以下资料仅供参考：                                                                                                                                              

                                                                                                                                            文案整理：Dr. Jasmine Ding

哌柏西利使用说明书：    

全球首个CDK4/6激酶抑制剂

美国FDA初次批准：2015

请仔细阅读说明书并在医师指导下使用：

【商品名称】

  通用名称：哌柏西利胶囊

  品牌名称：Ibrance,

  通用英文名称：Palbociclib Capsules

  其他名称：帕泊昔布，Palbace，帕博西尼

【成分】

本品主要成份为哌柏西利（palbociclib）。 其化学名称为： 6-乙酰基-8-环戊基-5-甲基-2-[[5-(1-哌嗪基)-2-吡啶基]氨基]吡啶[2,3-d]嘧啶-7(8H)-酮 分子量：447.54 辅料名称：微晶纤维素、单水乳糖、羧甲基淀粉钠、胶态二氧化硅、硬脂酸镁 

化学名：6-乙酰-8环戊基-5甲基-2-5{【（哌嗪-1-基）吡啶-2-基】氨基}吡啶并【2，3 d】嘧啶-7(8H)酮

分子式：C24H29N702

分子量：447.54克/摩尔。

【适应症/功能主治】

      本品适用于激素受体（HR）阳性、人表皮生长因子受体2（HER2）阴性的局部晚期或转移性乳腺癌，应与芳香化酶抑制剂联合使用作为绝经后女性患者的初始内分泌治疗。

      这个适应证是根据无进展生存(PFS)在加速批准下被批准。剂型批准此适应证可能取决于在验证性试验中临床获益的证明和描述

      其他适应症正在进行临床试验（非小细胞肺癌、淋巴瘤、多发性骨髓瘤）

【规格型号】胶囊100mg 

                     21粒/瓶

【用法用量】

      应由具抗癌药物使用经验的医生开始并监督本品治疗。 推荐剂量 哌柏西利的推荐剂量为125mg，每天一次，连续服用21天，之后停药7天（3/1给药方案），28天为一个治疗周期。治疗应当持续进行，除非患者不再有临床获益或出现不可接受的毒性。 当与来曲唑联用时，来曲唑的推荐剂量为2.5mg，口服，每天一次，在整个28天治疗周期连续服药。具体请参见来曲唑批准的说明书。 给药方法 口服。应与食物同服，最好随餐服药以确保哌柏西利暴露量一致（见[药代动力学]）。哌柏西利不得与葡萄柚或葡萄柚汁同服（见[药物相互作用]）。 哌柏西利胶囊应整粒吞服（吞服前不得咀嚼、压碎或打开胶囊）。如果胶囊出现破损、裂纹或其他不完整的情况，则不得服用。 应鼓励患者在每天大约相同的时间服药。如果患者呕吐或者漏服，当天不得补服。应照常进行下次服药。 剂量调整 建议根据个体安全性和耐受性调整哌柏西利的剂量。 出现某些不良反应时可能需要暂时中断/延迟给药和/或减低剂量，或永久停药来进行控制，请参照表1、2和3中提供的方案进行剂量调整（见[注意事项]和[不良反应]）。 在开始哌柏西利治疗前、每个治疗周期开始时、前2个治疗周期的第15天以及有临床指征时应监测全血细胞计数。 对于前6个治疗周期内发生最高严重程度为1或2级中性粒细胞减少症的患者，其后续周期的全血细胞计数监测时间应为每3个月一次、各周期开始之前以及有临床指征时。 建议在中性粒细胞绝对计数（AbsoluteNeutrophilCount,ANC）≥1,000/mm3且血小板计数≥50,000/mm3时接受哌柏西利。 特殊人群 老年人 ≥65岁的患者无需调整哌柏西利的剂量（见[药代动力学]）。 儿科人群 尚未确定哌柏西利在≤18岁儿童和青少年患者中的安全性和疗效。没有数据可用。 肝损伤 轻度或中度肝损伤患者（Child-PughA级和B级）无需调整哌柏西利的剂量。重度肝损伤（Child-PughC级）患者的推荐剂量为75mg，每天一次，采用3/1给药方案（见[注意事项]和[药代动力学]）。 肾损伤 轻度、中度或重度肾损伤患者（肌酐清除率[CreatinineClearance,CrCl]≥15 mL/min）无需调整哌柏西利的剂量。需要血液透析患者的数据不充分，无法对该人群提供任何剂量调整建议（见[注意事项]和[药代动力学]）。 与CYP3A强效抑制剂合用时的剂量调整 避免伴随使用CYP3A强效抑制剂，考虑替换为没有或只有微弱CYP3A抑制作用的其他伴随用药。如果患者必须合用CYP3A强效抑制剂，则将哌柏西利的剂量减少至75mg，每天一次。如果停用强效抑制剂，则将哌柏西利的剂量增加至开始使用CYP3A强效抑制剂之前的剂量（在抑制剂的3至5个半衰期后）[参见[药物相互作用]和[药代动力学]] 

【不良反应】

       本说明书描述了在临床试验中观察到的判断为可能由哌柏西利引起的不良反应及其近似的发生率。由于每项临床试验的条件各不相同，在一个临床试验中观察到的不良反应的发生率不能与另一个临床试验观察到的不良反应发生率直接比较，也可能不能反映临床实践中的实际发生率。 安全性特征概要 哌柏西利的总体安全性特征评估来自在HR阳性、HER2阴性晚期或转移性乳腺癌随机研究中接受哌柏西利与内分泌疗法联合治疗（527例与来曲唑联用和345例与氟维司群联用）的872例患者的合并数据[包括研究PALOMA-1(A5481003)，研究PALOMA-2(A5481008)，研究PALOMA-3(A5481023)]。 临床研究中，接受哌柏西利治疗的患者报告的最常见（≥20％）的任何级别的不良反应为中性粒细胞减少症、感染、白细胞减少症、疲乏、恶心、口腔炎、贫血、脱发和腹泻。哌柏西利的最常见（≥2％）的≥3级不良反应为中性粒细胞减少症、白细胞减少症、贫血、疲乏和感染。 在研究PALOMA-2中评估了哌柏西利（125mg/天）联合来曲唑（2.5mg/天）治疗对照安慰剂联合来曲唑治疗的安全性。哌柏西利联合来曲唑的中位治疗持续时间为19.8个月，而安慰剂联合来曲唑的中位治疗持续时间为13.8个月。在接受哌柏西利联合来曲唑治疗的患者中，有36％的患者因任何级别的不良反应而减量。43/444（9.7％）例接受哌柏西利联合来曲唑治疗的患者以及13/222（5.9％）例接受安慰剂联合来曲唑治疗的患者发生了与不良反应相关的永久停药。导致接受哌柏西利联合曲唑治疗的患者永久停药的不良反应包括中性粒细胞减少症（1.1％）和丙氨酸转氨酶升高（0.7％）。 不良反应列表 表4报告了3项随机研究[研究PALOMA-1(A5481003)，研究PALOMA-2(A5481008)，研究PALOMA-3(A5481023)]的合并数据集中的不良反应。合并数据集中哌柏西利治疗的中位持续时间为12.7个月。 表5报告了3项随机研究的合并数据集中的实验室检查异常。 按系统器官分类和发生频率列出不良反应。发生频率定义为：十分常见（≥1/10）、常见（≥1/100至<1/10）和偶见（≥1/1,000至<1/100）。 在PALOMA-2和PALOMA-3两项研究中，纳入了200例亚裔患者。在接受哌柏西利的亚裔患者中报告的3级或4级中性粒细胞减少症和白细胞减少症发生率高于非亚裔患者，因而在亚裔患者中的剂量中断、剂量减少和周期延迟发生频率也略高于非亚裔患者，但通过方案规定的剂量调整可控制总体安全性，亚裔患者与非亚裔患者具有相似的中位治疗持续时间。根据对已有的哌柏西利剂量暴露、安全性和疗效数据进行的累积分析，将125mg每日一次作为亚裔患者的起始剂量是恰当的。需根据患者个体的安全性和耐受性，严格遵循说明书调整哌柏西利剂量。 特定不良反应的描述 总体而言，3项随机研究中有703例（80.6％）无论以何种联用方案接受哌柏西利治疗的患者报告了任何级别的中性粒细胞减少症，其中分别有482例（55.3％）和88例（10.1％）患者报告3级和4级中性粒细胞减少症（见表4）。 3项随机临床研究中，至首次发生任何级别中性粒细胞减少症的中位时间为15天（12-700天），≥3级中性粒细胞减少症的中位持续时间为7天。 0.9％接受哌柏西利与氟维司群联用和2.1％接受哌柏西利与来曲唑联用的患者报告了发热性中性粒细胞减少症。 在总体临床研究中，大约2％接受哌柏西利治疗的患者曾报告过发热性中性粒细胞减少症。 

