Dexrazoxane is a cytoprotective agent. It is used 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 who will continue to receive doxorubicin therapy to maintain tumor control. It is also used for the treatment of extravasation resulting from intravenous anthracycline chemotherapy. Dexrazoxane may increase the myelosuppressive effects of chemotherapeutic agents; hematologic monitoring is recommended when dexrazoxane is used as a cytoprotective agent for cardiomyopathy.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 2
-NIOSH (Draft) 2020 List: Table 1
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
-Wash the area immediately with soap and water if dexrazoxane powder or solution contacts the skin or mucosa.
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Dexrazoxane is available as a 250-mg or 500-mg lyophilized powder vial from multiple manufacturers.
-Recommended vial diluent, dilution solutions, and storage following reconstitution and dilution differ among products; refer to the manufacturer package insert for specific instructions.
-All dexrazoxane products are indicated for use as a cardioprotective agent; however, only the Totect product is indicated for the treatment of extravasation.
-Do not mix dexrazoxane with other drugs.
Reconstitution:
-Add 25 mL of diluent to the 250-mg lyophilized powder vial or 50 mL of diluent to the 500-mg lyophilized powder vial for a final concentration of 10 mg/mL.
-Storage following reconstitution: Recommended storage times depend on the product used.
Dilution:
-Withdraw the appropriate dose from the reconstituted vial and further dilute to a final admixture concentration between 1.3 to 3 mg/mL (or 1.3 to 5 mg/mL for the Mylan generic product only).
-When using the Totect product for treatment of extravasation, add the calculated dose to 1,000 mL of Lactated Ringer's injection.
-Storage following dilution: Recommended storage times depend on the product used.
Intravenous (IV) infusion
Extravasation Treatment (Totect only)
-Initiate dexrazoxane as soon as possible and within the first 6 hours after extravasation.
-Remove cooling devices (e.g., ice packs) from the extravasation area at least 15 minutes before dexrazoxane administration.
-Administer as an IV infusion over 1 to 2 hours in a large caliber vein in an extremity/area other than the one affected by the extravasation.
-Infusions on days 2 and 3 should start at the same hour (or within 3 hours) as on the first day.
-Regularly monitor the extravasation site after treatment and until resolution.
Cytoprotective Agent Use
-Administer as an IV infusion over 15 minutes.
-Give the doxorubicin dose within 30 minutes after the dexrazoxane infusion ends.
-Only the Mylan generic product may be given as an IV push or rapid IV infusion.
-All other products should NOT be administered as an IV push.
In pooled results from 2 clinical studies (n = 80), musculoskeletal adverse events (13%) and vascular disorders (15%) occurred in patients who received dexrazoxane for the treatment of extravasation following single-agent IV anthracycline therapy.
Phlebitis (6% vs. 3%), injection site reaction/pain (12% vs. 3%), and streaking/erythema (5% vs. 4%) were reported more often in patients with metastatic breast cancer who received 6 cycles of fluorouracil, doxorubicin, and cyclophosphamide (FAC regimen) plus chemoprotection with dexrazoxane (n = 413) compared with FAC plus placebo (n = 458) in a randomized trial. Extravasation (3% vs. 2%), injection site pain (13% vs. 0%), and streaking/erythema (4% vs. 2%) occurred more often in patients who received FAC plus dexrazoxane (n = 102) compared with FAC plus placebo (n = 99) beyond 6 cycles of therapy. In pooled results from 2 clinical studies (n = 80), injection site pain/discomfort (16%) and injection site phlebitis (6%) occurred in patients who received dexrazoxane for the treatment of extravasation following single-agent IV anthracycline therapy in pooled results from 2 clinical studies (n = 80).
New primary malignancy including acute myelogenous leukemia and myelodysplastic syndrome has been reported in patients who received dexrazoxane in combination with other chemotherapy agents know to be carcinogenic.
Fatigue/malaise was reported more often in 413 patients with metastatic breast cancer who received 6 cycles of fluorouracil, doxorubicin, and cyclophosphamide (FAC regimen) plus chemoprotection with dexrazoxane (61%) compared with 458 patients who received FAC plus placebo (58%) in a randomized trial. In pooled results from 2 clinical studies (n = 80), fatigue occurred in 13% of patients who received dexrazoxane for the treatment of extravasation following single-agent IV anthracycline therapy.
