1、PAGE 1PAGE 20核準和修改日期：核準日期：2005年9月12日修改日期：2006年6月19日重組人血管內皮抑制素注射液說明書請仔細閱讀說明書并在醫師指導下使用【藥品名稱】通用名稱：重組人血管內皮抑制素注射液商品名稱：恩 度 ENDOSTAR 英文名稱：Recombinant Human Endostatin Injection漢語拼音：Chongzu Ren Xueguanneipiyizhisu Zhusheye【成份】主要成分：重組人血管內皮抑制素來 源：大腸桿菌工程菌發酵產品輔 料：醋酸鈉，冰醋酸，甘露醇【性狀】本品為無色澄明液體， pH 5.50.5。【適應癥】本品聯合NP化

2、療方案用于治療初治或復治的/期非小細胞肺癌患者。此適應癥的依據來源于一項已完成的期多中心臨床試驗（詳見【臨床試驗】項）。【規格】 15 mg/3ml/支(2.4105 U/支)【用法用量】本品為靜脈給藥，臨用時將本品加入250500 ml生理鹽水中，勻速靜脈點滴，滴注時間34小時。與NP化療方案聯合給藥時，本品在治療周期的第114日，每天給藥一次，每次7.5 mg /m2（1.2105U/m2），連續給藥14天，休息一周，再繼續下一周期治療。通常可進行24個周期的治療。臨床推薦醫師在患者能耐受的情況下可適當延長本品的使用時間。【不良反應】在期臨床研究中，共有470例晚期非小細胞肺癌（NSCLC

3、）患者使用了本品，常見的藥物不良反應（1/100,1/10）主要有心臟不良反應，少見的藥物不良反應（1/1000,1/100）主要有消化系統反應、皮膚及附件的過敏反應。 心臟反應：用藥初期少數患者可出現輕度疲乏、胸悶、心慌，絕大多數不良反應經對癥處理后可以好轉，不影響繼續用藥，極個別病例因上述癥狀持續存在而停止用藥。發生心臟不良反應的患者共有30例（6.38），主要表現為用藥后第27天內發生心肌缺血，心臟不良反應均為、度或輕、中度不良反應，未危及患者生命，其中6.4 的患者癥狀較為明顯，但均為可逆性，且多數不影響本品的繼續使用，不需要對癥治療即可緩解。因心臟反應而停止治療的患者僅占2.1 。常

4、見的心臟不良反應癥狀有竇性心動過速、輕度ST-T改變、房室傳導阻滯、房性早搏、偶發室性早搏等，常見于有冠心病、高血壓病史患者。為確保患者安全，建議在臨床應用過程中定期檢測心電圖，對有心臟不良反應的患者使用心電監護，對有嚴重心臟病史疾病未控者應在醫囑指導下使用。 消化系統反應：偶見腹瀉，肝功能異常，主要包括無癥狀性轉氨酶升高，黃疸，主要為輕度及中度，罕見重度。此不良反應均為可逆，輕度患者無需對癥處理，中、重度經減緩滴注速度或暫停藥物使用后適當對癥處理可緩解，僅有少數病例需對癥治療，但通常不影響藥物的繼續使用。 皮膚及附件：過敏反應表現為全身斑丘疹，伴瘙癢。此不良反應為可逆，暫停使用藥物后可緩解。

5、發熱，乏力，多為輕中度。在此項多中心的臨床研究中，接受本品治療的470例患者中，未觀察到與藥物不良反應相關的死亡病例。【禁忌】心、腎功能不全者慎用。【注意事項】 過敏體質或對蛋白類生物制品有過敏史者慎用； 有嚴重心臟病或病史者，包括：有記錄的充血性心力衰竭病史、高危性不能控制的心率失常、需藥物治療的心絞痛、臨床明確診斷心瓣膜疾病、心電圖嚴重心肌梗塞病史以及頑固性高血壓者慎用。本品臨床使用過程中應定期進行心電檢測，出現心臟不良反應者應進行心電監護； 本品為無色澄明液體，如遇有渾濁、沉淀等異常現象，則不得使用。包裝瓶有損壞、過期失效不能使用。【孕婦及哺乳期婦女用藥】本品尚未在孕婦及哺乳期婦女中使用