【禁忌】

        对活性成分或章节[成分]项下所列的任一辅料过敏者禁用。 禁止使用含圣约翰草的制品（见[药代相互作用]）。 

【注意事项】

       绝经前/围绝经期女性 鉴于芳香化酶抑制剂的作用机制，绝经前/围绝经期女性接受哌柏西利与芳香化酶抑制剂联合治疗时，必须进行卵巢切除或使用促黄体生成激素释放激素（LuteinizingHormoneReleasingHormone,LHRH）激动剂抑制卵巢功能。哌柏西利联合氟维司群用于绝经前/围绝经期女性的研究中，仅与LHRH激动剂联合用药。 危重内脏疾病（转移） 尚未在危重的有内脏疾病（转移）患者中研究哌柏西利的疗效和安全性（见[临床试验]）。 血液学毒性 中性粒细胞减少症是临床研究中最常报告的不良反应，临床研究中大约有2％的接受哌柏西利治疗的患者曾报告过发热性中性粒细胞减少症，并报告了1例中性粒细胞减少性败血症引起的死亡。应在哌柏西利治疗开始前、每个周期开始时、前两个周期的第15天以及出现临床指征时监测全血细胞计数。对于出现3或4级中性粒细胞减少症的患者，建议中断给药、减少剂量或延迟开始治疗周期，并进行密切监测。（见[用法用量]和[不良反应]）。医生应告知患者立即报告任何发热事件。 感染 因为哌柏西利具有骨髓抑制特性，其可使患者易于出现感染。 多项随机研究报道了哌柏西利组患者的感染率高于各自的对照组患者。分别有4.5％和0.7％的接受哌柏西利任何联用方案治疗的患者发生了3级和4级感染（见[不良反应]）。 应监测患者的感染体征和症状并且适当时应给予治疗（见[用法用量]）。 患者在出现任何骨髓抑制或感染体征或症状时立即报告，例如发热、寒战、头晕、气短、无力或出血和/或瘀伤倾向加重。 肝损伤 中度或重度肝损伤患者应慎用哌柏西利，并密切监测毒性体征（见[用法用量]和[药代动力学]）。 肾损伤 中度或重度肾损伤患者应慎用哌柏西利，并密切监测毒性体征（见[用法用量]和[药代动力学]）。 与CYP3A4抑制剂或诱导剂联合治疗 强效CYP3A4抑制剂可导致毒性增加（见[药物相互作用]）。哌柏西利治疗期间应避免与强效CYP3A抑制剂合用。仅在认真评估潜在获益和风险后才可考虑同时使用。如不能避免与强效CYP3A抑制剂同时使用，应将哌柏西利的剂量降至75 mg每天一次。停止使用强效抑制剂时，应将哌柏西利的剂量(抑制剂的3-5个半衰期后)增加至开始使用强效CYP3A抑制剂前的剂量（见[药物相互作用]）。 与CYP3A诱导剂同时使用可导致哌柏西利的暴露量降低，所以有缺乏疗效的风险。因此，应避免哌柏西利与强效CYP3A4诱导剂合用。哌柏西利与中效CYP3A诱导剂同时使用时无需调整剂量（见[药物相互作用]）。 有生育能力的女性或其配偶 有生育能力的女性或其男性配偶在使用哌柏西利治疗期间必须使用一种高效的避孕方法（见[孕妇及哺乳期妇女用药]）。 乳糖 哌柏西利含乳糖。存在半乳糖不耐症、Lapp乳糖酶缺乏症或葡萄糖-半乳糖吸收不良症等罕见遗传疾病的患者不得服用哌柏西利。 对驾驶和操作机器能力的影响 哌柏西利对驾驶和操作机器能力的影响很小。但是，哌柏西利可能引起疲乏，患者在驾驶或操作机器时应谨慎。 

【孕妇及哺乳期妇女用药】

       有生育能力的女性/避孕 接受本药品治疗的有生育能力的女性或其男性配偶，应在治疗期间以及完成治疗后分别至少3周（女性）或14周（男性）内采取充分的避孕措施（如，双重屏障避孕）（见[药物相关作用]）。 妊娠 尚缺乏关于孕妇使用哌柏西利的数据或数据有限。动物研究显示哌柏西利具有生殖毒性（见[药理毒理]）。不建议孕妇和未采取避孕措施的有生育能力的女性使用哌柏西利。 哺乳 尚未在人体或动物中进行相关研究以评价哌柏西利对乳汁生成的影响、是否存在于母乳中或对母乳喂养婴儿的影响。尚不清楚哌柏西利是否会分泌至人类乳汁中。接受哌柏西利治疗的患者不应哺乳。 生育力 在非临床生殖毒性研究中，未发现对大鼠的发情周期（雌性）或交配和生育力（雄性和雌性）有影响。尚未获得对人类生育力影响的临床数据。根据非临床安全性研究中雄性生殖器官的变化（睾丸曲细精管变性、附睾精子减少、精子活力和密度降低以及前列腺分泌减少），哌柏西利治疗可能会损害男性的生育力（见[药理毒理]）。因此，男性在开始哌柏西利治疗前应考虑保存精液。 

【儿童用药】
       尚未确定哌柏西利在18岁及以下的儿童和青少年患者中的安全性和疗效。尚无相关数据。 

【老年用药】

      在PALOMA-2研究中接受哌柏西利治疗的444例患者中，181（41％）例患者≥65岁，48（11％）例患者≥75岁。未发现上述患者与年轻患者在哌柏西利的安全性或有效性方面存在差异。65岁及以上患者无需调整哌柏西利的剂量（见[药代动力学]）。 

【特殊人群用药】

肝损伤：基于183例患者的药代动力学分析，其中40例患者轻度肝损害，对Ibrance暴露无影响。药代动力学对于中度或重度肝损伤患者，尚未进行研究。

肾损伤：基于183例患者的药代动力学分析，其中73例患者轻度肾损伤（60 mL / min≤CrCl <90 mL / min），29例患者中度肾损伤（30 mL / min≤CrCl <60 mL / min），palbociclib对轻度和中度肾损伤患者无影响。在严重肾脏的患者中尚未有研究。

【药理毒理】

       药理作用 哌柏西利是细胞周期蛋白依赖性激酶（CDK）4和6的抑制剂。周期蛋白D1和CDK4/6位于细胞增殖信号通路的下游。在体外，通过阻滞细胞从G1期进入S期，而减少雌激素受体（ER）阳性乳腺癌细胞系的细胞增殖。哌柏西利和雌激素拮抗剂联合作用于乳腺癌细胞系时，可降低视网膜母细胞瘤（Rb）蛋白磷酸化，从而导致E2F表达，及其信号传导下降，与药物各自单用相比具有更强的生长抑制作用。哌柏西利和雌激素拮抗剂联合作用于ER阳性的乳腺癌细胞系时，与药物各自单用相比，可使细胞老化增加，这一效应在哌柏西利停药后最多维持6天，但抗雌激素治疗继续进行时，可导致更大程度的细胞老化。人源性ER阳性乳腺癌异种移植模型体内研究显示，与药物各自单用相比，哌柏西利与来曲唑联用可对Rb磷酸化、下游信号传导以及肿瘤生长产生更强的抑制作用。 人骨髓单核细胞体外给予哌柏西利，无论有无抗雌激素处理，未见细胞发生老化，去除哌柏西利后细胞可恢复增殖。 毒理研究 一般毒性：在犬遥测试验中，给药剂量在人体临床暴露量（Cmax）4倍以上时，可见心血管影响（QTc延长、心率下降、RR间期延长和收缩压升高）。 在一项大鼠27周重复给药毒性试验中，大鼠在试验早期尚未成熟，发现与胰腺（胰岛细胞空泡形成）、眼睛（白内障、晶状体变性）、肾脏（肾小管空泡形成、慢性进行性肾病）和脂肪组织（萎缩）变化相关的葡萄糖代谢改变（尿糖、高血糖症、胰岛素下降），这种现象在哌柏西利经口给药剂量≥30mg/kg/天（AUC约为临床推荐剂量下的成人人体暴露量的11倍）的雄鼠中发生率最高。其中一些不良反应（尿糖/高血糖症、胰岛细胞空泡形成和肾小管空泡形成）在未成熟大鼠中进行的15周重复给药毒性试验中发生率和严重程度较低。在试验开始时已成熟的大鼠中进行的27周重复给药毒性试验，以及39周犬重复给药毒性试验中未见葡萄糖代谢改变或胰腺、眼睛、肾脏和脂肪组织相关变化。在大鼠中可见与葡萄糖代谢改变无关的牙齿毒性。哌柏西利以100mg/kg给药剂量给药27周（AUC约为临床推荐剂量下的成人人体暴露量的15倍）可导致大鼠切牙生长异常（变色、造釉细胞变性/坏疽、单核细胞浸润）。 遗传毒性：哌柏西利Ames试验和体外人淋巴细胞染色体畸变试验结果阴性，中国仓鼠卵巢细胞体外试验、雄性大鼠骨髓试验微核试验结果阳性。 生殖毒性：在雌性大鼠生育力试验中，给药剂量高达300mg/kg/天（AUC约为人体临床暴露量的4倍）时，未见哌柏西利对动物交配或生育力产生影响。在大鼠、犬重复给药毒性试验中，大鼠给药剂量高达300mg/kg/天，犬给药剂量高达3mg/kg/天（AUC分别约为临床推荐剂量下人体暴露量的6倍以及与人体暴露量相当）时，未见哌柏西利对雌性动物生殖器官产生任何不良影响。在大鼠和犬重复给药毒性试验、以及大鼠雄性生育力试验中可见哌柏西利对雄性生殖系统和生育力产生不良影响。重复给药毒性试验中，大鼠和犬分别给予哌柏西利≥30mg/kg/天和≥0.2mg/kg/天（AUC分别约为临床推荐剂量下人体暴露量的≥10倍和≥0.1倍）时，可见给药相关的睾丸、附睾、前列腺和精囊器官重量下降、萎缩或变性、精子减少、小管内细胞碎片和分泌减少，分别经过4周和12周的停药期后，上述对大鼠和犬雄性生殖器官的影响部分可逆。在雄性大鼠生育力和早期胚胎发育毒性试验中，哌柏西利给药剂量为100mg/kg/天（推算AUC约为临床推荐剂量下人体暴露量的20倍）时未见对交配产生影响，但生育力出现轻微下降，表现为精子活力和密度较低。在雌性大鼠生育力和早期胚胎发育毒性试验中，从交配前15天至妊娠第7天经口给予哌柏西利，在剂量达到300mg/kg/天（母体全身暴露约为临床推荐剂量下的人体暴露量的4倍）时未见导致胚胎毒性。 在大鼠和兔胚胎-胎仔发育试验中，妊娠动物在器官形成期分别经口给予哌柏西利高达300mg/kg/天和20mg/kg/天，大鼠在母体毒性剂量300mg/kg/天时可引起胎仔毒性，导致胎仔体重下降，剂量≥100mg/kg/天时，骨骼变异的发生率增加（第七颈椎出现肋骨的发生率增加）。兔在母体毒性剂量20mg/kg/天时，骨骼变异（包括前肢小趾骨）的发生率增加。大鼠剂量为300mg/kg/天和兔剂量为20mg/kg/天时，母体全身暴露量（AUC）分别约为临床推荐剂量下人体暴露量的4倍和9倍。 文献报道，CDK4/6双基因敲除小鼠在胎仔发育晚期（妊娠第14.5天至出生）因重度贫血死亡。但是由于靶点抑制程度存在差异，基因敲除小鼠数据可能无法预测对人的影响。 致癌性：尚未进行致癌性试验。 

