin dose.

INDICATIONS AND USAGE
Dexrazoxane 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. lt is not recommended for use with the initiation of doxorubicin therapy (see WARNINGS).

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Totect® is indicated for the treatment of extravasation resulting from intravenous anthracycline chemotherapy.

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

WARNINGS
Dexrazoxane 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 cyclophosohamide (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 PACKAGE INSERT FOR CLINICAL PHARMACOLOGY: Clinical Studies). Therefore, dexrazoxane 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 dexrazoxane may receive a higher cumulative dose of doxorubicin before experiencing cardiac toxicity than patients receiving FAC without dexrazoxane, the use of dexrazoxane in patients who have already received a cumulative dose of doxorubicin of 300 mg/m2 without dexrazoxane, 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, a 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 dexrazoxane:doxorubicin is 10:1 (e.g., 500 mg/m2 dexrazoxane:50 mg/m2 doxorubicin). In patients with moderate to severe renal dysfunction (creatinine clearance values <40 mL/min), the recommended dosage ratio of dexrazoxane:doxorubicin is 5:1 (e.g., 250 mg/m2 dexrazoxane: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 dexrazoxane dosage should be proportionately reduced (maintaining the 10:1 ratio) in patients with hepatic impairment.

Preparation:
Dexrazoxane must be reconstituted with 0.167 Molar (M/6) Sodium Lactate Injection USP to give a concentration of 10 mg dexrazoxane for each mL of sodium lactate. The reconstituted solution should be given by slow I.V. push or rapid drip intravenous infusion from a bag. After completing the infusion of dexrazoxane, and prior to a total elapsed time of 30 minutes (from the beginning of the dexrazoxane infusion), the intravenous injection of doxorubicin should be given.

Reconstituted dexrazoxane, when transferred to an empty infusion bag, is stable for 6 hours from the time of reconstitution when stored at 20° to 25°C (68° to 77°F), see USP controlled room temperature, or under refrigeration, 2° to 8°C (36° to 46°F). DISCARD UNUSED SOLUTIONS.

The reconstituted dexrazoxane solution may be diluted with either 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration range of 1.3 to 5 mg/mL in intravenous infusion bags. The resultant solutions are stable for 6 hours when stored at 20° to 25°C (68° to 77°F), see USP controlled room temperature, or under refrigeration, 2° to 8°C (36° to 46°F). DISCARD UNUSED SOLUTIONS.

Incompatibility
Dexrazoxane should not be mixed with other drugs.

Handling and Disposal
Caution in the handling and preparation of the reconstituted solution must be exercised and the use of gloves is recommended. If dexrazoxane 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 dexrazoxane. 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.

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

HOW SUPPLIED
Dexrazoxane for Injection is available as a sterile, pyrogen-free Iyophilizate.

NDC 55390-014-02 250 mg single dose vial of Dexrazoxane for Injection packaged in a dual carton with one 25 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP.

NDC 55390-060-02 500 mg single dose vial of Dexrazoxane for Injection packaged in a dual carton with one 50 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP.

Store at 20° to 25°C (68° to 77°F). See USP controlled room temperature. Reconstituted solutions of dexrazoxane are stable for 6 hours at controlled room temperature or under refrigeration, 2° to 8°C (36° to 46°F). DISCARD UNUSED SOLUTIONS.

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TOTECT (dexrazoxane) kit
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2.  DOSAGE AND ADMINISTRATION
Vial contents must be mixed and diluted before use.

2.1 Recommended Dose
Totect® should be given once daily for 3 consecutive days. The first infusion should be initiated as soon as possible and within the first six hours after extravasation.

The individual dosage is based on calculation of the Body Surface Area (BSA) up to a maximum dose of 2000 mg (each on Day 1 and 2) and 1000 mg (Day 3), corresponding to a BSA of 2 m2.

The recommended dose is:       Maximum daily dose:
Day one: 1000 mg/m2                2000 mg
Day two: 1000 mg/m2                2000 mg
Day three: 500 mg/m2               1000 mg

2.2 Dose Modifications
The Totect® dose should be reduced by 50% in patients with creatinine clearance values < 40 mL/min.

2.3 Directions for Mixing and Final Dilution
Read this entire section carefully before mixing and diluting.

Aseptic technique should be used during preparation.

Caution must be exercised when handling Totect® and preparing the mixed solution. [see How Supplied/Storage and Handling (16)]

Totect® should not be mixed or administered with any other drug during the infusion.

Preparation of Totect®
Step 1. Each vial of Totect® (dexrazoxane for injection) (500 mg) must first be mixed with 50 mL of the enclosed diluent. The resultant solution contains 10 mg/mL. This resultant solution should be used immediately (within 2 hours) after preparation. It contains no antibacterial preservative.

Step 2. Withdraw the recommended dose from the solution containing 10 mg/mL as prepared in Step 1 and further dilute into an infusion bag containing 1000 mL 0.9% Sodium Chloride. In order to obtain the required dose more than one vial may be needed. Totect® must not be mixed with any other drugs.

The infusion bag should be used immediately after preparation. The product is stable for 4 hours from the time of preparation when stored below 25ºC (77ºF).

The solution of Totect® is slightly yellow.

Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit. Solutions containing a precipitate should be discarded. Vials are for single use only. Unused solution should be discarded.

2.4 Administration
Totect® should not be mixed or administered with any other drug during the infusion. Administer as an intravenous infusion over 1 to 2 hours at room temperature and normal light conditions in a large caliber vein in an extremity/area other than the one affected by the extravasation. Cooling procedures such as ice packs, if used, should be removed from the extravasation area at least 15 minutes before Totect® administration in order to allow sufficient blood flow to the area of extravasation. Treatment on Day 2 and Day 3 should start at the same hour (+/- 3 hours) as on the first day.

3. DOSAGE FORMS AND STRENGTHS
Totect® is packaged as an urgent treatment kit for single patient use. Each kit contains 10 vials of Totect® (dexrazoxane for injection) 500 mg and 10 vials of 50 mL diluent, which provides a complete three day treatment.

HOW SUPPLIED/STORAGE AND HANDLING
Totect® is available as an urgent treatment kit for single patient use. Each kit contains 10 vials of Totect® (dexrazoxane for injection) 500 mg and 10 vials of 50 mL diluent, which provides a complete three day treatment.

NDC 38423-110-01

Store at 25ºC (77ºF); excursions permitted between 15-30ºC (59-86ºF) [see USP Controlled Room Temperature]. Protect from light. Keep vials in carton until ready for use.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-4 Direct contact of Totect® with the skin or mucous membrances prior to and following reconstitution should be avoided. If contact occurs, wash immediately and thoroughly with water.

Totect® is a registered trademark of TopoTarget A/S, Copenhagen, Denmark.

2)  PACKAGE INSERT DATA:   TOTECT® (dexrazoxane) kit. TopoTarget USA Inc. 100 Enterprise Drive, Rockaway, New Jersey 07866. November 2009.

Handling and Disposal: ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh,PA; Oncology Nursing Society; 1999:32-41. 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. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics JAMA. 1985 March 15. 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. Clinical Oncological Society of Australia. Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia. 1983; 1:426-428. 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. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990; 47:1033-1049. Controlling Occupational Exposure to Hazardous Drugs. (OSHA WORK-PRACTICE GUIDELINES). Am J Health-Syst Pharm 1996; 53:1669-1685.