Dexrazoxane: Package Insert and Label Information (Page 2 of 2)

8.5 Geriatric Use

Clinical studies of Dexrazoxane for Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Females of Reproductive Potential

Contraception
Dexrazoxane for Injection can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment [see Use in Specific Populations (8.1)].

8.7 Renal Impairment

Greater exposure to dexrazoxane may occur in patients with compromised renal function. Reduce the Dexrazoxane for Injection dose by 50% in patients with creatinine clearance values <40 mL/min [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

There are no data on overdosage in the cardioprotective trials; the maximum dose administered during the cardioprotective trials was 1000 mg/m2 every three weeks.
Disposition studies with Dexrazoxane for Injection have not been conducted in cancer patients undergoing dialysis, but retention of a significant dose fraction (>0.4) of the unchanged drug in the plasma pool, minimal tissue partitioning or binding, and availability of greater than 90% of the systemic drug levels in the unbound form suggest that it could be removed using conventional peritoneal or hemodialysis.
There is no known antidote for dexrazoxane. Instances of suspected overdose should be managed with good supportive care until resolution of myelosuppression and related conditions is complete. Management of overdose should include treatment of infections, fluid regulation, and maintenance of nutritional requirements.

11 DESCRIPTION

Dexrazoxane for injection, a cardioprotective agent for use in conjunction with doxorubicin, is a sterile, pyrogen-free lyophilizate intended for intravenous administration.Chemically, dexrazoxane is (S)-4,4′-(1-methyl-1,2-ethanediyl)bis-2,6-piperazinedione. The structural formula is as follows:

structure
(click image for full-size original)

C11 H16 N4 O4 M.W. 268.28
Dexrazoxane, an 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.
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 Dexrazoxane for Injection solutions prepared from Sterile Water for Injection, USP, are intended for further dilution with Lactated Ringer’s Injection, USP, for rapid intravenous drip infusion. DO NOT ADMINISTER VIA AN INTRAVENOUS PUSH [see Dosage and Administration (2.1 , 2.3)].

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism by which Dexrazoxane for Injection exerts its cytoprotective activity is not fully understood. Dexrazoxane is a cyclic derivative of EDTA that penetrates cell membranes. Results of laboratory studies suggest that dexrazoxane is converted intracellularly to a ring-opened chelating agent that interferes with iron-mediated free radical generation thought to be responsible, in part, for anthracycline-induced cardiomyopathy.

12.3 Pharmacokinetics

The pharmacokinetics of dexrazoxane have been studied in advanced cancer patients with normal renal and hepatic function. The pharmacokinetics of dexrazoxane can be adequately described by a two-compartment open model with first-order elimination. Dexrazoxane has been administered as a 15 minute infusion over a dose range of 60 to 900 mg/m2 with 60 mg/m2 of doxorubicin, and at a fixed dose of 500 mg/m2 with 50 mg/m2 doxorubicin. The disposition kinetics of dexrazoxane are dose-independent, as shown by linear relationship between the area under plasma concentration-time curves and administered doses ranging from 60 to 900 mg/m2. The mean peak plasma concentration of dexrazoxane was 36.5 μg/mL at 15- minute after intravenous administration of 500 mg/m2 dose of Dexrazoxane for Injection over 15 to 30 minutes prior to the 50 mg/m2 doxorubicin dose.The important pharmacokinetic parameters of dexrazoxane are summarized in Table 2:

Table 2: SUMMARY OF MEAN (%CVa) DEXRAZOXANE PHARMACOKINETIC PARAMETERS AT A DOSAGE RATIO OF 10:1 OF DEXRAZOXANE FOR INJECTION: DOXORUBICIN