【药代动力学】

     在实体瘤患者（包括晚期乳腺癌）和健康志愿者中研究了哌柏西利的药代动力学特征。 吸收 哌柏西利一般在口服后6-12小时之间达峰浓度（Cmax）。口服125 mg哌柏西利后，其平均绝对生物利用度为46％。在25-225mg剂量范围时，血药浓度时间曲线下面积（AreaUndertheCurve,AUC）和Cmax通常随剂量成比例增加。在每天一次重复给药后8天内达到稳态。哌柏西利按每天一次重复给药可出现蓄积，中位蓄积比为2.4（范围：1.54.2）。 食物影响 在大约13％的空腹人群中，哌柏西利的吸收和暴露量极低。在这一小部分人群中，进食增加了哌柏西利的暴露量，但在其余人群中，进食对哌柏西利的暴露量没有临床相关影响。与禁食过夜后给药相比，哌柏西利与高脂食物同服时AUCinf和Cmax分别升高了21％和38％，与低脂食物同服时分别升高了12％和27％，而在哌柏西利给药前1小时和给药后2小时进食中脂食物时分别升高了13％和24％。此外，进食还显著降低了个体间和个体自身的哌柏西利暴露量差异。根据上述结果，哌柏西利应与食物同服（见[用法用量]）。 分布 哌柏西利在体外与人血浆蛋白的结合率为85％，无浓度依赖性。在体内，人体血浆中哌柏西利的平均游离分数（fu）随肝功能恶化程度逐渐增加。在体内，随肾功能恶化，人体血浆中哌柏西利的平均fu无明显变化趋势。在体外，人体肝细胞主要通过被动扩散摄取哌柏西利。哌柏西利不是OATP1B1或OATP1B3的底物。 生物转化 体外和体内研究表明哌柏西利经由肝细胞进行广泛代谢。人单次口服[14C]标记的哌柏西利125mg后，哌柏西利的主要代谢途径是磺化和氧化，次要途径是葡萄糖苷酸化和酰化。血循环中检测到的主要为哌柏西利原型药。 大部分以代谢物形式排泄。哌柏西利的氨基磺酸结合物是在粪便中发现的主要药物相关成分，占给药剂量的25.8％。采用人肝细胞、肝胞浆和人肝S9组份以及重组磺基转移酶（SULT）酶进行的体外研究表明主要参与哌柏西利代谢的酶为CYP3A和SULT2A1。 消除 在晚期乳腺癌患者中，哌柏西利的几何平均表观口服清除率（CL/F）为63L/h，平均血浆消除半衰期为28.8小时。6例健康男性受试者单次口服[14C]哌柏西利后，在15天内回收到了总放射量的92％（中位数）；粪便（剂量的74％）为主要排泄途径，尿中回收了17％的剂量。经粪便和尿液排泄的哌柏西利原型药的回收率分别占给药剂量的2％和7％。 在体外研究中，在临床相关浓度时，哌柏西利不是CYP1A2、2A6、2B6、2C8、2C9、2C19和2D6的抑制剂，也不是CYP1A2、2B6、2C8和3A4的诱导剂。 体外评价表明，在临床相关浓度时，哌柏西利对有机阴离子转运体（OrganicAnionTransporter,OAT）1、OAT3、有机阳离子转运体（OrganicCationTransporter,OCT）2、有机阴离子转运多肽（OrganicAnionTransportingPolypeptide,OATP）1B1、OATP1B3和胆盐输出泵（BileSaltExportPump,BSEP）活性的抑制作用较弱。 特殊人群 年龄、性别和体重 基于一项包括183例癌症患者（50例男性和133例女性患者，年龄范围：22-89岁，体重范围：38-123kg）的群体药代动力学分析，性别对哌柏西利的暴露量没有影响，年龄和体重对哌柏西利的暴露量没有具临床意义的影响。 儿科人群 尚未在年龄18岁的患者中评估哌柏西利的药代动力学。 肝损伤 在不同程度肝功能受试者中进行了一项药代动力学试验，数据表明，与肝功能正常受试者相比，轻度肝损伤（Child-PughA级）受试者中游离的哌柏西利暴露量（游离AUCinf）降低17％，而中度（Child-PughB级）和重度（Child-PughC级）肝损伤受试者分别增加34％和77％；轻度、中度和重度肝损伤受试者中游离的哌柏西利峰浓度（Cmax）分别增加7％、38％和72％。此外，基于一项包括183例晚期癌症患者的群体药代动力学分析，其中包括40例轻度肝损伤患者（基于，NCI分类；总胆红素≤ULN和AST>ULN，或总胆红素>1.01.5×ULN和任意水平AST），轻度肝损伤对哌柏西利的药代动力学无影响。 肾损伤 在不同程度肾功能受试者中进行了一项药代动力学试验，数据表明，与肾功能正常（CrCl ≥90 mL/min）受试者相比，轻度（60mL/min≤CrCl<90mL/min）、中度（30mL/min≤CrCl<60mL/min）和重度（CrCl<30mL/min）肾损伤受试者对哌柏西利的总暴露量（AUCinf）分别增加39％、42％和31％；哌柏西利峰暴露量（Cmax）分别增加17％、12％和15％。此外，基于一项包括183例晚期癌症患者的群体药代动力学分析，其中包括73例轻度肾损伤患者和29例中度肾损伤，轻度和中度肾损伤对哌柏西利的药代动力学无影响。尚未在需要血液透析患者中研究哌柏西利的药代动力学。 亚裔人群 在日本健康志愿者中进行了一项药代动力学，与非亚裔受试者相比，日本受试者单次口服给药后的哌柏西利AUCinf和Cmax分别高出30％和35％。但在后续研究中，日本或亚裔乳腺癌患者接受多次给药后未观察到上述结果。基于亚裔和非亚裔人群的累积药代动力学、安全性和疗效数据分析，不需要基于亚裔人种进行剂量调整。 中国人群 研究A5481019(n=26)在既往未接受过任何针对晚期疾病的全身性抗癌治疗的ER阳性、HER2阴性的绝经后晚期乳腺癌中国患者中评价哌柏西利与来曲唑联合治疗的PK特征。该研究中所观测到的中国患者哌柏西利的药代动力学特征与PALOMA-2和PALOMA-3研究中非中国患者的药代动力学特征一致。在A5481019研究中的中国患者的谷浓度与PALOMA-2研究中所观测到的谷浓度一致，不需要基于中国人群进行剂量调整。 

吸收和分布

  口服Palbociclib后，平均C max浓度通常在6至12小时（达到最大浓度Tmax）观察到。口服125 mg剂量后，IBRANCE的平均绝对生物利用度为46％。在25mg至225mg的给药范围内，AUC和Cmax升高与剂量成正比。每日给药一次，重复8天内达稳定状态。每天重复给药，palbociclib中位数累积比为2.4（范围1.5-4.2）。

食物效应：在约13％的人群中，在禁食条件下，palbociclib吸收和暴露非常低。食物摄入支持IBRANCE可与食物同服。

与人体血浆蛋白在体外的结合率约为85％，在500 ng / mL到5000 ng / mL之间无浓度依赖性。 几何平均明显分布体积（Vz / F）为2583L（26％CV）。

代谢与清除

     体外和体内研究表明，palbociclib在人体经由肝代谢。单次口服125毫克剂量的[14C] palbociclib，主要代谢途径为palbociclib的氧化和磺化，而酰化和葡糖苷酸作为次要途径。

Palbociclib是主要的血浆中循环药物衍生物（23％）。主要的循环代谢物是palbociclib的葡糖苷酸缀合物，尽管它仅占排泄物中给药剂量的1.5％。 Palbociclib代谢物占粪便和尿液中放射活性的2.3％和6.9％。在粪便中，palbociclib的氨基磺酸结合物是主要的药物相关成分，占给药剂量的26％。人肝细胞体外研究表明，肝细胞溶质和S9片段，重组SULT酶标明CYP3A和SULT2A1主要参与palbociclib的新陈代谢。

palbociclib的几何平均口服清除率（CL / F）为63.1L / hr（29％CV），晚期乳癌患者的平均（±标准差）血浆消除半衰期为29（±5）小时。 给予单次口服剂量[14C] palbociclib的6名健康男性受试者，中位数91.6％的总给药放射活性剂量在15天内恢复; 粪便（占74.1％）是主要的排泄途径，尿中17.5％的剂量回收。 大部分被作为代谢物排泄掉。

年龄，性别和体重

根据183例癌症患者的群体药代动力学分析（男性50例，女性133例）患者年龄范围为22〜89岁，体重范围为37.9〜123公斤），性别对palbociclib的暴露无影响，年龄和体重也无明显影响。

