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使用说明书

通用名：注射用曲妥珠单抗

商品名：赫赛汀

【生产企业】

Roche Pharma (Schweiz) Ltd

【成份】

活性成分：曲妥珠单抗

曲妥珠单抗是一种重组DNA衍生的人源化单克隆抗体，是由悬浮培养于无菌培养基中的哺乳动物细胞（中国仓鼠卵巢细胞CHO）生产的，纯化过程包括特定的病毒灭活和去除步骤，采用的是用亲合色谱法和离子交换法。

稀释液为含1.1%苯甲醇的20ml灭菌注射用水（以下称稀释液）。

赋形剂：L-盐酸组氨酸，L-组氨酸，α，α-双羧海藻糖，聚山梨醇酯20。

【适应症】

转移性乳腺癌：

本品适用于HER2过度表达的转移性乳腺癌：作为单一药物治疗已接受过1个或多个化疗方案的转移性乳腺癌；与紫杉醇或者多西他赛联合，用于未接受化疗的转移性乳腺癌患者。

乳腺癌辅助治疗：

本品单药适用于接受了手术、含蒽环类抗生素辅助化疗和放疗（如果适用）后的HER2过度表达乳腺癌的辅助治疗。

转移性胃癌：

本品联合卡培他滨或5-氟尿嘧啶和顺铂适用于既往未接受过针对转移性疾病治疗的HER2过度表达的转移性胃腺癌或胃食管交界腺癌患者。

曲妥珠单抗只能用于HER2过度表达的转移性胃癌患者，HER2过度表达的定义为使用已验证的检测方法得到的IHC3+或IHC2+/FISH+结果。

【规格】

440mg（20ml）/瓶。

【用法用量】

请按‘输液准备’的要求对复溶后药品进行充分稀释后使用。

请勿静推或静脉快速注射。

在本品治疗前，应进行HER2检测。

本品应通过静脉输注给药。

转移性乳腺癌

初始负荷剂量：建议本品的初始负荷量为4mg/kg。静脉输注90分钟以上。应观察病人是否出现发热，寒战或其它输注相关症状 （见不良反应） 。停止输注可控制这些症状，待症状消失后可继续输注。

维持剂量：建议本品每周用量为2mg/kg。如果患者在首次输注时耐受性良好，则后输注可改为30分钟。维持治疗直至疾病进展。

乳腺癌辅助治疗

在完成所有化疗后开始曲妥珠单抗治疗。曲妥珠单抗的给药方案为：8mg/kg初始负荷量后接着每3周6mg/kg维持量，静脉滴注约90分钟。共使用17剂 （疗程52周） 。

转移性胃癌

建议采用每三周一次的给药方案，初始负荷剂量为8mg/kg，随后6mg/kg每三周给药一次。首次输注时间约为90分钟。如果患者在首次输注时耐受性良好，后续输注可改为30分钟。维持治疗直至疾病进展。

疗程

临床试验中，转移性乳腺癌或转移性胃癌患者使用曲妥珠单抗治疗至疾病进展，乳腺癌早期患者使用曲妥珠单抗作为辅助治疗持续时间为1年（52周）或至疾病复发（视何者为先）。

剂量调整

输注反应

· 对发生轻至中度输注反应患者应降低输注速率

· 对呼吸困难或临床明显低血压患者应中断输注

· 对发生严重和危及生命的输注反应患者：强烈建议永久停止曲妥珠单抗的输注

心脏毒性

曲妥珠单抗开始治疗前应进行左室射血分数（LVEF） 的检测，治疗期间也须经常密切监测LVEF。出现下列情况时，应停止曲妥珠单抗治疗至少4周，并每4周检测1次LVEF

· LVEF较治疗前绝对数值下降≥16%。

· LVEF低于该检测中心正常范围并且LVEF较治疗前绝对数值下降≥10%。

· 4-8周内LVEF回升至正常范围或LVEF较治疗前绝对数值下降≤15%，可恢复使用曲妥珠单抗。

· LVEF持续下降 （＞8周） ，或者3次以上因心脏毒性而停止曲妥珠单抗治疗，应永久停止使用曲妥珠单抗。

减量

临床试验中未减量使用过曲妥珠单抗。在可逆的化疗导致的骨髓抑制过程中患者仍可继续使用本品，是否减少或持续使用化疗药剂量需特别指导，在此期间应密切监测患者是否出现中性粒细胞减少并发症。

漏用

如果患者漏用曲妥珠单抗未超过一周，应尽快对其给予常规维持剂量的曲妥珠单抗（每周一次的给药方案：2mg/kg；每三周一次的给药方案：6mg/kg），不需等待至下一治疗周期。此后应按照原给药方案给予维持剂量的曲妥珠单抗（每周一次的给药方案：2mg/kg；每三周一次的给药方案：6mg/kg）。

如果患者漏用曲妥珠单抗已超过一周，应重新给予初始负荷剂量的曲妥珠单抗（每周一次的给药方案：4mg/kg；每三周一次的给药方案：8mg/kg），输注时间约为90分钟。此后应按照原给药方案给予维持剂量的曲妥珠单抗（每周一次的给药方案：2mg/kg；每三周一次的给药方案：6mg/kg）。

输液准备

溶液配制

应采用正确的无菌操作。每瓶注射用曲妥珠单抗应由同时配送的稀释液稀释，配好的溶液可多次使用，曲妥珠单抗的浓度为21mg/ml，pH值约6.0。配制成的溶液为无色至淡黄色的透明液体。溶液注射前应目测有无颗粒产生和变色点。配制好的溶液超过28天应丢弃。

注射用水 （未提供） 也可以用于单剂量输液准备。其它液体不能用于配制溶液。应避免使用配送的稀释液之外的溶剂，除非有禁忌症。对苯甲醇过敏的患者，曲妥珠单抗必须使用无菌注射用水配制。

根据曲妥珠单抗初次负荷量4mg/kg或之后每1周2mg/kg维持量计算所需溶液的体积：

所需溶液的体积=体重（Kg）×剂量（4mg/Kg负荷量或2mg/Kg维持量）/21（mg/ml，配置好溶液的浓度）

根据曲妥珠单抗初次负荷量8mg/kg或之后的每3周6mg/kg计算所需溶液的体积：

所需溶液的体积=体重（Kg）×剂量（8mg/Kg负荷量或6mg/Kg维持量）/21（mg/ml，配置好溶液的浓度）

所需的溶液量从小瓶中吸出后加入250ml O.9%氯化钠输液袋中，不可使用5%的葡萄糖液（见配伍禁忌） 。输液袋轻轻翻转混匀，防止气泡产生。所有肠外用药均应在使用前肉眼观察有无颗粒产生或变色。一旦输注液配好即应马上使用。如果在无菌条件下稀释的，可在2-8℃冰箱中保存24小时。

配伍禁忌

使用聚氯乙烯、聚乙烯或者聚丙烯袋未观察到本品失效。

不能使用5%的葡萄糖溶液，因其可使蛋白聚集。

本品不可与其它药混合或稀释。

未使用的药品/过期药品的处理

应最大程度地减少药品在环境中的释放。不可将药物丢弃于废水或生活垃圾中。如当地具备药物回收系统，应使用该系统对未使用的药品或过期药品进行回收。

【不良反应】

以下不良反应会在说明书的其他部分进行更详细的讨论：

· 心功能不全[见注意事项]

· 输注反应[见注意事项]

· 化疗引起的中性粒细胞减少症加重[见注意事项]

· 肺部反应[见注意事项]

