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

Rubraca被指定用于对铂类化学疗法有完全或部分反应的复发性上皮性卵巢癌，输卵管癌或原发性腹膜癌的成年患者的维持治疗[见剂量和用法（2.1）]。

1.2两次或更多次化学疗法后BRCA突变的卵巢癌的治疗

Rubraca被指定用于治疗患有有害的BRCA突变（生殖细胞和/或体细胞）相关的上皮性卵巢癌，输卵管癌或原发性腹膜癌的成年患者，这些患者已经接受了两种或更多种化学疗法的治疗。根据FDA批准的Rubraca伴随诊断选择患者进行治疗[请参阅剂量和给药方法（2.1）]。

2用法用量

2.1推荐剂量

Rubraca的推荐剂量为600毫克（两片300毫克片剂），每天口服两次，含或不含食物。

继续治疗直至疾病进展或出现不可接受的毒性。

如果患者错过了Rubraca剂量，请指示患者在其预定时间服用下一剂。呕吐的剂量不应更换。

2.2不良反应的剂量修改

要处理不良反应，请考虑中断治疗或降低剂量。推荐的剂量减少在表1中示出。

表1.建议的剂量调整

2.3治疗BRCA突变的卵巢癌的患者选择

根据存在有害的BRCA突变（生殖细胞和/或体细胞），选择使用 Rubraca治疗上皮性卵巢癌，输卵管癌或原发性腹膜癌的患者[参见适应症和用法（1.2）和临床研究（14.2）]。有关FDA批准的检测卵巢癌患者肿瘤BRCA突变的测试的信息，请访问：http://www.fda.gov/CompanionDiagnostics。

3剂型和强度

• 片剂（200毫克）：蓝色，圆形，速释，薄膜包衣，凹陷有“ C2”。
• 片剂（250毫克）：白色，钻石，速释，薄膜包衣，压花“ C25”。
• 片剂（300毫克）：黄色，椭圆形，速释，薄膜包衣，凹陷有“ C3”。

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

骨髓增生异常综合症（MDS）/急性髓性白血病（AML）在使用Rubraca治疗的患者中很少发生，并且可能是致命的不良反应。在大约1100名接受治疗的患者中，MDS / AML发生在12名患者中（1.1％），其中包括长期随访的患者。其中5例发生在治疗期间或28天安全性随访期间（0.5％）。诊断MDS / AML之前Rubraca治疗的持续时间为1个月至大约28个月。这些病例是典型的继发于MDS /癌症治疗的AML。在所有情况下，患者均已接受过先前的含铂化疗方案和/或其他DNA破坏剂。

在患者因先前的化疗（≤1级）引起的血液学毒性恢复后，才开始使用Rubraca。监测基线和此后每月进行血细胞减少的全血细胞计数，以了解治疗期间的临床显着变化。对于延长的血液学毒性（> 4周），请按照表1 [参见剂量和用法（2.2）]中断Rubraca或降低剂量，并每周监测血球计数直至恢复。如果在4周后仍未恢复到1级或更低的水平，或者怀疑是MDS / AML，请将该患者转介至血液科医生进行进一步检查，包括进行骨髓分析和血液样本进行细胞遗传学检查。如果确认了MDS / AML，请中止Rubraca。

5.2胚胎-胎儿毒性

根据Rubraca的作用机理和动物研究发现，对孕妇服用Rubraca可能会对胎儿造成伤害。在一项动物生殖研究中，在器官生成期间向怀孕的大鼠投予rucaparib会导致接受每日两次建议的600 mg人类剂量的患者在暴露时的胚胎-胎儿死亡是AUC 0-24h的 0.04倍。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6个月以下的Rubraca最后剂量[见特殊人群中使用（8.1，8.3）和临床药理学（12.1）]。

6不良反应

标签中其他地方还讨论了以下严重不良反应：

• 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）]。

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。

复发性卵巢癌的维持治疗

在ARIEL3中研究了Rubraca维持治疗上皮性卵巢癌，输卵管癌或原发性腹膜癌的安全性，ARIEL3是一项随机（2：1），双盲，安慰剂对照研究，其中561例患者接受了Rubraca 600的治疗毫克BID（n = 372）或安慰剂（n = 189），直到疾病进展或不可接受的毒性。接受Rubraca的患者的研究治疗中位时间为8.3个月（范围：<1个月至35个月），接受安慰剂的患者为5.5个月。

65％的接受Rubraca的患者和10％的接受安慰剂的患者均因任何级别的不良反应而导致剂量中断；55％的Rubraca患者和4％的安慰剂患者因不良反应而使剂量减少。导致卢布拉卡剂量中断或减少剂量的最常见不良反应是血小板减少症（18％），贫血（17％），恶心（15％）和疲劳/乏力（13％）。15％的Rubraca患者和2％的安慰剂患者因不良反应而停药。Rubraca治疗的患者中最经常导致停药的具体不良反应是贫血（3％），血小板减少症（3％）和恶心（3％）。

表2.≥20％的患者发生ARIEL3不良反应

接受Rubraca治疗的患者中发生的不良反应<20％，包括头痛（18％），头晕（19％），消化不良（19％），失眠（15％），呼吸困难（17％），发热（13％），周围性水肿（11％）和抑郁症（11％）。

表3.≥25％的患者发生的ARIEL3实验室异常

2次或更多次化学疗法后治疗BRCA突变的复发性卵巢癌

还对377例上皮性卵巢癌，输卵管癌或原发性腹膜癌患者进行了两次每日两次Rubraca 600 mg单药治疗的研究，该患者在两项开放标签的单臂试验中，经过两次或两次以上的化学疗法后进展。在这些患者中，中位年龄为62岁（范围：31至86岁），ECOG表现状态为0或1的患者为10​​0％，卵巢癌BRCA突变的患者为38％，先前接受过3次或以上化疗的患者为45％ ，自卵巢癌诊断以来的中位时间为43个月（范围：6至197）。

表4.研究10和ARIEL2中经Rubraca治疗的≥2种化学疗法后≥20％的卵巢癌患者报告的不良反应

在每天两次Rubraca 600 mg治疗的377例患者中，<20％出现以下不良反应：头晕（17％），中性粒细胞减少症（15％），皮疹（包括皮疹，皮疹红斑，皮疹，皮疹和皮炎）（13 ％），发热（11％），光敏反应（10％），瘙痒（包括瘙痒和全身性瘙痒）（9％），掌-红斑感觉综合征（2％）和发热性中性粒细胞减少症（1％）。