【药物相互作用】

　　哌柏西利主要被CYP3A和磺基转移酶（Sulphotransferase,SULT）SULT2A1代谢。在体内，哌柏西利是CYP3A的时间-依赖性弱抑制剂。 其它药品对哌柏西利药代动力学的影响 CYP3A抑制剂的影响 同时给予多剂量200mg伊曲康唑与单剂量125mg哌柏西利，相对于单独给予单剂量125mg哌柏西利，哌柏西利的全身暴露量（AUCinf）和峰浓度（Cmax）分别增加了约87％和34％。 应避免与强效CYP3A抑制剂合用，包括但不限于：克拉霉素、茚地那韦、伊曲康唑、酮康唑、洛匹那韦/利托那韦、奈法唑酮、奈非那韦、泊沙康唑、沙奎那韦、特拉匹韦、泰利霉素、伏立康唑和葡萄柚或葡萄柚汁（见[用法用量]和[注意事项]）。 与轻度和中度CYP3A抑制剂合用时无需调整剂量。 CYP3A诱导剂的影响 同时给予多剂量600 mg利福平与单剂量125mg哌柏西利，相对于单独给予单剂量125mg哌柏西利，哌柏西利AUCinf和Cmax分别降低了约85％和70％。 应避免与强效CYP3A诱导剂合用，包括但不限于：卡马西平、恩杂鲁胺、苯妥英、利福平和圣约翰草（见[禁忌]和[注意事项]）。 同时给予多剂量每天400 mg莫达非尼（一种中效CYP3A诱导剂）与单剂量125mg哌柏西利，相对于单独给予单剂量125mg哌柏西利，哌柏西利AUCinf和Cmax分别降低了约32％和11％。与中效CYP3A诱导剂合用时无需调整剂量（见[注意事项]）。 抗酸药的影响 餐后（摄入中脂餐）同时给予多剂量质子泵抑制剂（ProtonPumpInhibitor,PPI）雷贝拉唑与单剂量125mg哌柏西利，相对于单独给予单剂量125mg哌柏西利，哌柏西利Cmax降低了41％，但对AUCinf的影响有限（降低了13％）。 空腹条件下同时给予多剂量质子泵抑制剂（PPI）雷贝拉唑与单剂量125mg哌柏西利，哌柏西利AUCinf和Cmax分别降低了62％和80％。因此，哌柏西利应与食物同服，最好随餐服用（见[用法用量]和[药代动力学]）。 鉴于H2受体拮抗剂和局部抗酸剂与PPI相比对胃内pH的影响较小，哌柏西利与食物同服时，预期H2受体拮抗剂或局部抗酸剂对哌柏西利的暴露量无临床相关影响。 哌柏西利对其它药品药代动力学的影响 在每天给予125mg达到稳态后，哌柏西利是一种弱的时间-依赖性CYP3A抑制剂。与咪达唑仑单独给药相比，多剂量哌柏西利与咪达唑仑同时给药时，咪达唑仑AUCinf和Cmax值分别增加了61％和37％。 治疗指数狭窄的敏感CYP3A4底物（如，阿芬太尼、环孢素、双氢麦角胺、麦角胺、依维莫司、芬太尼、匹莫齐特、奎尼丁、西罗莫司和他克莫司）与哌柏西利同时使用时可能需要降低剂量，因为哌柏西利可增加它们的暴露量。 哌柏西利与来曲唑之间的药物相互作用 一项乳腺癌患者临床研究的药物相互作用（Drug-DrugInteraction,DDI）评价部分的数据表明，哌柏西利与来曲唑联用时，两种药品之间无药物相互作用。 他莫昔芬对哌柏西利暴露量的影响 在健康男性受试者中进行的一项DDI研究的数据表明，单剂量哌柏西利与多剂量他莫昔芬同时给药，与哌柏西利单独给药时的暴露量相当。 哌柏西利与氟维司群之间的药物相互作用 在乳腺癌患者中进行的一项临床研究的数据表明，哌柏西利与氟维司群联用时，两种药品之间无临床相关药物相互作用。 哌柏西利与口服避孕药之间的药物相互作用 尚未对哌柏西利与口服避孕药之间的DDI进行研究（见[孕妇和哺乳期妇女用药]）。 与转运蛋白的体外研究 根据体外研究数据，预计哌柏西利抑制肠道P-糖蛋白（P-Glycoprotein,P-gp）和乳腺癌耐药蛋白质（BreastCancerResistanceProtein,BCRP）介导的转运。因此，哌柏西利与P-gp（如，地高辛、达比加群、秋水仙碱）或BCRP（如，普伐他汀、瑞舒伐他汀、柳氮磺胺吡啶）的底物类药品合并用药可增加它们的治疗作用和不良反应。 根据体外研究数据，哌柏西利可抑制摄取转运体有机阳离子转运蛋白OCT1，因此可增加该转运蛋白的底物类药品（如，二甲双胍）的暴露量。 

【药物过量 】

     尚无针对哌柏西利的特效解毒药。如果哌柏西利用药过量，可能出现胃肠道（如，恶心、呕吐）和血液学（如，中性粒细胞减少症）毒性，应给予一般的支持性治疗。 

【临床试验 】

        随机Ⅲ期研究PALOMA-2：哌柏西利与来曲唑联用作为雌激素受体（ER）阳性、HER2阴性的晚期或转移性乳腺癌患者初始内分泌治疗 在ER阳性、HER2阴性的不能通过手术切除或放疗治愈的局部晚期乳腺癌患者或既往未接受过针对转移灶的全身治疗的晚期乳腺癌患者中进行了一项随机、双盲、安慰剂对照、国际多中心研究，评价了哌柏西利与来曲唑联用和来曲唑与安慰剂联用的疗效。 共计666例绝经后妇女以2:1的比例随机分配至哌柏西利 来曲唑组或安慰剂 来曲唑组，并按病灶部位（内脏、非内脏）、从完成（新）辅助治疗至疾病复发的无病间期（新发转移、12个月、>12个月）、既往（新）辅助抗肿瘤治疗的类型（既往激素治疗、无既往激素治疗）分层。研究排除了存在晚期、症状性、内脏转移，短期内可能出现危及生命的并发症（包括大量积液无法控制[胸膜积液、心包液、腹膜积液]、肺淋巴管炎以及肝脏受累面积超过50％）的患者。 患者持续接受分配的治疗，直到发生客观疾病进展、症状恶化、不可接受的毒性、死亡或撤销同意书，以先发生者为准。不允许治疗组间交叉治疗。 哌柏西利 来曲唑组与安慰剂 来曲唑组之间患者的基线人口统计学以及预后特征具有可比性。入组本研究的患者的中位年龄为62岁（范围：28-89岁），多数患者为白种人（78％），且多数患者的美国东部肿瘤协作组（ECOG）体力状态（PS）为0或1（98％）。在诊断为晚期乳腺癌前，48.3％患者接受过化疗和56.3％患者接受过抗激素治疗，37.2％的患者既往未接受过全身治疗。大多数患者（97.4％）在基线时有转移病灶，23.6％的患者只有骨转移，49.2％的患者有内脏转移。 
研究的主要终点是由研究者按照实体瘤疗效评价标准(ResponseEvaluationCriteriainSolidTumors,RECIST)v1.1评估的无进展生存期（Progression-FreeSurvival,PFS）。次要疗效终点包括客观缓解率（ObjectiveResponseRate,ORR）、临床获益缓解（ClinicalBenefitResponse,CBR）、安全性和生活质量（QualityofLife,QoL）变化。 研究达到了主要终点。哌柏西利 来曲唑组与安慰剂 来曲唑组患者的中位PFS分别为24.8个月（95％CI：22.1，NE）和14.5个月（95％CI：12.9，17.1）。风险比（HazardRatio,HR）为0.576（95％CI：0.46,0.72)，单侧分层对数秩检验p值<0.000001。 PALOMA-2研究的疗效数据总结于表6中，PFS的Kaplan-Meier曲线见图1。 基于预后因素和基线特征进行一系列预先定义的亚组PFS分析以考察治疗效果的内部一致性。在所有个体患者亚组（按分层因素以及基线特征定义）中观察到了哌柏西利 来曲唑组可降低疾病进展风险或死亡风险。该结果在以下患者中较为显著：内脏转移患者（HR=0.67[95％CI:0.50,0.89]，mPFS为19.2个月与12.9个月），或不伴内脏转移的患者(HR=0.48[95％CI:0.34,0.67]，mPFS为未达到[NR]与16.8个月），或仅发生骨转移的患者(HR=0.36[95％CI:0.22,0.59]，mPFS为NR与11.2个月），或没有仅骨转移的患者(HR=0.65[95％CI:0.51,0.84],mPFS为22.2个月与14.5个月)。与之相似，在512例通过免疫组化（Immunohistochemistry,IHC）检测肿瘤Rb蛋白质表达结果呈阳性的患者中，观察到哌柏西利 来曲唑的疾病进展或死亡风险下降(HR=0.531[95％CI:0.42,0.68],mPFS为24.2个月与13.7个月)。在51例通过IHC检测肿瘤Rb蛋白质表达结果呈阴性的患者中，虽不具有统计学显著性，但哌柏西利联合来曲唑有利于疾病进展或死亡风险的下降(HR=0.675[95％CI:0.31,1.48],mPFS为NR与18.5个月)。 在伴或不伴内脏转移的患者亚组中评估的其它疗效指标（ORR和TTR）见表7。 