6、，也未進行動物生殖毒性研究，需要時應在醫師嚴密觀察下使用。【兒童用藥】本品尚無兒童患者用藥研究資料，確實需要用藥時，應在醫生指導下使用。【老年用藥】對有嚴重心臟病史的老年腫瘤患者，應在醫師嚴密觀察下應用。【藥物相互作用】未系統研究過本品與其它藥物的相互作用。在臨床使用時，應注意勿與可能影響本品酸堿度的其它藥物或溶液混合使用。【藥物過量】本品臨床研究中，單次靜脈滴注給藥量達到30210 mg/m2（4.8105 33.6105 U/m2）或連續28天靜脈滴注7.530 mg/m2（1.21054.8105 U/m2）時出現的人體反應見【不良反應】項下描述的情況，尚無更大使用劑量的臨床使用數據資料

7、。【臨床試驗】多中心臨床研究由中國醫學科學院腫瘤醫院、國家新藥(抗腫瘤)臨床研究中心以孫燕教授為主要研究者的研究小組共同完成。單藥治療：本品的A期臨床試驗（單藥）采用單藥、隨機、開放、對照、多中心的研究方法，主要評價本品的治療效果，比較7.5 mg/m2（1.2105 U/m2）和15 mg/m2（2.4105 U/m2）的量效關系和安全性的差異，從而確定臨床用藥的最佳有效劑量。受試者均為經病理學和/或細胞學明確診斷為非小細胞肺癌（NSCLC）的復治腫瘤患者。試驗分為7.5 mg/m2和15 mg/m2兩個劑量組，分別靜脈滴注312小時，每日一次，連續給藥28天，給藥結束后評價療效。療效評價依

8、據WHO的實體瘤評價標準，有8家醫院參加了試驗，共觀察NSCLC的患者68例，其中60例患者完成了療效評估，結果見表1。表1.本品單藥治療效果給 藥 劑 量7.5 mgm215 mgm2P值病 例 數N=31N=29有 效 率（）33P0.05臨床受益率（）6866P0.05中位腫瘤進展時間（天）10094P0.05注：有效率（CRPR總例數100）、臨床受益率（CRPRMRSD總例數100）試驗結果表明，7.5 mg/m2（1.2105 U/m2）劑量組和15 mg/m2（2.4105 U/m2）劑量組在療效和安全性方面無明顯差異，故推薦7.5 mg/m2作為臨床常規使用劑量。聯合治療：在4

9、93例晚期非小細胞肺癌（NSCLC）患者中進行了本品聯合NP方案的隨機、雙盲對照、多中心的期臨床試驗。給藥方案如下：試驗組NVB 25 mg/m2第1、5天；DDP 30 mg/m2，第2、3、4天；本品7.5 mg/m2（1.2105 U/m2），第114天連續給藥；對照組： NVB 25 mg/m2 ，第1、5天；DDP 30 mg/m2，第2、3、4天；生理鹽水（NS），第114天。研究的終點為臨床有效率（CR+PR/總例數100%）、臨床受益率（CR+PR+MR+SD/總例數100%）、腫瘤進展時間（TTP）、中位生存時間、1年生存率、生活質量（QOL）以及安全性。其中486例可評價療

10、效，試驗組對照組322164例，初治復治347139例。結果見表2。表2.本品聯合化療治療效果總病例（N=486）一線治療（初治，N=347）二線治療（復治，N=139）NP恩 度NPNSNP恩 度NPNSNP恩 度NPNS有效率（）P值35.4019.5140.0023.9323.918.51P0.01P0.01P0.05臨床受益率（）P值73.2964.0276.5264.9665.2261.70P0.05P0.05P0.05中位腫瘤進展時間(月)P值6.253.596.613.655.723.16P0.001P0.001P0.001中位生存時間(月)P值14.879.9015.169.7

