Dosage Forms
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)
Pharmacology
Mechanism of Action
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.
Pharmacokinetics/Pharmacodynamics
Distribution
Distributes to heart, liver, and kidneys; Vd: Children: 0.96 L/kg; Adults: 22 to 25 L/m2
Metabolism
Hydrolyzed by dihydropyrimidine aminohydrolase and dihydroorotase
Excretion
Urine (42%)
Half-Life Elimination
2.1 to 2.5 hours
Protein Binding
None
Use in Specific Populations
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.
Note: American Society of Clinical Oncology guidelines for prevention and monitoring of cardiac dysfunction in survivors of adult cancers (ASCO [Armenian 2017]) indicate that dexrazoxane may be considered to prevent cardiotoxicity in patients planning to receive high-dose anthracyclines (eg, doxorubicin ≥250 mg/m2 or epirubicin ≥600 mg/m2).
Extravasation of anthracyclines (Totect): Treatment of extravasation resulting from intravenous anthracycline chemotherapy.
Use: Off Label
Cardioprotectant for doxorubicin in malignancies other than breast canceryes
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.
American Society of Clinical Oncology guidelines for prevention and monitoring of cardiac dysfunction in survivors of adult cancers indicate that dexrazoxane may be considered to prevent cardiotoxicity in patients planning to receive high-dose anthracyclines (eg, doxorubicin ≥250 mg/m2 or epirubicin ≥600 mg/m2).
Cardioprotectant for epirubicin in advanced breast canceryes
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].
American Society of Clinical Oncology guidelines for prevention and monitoring of cardiac dysfunction in survivors of adult cancers indicate that dexrazoxane may be considered to prevent cardiotoxicity in patients planning to receive high-dose anthracyclines (eg, doxorubicin ≥250 mg/m2 or epirubicin ≥600 mg/m2).
Contraindications
Zinecard: Use with chemotherapy regimens that do not contain an anthracycline.
Canadian labeling: Additional contraindications (not in the US labeling): Known hypersensitivity to dexrazoxane or any component of the formulation; use as a chemotherapeutic agent
Totect: There are no contraindications listed in the manufacturer's labeling.
Dosage and Administration
Dosing: Adult
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: 2,000 mg/day), followed by 500 mg/m2 on day 3 (maximum dose: 1,000 mg/day); begin treatment as soon as possible, within 6 hours of extravasation
Dosing: Geriatric
Refer to adult dosing.
Dosing: Pediatric
Prevention of anthracycline cardiomyopathy associated with acute lymphoblastic leukemia (ALL): Limited data available: Infants, Children, and Adolescents: IV: A 10:1 dose ratio of dexrazoxane:doxorubicin (example: 300 mg/m2 dexrazoxane: 30 mg/m2 doxorubicin) (Lipshultz 2010; Moghrabi 2007; Silverman 2010). Note: Cardiac monitoring should continue during dexrazoxane therapy; anthracycline/dexrazoxane should be discontinued in patients who develop a decline in LVEF or clinical CHF.
Reconstitution
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:
Preparation using SWFI and LR: Reconstitute 500 mg vial with 50 mL of SWFI to a reconstituted concentration of 10 mg/mL. Prior to infusion, further dilute reconstituted dexrazoxane solution in LR 1,000 mL.
Preparation using 0.167 Molar sodium lactate and NS: 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.
Administration
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; withhold cooling beginning at least 15 minutes before dexrazoxane infusion and continue withholding cooling during infusion (Pérez Fidalgo 2012). Do not use DMSO in combination with dexrazoxane; may lessen efficacy.
Storage
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 30 minutes (must be further diluted within 30 minutes). Solutions diluted for infusion are stable for 4 hours at room temperature or 12 hours refrigerated (2°C to 8°C [36°F to 46°F]). Note: The stability of the reconstituted solution (10 mg/mL) was changed from 2 hours to 30 minutes in the November 2018 Totect prescribing information.
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).
Drug Interactions
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
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination
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. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification
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
Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
Adverse Reactions
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)
Anthracycline extravasation:
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%)
Warnings/Precautions
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. When used for management of anthracycline extravasation (with cytotoxic chemotherapy), the nadir has occurred at days 10 to 12. Neutropenic fever has been reported when used with cytotoxic chemotherapy for management of anthracycline extravasation. Monitor complete blood cell count.
