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描述

用于注射的EMEND（fosaprepitant）是一种无菌冻干制剂，含有福沙那坦二葡萄胺，阿瑞匹坦的前体药物，物质P /神经激肽-1（NK1）受体拮抗剂，止吐剂，化学上描述为1-脱氧-1-（甲基氨基）-D-葡萄糖醇[3 - [[（2R，3S）-2 - [（1R）-1-[3,5-双（三氟甲基）苯基]乙氧基] -3-（4-氟苯基）-4-吗啉基]甲基] -2,5-二氢-5-氧代-1H-1,2,4-三唑-1-基]膦酸二乙酯（2:1）（盐）。

其经验式为C23H22F7N4O6P•2（C7H17NO5），其结构式为：

 

Fosaprepitant dimeglumine是一种白色至灰白色的无定形粉末，分子量为1004.83。 它易溶于水。

每瓶用于静脉注射给药的注射用EMEND包含150mg福沙匹坦（相当于245.3mg福沙那坦二葡胺）和以下非活性成分：乙二胺四乙酸二钠（5.4mg），聚山梨酯80（75mg），无水乳糖（375mg） mg），氢氧化钠和/或盐酸（用于pH调节）。

 

适应症

用于注射的EMEND®与其他止吐剂一起用于成人预防：

•急性和迟发性恶心和呕吐与高剂量顺铂诱导化疗（HEC）的初始和重复过程有关，包括高剂量顺铂。

•延缓中度致吐性癌症化疗（MEC）的初始和重复过程引起的恶心和呕吐。

使用限制

•尚未研究EMEND治疗既定恶心和呕吐。

剂量和给药

预防与HEC和MEC相关的恶心和呕吐

表1或表2中分别显示了推荐剂量的EMEND注射剂，地塞米松和5-HT 3拮抗剂在成人中用于预防与施用HEC或MEC相关的恶心和呕吐。 化疗前约30分钟，在第1天以20-30分钟给予注射用EMEND作为静脉输注。

 

 

 

 

 

小心：不要混合或重组用于注射的EMEND与尚未建立物理和化学兼容性的溶液。 用于注射的EMEND与含有二价阳离子（例如Ca 2+，Mg 2+）的任何溶液（包括乳酸林格溶液和哈特曼溶液）不兼容。

存储

重组的最终药物溶液在环境室温下[在或低于25℃（77℉）]下稳定24小时。

如何提供

剂型和强度

用于注射的EMEND：150mg，在单剂量玻璃瓶中用于重构的白色至灰白色冻干粉末

存储和处理

第3941号 - 在单剂量玻璃瓶中一个150-mg W白色至灰白色冻干粉，用于重新配制。 提供如下：

NDC 0006-3941-32每箱1瓶。

存储

注射剂瓶必须冷藏，储存在2°C-8°C（36°F-46°F）。

重组的最终药物溶液在环境室温下[在或低于25℃（77℉）]下稳定24小时。

 

 

副作用

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，所以在临床试验中观察到的不良反应率不能直接与另一种药物的临床试验中的比率相比较，并且可能不反映临床实践中观察到的比率。

用于注射的EMEND的总体安全性在约1600人中进行了评估。

预防与MEC相关的恶心和呕吐的不良反应

在接受MEC的患者的主动对照临床试验中，与单用昂丹司琼和地塞米松（标准疗法）的497名患者相比，接受单剂量EMEND注射联合恩丹西酮和地塞米松（EMEND方案）的504名患者的安全性得到评估。 表4列出了最常见的不良反应。

 

 

 

用EMEND方案治疗的患者中有2.2％报道有输注部位反应，而用标准治疗方案治疗的患者为0.6％。输注部位反应包括：输注部位疼痛（1.2％，0.4％），注射部位刺激（0.2％，0.0％），血管穿刺部位疼痛（0.2％，0.0％）和输注部位血栓性静脉炎0.6％，0.0％），分别与标准治疗相比，EMEND方案报告。

不良反应预防与HEC相关的恶心和呕吐

在接受HEC治疗的患者中进行的一项主动对照临床研究中，接受单剂量EMEND注射的1143名患者与接受3天口服EMEND（阿瑞吡坦）方案的1169名患者[参见临床研究]进行了安全性评估。安全性概况与MEC研究中用fosaprepitant和之前用阿瑞匹坦进行的HEC研究所见相似。然而，与阿瑞吡坦组（0.5％）相比，福沙普汀组患者发生输注部位反应的发生率更高（3.0％）。在HEC研究中发生以下另外的输注 - 部位反应，并且在上述MEC研究中未报道：输注部位红斑（0.5％，0.1％），输注部位瘙痒（0.3％，0.0％）和输注部位fosaprepitant组报道的硬结（0.2％，0.1％）分别与阿瑞匹坦组相比。

由于fosaprepitant被转换成阿瑞吡坦，那些与阿瑞匹坦相关的不良反应也可能在EMEND注射时发生。有关使用口服阿瑞吡坦进行研究的完整安全信息，请参阅EMEND胶囊的完整处方信息。

上市后体验

在批准后使用EMEND期间已发现以下不良反应。由于这些反应是由不确定大小的人群自愿报告的，因此并不总是可以可靠地估计它们的频率或建立与药物暴露的因果关系。

皮肤和皮下组织疾病：瘙痒，皮疹，荨麻疹，史蒂文斯 - 约翰逊综合征/中毒性表皮坏死松解症。

免疫系统疾病：包括过敏反应在内的过敏反应[见禁忌症]。

神经系统疾病：EMEND和异环磷酰胺联合用药后报道异环磷酰胺诱导的神经毒性。

药物相互作用

福沙匹坦/阿瑞匹坦对其他药物药代动力学的影响

当静脉内给药后，在30分钟内将fosaprepitant，aprepitant的前药转化为阿瑞吡坦。因此，注射EMEND后药物相互作用可能会与口服阿瑞匹坦相互作用的药物发生。

Fosaprepitant作为单次150mg剂量给药是CYP3A4的弱抑制剂，并且CYP3A4的弱抑制在单剂量给药后持续2天。单次服用福沙普汀不会诱导CYP3A4。阿瑞匹坦是CYP3A4的底物，抑制剂和诱导剂。阿瑞吡坦也是CYP2C9的诱导剂[见临床药理学]。

CYP3A4的一些底物禁用EMEND [见禁忌症]。如表5所示，可能需要调整某些CYP3A4和CYP2C9底物的剂量。

 

 

 

 

 

其他药物对Fosaprepitant / Aprepitant药代动力学的影响

阿瑞匹坦是一种CYP3A4底物[见临床药理学]。 如表6所示，EMEND与作为CYP3A4抑制剂或诱导剂的药物共同给药可能分别导致阿瑞匹坦血浆浓度升高或降低。

 

