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【倍林达药品名称】
商品名：倍林达
通用名：替格瑞洛片
英文名：TicagrelorTablets

剂型：片剂

【倍林达成份】
替格瑞洛Ticagrelor

【倍林达性状】
倍林达活性成份为替格瑞洛，其化学名称为：(1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-二氟苯)环丙基]氨基}-5-(丙基硫氧嘧啶)-3H-[1,2,3]-三唑磷[4,5-d]嘧啶-3-基]-5-(2-羟乙基)环戊烷-1,2-二醇。分子式：C23H28F2N6O4S，分子量：522.57。
性状：倍林达为黄色薄膜衣片，除去包衣后显白色或类白色。

【倍林达适应症】
倍林达用于急性冠脉综合征（不稳定性心绞痛、非ST段抬高心肌梗死或ST段抬高心肌梗死）患者，包括接受药物治疗和经皮冠状动脉介入（PCI）治疗的患者，降低血栓性心血管事件的发生率。与氯吡格雷相比，倍林达可以降低心血管死亡、心肌梗死或卒中复合终点的发生率，两治疗组之间的差异来源于心血管死亡和心肌梗死，而在卒中方面无差异。
在ACS患者中，对倍林达与阿司匹林联合用药进行了研究。结果发现，阿司匹林维持剂量大于100mg会降低替格瑞洛减少复合终点事件的临床疗效，因此，阿司匹林的维持剂量不能超过每日100mg。

【倍林达用法用量】
口服。倍林达可在饭前或饭后服用。
倍林达起始剂量为单次负荷量180mg（90mg×2片），此后每次1片（90mg），每日2次。
除非有明确禁忌，倍林达应与阿司匹林联合用药。在服用首剂负荷阿司匹林后，阿司匹林的维持剂量为每日1次，每次75-100mg。
已经接受过负荷剂量氯吡格雷的ACS患者，可以开始使用替格瑞洛。
治疗中应尽量避免漏服。如果患者漏服了一剂，应在预定的下次服药时间服用1片90mg（患者的下一个剂量）。
倍林达的治疗时间可长达12个月，除非有临床指征需要中止倍林达治疗（见药理毒理）。超过12个月的用药经验目前尚有限。
急性冠脉综合征患者过早中止任何抗血小板药物（包括倍林达）治疗，可能会使基础病引起的心血管死亡或心肌梗死的风险增加，因此，应避免过早中止治疗。

【倍林达药理作用】
替格瑞洛是一种环戊三唑嘧啶（CPTP）类化合物。替格瑞洛及其主要代谢产物能可逆性地与血小板P2Y12ADP受体相互作用，阻断信号传导和血小板活化。替格瑞洛及其活性代谢产物的活性相当。
在一项6周研究中，比较替格瑞洛和氯吡格雷抑制血小板聚集（IPA）的作用，对以20uMADP作为血小板聚集激动剂的急性和慢性血小板抑制效应进行了研究。
负荷剂量替格瑞洛180mg或氯吡格雷600mg给药后，在研究第1天对IPA起始作用进行了评价。替格瑞洛所有时间点的IPA均较高。约在2小时时，达到了替格瑞洛IPA作用，并持续了至少8小时。
用药6周后，评价替格瑞洛每次90mg每日2次或氯吡格雷每次75mg每日1次给药后，IPA消退情况，同样是对20uMADP的反应。
替格瑞洛末次给药后的平均IPA为88％，氯吡格雷的为62％。24小时后，替格瑞洛组的IPA（58％）与氯吡格雷组IPA（52％）相似，这表明漏服替格瑞洛患者的IPA可保持与氯吡格雷治疗患者的IPA谷值相似。5天后，替格瑞洛组的IPA与安慰剂组的IPA相似。对于替格瑞洛或氯吡格雷，均不了解出血风险或血栓形成风险是否与IPA有关。
由氯吡格雷换成替格瑞洛，会使IPA增加26.4％，而由替格瑞洛换成氯吡格雷时，会使IPA下降24.5％。患者可从氯吡格雷换成替格瑞洛，抗血小板作用不会中断（见用法用量）。

【倍林达毒理研究】
遗传毒性：替格瑞洛Ames试验、小鼠淋巴瘤试验、大鼠微核试验结果均为阴性。替格瑞洛活性O-脱甲基代谢产物Ames试验与小鼠淋巴瘤试验结果均为阴性。
生殖毒性：雄性大鼠和雌性大鼠经口给予替格瑞洛剂量分别达180与200mg/kg/天[按AUC计算，相当于60kg人推荐人用剂量90mg，每日2次（MRHD）时暴露量的>15倍]，未见对生育力的明显影响。雌性大鼠在剂量为≥10mg/kg/天（按AUC计算，相当于MRHD时暴露量的1.5倍）时可见动情周期异常发生率增加。
妊娠大鼠胚胎胎仔发育毒性试验中，经口给予替格瑞洛20-300mg/kg/天（按mg/m2计算，20mg/kg/天相当于MRHD）。300mg/kg/天（按mg/m2计算，相当于MRHD的16.5倍）剂量组可见子代异常，包括肝叶与肋骨增多、胸骨骨化不完全、盆骨关节错位以及胸骨畸形。妊娠家兔给予替格瑞洛21-63mg/kg/天，高剂量（按mg/m2计算，相当于MRHD的6.8倍）下可见胆囊发育延迟以及舌骨、耻骨与胸骨骨化不完全。
围产期毒性试验中，妊娠大鼠给予替格瑞洛10-180mg/kg/天，高剂量（按mg/m2计算，相当于MRHD的10倍）下可见幼仔死亡和对幼仔生长的影响。10与60mg/kg/天（按mg/m2计算，相当于MRHD的1.5和3.2倍）可见相对轻微的影响，包括耳廓张开、眼睁开时间延迟。
致癌性：小鼠与雄性大鼠经口给予替格瑞洛剂量分别达250mg/kg/天和120mg/kg/天（按AUC计算，分别相当于MRHD时暴露量的19倍和15倍），未见给药相关的肿瘤发生率增加。雌性大鼠在剂量为180mg/kg/天（按AUC计算，相当于MRHD时暴露量的29倍）时可见子宫癌、子宫腺癌和肝细胞腺瘤发生率增加，剂量为60mg/kg/天（MRHD时AUC的8倍）时未见肿瘤发生率增加。

【倍林达临床试验】
替格瑞洛临床疗效证据源自PLATO研究，一项随机、双盲研究，在急性冠状动脉综合征（ACS）患者中比较替格瑞洛（N=9333）和氯吡格雷（N=9291）的疗效，两个药物均是与阿司匹林及其他标准治疗药物进行联合用药治疗。患者接受至少6个月多直至12个月治疗。即使是已中止用药的病例，研究终点在研究完成时获得。
对于近在24小时内有胸痛或症状发作的患者，随机分配至替格瑞洛或氯吡格雷治疗组。对于已经接受氯吡格雷治疗的患者，可入选并随机分配至任一研究治疗组。无论是拟采用药物或介入治疗的ACS患者均可以入选，但是患者的随机并不取决于将要采取的治疗方式。氯吡格雷组受试者如果在随机前未接受过氯吡格雷治疗，则给予氯吡格雷初始负荷剂量为300mg。对于进行PCI治疗的患者，可根据研究者决定额外接受氯吡格雷300mg剂量治疗。所有随机分入替格瑞洛组的受试者均接受180mg负荷剂量治疗，随后接受90mg每日2次维持剂量的治疗。推荐阿司匹林合并用药的负荷剂量为160-500mg，推荐阿司匹林的维持剂量为每日75-100mg，但可根据本地具体情况增加阿司匹林的维持剂量。
因为替格瑞洛经CYP3A酶代谢，研究方案建议在两个研究治疗组中限制辛伐他汀和洛伐他汀剂量不超过40mg。因出血风险增加，研究排除了过去6个月内曾出现颅内出血、胃肠道出血或存在其它可诱发出血因素的患者。
PLATO研究的患者主要为男性（72％）和高加索人（92％），约43％患者>65岁，15％患者>75岁。
研究主要终点为首次心血管死亡、非致死性心肌梗死（MI）（无症状MI除外）或非致死性卒中的复合终点。其中各项组成部分作为次要终点被评估。
研究药物中位暴露时间为277天，约半数患者研究前接受氯吡格雷治疗，约99％患者在PLATO研究期间接受一定时间的阿司匹林治疗。基线时约35％患者正在接受他汀类药物治疗，93％患者在PLATO研究期间接受一定时间的他汀类药物治疗。
两治疗组间复合终点的差异来源于CV死亡和MI，两者作为次要终点均具有统计学差异，但卒中没有显著的差别。对于全因死亡的获益具有统计学显著性（P=0.0003），风险比为0.78。
PLATO研究期间置入任意支架的11289例PCI患者中，替格瑞洛组支架置入术后血栓形成的风险（判定为"确定"的达1.3％）低于氯吡格雷组（1.9％）（HR0.67，95％CI0.50-0.91；P=0.0091），药物洗脱支架组和金属裸支架组的结果相似。
在整个研究中，至首次CV死亡、非致死性MI或非致死性卒中主要复合终点时间的Kaplan-Meier曲线图显示，曲线在30天时开始分离（RRR12％），而且在整个12个月的治疗期间，一直保持着分离状态。
研究了广泛的人口学、基线合并用药和其他不同治疗方法对结果的作用，大部分研究结果见表3。对于这些分析结果需谨慎解读，因为在大量分析结果中存在偶然性因素。虽然大部分分析结果显示的疗效与整体结果相一致，但是有两个明显的例外情况：地域性的差异和阿司匹林维持剂量的显著影响。这些结果将在下面内容进一步讨论。
表3显示的大部分为基线特征，但部分反映出随机化后的测定结果（如终诊断、阿司匹林维持剂量、PCI使用情况）。患者未按初始诊断分层，但是在不稳定性心绞痛亚组（随机化后测定）中的疗效小于STEMI和STEMI亚组的疗效
亚组分析
PLATO研究中中国患者亚组的研究结果：
共纳入了416名中国患者，其中209名患者随机接受替格瑞洛治疗，207名患者随机接受氯吡格雷治疗。
在中国亚组中，替格瑞洛与氯吡格雷相比在CV死亡、MI和卒中组成的主要复合终点的HR=0.77（95％CI：0.42,1.43），该结果与显示替格瑞洛疗效更优的PLATO总人群结论大体一致。
与PLATO研究的总体结果比较，中国亚组的主要出血事件发生率相对较低。
在中国亚组中，替格瑞洛组、氯吡格雷组"总体主要出血事件"的发生率分别为6.8％（14/207）、3.9％（8/203），主要致命性/危及生命出血事件的发生率分别为5.3％（11/207）、3.0％（6/203），数据显示替格瑞洛组的出血事件发生率在数值上高于氯吡格雷组，但是，因病例数有限，组间比较差异无统计学意义。
Holter亚研究：为了研究PLATO研究中室性间歇和其它心律失常发作的发生，研究者在一组涉及近3000例患者的亚组中进行了Holter监测，在这些患者中有2000例患者有ACS急性阶段和1个月后的记录。关注的主要变量为≥3秒的室性间歇的发生率。急性期中替格瑞洛组（6.0％）比氯吡格雷组（3.5％）有更多的患者出现了室性间歇；而在1个月之后，替格瑞洛组为2.2％，氯吡格雷组为1.6％。替格瑞洛组患者中，有充血性心力衰竭（CHF）病史的患者在ACS急性期发生室性间歇频率的增加更为明显（9.2％，无CHF病史者为5.4％；氯吡格雷组患者有CHF病史者为4.0％，无CHF病史者为3.6％）。在一个月时未发生此类不平衡：替格瑞洛组有和无CHF病史的患者发生率分别为2.0％和2.1％，氯吡格雷组分别为3.8％和1.4％。但在此患者人群中未出现与此不平衡情况（包括起搏器植入术）相关的不良临床结果。
PLATO遗传亚研究：PLATO研究中，对10285例患者进行了CYP2C19和ABCB1基因检测，提供了基因型分组与PLATO结果之间的关系。与氯吡格雷相比，替格瑞洛在降低主要CV事件方面的优效性不受患者CYP2C19或ABCB1基因型的显著影响。与总体PLATO研究相似，无论是CYP2C19或ABCB1的基因型，替格瑞洛和氯吡格雷治疗组中总体PLATO主要出血无差异。与氯吡格雷组相比，替格瑞洛组非CABG的PLATO主要出血在携带1个或多个CYP2C19功能缺失等位基因的患者中增加，但在无功能缺失等位基因的患者与氯吡格雷组相似。
联合有效性和安全性复合终点：联合有效性和安全性复合终点（CV死亡、MI、卒中或PLATO定义"总体主要"出血）显示，与氯吡格雷相比，在ACS事件后的12月内，替格瑞洛疗效的获益未因主要出血事件（ARR1.4％，RRR8％，HR0.92；P=0.0257）而抵消。

