【商品名】思而赞
【通用名】注射用伊米苷酶
【英文名】Cerezyme
【汉语拼音】sierzan 
【主要成分】伊米苷酶(Imiglucerase)
【性状】本药为白色至类白色的冻干产品。 

【适应症】用于确诊患有导致下列1种或多种病症的I型戈谢氏病(Gaucher disease)的儿童及成人患者的长期酶替代疗法：贫血、血小板减少、骨病、肝肿大或脾肿大。 

【用法用量】静脉滴注，滴注时间为1-2小时。剂量应根据患者个体情况调整。初始剂量范围为2.5U/kg，每周3次，到60U/kg，每2周1次。2年后若达到治疗目标，剂量可改为45U/Kg。60U/kg每2周1次是获得数据最多的剂量。病情严重时可能要求较高的剂量或较多的给药次数。应根据每位患者的个体情况调整剂量，并应定期进行全面评估患者的临床表现，根据是否达到治疗目的而上调或下调剂量。 

本品应存放在2-8°C(36-46°F)。重新配制后，在使用之前应目视检查。由于本品是一种蛋白溶液，因此稀释后偶尔会出现轻微絮凝(即生成轻度不透明的纤维)。给药时，稀释后的溶液可通过与输液管相连的0.2m滤器膜过滤(该滤器膜不吸附蛋白或吸附程度甚微)。重新配置溶解后如出现不透明颗粒物或变色，则不能使用。 

给药当天，确定患者使用剂量后，取出相应数量的小瓶，按下表用无菌注射用水重新配制。下面为最终浓度和给药体积：
200单位/瓶：配制用无菌水5.1mL，配制后最终体积5.3mL，重新配制后的浓度为40U/mL，可抽取的体积为5.0mL。
400单位/瓶：配制用无菌水10.2mL，配制后最终体积10.6mL，重新配制后的浓度为40U/mL，可抽取的体积为10.0mL。
从每200单位小瓶抽取5.0mL(400单位小瓶取10.0mL)，用0.9%氯化钠溶液最终稀释到100-200mL。静脉滴注应进行1-2小时，在无菌条件进行。由于本品不含任何防腐剂，配制后应立即稀释，不得放置用于以后使用。本品配置后在室温(25°C)及2-8°C下可稳定12小时。经稀释后，在2-8°C下可稳定12小时。 

伊米苷酶毒性相对较低，其作用时间较长，因此可以偶尔进行小幅的剂量调整，使每瓶药量都得以利用，避免药品的浪费，只要每月的给药剂量基本不变。 

【药物过量】已有报道每2周剂量达240U/kg的用药经验。在此剂量水平下，未有明显毒性的报告。 

【禁忌】中国患者使用人群和积累数据有限，尚未报道伊米苷酶使用的已知禁忌症。如果出现明显的药物过敏临床证据，则应仔细地对伊米苷酶治疗重新进行评价。 

【警告】迄今为止，约15%的患者在第1年治疗期间出现抗伊米苷酶(注射用伊米苷酶)IgG抗体。其中大多数出现于治疗6个月的期间内，治疗12个月后出现抗伊米苷酶抗体者罕见。约46%的IgG抗体阳性的患者出现过敏症状。 

出现抗伊米苷酶抗体的患者发生过敏性反应的风险较高。但并不是所有出现过敏症状的患者都能检出IgG抗体。建议在第1年治疗期间内定期监测患者的IgG抗体形成。
出现本品过敏症状的患者在进行本品治疗时应谨慎。
已在不到1%的患者人群中报告有过敏性样反应。进一步接受伊米苷酶治疗时应谨慎。多数患者在降低滴注速率以及采用抗组胺药和/或皮质内固醇预治疗后可成功地继续进行治疗。 