表5.研究10和ARIEL2中经Rubraca治疗的≥2种化学疗法后≥35％的卵巢癌患者报告的实验室异常

7药物相互作用

7.1 卢卡泊利对细胞色素p450（CYP）底物的影响

rucaparib的共同给药可增加CYP1A2，CYP3A，CYP2C9或CYP2C19底物的全身暴露[见临床药理学（12.3）]，这可能会增加这些药物毒性的风险。

如果临床上有适应症，请调整CYP1A2，CYP3A，CYP2C9或CYP2C19底物的剂量。如果无法避免与华法林（CYP2C9底物）合用，应考虑增加国际标准化比率（INR）监测的频率。

8在特定人群中的使用

8.1怀孕

风险摘要

根据动物研究的发现及其作用机理，对孕妇服用卢巴拉卡（Rubraca）会造成胎儿伤害。孕妇没有可用的数据来告知与药物相关的风险。在一项动物生殖研究中，在器官形成过程中对怀孕的大鼠给予rucaparib会导致母体暴露时胚胎-胎儿死亡，这是接受每日两次600 mg推荐剂量的患者的AUC 0-24h的 0.04倍[见数据 ]。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％。

数据

动物资料

在剂量范围确定的胚胎-胎儿发育研究中，怀孕的大鼠在器官发生期间接受了50、150、500或1000 mg / kg /天的rucaparib口服剂量。在所有动物中，以大于或等于50 mg / kg /天的剂量观察到植入后损失（100％的早期吸收）（母体全身暴露量约为人类以AUC 0-24h推荐剂量的暴露量的0.04倍）。 。

8.2哺乳

风险摘要

没有关于人乳中存在rucaparib或其对产奶量或母乳喂养孩子的影响的信息。由于来自Rubraca的母乳喂养的孩子有发生严重不良反应的可能性，因此建议哺乳期妇女在用Rubraca进行治疗期间以及末次给药后2周内不要母乳喂养。

8.3生殖潜力的男性和女性

验孕

建议在开始Rubraca之前对具有生殖能力的女性进行妊娠试验。

避孕

女性

当给予孕妇卢贝拉卡（Rubraca）可能会造成胎儿伤害[见在特定人群中使用（8.1）]。劝告有生殖潜能的女性在治疗期间和最后一次服用Rubraca后6个月内使用有效的避孕方法。

8.4小儿使用

尚未确定Rubraca在儿科患者中的安全性和有效性。

8.5老年人使用

在临床研究中，使用Rubraca治疗的卵巢癌患者中40％（297/749）为65岁或65岁以上，9％（65/749）为75岁或75岁以上。65岁或以上的患者中65％的患者和75岁或以上的患者中63％的患者发生3-4级不良反应。对于65岁或65岁以上的患者，最常见的3-4级不良反应为贫血，疲劳/乏力和ALT / AST升高。在这些患者和较年轻的患者之间，在两次或更多次化学疗法后，维持卵巢癌复发或BRCA突变型卵巢癌的安全性未见主要差异。

8.6肝功能不全

对于轻度肝功能不全（总胆红素小于或等于正常[ULN]上限且AST大于ULN，或总胆红素在ULN和任何AST之间的1.0至1.5倍之间）的患者，不建议调整起始剂量。由于缺乏数据，对于中度至重度肝功能不全（总胆红素大于ULN的1.5倍）的患者，尚无开始剂量调整的建议[请参见临床药理学（12.3）]。

8.7肾功能不全

对于轻度至中度肾功能不全（根据Cockcroft-Gault方法估算，基线肌酐清除率[CLcr]在30至89 mL / min之间）的患者，不建议调整起始剂量。对于CLcr低于30 mL / min的患者或因缺乏数据而接受透析的患者，没有建议的起始剂量[参见临床药理学（12.3）]。

10过量

Rubraca过量时没有特殊的治疗方法，也没有症状。如果怀疑过量，医生应采取一般的支持措施并应对症治疗。

11说明

Rucaparib是哺乳动物多腺苷5'-二磷酸核糖聚合酶（PARP）酶的抑制剂。化学名称是8-氟-2- {4-[（（甲基氨基）甲基]苯基] -1,3,4,5-四氢-6H-叠氮庚[5,4,3-cd]吲哚-6-（ （1S，4R）-7，7-二甲基-2-氧代双环[2.2.1]庚-1-基）甲磺酸盐。枸 cap 酸卡巴拉普的化学式为C 19 H 18 FN 3 O•C 10 H 16 O 4 S，相对分子质量为555.67道尔顿。

枸 cap 酸卡培拉特的化学结构如下所示：

甘草酸鲁卡帕里布为白色至浅黄色粉末。制成用于口服的片剂。Rucaparib在整个生理pH范围内均显示出与pH无关的低溶解度，约为1 mg / mL。

Rubraca（rucaparib）片剂含有甘草酸鲁卡帕里布作为有效成分。每片200毫克的片剂含有344毫克的rucaparib camsylate，相当于200 mg的rucaparib游离碱。每片250毫克的片剂含有430毫克的樟脑茶碱rucaparib等效于250毫克的rucaparib游离碱。每片300毫克的片剂含有516毫克的樟脑茶碱rucaparib等效于300毫克的rucaparib游离碱。

Rubraca片剂中的非活性成分包括：微晶纤维素，羟乙酸淀粉钠，胶体二氧化硅和硬脂酸镁。用于200毫克片剂的化妆品蓝色薄膜包衣，用于250毫克片剂的化妆品白色薄膜包衣和用于300毫克片剂的化妆品黄色薄膜包衣是包含聚乙烯醇，二氧化钛，聚乙二醇/宏醇和滑石粉的欧巴代II。使用亮蓝色铝色淀和靛红色胭脂红铝色淀将涂层着色为蓝色，或者使用黄色氧化铁将涂层着色为黄色。

12临床药理学

12.1行动机制

Rucaparib是聚（ADP-核糖）聚合酶（PARP）酶的抑制剂，包括在DNA修复中起作用的PARP-1，PARP-2和PARP-3。体外研究表明，rucaparib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，凋亡和癌细胞死亡。在具有BRCA1 / 2和其他DNA修复基因缺陷的肿瘤细胞系中观察到了rucaparib诱导的细胞毒性和抗肿瘤活性的增加。Rucaparib已被证明在患有或缺乏BRCA的人类癌症小鼠异种移植模型中可以减少肿瘤的生长。