Dose Doxirubicin (mg/m2) DoseDexrazoxane for Injection(mg/m2) Number of Subjects Elimination Half-Life (h) Plasma Clearance (L/h/m2) Renal Clearance (L/h/m2) b Volume of Distribution(L/m2)
5060 500600 105 2.5(16)2.1 (29) 7.88 (18)6.25 (31) 3.35 (36)——- 22.4 (22)22.0 (55)

a Coefficient of variation
b Steady-state volume of distribution
Distribution
Following a rapid distributive phase (0.2 to 0.3 hours), dexrazoxane reaches post-distributive equilibrium within two to four hours. The estimated mean steady-state volume of distribution of dexrazoxane is 22.4 L/m2 after 500 mg/m2 of Dexrazoxane for Injection dose followed by 50 mg/m2 of doxorubicin, suggesting distribution throughout total body water (25 L/m2).
In vitro studies have shown that dexrazoxane is not bound to plasma proteins.
Metabolism
Qualitative metabolism studies with dexrazoxane have confirmed the presence of unchanged drug, a diacid-diamide cleavage product, and two monoacid-monoamide ring products in the urine of animals and man. The metabolite levels were not measured in the pharmacokinetic studies.
Excretion
Urinary excretion plays an important role in the elimination of dexrazoxane. Forty-two percent of a 500 mg/m2 dose of Dexrazoxane for Injection was excreted in the urine. Renal clearance averages 3.35 L/h/m2 after the 500 mg/m2 Dexrazoxane for Injection dose followed by 50 mg/m2 of doxorubicin.
Specific Populations
Pediatric
Pharmacokinetics following Dexrazoxane for Injection administration have not been evaluated in pediatric patients.
Effect of Renal Impairment
The pharmacokinetics of dexrazoxane were assessed following a single 15-minute IV infusion of 150 mg/m2 of Dexrazoxane for Injection. Dexrazoxane clearance was reduced in subjects with renal dysfunction. Compared with controls, the mean AUC0-inf value was two-fold greater in subjects with moderate (CLCR 30-50 mL/min) to severe (CLCR <30 mL/min) renal dysfunction. Modeling demonstrated that equivalent exposure (AUC0-inf ) could be achieved if dosing were reduced by 50% in subjects with creatinine clearance values <40 mL/min compared with control subjects (CLCR >80 mL/min) [see Use in Specific Populations (8.7) and Dosage and Administration (2.2)].

Effect of Hepatic Impairment
Pharmacokinetics following Dexrazoxane for Injection administration have not been evaluated in patients with hepatic impairment. The Dexrazoxane for Injection dose is dependent upon the dose of doxorubicin [see Dosage and Administration (2.2)].
Drug Interactions
There was no significant change in the pharmacokinetics of doxorubicin (50 mg/m2) and its predominant metabolite, doxorubicinol, in the presence of dexrazoxane (500 mg/m2) in a crossover study in cancer patients.

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).
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:
a. Cardiomegaly by X-ray
b. Basilar Rales
c. S3 Gallop
d. 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)

15 REFERENCES

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Dexrazoxane for injection is available in the following strength as sterile, pyrogen-free lyophilized.
NDC 72611-716-72
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), (5.6)].

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:
Gland Pharma Limited
D.P.Pally, Dundigal Post
Hyderabad — 500 043, India

Manufactured for:
Almaject, Inc.
Morristown, NJ 07960 USA

Product of India

Novaplus is a registered trademark of Vizient, Inc.

logo

Revised: January 2022 PI716-00-NP

Rx only

PRINCIPAL DISPLAY PANEL — vial

NDC 72611-716-72 Rx ONLY

Dexrazoxane for Injection

500 mg*/vial

FOR INTRAVENOUS USE ONLY

Single-Dose Vial

Sterile, Pyrogen-Free Lyophilized

*Each vial contains: dexrazoxane hydrochloride equivalent to 500 mg dexrazoxane. The pH is adjusted with hydrochloric acid, NF.

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

PRINCIPAL DISPLAY PANEL — carton

NDC 72611-716-72

Dexrazoxane for Injection

500 mg*/vial

FOR INTRAVENOUS USE ONLY

Single-Dose Vial

Sterile, Pyrogen-Free Lyophilized

Rx ONLY

*Each vial contains: dexrazoxane hydrochloride equivalent to 500 mg dexrazoxane. The pH is adjusted with hydrochloric acid, NF.

carton
(click image for full-size original)
DEXRAZOXANE dexrazoxane for injection injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:72611-716
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:72611-716-72 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 (72611-716-72)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA207321 06/01/2022
Labeler — Almaject, Inc. (116626205)

Revised: 01/2022 Almaject, Inc.

Page 2 of 2 1 2

DrugInserts.com provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by DrugInserts.com. Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.

As the leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. Our material is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2022. All Rights Reserved.