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4.9 Overdose No case of overdose has been reported. In patients dosages up to 240 U/kg body weight once every two weeks have been used. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Enzymes-Imiglucerase (recombinant macrophage targeted β-glucocerebrosidase), ATC code: A16AB02. Gaucher disease is a rare recessively inherited metabolic disorder that results from a deficiency of the lysosomal enzyme acid β-glucosidase. This enzyme breaks down glucosylceramide, a key component of the lipid structure of cell membranes, into glucose and ceramide. In individuals with Gaucher disease, glucosylceramide degradation is insufficient, leading to accumulation of large quantities of this substrate within the lysosomes of macrophages (termed 'Gaucher cells'), leading to widespread secondary pathology. Gaucher cells are typically found in liver, spleen and bone marrow and occasionally in lung, kidney and intestine. Clinically, Gaucher disease is a heterogeneous phenotypic spectrum. The most frequent disease manifestations are hepatosplenomegaly, thrombocytopenia, anaemia, and skeletal pathology, The skeletal abnormalities are frequently the most debilitating and disabling features of Gaucher disease. These skeletal manifestations include bone marrow infiltration, osteonecrosis, bone pain and bone crises, osteopenia and osteoporosis, pathological fractures, and growth impairment. Gaucher disease is associated with increased glucose production and increased resting energy expenditure rate, which may contribute to fatigue and cachexia. Patients with Gaucher disease may also have a low grade inflammatory profile. In addition, Gaucher disease has been associated with an increased risk of immunoglobulin abnormalities such as hyperimmunoglobulinemia, polyclonal gammopathy, monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma. The natural history of Gaucher disease usually shows progression, with the risk of irreversible complications arising in various organs over time. The clinical manifestations of Gaucher disease can adversely affect quality of life. Gaucher disease is associated with increased morbidity and early mortality. Signs and symptoms presenting in childhood typically represent more severe Gaucher disease. In children, Gaucher disease can lead to growth retardation and delayed puberty. Pulmonary hypertension is a known complication of Gaucher disease. Patients who have undergone a splenectomy have an increased risk of pulmonary hypertension. Cerezyme therapy reduces the requirement for splenectomy in most cases and early treatment with Cerezyme has been associated with a reduced risk of pulmonary hypertension. Routine evaluation to detect the presence of pulmonary hypertension after diagnosis of Gaucher disease and over time is recommended. Patients diagnosed with pulmonary hypertension, in particular, should receive adequate doses of Cerezyme to ensure control of underlying Gaucher disease as well as be evaluated for the need of additional pulmonary hypertension specific treatments. Imiglucerase (recombinant macrophage targeted acid ß‑glucosidase) replaces the deficient enzyme activity, hydrolysing glucosylceramide, thus correcting initial pathophysiology and preventing secondary pathology. Cerezyme reduces spleen and liver size, improves or normalises thrombocytopenia and anaemia, improves or normalises bone mineral density and bone marrow burden, and reduces or eliminates bone pain and bone crises. Cerezyme reduces resting energy expenditure rate. Cerezyme has been shown to improve both mental and physical aspects in the quality of life of Gaucher disease. Cerezyme decreases chitotriosidase, a biomarker for glucosylceramide accumulation in macrophages and response to treatment. In children, Cerezyme has been shown to enable normal pubertal development, and to induce catch-up growth, leading to normal height and bone mineral density in adulthood. The rate and extent of response to Cerezyme treatment is dose-dependent. Generally, improvements in organ systems with a faster turnover rate, such as the haematological, can be noted far more