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药品说明 拜瑞妥 薄膜衣片 [Xarelto®] 成份: 利伐沙班 Rivaroxaban 适应症 用于择期髋关节或膝关节置换手术成年患者，以预防静脉血栓形成（VTE）。 用法用量 推荐剂量为口服利伐沙班10 mg，每日1次。如伤口已止血，首次用药时间应于手术后6-10小时之间进行。 治疗疗程长短依据每个患者发生静脉血栓栓塞事件的风险而定，即由患者所接受的骨科手术类型而定。 对于接受髋关节大手术的患者，推荐一个治疗疗程为服药5周。 对于接受膝关节大手术的患者，推荐一个治疗疗程为服药2周。 如果发生漏服1次用药，患者应立即服用利伐沙班，并于次日继续每天服药1次。 患者可以在进餐时服用利伐沙班，也可以单独服用。 药物过量 由于利伐沙班的药效学性质，用药过量可能导致出血并发症。 尚无对抗利伐沙班药效的特异性解毒剂。 如果发生利伐沙班用药过量，可以考虑使用活性炭来减少吸收。 如果发生出血，对出血的处理采取以下步骤 ： 推迟下次利伐沙班的给药时间或适时终止治疗。利伐沙班的平均终末半衰期为7-11小时。 适当的对症治疗，例如 ：机械性地压迫、外科手术、补液以及血液动力学的支持、应当考虑输注血制品或成分输血。 如果采用上述措施无法控制危及生命的出血，可以考虑给予重组因子VIIa。但是，目前尚无将重组因子VIIa用于服用利伐沙班的患者的经验。上述建议是基于有限的非临床数据。应考虑重组因子VIIa重复给药，并根据出血改善情况进行滴定。 硫酸鱼精蛋白和维生素K不会影响利伐沙班的抗凝活性。对服用利伐沙班的患者使用全身止血剂的获益或经验缺乏科学依据，(如 ：去氨加压素、抑肽酶、氨甲环酸、氨基己酸)。由于利伐沙班的血浆蛋白结合率较高，因此利伐沙班是不可透析的。 服药与进食 服药不受进食影响 禁忌 对利伐沙班或片剂中任何辅料过敏的患者 ；有临床明显活动性出血的患者 ；具有凝血异常和临床相关出血风险的肝病患者 ；孕妇及哺乳期妇女禁用。 注意事项 出血风险 ：如下详述，一些亚群的患者的出血风险较高。治疗开始后，要对这些患者实施密切监测，观察是否有出血并发症征象。这可以通过定期对患者进行体格检查，对外科伤口引流液进行密切观察以及定期测定血红蛋白来实现。 对于任何不明原因的血红蛋白或血压降低都应寻找出血部位。 肾损害 ：在重度肾损害(肌酐清除率<30 mL/min)患者中，利伐沙班的血药浓度可能显著升高，进而导致出血风险升高。不建议将利伐沙班用于肌酐清除率<15 mL/min的患者。肌酐清除率为15-29 mL/min的患者应慎用利伐沙班。 当合并使用可以升高利伐沙班血药浓度的其它药物时，中度肾损害(肌酐清除率30-49 mL/min)患者应该慎用利伐沙班。 肝损害 ：在中度肝损害(Child Pugh B类)的肝硬化患者中，利伐沙班血药浓度可能显著升高，进而导致出血风险升高。利伐沙班禁用于伴有凝血异常和临床相关出血风险的肝病患者。对于中度肝损害(Child Pugh B类)的肝硬化患者，如果不伴有凝血异常，可以谨慎使用利伐沙班。 与其它药物的相互作用 ：在吡咯-抗真菌剂(例如酮康唑、伊曲康唑、伏立康唑和泊沙康唑)或HIV蛋白酶抑制剂(例如利托那韦)全身用药的患者中，不推荐同时使用利伐沙班。这些活性物质是CYP3A4和P-gp的强效抑制剂，因此，可能会升高利伐沙班血药浓度，引起临床相关的出血风险升高。氟康唑被认为对于利伐沙班血药浓度的影响较小，可以谨慎地合并给药。 在合并使用影响止血作用的药物(例如非甾体抗炎药(NSAIDs)、乙酰水杨酸、血小板聚集抑制剂或其它抗血栓药)的患者中，需小心用药。 其它出血风险 ：与其它抗血栓药一样，伴有以下出血风险的患者应慎用利伐沙班 ：先天性或后天性出血障碍、没有控制的严重动脉高血压、活动期胃肠溃疡性疾病、近期胃肠溃疡、血管源性视网膜病、近期的颅内或脑内出血、脊柱内或脑内血管异常、近期接受脑、脊柱或眼科手术。 髋部骨折手术 ：对于这些患者，髋部骨折手术用利伐沙班治疗，尚未进行循证医学的研究，如有效性和安全性的临床试验，尚无证据推荐在这些患者使用利伐沙班。 脊柱/硬膜外麻醉或穿刺 ：在采用轴索麻醉(脊柱/硬膜外麻醉)或脊柱/硬膜外穿刺时，接受抗血栓药预防血栓形成并发症的患者有发生硬膜外或脊柱血肿的风险，这可能导致长期或永久性瘫痪。术后使用硬膜外留置导管或伴随使用影响止血作用的药物可能提高发生上述事件的风险。创伤或重复硬膜外或脊柱穿刺也可能提高上述风险。应对患者实施经常性监测，观察是否有神经功能损伤症状和体征(例如腿部麻木或无力，肠或膀胱功能障碍)。如果观察到神经功能损伤，必须立即进行诊断和治疗。对于接受抗凝治疗的患者和为了预防血栓计划接受抗凝治疗的患者，在实施轴索介入之前医师应衡量潜在的获益和风险。 利伐沙班末次给药18小时后才能取出硬膜外导管。取出导管6小时后才能服用利伐沙班。如果实施微创穿刺，利伐沙班给药需延迟24小时。 与CYP 3A4诱导剂之间的相互作用 ：将利伐沙班与强效CYP 3A4诱导剂(例如利福平、苯妥英、卡马西平、苯巴比妥或圣约翰草)合并使用可能导致利伐沙班血药浓度降低。合并使用强效CYP 3A4诱导剂时应谨慎。 辅料信息 ：利伐沙班片内含有乳糖。有罕见的遗传性半乳糖不耐受、Lapp乳糖酶缺乏或葡萄糖-半乳糖吸收不良问题的患者不能服用该药物。 对驾驶及操作机器能力的影响 ：尚无对驾车和使用机械能力的影响的研究。 在术后有过晕厥和头晕报告，可能影响驾车和使用机械能力，报告指出这些不良反应并不常见。出现这些不良反应的患者不应驾车或使用机械。 未观察到与食物之间有临床意义的相互作用。 实验室参数 ：正如预期，凝血参数(如PT、aPTT、HepTest)受到利伐沙班作用方式的影响。 儿童用药 由于缺乏安全性和疗效方面的数据，不推荐将利伐沙班用于18岁以下的青少年或儿童。 老年患者用药 对老年患者（>65岁）无需调整剂量。 孕妇及哺乳期妇女用药 孕妇 ：尚无利伐沙班用于妊娠期妇女的充分数据。动物研究显示有生殖毒性。由于潜在的生殖毒性、固有的出血风险以及利伐沙班可以通过胎盘，因此，利伐沙班禁用于妊娠期妇女。 育龄妇女在接受利伐沙班治疗期间应避孕。 哺乳期 ：尚无哺乳期妇女使用利伐沙班的资料。动物研究的数据显示利伐沙班能进入母乳。因此利伐沙班禁用于哺乳期妇女。必须决定究竟是停止哺乳还是停止利伐沙班治疗。 不良反应 在3项III期研究中评价了利伐沙班10 mg的安全性，这3项研究中接受下肢骨科大手术(全髋关节置换术或全膝关节置换术)的患者共有4571例接受了最长39天的利伐沙班治疗。 接受治疗的患者中，共计约14%发生了不良反应。分别有大约3.3%和1%的患者发生了出血和贫血。其它常见不良反应包括恶心、GGT升高和转氨酶升高。应该在手术背景下对不良反应做出解释。 由于其药理学作用方式，利伐沙班可能会引起一些组织或器官的隐性或显性出血风险升高，可能导致出血后贫血。由于出血部位、程度或范围不同，出血的体征、症状和严重程度(包括可能的致死性结果)将有所差异。出血风险在特定患者群中可能升高，例如没有控制的重度动脉高血压患者和/或合并使用其它影响止血作用的药物的患者。 出血性并发症可能表现为虚弱、无力、苍白、头晕、头痛或原因不明的肿胀。因此，在评估使用抗凝药的患者时，应考虑出血可能性。 下表中依照系统器官分类(MedDRA)和发生频率列出了3项III期研究中的不良反应。频率定义如下 ： 常见：≥1/100至<1/10， 少见：≥1/1000至<1/100， 罕见：≥1/10000至<1/1000， 非常罕见：<1/10000， 未知：无法根据现有数据做出估计（对下肢接受大型骨科手术的患者实施的3项III期研究以外的其它临床研究中报告的不良事件）。 *治疗中出现的不良反应 检查 ：常见γ-谷氨酰转肽酶升高，转氨酶升高（包括丙氨酸氨基转氨酶升高、天冬氨酸氨基转氨酶升高）；少见脂肪酶升高、淀粉酶升高、血液胆红素升高、乳酸脱氢酶升高、碱性磷酸酶升高 ；罕见结合胆红素升高(伴或不伴丙氨酸转氨酶升高)。 心脏异常 ：少见心动过速。 血液和淋巴系统异常 ：常见贫血(包括相应的实验室参数) ；少见血小板增多(包括血小板计数升高)。 神经系统疾病 ：少见晕厥(包括意识丧失)、头晕、头痛。 胃肠道异常 ：常见恶心 ；少见便秘、腹泻、腹部和胃肠疼痛(包括上腹痛、胃部不适)、消化不良(包括上腹部不适)、口干、呕吐。 肾脏和泌尿系统异常 ：少见肾损害(包括血肌酐升高、血尿素升高)。 皮肤和皮下组织异常 ：少见瘙痒(包括罕见的全身瘙痒)、皮疹、荨麻疹(包括罕见的全身荨麻疹)、挫伤。 肌肉骨骼系统异常 ：少见肢端疼痛。 受伤、中毒及手术的并发症 ：少见伤口分泌物。 血管异常 ：常见术后出血(包括术后贫血和伤口出血) ；少见出血（包括血肿和罕见的肌肉出血）、胃肠道出血(包括齿龈出血、直肠出血、呕血)、血尿症（包括出现血尿）、生殖道出血(包括月经过多)、低血压(包括血压下降、手术引起的低血压)、鼻出血 ；未知关键器官(例如脑)内出血、肾上腺出血、结膜出血、咯血。 全身和给药部位异常 ：少见局部水肿、外周性水肿、感觉不适（包括疲乏、无力）、发热。 免疫系统异常 ：罕见过敏性皮炎 ；未知超敏反应。 肝胆异常 ：罕见肝功能异常 ；未知黄疸。 药物相互作用 CYP 3A4和P-gp抑制剂 ：将利伐沙班和酮康唑(400 mg，每日1次[od])或利托那韦(600 mg，每日2次[bid])合用时，利伐沙班的平均AUC升高了2.6倍/2.5倍，利伐沙班的平均Cmax升高了1.7倍/1.6倍，同时药效显著提高，可能导致出血风险升高。因此，不建议将利伐沙班与吡咯-抗真菌剂(例如酮康唑、伊曲康唑、伏立康唑和泊沙康唑)或HIV蛋白酶抑制剂全身用药时合用。这些活性物质是CYP 3A4和P-gp的强效抑制剂。预计氟康唑对于利伐沙班血药浓度的影响较小，可以谨慎地合并用药。 作用于利伐沙班两条消除途径之一(CYP 3A4或P-gp)的强效抑制剂将使利伐沙班的血药浓度轻度升高，例如被视为强效CYP 3A4抑制剂和中度P-gp抑制剂的克拉霉素(500 mg，每日2次)使利伐沙班的平均AUC升高了1.5倍，使Cmax升高了1.4倍。以上升高并不视为具有临床相关性。 