【倍林达药代动力学】
一般特征：替格瑞洛的药代动力学呈线性，替格瑞洛及其活性代谢产物（AR-C124910XX）的暴露量与用药剂量大致成比例。
吸收：替格瑞洛吸收迅速，中位Tmax约为1.5小时。替格瑞洛可生成其主要循环代谢产物AR-C124910XX（也是活性物质），中位Tmax约为2.5小时（1.5-5.0）。在所研究的剂量范围（30-1260mg）内，替格瑞洛与其活性代谢产物的Cmax和AUC与用药剂量大致成比例增加。
替格瑞洛的平均生物利用度约为36％（范围为25.4-64.0％）。摄食高脂肪食物可使替格瑞洛的AUC增加21％、活性代谢物的Cmax下降22％，但对替格瑞洛的Cmax或活性代谢物的AUC无影响。一般认为这些微小变化的临床意义不大，因此替格瑞洛可在饭前或饭后服用。
分布：替格瑞洛的稳态分布容积为87.5L。替格瑞洛及其代谢产物与人血浆蛋白广泛结合（>99％）。
代谢：替格瑞洛主要经CYP3A4代谢，少部分由CYP3A5代谢。
替格瑞洛的主要代谢产物为AR-C124910XX，经体外试验评估显示其亦具有活性，可与血小板P2Y12ADP-受体结合。活性代谢产物的全身暴露约为替格瑞洛的30-40％。
排泄：替格瑞洛主要通过肝脏代谢消除。通过使用替格瑞洛放射示踪测得放射物的平均回收率约为84％（粪便中含57.8％，尿液中含26.5％）。替格瑞洛及其活性代谢产物在尿液中的回收率均小于给药剂量的1％。活性代谢产物的主要消除途径为经胆汁分泌。替格瑞洛的平均t1/2约为7小时，活性代谢产物为9小时。

【倍林达特殊人群】
老年人：群体药代动力学分析显示，与年轻受试者相比，替格瑞洛在老年ACS患者（>75岁）中的暴露量增加（Cmax和AUC均约为25％），活性代谢产物的暴露量也增加。这些差异无临床意义。
儿童患者：尚未在儿童人群中对替格瑞洛进行评估。
性别：与男性患者相比，女性患者对替格瑞洛（Cmax和AUC分别为52％和37％）及其活性代谢产物（Cmax和AUC均约为50％）的暴露较高。这些差异无临床意义。
肾损害：与肾功能正常的受试者相比，替格瑞洛及其活性代谢产物在严重肾损害（肌酐清除率<30mL/分钟）患者中的暴露量低20％。
肝损害：与健康受试者相比，替格瑞洛在轻度肝损害患者中的Cmax和AUC分别高12％和23％。目前尚未在中度或重度肝损害的患者中对替格瑞洛进行研究。
种族：亚裔患者的平均生物利用度比高加索裔患者高39％。自我确认为黑人患者的替格瑞洛生物利用度比高加索裔患者低18％。在临床药理学研究中，替格瑞洛在日本人受试者中的暴露量（Cmax和AUC）约比高加索人高40％（校正体重后约为20％），替格瑞洛在健康中国受试者中暴露量比高加索人高40％。
MIMS药物分类
抗凝血、抗血小板和纤维蛋白溶解剂(Anticoagulants,Antiplatelets&Fibrinolytics(Thrombolytics))

【倍林达药物过量】
目前还没有逆转替格瑞洛作用的解毒药，预计替格瑞洛不可通过透析清除（见注意事项）。应根据当地标准医疗实践处置用药过量。出血为可以预期的药物过量药理效应，如发生出血，应采取适当的支持性治疗措施。
替格瑞洛片单剂量给药高达900mg可很好耐受。单剂量递增研究结果显示，倍林达的剂量限制反应为胃肠道毒性，包括恶心、呕吐、腹泻等。药物过量可能引起的具有临床意义的其它不良反应包括呼吸困难和室性停搏，应进行心电图监测。

【倍林达警告】
出血风险：
-与其它抗血小板药物相同，倍林达可导致显著的、有时甚至是致命的出血。
-请勿在患有活动性病理性出血或具有颅内出血病史的患者中使用倍林达。
-请勿在计划接受急诊冠状动脉旁路移植术（CABG）的患者中使用倍林达，如可能，应在任何手术前至少7天停用倍林达。
-对于在近期接受冠状动脉血管造影术、经皮冠状动脉介入疗法（PCI）、CABG或其它外科手术过程中应用替格瑞洛的任何患者，如出现低血压，则怀疑有出血。
-如可能，请在不停用倍林达的情况下对出血进行治疗。停用倍林达会增加后续心血管事件的风险。
阿司匹林剂量和倍林达的疗效：阿司匹林维持剂量大于100mg会降低替格瑞洛减少复合终点事件的临床疗效，因此，在给予任何初始剂量后，阿司匹林维持剂量为75-100mg/天。

【倍林达注意事项】
1出血风险
在3期关键性试验（PLATO血小板抑制和患者结果，18624例患者）中，关键排除标准包括过去6个月内发生出血风险增加、具有临床意义的血小板减少或贫血、既往颅内出血、胃肠道出血，或过去30天内接受了大手术。在用替格瑞洛和阿司匹林联合治疗的急性冠脉综合征患者中，非CABG主要出血的风险增加，需要临床关注的出血（非致死或危及生命的"主要+次要PLATO出血"）亦更多见。
因此，应衡量替格瑞洛用药对患者带来的已知出血风险增加与预防动脉粥样硬化血栓事件获益之间的平衡。如有临床指证，以下患者应慎用替格瑞洛：
-有出血倾向（例如近期创伤、近期手术、凝血功能障碍、活动性或近期胃肠道出血）的患者慎用倍林达。有活动性病理性出血的患者、有颅内出血病史的患者、中-重度肝损害的患者禁用倍林达。
-在服用替格瑞洛片后24小时内联合使用其它可能增加出血风险药品[例如用非甾体抗炎药（NSAIDS）、口服抗凝血药和/或纤溶剂]的患者，慎用倍林达。
目前尚无有关替格瑞洛对血小板成分输血时止血作用的数据；循环中的替格瑞洛可能会抑制已输注的血小板。由于合并使用替格瑞洛和去氨加压素不会降低模板法出血时间，因此去氨加压素可能对临床出血事件没有作用。
抗纤维蛋白溶解疗法（氨基己酸或氨甲环酸）和/或重组因子Ⅶa可能会增强止血作用。在确定出血原因且控制出血后，可重新使用替格瑞洛片。
2手术
应告知每一位患者，在他们将要接受任何预定的手术之前和服用任何新药之前，应告诉医师和牙医其正在使用替格瑞洛。
在PLATO研究中，对于进行冠状动脉旁路移植术（CABG）的患者，当在手术前一天停药时，替格瑞洛引起的出血事件多于氯吡格雷，但是，在手术前2天或更多天停药时，则两组的主要出血事件发生率相当。对于实施择期手术的患者，如果抗血小板药物治疗不是必须的，应在术前7天停止使用替格瑞洛。
处于心动过缓事件危险中的患者
由于在早期临床研究中经常观察到无症状的室性间歇，因此在评估替格瑞洛的安全性和有效性的主要研究PLATO中，均排除了心动过缓事件风险很大的患者（例如患有病态窦房结综合征、2度或3度房室传导阻滞或心动过缓相关晕厥但未装起搏器的患者）。由于在这些患者中的临床经验有限，因此需要谨慎使用替格瑞洛。
此外，在替格瑞洛与已知可引起心动过缓的药物联合用药时也应该小心。但在PLATO试验中，在与一种或多种已知可引起心动过缓的药物（例如96％β-受体阻滞剂、33％钙通道阻滞剂地尔硫卓和维拉帕米以及4％地高辛）合用后，却未观察到具有临床意义的不良事件发生。
PLATO的Holter亚组研究期间，在ACS急性期，替格瑞洛组发生室性间歇>3秒的患者多于氯吡格雷组。在ACS急性期内，在替格瑞洛治疗中，Holter监测发现慢性心力衰竭（CHF）患者室性间歇的增加高于总体研究人群，但是在用替格瑞洛治疗1个月或与氯吡格雷相比却未出现此类状况。在此患者人群中，未出现与此不平衡情况（包括晕厥和起搏器植入术）相关的不良临床结果。
3呼吸困难
替格瑞洛治疗的患者中有13.8％报告有呼吸困难，氯吡格雷治疗的患者中有7.8％。研究者认为有2.2％的患者发生的呼吸困难与替格瑞洛有因果关系。通常为轻、中度呼吸困难，无需停药即可缓解。哮喘/COPD患者在替格瑞洛治疗中发生呼吸困难的风险可能加大，有哮喘和/或COPD病史的患者应慎用替格瑞洛。倍林达导致呼吸困难的机制目前仍不清楚。如果患者报告出现了新的、持续的或加重的呼吸困难，那么应该对其进行仔细研究，如果无法耐受，则应停止倍林达治疗。
在一项亚组研究中，对PLATO试验中的199例患者（无论是否报告有呼吸困难）进行了肺功能检查，结果发现两治疗组之间的FEV1不存在显著差异。对1个月或至少6个月的长期治疗后测得的肺功能无不良影响。
4停药
应避免中断替格瑞洛片治疗。如果必须暂时停用替格瑞洛（如治疗出血或择期外科手术），则应尽快重新开始给予治疗。停用替格瑞洛将会增加心肌梗死、支架血栓和死亡的风险。
肌酐水平升高
在替格瑞洛治疗期间肌酐水平可能会升高，其发病机制目前仍不清楚。治疗一个月后需对肾功进行检查，以后则按照常规治疗需要而进行肾功检查，需要特别关注≥75岁的患者、中度/重度肾损害患者和接受ARB合并治疗的患者。
5血尿酸增加
在PLATO研究中，替格瑞洛治疗患者的高尿酸血症发病风险高于氯吡格雷治疗患者。对于有既往高尿酸血症或痛风性关节炎的患者应慎用替格瑞洛。为谨慎起见，不建议尿酸性肾病患者使用替格瑞洛。
6其它
基于在PLATO试验中观察到的阿司匹林维持剂量对于替格瑞洛相较于氯吡格雷疗效的关系，不推荐替格瑞洛与维持剂量>100mg的阿司匹林联合用药（见临床试验）。
应避免替格瑞洛与CYP3A4强抑制剂合并使用（如酮康唑、克拉霉素、萘法唑酮、利托那韦和阿扎那韦），因为合并用药可能会使替格瑞洛的暴露显著增加（见药物相互作用）。
不建议替格瑞洛与CYP3A4强诱导剂（如利福平、地塞米松、苯妥英、卡马西平和苯巴比妥）联合用药，因为合并用药可能会导致替格瑞洛的暴露量和有效性下降。
不建议替格瑞洛与治疗指数窄的CYP3A4底物（即西沙必利和麦角生物碱类）联合用药，因为替格瑞洛可能会使这些药物的暴露量增加。
不建议替格瑞洛与>40mg的辛伐他汀或洛伐他汀联合用药。
在地高辛与替格瑞洛合并用药时，建议进行密切的临床和实验室监测。
尚无替格瑞洛与强效P-糖蛋白（P-gp）抑制剂（如维拉帕米、奎尼丁、环孢素）联合用药可能会增加替格瑞洛暴露的数据。如果无法避免联合用药，则用药时应谨慎。
对驾驶和操作机器能力的影响：目前还无替格瑞洛对驾驶和机械操作能力影响的研究。替格瑞洛对驾驶和机械操作能力无影响或只具有微小的影响。
据报道在急性冠脉综合征治疗期间会出现头晕和意识模糊症状，因此，出现这些症状的患者在驾驶或操作机械时应格外小心。


