(deks ray ZOKS ane)
- Dexrazoxane HCl
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous:
Totect: 500 mg (1 ea) [pyrogen free]
Zinecard: 250 mg (1 ea); 500 mg (1 ea) [pyrogen free]
Generic: 250 mg (1 ea); 500 mg (1 ea)
Solution Reconstituted, Intravenous [preservative free]:
Generic: 250 mg (1 ea); 500 mg (1 ea)
Brand Names: U.S.
- Antidote, Extravasation
- Chemoprotective Agent
Dexrazoxane is a derivative of ethylenediaminetetraacetic acid (EDTA); a potent intracellular chelating agent. As a cardioprotectant, dexrazoxane appears to be converted intracellularly to a ring-opened chelating agent that interferes with iron-mediated oxygen free radical generation thought to be responsible, in part, for anthracycline-induced cardiomyopathy. In the management of anthracycline extravasation, dexrazoxane may act by reversibly inhibiting topoisomerase II, protecting tissue from anthracycline cytotoxicity, thereby decreasing tissue damage.
Distributes to heart, liver, and kidneys; Vd: Children: 0.96 L/kg; Adults: 22 to 25 L/m2
Hydrolyzed by dihydropyrimidine aminohydrolase and dihydroorotase
2.1 to 2.5 hours
Special Populations: Renal Function Impairment
Clearance is reduced in patients with renal function impairment. The mean AUC was 2-fold higher in patients with moderate (CrCl 30 to 50 mL/minute) to severe (CrCl <30 mL/minute) renal impairment.
Use: Labeled Indications
Prevention of cardiomyopathy associated with doxorubicin (Zinecard, generic products): To reduce 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 will benefit from continuing doxorubicin therapy to maintain tumor control. Not recommended for use with initial doxorubicin therapy.
Extravasation of anthracyclines (Totect): Treatment of extravasation resulting from intravenous anthracycline chemotherapy.
Off Label Uses
Cardioprotectant for doxorubicin in malignancies other than breast cancer
Based on the American Society of Clinical Oncology guidelines for the use of chemotherapy and radiotherapy protectants, dexrazoxane may be considered as a cardioprotectant in adults who have received more than 300 mg/m2 of doxorubicin for the treatment of malignancies other than breast cancer.
Cardioprotectant for epirubicin in advanced breast cancer
Based on the American Society of Clinical Oncology guidelines for the use of chemotherapy and radiotherapy protectants, dexrazoxane may be considered as a cardioprotectant for anthracyclines other than doxorubicin (epirubicin) when continued therapy is clinically indicated [ASCO [Hensley 2008]], [ASCO [Schuchter 2002]].
Cardioprotectant for doxorubicin in acute lymphoblastic leukemia (ALL) treatment (children)
Long-term follow data from a randomized controlled study and follow up on ALL protocols support the use of dexrazoxane as a cardioprotectant for in children with ALL receiving doxorubicin [Lipshultz 2010], [Moghrabi 2007], [Silverman 2010].
US labeling: Use with chemotherapy regimens that do not contain an anthracycline
Canadian labeling: Hypersensitivity to dexrazoxane or any component of the formulation; use with chemotherapy regimens that do not contain an anthracycline; use as a chemotherapeutic agent
Totect: There are no contraindications listed in the manufacturer's labeling.
Prevention of doxorubicin cardiomyopathy: IV: A 10:1 ratio of dexrazoxane:doxorubicin (dexrazoxane 500 mg/m2:doxorubicin 50 mg/m2). Note: Cardiac monitoring should continue during dexrazoxane therapy; doxorubicin/dexrazoxane should be discontinued in patients who develop a decline in LVEF or clinical CHF.
Treatment of anthracycline extravasation: IV: 1000 mg/m2 on days 1 and 2 (maximum dose: 2000 mg), followed by 500 mg/m2 on day 3 (maximum dose: 1000 mg); begin treatment as soon as possible, within 6 hours of extravasation
Refer to adult dosing.
Prevention of doxorubicin cardiomyopathy associated with acute lymphoblastic leukemia treatment (high-risk patients; off-label use): IV: A 10:1 ratio of dexrazoxane:doxorubicin (eg, dexrazoxane 300 mg/m2:doxorubicin 30 mg/m2) was used in patients with high-risk acute lymphoblastic leukemia; dexrazoxane is administered immediately prior to the doxorubicin dose (Lipshultz 2010; Moghrabi 2007; Silverman 2010)
Dosing: Renal Impairment
Note: Renal function may be estimated using the Cockcroft-Gault formula.
Mild (CrCl ≥40 mL/minute) impairment: No dosage adjustment necessary.
