部份中文思而赞处方资料（仅供参考） 药品英文名 Imiglucerace 药品别名 伊米格西酶、思而赞、Cerzyme 药物剂型 注射剂：25U/支；200U/支；400U/支。2～8℃冷藏保存，注意防冻。 药理作用 本品是基因重组技术生产的葡萄糖脑苷酯酶的类似物，为具有497个氨基酸的糖蛋白，含有4个N-环连接的糖基化位点。戈谢病是先天葡萄糖脑苷酯酶缺乏引起的罕见代谢遗传病，缺乏这种酶会导致葡萄糖脑苷酯在巨噬细胞内蓄积而成为戈谢细胞。戈谢病主要症状是贫血、血小板减少、骨痛、肝脾肿大。 本品通过催化葡萄糖脑苷酯水解使其降解成葡萄糖和神经酰胺，改善贫血和血小板减少症状，使肝脏和脾体积减小。 药动学 静滴本品1h(7.5U/kg、15U/kg、30U/kg、60U/kg)，30min后血浆酶浓度达稳态。停止滴注后血浆酶浓度迅速降低，半衰期为3.6～10.4min，血浆清除率为9.8～20.3ml/(min·kg)，表观分布容积为0.09～0.15L/kg。对本品产生了IgG抗体的患者，本品分布容积和清除率降低，消除半衰期延长。 适应证 用于治疗Ⅰ型戈谢病(Gaueher disease)导致的贫血、血小板减少、骨骼疾病和肝脾肿大。最新补充临床应用还包括，确诊为Ⅲ型代谢病且有显著非神经临床表现的患者的长期酶替代治疗。 禁忌证 对本品过敏者禁用。 注意事项 1.在IgG抗体形成的监测周期期间慎用。 2.对阿糖苷酶(Geredase)有抗体形成或过敏反应者慎用。 3.妊娠和哺乳期妇女慎用。 不良反应 不良反应包括：不适、瘙痒、烧灼感、水肿、无菌脓肿，发生率1%。过敏反应发生率为6.6%，包括瘙痒、脸红、荨麻疹、血管性水肿、胸部不适、发绀、低血压，也有类过敏反应报道。可在使用本品前使用抗组胺药或肾上腺皮质激素以防止过敏反应的发生。发生率少于1.5%的不良反应包括：恶心、腹痛、腹泻、脸红、疲乏、头痛、发烧、头晕、寒战、背痛、心动过速等。2～12岁儿童常见不良反应为呼吸困难、发热、恶心、脸红、呕吐、咳嗽，而成人常见不良反应为头痛、瘙痒、药疹。 用法用量 最初剂量每次2.5U/kg，静滴1～2h，1周3次；以后60U/kg，每周1次或减少到每4周1次。患者出现疗效后应减少剂量，剂量个体化。 CEREZYME (imiglucerase) injection, powder, lyophilized, for solution [Genzyme Corporation] DESCRIPTION Cerezyme® (imiglucerase for injection) is an analogue of the human enzyme β-glucocerebrosidase, produced by recombinant DNA technology. β-Glucocerebrosidase (β-D-glucosyl-N-acylsphingosine glucohydrolase, E.C. 3.2.1.45) is a lysosomal glycoprotein enzyme which catalyzes the hydrolysis of the glycolipid glucocerebroside to glucose and ceramide. Cerezyme® is produced by recombinant DNA technology using mammalian cell culture (Chinese hamster ovary). Purified imiglucerase is a monomeric glycoprotein of 497 amino acids, containing 4 N-linked glycosylation sites (Mr = 60,430). Imiglucerase differs from placental glucocerebrosidase by one amino acid at position 495, where histidine is substituted for arginine. The oligosaccharide chains at the glycosylation sites have been modified to terminate in mannose sugars. The modified carbohydrate structures on imiglucerase are somewhat different from those on placental glucocerebrosidase. These mannose-terminated oligosaccharide chains of imiglucerase are specifically recognized by endocytic carbohydrate receptors on macrophages, the cells that accumulate lipid in Gaucher disease. Cerezyme® is supplied as a sterile, non-pyrogenic, white to off-white lyophilized product. The quantitative composition of the lyophilized drug is provided in the following table: Ingredient 200 Unit Vial 400 Unit Vial    This provides a respective withdrawal dose of 200 and 400 units of imiglucerase. Imiglucerase (total amount)*   212 units 424 units Mannitol 170 mg 340 mg Sodium Citrates     (Trisodium Citrate)     (Disodium Hydrogen Citrate) 70 mg (52 mg) (18 mg) 140 mg (104 mg) (36 mg) Polysorbate 80, NF 0.53 mg 1.06 mg Citric Acid and/or Sodium Hydroxide may have been added at the time of manufacture to adjust pH. An enzyme unit (U) is defined as the amount of enzyme that catalyzes the hydrolysis of 1 micromole of the synthetic substrate para-nitrophenyl-β-D-glucopyranoside (pNP-Glc) per minute at 37°C. The product is stored at 2-8°C (36-46°F). After reconstitution with Sterile Water for