 

 

警告

作为预防措施部分的一部分。

注意事项

临床显着的CYP3A4药物相互作用

Fosaprepitant是aprepitant的前药，是CYP3A4的弱抑制剂，aprepitant是CYP3A4的底物，抑制剂和诱导剂。

•将EMEND与CYP3A4底物的其他药物一起使用可能会导致伴随药物的血浆浓度升高。

o由于pimozide血浆浓度显着升高的风险，可能导致QT间期延长（一种已知的匹莫齐特不良反应）[见禁忌症]，因此禁用pimozide与EMEND。

•使用EMEND与强或中等CYP3A4抑制剂（如酮康唑，地尔硫卓）可能会增加阿瑞匹坦的血浆浓度，并导致与EMEND相关的不良反应风险增加。

•对强CYP3A4诱导剂（如利福平）使用EMEND可能导致阿司匹林血浆浓度降低和EMEND功效降低。

有关潜在重要药物相互作用的清单见表5和表6 [见药物相互作用]。

超敏反应

有报道输注fosaprepitant期间的过敏反应，包括潮红，红斑，呼吸困难和过敏反应。如果出现症状，停止输注并进行适当的药物治疗。在第一次使用时不要重新输液给出现这些症状的患者。

伴随华法林降低INR

EMEND与CYP2C9底物华法林联合应用可能导致凝血酶原时间的国际标准化比率（INR）临床显着下降[见临床药理学]。在每个化疗周期开始EMEND后，在2周内监测慢性华法林治疗患者的INR，尤其是7至10天[见药物相互作用]。

减少荷尔蒙避孕药效力的风险

与EMEND联合给药时，在最后一剂EMEND给药后28天内可以减少激素避孕药的疗效[见临床药理学]。建议患者在EMEND治疗期间和EMEND给药后1个月内使用有效的替代或备用避孕方法[见药物相互作用，在特定人群中使用]。

患者咨询信息

建议患者阅读FDA批准的患者标签（患者信息）。

超敏反应和输液部位反应

在服用EMEND的患者中已经报告过敏反应，包括过敏反应。建议患者如果遇到过敏反应的征兆或症状，如荨麻疹，皮疹和瘙痒，皮肤脱皮或溃疡，或呼吸困难或吞咽困难，请停止服用EMEND并立即寻求医疗救助。建议发生输注部位反应的患者，如红斑，水肿，疼痛或血栓性静脉炎如何护理局部反应以及何时寻求进一步评估。

药物相互作用

建议患者讨论他们正在服用的所有药物，包括其他处方，非处方药物或草药产品[见禁忌症，警告和注意事项]。

华法林：指导患者进行慢性华法林治疗，遵循医务人员关于抽血的指示，以便在每个化疗周期开始EMEND后的2周内，特别是7至10天内监测INR [见警告和注意事项] 。

荷尔蒙避孕药：建议患者服用EMEND可能会降低荷尔蒙避孕药的疗效。指导患者在EMEND治疗期间和EMEND治疗后1个月内使用有效的替代或备用避孕方法（如安全套和杀精子剂）[见警告和注意事项，在特定人群中使用]。

非临床毒理学

癌变，突变，生育力受损

致癌

在Sprague-Dawley大鼠和CD-1小鼠中进行致癌性研究2年。在大鼠致癌性研究中，每天两次用0.05-1000mg / kg的口服剂量处理动物。最高剂量产生的全身性暴露于约50mg RHD的人暴露约为（雌性大鼠）或小于（雄性大鼠）的阿瑞吡坦。用剂量为5至1000mg / kg的阿瑞吡坦治疗每天两次导致雄性大鼠中甲状腺滤泡细胞腺瘤和癌症的发病率增加。在雌性大鼠中，它每天两次产生5-1000mg / kg的肝细胞腺瘤和每天两次125-1000mg / kg的肝细胞癌和甲状腺滤泡细胞腺瘤。在小鼠致癌性研究中，用2.5至2000mg / kg /天的口服剂量处理动物。最高剂量在150毫克的RHD时产生大约2倍于人类暴露的全身性暴露。使用阿瑞匹坦产生的皮肤进行治疗

 

在特定人群中使用

怀孕

风险摘要

关于孕妇使用EMEND的资料不足以说明药物相关的风险。在动物繁殖研究中，在器官发生期间暴露于大鼠或兔子的全身药物水平（AUC）大约相当于推荐人剂量（RHD）为150mg [见数据]暴露时，未观察到不利的发育影响。

所指定人群的主要出生缺陷和流产的估计背景风险是未知的。在美国普通人群中，临床认可怀孕中主要出生缺陷和流产的估计背景风险分别为2％至4％和15％至20％。

数据

动物数据

在大鼠和兔子的胚胎胎儿发育研究中，在器官发生期间口服剂量高达1000mg / kg每天两次（大鼠）并达到最大耐受剂量25mg / kg /天（兔）的阿瑞吡坦被施用。在任何物种的任何剂量水平都没有观察到胚胎胎儿死亡或畸形。怀孕大鼠1000mg / kg每日两次和怀孕兔125mg / kg /天的暴露量（AUC）大约相当于RHD 150mg暴露量。阿瑞匹坦在大鼠和兔子中穿过胎盘。

哺乳期

风险摘要

尚未开展哺乳研究以评估人乳中阿瑞吡坦的存在，对母乳喂养婴儿的影响或对产奶的影响。阿瑞匹坦存在于大鼠牛奶中。应该考虑母乳喂养对发育和健康的益处，以及母亲对EMEND的临床需求以及EMEND或母亲潜在的母体疾病对母乳喂养婴儿的任何潜在不良影响。

生殖潜能的女性和男性

避孕

服用EMEND后，荷尔蒙避孕药的疗效可能会降低。在EMEND治疗期间以及最后一次给药后1个月，使用荷尔蒙避孕药，建议女性使用激素避孕药来使用有效的替代或备用非激素避孕药（如避孕套和杀精子剂）[见药物相互作用，临床药理学]。

儿科用途

EMEND注射的安全性和有效性尚未在儿科患者中确定。

老年人使用

在HEC和MEC临床研究中，用EMEND静脉注射治疗的1649例成人癌症患者中，27％为65岁及以上，而5％为75岁及以上。其他报道的EMEND临床经验尚未发现老年人与年轻患者之间的反应差异。一般来说，给老年患者服用时要小心，因为他们的肝，肾或心脏功能降低以及伴随疾病或其他药物治疗的频率更高[见临床药理学]。

肝损伤患者

阿瑞匹坦在轻度和中度肝损伤患者中的药代动力学与肝功能正常的健康人相似。对于轻度至中度肝受损患者（Child-Pugh评分5至9），不需要调整剂量。严重肝受损患者（Child-Pugh评分大于9）没有临床或药代动力学数据。因此，当给予EMEND时，可能需要对这些患者进行额外的不良反应监测[见临床药理学]。