Diarrhea occurred more often in 102 patients with metastatic breast cancer who received fluorouracil, doxorubicin, and cyclophosphamide (FAC regimen) plus chemoprotection with dexrazoxane (14%) compared with 99 patients who received FAC plus placebo (7%) beyond 6 cycles of therapy in a randomized trial. In pooled results from 2 clinical studies (n = 80), gastrointestinal adverse events (55%) including nausea (43%), vomiting (19%), diarrhea (11%), abdominal pain (6%), and constipation (6%) occurred in patients who received dexrazoxane for the treatment of extravasation following single-agent IV anthracycline therapy.
Fever was reported more often in 413 patients with metastatic breast cancer who received 6 cycles of fluorouracil, doxorubicin, and cyclophosphamide (FAC regimen) plus chemoprotection with dexrazoxane (34%) compared with 458 patients who received FAC plus placebo (29%) in a randomized trial. Fever also occurred more often in 102 patients who received FAC plus dexrazoxane (22%) compared with 99 patients who received FAC plus placebo (18%) beyond 6 cycles of therapy. In pooled results from 2 clinical studies (n = 80), fever occurred in 21% of patients who received dexrazoxane for the treatment of extravasation following single-agent IV anthracycline therapy.
Neurotoxicity was reported more often in 413 patients with metastatic breast cancer who received 6 cycles of fluorouracil, doxorubicin, and cyclophosphamide (FAC regimen) plus chemoprotection with dexrazoxane (17%) compared with 458 patients who received FAC plus placebo (13%) in a randomized trial. Neurotoxicity also occurred more often in 102 patients who received FAC plus dexrazoxane (10%) compared with 99 patients who received FAC plus placebo (5%) beyond 6 cycles of therapy. In pooled results from 2 clinical studies (n = 80), nervous system disorders (24%) including dizziness (11%) and headache (6%) occurred in patients who received dexrazoxane for the treatment of extravasation following single-agent IV anthracycline therapy.
Bleeding occurred more often in 102 patients with metastatic breast cancer who received fluorouracil, doxorubicin, and cyclophosphamide (FAC regimen) plus chemoprotection with dexrazoxane (3%) compared with 99 patients who received FAC plus placebo (1%) beyond 6 cycles of therapy in a randomized trial.
Infection (23% vs. 18%) including sepsis (17% vs. 14%) occurred more often in patients with metastatic breast cancer who received 6 cycles of fluorouracil, doxorubicin, and cyclophosphamide (FAC regimen) plus chemoprotection with dexrazoxane (n = 413) compared with FAC plus placebo (n = 458) in a randomized trial. Sepsis was reported more often in 102 patients who received FAC plus dexrazoxane (12%) compared with 99 patients who received FAC plus placebo (9%) beyond 6 cycles of therapy. In pooled results from 2 clinical studies (n = 80), infection (30%) including postoperative infection (16%) occurred in patients who received dexrazoxane for the treatment of extravasation following single-agent IV anthracycline therapy.
Alopecia (100% vs. 98%), urticaria (2% vs. 0%), and radiation recall reaction (1% vs. 0%) occurred more often in patients with metastatic breast cancer who received fluorouracil, doxorubicin, and cyclophosphamide (FAC regimen) plus chemoprotection with dexrazoxane (n = 102) compared with FAC plus placebo (n = 99) beyond 6 cycles of therapy. In pooled results from 2 clinical studies (n = 80), skin adverse events (18%) including alopecia (14%) occurred in patients who received dexrazoxane for the treatment of extravasation following single-agent IV anthracycline therapy.
Hematologic toxicity has been reported with dexrazoxane therapy; myelosuppression may be additive with cytotoxic chemotherapy. Obtain complete blood counts prior to each course of therapy when dexrazoxane is used as a chemoprotective agent; do not administer dexrazoxane until adequate hematologic parameters are met. In pooled results from 2 clinical studies (n = 80), hematologic toxicity including anemia (6%), decreased white blood cell count/leukopenia (grade 2, 18%; grade 3 or 4, 55%), decreased neutrophil count/neutropenia (grade 2, 15%; grade 3 or 4, 46%), decreased platelet count/thrombocytopenia (grade 2, 5%; grade 3, 21%), and febrile neutropenia (2.5%) occurred in patients who received dexrazoxane for the treatment of extravasation following single-agent IV anthracycline therapy.
