温馨提醒：本说明书仅供参考，最新的说明书详见药品附带的说明书。

1适应症和用途

1.1复发性卵巢癌的维持治疗

ZEJULA ®指示用于维持治疗成年患者复发性卵巢上皮，输卵管，或原发性腹膜癌谁在基于铂的化疗完全或部分响应。

1.2三种或三种以上化学疗法后晚期卵巢癌的治疗

ZEJULA ®指示用于谁已经用三个或更多个之前化疗方案治疗的成人患有晚期卵巢，输卵管，或原发性腹膜癌的治疗和其癌症与同源重组缺乏（HRD）由任一定义的正状态关联：

• 有害或怀疑有害的BRCA突变，或
• 基因组不稳定以及对最近的铂类化学疗法有反应后进展超过六个月的患者[参见临床研究（14.2） ]。

根据FDA批准的ZEJULA伴随诊断选择患者进行治疗。

2用法用量

2.1三种或多种化学疗法后治疗晚期卵巢癌的患者选择

根据有害的或可疑的有害BRCA突变和/或基因组不稳定评分（GIS），选择在与HRD阳性状态相关的三种或更多种化疗方案后选择治疗晚期卵巢癌的患者[参见临床研究（14.2） ]。

有关此指征的有害或怀疑有害BRCA突变或基因组不稳定性的检测，有关FDA批准的检测的信息，可从以下网址获得：http://www.fda.gov/CompanionDiagnostics。

2.2推荐剂量

ZEJULA的建议剂量为每天口服一次300毫克（三100毫克胶囊）。

为了维持复发性卵巢癌，患者应在最近的含铂治疗方案后不超过8周开始使用ZEJULA治疗。

ZEJULA治疗应继续进行，直到疾病进展或出现不可接受的毒性。

指导患者每天大约在同一时间服用ZEJULA。每个胶囊应全部吞下。ZEJULA可以带或不带食物一起服用。就寝时间管理可能是解决恶心的一种潜在方法。

如果错过剂量的ZEJULA，请指示患者在有规律的时间服用下一次剂量。如果患者呕吐或错过了ZEJULA剂量，则不应再服用其他剂量。

2.3不良反应的剂量调整

要处理不良反应，请考虑中断治疗，降低剂量或停药。表1、2和3列出了建议的不良反应剂量调整方法。

表1：建议的不良反应剂量调整

表2：非血液学不良反应的剂量调整

表3：血液学不良反应的剂量调整

3剂型和强度

100毫克胶囊，白色的身体上用黑色墨水印有“ 100毫克”，紫色的帽子上的白色墨水印有“ 尼拉帕利 ”。

4禁忌症

没有。

5警告和注意事项

5.1骨髓增生异常综合症/急性髓性白血病

据报道，接受ZEJULA治疗的患者患有骨髓增生异常综合症/急性髓性白血病（MDS / AML），包括具有致命后果的病例。在临床试验中，在190例接受ZEJULA治疗的患者中，有14例患者发生了MDS / AML（0.7％）。

发生继发性MDS /癌症治疗相关AML的患者使用ZEJULA治疗的持续时间从<2个月到> 4年不等。所有这些患者以前都接受过铂类药物和/或其他DNA破坏性药物（包括放疗）的化学疗法。如果确认了MDS / AML，请中止ZEJULA。

5.2骨髓抑制

ZEJULA治疗的患者有血液学不良反应（血小板减少，贫血和中性粒细胞减少）。在NOVA接受ZEJULA治疗的患者中，分别报告有≥3级血小板减少，贫血和中性粒细胞减少症。分别有3％，1％和2％的患者因血小板减少，贫血和嗜中性白血球减少而停药。

在QUADRA中，接受ZEJULA治疗的患者中分别报告了≥3级的血小板减少症，贫血和中性粒细胞减少症。分别有4％，2％和1％的患者因血小板减少，贫血和嗜中性白血球减少而停药。

在患者从先前的化学疗法（≤1级）引起的血液学毒性中恢复过来之前，请勿开始使用ZEJULA。在治疗的第一个月每周监测全血细胞计数，在接下来的11个月每月监测一次，此后定期监测。如果在中断后28天内血液学毒性仍未消失，请中断ZEJULA的治疗，然后将患者转介给血液学家进行进一步检查，包括进行骨髓分析和血液样本进行细胞遗传学检查（参见剂量和给药方法（2.3））。

5.3心血管效应

据报道，使用ZEJULA治疗的患者患有高血压和高血压危机。9％的ZEJULA治疗患者发生3-4级高血压，而NOVA安慰剂治疗的患者则为2％，首次给药至首次发作的中位时间为77天（范围：4至504天），中位持续时间为15天（范围：1到86天）。少于1％的患者因高血压而停药。QUADRA接受ZEJULA治疗的患者中，有5％发生3-4级高血压，从首次给药到首次发病的中位时间为15天（范围：1至316天），中位持续时间为7天（范围：1至1天）。 118天）。<0.2％的患者因高血压而停药。

在头两个月中至少每周一次监测血压和心率，然后在第一年每月监测一次，此后在使用ZEJULA治疗期间定期监测。密切监视患有心血管疾病，尤其是冠状动脉供血不足，心律不齐和高血压的患者。如有必要，可通过降压药物和调整ZEJULA剂量对高血压进行医学治疗[请参阅剂量和用法（2.3）和非临床毒理学（13.2） ]。

5.4胚胎-胎儿毒性

基于其作用机理，ZEJULA对孕妇给药可引起胎儿伤害[见临床药理学（12.1） ]。 ZEJULA具有潜在的致畸性和/或胚胎死亡，因为尼拉帕利布具有遗传毒性，并以动物和患者（例如骨髓）中的活跃分裂细胞为目标[见警告和注意事项（5.2）和非临床毒理学（13.1） ]。由于基于其作用机理对胎儿的潜在风险，因此未使用尼拉帕利进行动物发育和生殖毒理学研究。

告知孕妇可能对胎儿造成危险。繁殖潜力的指教女性治疗期间使用有效的避孕和为ZEJULA在最后一剂后6个月[参见特殊人群中使用（8.1，8.3） ]。

6不良反应

标签上其他地方描述了以下临床上显着的不良反应：

• 骨髓增生异常综合症/急性髓性白血病[请参阅警告和注意事项（5.1） ]
• 骨髓抑制[请参阅警告和注意事项（5.2） ]
• 心血管作用[请参阅警告和注意事项（5.3） ]

6.1临床试验经验

由于临床试验是在广泛不同的条件下进行的，因此无法将在某种药物的临床试验中观察到的不良反应率直接与另一种药物的临床试验中观察到的不良反应率进行比较，并且可能无法反映实际中观察到的不良反应率。

在NOVA和QUADRA试验（830例）中，接受ZEJULA治疗的830名患者中，最常见的不良反应为（10％）为恶心（70％），疲劳（58％），血小板减少症（56％），贫血（50％） ，呕吐（40％），便秘（38％），腹痛（35％），肌肉骨骼疼痛（34％），食欲下降（26％），中性粒细胞减少症（25％），失眠（23％），头痛（22％ ），呼吸困难（21％），腹泻（18％），高血压（16％），咳嗽（15％），头晕（13％），低镁血症（13％），尿路感染（13％），急性肾损伤（ 13％），白细胞计数下降（11％）。