rapidly than in those with a slower turnover, such as the bone. In an ICGG Gaucher Registry analysis of a large cohort of patients (n=528) with Gaucher disease type 1, a time- and dose-dependent effect for Cerezyme was observed for haematological and visceral parameters (platelet count, haemoglobin concentration, spleen and liver volume) within the dose range of 15, 30 and 60 U/kg body weight once every 2 weeks. Patients treated with 60 U/kg body weight every 2 weeks showed a faster improvement and a greater maximum treatment effect as compared to patients receiving the lower doses. Similarly, in an ICGG Gaucher Registry analysis of bone mineral density using dual-energy X-ray absorptiometry (DXA) in 342 patients, after 8 years of treatment normal bone mineral density was achieved with a Cerezyme dose of 60 U/kg body weight once every 2 weeks, but not with lower doses of 15 and 30 U/kg body weight once every 2 weeks (Wenstrup et al, 2007). In a study investigating 2 cohorts of patients treated with a median dose of 80 U/kg body weight every 4 weeks and a median dose of 30 U/kg body weight every 4 weeks, among the patients with bone marrow burden score ≥ 6, more patients in the higher dose cohort (33%; n=22) achieved a decrease in the score of 2 points after 24 months of Cerezyme treatment compared with patients in the lower dose cohort (10%; n=13) (de Fost, 2006). Treatment with Cerezyme at a dose of 60 U/kg body weight once every 2 weeks, showed improvement in bone pain as early as 3 months, decrease in bone crises within 12 months, and improvement in bone mineral density after 24 months of treatment (Sims et al, 2008). The usual frequency of infusion is once every 2 weeks (see section 4.2). Maintenance therapy every 4 weeks (Q4) at the same cumulative dose as the bi-weekly (Q2) dose has been studied in adult patients with stable residual Gaucher disease type 1. Changes from baseline in hemoglobin, platelets, liver and spleen volumes, bone crisis, and bone disease comprised a predefined composite endpoint; achievement or maintenance of established Gaucher disease therapeutic goals for the hematologic and visceral parameters comprised an additional endpoint. Sixty-three percent of Q4- and 81% of Q2-treated patients met the composite endpoint at Month 24; the difference was not statistically significant based on the 95% CI (-0.357, 0.058). Eighty-nine percent of Q4- and 100% of Q2-treated patients met the therapeutic goals-based endpoint; the difference was not statistically significant based on the 95% CI (-0.231, 0.060). A Q4 infusion regimen may be a therapeutic option for some adult patients with stable residual Gaucher disease type 1, but clinical data are limited. No controlled clinical studies have been conducted on the efficacy of Cerezyme on neurological manifestations of the disease. Therefore no conclusions on the effect of enzyme replacement therapy on the neurological manifestations of the disease can be drawn. Medical or healthcare professionals are encouraged to register Gaucher patients, including those with chronic neuronopathic manifestations of the disease, in the “ICGG Gaucher Registry”. Patient data will be anonymously collected in this Registry. The objectives of the “ICGG Gaucher Registry” are to enhance the understanding of Gaucher disease and to evaluate the effectiveness of enzyme replacement therapy, ultimately leading to improvement in the safe and efficacious use of Cerezyme. 5.2 Pharmacokinetic properties During 1 hour intravenous infusions of 4 doses (7.5, 15, 30, 60 U/kg) of imiglucerase, 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 (mean ± S.D 0.12 ± 0.02 l/kg). These variables do not appear to be influenced by dose or duration of infusion, however, only 1 or 2 patients were studied at each dose level and infusion rate. 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity, and genotoxicicty. 6. Pharmaceutical particulars 6.1 List of excipients Mannitol, Sodium citrate (to adjust pH), Citric acid monohydrate (to adjust pH), Polysorbate 80 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life Unopened vials: 2 years. Diluted solution: From a microbiological safety point of view, the product should be used immediately. If not used immediately, in-use storage and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2°C - 8°C under protection from light. 