2.1 Recommended Dose

Administer Dexrazoxane for Injection via intravenous infusion over 15 minutes. DO NOT ADMINISTER VIA AN INTRAVENOUS PUSH.

The recommended dosage ratio of Dexrazoxane for Injection to doxorubicin is 10:1 (e.g., 500 mg/m 2 Dexrazoxane for Injection to 50 mg/m 2 doxorubicin). Do not administer doxorubicin before Dexrazoxane for Injection. Administer doxorubicin within 30 minutes after the completion of Dexrazoxane for Injection infusion.

2.2 Dose Modifications

Dosing in Patients with Renal Impairment

Reduce Dexrazoxane for Injection dosage in patients with moderate to severe renal impairment (creatinine clearance values less than 40 mL/min) by 50% (Dexrazoxane for Injection to doxorubicin ratio reduced to 5:1; such as 250 mg/m2 Dexrazoxane for Injection to 50 mg/m2 doxorubicin) [ see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Dosing in Patients with Hepatic Impairment

Since a doxorubicin dose reduction is recommended in the presence of hyperbilirubinemia, reduce the Dexrazoxane for Injection dosage proportionately (maintaining the 10:1 ratio) in patients with hepatic impairment.

2.3 Preparation and Administration

Preparation and Handling of Infusion Solution



Reconstitute Dexrazoxane for Injection with Sterile Water for Injection, USP. Reconstitute with 25 mL for a Dexrazoxane for Injection 250 mg vial and 50 mL for a Dexrazoxane for Injection 500 mg vial to give a concentration of 10 mg/mL. Dilute the reconstituted solution further with Lactated Ringer's Injection, USP to a concentration of 1.3 to 3.0 mg/mL in intravenous infusion bags for intravenous infusion.

Following reconstitution with Sterile Water for Injection, USP, Dexrazoxane for Injection is stable for 30 minutes at room temperature or if storage is necessary, up to 3 hours from the time of reconstitution when stored under refrigeration, 2° to 8°C (36° to 46°F). The pH of the resultant solution is 1.0 to 3.0. DISCARD UNUSED SOLUTIONS. The diluted infusion solutions are stable for one hour at room temperature or if storage is necessary, up to 4 hours when stored under refrigeration, 2° to 8°C (36° to 46°F). The infusion solutions have a pH of 3.5 to 5.5. DISCARD UNUSED SOLUTIONS.







Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Solutions containing a precipitate should be discarded.

Use caution when handling and preparing the reconstituted solution. The use of gloves is recommended. If Dexrazoxane for Injection powder or solutions contact the skin or mucosae, wash exposed area immediately and thoroughly with soap and water. Follow special handling and disposal procedures 1.

Administration



Do not mix Dexrazoxane for Injection with other drugs.

Administer the final diluted solution of Dexrazoxane for Injection by intravenous infusion over 15 minutes before the administration of doxorubicin. DO NOT ADMINISTER VIA AN INTRAVENOUS PUSH. Administer doxorubicin within 30 minutes after the completion of Dexrazoxane for Injection infusion.

5.1 Myelosuppression

Dexrazoxane for Injection may add to the myelosuppression caused by chemotherapeutic agents. Obtain a complete blood count prior to and during each course of therapy, and administer Dexrazoxane for Injection and chemotherapy only when adequate hematologic parameters are met.

5.2 Concomitant Chemotherapy

Only use Dexrazoxane for Injection in those patients who have received a cumulative doxorubicin dose of 300 mg/m 2 and are continuing with doxorubicin therapy. Do not use with chemotherapy initiation as Dexrazoxane for Injection may interfere with the antitumor activity of the chemotherapy regimen. In a trial conducted in patients with metastatic breast cancer who were treated with fluorouracil, doxorubicin, and cyclophosphamide (FAC) with or without Dexrazoxane for Injection starting with their first cycle of FAC therapy, patients who were randomized to receive Dexrazoxane for Injection had a lower response rate (48% vs. 63%) and shorter time to progression than patients who were randomized to receive placebo.

5.3 Cardiac Toxicity

Treatment with Dexrazoxane for Injection does not completely eliminate the risk of anthracycline-induced cardiac toxicity. Monitor cardiac function before and periodically during therapy to assess left ventricular ejection fraction (LVEF). In general, if test results indicate deterioration in cardiac function associated with doxorubicin, the benefit of continued therapy should be carefully evaluated against the risk of producing irreversible cardiac damage.

5.4 Secondary Malignancies

Secondary malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have been reported in studies of pediatric patients who have received Dexrazoxane for Injection in combination with chemotherapy. Dexrazoxane for Injection is not indicated for use in pediatric patients. Some adult patients who received Dexrazoxane for Injection in combination with anti-cancer agents known to be carcinogenic have also developed secondary malignancies, including AML and MDS.



Razoxane is the racemic mixture, of which dexrazoxane is the S(+)-enantiomer. Secondary malignancies (primarily acute myeloid leukemia) have been reported in patients treated chronically with oral razoxane. In these patients, the total cumulative dose of razoxane ranged from 26 to 480 grams and the duration of treatment was from 42 to 319 weeks. One case of T-cell lymphoma, one case of B-cell lymphoma, and six to eight cases of cutaneous basal cell or squamous cell carcinoma have also been reported in patients treated with razoxane. Long-term administration of razoxane to rodents was associated with the development of malignancies [see Nonclinical Toxicology (13.1)].