In pooled results from 2 clinical studies (n = 80), peripheral edema occurred in 10% of patients who received dexrazoxane for the treatment of extravasation following single-agent IV anthracycline therapy.
In pooled results from 2 clinical studies (n = 80), respiratory adverse events (16%) including dyspnea (8%), pneumonia (6%), and cough (5%) occurred in patients who received dexrazoxane for the treatment of extravasation following single-agent IV anthracycline therapy.
In pooled results from 2 clinical studies (n = 80), psychiatric adverse events (14%) including depression (8%) and insomnia (5%) occurred in patients who received dexrazoxane for the treatment of extravasation following single-agent IV anthracycline therapy.
In pooled results from 2 clinical studies (n = 80), metabolic adverse events (10%) including anorexia (5%) occurred in patients who received dexrazoxane for the treatment of extravasation following single-agent IV anthracycline therapy.
Monitor cardiac function before and periodically during therapy to assess left ventricular ejection fraction in patients receiving dexrazoxane as a cardioprotectant. If deterioration in cardiac function associated with doxorubicin is noted, re-evaluate the benefit of continued dexrazoxane therapy. In pooled results from 2 clinical studies (n = 80), cardiotoxicity occurred in 5% of patients who received dexrazoxane for the treatment of extravasation following single-agent IV anthracycline therapy.
In pooled results from 2 clinical studies (n = 80), decreased sodium level/hyponatremia (grade 3 or 4, 6%) and increased total calcium level/hypercalcemia (grade 2, 3%; grade 3 or 4, 4%) occurred in patients who received dexrazoxane for the treatment of extravasation following single-agent IV anthracycline therapy.
Dexrazoxane exposure may be increased in patients with renal dysfunction. An initial dose adjustment is recommended in patients with a creatinine clearance less than 40 mL/min. In pooled results from 2 clinical studies (n = 80), nephrotoxicity/increased serum creatinine level (grade 2, 10%; grade 3 or 4, 4%) occurred in patients who received dexrazoxane for the treatment of extravasation following single-agent IV anthracycline therapy.
Hepatotoxicity including elevated hepatic enzymes may occur with dexrazoxane therapy, particularly with doses greater than 1,000 mg/m2. Monitor liver function tests prior to the dexrazoxane dose in patients with known liver disorders. Dexrazoxane is not recommended for the treatment of extravasation in patients with hepatic impairment. In pooled results from 2 clinical studies (n = 80), increased bilirubin level/hyperbilirubinemia (grade 2, 9%; grade 3, 2%), increased AST level (grade 2, 26%; grade 3 or 4, 2%), increased ALT level (grade 2, 16%; grade 3 or 4, 6%), increased alkaline phosphatase level (grade 3 or 4, 4%), and increased LDH level (grade 3 or 4, 5%) occurred in patients who received dexrazoxane for the treatment of extravasation following single-agent IV anthracycline therapy.
Hypersensitivity reactions including anaphylactoid reactions, angioedema, skin reactions, bronchospasm, respiratory distress, hypotension, and loss of consciousness have been reported in patients who received dexrazoxane and anthracycline agents. Consider permanent discontinuation of dexrazoxane therapy in patients who develop a severe hypersensitivity reaction.
Use dexrazoxane with caution in patients with renal impairment. An initial dose adjustment is recommended in patients with a creatinine clearance less than 40 mL/min. Because dexrazoxane exposure may be increased in patients with renal dysfunction, monitor these patients for signs of hematological toxicity.
Hematologic toxicity (e.g., leukopenia, neutropenia, and thrombocytopenia) has been reported with dexrazoxane therapy; myelosuppression may be additive with cytotoxic chemotherapy. Obtain complete blood counts prior to each course of therapy when dexrazoxane is used as a chemoprotective agent; do not administer dexrazoxane until adequate hematologic parameters are met.
Dexrazoxane is not recommended for the treatment of extravasation in patients with hepatic disease/impairment. Hepatotoxicity may occur, particularly with doses greater than 1,000 mg/m2. When using dexrazoxane to treat extravasation, monitor liver function tests prior to each dose in patients with known liver disorders. When using dexrazoxane as a chemoprotective agent, reduce the dose if the doxorubicin dose is reduced due to hepatic impairment (e.g., hyperbilirubinemia); maintain the 10:1 dose ratio of dexrazoxane to doxorubicin.