 

 

过量和禁忌症

过量

没有关于用福沙普坦或阿瑞吡坦治疗过量的具体信息。

在服用过量的情况下，应该停止EMEND，并提供一般的支持治疗和监测。由于EMEND的止吐作用，药物诱发的呕吐在EMEND剂量过量的情况下可能无效。

Aprepitant不会被血液透析清除。

禁忌症

EMEND在患者中禁用：

•谁对产品的任何组件过度敏感。过敏反应包括过敏反应，潮红，红斑和呼吸困难已有报道[见不良反应]。

•服用pimozide。 aprepitant（活性部分）对CYP3A4的抑制可导致该药物（其为CYP3A4底物）的血浆浓度升高，潜在地导致严重或危及生命的反应，如QT延长，这是已知的匹莫齐特的不良反应[见警告和注意事项]。

 

临床药理学

临床药理学

行动机制

Fosaprepitant是aprepitant的前体药物，因此它的止吐作用可归因于aprepitant。

阿瑞吡坦是人P物质/神经激肽1（NK1）受体的选择性高亲和力拮抗剂。阿瑞吡坦对5-羟色胺（5-HT 3），多巴胺和皮质类固醇受体（化疗引起的恶心和呕吐的现有疗法（CINV）的靶点）具有很少或没有亲和力。在动物模型中已经显示阿瑞匹坦通过中枢作用来抑制由细胞毒性化疗剂如顺铂诱导的呕吐。

 

药效学

心脏电生理学

在一项随机，双盲，阳性对照，全面QTc研究中，单次200 mg剂量的fosaprepitant（约为推荐剂量的1.3倍）对QTc间期没有影响。

药代动力学

在Fosaprepitant管理后的阿片剂

给予单次静脉注射150mg剂量福沙匹坦，一种阿瑞匹坦前药作为20分钟输注给予健康受试者，阿瑞匹坦的平均AUC 0-∞为37.4（±14.8）mcg•hr / mL，平均值最大阿瑞吡坦浓度（C max）为4.2（±1.2）mcg / mL。 fosaprepitant的血浆浓度低于输注完成后30分钟内的定量限度（10ng / mL）。

分配

阿瑞吡坦大于95％与血浆蛋白结合。在稳定状态下的平均表观分布容积（Vd ss）在人体中约为70L。

Aprepitant穿过人类的血脑屏障[见作用机制]。

消除

代谢

Fosaprepitant在与人类肝脏制剂的体外孵育和来自多种其他人类组织（包括肾，肺和回肠）的S9制剂中转化为阿瑞吡坦。因此，看起来除了肝以外，福沙匹坦至阿瑞匹坦的转化可以发生在多个肝外组织中。

阿瑞吡坦经历广泛的新陈代谢。使用人肝微粒体的体外研究表明，阿瑞吡坦主要由CYP3A4代谢，CYP1A2和CYP2C19代谢较少。代谢主要通过吗啉环及其侧链上的氧化作用来实现。没有检测到CYP2D6，CYP2C9或CYP2E1的代谢。

在健康的年轻成年人中，单次口服300mg剂量的[14C] - 普瑞匹坦后72小时内，阿瑞吡坦约占血浆放射性的24％，表明血浆中存在大量代谢物。已经在人血浆中鉴定出仅具有弱活性的阿瑞匹坦的七种代谢物。

排泄

给健康受试者静脉注射100mg剂量的[14C] - 福沙匹坦后，57％的放射性在尿液中回收，45％在粪便中回收。

阿瑞匹坦主要通过代谢被消除;阿瑞吡坦没有经肾排泄。表观终末半衰期为约9至13小时。

 

 

 

 

 

 

年龄：老年人口

在第1天和第2天至第5天口服给予单次125mg剂量的阿瑞吡坦并且在第2天至第5天每天一次口服80mg之后，阿瑞匹坦的AUC 0-24小时在第1天增加21％，在老年人第5天增加36％ 65岁及以上）相对于年轻成年人。相对于年轻人，C max在第1天高出10％，在第5天高于老年人24％。这些差异不被认为具有临床意义[参见在特定人群中使用]。

性别

在口服单剂量阿哌替滨，剂量范围从40mg到375mg之后，女性中AUC 0-24hr和Cmax分别比男性高14％和22％。阿瑞匹坦的半衰期与女性相比女性低25％，T max几乎同时发生。这些差异不被认为具有临床意义。

种族/民族

口服单剂量阿哌替啶后，范围从40毫克到375毫克，与高加索人相比，西班牙裔的AUC 0-24小时和C max大约高42％和29％。与高加索人相比，亚洲人的AUC 0-24hr和C max分别高62％和41％。高加索人和黑人之间的AUC 0-24hr或C max没有差异。这些差异不被认为具有临床意义。

肾功能不全

对患有严重肾损伤（通过24小时尿肌酐清除率测量的肌酐清除率小于30mL / min / 1.73m 2）的患者和患有终末期肾病（ESRD）的患者施用单一的240mg口服剂量的阿瑞匹坦需要血液透析。

在严重肾损伤患者中，相对于健康受试者，总阿瑞吡坦的AUC 0-∞（未结合的和蛋白结合的）降低21％，C max降低32％（通过Cockcroft- Gault法）。在接受血液透析的ESRD患者中，总阿瑞吡坦的AUC 0-∞降低42％，C max降低32％。由于阿瑞匹坦在肾病患者中蛋白质结合的适度下降，与健康受试者相比，具有药理学活性的未结合药物的AUC对肾损伤患者没有显着影响。给药后4或48小时进行血液透析对阿瑞吡坦的药代动力学没有显着影响;在透析液中回收小于0.2％的剂量。

肝损伤

福沙匹坦在各种肝外组织中被代谢;因此预计肝脏损害不会改变福沙吡坦转变为阿瑞吡坦。

在第1天给予单剂125mg阿瑞吡坦并在第2天和第3天给予轻度肝受损（Child-Pugh评分5至6）患者80mg，每天一次，阿瑞匹坦的AUC 0-24小时为11与健康受试者相同的方案相比，在第1天降低了百分之三十，在第三天降低了36％。在患有中度肝受损（Child-Pugh评分7至9）的患者中，与同样方案的健康受试者相比，阿瑞吡坦的AUC 0-24hr在第1天高出10％，在第3天高出18％。这些AUC 0-24hr的差异不被认为是临床上有意义的。在严重肝损伤患者（Child-Pugh评分大于9）中没有临床或药代动力学数据[见特殊人群中的使用]。

体重指数（BMI）

每增加5公斤/平方米体重指数，AUC 0-24小时和阿司匹林的C max下降11％。分析中受试者的BMI范围为18 kg /m²至36 kg /m²。这种改变不被认为具有临床意义。