【贮藏】

应在20--25°C；外出允许至15°-30°C。

【有效期】36个月 

                                                                                                                                             文案整理：Dr. Jasmine Ding

HIGHLIGHTS OF PRESCRIBING INFORMATION

 These highlights do not include all the information needed to use IBRANCE safely and ively. See full prescribing information for IBRANCE. IBRANCE® (palbociclib) capsules, for oral use Initial U.S. Approval: 2015 ------------------

INDICATIONS AND USAGE

---------------------------­ IBRANCE is a kinase inhibitor indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. This indication is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. (1) --------

DOSAGE AND ADMINISTRATION

 IBRANCE capsules are taken orally with food in combination with letrozole. (2) • Recommended starting dose: 125 mg once daily taken with food for 21 days followed by 7 days off treatment. (2.1) • Dosing interruption and/or dose reductions are recommended based on individual safety and tolerability. (2.2) --------------------- 

DOSAGE FORMS AND STRENGTHS-

--------------------­ Capsules: 125 mg, 100 mg, and 75 mg (3) ------------------------------

 CONTRAINDICATIONS

 -----------------------------­ None (4) -----------------------

 WARNINGS AND PRECAUTIONS 

----------------------­ • Hematologic: Neutropenia may occur. Monitor complete blood count prior to start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated. (5.1) • Infections: Monitor for signs and symptoms and withhold dosing as appropriate. (5.2) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. (5.4, 8.1, 8.3) ------------------------------

 ADVERSE REACTIONS -

----------------------------­ Most common adverse reactions (incidence ≥10%) were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis. (6) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------

-

DRUG INTERACTIONS

  CYP3A Inhibitors: 

Avoid concurrent use of IBRANCE with strong CYP3A inhibitors. If the strong inhibitor cannot be avoided, reduce the IBRANCE dose. (2.2, 7.1) •

CYP3A Inducers: 

Avoid concurrent use of IBRANCE with strong and moderate CYP3A inducers. (7.2) •

CYP3A Substrates: The dose of sensitive CYP3A4 substrates with narrow therapeutic indices may need to be reduced when given concurrently with IBRANCE. (7.3) See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient labeling. Revised: [02/2015] 

FULL PRESCRIBING INFORMATION: CONTENTS* 

1 INDICATIONS AND USAGE 

2 DOSAGE AND ADMINISTRATION 

2.1 General Dosing Information 

2.2 Dose Modification 

3 DOSAGE FORMS AND STRENGTHS 

4 CONTRAINDICATIONS 

5 WARNINGS AND PRECAUTIONS 

5.1 Neutropenia 5.2 Infections 5.3 Pulmonary Embolism 5.4 Embryo-Fetal Toxicity

 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience 

7 DRUG INTERACTIONS

 7.1 Agents That May Increase Palbociclib Plasma Concentrations 7.2 Agents That May Decrease Palbociclib Plasma Concentrations 7.3 Drugs That May Have Their Plasma Concentrations Altered by Palbociclib 

8 USE IN SPECIFIC POPULATIONS 

8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 

10 OVERDOSAGE 

11 DESCRIPTION 

12 CLINICAL PHARMACOLOGY 

12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY 

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 

14 CLINICAL STUDIES 

16 HOW SUPPLIED/STORAGE AND HANDLING 

17 PATIENT COUNSELING INFORMATION 

*Sections or subsections omitted from the full prescribing information are not listed. 1 Reference ID: 3696527 

FULL PRESCRIBING INFORMATION 

1 INDICATIONS AND USAGE

 IBRANCE is indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. This indication is approved under accelerated approval based on progression-free survival (PFS) [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. 

2 DOSAGE AND ADMINISTRATION

 2.1 General Dosing Information 

The recommended dose of IBRANCE is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. IBRANCE should be taken with food [see Clinical Pharmacology (12.3)] in combination with letrozole 2.5 mg once daily given continuously throughout the 28-day cycle. Patients should be encouraged to take their dose at approximately the same time each day. If the patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. IBRANCE capsules should be swallowed whole (do not chew, crush or open them prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact. 2.2 Dose Modification Dose modification of IBRANCE is recommended based on individual safety and tolerability [see Warnings and Precautions (5)]. Management of some adverse reactions [see Warnings and Precautions (5)] may require temporary dose interruptions/delays and/or dose reductions, or permanent discontinuation as per dose reduction schedules provided in Tables 1, 2 and 3 [see Warnings and Precautions (5), Adverse Reactions (6) and Clinical Studies (14)]. 

Table 1. Recommended Dose Modification for Adverse Reactions

 Dose Level 

Dose Recommended starting dose 125 mg/day First dose reduction 100 mg/day Second dose reduction 75 mg/day* *If further dose reduction below 75 mg/day is required, discontinue the treatment. 2 Reference ID: 3696527 Table 2. Dose Modification and Managementa – Hematologic Toxicities CTCAE Grade Dose Modifications Grade 1 or 2 No dose adjustment is required. Grade 3b No dose adjustment is required. Consider repeating complete blood count monitoring one week later. Withhold initiation of next cycle until recovery to Grade ≤2. Grade 3 ANC (<1000 to 500/mm3 ) + Fever ≥38.5ºC and/or infection Withhold IBRANCE and initiation of next cycle until recovery to Grade ≤2 (≥1000/mm3 ). Resume at next lower dose. Grade 4b Withhold IBRANCE and initiation of next cycle until recovery to Grade ≤2. Resume at next lower dose. Grading according to CTCAE Version 4.0. ANC=absolute neutrophil count; CTCAE=Common Terminology Criteria for Adverse Events. a Monitor complete blood count prior to the start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated. b Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections). 

Table 3. Dose Modification and Management – Non-Hematologic Toxicities CTCAE Grade Dose Modifications Grade 1 or 2 No dose adjustment is required. Grade ≥3 non-hematologic toxicity (if persisting despite medical treatment) Withhold until symptoms resolve to: • Grade ≤1; • Grade ≤2 (if not considered a safety risk for the patient) Resume at the next lower dose. Grading according to CTCAE Version 4.0. CTCAE=Common Terminology Criteria for Adverse Events. See manufacturer’s prescribing information for the coadministered product, letrozole, dose adjustment guidelines in the event of toxicity and other relevant safety information or contraindications. Dose Modifications for Use With Strong CYP3A Inhibitors Avoid concomitant use of strong CYP3A inhibitors and consider an alternative concomitant medication with no or minimal CYP3A inhibition. If patients must be coadministered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg once daily. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3–5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. 

3 DOSAGE FORMS AND STRENGTHS 

125 mg capsules: opaque hard gelatin capsules, size 0, with caramel cap and body, printed with white ink “Pfizer” on the cap, “PBC 125” on the body. 100 mg capsules: opaque hard gelatin capsules, size 1, with caramel cap and light orange body, printed with white ink “Pfizer” on the cap, “PBC 100” on the body. 75 mg capsules: opaque hard gelatin capsules, size 2, with light orange cap and body, printed with white ink “Pfizer” on the cap, “PBC 75” on the body. 3 Reference ID: 3696527 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Neutropenia Decreased neutrophil counts have been observed in clinical trials with IBRANCE. Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole in the randomized clinical trial (Study 1). Median time to first episode of any grade neutropenia per laboratory data was 15 days (13-117 days). Median duration of Grade ≥3 neutropenia was 7 days [see Adverse Reactions (6.1)]. Febrile neutropenia events have been reported in the IBRANCE clinical program, although no cases of febrile neutropenia have been observed in Study 1. Monitor complete blood count prior to starting IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated. Dose interruption, dose reduction or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia [see Dosage and Administration (2.2)]. 5.2 Infections Infections have been reported at a higher rate in patients treated with IBRANCE plus letrozole compared to patients treated with letrozole alone in Study 1. Grade 3 or 4 infections occurred in 5% of patients treated with IBRANCE plus letrozole whereas no patients treated with letrozole alone experienced a Grade 3 or 4 infection. Monitor patients for signs and symptoms of infection and treat as medically appropriate. 5.3 Pulmonary Embolism Pulmonary embolism has been reported at a higher rate in patients treated with IBRANCE plus letrozole (5%) compared with no cases in patients treated with letrozole alone in Study 1. Monitor patients for signs and symptoms of pulmonary embolism and treat as medically appropriate. 5.4 Embryo-Fetal Toxicity Based on findings in animals and mechanism of action, IBRANCE can cause fetal harm. IBRANCE caused embryo-fetal toxicities in rats and rabbits at maternal exposures that were greater than or equal to 4 times the human clinical exposure based on area under the curve (AUC). Advise females of reproductive potential to use effective contraception during therapy with IBRANCE and for at least two weeks after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)]. 6 ADVERSE REACTIONS The following topics are described below and elsewhere in the labeling: • Neutropenia [see Warnings and Precautions (5.1)] • Infections [see Warnings and Precautions (5.2)] • Pulmonary Embolism [see Warnings and Precautions (5.3)] 4 Reference ID: 3696527 6.1 Clinical Studies Experience Because clinical trials are conducted under varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. The safety of IBRANCE (125 mg/day) plus letrozole (2.5 mg/day) versus letrozole alone was evaluated in Study 1. The data described below reflect exposure to IBRANCE in 83 out of 160 patients with ER-positive, HER2-negative advanced breast cancer who received at least 1 dose of treatment in Study 1. The median duration of treatment for palbociclib was 13.8 months while the median duration of treatment for letrozole on the letrozole-alone arm was 7.6 months. Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving IBRANCE plus letrozole. No dose reduction was allowed for letrozole in Study 1. Permanent discontinuation due to an adverse reaction occurred in 7 of 83 (8%) patients receiving IBRANCE plus letrozole and in 2 of 77 (3%) patients receiving letrozole alone. Adverse reactions leading to discontinuation for those patients receiving IBRANCE plus letrozole included neutropenia (6%), asthenia (1%), and fatigue (1%). The most common adverse reactions (≥10%) of any grade reported in patients in the IBRANCE plus letrozole arm were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis. The most frequently reported serious adverse reactions in patients receiving IBRANCE plus letrozole were pulmonary embolism (3 of 83; 4%) and diarrhea (2 of 83; 2%). An increase incidence of infections events was observed in the palbociclib plus letrozole arm (55%) compared to the letrozole alone arm (34%). Febrile neutropenia events have been reported in the IBRANCE clinical program, although no cases were observed in Study 1. Grade ≥3 neutropenia was managed by dose reductions and/or dose delay or temporary discontinuation consistent with a permanent discontinuation rate of 6% due to neutropenia [see Dosage and Administration (2.2)]. Adverse drug reactions (≥10%) reported in patients who received IBRANCE plus letrozole or letrozole alone in Study 1 are listed in Table 4. 5 Reference ID: 3696527 Table 4. Adverse Reactions* (≥10%) in Study 1 IBRANCE + Letrozole (N=83) System Organ Class All Grades Grade 3 Grade 4 Adverse Reaction % % % Infections and infestations URIa 31 1 0 Blood and lymphatic system disorders Neutropenia 75 Leukopenia 43 Anemia 35 Thrombocytopenia 17 48 19 5 2 6 0 1 0 Metabolism and nutrition disorders Decreased appetite 16 1 0 Nervous system disorders Peripheral neuropathyb 13 0 0 Respiratory, thoracic and mediastinal disorders Epistaxis 11 0 0 Gastrointestinal disorders Stomatitisc Nausea Diarrhea Vomiting 25 25 21 15 0 2 4 0 0 0 0 0 Skin and subcutaneous tissue disorders Alopecia 22d N/A N/A General disorders and administration site conditions Fatigue 41 2 Asthenia 13 2 2 0 Letrozole Alone (N=77) All Grades Grade 3 Grade 4 % % % 18 0 0 5 1 0 3 0 0 7 1 0 1 0 0 7 0 0 5 0 0 1 0 0 7 1 0 13 1 0 10 0 0 4 1 0 3e N/A N/A 23 1 0 4 0 0 