Dexrazoxane may cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies. Advise females of reproductive potential to avoid pregnancy while taking dexrazoxane. Discuss the potential hazard to the fetus if dexrazoxane is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicities including imperforate anus, microphthalmia, and anophthalmia in rats and short tail, rib, and thoracic malformations; subcutaneous, eye, and cardiac hemorrhagic areas; and agenesis of the gallbladder and of the intermediate lobe of the lung in rabbits were observed when pregnant animals received dexrazoxane at doses that were 0.1- and 0.2-times doses used in humans.
Counsel patients about the reproductive risk and contraception requirements during dexrazoxane treatment. Females of reproductive potential should avoid pregnancy and use effective contraception during and for 6 months after treatment with dexrazoxane. Due to male-mediated teratogenicity, men with female partners of reproductive potential should avoid fathering a child and use effective contraception during therapy and for 3 months following the final dose of dexrazoxane. Based on data from animal studies, infertility may occur in male patients who receive dexrazoxane.
It is not known if dexrazoxane is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during dexrazoxane therapy and for 2 weeks after the last dose.
For anthracycline-induced cardiomyopathy prophylaxis:
NOTE: Dexrazoxane has been designated an orphan drug by the FDA for the prevention of cardiomyopathy associated with doxorubicin administration.
-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 who will continue to receive doxorubicin therapy to maintain tumor control:
Intravenous Dosage:
Adults: Calculate the dose as a 10:1 ratio to doxorubicin (e.g., 500 mg/m2 dexrazoxane to 50 mg/m2 doxorubicin); administer as an IV infusion over 15 minutes. Give doxorubicin within 30 minutes after the completion of the dexrazoxane dose.
-for patients receiving epirubicin chemotherapy*:
Intravenous Dosage:
Adults: Dexrazoxane IV in a 10:1 ratio to epirubicin (e.g., 1,000 mg/m2 dexrazoxane to 100 mg/m2 epirubicin) has been suggested. In a randomized trial, dexrazoxane, given in a ratio of 10:1 to epirubicin, protected against epirubicin-induced cardiac toxicity. In this trial, dexrazoxane did not affect the non-cardiac toxicity or clinical efficacy of epirubicin. There is no evidence supporting the optimal epirubicin dose at which dexrazoxane should be instituted. The National Cancer Institute of Canada recommends the institution of dexrazoxane when the cumulative dose of epirubicin reaches 550 mg/m2.
For the treatment of extravasation resulting from IV anthracycline chemotherapy:
Intravenous Dosage (Totect):
Adults: 1,000 mg/m2 IV (maximum dose of 2,000 mg) on days 1 and 2 and then dexrazoxane 500 mg/m2 IV (maximum dose of 1,000 mg) on day 3; administer IV over 1 to 2 hours via a large caliber vein in an extremity/area other than the one affected by the extravasation. Begin the first infusion as soon as possible and within the 6 hours after extravasation. Infusions on days 2 and 3 should start at the same hour (or within 3 hours) as on the first day. Regularly monitor the extravasation site after treatment and until resolution.
Maximum Dosage Limits:
-Adults
Maximum dose as a cytoprotective agent is dependent on the doxorubicin dose; Maximum dose as extravasation treatment is 1,000 mg/m2 (up to 2,000 mg).
-Geriatric
Maximum dose as a cytoprotective agent is dependent on the doxorubicin dose; Maximum dose as extravasation treatment is 1,000 mg/m2 (up to 2,000 mg).
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Cytoprotective Agent Use
If the doxorubicin dosage is reduced due to hepatic impairment (e.g., hyperbilirubinemia), the dexrazoxane dose should be proportionally reduced (maintaining the 10:1 ratio).
Extravasation Treatment
Dexrazoxane use in patients with hepatic impairment is not recommended.
Patients with Renal Impairment Dosing
Creatinine Clearance (CrCl) of 40 mL/min or higher: No dexrazoxane dosage adjustment is required.
CrCl less than 40 mL/min: Decrease the dexrazoxane dose by 50%.
*non-FDA-approved indication
Doxorubicin Liposomal: (Moderate) Dexrazoxane is a cardioprotectant administered prior to doxorubicin-containing chemotherapy regimens 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. Monitor blood counts if these agents are used together; additive myelosuppression may occur. Do not use dexrazoxane as a cardioprotectant when doxorubicin therapy is first begun; significantly lower tumor response rates and a shorter time to disease progression were reported in women with metastatic breast cancer who received dexrazoxane at the start of doxorubicin therapy in a randomized trial.
