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Repatha(evolocumab)使用说明书 
批准日期：2015年8月27日；

公司：Amgen Inc.

[适应症和用途]

        REPATHA是一种PCSK9(人前蛋白转化酶枯草杆菌蛋白酶Kexin类型9)抑制剂抗体适用为一种对膳食辅助和：
        ●最大耐受他汀治疗有杂合子家族性高胆固醇血症(HeFH)或临床动脉粥样硬化心血管疾病(CVD)需要另外降低低密度脂蛋白胆固醇(LDL-C)成年的治疗。(1.1)
        ● 其他降LDL治疗(如，他汀类，依泽替米贝[ezetimibe]，LDL 血浆分离置换)在有纯合子家族性高胆固醇血症(HoFH)需要另外降低LDL-C患者.(1.2)

[使用限制]
        未曾确定REPATHA对心血管患病率和死亡率的影响。(1.3)

[剂量和给药方法]
        通过皮下注射给药(2.1)
        原发性高脂血症有确定的临床动脉粥样硬化CVD或HeFH：140 mg每2周或420 mg每月1次在腹部，大腿，或上臂。(2.1)
        HoFH：420 mg每月1次。(2.1)
        给予420 mg，在30分钟内连续给予3次REPATHA注射。(2.2)
        见剂量和给药方法对重要给药指导。(2.2)

[剂型和规格]
        注射液：140 mg/mL在一个单次使用预装注射器(3)
        注射液：140 mg/mL在一个单次使用预装SureClick®自动注射器(3)

[禁忌症]
        有对REPATHA严重过敏反应病史患者。(4)

[警告和注意事项]
        过敏反应：曾发生皮疹和荨麻疹。如发生严重过敏反应的体征或症状，终止用REPATHA治疗，按照标准医护，和监视直至体征和症状解决。(5.1)

[不良反应]
        在临床试验中常见不良反应(用REPATHA治疗患者>5%和比安慰剂发生更频)：鼻咽炎，上呼吸道感染，流感，背痛，和注射部位反应。.(6)


完整处方资料
1 适应症和用途
1.1 原发性高脂血症
REPATHA™ 适用为一种对膳食和最大耐受他汀治疗辅助为有杂合子家族性高胆固醇血症(HeFH)或临床动脉粥样硬化心血管疾病(CVD)，需要另外降低低密度脂蛋白胆固醇(LDL-C) 成年的治疗。
1.2 纯合子家族性高胆固醇血症
REPATHA 适用为对膳食和其他降LDL治疗(如，他汀类，依泽替米贝，LDL血浆分离置换)一种辅助为有纯合子家族性高胆固醇血症(HoFH)患者需要另外降低LDL-C的治疗。
1.3 使用限制
未曾确定REPATHA对心血管患病率和死亡率的影响。
2 剂量和给药方法
2.1 推荐剂量
在有HeFH或患者有原发性高脂血症与确定的临床动脉粥样硬化CVD患者REPATHA的推荐皮下剂量是或140 mg每2周或420 mg每月1次。当转换剂量方案时，在前方案的下一次时间日期给予新方案的首次剂量。
有HoFH患者REPATHA的推荐的皮下剂量是420 mg每月1次。在有HoFH患者中，开始REPATHA后4至8周测量LDL-C水平，因为对治疗反应将依赖于LDL-受体功能程度。
如一个每2周或每月1次剂量被缺失，指导患者：
●如果直至下一次时间表剂量是长于7天尽可能立即给予REPATHA，或，
●省略缺失剂量和按照原来给药时间表给予下一次剂量。
2.2 重要给药指导
●为给予420 mg剂量，在30分钟内连续地给予3次REPATHA注射。
●使用前对患者和/或护理人员对如何准备和给予REPATHA提供适当训练，按照使用指导，包括无菌术。指导患者和/或护理人员他们每次使用REPATHA阅读和遵循指导。
保存REPATHA在冰箱。用前，让REPATHA加温至室温至少30分钟。不要用任何其它方法加温。另外，对患者和护理人员，REPATHA可保持在室温(至25°C(77°F))在原纸盒内。但是，在这些条件下，必须在30天使用REPATHA[见如何供应/贮存和处置(16)]。
●给药前肉眼观察REPATHA有无颗粒和变色。REPATHA是透明至乳白色，无色至淡黄色溶液。如溶液是云雾状或变色或含颗粒不要使用。
●利用单次使用预装注射器或单次使用预装自动注射器通过皮下注射至没有触痛，瘀伤，红，或硬皮腹部，大腿，或上臂给予REPATHA。
●REPATHA不要在相同注射部位与其它可注射药物共同给药。
●每次注射轮转注射部位。
3 剂型和规格
REPATHA是一种无菌，透明至乳白色，无色至淡黄色溶液可得到以下：
● 注射液：140 mg/mL溶液在一个单次使用预装注射器
● 注射液：140 mg/mL溶液在一个单次使用预装SureClick®自动注射器
4 禁忌症
对REPATHA严重过敏反应史患者禁忌REPATHA[见警告和注意事项(5.1)]。
5 警告和注意事项
5.1 过敏反应
用REPATHA治疗患者中曾报道超敏性反应(如，皮疹，荨麻疹)，包括有些导致治疗终止。如发生严重过敏反应的体征或症状，终止用REPATHA治疗，按照标准医护治疗，和监视直至体征和症状解决。
6 不良反应
在说明书其他节还讨论以下不良反应：
● 过敏反应[见警告和注意事项(5.1)]
6.1 临床试验经验
因为临床试验是在广泛不同情况下进行的，临床试验观察到不良反应率不能与另一种药临床试验发生率直接比较而且可能不反映实践中观察到的发生率。
在有原发性高脂血症和在患者有杂合子家族性高胆固醇血症患者中不良反应
在患者无家族性高胆固醇血症或动脉粥样硬化CVD不适用REPATHA[见适应症和用途(1.1)]。
下面描述数据反映在8项安慰剂-对照试验包括2651例用REPATHA治疗患者，包括557例暴露共6个月和515例暴露共1年(中位治疗时间12周)暴露至REPATHA。人群中位年龄为57岁，人群49%为妇女，85%为白种人，6%为黑种人，8%为亚裔，和2%为其它种族。
在一项52-周对照试验不良反应
在一项52-周，双盲，随机化，安慰剂-对照试验(研究2)，599例患者接受420 mg的REPATHA皮下每月1次[见临床研究(14.1)]。均数年龄56岁(范围: 22至75岁)，23%是大于65岁，52%是妇女，80%白种人，8%黑种人，6%亚裔，和6%西班牙裔。在表1中显示在研究2中至少3%REPATHA-治疗患者报道不良反应，和比安慰剂-治疗患者更频。2.2%的REPATHA-治疗患者不良反应导致终止治疗和安慰剂-治疗患者为1%。最常见不良反应导致REPATHA治疗终止和发生率大于安慰剂是肌痛(对REPATHA和安慰剂分别0.3%相比0%)。

在7项合并12-周对照试验中不良反应
在七项合并的12-周，双盲，随机化，安慰剂-对照试验，993例患者接受140 mg的REPATHA皮下每2周和1059例患者接受420 mg的REPATHA皮下每月。均数年龄为57岁(范围，18至80 岁)，29%是大于65岁，49%为妇女，85%白种人，5%黑种人，9%亚裔，和5%西班牙裔。在表2中显示至少1%的REPATHA-治疗患者，和比安慰剂-治疗患者更频报道的不良反应。