复发性卵巢癌的维持治疗

在NOVA试验中，已对367例对铂敏感的复发性卵巢癌，输卵管癌和原发性腹膜癌患者的ZEJULA单药300 mg每日安全性进行了研究。NOVA的不良反应导致69％的患者剂量减少或中断，最常见的是血小板减少症（41％）和贫血（20％）。NOVA中由于不良反应引起的永久停药率为15％。这些患者的ZEJULA中位暴露时间为250天。

表4和表5分别总结了在NOVA中接受ZEJULA治疗的患者中常见的不良反应和实验室异常发现。

表4：在NOVA中接受ZEJULA的患者中≥10％报告不良反应

表5：NOVA中接受ZEJULA的患者中≥25％的实验室检查异常

在NOVA试验中，在接受ZEJULA的367例患者中，≥1至<10％确认了以下不良反应和实验室异常，但未包括在表中：心动过速，外周水肿，低钾血症，支气管炎，结膜炎，γ-谷氨酰转移酶升高，血肌酐增加，血碱性磷酸酶增加，体重下降，抑郁，鼻st。

三种或三种以上化学疗法治疗晚期卵巢癌

QUADRA已对ZEJULA单药300 mg的每日安全性进行了研究，QUADRA是一项单臂研究，研究了463例复发性高级别浆液性上皮性卵巢癌，输卵管癌或原发性腹膜癌患者，这些患者曾接受过3种或以上的顺铂治疗治疗。总体研究治疗的中位时间为3个月（范围：0.03到32个月）。对于指定的QUADRA人群，中位持续时间为4个月（范围：0.1到30个月）。

致命不良反应发生在2％的患者中，包括心脏骤停。

接受ZEJULA治疗的患者中有43％发生了严重的不良反应。在> 3％的患者中，严重的不良反应为小肠梗阻（7％），呕吐（6％），恶心（5％）和腹痛（4％）。

接受ZEJULA治疗的患者中有21％因不良反应而永久停药（1-4级）。

不良反应导致73％的ZEJULA患者减少剂量或中断治疗。导致ZEJULA剂量减少或中断的最常见不良反应（≥5％）是血小板减少症（40％），贫血（21％），中性粒细胞减少症（11％），恶心（13％），呕吐（11％），疲劳（9％）和腹痛（5％）。

表6和表7分别总结了在QUADRA中接受ZEJULA治疗的患者的常见不良反应和实验室异常发现。

表6：在QUADRA中接受ZEJULA的患者中≥10％报告不良反应

表7：在QUADRA中接受ZEJULA的患者中≥25％的实验室检查结果异常

6.2售后经验

在ZEJULA的批准后使用过程中，已经确认了以下不良反应。由于这些反应是从不确定大小的人群中自愿报告的，因此并非总是能够可靠地估计其发生频率或建立与药物暴露的因果关系。

免疫系统疾病：过敏（包括过敏反应）

神经系统疾病：后可逆性脑病综合征（PRES）

精神病：神志不清/迷失方向，幻觉

呼吸，胸和纵隔疾病：非感染性肺炎

皮肤和皮下组织疾病：光敏性

8在特定人群中的使用

8.1怀孕

风险摘要

基于其作用机理，ZEJULA对孕妇给药可引起胎儿伤害[见临床药理学（12.1） ]。没有关于在孕妇中使用ZEJULA来告知与药物相关的风险的数据。ZEJULA具有潜在的致畸性和/或胚胎死亡，因为尼拉帕利布具有遗传毒性，并以动物和患者（例如骨髓）中的活跃分裂细胞为目标[见警告和注意事项（5.2）和非临床毒理学（13.1） ]。由于基于其作用机理对胎儿的潜在风险，因此未使用尼拉帕利进行动物发育和生殖毒理学研究。告知孕妇可能对胎儿造成危险。

对于所指示的人群，主要出生缺陷和流产的背景风险尚不清楚。在美国普通人群中，临床公认的怀孕中主要先天缺陷和流产的估计背景风险分别为2％至4％和15％至20％。

8.2哺乳

风险摘要

关于人乳中尼拉帕利或其代谢物的存在，或其对母乳喂养婴儿或乳汁生产的影响，尚无可用数据。由于ZEJULA的母乳喂养婴儿可能会出现严重的不良反应，因此建议哺乳期妇女在使用ZEJULA治疗期间以及接受最终剂量后的1个月内不要母乳喂养。

8.3生殖潜力的男性和女性

验孕

ZEJULA对孕妇给药可能会造成胎儿伤害[见在特定人群中使用（8.1） ]。

建议在开始ZEJULA治疗之前对具有生殖能力的女性进行妊娠试验。

避孕

女性

ZEJULA对孕妇给药可能会造成胎儿伤害[见在特定人群中使用（8.1） ]。

建议有生殖能力的女性在最后一次服药后至少六个月内使用ZEJULA进行有效的避孕治疗。

不孕症

雄性

根据动物研究，ZEJULA可能会损害具有生殖潜力的男性的生育能力[请参阅非临床毒理学（13.1） ]。

8.4小儿使用

ZEJULA的安全性和有效性尚未在儿科患者中确定。

8.5老年人使用

在NOVA中，35％的患者年龄≥65岁，8％的患者年龄≥75岁。在这些患者和年轻患者之间未观察到ZEJULA的安全性和有效性的总体差异，但不能排除某些老年患者更高的敏感性。

8.6肾功能不全

轻度（CLcr：60至89 mL / min）至中度（CLcr：30至59 mL / min）肾功能不全的患者无需调整剂量。肾功能不全的程度由Cockcroft-Gault方程估算的肌酐清除率确定。ZEJULA在患有严重肾功能不全或接受血液透析的终末期肾脏疾病患者中的安全性尚不清楚。

8.7肝功能不全

根据国家癌症研究所–器官功能障碍工作组（NCI-ODWG）的标准，轻度肝功能不全患者无需调整剂量。ZEJULA在中度至重度肝功能不全患者中的安全性尚不清楚。

10过量

ZEJULA用药过量时没有具体治疗方法，也没有症状。如果服药过量，医护人员应采取一般的支持措施并应对症治疗。

11说明

Niraparib是一种口服聚（ADP-核糖）聚合酶（PARP）抑制剂。

甲磺酸尼拉帕利一水合物的化学名称为2- {4-[（3S）-哌啶-3-基]苯基} -2H-吲唑7-羧酰胺4-甲基苯磺酸盐水合物（1：1：1）。分子式为C 26 H 30 N 4 O 5 S，分子量为510.61 amu。分子结构如下：

甲苯磺酸尼拉帕利一水合物是白色至灰白色的非吸湿性结晶固体。Niraparib的溶解度在9.95的pKa以下与pH无关，在整个生理pH范围内，其游离碱的水溶液溶解度为0.7 mg / mL至1.1 mg / mL。