曲妥珠单抗辅助治疗乳腺癌及用于转移性乳腺癌治疗中最常见的不良反应是：发热、恶心、呕吐、输注反应、腹泻、感染、咳嗽加重、头痛、乏力、呼吸困难、皮疹、中性粒细胞减少症、贫血和肌痛。需要中断或停止曲妥珠单抗治疗的不良反应包括：充血性心衰、左心室功能明显下降、严重的输注反应和肺部反应。

曲妥珠单抗用于胃癌治疗中，最常见的不良反应（＞10%），即与化疗组相比曲妥珠单抗组增加大于5%的不良反应是：中性粒细胞减少症、腹泻、乏力、贫血、口腔炎、体重减轻、上呼吸道感染、发热、血小板减少症、粘膜炎症、鼻咽炎和味觉障碍。除了疾病进展外，最常见的导致停止治疗的不良反应是感染、腹泻和发热性中性粒细胞减少症。

本部分采用下列发生率分类：极常见（≥1/10）、常见（≥1/100至＜1/10）、不常见（≥1/1000至＜1/100）、罕见（≥1/10000至＜1/1000）、极罕见（1/10000）、未知（无法从现有数据估测）。在每种发生率分类内，不良反应按发生率由高到低的顺序列出。

下列不良反应一览表是在关键临床试验中曲妥珠单抗单用或与其他化疗药物联用所报告的不良反应。所有术语都基于关键临床试验中的最高发生率。由于曲妥珠单抗常与其他化疗和放疗联合使用，因此很难确定不良事件与特定药物/放疗的因果关系。

表1 药物不良反应

*药物不良反应（ADR）确定为在至少一项主要随机临床试验中与对照组相比发生率相差至少为2%的不良事件。此表中的ADRs是按其在所有主要临床试验中的最高发生率归入到适当的系统器官分类（SOC）分类中。

+表示已有报道这些不良反应与死亡结局有关

1表示不良反应主要与输注相关反应有关。尚未获得这些不良反应的具体百分比。

心功能不全

接受曲妥珠单抗治疗患者中，观察到心功能不全的体征和症状，如呼吸困难、端坐呼吸、咳嗽增加、肺水肿、S3奔马律或射血分数减少（参见注意事项）。

转移性乳腺癌

在关键性转移性试验中，根据以往心功能不全定义的标准，与紫杉醇单药治疗组（1%-4%）相比，曲妥珠单抗+紫杉醇组中患者的发病率为9%-12%，在曲妥珠单抗单药治疗组中，发病率为6%-9%。曲妥珠单抗+葸环类抗生素/环磷酰胺治疗组（27%）中患者出现心功能不全的比率最高，并显著高于葸环类抗生素/环磷酰胺治疗组（7%-10%）。在对心功能前瞻性监测的后续试验中，与多西他赛单药治疗组（0%）相比，曲妥珠单抗+多西他赛治疗组中患者出现有症状的心力衰竭的发病率为2.2%。这些试验中，出现心功能不全的大部分患者（79%）接受心力衰竭标准治疗后均有所改善。

早期乳腺癌（辅助治疗）

乳腺癌辅助治疗临床试验中，连续监测心功能（LVEF）。在B016348试验中，中位随访时间为12.6个月（观察组12.4个月，曲妥珠单抗治疗1年组12.6个月）；在NSABP B31和NCCTG N9831中，AC-TH组中位随访时间分别为23个月和24个月。在NSABP B31和NCCTG N9831中，6%的患者在AC方案化疗后因出现心功能不全（AC方案化疗结束时LVEF＜50%或相对基线值降低≥15%）而没有开始曲妥珠单抗治疗。在NSABP B31和NCCTG N9831中，曲妥珠单抗治疗开始后，曲妥珠单抗+紫杉醇组的剂量限制性心功能不全发生率高于紫杉醇单药组，在B016348试验中，曲妥珠单抗单药治疗时剂量限制性心功能不全发生率高于安慰剂组（见表2，图1、图2）。

表2 NSABP B31、NCCTG N9831和B016348试验中心功能不全（检测指标LVEF）的患者比例

图1 NSABP B31和NCCTG N9831：首次出现LVEF较基线下降≥10%并且绝对值低于50%的累积发生率，死亡为竞争性风险事件

图2 8016348试验：首次出现LVEF较基线下降＞10%并且绝对值低于50%的累积发生率，死亡为竞争性风险事件

在曲妥珠单抗联合化疗的三项关键性临床试验中，单独化疗患者中3/4级心功能不全（有症状的充血性心力衰竭（CHF））发生率与紫衫烷序贯曲妥珠单抗治疗的患者相似（0.3-0.4%）。紫杉烷加曲妥珠单抗联合治疗患者发生率最高（2.0%）。第3年，接受AC→P（多柔比星+环磷酰胺之后用紫杉醇治疗）+H（曲妥珠单抗）治疗患者心脏不良事件发生率达3.2%，而AC→P治疗组患者为0.8%。5年随访期未见累计心脏不良事件发病率增加。

在5.5年时，AC→D（多柔比星+环磷酰胺之后用多西他赛）、AC→DH（多柔比星+环磷酰胺，之后用多西他赛+曲妥珠单抗）和DCarbH（多西他赛、卡铂和曲妥珠单抗）治疗组有症状的心脏事件或LVEF事件分别为1.0%、2.3%和1.1%。对于有症状的CHF（3-4级），AC→D、AC→DH和DCarbH治疗组5年发生率分别为0.6%、1.9%和0.4%。发生有症状的心脏事件的整体风险较低，并且AC→D与DCarbH组患者相似；相对AC→D和DCarbH治疗组，AC→DH治疗组发生有症状的心脏不良事件的风险增加，表现为有症状的心脏不良事件或LVEF事件累计发生率持续增至2.3%，而两个对照治疗组（AC→D和DCarbH）约为1%。

1年治疗组中，完成辅助化疗后接受曲妥珠单抗治疗的患者出现NYHA Ⅲ-IV级心力衰竭的比率为0.6%。中位随访期3.6年后，接受曲妥珠单抗治疗一年后的重度CHF和左心室功能不全发生率分别为0.8%和9.8%。所有重度症状性CHF以及确认的显著LVEF水平降低的60例患者中的51例均出现在曲妥珠单抗治疗期间。出现心功能不全的大部分患者在6个月内恢复。截至中位随访期3.6年，心脏不良事件终点发生率仍然较低。曲妥珠单抗相关的心功能不全主要发生在曲妥珠单抗治疗期间（与葸环类抗生素治疗组不同，心功能不全通常在开始治疗后数月或数年表现出来）。

早期乳腺癌（新辅助疗法）

在临床试验中，共3至4个周期曲妥珠单抗联合葸环类抗生素的新辅助化疗（累积多柔比星剂量180mg/m2或表柔比星剂量360mg/m2），曲妥珠单抗治疗组中有症状的心功能不全发生率达1.7%。

转移性胃癌

在B018255试验中，筛选期时，氟尿嘧啶/顺铂（FP）组和曲妥珠单抗+氟尿嘧啶/顺铂（H+FP）组的中位LVEF值分别为64%（范围48%-90%）和65%（范围50%-86%）。除含曲妥珠单抗治疗组中1名患者（其LVEF的下降伴有心力衰竭）外，B018255试验中记录的多数LVEF下降均无临床症状。