11、714.6710.00P0.001P0.001P0.051年生存率（）P值62.7531.4664.0831.8359.4529.87P0.001P0.001P0.05【藥理毒理】 藥理作用重組人血管內皮抑制素為血管生成抑制類新生物制品，其作用機理是通過抑制形成血管的內皮細胞遷移來達到抑制腫瘤新生血管的生成，阻斷了腫瘤細胞的營養供給，從而達到抑制腫瘤增殖或轉移目的。體外實驗結果顯示，本品對人微血管內皮細胞株HHEC的遷移、Tube 形成有抑制作用，并能明顯抑制雞胚尿囊膜血管生成，提示本品具有一定的體外抗血管生成作用。此外，本品對人肺腺癌細胞SPC-A4有一定的生長抑制作用。體內實驗結果顯示，本

12、品對鼠腫瘤模型（S180肉瘤、H22肝癌），人異種移植腫瘤（SPC-A4肺腺癌、SGC7901胃癌、Hela宮頸癌、SMMC-7721 和Bel7402肝癌）有抑瘤作用。 毒理作用安全藥理學：靜脈注射本品高、中、低劑量組1.5、3、6 mgkg（2.4104、4.8104、9.6104 U/kg），麻醉犬的血壓、呼吸及心電圖指標在給藥前、后無明顯改變，小鼠自主活動次數未受影響。動物溶血性、刺激性和過敏反應：本品0.08 mgml在觀察時間內無溶血及紅細胞凝集現象；豚鼠間日腹腔注射本品0.5 ml只（0.036 mgml），連續3次，第一次給藥后14天及21天靜脈注射本品1 ml只（0.036

13、mgml），均未發生過敏反應；家兔靜脈刺激性試驗未見明顯的血管擴張、紅腫等刺激反應，未見管壁增厚等形態學改變。急性毒性：本品小鼠靜脈或腹腔給藥的LD50大于450.5 mg（7.2106U）/kg。長期毒性：大鼠的長期毒性試驗顯示，連續腹腔注射3、6、12 mg/kg/day（4.8104 、9.6104 、19.2104 U/kg/day）三個劑量組共45天，給藥結束后及停藥21天，各組動物的臟器如心、肝、脾、肺、腦、胃、小腸、子宮、睪丸等臟器與對照組比較均未見明顯病理形態學改變。Beagle犬的長期毒性試驗顯示，連續靜脈注射2、10、25 mg/kg/day（3.2104 、16.0104

14、 、40.0104 U/kg/day）三個劑量組共13周，對Beagle犬無明顯毒性靶器官，不良反應為血液網織紅細胞增高，但停藥后可恢復，并無延遲性毒性反應。獼猴的長期毒性試驗顯示，連續靜脈注射3 mg（4.8104 U）/kg/day (50.4 mg/m2)，10 mg（1.6105 U）/kg/day (167.9 mg/m2)，30 mg（4.8105 U）/kg/day (503.7 mg/m2)三個劑量組共9個月，各組獼猴體征、外觀行為、活動等均未見明顯異常反應。體重與進食量、血液學、血液生化學、心電圖和尿液檢查結果均在正常值范圍內波動，提示對肝、腎功能無明顯損傷。此外，蛋白質、脂

15、肪、糖代謝基本正常。病理組織學結果顯示，連續9個月靜脈給藥，32只獼猴臟器系數各組無明顯差異，未見與藥物劑量相關的異常變化，提示本品在小于30 mg（4.8105 U）/kg/day (503.7 mg/m2)的劑量范圍內連續靜脈注射給藥9個月，未見明顯毒性反應，為安全劑量。【藥代動力學】健康志愿者單次30 min內靜脈滴注本品30 mg（4.8105 U）和60 mg（9.6105 U）/m2，及120 min內靜脈滴注120 mg（19.2105 U）和210 mg（33.6105 U）/m2（滴注速率分別為1、2及1和1.75 mg/m2/min），其末端消除半衰期（t1/2）為10小時