Moderate-to-severe (CrCl <40 mL/minute) impairment:
Prevention of cardiomyopathy: Reduce dose to 50% of the usual dose, using a 5:1 dexrazoxane:doxorubicin ratio (eg, dexrazoxane 250 mg/m2:doxorubicin 50 mg/m2)
Anthracycline extravasation: Reduce dose to 50% of the usual dose
Dosing: Hepatic Impairment
Prevention of cardiomyopathy: Since doxorubicin dosage is reduced in hyperbilirubinemia, a proportional reduction in dexrazoxane dosage is recommended (maintain a 10:1 ratio of dexrazoxane:doxorubicin)
Anthracycline extravasation: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Note: Preparation and storage are product specific; refer to individual product labeling for further details. Discard unused solutions. Do not mix in the same container with other medications.
Totect: Reconstitute 500 mg vial with 50 mL of 0.167 Molar sodium lactate injection solution to a reconstituted concentration of 10 mg/mL. To prepare the diluent, add 1.67 mL of 5 mEq/mL sodium lactate injection to 50 mL SWFI to make 50 mL of 0.167 Molar sodium lactate injection. Prior to infusion, further dilute reconstituted dexrazoxane solution in NS 1,000 mL.
Zinecard: Reconstitute vial with sterile water for injection to a reconstituted concentration of dexrazoxane 10 mg/mL. Prior to infusion, further dilute reconstituted dexrazoxane solution in LR injection to a final concentration of 1.3 to 3 mg/mL.
Dexrazoxane generic formulation (Mylan): Reconstitute with the supplied diluent (0.167 Molar sodium lactate injection) to a reconstituted concentration of 10 mg/mL. Prior to infusion, further dilute reconstituted dexrazoxane solution with D5W or NS to a final concentration of 1.3 to 5 mg/mL.
IV: Prevention of doxorubicin cardiomyopathy: Administer doxorubicin within 30 minutes after completion of the dexrazoxane infusion (do not administer doxorubicin before dexrazoxane).
Zinecard: Administer by rapid drip infusion over 15 minutes; do not administer by IV push
Dexrazoxane generic formulation (Mylan): Administer by slow IV push or rapid drip infusion
Treatment of anthracycline extravasation: Stop vesicant infusion immediately and disconnect IV line (leave needle/cannula in place); gently aspirate extravasated solution from the IV line (do NOT flush the line); remove needle/cannula; elevate extremity. Administer dexrazoxane IV over 1 to 2 hours; begin infusion as soon as possible, within 6 hours of extravasation. Day 2 and 3 doses should be administered at approximately the same time (± 3 hours) as the dose on day 1. Infusion solution should be at room temperature prior to administration. Infuse in a large vein in an area remote from the extravasation. For IV administration only; not for local infiltration into extravasation.
Apply dry cold compresses for 20 minutes 4 times daily for 1 to 2 days (Pérez Fidalgo 2012); withhold cooling beginning 15 minutes before dexrazoxane infusion; continue withholding cooling until 15 minutes after infusion is completed. Do not use DMSO in combination with dexrazoxane; may lessen efficacy.
Note: Preparation and storage are product specific; refer to individual product labeling for further details. Discard unused solutions.
Totect: Store intact vials at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light. Reconstituted solution (10 mg/mL) is stable for 2 hours (must be further diluted within 2 hours). Solutions diluted for infusion in NS are stable for 4 hours when stored at <25°C (77°F).
Zinecard: Store intact vials at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). When reconstituted with SWFI, the reconstituted solution is stable for 30 minutes at room temperature or 3 hours refrigerated at 2°C to 8°C (36°F to 46°F). Solutions diluted for infusion in LR are stable for 1 hour when stored at room temperature or 4 hours refrigerated.
Dexrazoxane generic formulation (Mylan): Store intact vials at 20°C to 25°C (68°F to 77°F). Reconstituted solutions and solutions diluted for infusion in NS or D5W are stable for 6 hours when stored at room temperature or refrigerated at 2°C to 8°C (36°F to 46°F).
Additional stability information: When studied as a 24-hour continuous infusion for the prevention of cardiomyopathy, solutions prepared with sodium lactate diluent and diluted to a final concentration of 0.1 or 0.5 mg/mL in D5W were found to retain ≥90% of their initial concentration when stored at room temperature (ambient light conditions) for ≤24 hours (Tetef, 2001).