Injection, USP, the imiglucerase concentration is 40 U/mL (see DOSAGE AND ADMINISTRATION for final concentrations and volumes). Reconstituted solutions have a pH of approximately 6.1. CLINICAL PHARMACOLOGY Mechanism of Action/Pharmacodynamics Gaucher disease is characterized by a deficiency of β-glucocerebrosidase activity, resulting in accumulation of glucocerebroside in tissue macrophages which become engorged and are typically found in the liver, spleen, and bone marrow and occasionally in lung, kidney, and intestine. Secondary hematologic sequelae include severe anemia and thrombocytopenia in addition to the characteristic progressive hepatosplenomegaly, skeletal complications, including osteonecrosis and osteopenia with secondary pathological fractures. Cerezyme® (imiglucerase for injection) catalyzes the hydrolysis of glucocerebroside to glucose and ceramide. In clinical trials, Cerezyme improved anemia and thrombocytopenia, reduced spleen and liver size, and decreased cachexia to a degree similar to that observed with Ceredase® (alglucerase injection). Pharmacokinetics During one-hour intravenous infusions of four doses (7.5, 15, 30, 60 U/kg) of Cerezyme® (imiglucerase for injection), steady-state enzymatic activity was achieved by 30 minutes. Following infusion, plasma enzymatic activity declined rapidly with a half-life ranging from 3.6 to 10.4 minutes. Plasma clearance ranged from 9.8 to 20.3 mL/min/kg (mean ± S.D., 14.5 ± 4.0 mL/min/kg). The volume of distribution corrected for weight ranged from 0.09 to 0.15 L/kg (0.12 ± 0.02 L/kg). These variables do not appear to be influenced by dose or duration of infusion. However, only one or two patients were studied at each dose level and infusion rate. The pharmacokinetics of Cerezyme do not appear to be different from placental-derived alglucerase (Ceredase®). In patients who developed IgG antibody to Cerezyme, an apparent effect on serum enzyme levels resulted in diminished volume of distribution and clearance and increased elimination half-life compared to patients without antibody (see WARNINGS). INDICATIONS AND USAGE Cerezyme® (imiglucerase for injection) is indicated for long-term enzyme replacement therapy for pediatric and adult patients with a confirmed diagnosis of Type 1 Gaucher disease that results in one or more of the following conditions: a. anemia b. thrombocytopenia c. bone disease d. hepatomegaly or splenomegaly CONTRAINDICATIONS There are no known contraindications to the use of Cerezyme® (imiglucerase for injection). Treatment with Cerezyme should be carefully re-evaluated if there is significant clinical evidence of hypersensitivity to the product. WARNINGS Approximately 15% of patients treated and tested to date have developed IgG antibody to Cerezyme® (imiglucerase for injection) during the first year of therapy. Patients who developed IgG antibody did so largely within 6 months of treatment and rarely developed antibodies to Cerezyme after 12 months of therapy. Approximately 46% of patients with detectable IgG antibodies experienced symptoms of hypersensitivity. Patients