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英文药名：注射用VPRIV(velaglucerase alfa solution for infusion) 中文药名：阿葡糖苷酶α稀释冻干粉 生产厂家：希尔生物制药
The safety profile of VPRIV in clinical studies involving children and adolescents aged 4 to 17 years was similar to that observed in adult patients. Elderly population (≥65 years) The safety profile of VPRIV in clinical studies involving patients aged 65 years and above was similar to that observed in other adult patients. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: United Kingdom: Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard Ireland: HPRA Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.hpra.ie e-mail: medsafety@hpra.ie 4.9 Overdose There is no experience with overdose of velaglucerase alfa. The maximum dose of velaglucerase alfa in clinical studies was 60 Units/kg. See section 4.4. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other alimentary tract and metabolism products – enzymes, ATC code: A16AB10. Gaucher disease is an autosomal recessive disorder caused by mutations in the GBA gene which results in a deficiency of the lysosomal enzyme beta-glucocerebrosidase. This enzymatic deficiency causes an accumulation of glucocerebroside primarily in macrophages, giving rise to foam cells or "Gaucher cells". In this lysosomal storage disorder (LSD), clinical features are reflective of the distribution of Gaucher cells in the liver, spleen, bone marrow, skeleton, and lungs. The accumulation of glucocerebroside in the liver and spleen leads to organomegaly. Bone involvement results in skeletal abnormalities and deformities as well as bone pain crises. Deposits in the bone marrow and splenic sequestration lead to clinically significant anaemia and thrombocytopenia. The active substance of VPRIV is velaglucerase alfa, which is produced by gene activation technology in a human cell line. Velaglucerase alfa is a glycoprotein. The monomer is approximately 63 kDa, has 497 amino acids, and the same amino acid sequence as the naturally occurring human enzyme, glucocerebrosidase. There are 5 potential N-linked glycosylation sites, four of which are occupied. Velaglucerase alfa is manufactured to contain predominantly high-mannose-type glycans to facilitate internalisation of the enzyme by the phagocytic target cells via the mannose receptor. Velaglucerase alfa supplements or replaces beta-glucocerebrosidase, the enzyme that catalyzes the hydrolysis of glucocerebroside to glucose and ceramide in the lysosome, reducing the amount of accumulated glucocerebroside and correcting the pathophysiology of Gaucher disease. Velaglucerase alfa increases haemoglobin concentration and platelet counts and reduces liver and spleen volumes in patients with type 1 Gaucher disease. In Studies 025EXT and 034, patients were offered home therapy. In Study 025EXT, 7 of 10 patients received home therapy at least once during 60 months of treatment. In Study 034, 25 of 40 patients received home therapy at least once during the 12-month study. Clinical efficacy and safety Studies in treatment naïve patients Study 025 was a 9 month, open-label study in 12 adult (≥18 years) patients who were naïve to ERT (defined as having not been treated with ERT for at least 12 months prior to study entry). Velaglucerase alfa was initially administered in a dose-escalating fashion in the first 3 patients (15, 30, 60 Units/kg) and the 9 remaining patients began treatment with 60 Units/kg. Clinically meaningful improvements from baseline were observed in haemoglobin concentration and platelet counts as early as 3 months and in liver and spleen volumes at both 6 months and 9 months following the initiation of treatment with velaglucerase alfa. Ten patients who completed Study 025 enrolled in an open-label extension study (025EXT), 8 of whom completed the study. After a minimum of 12 months of continuous treatment with velaglucerase alfa, all patients qualified to have the dose of velaglucerase alfa reduced in a step-wise fashion from 60 to 30 Units/kg after achieving at least 2 of the 4 “Year 1” therapeutic goals of ERT for type 1 Gaucher disease. Patients received doses ranging from 30 to 60 Units/kg (median dose 35 