Ruconest(conestat alfa,中文药名:阿法可奈司他注射剂)第一个重组C1-Esterase抑制剂已获批为成年和青少年有遗传性血管水肿(HAE)患者急性发作治疗新药。
No clinical information on overdose is available. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group and ATC code: not yet assigned The plasma protein C1INH is the main regulator of activation of the contact and complement systems in vivo. HAE patients have a heterozygous deficiency of the plasma protein C1INH. As a result they may suffer from uncontrolled activation of contact and complement systems, with formation of inflammatory mediators, which clinically becomes manifest as the occurrence of acute angioedema attacks. Conestat alfa, recombinant human complement component 1 (C1) esterase inhibitor (rhC1INH), is an analogue of human C1INH and is obtained from the milk of rabbits expressing the gene encoding for human C1INH. The amino acid sequence of conestat alfa is identical to that of endogenous C1INH. C1INH exerts an inhibitory effect on several proteases (target proteases) of the contact and complement systems. The effect of conestat alfa on the following target proteases was assessed in vitro: activated C1s, kallikrein, factor XIIa and factor XIa. Inhibition kinetics were found to be comparable with those observed for plasma-derived human C1INH. The complement component (protein) C4, is a substrate for activated C1s. Patients with HAE have low levels of C4 in the circulation. As for plasma-derived C1INH, the pharmacodynamic effects of conestat alfa on C4 show dose-dependent restoration of complement homeostasis in HAE patients at a plasma C1INH activity level greater than 0.7 U/ml, which is the lower limit of the normal range. In HAE patients, Ruconest at a dose of 50 U/kg increases plasma C1INH activity level to greater than 0.7 U/ml for approximately 2 hours (see section 5.2). The efficacy and safety of Ruconest as a treatment of acute angioedema attacks in patients with HAE has been evaluated in two double blind randomized placebo controlled and four open label clinical studies. The doses evaluated in the clinical studies ranged from a single vial of 2100 U (corresponding to 18-40 U/kg), to 50 and 100 U/kg. Efficacy of Ruconest as a treatment for acute angioedema attacks was demonstrated by significantly shorter time to beginning of relief of symptoms and time to minimal symptoms and few therapeutic failures. The table below shows the results (primary and secondary endpoints) of the two randomized controlled trials:
In the randomized controlled trials 39/41 (95%) of patients treated with Ruconest reached time to beginning of relief within 4 hours. In an open label study 114/119 (95%) attacks treated with a single dose of 50 U/kg reached time to beginning of relief within 4 hours. An additional dose of 50 U/kg was administered for 13/133 (10%) attacks. Paediatric population Nine adolescent HAE patients (aged 13 to 17 years) were treated with 50 U/kg for 26 acute angioedema attacks, and 7 (aged 16 to 17 years) with 2100 U for 24 acute angioedema attacks. The European Medicines Agency has deferred the obligation to submit the results of studies with Ruconest in one or more subsets of the paediatric population in treatment of acute angioedema attacks (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Distribution No formal distribution studies have been performed. The distribution volume of conestat alfa was approximately 3 L, comparable to plasma volume. Biotransformation and elimination Based on animal data, conestat alfa is cleared from the circulation by the liver via receptor-mediated endocytosis followed by complete hydrolysis/degradation. After administration of Ruconest (50 U/kg) to asymptomatic HAE patients, a Cmax of 1.36 U/ml was observed. The elimination half-life of conestat alfa was approximately 2 hours. Excretion There is no excretion, as conestat alfa is cleared from the circulation via receptor-mediated endocytosis followed by complete hydrolysis/degradation in the liver. 