中度抑制CYP 3A4和P-gp的红霉素(500 mg，每日3次)使利伐沙班的平均AUC和Cmax升高了1.3倍。以上升高并不视为具有临床相关性。 抗凝血药 ：合用依诺肝素(40 mg，单次给药)和利伐沙班(10 mg，单次给药)，在抗因子Xa活性上有相加作用，而对凝血试验(PT，aPTT)无任何相加作用。依诺肝素不影响利伐沙班的药代动力学。 如果患者同时接受任何其它抗凝血药治疗，由于出血风险升高，应该特别谨慎。 非甾体抗炎药/血小板聚集抑制剂 ：将利伐沙班和500 mg萘普生合用，未观察到出血时间有临床意义的延长。尽管如此，某些个体可能产生更加明显的药效学作用。 将利伐沙班与500 mg乙酰水杨酸合用，并未观察到有临床显著性的药代动力学或药效学相互作用。 氯吡格雷(300 mg负荷剂量，随后75 mg维持剂量)并未显示出药代动力学相互作用，但是在一个亚组的患者中观察到了相关的出血时间的延长，它与血小板聚集、P选择蛋白或GP IIb/IIIa受体水平无关。 当使用利伐沙班的患者合用非甾体抗炎药(包括乙酰水杨酸)和血小板聚集抑制剂时，应小心使用，因为这些药物通常会提高出血风险。 CYP 3A4诱导剂 ：合用利伐沙班与强效CYP 3A4诱导剂利福平，使利伐沙班的平均AUC下降约50%，同时药效也平行降低。将利伐沙班与其它强效CYP 3A4诱导剂(例如苯妥英、卡马西平、苯巴比妥或圣约翰草)合用，也可能使利伐沙班血药浓度降低。合用强效CYP 3A4 诱导剂时，应谨慎。 其它合并用药 ：将利伐沙班与咪达唑仑(CYP 3A4底物)、地高辛(P-gp底物)或阿托伐他汀(CYP 3A4和P-gp底物)合用时，未观察到有临床显著性的药代动力学或药效学相互作用。利伐沙班对于任何主要CYP亚型(例如CYP 3A4)既无抑制作用也无诱导作用。 贮藏/有效期 常温（10-30°C）密封保存。有效期36个月。 性状 利伐沙班的化学名称 ：5-氯-氮-((5S)-2-氧-3-[-4-（3-氧-4-吗啉基）苯基]-1,3-唑烷-5-基-2-噻吩-羧酰胺，分子式 ：C19H18ClN3O5S， 分子量 ：435.89。 本品为红色薄膜衣片。 药理作用 利伐沙班是一种高选择性，直接抑制因子Xa的口服药物。通过抑制因子Xa可以中断凝血瀑布的内源性和外源性途径，抑制凝血酶的产生和血栓形成。利伐沙班并不抑制凝血酶(活化因子II)，也并未证明其对于血小板有影响。 在人体中观察到了利伐沙班对因子Xa活性呈剂量依赖性抑制的作用。利伐沙班对凝血酶原时间(PT)的影响具有量效关系，若用NeopLastin进行含量测定，则与血浆浓度密切相关(相关系数为0.98)。使用其它试剂会出现不同的结果。读取PT应在数秒内完成，因为国际标准化比率(INR)仅对香豆素类进行了校准和验证，不能用于其它抗凝药。在接受骨科大手术的患者中，服用片剂后2-4小时(作用最强时)，5/95（百分位数）的PT为(NeopLastin)13-25秒(手术前的基线值为12-15秒)。 活化的部分凝血激酶时间(aPTT)和HepTest延长也具有剂量依赖性 ；但不推荐将其用于评估利伐沙班的药效。利伐沙班对抗因子Xa活性也有影响，然而，目前尚无校准的标准。 在临床常规使用利伐沙班时不需要监测凝血参数。 [临床试验] 设计临床试验是为了验证利伐沙班预防下肢骨科大手术患者中静脉血栓栓塞事件(VTE)的疗效，即 ：近端和远端深静脉血栓形成(DVT)和肺栓塞(PE)。在随机、对照、双盲的Ⅲ期临床研究(RECORD研究)中，对9500例以上患者(7050例接受全髋关节置换术，2531例接受全膝关节置换术)进行了研究。 研究中，患者服用利伐沙班10 mg，每日1次(术后至少6小时后开始给药)，或注射依诺肝素40 mg，每日1次(术前12小时开始给药)，比较了两者疗效。 在全部3项III期研究中(参见下表)，利伐沙班显著减少所有VTE(所有通过静脉造影术检测到的或症状性DVT，非致死性PE及死亡)以及重大VTE事件(近端DVT、非致死性PE和VTE相关的死亡)的发生率，这些都是预先设定的主要和次要疗效终点。此外，在所有3项研究中，利伐沙班组症状性VTE的发生率(症状性DVT、非致死性PE以及VTE相关的死亡)低于依诺肝素组。 利伐沙班10 mg治疗组与依诺肝素40 mg治疗组的主要安全终点 - 大出血的发生率相当。 III期临床研究中的疗效和安全性结果 对III期临床研究的合并分析进一步确证了在单个研究中获得的数据 ：与依诺肝素40 mg每日1次相比，利伐沙班10 mg每日1次明显减少了总VTE、重大VTE和症状性VTE。 毒理研究 基于传统的安全性药理学、单剂量毒性、光毒性和遗传毒性研究，非临床数据显示对人体无特殊危害。 在重复剂量毒性研究中所观察到的效应主要是由于利伐沙班的扩大药效学活性导致的。在大鼠中，在有临床意义的血药浓度水平下，观察到IgG和IgA血药浓度升高。 动物研究显示了生殖毒性与利伐沙班的药理学作用机制相关(例如出血并发症)。在有临床意义的血药浓度下，观察到胚胎-胎儿毒性(植入后丢失、骨化延迟/进展、肝脏多发性浅色斑点)和常见畸形发生率升高以及胎盘改变。在对大鼠进行的出生前和出生后研究中，在对母体有毒性的剂量下，观察到后代生存力降低。 药代动力学 吸收 ：10 mg的利伐沙班的绝对生物利用度较高(80-100%)。利伐沙班吸收迅速，服用后2-4小时达到最大浓度(Cmax)。进食对利伐沙班10 mg片剂的AUC或Cmax无明显影响，因此服用利伐沙班10 mg片剂的时间不受就餐时间的限制。利伐沙班的药代动力学基本呈线性，直至达到约每日1次15 mg剂量。更高剂量时，利伐沙班显示出溶出限制性吸收，生物利用度和吸收随着剂量增高而下降。这一现象在空腹状态下比在饱食状态下更为明显。利伐沙班药代动力学的变异性中等，个体间变异性(CV%)范围是30-40%，但在手术当日和术后第1天暴露中变异性高(70%)。 分布 ：利伐沙班与血浆蛋白（主要是血清白蛋白）的结合率较高，在人体中约为92-95%。分布容积中等，稳态下分布容积约为50升。 代谢和消除 ：在利伐沙班用药剂量中，约有2/3通过代谢降解，然后其中一半通过肾脏排出，另外一半通过粪便途径排出。其余1/3用药剂量以活性药物原型的形式直接通过肾脏在尿液中排泄，主要是通过肾脏主动分泌的方式。 利伐沙班通过CYP 3A4、CYP 2J2和不依赖CYP机制进行代谢。吗啉酮部分的氧化降解和酰胺键的水解是主要的生物转化部位。体外研究表明，利伐沙班是转运蛋白P-gp(P-糖蛋白)和Bcrp(乳腺癌耐药蛋白)的底物。 利伐沙班原型是人体血浆内最重要的化合物，尚未发现主要的或具有活性的循环代谢产物。利伐沙班全身清除率约为10 L/小时，为低清除率药物。以1 mg剂量静脉给药后的清除半衰期约为4.5小时。以10 mg剂量口服给药后的清除率受到吸收率的限制，平均消除半衰期为7-11小时。 老年用药（>65岁）/性别 ：老年患者的血药浓度比年轻患者高，其平均AUC值约为年轻患者的1.5倍，主要是由于老年患者总清除率和肾脏清除率(明显)降低。无需调整剂量。 药代动力学和药效学无性别差异。 体重差异 ：极端体重(<50 kg或>120 kg)对于利伐沙班的血浆浓度仅有轻微影响(小于25%)，无需调整剂量。 种族差异 ：在白种人、非洲裔美国人、西班牙人、日本人或中国人患者中，未观察到利伐沙班药代动力学和药效学具有临床意义的种族间差异。 肝损害 ：在轻度肝损害(Child Pugh A类)的肝硬化患者中，利伐沙班药代动力学仅发生轻微变化(平均AUC升高1.2倍)，与健康对照组相近。在中度肝损害(Child Pugh B类)的肝硬化患者中，利伐沙班的平均AUC与健康志愿者相比显著升高了2.3倍。非结合AUC升高了2.6倍。这些患者中，利伐沙班肾脏清除率也有所下降，与中度肾损害患者类似。尚无重度肝损害患者的数据。 与健康志愿者相比，在中度肝损害患者中对于因子Xa活性的抑制作用升高了2.6倍；与之类似，PT也延长了2.1倍。中度肝损害患者对利伐沙班更加敏感，导致浓度和PT之间PK/PD关系的斜率更高。 利伐沙班禁用于伴有凝血异常和临床相关出血风险的肝病患者。对于中度肝损害(Child Pugh B)的肝硬化患者，如果不伴有凝血异常，可以谨慎使用利伐沙班。对于患有其它肝脏疾病的患者，无需调整剂量。 肾损害 ：通过对肌酐清除率的测定，发现利伐沙班血药浓度的增加与肾功能的减退负相关。利伐沙班血浆浓度(AUC)在轻度(肌酐清除率50-80 mL/分钟)、中度(肌酐清除率30-49 mL/分钟)和重度(肌酐清除率15-29 mL/分钟)肾损害患者中分别升高1.4、1.5和1.6倍。药效增强更为明显。与健康受试者相比，在轻度、中度和重度肾损害患者中对因子Xa的总抑制率分别增加了1.5、1.9和2.0倍 ；与之类似，凝血酶原时间分别延长了1.3、2.2和2.4倍。尚无肌酐清除率<15 mL/分钟的患者的数据。 由于利伐沙班的血浆蛋白结合率较高，因此利伐沙班是不可透析的。 对于轻度(肌酐清除率 ：50-80 mL/min)或中度肾脏损害(肌酐清除率 ：30-49 mL/min)的患者，无需调整利伐沙班剂量。 关于严重肾功能损害(肌酐清除率 ：15-29 mL/min)患者的有限临床资料表明，利伐沙班的血药浓度在这一患者人群中明显升高。因此，这些患者使用利伐沙班必须谨慎。不建议肌酐清除率<15 mL/min的患者使用利伐沙班（参见【注意事项】）。 药代动力学/药效学关系 ：宽范围剂量(5-30 mg每日2次)给药之后评价了利伐沙班血药浓度与多个药效学终点(因子Xa抑制、PT、aPTT、Heptest)之间的药代动力学/药效学(PK/PD)关系。利伐沙班10 mg，1天1次给药后的稳态Cmax约为125 ug/L。通过Emax模型可以最佳地描述利伐沙班浓度和因子Xa活性之间的关系。对于PT，使用线性截距模型通常可以更好地描述数据。根据所使用的PT试剂不同，斜率有相当大的差异。使用NeopLastinPT时，基线PT约为13秒，斜率约为3-4秒/(100 ug/L)。II期研究中PK/PD分析结果与在健康受试者中所确定的数据一致。在患者中，基线因子Xa和PT会受到手术影响，导致手术后第1天和稳态之间的浓度-PT斜率有差异