表3 LVEF相对于筛选期的变化情况总结（B018255试验）

表4 心脏不良事件（B018255试验）

总体而言，心功能不全事件在治疗组和对照组之间未出现显著性差异。

输注相关反应（IRR）/超敏反应

静脉输注曲妥珠单抗观测到IRR/超敏反应，如寒战和/或发热、呼吸困难、低血压、哮鸣、支气管痉挛、心动过速、氧饱和度下降和呼吸性窘迫（参见注意事项）。

无论曲妥珠单抗与化疗合并治疗或单药治疗，根据不同适应症和数据采集方法，各研究之间的各级IRR的发生率也不同。

转移性乳腺癌患者中，曲妥珠单抗联合治疗组IRR发生率在4g%至54%之间，而对照药治疗组在36%至58%之间（可能包含其他化疗）。曲妥珠单抗联合治疗组，重度IRR（3级及以上）达5%至7%，对照药治疗组达5%至6%。

早期乳腺癌患者中，曲妥珠单抗联合治疗组IRR发生率在18%至54%之间，而对照药治疗组在6%至50%之间（可能包含其他化疗）。曲妥珠单抗联合治疗组，重度IRR（3级及以上）达0.5%至6%，对照药治疗组达0.3%至5%。

在个别病例中观察到过敏样反应。

血液学毒性

乳腺癌

血液学毒性在接受曲妥珠单抗单药治疗的转移性患者中不常见，WHO分级3级的白细胞减少症、血小板减少和贫血发生率低于1%。未观察到WHO分级4级的毒性。

曲妥珠单抗联合紫杉醇治疗WHO分级3级或4级的血液学毒性高于紫杉醇单药治疗的患者（34%比21%）。曲妥珠单抗联合多西他赛治疗3级或4级的血液学毒性高于多西他赛单药治疗的患者（32%比22%，用NCI-CTC标准）。曲妥珠单抗联合多西他赛治疗的患者发热性中性粒细胞减少或中性粒细胞减少性脓毒症高于多西他赛单药治疗的患者（23%比17%）。

用NCI-CTC标准，在B016348试验中，曲妥珠单抗治疗组0.4%患者从基线水平上升到3或4级，对照组为0.6%。

贫血

随机对照的临床试验中，贫血的总体发生率（30% vs 21%[B016348试验]）、NCI-CTC 2-5级贫血的总体发生率（12.5% vs 6.6[NSABP B31]），和需要输血的贫血总体发生率（0.1% vs O[NCCTG N9831]），曲妥珠单抗联合化疗的患者高于单独化疗的患者。曲妥珠单抗单药（H0649g中）治疗后，NCI-CTC 3级贫血发生率＜1%。

中性粒细胞减少症

乳腺癌辅助治疗的随机对照临床试验中，NCI-CTC 4~5级中性粒细胞减少症的发生率（2% vs 0.7%[NCCTG N9831]）和2~5级中性粒细胞减少症的发生率（7.1% vs 4.5%[NSABP B31]），曲妥珠单抗联合化疗组高于单独化疗的患者。转移性乳腺癌的随机对照临床试验中，NCI-CTC 3/4级中性粒细胞减少症的发生率（32% vs 22%）和发热性中性粒细胞减少症的发生率（23% vs 17%），曲妥珠单抗联合化疗的患者也高于单独化疗的患者。

转移性胃癌

根据血液及淋巴系统疾病SOC中的分类方法，对报告最多的不良事件（≥3级，在各组中发生率≥1%）总结见下表。

表5 SOC中血液导淋巴系统异常中≥3级的常见AE

氟尿嘧啶/顺铂组和曲妥珠单抗/氟尿嘧啶/顺铂组中出现的≥3级（NCI-CTCAE 3.0版）不良事件（根据SOC的分类方法）的患者比例分别为38%和40%。

总体而言，血液学毒性反应在治疗组和对照组之间未出现显著性差异。

肝脏和肾脏毒性

乳腺癌

曲妥珠单抗单药治疗转移癌患者时，有12%患者会出现WHO Ⅲ或Ⅳ级肝脏毒性，该毒性与其中60%患者的肝脏疾病恶化有关。

与紫杉醇单药治疗患者相比，使用曲妥珠单抗联合紫杉醇治疗的患者发生WHO Ⅲ或Ⅳ级肝毒性的频率更低（7% vs 15%）。并且没有观察到WHO Ⅲ或Ⅳ级肾脏毒性的发生。

上市后，经病理证实有肾小球病变的肾病综合征鲜有报告。肾病发生的时间在曲妥珠单抗治疗开始4个月到大约18个月间。肾脏的病理表现有：膜性肾小球肾炎、局灶性肾小球硬化、纤维样肾小球肾炎。肾病的并发症有容量负荷过重和充血性心力衰竭。

转移性胃癌

在B018255试验中，未观察到两治疗组在肝脏和肾脏毒性方面出现显著性差异。NCI-CTC AE（3.0版）≥3级肾脏毒性反应在FP+H组中的发生率未显著高于FP组（两组发生率分别为3%和2%）。

NCI-CTC AE（3.0版）≥3级不良事件（SOC中所收录的肝胆疾病不良事件）：报告的唯一不良事件为高胆红素血症，其在FP+H组中的发生率未显著高于FP组（两组发生率分别为1%和＜1%）。

感染

曲妥珠单抗联合化疗的患者，感染的总体发生率（46% vs 30%[H0648g]）、NCI-CTC2-5级感染的总体发生率（22% vs 14%[NSABP B31]）和3-5级感染/发热性中性粒细胞减少症的总体发生率（3.3% vs 1.4%[NCCTG N9831]），高于单独化疗的患者。辅助治疗中感染发生的最常见部位有：上呼吸道、皮肤和尿道。

治疗转移性乳腺癌的随机对照临床试验中，曲妥珠单抗联合骨髓抑制的化疗药物组患者报告的发热性中性粒细胞减少症的发生率高于（23% vs 17%）单独化疗的患者。

曲妥珠单抗治疗的患者观察到感染的发生率增加，主要是临床意义较小的轻度上呼吸道感染或尿道感染。

肺部反应

乳腺癌辅助治疗

乳腺癌辅助治疗的女性患者中，NCI-CTC 2~5级肺部反应的发生率（14% vs 5%[NSABP B31]），NCI-CTC 3~5级肺部反应和自发报道的2级呼吸困难发生率（3.4% vs 1%[NCCTG N9831]），曲妥珠单抗联合化疗的患者高于单独化疗的患者。曲妥珠单抗联合化疗和单独化疗的患者最常见的肺部反应为呼吸困难（NCI-CTC 2~5级：12% vs 4%[NSABP B31]；NCI-CTC 2~5级：2.5% vs 0.1%[NCCTG N9831]）。

肺炎朋市浸润的发生率，曲妥珠单抗治疗的患者为0.7%，单独化疗的患者为0.3%。曲妥珠单抗治疗的患者中，3例发生致死性呼吸衰竭，其中1例表现为多脏器功能衰竭综合征。单独化疗的患者中，1例发生致死性呼吸衰竭。

转移性乳腺癌

接受曲妥珠单抗治疗的转移性乳腺癌女性患者肺部毒性的发生率也有增加。肺部的不良事件作为输注反应的一部分在上市后有报道。肺不良事件包括：支气管痉挛、低氧血症、呼吸困难、肺浸润、胸腔积液、非心源性肺水肿和急性呼吸窘迫综合征。具体描述见注意事项。

血栓/栓塞

在三项随机对照的临床试验中，两项试验发现，曲妥珠单抗联合化疗患者血栓形成的发生率高于单独化疗的患者（3.0% vs 1.3%[NSABP B31]和2.1% vs 0%[H0648g]）。