- 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. The American Society of Clinical Oncology guidelines for prevention and monitoring of cardiac dysfunction in survivors of adult cancers indicate that dexrazoxane may be considered to prevent cardiotoxicity in patients planning to receive high-dose anthracyclines (eg, doxorubicin ≥250 mg/m2 or epirubicin ≥600 mg/m2) (ASCO [Armenian 2017]). When used as a cardioprotectant, the ASCO guidelines recommend screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking and an echocardiogram (prior to chemotherapy treatment). In patients who develop signs/symptoms of cardiac dysfunction during cancer therapy, an echocardiogram is recommended for diagnostic workup; if echocardiogram is not available or feasible, a cardiac MRI (preferred) or multigated acquisition (MUGA) scan may be utilized; obtain serum cardiac biomarkers.
- Hypersensitivity: Hypersensitivity reactions, including anaphylactic reactions, angioedema, skin reactions, bronchospasm, respiratory distress, hypotension, and loss of consciousness have been reported; consider permanent discontinuation in patients with severe hypersensitivity reactions. Use with caution. Carefully consider prior to use in patients with a previous allergy to dexrazoxane products.
- 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).
Disease-related concerns:
- Hepatic impairment: Due to dosage adjustments for doxorubicin in hepatic impairment, when used for prevention of cardiomyopathy, a proportional dose reduction in dexrazoxane is recommended to maintain the dosage ratio of 10:1. For anthracycline extravasation, monitor liver function tests prior to each dose; hepatic dysfunction (manifested as transaminase and bilirubin elevations) may occur, particularly with doses above 1,000 mg/m2; use in patients with hepatic impairment is not recommended.
- Renal impairment: Use with caution in patients with renal dysfunction (clearance is reduced); dosage adjustment required for CrCl <40 mL/minute. Monitor for signs of hematologic toxicity in patients with renal impairment.
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.
Other warnings/precautions:
- 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. Dexrazoxane is not effective against the effects of vesicants other than anthracyclines; if other vesicants (eg, vinca alkaloids, mitomycin) were also infused through the same extravasated IV access, consider extravasation management for those agents as well.
- 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).
Monitoring Parameters
CBC with differential (frequent); liver function tests prior to each dose (in patients with known liver function disorders); serum creatinine. Monitor site of extravasation (including after treatment and until resolution). Monitor for signs of hematologic toxicity in patients with renal impairment.
Cardiovascular monitoring (ASCO [Armenian 2017]) for adult patients receiving dexrazoxane as a cardioprotectant: Comprehensive assessment prior to chemotherapy, including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking; echocardiogram (prior to chemotherapy treatment). In patients who develop signs/symptoms of cardiac dysfunction during cancer therapy, an echocardiogram is recommended for diagnostic workup; if echocardiogram is not available or feasible, a cardiac MRI (preferred) or multigated acquisition (MUGA) scan may be utilized; obtain serum cardiac biomarkers.
Pregnancy
Pregnancy Considerations
Based on the mechanism of action and findings in animal reproduction studies, dexrazoxane may cause fetal harm if administered during pregnancy. Females of reproductive potential should use highly effective contraception to prevent pregnancy during treatment and for 6 months after the last dexrazoxane dose. Males with female partners of reproductive potential should use effective contraception during therapy and for 3 months after the last dexrazoxane dose.
Patient Education
What is this drug used for?
- It is used to lower the side effects of doxorubicin.
- It is used to treat tissue damage caused by some drugs if they leak from the vein while they are being given.
- It may be given to you for other reasons. Talk with the doctor.
Frequently reported side effects of this drug
- Nausea
- Vomiting
- Headache
- Constipation
- Abdominal pain
- Diarrhea
- Lack of appetite
- Trouble sleeping
- Injection site pain
- Mouth irritation
- Mouth sores
- Hair loss
Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:
- Infection
- Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; 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.
- Dizziness
- Passing out
- Shortness of breath
- Excessive weight gain
- Swelling of arms or legs
- Severe loss of strength and energy
- Burning or numbness feeling
- Depression
- Severe injection site irritation
- Signs of a significant reaction like 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. Talk to your doctor if you have questions.
Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.