 

Drug Description

 

 

XARELTO
(rivaroxaban) Tablets

WARNING

(A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS,
(B) SPINAL/EPIDURAL HEMATOMA

A. Premature discontinuation of XARELTO increases the risk of thrombotic events

Premature discontinuation of any oral anticoagulant, including XARELTO, increases the risk of thrombotic events. If anticoagulation with XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and Clinical Studies].

B. Spinal/epidural hematoma

Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal

· use of indwelling epidural catheters

· concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants

· a history of traumatic or repeated epidural or spinal punctures

· a history of spinal deformity or spinal surgery

· optimal timing between the administration of XARELTO and neuraxial procedures is not known

[see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see WARNINGS AND PRECAUTIONS].

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see WARNINGS AND PRECAUTIONS].

DESCRIPTION

Rivaroxaban, a factor Xa (FXa) inhibitor, is the active ingredient in XARELTO Tablets with the chemical name 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5- yl}methyl)-2-thiophenecarboxamide. The molecular formula of rivaroxaban is C19H18ClN3O5S and the molecular weight is 435.89. The structural formula is:

Rivaroxaban is a pure (S)-enantiomer. It is an odorless, non-hygroscopic, white to yellowish powder. Rivaroxaban is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media.

Each XARELTO tablet contains 10 mg, 15 mg, or 20 mg of rivaroxaban. The inactive ingredients of XARELTO are: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. Additionally, the proprietary film coating mixture used for XARELTO 10 mg tablets is Opadry® Pink and for XARELTO 15 mg tablets is Opadry®Red, both containing ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide, and for XARELTO 20 mg tablets is Opadry® II Dark Red, containing ferric oxide red, polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.

Indications

INDICATIONSReduction Of Risk Of Stroke And Systemic Embolism In Nonvalvular Atrial Fibrillation

XARELTO is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled [see Clinical Studies].

Treatment Of Deep Vein Thrombosis

XARELTO is indicated for the treatment of deep vein thrombosis (DVT).

Treatment Of Pulmonary Embolism

XARELTO is indicated for the treatment of pulmonary embolism (PE).

Reduction In The Risk Of Recurrence Of Deep Vein Thrombosis And/Or Pulmonary Embolism

XARELTO is indicated for the reduction in the risk of recurrence of DVT and/or PE in patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months.

Prophylaxis Of Deep Vein Thrombosis Following Hip Or Knee Replacement Surgery

XARELTO is indicated for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.

Dosage

DOSAGE AND ADMINISTRATIONRecommended Dosage Important Food Effect Information

The 15 mg and 20 mg XARELTO tablets should be taken with food, while the 10 mg tablet can be taken with or without food [see CLINICAL PHARMACOLOGY].

In the nonvalvular atrial fibrillation efficacy study XARELTO was taken with the evening meal.

Switching To And From XARELTOSwitching From Warfarin To XARELTO

When switching patients from warfarin to XARELTO, discontinue warfarin and start XARELTO as soon as the International Normalized Ratio (INR) is below 3.0 to avoid periods of inadequate anticoagulation.

Switching From XARELTO To Warfarin

No clinical trial data are available to guide converting patients from XARELTO to warfarin. XARELTO affects INR, so INR measurements made during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin. One approach is to discontinue XARELTO and begin both a parenteral anticoagulant and warfarin at the time the next dose of XARELTO would have been taken.

Switching From XARELTO To Anticoagulants Other Than Warfarin

For patients currently taking XARELTO and transitioning to an anticoagulant with rapid onset, discontinue XARELTO and give the first dose of the other anticoagulant (oral or parenteral) at the time that the next XARELTO dose would have been taken [see DRUG INTERACTIONS].

Switching From Anticoagulants Other Than Warfarin To XARELTO

For patients currently receiving an anticoagulant other than warfarin, start XARELTO 0 to 2 hours prior to the next scheduled evening administration of the drug (e.g., low molecular weight heparin or non-warfarin oral anticoagulant) and omit administration of the other anticoagulant. For unfractionated heparin being administered by continuous infusion, stop the infusion and start XARELTO at the same time.

Nonvalvular Atrial Fibrillation

For patients with creatinine clearance (CrCl) >50 mL/min, the recommended dose of XARELTO is 20 mg taken orally once daily with the evening meal. For patients with CrCl 15 to 50 mL/min, the recommended dose is 15 mg once daily with the evening meal [see Use In Specific Populations].

Treatment Of Deep Vein Thrombosis (DVT) And/Or Pulmonary Embolism (PE)

The recommended dose of XARELTO for the initial treatment of acute DVT and/or PE is 15 mg taken orally twice daily with food for the first 21 days. After this initial treatment period, the recommended dose of XARELTO is 20 mg taken orally once daily with food, at approximately the same time each day [see Clinical Studies].