在八项合并的对照试验不良反应(七项12-周试验和一项52-周试验)
下面描述不良反应是来自52-周试验(研究2)和七项12-周试验的合并。在这个八项试验REPATHA合并的均数和中位暴露时间分别是20周和12周。
局部注射部位反应
REPATHA-治疗和安慰剂-治疗患者注射部位反应发生分别3.2%和3.0%。最常见注射部位反应 是红斑，疼痛，和瘀伤。REPATHA-治疗患者和安慰剂-治疗患者由于局部注射部位反应终止治疗患者的比例分别为0.1%和0%。
过敏反应
REPATHA-治疗和安慰剂-治疗患者发生过敏反应分别5.1%和4.6%。最常见过敏反应为皮疹(对REPATHA和安慰剂分别1.0%相比0.5%)，湿疹(0.4%相比0.2%)，红斑(0.4%相比0.2%)，和荨麻疹(0.4%相比0.1%)。
神经认知事件
在安慰剂-对照试验中，REPATHA-治疗和安慰剂-治疗患者被报道神经认知事件低于或等于0.2%。
低LDL-C水平
安慰剂-和阳性-对照试验，以及随后的开放延伸研究的合并，总共1609例用REPATHA治疗患者有至少一次LDL-C指< 25 mg/dL。对低LDL-C值反应中对背景脂质-改变治疗没有改变，而没有在这个基础修饰或中断REPATHA给药。虽然在这些试验中没有确定非常低LDL-C不良后果，不知道被REPATHA诱导LDL-C非常低水平的长期影响。
肌肉骨骼事件
REPATHA-治疗患者报道肌肉骨骼不良反应14.3%和安慰剂-治疗患者为12.8%。发生率大于安慰剂最常见不良反应是背痛(对REPATHA和安慰剂分别3.2%相比2.9%)，关节痛(2.3%相比2.2%)，和肌痛(2.0%相比1.8%)。
在有纯合子家族性高胆固醇血症患者中不良反应
在一项12-周，双盲，随机化，安慰剂-对照试验49例患者有HoFH(研究4)，33例患者接受420 mg 的REPATHA皮下每月1次[见临床研究(14.3)]。均数年龄为31岁(范围：13至57岁)，49%为妇和比安慰剂-治疗患者更频，包括：
●上呼吸道感染(9.1%相比6.3%)
●流感(9.1%相比0%)
●胃肠炎(6.1%相比0%)
●鼻咽炎(6.1%相比0%)
6.2 免疫原性
如同所有治疗性蛋白，有免疫原性潜能。利用一种免疫荧光桥接筛选免疫分析为结合药物抗体的检测曽评价 REPATHA的免疫原性。对在筛选免疫分析其被测试血清阳性，进行体外生物学分析以检测中和抗体。
在一项安慰剂-和阳性-对照临床试验的合并中，对结合抗体发生0.1%被治疗患者有至少一剂被试REPATHA阳性。其被测试血清对结合抗体阳性患者被进一步评价中和抗体；没有被测试患者对中和抗体阳性。
没有证据存在抗药结合抗体影响药代动力学图形，临床反应，或REPATHA的安全性，但不知道存在抗-药结合抗体继续REPATHA治疗的长期后果。
抗体形成的检测是高度依赖于分析的灵敏度和特异性。此外，在某个分析观察到抗体阳性的发生率可能受几种因子影响包括分析方法学，样品处置，采样时间，同时药物，和所患疾病。因为这些理由，比较对REPATHA抗体发生率与其他产品抗体的发生率可能是误导。
8 特殊人群中使用
8.1 妊娠
风险总结
在妊娠妇女中没有REPATHA的使用可得到数据告知药物相关风险。在动物生殖研究中，当猴被皮下给予evolocumab从器官形成期至分娩在剂量暴露至最大推荐人剂量420 mg每月暴露的12倍对妊娠或新生儿/婴儿发育每月影响。在一项相似研究用PCSK9抑制剂抗体类别中另外药物，在子宫内暴露至该药所有剂量的婴猴中观察到体液免疫抑制。在婴猴发生免疫抑制暴露是大于临床期望。对在婴猴中用evolocumab进行免疫抑制无评估。在婴猴出生时观察到可测量到的血清浓度与母体血清可比性水平，表明evolocumab，像其它IgG抗体，跨越胎盘屏障。 ’s FDA在人中用单克隆抗体的经验表明在妊娠第一个三个月可能不跨越胎盘；但是，在第二和第三个三个月它们可能增加量跨越胎盘。在对妊娠妇女处方REPATHA前考虑REPATHA的获益和风险和对胎儿风险可能性。
在美国一般人群中，主要出生缺陷和在临床上公认妊娠中流产的估算的背景风险分别是2-4%和15-20%。
数据
动物数据
在食蟹猴中，当在器官形成期至分娩期间通过皮下途径给予evolocumab在50 mg/kg每2周1次在推荐人剂量140 mg每2周和420 mg每月1次根据血浆AUC暴露分别为30-和12-倍观察到对胚胎-胎儿或产后发育无影响(至6个月龄)。在婴猴中未用evolocumab进行体液免疫测试。
8.2 哺乳
风险总结
没有在人乳汁中关于存在evolocumab，对哺乳喂养婴猴，对乳汁生成影响的资料。哺乳喂养的发育和健康获益应与母亲对REPATHA临床需要和哺乳喂养婴儿来自REPATHA或来自母体所处条件任何潜在不良影响一起考虑。在人乳汁中存在人IgG，但发表数据提示乳汁抗体不进入实质量至新生儿和婴儿循环。
8.4 儿童使用
根据来自一项需要另外降低LDL-C的有HoFH青少年的12-周，安慰剂-对照试验中包括10例年龄13至17岁有HoFH青少年数据确定REPATHA与膳食和其它降低LDL-C-治疗联用的安全性和有效性[见临床研究(14.3)]。在这项试验中，7青少年接受REPATHA 420 mg皮下每月1次和3例青少年接受安慰剂。REPATHA对LDL-C影响是一般地与有HoFH成年患者中观察到相似。包括来自开放，无对照研究经验，总共14例有HoFH青少年曾被REPATHA治疗，有一个中位暴露时间9个月。在这些青少年中REPATHA的安全图形与对有HoFH成年患者描述相似。
未曾确定在小于13岁有HoFH儿童患者中REPATHA的安全性和有效性。
未曾确定在有原发性高脂血症或HeFH儿童患者中用REPATHA的安全性和有效性。
8.5 老年人使用
在对照研究中，1420例用REPATHA治疗患者是 ≥ 65岁和171例是≥ 75岁。这些患者和较年轻患者间未观察到安全性或有效性中总体差别，而其它临床经验报告没有确定老年和较年轻患者间反应中差别，但不能除外有些老年个体更大灵敏度。
8.6 肾受损
有轻度至中度肾受损患者中无需剂量调整。不能得到有严重肾受损患者数据[见临床药理学(12.3)]。
8.7 肝受损
在有轻度至中度肝受损(Child-Pugh A或B)患者中无需剂量调整。不能得到有严重肝受损患者数据[见临床药理学(12.3)]。
11 一般描述
Evolocumab是一种直接对人前蛋白转化酶枯草杆菌蛋白酶Kexin9(PCSK9)的人单克隆免疫球蛋白G2(IgG2)。Evolocumab有近似分子量(MW)144 kDa和在遗传工程化哺乳动物(中国仓鼠卵巢)细胞中生产。