每个ZEJULA胶囊均含有159.4 mg 甲苯磺酸尼拉帕利一水合物，相当于100 mg 尼拉帕利游离碱作为活性成分。胶囊填充物中的非活性成分是硬脂酸镁和乳糖一水合物。该胶囊壳由二氧化钛，明胶在白色的胶囊主体的; 紫色胶囊盖中有FD＆C蓝色＃1，FD＆C红色＃3，FD＆C黄色＃5和明胶。的黑色油墨由虫胶，无水乙醇，异丙醇，丁醇，丙二醇，纯净水，浓氨溶液，氢氧化钾和黑色氧化铁。该白色印刷油墨由虫胶，脱水醇，异丙醇，丁醇，丙二醇，氢氧化钠，聚维酮和二氧化钛组成。

12临床药理学

12.1行动机制

Niraparib是聚（ADP-核糖）聚合酶（PARP）酶PARP-1和PARP-2的抑制剂，它们在DNA修复中起作用。体外研究表明，尼拉帕利诱导的细胞毒性可能涉及抑制PARP酶活性和增加PARP-DNA复合物的形成，从而导致DNA损伤，凋亡和细胞死亡。在有或没有BRCA1 / 2缺陷的肿瘤细胞系中观察到了尼拉帕利诱导的细胞毒性增加。Niraparib在BRCA1 / 2缺陷的人类癌细胞系的小鼠异种移植模型中以及在突变或野生型同源重组缺陷的人类患者来源的异种移植瘤模型中均降低了肿瘤的生长BRCA1 / 2。

12.2药效学

尼拉帕利的药效学反应尚未确定。

心血管作用

尼拉帕利有可能对接受推荐剂量的患者产生脉搏率和血压的影响，这可能与多巴胺转运蛋白（DAT），去甲肾上腺素转运蛋白（NET）和5-羟色胺转运蛋白（SERT）的药理抑制有关[请参阅非临床毒理学（（13.2） ]。

在NOVA研究中，在所有研究评估中，相对于安慰剂组，尼拉帕利布组的平均脉搏率和血压均高于基线。Niraparib和安慰剂组的平均脉搏率从基线的最大增加分别为24.1和15.8次/分钟。尼拉帕利布组和安慰剂组的收缩压平均较基线最大增加分别为24.5和18.3 mmHg 。尼拉帕利组和安慰剂组的舒张压平均较基线最大增加分别为16.5和11.6 mmHg 。

心脏电生理学

对于QTc延长与潜在niraparib在癌症患者中（367名患者随机化，安慰剂对照试验进行评价niraparib和179分服用安慰剂的患者）。每日一次尼拉帕利 300 mg 治疗后，该试验中未发现平均QTc间隔（> 20 ms）有大变化。

12.3药代动力学

单次给药300 mg 尼拉帕利后，平均血浆血浆峰浓度（C max）为804（±403）ng / mL。尼拉帕利的暴露量（C max和AUC）以剂量成比例的方式增加，每日剂量范围从30 mg（批准的推荐剂量的0.1倍）到400 mg（批准的推荐剂量的1.3倍）。对于30 mg至400 mg的剂量，每天重复21天服用尼拉帕利的累积比率约为2倍。

吸收性

尼拉帕利的绝对生物利用度约为73％。口服尼拉帕利后，在3小时内达到血浆峰值浓度C max。

高脂餐（800-1,000卡路里，约占餐总热量的50％来自脂肪）的同时使用对尼拉帕利的药代动力学没有显着影响。

分配

Niraparib与人类血浆蛋白的结合率为 83.0％。平均（±SD）表观分布体积（Vd / F）为1220（±1114）L。在人群药代动力学分析中，癌症患者尼拉帕利的Vd / F为1074L。

消除

每日多次服用300 mg 尼拉帕利后，平均半衰期（t 1/2）为36小时。在人群药代动力学分析中，癌症患者尼拉帕利的表观总清除率（CL / F）为16.2 L / h。

代谢

尼拉帕利布被羧酸酯酶（CEs）代谢形成主要的无活性代谢物，随后其进行葡萄糖醛酸化。

排泄

在单次口服300 mg放射性标记的尼拉帕利后，在21天的尿液中平均回收率百分比为47.5％（范围为33.4％至60.2％），为38.8％（范围为28.3％至47.0％） ）在粪便中。在6天的收集样本中，未改变的尼拉帕利分别占尿液和粪便中回收剂量的11％和19％。

特定人群

年龄（18至65岁），种族/民族，轻度至中度肾功能不全以及轻度肝功能不全对尼拉帕利的药代动力学无临床显着影响。

尚不清楚严重的肾功能不全或接受血液透析的终末期肾脏疾病对尼拉帕利的药代动力学的影响。

中度或重度肝功能损害对尼拉帕利药代动力学的影响尚不清楚。

药物相互作用研究

ZEJULA尚未进行临床药物相互作用研究。

体外研究

的CYP的抑制：无论niraparib也不是主要的初级代谢产物M1是CYP1A2，CYP2B6，CYP2C8，CYP2C9，CYP2C19，CYP2D6，和CYP3A4的抑制剂。

CYPs的诱导：niraparib和M1 都不是CYP3A4诱导剂。Niraparib在体外弱诱导CYP1A2。

CYP的底物： Niraparib是羧酸酯酶（CEs）的底物，所得的M1在体内通过葡萄糖醛酸苷的形成进一步代谢。

转移酶的抑制： Niraparib没有表现出对抗UGT亚型（UGT1A1，UGT1A4，UGT1A9和UGT2B7）抑制作用高达200μM体外。因此，对于通过转移酶的临床相关的抑制潜在niraparib是最小的。

转运蛋白系统的抑制： 尼拉帕利布是乳腺癌抗性蛋白（BCRP）的弱抑制剂，但不抑制P-糖蛋白（P-gp），胆盐输出泵（BSEP）或多药耐药性相关蛋白2（MRP2） 。

Niraparib是多药和毒素挤出（MATE）1和2的抑制剂，IC 50分别为0.18 µM和≤0.14 µM。不能排除这些转运蛋白（例如二甲双胍）的共同给药药物的血浆浓度升高。

M1代谢产物不是P-gp，BCRP，BSEP，MRP2或MATE1或2 的抑制剂。尼拉帕利布或M1 都不是有机阴离子转运多肽1B1（OATP1B1），1B3（OATP1B3）或有机阳离子转运蛋白1的抑制剂。 （OCT1），有机阴离子转运蛋白1（OAT1），有机阴离子转运蛋白3（OAT3）或有机阳离子转运蛋白2（OCT2）。

转运系统的底物： Niraparib是P-gp和BCRP的底物。Niraparib不是BSEP，MRP2或MATE1或2的底物。M1代谢物不是P-gp，BCRP，BSEP或MRP2 的底物，而是MATE1和2。Niraparib和M1 都不是OATP1B1，OATP1B3的底物。 ，OCT1，OAT1，OAT3或OCT2。

13毒理学

13.1致癌，诱变，生育力受损

尚未对尼拉帕利进行致癌性研究。

Niraparib在体外哺乳动物染色体畸变测定和体内大鼠骨髓微核测定中具有致死性。这种致裂性与尼拉帕利布的主要药理作用导致的基因组不稳定性一致，并表明了对人类遗传毒性的潜力。尼拉帕利布在细菌反向突变试验（Ames）中没有致突变性。