Reduction In The Risk Of Recurrence Of Deep Vein Thrombosis (DVT) And/Or Pulmonary Embolism (PE)

The recommended dose of XARELTO for the reduction in the risk of recurrence of DVT and/or PE after at least 6 months of standard anticoagulant treatment in patients at continued risk of DVT and/or PE is 10 mg taken orally once daily with or without food [see Clinical Studies].

Prophylaxis Of Deep Vein Thrombosis Following Hip Or Knee Replacement Surgery

The recommended dose of XARELTO is 10 mg taken orally once daily with or without food. The initial dose should be taken 6 to 10 hours after surgery provided that hemostasis has been established [see Discontinuation For Surgery And Other Interventions].

· For patients undergoing hip replacement surgery, treatment duration of 35 days is recommended.

· For patients undergoing knee replacement surgery, treatment duration of 12 days is recommended.

Discontinuation For Surgery And Other Interventions

If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, XARELTO should be stopped at least 24 hours before the procedure to reduce the risk of bleeding [see WARNINGS AND PRECAUTIONS]. In deciding whether a procedure should be delayed until 24 hours after the last dose of XARELTO, the increased risk of bleeding should be weighed against the urgency of intervention. XARELTO should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established, noting that the time to onset of therapeutic effect is short [see WARNINGS AND PRECAUTIONS]. If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant.

Missed Dose

If a dose of XARELTO is not taken at the scheduled time, administer the dose as soon as possible on the same day as follows:

· For patients receiving 15 mg twice daily: The patient should take XARELTO immediately to ensure intake of 30 mg XARELTO per day. In this particular instance, two 15 mg tablets may be taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended on the following day.

· For patients receiving 20 mg, 15 mg or 10 mg once daily: The patient should take the missed XARELTO dose immediately.

Administration Options

For patients who are unable to swallow whole tablets, 10 mg, 15 mg or 20 mg XARELTO tablets may be crushed and mixed with applesauce immediately prior to use and administered orally. After the administration of a crushed XARELTO 15 mg or 20 mg tablet, the dose should be immediately followed by food [see Important Food Effect Information, Nonvalvular Atrial Fibrillation, Treatment Of Deep Vein Thrombosis (DVT) And/Or Pulmonary Embolism (PE) and CLINICAL PHARMACOLOGY].

Administration Via Nasogastric (NG) Tube Or Gastric Feeding Tube

After confirming gastric placement of the tube, 10 mg, 15 mg or 20 mg XARELTO tablets may be crushed and suspended in 50 mL of water and administered via an NG tube or gastric feeding tube. Since rivaroxaban absorption is dependent on the site of drug release, avoid administration of XARELTO distal to the stomach which can result in reduced absorption and thereby, reduced drug exposure. After the administration of a crushed XARELTO 15 mg or 20 mg tablet, the dose should then be immediately followed by enteral feeding [see CLINICAL PHARMACOLOGY].

Crushed 10 mg, 15 mg or 20 mg XARELTO tablets are stable in water and in applesauce for up to 4 hours. An in vitro compatibility study indicated that there is no adsorption of rivaroxaban from a water suspension of a crushed XARELTO tablet to PVC or silicone nasogastric (NG) tubing.

HOW SUPPLIEDDosage Forms And Strengths

· 10 mg tablets: Round, light red, biconvex and film-coated with a triangle pointing down above a “10” marked on one side and “Xa” on the other side

· 15 mg tablets: Round, red, biconvex, and film-coated with a triangle pointing down above a “15” marked on one side and “Xa” on the other side

· 20 mg tablets: Triangle-shaped, dark red, and film-coated with a triangle pointing down above a “20” marked on one side and “Xa” on the other side

Storage And Handling

XARELTO (rivaroxaban) Tablets are available in the strengths and packages listed below:

· 10 mg tablets are round, light red, biconvex film-coated tablets marked with a triangle pointing down above a “10” on one side, and “Xa” on the other side. The tablets are supplied in the packages listed:

NDC 50458-580-30 - containing 30 tablets
NDC 50458-580-90 - containing 90 tablets
NDC 50458-580-10      Blister package containing 100 tablets (10 blister cards containing 10 tablets each)

· 15 mg tablets are round, red, biconvex film-coated tablets with a triangle pointing down above a “15” marked on one side and “Xa” on the other side. The tablets are supplied in the packages listed:

NDC 50458-578-30 - containing 30 tablets
NDC 50458-578-90 - containing 90 tablets
NDC 50458-578-10 - Blister package containing 100 tablets (10 blister cards containing 10 tablets each)

· 20 mg tablets are triangle-shaped, dark red film-coated tablets with a triangle pointing down above a “20” marked on one side and “Xa” on the other side. The tablets are supplied in the packages listed:

NDC 50458-579-30 - containing 30 tabletsNDC 50458-579-90 - containing 90 tablets
NDC 50458-579-10 - Blister package containing 100 tablets (10 blister cards containing 10 tablets each)

· Starter Pack for treatment of deep vein thrombosis and treatment of pulmonary embolism:

NDC 50458-584-51 - 30-day starter blister pack containing 51 tablets: 42 tablets of 15 mg and 9 tablets of 20 mg

Store at 25°C (77°F) or room temperature; excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

Keep out of the reach of children.

Manufactured by: Janssen Ortho LLC Gurabo, PR 00778 or Bayer AG 51368 Leverkusen, Germany. Revised: July 2018

Side Effects

SIDE EFFECTS

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

· Increased risk of stroke after discontinuation in nonvalvular atrial fibrillation [see BOX WARNING and WARNINGS AND PRECAUTIONS]

· Bleeding risk [see WARNINGS AND PRECAUTIONS]

· Spinal/epidural hematoma [see BOX WARNING and WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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

During clinical development for the approved indications, 18560 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF); 6962 patients who received XARELTO 15 mg orally twice daily for three weeks followed by 20 mg orally once daily to treat DVT or PE (EINSTEIN DVT, EINSTEIN PE), 10 mg or 20 mg orally once daily (EINSTEIN Extension, EINSTEIN CHOICE) to reduce the risk of recurrence of DVT and/or PE; and 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3).

Hemorrhage

The most common adverse reactions with XARELTO were bleeding complications [see WARNINGS AND PRECAUTIONS].

Nonvalvular Atrial Fibrillation

In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.

Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial.

Table 1: Bleeding Events in ROCKET AF*- On Treatment Plus 2 Days

Figure 1 shows the risk of major bleeding events across major subgroups.

Figure 1: Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF – On Treatment Plus 2 Days

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup, but was a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE)

EINSTEIN DVT and EINSTEIN PE Studies

In the pooled analysis of the EINSTEIN DVT and EINSTEIN PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with XARELTO vs. enoxaparin/Vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%, respectively. The mean duration of treatment was 208 days for XARELTO-treated patients and 204 days for enoxaparin/VKA-treated patients.

Table 2 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies.

Table 2: Bleeding Events* in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies

Reduction in the Risk of Recurrence of DVT and/or PE

EINSTEIN CHOICE Study

In the EINSTEIN CHOICE clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1% for XARELTO 10 mg, 2% for XARELTO 20 mg, and 1% for acetylsalicylic acid (aspirin) 100 mg. The mean duration of treatment was 293 days for XARELTO 10 mg-treated patients and 286 days for aspirin 100 mg-treated patients.

Table 3 shows the number of patients experiencing bleeding events in the EINSTEIN CHOICE study.

Table 3: Bleeding Events* in EINSTEIN CHOICE

In the EINSTEIN CHOICE study, there was an increased incidence of bleeding, including major and CRNM bleeding in the XARELTO 20 mg group compared to the XARELTO 10 mg or aspirin 100 mg groups.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with XARELTO.

The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in Table 4.

Table 4: Bleeding Events* in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1-3)

Following XARELTO treatment, the majority of major bleeding complications (≥60%) occurred during the first week after surgery.

Other Adverse Reactions

Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies are shown in Table 5.

Table 5: Other Adverse Reactions* Reported by ≥1% of XARELTO-Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies

Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in RECORD 1-3 studies are shown in Table 6.

Table 6: Other Adverse Drug Reactions* Reported by ≥1% of XARELTO-Treated Patients in RECORD 1-3 Studies

Other clinical trial experience: In an investigational study of acute medically ill patients being treated with XARELTO 10 mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.

Postmarketing Experience

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

Blood and lymphatic system disorders: agranulocytosis, thrombocytopenia

Gastrointestinal disorders: retroperitoneal hemorrhage

Hepatobiliary disorders: jaundice, cholestasis, hepatitis (including hepatocellular injury)

Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema

Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome

Drug Interactions

DRUG INTERACTIONSGeneral Inhibition And Induction Properties

Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding. Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.

Drugs That Inhibit Cytochrome P450 3A Enzymes And Drug Transport SystemsInteraction With Combined P-Gp And Strong CYP3A Inhibitors

Avoid concomitant administration of XARELTO with known combined P-gp and strong CYP3A inhibitors (e.g., ketoconazole and ritonavir) [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Although clarithromycin is a combined P-gp and strong CYP3A inhibitor, pharmacokinetic data suggests that no precautions are necessary with concomitant administration with XARELTO as the change in exposure is unlikely to affect the bleeding risk [see CLINICAL PHARMACOLOGY].

Interaction With Combined P-Gp And Moderate CYP3A Inhibitors In Patients With Renal Impairment

XARELTO should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A inhibitors (e.g., erythromycin) unless the potential benefit justifies the potential risk [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Drugs That Induce Cytochrome P450 3A Enzymes And Drug Transport Systems

Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Anticoagulants And NSAIDs/Aspirin

Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding [see CLINICAL PHARMACOLOGY].

Avoid concurrent use of XARELTO with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see WARNINGS AND PRECAUTIONS].

