USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Nursing Mothers: Discontinue drug or nursing. 8.3) 8.1 Pregnancy. Pregnancy Category DRisk SummaryDexrazoxane 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 fetus [see Warnings and Precautions (5.5)]. Animal DataDexrazoxane resulted in maternal toxicity in rats at doses of >=2 mg/kg (1/40 the human dose on mg/m basis) and embryotoxicity and teratogenicity at mg/kg (approximately 1/10 the human dose on mg/m 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 mg/kg. In rabbits, doses of >=5 mg/kg (approximately 1/10 the human dose on mg/m basis) daily during the period of organogenesis caused maternal toxicity and doses of 20 mg/kg (1/2 the human dose on mg/m 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, 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)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. In clinical studies, Dexrazoxane for Injection was administered to patients also receiving chemotherapeutic agents for cancer. Pain on injection was observed more frequently in patients receiving Dexrazoxane for Injection versus placebo. 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Fosun Pharma USA Inc. at 866-611-3762 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 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 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 through are displayed for patients receiving Dexrazoxane for Injection or placebo with FAC beginning with their first course of therapy (columns and 3, respectively). Adverse experiences occurring at course 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 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 1Adverse Reaction Percentage (%) of Brea st Cancer Patients With Adverse Reaction FAC Dexrazoxane for Injection FAC Placebo Courses 1- N 413 Courses >= N 102 Courses 1- N 458 Courses >= N 99 Alopecia 94 100 97 98 Nausea 77 51 84 60 Vo miting 59 42 72 49 Fatigue/Malaise 61 48 58 55 Anorexia 42 27 47 38 Sto matitis 34 26 41 28 Fever 34 22 29 18 Infection 23 19 18 21 Diarrhea 21 14 24 Pain on Injection 12 13 0 Sepsis 17 12 14 Neurotoxicity 17 10 13 Streaking/Erythe ma 4 2 Phlebitis 3 5 Esophagitis 3 4 Dysphagia 0 10 H morrhage 3 1 Extravasation 3 2 Urticaria 2 0 Recall Skin Reaction 1 0.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Myelosuppression: Dexrazoxane for Injection may increase the myelosuppresive effects of chemotherapeutic agents. Perform hematological monitoring. 5.1) Embryo-Fetal Toxicity: Can cause fetal harm. Advise female patients of reproductive potential of the potential hazard to the fetus. 5.5, 8.1) 5.1 Myelosuppression. Dexrazoxane for Injection may add to the myelosuppression caused by chemotherapeutic agents. Obtain 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 cumulative doxorubicin dose of 300 mg/m 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 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 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 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)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis Mutagenesis Impairment Of Fertility. No long-term carcinogenicity studies have been carried out with dexrazoxane in animals. Nevertheless, 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 weeks in rats (1/3 the human dose on mg/m basis) and as low as 20 mg/kg weekly for 13 weeks in dogs (approximately equal to the human dose on mg/m basis).

CLINICAL PHARMACOLOGY SECTION.

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 cyclic derivative of EDTA that penetrates cell membranes. Results of laboratory studies suggest that dexrazoxane is converted intracellularly to 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 two-compartment open model with first-order elimination. Dexrazoxane has been administered as 15 minute infusion over dose range of 60 to 900 mg/m with 60 mg/m of doxorubicin, and at fixed dose of 500 mg/m with 50 mg/m 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 ug/mL at 15- minute after intravenous administration of 500 mg/m dose of Dexrazoxane for Injection over 15 to 30 minutes prior to the 50 mg/m doxorubicin dose. The important pharmacokinetic parameters of dexrazoxane are summarized in Table 2: Table 2: SUMMARY OF MEAN (%CV a) DEXRAZOXANE PHARMACOKINETIC PARAMETERS AT DOSAGE RATIO OF 10:1 OF DEXRAZOXANE FOR INJECTION: DOXORUBICIN Dose Doxirubicin (mg/m 2) Dose Dexrazoxane for Injection (mg/m 2) Number of Subjects Elimination Half-Life (h) Plasma Clearence (L/h/m 2) Renal Clearence (L/h/m 2) bVolume of Distribution (L/m 2) 50 60 500 600 10 2.5(16) 2.1 (29) 7.88 (18) 6.25 (31) 3.35 (36) ------- 22.4 (22) 22.0 (55) Coefficient of variation Steady-state volume of distribution Distribution Following 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 after 500 mg/m of Dexrazoxane for Injection dose followed by 50 mg/m 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, 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 500 mg/m dose of Dexrazoxane for Injection was excreted in the urine. Renal clearance averages 3.35 L/h/m after the 500 mg/m Dexrazoxane for Injection dose followed by 50 mg/m 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 single 15-minute IV infusion of 150 mg/m 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 crossover study in cancer patients.

CLINICAL STUDIES SECTION.

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 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 lower response rate (48% vs. 63%) and 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 cumulative dose of doxorubicin above 300 mg/m 2. Retrospective historical analyses showed that the risk of experiencing cardiac event (see Table for definition) at cumulative dose of doxorubicin above 300 mg/m 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 shows the number of patients still on treatment at increasing cumulative doses. Figure Cumulative Number of Patients on Treatment FAC vs. FAC/Dexrazoxane for Injection Patients Patients Receiving at Least Seven Courses of Treatment Dexrazoxane-image2.

DESCRIPTION SECTION.