with antibody to Cerezyme have a higher risk of hypersensitivity reaction. Conversely, not all patients with symptoms of hypersensitivity have detectable IgG antibody. It is suggested that patients be monitored periodically for IgG antibody formation during the first year of treatment. Treatment with Cerezyme should be approached with caution in patients who have exhibited symptoms of hypersensitivity to the product. Anaphylactoid reaction has been reported in less than 1% of the patient population. Further treatment with imiglucerase should be conducted with caution. Most patients have successfully continued therapy after a reduction in rate of infusion and pretreatment with antihistamines and/or corticosteroids. PRECAUTIONS General In less than 1% of the patient population, pulmonary hypertension and pneumonia have also been observed during treatment with Cerezyme® (imiglucerase for injection). Pulmonary hypertension and pneumonia are known complications of Gaucher disease and have been observed both in patients receiving and not receiving Cerezyme. No causal relationship with Cerezyme has been established. Patients with respiratory symptoms in the absence of fever should be evaluated for the presence of pulmonary hypertension. Therapy with Cerezyme should be directed by physicians knowledgeable in the management of patients with Gaucher disease. Caution may be advisable in administration of Cerezyme to patients previously treated with Ceredase® (alglucerase injection) and who have developed antibody to Ceredase® or who have exhibited symptoms of hypersensitivity to Ceredase®. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies have not been conducted in either animals or humans to assess the potential effects of Cerezyme® (imiglucerase for injection) on carcinogenesis, mutagenesis, or impairment of fertility. Teratogenic Effects: Pregnancy Category C Animal reproduction studies have not been conducted with Cerezyme® (imiglucerase for injection). It is also not known whether Cerezyme can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Cerezyme should not be administered during pregnancy except when the indication and need are clear and the potential benefit is judged by the physician to substantially justify the risk. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Cerezyme® (imiglucerase for injection) is administered to a nursing woman. Pediatric Use The safety and effectiveness of Cerezyme® (imiglucerase for injection) have been established in patients between 2 and 16 years of age. Use of Cerezyme in this age group is supported by evidence from adequate and well-controlled studies of Cerezyme and Ceredase® (alglucerase injection) in adults and pediatric patients, with additional data obtained from the medical literature and from long-term postmarketing experience. Cerezyme has been administered to patients younger than 2 years of age, however the safety and effectiveness in patients younger than 2 have not been established. ADVERSE REACTIONS Since the approval of Cerezyme® (imiglucerase for injection) in May 1994, Genzyme