部份中文右雷佐生资料（仅供参考） 右雷佐生由美国Chiron公司开发，1992年首先在意大利上市，1995年7月获FDA批准。后陆续在欧洲、亚洲、非洲等多国上市。右雷佐生临床适用于预防蒽环类药物诱发的心脏毒性。上市剂型为注射剂，规格为250mg和500mg两种，稀释液分别为0.167mol/l乳酸钠25ml，50ml。 右雷佐生（dexrazoxane）是消旋雷佐生（razoxane）的d-异构体，也是螯合剂乙二胺四乙酸（EDTA）的亲脂性衍生物，能迅速透过细胞膜，降低多柔比星等蒽环类抗肿瘤抗生素的心脏毒性，右雷佐生在细胞内水解为TCRE-198，再与细胞内的铁螯合，使三价铁离子与多柔比星等蒽环类抗肿瘤药物的复合物减少，防止自由基的形成而起效的。右雷佐生还能抑制拓朴异构酶II产生的细胞毒性作用，在动物模型中对某些抗肿瘤药物的细胞毒性有增强或拮抗作用。右雷佐生是目前临床上认可的唯一用于预防蒽环类药心脏毒性的药物，目前在欧美国家的临床试验表明，该药有望成为蒽环类抗肿瘤药物的标准配伍用药。尽管目前右雷佐生主要用于预防蒽环类药物诱发的心脏毒性，但该药在调节拓朴异构酶II的活性和细胞铁代谢等方面的潜力，未来在癌症治疗、免疫学、感染性疾病等方面的应用将可能成为重点。       大量临床试验已证实，对于蒽环类药物引起的心肌损害，右雷佐生能提供有效的预防作用，不仅不影响化疗药物的抗癌活性，而且允许化疗药物给予较高的累积剂量。右雷佐生在许多国家已得到批准，用于降低蒽环类药物引发的心脏毒性。采用超声波心动描记法或左心室射血分数（LVEF）及心肌内膜活检作为心脏毒性的参数。当本品与多柔比星的比率为20:1或10：1时，本品能降低多柔比星引起的心脏毒性。本品组病人心脏事件的危险率比对照组低50%～67%，充血性心衰的危险率比对照组低87.5%～90%。本品组病人能耐受较高累积剂量的多柔比星，多柔比星从300mg/m2之后开始用药时仍有心脏保护作用，发生心脏事件的危险性下降77.80%。与高剂量表柔比星联合治疗时，右雷佐生与表柔比星的剂量比为10：1时具有心脏保护作用。右雷佐生对接受含阿霉素化疗方案治疗的儿童患者亦是有益的。上述数据表明本品是一安全、有效的心脏保护剂。 近年来DOX与PAC联用也是治疗晚期乳腺癌的一个有效方案，客观有效率可达50%～90%。紫杉醇也具有心脏毒性，可导致心动过缓等，已有建议将右雷佐生加入到这一方案中。动物实验显示，紫杉醇不加剧DOX诱发的慢性心肌病变，右雷佐生加入到DOX和紫杉醇联合方案中，对DOX诱发的心脏毒性仍具有预防作用，且不增加非心脏毒性。为了降低蒽环类药与紫杉烷类药联用的心脏毒性，目前提出了多种方案（包括使用右雷佐生），有关右雷佐生在上述联用方案中的实际效果尚需在临床试验中进行评价。 研究表明，接受过蒽环类药物治疗有可能长期存活的癌症者，有发生进行性心脏毒性的危险。早期就开始使用心脏保护剂是否能降低这种危险，有待进一步研究。 右雷佐生（DEXRAZOXANE）-辛卡德（ZINECARD）-250毫克、500毫克/瓶 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ZINECARD safely and effectively. See full prescribing information for ZINECARD. ZINECARD ® (dexrazoxane) for injection Initial U.S. Approval: 1995 INDICATIONS AND USAGE ZINECARD 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/m2 and who will continue to receive doxorubicin therapy to maintain tumor control. Do not use ZINECARD with doxorubicin initiation. (1) DOSAGE AND ADMINISTRATION Reconstitute vial contents and dilute before use. (2.3) Administer ZINECARD by intravenous infusion over 15 minutes. DO NOT ADMINISTER VIA AN INTRAVENOUS PUSH. (2.1, 2.3) The recommended dosage ratio of ZINECARD to doxorubicin is 10:1 (e.g., 500 mg/m2 ZINECARD to 50 mg/m2 doxorubicin). Do not administer doxorubicin before ZINECARD. (2.1) Reduce dose by 50% for patients with creatinine clearance <40 mL/min. (2.2, 8.7) DOSAGE FORMS AND STRENGTHS 250 mg or 500 mg single dose vials as sterile, pyrogen-free lyophilizates. (3) CONTRAINDICATIONS ZINECARD should not be used with non-anthracycline chemotherapy regimens. (4) WARNINGS AND PRECAUTIONS Myelosuppression: ZINECARD 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) ADVERSE REACTIONS In clinical studies, ZINECARD was administered to patients also receiving chemotherapeutic agents for cancer. Pain on injection was observed more frequently in patients receiving ZINECARD versus placebo. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. USE IN SPECIFIC POPULATIONS Nursing Mothers: Discontinue drug or nursing. (8.3) See 17 for PATIENT COUNSELING INFORMATION. Revised: 4/2014 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE ZINECARD 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/m2 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)]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose Administer ZINECARD Injection via intravenous infusion over 15 minutes. DO NOT ADMINISTER VIA AN INTRAVENOUS PUSH. The recommended dosage ratio of ZINECARD to doxorubicin is 10:1 (e.g., 500 mg/m2 ZINECARD to 50 mg/m2 doxorubicin). Do not administer doxorubicin before ZINECARD. Administer doxorubicin within 30 minutes after the completion of ZINECARD infusion. 