 

 

 

 

药物相互作用研究

Fosaprepitant作为单次150mg剂量给药，是CYP3A4的弱抑制剂，没有在第4天观察到的CYP3A4抑制或诱导的证据。在单次剂量给予fosaprepitant后，对CYP3A4的弱抑制持续2天。阿瑞匹坦是CYP3A4的底物，抑制剂和诱导剂。阿瑞匹坦还是CYP2C9的诱导物。

Fosaprepitant或aprepitant不太可能与作为P糖蛋白转运蛋白底物的药物相互作用。

福沙匹坦/阿瑞吡坦对其他药物药代动力学的影响

CYP3A4底物

咪达唑仑：在第1天以单次静脉内剂量给药的Fosaprepitant 150mg在第1天使咪达唑仑的AUC 0-∞增加约1.8倍，并且在第4天时当咪达唑仑以2mg的单一口服剂量共同给药时对第4天无效第1天和第4天。

皮质类固醇

地塞米松：在第1天以单次150mg静脉内剂量给药的Fosaprepitant增加地塞米松的AUC 0-24hr，在第1,2和3天以单剂8-mg口服剂量给药，第1天和第3天以约2倍2 [见剂量和用法，药物相互作用]。

甲基泼尼松龙：口服阿瑞吡坦作为3天方案（125 mg / 80 mg / 80 mg）在第1天静脉注射甲泼尼龙125 mg，第2天和第3天口服甲泼尼龙40 mg，甲基强的松龙的AUC在第1天增加了1.34倍，在第3天增加了2.5倍[见药物相互作用]。

化疗药物

多西紫杉醇：在药代动力学研究中，口服阿瑞吡坦作为3天方案（125mg / 80mg / 80mg）不影响多西他赛的药代动力学。

长春瑞滨：在一项药代动力学研究中，口服阿瑞吡坦作为3天方案（125mg / 80mg / 80mg）不影响长春瑞滨在临床显着程度的药代动力学。

口服避孕药：口服阿瑞吡坦作为3天方案（125mg / 80mg / 80mg）与昂丹司琼和地塞米松一起给药，并与含炔雌醇和炔诺酮的口服避孕药共同施用，炔雌醇和炔诺酮两者的谷浓度炔诺酮在治疗3周后降低多达64％[见药物相互作用]。

CYP2C9底物（华法林，甲苯磺丁脲）

华法林：在第1天给予单次125mg口服阿瑞吡坦剂量，第2天和第3天给予80mg /天给予稳定在慢性华法林治疗的受试者。尽管口服阿瑞吡坦对第3天测定的R（+）或S（ - ）华法林的血浆AUC没有影响，但S（ - ）华法林谷浓度降低34％，伴随着14％的降低凝血酶原时间（以国际标准化比率或INR报告）用口服阿瑞吡坦完成给药后5天[见药物相互作用]。

甲苯磺丁脲：当口服阿瑞吡坦在第1天以125mg和第2天和第3天以80mg /天给药时，第4天时甲苯磺丁脲的AUC降低23％，第8天时降低28％，第15天时降低15％在口服阿瑞吡坦3天方案给药之前和第4,8和15天给予单剂量的甲苯磺丁脲500 mg。这种效应在临床上并不重要。

其他药物

P-糖蛋白底物：Aprepitant不太可能与作为P糖蛋白转运蛋白底物的药物相互作用，正如临床药物相互作用研究中缺乏口服阿瑞匹坦与地高辛的相互作用所证实的。

5-HT3拮抗剂：在临床药物相互作用研究中，阿瑞匹坦对昂丹司琼，格拉司琼或加氢舒口器（多拉司琼的活性代谢物）的药代动力学没有临床重要影响。

 

 

 

 

 

 

 

 

其他药物对Fosaprepitant / Aprepitant药代动力学的影响

利福平：在600mg /天利福平14天方案的第9天，强效CYP3A4诱导剂，阿瑞吡坦的AUC降低大约11倍，平均末端给药时，单剂量375mg口服阿瑞吡坦给药半衰期减少约3倍[见药物相互作用]。

酮康唑：单剂量125 mg口服阿瑞吡坦在400 mg / d酮康唑（一种强效CYP3A4抑制剂）的10天方案的第5天给药，阿瑞匹坦的AUC增加约5倍，平均末端阿瑞吡坦的半衰期增加约3倍[见药物相互作用]。

Diltiazem：在一项针对10例轻度至中度高血压患者的研究中，给予100 mg福沙吡坦作为静脉输注120 mg地尔硫卓（一种每日三次给予中度CYP3A4抑制剂）导致阿瑞匹坦AUC增加1.5倍和地尔硫卓AUC增加1.4倍。

当使用地尔硫卓与地尔硫治疗时，舒张压平均最大下降幅度明显大于单独使用地尔硫组[分别为24.3±10.2 mm Hg与fosaprepitant与15.6±4.1 mm Hg无fosaprepitant]。在地尔硫与fosaprepitant联合给药后，平均最大收缩压下降幅度也大于单独使用地尔硫组[分别为29.5±7.9 mm Hg与fosaprepitant与23.8±4.8 mm Hg无fosaprepitant]。联合使用fosaprepitant和地尔硫卓;然而，除了单用地尔硫卓所观察到的变化之外，没有导致心率或PR间期的任何额外临床显着变化[见药物相互作用]。

帕罗西汀：每日一次口服阿瑞吡坦170mg与帕罗西汀20mg每日一次共同给药，导致阿瑞吡坦和帕罗西汀的AUC降低约25％和C max降低约20％。这种影响在临床上并不重要。

临床研究

预防与HEC有关的恶心和呕吐

在一项随机，平行，双盲，主动对照研究中，接受注射EMEND 150 mg作为单次静脉输注（N = 1147）与接受HEC的患者3天口服EMEND方案（N = 1175）包括顺铂（≥70 mg /m²）的方案。两组所有患者均接受地塞米松和昂丹司琼（见表7）。两个治疗组的患者人口统计学相似。在2322名患者中，63％为男性，56％为白人，26％为亚洲人，3％为美洲印第安人/阿拉斯加原住民，2％为黑人，13％为多种族，33％为西班牙裔/拉丁裔族裔。患者年龄19-86岁，平均年龄56岁。其他常用化疗药物包括氟尿嘧啶（17％），吉西他滨（16％），紫杉醇（15％）和依托泊苷（12％）。

 

EMEND用于注射的效力基于表8中列出的主要和次要终点进行评估，并且在每个评估阶段中显示出不劣于3天口服阿瑞吡坦方案关于完全应答的效果。 在整个阶段完成反应的预先指定的非劣效性边界为7％。 预先规定的延迟期完全缓解的非劣效边缘率为7.3％。 在整个阶段中，无呕吐的预先规定的非劣效性边界为8.2％。

 

 

 

 

 

 

 

 

 

Drug Description

EMEND 
(fosaprepitant) for Injection

DESCRIPTION

EMEND (fosaprepitant) for injection is a sterile, lyophilized formulation containing fosaprepitant dimeglumine, a prodrug of aprepitant, a substance P/neurokinin-1 (NK1) receptor antagonist, an antiemetic agent, chemically described as 1-Deoxy-1-(methylamino)-D-glucitol[3-[[(2R,3S)-2-[(1R)-1-[3,5bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4triazol-1-yl]phosphonate (2:1) (salt).