16、左右，全身清除率(CLs)為2.8 L/h/m2左右。本品在30120 mg/m2（4.8105 19.2105 U/m2）劑量范圍于正常人體內呈近似線性藥代動力學，可以用線性模型預測不同劑量、滴注速率和時間的血藥濃度。滴注速率、時間和總劑量均可影響AUC和峰濃度水平。腫瘤患者每日2小時內靜脈滴注本品，連續28天，個體間藥時曲線差異性很大。谷濃度隨給藥次數增加有持續增高的趨勢，總劑量和滴注次數可影響峰濃度和谷濃度水平。正常小鼠靜脈給藥后泌尿排泄系統的濃度最高，腎、尿、肺和肝高于血漿，其它組織均低于血漿，肌肉、脂肪、和腦濃度最低。荷瘤小鼠靜脈注射本品后全身分布與正常小鼠相近，腫瘤組織中分布不高，

17、與肌肉和脂肪組織濃度相近。【抗體產生】用酶聯免疫吸附試驗間接ELISA法檢測獼猴連續9個月靜脈注射重組人血管內皮抑制素血清中抗體IgG。給藥后產生的抗體與劑量、時間有關，劑量越高產生抗體的獼猴數量越多，且產生抗體的滴度也越高。抗體在給藥1個月后就能檢測到抗體、抗體滴度隨時間發生變化，一般給藥前3個月抗體滴度較穩定，而5、7、9、10個月抗體滴度下降，甚至抗體消失。通過采用細胞測活方法分析血清中本品的活性，結果活性沒有變化，表明產生的抗體為非中和抗體。人的抗體測定方法同上，檢測患者血清中抗本品的IgA、IgG、IgM、IgE及抗His-tag抗體。在接受檢測的31例受試患者中，治療組20例，對照

18、組11例，結果治療組2例出現顯示抗本品抗體IgA陽性，產生時間分別是第32 天、24月，1例出現抗His-tag抗體IgA陽性，對照組2例顯示IgG陽性，滴度均為110，其余患者治療后均檢測不出抗體反應。低滴度（110）的抗血清抗體體外試驗未見中和本品生物活性的作用。【貯藏】于28避光保存和運輸。【包裝】3.0 ml預灌封注射器包裝，PVC吸塑泡罩密封包裝，每盒 1 支，14 支/中盒，8 中盒/箱。【有效期】暫定18個月【執行標準】試行標準 YBS01242005【批準文號】國藥準字S20050088【生產企業】企業名稱：煙臺山東先聲麥得津生物工程股份制藥有限公司 (Yantai Medge

19、nn Co., Ltd.)生產地址：山東省煙臺經濟技術開發區榮昌路1號郵政編碼：264006電話6383080 免費電話：800-8289800傳真址： HYPERLINK E-mail： HYPERLINK mailto:office officeApproved on September 12, 2005 Revised on June 19, 2006Preparation guide for use with Recombinant Human Endostatin InjectionRead the entire content

20、s prior to the preparation of Endostar and use under doctors instruction【Drug names】Generic Name: Recombinant Human Endostatin Injection Trade Name: ENDOSTAREnglish Name：Recombinant Human Endostatin Injection Chinese Name (Pinyin): Chongzu Ren Xueguanneipiyizhisu Zhusheye【Composition】 Main compositi

21、on: Recombinant Human Endostatin Excipients：Soddium acetate, Acetic acid , Mannitol【Description】Colorless transparent liquid. pH 5.50.5【Indications】ENDOSTAR + NP chemotherapy regimen is used to treat Stage III/IV NSCLC patients either untreated or pretreated. This indication is based on a completed