2.2 Dose Modifications Dosing in Patients with Renal Impairment Reduce ZINECARD dosage in patients with moderate to severe renal impairment (creatinine clearance values less than 40 mL/min) by 50% (ZINECARD to doxorubicin ratio reduced to 5:1; such as 250 mg/m2 ZINECARD 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 ZINECARD dosage proportionately (maintaining the 10:1 ratio) in patients with hepatic impairment. 2.3 Preparation and Administration Preparation and Handling of Infusion Solution Reconstitute ZINECARD with Sterile Water for Injection, USP. Reconstitute with 25 mL for a ZINECARD 250 mg vial and 50 mL for a ZINECARD 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, ZINECARD 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 ZINECARD 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 ZINECARD with other drugs. Administer the final diluted solution of ZINECARD 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 ZINECARD infusion. 3 DOSAGE FORMS AND STRENGTHS ZINECARD (dexrazoxane for injection) is available in 250 mg or 500 mg single dose vials as sterile, pyrogen-free lyophilizates. 4 CONTRAINDICATIONS Do not use ZINECARD with non-anthracycline chemotherapy regimens. 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression ZINECARD may add to the myelosuppression caused by chemotherapeutic agents. Obtain a complete blood count prior to and during each course of therapy, and administer ZINECARD and chemotherapy only when adequate hematologic parameters are met. 5.2 Concomitant Chemotherapy Only use ZINECARD in those patients who have received a cumulative doxorubicin dose of 300 mg/m2 and are continuing with doxorubicin therapy. Do not use with chemotherapy initiation as ZINECARD 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 ZINECARD starting with their first cycle of FAC therapy, patients who were randomized to receive ZINECARD 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 ZINECARD 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 ZINECARD in combination with chemotherapy. ZINECARD is not indicated for use in pediatric patients. Some adult patients who received ZINECARD 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 ZINECARD 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 ADVERSE REACTIONS 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 ZINECARD. The dose of doxorubicin was 50 mg/m2 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 ZINECARD experienced more severe leukopenia, granulocytopenia, and thrombocytopenia than patients receiving FAC without ZINECARD [see Warnings and Precautions (5.1)]. Table 1 below lists the incidence of adverse reactions for patients receiving FAC with either ZINECARD or placebo in the breast cancer