Zinecard

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Zinecard

Classes

Chelating Agents
Cytoprotectant Agents

Administration

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.

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.

Adverse Reactions
Severe

leukopenia / Delayed / 0-55.0
neutropenia / Delayed / 0-46.0
thrombocytopenia / Delayed / 0-21.0
hyponatremia / Delayed / 0-6.0
elevated hepatic enzymes / Delayed / 0-6.0
cardiotoxicity / Delayed / 0-5.0
hypercalcemia / Delayed / 0-4.0
nephrotoxicity / Delayed / 0-4.0
hyperbilirubinemia / Delayed / 0-2.0
new primary malignancy / Delayed / Incidence not known
bronchospasm / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
angioedema / Rapid / Incidence not known

Moderate

neurotoxicity / Early / 10.0-24.0
peripheral edema / Delayed / 0-10.0
dyspnea / Early / 0-8.0
depression / Delayed / 0-8.0
phlebitis / Rapid / 6.0-6.0
constipation / Delayed / 0-6.0
anemia / Delayed / 0-6.0
erythema / Early / 0-5.0
bleeding / Early / 0-3.0
radiation recall reaction / Delayed / 0-1.0
hypotension / Rapid / Incidence not known

Mild

alopecia / Delayed / 0-100.0
malaise / Early / 0-61.0
fatigue / Early / 13.0-61.0
nausea / Early / 0-43.0
fever / Early / 21.0-34.0
infection / Delayed / 0-30.0
vomiting / Early / 0-19.0
injection site reaction / Rapid / 12.0-16.0
diarrhea / Early / 11.0-14.0
dizziness / Early / 0-11.0
abdominal pain / Early / 0-6.0
headache / Early / 0-6.0
cough / Delayed / 0-5.0
insomnia / Early / 0-5.0
anorexia / Delayed / 0-5.0
urticaria / Rapid / 0-2.0

Common Brand Names

Totect, Zinecard

Dea Class

Rx

Description

Cytoprotective agent
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 for the treatment of extravasation resulting from IV anthracycline chemotherapy
May increase the myelosuppressive effects of chemotherapy

Dosage And Indications
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.

Dosing Considerations
Hepatic Impairment

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.

Renal Impairment

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%.

Drug Interactions

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.

How Supplied

Dexrazoxane/Dexrazoxane Hydrochloride/Totect/Zinecard Intravenous Inj Pwd F/Sol: 250mg, 500mg

Maximum Dosage
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.

Mechanism Of Action

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.

Pharmacokinetics

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.

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.

Pregnancy And Lactation
Pregnancy

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.

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.