Dexrazoxane (Page 3 of 3)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis and Mutagenesis and 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).

14 CLINICAL STUDIES

The ability of dexrazoxane for injection 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 dexrazoxane for injection 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 dexrazoxane for injection 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 dexrazoxane for injection 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 dexrazoxane for injection 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 dexrazoxane for injection beginning with their seventh course of FAC than in the patients who did receive dexrazoxane for injection (HR=13.08; 95% CI: 3.72, 46.03; p<0.001). Overall, 3% of patients treated with dexrazoxane for injection developed CHF compared with 22% of patients not receiving dexrazoxane for injection.

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/Dexrazoxane for Injection Patients

Patients Receiving at Least Seven Courses of Treatment

Figure 1
(click image for full-size original)

Figure 1

15 REFERENCES

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

16 HOW SUPPLIED

Dexrazoxane for Injection is available in the following strengths as sterile, pyrogen-free lyophilizates.

NDC 0143-9247-01 250 mg single dose vial with a gray flip-top seal, packaged in single vial packs.

NDC 0143-9248-01 500 mg single dose vial with a blue flip-top seal, packaged in single vial packs.

Store at 20° to 25°C (68° to 77° F) [See USP Controlled Room Temperature].

Follow special handling and disposal procedures.1

17 PATIENT COUNSELING INFORMATION

17.1 Myelosuppression

Treatment with dexrazoxane for injection 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 dexrazoxane for injection 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)].

Manufactured By:

THYMOORGAN PHARMAZIE GmbH,

Schiffgraben 23, 38690 Goslar, Germany

Manufactured for:

West-Ward Pharmaceuticals

Eatontown, NJ 07724 USA

Revised December 2016

127.207.025/00

Vial Label 250 mg

250 mg vial label
(click image for full-size original)

250 mg vial label

NDC 0143-9247-01 Rx only

Dexrazoxane for Injection

250 mg/vial

For Intravenous Use Only

STERILE, PYROGEN-FREE,

LYOPHILIZATE

Single-Dose Vial

SERIALIZATION IMAGE 250 mg Carton

Representative Carton Serialization Image

Representative Carton Serialization Image

Vial Label 500 mg

NDC 0143-9248-01 Rx only

Dexrazoxane for Injection

500 mg/vial

For Intravenous Use Only

STERILE, PYROGEN-FREE,

LYOPHILIZATE

Single-Dose Vial

500 mg vial label
(click image for full-size original)

500 mg vial label

SERIALIZATION IMAGE 500 mg Carton

Representative Carton Serialization Image

Representative Carton Serialization Image

DEXRAZOXANE
dexrazoxane injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0143-9247
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DEXRAZOXANE HYDROCHLORIDE (DEXRAZOXANE) DEXRAZOXANE 10 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
HYDROCHLORIC ACID
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0143-9247-01 1 VIAL in 1 BOX contains a VIAL
1 25 mL in 1 VIAL This package is contained within the BOX (0143-9247-01)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA076068 03/31/2005
DEXRAZOXANE
dexrazoxane injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0143-9248
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DEXRAZOXANE HYDROCHLORIDE (DEXRAZOXANE) DEXRAZOXANE 10 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
HYDROCHLORIC ACID
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0143-9248-01 1 VIAL in 1 BOX contains a VIAL
1 50 mL in 1 VIAL This package is contained within the BOX (0143-9248-01)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA076068 03/31/2005
Labeler — Hikma Pharmaceuticals USA Inc. (001230762)

Revised: 12/2019 Hikma Pharmaceuticals USA Inc.

Page 3 of 3 1 2 3

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2022. All Rights Reserved.