腹泻

乳腺癌

乳腺癌辅助治疗的女性患者，NCI-CTC 2~5级腹泻发生率（6.2% vs 4.8[NSABPB31]）、NCI-CTC 3~5级腹泻发生率（1.6% vs O%[NCCTG N9831]）、NCI-CTC 1~4级腹泻发生率（7% vs 1%[B016348]），曲妥珠单抗联合化疗的患者高于单独化疗的患者。接受曲妥珠单抗单药治疗的转移性乳腺癌患者腹泻发生率为27%。接受曲妥珠单抗联合紫杉醇治疗较仅接受紫杉醇治疗的转移性乳腺癌患者腹泻的发生率增加，主要是轻到中度。

转移性胃癌

在B018255试验中，含曲妥珠单抗治疗组和对照组中分别有109名患者（37%）和80名患者（28%）出现了所有严重度级别的腹泻。根据NCI-CTCAE 3.0版的严重度标准，FP组和FP+H组分别有4%和9%的患者出现了≥3级腹泻。

免疫原性

对于所有治疗用蛋白质，都有发生免疫原性的可能。在903例接受曲妥珠单抗治疗的转移性乳腺癌女性患者中，有1例患者通过酶链免疫吸附法（ELISA）被检测出人抗曲妥珠单抗抗体（ADA），这例患者未出现过敏症状。采用乳腺癌辅助治疗试验中未收集ADA评估样本。

抗体生成发生率高度依赖于检测方法的灵敏性和特异性。另外，试验中检测到的抗体阳性率（包括中和抗体）还会受到其它因素影响，包括分析方法、样本的处理、样本的收集时间、伴随的药物治疗和其它的合并疾病。由于这些原因，比较ADA的阳性率和其它产品抗体的阳性率可能会使人误解。

上市后经验

曲妥珠单抗批准上市后，报告了以下不良反应。由于这些不良反应是在大小不等的人群中报告的，因此无法准确估计其发生率或确定与曲妥珠单抗治疗之间的因果关联。

表6 上市后治疗中报告的不良反应

不良事件

下表给出了以往接受曲妥珠单抗治疗的患者所报告的不良事件。由于没有证据表明曲妥珠单抗与这些事件之间存在因果关系，这些事件不是报告给管理部门的预期事件。

表7 不良事件

【禁忌】

禁用于已知对曲妥珠单抗过敏或者对任何本品辅料过敏的患者。

本品使用苯甲醇作为溶媒，禁止用于儿童肌肉注射。

【注意事项】

心功能不全

一般考虑要点

曲妥珠单抗可引起左心室功能不全、心律失常、高血压、有症状的心力衰竭、心肌病、和心源性死亡，也可引起有症状的左心室射血分数（LVEF）降低。曲妥珠单抗治疗患者充血性心力衰竭（CHF）（纽约心脏病协会[NYHA]Ⅱ-Ⅳ级）或无症状心功能不全的风险可能增加。

这些事件可见于接受曲妥珠单抗单药或葸环类（多柔比星或表柔比星）化疗序贯曲妥珠单抗联合紫杉类治疗的患者。程度中至重度并与死亡相关。另外，心脏风险增加的患者慎用本品（例如高血压、冠状动脉疾病、CHF、舒张功能不全、老年人）。

曲妥珠单抗半衰期约28-38天，因此停药27周后，血液循环中仍可能有曲妥珠单抗残留。停用曲妥珠单抗后，接受葸环类抗生素治疗患者的心功能不全风险仍然可能增加。

医师应尽可能避免在停用曲妥珠单抗后27周内给予葸环类抗生素类药物治疗。若需要使用葸环类抗生素治疗，则应密切监测患者的心脏功能。

给予首剂曲妥珠单抗之前，特别是先前暴露过葸环类抗生素的患者，均应进行基线心脏评估，包括病史、体格检查、心电图（ECG）以及通过超声心动图和/或MUGA（放射性心血管造影）扫描。监测可帮助识别出现心功能不全的患者，包括CHF 体征和症状。基线时进行心脏评估，治疗期间每3个月重复一次，中止治疗后每6个月重复一次，直至停止曲妥珠单抗给药治疗后24个月。

若LVEF值相对基线下降10个百分点，或下降至50%以下，则应暂停使用曲妥珠单抗，并在约3周内重复评估LVEF。若LVEF无改善，或进一步下降，则强烈建议终止曲妥珠单抗用药，除非认为患者的获益大于风险。对于发生无症状心功能不全的患者，应频繁监测（如每6-8周一次）。若患者的左心室功能持续减退，但仍保持无症状，在观察不到曲妥珠单抗临床获益时，医师应考虑中断治疗。

若在曲妥珠单抗治疗期间发生有症状的心力衰竭，则患者应按此类疾病的标准治疗方案进行治疗。对于有临床意义的心力衰竭患者，强烈建议停止曲妥珠单抗用药，除非患者个体获益大于风险。

对于已出现心脏毒性的患者继续或重新开始使用曲妥珠单抗的安全性，目前尚无前瞻性研究。在关键性试验中，大多数发生心力衰竭或无症状的心功能不全的患者给予标准治疗后症状得到了改善。这些标准治疗包括血管紧张素转化酶抑制剂（ACE）或血管紧张素受体阻滞剂（ARB）和β阻滞剂。大多数有心脏症状的曲妥珠单抗临床获益的患者，在继续接受曲妥珠单抗治疗过程中，未出现其它临床心脏事件。

转移性乳腺癌（MBC）

在转移性乳腺癌治疗中，曲妥珠单抗和葸环类抗生素不能合并使用。

早期乳腺癌（EBC）

对于EBC患者，基线时进行心脏评估，治疗期间每3个月重复一次，终止治疗后每6个月重复一次，直至停止曲妥珠单抗给药治疗后24个月。接受含葸环类抗生素化疗的患者建议进一步监测，并且应每年一次，直至停止曲妥珠单抗给药治疗后5年，或者在LVEF持续下降情况下监测时间更长。

曲妥珠单抗乳腺癌辅助治疗临床试验排除有心肌梗死（MI）史、需药物治疗的心绞痛、CHF（NYHA Ⅱ-Ⅳ）或病史、其他心肌病、需药物治疗的心律失常、具有临床意义的心脏瓣膜疾病或病史、高血压控制不佳（标准药物控制好的高血压可接受曲妥珠单抗治疗）和心包积液影响血液动力学的患者。

辅助治疗

辅助治疗中，曲妥珠单抗和葸环类抗生素不能合并用药。

EBC患者中，与联合多西他赛和卡铂等非葸环类药物治疗相比，含葸环类药物化疗后接受曲妥珠单抗治疗患者，有症状和无症状心脏事件发生率增加。曲妥珠单抗与紫杉烷类合并用药治疗中有症状和无症状心脏事件发生率比紫衫烷序贯曲妥珠单抗治疗更明显。无论采用何种方案，大部分有症状心脏不良事件均发生在治疗的前18个月内。

4项大型辅助治疗研究显示，心脏事件风险因素包括老年（＞50岁）、LVEF基线水平低和LVEF水平下降（＜55%）、紫杉醇、曲妥珠单抗治疗前或治疗后LVEF水平低和既往用过或正在使用抗高血压药物治疗。完成辅助化疗后接受曲妥珠单抗治疗患者中，心功能不全风险与曲妥珠单抗开始治疗前给予的葸环类抗生素治疗蓄积剂量较高和体重指数（BMI）高有关。新辅助治疗在新辅助治疗的EBC患者中，应慎用曲妥珠单抗与葸环类抗生素合并治疗，并且仅用于初次接受化疗的患者。低剂量蒽环类抗生素治疗方案的最大蓄积剂量不超过180mg/m2（多柔比星）或360mg/m2（表柔比星）。