has maintained a worldwide post-marketing database of spontaneously reported adverse events and adverse events discussed in the medical literature. The percentage of events for each reported adverse reaction term has been calculated using the number of patients from these sources as the denominator for total patient exposure to Cerezyme since 1994. Actual patient exposure is difficult to obtain due to the voluntary nature of the database and the continuous accrual and loss of patients over that span of time. The actual number of patients exposed to Cerezyme since 1994 is likely to be greater than estimated from these voluntary sources and, therefore, the percentages calculated for the frequencies of adverse reactions are most likely greater than the actual incidences. Experience in patients treated with Cerezyme® has revealed that approximately 13.8% of patients experienced adverse events which were judged to be related to Cerezyme administration and which occurred with an increase in frequency. Some of the adverse events were related to the route of administration. These include discomfort, pruritus, burning, swelling or sterile abscess at the site of venipuncture. Each of these events was found to occur in < 1% of the total patient population. Symptoms suggestive of hypersensitivity have been noted in approximately 6.6% of patients. Onset of such symptoms has occurred during or shortly after infusions; these symptoms include pruritus, flushing, urticaria, angioedema, chest discomfort, dyspnea, coughing, cyanosis, and hypotension. Anaphylactoid reaction has also been reported (see WARNINGS). Each of these events was found to occur in < 1.5% of the total patient population. Pre-treatment with antihistamines and/or corticosteroids and reduced rate of infusion have allowed continued use of Cerezyme in most patients. Additional adverse reactions that have been reported in approximately 6.5% of patients treated with Cerezyme include: nausea, abdominal pain, vomiting, diarrhea, rash, fatigue, headache, fever, dizziness, chills, backache, and tachycardia. Each of these events was found to occur in < 1.5% of the total patient population. Incidence rates cannot be calculated from the spontaneously reported adverse events in the post-marketing database. From this database, the most commonly reported adverse events in children (defined as ages 2 – 12 years) included dyspnea, fever, nausea, flushing, vomiting, and coughing, whereas in adolescents (>12 – 16 years) and in adults (>16 years) the most commonly reported events included headache, pruritis, and rash. In addition to the adverse reactions that have been observed in patients treated with Cerezyme, transient peripheral edema has been reported for this therapeutic class of drug. OVERDOSE Experience with doses up to 240 U/kg every 2 weeks have been reported. At that dose there have been no reports of obvious toxicity. DOSAGE AND ADMINISTRATION Cerezyme® (imiglucerase for injection) is administered by intravenous infusion over 1-2 hours. Dosage should be individualized to each patient. Initial dosages range from 2.5 U/kg of body weight 3 times a week to 60 U/kg once every 2 weeks. 