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部份中文Fasturtec处方资料（仅供参考）
From post-marketing experience + Uncommon G3/4 ++ Common G3/4 Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. 4.9 Overdose In view of the mechanism of action of Fasturtec, an overdose will lead to low or undetectable plasma uric acid concentrations and increased production of hydrogen peroxide. Thus patients suspected of receiving an overdose should be monitored for haemolysis, and general supportive measures should be initiated as no specific antidote for Fasturtec has been identified. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment, ATC code: V03AF07. Mechanism of action In humans, uric acid is the final step in the catabolic pathway of purines. The acute increase in plasma levels of uric acid subsequent to the lysis of large numbers of malignant cells and during cytoreductive chemotherapy may lead to impairment of renal function and renal failure resulting from the precipitation of crystals of uric acid in renal tubules. Rasburicase is a highly potent uricolytic agent that catalyses enzymatic oxidation of uric acid into allantoin, a water soluble product, easily excreted by the kidneys in the urine. The enzymatic oxidation of uric acid leads to stoichiometric formation of hydrogen peroxide. The increased of hydrogen peroxide over ambient levels can be eliminated by endogenous antioxidants and the only increased risk is for haemolysis in G6PD deficient and inherited anaemia patients. In healthy volunteers, a marked dose-related decrease in plasma uric acid levels was observed across the dose range 0.05 mg/kg to 0.20 mg/kg of Fasturtec. Clinical efficacy and safety In a randomised comparative phase III study, performed in 52 paediatric patients, 27 patients were treated with rasburicase at the recommended dose of 0.20 mg/kg/day, intravenously, for 4 to 7 days (< 5 years: n=11; 6-12 years: n=11; 13-17 years: n=5), and 25 patients with allopurinol daily oral doses for 4 to 8 days. Results showed a significantly more rapid onset of action of Fasturtec in comparison with allopurinol. At 4 hours post first dose, there was a significant difference in the mean percentage change from baseline plasma uric acid concentration (p <0.0001) in the Fasturtec group (-86.0%) compared to that for the allopurinol group (-12.1%). Time to first confirmation of normal levels of uric acid in hyperuricaemic patients is four hours for Fasturtec and 24 hours for allopurinol. In addition this rapid control of uric acid in this population is accompanied by improvements in renal function. In turn, this allows efficient excretion of the serum phosphate load preventing further deterioration of renal function from calcium/phosphorus precipitation. In a randomized (1:1:1), multi-center, open-label study, 275 adult patients with leukemia and lymphoma at risk for hyperuricemia and tumour lysis syndrome (TLS) were treated with either rasburicase at a dose of 0.2 mg/kg/day, intravenously, for 5 days (arm A: n=92), rasburicase at a dose of 0.2 mg/kg/day, intravenously, from day 1 through day 3 followed by oral allopurinol at a dose of 300 mg once a day from day 3 through day 5 (overlap on day 3: rasburicase