REPATHA是一种无菌，无防腐剂，透明至乳白色，无色至淡黄色溶液为皮下注射。每1 mL单次使用预装注射器和单次使用预装SureClick®自动注射器含140 mg evolocumab，醋酸盐(1.2 mg)，聚山梨醇80(0.1 mg)，脯氨酸(25 mg)，在注射用水，USP。可能用氢氧化钠调节pH至5.0。
12 临床药理学
12.1 作用机制
Evolocumab是一种直接对人前蛋白转化酶枯草杆菌蛋白酶Kexin9(PCSK9)人单克隆IgG2。Evolocumab结合至PCSK9和抑制循环PCSK9避免结合至低密度脂蛋白(LDL)受体(LDLR)，阻止PCSK9-介导的LDLR降解和允许LDLR回收返回至肝细胞表面。通过抑制PCSK9结合至LDLR，evolocumab增加可得到从血液清除LDL的LDLRs数，因此降低LDL-C水平。
12.2 药效动力学
单次皮下给予140 mg或420 mg的evolocumab后，循环未结合PCSK9的最大抑制发生在4小时。当evolocumab浓度减低低于定量低限时未结合PCSK9浓度返回趋向基线。
12.3 药代动力学
作为结合至PCSK9的结果Evolocumab表现为非-线性动力学。在健康志愿者中给予140 mg 剂量导致一个Cmax均数([SD])为18.6(7.3) μg/mL和AUClast均数(SD)188(98.6) day•μg/mL。在健康志愿者中给予420 mg剂量导致一个Cmax均数(SD)59.0(17.2) μg/mL和AUClast均数(SD)924(346)day•μμg/mL。在健康志愿者中给予420 mg剂量导致一个Cmax均数(SD)59.0(17.2) μg/mL和AUClast均数(SD)924(346) day•μg/mL。单次420 mg静脉剂量后，均数(SD)全身清除率被估算是12(2) mL/hr。140 mg剂量给予皮下每2周后或420 mg剂量给予皮下每月后观察到在谷血清浓度(Cmin[SD] 7.21[6.6])(Cmin[SD] 11.2[10.8])积蓄接近2-至3-倍，和至给药的12周血清谷浓度接近稳态。
吸收
单次皮下剂量140 mg或420 mg evolocumab给予健康成年后，在3至4天达到中位峰血清浓度，和估算的绝对生物利用度是72%。
分布
单次420 mg静脉剂量后，均数(SD)稳态分布容积估算是3.3(0.5) L。
代谢和消除
对REPATHA观察到两个消除相。在低浓度，消除是主要地通过饱和结合至靶点(PCSK9)，而在较高浓度REPATHA的消除主要是通过非饱和蛋白水解途径。REPATHA被估算有一个有效半衰期11至17天。
特殊人群
跨越所有被批准人群Evolocumab的药代动力学不受年龄，性别，种族，或肌酐清除率影响[见特殊人群中使用(8.5)]。
Evolocumab的暴露随体重减低。这些差别每月临床意义。
肾受损
因为单克隆抗体是知道不通过肾途径消除，肾功能预期不影响evolocumab的药代动力学。未曾在有严重肾受损患者(估算的肾小球滤过率[eGFR] < 30 mL/min/1.73 m2)研究。
肝受损
在有轻度或中度肝受损患者中单次140 mg皮下剂量evolocumab后，与健康患者比较观察到一个20-30%较低均数Cmax和40-50%较低均数AUC；但是，在这些患者无需剂量调整。
妊娠
未曾研究妊娠对evolocumab药代动力学研究[见特殊人群中使用(8.1)]。
药物相互作用研究
在与一个高-强度他汀方案共同给药患者中观察到evolocumab的Cmax和AUC接近减低20%。这个差别每月临床意义和不影响给药建议。
13 非临床毒理学
13.1 癌发生，突变发生，生育力受损
在仓鼠中在剂量水平10，30，和100 mg/kg给药每2周进行一项寿命研究评价evolocumab的致癌性潜能。在最高剂量根据血浆 AUC在全身暴露直至推荐人剂量140 mg每2周和420 mg每月1次分别38-和15-倍没有evolocumab-相关肿瘤。没有评价evolocumab的致突变潜能；但是，单克隆抗体是期望不改变DNA或染色体。
对生育力没有不良影响(包括动情周期，精子分析，交配性能，和胚胎发育)在最高剂量在一项生育力和早期胚胎发育毒理学研究在仓鼠当evolocumab被皮下给予在10，30，和100 mg/kg每2周。最高试验剂量根据血浆AUC相当于对全身暴露至推荐人剂量140 mg每2周和420 mg每月1次分别30-和12倍。此外，在一项6-个月慢性毒理学研究在性成熟猴皮下给予evolocumab在3，30，和300 mg/kg每周1次生育力替代性标志(生殖器官组织学，月经周期，或镜子参数)没有evolocumab-相关不良影响。根据血浆AUC最高试验剂量相当于推荐人剂量140 mg每2周和420 mg每月1次分别744-和300-倍。
13.2 动物毒理学和/或药理学
一项在成年猴3-个月毒理学研究期间10和100 mg/kg每2周1次evolocumab与5 mg/kg 每天1次罗苏伐他汀联用，在1至2个月暴露后evolocumab对对钥孔血蓝蛋白[keyhole limpet hemocyanin(KLH)]体液免疫反应没有影响。根据血浆AUC最高试验剂量暴露相当于较高于推荐人剂量140 mg每2周和420 mg每月1次分别54-和21-倍。相似地，在一项6-个月研究在食蟹猴在剂量水平至300 mg/kg每周1次evolocumab根据血浆AUC相当于暴露大于推荐人剂量140 mg每2周和420 mg每月1次分别744-和300-倍evolocumab对钥孔血蓝蛋白KLH体液免疫反应(3至4个月暴露后)没有影响。
14 临床研究
14.1 在有临床动脉粥样硬化心血管疾病患者中原发性高脂血症
研究1是一项多中心，双盲，随机化对照试验其中患者初始地被随机化至一个开放特异性他汀方案共一个4-周脂质稳定化期接着随机赋予皮下注射REPATHA 140 mg每2周，REPATHA 420 mg每月1次，或安慰剂共12周。试验包括296例有动脉粥样硬化CVD患者接受REPATHA或安慰剂作为添加治疗至每天剂量阿托伐他汀[atorvastatin]80 mg，罗苏伐他汀[rosuvastatin]40 mg，或辛伐他汀[simvastatin]40 mg。这些患者中，在基线时均数年龄为63岁(范围：32至80岁)，45%为≥ 65岁，33%为妇女，98%为白种人，2%为黑种人，< 1% 为亚裔和5%为西班牙或拉丁美洲人。4周他汀治疗后，均数基线LDL-C为108 mg/dL。
在这些有动脉粥样硬化CVD患者是用最大剂量他汀治疗， REPATHA和安慰剂间LDL-C从基线至周12均数百分率变化对140 mg每2周和420 mg每月1次剂量差别分别为-71%(95% CI：-81%，-61%；p < 0.0001)和-63%(95% CI：-76%，-50%；p ˂ 0.0001)。对另外结果见表3和图1。