Doxorubicin: (Moderate) Dexrazoxane is a cardioprotectant administered prior to doxorubicin-containing chemotherapy regimens 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. Monitor blood counts if these agents are used together; additive myelosuppression may occur. Do not use dexrazoxane as a cardioprotectant when doxorubicin therapy is first begun; significantly lower tumor response rates and a shorter time to disease progression were reported in women with metastatic breast cancer who received dexrazoxane at the start of doxorubicin therapy in a randomized trial.
Dexrazoxane acts as an intracellular heavy metal chelator and protects against anthracycline-induced free radical damage to the myocardium. Dexrazoxane rapidly enters cardiac cells and is immediately hydrolyzed to a compound with metal chelating properties, similar to EDTA. In cardiac tissues, anthracyclines are reduced to an anthracycline free radical which is rapidly oxidized to form the original drug and superoxide anions. Normally, these superoxide radicals are converted back to oxygen with the generation of hydrogen peroxide (H2O2). Superhydroxide free radicals cause severe lipid peroxidation of the inner mitochondrial membrane that leads to extensive mitochondrial destruction. Since cardiac cells and malignant cells are rich in mitochondria, these cells are highly affected by doxorubicin administration. By chelating with intracellular iron, dexrazoxane decreases the ability of iron to react with superoxide anions and H2O2 to produce highly toxic superhydroxide radicals. The recycling of ferrous ion back to ferric ion for use by superoxide anion radicals is also prevented. Clinically, there is reduced incidence of doxorubicin-induced cardiomyopathy and enhanced urinary excretion of iron. It is unknown how dexrazoxane diminishes tissue damage caused by IV anthracycline extravasation. One possible mechanism involves reversible inhibition of topoisomerase II.
Dexrazoxane is administered by intravenous (IV) infusion. It is not bound to plasma proteins. The steady-state Vd was 22.4 L/m2 (coefficient of variation (CV), 22%), the elimination half-life was 2.5 hours (CV, 16%), the renal clearance was 3.35 L/hour/m2 (CV, 36%), and the total plasma clearance was 7.88 L/hour/m2 (CV, 18%) following the administration of dexrazoxane 500 mg/m2 IV over 15 minutes in 10 patients with advanced cancer. The unchanged drug, a diacid-diamide cleavage product, and 2 monoacid-monoamide ring products are excreted primarily in the urine; 42% of a 500-mg/m2 dose was excreted in the urine. Dexrazoxane does not appear to be metabolized via CYP450 isoenzymes. When dexrazoxane was administered for the treatment of anthracycline extravasation (1,000 mg/m2 IV on days 1 and 2 and 500 mg/m2 IV on day 3) in 6 female patients, the Vd ranged from 17.9 to 22.6 L/m2, the terminal elimination half-life was 2.1 to 2.2 hours, and the systemic clearance ranged from 5.9 to 7.9 L/hour/m2.
-Route-Specific Pharmacokinetics
Intravenous Route
The mean Cmax value was 36.5 micrograms/mL following the administration of dexrazoxane 500 mg/m2 IV over 15 minutes in 10 patients with advanced cancer. Following a rapid distribution of approximately 0.2 to 0.3 hours, steady-state dexrazoxane concentrations are achieved within 2 to 4 hours. Dexrazoxane exhibits linear kinetics for exposure (AUC) over a dose range of 60 to 900 mg/m2.
-Special Populations
Renal Impairment
The clearance of dexrazoxane was reduced in patients with renal impairment following a single dose of dexrazoxane 150 mg/m2 IV given over 15 minutes. Moderate (creatinine clearance (CrCl) of 30 to 50 mL/min) to severe (CrCl less than 30 mL/min) renal dysfunction was associated with a 2-fold increase in the AUC(0-inf) value compared with controls in a pharmacokinetic (PK) study in subjects with varying degrees of renal dysfunction (determined by a 24-hour urinary creatinine collection). Compared with subjects who have a CrCl greater than 80 mL/min, equivalent exposure may be achieved in subjects with CrCl less than 40 mL/min who receive dexrazoxane at a 50% reduced dose according to PK modeling data.
Gender Differences
Gender does not affect the pharmacokinetic parameters of dexrazoxane.