Warnings & Precautions

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONSIncreased Risk Of Thrombotic Events After Premature Discontinuation

Premature discontinuation of any oral anticoagulant, including XARELTO, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see DOSAGE AND ADMINISTRATION and Clinical Studies].

Risk Of Bleeding

XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue XARELTO in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.

Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs) [see DRUG INTERACTIONS], selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.

Concomitant use of drugs that are known combined P-gp and strong CYP3A inhibitors increases rivaroxaban exposure and may increase bleeding risk [see DRUG INTERACTIONS].

Reversal Of Anticoagulant Effect

An agent to reverse the anti-factor Xa activity of rivaroxaban is available. Because of high plasma protein binding, rivaroxaban is not dialyzable [see CLINICAL PHARMACOLOGY]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not been evaluated in clinical efficacy and safety studies. Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not recommended.

Spinal/Epidural Anesthesia Or Puncture

When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see BOX WARNING].

To reduce the potential risk of bleeding associated with the concurrent use of XARELTO and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of XARELTO [see CLINICAL PHARMACOLOGY]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of XARELTO is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.

An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (i.e., 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of XARELTO [see CLINICAL PHARMACOLOGY]. The next XARELTO dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of XARELTO for 24 hours.

Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.

Use In Patients With Renal ImpairmentNonvalvular Atrial Fibrillation

Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly [see DOSAGE AND ADMINISTRATION]. Consider dose adjustment or discontinuation of XARELTO in patients who develop acute renal failure while on XARELTO [see Use In Specific Populations].

Treatment Of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), And Reduction In The Risk Of Recurrence Of DVT And Of PE

Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population [see Use In Specific Populations].

Prophylaxis Of Deep Vein Thrombosis Following Hip Or Knee Replacement Surgery

Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Patients who develop acute renal failure while on XARELTO should discontinue the treatment [see Use In Specific Populations].

Use In Patients With Hepatic Impairment

No clinical data are available for patients with severe hepatic impairment.

Avoid use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased [see Use In Specific Populations].

Use With P-Gp And Strong CYP3A Inhibitors Or Inducers

Avoid concomitant use of XARELTO with known combined P-gp and strong CYP3A inhibitors [see DRUG INTERACTIONS].

Avoid concomitant use of XARELTO with drugs that are known combined P-gp and strong CYP3A inducers [see DRUG INTERACTIONS].

Risk Of Pregnancy-Related Hemorrhage

In pregnant women, XARELTO should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress) [see Risk Of Bleeding].

Patients With Prosthetic Heart Valves

The safety and efficacy of XARELTO have not been studied in patients with prosthetic heart valves. Therefore, use of XARELTO is not recommended in these patients.

Acute PE In Hemodynamically Unstable Patients Or Patients Who Require Thrombolysis Or Pulmonary Embolectomy

Initiation of XARELTO is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION).

Instructions For Patient Use

· Advise patients to take XARELTO only as directed.

· Remind patients to not discontinue XARELTO without first talking to their healthcare professional.

· Advise patients with atrial fibrillation to take XARELTO once daily with the evening meal.

· Advise patients for initial treatment of DVT and/or PE to take XARELTO 15 mg or 20 mg tablets with food at approximately the same time every day [see DOSAGE AND ADMINISTRATION].

· Advise patients who are at a continued risk of recurrent DVT and/or PE after at least 6 months of initial treatment, to take XARELTO 10 mg once daily with or without food [see DOSAGE AND ADMINISTRATION].

· Advise patients who cannot swallow the tablet whole to crush XARELTO and combine with a small amount of applesauce followed by food [see DOSAGE AND ADMINISTRATION].

· For patients requiring an NG tube or gastric feeding tube, instruct the patient or caregiver to crush the XARELTO tablet and mix it with a small amount of water before administering via the tube [see DOSAGE AND ADMINISTRATION].

· If a dose is missed, advise the patient to take XARELTO as soon as possible on the same day and continue on the following day with their recommended daily dose regimen.

Bleeding Risks

· Advise patients to report any unusual bleeding or bruising to their physician. Inform patients that it might take them longer than usual to stop bleeding, and that they may bruise and/or bleed more easily when they are treated with XARELTO [see WARNINGS AND PRECAUTIONS].

· If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs or platelet inhibitors, advise patients to watch for signs and symptoms of spinal or epidural hematoma, such as back pain, tingling, numbness (especially in the lower limbs), muscle weakness, and stool or urine incontinence. If any of these symptoms occur, advise the patient to contact his or her physician immediately [see BOX WARNING].

Invasive Or Surgical Procedures

Instruct patients to inform their healthcare professional that they are taking XARELTO before any invasive procedure (including dental procedures) is scheduled.

Concomitant Medication And Herbals

Advise patients to inform their physicians and dentists if they are taking, or plan to take, any prescription or over-the-counter drugs or herbals, so their healthcare professionals can evaluate potential interactions [see DRUG INTERACTIONS].

Pregnancy And Pregnancy-Related Hemorrhage

· Advise patients to inform their physician immediately if they become pregnant or intend to become pregnant during treatment with XARELTO [see Use In Specific Populations].

· Advise pregnant women receiving XARELTO to immediately report to their physician any bleeding or symptoms of blood loss [see WARNINGS AND PRECAUTIONS].

Lactation

Advise patients to discuss with their physician the benefits and risks of XARELTO for the mother and for the child if they are nursing or intend to nurse during anticoagulant treatment [see Use In Specific Populations].

Females And Males Of Reproductive Potential

Advise patients who can become pregnant to discuss pregnancy planning with their physician [see Use In Specific Populations].

Nonclinical ToxicologyCarcinogenesis, Mutagenesis, Impairment Of Fertility

Rivaroxaban was not carcinogenic when administered by oral gavage to mice or rats for up to 2 years. The systemic exposures (AUCs) of unbound rivaroxaban in male and female mice at the highest dose tested (60 mg/kg/day) were 1- and 2-times, respectively, the human exposure of unbound drug at the human dose of 20 mg/day. Systemic exposures of unbound drug in male and female rats at the highest dose tested (60 mg/kg/day) were 2- and 4-times, respectively, the human exposure.

Rivaroxaban was not mutagenic in bacteria (Ames-Test) or clastogenic in V79 Chinese hamster lung cells in vitro or in the mouse micronucleus test in vivo.

No impairment of fertility was observed in male or female rats when given up to 200 mg/kg/day of rivaroxaban orally. This dose resulted in exposure levels, based on the unbound AUC, at least 13 times the exposure in humans given 20 mg rivaroxaban daily.

Use In Specific PopulationsPregnancyRisk Summary

The limited available data on XARELTO in pregnant women are insufficient to inform a drugassociated risk of adverse developmental outcomes. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Consider the benefits and risks of XARELTO for the mother and possible risks to the fetus when prescribing XARELTO to a pregnant woman [see WARNINGS AND PRECAUTIONS].

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. 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 2–4% and 15–20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Pregnancy is a risk factor for venous thromboembolism and that risk is increased in women with inherited or acquired thrombophilias. Pregnant women with thromboembolic disease have an increased risk of maternal complications including pre-eclampsia. Maternal thromboembolic disease increases the risk for intrauterine growth restriction, placental abruption and early and late pregnancy loss.

Fetal/Neonatal Adverse Reactions

Based on the pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate.

Labor or Delivery

All patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery [see WARNINGS AND PRECAUTIONS]. The risk of bleeding should be balanced with the risk of thrombotic events when considering the use of XARELTO in this setting.

Data

Human Data

There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. Post-marketing experience is currently insufficient to determine a rivaroxaban-associated risk for major birth defects or miscarriage. In an in vitroplacenta perfusion model, unbound rivaroxaban was rapidly transferred across the human placenta.

Animal Data

Rivaroxaban crosses the placenta in animals. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg during the period of organogenesis. This dose corresponds to about 14 times the human exposure of unbound drug. In rats, peripartal maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day).

LactationRisk Summary

Rivaroxaban has been detected in human milk. There are insufficient data to determine the effects of rivaroxaban on the breastfed child or on milk production. Rivaroxaban and/or its metabolites were present in the milk of rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XARELTO and any potential adverse effects on the breastfed infant from XARELTO or from the underlying maternal condition (see Data).

Data

Animal Data

Following a single oral administration of 3 mg/kg of radioactive [14C]-rivaroxaban to lactating rats between Day 8 to 10 postpartum, the concentration of total radioactivity was determined in milk samples collected up to 32 hours post-dose. The estimated amount of radioactivity excreted with milk within 32 hours after administration was 2.1% of the maternal dose.

Females And Males Of Reproductive Potential

Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the total number of patients in the RECORD 1-3 clinical studies evaluating XARELTO, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were >75 years. In EINSTEIN CHOICE, approximately 39% were 65 years and over and about 12% were >75 years. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups [see CLINICAL PHARMACOLOGY and Clinical Studies].

Renal Impairment

In pharmacokinetic studies, compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see CLINICAL PHARMACOLOGY].

Nonvalvular Atrial Fibrillation

In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl 15 to 30 mL/min were not studied, but administration of XARELTO 15 mg once daily is also expected to result in serum concentrations of rivaroxaban similar to those in patients with normal renal function [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Patients With End-Stage Renal Disease On Dialysis

Clinical efficacy and safety studies with XARELTO did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 15 mg once daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in the ROCKET AF study [see CLINICAL PHARMACOLOGY]. It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ROCKET AF.

Treatment Of DVT And/Or PE And Reduction In The Risk Of Recurrence Of DVT And/Or PE

In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies. Avoid the use of XARELTO in patients with CrCl <30 mL/min.

