英文药名：Refixia（Nonacog Beta Pegol[Genetical Recombination]）

中文药名：聚乙二醇化重组凝血因子IX注射剂

生产厂家：诺和诺德制药

レフィキシア静注用500／レフィキシア静注用1000／レフィキシア静注用2000

药物分类名称
聚乙二醇化基因重组凝血因子IX制剂
批准日期：2018年9月
商標名
Refixia
一般名
ノナコグ ベータ ペゴル（遺伝子組換え）［命名法：JAN］
Nonacog Beta Pegol（Genetical Recombination）［命名法：JAN］
分子式
C2041H3114N558O641S25（タンパク質部分）
本　質
Nonacog Beta pegol是一种重组人凝血因子IX类似物（分子量：约98,000），加入Asn 157或Asn 167的两条糖链有两条聚乙二醇链 总平均分子量：约42,000）与氨基结合。 糖蛋白部分由415个氨基酸组成，由中国仓鼠卵巢细胞产生。
处理注意事项
保存记录
由于该药物不是特定生物体的产品，而是血液制品替代药物，当将该药物（处方）给予凝血因子IX缺乏的患者，药物名称及其序列号，给药（处方） 记录日期，使用的患者姓名，地址等，并保存至少20年。
批准条件
制定药品风险管理计划并适当实施。
药用药理学
1.作用机制
通过去除聚乙二醇化的活化肽激活Nonacog Beta pegol，并将其转化为具有与内源性活化凝血因子IX相同的结构和功能特性的分子，以改善凝血因子IX的缺乏。暂时纠正出血倾向。 此外，认为PEG化延长半衰期并长时间维持血液凝固因子IX活性。
2.主要的非临床研究
在血友病B小鼠的尾部出血模型和膝关节损伤模型中观察到止血效果（FIX敲除：FIX-KO）5）。
此外，血友病B犬的全血凝固时间正常化
适应症
抑制血液凝固因子IX缺乏患者的出血倾向
用法与用量
将该产品溶解在所提供的专用溶解溶液的总量中，并以不超过4mL / min的速率静脉内缓慢注射，如下所述。

用法・用量
出血时给药：轻度至中度	施用40IU / kg。根据患者的情况，可以给予额外剂量40 IU / kg一次。
出血时给药：严重或危及生命的出血	施用80IU / kg。
手术治疗：小手术	手术前给予40 IU / kg。
手术期间给药：大手术	在手术前施用80IU / kg，但必要时调整以在手术期间将血液凝固因子IX活性维持在约100％（1IU / mL）。 手术后，在术前给药后24至48小时给予40IU / kg，这取决于血液中凝血因子IX活性的目标值。 在手术后的前七天，血液中的凝血因子IX活性应保持在约50％（0.5IU / mL）。
定期管理	每周施用40IU / kg一次。

临床结果
成人和小儿患者的血友病B（FIX活性2％）105例如预先处理（0-6岁：12名患者，7-12岁：13名患者，13-17岁的年龄：18例，18〜70岁：62例），进行III期临床试验以检查预防性替代疗法，出血治疗和手术使用的安全性和有效性。
1.定期管理
在两个国际协作III期临床试验血友病B患者先前用（FIX活性2％或更少）和目标，年处理在接收本发明的药剂的给药定期患者（40 IU/kg的每周一次）转换出血率如下。 （见表4）
2.对止血的止血作用
13〜70岁患者的出血的止血效果的百分比评价为“完全应答”或“有效”为92.4％（三百四十一分之三百一十五次）。
另外，患者的0至12岁的年龄，出血的止血效果的比例被评价为“完全反应”或“有效”的为92.9％（39/42倍）。
3.围手术期止血效果
13例患者（13〜56岁）以13外科手术进行，在所有的外科手术止血效果是“完全反应”或“有效”。
包装
500 x1小瓶静脉注射Refixia
[溶解（L-组氨酸溶液）预充式注射器4mL×1注射器的专用溶液]
1000x1小瓶静脉注射Refixia
[溶解（L-组氨酸溶液）预充式注射器4mL×1注射器的专用溶液]
2000x1小瓶静脉注射Refixia
[溶解（L-组氨酸溶液）预充式注射器4mL×1注射器的专用溶液]
制造供应商
诺和诺德制药有限公司
注：以上中文资料不够完整，使用者以原资料为准。
完整说明书附件：http://www.info.pmda.go.jp/go/pack/6343452D1026_1_01/
Nonagogue Beta Pegol (Refixia) Hemophilia B therapeutic agent that pegylates factor IX and prolongs its half-life
On July 2, 2018, manufacture and sale of pegylated genetically recombinant blood coagulation factor IX preparation nonacoga beta pegol (commodity name Refixia for IV 500, same 1000 for intravenous injection, 2000 for same) approved It was done. A formulation consisting of a drug vial and a special dissolving solution (L-histidine solution) prefilled syringe. Adaptation is "suppression of bleeding tendency in patients with blood clotting factor IX deficiency", dosage regimen is "dissolved in the total amount of exclusive dissolution solution (4 mL) attached, under various circumstances [at bleeding (mild to moderate, severe or life (Refer to the latest attached document for details) determined for each operation (small bleeding, major surgery), periodic], in any case at a rate not exceeding 4 mL / min Note "has become.
Haemophilia B is a congenital hemorrhagic disease (rare disease) caused by a decrease in plasma FIX activity associated with quantitative or qualitative abnormalities of blood coagulation factor IX (FIX). Specific symptoms are characterized by bleeding which seeps out from deep tissue, most of bleeding sites are subcutaneous bleeding, intra-articular bleeding and intramuscular bleeding. Hemophilia B is mostly a disease seen in men, domestic statistics are affected by 1 to 2 people per 100,000 men and the number of patients is estimated to be about 1000 people.
Treatment is replacement therapy that administers the required amount of FIX formulation reversibly and promptly during bleeding, and regular replacement therapy to prevent progression of haemophilic arthropathy and the like. As a FIX formulation that has been clinically used in the past, it has been proposed to use human plasma derived [dry concentrated human blood coagulation factor IX preparation (Chris machine M, Novact M), dry person blood coagulation factor IX complex formulation (PPSB - HT) There is a preparation of recombinant [blood coagulation Factor IX preparation (Benefit, Lixvis)]. Recently, a FIX agent preparation with extended plasma half-life, gene recombination [blood coagulation Factor IX factor Fc region fusion protein preparation (Orprolix), blood coagulation factor IX albumin fusion protein preparation (IDERBION)] has appeared, The burden on the patient has also been greatly alleviated.
Nonacog Betapagol is a three-component preparation as a FIX agent preparation with prolonged plasma half-life, and is a drug whose half-life is prolonged by modifying (pegylation) the recombinant FIX factor. In the blood clotting process, the activation removes the pegylated activation peptide and converts it into a molecule having the same structure and functional properties as the endogenous active FIX factor, improving the deficiency of the FIX factor, temporal .
In multiple international joint Phase III clinical trials of admission and pediatric hemophilia B patients (including Japanese patients) with treatment history, regular replacement therapy by administration of this drug, hemostatic effect at bleeding, perioperative The effectiveness of the hemostatic effect in the period was confirmed. Overseas, as of May 2018, it is sold in Austria, Canada, Denmark, Germany, the Netherlands, Switzerland and the United States.
In the international joint examination, side effects are recognized in 6.0%. Main side effects are injection site response, pruritus, hypersensitivity, and as a serious side effect, shock, anaphylaxis, thromboembolism may occur, so be careful.