and allopurinol administered approximately 12 hours apart) (arm B: n=92), or oral allopurinol at a dose of 300 mg once a day for 5 days (arm C: n=91). The uric acid response rate (proportion of patients with plasma uric acid levels ≤7.5 mg/dl from day 3 to day 7 after initiation of antihyperuricemic treatment) was 87% in arm A, 78% in arm B, and 66% in arm C. The response rate in arm A was significantly greater than in arm C (p=0.0009); the response rate was higher for arm B compared to arm C although this difference was not statistically significant. Uric acid levels were <2 mg/dl in 96% of patients in the two arms containing rasburicase and 5% of patients in the allopurinol arm at 4 hours of the day 1 dose. The safety results of patients treated with Fasturtec in Study EFC4978 were consistent with the adverse events profile observed in previous clinical studies with predominantly paediatric patients. In pivotal clinical studies, 246 paediatric patients ( mean age 7 years, range 0 to17) were treated with rasburicase at doses of 0.15 mg/kg/day or 0.20 mg/kg/day for 1 to 8 days (mainly 5 to 7 days). Efficacy results on 229 evaluable patients showed an overall response rate (normalization of plasma uric acid levels) of 96.1%. Safety results on 246 patients were consistent with the adverse events profile in the overall population. In long term safety studies, an analysis of data from 867 paediatric patients (mean age 7.3 years, range 0 to17) treated with rasburicase at 0.20 mg/kg/day for 1 to 24 days (mainly 1 to 4 days) showed consistent findings with pivotal clinical studies in terms of efficacy and safety. 5.2 Pharmacokinetic properties The pharmacokinetics of rasburicase were evaluated in both paediatric and adult patients with leukaemia, lymphoma or other haematological malignancies. Absorption After infusion of rasburicase at a dose of 0.20 mg/kg/day, steady state is achieved at day 2 - 3. Minimal accumulation of rasburicase (<1.3 fold) was observed between days 1 and 5 of dosing. Distribution The mean volume of distribution ranged from 110 - 127 ml/kg in paediatric patients and from 75.8 to 138 ml/kg in adult patients, respectively, which is comparable to the physiological vascular volume. Metabolism Rasburicase is a protein, and therefore: 1) not expected to bind to proteins, 2) expected that metabolic degradation will follow the pathways of other proteins, i.e. peptide hydrolysis, 3) unlikely to be candidate for drug-drug interactions. Elimination Clearance of rasburicase was ca. 3.5 ml/h/kg. The mean terminal half-life was similar between paediatric and adult patients and ranged from 15.7 to 22.5 hours. Clearance is increased (ca. 35%) in children and adolescents compared to adults, resulting in a lower systemic exposure. Renal elimination of rasburicase is considered to be a minor pathway for rasburicase clearance. Special patient populations In adults (≥ the age of 18 years), age, gender, baseline liver enzymes and creatinine clearance did not impact the pharmacokinetics of rasburicase. A cross-study comparison revealed that after administration of rasburicase at 0.15 or 0.20 mg/kg, the geometric mean values of body-weight normalized clearance were approximately 40% lower in Japanese (n=20) than that in Caucasians (n=26). As metabolism is expected to occur by peptide hydrolysis, an impaired liver function is not expected to affect the pharmacokinetics. 