22、multi-center Phase III clinical trial (see Clinical Studies). 【Strength】15mg/3ml/vial (2.4105 U/ vial)【Dose and administration】Add ENDOSTAR into 250500ml NS just before the use, drip intravenously at uniform speed for 34h. At combined administration with NP chemotherapy regimen, ENDOSTAR is administ

23、ered continuously at 7.5mg/m2 (1.2105U/m2) once a day during Day 114 of treatment cycle, and then continues the next treatment cycle only after the rest for 1 week rest (generally 24 treatment cycles). The physician is recommended to properly extend its administration time in clinical application wi

24、thin the tolerance of patients. 【Adverse Reactions】During Phase IIII clinical trial, ENDOSTAR is administered in 470 advanced NSCLC patients. The frequent adverse eventsreactions (1-10%) mainly occurred inon heart, and rare adverse eventsreactions (0.1-1%) mainly occurred in digestive system and ski

25、n/annexa allergy. 1. Heart: At the early stage of administration, few patients have mild fatigue, chest distress and palpitation. In most cases, these symptoms may improve enough so as not to influence the administration continuation after the symptomatic treatment. But they can persist to discontin

26、ue the administration in very few cases. A minority of cases had to stop the drug for the continuing above-mentioned symptoms. 30 patients (6.38%) have Degree I/II or mild/moderate cardiologic adverse eventreactions of mainly myocardial ischemia within Days 27 after the administration and posing no

27、dangers to the patients life. 6.4 of these cases have more evident but reversible symptoms, which does not influence the administration continuation but can alleviate without any symptomatic treatment. Only 2.1 of the cases stop the treatment due to adverse eventsreactions. In the patients with prev

28、ious coronary heart disease and hypertension, ENDOSTAR causes the following frequent cardiologic adverse eventsreactions: sinus tachycardia, mild ST-T change, AV conduction blocking, atrial premature beat and rare ventricular premature beat. Thus, to guarantee patients safety, regular ECG examinatio

29、n is recommended for the patients with cardiologic adverse eventreactions during clinical application. The Ppatients with previous uncontrolled serious heart diseases must use ENDOSTAR carefully under the guidance of physicians. 2. Digestive System: Rare diarrhea and liver dysfunction (mainly sympto

30、m-free transaminase elevation and jaundice). All these adverse eventreactions are mainly mild/moderate but rarely serious. Most are reversible and mild cases do not require symptomatic treatment; Moderate or serious cases may be alleviated through the slowing of dripping speed or through the proper

31、symptomatic treatment after drug withdrawal; and only few cases require symptomatic treatment but generally have no influence on administration continuation. 3. Skin/Annexa: The allergy mainly includes reversible systemic maculopapule accompanied with itching (relievable after drug withdrawal) and m

32、ostly mild/moderate fever and fatigue. No death related to adverse eventreactions was observed in this multi-center clinical trial inon all 470 ENDOSTAR-treated patients. 【Contraindications】Use carefully in the patients with heart/renal hypofunction. 【Precautions】1. Use carefully for the personpatie

33、nts with allergic constitution or previous allergy to protein biological products; 2. Use carefully for the patient with existing or previous serious heart diseases, including: congestive heart failure, high-risk uncontrollable arrhythmia, angina pectoris requiring drug treatment, valvular disease o

34、f definite clinical diagnosis, serious myocardial infarction on ECG and persistent hypertension. ECG examination shall be regularly made during its clinical application, and ECG monitoring performed for the patients with cardiologic adverse reactions; 3. This product is colorless transparent liquid,

35、 and must not be used in case of abnormalities (such as turbidity and sediment), broken packaging vial and expired. 【Pregnancy and lactation】Never used in pregnant and lactating women, no previous animal experiment on its genital toxicity. Thus, use only under the close supervision of physicians. 【P

36、ediatric use】No previous clinical trial on its administration in pediatric patients. Used only if medication is absolutely needed and only under the guidance of physicians. 【Geriatric use】Use only under the close observation of physicians for the old tumor patients with previous serious heart diseas