5.3 Preclinical safety data Preclinical data do not indicate any safety concern for the use of conestat alfa in humans based on studies of safety pharmacology, single-dose toxicity, two-week sub-chronic toxicity and local tolerance in various animal species including rats, dogs, rabbits and cynomolgus monkeys. Genotoxic and carcinogenic potential is not expected. Embryofetal studies in rat and rabbit; Daily single doses of vehicle or 625 U/kg/administration of rhC1INH were administered intravenously to mated rats and rabbits. In the study in rats there were no malformed fetuses in either the conestat alfa or the control group. In a rabbit embryotoxicity study an increase in the incidence of fetal cardiac vessel defects (1.12% in the treatment group versus 0.03% in historical controls) was observed for animals that were administered conestat alfa. 6. Pharmaceutical particulars 6.1 List of excipients Sucrose Sodium citrate (E331) Citric acid (E330) 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 4 years. Reconstituted solution Chemical and physical in-use stability has been demonstrated for 48 hours between 5˚C and 25˚C. 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 would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions. 6.4 Special precautions for storage Do not store above 25°C. Store in the original package in order to protect from light. For storage conditions after reconstitution of the medicinal product, see section 6.3. 6.5 Nature and contents of container 2100 U of conestat alfa in a powder in a 25 ml vial (type 1 glass) with a stopper (siliconized chlorobutyl rubber) and a flip-off seal (aluminium and coloured plastic). Pack size of 1. 6.6 Special precautions for disposal and other handling Each vial of Ruconest is for single use only. An aseptic technique should be used for reconstitution, combining and mixing the solutions. Reconstitution Each vial of Ruconest (2100 U) should be reconstitued with 14 ml water for injections. Water for injections should be added slowly to avoid forceful impact on the powder and mixed gently to avoid foaming of the solution. The reconstituted solution contains 150 U/ml conestat alfa and appears as a clear colourless solution. The reconstituted solution in each vial should be visually inspected for particulate matter and discoloration. A solution exhibiting particulates or discoloration should not be used. The medicinal product should be used immediately (see section 6.3). There are no special requirements for disposal. 7. Marketing authorisation holder Pharming Group N.V., Darwinweg 24, NL-2333 CR LEIDEN, The Netherlands 8. Marketing authorisation number(s) EU/1/10/641/001 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 28 October 2010 10. Date of revision of the text 04/2013 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. FDA批准首个遗传性血管水肿生物抑制剂Ruconest 2014年7月17日,美国食品和药物管理局(FDA)批准了第一个重组 C1-Esterase抑制剂Ruconest,一款用于治疗急性成人和青少年患者遗传性血管性水肿发作的产品。 遗传性血管性水肿系常染色体遗传性疾病,可发生于任何年龄,而多见于成年早期。其病因是患者血清中C1脂酶抑制因子(一种α2球蛋白)减少或功能缺损,以致C1过度活化,C4及C2的裂解失控,所生成的补体激肽增多,以致使微血管通透性增高,引起水肿。在美国影响大约6000到10000人。 Ruconest是一种重组人类C1酯酶抑制因子,用于治疗遗传性血管性水肿(HAE)的药物 FDA生物制品评价和研究中心主任Karen Midthun医学博士说,“遗传性血管性水肿是一种罕见的和潜在的威胁生命的疾病,FDA的批准为这些患者提供了一个重要的治疗选择。” 2012年7月5日,荷兰生物技术公司Pharming曾宣布,其在美国进行的关键性III期临床试验患者招募已全面完成,该研究旨在评价其研究性新药Ruconest(重组人C1酯酶抑制剂)用于治疗遗传性血管水肿(HAE)患者血管性水肿急性发作的疗效。 2012年11月,Stantarus和Pharming集团宣布Ruconest III期临床研究达到初级终末点。 2013年6月,Santarus和Pharming宣布美国食品药品监督管理局(FDA)已同意对他们递交的RUCONEST生物制剂上市许可申请进行审查。 http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm405526.htm |
Ruconest(conestat alfa,中文药名:阿法可奈司他注射剂)简介:
Ruconest(conestat alfa,中文药名:阿法可奈司他注射剂)第一个重组C1-Esterase抑制剂已获批为成年和青少年有遗传性血管水肿(HAE)患者急性发作治疗新药。Ruconest 2100 U powder for solution for inje ... 责任编辑:admin |
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