如果接受新辅助治疗的患者接受低剂量葸环类抗生素与曲妥珠单抗合并用药治疗，则术后不得再接受细胞毒性化疗。

65岁以上患者中新辅助治疗的临床经验有限。

心功能监测

给予首剂曲妥珠单抗之前，应充分评估患者心功能，包括病史、体格检查、并通过超声心动图或MUGA（放射性心血管造影）扫描检查测定LVEF值。在临床试验中，按下述时间安排进行心功能监测：

开始曲妥珠单抗治疗前测量LVEF基线值。

· 曲妥珠单抗治疗期间每3个月进行一次LVEF测量，且在治疗结束时进行一次。

· 曲妥珠单抗治疗结束后至少两年内每6个月进行一次LVEF测量。

· 曲妥珠单抗因严重左心室功能不全停药后，每4周进行一次LVEF测量[见用法用量]。

在NSABP B31中，16%（136/844）的患者由于心功能不全或严重的LVEF（左室射血分数）下降的临床证据而中断曲妥珠单抗治疗。

在B016348试验中，有2.6%（44/1678例）的患者因心脏毒性停止使用曲妥珠单抗。在B016348试验中排除了下述早期乳腺癌患者，因此没有关于这部分患者的风险效益评估数据，所以不推荐这些患者使用曲妥珠单抗治疗：

· 充血性心力衰竭病史。

· 高危未控制的心律失常。

· 需要药物治疗的心绞痛。

· 有临床意义的瓣膜疾病。

· 心电图显示透壁心肌梗死。

· 控制不佳的高血压。

在32位接受辅助化疗出现充血性心力衰竭（CHF）的患者中（NSABP B31、NCCTGN9831），1位患者死于心肌病，所有其他患者在后来的随访中接受了心脏药物治疗。生存病人继续药物治疗，约半数在末次随访时LVEF恢复正常（定义为≥50%）。曲妥珠单抗诱导的左室功能不全的患者继续或恢复曲妥珠单抗治疗的安全性还未被研究。

表8 乳腺癌的曲妥珠单抗辅助治疗试验中充血性心力衰竭的发生率

表9 转移性乳腺癌试验中心功能不全*发生率

输注相关反应（IRR）

使用曲妥珠单抗注射液时常见IRR。可采取预治疗降低发生IRR的风险。

输注反应包括一系列症状，表现为发热、寒战，偶尔会有恶心、呕吐、疼痛（某些病例在肿瘤部位）、头疼、晕眩、呼吸困难、低血压、皮疹和衰弱（见不良反应）。

在上市后报道中，有严重的和致死的输注反应报道。严重的反应包括呼吸困难、哮鸣、支气管痉挛、过敏反应、血管性水肿、缺氧、心动过速、氧饱和度下降、呼吸窘迫和严重的低血压，通常发生在刚开始输注过程中或之后。但是，发作和临床过程变化很大，包括渐进性恶化、最初改善而后恶化、或延迟的输注后事件并且临床迅速恶化。死亡病例发生在严重的输注反应后几小时甚至几天内。应观测患者IRR情况。中断静脉滴注有助于控制此类症状，症状减轻后，可恢复滴注给药。镇痛药或解热镇痛药可治疗以上症状，如哌替啶或乙酰氨基酚、或抗组胺药（如苯海拉明）。严重反应经吸氧、β-受体兴奋剂、皮质激素支持治疗可成功治疗。这些反应甚至可能导致少数患者死亡。

由于晚期恶性肿瘤并发症或合并症导致发生休息时呼吸困难的患者，可能会增加致命性输注反应的风险。因此，对这些病人的治疗应非常谨慎，并考虑每位病人的风险/获益比。

所有发生呼吸困难或临床严重低血压的患者，曲妥珠单抗输注应该中断，同时给予药物治疗。药物包括肾上腺素、皮质类固醇激素、苯海拉明、支气管扩张剂和氧气。应该评估和谨慎地监测患者直到症状和体征完全缓解。所有发生严重输注反应的患者应考虑永久停药。

目前没有关于鉴别在经历了严重的输注反应后还可以再次安全地接受曲妥珠单抗治疗的患者的最合适方法的资料。在再次接受曲妥珠单抗治疗之前，经历了严重输注反应的患者预防性应用抗组胺药和/或糖皮质激素，一些患者能耐受再次曲妥珠单抗治疗，而另一些患者尽管应用了预防性用药但还是发生了严重的反应。

苯甲醇

用作440mg规格中无菌注射用水防腐剂的苯甲醇引起了新生儿和3岁以下儿童的毒性反应。已知对苯甲醇过敏的患者在给于曲妥珠单抗时应使用注射用水复溶，每瓶曲妥珠单抗只给药1次。弃去未使用部分。

胚胎毒性

孕期妇女使用曲妥珠单抗会对胎儿造成伤害。上市后报道中，孕期使用曲妥珠单抗会导致羊水过少及其造成肺发育不全、骨骼异常和新生儿死亡，应告知患者孕期使用曲妥珠单抗可能会对胎儿造成伤害，并对育龄患者提供避孕咨询服务（见孕妇及哺乳期妇女用药）。

肺部反应

在上市后曲妥珠单抗的临床应用中有报道严重肺部反应事件，这些事件偶尔会导致死亡，可以是IRR的部分表现或延迟表现。此外，已报道病例有间质性肺疾病（包括肺浸润）、急性呼吸窘迫综合征、肺炎、非感染性肺炎、胸腔积液、呼吸窘迫、急性肺水肿和呼吸功能不全。

导致间质性肺病的风险因素包括之前或合并使用已知可引起间质性肺病的其他抗肿瘤治疗，如紫杉烷类、吉西他滨、长春瑞滨和放疗。因晚期恶性肿瘤并发症和合并疾病而发生静止时呼吸困难的患者可能发生肺部反应的风险更高。因此，这些患者不应接受曲妥珠单抗治疗。

化疗诱导的中性粒细胞减少症加重

在曲妥珠单抗联合化疗治疗转移性乳腺癌的随机、对照临床试验中，联合骨髓抑制化疗药物治疗组中NCI CTC 3~4级中性粒细胞减少症和发热性中性粒细胞减少症的发生率比单纯化疗组高。因败血症死亡的发生率并没有显著提高（见[不良反应]）。

HER2检测

检测HER2蛋白过度表达是筛选适合接受曲妥珠单抗治疗的患者所必须的，因为只有HER2过度表达的患者被证明能从治疗中受益的。HER2过度表达和HER2基因扩增的检测应该由被认证精通此项特殊技术的实验室完成。不正确的操作，包括使用未达最佳固定标准的组织、没有应用特定试剂、背离特定技术指南和没有包括合适的实验对照，可能会导致不可靠的结果。

一些已获批准的商业检测有助于接受曲妥珠单抗治疗患者的选择。这些方法包括HercepTestTM、和口CONFIRMTM anti-HER-2/neu （4B5） Primary Antibody（HER-2/NEU抗体）（IHC检测）；HER2 FISH pharmDxTM、INFORM HER2 DNA Probe （HER2 DNA探针）、Rabbit anti-DNP Antibody（DNP抗体试剂）和INFORM Chromosome 17 Probe（17号染色体探针）以及DDISH HER2 Probe（DDISH HER2探针） （FISH检测）。

