Dexrazoxane

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Some cancer medications may be less effective if they are used with dexrazoxane. Tell your doctor if your chemotherapy medications include:

• fluorouracil (5-FU, Adrucil);
• cyclophosphamide (Cytoxan, Neosar).

This list is not complete and other drugs may interact with dexrazoxane. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Dexrazoxane is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting.

Totect is usually started within 6 hours after extravasation, and continued once daily for 3 days.

Zinecard is usually started 30 minutes before you receive your doxorubicin injection.

Dexrazoxane can add to the bone marrow lowering effects of chemotherapy. This can weaken your immune system, making it easier for you to get sick from being around others who are ill.

To be sure this medication is not causing harmful effects, your blood cells and kidney function will need to be tested often. Do not miss any follow up visits to your doctor for blood or urine tests.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Since dexrazoxane is given by a healthcare professional as part of your chemotherapy treatment, you are not likely to miss a dose.

Call your doctor if you miss a chemotherapy appointment.

ZINECARD® (dexrazoxane for injection) is a sterile, pyrogen-free lyophilizate intended for intravenous administration. It is a cardioprotective agent for use in conjunction with doxorubicin.

Chemically, dexrazoxane is (S)-4,4'-(1-methyl-1,2-ethanediyl)bis-2,6-piperazinedione. The structural formula is as follows:

Dexrazoxane, a potent intracellular chelating agent is a derivative of EDTA.

Dexrazoxane is a whitish crystalline powder that melts at 191° to 197°C. It is sparingly soluble in water and 0.1 N HCl, slightly soluble in ethanol and methanol, and practically insoluble in nonpolar organic solvents. The pKa is 2.1. Dexrazoxane has an octanol/water partition coefficient of 0.025 and degrades rapidly above a pH of 7.0.

ZINECARD is available in 250 mg and 500 mg single use only vials. ZINECARD must be reconstituted with Sterile Water for Injection, USP.

Each 250 mg vial contains dexrazoxane hydrochloride equivalent to 250 mg dexrazoxane. Hydrochloric Acid, NF is added for pH adjustment.. When reconstituted as directed with 25 mL of Sterile Water for Injection, USP, each mL contains: 10 mg dexrazoxane. The pH of the resultant solution is 1.0 to 3.0.

Each 500 mg vial contains dexrazoxane hydrochloride equivalent to 500 mg dexrazoxane. Hydrochloric Acid, NF is added for pH adjustment.. When reconstituted as directed with 50 mL of Sterile Water for Injection, USP, each mL contains: 10 mg dexrazoxane. The pH of the resultant solution is 1.0 to 3.0.

The reconstituted ZINECARD solutions prepared from Sterile Water for Injection, USP, is intended for further dilution with Lactated Ringer's Injection, USP, for rapid intravenous drip infusion. DO NOT ADMINISTER VIA IV PUSH (see DOSAGE AND ADMINISTRATION).

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Dexrazoxane falls into category D:

It has been shown that use of Dexrazoxane in pregnant women caused some babies to be born with problems. However, in some serious situations, the benefit of using this medication may be greater than the risk of harm to the baby.

• 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.

Use dexrazoxane as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as an infusion into a vein over a period of time.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

Dexrazoxane for Injection is indicated for reducing 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. Do not use with the initiation of doxorubicin therapy [see Warnings and Precautions (5.2)].

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term carcinogenicity studies have been carried out with Dexrazoxane in animals. Nevertheless, a study by the National Cancer Institute has reported that long-term dosing with razoxane (the racemic mixture of Dexrazoxane, ICRF-187, and its enantiomer ICRF-186) is associated with the development of malignancies in rats and possibly in mice [see Warnings and Precautions (5.4)].

Dexrazoxane was not mutagenic in the bacterial reverse mutation (Ames) test, but was found to be clastogenic to human lymphocytes in vitro and to mouse bone marrow erythrocytes in vivo (micronucleus test).

Dexrazoxane for Injection has the potential to impair fertility in male patients based on effects in repeat-dose toxicology studies. Testicular atrophy was seen with Dexrazoxane administration at doses as low as 30 mg/kg weekly for 6 weeks in rats (1/3 the human dose on a mg/m2 basis) and as low as 20 mg/kg weekly for 13 weeks in dogs (approximately equal to the human dose on a mg/m2 basis).

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

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)

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).

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).

Disease-related concerns:

• 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.

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.

• 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).

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.