尼拉帕利尚未进行过动物生育能力研究。在重复剂量的口服毒性研究中，尼拉帕利每天在大鼠和狗中给药，持续时间长达3个月。在大鼠和狗中，在≥10mg / kg和≥1.5mg / kg的剂量下，附睾和睾丸中的精子，精子和生殖细胞减少。在每天300 mg的推荐剂量下，这些剂量水平导致的全身暴露分别约为人暴露（AUC 0-24hr）的0.3和0.012倍。停止服药4周后，这些发现有可逆性趋势。

13.2动物毒理学和/或药理学

尼拉帕利在体外与多巴胺转运蛋白（DAT），去甲肾上腺素转运蛋白（NET）和5-羟色胺转运蛋白（SERT）结合，并抑制了患者体内稳态时IC 50值低于C min的细胞中去甲肾上腺素和多巴胺的摄取。接受推荐剂量。 Niraparib有可能在患者中引起与抑制这些转运蛋白（例如心血管或CNS）相关的作用。

在30分钟内以1，3和10 mg / kg的剂量对经阴道切除的狗静脉注射尼拉帕利导致动脉压范围增加13-20％，18-27和19-25％，心率范围增加2-11分别比给药前水平高4-17％和12-21％。在这些剂量水平下，狗中尼拉帕利的未结合血浆浓度约为接受推荐剂量的患者稳态时未结合C max的0.5、1.5和5.8倍。

此外，尼拉帕利在口服后穿越了大鼠和猴子的血脑屏障。口服给予两只恒河猴的尼拉帕利的脑脊髓液（CSF）：血浆C 最大比值分别为0.10和0.52。

14临床研究

14.1复发性卵巢癌的维持治疗

NOVA（NCT01847274）是一项双盲，安慰剂对照试验，其中对铂敏感复发性上皮性卵巢癌，输卵管癌或原发性腹膜癌患者（n = 553）每天2：1随机分配至ZEJULA 300 mg或匹配最后一次治疗后8周内服用安慰剂。继续治疗直至疾病进展或不可接受的毒性。所有患者均已接受至少两种先前的含铂方案，并且对他们最近的基于铂的方案有反应（完全或部分）。

倒数第二次铂治疗后（6至<12个月且≥12个月），按进展时间对随机分组。将贝伐单抗与倒数第二个或最后一个白金方案一起使用（是/否）；在最近的白金疗程中有最佳反应（完全反应和部分反应）。根据BRACAnalysis CDx的结果，将符合条件的患者分配到两个队列之一。将具有有害或疑似有害生殖系BRCA突变（gBRCAm）的患者分配给生殖系BRCA突变（g BRCA mut）队列（n = 203），将没有生殖系BRCA突变的患者分配给非g BRCA mut队列（n = 350）。

主要疗效指标PFS（无进展生存期）主要是根据RECIST（实体肿瘤反应评估标准，版本1.1）通过中央独立评估确定的。在某些情况下，还采用了RECIST以外的其他标准，例如临床体征和症状以及CA-125升高。

ZEJULA治疗的患者中位年龄为57-64岁，安慰剂治疗的患者中位年龄为58-67岁。所有患者中百分之八十六为白人。在研究基线时，接受ZEJULA的患者中有67％，接受安慰剂的患者中有69％的ECOG为0。大约40％的患者入选美国或加拿大，所有患者中的51％对最近的铂类药物疗法完全反应，自倒数第二次铂类药物疗法以来，两组均39％的患者间隔了6-12个月。接受过ZEJULA治疗的患者中有26％接受了安慰剂治疗，接受安慰剂的患者中有31％接受了贝伐单抗治疗。大约40％的患者接受了3种或更多的治疗。

该试验证明了具有统计学显著改善PFS与在克安慰剂相比的患者随机化至ZEJULA BRCA MUT队列和非克BRCA MUT队列（表8中，和图1和2）。

表8：疗效结果-NOVA（IRC评估*，意向性治疗人群）

图1：基于IRC评估的g BRCA mut队列无进展生存期（ITT人群，N = 203）

图2：基于IRC评估的非g BRCA mut队列总体无进展生存期（ITT人群，N = 350）

在进行PFS分析时，只有有限的总体生存数据，在这两个队列中有17％的死亡。

14.2三种或三种以上化学疗法后晚期卵巢癌的治疗

在单臂QUADRA（NCT02354586）试验中，ZEJULA的功效在98例患有同源重组缺陷（HRD）阳性肿瘤的晚期卵巢癌患者中进行了研究。要求患者接受过三个或三个以上的先前化疗方案的治疗，而那些先前暴露于PARP抑制剂的患者除外。使用临床试验分析法选择患者。那些没有BRCA突变的人必须在最后一剂铂类药物治疗后至少六个月发展。所有患者均以单药每日300毫克的起始剂量接受ZEJULA胶囊治疗，直至疾病进展或出现不可接受的毒性。

使用无数myChoice CDx作为t BRCA m（n = 63）和/或基因组不稳定评分（GIS）≥42 （n = 35）确定HRD阳性状态。GIS是对杂合性丢失（LOH），端粒等位基因失衡（TAI）和大规模状态转换（LST）的算法测量。

主要的疗效结局指标是研究者根据RECIST v。1.1评估的客观缓解率（ORR）和缓解持续时间（DOR）。

患者的中位年龄为63岁（范围39-91）。大部分是白人（82％），所有的ECOG PS分别为0（59％）或1（41％）。

表9总结了QUADRA的疗效结果。

表9：疗效结果-QUADRA（研究者评估）

对于t BRCA卵巢癌患者，研究者评估的铂敏感性疾病患者的ORR为39％（7/18; 95％CI：[17，64]），29％（6/21; 95％CI： [11，52]）患有铂耐药性疾病的患者，19％（3/16; 95％CI：[4，46]）患有铂耐药性疾病的患者。

对于铂敏感的GIS阳性疾病（无BRCA突变）（n = 35）的患者，研究者评估的ORR为20％（95％CI [8，37]）。

16供应/存储和处理方式

ZEJULA可作为胶囊使用，胶囊的白色主体用黑色墨水印刷“ 100 mg”，而紫色盖上用白色墨水印刷“ Niraparib ”。

每个胶囊含100 mg 尼拉帕利游离碱。

ZEJULA胶囊包装为

存放在20°C至25°C（68°F至77°F）; 允许在15°C到30°C（59°F到86°F）之间进行偏移[请参阅USP控制的室温]。

17患者咨询信息

建议患者阅读FDA批准的患者标签（患者信息）。

MDS /反洗钱

如果患者出现虚弱，感到疲倦，发烧，体重减轻，经常感染，青肿，容易流血，呼吸困难，尿液或粪便中的血液和/或实验室检查到的血细胞计数低或需要，建议患者与他们的医疗保健提供者联系用于输血。这可能是血液毒性或骨髓增生异常综合症（MDS）或急性髓细胞性白血病（AML）的征兆，在ZEJULA治疗的患者中已有报道[见警告和注意事项（5.1） ]。

骨髓抑制

告知患者需要定期监测其血球计数。建议患者就新的出血，发烧或感染症状与他们的医疗保健提供者联系[请参阅警告和注意事项（5.2） ]。

心血管作用

建议患者至少在头两个月每周进行一次血压和心率监测，然后在治疗的第一年每月进行一次血压监测，之后再定期进行监测。如果血压升高，建议患者联系其医疗保健提供者[请参阅警告和注意事项（5.3） ]。