37、e. 【Drug interactions】No previous systematic research on its interaction with other drugs. During the clinical application, do not mix with other drugs or solutions possibly influencing its pH value. 【Overdose】In this clinical trial, the above-mentioned adverse reactions occur after the single intra

38、venous drip of 30210mg/m2 (4.810533.6105U/m2) or after the continuous intravenous drip of 7.530mg/m2 (1.21054.8105U/m2) for 28d. There is no clinical data of higher dose. See under section of Adverse Effect. 【Clinical studies】The National Clinical Trial Center for New Drugs (Anti-Tumor) of Cancer Ho

39、spital, Chinese Academy of Medical Sciences, led a research team to jointly conduct a multi-center clinical trial.Single-drug Administration: Phase A clinical trial (single-drug administration) adopts the randomly controlled, open-labeled and multi-center research method. It mainly assesses the effi

40、cacy of ENDOSTAR, compares the dose-efficacy relation and safety difference of 7.5mg/m2 (1.2105U/m2) and 15mg/m2 (2.4105U/m2), and thus determines the optimum effective dose for clinical application. All subjects are retreated tumor patients pathologically and/or cytologically diagnosed definitely a

41、s non-small-cell lung cancer (NSCLC). The subjects are divided into 7.5mg/m2 and 15mg/m2 dose group at intravenous drip for 312h once a day continuously for 28d respectively. After the completion of administration, the efficacy is assessed according to the Efficacy Evaluation Criterion on Solid Tumo

42、r (WHO). A total of 8 hospitals participates in this trial to observe 68 NSCLC patients, among which 60 patients complete efficacy assessment (Table 1). Table 1 Efficacy after Single-drug AdministrationDose7.5 mgm215 mgm2Value P Number of cases N=31N=29Response rate （）33P0.05Clinical benefit rate （）

43、6866P0.05Median time to progress (TTP, d) 10094P0.05As shown by test results, 7.5mg/m2 (1.2105U/m2) dose group and 15mg/m2 (2.4105U/m2) dose group are significantly different in efficacy and safety. Thus, 7.5mg/m2 is recommended as routine clinical dose. Combination treatment: A randomly controlled,

44、 open-labeled and multi-center Phase III clinical trial is made on the combined administration of ENDOSTAR and NP regimen in 493 advanced NSCLC patients. Administration regimen of test group: 25mg/m2 NVB at Day 1 and Day 5; 30mg/m2 DDP at Day 2, Day 3, and Day 4; and 7.5mg/m2 (1.2105U/m2) ENDOSTAR c

45、ontinuously during Day 114. Administration regimen of control group: 25mg/m2 NVB at Day 1 and Day 5; 30mg/m2 DDP at Day 2, Day 3, and Day 4; and normal saline (NS) during Day 114. The endpoint research index includes: response rate （CRPRtotal cases100）, clinical benefit rate （CRPRMRSDtotal cases100）

46、, TTP, median survive time, one-year survival rate, quality of life (QOL) and safety. There are 486 cases with evaluable efficacy, i.e. test group: control group =322:164 (cases), and untreated: pretreated =347:139 (cases). (Table 2) .Table 2 Efficacy of Chemotherapy + ENDOSTARTotal Number of Cases

47、（N=486） First-Line Treatment (untreated, n=347)Second-Line Treatment (pretreated, n= 139) NP + ENDOSTARNP+ NSNP + ENDOSTARNP+ NSNP + ENDOSTARNP+ NSResponse rate (%) value P35.4019.5140.0023.9323.918.51P0.01P0.01P0.05Clinical benefit rate (%) value P73.2964.0276.5264.9665.2261.70P0.05P0.05P0.05Median