12.2药效学

rucaparib的药效学反应尚未确定。

心脏电生理学

在一项开放性单臂研究中，对56例实体瘤患者进行了多次标签的Rubraca多次给药对QTc间隔的影响，这些患者接受了连续的Rubraca剂量，每日一次40 mg（批准的推荐剂量的0.03倍）至840每日两次（1.4倍于批准的推荐剂量）。在每天两次稳定的600 mg rucaparib的稳态下，人群药代动力学估计的平均QTcF从基线（90％置信区间[CI]）增加到第 95 个百分位数C max（3019 ng / mL），为14.9毫秒（11.1-18.7毫秒）。

12.3药代动力学

rucaparib在癌症患者中的药代动力学特征已得到表征。鲁卡帕利（Rucaparib）每天两次在240至840 mg的剂量范围内显示线性药代动力学，具有时间独立性和剂量比例性。在批准的推荐剂量下，稳态rucaparib C max的平均值为1940 ng / mL（54％变异系数[CV]），AUC 0-12h为16900 h·ng / mL（54％CV）。积累是3.5至6.2倍。

吸收性

在批准的推荐剂量下，中值T max为1.9小时。rucaparib速释片的平均绝对生物利用度为36％，范围为30％至45％。

与在禁食条件下给药相比，高脂餐后C max增加20％，AUC 0-24h增加38％，T max延迟2.5小时[参见剂量和给药方法（2.2） ]。

分配

在单次静脉注射12 mg至40 mg rucaparib后，rucaparib的稳态分布容积为113 L至262L。

在体外，在治疗浓度下，rucaparib在人血浆中的蛋白质结合率为70％。Rucaparib优先分配给血红细胞，血浆与血浆的浓度比为1.83。

消除

单次口服600 mg rucaparib后，rucaparib的平均末端T 1/2为17至19小时。每天两次两次卡百卡单抗 600 mg后，表观清除率范围为15.3至79.2 L /小时。单次静脉注射剂量的rucaparib 12 mg至40 mg后，清除率范围为13.9至18.4 L /小时。

代谢

在体外，rucaparib的代谢转换率低，主要通过CYP2D6代谢，而通过CYP1A2和CYP3A4代谢的程度较小。

特定人群

年龄，种族和体重

根据人群的药代动力学分析，年龄，种族和体重对rucaparib的暴露没有临床意义的影响。

肾功能不全

在每天两次接受Rubraca 600 mg的患者中，轻度肾功能不全的患者（N = 148；基线Ccrr在60至89 mL / min之间，根据Cockcroft-Gault方法估计）和中度肾功能不全的患者（N = 72；与正常肾功能的患者（N = 143； CLcr大于或等于90 mL / min）相比，介于30和59 mL / min之间的CLcr分别显示稳态AUC分别高出约15％和32％。氯吡格雷在CLcr小于30 mL / min的患者或接受透析的患者中的药代动力学特征尚不清楚。

肝功能不全

根据人群药代动力学分析，在接受Rubraca的34例轻度肝功能不全（总胆红素小于或等于ULN且AST大于ULN或总胆红素为ULN的1.0到1.5倍，且为任何AST）的患者中，未观察到明显的药代动力学差异。与具有正常肝功能的患者相比，每天两次600 mg（N = 337）。未知中重度肝功能不全（总胆红素大于ULN的1.5倍）的患者中，rucaparib的药代动力学特征。

CYP酶多态性

根据人群药代动力学分析，rucaparib 600 mg每日两次后的稳态浓度在CYP2D6或CYP1A2基因型亚组中无显着差异。

药物相互作用研究

的影响Rucaparib对其他药物

临床研究

rucaparib 600 mg rucaparib之前和之后每天两次单次给药，共7天。的C 最大值每个共同施用药物的是≤1.13倍，而AUC改变如下：

• 咖啡因（CYP1A2）：咖啡因AUC增加2.55倍
• 咪达唑仑（CYP3A4）：咪达唑仑AUC增加1.38倍
• 华法林（CYP2C9）：华法林AUC增加1.49倍
• 奥美拉唑（CYP2C19）：奥美拉唑AUC增加1.55倍
• 地高辛（P-糖蛋白）：地高辛AUC增加1.20倍

体外研究

Rucaparib抑制CYP2C8，CYP2D6和尿苷二磷酸葡萄糖醛酸转移酶1A1（UGT1A1）。Rucaparib诱导CYP1A2，并下调CYP3A4和CYP2B6。

Rucaparib抑制P-糖蛋白（P-gp）外排转运蛋白，乳腺癌抗性蛋白（BCRP），有机阴离子转运蛋白1B1和1B3（OATP1B1和OATP1B3），有机阴离子转运蛋白1和3（OAT1和OAT3），多种药物和毒素挤出1和2-k（MATE1和MATE2-K），有机阳离子转运蛋白1和2（OCT1和OCT2）以及与多药耐药相关的蛋白质4（MRP4）。对于MRP2，MRP3或BSEP，没有观察到明显的抑制作用。

其他药物对雷卡帕利的影响

临床研究

在人群药代动力学（PPK）分析中，与质子泵抑制剂共同给药对rucaparib的稳态浓度无临床显着影响。

体外研究

Rucaparib是P-gp和BCRP的底物；但是，rucaparib不是OATP1B1，OATP1B3，OAT1，OAT3和OCT2的底物。

13毒理学

13.1致癌，诱变，生育力受损

rucaparib尚未进行致癌性研究。

Rucaparib是在诱裂体外染色体畸变试验在培养的人淋巴细胞。根据rucaparib的作用机理，预期在有丝分裂刺激的细胞中发生了克拉斯汀反应，  并表明了对人类的潜在遗传毒性。在细菌逆向突变（Ames）测试中，rucaparib没有致突变性。

尚未进行rucaparib的生育力研究。在3个月的重复剂量一般毒理学研究中，在大鼠和狗中，rucaparib分别对高达100 mg / kg / day和20 mg / kg / day的剂量对雄性和雌性生殖器官没有影响。在推荐剂量下，这些剂量水平导致的全身暴露分别约为人暴露（AUC 0-24h）的0.3和0.09倍。