加药说明

告知患者如何服用ZEJULA [见剂量和用法（2.2） ]。ZEJULA应该每天服用一次。指导患者，如果他们错过一剂ZEJULA，不要服用额外的剂量来弥补他们错过的一剂。他们应该在预定的时间服用下一次剂量。每个胶囊应全部吞下。ZEJULA可以带或不带食物一起服用。就寝时间管理可能是解决恶心的一种潜在方法。

胚胎-胎儿毒性

如果女性怀孕或怀孕，建议女性告知其医疗保健提供者。告知女性患者胎儿的风险和潜在的怀孕损失[参见警告和注意事项（5.4）和在特定人群中的使用（8.1） ]。

避孕

劝告有生殖潜力的女性在使用ZEJULA治疗期间以及在接受最后一剂药物后至少6个月内使用有效的避孕药[见在特定人群中使用（8.3） ]。

哺乳期

建议患者在服用ZEJULA期间和最后一次服药后1个月内不要母乳喂养[见特殊人群的使用（8.2） ]。

生产厂商：TESARO，Inc. 1000 Winter St.，Waltham，MA 02451

ZEJULA是TESARO，Inc.的注册商标。此处引用的所有其他商标均为其各自所有者的财产。

©2017、2018、2019 TESARO，Inc.保留所有权利。
123501

主要显示面板-90胶囊瓶标签

仅 NDC 69656-103-90
Rx

Zejula ®
niraparib
胶囊

100毫克

90粒

TESARO ®

主要显示面板-30胶囊瓶标签

仅 NDC 69656-103-30
Rx

Zejula ®
niraparib
胶囊

100毫克

30粒

TESARO ®

温馨提醒：本说明书仅供参考，最新的说明书详见药品附带的说明书。

本说明书来源于：美国FDA

https://nctr-crs.fda.gov/fdalabel/services/spl/set-ids/0fe9d533-67a9-4981-978a-1e84755ae30b/spl-doc?hl=Niraparib

温馨提醒：

①建议您用 谷歌浏览器  在电脑上或手机  打开以上链接，就可以自动翻译成简体中文，而且翻译的还比较准确。

②本说明书仅供参考，最新的说明书详见药品附带的说明书

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Maintenance Treatment of Recurrent Ovarian Cancer

ZEJULA® is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

1.2 Treatment of Advanced Ovarian Cancer after Three or More Chemotherapies

ZEJULA® is indicated for the treatment of adult patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who have been treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either:

• a deleterious or suspected deleterious BRCA mutation, or
• genomic instability and who have progressed more than six months after response to the last platinum-based chemotherapy [see Clinical Studies (14.2)].

Select patients for therapy based on an FDA-approved companion diagnostic for ZEJULA.

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection for Treatment of Advanced Ovarian Cancer after Three or More Chemotherapies

Select patients for treatment of advanced ovarian cancer after three or more chemotherapy regimens associated with HRD positive status based on either deleterious or suspected deleterious BRCA mutation and/or genomic instability score (GIS) [see Clinical Studies (14.2)].

Information on FDA-approved tests for the detection of either deleterious or suspected deleterious BRCA mutation or genomic instability for this indication is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosage

The recommended dose of ZEJULA is 300 mg (three 100 mg capsules) taken orally once daily.

For the maintenance treatment of recurrent ovarian cancer, patients should start treatment with ZEJULA no later than 8 weeks after their most recent platinum-containing regimen.

ZEJULA treatment should be continued until disease progression or unacceptable toxicity.

Instruct patients to take their dose of ZEJULA at approximately the same time each day. Each capsule should be swallowed whole. ZEJULA may be taken with or without food. Bedtime administration may be a potential method for managing nausea.

In the case of a missed dose of ZEJULA, instruct patients to take their next dose at its regularly scheduled time. If a patient vomits or misses a dose of ZEJULA, an additional dose should not be taken.

2.3 Dosage Adjustments for Adverse Reactions

To manage adverse reactions, consider interruption of treatment, dose reduction, or dose discontinuation. The recommended dose modifications for adverse reactions are listed in Tables 1, 2 and 3.

Table 1: Recommended dose modifications for adverse reactions

*If further dose reduction below 100 mg/day is required, discontinue ZEJULA.

Table 2: Dose modifications for non-hematologic adverse reactions

*CTCAE=Common Terminology Criteria for Adverse Events

Table 3: Dose modifications for hematologic adverse reactions

3 DOSAGE FORMS AND STRENGTHS

100 mg capsule having a white body with "100 mg" printed in black ink, and a purple cap with "Niraparib" printed in white ink.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML), including cases with fatal outcome, have been reported in patients who received ZEJULA. In 1902 patients treated with ZEJULA in clinical trials, MDS/AML occurred in 14 patients (0.7%).

The duration of therapy with ZEJULA in patients who developed secondary MDS/cancer therapy-related AML varied from <2 months to >4 years. All of these patients had received previous chemotherapy with platinum agents and/or other DNA-damaging agents including radiotherapy. Discontinue ZEJULA if MDS/AML is confirmed.

5.2 Bone Marrow Suppression

Hematologic adverse reactions (thrombocytopenia, anemia and neutropenia) have been reported in patients treated with ZEJULA. Grade ≥3 thrombocytopenia, anemia and neutropenia were reported, respectively, in 29%, 25%, and 20% of patients receiving ZEJULA in NOVA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred, respectively, in 3%, 1%, and 2% of patients.

Grade ≥3 thrombocytopenia, anemia and neutropenia were reported, respectively, in 28%, 27%, and 13% of patients receiving ZEJULA in QUADRA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred, respectively, in 4%, 2%, and 1% of patients.

Do not start ZEJULA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically after this time. If hematological toxicities do not resolve within 28 days following interruption, discontinue ZEJULA, and refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics [see Dosage and Administration (2.3)].

5.3 Cardiovascular Effects

Hypertension and hypertensive crisis have been reported in patients treated with ZEJULA. Grade 3-4 hypertension occurred in 9% of ZEJULA treated patients compared to 2% of placebo treated patients in NOVA with a median time from first dose to first onset of 77 days (range: 4 to 504 days) and with a median duration of 15 days (range: 1 to 86 days). Discontinuation due to hypertension occurred in <1% of patients. Grade 3-4 hypertension occurred in 5% of ZEJULA-treated patients in QUADRA with a median time from first dose to first onset of 15 days (range: 1 to 316 days) and with a median duration of 7 days (range: 1 to 118 days). Discontinuation due to hypertension occurred in <0.2% of patients.

Monitor blood pressure and heart rate at least weekly for the first two months, then monthly for the first year and periodically thereafter during treatment with ZEJULA. Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Medically manage hypertension with antihypertensive medications and adjustment of the ZEJULA dose, if necessary [see Dosage and Administration (2.3) and Nonclinical Toxicology (13.2)].

5.4 Embryo-Fetal Toxicity

Based on its mechanism of action, ZEJULA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. ZEJULA has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow) [see Warnings and Precautions (5.2) and Nonclinical Toxicology (13.1)]. Due to the potential risk to a fetus based on its mechanism of action, animal developmental and reproductive toxicology studies were not conducted with niraparib.

Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of ZEJULA [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Myelodysplastic Syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1)]
• Bone Marrow Suppression [see Warnings and Precautions (5.2)]
• Cardiovascular Effects [see Warnings and Precautions (5.3)]

6.1 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 practice.

The most common adverse reactions in >10% of 830 patients who received ZEJULA in the NOVA and QUADRA trials (n = 830) were nausea (70%), fatigue (58%), thrombocytopenia (56%), anemia (50%), vomiting (40%), constipation (38%), abdominal pain (35%), musculoskeletal pain (34%), decreased appetite (26%), neutropenia (25%), insomnia (23%), headache (22%), dyspnea (21%), diarrhea (18%), hypertension (16%), cough (15%), dizziness (13%), hypomagnesemia (13%), urinary tract infection (13%), acute kidney injury (13%), and white blood cell count decreased (11%).

Maintenance Treatment of Recurrent Ovarian Cancer

The safety of ZEJULA monotherapy 300 mg once daily has been studied in 367 patients with platinum-sensitive recurrent ovarian, fallopian tube, and primary peritoneal cancer in the NOVA trial. Adverse reactions in NOVA led to dose reduction or interruption in 69% of patients, most frequently from thrombocytopenia (41%) and anemia (20%). The permanent discontinuation rate due to adverse reactions in NOVA was 15%. The median exposure to ZEJULA in these patients was 250 days.

Table 4 and Table 5 summarize the common adverse reactions and abnormal laboratory findings, respectively, observed in patients treated with ZEJULA in NOVA.

Table 4: Adverse Reactions Reported in ≥10% of Patients Receiving ZEJULA in NOVA

Table 5: Abnormal Laboratory Findings in ≥25% of Patients Receiving ZEJULA in NOVA

N=number of patients; WBC=white blood cells; ALT=Alanine aminotransferase; AST=Aspartate aminotransferase

The following adverse reactions and laboratory abnormalities have been identified in ≥1 to <10% of the 367 patients receiving ZEJULA in the NOVA trial and not included in the table: tachycardia, peripheral edema, hypokalemia, bronchitis, conjunctivitis, gamma-glutamyl transferase increased, blood creatinine increased, blood alkaline phosphatase increased, weight decreased, depression, epistaxis.

Treatment of Advanced Ovarian Cancer after Three or More Chemotherapies

The safety of ZEJULA monotherapy 300 mg once daily has been studied in QUADRA, a single-arm study in 463 patients with recurrent high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with 3 or more prior lines of therapy. The median duration of overall study treatment was 3 months (range: 0.03 to 32 months). For the indicated QUADRA population, the median duration was 4 months (range: 0.1 to 30 months).

Fatal adverse reactions occurred in 2% of patients, including cardiac arrest.

Serious adverse reactions occurred in 43% of patients receiving ZEJULA. Serious adverse reactions in >3% of patients were small intestinal obstruction (7%), vomiting (6%), nausea (5%), and abdominal pain (4%).

Permanent discontinuation due to adverse reactions (Grade 1-4) occurred in 21% of patients who received ZEJULA.

Adverse reactions led to dose reduction or interruption in 73% of patients receiving ZEJULA. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of ZEJULA were thrombocytopenia (40%), anemia (21%), neutropenia (11%), nausea (13%), vomiting (11%), fatigue (9%), and abdominal pain (5%).

Table 6 and Table 7 summarize the common adverse reactions and abnormal laboratory findings, respectively, observed in patients treated with ZEJULA in QUADRA.

Table 6: Adverse Reactions Reported in ≥10% of Patients Receiving ZEJULA in QUADRA

Table 7: Abnormal Laboratory Findings in ≥25% of Patients Receiving ZEJULA in QUADRA

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ZEJULA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: hypersensitivity (including anaphylaxis)

Nervous System Disorders: posterior reversible encephalopathy syndrome (PRES)

Psychiatric Disorders: confusional state/disorientation, hallucination

Respiratory, Thoracic, and Mediastinal Disorders: non-infectious pneumonitis

Skin and Subcutaneous Tissue Disorders: photosensitivity

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on its mechanism of action, ZEJULA can cause fetal harm when administered to pregnant women [see Clinical Pharmacology (12.1)]. There are no data regarding the use of ZEJULA in pregnant women to inform the drug-associated risk. ZEJULA has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow) [see Warnings and Precautions (5.2) and Nonclinical Toxicology (13.1)]. Due to the potential risk to a fetus based on its mechanism of action, animal developmental and reproductive toxicology studies were not conducted with niraparib. Apprise pregnant women of the potential risk to a fetus.

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

8.2 Lactation

Risk Summary

No data are available regarding the presence of niraparib or its metabolites in human milk, or on its effects on the breastfed infant or milk production. Because of the potential for serious adverse reactions in breastfed infants from ZEJULA, advise a lactating woman not to breastfeed during treatment with ZEJULA and for 1 month after receiving the final dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

ZEJULA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

A pregnancy test is recommended for females of reproductive potential prior to initiating ZEJULA treatment.

Contraception

Females

ZEJULA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception treatment with ZEJULA and for at least for 6 months following the last dose.

Infertility

Males

Based on animal studies, ZEJULA may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness of ZEJULA have not been established in pediatric patients.

8.5 Geriatric Use

In NOVA, 35% of patients were aged ≥65 years and 8% were aged ≥75 years. No overall differences in safety and effectiveness of ZEJULA were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment

No dose adjustment is necessary for patients with mild (CLcr:60 to 89 mL/min) to moderate (CLcr:30 to 59 mL/min) renal impairment. The degree of renal impairment was determined by creatinine clearance as estimated by the Cockcroft-Gault equation. The safety of ZEJULA in patients with severe renal impairment or end stage renal disease undergoing hemodialysis is unknown.

8.7 Hepatic Impairment

No dose adjustment is needed in patients with mild hepatic impairment according to the National Cancer Institute – Organ Dysfunction Working Group (NCI-ODWG) criteria. The safety of ZEJULA in patients with moderate to severe hepatic impairment is unknown.

10 OVERDOSAGE

There is no specific treatment in the event of ZEJULA overdose, and symptoms of overdose are not established. In the event of an overdose, healthcare practitioners should follow general supportive measures and should treat symptomatically.

11 DESCRIPTION

Niraparib is an orally available poly(ADP-ribose) polymerase (PARP) inhibitor.

The chemical name for niraparib tosylate monohydrate is 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole 7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1). The molecular formula is C26H30N4O5S and it has a molecular weight of 510.61 amu. The molecular structure is shown below:

Niraparib tosylate monohydrate is a white to off-white, non-hygroscopic crystalline solid. Niraparib solubility is pH independent below the pKa of 9.95, with an aqueous free base solubility of 0.7 mg/mL to 1.1 mg/mL across the physiological pH range.

Each ZEJULA capsule contains 159.4 mg niraparib tosylate monohydrate equivalent to 100 mg niraparib free base as the active ingredient. The inactive ingredients in the capsule fill are magnesium stearate and lactose monohydrate. The capsule shell consists of titanium dioxide, gelatin in the white capsule body; and FD&C Blue #1, FD&C Red #3, FD&C Yellow #5 and gelatin in the purple capsule cap. The black printing ink consists of shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, purified water, strong ammonia solution, potassium hydroxide and black iron oxide. The white printing ink consists of shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, sodium hydroxide, povidone and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Niraparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2, which play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis and cell death. Increased niraparib-induced cytotoxicity was observed in tumor cell lines with or without deficiencies in BRCA1/2. Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and in human patient-derived xenograft tumor models with homologous recombination deficiency that had either mutated or wild type BRCA1/2.