【倍林达药物相互作用】
替格瑞洛主要经CYP3A4代谢，少部分由CYP3A5代谢。
其他药物对替格瑞洛的影响
CYP3A抑制剂：合并使用酮康唑可使替格瑞洛的Cmax和AUC分别增加2.4倍和7.3倍，活性代谢产物的Cmax和AUC分别下降89％和56％；其它CYP3A4的强抑制剂也会有相似的影响。应避免倍林达与CYP3A强效抑制剂（酮康唑、伊曲康唑、伏立康唑、克拉霉素、奈法唑酮、利托那韦、沙奎那韦、奈非那韦、茚地那韦、阿扎那韦和泰利霉素等）联合使用（见禁忌和药代动力学）。
CYP3A诱导剂：合并使用利福平可使替格瑞洛的Cmax和AUC分别降低73％和86％，活性代谢产物的Cmax未发生改变，AUC降低46％。预期其它CYP3A4诱导剂（如地塞米松、苯妥英、卡马西平和苯巴比妥）也会降低替格瑞洛的暴露。倍林达应避免与CYP3A强效诱导剂联合使用。
阿司匹林：与大于100mg维持剂量阿司匹林合用时，会降低替格瑞洛减少复合终点事件的临床疗效。
其它：临床药理学相互作用研究显示，替格瑞洛与肝素、依诺肝素和阿司匹林或去氨加压素合用时，与替格瑞洛单独用药相比，对替格瑞洛或其活性代谢产物的PK、ADP诱导的血小板聚集没有任何影响。

【倍林达替格瑞洛对其它药物的影响】
替格瑞洛是CYP3A4/5和P-糖蛋白转运体的抑制剂。
辛伐他汀、洛伐他汀：因为通过CYP3A4代谢，替格瑞洛可使其血清浓度升高。替格瑞洛使辛伐他汀的Cmax增加81％、AUC增加56％，辛伐他汀酸的Cmax增加64％、AUC增加52％，有些患者会增加至2-3倍。辛伐他汀对替格瑞洛的血浆浓度无影响。替格瑞洛可能对洛伐他汀有相似的影响。在与替格瑞洛合用时，辛伐他汀、洛伐他汀的给药剂量不得大于40mg。
阿托伐他汀：阿托伐他汀和替格瑞洛联合用药，可使阿托伐他汀酸的Cmax增加23％、AUC增加36％。所有阿托伐他汀酸代谢产物的AUC和Cmax也会出现类似增加。考虑这些增加没有临床显著意义。
通过CYP2C9代谢的药物：替格瑞洛和甲苯磺丁脲联合用药，两种药物的血浆浓度均无改变，提示替格瑞洛不是CYP2C9的抑制剂，不太可能改变CYP2C9介导的药物（如华法林和甲苯磺丁脲）的代谢。
口服避孕药：替格瑞洛与左炔诺孕酮和炔雌醇合用时会使炔雌醇的暴露增加约20％，但不会改变左炔诺孕酮的PK。当替格瑞洛与左炔诺孕酮和炔雌醇合并使用时，预期不会对口服避孕药的有效性产生具有临床意义的影响。
地高辛（P-gp底物）：替格瑞洛和地高辛联合用药可使后者的Cmax增加75％和AUC增加28％。因此建议替格瑞洛与治疗指数较窄的P-gp依赖性药物（如地高辛、环孢霉素）联合使用时，应进行适当的临床和/或实验室监测。

【倍林达与其它药物联合治疗】
已知可诱导心动过缓的药物：由于观察到无症状的室性间歇和心动过缓，因此在替格瑞洛与已知可诱导心动过缓的药物联合用药时，应谨慎用药。
在PLATO研究中，常常将替格瑞洛与阿司匹林、质子泵抑制剂、他汀类药物、β-受体阻滞剂、血管紧张素转换酶抑制剂和血管紧张素受体阻滞剂联合用药用于伴随疾病的长期治疗，与肝素、低分子肝素和静脉GpIIb/IIIa抑制剂联合用药用于伴随疾病的短期治疗。未观察到与这些药物有关的有临床意义的不良作用出现。
替格瑞洛与肝素、依诺肝素或去氨加压素联合用药对活化部分凝血酶时间（aPTT）、活化凝血时间（ACT）或Xa因子含量测定无影响。但是由于潜在的药效学相互作用，当替格瑞洛与已知可改变止血的药物合用时应谨慎。
由于SSRI治疗中报告有出血异常（如帕罗西汀、舍曲林和西酞普兰），因此建议SSRI应慎与替格瑞洛合用，合用可能会增加出血风险。
查看倍林达[Brilinta]详细药物相互作用信息
FDA妊娠分级
C级:动物研究证明药物对胎儿有危害性（致畸或胚胎死亡等），或尚无设对照的妊娠妇女研究，或尚未对妊娠妇女及动物进行研究。本类药物只有在权衡对孕妇的益处大于对胎儿的危害之后，方可使用。

【倍林达药物过量】
目前还没有逆转替格瑞洛作用的解毒药，预计替格瑞洛不可通过透析清除（见注意事项）。应根据当地标准医疗实践处置用药过量。出血为可以预期的药物过量药理效应，如发生出血，应采取适当的支持性治疗措施。
替格瑞洛片单剂量给药高达900mg可很好耐受。单剂量递增研究结果显示，倍林达的剂量限制反应为胃肠道毒性，包括恶心、呕吐、腹泻等。药物过量可能引起的具有临床意义的其它不良反应包括呼吸困难和室性停搏，应进行心电图监测。

【倍林达服药与进食】
服药不受进食影响。

【倍林达禁忌】
对替格瑞洛或倍林达任何辅料成分过敏者。
活动性病理性出血（如消化性溃疡或颅内出血）的患者。
有颅内出血病史者。
中-重度肝脏损害患者。
因联合用药可导致替格瑞洛的暴露量大幅度增加，禁止替格瑞洛片与强效CYP3A4抑制剂（如酮康唑、克拉霉素、奈法唑酮、利托那韦和阿扎那韦）联合用药。