Units/kg) every other week for up to 84 months (7 years). Sustained clinical activity continued to be demonstrated during treatment as observed by improvements in haemoglobin concentrations and platelet counts and reduced liver and spleen volumes. By month 57, 8 out of the 8 patients had achieved a reduction of at least 2 points in the lumbar spine Bone Marrow Burden (BMB) score as assessed by MRI scan. Improvement from baseline in mean lumbar spine and femoral neck bone mineral density (BMD) Z-scores were observed at month 24 (0.4; 95% CI 0.1, 0.7) and month 33 (0.4; 95% CI 0.2, 0.6), respectively. After seven years of treatment, the mean increase from baseline in Z-scores were 0.7 (95% CI 0.4, 1.0) for the lumbar spine and 0.5 (95% CI 0.2, 0.7) for the femoral neck. No patients were classified at a more severe WHO classification of bone density compared to baseline. Study 032 was a 12-month, randomized, double-blind, parallel-group efficacy study in 25 patients aged 2 years and older who were naïve to ERT (defined as having not been treated with ERT for at least 30 months prior to study entry). Patients were required to have Gaucher disease-related anaemia and either thrombocytopenia or organomegaly. Patients were randomized to receive velaglucerase alfa at a dose of either 45 Units/kg (N=13) or 60 Units/kg (N=12) every other week. Velaglucerase alfa 60 Units/kg given intravenously every other week demonstrated clinically meaningful increases from baseline in mean haemoglobin concentration (+2.4 g/dl) and platelet count (+50.9 x 109/l), liver volume was reduced from 1.46 to 1.22 times normal (mean reduction of 17%) and spleen volume was reduced from 14.0 to 5.75 times normal (mean reduction of 50%). Meaningful increases from baseline were observed in the 45 Units/kg dose group in haemoglobin concentration (+2.4 g/dl) and platelet count (+40.9 x 109/l), liver volume was reduced from 1.40 to 1.24 times normal (mean reduction of 6%) and spleen volume was reduced from 14.5 to 9.50 times normal (mean reduction of 40%). Study 039 was a 9-month, randomized, double-blind, non-inferiority, active-comparator (imiglucerase) controlled, parallel-group efficacy study in 34 patients aged 2 years and older who were naïve to ERT (defined as having not been treated with ERT for at least 12 months prior to study entry). Patients were required to have Gaucher disease-related anaemia and either thrombocytopenia or organomegaly. Patients received either 60 Units/kg of velaglucerase alfa (N=17) or 60 Units/kg of imiglucerase (N=17) every other week. The mean absolute increase from baseline in haemoglobin concentrations was 1.624 g/dl (±0.223 SE) following 9 months of treatment with velaglucerase alfa. This increase in haemoglobin concentration was demonstrated to be clinically and statistically non-inferior to imiglucerase (mean treatment difference of change from baseline to 9 months [velaglucerase alfa – imiglucerase]: 0.135 g/dl). There were no statistically significant differences between velaglucerase alfa and imiglucerase in changes in platelet counts and liver and spleen volumes after 9 months of velaglucerase alfa treatment, and in the time to first haemoglobin response (defined as 1 g/dl increase from baseline). Study in patients switching from imiglucerase treatment to VPRIV Study 034 was a 12-month, open-label safety study in 40 patients aged 2 years and older who had been receiving treatment with imiglucerase at doses ranging from 15 to 60 Units/kg for a minimum of 30 consecutive months. Patients were required to have a stable dose of imiglucerase for at least 6 months prior to study enrolment. Treatment with velaglucerase alfa was administered as the same number of units and regimen as their imiglucerase dose. Haemoglobin concentration and platelet counts were evaluated as changes from baseline, which was defined as the end of the patient's treatment with imiglucerase. In patients who switched from imiglucerase to velaglucerase alfa, haemoglobin concentrations and platelet counts were sustained at therapeutic levels through 12 months of treatment. Study 058 was an open-label clinical safety study in 211 patients including 205 patients