DEXRAZOXANE

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: Dexrazoxane, an intracellular chelating agent, is a derivative of EDTA. Dexrazoxane for injection is a white to off-white or pale pink lyophilized powder or cake 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 250 mg vial contains dexrazoxane hydrochloride equivalent to 250 mg dexrazoxane. Hydrochloric Acid, NF is added for pH adjustment. When reconstituted as directed with the 25 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP diluent provided, each mL contains: 10 mg dexrazoxane. The pH of the resultant solution is 3.5 to 5.5. 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 the 50 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP diluent provided, each mL contains: 10 mg dexrazoxane. The pH of the resultant solution is 3.5 to 5.5. dexrazoxane-str

Dexrazoxane for injection is indicated for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300 mg/m 2 and who will continue to receive doxorubicin therapy to maintain tumor control. Do not use with the initiation of doxorubicin therapy [see Warnings and Precautions (5.2) ] . Dexrazoxane for injection is a cytoprotective agent indicated for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300 mg/m 2 and who will continue to receive doxorubicin therapy to maintain tumor control. Do not use dexrazoxane for injection with doxorubicin initiation.

Reconstitute vial contents and dilute before use. ( 2.3 ) Administer dexrazoxane for injection by slow I.V. push or rapid drip intravenous infusion from a bag. ( 2.1 , 2.3 ) 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. ( 2.1 ) Reduce dose by 50% for patients with creatinine clearance < 40 mL/min. ( 2.2 , 8.7 ) 2.1 Recommended Dose Administer dexrazoxane for injection by slow I.V. push or rapid drip intravenous infusion from a bag. 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/m 2 dexrazoxane for injection to 50 mg/m 2 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: Dexrazoxane for injection must be reconstituted with 0.167 Molar (M/6) sodium lactate injection, USP, to give a concentration of 10 mg dexrazoxane for injection for each mL of sodium lactate. The reconstituted solution should be given by slow I.V. push or rapid drip intravenous infusion from a bag. After completing the infusion of dexrazoxane for injection, and prior to a total elapsed time of 30 minutes (from the beginning of the dexrazoxane for injection infusion), the intravenous injection of doxorubicin should be given. Reconstituted dexrazoxane for injection, when transferred to an empty infusion bag, is stable for 6 hours from the time of reconstitution when stored at controlled room temperature, 20° to 25°C (68° to 77°F) or under refrigeration, 2° to 8°C (36° to 46°F). Discard unused solutions. The reconstituted dexrazoxane for injection solution may be diluted with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to a concentration range of 1.3 to 5 mg/mL in intravenous infusion bags. The resultant solutions are stable for 6 hours when stored at controlled room temperature, 20° to 25°C (68° to 77°F) or under refrigeration, 2° to 8°C (36° to 46°F). 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. The reconstituted solution should be given by slow I.V. push or rapid drip intravenous infusion from a bag. After completing the infusion of dexrazoxane for injection, and prior to a total elapsed time of 30 minutes (from the beginning of the dexrazoxane for injection infusion), the intravenous injection of doxorubicin should be given.

Do not use dexrazoxane for injection with non-anthracycline chemotherapy regimens. Dexrazoxane for injection should not be used with non-anthracycline chemotherapy regimens.

In clinical studies, dexrazoxane was administered to patients also receiving chemotherapeutic agents for cancer. Pain on injection was observed more frequently in patients receiving dexrazoxane versus placebo. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eugia US LLC at 1-866-850-2876 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. 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 experienced more severe leukopenia, granulocytopenia, and thrombocytopenia than patients receiving FAC without dexrazoxane [see Warnings and Precautions (5.1) ] . Table 1 below lists the incidence of adverse reactions for patients receiving FAC with either dexrazoxane or placebo in the breast cancer studies. Adverse experiences occurring during courses 1 through 6 are displayed for patients receiving dexrazoxane 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 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 arm, as compared to placebo. Table 1: Adverse Reaction Percentage (%) of Breast Cancer Patients with Adverse Reaction FAC + Dexrazoxane FAC + Placebo Courses 1 to 6 N = 413 Courses ≥ 7 N = 102 Courses 1 to 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

No drug interactions have been identified [see Clinical Pharmacology (12.3) ] .