*Adverse Reaction rates reported in the table include all reported events regardless of causality

. Grading according to CTCAE Version 3.0. CTCAE=Common Terminology Criteria for Adverse Events; N=number of subjects; N/A=not applicable; URI=Upper respiratory infection. a URI includes: Influenza, Influenza like illness, Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Sinusitis, Upper respiratory tract infection. b Peripheral neuropathy includes: Neuropathy peripheral, Peripheral sensory neuropathy. c Stomatitis includes: Aphthous stomatitis, Cheilitis, Glossitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral pain, Oropharyngeal discomfort, Oropharyngeal pain, Stomatitis. d Grade 1 events - 21%; Grade 2 events - 1%. e Grade 1 events - 3%. Table 5. Laboratory Abnormalities for Patients in Study 1 IBRANCE + Letrozole (N=83) Laboratory All Grades Grade 3 Grade 4 Abnormality % % % White blood cells decreased 95 44 0 Neutrophils decreased 94 57 5 Lymphocytes decreased 81 17 1 Hemoglobin decreased 83 5 1 Platelets decreased 61 3 0 Letrozole Alone (N=77) All Grades Grade 3 Grade 4 % % % 26 0 0 17 3 0 35 3 0 40 3 0 16 3 0 N=number of patients. 7 DRUG INTERACTIONS Palbociclib is primarily metabolized by CYP3A and sulfotransferase (SULT) enzyme SULT2A1. In vivo, palbociclib is a time-dependent inhibitor of CYP3A. 6 Reference ID: 3696527 7.1 Agents That May Increase Palbociclib Plasma Concentrations Effect of CYP3A Inhibitors Coadministration of a strong CYP3A inhibitor (itraconazole) increased the plasma exposure of palbociclib in healthy subjects by 87%. Avoid concomitant use of strong CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, and voriconazole). Avoid grapefruit or grapefruit juice during IBRANCE treatment. If coadministration of IBRANCE with a strong CYP3A inhibitor cannot be avoided, reduce the dose of IBRANCE [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. 7.2 Agents That May Decrease Palbociclib Plasma Concentrations Effect of CYP3A Inducers Coadministration of a strong CYP3A inducer (rifampin) decreased the plasma exposure of palbociclib in healthy subjects by 85%. Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine and St John’s Wort) [see Clinical Pharmacology (12.3)]. Coadministration of moderate CYP3A inducers may also decrease the plasma exposure of IBRANCE. Avoid concomitant use of moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) [see Clinical Pharmacology (12.3)]. 7.3 Drugs That May Have Their Plasma Concentrations Altered by Palbociclib Coadministration of midazolam with multiple doses of IBRANCE increased the midazolam plasma exposure by 61%, in healthy subjects, compared with administration of midazolam alone. The dose of the sensitive CYP3A substrate with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus) may need to be reduced as IBRANCE may increase their exposure [see Clinical Pharmacology (12.3)]. 

8 USE IN SPECIFIC POPULATIONS 

8.1 Pregnancy Risk Summary Based on findings in animals and mechanism of action, IBRANCE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. In animal studies, palbociclib was teratogenic and fetotoxic at maternal exposures that were ≥4 times the human clinical exposure based on AUC at the recommended human dose. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. 7 Reference ID: 3696527 Data Animal Data In a fertility and early embryonic development study in female rats, palbociclib was administered orally for 15 days before mating through to Day 7 of pregnancy, which did not cause embryo toxicity at doses up to 300 mg/kg/day with maternal systemic exposures approximately 4 times the human exposure (AUC) at the recommended dose. In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses up to 300 mg/kg/day and 20 mg/kg/day palbociclib, respectively, during the period of organogenesis. The maternally toxic dose of 300 mg/kg/day was fetotoxic in rats, resulting in reduced fetal body weights. At doses ≥100 mg/kg/day in rats, there was an increased incidence of a skeletal variation (increased incidence of a rib present at the seventh cervical vertebra). At the maternally toxic dose of 20 mg/kg/day in rabbits, there was an increased incidence of skeletal variations, including small phalanges in the forelimb. At 300 mg/kg/day in rats and 20 mg/kg/day in rabbits, the maternal systemic exposures were approximately 4 and 9 times the human exposure (AUC) at the recommended dose. CDK4/6 double knockout mice have been reported to die in late stages of fetal development (gestation Day 14.5 until birth) due to severe anemia. However, knockout mouse data may not be predictive of effects in humans due to differences in degree of target inhibition. 8.2 Lactation Risk Summary There are no data on the presence of palbociclib in human milk, the effects of IBRANCE on the breastfed child, or the effects of IBRANCE on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IBRANCE, advise a nursing woman to discontinue breastfeeding during treatment with IBRANCE. 8.3 Females and Males of Reproductive Potential Contraception Females Advise females of reproductive potential to use effective contraception during treatment with IBRANCE and for at least two weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with IBRANCE [see Use in Specific Populations (8.1)]. Infertility Males Based on findings in animals, male fertility may be compromised by treatment with IBRANCE [see Carcinogenesis, Mutagenesis, Impairment of Fertility (13.1)]. 8 Reference ID: 3696527 N N N N N N MMe e HHN N OO O O MMe e N N NN H H N N 8.4 Pediatric Use The safety and efficacy of IBRANCE in pediatric patients have not been studied. 8.5 Geriatric Use Of 84 patients who received IBRANCE in Study 1, 37 patients (44%) were ≥65 years of age and 8 patients (10%) were ≥75 years of age. No overall differences in safety or effectiveness of IBRANCE were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment Based on a population pharmacokinetic analysis that included 183 patients, where 40 patients had mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no effect on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients with moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST) [see Clinical Pharmacology (12.3)]. 8.7 Renal Impairment Based on a population pharmacokinetic analysis that included 183 patients, where 73 patients had mild renal impairment (60 mL/min ≤ CrCl <90 mL/min) and 29 patients had moderate renal impairment (30 mL/min ≤ CrCl <60 mL/min), mild and moderate renal impairment had no effect on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients with severe renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no known antidote for IBRANCE. The treatment of overdose of IBRANCE should consist of general supportive measures. 11 DESCRIPTION IBRANCE capsules for oral administration contain 125 mg, 100 mg, or 75 mg of palbociclib, a kinase inhibitor. The molecular formula for palbociclib is C24H29N7O2. The molecular weight is 447.54 daltons. The chemical name is 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2­ yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, and its structural formula is: Palbociclib is a yellow to orange powder with pKa of 7.4 (the secondary piperazine nitrogen) and 3.9 (the pyridine nitrogen). At or below pH 4, palbociclib behaves as a high-solubility compound. Above pH 4, the solubility of the drug substance reduces significantly. 9 Reference ID: 3696527 Inactive ingredients: Microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, and hard gelatin capsule shells. The light orange, light orange/caramel and caramel opaque capsule shells contain gelatin, red iron oxide, yellow iron oxide, and titanium dioxide; and the printing ink contains shellac, titanium dioxide, ammonium hydroxide, propylene glycol and simethicone. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Palbociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream of signaling pathways which lead to cellular proliferation. In vitro, palbociclib reduced cellular proliferation of estrogen receptor (ER)-positive breast cancer cell lines by blocking progression of the cell from G1 into S phase of the cell cycle. Treatment of breast cancer cell lines with the combination of palbociclib and antiestrogens leads to decreased retinoblastoma protein (Rb) phosphorylation resulting in reduced E2F expression and signaling and increased growth arrest compared to treatment with each drug alone. In vitro treatment of ER-positive breast cancer cell lines with the combination of palbociclib and antiestrogens leads to increased cell senescence, which was sustained for up to 6 days following drug removal. In vivo studies using a patient-derived ER-positive breast cancer xenograft model demonstrated that the combination of palbociclib and letrozole increased the inhibition of Rb phosphorylation, downstream signaling and tumor growth compared to each drug alone. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of palbociclib on the QTc interval was evaluated in 184 patients with advanced cancer. No large change (i.e., >20 ms) in the QTc interval was detected at the mean observed maximal steady-state palbociclib concentration following a therapeutic schedule (e.g., 125 mg daily for 21 consecutive days followed by 7 days off to comprise a complete cycle of 28 days). 12.3 Pharmacokinetics The pharmacokinetics of palbociclib were characterized in patients with solid tumors including advanced breast cancer and in healthy subjects. Absorption The mean Cmax of palbociclib is generally observed between 6 to 12 hours (time to reach maximum concentration, Tmax) following oral administration. The mean absolute bioavailability of IBRANCE after an oral 125 mg dose is 46%. In the dosing range of 25 mg to 225 mg, the AUC and Cmax increased proportionally with dose in general. Steady state was achieved within 8 days following repeated once daily dosing. With repeated once daily administration, palbociclib accumulated with a median accumulation ratio of 2.4 (range 1.5-4.2). Food effect: Palbociclib absorption and exposure were very low in approximately 13% of the population under the fasted condition. Food intake increased the palbociclib exposure in this small subset of the population, but did not alter palbociclib exposure in the rest of the population to a clinically relevant extent. Therefore, food intake reduced the intersubject variability of palbociclib exposure, which supports administration of IBRANCE with food. Compared to IBRANCE given under overnight fasted 10 Reference ID: 3696527 conditions, the population average AUCinf and Cmax of palbociclib increased by 21% and 38%, respectively, when given with high-fat, high-calorie food (approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate and fat, respectively), by 12% and 27%, respectively, when given with low-fat, low-calorie food (approximately 400 to 500 calories with 120, 250, and 28 to 35 calories from protein, carbohydrate and fat, respectively), and by 13% and 24%, respectively, when moderate-fat, standard calorie food (approximately 500 to 700 calories with 75 to 105, 250 to 350 and 175 to 245 calories from protein, carbohydrate and fat, respectively) was given one hour before and two hours after IBRANCE dosing. Distribution Binding of palbociclib to human plasma proteins in vitro was approximately 85%, with no concentration dependence over the concentration range of 500 ng/mL to 5000 ng/mL. The geometric mean apparent volume of distribution (Vz/F) was 2583 L (26% CV). Metabolism In vitro and in vivo studies indicated that palbociclib undergoes hepatic metabolism in humans. Following oral administration of a single 125 mg dose of [14C]palbociclib to humans, the primary metabolic pathways for palbociclib involved oxidation and sulfonation, with acylation and glucuronidation contributing as minor pathways. Palbociclib was the major circulating drug-derived entity in plasma (23%). The major circulating metabolite was a glucuronide conjugate of palbociclib, although it only represented 1.5% of the administered dose in the excreta. Palbociclib was extensively metabolized with unchanged drug accounting for 2.3% and 6.9% of radioactivity in feces and urine, respectively. In feces, the sulfamic acid conjugate of palbociclib was the major drug-related component, accounting for 26% of the administered dose. In vitro studies with human hepatocytes, liver cytosolic and S9 fractions, and recombinant SULT enzymes indicated that CYP3A and SULT2A1 are mainly involved in the metabolism of palbociclib. Elimination The geometric mean apparent oral clearance (CL/F) of palbociclib was 63.1 L/hr (29% CV), and the mean (± standard deviation) plasma elimination half-life was 29 (±5) hours in patients with advanced breast cancer. In 6 healthy male subjects given a single oral dose of [14C]palbociclib, a median of 91.6% of the total administered radioactive dose was recovered in 15 days; feces (74.1% of dose) was the major route of excretion, with 17.5% of the dose recovered in urine. The majority of the material was excreted as metabolites. Age, Gender, and Body Weight Based on a population pharmacokinetic analysis in 183 patients with cancer (50 male and 133 female patients, age range from 22 to 89 years, and body weight range from 37.9 to 123 kg), gender had no effect on the exposure of palbociclib, and age and body weight had no clinically important effect on the exposure of palbociclib. Pediatric Population Pharmacokinetics of IBRANCE have not been evaluated in patients <18 years of age. 