5.5 Embryo-Fetal Toxicity

Dexrazoxane for Injection can cause fetal harm when administered to pregnant women. Dexrazoxane administration during the period of organogenesis resulted in maternal toxicity, embryotoxicity and teratogenicity in rats and rabbits at doses significantly lower than the clinically recommended dose [see Use in Specific Populations (8.1)]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.



Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception during treatment [see Use in Specific Populations (8.6)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.







The adverse reaction profile described in this section was identified from randomized, placebo controlled, double-blind studies in patients with metastatic breast cancer who received the combination of the FAC chemotherapy regimen with or without Dexrazoxane for Injection. The dose of doxorubicin was 50 mg/m 2 in each of these trials. Treatment was administered every three weeks until disease progression or cardiac toxicity.







Patients in clinical trials who received FAC with Dexrazoxane for Injection experienced more severe leukopenia, granulocytopenia, and thrombocytopenia than patients receiving FAC without Dexrazoxane for Injection [see Warnings and Precautions (5.1)].







Table 1 below lists the incidence of adverse reactions for patients receiving FAC with either Dexrazoxane for Injection or placebo in the breast cancer studies. Adverse experiences occurring during courses 1 through 6 are displayed for patients receiving Dexrazoxane for Injection or placebo with FAC beginning with their first course of therapy (columns 1 and 3, respectively). Adverse experiences occurring at course 7 and beyond for patients who received placebo with FAC during the first six courses and who then received either Dexrazoxane for Injection or placebo with FAC are also displayed (columns 2 and 4, respectively).



The adverse reactions listed below in Table.1 demonstrate that the frequency of adverse reaction “Pain on Injection” has been greater for Dexrazoxane for Injection arm, as compared to placebo.

Table 1

8.1 Pregnancy

Pregnancy Category D

Risk Summary

Dexrazoxane for Injection can cause fetal harm when administered to pregnant women. Dexrazoxane administration resulted in maternal toxicity, embryotoxicity and teratogenicity in rats and rabbits at doses significantly lower than the clinically recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.5)].

Animal Data

Dexrazoxane resulted in maternal toxicity in rats at doses of ≥2 mg/kg (1/40 the human dose on a mg/m 2 basis) and embryotoxicity and teratogenicity at 8 mg/kg (approximately 1/10 the human dose on a mg/m 2 basis) when given daily to pregnant rats during the period of organogenesis. Teratogenic effects in the rat included imperforate anus, microphthalmia, and anophthalmia. In offspring allowed to develop to maturity, fertility was impaired in the male and female rats treated in utero during organogenesis at 8 mg/kg. In rabbits, doses of  ≥5 mg/kg (approximately 1/10 the human dose on a mg/m 2 basis) daily during the period of organogenesis caused maternal toxicity and doses of 20 mg/kg (1/2 the human dose on a mg/m 2 basis) were embryotoxic and teratogenic. Teratogenic effects in the rabbit included several skeletal malformations such as short tail, rib and thoracic malformations, and soft tissue variations including subcutaneous, eye and cardiac hemorrhagic areas, as well as agenesis of the gallbladder and of the intermediate lobe of the lung.

8.3 Nursing Mothers

It is not known whether dexrazoxane or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from dexrazoxane, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of dexrazoxane in pediatric patients have not been established [see Warnings and Precautions (5.4)].

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)].

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 adequatelydescribed 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/m 2 with 60 mg/m 2 of doxorubicin, and at a fixed dose of 500 mg/m 2 with 50 mg/m 2 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/m 2. The mean peak plasma concentration of dexrazoxane was 36.5 μg/mL at 15- minute after intravenous administration of 500 mg/m 2 dose of Dexrazoxane for Injection over 15 to 30 minutes prior to the 50 mg/m 2 doxorubicin dose.



The important pharmacokinetic parameters of dexrazoxane are summarized in Table 2:

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

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/m 2 after 500 mg/m 2 of Dexrazoxane for Injection dose followed by 50 mg/m 2 of doxorubicin, suggesting distribution throughout total body water (25 L/m 2).



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/m 2 dose of Dexrazoxane for Injection was excreted in the urine. Renal clearance averages 3.35 L/h/m 2 after the 500 mg/m 2 Dexrazoxane for Injection dose followed by 50 mg/m 2 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/m 2 of Dexrazoxane for Injection. Dexrazoxane clearance was reduced in subjects with renal dysfunction. Compared with controls, the mean AUC 0-inf value was two-fold greater in subjects with moderate (CL CR 30-50 mL/min) to severe (CL CR <30 mL/min) renal dysfunction. Modeling demonstrated that equivalent exposure (AUC 0-inf) could be achieved if dosing were reduced by 50% in subjects with creatinine clearance values <40 mL/min compared with control subjects (CL CR >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/m 2) and its predominant metabolite, doxorubicinol, in the presence of dexrazoxane (500 mg/m 2) in a crossover study in cancer patients.

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/m 2 basis) and as low as 20 mg/kg weekly for 13 weeks in dogs (approximately equal to the human dose on a mg/m 2 basis).

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)].

Distributed by:

Fosun Pharma USA Inc.







Princeton, NJ 08540

Made in India

April 2021