60 U/kg every 2 weeks is the dosage for which the most data are available. Disease severity may dictate that treatment be initiated at a relatively high dose or relatively frequent administration. Dosage adjustments should be made on an individual basis and may increase or decrease, based on achievement of therapeutic goals as assessed by routine comprehensive evaluations of the patient’s clinical manifestations. Cerezyme® should be stored at 2-8°C (36-46°F). After reconstitution, Cerezyme should be inspected visually before use. Because this is a protein solution, slight flocculation (described as thin translucent fibers) occurs occasionally after dilution. The diluted solution may be filtered through an in-line low protein-binding 0.2 μm filter during administration. Any vials exhibiting opaque particles or discoloration should not be used. DO NOT USE Cerezyme after the expiration date on the vial. On the day of use, after the correct amount of Cerezyme to be administered to the patient has been determined, the appropriate number of vials are each reconstituted with Sterile Water for Injection, USP. The final concentrations and administration volumes are provided in the following table: 200 Unit Vial 400 Unit Vial Sterile water for reconstitution 5.1 mL 10.2 mL Final volume of reconstituted product 5.3 mL 10.6 mL Concentration after reconstitution 40 U/mL 40 U/mL Withdrawal volume 5.0 mL 10.0 mL Units of enzyme within final volume 200 units 400 units A nominal 5.0 mL for the 200 unit vial (10.0 mL for the 400 unit vial) is withdrawn from each vial. The appropriate amount of Cerezyme for each patient is diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 100 – 200 mL. Cerezyme is administered by intravenous infusion over 1-2 hours. Aseptic techniques should be used when diluting the dose. Since Cerezyme does not contain any preservative, after reconstitution, vials should be promptly diluted and not stored for subsequent use. Cerezyme, after reconstitution, has been shown to be stable for up to 12 hours when stored at room temperature (25°C) and at 2-8°C. Cerezyme, when diluted, has been shown to be stable for up to 24 hours when stored at 2-8°C. Relatively low toxicity, combined with the extended time course of response, allows small dosage adjustments to be made occasionally to avoid discarding partially used bottles. Thus, the dosage administered in individual infusions may be slightly increased or decreased to utilize fully each vial as long as the monthly administered dosage remains substantially unaltered. HOW SUPPLIED Cerezyme® (imiglucerase for injection) is supplied as a sterile, non-pyrogenic, lyophilized product. It is available as follows: 200 Units per Vial NDC 58468-1983-1 400 Units per Vial NDC 58468-4663-1 Store at 2-8°C (36-46°F). Rx only Cerezyme® (imiglucerase for injection) is manufactured by: Genzyme Corporation 500 Kendall Street Cambridge, MA 02142 USA Certain manufacturing operations may have been performed by other firms. Cerezyme and Genzyme are registered trademarks of Genzyme Corporation. Package Label - Principal Display Panel – 200U —Cerezyme(伊米苷酶)治疗罕见戈谢病(高雪氏病) Genzyme公司日前宣布，欧盟批准Cerezyme (伊米苷酶,imiglucerase)的一项新适应证，用于治疗III型代谢病。