11 DESCRIPTION. Dexrazoxane for injection, cardioprotective agent for use in conjunction with doxorubicin, is 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: 11H 16N 4O M.W.268.28 Dexrazoxane, an intracellular chelating agent, is derivative of EDTA. Dexrazoxane is whitish crystalline powder that melts at 191 to 197C. It is sparingly soluble in water and 0.1 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 pH of 7.0. 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 Dexrazoxane for Injection solutions prepared from Sterile Water for Injection, USP, are intended for further dilution with Lactated Ringers Injection, USP, for rapid intravenous drip infusion. DO NOT ADMINISTER VIA AN INTRAVENOUS PUSH [see Dosage and Administration (2.1, 2.3)]. Dexrazoxane-image1.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE ADMINISTRATION. Reconstitute vial contents and dilute before use. 2.3) Administer Dexrazoxane for Injection by intravenous infusion over 15 minutes. DO NOT ADMINISTER VIA AN INTRAVENOUS PUSH. 2.1, 2.3) The recommended dosage ratio of Dexrazoxane for Injection to doxorubicin is 10:1 (e.g., 500 mg/m Dexrazoxane for Injection to 50 mg/m doxorubicin). Do not administer doxorubicin before Dexrazoxane. 2.1) Reduce dose by 50% for patients with creatinine clearance <40 mL/min. 2.2, 8.7) 2.1 Recommended Dose. d inister Dexrazoxane for Injection via intravenous infusion over 15 inutes. DO NOT ADMINIS TER VIA AN INTRAV ENOUS PU H.The recommended dosage ratio of Dexrazoxane for Injection to doxorubicin is 10:1 (e.g., 500 mg/ 2 Dexrazoxane for Injection to 50 mg m 2doxorubicin). Do not ad inister doxorubicin before Dexrazoxane for Injection. Ad inister doxorubicin within 30 inutes after the co mpletion of Dexrazoxane for Injection infu sion. 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 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 Dexrazoxane for Injection 250 mg vial and 50 mL for Dexrazoxane for Injection 500 mg vial to give concentration of 10 mg/mL. Dilute the reconstituted solution further with Lactated Ringers Injection, USP to 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 hours from the time of reconstitution when stored under refrigeration, to 8C (36 to 46F). 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 hours when stored under refrigeration, to 8C (36 to 46F). The infusion solutions have 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 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.

INDICATIONS & USAGE SECTION.

1 INDICATIONS USAGE. Dexrazoxane for Injection is indicated for reducing the incid ence and severity of cardiomyopathy associated with doxorubicin ad inistration in wo men with metastatic breast cancer who have received cu mulative doxorubicin dose of 300 mg m 2and who will ontinue to receive doxor ubicin therapy to maintain tu mor control. Do not use with the initiat ion of doxorubicin therapy [see Warnings and Precautions (5.2 ]. Dexrazoxane for Injection is cytoprotective agent indicated for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received cumulative doxorubicin dose of 300 mg/m2 and who will continue to receive doxorubicin therapy to maintain tumor control. Do not use Dexrazoxane for Injection with doxorubicin initiation. 1).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis Mutagenesis Impairment Of Fertility. No long-term carcinogenicity studies have been carried out with dexrazoxane in animals. Nevertheless, 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 weeks in rats (1/3 the human dose on mg/m basis) and as low as 20 mg/kg weekly for 13 weeks in dogs (approximately equal to the human dose on mg/m basis).

OVERDOSAGE SECTION.

10 OVERDOSAGE. There are no data on overdosage in the cardioprotective trials; the maximum dose administered during the cardioprotective trials was 1000 mg/m every three weeks. Disposition studies with Dexrazoxane for Injection have not been conducted in cancer patients undergoing dialysis, but retention of 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.

PHARMACOKINETICS SECTION.

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 two-compartment open model with first-order elimination. Dexrazoxane has been administered as 15 minute infusion over dose range of 60 to 900 mg/m with 60 mg/m of doxorubicin, and at fixed dose of 500 mg/m with 50 mg/m 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 ug/mL at 15- minute after intravenous administration of 500 mg/m dose of Dexrazoxane for Injection over 15 to 30 minutes prior to the 50 mg/m doxorubicin dose. The important pharmacokinetic parameters of dexrazoxane are summarized in Table 2: Table 2: SUMMARY OF MEAN (%CV a) DEXRAZOXANE PHARMACOKINETIC PARAMETERS AT DOSAGE RATIO OF 10:1 OF DEXRAZOXANE FOR INJECTION: DOXORUBICIN Dose Doxirubicin (mg/m 2) Dose Dexrazoxane for Injection (mg/m 2) Number of Subjects Elimination Half-Life (h) Plasma Clearence (L/h/m 2) Renal Clearence (L/h/m 2) bVolume of Distribution (L/m 2) 50 60 500 600 10 2.5(16) 2.1 (29) 7.88 (18) 6.25 (31) 3.35 (36) ------- 22.4 (22) 22.0 (55) Coefficient of variation Steady-state volume of distribution Distribution Following 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 after 500 mg/m of Dexrazoxane for Injection dose followed by 50 mg/m 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, 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 500 mg/m dose of Dexrazoxane for Injection was excreted in the urine. Renal clearance averages 3.35 L/h/m after the 500 mg/m Dexrazoxane for Injection dose followed by 50 mg/m 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 single 15-minute IV infusion of 150 mg/m 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 crossover study in cancer patients.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category DRisk SummaryDexrazoxane 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 fetus [see Warnings and Precautions (5.5)]. Animal DataDexrazoxane resulted in maternal toxicity in rats at doses of >=2 mg/kg (1/40 the human dose on mg/m basis) and embryotoxicity and teratogenicity at mg/kg (approximately 1/10 the human dose on mg/m 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 mg/kg. In rabbits, doses of >=5 mg/kg (approximately 1/10 the human dose on mg/m basis) daily during the period of organogenesis caused maternal toxicity and doses of 20 mg/kg (1/2 the human dose on mg/m 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.