12.2 Pharmacodynamics

The pharmacodynamic response of niraparib has not been characterized.

Cardiovascular Effects

Niraparib has the potential to cause effects on pulse rate and blood pressure in patients receiving the recommended dose, which may be related to pharmacological inhibition of the dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT) [see Nonclinical Toxicology (13.2)].

In the NOVA study, mean pulse rate and blood pressure increased over baseline in the niraparib arm relative to the placebo arm at all on-study assessments. Mean greatest increases from baseline in pulse rate on treatment were 24.1 and 15.8 beats/min in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in systolic blood pressure on treatment were 24.5 and 18.3 mmHg in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in diastolic blood pressure on treatment were 16.5 and 11.6 mmHg in the niraparib and placebo arms, respectively.

Cardiac Electrophysiology

The potential for QTc prolongation with niraparib was evaluated in a randomized, placebo-controlled trial in cancer patients (367 patients on niraparib and 179 patients on placebo). No large changes in the mean QTc interval (>20 ms) were detected in the trial following the treatment of niraparib 300 mg once daily.

12.3 Pharmacokinetics

Following a single-dose administration of 300 mg niraparib, the mean (±SD) peak plasma concentration (Cmax) was 804 (± 403) ng/mL. The exposure (Cmax and AUC) of niraparib increased in a dose proportional manner with daily doses ranging from 30 mg (0.1 times the approved recommended dosage) to 400 mg (1.3 times the approved recommended dosage). The accumulation ratio of niraparib exposure following 21 days of repeated daily doses was approximately 2 fold for doses ranging from 30 mg to 400 mg.

Absorption

The absolute bioavailability of niraparib is approximately 73%. Following oral administration of niraparib, peak plasma concentration, Cmax, is reached within 3 hours.

Concomitant administration of a high fat meal (800-1,000 calories with approximately 50% of total caloric content of the meal from fat) did not significantly affect the pharmacokinetics of niraparib.

Distribution

Niraparib is 83.0% bound to human plasma proteins. The average (±SD) apparent volume of distribution (Vd/F) was 1220 (±1114) L. In a population pharmacokinetic analysis, the Vd/F of niraparib was 1074 L in cancer patients.

Elimination

Following multiple daily doses of 300 mg niraparib, the mean half-life (t1/2) is 36 hours. In a population pharmacokinetic analysis, the apparent total clearance (CL/F) of niraparib was 16.2 L/h in cancer patients.

Metabolism

Niraparib is metabolized by carboxylesterases (CEs) to form a major inactive metabolite, which subsequently undergoes glucuronidation.

Excretion

Following administration of a single oral 300 mg dose of radio-labeled niraparib, the average percent recovery of the administered dose over 21 days was 47.5% (range 33.4% to 60.2%) in urine, and 38.8% (range 28.3% to 47.0%) in feces. In pooled samples collected over 6 days, unchanged niraparib accounted for 11% and 19% of the administered dose recovered in urine and feces, respectively.

Specific Populations

Age (18 to 65 years old), race/ethnicity, mild to moderate renal impairment, and mild hepatic impairment had no clinically significant effect on the pharmacokinetics of niraparib.

The effect of severe renal impairment or end-stage renal disease undergoing hemodialysis on the pharmacokinetics of niraparib is unknown.

The effect of moderate or severe hepatic impairment on the pharmacokinetics of niraparib is unknown.

Drug Interaction Studies

No clinical drug interaction studies have been performed with ZEJULA.

In Vitro Studies

Inhibition of CYPs: Neither niraparib nor the major primary metabolite M1 is an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.

Induction of CYPs: Neither niraparib nor M1 is a CYP3A4 inducer. Niraparib weakly induces CYP1A2 in vitro.

Substrate of CYPs: Niraparib is a substrate of carboxylesterases (CEs) and and the resulting M1 is further metabolized through the formation of a glucuronide in vivo.

Inhibition of UGTs: Niraparib did not exhibit inhibitory effect against the UGT isoforms (UGT1A1, UGT1A4, UGT1A9, and UGT2B7) up to 200 µM in vitro. Therefore, the potential for a clinically relevant inhibition of UGTs by niraparib is minimal.

Inhibition of transporter systems: Niraparib is a weak inhibitor of breast cancer resistance protein (BCRP), but does not inhibit P-glycoprotein (P-gp), bile salt export pump (BSEP), or multidrug resistance-associated protein 2 (MRP2).

Niraparib is an inhibitor of multidrug and toxin extrusion (MATE)1 and 2 with IC50 of 0.18 µM and ≤ 0.14 µM, respectively. Increased plasma concentrations of co-administered drugs that are substrates of these transporters (e.g., metformin) cannot be excluded.

The M1 metabolite is not an inhibitor of P-gp, BCRP, BSEP, MRP2, or MATE1 or 2. Neither niraparib nor M1 is an inhibitor of organic anion transport polypeptide 1B1 (OATP1B1), 1B3 (OATP1B3), or organic cation transporter 1 (OCT1), organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3), or organic cation transporter 2 (OCT2).

Substrate of transporter systems: Niraparib is a substrate of P-gp and BCRP. Niraparib is not a substrate of BSEP, MRP2, or MATE1 or 2. The M1 metabolite is not a substrate of P-gp, BCRP, BSEP, or MRP2, but MATE1 and 2. Neither niraparib nor M1 is a substrate of OATP1B1, OATP1B3, OCT1, OAT1, OAT3, or OCT2.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with niraparib.

Niraparib was clastogenic in an in vitro mammalian chromosomal aberration assay and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of niraparib and indicates potential for genotoxicity in humans. Niraparib was not mutagenic in a bacterial reverse mutation assay (Ames) test.

Fertility studies in animals have not been conducted with niraparib. In repeat-dose oral toxicity studies, niraparib was administered daily for up to 3 months duration in rats and dogs. Reduced sperm, spermatids and germ cells in epididymides and testes were observed at doses ≥10 mg/kg and ≥1.5 mg/kg in rats and dogs, respectively. These dose levels resulted in systemic exposures approximately 0.3 and 0.012 times, respectively, the human exposure (AUC0-24hr) at the recommended dose of 300 mg daily. There was a trend toward reversibility of these findings 4 weeks after dosing was stopped.

13.2 Animal Toxicology and/or Pharmacology

In vitro, niraparib bound to the dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT) and inhibited uptake of norepinephrine and dopamine in cells with IC50 values that were lower than the Cmin at steady-state in patients receiving the recommended dose. Niraparib has the potential to cause effects in patients related to inhibition of these transporters (e.g., cardiovascular or CNS).

Intravenous administration of niraparib to vagotomized dogs over 30 minutes at 1, 3 and 10 mg/kg resulted in an increased range of arterial pressures of 13-20, 18-27 and 19-25% and increased range of heart rates of 2-11, 4-17 and 12-21% above pre-dose levels, respectively. The unbound plasma concentrations of niraparib in dogs at these dose levels were approximately 0.5, 1.5 and 5.8 times the unbound Cmax at steady-state in patients receiving the recommended dose.