【倍林达注意事项】
1出血风险
在3期关键性试验（PLATO血小板抑制和患者结果，18624例患者）中，关键排除标准包括过去6个月内发生出血风险增加、具有临床意义的血小板减少或贫血、既往颅内出血、胃肠道出血，或过去30天内接受了大手术。在用替格瑞洛和阿司匹林联合治疗的急性冠脉综合征患者中，非CABG主要出血的风险增加，需要临床关注的出血（非致死或危及生命的"主要XxX次要PLATO出血"）亦更多见。
因此，应衡量替格瑞洛用药对患者带来的已知出血风险增加与预防动脉粥样硬化血栓事件获益之间的平衡。如有临床指证，以下患者应慎用替格瑞洛：
-有出血倾向（例如近期创伤、近期手术、凝血功能障碍、活动性或近期胃肠道出血）的患者慎用倍林达。有活动性病理性出血的患者、有颅内出血病史的患者、中-重度肝损害的患者禁用倍林达。
-在服用替格瑞洛片后24小时内联合使用其它可能增加出血风险药品[例如用非甾体抗炎药（NSAIDS）、口服抗凝血药和/或纤溶剂]的患者，慎用倍林达。
目前尚无有关替格瑞洛对血小板成分输血时止血作用的数据；循环中的替格瑞洛可能会抑制已输注的血小板。由于合并使用替格瑞洛和去氨加压素不会降低模板法出血时间，因此去氨加压素可能对临床出血事件没有作用。
抗纤维蛋白溶解疗法（氨基己酸或氨甲环酸）和/或重组因子Ⅶa可能会增强止血作用。在确定出血原因且控制出血后，可重新使用替格瑞洛片。
2手术
应告知每一位患者，在他们将要接受任何预定的手术之前和服用任何新药之前，应告诉医师和牙医其正在使用替格瑞洛。
在PLATO研究中，对于进行冠状动脉旁路移植术（CABG）的患者，当在手术前一天停药时，替格瑞洛引起的出血事件多于氯吡格雷，但是，在手术前2天或更多天停药时，则两组的主要出血事件发生率相当。对于实施择期手术的患者，如果抗血小板药物治疗不是必须的，应在术前7天停止使用替格瑞洛。
处于心动过缓事件危险中的患者
由于在早期临床研究中经常观察到无症状的室性间歇，因此在评估替格瑞洛的安全性和有效性的主要研究PLATO中，均排除了心动过缓事件风险很大的患者（例如患有病态窦房结综合征、2度或3度房室传导阻滞或心动过缓相关晕厥但未装起搏器的患者）。由于在这些患者中的临床经验有限，因此需要谨慎使用替格瑞洛。
此外，在替格瑞洛与已知可引起心动过缓的药物联合用药时也应该小心。但在PLATO试验中，在与一种或多种已知可引起心动过缓的药物（例如96％β-受体阻滞剂、33％钙通道阻滞剂地尔硫卓和维拉帕米以及4％地高辛）合用后，却未观察到具有临床意义的不良事件发生。
PLATO的Holter亚组研究期间，在ACS急性期，替格瑞洛组发生室性间歇>3秒的患者多于氯吡格雷组。在ACS急性期内，在替格瑞洛治疗中，Holter监测发现慢性心力衰竭（CHF）患者室性间歇的增加高于总体研究人群，但是在用替格瑞洛治疗1个月或与氯吡格雷相比却未出现此类状况。在此患者人群中，未出现与此不平衡情况（包括晕厥和起搏器植入术）相关的不良临床结果。
3呼吸困难
替格瑞洛治疗的患者中有13.8％报告有呼吸困难，氯吡格雷治疗的患者中有7.8％。研究者认为有2.2％的患者发生的呼吸困难与替格瑞洛有因果关系。通常为轻、中度呼吸困难，无需停药即可缓解。哮喘/COPD患者在替格瑞洛治疗中发生呼吸困难的风险可能加大，有哮喘和/或COPD病史的患者应慎用替格瑞洛。倍林达导致呼吸困难的机制目前仍不清楚。如果患者报告出现了新的、持续的或加重的呼吸困难，那么应该对其进行仔细研究，如果无法耐受，则应停止倍林达治疗。
在一项亚组研究中，对PLATO试验中的199例患者（无论是否报告有呼吸困难）进行了肺功能检查，结果发现两治疗组之间的FEV1不存在显著差异。对1个月或至少6个月的长期治疗后测得的肺功能无不良影响。
4停药
应避免中断替格瑞洛片治疗。如果必须暂时停用替格瑞洛（如治疗出血或择期外科手术），则应尽快重新开始给予治疗。停用替格瑞洛将会增加心肌梗死、支架血栓和死亡的风险。
肌酐水平升高
在替格瑞洛治疗期间肌酐水平可能会升高，其发病机制目前仍不清楚。治疗一个月后需对肾功进行检查，以后则按照常规治疗需要而进行肾功检查，需要特别关注≥75岁的患者、中度/重度肾损害患者和接受ARB合并治疗的患者。
5血尿酸增加
在PLATO研究中，替格瑞洛治疗患者的高尿酸血症发病风险高于氯吡格雷治疗患者。对于有既往高尿酸血症或痛风性关节炎的患者应慎用替格瑞洛。为谨慎起见，不建议尿酸性肾病患者使用替格瑞洛。
6其它
基于在PLATO试验中观察到的阿司匹林维持剂量对于替格瑞洛相较于氯吡格雷疗效的关系，不推荐替格瑞洛与维持剂量>100mg的阿司匹林联合用药（见临床试验）。
应避免替格瑞洛与CYP3A4强抑制剂合并使用（如酮康唑、克拉霉素、萘法唑酮、利托那韦和阿扎那韦），因为合并用药可能会使替格瑞洛的暴露显著增加（见药物相互作用）。
不建议替格瑞洛与CYP3A4强诱导剂（如利福平、地塞米松、苯妥英、卡马西平和苯巴比妥）联合用药，因为合并用药可能会导致替格瑞洛的暴露量和有效性下降。
不建议替格瑞洛与治疗指数窄的CYP3A4底物（即西沙必利和麦角生物碱类）联合用药，因为替格瑞洛可能会使这些药物的暴露量增加。
不建议替格瑞洛与>40mg的辛伐他汀或洛伐他汀联合用药。
在地高辛与替格瑞洛合并用药时，建议进行密切的临床和实验室监测。
尚无替格瑞洛与强效P-糖蛋白（P-gp）抑制剂（如维拉帕米、奎尼丁、环孢素）联合用药可能会增加替格瑞洛暴露的数据。如果无法避免联合用药，则用药时应谨慎。
对驾驶和操作机器能力的影响：目前还无替格瑞洛对驾驶和机械操作能力影响的研究。替格瑞洛对驾驶和机械操作能力无影响或只具有微小的影响。
据报道在急性冠脉综合征治疗期间会出现头晕和意识模糊症状，因此，出现这些症状的患者在驾驶或操作机械时应格外小心。

【倍林达儿童用药】
倍林达对18岁以下儿童的安全性和有效性尚未确立。

【倍林达老年患者用药】
老年患者无需调整剂量。见用法用量。
在PLATO研究中，43％的患者≥65岁，15％的患者≥75岁。各治疗组和年龄组
的相对出血风险是相似的。
老年患者与年轻患者的安全性或有效性总体无差异。然而，根据临床经验并不能确定老年与年轻患者之间的药效差异是一致的，某些老年患者对药物更为敏感的情况不能排除。

【倍林达孕妇及哺乳期妇女用药】
妊娠：尚无有关怀孕妇女使用替格瑞洛治疗的对照研究。动物研究显示，母体接受约5-7倍人体推荐用药剂量（MRHD，根据体表面积）时，替格瑞洛会引发胎儿畸形。只有潜在获益大于对胎儿的风险时，才能在怀孕期间使用替格瑞洛。
哺乳：替格瑞洛或其活性代谢产物是否会分泌到人乳中仍是未知。替格瑞洛可通过大鼠乳汁分泌。由于许多药物可分泌至人乳中，且替格瑞洛对哺乳婴儿有潜在严重不良反应可能，因此，应在考虑替格瑞洛对母亲的重要性后，在决定是停止哺乳还是中止药物。

【倍林达不良反应】
在一项大规模3期研究（PLATO研究）中，对替格瑞洛在急性冠脉综合征[不稳定性心绞痛（UA），非ST段抬高的心肌梗死（NSTEMI）和ST段抬高的心肌梗死（STEMI）]患者的安全性进行了评估，对接受替格瑞洛治疗的患者（倍林达起始剂量为180mg，维持剂量为90mg每日2次）与接受氯吡格雷治疗的患者（起始剂量为300-600mg，维持剂量为75mg每日1次）进行了比较，两种治疗均联合使用阿司匹林（ASA）和其它标准疗法。
在10000例患者中对替格瑞洛片的安全性进行了评价，其中包括治疗期超过1年的3000多例患者。在替格瑞洛治疗的患者中，常报告的不良反应为呼吸困难、挫伤和鼻出血，这些事件的发生率高于氯吡格雷组患者。

【倍林达不良事件总结列表】
在替格瑞洛的临床研究中出现以下不良反应。
不良反应按照发生频率和系统器官分类。发生频率分组按照以下方式定义：十分常见（≥1/10）、常见（≥1/100，<1/10）、偶见（≥1/1000，<1/100）、罕见（≥1/10000，<1/1000），十分罕见（<1/10000），未知（无法从现有数据估计）。
按发生频率和系统器官分类（SOC）归类的不良事件
代谢及营养类疾病：罕见：高尿酸血症（包括高尿酸血症，血尿酸升高）。
精神病类：罕见：意识混乱。
各类神经系统疾病：偶见：颅内出血（包括脑出血，颅内出血，出血性卒中），头晕，头痛；罕见：感觉异常。
眼器官疾病：偶见：眼出血（眼内、结膜、视网膜）。
耳及迷路类疾病：罕见：耳出血、眩晕。
呼吸系统、胸及纵隔疾病：常见：呼吸困难（包括呼吸困难、劳力性呼吸困难，静息时呼吸困难，夜间呼吸困难），鼻出血；偶见：咯血。
胃肠系统疾病：常见：胃肠道出血（包括胃肠道出血、直肠出血、小肠出血、黑便、潜血）；偶见：呕血、胃肠道溃疡出血（包括胃肠溃疡出血、胃溃疡出血、十二指肠溃疡出血、消化性溃疡出血）、痔疮出血、胃炎、口腔出血（包括牙龈出血）、呕吐、腹泻、腹痛、恶心、消化不良；罕见：腹膜后出血、便秘。
皮肤及皮下组织类疾病：常见：皮下或真皮出血（包括皮下血肿、皮肤出血、皮下出血、瘀点），瘀斑（包括挫伤、血肿、瘀斑、挫伤增加倾向、创伤性血肿）；偶见：皮疹、瘙痒。
各种肌肉骨骼及结缔组织疾病：罕见：关节积血[PLATO研究中替格瑞洛组（N=9235）未报告关节积血ADR，发病频率是按点估计的95％置信区间上限计算的（基于3/X，其中X代表总样本量，如9235）。计算得该发病频率为3/9235，这属于"罕见"类发病率。]
肾脏及泌尿系统疾病：偶见：尿道出血（包括血尿、尿中带血、尿道出血）。
生殖系统及乳腺疾病：偶见：阴道出血（包括子宫出血）。
各类检查：罕见：血肌酐升高。
各类损伤、中毒及手术并发症：常见：操作部位出血（包括血管穿刺部位出血、血管穿刺部位血肿、注射部位出血、穿刺部位出血、导管部位出血）；偶见：操作后出血、出血；罕见：伤口出血、创伤性出血。