图1. 在有动脉粥样硬化CVD患者中当REPATHA与他汀类联用时对LDL-C的影响(在研究1从基线至12周均数%变化)
研究2是一项多中心，双盲，随机化，安慰剂-对照，52-周试验包括139例有动脉粥样硬化CVD患者接受方案-确定背景降脂治疗阿托伐他汀80 mg每天7有或无依泽替米贝10 mg每天。在用背景治疗稳定化后，患者被随机赋予添加安慰剂或REPATHA 420 mg皮下给予每月1次。这些患者中，在基线均数年龄为59岁(范围，35至75岁)，25%是 ≥ 65岁，40%为妇女，80%为白种人，3%为黑种人，5%为亚裔，和< 1%为西班牙或拉丁美洲人。在赋予背景治疗稳定化后，均数基线LDL-C为105 mg/dL。
在这些有动脉粥样硬化CVD患者用最大-剂量阿托伐他汀治疗有或无依泽替米贝，REPATHA 420 mg每月1次和安慰剂间LDL-C从基线至周52 均数百分率变化差别为-54 %(95% CI：-65%，-42%; p ˂.0001)(表4和图2)。对另外结果见表4。

估算值根据一个考虑对治疗坚持多次计算模型。误差棒表示95%可信区间。
图2：在有动脉粥样硬化CVD患者中用阿托伐他汀80 mg有或无依泽替米贝10 mg每天REPATHA 420 mg每月1次对LDL-C的影响。
14.2 杂合子家族性高胆固醇血症(HeFH)
研究3是一项多中心，双盲，随机化，安慰剂-对照，12-周试验在329例有杂合子家族性高胆固醇血症(HeFH)用他汀类有或无其它脂质-降低治疗患者。患者被随机化接受REPATHA 140 mg每2周，420 mg每月1次，或安慰剂的皮下注射。HeFH是通过Simon Broome标准诊断(1991)。在研究3中，38%患者有临床动脉粥样硬化心血管疾病。在基线时均数年龄为51岁(范围，19至79岁)，15%患者为 ≥ 65岁，42%为妇女，90%为白种人，5%为亚裔，和1%为黑种人。在基线时平均LDL-C为156 mg/dL有76%患者用高-强度他汀治疗。
在这些有HeFH用他汀类有或无其它降脂质治疗患者中，对140 mg每2周和420 mg每月1次剂量REPATHA和安慰剂间LDL-C从基线至周12均数百分率变化差别分别是-61%(95%CI：-67%，-55%；p < 0.0001)和-60%(95%CI：-68%，-52%；p < 0.0001)。对另外结果见表5。

    
14.3 纯合子家族性高胆固醇血症
研究4是一项在49例(不用脂质-血浆分离置换治疗)有纯合子家族性高胆固醇血症(HoFH)患者多中心，双盲，随机化，安慰剂-对照，12-周试验。在这个试验中，33例患者接受的皮下注射420 mg of REPATHA每月1次和16例患者接受安慰剂作为一个辅助其他脂质-降低治疗(如，他汀类，依泽替米贝)。在基线时均数年龄为31岁，49%为妇女，90%白种人，4%为亚裔，和6%其他。试验包括10例青少年(年龄13至17岁)，其中7例接受REPATHA。在基线 时均数LDL-C 为349 mg/dL有所有患者用他汀类(阿托伐他汀或罗苏伐他汀)和92%用依泽替米贝。HoFH的诊断是通过遗传学确认或根据一个临床诊断一个未治疗LDL-C浓度> 500 mg/dL病史与或10岁前黄瘤病[xanthoma]或在双亲中HeFH的证据一起。
在这些有HoFH患者中，REPATHA和安慰剂间在LDL-C从基线至周12均数百分率变化差别是-31%(95%CI：-44%，-18%; p < 0.0001)。对另外结果见表6。
患者已知有两个LDL-受体阴性等位基因(残留功能很少或没有)对REPATHA不反应。

16 如何供应/贮存和处置
REPATHA是一个无菌，透明至乳白色，无色至 淡黄色溶液为皮下注射在一个单次使用预装注射器或一个单次使用预装SureClick®自动注射器供应。每个REPATHA的单次使用预装注射器或单次使用预装SureClick®自动注射器被设计输送1 mL的140 mg/mL溶液。

药房
在原纸盒中贮存在冰箱在2°至8°C(36°至46°F)避光保护。不要冻结。不要摇晃。
对患者/护理人员
在原纸盒内贮存在冰箱2°至8°C(36°至46°F)。另外，REPATHA在原纸盒内可被保持在室温(至25°C(77°F))；但是，在这些条件下，REPATHA必须在30天内使用。如30天内未使用，遗弃REPATHA。
保护REPATHA避免光直接照和不要暴露在25°C(77°F)以上。

 

REPATHA®
(evolocumab) Injection, for Subcutaneous Use

DESCRIPTION

Evolocumab is a human monoclonal immunoglobulin G2 (IgG2) directed against human proprotein convertase subtilisin kexin 9 (PCSK9). Evolocumab has an approximate molecular weight (MW) of 144 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells.

REPATHA is a sterile, preservative-free, clear to opalescent, colorless to pale yellow solution for subcutaneous administration. Each 1 mL single-use prefilled syringe and single-use prefilled SureClick®autoinjector contains 140 mg evolocumab, acetate (1.2 mg), polysorbate 80 (0.1 mg), proline (25 mg) in Water for Injection, USP. Sodium hydroxide may be used to adjust to a pH of 5.0. Each single-use Pushtronex®system (on-body infusor with prefilled cartridge) delivers a 3.5 mL solution containing 420 mg evolocumab, acetate (4.2 mg), polysorbate 80 (0.35 mg), proline (89 mg) in Water for Injection, USP. Sodium hydroxide may be used to adjust to a pH of 5.0.

 

Indications & Dosage

INDICATIONSPrevention Of Cardiovascular Events

In adults with established cardiovascular disease, REPATHA® is indicated to reduce the risk of myocardial infarction, stroke, and coronary revascularization.

Primary Hyperlipidemia (Including Heterozygous Familial Hypercholesterolemia)

REPATHA is indicated as an adjunct to diet, alone or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for the treatment of adults with primary hyperlipidemia to reduce low-density lipoprotein cholesterol (LDL-C).

Homozygous Familial Hypercholesterolemia

REPATHA is indicated as an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) for the treatment of patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C.

DOSAGE AND ADMINISTRATIONRecommended Dosage

The recommended subcutaneous dosage of REPATHA in adults with established cardiovascular disease or in adults with primary hyperlipidemia (including heterozygous familial hypercholesterolemia [HeFH]) is either 140 mg every 2 weeks OR 420 mg once monthly, based on patient preference for dosing frequency and injection volume. When switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen.

The recommended subcutaneous dosage of REPATHA in patients with HoFH is 420 mg once monthly. In patients with HoFH, measure LDL-C levels 4 to 8 weeks after starting REPATHA, since response to therapy will depend on the degree of LDL-receptor function.

When monitoring LDL-C for patients receiving REPATHA 420 mg once monthly, note that LDL-C can vary considerably during the dosing interval in some patients [see Clinical Studies].

If a dose is missed, instruct the patient to administer REPATHA within 7 days from the missed dose and resume the patient’s original schedule.

· If an every-2-week dose is not administered within 7 days, instruct the patient to wait until the next dose on the original schedule.

· If a once-monthly dose is not administered within 7 days, instruct the patient to administer the dose and start a new schedule based on this date.

Important Administration Instructions

· The 420 mg dose of REPATHA can be administered:

o over 9 minutes by using the single-use on-body infusor with prefilled cartridge, or

o by giving 3 injections consecutively within 30 minutes using the single-use prefilled autoinjector or single-use prefilled syringe.

· Provide proper training to patients and/or caregivers on how to prepare and administer REPATHA prior to use, according to the Instructions for Use, including aseptic technique. Instruct patients and/or caregivers to read and follow the Instructions for Use each time they use REPATHA.

· Keep REPATHA in the refrigerator. Prior to use, allow REPATHA to warm to room temperature for at least 30 minutes for the single-use prefilled autoinjector or single-use prefilled syringe and for at least 45 minutes for the single-use on-body infusor with prefilled cartridge. Do not warm in any other way. Alternatively, for patients and caregivers, REPATHA can be kept at room temperature at 68°F to 77°F (20°C to 25°C) in the original carton. However, under these conditions, REPATHA must be used within 30 days [see HOW SUPPLIED].