【注意事项】在不到1%的患者人群中，伊米苷酶治疗期间出现肺动脉压过高和肺炎。肺动脉压过高和肺炎为戈谢病的已知并发症，在接受过或未接受过伊米苷酶的患者中都曾发现。尚不清楚伊米苷酶和这些症状的的因果关系。应对无发热呼吸道症状的患者进行检查判断是否存在肺动脉压过高。
使用伊米苷酶的治疗应在对戈谢病有治疗经验的医生指导下进行。
曾接受过阿糖苷酶(Ceredase)注射液治疗，并出现抗阿糖苷酶抗体或是出现阿糖苷酶过敏症状的患者在以伊米苷酶用药时应谨慎。 

【儿童用药】本品在2-16岁之间患者中的安全性和有效性已经明确。大量的及对照良好的注射用伊米苷酶和阿糖苷酶成年和儿童患者的临床试验证据，以及医学文献和上市后长期用药经验中获得的其它资料支持本品用于此年龄组患者。本品已经用于年龄不足2岁的患者，但本品在年龄不足2岁患者的安全性和有效性尚未明确。 

【老年患者用药】尚无该项实验资料及可参考文献。 

【孕妇及哺乳期妇女用药】尚未进行注射用伊米苷酶的动物生殖毒性试验。同时不清楚孕妇用药时伊米苷酶是否能导致胚胎损害或是能否影响生殖能力。除非适应症及需要都十分明确，而且医生断定潜在受益明显高于风险，否则怀孕期间不得使用本品。 

致畸作用：怀孕C类
尚不清楚本品是否分泌到人乳汁中。由于很多药物能分泌到人乳汁中，因此哺乳妇女使用本品时应谨慎。 

【不良反应】本品自1994年5月在美国批准上市以来，Genzyme公司已经建立了全球上市后数据库，该数据库包括自发报告的不良事件和医学文献中讨论的不良事件。采用上述来源的患者人数作为自1994年以来的用药患者的总数，计算出每种被报告过的不良反应的发生率。由于数据库的自愿性质以及上述一段时间内患者持续累积及丢失，实际的用药患者总人数很难统计。自1994年以来接受过本品治疗的患者实际人数很可能高于上述自愿来源的估计人数，因此计算的不良反应率很可能高于实际发生率。 

本品治疗的经验显示，约13.8%的患者出现与伊米苷酶给药有关的、且发生率增加的不良事件。某些不良事件与给药途径有关。不良反应包括不适、瘙痒、烧灼感、滴注部位处肿胀或无菌性脓肿。上述各种事件发生在不到1%的患者。 

约在6.6%的患者中出现提示过敏的症状。此类过敏症状出现于滴注期间或滴注后不久；过敏症状包括瘙痒、潮红、荨麻疹、血管水肿、胸部不适、呼吸困难、咳嗽、紫癫和低血压。还报导有过敏样不良反应(参见警告)。上述各种事件见于<1.5%的患者中。抗组胺药和/或皮质内固醇预治疗和降低滴注速度可使多数患者继续使用本品。 

约在6.5%使用伊米苷酶治疗的患者中报告的其它不良反应包括：恶心、腹痛、呕吐、腹泻、皮疹、疲劳、头痛、发热、头晕、寒战、背痛和心动过速。上述每种事件出现于<1.5%的患者中。 

不能从上市后数据库的自发报告不良事件中计算出发生率。从此数据库中看，儿童(定义为2-12岁)中最常报告的不良事件包括：呼吸困难、发热、恶心、潮红、呕吐和咳嗽，而青少年(>12-16岁)和成人(>16岁)最常报告的不良事件包括：头痛、瘙痒和皮疹。 

除以伊米苷酶治疗患者中已经发现的不良反应之外，此类治疗药物中还有过暂时性外周水肿的报告。 

【药物相互作用】尚无该项实验资料及可参考文献。目前没有已知的药物相互作用。 

【FDA妊娠分级】C级:动物研究证明药物对胎儿有危害性(致畸或胚胎死亡等)，或尚无设对照的妊娠妇女研究，或尚未对妊娠妇女及动物进行研究。本类药物只有在权衡对孕妇的益处大于对胎儿的危害之后，方可使用。 

