Dexrazoxane

Pronunciation: dex-ray-ZOX-ane
Class: Cytoprotective agent

Trade Names

Totect
- Injection, lyophilized powder for solution 500 mg

Zinecard
- Injection, lyophilized powder for solution 250 mg (10 mg/mL reconstituted)
- Injection, lyophilized powder for solution 500 mg (10 mg/mL reconstituted)

Pharmacology

Dexrazoxane is a potent intracellular chelating agent. The mechanism by which dexrazoxane exerts its cardioprotective activity is not fully understood.

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Pharmacokinetics

Absorption

C _max is 36.5 mcg/mL (at end of infusion).

Distribution

Vd approximately 22 L/m ² . Not bound to plasma proteins.

Metabolism

Metabolized to a diacid-diamide cleavage product and 2 monoacid-monoamide ring products.

Elimination

Elimination t _½ is 2.1 to 2.5 h. Plasma Cl is 6.25 to 7.88 L/h/m ² . Renal Cl is 3.35 L/h/m ² ; 42% excreted in urine.

Special Populations

Renal Function Impairment

Cl is reduced in patients with renal function impairment.

Hepatic Function Impairment

Pharmacokinetics have not been evaluated.

Elderly

No pharmacokinetic differences have been observed in patients 65 yr of age and older with healthy renal function compared with younger patients.

Children

Pharmacokinetics have not been evaluated.

Gender

Pharmacokinetics not affected by gender.

Indications and Usage

Totect

Treatment of extravasation resulting from IV anthracycline chemotherapy.

Zinecard

Reduce incidence and severity of cardiomyopathy in women with breast cancer patients who have received a cumulative doxorubicin dose of 300 mg/m ² and who may benefit from additional doxorubicin therapy. It is not recommended for use with the initiation of doxorubicin therapy.

Unlabeled Uses

Cardioprotectant for other anthracyclines.

Contraindications

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Standard considerations.

Zinecard

Do not use with chemotherapy regimens that do not contain an anthracycline.

Dosage and Administration

Cardiomyopathy
Adults

IV The recommended IV dosage ratio of dexrazoxane:doxorubicin is 10:1 (eg, dexrazoxane 500 mg/m ² would be given with doxorubicin 50 mg/m ² ). In patients with moderate to severe renal function impairment (CrCl less than 40 mL/min), the recommended dosage ratio is 5:1. Doxorubicin must be administered within 30 min after starting the dexrazoxane infusion.

Extravasation
Adults

IV Once daily for 3 consecutive days with the first dose administered as soon as possible and within 6 h after extravasation. Day 1: 1,000 mg/m ² (max, 2,000 mg). Day 2: 1,000 mg/m ² (max, 2,000 mg). Day 3: 500 mg/m ² (max, 1,000 mg). Reduce the dose by 50% in patients with CrCl less than 40 mL/min.

General Advice

• Totect
• Administer IV infusion over 1 to 2 h.
• Administer in a large caliber vein in an extremity other than the one affected by extravasation.
• Cooling procedures (eg, ice packs) should be removed from the area at least 15 min before administration to allow blood flow to the extravasation area.
• Start treatment on days 2 and 3 at the same hour as on day one.
• Do not mix with any other drug.

• Zinecard
• Only for use in combination with chemotherapy regimens containing anthracyclines.
• For IV administration only.
• Follow institutional procedures for handling, administration, and disposal of anticancer drugs. Use caution in preparing and handling the reconstituted solution; use of gloves is recommended. If dexrazoxane powder or solution contact the skin or mucosa, immediately wash exposed area with soap and water.
• Reconstitute powder for injection using the provided sodium lactate solution to give a dexrazoxane concentration of 10 mg/mL. This solution may be administered without further dilution or further diluted with dextrose 5% injection or sodium chloride 0.9% injection to provide a final dexrazoxane concentration of 1.3 to 5 mg/mL.
• Do not administer if cloudiness or particulate matter is noted.
• Administer prescribed dose by slow IV push or rapid IV infusion.