使用者应查询这些检测试剂盒包装中的说明书，以了解每项检测的验证结果和操作方法。

检验精确性（特别是IHC方法）的限制、检测结果和曲妥珠单抗靶点过度表达的直接关系（FISH方法）的限制，使得仅依赖一个方法排除曲妥珠单抗治疗的潜在受益不可取。FISH阴性结果不能排除HER2过度表达和从曲妥珠单抗治疗中潜在受益的可能。转移性乳腺癌（H0648g）治疗中IHC和FISH检测与治疗结果的关系见表13。乳腺癌辅助治疗（NCCTG N9831和B016348）中IHC和FISH检测与治疗结果的关系见表10。

评估胃癌中HER2过度表达和HER2基因扩增应使用被批准的检测方法，这一点对胃癌尤为重要，这是由于胃和乳腺的组织病理学差异，包括不完全膜染色和胃癌中HER2基因更多异质表达。B018255试验中阐述了基因扩增和蛋白质过度表达的相关性不如在乳腺癌中那样好。基于HER2基因扩增（B018255试验）和蛋白质过度表达（IHC）检测结果的胃癌治疗效果见表16。

乳腺癌HER2过度表达或HER2基因扩增的检测

曲妥珠单抗仅可以在使用准确和有效检测方法确定HER2过度表达或HER2基因扩增的患者中使用。HER2过度表达采用基于免疫组织化学（IHC）的固定肿瘤组织块评价法。HER2基因扩增采用固定肿瘤组织块的荧光原位杂交法（FISH）或显色原位杂交法（CISH）。如果患者的HER2过度表达强度分数达3+（IHC）或FISH或CISH结果阳性，则符合曲妥珠单抗治疗要求。

为保证结果的准确性和重现性，试验必须在专门实验室实施，以充分保证试验步骤的有效性。

推荐的评价IHC染色类型的分数系统如下：

一般情况下，如果每个肿瘤细胞HER2基因拷贝数与染色体17拷贝数的比率大于或等于2，或者在无染色体17对比情况下，如果每个肿瘤细胞HER2基因拷贝数大于4，则视为FISH阳性。

一般情况下，如果大于50%的肿瘤细胞中的每个细胞核HER2基因拷贝数超过5个，则视为CISH阳性。

有关详细的检测方法和解释的操作指南，请参考FISH和CISH有效检测方法的说明书，也可以采用官方对HER2检测的建议。

如果采用任何其它方法评估HER2蛋白或基因表达，则必须在能够提供最先进的有效检查方法的实验室中实施。此类方法必须具有足够的精密度和准确度，以检测出HER2过度表达，并且必须能够区分中等阳性（2+）与强阳性（3+） HER2过度表达之间的差异。

胃癌HER2过度表达或HER2基因扩增的检测

必须采用准确和有效的方法检测HER2过度表达或HER2基因扩增，推荐IHC作为首选检测方式，如果还需要检测HER2基因扩增状况，则必须采用银增强原位杂交法（SISH）或FISH检测法。但是，如果需要同时进行肿瘤组织学和形态学的评价，则推荐采用SISH检测法。为保证检测方法的有效性并获得具有准确度和重现性的结果，必须在配备专业工作人员的实验室实施HER2检测。有关检测方法和结果解释的详细说明，请见所采用的HER2检测方法试剂盒提供的产品信息说明书。

在B018255试验中，肿瘤检测结果呈IHC3+或FISH阳性的患者被定为HER2阳性并入组试验。基于该临床试验结果，有效性局限于HER2蛋白过度表达水平最高的患者，即IHC分数为3+，或IHC分数为2+并且FISH结果呈阳性。

在一项方法比较研究中（D008548试验），SISH和FISH检测法对胃癌患者的HER2基因扩增检测结果高度一致（＞95%）。

在采用IHC或ISH检测HER2的表达时，应采用相对应的肿瘤组织固定模式。

推荐的评价IHC染色类型的分数系统如下：

一般情况下，如果每个肿瘤细胞HER2基因拷贝数与染色体17拷贝数之间比率大于或等于2，则视为SISH或FISH呈阳性。

驾车和操作机器的能力

尚未进行对驾车和操作机器能力影响的研究。出现输注相关症状的患者在其症状完全消退前不得驾车或操作机器。

【药物相互作用】

在临床试验中，曲妥珠单抗与紫杉醇联用时，曲妥珠单抗血清浓度相对基线升高1.5倍。在药物相互作用研究中，与曲妥珠单抗联用时，多西他赛和紫杉醇的药代动力学没有发生改变。

在试验B015935中对曲妥珠单抗与紫杉醇之间的药物相互作用进行了评估，这两种药物之间没有明显的相互作用。在试验M77004中，对HER2-阳性的转移性乳腺癌女性患者接受曲妥珠单抗与多柔比星+紫杉醇治疗、之后每周一次接受紫杉醇治疗的药代动力学进行了评价，该试验中曲妥珠单抗与紫杉醇和多柔比星（及其主要代谢物）之间未见明显的相互作用。试验JP16003是在HER2-阳性的转移性乳腺癌日本女性患者进行的一项单组试验。在该试验中，曲妥珠单抗与多柔比星之间没有明显的药物相互作用（DDI）。

试验JP19959是B018255试验的一个子试验，在日本男性和女性晚期胃癌患者中进行，旨在研究卡培他滨和顺铂与或不与曲妥珠单抗合并用药的药代动力学（PK）。该小型子试验的结果表明，卡培他滨（及其代谢物）的药代动力学不受顺铂合并用药或顺铂+曲妥珠单抗合并用药的影响。数据还表明，顺铂的药代动力学不受卡培他滨合并用药或卡培他滨+曲妥珠单抗合并用药的影响。该试验未对曲妥珠单抗的药代动力学进行评价。

与阿那曲唑联合治疗未明显影响曲妥珠单抗的药代动力学。

【包装】

1瓶/盒（含稀释液），稀释液为含1.1%苯甲醇的20ml灭菌注射用水。

 Pronunciation

(tras TU zoo mab)

  Index Terms

anti-c-erB-2

anti-ERB-2

Conventional Trastuzumab

MOAB HER2

rhuMAb HER2

Trastuzumab (Conventional)

      Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Herceptin: 440 mg (1 ea) [contains benzyl alcohol, mouse (murine) and/or hamster protein]

Solution Reconstituted, Intravenous [preservative free]:

Herceptin: 150 mg (1 ea)

Brand Names: U.S.HerceptinPharmacologic CategoryAntineoplastic Agent, Anti-HER2Antineoplastic Agent, Monoclonal AntibodyPharmacology

Trastuzumab is a monoclonal antibody which binds to the extracellular domain of the human epidermal growth factor receptor 2 protein (HER-2); it mediates antibody-dependent cellular cytotoxicity by inhibiting proliferation of cells which overexpress HER-2 protein.

Excretion

In most patients, trastuzumab concentrations will decrease to ~3% (~97% washout) by 7 months following discontinuation.

Use: Labeled Indications

Breast cancer, adjuvant treatment: Treatment (adjuvant) of human epidermal growth receptor 2 (HER2)-overexpressing node positive or node negative (estrogen receptor/progesterone receptor negative or with 1 high risk feature) breast cancer as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; with docetaxel and carboplatin; or as a single agent following multimodality anthracycline-based therapy.

Breast cancer, metastatic: First-line treatment of HER2-overexpressing metastatic breast cancer (in combination with paclitaxel); single agent treatment of HER2-overexpressing breast cancer in patients who have received 1 or more chemotherapy regimens for metastatic disease.

Gastric cancer, metastatic: Treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma (in combination with cisplatin and either capecitabine or 5-fluorouracil) in patients who have not received prior treatment for metastatic disease.