studies. Adverse experiences occurring during courses 1 through 6 are displayed for patients receiving ZINECARD 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 ZINECARD 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 ZINECARD arm, as compared to placebo. Table 1  Adverse Reaction Percentage (%) of Breast Cancer Patients With Adverse Reaction FAC + ZINECARD 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 7 DRUG INTERACTIONS No drug interactions have been identified [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary ZINECARD 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/m2 basis) and embryotoxicity and teratogenicity at 8 mg/kg (approximately 1/10 the human dose on a mg/m2 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/m2 basis) daily during the period of organogenesis caused maternal toxicity and doses of 20 mg/kg (1/2 the human dose on a mg/m2 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 ZINECARD 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 ZINECARD 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 ZINECARD 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 ZINECARD 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 ZINECARD (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: C11H16N4O4    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 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 ZINECARD 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 ZINECARD 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 ZINECARD 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 (%CV*) DEXRAZOXANE PHARMACOKINETIC PARAMETERS AT A DOSAGE RATIO OF 10:1 OF ZINECARD:DOXORUBICIN  Dose Doxorubicin (mg/m2) Dose ZINECARD (mg/m2) Number of Subjects Elimination Half-Life (h) Plasma Clearance (L/h/m2) Renal Clearance (L/h/m2) †Volume of Distribution (L/m2) 50 500 10 2.5 (16) 7.88 (18) 3.35 (36) 22.4 (22) 60 600 5 2.1 (29) 6.25 (31) — 22.0 (55) Coefficient of variation 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 ZINECARD 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 ZINECARD was excreted in the urine. Renal clearance averages 3.35 L/h/m2 after the 500 mg/m2 ZINECARD dose followed by 50 mg/m2 of doxorubicin. Specific Populations Pediatric Pharmacokinetics following ZINECARD 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 ZINECARD. 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 (AUC-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 ZINECARD administration have not been evaluated in patients with hepatic impairment. The ZINECARD 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). ZINECARD 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 ZINECARD 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 ZINECARD 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 ZINECARD 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 ZINECARD 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 ZINECARD 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 ZINECARD beginning with their seventh course of FAC than in the patients who did receive ZINECARD (HR=13.08; 95% CI: 3.72, 46.03; p<0.001). Overall, 3% of patients treated with ZINECARD developed CHF compared with 22% of patients not receiving ZINECARD. 