【倍林达对特定不良反应的说明】
出血
在PLATO研究中使用了以下出血定义：
主要致命/危及生命的出血：致命性或颅内出血、或伴有心包填塞的心包内出血、或由于出血所导致的低血容量休克或严重低血压需要升压药或手术、或临床显著或明显出血导致的血红蛋白下降（>50g/L）、或因出血而输血4个单位或以上[全血或浓集红细胞（PRBC）]等。
其它主要出血：显著的功能丧失（如眼内出血伴性失明）、或临床显著或明显出血有关的血红蛋白下降（30-50g/L）、或因出血而输血2-3个单位（全血或PRBC）等。
次要出血：需要医学干预止血或治疗出血（如需要到医院进行填塞治疗的鼻出血）。
轻微出血：其它所有无需干预或治疗的出血事件（例如擦伤、牙龈出血、注射部位渗血等）。
另外，将PLATO中报告的出血事件与TIMI（心肌梗死溶栓）量表进行了一一对应，以便与其它相似研究进行比较。TIMI主要出血的定义是与血红蛋白下降>5g/dL或颅内出血有关的临床显著出血事件；TIMI次要事件的定义是与血红蛋白下降3g/dL，但≤5g/dL有关的显著出血事件。
替格瑞洛和氯吡格雷治疗后PLATO主要致命/危及生命的出血、PLATO总体主要出血、TIMI主要出血或TIMI次要出血（表1）的发生率无差异。但替格瑞洛组PLATO主要XxX次要出血之和多于氯吡格雷组。PLATO研究中发生致命出血的患者很少：替格瑞洛组有20例（0.2％），氯吡格雷组有23例（0.3％）。
年龄、性别、体重、种族、地理区域、伴随状况、合并用药治疗和病史（包括既往卒中或短暂性脑缺血发作）均不能预示总体或非操作性PLATO主要出血。因此，无特别的人群组处于这些亚类出血的风险中。
CABG相关出血：在PLATO研究中，1584例（队列的12％）患者进行了冠状动脉旁路移植（CABG）手术，其中有42％发生了PLATO主要致命/危及生命的出血，且在两个治疗组间无差异。每组中有6例患者发生了致命性CABG出血。
非-CABG相关出血和非操作相关出血：替格瑞洛与氯吡格雷组的非-CABG相关的PLATO-定义的主要致命/危及生命的出血发生率无差异，但PLATO定义的总体主要出血、TIMI主要出血和TIMI主要XxX次要出血在替格瑞洛组更为常见。同样，去掉所有的操作相关出血，替格瑞洛组发生的出血多于氯吡格雷组（表1）。替格瑞洛组由于非操作相关出血而导致停止治疗的发生率（2.9％）高于氯吡格雷组（1.2％；P<0.001）。
颅内出血：替格瑞洛组发生的颅内非操作性出血的数量（26例患者发生27例次出血，0.3％）多于氯吡格雷组（N=14例次出血，0.2％），其中，替格瑞洛组的11例出血和氯吡格雷的1例出血是致命的。两组的总体致命性出血无差异。
呼吸困难
应用替格瑞洛治疗的患者中有呼吸困难（感觉呼吸急促）的报告。在PLATO研究中，替格瑞洛组和氯吡格雷组分别有13.8％和7.8％的患者报告了呼吸困难的不良反应（包括呼吸困难、静息时呼吸困难、劳累性呼吸困难、阵发性夜间呼吸困难和夜间呼吸困难）。研究者认为替格瑞洛组2.2％的患者和氯吡格雷组0.6％的患者发生的呼吸困难与接受的治疗有因果关系，其中少数为严重不良反应（替格瑞洛组0.14％，氯吡格雷组0.02％）。呼吸困难症状多为轻度至中度，多数在治疗开始后早期单次发作。
与氯吡格雷相比，接受替格瑞洛治疗的哮喘/COPD患者发生非严重呼吸困难（替格瑞洛组3.29％，氯吡格雷组0.53％）和严重呼吸困难（替格瑞洛组0.38％，氯吡格雷组0.00％）的风险加大。在值方面，该组的风险高于总体PLATO人群的风险。
这些呼吸困难事件中约有30％在7天内消除。PLATO中包括了基线即有充血性心力衰竭、慢性阻塞性肺病或哮喘的患者，这些患者和老年患者中报告呼吸困难者更多。替格瑞洛组0.9％的患者因呼吸困难停用研究药物，氯吡格雷组为0.1％。替格瑞洛组较高的呼吸困难发生率与新发或恶化的心肺疾病无关。替格瑞洛对肺功能检查无影响。
实验室检查
肌酐水平升高：在PLATO研究中，替格瑞洛组、氯吡格雷组分别有25.5％、21.3％的患者血清肌酐浓度显著增加>30％；分别有8.3％、6.7％的患者血清肌酐浓度显著增加>50％。肌酐升高>50％的情况在>75岁的患者（替格瑞洛13.6％相比氯吡格雷8.8％）、基线时即有重度肾损伤（替格瑞洛17.8％相比氯吡格雷12.5％）和接受ARB合并用药治疗的患者（替格瑞洛11.2％相比氯吡格雷7.1％）中更为显著。在这些亚组人群，两组中导致停用研究药物的肾相关严重不良事件和不良事件相似。替格瑞洛组报告的肾不良事件总数为4.9％，氯吡格雷组为3.8％，但研究者认为与治疗有因果关系的事件发生比率两组相似：替格瑞洛组有54（0.6％），氯吡格雷组有43（0.5％）。
尿酸水平升高：在PLATO研究中，替格瑞洛组、氯吡格雷组分别有22％、13％患者的血清尿酸浓度升高超出正常上限，替格瑞洛组平均血清尿酸浓度约升高15％，氯吡格雷组约为7.5％，而在停止治疗后，替格瑞洛组下降至约7％，而氯吡格雷组没有下降。替格瑞洛组报告的高尿酸血症不良事件的发生率为0.5％，氯吡格雷组为0.2％。在这些不良事件中，研究者认为替格瑞洛组有0.05％与治疗有因果关系，氯吡格雷组为0.02％。替格瑞洛组报告的痛风性关节炎不良事件为0.2％，氯吡格雷组为0.1％，研究者评估认为这些不良事件均与治疗无因果关系。
心动过缓
临床研究显示，替格瑞洛可增加Holter检出的缓慢性心律失常（包括室性间歇）。PLATO排除了心动过缓事件风险增加的患者（例如患有病态窦房结综合征、2度或3度AV阻滞或心动过缓所致晕厥而无起搏器保护的患者）。在PLATO研究中，替格瑞洛治疗的患者和氯吡格雷治疗的患者中分别有1.7％、1.5％报告有晕厥、先兆晕厥和意识丧失。
PLATO研究的Holter亚组（约3000位患者）中，在急性期，替格瑞洛组出现室性间歇的患者（6.0％）多于氯吡格雷组（3.5％）；1个月后，替格瑞洛组室性间歇的发生率为2.2％，氯吡格雷组为1.6％。
男子乳腺发育
PLATO研究显示，替格瑞洛组男性患者有0.23％报告有男子乳腺发育，而氯吡格雷组为0.05％。
PLATO研究显示，两治疗组间其他性激素相关不良反应（包括性器官恶性肿瘤）并无差异。

【倍林达上市后经验】
在倍林达的上市后使用过程中出现了一些不良反应的报告。由于这些反应都是自发报告，来自样本量不确定的人群，因此无法可靠估计这些不良反应的发生率。
免疫系统疾病-过敏反应，包括血管性水肿。

【倍林达药物相互作用】
替格瑞洛主要经CYP3A4代谢，少部分由CYP3A5代谢。
其他药物对替格瑞洛的影响
CYP3A抑制剂：合并使用酮康唑可使替格瑞洛的Cmax和AUC分别增加2.4倍和7.3倍，活性代谢产物的Cmax和AUC分别下降89％和56％；其它CYP3A4的强抑制剂也会有相似的影响。应避免倍林达与CYP3A强效抑制剂（酮康唑、伊曲康唑、伏立康唑、克拉霉素、奈法唑酮、利托那韦、沙奎那韦、奈非那韦、茚地那韦、阿扎那韦和泰利霉素等）联合使用（见禁忌和药代动力学）。
CYP3A诱导剂：合并使用利福平可使替格瑞洛的Cmax和AUC分别降低73％和86％，活性代谢产物的Cmax未发生改变，AUC降低46％。预期其它CYP3A4诱导剂（如地塞米松、苯妥英、卡马西平和苯巴比妥）也会降低替格瑞洛的暴露。倍林达应避免与CYP3A强效诱导剂联合使用。
阿司匹林：与大于100mg维持剂量阿司匹林合用时，会降低替格瑞洛减少复合终点事件的临床疗效。
其它：临床药理学相互作用研究显示，替格瑞洛与肝素、依诺肝素和阿司匹林或去氨加压素合用时，与替格瑞洛单独用药相比，对替格瑞洛或其活性代谢产物的PK、ADP诱导的血小板聚集没有任何影响。

【倍林达贮藏】
30℃以下保存。

【倍林达生产企业】
企业名称：AstraZenecaAB（瑞典）

 

BRILINTA® 
(ticagrelor) Tabletse

WARNING

(A) BLEEDING RISK, (B) ASPIRIN DOSE AND BRILINTA EFFECTIVENESS

A. Bleeding Risk

o BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal bleeding.

o Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage.

o Do not start BRILINTA in patients undergoing urgent coronary artery bypass graft surgery (CABG).

o If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events.

B. Aspirin Dose And Brilinta Effectiveness

o Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided.

DESCRIPTION

BRILINTA contains ticagrelor, a cyclopentyltriazolopyrimidine, inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP-receptor. Chemically it is (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. The empirical formula of ticagrelor is C23H28F2N6O4S and its molecular weight is 522.57. The chemical structure of ticagrelor is:

Ticagrelor is a crystalline powder with an aqueous solubility of approximately 10 μg/mL at room temperature.

BRILINTA 90 mg tablets for oral administration contain 90 mg of ticagrelor and the following ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, talc, polyethylene glycol 400, and ferric oxide yellow.

BRILINTA 60 mg tablets for oral administration contain 60 mg of ticagrelor and the following ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol 400, ferric oxide black, and ferric oxide red.

Indications & Dosage

INDICATIONS

BRILINTA is indicated to reduce the rate of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome (ACS) or a history of myocardial infarction (MI). For at least the first 12 months following ACS, it is superior to clopidogrel.

BRILINTA also reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS [see Clinical Studies].

DOSAGE AND ADMINISTRATION

Dosing

In the management of ACS, initiate BRILINTA treatment with a 180 mg loading dose. Administer 90 mg twice daily during the first year after an ACS event. After one year administer 60 mg twice daily.

Do not administer BRILINTA with another oral P2Y12 platelet inhibitor.

Use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg [see WARNINGS AND PRECAUTIONS and Clinical Studies]. A patient who misses a dose of BRILINTA should take one tablet (their next dose) at its scheduled time.

Administration

For patients who are unable to swallow tablets whole, BRILINTA tablets can be crushed, mixed with water and drunk. The mixture can also be administered via a nasogastric tube (CH8 or greater) [seeCLINICAL PHARMACOLOGY].

HOW SUPPLIED

Dosage Forms And Strengths

BRILINTA (ticagrelor) 90 mg is supplied as a round, biconvex, yellow, film-coated tablet marked with a “90” above “T” on one side.

BRILINTA (ticagrelor) 60 mg is supplied as a round, biconvex, pink, film-coated tablet marked with “60” above “T” on one side.

BRILINTA (ticagrelor) 90 mg is supplied as a round, biconvex, yellow, film-coated tablet with a “90” above “T” on one side:

Bottles of 60 - NDC 0186-0777-60
100 count Hospital Unit Dose - NDC 0186-0777-39

BRILINTA (ticagrelor) 60 mg is supplied as a round, biconvex, pink, film-coated tablet with a “60” above “T” on one side:

Bottles of 60 - NDC 0186-0776-60

Storage And Handling

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

Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850. Revised: Mar 2018

Side Effects

SIDE EFFECTS

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

· Bleeding [see WARNINGS AND PRECAUTIONS]

· Dyspnea [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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

BRILINTA has been evaluated for safety in more than 27000 patients, including more than 13000 patients treated for at least 1 year.

Bleeding In PLATO (Reduction In Risk Of Thrombotic Events In ACS)

Figure 1 is a plot of time to the first non-CABG major bleeding event.

Figure 1 : Kaplan-Meier estimate of time to first non-CABG PLATO-defined major bleeding event(PLATO)

Frequency of bleeding in PLATO is summarized in Tables 1 and 2. About half of the non-CABG major bleeding events were in the first 30 days.