· Visually inspect REPATHA for particles and discoloration prior to administration. REPATHA is a clear to opalescent, colorless to pale yellow solution. Do not use if the solution is cloudy or discolored or contains particles.

· Administer REPATHA subcutaneously into areas of the abdomen, thigh, or upper arm that are not tender, bruised, red, or indurated using a single-use prefilled syringe, single-use prefilled autoinjector, or single-use on-body infusor with prefilled cartridge.

· Do not co-administer REPATHA with other injectable drugs at the same administration site.

· Rotate the site of each subcutaneous administration.

HOW SUPPLIEDDosage Forms And Strengths

REPATHA is a sterile, clear to opalescent, colorless to pale yellow solution available as follows:

· Injection: 140 mg/mL solution in a single-use prefilled syringe

· Injection: 140 mg/mL solution in a single-use prefilled SureClick® autoinjector

· Injection: 420 mg/3.5 mL solution in a single-use Pushtronex® system (on-body infusor with prefilled cartridge)

Storage And Handling

REPATHA is a sterile, clear to opalescent, colorless to pale yellow solution for subcutaneous administration supplied in a single-use prefilled syringe, a single-use prefilled SureClick® autoinjector, or a single-use Pushtronex® system (on-body infusor with prefilled cartridge). Each single-use prefilled syringe or single-use prefilled SureClick® autoinjector of REPATHA is designed to deliver 1 mL of 140 mg/mL solution. Each single-use Pushtronex® system (on-body infusor with prefilled cartridge) is designed to deliver 420 mg evolocumab in 3.5 mL solution.

Pharmacy

Store refrigerated at 2°C to 8°C (36° to 46°F) in the original carton to protect from light. Do not freeze. Do not shake.

For Patients/Caregivers

Store refrigerated at 2°C to 8°C (36° to 46°F) in the original carton. Alternatively, REPATHA can be kept at room temperature at 68°F to 77°F (20°C to 25°C) in the original carton; however, under these conditions, REPATHA must be used within 30 days. If not used within the 30 days, discard REPATHA.

Protect REPATHA from direct light and do not expose to temperatures above 25°C (77°F).

 

Side Effects & Drug Interactions

SIDE EFFECTS

The following adverse reactions are also discussed in other sections of the label:

· Allergic Reactions [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adverse Reactions In Adults With Primary Hyperlipidemia (Including Heterozygous Familial Hypercholesterolemia)

The data described below reflect exposure to REPATHA in 8 placebo-controlled trials that included 2651 patients treated with REPATHA, including 557 exposed for 6 months and 515 exposed for 1 year (median treatment duration of 12 weeks). The mean age of the population was 57 years, 49% of the population were women, 85% White, 6% Black, 8% Asians, and 2% other races.

Adverse Reactions in a 52-Week Controlled Trial

In a 52-week, double-blind, randomized, placebo-controlled trial (Study 3 [DESCARTES, NCT01516879]), 599 patients received 420 mg of REPATHA subcutaneously once monthly [see Clinical Studies]. The mean age was 56 years (range: 22 to 75 years), 23% were older than 65 years, 52% women, 80% White, 8% Black, 6% Asian; 6% identified as Hispanic ethnicity. Adverse reactions reported in at least 3% of REPATHA-treated patients, and more frequently than in placebo-treated patients in DESCARTES, are shown in Table 1. Adverse reactions led to discontinuation of treatment in 2.2% of REPATHA-treated patients and 1% of placebo-treated patients. The most common adverse reaction that led to REPATHA treatment discontinuation and occurred at a rate greater than placebo was myalgia (0.3% versus 0% for REPATHA and placebo, respectively).

Table 1. Adverse Reactions Occurring in Greater than or Equal to 3% of REPATHA-treated Patients and More Frequently than with Placebo in DESCARTES

Adverse Reactions in Seven Pooled 12-Week Controlled Trials

In seven pooled 12-week, double-blind, randomized, placebo-controlled trials, 993 patients received 140 mg of REPATHA subcutaneously every 2 weeks and 1059 patients received 420 mg of REPATHA subcutaneously monthly. The mean age was 57 years (range: 18 to 80 years), 29% were older than 65 years, 49% women, 85% White, 5% Black, 9% Asian; 5% identified as Hispanic ethnicity. Adverse reactions reported in at least 1% of REPATHA-treated patients, and more frequently than in placebo-treated patients, are shown in Table 2.

Table 2. Adverse Reactions Occurring in Greater than 1% of REPATHA-treated Patients and More Frequently than with Placebo in Pooled 12-Week Trials

Adverse Reactions in Eight Pooled Controlled Trials (Seven 12-Week Trials and One 52-Week Trial)

The adverse reactions described below are from a pool of the 52-week trial (DESCARTES) and seven 12-week trials. The mean and median exposure durations of REPATHA in this pool of eight trials were 20 weeks and 12 weeks, respectively.

Local Injection Site Reactions

Injection site reactions occurred in 3.2% and 3.0% of REPATHA-treated and placebo-treated patients, respectively. The most common injection site reactions were erythema, pain, and bruising. The proportions of patients who discontinued treatment due to local injection site reactions in REPATHA-treated patients and placebo-treated patients were 0.1% and 0%, respectively.

Allergic Reactions

Allergic reactions occurred in 5.1% and 4.7% of REPATHA-treated and placebo-treated patients, respectively. The most common allergic reactions were rash (1.0% versus 0.5% for REPATHA and placebo, respectively), eczema (0.4% versus 0.2%), erythema (0.4% versus 0.2%), and urticaria (0.4% versus 0.1%).

Adverse Reactions In The Cardiovascular Outcomes Trial

In a double-blind, randomized, placebo-controlled cardiovascular outcomes trial (Study 1 [REPATHA Cardiovascular Outcomes Trial, FOURIER, NCT01764633]), 27,525 patients received at least one dose of REPATHA or placebo [see Clinical Studies]. The mean age was 62.5 years (range: 40 to 86 years), 45% were 65 years or older, 9% were 75 years or older, 25% women, 85% White, 2% Black and 10% Asian; 8% identified as Hispanic ethnicity. Patients were exposed to REPATHA or placebo for a median of 24.8 months; 91% of patients were exposed for ≥ 12 months, 54% were exposed for ≥ 24 months and 5% were exposed for ≥ 36 months.

The safety profile of REPATHA in this trial was generally consistent with the safety profile described above in the 12-and 52-week controlled trials involving patients with primary hyperlipidemia (including HeFH). Serious adverse events occurred in 24.8% and 24.7% of REPATHA-treated and placebo-treated patients, respectively. Adverse events led to discontinuation of study treatment in 4.4% of patients assigned to REPATHA and 4.2% assigned to placebo. Common adverse reactions (>5% of patients treated with REPATHA and occurring more frequently than placebo) included diabetes mellitus (8.8% REPATHA, 8.2% placebo), nasopharyngitis (7.8% REPATHA, 7.4% placebo), and upper respiratory tract infection (5.1% REPATHA, 4.8% placebo).

Among the 16,676 patients without diabetes mellitus at baseline, the incidence of new-onset diabetes mellitus during the trial was 8.1% in patients assigned to REPATHA compared with 7.7% in those assigned to placebo.