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination
Dimethyl Sulfoxide: May diminish the therapeutic effect of Dexrazoxane. Avoid combination
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination
DOXOrubicin (Conventional): Dexrazoxane may diminish the therapeutic effect of DOXOrubicin (Conventional). Management: Do not administer dexrazoxane for cardioprotection at the time of doxorubicin initiation. This recommendation does not apply to the use of dexrazoxane for other indications (e.g., extravasation), or to the use of dexrazoxane later in treatment. Consider therapy modification
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
Note: Most adverse reactions are thought to be attributed to chemotherapy, except for increased myelosuppression, pain at injection site, and phlebitis.
Prevention of doxorubicin cardiomyopathy (reactions listed are those which were greater in the dexrazoxane arm in a comparison of chemotherapy plus dexrazoxane vs chemotherapy alone):
Cardiovascular: Phlebitis (6%)
Central nervous system: Fatigue (61%), neurotoxicity (17%)
Dermatologic: Erythema (5%)
Hematologic & oncologic: Bone marrow depression, granulocytopenia, leukopenia, thrombocytopenia
Infection: Infection (23%), sepsis (17%)
Local: Pain at injection site pain (12%)
Miscellaneous: Fever (34%)
Postmarketing, and/or case reports: Metastases (including acute myeloid leukemia, myelodysplastic syndrome)
Cardiovascular: Peripheral edema (10%), localized phlebitis (6%)
Central nervous system: Fatigue (13%), dizziness (11%), depression (8%), headache (6%), insomnia (5%)
Dermatologic: Alopecia (14%)
Endocrine & metabolic: Hypercalcemia (7%), hyponatremia (6%), increased lactate dehydrogenase (5%)
Gastrointestinal: Nausea (43%), vomiting (19%), diarrhea (11%), abdominal pain (6%), constipation (6%), anorexia (5%)
Hematologic & oncologic: Decreased white blood cell count (73%; grade 3: 25%; grade 4: 20%), decreased neutrophils (61%; grade 3: 22%; grade 4: 24%), decreased hemoglobin (43%; grade 3: 3%), anemia (6%), febrile neutropenia (3%), neutropenia (3%), leukopenia, thrombocytopenia
Hepatic: Increased serum AST (28%), increased serum ALT (22%), increased serum bilirubin (11%), increased serum alkaline phosphatase (4%)
Infection: Postoperative infection (16%)
Local: Pain at injection site (16%)
Renal: Increased serum creatinine (14%)
Respiratory: Dyspnea (8%), pneumonia (6%), cough (5%)
Miscellaneous: Fever (21%)
Concerns related to adverse effects:
• Bone marrow suppression: Dexrazoxane may cause mild myelosuppression (leukopenia, neutropenia, and thrombocytopenia); myelosuppression may be additive with concurrently administered chemotherapeutic agents.
• Cardioprotection: Dexrazoxane does not eliminate the potential for anthracycline-induced cardiac toxicity; carefully monitor cardiac function (left ventricular ejection fraction [LVEF]) prior to and periodically during treatment.
• Secondary malignancies: Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have been reported in pediatric patients and some adult patients receiving dexrazoxane in combination with chemotherapy.
• Tumor response: Dexrazoxane may interfere with the antitumor effect of chemotherapy when given concurrently with fluorouracil, doxorubicin, and cyclophosphamide (FAC).
• Hepatic impairment: Due to dosage adjustments for doxorubicin in hepatic impairment, a proportional dose reduction in dexrazoxane is recommended to maintain the dosage ratio of 10:1.
• Renal impairment: Use with caution in patients with renal dysfunction (clearance is reduced); dosage adjustment required for CrCl <40 mL/minute.
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Administration (extravasation): For IV administration; not for local infiltration into extravasation site. Do not use DMSO in patients receiving dexrazoxane for anthracycline extravasation; may diminish dexrazoxane efficacy.
• Administration sequence (cardioprotection): When used for the prevention of cardiomyopathy, doxorubicin should be administered within 30 minutes after completion of the dexrazoxane infusion (do not administer doxorubicin before dexrazoxane).
CBC with differential (frequent); liver function; serum creatinine; cardiac function (repeat monitoring at 400 mg/m2, 500 mg/m2 and with every 50 mg/m2 of doxorubicin thereafter); monitor site of extravasation
Pregnancy Risk Factor
Adverse events were observed in animal reproduction studies using doses less than the equivalent human dose (based on BSA). Based on the mechanism of action, dexrazoxane may cause fetal harm if administered during pregnancy. Women of reproductive potential should use highly effective contraception to prevent pregnancy during treatment.
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience nausea, vomiting, headache, dizziness, constipation, abdominal pain, diarrhea, lack of appetite, insomnia, injection site pain, mouth irritation, mouth sores, or hair loss. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding); shortness of breath; excessive weight gain; swelling of arms or legs; severe loss of strength and energy; burning or numbness feeling; depression; or severe injection site irritation (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.
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