Table 1 : Non-CABG related bleeds (PLATO)

No baseline demographic factor altered the relative risk of bleeding with BRILINTA compared to clopidogrel.

In PLATO, 1584 patients underwent CABG surgery. The percentages of those patients who bled are shown in Figure 2 and Table 2.

Figure 2 : ‘Major fatal/life-threatening' CABG-related bleeding by days from last dose of study drug to CABG procedure (PLATO)

X-axis is days from last dose of study drug prior to CABG. 
The PLATO protocol recommended a procedure for withholding study drug prior to CABG or other major surgery without unblinding. If surgery was elective or non-urgent, study drug was interrupted temporarily, as follows: If local practice was to allow antiplatelet effects to dissipate before surgery, capsules (blinded clopidogrel) were withheld 5 days before surgery and tablets (blinded ticagrelor) were withheld for a minimum of 24 hours and a maximum of 72 hours before surgery. If local practice was to perform surgery without waiting for dissipation of antiplatelet effects capsules and tablets were withheld 24 hours prior to surgery and use of aprotinin or other haemostatic agents was allowed. If local practice was to use IPA monitoring to determine when surgery could be performed both the capsules and tablets were withheld at the same time and the usual monitoring procedures followed. 
T Ticagrelor; C Clopidogrel.

Table 2 : CABG-related bleeding (PLATO)

When antiplatelet therapy was stopped 5 days before CABG, major bleeding occurred in 75% of BRILINTA treated patients and 79% on clopidogrel.

Other Adverse Reactions In PLATO

Adverse reactions that occurred at a rate of 4% or more in PLATO are shown in Table 3.

Table 3 : Percentage of patients reporting non-hemorrhagic adverse reactions at least 4% or more in either group and more frequently on BRILINTA (PLATO)

Bleeding In PEGASUS (Secondary Prevention in Patients with a History of Myocardial Infarction)

Overall outcome of bleeding events in the PEGASUS study are shown in Table 4.

Table 4 :Bleeding events (PEGASUS)

The bleeding profile of BRILINTA 60 mg compared to aspirin alone was consistent across multiple pre-defined subgroups (e.g., by age, gender, weight, race, geographic region, concurrent conditions, concomitant therapy, stent, and medical history) for TIMI Major and TIMI Major or Minor bleeding events.

Other Adverse Reactions In PEGASUS

Adverse reactions that occurred in PEGASUS at rates of 3% or more are shown in Table 5.

Table 5 : Non-hemorrhagic adverse reactions reported in >3.0% of patients in the ticagrelor 60 mg treatment group (PEGASUS)

Bradycardia

In a Holter substudy of about 3000 patients in PLATO, more patients had ventricular pauses with BRILINTA (6.0%) than with clopidogrel (3.5%) in the acute phase; rates were 2.2% and 1.6%, respectively, after 1 month. PLATO and PEGASUS excluded patients at increased risk of bradycardic events (e.g., patients who have sick sinus syndrome, 2nd or 3rd degree AV block, or bradycardic-related syncope and not protected with a pacemaker). In PLATO, syncope, presyncope and loss of consciousness were reported by 1.7% and 1.5% of BRILINTA 90 mg and clopidogrel patients, respectively. In PEGASUS, syncope was reported by 1.2% and 0.9% of patients on BRILINTA 60 mg and aspirin alone, respectively.

Lab Abnormalities

Serum Uric Acid

In PLATO, serum uric acid levels increased approximately 0.6 mg/dL from baseline on BRILINTA 90 mg and approximately 0.2 mg/dL on clopidogrel. The difference disappeared within 30 days of discontinuing treatment. Reports of gout did not differ between treatment groups in PLATO (0.6% in each group).

In PEGASUS, serum uric acid levels increased approximately 0.2 mg/dL from baseline on BRILINTA 60 mg and no elevation was observed on aspirin alone. Gout occurred more commonly in patients on BRILINTA than in patients on aspirin alone (1.5%, 1.1%). Mean serum uric acid concentrations decreased after treatment was stopped.

Serum Creatinine

In PLATO, a >50% increase in serum creatinine levels was observed in 7.4% of patients receiving BRILINTA 90 mg compared to 5.9% of patients receiving clopidogrel. The increases typically did not progress with ongoing treatment and often decreased with continued therapy. Evidence of reversibility upon discontinuation was observed even in those with the greatest on treatment increases. Treatment groups in PLATO did not differ for renal-related serious adverse events such as acute renal failure, chronic renal failure, toxic nephropathy, or oliguria.

In PEGASUS, serum creatinine concentration increased by >50% in approximately 4% of patients receiving BRILINTA 60 mg, similar to aspirin alone. The frequency of renal related adverse events was similar for ticagrelor and aspirin alone regardless of age and baseline renal function.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of BRILINTA. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency.

Immune system disorders: Hypersensitivity reactions including angioedema [see CONTRAINDICATIONS].

Skin and subcutaneous tissue disorders: Rash

Drug Interactions

DRUG INTERACTIONS

Strong CYP3A Inhibitors

Strong CYP3A inhibitors substantially increase ticagrelor exposure and so increase the risk of dyspnea, bleeding, and other adverse events. Avoid use of strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin) [see CLINICAL PHARMACOLOGY].

Strong CYP3A Inducers

Strong CYP3A inducers substantially reduce ticagrelor exposure and so decrease the efficacy of ticagrelor. Avoid use with strong inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine and phenobarbital) [see CLINICAL PHARMACOLOGY].

Aspirin

Use of BRILINTA with aspirin maintenance doses above 100 mg reduced the effectiveness of BRILINTA [see WARNINGS AND PRECAUTIONS and Clinical Studies].

Opioids

As with other oral P2Y12 inhibitors, co-administration of opioid agonists delay and reduce the absorption of ticagrelor and its active metabolite presumably because of slowed gastric emptying [see CLINICAL PHARMACOLOGY]. Consider the use of a parenteral anti-platelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists.

Simvastatin, Lovastatin

BRILINTA increases serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg [see CLINICAL PHARMACOLOGY].

Digoxin

BRILINTA inhibits the P-glycoprotein transporter; monitor digoxin levels with initiation of or change in BRILINTA therapy [see CLINICAL PHARMACOLOGY].

Warnings & Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

General Risk Of Bleeding

Drugs that inhibit platelet function including BRILINTA increase the risk of bleeding [see ADVERSE REACTIONS].

If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events [see Discontinuation of BRILINTA and ADVERSE REACTIONS].

Concomitant Aspirin Maintenance Dose

In PLATO the use of BRILINTA with maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Therefore, after the initial loading dose of aspirin, use BRILINTA with a maintenance dose of aspirin of 75100 mg [see DOSAGE AND ADMINISTRATION and Clinical Studies].

Dyspnea

In clinical trials, about 14% of patients treated with BRILINTA developed dyspnea. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment, but led to study drug discontinuation in 0.9% of BRILINTA and 0.1% of clopidogrel patients in PLATO and 4.3% of BRILINTA 60 mg and 0.7% on aspirin alone patients in PEGASUS.

In a substudy of PLATO, 199 subjects underwent pulmonary function testing irrespective of whether they reported dyspnea. There was no indication of an adverse effect on pulmonary function assessed after one month or after at least 6 months of chronic treatment.

If a patient develops new, prolonged, or worsened dyspnea that is determined to be related to BRILINTA, no specific treatment is required; continue BRILINTA without interruption if possible. In the case of intolerable dyspnea requiring discontinuation of BRILINTA, consider prescribing another antiplatelet agent.

Discontinuation Of BRILINTA

Discontinuation of BRILINTA will increase the risk of myocardial infarction, stroke, and death. If BRILINTA must be temporarily discontinued (e.g., to treat bleeding or for significant surgery), restart it as soon as possible. When possible, interrupt therapy with BRILINTA for five days prior to surgery that has a major risk of bleeding. Resume BRILINTA as soon as hemostasis is achieved.

Bradyarrhythmias

Ticagrelor can cause ventricular pauses [see ADVERSE REACTIONS]. Bradyarrhythmias including AV block have been reported in the postmarketing setting. Patients with a history of sick sinus syndrome, 2nd or 3rd degree AV block or bradycardia-related syncope not protected by a pacemakerwere excluded from PLATO and PEGASUS and may be at increased risk of developing bradyarrhythmias with ticagrelor.

Severe Hepatic Impairment

Avoid use of BRILINTA in patients with severe hepatic impairment. Severe hepatic impairment is likely to increase serum concentration of ticagrelor. There are no studies of BRILINTA patients with severe hepatic impairment [see CLINICAL PHARMACOLOGY].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Advise patients daily doses of aspirin should not exceed 100 mg and to avoid taking any other medications that contain aspirin.

Advise patients that they:

· Will bleed and bruise more easily

· Will take longer than usual to stop bleeding

· Should report any unanticipated, prolonged or excessive bleeding, or blood in their stool or urine.

Advise patients to contact their doctor if they experience unexpected shortness of breath, especially if severe.

Advise patients to inform physicians and dentists that they are taking BRILINTA before any surgery or dental procedure.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Ticagrelor was not carcinogenic in the mouse at doses up to 250 mg/kg/day or in the male rat at doses up to 120 mg/kg/day (19 and 15 times the MRHD of 90 mg twice daily on the basis of AUC, respectively). Uterine carcinomas, uterine adenocarcinomas and hepatocellular adenomas were seen in female rats at doses of 180 mg/kg/day (29-fold the maximally recommended dose of 90 mg twice daily on the basis of AUC), whereas 60 mg/kg/day (8-fold the MRHD based on AUC) was not carcinogenic in female rats.

Mutagenesis

Ticagrelor did not demonstrate genotoxicity when tested in the Ames bacterial mutagenicity test, mouse lymphoma assay and the rat micronucleus test. The active O-demethylated metabolite did not demonstrate genotoxicity in the Ames assay and mouse lymphoma assay.

Impairment Of Fertility

Ticagrelor had no effect on male fertility at doses up to 180 mg/kg/day or on female fertility at doses up to 200 mg/kg/day (>15-fold the MRHD on the basis of AUC). Doses of ≥10 mg/kg/day given to female rats caused an increased incidence of irregular duration estrus cycles (1.5-fold the MRHD based on AUC).

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of BRILINTA use in pregnant women. In animal studies, ticagrelor caused structural abnormalities at maternal doses about 5 to 7 times the maximum recommended human dose (MRHD) based on body surface area. BRILINTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In reproductive toxicology studies, pregnant rats received ticagrelor during organogenesis at doses from 20 to 300 mg/kg/day. 20 mg/kg/day is approximately the same as the MRHD of 90 mg twice daily for a 60 kg human on a mg/m² basis. Adverse outcomes in offspring occurred at doses of 300 mg/kg/day (16.5 times the MRHD on a mg/m² basis) and included supernumerary liver lobe and ribs, incomplete ossification of sternebrae, displaced articulation of pelvis, and misshapen/misaligned sternebrae. At the mid-dose of 100 mg/kg/day, delayed development of liver and skeleton was seen. When pregnant rabbits received ticagrelor during organogenesis at doses from 21 to 63 mg/kg/day, fetuses exposed to the highest maternal dose of 63 mg/kg/day (6.8 times the MRHD on a mg/m² basis) had delayed gall bladder development and incomplete ossification of the hyoid, pubis and sternebrae occurred.