Adverse Reactions In Patients With Homozygous Familial Hypercholesterolemia

In a 12-week, double-blind, randomized, placebo-controlled trial of 49 patients with HoFH (Study 6 [TESLA, NCT01588496]), 33 patients received 420 mg of REPATHA subcutaneously once monthly [see Clinical Studies]. The mean age was 31 years (range: 13 to 57 years), 49% were women, 90% White, 4% Asian, and 6% other. The adverse reactions that occurred in at least two (6.1%) REPATHA-treated patients, and more frequently than in placebo-treated patients, included:

· Upper respiratory tract infection (9.1% versus 6.3%)

· Influenza (9.1% versus 0%)

· Gastroenteritis (6.1% versus 0%)

· Nasopharyngitis (6.1% versus 0%)

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to REPATHA in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

The immunogenicity of REPATHA has been evaluated using an electrochemiluminescent bridging screening immunoassay for the detection of binding anti-drug antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.

In a pool of placebo-and active-controlled clinical trials, 0.3% (48 out of 17,992) of patients treated with at least one dose of REPATHA tested positive for the development of binding antibodies. Patients whose sera tested positive for binding antibodies were further evaluated for neutralizing antibodies; none of the patients tested positive for neutralizing antibodies.

There was no evidence that the presence of anti-drug binding antibodies impacted the pharmacokinetic profile, clinical response, or safety of REPATHA, but the long-term consequences of continuing REPATHA treatment in the presence of anti-drug binding antibodies are unknown.

 

Warnings & Precautions

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONSAllergic Reactions

Hypersensitivity reactions (e.g., rash, urticaria) have been reported in patients treated with REPATHA, including some that led to discontinuation of therapy. If signs or symptoms of serious allergic reactions occur, discontinue treatment with REPATHA, treat according to the standard of care, and monitor until signs and symptoms resolve.

Patient Counseling Information

Advise the patient and/or caregiver to read the FDA-approved patient labeling [PATIENT INFORMATIONand Instructions for Use (IFU)] before the patient starts using REPATHA, and each time the patient gets a refill as there may be new information they need to know.

Provide guidance to patients and caregivers on proper subcutaneous administration technique, including aseptic technique, and how to use the single-use prefilled autoinjector, single-use prefilled syringe, or single-use on-body infusor with prefilled cartridge correctly (see Instructions for Use leaflet). Inform patients that it may take up to 15 seconds to administer REPATHA using the single-use prefilled autoinjector or single-use prefilled syringe and about 9 minutes to administer REPATHA using the single-use on-body infusor with prefilled cartridge.

Advise latex-sensitive patients that the following components contain dry natural rubber (a derivative of latex) that may cause allergic reactions in individuals sensitive to latex: the needle cover of the glass single-use prefilled syringe and the single-use prefilled autoinjector.

The single-use on-body infusor with prefilled cartridge is not made with natural rubber latex.

For more information about REPATHA, go to www.REPATHA.com or call 1-844-REPATHA (1-844-737-2842).

Nonclinical ToxicologyCarcinogenesis, Mutagenesis, Impairment Of Fertility

The carcinogenic potential of evolocumab was evaluated in a lifetime study conducted in the hamster at dose levels of 10, 30, and 100 mg/kg administered every 2 weeks. There were no evolocumab-related tumors at the highest dose at systemic exposures up to 38-and 15-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. The mutagenic potential of evolocumab has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.

There were no adverse effects on fertility (including estrous cycling, sperm analysis, mating performance, and embryonic development) at the highest dose in a fertility and early embryonic developmental toxicology study in hamsters when evolocumab was subcutaneously administered at 10, 30, and 100 mg/kg every 2 weeks. The highest dose tested corresponds to systemic exposures up to 30-and 12-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. In addition, there were no adverse evolocumab-related effects on surrogate markers of fertility (reproductive organ histopathology, menstrual cycling, or sperm parameters) in a 6-month chronic toxicology study in sexually mature monkeys subcutaneously administered evolocumab at 3, 30, and 300 mg/kg once weekly. The highest dose tested corresponds to 744-and 300-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC.

Use In Specific PopulationsPregnancy

Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to REPATHA during pregnancy.

Please contact 1-877-311-8972 or https://mothertobaby.org/ongoing-study/repatha/ to enroll in or to obtain information about the registry.

Risk Summary

There are no data available on use of REPATHA in pregnant women to inform a drug-associated risk. In animal reproduction studies, there were no effects on pregnancy or neonatal/infant development when monkeys were subcutaneously administered evolocumab from organogenesis through parturition at dose exposures up to 12 times the exposure at the maximum recommended human dose of 420 mg every month. In a similar study with another drug in the PCSK9 inhibitor antibody class, humoral immune suppression was observed in infant monkeys exposed to that drug in utero at all doses. The exposures where immune suppression occurred in infant monkeys were greater than those expected clinically. No assessment for immune suppression was conducted with evolocumab in infant monkeys. Measurable evolocumab serum concentrations were observed in the infant monkeys at birth at comparable levels to maternal serum, indicating that evolocumab, like other IgG antibodies, crosses the placental barrier. FDA’s experience with monoclonal antibodies in humans indicates that they are unlikely to cross the placenta in the first trimester; however, they are likely to cross the placenta in increasing amounts in the second and third trimester. Consider the benefits and risks of REPATHA and possible risks to the fetus before prescribing REPATHA to pregnant women.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

In cynomolgus monkeys, no effects on embryo-fetal or postnatal development (up to 6 months of age) were observed when evolocumab was dosed during organogenesis to parturition at 50 mg/kg once every 2 weeks by the subcutaneous route at exposures 30-and 12-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. No test of humoral immunity in infant monkeys was conducted with evolocumab.

LactationRisk Summary

There is no information regarding the presence of evolocumab in human milk, the effects on the breastfed infant, or the effects on milk production. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for REPATHA and any potential adverse effects on the breastfed infant from REPATHA or from the underlying maternal condition. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts.

Pediatric Use

The safety and effectiveness of REPATHA in combination with diet and other LDL-C-lowering therapies in adolescents with HoFH who require additional lowering of LDL-C were established based on data from a 12-week, placebo-controlled trial that included 10 adolescents (ages 13 to 17 years old) with HoFH [see Clinical Studies]. In this trial, 7 adolescents received REPATHA 420 mg subcutaneously once monthly and 3 adolescents received placebo. The effect of REPATHA on LDL-C was generally similar to that observed among adult patients with HoFH. Including experience from open-label, uncontrolled studies, a total of 14 adolescents with HoFH have been treated with REPATHA, with a median exposure duration of 9 months. The safety profile of REPATHA in these adolescents was similar to that described for adult patients with HoFH.

The safety and effectiveness of REPATHA have not been established in pediatric patients with HoFH who are younger than 13 years old.

The safety and effectiveness of REPATHA have not been established in pediatric patients with primary hyperlipidemia or HeFH.

Geriatric Use

In controlled trials, 7656 (41%) patients treated with REPATHA were ≥ 65 years old and 1500 (8%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment

No dose adjustment is needed in patients with renal impairment. [see CLINICAL PHARMACOLOGY].

Hepatic Impairment

No dose adjustment is needed in patients with mild to moderate hepatic impairment (Child-Pugh A or B). No data are available in patients with severe hepatic impairment [see CLINICAL PHARMACOLOGY].

 

 

Overdosage & Contraindications

OVERDOSE

No Information Provided

CONTRAINDICATIONS

REPATHA is contraindicated in patients with a history of a serious hypersensitivity reaction to REPATHA [see WARNINGS AND PRECAUTIONS].