Prophylaxis Of DVT Following Hip Or Knee Replacement Surgery

The combined analysis of the RECORD 1-3 clinical efficacy studies did not show an increase in bleeding risk for patients with CrCl 30 to 50 mL/min and reported a possible increase in total venous thromboemboli in this population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Avoid the use of XARELTO in patients with CrCl <30 mL/min.

Hepatic Impairment

In a pharmacokinetic study, compared to healthy subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (Child-Pugh B). The safety or PK of XARELTO in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated [see CLINICAL PHARMACOLOGY].

Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

Overdosage & Contraindications

OVERDOSE

Overdose of XARELTO may lead to hemorrhage. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not dialyzable [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products. An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

CONTRAINDICATIONS

XARELTO is contraindicated in patients with:

· active pathological bleeding [see WARNINGS AND PRECAUTIONS]

· severe hypersensitivity reaction to XARELTO (e.g., anaphylactic reactions) [see ADVERSE REACTIONS]

Clinical Pharmacology

CLINICAL PHARMACOLOGYMechanism Of Action

XARELTO is a selective inhibitor of FXa. It does not require a cofactor (such as Anti-thrombin III) for activity. Rivaroxaban inhibits free FXa and prothrombinase activity. Rivaroxaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, rivaroxaban decreases thrombin generation.

Pharmacodynamics

Dose-dependent inhibition of FXa activity was observed in humans. Neoplastin® prothrombin time (PT), activated partial thromboplastin time (aPTT) and HepTest® are also prolonged dosedependently. Anti-factor Xa activity is also influenced by rivaroxaban.

Specific PopulationsRenal Impairment

The relationship between systemic exposure and pharmacodynamic activity of rivaroxaban was altered in subjects with renal impairment relative to healthy control subjects [see Use In Specific Populations].

Table 7: Percentage Increase in Rivaroxaban PK and PD Measures in Subjects with Renal Impairment Relative to Healthy Subjects from Clinical Pharmacology Studies

Hepatic Impairment

Anti-Factor Xa activity was similar in subjects with normal hepatic function and in mild hepatic impairment (Child-Pugh A class). There is no clear understanding of the impact of hepatic impairment beyond this degree on the coagulation cascade and its relationship to efficacy and safety.

Pharmacokinetics

Absorption

The absolute bioavailability of rivaroxaban is dose-dependent. For the 10 mg dose, it is estimated to be 80% to 100% and is not affected by food. XARELTO 10 mg tablets can be taken with or without food. For the 20 mg dose in the fasted state, the absolute bioavailability is approximately 66%. Coadministration of XARELTO with food increases the bioavailability of the 20 mg dose (mean AUC and Cmax increasing by 39% and 76% respectively with food). XARELTO 15 mg and 20 mg tablets should be taken with food [see DOSAGE AND ADMINISTRATION].

The maximum concentrations (Cmax) of rivaroxaban appear 2 to 4 hours after tablet intake. The pharmacokinetics of rivaroxaban were not affected by drugs altering gastric pH. Coadministration of XARELTO (30 mg single dose) with the H2-receptor antagonist ranitidine (150 mg twice daily), the antacid aluminum hydroxide/magnesium hydroxide (10 mL) or XARELTO (20 mg single dose) with the PPI omeprazole (40 mg once daily) did not show an effect on the bioavailability and exposure of rivaroxaban (see Figure 3).

Absorption of rivaroxaban is dependent on the site of drug release in the GI tract. A 29% and 56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is released in the proximal small intestine. Exposure is further reduced when drug is released in the distal small intestine, or ascending colon. Avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and related drug exposure.

In a study with 44 healthy subjects, both mean AUC and Cmax values for 20 mg rivaroxaban administered orally as a crushed tabletmixed in applesauce were comparable to that after the whole tablet. However, for the crushed tablet suspended in water and administered via an NG tube followed by a liquid meal, only mean AUC was comparable to that after the whole tablet, and Cmax was 18% lower.

Distribution

Plasma protein binding of rivaroxaban in human plasma is approximately 92% to 95%, with albuminbeing the main binding component. The steady-state volume of distribution in healthy subjects is approximately 50 L.

Metabolism

Approximately 51% of an orally administered [14C]-rivaroxaban dose was recovered as inactive metabolites in urine (30%) and feces (21%). Oxidative degradation catalyzed by CYP3A4/5 and CYP2J2 and hydrolysis are the major sites of biotransformation. Unchanged rivaroxaban was the predominant moiety in plasma with no major or active circulating metabolites.

Excretion

In a Phase 1 study, following the administration of [14C]-rivaroxaban, approximately one-third (36%) was recovered as unchanged drug in the urine and 7% was recovered as unchanged drug in feces. Unchanged drug is excreted into urine, mainly via active tubular secretion and to a lesser extent via glomerular filtration (approximate 5:1 ratio). Rivaroxaban is a substrate of the efflux transporter proteins P-gp and ABCG2 (also abbreviated Bcrp). Rivaroxaban’s affinity for influx transporter proteins is unknown.

Rivaroxaban is a low-clearance drug, with a systemic clearance of approximately 10 L/hr in healthy volunteers following intravenous administration. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.

Specific Populations

The effects of level of renal impairment, age, body weight, and level of hepatic impairment on the pharmacokinetics of rivaroxaban are summarized in Figure 2.

Figure 2: Effect of Specific Populations on the Pharmacokinetics of Rivaroxaban

Gender

Gender did not influence the pharmacokinetics or pharmacodynamics of XARELTO.

Race

Healthy Japanese subjects were found to have 20 to 40% on average higher exposures compared to other ethnicities including Chinese. However, these differences in exposure are reduced when values are corrected for body weight.

Elderly

The terminal elimination half-life is 11 to 13 hours in the elderly subjects aged 60 to 76 years [see Use In Specific Populations].

Renal Impairment

The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects [CrCl ≥80 mL/min (n=8)] and in subjects with varying degrees of renal impairment (see Figure 2). Compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Use In Specific Populations].

Hemodialysis in ESRD subjects

Systemic exposure to rivaroxaban administered as a single 15 mg dose in ESRD subjects dosed 3 hours after the completion of a 4-hour hemodialysis session (postdialysis) is 56% higher when compared to subjects with normal renal function (see Table 7). The systemic exposure to rivaroxaban administered 2 hours prior to a 4-hour hemodialysis session with a dialysate flow rate of 600 mL/min and a blood flow rate in the range of 320 to 400 mL/min is 47% higher compared to those with normal renal function. The extent of the increase is similar to the increase in patients with CrCl 15 to 50 mL/min taking XARELTO 15 mg. Hemodialysis had no significant impact on rivaroxaban exposure. Protein binding was similar (86% to 89%) in healthy controls and ESRD subjects in this study.

Hepatic Impairment

The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects (n=16) and subjects with varying degrees of hepatic impairment (see Figure 2). No patients with severe hepatic impairment (Child-Pugh C) were studied. Compared to healthy subjects with normal liver function, significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment (Child-Pugh B) (see Figure 2). Increases in pharmacodynamic effects were also observed [see Use In Specific Populations].

Drug Interactions

In vitro studies indicate that rivaroxaban neither inhibits the major cytochrome P450 enzymes CYP1A2, 2C8, 2C9, 2C19, 2D6, 2J2, and 3A nor induces CYP1A2, 2B6, 2C19, or 3A. In vitro data also indicates a low rivaroxaban inhibitory potential for P-gp and ABCG2 transporters.

The effects of coadministered drugs on the pharmacokinetics of rivaroxaban exposure are summarized in Figure 3 [see DRUG INTERACTIONS for dosing recommendations].

Figure 3: Effect of Coadministered Drugs on the Pharmacokinetics of Rivaroxaban

Anticoagulants

In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and XARELTO (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. In another study, single doses of warfarin (15 mg) and XARELTO (5 mg) resulted in an additive effect on factor Xa inhibition and PT. Neither enoxaparin nor warfarin affected the pharmacokinetics of rivaroxaban (see Figure 3).

NSAIDs/Aspirin

In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO. Neither naproxen nor aspirin affected the pharmacokinetics of rivaroxaban (see Figure 3).

Clopidogrel

In two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and XARELTO (15 mg single dose) were coadministered in healthy subjects, an increase in bleeding time to 45 minutes was observed in approximately 45% and 30% of subjects in these studies, respectively. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. There was no change in the pharmacokinetics of either drug.

Drug-Disease Interactions With Drugs That Inhibit Cytochrome P450 3A Enzymes And Drug Transport Systems

In a pharmacokinetic trial, XARELTO was administered as a single dose in subjects with mild (CrCl = 50 to 79 mL/min) or moderate renal impairment (CrCl = 30 to 49 mL/min) receiving multiple doses of erythromycin (a combined P-gp and moderate CYP3A inhibitor). Compared to XARELTO administered alone in subjects with normal renal function (CrCl >80 mL/min), subjects with mild and moderate renal impairment concomitantly receiving erythromycin reported a 76% and 99% increase in AUCinf and a 56% and 64% increase in Cmax, respectively. Similar trends in pharmacodynamic effects were also observed.

QT/QTc Prolongation

In a thorough QT study in healthy men and women aged 50 years and older, no QTc prolonging effects were observed for XARELTO (15 mg and 45 mg, single-dose).