In a prenatal/postnatal study, pregnant rats received ticagrelor at doses of 10 to 180 mg/kg/day during late gestation and lactation. Pup death and effects on pup growth were observed at 180 mg/kg/day (approximately 10 times the MRHD on a mg/m² basis). Relatively minor effects such as delays in pinna unfolding and eye opening occurred at doses of 10 and 60 mg/kg (approximately one-half and 3.2 times the MRHD on a mg/m² basis).

Nursing Mothers

It is not known whether ticagrelor or its active metabolites are excreted in human milk. Ticagrelor is excreted in rat milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from BRILINTA, a decision should be made whether to discontinue nursing or to discontinue BRILINTA.

Pediatric Use

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

Geriatric Use

In PLATO and PEGASUS, about half of patients in each study were ≥65 years of age and about 15% were ≥75 years of age. No overall differences in safety or effectiveness were observed between elderly and younger patients.

Hepatic Impairment

Ticagrelor is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Avoid use of BRILINTA in patients with severe hepatic impairment. There is limited experience with BRILINTA in patients with moderate hepatic impairment; consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor. No dosage adjustment is needed in patients with mild hepatic impairment [see WARNINGS AND PRECAUTIONSand CLINICAL PHARMACOLOGY].

Renal Impairment

No dosage adjustment is needed in patients with renal impairment. Patients receiving dialysis have not been studied [see CLINICAL PHARMACOLOGY].

Overdosage & Contraindications

OVERDOSE

There is currently no known treatment to reverse the effects of BRILINTA, and ticagrelor is not expected to be dialyzable. Treatment of overdose should follow local standard medical practice. Bleeding is the expected pharmacologic effect of overdosing. If bleeding occurs, appropriate supportive measures should be taken.

Platelet transfusion did not reverse the antiplatelet effect of BRILINTA in healthy volunteers and is unlikely to be of clinical benefit in patients with bleeding.

Other effects of overdose may include gastrointestinal effects (nausea, vomiting, diarrhea) or ventricular pauses. Monitor the ECG.

CONTRAINDICATIONS

History Of Intracranial Hemorrhage

BRILINTA is contraindicated in patients with a history of intracranial hemorrhage (ICH) because of a high risk of recurrent ICH in this population [see Clinical Studies].

Active Bleeding

BRILINTA is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Hypersensitivity

BRILINTA is contraindicated in patients with hypersensitivity (e.g., angioedema) to ticagrelor or any component of the product.

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism Of Action

Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12 ADP-receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent.

Pharmacodynamics

The inhibition of platelet aggregation (IPA) by ticagrelor and clopidogrel was compared in a 6-week study examining both acute and chronic platelet inhibition effects in response to 20 μM ADP as the platelet aggregation agonist.

The onset of IPA was evaluated on Day 1 of the study following loading doses of 180 mg ticagrelor or 600 mg clopidogrel. As shown in Figure 3, IPA was higher in the ticagrelor group at all time points. The maximum IPA effect of ticagrelor was reached at around 2 hours, and was maintained for at least 8 hours.

The offset of IPA was examined after 6 weeks on ticagrelor 90 mg twice daily or clopidogrel 75 mg daily, again in response to 20 μM ADP.

As shown in Figure 4, mean maximum IPA following the last dose of ticagrelor was 88% and 62% for clopidogrel. The insert in Figure 4 shows that after 24 hours, IPA in the ticagrelor group (58%) was similar to IPA in clopidogrel group (52%), indicating that patients who miss a dose of ticagrelor would still maintain IPA similar to the trough IPA of patients treated with clopidogrel. After 5 days, IPA in the ticagrelor group was similar to IPA in the placebo group. It is not known how either bleeding risk or thrombotic risk track with IPA, for either ticagrelor or clopidogrel.

Figure 3 : Mean inhibition of platelet aggregation (±SE) following single oral doses of placebo, 180 mg ticagrelor or 600 mg clopidogrel

Figure 4 : Mean inhibition of platelet aggregation (IPA) following 6 weeks on placebo, ticagrelor 90 mg twice daily, or clopidogrel 75 mg daily

Transitioning from clopidogrel to BRILINTA resulted in an absolute IPA increase of 26.4% and from BRILINTA to clopidogrel resulted in an absolute IPA decrease of 24.5%. Patients can be transitioned from clopidogrel to BRILINTA without interruption of antiplatelet effect [see DOSAGE AND ADMINISTRATION].

Pharmacokinetics

Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and healthy volunteers.

Absorption

BRILINTA can be taken with or without food. Absorption of ticagrelor occurs with a median tmax of 1.5 h (range 1.0– 4.0). The formation of the major circulating metabolite AR-C124910XX (active) from ticagrelor occurs with a median tmax of 2.5 h (range 1.5-5.0).

The mean absolute bioavailability of ticagrelor is about 36% (range 30%-42%). Ingestion of a high-fat meal had no effect on ticagrelor Cmax, but resulted in a 21% increase in AUC. The Cmax of its major metabolite was decreased by 22% with no change in AUC.

BRILINTA as crushed tablets mixed in water, given orally or administered through a nasogastric tube into the stomach, is bioequivalent to whole tablets (AUC and Cmax within 80-125% for ticagrelor and AR-C124910XX) with a median tmax of 1.0 hour (range 1.0 – 4.0) for ticagrelor and 2.0 hours (range 1.0 –8.0) for AR-C124910XX.

Distribution

The steady state volume of distribution of ticagrelor is 88 L. Ticagrelor and the active metabolite are extensively bound to human plasma proteins (>99%).

Metabolism

CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. Ticagrelor and its major active metabolite are weak P-glycoprotein substrates and inhibitors. The systemic exposure to the active metabolite is approximately 30-40% of the exposure of ticagrelor.

Excretion

The primary route of ticagrelor elimination is hepatic metabolism. When radiolabeled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (58% in feces, 26% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the major metabolite of ticagrelor is most likely to be biliarysecretion. The mean t½ is approximately 7 hours for ticagrelor and 9 hours for the active metabolite.

Specific Populations

The effects of age, gender, ethnicity, renal impairment and mild hepatic impairment on the pharmacokinetics of ticagrelor are presented in Figure 5. Effects are modest and do not require dose adjustment.

Figure 5 :Impact of intrinsic factors on the pharmacokinetics of ticagrelor

Effects Of Other Drugs On BRILINTA

CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. The effects of other drugs on the pharmacokinetics of ticagrelor are presented in Figure 6 as change relative to ticagrelor given alone (test/reference). Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, and clarithromycin) substantially increase ticagrelor exposure. Moderate CYP3A inhibitors have lesser effects (e.g., diltiazem). CYP3A inducers (e.g., rifampin) substantially reduce ticagrelor blood levels. P-gp inhibitors (e.g., cyclosporine) increase ticagrelor exposure.

Co-administration of 5 mg intravenous morphine with 180 mg loading dose of ticagrelor decreased observed mean ticagrelor exposure by up to 25% in healthy adults and up to 36% in ACS patients undergoing PCI. Tmax was delayed by 1-2 hours. Exposure of the active metabolite decreased to a similar extent. Morphine co-administration did not delay or decrease platelet inhibition in healthy adults. Mean platelet aggregation was higher up to 3 hours post loading dose in ACS patients co-administered with morphine.

Co-administration of intravenous fentanyl with 180 mg loading dose of ticagrelor in ACS patients undergoing PCI resulted in similar effects on ticagrelor exposure and platelet inhibition.

Figure 6 : Effect of co-administered drugs on the pharmacokinetics of ticagrelor

Effects Of BRILINTA On Other Drugs

In vitro metabolism studies demonstrate that ticagrelor and its major active metabolite are weak inhibitors of CYP3A4, potential activators of CYP3A5 and inhibitors of the P-gp transporter. Ticagrelor and AR-C124910XX were shown to have no inhibitory effect on human CYP1A2, CYP2C19, and CYP2E1 activity. For specific in vivo effects on the pharmacokinetics of simvastatin, atorvastatin, ethinyl estradiol, levonorgesterol, tolbutamide, digoxin and cyclosporine, see Figure 7.

Figure 7 : Impact of BRILINTA on the pharmacokinetics of co-administered drugs

Pharmacogenetics

In a genetic substudy cohort of PLATO, the rate of thrombotic CV events in the BRILINTA arm did not depend on CYP2C19 loss of function status.

Clinical Studies

Acute Coronary Syndromes And Secondary Prevention After Myocardial Infarction

PLATO

PLATO was a randomized double-blind study comparing BRILINTA (N=9333) to clopidogrel (N=9291), both given in combination with aspirin and other standard therapy, in patients with acute coronary syndromes (ACS), who presented within 24 hours of onset of the most recent episode of chest pain or symptoms. The study’s primary endpoint was the composite of first occurrence of cardiovascular death, non-fatal MI (excluding silent MI), or non-fatal stroke.

Patients who had already been treated with clopidogrel could be enrolled and randomized to either study treatment. Patients with previous intracranial hemorrhage, gastrointestinal bleeding within the past 6 months, or with known bleeding diathesis or coagulation disorder were excluded. Patients taking anticoagulants were excluded from participating and patients who developed an indication for anticoagulation during the trial were discontinued from study drug. Patients could be included whether there was intent to manage the ACS medically or invasively, but patient randomization was not stratified by this intent.

All patients randomized to BRILINTA received a loading dose of 180 mg followed by a maintenance dose of 90 mg twice daily. Patients in the clopidogrel arm were treated with an initial loading dose of clopidogrel 300 mg, if clopidogrel therapy had not already been given. Patients undergoing PCI could receive an additional 300 mg of clopidogrel at investigator discretion. A daily maintenance dose of aspirin 75-100 mg was recommended, but higher maintenance doses of aspirin were allowed according to local judgment. Patients were treated for at least 6 months and for up to 12 months.

PLATO patients were predominantly male (72%) and Caucasian (92%). About 43% of patients were >65 years and 15% were >75 years. Median exposure to study drug was 277 days. About half of the patients received pre-study clopidogrel and about 99% of the patients received aspirin at some time during PLATO. About 35% of patients were receiving a statin at baseline and 93% received a statin sometime during PLATO.

Table 6 shows the study results for the primary composite endpoint and the contribution of each component to the primary endpoint. Separate secondary endpoint analyses are shown for the overall occurrence of CV death, MI, and stroke and overall mortality.

Table 6 : Patients with outcome events (KM%)(PLATO)

The Kaplan-Meier curve (Figure 8) shows time to first occurrence of the primary composite endpoint of CV death, nonfatal MI or non-fatal stroke in the overall study.

Figure 8 : Time to first occurrence of CV death, MI, or stroke (PLATO)

The curves separate by 30 days [relative risk reduction (RRR) 12%] and continue to diverge throughout the 12-month treatment period (RRR 16%).