previously treated with imiglucerase 6 treatment-naïve patients and 57 patients aged 65 years or older (56/57 had switched from imiglucerase to velaglucerase alfa). Patients transferring from imiglucerase were administered velaglucerase alfa infusions every other week at the same number of units as imiglucerase within the range of 15 to 60 Units/kg. Patients transferring from a dose of <15 Units/kg imiglucerase were administered 15 Units/kg of velaglucerase alfa. Patients previously treated with imiglucerase received a median of 8 velaglucerase alfa infusions with median duration of treatment of 15.1 weeks. The safety profile in these patients was similar to that observed in other clinical trials. Only 1 out of 163 patients assessed developed anti-velaglucerase alfa antibodies during the study. The mean haemoglobin concentration and platelet count of patients previously treated with imiglucerase were maintained throughout the study and remained within the reference intervals. Extension Study 044 A total of 95 patients (73 adult and 22 paediatric) who participated in studies 032, 034, and 039 enrolled in the open label extension study and were treated with velaglucerase alfa. 57 patients were treatment-naïve. All patients received at least 2 years of ERT and were followed for a mean of 4.5 years (min. 2.3 years, max 5.8 years). In this study, haemoglobin concentration, platelet count, liver volume and spleen volume were assessed in treatment-naïve patients after 24 months of treatment. The results are presented in Table 2. Table 2: Results at 24 months - Change from Baseline – Study 044 ITT Population
In the paediatric population (ages 4 to 17 years studied), increases in the mean height Z-score were seen through 60 months of treatment in the overall treatment-naïve population, suggesting a beneficial treatment effect with velaglucerase alfa on linear growth. Similar treatment effects were seen through 48 months in the paediatric population who received 9 months of imiglucerase followed by velaglucerase alfa. Paediatric subjects who switched from long-term imiglucerase to velaglucerase alfa in study 034 had greater mean height Z-scores at baseline and their mean height Z-scores remained stable over time. These treatment effects on haemoglobin, platelet count, organ volumes, bone mineral density and height were maintained through the end of the study. Paediatric population Use in the age group 4 to 17 is supported by evidence from controlled studies in adults and paediatric [20 of 94 (21%)] patients. The safety and efficacy profiles were similar between paediatric and adult patients. The studies allowed the inclusion of patients 2 years and older and the safety and efficacy profiles are expected to be similar down to the age of 2 years. However, no data are available for children under the age of 4 years. The effect on height was assessed in the study 044 (see section 5.1, Extension Study 044). The European Medicines Agency has waived the obligation to submit the results of studies with VPRIV in all subsets of the paediatric population with type 2 Gaucher disease and has deferred the obligation to submit the results of studies with VPRIV in one or more subsets of the paediatric population in Gaucher disease type 1 and 3 (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties There were no apparent pharmacokinetic differences between male and female patients with type 1 Gaucher disease. None of the subjects in the pharmacokinetic studies were positive for anti-velaglucerase alfa antibodies on the days of pharmacokinetic evaluation. Therefore, it was not possible to evaluate the effect of antibody response on the pharmacokinetic profile of velaglucerase alfa. Absorption Velaglucerase alfa serum concentrations rose rapidly for the first 20 minutes of the 60-minute infusion before leveling off, and Cmax was typically attained between 40 and 60 minutes after the start of the infusion. After the end of the infusion, velaglucerase alfa serum concentrations fell rapidly in a monophasic or biphasic fashion with a mean t1/2 ranging from 5 to 12 minutes at doses of 15, 30, 45, and 60 Units/kg. Distribution Velaglucerase alfa exhibited