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米泊美生钠注射液Kynamro（mipomersen sodium）

2013-02-06 18:38:09 作者：新特药房来源：互联网浏览次数：1385 文字大小：【大】【中】【小】

简介： 美国食品药品管理局（FDA）1月29日宣布批准注射用胆固醇药物Kynamro（米泊美生钠），该药物可以和其它降脂药物及饮食一起用于一种罕见的高胆固醇疾病纯合子家族性高胆固醇血症(HoFH)。米泊美生钠的添 ...

关键字：米泊美生钠注射液 Kynamro（mipomersen sodium）纯合子家族性高胆固醇

美国食品药品管理局（FDA）1月29日宣布批准注射用胆固醇药物Kynamro（米泊美生钠），该药物可以和其它降脂药物及饮食一起用于一种罕见的高胆固醇疾病纯合子家族性高胆固醇血症(HoFH)。米泊美生钠的添加使用有助于降低低密度脂蛋白胆固醇 (LDL-C)、载脂蛋白B、总胆固醇（TC）以及非高密度脂蛋白胆固醇（非HDL-C）。
HoFH是一种遗传病，影响着百万分之的美国人，当身体不能将血液中一种被称为“坏”胆固醇的低密度脂蛋白胆固醇移除时，会引起血液中低密度脂蛋白胆固醇的水平异常升高。对于那些患有 HoFH的患者，在30岁之前通常会出现心脏病及死亡。米泊美生钠以孤儿药资格批准，意味着该药物开发的目的是治疗不超过20万人的HoFH患者。2012年12月份，FDA批准Juxtapid用于降低 HoFH患者的低密度脂蛋白胆固醇、总胆固醇、载脂蛋白B及非高密度脂蛋白胆固醇。
Kynamro一周注射一次，与其它降脂药物及饮食用于损坏最终能引起低密度脂蛋白胆固醇升高的脂质粒子产生，FDA药物评价和研究中心代谢和内分泌产品部的副主任 Eric Colman医学博士说。
根据51位HoFH患者参与的临床试验，对Kynamro的安全性和有效性进行了评估。在临床试验头26周，服药患者低密度脂蛋白胆固醇水平平均降低25%。同时Kynamro也有一项严重肝毒性黑框警告，因为随着该药物的长期使用，可导致肝脏疾病的进展。
FDA在批准Kynamro时采用风险评估与减轻策略(REMS)原理以确保该药物能安全使用，内容包括开药者及药房认证，具备安全使用条件的文件，经此要求每一新处方要有一个处方授权书。
该药物在临床试验中最常见的副作用是注射部位反应、流感症状、恶心、头疼及肝酶升高（血清转氨酶）。FDA要求对该产品进行四项上市的研究：该药物约束双链DNA的敏感性分析研究；Kynamro服药患者双链DNA抗体存在的评估研究；对HoFH患者进行长期登记以确定Kynamro长期安全性；加强药物警戒以监测Kynamro服药患者恶性肿瘤、免疫介导反应及肝异常的报道。

FDA的药物评价和研究中心代谢和内分泌产品部副主任Eric Colman,M.D说：“Kynamro，一种注射剂，每周1次，与其他降脂药物和饮食一起作用削弱最终生成LDL-C的脂质颗粒的创建。”
Kynamro由赛诺菲旗下健赞公司生产。

批准日期：2013年1月29日；公司：Genzyme和Isis Pharmaceuticals, Inc.

KYNAMRO (mipomersen sodium)为皮下注射注射液

美国初次批准：2013

一般描述
KYNAMRO (mipomersen sodium)注射剂是一种无菌，无防腐剂，透明，无色至微黄色，为皮下注射水溶液。KYNAMRO以单次使用在单次使用，2 mL，透明玻璃小瓶或单次使用，1 mL，充填输送1 mL溶液的透明玻璃预装注射器供应含200 mg的mipomersen sodium(200 mg每1 mL)。为注射KYNAMRO是在水中制剂化和可能包括盐酸和/或氢氧化钠为调整pH至7.5 – 8.5。
Mipomersen sodium是一种apo B-100合成的寡核苷酸抑制剂。ApoB是LDL主要的载脂蛋白和其代谢前体，极低密度脂蛋白(VLDL). Mipomersen通过序列特异性结合至其信使核糖核酸(mRNA)抑制apoB合成导致 mRNA的降解通过酶介导途径或单独通过结合破坏mRNA功能。
Mipomersen sodium是一种合成的硫代磷酸寡核苷酸钠盐，长度20个核苷酸，有以下序列：
5-GMeCMeCMeUMeC AGTMeCTGMeCTTMeC GMeCAMeCMeC- 3
其中下横线残基是2′-O-(2-甲氧乙基)核苷酸；所有其他残基是2′-脱氧核苷。取代位于. Substitution at the胞嘧啶(C)和尿嘧啶(U)碱基的5-位用一个以Me指示的甲基取代。Mipomersen sodium结构式如下：