Its empirical formula is C23H22F7N4O6P • 2(C7H17NO5) and its structural formula is:

Fosaprepitant dimeglumine is a white to off-white amorphous powder with a molecular weight of 1004.83. It is freely soluble in water.

Each vial of EMEND for injection for administration as an intravenous infusion contains 150 mg of fosaprepitant (equivalent to 245.3 mg of fosaprepitant dimeglumine) and the following inactive ingredients: edetate disodium (5.4 mg), polysorbate 80 (75 mg), lactose anhydrous (375 mg), sodium hydroxide and/or hydrochloric acid (for pH adjustment).

 

 

Indications & Dosage

INDICATIONS

EMEND® for injection, in combination with other antiemetic agents, is indicated in adults for the prevention of:

· acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin.

· delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).

Limitations of Use

· EMEND has not been studied for the treatment of established nausea and vomiting.

DOSAGE AND ADMINISTRATIONPrevention Of Nausea And Vomiting Associated With HEC And MEC

The recommended dosage of EMEND for injection, dexamethasone, and a 5-HT 3 antagonist in adults for the prevention of nausea and vomiting associated with administration of HEC or MEC is shown in Table 1 or Table 2, respectively. Administer EMEND for injection as an intravenous infusion on Day 1 over 20 to 30 minutes approximately 30 minutes prior to chemotherapy.

Table 1 : Recommended Dosing for the Prevention of Nausea and Vomiting Associated with HEC

Table 2 : Recommended Dosing for the Prevention of Nausea and Vomiting Associated with MEC

Preparation Of EMEND For Injection

Table 3 : Preparation Instructions for EMEND for Injection

Caution: Do not mix or reconstitute EMEND for injection with solutions for which physical and chemical compatibility have not been established. EMEND for injection is incompatible with any solutions containing divalent cations (e.g., Ca2+ , Mg2+), including Lactated Ringer's Solution and Hartmann's Solution.

Storage

The reconstituted final drug solution is stable for 24 hours at ambient room temperature [at or below 25°C (77°F)].

HOW SUPPLIEDDosage Forms And Strengths

EMEND for injection: 150 mg, white to off-white lyophilized powder in single-dose glass vial for reconstitution

Storage And Handling

No. 3941 — One 150-mg W hite to off-white lyophilized powder in single-dose glass vial, for reconstitution. Supplied as follows:

NDC 0006-3941-32 1 vial per carton.

Storage

Emend for injection vials must be refrigerated, store at 2°C-8°C (36°F-46°F).

The reconstituted final drug solution is stable for 24 hours at ambient room temperature [at or below 25°C (77°F)].

Side Effects & Drug Interactions

SIDE EFFECTSClinical 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.

The overall safety of EMEND for injection was evaluated in approximately 1600 individuals.

Adverse Reactions for the Prevention of Nausea and Vomiting Associated with MEC

In an active-controlled clinical trial in patients receiving MEC, safety was evaluated in 504 patients receiving a single dose of EMEND for injection in combination with ondansetron and dexamethasone(EMEND regimen) compared to 497 patients receiving ondansetron and dexamethasone alone (standard therapy). The most common adverse reactions are listed in Table 4.

Table 4 : Most Common Adverse Reactions in Patients Receiving MEC*

Infusion-site reactions were reported in 2.2% of patients treated with the EMEND regimen compared to 0.6% of patients treated with standard therapy. The infusion-site reactions included: infusion-site pain (1.2%, 0.4%), injection-site irritation (0.2%, 0.0%), vessel puncture-site pain (0.2%, 0.0%), and infusion-site thrombophlebitis (0.6%, 0.0%), reported in the EMEND regimen compared to standard therapy, respectively.

Adverse Reactions for the Prevention of Nausea and Vomiting Associated with HEC

In an active-controlled clinical study in patients receiving HEC, safety was evaluated for 1143 patients receiving a single dose of EMEND for injection compared to 1169 patients receiving the 3-day regimen of oral EMEND (aprepitant) [see Clinical Studies]. The safety profile was generally similar to that seen in the MEC study with fosaprepitant and prior HEC studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients in the fosaprepitant group (3.0%) compared to those in the aprepitant group (0.5%). The following additional infusion-site reactions occurred in HEC study and were not reported in the MEC study described above: infusion-site erythema (0.5%, 0.1%), infusion-site pruritus(0.3%, 0.0%), and infusion-site induration (0.2%, 0.1%), reported in the fosaprepitant group compared to the aprepitant group, respectively.

Since fosaprepitant is converted to aprepitant, those adverse reactions associated with aprepitant might also be expected to occur with EMEND for injection. See the full prescribing information for EMEND capsules for complete safety information regarding studies performed with oral aprepitant.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of EMEND. 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.

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, Stevens-Johnson syndrome/toxic epidermal necrolysis.

Immune system disorders: hypersensitivity reactions including anaphylactic reactions [seeCONTRAINDICATIONS].

Nervous system disorders: ifosfamide-induced neurotoxicity reported after EMEND and ifosfamide coadministration.

DRUG INTERACTIONSEffect Of Fosaprepitant/Aprepitant On The Pharmacokinetics Of Other Drugs

W hen administered intravenously, fosaprepitant, a prodrug of aprepitant, is converted to aprepitant within 30 minutes. Therefore, drug interactions following administration of EMEND for injection are likely to occur with drugs that interact with oral aprepitant.

Fosaprepitant, given as a single 150-mg dose, is a weak inhibitor of CYP3A4, and the weak inhibition of CYP3A4 continues for 2 days after single dose administration. Single dose fosaprepitant does not induce CYP3A4. Aprepitant is a substrate, an inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9 [see CLINICAL PHARMACOLOGY].

Some substrates of CYP3A4 are contraindicated with EMEND [see CONTRAINDICATIONS]. Dosage adjustment of some CYP3A4 and CYP2C9 substrates may be warranted, as shown in Table 5.