14临床研究

14.1复发性卵巢癌的维持治疗

在一项双盲，多中心临床试验ARIEL3（NCT01968213）中研究了Rubraca的疗效，该研究对564例因铂类化学疗法应答的复发性上皮性卵巢癌，输卵管癌或原发性腹膜癌患者进行了随机分组（2： 1）每天两次口服（600毫克）Rubraca片剂（n = 375）或安慰剂（n = 189）。继续治疗直至疾病进展或不可接受的毒性。所有患者都对他们最近的铂类化学疗法有反应（完全或部分）。根据对最后一种铂（完全或部分）的最佳反应，倒数第二次铂治疗（6至≤12个月和> 12个月）的进展时间以及肿瘤生物标志物状态，对随机分组。

接受Rubraca的患者的中位年龄为61岁（范围：39至84），而接受安慰剂的患者的中位年龄为62岁（范围：36至85）。多数是白人（80％）；100％的ECOG表现状态为0或1。所有患者先前至少接受过两次铂类化学疗法（范围：2至7）。共有34％的患者对其最新疗法具有完全反应（CR）。在40％的患者中，倒数第二次铂的无进展间隔为6-12个月，在60％的患者中为12个月以上。据报道，先前接受贝伐单抗治疗的患者中有22％接受Rubraca的患者和23％的接受安慰剂的患者。37％的患者基线存在可测量的疾病。

使用临床试验分析（CTA）（N = 564）和FoundationFocus™CDx BRCA LOH测试（n = 518）测试肿瘤组织样品  。在两项测试中评估的样品中，FoundationFocus™CDx BRCA LOH测试证实了94％的同源重组缺陷（HRD）阳性状态（定义为存在有害的BRCA突变或高基因组杂合性缺失）  （313 / 332）由CTA确定的HRD阳性患者；其中，FoundationFocus™CDx BRCA LOH证实了肿瘤BRCA（tBRCA）突变体的状态 CTA确定99％（177/178）的tBRCA阳性患者接受了检测。使用中央血液种系BRCA测试评估了94％（186/196）的tBRCA患者的血样。根据这些结果，tBRCA患者中有70％（130/186）有种系BRCA突变，而30％（56/186）有体细胞BRCA突变。

ARIEL3在所有患者以及HRD和tBRCA亚组中，与安慰剂相比，随机分配至Rubraca的患者的PFS有统计学意义的改善。盲法独​​立放射学检查的结果是一致的。在分析PFS时，总体生存（OS）数据还不成熟（有22％的事件发生）。

功效结果总结在表6和图1，2，和3。

表6.疗效结果-ARIEL3（研究者评估）

图1.研究者评估的ARIEL3中无进展生存期的Kaplan-Meier曲线 ：所有患者

图2.研究者评估的ARIEL3中无进展生存的Kaplan-Meier曲线：HRD组

图3.研究者评估的ARIEL3中无进展生存的Kaplan-Meier曲线：tBRCA组

14.2进行2次或更多次化学疗法后BRCA突变的卵巢癌的治疗

在两项多中心，单臂，开放标签的临床试验（研究10（NCT01482715）和ARIEL2（NCT01891344））中，对106例患者进行了Rubraca的疗效研究，以研究其BRCA突变的晚期卵巢癌患者在2次或更多次后进展先前的化学疗法。所有106例患者均接受每天两次口服Rubraca 600 mg的单药治疗，直至疾病进展或出现不可接受的毒性。研究者和IRR根据RECIST v1.1评估了客观缓解率（ORR）和缓解持续时间（DOR）。

患者的中位年龄为59岁（范围：33至84岁），大多数为白人（78％），并且100％的ECOG表现状态为0或1。所有患者均已接受过至少两次先前的铂类药物治疗化疗和43％的患者先前接受过3种或更多铂类化学疗法治疗。在肿瘤组织而非全血标本中检出有害BRCA突变的患者为18/106名（占17％）。伴有诊断性FoundationFocus™CDx BRCA检验的患者中，有96％（64/67）可获得肿瘤组织样品的患者回顾性地证实了肿瘤BRCA突变状态，该试验已被FDA批准用于选择Rubraca治疗的患者。

功效结果总结在表7中。

表7.在研究10和ARIEL2中接受2种或更多种化学疗法的BRCA突变卵巢癌患者的总体缓解和缓解持续时间

独立放射学检查的反应评估为4​​2％（95％CI [32，52]），中位DOR为6.7个月（95％CI [5.5，11.1]）。在铂敏感的患者中，研究者评估的ORR为66％（52/79; 95％CI [54，76]），在铂耐药的患者中为25％（5/20; 95％CI [9，49]），以及在铂难治性患者中，0％（0/7; 95％CI [0，41]）。对于具有BRCA1基因突变或BRCA2基因突变的患者，ORR相似。

16供应/存储和处理方式

16.1供应方式

Rubraca有200 mg，250 mg和300 mg片剂。

200毫克片剂：

• 蓝色，圆形，凹陷，一侧带有“ C2”
• 每瓶60片（NDC：69660-201-91）

250毫克片剂：

• 白色，钻石，并在一侧凹陷有“ C25”
• 每瓶60片（NDC：69660-202-91）

300毫克片剂：

• 黄色，椭圆形，凹陷，一侧带有“ C3”
• 每瓶60片（NDC：69660-203-91）

16.2储存

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）之间的偏移[ 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 / AML：如果患者出现虚弱，感到疲倦，发烧，体重减轻，频繁感染，青肿，容易出血，呼吸困难，尿液或粪便中的血液和/或实验室检查到的低血细胞计数，建议患者与医疗保健提供者联系，或者需要输血。这些可能是血液毒性的征兆或更严重的罕见骨髓问题，称为“骨髓增生异常综合症”（MDS）或“急性骨髓性白血病”（AML），已在Rubraca治疗的患者中报告[见警告和注意事项（5.1）]。。

胚胎胎儿毒性：建议女性如果怀孕或怀孕，应告知其医疗保健提供者。告知女性患者胎儿的风险和可能的怀孕损失[请参见“在特定人群中使用（8.1）”。繁殖潜力的指教雌性于接收Rubraca的最后一次给药后治疗期间和6个月使用有效的避孕方法[见警告和注意事项（5.2），并使用在特殊人群中（8.1，8.3）]。

光敏性：建议患者在服用Rubraca时因晒伤的敏感性增加而建议使用适当的防晒剂[见不良药物反应（6.1）]。

哺乳期：建议女性在治疗期间以及最后一剂卢巴拉卡（Rubraca）服用后两周内不要母乳喂养[见在特定人群中使用（8.2）]。

剂量说明：指导患者每天两次口服或不服用任何食物。剂量应间隔大约12小时服用。告诫患者，如果错过了一定剂量的Rubraca或患者在服用一定剂量的Rubraca后呕吐，则患者不应再服用额外的剂量，而应在常规时间服用下一剂[见剂量和用法（2.1）]。