Mipomersen sodium的分子式为C230H305N67O122P19S19Na19和分子量为7594.9 g/mol.
作用机制
Mipomersen是一种反义[antisense]寡核苷酸靶向对apo B-100人信使核糖核酸(mRNA)，LDL的主要载脂蛋白和其代谢前体，VLDL。Mipomersen是与对apo B-100mRNA的编码区互补，并通过Watson和Crick碱基配对结合。Mipomersen 与同源[cognate]mRNA的杂交导致RNase H-介导的同源mRNA的降解因此apo B-100 蛋白的转录被抑制。
在人肝细胞株(HepG2，Hep3B)和在人和食蟹猴原代肝细胞描述mipomersen的体外药理学活性。在这些实验中，mipomersen以浓度和时间依赖方式选择性减低apo B mRNA，蛋白和分泌蛋白。显示mipomersen作用是高序列特异性。对mipomersen的结合位点位于apo B mRNA编码区，相当于已发表序列 GenBank取出序列号NM_000384.1的第3249-3268核苷酸。
适应证和用途
KYNAMRO™是一种寡核苷酸载脂蛋白B-100合成的抑制剂适用在有纯合子家族性高胆固醇血症homozygous familial hypercholesterolemia(HoFH)患者中作为辅助降脂药物和饮食减低低密度脂蛋白胆固醇(LDL-C)，载脂蛋白B(apo B)，总胆固醇(TC)，和非高密度脂蛋白-胆固醇(non HDL-C)。(1)

使用的限制：
（1）尚未确定在没有HoFH的高胆固醇血症患者KYNAMRO的安全性和有效性。
（2）尚未确定KYNAMRO对心血管患病率和死亡率的影响。
（3）建议不要使用KYNAMRO辅助用于LDL血浆置换。
剂量和给药方法
（1）200 mg每周1次作为皮下注射(2.1)
（2）治疗前，测量ALT，AST，碱性磷酸酶，和总胆红素。(2.1)
剂型和规格
（1）单次使用小瓶含1 mL的200 mg/mL溶液(3)
（2）单次使用预装注射器含1 mL的200 mg/mL溶液(3)
禁忌证
（1）中度和严重肝受损，或活动性肝病，包括原因不明的血清转氨酶持续升高。(4)
（2）已知对产品成分过敏(4)
警告和注意事项
（1）在84%患者发生注射部位反应和典型地由以下1种或更多组成：红斑，疼痛，压痛，瘙痒和局部肿胀。(5.3)
（2）流感样症状，典型地发生在注射2天内，发生在30%患者和包括1种或更多以下：流感样疾病，发热，畏寒，肌肉痛，关节痛，身体不适或疲劳。(5.4)
不良反应
最长报道的不良反应(发生率 ≥ 10%和大于安慰剂)是注射部位反应，流感样症状，恶心，头痛和血清转氨酶升高，特别是ALT。(5.4，6).
特殊人群中使用
（1）哺乳母亲：终止药物或哺乳 (8.3).
（2）儿童患者：未确定安全性和有效性(8.4).
如何供应/贮存和处置
KYNAMRO以单次使用，2mL，透明玻璃小瓶或单次使用，1mL，透明预装有针头注射器供应。每个KYNAMRO单次使用小瓶或单次使用预装注射器装有输送1mL的200 mg/mL溶液含200 mg mipomersen sodium。
可得到纸盒中含1或4小瓶和1或4预装注射器的KYNAMRO。
1小瓶包装：NDC 58468-0190-1
4小瓶包装：NDC 58468-0190-2
1预装注射器包装：NDC 58468-0191-1
4预装注射器包装：NDC 58468-0191-2
冰箱贮存KYNAMRO在2-8 °C(36-46 °F)。用前应避光保护KYNAMRO和保存在原纸盒内。当不能得到冰箱时KYNAMRO可贮存在或低于30 °C (86 °F)，离开热源至14天。不要使用超出标记过期的KYNAMRO。产品不含防腐剂，在抽吸1 mL后残留小瓶内任何未使用药物必须安全地遗弃。
患者咨询资料
见FDA-批准的说明书(用药指南)
忠告患者以下：
肝毒性的风险[见警告和注意事项(5.1)]
●KYNAMRO可能会导致转氨酶升高和肝细胞脂肪变性。与患者讨论用KYNAMRO前和以后定期监视肝相关实验室检验的重要性。
● 应忠告患者用KYNAMRO时如饮酒增加肝损伤风险的潜能。建议用KYNAMRO患者每天不多于一杯酒。
● 忠告患者及时报告可能肝损伤症状，如恶心，呕吐，发热，厌食，疲乏，黄疸，暗色尿，瘙痒，或腹痛。
KYNAMRO风险评估和减灾战略REMS[见警告和注意事项(5.2)]
● 只能通过受限制程序被称为KYNAMRO 风险评估和减灾战略REMS得到KYNAMRO和因此，只能从在程序中经认证药房得到KYNAMRO。电话1-877594 KYNAMRO (1-877-596-2676)可得到另外资料。.
注射部位反应[见警告和注意事项(5.3)]
● 曾报道接受KYNAMRO患者中频繁注射部位反应。
● 这些局部反应典型地由以下1种或更多组成：红斑，疼痛，压痛，瘙痒和局部肿胀。
流感样症状[见警告和注意事项(5.4)]
● 接受KYNAMRO患者中曾报道流感样症状。
● 流感样症状典型地发生在注射2天内和包括1或更多以下：流感样疾病，发热，畏寒，肌肉痛，关节痛，身体不适或疲劳。
给药[见剂量和给药方法(2)]
● 应指导患者或护理者为仔细使用复习KYNAMRO用药指南和指导。
● 皮下注射给予KYNAMRO每周1次。
● 当允许注射器至室温时不要从预装注射器取下针头覆盖物。
● 应通过医生或适宜合格的卫生保健专业人员指导患者或护理者以适宜计数给予皮下注射，包括无菌术。
● 患者和护理者应谨慎必须不再次使用针头或注射器和指导安全遗弃方法步骤。应提供一个为遗弃使用过针头注射器抗针穿过容器给予患者同时给予安全遗弃整个容器的指导。
● KYNAMRO应被注入腹部，大腿区或上臂外侧区域。忠告患者和护理者应轮换为皮下注射的部位。 KYNAMRO不应被注入有活动性皮肤病或损伤的区域例如晒伤，皮肤皮疹，炎症，皮肤感染，银屑病活动区，或皮肤纹身和瘢痕区。
● 忠告患者和护理者应应轮换皮下注射部位。应缓慢地和稳定地进行注射和直至注射完成前不要撤回针头。
● 避光保护KYNAMRO。不要与其他产品混合或共同给药。.