Among 11289 patients with PCI receiving any stent during PLATO, there was a lower risk of stent thrombosis (1.3% for adjudicated “definite”) than with clopidogrel (1.9%) (HR 0.67, 95% CI 0.50-0.91; p=0.009). The results were similar for drug-eluting and bare metal stents.

A wide range of demographic, concurrent baseline medications, and other treatment differences were examined for their influence on outcome. Some of these are shown in Figure 9. Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses. Most of the analyses show effects consistent with the overall results, but there are two exceptions: a finding of heterogeneity by region and a strong influence of the maintenance dose of aspirin. These are considered further below.

Most of the characteristics shown are baseline characteristics, but some reflect post-randomization determinations (e.g., aspirin maintenance dose, use of PCI).

Figure 9: Subgroup analyses of (PLATO)

Note: The figure above presents effects in various subgroups most of which are baseline characteristics and most of which were pre-specified. 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.

Regional Differences

Results in the rest of the world compared to effects in North America (US and Canada) show a smaller effect in North America, numerically inferior to the control and driven by the US subset. The statistical test for the US/non-US comparison is statistically significant (p=0.009), and the same trend is present for both CV death and non-fatal MI. The individual results and nominal p-values, like all subset analyses, need cautious interpretation, and they could represent chance findings. The consistency of the differences in both the CV mortality and non-fatal MI components, however, supports the possibility that the finding is reliable.

A wide variety of baseline and procedural differences between the US and non-US (including intended invasive vs. planned medical management, use of GPIIb/IIIa inhibitors, use of drug eluting vs. bare-metal stents) were examined to see if they could account for regional differences, but with one exception, aspirin maintenance dose, these differences did not appear to lead to differences in outcome.

Aspirin Dose

The PLATO protocol left the choice of aspirin maintenance dose up to the investigator and use patterns were different in US sites from sites outside of the US. About 8% of non-US investigators administered aspirin doses above 100 mg, and about 2% administered doses above 300 mg. In the US, 57% of patients received doses above 100 mg and 54% received doses above 300 mg. Overall results favored BRILINTA when used with low maintenance doses (≤100 mg) of aspirin, and results analyzed by aspirin dose were similar in the US and elsewhere. Figure 10 shows overall results by median aspirin dose. Figure 10 shows results by region and dose.

Figure 10 : CV death, MI, stroke by maintenance aspirin dose in the US and outside the US (PLATO)

Like any unplanned subset analysis, especially one where the characteristic is not a true baseline characteristic (but may be determined by usual investigator practice), the above analyses must be treated with caution. It is notable, however, that aspirin dose predicts outcome in both regions with a similar pattern, and that the pattern is similar for the two major components of the primary endpoint, CV death and non-fatal MI.

Despite the need to treat such results cautiously, there appears to be good reason to restrict aspirin maintenance dosage accompanying ticagrelor to 100 mg. Higher doses do not have an established benefit in the ACS setting, and there is a strong suggestion that use of such doses reduces the effectiveness of BRILINTA.

PEGASUS

The PEGASUS TIMI-54 study was a 21162-patient, randomized, double-blind, placebo-controlled, parallel-group study. Two doses of ticagrelor, either 90 mg twice daily or 60 mg twice daily, co-administered with 75-150 mg of aspirin, were compared to aspirin therapy alone in patients with history of MI. The primary endpoint was the composite of first occurrence of CV death, non-fatal MI and non-fatal stroke. CV death and all-cause mortality were assessed as secondary endpoints.

Patients were eligible to participate if they were ≥50 years old, with a history of MI 1 to 3 years prior to randomization, and had at least one of the following risk factors for thrombotic cardiovascular events: age ≥65 years, diabetes mellitus requiring medication, at least one other prior MI, evidence of multivessel coronary artery disease, or creatinine clearance <60 mL/min. Patients could be randomized regardless of their prior ADP receptor blocker therapy or a lapse in therapy. Patients requiring or who were expected to require renal dialysis during the study were excluded. Patients with any previous intracranial hemorrhage, gastrointestinal bleeding within the past 6 months, or with known bleeding diathesis or coagulation disorder were excluded. Patients taking anticoagulants were excluded from participating and patients who developed an indication for anticoagulation during the trial were discontinued from study drug. A small number of patients with a history of stroke were included. Based on information external to PEGASUS, 102 patients with a history of stroke (90 of whom received study drug) were terminated early and no further such patients were enrolled.

Patients were treated for at least 12 months and up to 48 months with a median follow up time of 33 months.

Patients were predominantly male (76%) Caucasian (87%) with a mean age of 65 years, and 99.8% of patients received prior aspirin therapy. See Table 7 for key baseline features.

Table 7 : Baseline features (PEGASUS)

The Kaplan-Meier curve (Figure 11) shows time to first occurrence of the primary composite endpoint of CV death, nonfatal MI or non-fatal stroke.

Figure 11 :Time to First Occurrence of CV death, MI or Stroke (PEGASUS)

Both the 60 mg and 90 mg regimens of BRILINTA in combination with aspirin were superior to aspirin alone in reducing the incidence of CV death, MI or stroke. The absolute risk reductions for BRILINTA plus aspirin vs. aspirin alone were 1.27% and 1.19% for the 60 and 90 mg regimens, respectively. Although the efficacy profiles of the two regimens were similar, the lower dose had lower risks of bleeding and dyspnea.

Table 8 shows the results for the 60 mg plus aspirin regimen vs. aspirin alone.

Table 8 : Incidences of the primary composite endpoint, primary composite endpoint components, and secondary endpoints (PEGASUS)

In PEGASUS, the RRR for the composite endpoint from 1 to 360 days (17% RRR) and from 361 days and onwards (16% RRR) were similar.

The treatment effect of BRILINTA 60 mg over aspirin appeared similar across most pre-defined subgroups, see Figure 12.

Figure 12 : Subgroup analyses of ticagrelor 60 mg (PEGASUS)

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and most of which were pre-specified. 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.

Medication Guide

PATIENT INFORMATION

BRILINTA® 
(brih-LIN-tah)
(ticagrelor) Tablets

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

BRILINTA is used to lower your chance of having a heart attack or dying from a heart attack or stroke but BRILINTA (and similar drugs) can cause bleeding that can be serious and sometimes lead to death. In cases of serious bleeding, such as internal bleeding, the bleeding may result in the need for blood transfusions or surgery. While you take BRILINTA:

· you may bruise and bleed more easily

· you are more likely to have nose bleeds

· it will take longer than usual for any bleeding to stop

Call your doctor right away, if you have any of these signs or symptoms of bleeding while taking BRILINTA:

· bleeding that is severe or that you cannot control

· pink, red or brown urine

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

· red or black stools (looks like tar)

· coughing up blood or blood clots

Do not stop taking BRILINTA without talking to the doctor who prescribes it for you. People who are treated with a stent, and stop taking BRILINTA too soon, have a higher risk of getting a blood clotin the stent, having a heart attack, or dying. If you stop BRILINTA because of bleeding, or for other reasons, your risk of a heart attack or stroke may increase. Your doctor may instruct you to stop taking BRILINTA 5 days before surgery. This will help to decrease your risk of bleeding with your surgery or procedure. Your doctor should tell you when to start taking BRILINTA again, as soon as possible after surgery.

Taking BRILINTA with aspirin

BRILINTA is taken with aspirin. Talk to your doctor about the dose of aspirin that you should take with BRILINTA. You should not take a dose of aspirin higher than 100 mg daily because it can affect how well BRILINTA works. Do not take doses of aspirin higher than what your doctor tells you to take. Tell your doctor if you take other medicines that contain aspirin, and do not take new over-the-counter medicines with aspirin in them.

What is BRILINTA?

BRILINTA is a prescription medicine used to treat people who:

· have had a heart attack or severe chest pain that happened because their heart was not getting enough oxygen.

BRILINTA is used with aspirin to lower your chance of having another serious problem with your heart or blood vessels, such as heart attack, stroke, or blood clots in your stent. These can be fatal.

Platelets are blood cells that help with normal blood clotting. BRILINTA helps prevent platelets from sticking together and forming a clot that can block an artery.

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

Who should not take BRILINTA?

Do not take BRILINTA if you:

· have a history of bleeding in the brain

· are bleeding now

· are allergic to ticagrelor or any of the ingredients in BRILINTA. See the end of this Medication Guide for a complete list of ingredients in BRILINTA.

What should I tell my doctor before taking BRILINTA?

Before you take BRILINTA, tell your doctor if you:

· have had bleeding problems in the past

· have had any recent serious injury or surgery

· plan to have surgery or a dental procedure

· have a history of stomach ulcers or colon polyps

· have lung problems, such as COPD or asthma

· have liver problems

· have a history of stroke

· are pregnant or plan to become pregnant. It is not known if BRILINTA will harm your unborn baby. You and your doctor should decide if you will take BRILINTA.

· are breastfeeding or plan to breastfeed. It is not known if BRILINTA passes into your breast milk. You and your doctor should decide if you will take BRILINTA or breastfeed. You should not do both without talking with your doctor.

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

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. BRILINTA may affect the way other medicines work, and other medicines may affect how BRILINTA works.

Especially tell your doctor if you take:

· an HIV-AIDS medicine

· medicine for heart conditions or high blood pressure

· medicine for high blood cholesterol levels

· an anti-fungal medicine by mouth

· an anti-seizure medicine

· a blood thinner medicine

· rifampin (Rifater, Rifamate, Rimactane, Rifadin)

Ask your doctor or pharmacist if you are not sure if your medicine is listed above.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take BRILINTA?

· Take BRILINTA exactly as prescribed by your doctor.

· Your doctor will tell you how many BRILINTA tablets to take and when to take them.

· Take BRILINTA with a low dose (not more than 100 mg daily) of aspirin. You may take BRILINTA with or without food.

· Take your doses of BRILINTA around the same time every day.

· If you forget to take your scheduled dose of BRILINTA, take your next dose at its scheduled time. Do not take 2 doses at the same time unless your doctor tells you to.

· If you take too much BRILINTA or overdose, call your doctor or poison control center right away, or go to the nearest emergency room.

· If you are unable to swallow the tablet(s) whole, you may crush the BRILINTA tablet(s) and mix it with water. Drink all the water right away. Refill the glass with water, stir, and drink all the water.

What are the possible side effects of BRILINTA?

BRILINTA can cause serious side effects, including:

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

· Shortness of breath. Call your doctor if you have new or unexpected shortness of breath when you are at rest, at night, or when you are doing any activity. Your doctor can decide what treatment is needed.

These are not all of the possible side effects of BRILINTA. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store BRILINTA?

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

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

General information about BRILINTA

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use BRILINTA for a condition for which it was not prescribed. Do not give BRILINTA to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or doctor for information about BRILINTA that is written for health professionals.

What are the ingredients in BRILINTA?

Active ingredient: ticagrelor. 90 mg tablets:

Inactive ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, talc, polyethylene glycol 400, and ferric oxide yellow.

60 mg tablets:

Inactive ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol 400, ferric oxide black and ferric oxide red.