an approximately linear (i.e. first-order) pharmacokinetic profile, and Cmax and AUC increased approximately proportional to the dose over the dose range 15 to 60 Units/kg. The steady state volume of distribution was approximately 10% of the body weight. The high clearance of velaglucerase alfa from serum (mean 6.7 to 7.6 ml/min/kg) is consistent with the rapid uptake of velaglucerase alfa into macrophages via mannose receptors. Elimination The range of velaglucerase alfa clearance in paediatric patients (N=7, age range 4 to 17 years) was contained within the range of clearance values in adult patients (N=15, age range 19 to 62 years). 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and toxicity to reproduction and development. 6. Pharmaceutical particulars 6.1 List of excipients Sucrose Sodium citrate dihydrate (E331) Citric acid monohydrate (E330) Polysorbate 20 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 3 years. Reconstituted and diluted solution for infusion: Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C under protection from light. From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and must not exceed 24 hours at 2°C to 8°C. 6.4 Special precautions for storage Store in a refrigerator (2°C - 8°C). Do not freeze. Keep the vial in the outer carton in order to protect from light. For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3. 6.5 Nature and contents of container 20 ml vial (type I glass) with a stopper (fluoro-resin coated butyl rubber), one piece seal, and flip-off cap. Pack sizes of 1, 5 and 25 vials. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling VPRIV requires reconstitution and dilution, and is intended for intravenous infusion only. It is for single-use only and is administered through a 0.22 µm filter. Aseptic technique must be used. Prepare VPRIV as follows: 1. The number of vials to be reconstituted is determined based on the individual patient's weight and the prescribed dose. 2. The required vials are removed from the refrigerator. Each 400 Units vial is reconstituted with 4.3 ml of sterile water for injections. 3. Upon reconstitution, vials should be mixed gently. Vials should not be shaken. Each vial will contain an extractable volume of 4.0 ml (100 Units/ml). 4. Prior to further dilution, the solution in the vials should be visually inspected; the solution should be clear to slightly opalescent and colourless; the solution should not be used if it is discoloured or if foreign particulate matter is present. 5. The calculated volume of medicinal product is withdrawn from the appropriate number of vials and the total volume required is diluted in 100 ml of sodium chloride 9 mg/ml (0.9%) solution for infusion. The product should be mixed gently. It should not be shaken. The infusion should be initiated within 24 hours from the time of reconstitution. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Shire Pharmaceuticals Ireland Limited 5 Riverwalk Citywest Business Campus Dublin 24 Ireland 8. Marketing authorisation number(s) EU/1/10/646/002 EU/1/10/646/005 EU/1/10/646/006 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 26 August 2010 Date of latest renewal: 19 June 2015 10. Date of revision of the text 06/2015 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu VPRIV(注射用velaglucerase alfa)获准用于治疗戈谢病 2010年2月26日，美国食品药品管理局(FDA)和Shire公司宣布，VPRIV(注射用velaglucerase alfa)——一种葡萄糖脑苷脂特异性溶酶体水解酶，适宜用作小儿科和成人1型戈谢病患者的长期酶替代治疗(ERT)药。 据FDA称，VPRIV是Cerezyme(伊米苷酶)的替代药物，后者在供应方面存在问题。 戈谢病是一种由β-脑苷脂酶基因突变所致的常染色体隐性遗传病，其最常见类型为1型。这种酶缺乏可导致脑苷脂积聚，主要积聚在巨噬细胞内。戈谢病的临床特征可反映戈谢细胞在肝、脾、骨髓及其他脏器的分布状况。脑苷脂酶在肝和脾的积聚可导致脏器肿大。骨髓和脾中存在戈谢细胞时可引起具有临床意义的贫血和血小板减少。 在VPRIV的有效性评估方面进行了3项临床研究，共纳入99例1型戈谢病患者。82例4岁或4岁以上患儿接受VPRIV治疗，17例3岁或3岁以下患儿接受伊米苷酶治疗。第一、二项研究的受试者当时未接受戈谢病特异性治疗。第三项研究的受试者开始VPRIV治疗前即刻接受伊米苷酶治疗。在这些研究中，VPRIV均为静脉给药，持续60 min，剂量为15 U/kg~ 60 U/kg，两周1次。各项研究均达到了主要研究终点。 临床研究中接受VPRIV治疗的患者最常见的不良事件为输液相关反应。与输液相关反应有关的最常见的症状为头痛、头晕、低血压、高血压、恶心、发热以及乏力/无力。输液相关反应一般较轻，见于初次接受治疗的患者，主要发生于治疗的最初6个月中，随着时间延长，其发生率趋于降低。 与成人患者相比，小儿科患者中较常见(差异>10%)的不良反应包括皮疹、上呼吸道感染、活化部分凝血活酶时间延长以及发热。 在三项临床研究共82例4以上高歇氏病患者中评估VPRIV的安全性和有效性。研究中包括既往用Cerezyme 转用VPRIV的患者。 美国食品药品管理局批准日期：2010年2月 2日；公司：Shire plc | |||||||||||||||||||||||||||||||||||||||||||||||||||||