分发者：
Clovis Oncology，Inc.
Boulder，CO 80301
1-844-258-7662

Rubraca是Clovis Oncology，Inc.的注册商标。

主要显示面板-Rubraca片剂200 mg瓶标签

NDC 69660- 201 -91

卢布拉卡®

（rucaparib）片

200毫克*

60片

每片含344毫克rucaparib camsylate相当于200毫克rucaparib

仅Rx

请将本品放在儿童不能接触的地方

主要显示面板-Rubraca片剂250 mg瓶标签

NDC 69660- 202 -91

卢布拉卡®

（rucaparib）片

250毫克*

60片

每片含430毫克rucaparib camsylate相当于250毫克rucaparib

仅Rx

请将本品放在儿童不能接触的地方

主要显示面板-Rubraca片剂300 mg瓶标签

NDC 69660- 203 -91

卢布拉卡®

（rucaparib）片

300毫克*

60片

每片含有516毫克rucaparib camsylate，相当于300毫克rucaparib

仅Rx

请将本品放在儿童不能接触的地方

【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。

本说明书来源于：美国FDA

https://nctr-crs.fda.gov/fdalabel/services/spl/set-ids/a6d46c03-bb1d-417b-b8e5-3bffe352fe29/spl-doc?hl=Rucaparib

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。

1 INDICATIONS AND USAGE

1.1 Maintenance Treatment of Recurrent Ovarian Cancer

Rubraca 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 [see Dosage and Administration (2.1)].

1.2 Treatment of BRCA-mutated Ovarian Cancer After 2 or More Chemotherapies

Rubraca is indicated for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for Rubraca [see Dosage and Administration (2.1)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

The recommended dose of Rubraca is 600 mg (two 300 mg tablets) taken orally twice daily with or without food.

Continue treatment until disease progression or unacceptable toxicity.

If a patient misses a dose of Rubraca, instruct the patient to take the next dose at its scheduled time. Vomited doses should not be replaced.

2.2 Dose Modifications for Adverse Reactions

To manage adverse reactions, consider interruption of treatment or dose reduction. Recommended dose reductions are indicated in Table 1.

Table 1. Recommended Dose Adjustments

2.3 Patient Selection for Treatment of BRCA-mutated Ovarian Cancer

Select patients for the treatment of epithelial ovarian, fallopian tube, or primary peritoneal cancer with Rubraca based on the presence of a deleterious BRCA mutation (germline and/or somatic) [see Indications and Usage (1.2) and Clinical Studies (14.2)]. Information on the FDA-approved test for the detection of a tumor BRCA mutation in patients with ovarian cancer is available at: http://www.fda.gov/CompanionDiagnostics.

3 DOSAGE FORMS AND STRENGTHS

• Tablets (200 mg): blue, round, immediate-release, film-coated, debossed with “C2”.
• Tablets (250 mg): white, diamond, immediate-release, film-coated, debossed with “C25”.
• Tablets (300 mg): yellow, oval, immediate-release, film-coated, debossed with “C3”.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur uncommonly in patients treated with Rubraca, and are potentially fatal adverse reactions. In approximately 1100 treated patients, MDS/AML occurred in 12 patients (1.1%), including those in long term follow-up. Of these, 5 occurred during treatment or during the 28 day safety follow-up (0.5%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 28 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing chemotherapy regimens and/or other DNA damaging agents.

Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose according to Table 1 [see Dosage and Administration (2.2)] and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks or if MDS/AML is suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Rubraca.

5.2 Embryo-Fetal Toxicity

Rubraca can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings from animal studies. In an animal reproduction study, administration of rucaparib to pregnant rats during the period of organogenesis resulted in embryo-fetal death at exposures that were 0.04 times the AUC0-24h in patients receiving the recommended human dose of 600 mg twice daily. 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 following the last dose of Rubraca [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the labeling:

• Myelodysplastic Syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1)].

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.

Maintenance Treatment of Recurrent Ovarian Cancer

The safety of Rubraca for the maintenance treatment of patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer was investigated in ARIEL3, a randomized (2:1), double-blind, placebo-controlled study in which 561 patients received either Rubraca 600 mg BID (n=372) or placebo (n=189) until disease progression or unacceptable toxicity. The median duration of study treatment was 8.3 months (range: < 1 month to 35 months) for patients who received Rubraca and 5.5 months for patients who received placebo.

Dose interruptions due to an adverse reaction of any grade occurred in 65% of patients receiving Rubraca and 10% of those receiving placebo; dose reductions due to an adverse reaction occurred in 55% of Rubraca patients and 4% of placebo patients. The most frequent adverse reactions leading to dose interruption or dose reduction of Rubraca were thrombocytopenia (18%), anemia (17%), nausea (15%), and fatigue/asthenia (13%). Discontinuation due to adverse reactions occurred in 15% of Rubraca patients and 2% of placebo patients. Specific adverse reactions that most frequently led to discontinuation in patients treated with Rubraca were anemia (3%), thrombocytopenia (3%) and nausea (3%).

Table 2. Adverse Reactions in ARIEL3 Occurring in ≥ 20% of Patients

Adverse reactions occurring < 20% of patients treated with Rubraca include headache (18%), dizziness (19%), dyspepsia (19%), insomnia (15%), dyspnea (17%), pyrexia (13%), peripheral edema (11%), and depression (11%).

Table 3. Laboratory Abnormalities in ARIEL3 Occurring in ≥ 25% of Patients

Treatment of BRCA-mutated Recurrent Ovarian Cancer After 2 or More Chemotherapies

Rubraca 600 mg twice daily as monotherapy has also been studied in 377 patients with epithelial ovarian, fallopian tube or primary peritoneal cancer who have progressed after 2 or more prior chemotherapies in two open-label, single arm trials. In these patients, the median age was 62 years (range: 31 to 86), 100% had an ECOG performance status of 0 or 1, 38% had BRCA-mutated ovarian cancer, 45% had received 3 or more prior lines of chemotherapy, and the median time since ovarian cancer diagnosis was 43 months (range: 6 to 197).