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/ZINECARD Patients Patients Receiving at Least Seven Courses of Treatment  15 REFERENCES 1."OSHA Hazardous Drugs." OSHA http://www.osha.gov/SLTC/hazardousdrugs/index.html 16 HOW SUPPLIED/STORAGE AND HANDLING ZINECARD (dexrazoxane for injection) is available in the following strengths as sterile, pyrogen-free lyophilizates. NDC 0013-8717-62 250 mg single dose vial with a red flip-top seal, packaged in single vial packs. NDC 0013-8727-89 500 mg single dose vial with a blue flip-top seal, packaged in single vial packs. Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Follow special handling and disposal procedures.1 17 PATIENT COUNSELING INFORMATION 17.1 Myelosuppression Treatment with ZINECARD 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 ZINECARD 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)]. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f68a34ae-e17e-45b3-8c8e-8d7194b2124a ---------------------------------------- 注：以下产品不同规格和不同价格，购买时请以咨询为准！ ---------------------------------------- 【原产地英文商品名】ZINECARD-500mg/Vial 【原产地英文药品名】DEXRAZOXANE 【中文参考商品译名】 ·辛卡德-500毫克/瓶 ·辛卡德-250毫克/瓶 【中文参考化合物名称】右雷佐生 【生产厂家英文名】辉瑞公司 ---------------------------------------- 【原产地英文商品名】ZINECARD-500mg/Vial 【原产地英文药品名】DEXRAZOXANE 【中文参考商品译名】 ·辛卡德-500毫克/瓶 ·辛卡德-250毫克/瓶 【中文参考化合物名称】右雷佐生 【生产厂家英文名】Pharmacia & Upjohn Company 右雷佐生简介 Dexrazoxane（Cardioxane，Zinecard，右雷佐生）是依地酸（edetic acid）的衍生物，是位点特异的心脏保护药物，可以有效地对抗蒽环类抗癌药所引起的心脏损伤。Dexrazoxane在美国和一些欧洲国家已获得批准，用于接受阿霉素治疗的进展期或转移性乳腺癌病人的心脏保护。在有些国家Dexrazoxane被批准的适应症范围更为广泛，可用于接受蒽环类抗癌药治疗的多种肿瘤病人的心脏保护。 药效和药理学             临床试验显示，静脉注射Dexrazoxane可以显著降低接受蒽环类抗癌药治疗的进展期乳腺癌、软组织肉瘤和小细胞肺癌患者的充血性心力衰竭以及其他心脏不良反应的发生率。无论Dexrazoxane在抗癌药使用之前或之后给药，甚至当阿霉素累积剂量超过300mg/m2，Dexrazoxane都可表现出心脏保护作用。此外，当患者本身有心血管风险因子时，Dexrazoxane也具有心脏保护作用。而且Dexrazoxane并不影响蒽环类抗癌药的疗效。该产品的耐受性良好，其不良反应和安慰剂类似，主要的不良反应是Dexrazoxane可以引起比较高的白细胞减少症（分别为78%和68%，p<0.01）。           Dexrazoxane进入细胞后的水解产物具有金属螯合活性，可以螯合游离铁以及与蒽环类抗癌药结合的铁，防止具有心脏毒性的氧自由基的形成。实验动物给药阿霉素或表阿霉素，经Dexrazoxane处理后的实验动物心脏损伤的发生率显著降低，而生存率显著提高。实验动物研究显示，Dexrazoxane在阿霉素给药前立即给药或同时给药的效果要好于之后给药。此外，在第一次给药阿霉素之前给药，其心脏保护效果要优于延迟给药。 药代动力学 静脉注射Dexrazoxane的药代动力学遵循2室模型的一级清除动力学。在60-900mg/m2剂量范围内,Dexrazoxane的吸收动力学为线性。该药物的组织分布迅速，在2-4小时内达到平衡，肝脏和肾脏是母体药物和水解产物浓度最高的器官。血浆蛋白结合少量。该药物在肝脏、肾脏、心脏、红细胞和白细胞内被酶水解为活性更强的开环形式。清除主要通过肾脏以原型形式排出体外。在阿霉素或表阿霉素之前15-30分钟使用dexrazoxane，对两种药物的药代动力学都没有显著影响。 临床疗效 Dexrazoxane对接受蒽环类化疗药治疗的进展期乳腺癌病人有显著的心脏保护作用。总结所有Ⅲ期临床试验的数据，Dexrazoxane使用情况下心脏事件的发生率为0-15%，而不使用时的发生率为16-50%，前者显著少于后者。充血性心力衰竭的发生率在Dexrazoxane使用时为0-3%，而不使用时的发生率为8-27%。接受阿霉素治疗的小细胞肺癌病人以及接受高剂量表阿霉素治疗的软组织肉瘤病人联合使用Dexrazoxane时，心血管事件（软组织肉瘤病人还包括充血性心力衰竭）的发生率都显著降低。对接受以蒽环类抗生素为基础的化疗方案的儿童或青少年恶性肿瘤（包括急性淋巴细胞白血病和各种肉瘤）患者（年龄小于24岁），Dexrazoxane可以提供有效的短期和中期心脏保护效果，但长期数据目前还没有。       根据两项荟萃分析的研究结果，Dexrazoxane可以使蒽环类抗癌药诱导的心脏毒性的相对风险（与不使用dexrazoxane的情况相比）减少72-76%，而化疗失败的相对风险并没有增高，病人的生存率也没有降低。 耐受性 Dexrazoxane的耐受性良好，耐受性情况和安慰剂类似，不同的是Dexrazoxane相关的严重白细胞减少的病例显著增高。虽然儿童应用的数据还有限，但已有的结果显示儿童对Dexrazoxane的耐受性也比较好。Dexrazoxane与阿霉素无论是以10∶1或20∶1的剂量比例给药，耐受性类似。