 

Clinical Pharmacology

CLINICAL PHARMACOLOGYMechanism Of Action

Evolocumab is a human monoclonal IgG2 directed against human proprotein convertase subtilisin kexin 9 (PCSK9). Evolocumab binds to PCSK9 and inhibits circulating PCSK9 from binding to the low density lipoprotein (LDL) receptor (LDLR), preventing PCSK9-mediated LDLR degradation and permitting LDLR to recycle back to the liver cell surface. By inhibiting the binding of PCSK9 to LDLR, evolocumab increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels.

Pharmacodynamics

Following single subcutaneous administration of 140 mg or 420 mg of evolocumab, maximum suppression of circulating unbound PCSK9 occurred by 4 hours. Unbound PCSK9 concentrations returned toward baseline when evolocumab concentrations decreased below the limit of quantitation.

Pharmacokinetics

Evolocumab exhibits non-linear kinetics as a result of binding to PCSK9. Administration of the 140 mg dose in healthy volunteers resulted in a Cmax mean (standard deviation [SD]) of 18.6 (7.3) μg/mL and AUClast mean (SD) of 188 (98.6) day•μg/mL. Administration of the 420 mg dose in healthy volunteers resulted in a Cmax mean (SD) of 59.0 (17.2) μg/mL and AUClast mean (SD) of 924 (346) day•μg/mL. Following a single 420 mg intravenous dose, the mean (SD) systemic clearance was estimated to be 12 (2) mL/hr. An approximate 2-to 3-fold accumulation was observed in trough serum concentrations (Cmin [SD] 7.21 [6.6]) following 140 mg doses administered subcutaneously every 2 weeks or following 420 mg doses administered subcutaneously monthly (Cmin [SD] 11.2 [10.8]), and serum trough concentrations approached steady state by 12 weeks of dosing.

Absorption

Following a single subcutaneous dose of 140 mg or 420 mg evolocumab administered to healthy adults, median peak serum concentrations were attained in 3 to 4 days, and estimated absolute bioavailability was 72%.

Distribution

Following a single 420 mg intravenous dose, the mean (SD) steady-state volume of distribution was estimated to be 3.3 (0.5) L.

Metabolism And Elimination

Two elimination phases were observed for REPATHA. At low concentrations, the elimination is predominately through saturable binding to target (PCSK9), while at higher concentrations the elimination of REPATHA is largely through a non-saturable proteolytic pathway. REPATHA was estimated to have an effective half-life of 11 to 17 days.

Specific Populations

The pharmacokinetics of evolocumab were not affected by age, gender, race, or creatinine clearance across all approved populations [see Use In Specific Populations].

The exposure of evolocumab decreased with increasing body weight. These differences are not clinically meaningful.

Renal Impairment

Since monoclonal antibodies are not known to be eliminated via renal pathways, renal function is not expected to impact the pharmacokinetics of evolocumab.

In a clinical trial of 18 patients with either normal renal function (estimated glomerular filtration rate [eGFR] ≥ 90 mL/min/1.73 m2, n=6), severe renal impairment (eGFR < 30 mL/min/1.73 m2, n=6), or end-stage renal disease (ESRD) receiving hemodialysis (n=6), exposure to evolocumab after a single 140 mg subcutaneous dose was decreased in patients with severe renal impairment or ESRD receiving hemodialysis. Reductions in PCSK9 levels in patients with severe renal impairment or ESRD receiving hemodialysis was similar to those with normal renal function [see Use In Specific Populations].

Hepatic Impairment

Following a single 140 mg subcutaneous dose of evolocumab in patients with mild or moderate hepatic impairment, a 20-30% lower mean Cmax and 40-50% lower mean AUC were observed as compared to healthy patients; however, no dose adjustment is necessary in these patients.

Pregnancy

The effect of pregnancy on evolocumab pharmacokinetics has not been studied [see Use In Specific Populations].

Drug Interaction Studies

An approximately 20% decrease in the Cmax and AUC of evolocumab was observed in patients co-administered with a high-intensity statin regimen. This difference is not clinically meaningful and does not impact dosing recommendations.

Animal Toxicology And/Or Pharmacology

During a 3-month toxicology study of 10 and 100 mg/kg once every 2 weeks evolocumab in combination with 5 mg/kg once daily rosuvastatin in adult monkeys, there were no effects of evolocumab on the humoral immune response to keyhole limpet hemocyanin (KLH) after 1 to 2 months exposure. The highest dose tested corresponds to exposures 54-and 21-fold higher than the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. Similarly, there were no effects of evolocumab on the humoral immune response to KLH (after 3 to 4 months exposure) in a 6-month study in cynomolgus monkeys at dose levels up to 300 mg/kg once weekly evolocumab corresponding to exposures 744-and 300-fold greater than the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC.

Clinical StudiesPrevention Of Cardiovascular Events

Study 1 (FOURIER, NCT01764633) was a double-blind, randomized, placebo-controlled, event-driven trial in 27,564 (13,784 REPATHA, 13,780 placebo) adult patients with established cardiovascular disease and with LDL-C ≥70 mg/dL and/or non-HDL-C ≥100 mg/dL despite high-or moderate-intensity statin therapy. Patients were randomly assigned 1:1 to receive either subcutaneous injections of REPATHA (140 mg every 2 weeks or 420 mg once monthly) or placebo; 86% used the every-2-week regimen throughout the trial. The median follow-up duration was 26 months. Overall, 99.2% of patients were followed until the end of the trial or death.

The mean (SD) age at baseline was 63 (9) years, with 45% being at least 65 years old; 25% were women. The trial population was 85% White, 2% Black, and 10% Asian; 8% identified as Hispanic ethnicity. Regarding prior diagnoses of cardiovascular disease, 81% had prior myocardial infarction, 19% prior non-hemorrhagic stroke, and 13% had symptomatic peripheral arterial disease. Selected additional baseline risk factors included hypertension (80%), diabetes mellitus (1% type 1; 36% type 2), current daily cigarettesmoking (28%), New York Heart Association class I or II congestive heart failure (23%), and eGFR < 60 mL/min per 1.73 m2 (6%). Most patients were on a high-(69%) or moderate-intensity (30%) statin therapy at baseline, and 5% were also taking ezetimibe. Most patients were taking at least one other cardiovascular medication including anti-platelet agents (93%), beta blockers (76%), angiotensin converting enzyme (ACE) inhibitors (56%), or angiotensin receptor blockers (23%). On stable background lipid-lowering therapy, the median [Q1, Q3] LDL-C at baseline was 92 [80, 109] mg/dL; the mean (SD) was 98 (28) mg/dL.

REPATHA significantly reduced the risk for the primary composite endpoint (time to first occurrence of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; p<0.0001) and the key secondary composite endpoint (time to first occurrence of cardiovascular death, myocardial infarction, or stroke; p<0.0001). The Kaplan-Meier estimates of the cumulative incidence of the primary and key secondary composite endpoints over time are shown in Figure 1 and Figure 2 below.

The results of primary and secondary efficacy endpoints are shown in Table 3 below.

Table 3. Effect of REPATHA on Cardiovascular Events in Patients with Established Cardiovascular Disease in FOURIER

Figure 1. Estimated Cumulative Incidence of Primary Composite Endpoint Over 3 Years in FOURIER

Figure 2. Estimated Cumulative Incidence of Key Secondary Composite Endpoint Over 3 Years in FOURIER

The difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was -63% (95% CI: -63%, -62%) and from baseline to Week 72 was -57% (95% CI: -58%, -56%). At Week 48, the median [Q1, Q3] LDL-C was 26 [15, 46] mg/dL in the REPATHA group, with 47% of patients having LDL-C <25 mg/dL.