In addition, niraparib crossed the blood-brain barrier in rats and monkeys following oral administration. The cerebrospinal fluid (CSF):plasma Cmax ratios of niraparib administered at 10 mg/kg orally to two Rhesus monkeys were 0.10 and 0.52.

14 CLINICAL STUDIES

14.1 Maintenance Treatment of Recurrent Ovarian Cancer

NOVA (NCT01847274) was a double-blind, placebo-controlled trial in which patients (n=553) with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomized 2:1 to ZEJULA 300 mg orally daily or matched placebo within 8 weeks of the last therapy. Treatment was continued until disease progression or unacceptable toxicity. All patients had received at least two prior platinum-containing regimens and were in response (complete or partial) to their most recent platinum-based regimen.

Randomization was stratified by time to progression after the penultimate platinum therapy (6 to <12 months and ≥12 months); use of bevacizumab in conjunction with the penultimate or last platinum regimen (yes/no); and best response during the most recent platinum regimen (complete response and partial response). Eligible patients were assigned to one of two cohorts based on the results of the BRACAnalysis CDx. Patients with deleterious or suspected deleterious germline BRCA mutations (gBRCAm) were assigned to the germline BRCA mutated (gBRCAmut) cohort (n=203), and those without germline BRCA mutations were assigned to the non-gBRCAmut cohort (n=350).

The major efficacy outcome measure, PFS (progression-free survival), was determined primarily by central independent assessment per RECIST (Response Evaluation Criteria in Solid Tumors, version 1.1). In some cases, criteria other than RECIST, such as clinical signs and symptoms and increasing CA-125, were also applied.

The median age of patients ranged from 57-64 years among patients treated with ZEJULA and 58-67 years among patients treated with placebo. Eighty-six percent of all patients were white. Sixty-seven percent of patients receiving ZEJULA and 69% of patients receiving placebo had an ECOG of 0 at study baseline. Approximately 40% of patients were enrolled in the U.S. or Canada and 51% of all patients were in complete response to most recent platinum-based regimen, with 39% on both arms with an interval of 6-12 months since the penultimate platinum regimen. Twenty-six percent of those treated with ZEJULA and 31% treated with placebo had received prior bevacizumab therapy. Approximately 40% of patients had 3 or more lines of treatment.

The trial demonstrated a statistically significant improvement in PFS for patients randomized to ZEJULA as compared with placebo in the gBRCAmut cohort and the non-gBRCAmut cohort (Table 8, and Figures 1 and 2).

Table 8: Efficacy Results - NOVA (IRC Assessment*, Intent-To-Treat Population)

Figure 1: Progression-Free Survival in the gBRCAmut Cohort Based on IRC Assessment (ITT Population, N=203)

Figure 2: Progression-Free Survival in the Non-gBRCAmut Cohort Overall Based on IRC Assessment (ITT Population, N=350)

At the time of the PFS analysis, limited overall survival data were available with 17% deaths across the two cohorts.

14.2 Treatment of Advanced Ovarian Cancer after Three or More Chemotherapies

The efficacy of ZEJULA was studied in 98 patients with advanced ovarian cancer with homologous recombination deficiency (HRD) positive tumors in the single-arm QUADRA (NCT02354586) trial. Patients were required to have been treated with three or more prior lines of chemotherapy and those with prior exposure to PARP inhibitors were excluded. Patients were selected using a clinical trial assay. Those without BRCA mutations must have progressed at least six months after their last dose of platinum therapy. All patients received ZEJULA capsules at a starting dose of 300 mg once daily as monotherapy until disease progression or unacceptable toxicity.

HRD positive status was determined using the Myriad myChoice CDx as either tBRCAm (n=63) and/or a genomic instability score (GIS) ≥ 42 (n=35). GIS is an algorithmic measurement of Loss of Heterozygosity (LOH), Telomeric Allelic Imbalance (TAI), and Large-scale State Transitions (LST).

The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) as assessed by the investigator according to RECIST v. 1.1.

The median age of the patients was 63 years (range 39-91); the majority were white (82%) and all had an ECOG PS of 0 (59%) or 1 (41%).

The efficacy results for QUADRA are summarized in Table 9.

Table 9: Efficacy Results – QUADRA (Investigator Assessment)

For patients with tBRCAm ovarian cancer, investigator-assessed ORR was 39% (7/18; 95% CI: [17, 64]) in patients with platinum-sensitive disease, 29% (6/21; 95% CI: [11, 52]) in patients with platinum-resistant disease, and 19% (3/16; 95% CI: [4, 46]) in patients with platinum-refractory disease.

For patients with platinum-sensitive GIS-positive disease (without BRCAmut) (n=35), investigator-assessed ORR was 20% (95% CI [8, 37]).

16 HOW SUPPLIED/STORAGE AND HANDLING

ZEJULA is available as capsules having a white body printed with "100 mg" in black ink, and a purple cap printed with "Niraparib" in white ink.

Each capsule contains 100 mg of niraparib free base.

ZEJULA capsules are packaged as

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

MDS/AML

Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions. This may be a sign of hematological toxicity or myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) which has been reported in patients treated with ZEJULA [see Warnings and Precautions (5.1)].

Bone Marrow Suppression

Advise patients that periodic monitoring of their blood counts is required. Advise patients to contact their healthcare provider for new onset of bleeding, fever, or symptoms of infection [see Warnings and Precautions (5.2)].

Cardiovascular Effects

Advise patients to undergo blood pressure and heart rate monitoring at least weekly for the first two months, then monthly for the first year of treatment, and then periodically thereafter. Advise patients to contact their healthcare provider if blood pressure is elevated [see Warnings and Precautions (5.3)].

Dosing Instructions

Inform patients on how to take ZEJULA [see Dosage and Administration (2.2)]. ZEJULA should be taken once daily. Instruct patients that if they miss a dose of ZEJULA, not to take an extra dose to make up for the one that they missed. They should take their next dose at the regularly scheduled time. Each capsule should be swallowed whole. ZEJULA may be taken with or without food. Bedtime administration may be a potential method for managing nausea.

Embryo-Fetal Toxicity

Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)].

Contraception

Advise females of reproductive potential to use effective contraception during treatment with ZEJULA and for at least 6 months after receiving the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise patients not to breastfeed while taking ZEJULA and for 1 month after the last dose [see Use in Special Populations (8.2)].

Manufactured for: TESARO, Inc. 1000 Winter St., Waltham, MA 02451

ZEJULA is a registered trademark of TESARO, Inc. All other trademarks referenced herein are the property of their respective owners.

©2017, 2018, 2019 TESARO, Inc. All rights reserved.
123501

PRINCIPAL DISPLAY PANEL - 90 Capsule Bottle Label

NDC 69656-103-90
Rx only

Zejula®
niraparib
capsules

100 mg

90 capsules

TESARO®

PRINCIPAL DISPLAY PANEL - 30 Capsule Bottle Label

NDC 69656-103-30
Rx only

Zejula®
niraparib
capsules

100 mg

30 capsules

TESARO®

【备注】以上内容仅供参考，不作为用药依据，详情请参照药品附带说明书。