Limitations of use: Patients should be selected for breast and gastric cancer therapy based on an approved companion diagnostic test for tumor specimen for HER2 overexpression or HER2 gene amplification.

Off Label UsesHER2-positive metastatic breast cancer (in combination with pertuzumab and docetaxel) in patients who have not received prior anti-HER2 therapy or chemotherapy to treat metastatic disease

Data from a large, randomized, controlled phase III study supports the use of trastuzumab in combination with pertuzumab and docetaxel in the management of metastatic breast cancer [Baselga 2012].

Based on the American Society of Clinical Oncology (ASCO), Systemic Therapy for Patients with Advanced HER2-Positive Breast Cancer guidelines, trastuzumab in combination with pertuzumab and a taxane is recommended as first-line treatment, unless there are contraindications to taxanes.

HER2-positive metastatic breast cancer (in combination with pertuzumab and weekly paclitaxel)

Data from a small phase II study supports the use of trastuzumab in combination with pertuzumab and weekly paclitaxel in the management of metastatic breast cancer [Dang 2015]. Based on the American Society of Clinical Oncology (ASCO), Systemic Therapy for Patients with Advanced HER2-Positive Breast Cancer guidelines, trastuzumab in combination with pertuzumab and a taxane is recommended as first-line treatment, unless there are contraindications to taxanes; paclitaxel is a reasonable alternative in patients who are not good candidates for docetaxel [Giordano 2014].

HER2-positive metastatic breast cancer (in combination with either docetaxel or vinorelbine)

Data from a large phase III study supports the use of trastuzumab (in combination with either docetaxel or vinorelbine) for the treatment of metastatic or locally advanced HER2-positive breast cancer [Andersson 2011]. Additionally, a large randomized phase II trial supports the combination of trastuzumab and docetaxel for the management of metastatic HER2-positive disease [Marty 2005].

HER2 overexpressing metastatic breast cancer (in combination with lapatinib) which had progressed on prior trastuzumab containing therapy

Data from a phase III randomized controlled study supports the use of trastuzumab in combination with lapatinib in the management of metastatic breast cancer which has progressed on prior trastuzumab therapy [Blackwell 2012].

Based on the American Society of Clinical Oncology (ASCO), Systemic Therapy for Patients with Advanced HER2-Positive Breast Cancer guidelines, trastuzumab in combination with lapatinib is a third-line treatment option in patients whose disease has progressed during or after second line or greater HER2-targeted therapy.

Neoadjuvant treatment of HER2-positive locally advanced, inflammatory or early breast cancer

Data from a large randomized phase II study supports the use of trastuzumab in combination with pertuzumab and docetaxel in the neoadjuvant management of HER2-positive locally advanced, inflammatory or early breast cancer [Gianni 2012].

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to trastuzumab, Chinese hamster ovary (CHO) cell proteins, or any component of the formulation

Dosing: Adult

Note: Do NOT substitute conventional trastuzumab for or with ado-trastuzumab emtansine; products are different and are NOT interchangeable.

Breast cancer, adjuvant treatment, HER2+: IV: Note: Extending adjuvant treatment beyond 1 year is not recommended

With concurrent paclitaxel or docetaxel:

Initial loading dose: 4 mg/kg infused over 90 minutes, followed by

Maintenance dose: 2 mg/kg infused over 30 minutes weekly for total of 12 weeks, followed 1 week later (when concurrent chemotherapy completed) by 6 mg/kg infused over 30 to 90 minutes every 3 weeks for total therapy duration of 52 weeks

With concurrent docetaxel/carboplatin:

Initial loading dose: 4 mg/kg infused over 90 minutes, followed by

Maintenance dose: 2 mg/kg infused over 30 minutes weekly for total of 18 weeks, followed 1 week later (when concurrent chemotherapy completed) by 6 mg/kg infused over 30 to 90 minutes every 3 weeks for total therapy duration of 52 weeks

Following completion of multi-modality anthracycline-based chemotherapy:

Initial loading dose: 8 mg/kg infused over 90 minutes, followed by

Maintenance dose: 6 mg/kg infused over 30 to 90 minutes every 3 weeks for total therapy duration of 52 weeks

Breast cancer, metastatic, HER2+ (either as a single agent or in combination with paclitaxel): IV:

Initial loading dose: 4 mg/kg infused over 90 minutes, followed by

Maintenance dose: 2 mg/kg infused over 30 minutes weekly until disease progression

Gastric cancer, metastatic, HER2+ (in combination with cisplatin and either capecitabine or fluorouracil for 6 cycles followed by trastuzumab monotherapy; Bang 2010): IV:

Initial loading dose: 8 mg/kg infused over 90 minutes, followed by

Maintenance dose: 6 mg/kg infused over 30 to 90 minutes every 3 weeks until disease progression

Missed doses: If a dose is missed by ≤1 week, the usual maintenance dose should be administered as soon as possible (do not wait until the next planned cycle) and subsequent maintenance doses should be administered 7 or 21 days later (based on patient's maintenance dose/schedule); if a dose is missed by >1 week, then a re-loading dose (4 mg/kg if patient receives trastuzumab weekly; 8 mg/kg if on an every-3-week schedule) should be administered, followed by the usual maintenance dose administered 7 or 21 days later (based on patient's maintenance dose/schedule).

Breast cancer (early stage, locally advanced, or inflammatory), neoadjuvant treatment, HER2+ (off-label use): IV: Trastuzumab, pertuzumab, and docetaxel (in patients with operable disease who had received no prior chemotherapy): Initial: 8 mg/kg (cycle 1) followed by 6 mg/kg every 3 weeks for a total of 4 neoadjuvant cycles; postoperatively, administer 3 cycles of adjuvant FEC [fluorouracil, epirubicin, and cyclophosphamide] chemotherapy and continue trastuzumab to complete 1 year of treatment (Gianni 2012)

Breast cancer, metastatic, HER2+ (off-label combinations): IV: Note: There are multiple trastuzumab-containing regimens for the treatment of HER2+ metastatic breast cancer; commonly used regimens are listed below:

Trastuzumab, pertuzumab, and docetaxel (in patients with no prior anti-HER2 therapy or chemotherapy to treat metastatic disease): Initial: 8 mg/kg followed by a maintenance dose of 6 mg/kg every 3 weeks until disease progression or unacceptable toxicity (Baselga 2012)

Trastuzumab, pertuzumab, and weekly paclitaxel: Initial: 8 mg/kg followed by a maintenance dose of 6 mg/kg every 3 weeks until disease progression (Dang 2015)

Trastuzumab and lapatinib (in patients with progression on prior trastuzumab containing therapy): Initial: 4 mg/kg followed by a maintenance dose of 2 mg/kg every week (Blackwell 2010; Blackwell 2012)

Other trastuzumab combinations: Initial: 8 mg/kg followed by a maintenance dose of 6 mg/kg every 3 weeks until disease progression or unacceptable toxicity (in combination with docetaxel or vinorelbine) (Andersson 2011) or 4 mg/kg loading dose followed by a maintenance dose of 2 mg/kg weekly until disease progression (in combination with docetaxel) (Marty 2005)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl 30 to 90 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling, although no clinically significant pharmacokinetic differences have been observed.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

End-stage renal disease (ESRD) (with or without hemodialysis): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Adjustment for Toxicity

Cardiotoxicity: LVEF ≥16% decrease from baseline or LVEF below normal limits and ≥10% decrease from baseline: Withhold treatment for at least 4 weeks and repeat LVEF every 4 weeks. May resume trastuzumab treatment if LVEF returns to normal limits within 4 to 8 weeks and remains at ≤15% decrease from baseline value. Discontinue permanently for persistent (>8 weeks) LVEF decline or for >3 incidents of treatment interruptions for cardiomyopathy.