Table 4. Adverse Reactions Reported in ≥ 20% of Patients with Ovarian Cancer After ≥ 2 Chemotherapies Treated with Rubraca in Study 10 and ARIEL2

The following adverse reactions have been identified in < 20% of the 377 patients treated with Rubraca 600 mg twice daily: dizziness (17%), neutropenia (15%), rash (includes rash, rash erythematous, rash maculopapular and dermatitis) (13%), pyrexia (11%), photosensitivity reaction (10%), pruritus (includes pruritus and pruritus generalized) (9%), Palmar-plantar erythrodysaesthesia syndrome (2%), and febrile neutropenia (1%).

Table 5. Laboratory Abnormalities Reported in ≥ 35% of Patients with Ovarian Cancer After ≥ 2 Chemotherapies Treated with Rubraca in Study 10 and ARIEL2

7 DRUG INTERACTIONS

7.1 Effect of Rucaparib on Cytochrome p450 (CYP) Substrates

Co-administration of rucaparib can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates [see Clinical Pharmacology (12.3)], which may increase the risk of toxicities of these drugs.

Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing the frequency of international normalized ratio (INR) monitoring.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings from animal studies and its mechanism of action, Rubraca can cause fetal harm when administered to pregnant women. There are no available data in pregnant women to inform the drug-associated risk. In an animal reproduction study, administration of rucaparib to pregnant rats during organogenesis resulted in embryo-fetal death at maternal exposures that were 0.04 times the AUC0-24h in patients receiving the recommended dose of 600 mg twice daily [see Data]. 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.

Data

Animal Data

In a dose range-finding embryo-fetal development study, pregnant rats received oral doses of 50, 150, 500, or 1000 mg/kg/day of rucaparib during the period of organogenesis. Post-implantation loss (100% early resorptions) was observed in all animals at doses greater than or equal to 50 mg/kg/day (with maternal systemic exposures approximately 0.04 times the human exposure at the recommended dose based on AUC0-24h).

8.2 Lactation

Risk Summary

There is no information regarding the presence of rucaparib in human milk, or on its effects on milk production or the breast-fed child. Because of the potential for serious adverse reactions in breast-fed children from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks following the last dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to initiating Rubraca.

Contraception

Females

Rubraca 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 during treatment and for 6 months following the last dose of Rubraca.

8.4 Pediatric Use

The safety and effectiveness of Rubraca in pediatric patients have not been established.

8.5 Geriatric Use

In clinical studies 40% (297/749) of patients with ovarian cancer treated with Rubraca were 65 years of age or older and 9% (65/749) were 75 years or older. Grade 3-4 adverse reactions occurred in 65% of patients 65 years or older and in 63% of patients 75 years or older. For patients 65 years or older, the most common Grade 3-4 adverse reactions were anemia, fatigue/asthenia, and ALT/AST increase. No major differences in safety were observed between these patients and younger patients for the maintenance treatment of recurrent ovarian cancer or for the treatment of BRCA-mutated ovarian cancer after two or more chemotherapies.

8.6 Hepatic Impairment

No starting dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin less than or equal to upper limit of normal [ULN] and AST greater than ULN, or total bilirubin between 1.0 to 1.5 times ULN and any AST). No recommendation for starting dose adjustment is available for patients with moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN) due to a lack of data [See Clinical Pharmacology (12.3)].

8.7 Renal Impairment

No starting dose adjustment is recommended for patients with mild to moderate renal impairment (baseline creatinine clearance [CLcr] between 30 and 89 mL/min, as estimated by the Cockcroft-Gault method). There is no recommended starting dose for patients with CLcr less than 30 mL/min or patients on dialysis due to a lack of data [See Clinical Pharmacology (12.3)].

10 OVERDOSAGE

There is no specific treatment in the event of Rubraca overdose, and symptoms of overdose are not established. In the event of suspected overdose, physicians should follow general supportive measures and should treat symptomatically.

11 DESCRIPTION

Rucaparib is an inhibitor of the mammalian polyadenosine 5'-diphosphoribose polymerase (PARP) enzyme. The chemical name is 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt. The chemical formula of rucaparib camsylate is C19H18FN3O•C10H16O4S and the relative molecular mass is 555.67 Daltons.

The chemical structure of rucaparib camsylate is shown below:

Rucaparib camsylate is a white to pale yellow powder; formulated into a tablet for oral use. Rucaparib shows pH-independent low solubility of approximately 1 mg/mL across the physiological pH range.

Rubraca (rucaparib) tablets contain rucaparib camsylate as the active ingredient. Each 200 mg tablet contains 344 mg rucaparib camsylate equivalent to 200 mg rucaparib free base. Each 250 mg tablet contains 430 mg rucaparib camsylate equivalent to 250 mg rucaparib free base. Each 300 mg tablet contains 516 mg rucaparib camsylate equivalent to 300 mg rucaparib free base.

The inactive ingredients in Rubraca tablets include: microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate. The cosmetic blue film coating for 200 mg tablets, cosmetic white film coating for 250 mg tablets, and cosmetic yellow film coating for 300 mg tablets is Opadry II containing polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol, and talc. The coating is colorized as blue using brilliant blue aluminum lake and indigo carmine aluminum lake, or yellow using yellow iron oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Rucaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP-1, PARP-2, and PARP-3, which play a role in DNA repair. In vitro studies have shown that rucaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cancer cell death. Increased rucaparib-induced cytotoxicity and anti-tumor activity was observed in tumor cell lines with deficiencies in BRCA1/2 and other DNA repair genes. Rucaparib has been shown to decrease tumor growth in mouse xenograft models of human cancer with or without deficiencies in BRCA.

12.2 Pharmacodynamics

The pharmacodynamic response of rucaparib has not been characterized.

Cardiac Electrophysiology

The effect of multiple doses of Rubraca on QTc interval was evaluated in an open-label single-arm study in 56 patients with solid tumors who were administered continuous doses of Rubraca ranging from 40 mg once daily (0.03 times the approved recommended dose) to 840 mg twice daily (1.4 times the approved recommended dose). The mean QTcF increase from baseline (90% confidence interval [CI]) in population pharmacokinetics estimated 95th percentile Cmax (3019 ng/mL) at steady state of 600 mg rucaparib twice daily was 14.9 msec (11.1-18.7 msec).

12.3 Pharmacokinetics

The pharmacokinetic profile of rucaparib was characterized in patients with cancer. Rucaparib demonstrated linear pharmacokinetics over a dose range from 240 to 840 mg twice daily with time-independence and dose-proportionality. The mean steady-state rucaparib Cmax was 1940 ng/mL (54% coefficient of variation [CV]) and AUC0-12h was 16900 h·ng/mL (54% CV) at the approved recommended dose. Accumulation was 3.5 to 6.2 fold.