Clinical StudiesStroke Prevention In Nonvalvular Atrial Fibrillation

The evidence for the efficacy and safety of XARELTO was derived from Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonist for the prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) [NCT00403767], a multi-national, double-blind study comparing XARELTO (at a dose of 20 mg once daily with the evening meal in patients with CrCl >50 mL/min and 15 mg once daily with the evening meal in patients with CrCl 30 to 50 mL/min) to warfarin (titrated to INR 2.0 to 3.0) to reduce the risk of stroke and noncentral nervous system (CNS) systemic embolism in patients with nonvalvular atrial fibrillation (AF). Patients had to have one or more of the following additional risk factors for stroke:

· a prior stroke (ischemic or unknown type), transient ischemic attack (TIA) or non-CNS systemic embolism, or

· 2 or more of the following risk factors:

o age ≥75 years,

o hypertension,

o heart failure or left ventricular ejection fraction ≤35%, or

o diabetes mellitus

ROCKET AF was a non-inferiority study designed to demonstrate that XARELTO preserved more than 50% of warfarin’s effect on stroke and non-CNS systemic embolism as established by previous placebo-controlled studies of warfarin in atrial fibrillation.

A total of 14264 patients were randomized and followed on study treatment for a median of 590 days. The mean age was 71 years and the mean CHADS2 score was 3.5. The population was 60% male, 83% Caucasian, 13% Asian and 1.3% Black. There was a history of stroke, TIA, or non- CNS systemic embolism in 55% of patients, and 38% of patients had not taken a vitamin K antagonist (VKA) within 6 weeks at time of screening. Concomitant diseases of patients in this study included hypertension 91%, diabetes 40%, congestive heart failure 63%, and prior myocardial infarction 17%. At baseline, 37% of patients were on aspirin (almost exclusively at a dose of 100 mg or less) and few patients were on clopidogrel. Patients were enrolled in Eastern Europe (39%); North America (19%); Asia, Australia, and New Zealand (15%); Western Europe (15%); and Latin America (13%). Patients randomized to warfarin had a mean percentage of time in the INR target range of 2.0 to 3.0 of 55%, lower during the first few months of the study.

In ROCKET AF, XARELTO was demonstrated non-inferior to warfarin for the primary composite endpoint of time to first occurrence of stroke (any type) or non-CNS systemic embolism [HR (95% CI): 0.88 (0.74, 1.03)], but superiority to warfarin was not demonstrated. There is insufficient experience to determine how XARELTO and warfarin compare when warfarin therapy is wellcontrolled.

Table 8 displays the overall results for the primary composite endpoint and its components.

Table 8: Primary Composite Endpoint Results in ROCKET AF Study (Intent-to-Treat Population)

Figure 4 is a plot of the time from randomization to the occurrence of the first primary endpoint event in the two treatment arms.

Figure 4: Time to First Occurrence of Stroke (any type) or Non-CNS Systemic Embolism by Treatment Group (Intent-to-Treat Population)

Figure 5 shows the risk of stroke or non-CNS systemic embolism across major subgroups.

Figure 5: Risk of Stroke or Non-CNS Systemic Embolism by Baseline Characteristics in ROCKET AF* (Intent-to-Treat Population)

* Data are shown for all randomized patients followed to site notification that the study would end. Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup, but was a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

The efficacy of XARELTO was generally consistent across major subgroups.

The protocol for ROCKET AF did not stipulate anticoagulation after study drug discontinuation, but warfarin patients who completed the study were generally maintained on warfarin. XARELTO patients were generally switched to warfarin without a period of coadministration of warfarin and XARELTO, so that they were not adequately anticoagulated after stopping XARELTO until attaining a therapeutic INR. During the 28 days following the end of the study, there were 22 strokes in the 4637 patients taking XARELTO vs. 6 in the 4691 patients taking warfarin.

Few patients in ROCKET AF underwent electrical cardioversion for atrial fibrillation. The utility of XARELTO for preventing post-cardioversion stroke and systemic embolism is unknown.

Treatment Of Deep Vein Thrombosis (DVT) And/Or Pulmonary Embolism (PE)EINSTEIN Deep Vein Thrombosis And EINSTEIN Pulmonary Embolism Studies

XARELTO for the treatment of DVT and/or PE was studied in EINSTEIN DVT [NCT00440193] and EINSTEIN PE [NCT00439777], multi-national, open-label, non-inferiority studies comparing XARELTO (at an initial dose of 15 mg twice daily with food for the first three weeks, followed by XARELTO 20 mg once daily with food) to enoxaparin 1 mg/kg twice daily for at least five days with VKA and then continued with VKA only after the target INR (2.0-3.0) was reached. Patients who required thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent and patients with creatinine clearance <30 mL/min, significant liver disease, or active bleeding were excluded from the studies. The intended treatment duration was 3, 6, or 12 months based on investigator's assessment prior to randomization.

A total of 8281 (3449 in EINSTEIN DVT and 4832 in EINSTEIN PE) patients were randomized and followed on study treatment for a mean of 208 days in the XARELTO group and 204 days in the enoxaparin/VKA group. The mean age was approximately 57 years. The population was 55% male, 70% Caucasian, 9% Asian and about 3% Black. About 73% and 92% of XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies, respectively, received initial parenteral anticoagulant treatment for a median duration of 2 days. Enoxaparin/VKA-treated patients in the EINSTEIN DVT and EINSTEIN PE studies received initial parenteral anticoagulant treatment for a median duration of 8 days. Aspirin was taken as on treatment concomitant antithrombotic medication by approximately 12% of patients in both treatment groups. Patients randomized to VKA had an unadjusted mean percentage of time in the INR target range of 2.0 to 3.0 of 58% in EINSTEIN DVT study and 60% in EINSTEIN PE study, with the lower values occurring during the first month of the study.

In the EINSTEIN DVT and EINSTEIN PE studies, 49% of patients had an idiopathic DVT/PE at baseline. Other risk factors included previous episode of DVT/PE (19%), recent surgery or trauma (18%), immobilization (16%), use of estrogen-containing drug (8%), known thrombophilic conditions (6%), or active cancer (5%).

In the EINSTEIN DVT and EINSTEIN PE studies, XARELTO was demonstrated to be noninferior to enoxaparin/VKA for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE [EINSTEIN DVT HR (95% CI): 0.68 (0.44, 1.04); EINSTEIN PE HR (95% CI): 1.12 (0.75, 1.68)]. In each study the conclusion of non-inferiority was based on the upper limit of the 95% confidence interval for the hazard ratio being less than 2.0.

Table 9 displays the overall results for the primary composite endpoint and its components for EINSTEIN DVT and EINSTEIN PE studies.

Table 9: Primary Composite Endpoint Results* in EINSTEIN DVT and EINSTEIN PE Studies – Intent-to-Treat Population

Figures 6 and 7 are plots of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups in EINSTEIN DVT and EINSTEIN PE studies, respectively.

Figure 6: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) – EINSTEIN DVT Study

Figure 7: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) – EINSTEIN PE Study

Reduction In The Risk Of Recurrence Of DVT And/Or PEEINSTEIN CHOICE Study

XARELTO for reduction in the risk of recurrence of DVT and of PE was evaluated in the EINSTEIN CHOICE study [NCT02064439], a multi-national, double-blind, superiority study comparing XARELTO (10 or 20 mg once daily with food) to 100 mg acetylsalicylic acid (aspirin) once daily in patients who had completed 6 to 12 months of anticoagulant treatment for DVT and/or PE following the acute event. The intended treatment duration in the study was up to 12 months. Patients with an indication for continued therapeutic-dose anticoagulation were excluded.

Because the benefit-risk assessment favored the 10 mg dose versus aspirin compared to the 20 mg dose versus aspirin, only the data concerning the 10 mg dose is discussed below.

A total of 2275 patients were randomized and followed on study treatment for a mean of 290 days for the XARELTO and aspirin treatment groups. The mean age was approximately 59 years. The population was 56% male, 70% Caucasian, 14% Asian and 3% Black. In the EINSTEIN CHOICE study, 51% of patients had DVT only, 33% had PE only, and 16% had PE and DVT combined. Other risk factors included idiopathic VTE (43%), previous episode of DVT/PE (17%), recent surgery or trauma (12%), prolonged immobilization (10%), use of estrogen containing drugs (5%), known thrombophilic conditions (6%), Factor V Leiden gene mutation (4%), or active cancer (3%).

In the EINSTEIN CHOICE study, XARELTO 10 mg was demonstrated to be superior to aspirin 100 mg for the primary composite endpoint of time to first occurrence of recurrent DVT or nonfatal or fatal PE.

Table 10 displays the overall results for the primary composite endpoint and its components.

Table 10: Primary Composite Endpoint and its Components Results* in EINSTEIN CHOICE Study – Full Analysis Set

Figure 8 is a plot of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups.

Figure 8: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Full Analysis Set) – EINSTEIN CHOICE Study

Prophylaxis Of Deep Vein Thrombosis Following Hip Or Knee Replacement Surgery

XARELTO was studied in 9011 patients (4487 XARELTO-treated, 4524 enoxaparin-treated patients) in the REgulation of Coagulation in ORthopedic Surgery to Prevent DVT and PE, Controlled, Double-blind, Randomized Study of BAY 59-7939 in the Extended Prevention of VTE in Patients Undergoing Elective Total Hip or Knee Replacement (RECORD 1, 2, and 3) [NCT00329628, NCT00332020, NCT00361894] studies.