Table 5 : Effects of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Drugs

Effect Of Other Drugs On The Pharmacokinetics Of Fosaprepitant/Aprepitant

Aprepitant is a CYP3A4 substrate [see CLINICAL PHARMACOLOGY]. Co-administration of EMEND with drugs that are inhibitors or inducers of CYP3A4 may result in increased or decreased plasma concentrations of aprepitant, respectively, as shown in Table 6.

Table 6 :Effects of Other Drugs on Pharmacokinetics of Fosaprepitant/Aprepitant

 

 

 

 

Warnings & Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONSClinically Significant CYP3A4 Drug Interactions

Fosaprepitant, a prodrug of aprepitant, is a weak inhibitor of CYP3A4, and aprepitant is a substrate, inhibitor, and inducer of CYP3A4.

· Use of EMEND with other drugs that are CYP3A4 substrates, may result in increased plasma concentration of the concomitant drug.

o Use of pimozide with EMEND is contraindicated due to the risk of significantly increased plasma concentrations of pimozide, potentially resulting in prolongation of the QT interval, a known adverse reaction of pimozide [see CONTRAINDICATIONS].

· Use of EMEND with strong or moderate CYP3A4 inhibitors (e.g., ketoconazole, diltiazem) may increase plasma concentrations of aprepitant and result in an increased risk of adverse reactions related to EMEND.

· Use of EMEND with strong CYP3A4 inducers (e.g., rifampin) may result in a reduction in aprepitant plasma concentrations and decreased efficacy of EMEND.

See Table 5 and Table 6 for a listing of potentially significant drug interactions [see DRUG INTERACTIONS].

Hypersensitivity Reactions

Hypersensitivity reactions during infusion of fosaprepitant including flushing, erythema, dyspnea, andanaphylaxis have been reported. If symptoms occur, discontinue the infusion and administer appropriate medical therapy. Do not reinitiate the infusion in patients who experience these symptoms during first-time use.

Decrease In INR With Concomitant Warfarin

Coadministration of EMEND with warfarin, a CYP2C9 substrate, may result in a clinically significant decrease in the International Normalized Ratio (INR) of prothrombin time [see CLINICAL PHARMACOLOGY]. Monitor the INR in patients on chronic warfarin therapy in the 2-week period, particularly at 7 to 10 days, following initiation of EMEND with each chemotherapy cycle [see DRUG INTERACTIONS].

Risk Of Reduced Efficacy Of Hormonal Contraceptives

Upon coadministration with EMEND, the efficacy of hormonal contraceptives may be reduced during administration of and for 28 days following the last dose of EMEND [see CLINICAL PHARMACOLOGY]. Advise patients to use effective alternative or back-up methods of contraception during treatment with EMEND and for 1 month following administration of EMEND [see DRUG INTERACTIONS, Use in Specific Populations].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Hypersensitivity and Infusion Site Reactions

Advise patients that hypersensitivity reactions, including anaphylaxis, have been reported in patients taking EMEND. Advise patients to stop taking EMEND and seek immediate medical attention if they experience signs or symptoms of a hypersensitivity reaction, such as hives, rash and itching, skin peeling or sores, or difficulty in breathing or swallowing. Advise patients who develop an infusion site reaction such as erythema, edema, pain, or thrombophlebitis on how to care for the local reaction and when to seek further evaluation.

Drug Interactions

Advise patients to discuss all medications they are taking, including other prescription, nonprescription medication or herbal products [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].

Warfarin: Instruct patients on chronic warfarin therapy to follow instructions from their healthcare provider regarding blood draws to monitor their INR during the 2-week period, particularly at 7 to 10 days, following initiation of EMEND with each chemotherapy cycle [see WARNINGS AND PRECAUTIONS].

Hormonal Contraceptives: Advise patients that administration of EMEND may reduce the efficacy of hormonal contraceptives. Instruct patients to use effective alternative or back-up methods of contraception (such as condoms and spermicides) during treatment with EMEND and for 1 month following administration of EMEND [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].

Nonclinical ToxicologyCarcinogenesis, Mutagenesis, Impairment Of FertilityCarcinogenesis

Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced systemic exposures to aprepitant approximately equivalent to (female rats) or less than (male rats) the human exposure at the RHD of 150 mg. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure approximately 2 times the human exposure at the RHD of 150 mg. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice. Carcinogenicity studies were not conducted with fosaprepitant.

Mutagenesis

Aprepitant and fosaprepitant were not genotoxic in the Ames test, the human lymphoblastoid cell (TK6)mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test and the mouse micronucleus test.

Impairment of Fertility

Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant. In the fertility studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant. Oral aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the RHD of 150 mg and exposure in female rats approximately equivalent to the human exposure).

Use In Specific PopulationsPregnancyRisk Summary

There are insufficient data on use of EMEND in pregnant women to inform a drug associated risk. In animal reproduction studies, no adverse developmental effects were observed in rats or rabbits exposed during the period of organogenesis to systemic drug levels (AUC) approximately equivalent to the exposure at the recommended human dose (RHD) of 150 mg [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated populations 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 embryofetal development studies in rats and rabbits, aprepitant was administered during the period of organogenesis at oral doses up to 1000 mg/kg twice daily (rats) and up to the maximum tolerated dose of 25 mg/kg/day (rabbits). No embryofetal lethality or malformations were observed at any dose level in either species. The exposures (AUC) in pregnant rats at 1000 mg/kg twice daily and in pregnant rabbits at 125 mg/kg/day were approximately equivalent to the exposure at the RHD of 150 mg. Aprepitant crosses the placenta in rats and rabbits.

LactationRisk Summary

Lactation studies have not been conducted to assess the presence of aprepitant in human milk, the effects on the breastfed infant, or the effects on milk production. Aprepitant is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for EMEND and any potential adverse effects on the breastfed infant from EMEND or from the underlying maternal condition.

Females And Males Of Reproductive PotentialContraception

Upon administration of EMEND, the efficacy of hormonal contraceptives may be reduced. Advise females of reproductive potential using hormonal contraceptives to use an effective alternative or back-up non-hormonal contraceptive (such as condoms and spermicides) during treatment with EMEND and for 1 month following the last dose [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].

Pediatric Use

The safety and effectiveness of EMEND for injection have not been established in pediatric patients.

Geriatric Use

Of the 1649 adult cancer patients treated with intravenous EMEND in HEC and MEC clinicalstudies, 27% were aged 65 and over, while 5% were aged 75 and over. Other reported clinical experience with EMEND has not identified differences in responses between elderly and younger patients. In general, use caution when dosing elderly patients as they have a greater frequency ofdecreased hepatic, renal or cardiac function and concomitant disease or other drug therapy [see CLINICAL PHARMACOLOGY].

Patients With Hepatic Impairment

The pharmacokinetics of aprepitant in patients with mild and moderate hepatic impairment were similar to those of healthy subjects with normal hepatic function. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9). There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score greater than 9). Therefore, additional monitoring for adverse reactions in these patients may be warranted when EMEND is administered [see CLINICAL PHARMACOLOGY].

