Zinecard (Page 3 of 3)

13 NONCLINICAL TOXICOLOGY

13.1 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).

ZINECARD 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).

14 CLINICAL STUDIES

The ability of ZINECARD to prevent/reduce the incidence and severity of doxorubicin-induced cardiomyopathy was evaluated in three prospectively randomized placebo-controlled studies. In these studies, patients were treated with a doxorubicin-containing regimen and either ZINECARD or placebo starting with the first course of chemotherapy. There was no restriction on the cumulative dose of doxorubicin. Cardiac function was assessed by measurement of the LVEF, utilizing resting multigated nuclear medicine (MUGA) scans, and by clinical evaluations. Patients receiving ZINECARD had significantly smaller mean decreases from baseline in LVEF and lower incidences of congestive heart failure than the control group; however, in the largest study, patients with advanced breast cancer receiving FAC with ZINECARD had a lower response rate (48% vs. 63%) and a shorter time to progression than patients who received FAC versus placebo.

In the clinical trials, patients who were initially randomized to receive placebo were allowed to receive ZINECARD after a cumulative dose of doxorubicin above 300 mg/m2. Retrospective historical analyses showed that the risk of experiencing a cardiac event (see Table 3 for definition) at a cumulative dose of doxorubicin above 300 mg/m2 was greater in the patients who did not receive ZINECARD beginning with their seventh course of FAC than in the patients who did receive ZINECARD (HR=13.08; 95% CI: 3.72, 46.03; p<0.001). Overall, 3% of patients treated with ZINECARD developed CHF compared with 22% of patients not receiving ZINECARD.

Table 3: Definition of Cardiac Events:
  1. Development of congestive heart failure, defined as having two or more of the following:
    1. Cardiomegaly by X-ray
    2. Basilar Rales
    3. S3 Gallop
    4. Paroxysmal nocturnal dyspnea and/or orthopnea and/or significant dyspnea on exertion.
  2. Decline from baseline in LVEF by ≥10% and to below the lower limit of normal for the institution.
  3. Decline in LVEF by ≥20% from baseline value.
  4. Decline in LVEF to ≥5% below lower limit of normal for the institution.

Figure 1 shows the number of patients still on treatment at increasing cumulative doses.

Figure 1 Cumulative Number of Patients On Treatment FAC vs. FAC/ZINECARD Patients Patients Receiving at Least Seven Courses of Treatment
Figure 1
(click image for full-size original)

15 REFERENCES

  1. “OSHA Hazardous Drugs.” OSHA http://www.osha.gov/SLTC/hazardousdrugs/index.html.

16 HOW SUPPLIED/STORAGE AND HANDLING

ZINECARD (dexrazoxane for injection) is available in the following strengths as sterile, pyrogen-free lyophilizates.

NDC 0013-8717-62

250 mg single dose vial with a red flip-top seal, packaged in single vial packs.

NDC 0013-8727-89

500 mg single dose vial with a blue flip-top seal, packaged in single vial packs.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Follow special handling and disposal procedures.1

17 PATIENT COUNSELING INFORMATION

17.1 Myelosuppression

Treatment with ZINECARD is associated with leukopenia, neutropenia, and thrombocytopenia. Perform hematological monitoring [see Warnings and Precautions (5.1)].

17.2 Embryo-Fetal Toxicity

Counsel patients on pregnancy planning and prevention. Advise female patients of reproductive potential that ZINECARD can cause fetal harm and to use highly effective contraception during treatment [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1, 8.6)].

This product’s label may have been updated. For current full prescribing information, please visit www.pfizer.com.

logo

LAB-0060-10.0

PRINCIPAL DISPLAY PANEL — 250 mg Single-Dose Vial Label

NDC 0013-8717-62

Single-Dose Vial

Zinecard ®
(dexrazoxane) for
injection

250 mg*

Sterile, Pyrogen-Free Lyophilizate

For Intravenous Use Only

Rx only

PRINCIPAL DISPLAY PANEL -- 250 mg Single-Dose Vial Label
(click image for full-size original)

PRINCIPAL DISPLAY PANEL — 250 mg Vial Carton

NDC 0013-8717-62

Single-Dose Vial

Zinecard ®
(dexrazoxane) for
injection

250 mg*

Sterile, Pyrogen-Free Lyophilizate

For Intravenous Use Only

Pfizer Injectables

Rx only

PRINCIPAL DISPLAY PANEL -- 250 mg Vial Carton
(click image for full-size original)

PRINCIPAL DISPLAY PANEL — 500 mg Single-Dose Vial Label

NDC 0013-8727-89

Single-Dose Vial

Zinecard ®
(dexrazoxane) for injection

500 mg*

Sterile, Pyrogen-Free Lyophilizate

For Intravenous Use Only

Rx only

PRINCIPAL DISPLAY PANEL -- 500 mg Single-Dose Vial Label
(click image for full-size original)

PRINCIPAL DISPLAY PANEL — 500 mg Vial Carton

NDC 0013-8727-89

Single-Dose Vial

Zinecard ®
(dexrazoxane) for
injection

500 mg*

Sterile, Pyrogen-Free Lyophilizate

For Intravenous Use Only

Pfizer Injectables

Rx only

PRINCIPAL DISPLAY PANEL -- 500 mg Vial Carton
(click image for full-size original)
ZINECARD
dexrazoxane injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0013-8717
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DEXRAZOXANE HYDROCHLORIDE (DEXRAZOXANE) DEXRAZOXANE 250 mg in 25 mL
Inactive Ingredients
Ingredient Name Strength
HYDROCHLORIC ACID
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0013-8717-62 1 VIAL, SINGLE-DOSE in 1 CARTON contains a VIAL, SINGLE-DOSE
1 25 mL in 1 VIAL, SINGLE-DOSE This package is contained within the CARTON (0013-8717-62)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA020212 05/26/1995 04/30/2021
ZINECARD
dexrazoxane injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0013-8727
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DEXRAZOXANE HYDROCHLORIDE (DEXRAZOXANE) DEXRAZOXANE 500 mg in 50 mL
Inactive Ingredients
Ingredient Name Strength
HYDROCHLORIC ACID
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0013-8727-89 1 VIAL, SINGLE-DOSE in 1 CARTON contains a VIAL, SINGLE-DOSE
1 50 mL in 1 VIAL, SINGLE-DOSE This package is contained within the CARTON (0013-8727-89)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA020212 05/26/1995 02/28/2019
Labeler — Pharmacia and Upjohn Company LLC (618054084)

Revised: 07/2020 Pharmacia and Upjohn Company LLC

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