Kynamro Approved for Homozygous Familial Hypercholesterolemia
KYNAMRO (mipomersen sodium) 200mg/mL injection by Genzyme and Isis Genzyme and Isis announced that the FDA has approved its New Drug Application (NDA) for Kynamro (mipomersen sodium) injection. Kynamro is a weekly subcutaneous injection approved as an adjunct to lipid-lowering medications and diet to reduce low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (Apo B), total cholesterol (TC), and non-high density lipoprotein-cholesterol (non HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).
The approval was based on the randomized, double-blind, placebo-controlled, multi-center trial that enrolled patients age 12– 53 years (n=51), including patients age 12 to 16 years (n=7), who were maintaining a regimen of maximally-tolerated lipid lowering medications. Results showed that Kynamro further reduced LDL-C levels by an average of 113mg/dL, or 25%, from a treated baseline of 439mg/dL, and further reduced all measured endpoints for atherogenic particles.
Kynamro is an oligonucleotide inhibitor of apolipoprotein B-100 synthesis that reduces LDL-C by preventing the formation of atherogenic lipids. It acts by decreasing the production of apo-B, which provides the structural core for all atherogenic lipids, including LDL-C, which carry cholesterol through the bloodstream. Kynamro is an antisense drug and is metabolized without affecting the CYP450 pathways.
Due to its risk of hepatotoxicity, Kynamro is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called Kynamro REMS. Kynamro will be available in a 200mg/mL dosage strength as 1mL single-use vials and prefilled syringes.
KYNAMROTM (mipomersen sodium) Injection 200 mg/mL
INDICATIONS and USAGE
KYNAMROTM is an oligonucleotide inhibitor of apolipoprotein B-100 synthesis indicated as an adjunct to lipid-lowering medications and diet to reduce low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apo B), total cholesterol (TC), and non-high density lipoprotein-cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).
Limitations of use
•The safety and effectiveness of KYNAMRO have not been established in patients with hypercholesterolemia who do not have HoFH.
•The effect of KYNAMRO on cardiovascular morbidity and mortality has not been determined.
•The safety and effectiveness of KYNAMRO as an adjunct to LDL apheresis have not been established; therefore,the use of KYNAMRO as an adjunct to LDL apheresis is not recommended
IMPORTANT SAFETY INFORMATION
WARNING: RISK OF HEPATOTOXICITY
KYNAMRO can cause elevations in transaminases. In the KYNAMRO clinical trial in patients with HoFH, 4 (12%) of the 34 patients treated with KYNAMRO compared with 0% of the 17 patients treated with placebo had at least one elevation in alanine aminotransferase (ALT) ≥3x upper limit of normal (ULN). There were no concomitant clinically meaningful elevations of total bilirubin, international normalized ratio (INR) or partial thromboplastin time (PTT).
KYNAMRO also increases hepatic fat, with or without concomitant increases in transaminases. In the trials in patients with heterozygous familial hypercholesterolemia (HeFH) and hyperlipidemia, the median absolute increase in hepatic fat was 10% after 26 weeks of treatment, from 0% at baseline, measured by magnetic resonance imaging (MRI). Hepatic steatosis is a risk factor for advanced liver disease; including steatohepatitis and cirrhosis.
Measure ALT, AST, alkaline phosphatase, and total bilirubin before initiating treatment and then ALT, AST regularly as recommended. During treatment, withhold the dose of KYNAMRO if the ALT or AST are ≥3x ULN. Discontinue KYNAMRO for clinically significant liver toxicity.
Because of the risk of hepatotoxicity, KYNAMRO is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYNAMRO REMS.
CONTRAINDICATIONS
KYNAMRO is contraindicated in the following conditions:
•Moderate or severe hepatic impairment (Child-Pugh B or C) or active liver disease, including unexplained persistent elevations of serum transaminases.
•Patients with a known hypersensitivity to any component of this product.
WARNINGS AND PRECAUTIONS
KYNAMRO can cause elevations in transaminases and hepatic steatosis.
Prior to initiation of treatment with KYNAMRO, measure a full liver panel to include ALT, AST, total bilirubin, and alkaline phosphatase. If the baseline liver-related tests are abnormal, consider initiating KYNAMRO after an appropriate work-up and the baseline abnormalities are explained or resolved.
During the first year, conduct liver-related tests monthly (ALT and AST, at a minimum).
After the first year, conduct these tests at least every 3 months. Discontinue KYNAMRO for persistent or clinically significant elevations.
If transaminase elevations are accompanied by clinical symptoms of liver injury (e.g., nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin ≥2x ULN, or active liver disease, discontinue treatment with KYNAMRO and identify the probable cause.
Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. It is recommended that patients taking KYNAMRO should consume no more than one alcoholic drink per day.
Caution should be exercised when KYNAMRO is used with other medications known to have potential for hepatotoxicity, for example isotretinoin, amiodarone, acetaminophen (>4 g/day for ≥3 days/week), methotrexate, tetracyclines, and tamoxifen. The effect of concomitant administration of KYNAMRO with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
KYNAMRO has not been studied concomitantly with other LDL-lowering agents that can also increase hepatic fat. Therefore, the combined use of such agents is not recommended.
Injection site reactions have been reported in 84% of patients receiving KYNAMRO therapy. These local reactions typically consist of one or more of the following: erythema, pain, tenderness, pruritus and local swelling. To minimize the potential for injection site reactions, proper technique for subcutaneous administration should be followed. Injection site reactions do not occur with all injections but resulted in discontinuation of therapy in 5% of patients in pooled Phase 3 trials.
Flu-like symptoms have been reported in 30% of patients receiving KYNAMRO therapy and include one or more of the following: influenza-like illness, pyrexia, chills, myalgia, arthralgia, malaise or fatigue. Flu-like symptoms, which typically occur within 2 days after an injection, do not occur with all injections but resulted in discontinuation of therapy in 3% of patients in pooled Phase 3 trials.
USE IN SPECIFIC POPULATIONS
Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. KYNAMRO should be used during pregnancy only if clearly needed.
Nursing Mothers: It is not known whether KYNAMRO is excreted in human milk. Because many drugs are excreted in human milk a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Safety and effectiveness have not been established in pediatric patients.
Females of Reproductive Potential: KYNAMRO may cause fetal harm. Females who become pregnant during KYNAMRO therapy should notify their healthcare provider. Females of reproductive potential should use effective contraception during KYNAMRO therapy.
Renal Impairment: The safety and efficacy of KYNAMRO treatment in patients with known renal impairment or in patients undergoing renal dialysis have not been established. Due to the lack of clinical data and KYNAMRO’s renal safety profile, KYNAMRO is not recommended in patients with severe renal impairment, clinically significant proteinuria, or on renal dialysis.
ADVERSE REACTIONS
In clinical trials the most commonly-reported adverse reactions were injection site reactions (84%), flu-like symptoms (30%), nausea (14%), headache (12%), and elevations in serum transaminases, specifically ALT (10%).