 

 

Overdosage & Contraindications

OVERDOSE

There is no specific information on the treatment of overdosage with fosaprepitant or aprepitant.

In the event of overdose, EMEND should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of EMEND, drug-induced emesis may not be effective in cases of EMEND overdosage.

Aprepitant is not removed by hemodialysis.

CONTRAINDICATIONS

EMEND is contraindicated in patients:

· who are hypersensitive to any component of the product. Hypersensitivity reactions including anaphylactic reactions, flushing, erythema, and dyspnea have been reported [see ADVERSE REACTIONS].

· taking pimozide. Inhibition of CYP3A4 by aprepitant, the active moiety, could result in elevated plasma concentrations of this drug, which is a CYP3A4 substrate, potentially causing serious or life-threatening reactions, such as QT prolongation, a known adverse reaction of pimozide [seeWARNINGS AND PRECAUTIONS].

 

Clinical Pharmacology

CLINICAL PHARMACOLOGYMechanism Of Action

Fosaprepitant is a prodrug of aprepitant and accordingly, its antiemetic effects are attributable to aprepitant.

Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT 3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CINV). Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with aprepitant have shown that it crosses the blood brain barrier and occupies brain NK 1 receptors. Animal and human studies show that aprepitant augments the antiemetic activity of the 5-HT 3-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis.

PharmacodynamicsCardiac Electrophysiology

In a randomized, double-blind, positive-controlled, thorough QTc study, a single 200-mg dose of fosaprepitant (approximately 1.3 times the recommended dose) had no effect on the QTc interval.

PharmacokineticsAprepitant after Fosaprepitant Administration

Following administration of a single intravenous 150-mg dose of fosaprepitant, a prodrug of aprepitant administered as a 20-minute infusion to healthy subjects, the mean AUC 0-∞ of aprepitant was 37.4 (± 14.8) mcg•hr/mL and the mean maximal aprepitant concentration (C max ) was 4.2 (± 1.2) mcg/mL. Plasma concentrations of fosaprepitant are below the limits of quantification (10 ng/mL) within 30 minutes of the completion of infusion.

Distribution

Aprepitant is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vd ss) was approximately 70 L in humans.

Aprepitant crosses the blood brain barrier in humans [see Mechanism of Action].

Elimination

Metabolism

Fosaprepitant is converted to aprepitant in in vitro incubations with human liver preparations and in S9 preparations from multiple other human tissues including kidney, lung and ileum. Thus, it appears that the conversion of fosaprepitant to aprepitant can occur in multiple extrahepatic tissues in addition to the liver.

Aprepitant undergoes extensive metabolism. In vitro studies using human liver microsomes indicate that aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Metabolism is largely via oxidation at the morpholine ring and its side chains. No metabolism by CYP2D6, CYP2C9, or CYP2E1 was detected.

In healthy young adults, aprepitant accounts for approximately 24% of the radioactivity in plasma over 72 hours following a single oral 300-mg dose of [14C]-aprepitant, indicating a substantial presence of metabolites in the plasma. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma.

Excretion

Following administration of a single intravenous 100-mg dose of [14C]-fosaprepitant to healthy subjects, 57% of the radioactivity was recovered in urine and 45% in feces.

Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. The apparent terminal half-life ranged from approximately 9 to 13 hours.

Specific PopulationsAge: Geriatric Population

Following oral administration of a single 125-mg dose of aprepitant on Day 1 and 80 mg once daily on Days 2 through 5, the AUC 0-24hr of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly (65 years and older) relative to younger adults. The C max was 10% higher on Day 1 and 24% higher on Day 5 in elderly relative to younger adults. These differences are not considered clinically meaningful [see Use in Specific Populations].

Sex

Following oral administration of a single dose of aprepitant, ranging from 40 mg to 375 mg, the AUC 0-24hr and Cmax are 14% and 22% higher in females as compared with males. The half-life of aprepitant is 25% lower in females as compared with males and T max occurs at approximately the same time. These differences are not considered clinically meaningful.

Race/Ethnicity

Following oral administration of a single dose of aprepitant, ranging from 40 mg to 375 mg, the AUC 0-24hr and C max are approximately 42% and 29% higher in Hispanics as compared with Caucasians. The AUC 0-24hr and C max were 62% and 41% higher in Asians as compared to Caucasians. There was no difference in AUC 0-24hr or C max between Caucasians and Blacks. These differences are not considered clinically meaningful.

Renal Impairment

A single 240-mg oral dose of aprepitant was administered to patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m² as measured by 24-hour urinary creatinine clearance) and to patients with end stage renal disease (ESRD) requiring hemodialysis.

In patients with severe renal impairment, the AUC 0-∞ of total aprepitant (unbound and protein bound) decreased by 21% and C max decreased by 32%, relative to healthy subjects (creatinine clearance greater than 80 mL/min estimated by Cockcroft-Gault method). In patients with ESRD undergoing hemodialysis, the AUC 0-∞ of total aprepitant decreased by 42% and C max decreased by 32%. Due to modest decreases in protein binding of aprepitant in patients with renal disease, the AUC of pharmacologically active unbound drug was not significantly affected in patients with renal impairment compared with healthy subjects. Hemodialysis conducted 4 or 48 hours after dosing had no significant effect on the pharmacokinetics of aprepitant; less than 0.2% of the dose was recovered in the dialysate.

Hepatic Impairment

Fosaprepitant is metabolized in various extrahepatic tissues; therefore hepatic impairment is not expected to alter the conversion of fosaprepitant to aprepitant.

Following administration of a single 125-mg oral dose of aprepitant on Day 1 and 80 mg once daily on Days 2 and 3 to patients with mild hepatic impairment (Child-Pugh score 5 to 6), the AUC 0-24hr of aprepitant was 11% lower on Day 1 and 36% lower on Day 3, as compared with healthy subjects given the same regimen. In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), the AUC 0-24hr of aprepitant was 10% higher on Day 1 and 18% higher on Day 3, as compared with healthy subjects given the same regimen. These differences in AUC 0-24hr are not considered clinically meaningful. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score greater than 9) [see Use In Specific Populations].

Body Mass Index (BMI)

For every 5 kg/m² increase in BMI, AUC 0-24hr and C max of aprepitant decrease by 11%. BMI of subjects in the analysis ranged from 18 kg/m² to 36 kg/m² . This change is not considered clinically meaningful.

Drug Interactions Studies

Fosaprepitant, given as a single 150-mg dose, is a weak inhibitor of CYP3A4, with no evidence of inhibition or induction of CYP3A4 observed on Day 4. The weak inhibition of CYP3A4 continues for 2 days after single dose administration of fosaprepitant. Aprepitant is a substrate, an inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9.