6.4 Special precautions for storage Store in a refrigerator (2°C – 8°C). For storage conditions of the diluted medicinal product, see section 6.3 6.5 Nature and contents of container Cerezyme is supplied in type I borosilicate (clear) glass 20 ml vials. The closure consists of a siliconised butyl stopper with a tamper proof flip-off cap. To provide sufficient volume to allow accurate dispensing, each vial is formulated to contain an overfill of 0.6 ml. Package sizes: 1, 5 or 25 vials per carton. Not all package sizes may be marketed. 6.6 Special precautions for disposal and other handling Each vial of Cerezyme is for single use only. The powder for concentrate for solution for infusion has to be reconstituted with water for injections, diluted with 0.9% sodium chloride intravenous solution and then administered by intravenous infusion. Determine the number of vials to be reconstituted based on the individual patient's dosage regimen and remove the vials from the refrigerator. Occasionally, small dosage adjustments may be made to avoid discarding partially used vials. Dosages may be rounded to the nearest full vial, as long as the monthly administered dosage remains substantially unaltered. Use Aseptic Technique Reconstitution Reconstitute each vial with 10.2 ml water for injections; avoid forceful impact of water for injections on the powder and, by mixing gently, avoid foaming of the solution. The reconstituted volume is 10.6 ml. The pH of the reconstituted solution is approximately 6.1. After reconstitution it is a clear, colourless liquid, free from foreign matter. The reconstituted solution must be further diluted. Before further dilution, visually inspect the reconstituted solution in each vial for foreign particles and discoloration. Do not use vials exhibiting foreign particles or discoloration. After reconstitution, promptly dilute vials and do not store for subsequent use. Dilution The reconstituted solution contains 40 units imiglucerase per ml. The reconstituted volume allows accurate withdrawal of 10.0 ml (equal to 400 units) from each vial. Withdraw 10.0 ml reconstituted solution from each vial and combine the withdrawn volumes. Then dilute the combined volumes with 0.9% sodium chloride intravenous solution to a total volume of 100 to 200 ml. Mix the infusion solution gently. It is recommended to administer the diluted solution through an in-line low protein-binding 0.2 µm filter to remove any protein particles. This will not lead to any loss of imiglucerase activity. It is recommended that the diluted solution be administered within 3 hours. The product diluted in 0.9% sodium chloride intravenous solution will retain chemical stability if stored up to 24 hours at 2°C and 8°C under protection from light; but microbiological safety will depend on the reconstitution and dilution having been performed aseptically. Cerezyme contains no preservatives. Any unused product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Genzyme Europe B.V., Gooimeer 10, 1411 DD Naarden, The Netherlands 8. Marketing authorisation number(s) EU/1/97/053/003 EU/1/97/053/004 EU/1/97/053/005 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 17 November 1997 Date of latest renewal: 17 September 2007 10. Date of revision of the text 10/2010 Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu 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。 关于Cerezyme -酶替代治疗 适应症和用法 用于确诊患有导致下列一种或多种病症的I型戈谢氏病(Gaucher disease)的儿童及成人患者的长期酶替代疗法[4]: 贫血 血小板减少 骨病 肝肿大或脾肿大 治疗效果 Cerezyme(注射用伊米苷酶)已经被证实能安全有效地抑制、降低Ⅰ型戈谢氏病的许多症状和体征,甚至使患者恢复正常。 肝脏的反应 在治疗24个月后,能使肝脏体积缩小30%以上 在长达60个月的持续治疗后,改善的情况会持续进行 脾脏的反应 在治疗24个月后,能使脾脏体积缩小30%以上 在长达60个月的持续治疗后,改善的情况会持续进行 受到严重影响或过大的肝脏与脾脏,由于已经纤维化,一般不可能完全恢复正常。 已经被证实可增加血色素和血小板的数量,并且还能持续的改善。 血色素的反应 在24个月的治疗后,平均血色素会增加2.4g/dL 在长达60个月的持续治疗后,改善的情况会持续进行 血小板的反应 在24个月的治疗后,平均而言,血小板的数目会增加一倍 在长达60个月的持续治疗后,改善的情况会持续进行。 ---------------------------------------- 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 |