【药理作用】戈谢氏病(Gaucherdisease)的特征表现为-葡糖脑苷脂酶活性缺陷，导致组织巨噬细胞中葡糖脑苷脂蓄积，使得其变得肥大，常出现于肝脏、脾脏和骨髓，偶尔出现于肺脏、肾脏和肠中。继发的血液学后果包括：严重的贫血及血小板减少、此外还出现特征性的肝脾进展性肿大、骨骼并发症(包括骨坏死和骨质减少，继发病理学骨折)。注射用伊米苷酶催化葡糖脑苷脂水解成葡萄糖和神经酰胺。在临床试验中，本品能改善贫血及血小板减少、使肝脾缩小并改善恶病质，临床效果与Ceredase(阿糖苷酶注射液)相似。 

【毒理研究】伊米苷酶啮齿类动物和猴的急性和亚急性试验未见明显的毒性反应，最主要的反应可能为动物给予大量的外源蛋白后直接或间接引起的(如免疫反应)。Crl:CD-BRVAF/Plus大鼠急性毒性试验发现高剂量组(600U/kg)动物绝对和相对粒细胞计数升高，可能是动物给予大量外源蛋白后的正常生理反应。SD大鼠给予伊米苷酶13周毒性试验发现高剂量组(300U/kg)雄性动物肾脏轻度间质性炎症、肾小管扩张和透明管型，上述肾脏病变可能与给予外源蛋白导致的损伤有关，但也可能为大鼠年龄相关的慢性肾小球肾病。这种由α-2-微球蛋白介导的大鼠年龄相关的慢性肾小球肾病往往会因为高蛋白饮食等因素而加重，为大鼠所特有的病变，因此对于评价临床用药风险的参考价值较小。给予猴伊米苷酶13周毒性试验发现高剂量组(300U/kg)雌性动物脾脏绝对重量和相对重量升高，可能为动物重复给予高剂量外源蛋白后导致的抗体反应，这种抗体反应为动物的一种常见反应。大鼠和猴重复给药毒性试验发现超过50%的动物出现剂量依赖关系的抗体反应。血清生化、血液学和病理学检查结果均提示伊米苷酶用于临床风险较小。 

致癌性、致突变性、生育力的损害：尚未在动物或人体中进行过评价伊米苷酶致癌性、致突变性、或生育力损害潜在影响的试验。 

【药代动力学】静脉滴注4种剂量(7.5、15、30、60U/kg)的滴注时间为1小时，在30分钟时酶活性达到稳态。滴注后，血浆酶活性快速下降，半衰期在3.6-10.4分钟之间。血浆清除率在9.8-20.3mL/min/kg(14.5±4.0mL/min/kg)。经体重校正后的分布容积为0.09-0.15L/kg(平均值0.12L/kg,标准差±0.02L/kg)。上述变量似乎不受剂量或滴注时间的影响。但是，每种剂量水平及滴注速率下仅对1或2位患者进行了研究。注射用伊米苷酶的药代动力学似乎与胎盘源的阿糖苷酶没有任何差异。与未出现抗体的患者相比，出现抗伊米苷酶的IgG抗体的患者对血清酶水平有明显影响，可导致分布容积及清除率下降和清除半衰期延长(参见警告)。 

【贮藏】2-8°C避光保存和运输。 

【有效期】24个月。 

Cerezyme

Generic Name: imiglucerase
Dosage Form: injection, powder, lyophilized, for solution

Cerezyme®
(imiglucerase for injection)

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:

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.

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).

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).

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

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.

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.

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 receivingCerezyme. 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®.

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.

Animal reproduction studies have not been conducted withCerezyme® (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.

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.

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.

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.

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.

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:

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.

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,MA02142USA

Certain manufacturing operations may have been performed by other firms.

Cerezyme and Genzyme are registered trademarks of Genzyme Corporation.

6LE005D

NDC 58468-1983-1

Cerezyme®

imiglucerase for injection

200 Units

For Intravenous infusion only

genzyme 

NDC 58468-4663-1

Cerezyme®

imiglucerase for injection

400 Units

For Intravenous infusion only

genzyme

Revised: 03/2017

Genzyme Corporation