11 Reference ID: 3696527 

Drug Interactions 

In vitro data indicate that CYP3A and SULT enzyme SULT2A1 are mainly involved in the metabolism of palbociclib. Palbociclib is a weak time-dependent inhibitor of CYP3A following daily 125 mg dosing to steady state in humans. In vitro, palbociclib is not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 2D6, and is not an inducer of CYP1A2, 2B6, 2C8, and 3A4 at clinically relevant concentrations. CYP3A Inhibitors: Data from a drug interaction trial in healthy subjects (N=12) indicate that coadministration of multiple 200 mg daily doses of itraconazole with a single 125 mg IBRANCE dose increased palbociclib AUCinf and the Cmax by approximately 87% and 34%, respectively, relative to a single 125 mg IBRANCE dose given alone. CYP3A Inducers: Data from a drug interaction trial in healthy subjects (N=14) indicate that coadministration of multiple 600 mg daily doses of rifampin with a single 125 mg IBRANCE dose decreased palbociclib AUCinf and the Cmax by 85% and 70%, respectively, relative to a single 125 mg IBRANCE dose given alone. CYP3A Substrates: Palbociclib is a weak time-dependent inhibitor of CYP3A following daily 125 mg dosing to steady state in humans. In a drug interaction trial in healthy subjects (N=26), coadministration of midazolam with multiple doses of IBRANCE increased the midazolam AUCinf and the Cmax values by 61% and 37%, respectively, as compared with administration of midazolam alone. Gastric pH Elevating Medications: In a drug interaction trial in healthy subjects, coadministration of a single 125 mg dose of IBRANCE with multiple doses of the proton pump inhibitors (PPI) rabeprazole under fed conditions decreased palbociclib Cmax by 41%, but had limited impact on AUCinf (13% decrease), when compared to a single dose of IBRANCE administered alone. Given the reduced effect on gastric pH of H2-receptor antagonists and local antacids compared to PPIs, the effect of these classes of acid-reducing agents on palbociclib exposure under fed conditions is expected to be minimal. Under fed conditions there is no clinically relevant effect of PPIs, H2-receptor antagonists, or local antacids on palbociclib exposure. In another healthy subject study, coadministration of a single dose of IBRANCE with multiple doses of the PPI rabeprazole under fasted conditions decreased palbociclib AUCinf and Cmax by 62% and 80%, respectively, when compared to a single dose of IBRANCE administered alone. Letrozole: Data from a drug interaction trial in patients with breast cancer showed that there was no drug interaction between palbociclib and letrozole when the two drugs were coadministered. Effect of Palbociclib on Transporters: In vitro evaluations indicated that palbociclib has a low potential to inhibit the activities of drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2 and organic anion transporting polypeptide (OATP)1B1, OATP1B3 at clinically relevant concentrations. Effect of Transporters on Palbociclib: Based on in vitro data, P-gp and BCRP mediated transport are unlikely to affect the extent of oral absorption of palbociclib at therapeutic doses. 12 Reference ID: 3696527