这项决定是在2003年6月欧盟发布的有关专利药物Cerezyme扩大标签的积极意见的基础上作出的。 Cerezyme的标签将增补这么一条：该产品适用于确诊为I型或III型戈谢病的且有显著非神经临床表现的患者的长期酶替代治疗。 在欧洲扩大Cerezyme 的标签主要是为了确保治疗中的戈谢病患者能够持续以该药物治疗，而并不指望增加使用Cerezyme的病人总数。 戈谢病是一种常染色体隐性遗传所造成的葡糖脑苷脂沉积症，是脂类沉积症中最常见者。其临床特征为脾、肝肿大，脾功能亢进，骨骼病变，也可以出现造血系统和中枢神经系统症状。 病因和发病机制 本病系因β-葡糖脑苷脂酶缺乏，致使葡糖脑苷脂不能水解成神经酰胺和葡萄糖、大量沉积于全身的网状内皮系统细胞内，以脾、肝和骨骼等为主。β-葡糖脑苷脂酶的编码基因位于lq2l，长约7Kb，含有11个外显子，已知该基因突变种类繁多，包括点突变、插入和缺乏等，其中以点突变1226G和1448C最为多见，由此造成酶分子结构发生不同的变异，酶活性缺陷程度亦不等，在临床上本病有3种不同表现的类型。Ⅰ型戈谢病不同于Ⅱ、Ⅲ型，其脑组织中并无节苷脂降解生成的葡糖脑苷脂累积，可能是因为该型患者的脑组织中尚保留有β-葡糖脑苷脂酶同功酶的活性所致。 近年研究发现β-葡糖脑苷脂酶尚需与Sap-C结合成复合体后始能充分发挥其降解作用，Sap-C(或称Sap-2)是一种硫酸脑苷脂激活蛋白，它的编码基因位于10q21，已证实该基因的突变可导致Sap-C缺陷，并造成与Ⅲ型类似临床表现的类戈谢病。 病理 患儿全身网状内皮系统中均有特殊的戈谢细胞浸润。戈谢细胞是由脾脏的组织细胞、肝脏的Kupffer细胞、肺泡的巨噬细胞和其他器官内的单核细胞族转变形成；是一种直径达20～100μm的充满脂类的大型细胞，呈圆或卵圆形，含一个或数个偏心的圆形或不整形胞核，染色质粗糙，胞浆浅兰色，量多，有纤维条纹结构，如皱纹纸样。电镜下可见胞浆中有特异性的管状脑苷脂包涵体。糖原染色(PAS)和酸性磷酸酶染色呈强阳性，苏丹黑染色阳性。其浸润部位以脾髓质为主，其他如肝窦状隙、肾小球、肺泡毛细血管、淋巴结、骨髓以及脑神经组织等均可被侵犯，亦偶见于胰腺、甲状腺和肾上腺等内分泌腺体。 除具有戈谢细胞浸润特征外，患儿各器官尚可发生不同程度的其他病理改变，如：脾脏正常结构遭破坏和纤维化；肝脏有不同程度的纤维化；脊椎骨、股骨呈骨质囊性侵蚀和病理骨折；脑内的颅神经核、基底节、丘脑、小脑和锥体束等处的神经元退行性变等。 临床表现 根据临床症状的差异，本病可分为3型。同一家族中发病者都属相同类型。 1.Ⅰ型即慢性(非神经)型是最常见的一型，其β-葡糖脑苷脂酶活性约为正常人的18%～40%。发病年龄可自生后数月至70岁间的任何阶段，多数在学龄前期因肝、脾肿大和贫血就诊。在发病早期，仅有脾肿大和轻度贫血。随着病程进展，脾脏增大显著，并出现脾功能亢进现象，贫血显著，白细胞和血小板亦减少。至晚期时，生长发育显著落后，腹部明显膨胀，各种症状加重，贫血加重，白细胞和血小板明显减少，常伴有感染和皮肤粘膜出血倾向。淋巴结轻度肿大。肝功能受损，常见食道静脉曲张、Ⅸ因子等凝血因子缺乏。骨髓被浸润导致严重骨痛和关节肿胀，X线检查可见普遍性骨质疏松、髓腔增宽、股骨远端呈烧瓶状和股骨头无菌性坏死等局限性骨质破坏甚至骨折。年长患者面部和四肢暴露部位常见色素沉着和肺部浸润症状。 2.Ⅱ型又称为急性(神经)型发病年龄自新生儿期至18个月，以3～4个月为多见。其β-葡糖脑苷脂酶活性低于正常人的5%，是预后最差的一型。初起症状以哭声微弱、吸吮能力差和肝脾进行性增大为主，继而出现吞咽困难、斜视、头后仰等症状。多数患儿在6～9个月时发生肌张力增高、腱反射亢进、喉喘鸣、惊厥和病理反射等神经系统症状。肺内可有大量戈谢细胞浸润或并发肺炎，多有咳嗽、呼吸困难和紫绀。一般在2岁以内死于肺部感染。 3.Ⅲ型即亚急性(神经)型较少见，其β-葡糖脑苷脂酶活性约为正常人的12%～20%。本型常在2岁左右时发病，初起以脾肿大为主，肝脾肿大发展缓慢。经过3～7年的无明显症状期后逐渐出现神经系统症状，如斜视、肌痉挛、智能低下和惊厥发作等。晚期出现骨骼病变、脾功能亢进、全血细胞减少和出血症状。患儿常在神经症状出现后2年左右死亡。 诊断：对肝脾肿大患儿，不论是否伴有贫血、血小板减少、骨质缺损等其他疑似症状，都应考虑本病的可能性。论断依据为： 1.典型的临床症状和体征。 2.戈谢细胞检查 患儿骨髓、脾、肝或淋巴结穿刺液均可供检测。 3.血清酸性磷酸酶增高。 4.β-葡糖脑苷脂酶活性测定 通常采用外周血白细胞或培养皮肤成纤维细胞进行。由于人体组织中含有多种β-葡糖苷酶，如所选的方法不当，则结果不尽可靠，必须注意。 5.DNA分析较酶法诊断可靠，但是本病基因突变种类繁多，尚有目前尚未查明者，因此分析结果正常者亦不能完全排除本病。 治疗：对Ⅱ型主要为对症治疗。 产前诊断：对有本病家族史的孕妇，可测定培养羊水细胞或绒毛细胞中的β-葡糖脑苷脂酶活性、进行产前诊断。近来，亦已开始藉助PCR方法进行DNA分析，更为容易。 ---------------------------------------- 产地国家：美国 原产地英文商品名: CEREZYME 200IU SDV PWD DPSH 1/EA 原产地英文药品名: IMIGLUCERASE 中文参考商品译名: 思而赞注射剂 200单位/瓶 1瓶/盒 中文参考药品译名: 伊米苷酶 生产厂家中文参考译名: Genzyme 生产厂家英文名: Genzyme ---------------------------------------- 产地国家：美国 原产地英文商品名: CEREZYME 400IU SDV PWD DPSH 1/EA 原产地英文药品名: IMIGLUCERASE 中文参考商品译名: 思而赞注射剂 400单位/瓶 1瓶/盒 中文参考药品译名: 伊米苷酶 生产厂家中文参考译名: Genzyme 生产厂家英文名: Genzyme ---------------------------------------- 产地国家：美国 原产地英文商品名: CEREZYME VL 400UN DS 原产地英文药品名: Imiglucerase 中文参考商品译名: 思而赞注射剂 400单位/瓶 中文参考药品译名: 伊米苷酶 生产厂家中文参考译名: Genzyme 生产厂家英文名: Genzyme ---------------------------------------- 产地国家： 德国 原产地英文商品名: Cerezyme 400U/VIAL 5VIAL/box 原产地英文药品名: Imiglucerase 中文参考商品译名: 思而赞 400单位/瓶 5瓶/盒 中文参考药品译名: 伊米苷酶 生产厂家中文参考译名: Genzyme 生产厂家英文名: Genzyme