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)].

fusion. 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.

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 adverse reaction percentage (%) of breast cancer patients with adverse reaction fac + dexrazoxane for injection fac + placebo courses 1- 6 n = 413 courses ≥ 7 n = 102 courses 1- 6 n = 458 courses ≥ 7 n = 99 alopecia 94 100 97 98 nausea 77 51 84 60 vomiting 59 42 72 49 fatigue/malaise 61 48 58 55 anorexia 42 27 47 38 stomatitis 34 26 41 28 fever 34 22 29 18 infection 23 19 18 21 diarrhea 21 14 24 7 pain on injection 12 13 3 0 sepsis 17 12 14 9 neurotoxicity 17 10 13 5 streaking/erythema 5 4 4 2 phlebitis 6 3 3 5 esophagitis 6 3 7 4 dysphagia 8 0 10 5 hemorrhage 2 3 2 1 extravasation 1 3 1 2 urticaria 2 2 2 0 recall skin reaction 1 1 2 0

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)].

s 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.

endent, 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 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 ) b volume of distribution (l/m 2 ) 50 60 500 600 10 5 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/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.

v a ) dexrazoxane pharmacokinetic parameters at a 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 ) b volume of distribution (l/m 2 ) 50 60 500 600 10 5 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/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.

3 weeks in dogs (approximately equal to the human dose on a mg/m 2 basis).

tely equal to the human dose on a mg/m 2 basis).

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/m 2 . 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/m 2 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 dexrazoxane-image2