Absorption

The median Tmax was 1.9 hours at the approved recommended dose. The mean absolute bioavailability of rucaparib immediate-release tablet was 36% with a range from 30% to 45%.

Following a high-fat meal, the Cmax was increased by 20% and AUC0-24h was increased by 38%, and Tmax was delayed by 2.5 hours, as compared to dosing under fasted conditions [see Dosage and Administration (2.2)].

Distribution

Rucaparib had a steady-state volume of distribution of 113 L to 262 L following a single intravenous dose of 12 mg to 40 mg rucaparib.

In vitro, the protein binding of rucaparib was 70% in human plasma at therapeutic concentrations. Rucaparib preferentially distributed to red blood cells with a blood-to-plasma concentration ratio of 1.83.

Elimination

The mean terminal T1/2 of rucaparib was 17 to 19 hours, following a single oral dose of 600 mg rucaparib. The apparent clearance ranged from 15.3 to 79.2 L/hour, following rucaparib 600 mg twice daily. The clearance ranged from 13.9 to 18.4 L/hour, following a single intravenous dose of rucaparib 12 mg to 40 mg.

Metabolism

In vitro, rucaparib had a low metabolic turnover rate and was metabolized primarily by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4.

Specific Populations

Age, Race, and Body Weight

Based on population pharmacokinetic analyses, age, race, and body weight did not have a clinically meaningful effect on rucaparib exposure.

Renal Impairment

In patients who received Rubraca 600 mg twice daily, those with mild renal impairment (N=148; baseline CLcr between 60 and 89 mL/min, as estimated by the Cockcroft-Gault method) and those with moderate renal impairment (N=72; CLcr between 30 and 59 mL/min) showed approximately 15% and 32% higher steady-state AUC, respectively, compared to patients with normal renal function (N=143; CLcr greater than or equal to 90 mL/min). The pharmacokinetic characteristics of rucaparib in patients with CLcr less than 30 mL/min or patients on dialysis are unknown.

Hepatic Impairment

Based on population pharmacokinetic analyses, no apparent pharmacokinetic difference was observed in 34 patients with mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN, or total bilirubin between 1.0 to 1.5 times ULN and any AST) who received Rubraca 600 mg twice daily as compared to patients with normal hepatic function (N=337). The pharmacokinetic characteristics of rucaparib in patients with moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN) are unknown.

CYP Enzyme Polymorphism

Based on population pharmacokinetic analyses, steady-state concentrations following rucaparib 600 mg twice daily did not differ significantly across CYP2D6 or CYP1A2 genotype subgroups.

Drug Interaction Studies

Effect of Rucaparib on Other Drugs

Clinical Studies

A single dose of the following drugs was administered before and following rucaparib 600 mg twice daily for 7 days. The Cmax of each co-administered drug was ≤ 1.13-fold, and the AUC changed as follows:

• Caffeine (CYP1A2): caffeine AUC increased by 2.55-fold
• Midazolam (CYP3A4): midazolam AUC increased by 1.38-fold
• Warfarin (CYP2C9): warfarin AUC increased by 1.49-fold
• Omeprazole (CYP2C19): omeprazole AUC increased by 1.55-fold
• Digoxin (P-glycoprotein): digoxin AUC increased by 1.20-fold

In Vitro Studies

Rucaparib inhibited CYP2C8, CYP2D6, and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). Rucaparib induced CYP1A2, and down regulated CYP3A4 and CYP2B6.

Rucaparib inhibited the P-glycoprotein (P-gp) efflux transporter, breast cancer resistance protein (BCRP), organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3), organic anion transporters 1 and 3 (OAT1 and OAT3), multidrug and toxin extrusion 1 and 2-k (MATE1 and MATE2-K), organic cation transporters 1 and 2 (OCT1 and OCT2), and multidrug resistance-associated protein 4 (MRP4). No apparent inhibition was observed for MRP2, MRP3, or BSEP.

Effects of Other Drugs on Rucaparib

Clinical Studies

In a population pharmacokinetic (PPK) analysis, co-administration with proton pump inhibitors had no clinically significant effect on steady-state concentrations of rucaparib.

In Vitro Studies

Rucaparib was a substrate of P-gp and BCRP; however, rucaparib was not a substrate of OATP1B1, OATP1B3, OAT1, OAT3, and OCT2.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with rucaparib.

Rucaparib was clastogenic in an in vitro chromosomal aberration assay in cultured human lymphocytes. The clastogenic response in mitotically-stimulated cells was anticipated based on the mechanism of action of rucaparib and indicates potential genotoxicity in humans. Rucaparib was not mutagenic in a bacterial reverse mutation (Ames) test.

Fertility studies with rucaparib have not been conducted. In 3-month repeat-dose general toxicology studies, rucaparib had no effects on male and female reproductive organs at doses up to 100 mg/kg/day and 20 mg/kg/day in rats and dogs, respectively. These dose levels resulted in systemic exposures of approximately 0.3 and 0.09 times the human exposure (AUC0-24h), respectively, at the recommended dose.

14 CLINICAL STUDIES

14.1 Maintenance Treatment of Recurrent Ovarian Cancer

The efficacy of Rubraca was investigated in ARIEL3 (NCT01968213), a double-blind, multicenter clinical trial in which 564 patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who were in response to platinum-based chemotherapy were randomized (2:1) to receive Rubraca tablets 600 mg orally twice daily (n=375) or placebo (n=189). Treatment was continued until disease progression or unacceptable toxicity. All patients had achieved a response (complete or partial) to their most recent platinum-based chemotherapy. Randomization was stratified by best response to last platinum (complete or partial), time to progression following the penultimate platinum therapy (6 to ≤ 12 months and > 12 months), and tumor biomarker status. The major efficacy outcome was investigator-assessed progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (v1.1).

The median age was 61 years (range: 39 to 84) for patients receiving Rubraca and 62 years (range: 36 to 85) for those on placebo; the majority were White (80%); and 100% had an ECOG performance status of 0 or 1. All patients had received at least two prior platinum-based chemotherapies (range: 2 to 7). A total of 34% of patients were in complete response (CR) to their most recent therapy. The progression-free interval to penultimate platinum was 6-12 months in 40% of patients and > 12 months in 60%. Prior bevacizumab therapy was reported for 22% of patients who received Rubraca and 23% of patients who received placebo. Measurable disease was present at baseline in 37% of patients.