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 genotoxicity. The interpretation of the non-clinical studies is hampered due to the presence of endogenous urate oxidase in standard animal models. 6. Pharmaceutical particulars 6.1 List of excipients Powder: alanine mannitol disodium phosphate dodecahydrate disodium phosphate dihydrate sodium dihydrogen phosphate dihydrate Solvent: poloxamer 188 water for injection 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. Rasburicase solution should be infused through a different line than that used for infusion of chemotherapeutic agents to prevent any possible drug incompatibility. If use of a separate line is not possible, the line should be flushed out with saline solution between chemotherapeutic agent infusions and rasburicase. No filter should be used for infusion. Do not use any glucose solution for dilution due to potential incompatibility. 6.3 Shelf life 3 years. After reconstitution or dilution an immediate use is recommended. However, the in-use stability has been demonstrated for 24 hours between +2°C and 8°C. 6.4 Special precautions for storage Powder in vial: store in a refrigerator (2°C -8°C). Do not freeze. Store in the original package in order to protect from light. For storage conditions after reconstitution or dilution of the medicinal product, see section 6.3 6.5 Nature and contents of container Fasturtec is supplied as a pack of: 3 vials of 1.5 mg rasburicase and 3 ampoules of 1 ml solvent. The powder is supplied in 3 ml clear glass (type I) vial with a rubber stopper and the solvent in a 2 ml clear glass (type I) ampoule. 1 vial of 7.5 mg rasburicase and 1 ampoule of 5 ml solvent. The powder is supplied in 10 ml clear glass (type I) vial with a rubber stopper and the solvent in a 5 ml clear glass (type I) ampoule. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Rasburicase must be reconstituted with the entire volume of the supplied solvent ampoule (1.5 mg rasburicase vial to be reconstituted with the 1 ml solvent ampoule; 7.5 mg rasburicase vial to be reconstituted with the 5 ml solvent ampoule). Reconstitution results in a solution with a concentration of 1.5 mg/ml rasburicase to be further diluted with sodium chloride 9 mg/ml (0.9%) intravenous solution. Reconstitution of the solution: Add the content of one ampoule of solvent to one vial containing rasburicase and mix by swirling very gently under controlled and validated aseptic conditions. Do not shake. Inspect visually prior to use. Only clear and colourless solutions without particles should be used. For single-use only, any unused solution should be discarded. The solvent contains no preservative. Therefore the reconstituted solution should be diluted under controlled and validated aseptic conditions. Dilution before infusion: The required volume of the reconstituted solution depends on the patient's body weight. The use of several vials may be necessary to obtain the quantity of rasburicase required for one administration. The