Fosaprepitant or aprepitant is unlikely to interact with drugs that are substrates for the Pglycoprotein transporter.

Effects of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other DrugsCYP3A4 Substrates

Midazolam: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC 0-∞ of midazolam by approximately 1.8-fold on Day 1 and had no effect on Day 4 when midazolam was coadministered as a single oral dose of 2 mg on Days 1 and 4.

Corticosteroids

Dexamethasone: Fosaprepitant administered as a single 150 mg intravenous dose on Day 1 increased the AUC 0-24hr of dexamethasone, administered as a single 8-mg oral dose on Days 1, 2, and 3, by approximately 2-fold on Days 1 and 2 [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].

Methylprednisolone: W hen oral aprepitant as a 3-day regimen (125-mg/80-mg/80-mg) was administered with intravenous methylprednisolone 125 mg on Day 1 and oral methylprednisolone 40 mg on Days 2 and 3, the AUC of methylprednisolone was increased by 1.34-fold on Day 1 and by 2.5-fold on Day 3 [see DRUG INTERACTIONS].

Chemotherapeutic Agents

Docetaxel: In a pharmacokinetic study, oral aprepitant administered as a 3-day regimen (125mg/80-mg/80-mg) did not influence the pharmacokinetics of docetaxel.

Vinorelbine: In a pharmacokinetic study, oral aprepitant administered as a 3-day regimen (125mg/80-mg/80-mg) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree.

Oral contraceptives: W hen oral aprepitant was administered as a 3-day regimen (125-mg/80-mg/80mg) with ondansetron and dexamethasone, and coadministered with an oral contraceptive containing ethinylestradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for 3 weeks post-treatment [see DRUG INTERACTIONS].

CYP2C9 Substrates (Warfarin, Tolbutamide)

Warfarin: A single 125-mg dose of oral aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to subjects who were stabilized on chronic warfarin therapy. Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was a 34% decrease in S(-) warfarin trough concentration accompanied by a 14% decrease in the prothrombin time (reported asInternational Normalized Ratio or INR) 5 days after completion of dosing with oral aprepitant [see DRUG INTERACTIONS].

Tolbutamide: Oral aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15. This effect was not considered clinically important.

Other Drugs

P-glycoprotein substrates: Aprepitant is unlikely to interact with drugs that are substrates for the Pglycoprotein transporter, as demonstrated by the lack of interaction of oral aprepitant with digoxin in a clinical drug interaction study.

5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).

Effect of Other Drugs on the Pharmacokinetics of Fosaprepitant/Aprepitant

Rifampin: W hen a single 375-mg dose of oral aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold [see DRUG INTERACTIONS].

Ketoconazole: W hen a single 125-mg dose of oral aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold [see DRUG INTERACTIONS].

Diltiazem: In a study in 10 patients with mild to moderate hypertension, administration of 100 mg of fosaprepitant as an intravenous infusion with 120 mg of diltiazem, a moderate CYP3A4 inhibitor administered three times daily, resulted in a 1.5-fold increase in the aprepitant AUC and a 1.4-fold increase in the diltiazem AUC.

When fosaprepitant was administered with diltiazem, the mean maximum decrease in diastolic blood pressure was significantly greater than that observed with diltiazem alone [24.3 ± 10.2 mm Hg with fosaprepitant versus 15.6 ± 4.1 mm Hg without fosaprepitant]. The mean maximum decrease in systolicblood pressure was also greater after co-administration of diltiazem with fosaprepitant than administration of diltiazem alone [29.5 ± 7.9 mm Hg with fosaprepitant versus 23.8 ± 4.8 mm Hg without fosaprepitant]. Co-administration of fosaprepitant and diltiazem; however, did not result in any additional clinically significant changes in heart rate or PR interval, beyond those changes observed with diltiazem alone [see DRUG INTERACTIONS].

Paroxetine: Coadministration of once daily doses of oral aprepitant 170 mg, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and C max by approximately 20% of both aprepitant and paroxetine. This effect was not considered clinically important.

Clinical StudiesPrevention Of Nausea And Vomiting Associated With HEC

In a randomized, parallel, double-blind, active-controlled study, EMEND for injection 150 mg as a single intravenous infusion (N=1147) was compared to a 3-day oral EMEND regimen (N=1175) in patients receiving a HEC regimen that included cisplatin ( ≥ 70 mg/m²). All patients in both groups received dexamethasone and ondansetron (see Table 7). Patient demographics were similar between the two treatment groups. Of the total 2322 patients, 63% were men, 56% W hite, 26% Asian, 3% American Indian/Alaska Native, 2% Black, 13% Multi-Racial, and 33% Hispanic/Latino ethnicity. Patient ages ranged from 19 to 86 years of age, with a mean age of 56 years. Other concomitant chemotherapy agents commonly administered were fluorouracil (17%), gemcitabine (16%), paclitaxel (15%), and etoposide (12%).

Table 7 : Treatment Regimens in HEC Trial*

The efficacy of EMEND for injection was evaluated based on the primary and secondary endpoints listed in Table 8 and was shown to be non-inferior to that of the 3-day oral aprepitant regimen with regard to complete response in each of the evaluated phases. The pre-specified non-inferiority margin for complete response in the overall phase was 7%. The pre-specified non-inferiority margin for complete response in the delayed phase was 7.3%. The pre-specified non-inferiority margin for no vomiting in the overall phase was 8.2%.

 

 

 

Table 8 : Percent of Patients Receiving Highly Emetogenic Chemotherapy Responding by Treatment Group and Phase — Cycle 1

Prevention Of Nausea And Vomiting Associated With MEC

In a randomized, parallel, double-blind, active comparator-controlled study, EMEND for injection 150 mg as a single intravenous infusion (N=502) in combination with ondansetron and dexamethasone (EMEND regimen) was compared with ondansetron and dexamethasone alone (standard therapy) (N=498) (see Table 9) in patients receiving a MEC regimen. Patient demographics were similar between the two treatment groups. Of the total 1,000 patients included in the efficacy analysis, 41% were men, 84% W hite, 4% Asian, 1% American Indian/Alaska Native, 2% Black, 10% Multi-Racial, and 19% Hispanic/Latino ethnicity. Patient ages ranged from 23 to 88 years of age, with a mean age of 60 years. The most commonly administered MEC chemotherapeutic agents were carboplatin (51%), oxaliplatin (24%), and cyclophosphamide (12%).

Table 9 : Treatment Regimens in MEC Trial*

The primary endpoint was complete response (defined as no vomiting and no rescue therapy) in the delayed phase (25 to 120 hours) of chemotherapy-induced nausea and vomiting. The results by treatment group are shown in Table 10.

Table 10 : Percent of Patients Receiving Moderately Emetogenic Chemotherapy Responding by Treatment Group