Considering all assessments, among the patients treated with REPATHA, 10401 (76%) had at least one LDL-C value < 25 mg/dL. Although not a randomized comparison, the safety profile was similar between REPATHA-treated patients with post-baseline LDL-C < 25 mg/dL compared with REPATHA-treated patients with higher post-baseline LDL-C (LDL-C ≥ 40 mg/dL).

In EBBINGHAUS (NCT02207634), a substudy of 1974 patients enrolled in the FOURIER trial, REPATHA was non-inferior to placebo on selected cognitive function domains as assessed with the use of neuropsychological function tests over a median follow-up of 19 months.

Primary Hyperlipidemia (Including Heterozygous Familial Hypercholesterolemia)

Study 2 (LAPLACE-2, NCT01763866) was a multicenter, double-blind, randomized controlled 12-week trial in which patients were initially randomized to an open-label specific statin regimen for a 4-week lipid stabilization period followed by random assignment to subcutaneous injections of REPATHA 140 mg every 2 weeks, REPATHA 420 mg once monthly, or placebo for 12 weeks. The trial included 1896 patients with hyperlipidemia who received REPATHA, placebo, or ezetimibe as add-on therapy to daily doses of statins (atorvastatin, rosuvastatin, or simvastatin). Ezetimibe was also included as an active control only among those assigned to background atorvastatin. Overall, the mean age at baseline was 60 years (range: 20 to 80 years), 35% were ≥ 65 years old, 46% women, 94% White, 4% were Black, and 1% Asian; 5% identified as Hispanic or Latino ethnicity. After 4 weeks of background statin therapy, the mean baseline LDL-C ranged between 77 and 127 mg/dL across the five background therapy arms.

The difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was -71% (95% CI: -74%, -67%; p < 0.0001) and -63% (95% CI: -68%, -57%; p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. The difference between REPATHA and ezetimibe in mean percent change in LDL-C from baseline to Week 12 was -45% (95% CI: -52%, -39%; p < 0.0001) and -41% (95% CI: -47%, -35%; p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. For additional results see Table 4 and Figure 3.

Table 4. Effect of REPATHA on Lipid Parameters in Patients with Hyperlipidemia on Background Statin Regimens (Mean % Change from Baseline to Week 12 in LAPLACE-2)

Figure 3. Effect of REPATHA on LDL-C in Patients with Hyperlipidemia when Combined with Statins (Mean % Change from Baseline to Week 12 in LAPLACE-2)

Study 3 (DESCARTES, NCT01516879) was a multicenter, double-blind, randomized, placebo-controlled, 52-week trial that included 901 patients with hyperlipidemia who received protocol-determined background lipid-lowering therapy of a cholesterol-lowering diet either alone or in addition to atorvastatin (10 mg or 80 mg daily) or the combination of atorvastatin 80 mg daily with ezetimibe. After stabilization on background therapy, patients were randomly assigned to the addition of placebo or REPATHA 420 mg administered subcutaneously once monthly. Overall, the mean age at baseline was 56 years (range: 25 to 75 years), 23% were ≥ 65 years, 52% women, 80% White, 8% Black, and 6% Asian; 6% identified as Hispanic or Latino ethnicity. After stabilization on the assigned background therapy, the mean baseline LDL-C ranged between 90 and 117 mg/dL across the four background therapy groups.

In these patients with hyperlipidemia on a protocol-determined background therapy, the difference between REPATHA 420 mg once monthly and placebo in mean percent change in LDL-C from baseline to Week 52 was -55% (95% CI: -60%, -50%; p < 0.0001) (Table 5 and Figure 4). For additional results see Table 5.

Table 5. Effect of REPATHA on Lipid Parameters in Patients with Hyperlipidemia* (Mean % Change from Baseline to Week 52 in DESCARTES)

Figure 4. Effect of REPATHA 420 mg Once Monthly on LDL-C in Patients with Hyperlipidemia in DESCARTES

Study 4 (MENDEL-2, NCT01763827) was a multicenter, double-blind, randomized, placebo-and active-controlled, 12-week trial that included 614 patients with hyperlipidemia who were not taking lipid-lowering therapy at baseline. Patients were randomly assigned to receive subcutaneous injections of REPATHA 140 mg every 2 weeks, REPATHA 420 mg once monthly, or placebo for 12 weeks. Blinded administration of ezetimibe was also included as an active control. Overall, the mean age at baseline was 53 years (range: 20 to 80 years), 18% were ≥ 65 years old, 66% were women, 83% White, 7% Black, and 9% Asian; 11% identified as Hispanic or Latino ethnicity. The mean baseline LDL-C was 143 mg/dL.

The difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was -55% (95% CI: -60%, -50%; p < 0.0001) and -57% (95% CI: -61%, -52%; p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. The difference between REPATHA and ezetimibe in mean percent change in LDL-C from baseline to Week 12 was -37% (95% CI: -42%, -32%; p < 0.0001) and -38% (95% CI: -42%, -34%; p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. For additional results see Table 6.

Table 6. Effect of REPATHA on Lipid Parameters in Patients with Hyperlipidemia (Mean % Change from Baseline to Week 12 in MENDEL-2)

Study 5 (RUTHERFORD-2, NCT01763918) was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 329 patients with heterozygous familial hypercholesterolemia (HeFH) on statins with or without other lipid-lowering therapies. Patients were randomized to receive subcutaneous injections of REPATHA 140 mg every two weeks, 420 mg once monthly, or placebo. HeFH was diagnosed by the Simon Broome criteria (1991). In Study 5, 38% of patients had clinical atheroscleroticcardiovascular disease. The mean age at baseline was 51 years (range: 19 to 79 years), 15% of the patients were ≥ 65 years old, 42% were women, 90% were White, 5% were Asian, and 1% were Black. The average LDL-C at baseline was 156 mg/dL with 76% of the patients on high-intensity statin therapy.

The differences between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was -61% (95% CI: -67%, -55%; p < 0.0001) and -60% (95% CI: -68%, -52%; p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. For additional results see Table 7 and Figure 5.

Table 7. Effect of REPATHA on Lipid Parameters in Patients with HeFH (Mean % Change from Baseline to Week 12 in RUTHERFORD-2)

Figure 5. Effect of REPATHA on LDL-C in Patients with HeFH (Mean % Change from Baseline to Week 12 in RUTHERFORD-2)

Homozygous Familial Hypercholesterolemia (HoFH)

Study 6 (TESLA, NCT01588496) was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 49 patients (not on lipid-apheresis therapy) with homozygous familial hypercholesterolemia(HoFH). In this trial, 33 patients received subcutaneous injections of 420 mg of REPATHA once monthly and 16 patients received placebo as an adjunct to other lipid-lowering therapies (e.g., statins, ezetimibe). The mean age at baseline was 31 years, 49% were women, 90% White, 4% were Asian, and 6% other. The trial included 10 adolescents (ages 13 to 17 years), 7 of whom received REPATHA. The mean LDL-C at baseline was 349 mg/dL with all patients on statins (atorvastatin or rosuvastatin) and 92% on ezetimibe. The diagnosis of HoFH was made by genetic confirmation or a clinical diagnosis based on a history of an untreated LDL-C concentration > 500 mg/dL together with either xanthoma before 10 years of age or evidence of HeFH in both parents.

The difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was -31% (95% CI: -44%, -18%; p < 0.0001). For additional results see Table 8.

Patients known to have two LDL-receptor negative alleles (little to no residual function) did not respond to REPATHA.

Table 8. Effect of REPATHA on Lipid Parameters in Patients with HoFH (Mean % Change from Baseline to Week 12 in TESLA)