Storage/Stability

Store powder for injection at controlled room temperature (59° to 86°F). Reconstituted and diluted solutions are stable for 6 h at controlled room temperature or under refrigeration (36° to 46°F). Discard any unused solution.

Totect

Store unreconstituted vials at 59° to 86°F. Protect vials from light. Reconstituted product should be used immediately after mixing. The reconstituted product may be stored below 77°F for 4 h after mixing and diluting.

Drug Interactions

Fluorouracil, doxorubicin, and cyclophosphamide (FAC) regimen

Dexrazoxane may interfere with the antitumor efficacy of this regimen. Coadministration is not recommended.

Dimethylsulfoxide

Do not use with dexrazoxane to treat anthracycline-induced extravasation.

Other chemotherapeutic agents

May increase the myelosuppressive effects of other chemotherapeutic agents.

Incompatibility

Do not mix with other drugs.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Adverse reaction percentages reflect the use of dexrazoxane for the treatment of extravasation. The frequency of adverse reactions when dexrazoxane is used for the treatment of breast cancer is likely to be attributable to coadministration of doxorubicin or another concurrent regimen.

Cardiovascular

Vascular disorder (15%).

CNS

Pyrexia (21%); fatigue (13%); dizziness (11%); depression (8%); headache (6%); insomnia (5%); neurotoxicity.

Dermatologic

Alopecia (14%); recall skin reaction, streaking/erythema; urticaria.

GI

Nausea (43%); vomiting (19%); diarrhea (11%); abdominal pain, constipation (6%); anorexia (5%); dysphagia, esophagitis, stomatitis.

Hematologic-Lymphatic

Anemia (6%); neutropenia, thrombocytopenia.

Lab Tests

Decreased WBC (73%); decreased neutrophils (61%); decreased hemoglobin (43%); increased AST (28%); decreased platelets (26%); increased ALT (22%); increased creatinine (14%); increased bilirubin (11%); increased total calcium (7%); decreased sodium (6%); increased LDH (5%), increased alkaline phosphatase (4%).

Local

Injection-site pain (16%); phlebitis (6%); extravasation.

Metabolic-Nutritional

Anorexia (5%).

Musculoskeletal

Musculoskeletal and connective tissue disorders (13%).

Respiratory

Dyspnea (8%); pneumonia (6%); cough (5%).

Miscellaneous

Postoperative infection (16%); peripheral edema (10%); fever, hemorrhage, sepsis.

Precautions

Monitor Ensure that CBC with differential is evaluated before starting therapy and frequently during treatment. Monitor patient for signs or symptoms of infection or bleeding.

Pregnancy

Zinecard

Category C .

Totect

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Renal Function

Cl is reduced in patients with renal function impairment. Dosage adjustments may be necessary.

Hepatic Function

Dose reduction is recommended.

Carcinogenesis

Secondary malignancies (primarily acute myeloid leukemia) have been reported in patients treated chronically with razoxane.

Fertility

Testicular atrophy in animals.

Anthracycline-induced cardiac toxicity

Carefully monitor cardiac function.

Antitumor interference

The use of dexrazoxane concurrently with the initiation of fluorouracil, doxorubicin, cyclosporine (FAC) therapy may interfere with the antitumor efficacy of the regimen; this use is not recommended.

Extravasation risk

Local irritation or phlebitis may occur. Refer to institution-specific protocol.

Overdosage

Symptoms

No data on overdosage.

Patient Information

• Advise patient, family, or caregiver that medication will be prepared and administered by health care provider in a health care setting.
• Review dosing schedule with patient, family, or caregiver.
• Advise patient, family, or caregiver to immediately report any of the following to health care provider: fever, chills, or other signs of infection; flushing; hives; rash; sores in mouth; unusual bleeding or bruising.
• Advise patient, family, or caregiver to report any of the following to health care provider: pain, redness, or swelling at injection site; persistent nausea, vomiting, diarrhea, or appetite loss; persistent or worsening general body weakness; streaking or redness of skin.
• Advise women of childbearing potential that dexrazoxane may cause fetal harm.

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