 13 NONCLINICAL TOXICOLOGY 

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

 Carcinogenicity studies have not been conducted with palbociclib. Palbociclib was clastogenic in an in vitro micronucleus assay in Chinese Hamster Ovary cells and in vivo in the bone marrow of male rats that received doses ≥100 mg/kg/day for three weeks. Clastogenicity occurred via an aneugenic mechanism. Palbociclib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and did not induce structural chromosomal aberrations in the in vitro human lymphocyte chromosome aberration assay. In a fertility study in female rats, palbociclib did not affect mating or fertility at any dose up to 300 mg/kg/day (approximately 4 times human clinical exposure based on AUC) and no adverse effects were observed in the female reproductive tissues in repeat-dose toxicity studies up to 300 mg/kg/day in the rat and 3 mg/kg/day in the dog (approximately 6 times and similar to human exposure (AUC), at the recommended dose, respectively). Male fertility studies with palbociclib have not been conducted; however, in repeat-dose toxicity studies, testicular degeneration was observed in rats and dogs at 30 and 0.2 mg/kg/day, respectively (approximately 11 and 0.1 times human exposure (AUC), at the recommended dose, respectively), which was partially reversible in the rat and dog following a 12-week non-dosing period. 13.2 Animal Toxicology and/or Pharmacology Altered glucose metabolism (glycosuria, hyperglycemia, decreased insulin) associated with changes in the pancreas (islet cell vacuolation), eye (cataracts, lens degeneration), teeth (degeneration/necrosis of ameloblasts in actively growing teeth), kidney (tubule vacuolation, chronic progressive nephropathy), and adipose tissue (atrophy) were identified in the 27-week repeat-dose toxicology study in rats and were most prevalent in males at doses ≥30 mg/kg/day (approximately 11 times the human exposure (AUC) at the recommended dose). Some of these findings (glycosuria/hyperglycemia, pancreatic islet cell vacuolation, and kidney tubule vacuolation) were present in the 15-week repeat-dose toxicology study in rats, but with lower incidence and severity. The rats used in these studies were approximately 7 weeks old at the beginning of the studies. Altered glucose metabolism or associated changes in pancreas, eye, teeth, kidney, and adipose tissue were not identified in dogs in repeat-dose toxicology studies up to 39 weeks duration. 14 CLINICAL STUDIES Study 1 was a randomized, open-label, multicenter study of IBRANCE plus letrozole versus letrozole alone conducted in postmenopausal women with ER-positive, HER2-negative advanced breast cancer who had not received previous systemic treatment for their advanced disease. A total of 165 patients were randomized in Study 1. Randomization was stratified by disease site (visceral versus bone only versus other) and by disease-free interval (>12 months from the end of adjuvant treatment to disease recurrence versus ≤12 months from the end of adjuvant treatment to disease recurrence or de novo advanced disease). IBRANCE was given orally at a dose of 125 mg daily for 21 consecutive days followed by 7 days off treatment. Patients received study treatment until progressive disease, unmanageable toxicity, or consent withdrawal. Patients enrolled in this study had a median age of 63 years (range 38 to 89). The majority of patients were Caucasian (90%) and all patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Forty-three percent of patients had received chemotherapy and 13 Reference ID: 3696527 33% had received antihormonal therapy in the neoadjuvant or adjuvant setting prior to their diagnosis of advanced breast cancer. Forty-nine percent of patients had no prior systemic therapy in the neoadjuvant or adjuvant setting. The majority of patients (98%) had metastatic disease. Nineteen percent of patients had bone only disease and 48% of patients had visceral disease. The major efficacy outcome measure of the study was investigator-assessed PFS evaluated according to Response Evaluation Criteria in Solid Tumors Version 1.0 (RECIST). Major efficacy results from Study 1 are summarized in Table 6 and Figure 1. Consistent results were observed across patient subgroups of, disease-free interval, disease site and prior therapy. The treatment effect of the combination on PFS was also supported by a retrospective independent review of radiographs with an observed hazard ratio (HR) of 0.621 (95% CI: 0.378, 1.019). Overall response rate in patients with measurable disease as assessed by the investigator was higher in the IBRANCE plus letrozole compared to the letrozole alone arm (55.4% versus 39.4%). At the time of the final analysis of PFS, overall survival (OS) data was not mature with 37% of events. Table 6. Efficacy Results – Study 1 (Investigator Assessment, Intent-to-Treat Population) IBRANCE + Letrozole Letrozole (N=84) (N=81) Progression-Free Survival (PFS) Number of PFS Events (%) 41 (48.8%) 59 (72.8%) Hazard ratio (95% CI) 0.488 (0.319, 0.748) Median PFS [months] (95% CI) 20.2 (13.8, 27.5) 10.2 (5.7, 12.6) CI=confidence interval; N=number of patients. Figure 1. Kaplan-Meier Curves of Progression-Free Survival – Study 1 (Investigator Assessment, Intent-to-Treat Population) 0 10 20 30 40 50 60 70 80 90 100 Progression-Free Survival Probability (%) palbociclib+letrozole letrozole 0 4 8 12 16 20 24 28 32 36 40 PAL+LET 84 67 60 Number of patients at risk 47 Time (Month) 36 28 21 13 8 5 1 LET 81 48 36 28 19 14 6 3 3 1 LET=letrozole; PAL=palbociclib. 14 Reference ID: 3696527 16 HOW SUPPLIED/STORAGE AND HANDLING IBRANCE is supplied in the following strengths and package configurations: IBRANCE Capsules Package Configuration Capsule Strength (mg) NDC Capsule Description Bottles of 21 capsules 125 NDC 0069-0189-21 opaque, hard gelatin capsules, size 0, with caramel cap and body, printed with white ink “Pfizer” on the cap, “PBC 125” on the body Bottles of 21 capsules 100 NDC 0069-0188-21 opaque, hard gelatin capsules, size 1, with caramel cap and light orange body, printed with white ink “Pfizer” on the cap, “PBC 100” on the body Bottles of 21 capsules 75 NDC 0069-0187-21 opaque, hard gelatin capsules, size 2, with light orange cap and body, printed with white ink “Pfizer” on the cap, “PBC 75” on the body Store at 20 o C to 25 o C (68 o F to 77 o F); excursions permitted between 15 o C to 30 o C (59 o F to 86 o F). 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information). • Advise patients to immediately report any signs or symptoms of myelosuppression or infection, such as fever, chills, dizziness, shortness of breath, weakness or any increased tendency to bleed and/or to bruise [see Warnings and Precautions (5.2)]. • Advise patients to immediately report any signs or symptoms of pulmonary embolism, such as shortness of breath, chest pain, tachypnea, and tachycardia [see Warnings and Precautions (5.3)]. • Advise patients to take IBRANCE with food and swallow IBRANCE capsules whole. • IBRANCE may interact with grapefruit. Patients should not consume grapefruit products while on treatment with IBRANCE. • Inform patients to avoid strong CYP3A inhibitors and strong CYP3A inducers. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)]. • If the patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. IBRANCE capsules should be swallowed whole (do not chew, crush or open them prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact. 15 Reference ID: 3696527 • Advise females of reproductive potential to use effective contraception during IBRANCE therapy and for at least two weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with IBRANCE [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1 and 8.3)]. This product’s label may have been updated. For full prescribing information, please visit www.pfizer.com. LAB-0723-1.0 16 Reference ID: 3696527 PATIENT INFORMATION IBRANCE® (EYE-brans) (palbociclib) capsules What is the most important information I should know about IBRANCE? IBRANCE may cause serious side effects, including: Low white blood cell counts (neutropenia). Low white blood cell counts are common when taking IBRANCE. Your healthcare provider should check your white blood cell counts before and during treatment. If you develop low white blood cell counts during treatment with IBRANCE, your healthcare provider may stop your treatment, decrease your dose, or may tell you to wait to begin your treatment cycles. Infections. IBRANCE may cause serious or life-threatening infections. Tell your healthcare provider right away if you develop any signs and symptoms of an infection such as fever or chills. Blood clots in the arteries of your lungs (pulmonary embolism or PE). IBRANCE may cause serious or life-threatening blood clots in the arteries of your lungs. Tell your healthcare provider right away if you have any of the following signs and symptoms of a PE: • shortness of breath • rapid heart rate • sudden, sharp chest pain that may • rapid breathing become worse with deep breathing See “What are the possible side effects of IBRANCE?” for more information about side effects. What is IBRANCE? IBRANCE is a prescription medicine that is used along with the medicine letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as the first hormone-based therapy for their metastatic disease. It is not known if IBRANCE is safe and effective in children. 17 Reference ID: 3696527 What should I tell my healthcare provider before taking IBRANCE? Before you take IBRANCE, tell your healthcare provider if you: • have fever, chills, or any other signs or symptoms of infection. • have liver or kidney problems. • have any other medical conditions. • are pregnant, or plan to become pregnant. IBRANCE can harm your unborn baby. − Females who are able to become pregnant and who take IBRANCE should use effective birth control during treatment and for at least 2 weeks after stopping IBRANCE. − Talk to your healthcare provider about birth control methods that may be right for you during this time. − If you become pregnant or think you are pregnant, tell your healthcare provider right away. • are breastfeeding or plan to breastfeed. It is not known if IBRANCE passes into your breast milk. You and your healthcare provider should decide if you will take IBRANCE or breastfeed. You should not do both. Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. IBRANCE and other medicines may affect each other causing side effects. Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine. How should I take IBRANCE? • Take IBRANCE exactly as your healthcare provider tells you. • Take IBRANCE with food. • Swallow IBRANCE capsules whole. Do not chew, crush or open IBRANCE capsules before swallowing them. • Do not take any IBRANCE capsules that are broken, cracked, or that look damaged. • Avoid grapefruit and grapefruit products during treatment with IBRANCE. Grapefruit may increase the amount of IBRANCE in your blood. • Do not change your dose or stop taking IBRANCE unless your healthcare provider tells you. • If you miss a dose of IBRANCE or vomit after taking a dose of IBRANCE, do not take another dose on that day. Take your next dose at your regular time. • If you take too much IBRANCE, call your healthcare provider right away or go to the nearest hospital emergency room. 18 Reference ID: 3696527 What are the possible side effects of IBRANCE? IBRANCE may cause serious side effects. See “What is the most important information I should know about IBRANCE?” Low red blood cell counts and low platelet counts are common with IBRANCE. Call your healthcare provider right away if you develop any of these symptoms during treatment: • dizziness • shortness of breath • weakness Other common side effects of IBRANCE include: • tiredness • upper respiratory tract infection (see “What is the most important information I should know about IBRANCE?”) • nausea • numbness or tingling in your arms, hands, legs, and feet • bleeding or bruising more easily • nosebleeds • sore mouth • unusual hair thinning or hair loss • diarrhea • decreased appetite • vomiting • weakness Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of IBRANCE. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Pfizer, Inc. at 1-800-438-1985. How should I store IBRANCE? • Store IBRANCE at 68 °F to 77 °F (20 °C to 25 °C). Keep IBRANCE and all medicines out of the reach of children. General information about the safe and effective use of IBRANCE Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use IBRANCE for a condition for which it was not prescribed. Do not give IBRANCE to other people, even if they have the same symptoms you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for more information about IBRANCE that is written for health professionals. 

For more information, go to www.IBRANCE.com or call 1-800-438-1985. 19 

Reference ID: 3696527

 What are the ingredients in IBRANCE? 

Active ingredient: palbociclib 

Inactive ingredients: Microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, and hard gelatin capsule shells. Light orange, light orange/caramel and caramel opaque capsule shells contain: gelatin, red iron oxide, yellow iron oxide, and titanium dioxide. Printing ink contains: shellac, titanium dioxide, ammonium hydroxide, propylene glycol and simethicone. 

This Patient Information has been approved by the U.S. Food and Drug Administration. LAB-0724-1.0 Issued: 

February 2015 20

 Reference ID: 3696527