Tumor tissue samples were tested using a clinical trial assay (CTA) (N=564), and the FoundationFocus™ CDx BRCA LOH test (n=518). Of the samples evaluated with both tests, homologous recombination deficiency (HRD) positive status (as defined by the presence of a deleterious BRCA mutation or high genomic loss of heterozygosity) was confirmed by the FoundationFocus™ CDx BRCA LOH test for 94% (313/332) of HRD-positive patients determined by the CTA; and of these, tumor BRCA (tBRCA) mutant status was confirmed by the FoundationFocus™ CDx BRCA LOH test for 99% (177/178) of tBRCA-positive patients determined by the CTA. Blood samples for 94% (186/196) of the tBRCA patients were evaluated using a central blood germline BRCA test. Based on these results, 70% (130/186) of the tBRCA patients had a germline BRCA mutation and 30% (56/186) had a somatic BRCA mutation.

ARIEL3 demonstrated a statistically significant improvement in PFS for patients randomized to Rubraca as compared with placebo in all patients, and in the HRD and tBRCA subgroups. Results from a blinded independent radiology review were consistent. At the time of the analysis of PFS, overall survival (OS) data were not mature (with 22% of events).

Efficacy results are summarized in Table 6 and Figures 1, 2, and 3.

Table 6. Efficacy Results - ARIEL3 (Investigator Assessment)

Figure 1. Kaplan-Meier Curves of Progression-Free Survival in ARIEL3 as Assessed by Investigator: All Patients

Figure 2. Kaplan-Meier Curves of Pro

gression-Free Survival in ARIEL3 as Assessed by Investigator: HRD Group

Figure 3. Kaplan-Meier Curves of Progression-Free Survival in ARIEL3 as Assessed by Investigator: tBRCA Group

14.2 Treatment of BRCA-mutated Ovarian Cancer After 2 or More Chemotherapies

The efficacy of Rubraca was investigated in 106 patients in two multicenter, single-arm, open-label clinical trials, Study 10 (NCT01482715) and ARIEL2 (NCT01891344), in patients with advanced BRCA-mutant ovarian cancer who had progressed after 2 or more prior chemotherapies. All 106 patients received Rubraca 600 mg orally twice daily as monotherapy until disease progression or unacceptable toxicity. Objective response rate (ORR) and duration of response (DOR) were assessed by the investigator and IRR according to RECIST v1.1.

The median age of the patients was 59 years (range: 33 to 84), the majority were White (78%), and 100% had an ECOG performance status of 0 or 1. All patients had received at least two prior platinum-based chemotherapies and 43% had received 3 or more prior lines of platinum-based chemotherapy. There were 18/106 patients (17%) who had deleterious BRCA mutations detected in tumor tissue and not in whole blood specimens. Tumor BRCA mutation status was verified retrospectively in 96% (64/67) of the patients for whom a tumor tissue sample was available by the companion diagnostic FoundationFocus™ CDxBRCA test, which is FDA approved for selection of patients for Rubraca treatment.

Efficacy results are summarized in Table 7.

Table 7. Overall Response and Duration of Response in Patients with BRCA-mutant Ovarian Cancer Who Received 2 or More Chemotherapies in Study 10 and ARIEL2

Response assessment by independent radiology review was 42% (95% CI [32, 52]), with a median DOR of 6.7 months (95% CI [5.5, 11.1]). Investigator-assessed ORR was 66% (52/79; 95% CI [54, 76]) in platinum-sensitive patients, 25% (5/20; 95% CI [9, 49]) in platinum-resistant patients, and 0% (0/7; 95% CI [0, 41]) in platinum-refractory patients. ORR was similar for patients with a BRCA1 gene mutation or BRCA2 gene mutation.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Rubraca is available as 200 mg, 250 mg, and 300 mg tablets.

200 mg Tablets:

• Blue, round, and debossed with “C2” on one side
• Supplied in bottles of 60 tablets (NDC: 69660-201-91)

250 mg Tablets:

• White, diamond, and debossed with “C25” on one side
• Supplied in bottles of 60 tablets (NDC: 69660-202-91)

300 mg Tablets:

• Yellow, oval, and debossed with “C3” on one side
• Supplied in bottles of 60 tablets (NDC: 69660-203-91)

16.2 Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 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. These may be signs of hematological toxicity or a more serious uncommon bone marrow problem called ‘myelodysplastic syndrome’ (MDS) or ‘acute myeloid leukemia’ (AML) which have been reported in patients treated with Rubraca [see Warnings and Precautions (5.1)].

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 Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment and for 6 months after receiving the last dose of Rubraca [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.3)].

Photosensitivity: Advise patients to use appropriate sun protection due to the increased susceptibility to sunburn while taking Rubraca [see Adverse Drug Reactions (6.1)].

Lactation: Advise females not to breastfeed during treatment and for 2 weeks after the last dose of Rubraca [see Use in Specific Populations (8.2)].

Dosing Instructions: Instruct patients to take Rubraca orally twice daily with or without food. Doses should be taken approximately 12 hours apart. Advise patients that if a dose of Rubraca is missed or if the patient vomits after taking a dose of Rubraca, patients should not take an extra dose, but take the next dose at the regular time [see Dosage and Administration (2.1)].

Distributed by:
Clovis Oncology, Inc.
Boulder, CO 80301
1-844-258-7662

Rubraca is a registered trademark of Clovis Oncology, Inc.

Principal Display Panel - Rubraca tablets 200 mg Bottle Label

NDC 69660-201-91

Rubraca®

(rucaparib) tablets

200 mg*

60 tablets

Each tablet contains 344 mg rucaparib camsylate equivalent to 200 mg rucaparib

Rx only

Keep out of reach of children

Principal Display Panel - Rubraca tablets 250 mg Bottle Label

NDC 69660-202-91

Rubraca®

(rucaparib) tablets

250 mg*

60 tablets

Each tablet contains 430 mg rucaparib camsylate equivalent to 250 mg rucaparib

Rx only

Keep out of reach of children

Principal Display Panel - Rubraca tablets 300 mg Bottle Label

NDC 69660-203-91

Rubraca®

(rucaparib) tablets

300 mg*

60 tablets

Each tablet contains 516 mg rucaparib camsylate equivalent to 300 mg rucaparib

Rx only

Keep out of reach of children

【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。