The two randomized, double-blind, clinical studies (RECORD 1 and 2) in patients undergoing elective total hip replacement surgery compared XARELTO 10 mg once daily starting at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin 40 mg once daily started 12 hours preoperatively. In RECORD 1 and 2, a total of 6727 patients were randomized and 6579 received study drug. The mean age [± standard deviation (SD)] was 63 ± 12.2 (range 18 to 93) years with 49% of patients ≥65 years and 55% of patients were female. More than 82% of patients were White, 7% were Asian, and less than 2% were Black. The studies excluded patients undergoing staged bilateral total hip replacement, patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min, or patients with significant liver disease (hepatitis or cirrhosis). In RECORD 1, the mean exposure duration (± SD) to active XARELTO and enoxaparin was 33.3 ± 7.0 and 33.6 ± 8.3 days, respectively. In RECORD 2, the mean exposure duration to active XARELTO and enoxaparin was 33.5 ± 6.9 and 12.4 ± 2.9 days, respectively. After Day 13, oral placebo was continued in the enoxaparin group for the remainder of the double-blind study duration. The efficacy data for RECORD 1 and 2 are provided in Table 11.

Table 11: Summary of Key Efficacy Analysis Results for Patients Undergoing Total Hip Replacement Surgery - Modified Intent-to-Treat Population

One randomized, double-blind, clinical study (RECORD 3) in patients undergoing elective total knee replacement surgery compared XARELTO 10 mg once daily started at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin. In RECORD 3, the enoxaparin regimen was 40 mg once daily started 12 hours preoperatively. The mean age (± SD) of patients in the study was 68 ± 9.0 (range 28 to 91) years with 66% of patients ≥65 years. Sixty-eight percent (68%) of patients were female. Eighty-one percent (81%) of patients were White, less than 7% were Asian, and less than 2% were Black. The study excluded patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min or patients with significant liver disease (hepatitis or cirrhosis). The mean exposure duration (± SD) to active XARELTO and enoxaparin was 11.9 ± 2.3 and 12.5 ± 3.0 days, respectively. The efficacy data are provided in Table 12.

Table 12: Summary of Key Efficacy Analysis Results for Patients Undergoing Total Knee Replacement Surgery - Modified Intent-to-Treat Population

Medication Guide

PATIENT INFORMATION

XARELTO®
(zah-REL-toe)
(rivaroxaban) tablets

What is the most important information I should know about XARELTO?

· For people taking XARELTO for atrial fibrillation:

People with atrial fibrillation (an irregular heart beat) are at an increased risk of forming a blood clot in the heart, which can travel to the brain, causing a stroke, or to other parts of the body. XARELTO lowers your chance of having a stroke by helping to prevent clots from forming. If you stop taking XARELTO, you may have increased risk of forming a clot in your blood.

Do not stop taking XARELTO without talking to the doctor who prescribes it for you. Stopping XARELTO increases your risk of having a stroke.

If you have to stop taking XARELTO, your doctor may prescribe another blood thinner medicine to prevent a blood clot from forming.

· XARELTO can cause bleeding which can be serious, and rarely may lead to death. This is because XARELTO is a blood thinner medicine (anticoagulant) that reduces blood clotting. While you take XARELTO you are likely to bruise more easily and it may take longer for bleeding to stop.

You may have a higher risk of bleeding if you take XARELTO and take other medicines that increase your risk of bleeding, including:

o aspirin or aspirin containing products

o non-steroidal anti-inflammatory drugs (NSAIDs)

o warfarin sodium (Coumadin®, Jantoven®)

o any medicine that contains heparin

o clopidogrel (Plavix®)

o selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs)

o other medicines to prevent or treat blood clots

Tell your doctor if you take any of these medicines. Ask your doctor or pharmacist if you are not sure if your medicine is one listed above.

Call your doctor or get medical help right away if you develop any of these signs or symptoms of bleeding:

· unexpected bleeding or bleeding that lasts a long time, such as:

o nose bleeds that happen often

o unusual bleeding from the gums

o menstrual bleeding that is heavier than normal or vaginal bleeding

· bleeding that is severe or you cannot control

· red, pink or brown urine

· bright red or black stools (looks like tar)

· cough up blood or blood clots

· vomit blood or your vomit looks like “coffee grounds”

· headaches, feeling dizzy or weak

· pain, swelling, or new drainage at wound sites

· Spinal or epidural blood clots (hematoma). People who take a blood thinner medicine (anticoagulant) like XARELTO, and have medicine injected into their spinal and epidural area, or have a spinal puncture have a risk of forming a blood clot that can cause long-term or permanent loss of the ability to move (paralysis). Your risk of developing a spinal or epidural blood clot is higher if:

o a thin tube called an epidural catheter is placed in your back to give you certain medicine

o you take NSAIDs or a medicine to prevent blood from clotting

o you have a history of difficult or repeated epidural or spinal punctures

o you have a history of problems with your spine or have had surgery on your spine

If you take XARELTO and receive spinal anesthesia or have a spinal puncture, your doctor should watch you closely for symptoms of spinal or epidural blood clots. Tell your doctor right away if you have back pain, tingling, numbness, muscle weakness (especially in your legs and feet), loss of control of the bowels or bladder (incontinence).

· XARELTO is not for people with artificial heart valves.

What is XARELTO?

XARELTO is a prescription medicine used to:

· reduce the risk of stroke and blood clots in people who have a medical condition called atrial fibrillation. With atrial fibrillation, part of the heart does not beat the way it should. This can lead to the formation of blood clots, which can travel to the brain, causing a stroke, or to other parts of the body.

· treat blood clots in the veins of your legs (deep vein thrombosis or DVT) or lungs (pulmonary embolism or PE)

· reduce the risk of blood clots happening again in people who continue to be at risk for DVT or PE after receiving treatment for blood clots for at least 6 months.

· reduce the risk of forming a blood clot in the legs and lungs of people who have just had hip or knee replacement surgery

It is not known if XARELTO is safe and effective in children.

Do not take XARELTO if you:

· currently have certain types of abnormal bleeding. Talk to your doctor before taking XARELTO if you currently have unusual bleeding.

· are allergic to rivaroxaban or any of the ingredients in XARELTO. See the end of this leaflet for a complete list of ingredients in XARELTO.

Before taking XARELTO, tell your doctor about all of your medical conditions, including if you:

· have ever had bleeding problems

· have liver or kidney problems

· are pregnant or plan to become pregnant. It is not known if XARELTO will harm your unborn baby.

o Tell your doctor right away if you become pregnant during treatment with XARELTO. Taking XARELTO while you are pregnant may increase the risk of bleeding in you or in your unborn baby.

o If you take XARELTO during pregnancy tell your doctor right away if you have any signs or symptoms of bleeding or blood loss. See “What is the most important information I should know about XARELTO?” for signs and symptoms of bleeding.

· are breastfeeding or plan to breastfeed. XARELTO may pass into your breast milk. You and your doctor should decide if you will take XARELTO or breastfeed.

Tell all of your doctors and dentists that you are taking XARELTO. They should talk to the doctor who prescribed XARELTO for you before you have any surgery, medical or dental procedure.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some of your other medicines may affect the way XARELTO works. Certain medicines may increase your risk of bleeding. See “What is the most important information I should know about XARELTO?”

How should I take XARELTO?

· Take XARELTO exactly as prescribed by your doctor.

· Do not change your dose or stop taking XARELTO unless your doctor tells you to.

· Your doctor may change your dose if needed.

· If you take XARELTO for:

o atrial fibrillation:

§ Take XARELTO 1 time a day with your evening meal.

§ If you miss a dose of XARELTO, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.

o blood clots in the veins of your legs or lungs:

§ Take XARELTO 1 or 2 times a day as prescribed by your doctor.

§ For the 15 mg and 20 mg doses, XARELTO should be taken with food.

§ For the 10 mg dose, XARELTO may be taken with or without food.

§ Take your XARELTO doses at the same times each day.

§ If you miss a dose:

§ If you take the 15 mg dose of XARELTO 2 times a day (a total of 30 mg of XARELTO in 1 day): Take XARELTO as soon as you remember on the same day. You may take 2 doses at the same time to make up for the missed dose. Take your next dose at your regularly scheduled time.

§ If you take XARELTO 1 time a day: Take XARELTO as soon as you remember on the same day. Take your next dose at your regularly scheduled time.

o hip or knee replacement surgery:

§ Take XARELTO 1 time a day with or without food.

§ If you miss a dose of XARELTO, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.

· If you have difficulty swallowing the XARELTO tablet whole, talk to your doctor about other ways to take XARELTO.

· Your doctor will decide how long you should take XARELTO.

· Your doctor may stop XARELTO for a short time before any surgery, medical or dental procedure. Your doctor will tell you when to start taking XARELTO again after your surgery or procedure.

· Do not run out of XARELTO. Refill your prescription of XARELTO before you run out. When leaving the hospital following a hip or knee replacement, be sure that you will have XARELTO available to avoid missing any doses.

· If you take too much XARELTO, go to the nearest hospital emergency room or call your doctor right away.

What are the possible side effects of XARELTO?

· See “What is the most important information I should know about XARELTO?”

Call your doctor for medical advice about side effects that you have. You may report side effects to FDA at 1 800-FDA- 1088.

How should I store XARELTO?

· Store XARELTO at room temperature between 68°F to 77°F (20°C to 25°C).

Keep XARELTO and all medicines out of the reach of children.

General information about the safe and effective use of XARELTO.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use XARELTO for a condition for which it was not prescribed. Do not give XARELTO to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your pharmacist or doctor for information about XARELTO that is written for health professionals.

What are the ingredients in XARELTO?

Active ingredient: rivaroxaban

Inactive ingredients: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.

The proprietary film coating mixture for XARELTO 10 mg tablets is Opadry® Pink and contains: ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide.

The proprietary film coating mixture for XARELTO 15 mg tablets is Opadry® Red and contains: ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide.

The proprietary film coating mixture for XARELTO 20 mg tablets is Opadry® II Dark Red and contains: ferric oxide red, polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.