required volume of the reconstituted solution, taken from one or more vials, is to be further diluted with sodium chloride 9 mg/ml (0.9%) solution to make a total volume of 50 ml. The concentration of rasburicase in the final solution for infusion depends on the patient's body weight. The reconstituted solution contains no preservative. Therefore the diluted solution should be infused immediately. Infusion: The final solution should be infused over 30 minutes. Sample handling: If it is necessary to monitor a patient's uric acid level, a strict sample-handling procedure must be followed to minimise ex vivo degradation of the analyte. Blood must be collected into pre-chilled tubes containing heparin anticoagulant. Samples must be immersed in an ice/water bath. Plasma samples should immediately be prepared by centrifugation in a pre-cooled centrifuge (4°C). Finally, plasma must be maintained in an ice/water bath and analysed for uric acid within 4 hours. 7. Marketing authorisation holder sanofi-aventis groupe 54, rue La Boétie F - 75008 Paris France 8. Marketing authorisation number(s) EU/1/00/170/001-002 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 23 February 2001 Date of latest renewal: 23 February 2006 10. Date of revision of the text 07 July 2016 Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu 拉布立酶(rasburicase)—高尿酸血症新药 高尿酸血症是白血病和淋巴瘤及其治疗的一种常见并发症。对于骨髓增生性疾病或造血系统恶性肿瘤病人，核酸的分解代谢是恶性细胞群增加更新的结果，从而增加嘌呤的代谢，导致尿酸血浓度的增高。癌症的积极治疗方案可引起细胞溶解增多和嘌呤代谢物的释放。肿瘤溶解综合征的特征为严重高尿酸血症、高磷酸盐血症、高钾血症、高钙血症和急性肾衰。作为高尿酸血症的结果，当尿中的尿酸达到过饱和，肾小管和远端收集系统出现尿酸结晶会引起肾功能不全。 高尿酸血症的标准预防或治疗方案为使用别嘌醇治疗，进行尿液碱化，水合和渗透性利尿。别嘌醇通过抑制黄嘌呤氧化酶阻滞尿酸形成，但会增加肾脏排泄尿酸前体(次黄嘌呤和黄嘌呤)的负荷。与次黄嘌呤不同，黄嘌呤在尿中比尿酸难溶。有时别嘌醇治疗的病人也可出现黄嘌呤肾病和结石。此外，对于病人体内存留的尿酸的排泄，使用别嘌醇治疗无效。 拉布立酶为由来自曲霉菌DNA克隆的酿酒酿母基因工程突变 株产生的重组尿酸氧化酶。于2001年6月在德国和英国首次上市。尿酸氧化酶可催化尿酸的氧化，形成尿囊素，后者为一种比较容易排泄的代谢物，其溶解度为尿酸的5—10倍。大多数哺乳动物体内均有内源性尿酸氧化酶，但人体则缺乏这种酶。在血液学肿瘤病人化疗初期使用本品可预防和治疗高尿酸血症，进而预防急性肾衰。本品应在化疗前或化疗早期使用。 Pui等报道，131例接受治疗的病人(21岁以下，88例男孩，43例女孩)中，因白血病或淋巴瘤而出现高尿酸血症，或认为存在着发生这一并发症的高度危险，进行多中心公开标签的非随机无对照研究。这些病人血清乳酸脱氢酶升高。研究分为两个阶段，第一阶段是剂量调整期(确定有效剂量)，第二阶段是治疗期(确定有效性和安全性)。 第一阶段起始剂量为一日0．15mg／kg，基于志愿者的研究结果以及非重组产品的等效剂量。而后每次增加0．05mg／kg。调整后不再增加剂量。前ll例病人使用本品O．15mg／kg治疗，能有效地纠正或预防高尿酸血症。而第12例病人，为年仅13岁的男孩，患有III期小型未分化非霍奇金淋巴瘤(NHL)，48小时尿酸浓度出现一过性增高，尿酸水平为21．1mg／dl。根据研究设计，采用0．2mg／kg高剂量本品治疗。其后14例病人的治疗证明，该剂量有效并用于治疗期。 治疗期中2例在48小时时出现高尿酸血症，在24小时后消除。在48小时后有2例出现高尿酸血症，但经过治疗无1例持续24小时以上。131例病人的研究显示，本品的任何一种剂量均可显著降低尿酸浓度。而不管病人是否存在高尿酸血症。尽管由于强化化疗，两组病人中位尿酸浓度在整个疗程中均保持或接近0.5mg／dl。 拉布立酶能降低侵袭性淋巴瘤病人的尿酸水平 本报讯 在大多数伴有高尿酸血症的侵袭性淋巴瘤病人中，用重组尿酸氧化酶--拉布立酶（ｒａｓｂｕｒｉｃａｓｅ）的短疗程治疗可快速和极大地降低尿酸水平。这是法国研究者在美国血液学会第４４届年会上报告的。 法国Ｌｙｏｎ－Ｓｕｄ中心医院的Ｃoiffier医师和同事，采用拉布立酶治疗了100例至少有一个不良预后因素的侵袭性非霍奇金淋巴瘤（ＮＨＬ）病人，治疗剂量为0.20mg／kg／d，连续治疗３～７天，治疗与化疗同时或提前一天开始。 研究者观察到，在化疗前，66％的病人有乳酸脱氢酶（ＬＤＨ）升高，其中28％的病人ＬＤＨ高于1000U／ml”。 在该组病人中有11％的病人有高尿酸血症，研究者将高尿酸血症定义为尿酸水平超过450ｍmol／l。病人用各种化疗方案进行治疗，这些化疗方案包括：环磷酰胺，多柔比星，长春新碱，泼尼松（ＣＨＯＰ）；多柔比星，环磷酰胺，长春地辛，博来霉素和泼尼松（ＡＣＶＢＰ）；多柔比星，环磷酰胺，依托泊苷（ＡＣＥ）。２０％的病人在上述方案中联合使用了一种单克隆抗体（ｒｉｔｕｘｉｍａｂ）。 研究者报告，在拉布立酶治疗后，除１例病人外（这例病人在用拉布立酶治疗３天后出现高钾血症），所有病人均出现疗效反应。有疗效反应的定义为在整个化疗过程中，尿酸水平转为正常。 研究者还报告，在该组病人中，81％的病人用拉布立酶治疗３天就足以控制高尿酸血症；另外10％的病人需要治疗４天，仅有4％的病人需要治疗５天或６天才能达到正常。３例病人由于肝脏酶升高、１例病人由于与淋巴瘤相关的并发症而停止拉布立酶治疗。 coiffier说，高尿酸血症和肿瘤溶解综合征（ＴＬＳ）是ＮＨＬ治疗中的常见并发症。上述结果提示，在侵袭性ＮＨＬ的成年病人中，拉布立酶应被作为预防ＴＬＳ的首选治疗药物。 |