48、 TTP (month) value P6.253.596.613.655.723.16P0.001P0.001P0.001Median survival time (month)value P14.879.9015.169.7714.6710.00P0.001P0.001P0.05One-year survival rate (%) value P62.7531.4664.0831.8359.4529.87P0.001P0.001P0.05【Pharmacology and toxicology】1. Pharmacological action Rh-Endostatin is a new

49、 angiogenesis-inhibiting biological product. It inhibits the metastasis of angiogenesis endothelial cells, inhibits the formation of tumor new blood vessel, obstructs the nutrition supply of tumor cells, and thus inhibits the proliferation or metastasis of tumor. As shown by in vitro test results, E

50、NDOSTAR inhibits the metastasis of HHEC and the formation of Tube, significantly inhibits the angiogenesis of chicken embryo allantoic membrane. Thus, ENDOSTAR suppresses angiogenesis in vitro to a certain extent. In addition, it inhibits the growth of human lung adenocarcinoma cells SPC-A4 to a cer

51、tain extent. As shown by in vivo test results, ENDOSTAR has extensive effects of inhibiting the mouse tumor model (S180 sarcoma, H22 liver cancer) and human xenograft tumor (SPC-A4 lung adenocarcinoma, SGC7901 stomach cancer, Hela cervical carcinoma, SMMC-7721 and Bel7402 liver cancer). 2. Toxicolog

52、ical action General Pharmacology: After the intravenous injection of 1.5, 3 and 6mg/kg (2.4104 - 4.8104, and 9.6104U/kg)( low, medium and high dose group) , such parameters as blood pressure, respiration, and ECG index, etc. of anaesthetized dog remains same to those before the injection, and the au

53、tonomic activity frequency of mouse is not influenced. Hemolysis, Irritation & Allergy in Animal: There is no hemolysis or hemagglutinationin during the observation time after the administration of 0.08mg/ml ENDOSTAR; guinea-pig had no allergic reactions after first the intraperitoneal injection of

54、0.5ml/guinea-pig (0.036mg/ml) every other day continuously for 3 times and then the 1ml/guinea-pig (0.036mg/ml) 14d and 21d after the first administration; and rabbit had no evident irritant reactions (such as vasodilatation and red swelling) or morphological changes (such as vascular wall thickenin

55、g) in venous irritation test. Acute Toxicity: Mouse had a LD50 of more than 450.5mg （225.25106 U）/kg after the intravenous or intraperitoneal administration of ENDOSTAR. Long-term Toxicity: As shown by long-term toxicity test on rat, at the end of 21d after the withdrawal of continuous intraperitone

56、al injection of 3, 6, and 12mg/kg/day (4.8104, 9.6104, and 19.2104U/kg/day) for 45d respectively, all these three dose groups are not significantly different from control group in the pathomorphological changes of internal organs (such as heart, liver, spleen, lung, brain, stomach, small intestine,

57、uterus and testicle). As shown by long-term toxicity test on beagle dog, after the continuous intravenous injection of 2, 10 and 25mg/kg/day (3.2104, 16.0104, and 40.0104U/kg/day) for 13 weeks respectively, beagle dog does not have evident toxic reactions on target organs or delayed toxic reactions,

58、 but only have the adverse reaction of elevated reticuloerythrocyte which is reversible after the drug withdrawal. As shown by long-term toxicity test on rhesus, after the continuous intravenous injection of 3mg (4.8104U)/kg/day (50.4mg/m2), 10mg(1.6105U)/kg/day (167.9mg/m2), and 30mg (4.8105U)/kg/d

59、ay (503.7mg/m2) continuously for 9 months respectively, each dose group had no evident abnormal change in vital signs, appearance behavior, and activities; its examination results fluctuated within the range of normal value for weight, food intake, and hematological/blood biochemical/ECG/urine exami

60、nation (i.e. no evident impairment of liver and renal function; it had basically normal protein, fat, and glucose metabolism; and it is not significantly different in organ coefficient and had no dose-related abnormal change according to the histopathological results. In brief, no evident toxic reac