Infusion-related events:

Mild-moderate infusion reactions: Decrease infusion rate.

Dyspnea, clinically significant hypotension: Interrupt infusion.

Severe or life-threatening infusion reactions: Discontinue.

Reconstitution

Check vial labels to assure appropriate product is being reconstituted (conventional trastuzumab and ado-trastuzumab emtansine are different products and are NOT interchangeable).

Reconstitute each 420 mg vial (multidose vial) with 20 mL of bacteriostatic sterile water for injection (sterile water for injection may be used if a patient has a known hypersensitivity to benzyl alcohol). Reconstitute each 150 mg vial (single use vial) with 7.4 mL of sterile water for injection. Direct the stream of diluent into the lyophilized cake. The reconstituted solutions (in the vial) will have a concentration of 21 mg/mL. Swirl gently; do not shake. Slight foaming may occur during reconstitution. Allow vial to rest undisturbed for ~5 minutes. Solutions reconstituted with sterile water for injection must be used immediately. Further dilute the appropriate volume for the trastuzumab dose in 250 mL NS prior to administration; do not use D5W. Gently invert bag to mix.

440 mg vial [Canadian product]: Reconstitute each 440 mg vial with 20 mL bacteriostatic sterile water for injection (sterile water for injection may be used if a patient has a known hypersensitivity to benzyl alcohol) to a concentration of 21 mg/mL, then follow above for further instructions.

Administration

Check label to ensure appropriate product is being administered (conventional trastuzumab and ado-trastuzumab emtansine are different products and are NOT interchangeable).

Administered by IV infusion; loading doses are infused over 90 minutes; maintenance doses may be infused over 30 minutes if tolerated. Do not administer with D5W. Do not administer IV push or by rapid bolus. Do not mix with any other medications.

Observe patients closely during the infusion for fever, chills, or other infusion-related symptoms. Treatment with acetaminophen, diphenhydramine, and/or meperidine is usually effective for managing infusion-related events.

Storage

Prior to reconstitution, store intact vials at 2°C to 8°C (36°F to 46°F). Following reconstitution with bacteriostatic SWFI, the solution in the vial is stable refrigerated for 28 days from the date of reconstitution; do not freeze. Solutions reconstituted with sterile water for injection without preservatives must be used immediately. The solution diluted in polyvinylchloride or polyethylene bags containing 250 mL NS for infusion may be stored refrigerated for up to 24 hours prior to use; do not freeze.

Drug Interactions

Anthracyclines: Trastuzumab may enhance the cardiotoxic effect of Anthracyclines. Management: When possible, patients treated with trastuzumab should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab. Monitor closely for cardiac dysfunction in patients receiving anthracyclines with trastuzumab. Consider therapy modification

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Immunosuppressants: Trastuzumab may enhance the neutropenic effect of Immunosuppressants.Exceptions: Cytarabine (Liposomal). Monitor therapy

PACLitaxel (Conventional): Trastuzumab may decrease the serum concentration of PACLitaxel (Conventional). PACLitaxel (Conventional) may increase the serum concentration of Trastuzumab.Monitor therapy

Adverse Reactions

Percentages reported with single-agent therapy.

>10%:

Cardiovascular: Decreased left ventricular ejection fraction (4% to 22%)

Central nervous system: Pain (47%), chills (5% to 32%), headache (10% to 26%), insomnia (14%), dizziness (4% to 13%)

Dermatologic: Skin rash (4% to 18%)

Gastrointestinal: Nausea (6% to 33%), diarrhea (7% to 25%), vomiting (4% to 23%), abdominal pain (2% to 22%), anorexia (14%)

Infection: Infection (20%)

Neuromuscular & skeletal: Weakness (4% to 42%), back pain (5% to 22%)

Respiratory: Cough (5% to 26%), dyspnea (3% to 22%), rhinitis (2% to 14%), pharyngitis (12%)

Miscellaneous: Infusion related reaction (21% to 40%, chills and fever most common; severe: 1%), fever (6% to 36%)

1% to 10%:

Cardiovascular: Peripheral edema (5% to 10%), edema (8%), cardiac failure (2% to 7%; severe: <1%), tachycardia (5%), hypertension (4%), arrhythmia (3%), palpitations (3%)

Central nervous system: Paresthesia (2% to 9%), depression (6%), peripheral neuritis (2%), neuropathy (1%)

Dermatologic: Acne vulgaris (2%), nail disease (2%), pruritus (2%)

Gastrointestinal: Constipation (2%), dyspepsia (2%)

Genitourinary: Urinary tract infection (3% to 5%)

Hematologic & oncologic: Anemia (4%; grade 3: <1%), leukopenia (3%)

Hypersensitivity: Hypersensitivity reaction (3%)

Infection: Influenza (4%), herpes simplex infection (2%)

Neuromuscular & skeletal: Arthralgia (6% to 8%), ostealgia (3% to 7%), myalgia (4%), muscle spasm (3%)

Respiratory: Flu-like symptoms (2% to 10%), sinusitis (2% to 9%), nasopharyngitis (8%), upper respiratory tract infection (3%), epistaxis (2%), pharyngolaryngeal pain (2%)

Miscellaneous: Accidental injury (6%)

<1% (Limited to important or life-threatening; as a single-agent or with combination chemotherapy): Adult respiratory distress syndrome, amblyopia, anaphylaxis, apnea, ascites, asthma, ataxia, blood coagulation disorder, bronchitis, cardiogenic shock, cardiomyopathy, cellulitis, cerebrovascular accident, colitis, coma, confusion, deafness, dermal ulcer, dyspnea on exertion, erysipelas, esophageal ulcer, febrile neutropenia, gastroenteritis, glomerulopathy, hematemesis, hemorrhage, hemorrhagic cystitis, hepatic failure, hepatitis, herpes zoster, hydrocephalus, hydronephrosis, hypercalcemia, hypotension, hypothyroidism, hypoxia, immune thrombocytopenia, intestinal obstruction, interstitial pneumonitis, interstitial pulmonary disease, leukemia (acute), lymphangitis, madarosis, mania, meningitis, myopathy, neutropenia, neutropenic sepsis, oligohydramnios, onychoclasis, osteonecrosis, pancreatitis, pancytopenia, paresis, paroxysmal nocturnal dyspnea, pathological fracture, pericardial effusion, pleural effusion, pneumonitis, pneumothorax, pulmonary edema (noncardiogenic), pulmonary fibrosis, pulmonary hypertension, pyelonephritis, radiation injury, renal failure, respiratory failure, seizure, sepsis, syncope, stomatitis, thyroiditis (autoimmune), ventricular dysfunction

ALERT: U.S. Boxed Warning

Cardiomyopathy:

Trastuzumab can result in subclinical and clinical cardiac failure. The incidence and severity was highest in patients who received trastuzumab concurrently with anthracycline-containing chemotherapy regimens.

Evaluate left ventricular function in all patients prior to and during treatment with trastuzumab. Discontinue trastuzumab treatment in patients receiving adjuvant therapy, and withhold trastuzumab in patients with metastatic disease for clinically significant decrease in left ventricular function.

Infusion reactions and pulmonary toxicity:

Trastuzumab administration can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during or within 24 hours of administration of trastuzumab. Interrupt trastuzumab infusion for patients experiencing dyspnea or clinically significant hypotension. Monitor patients until signs and symptoms resolve completely. Discontinue trastuzumab for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.

Pregnancy:

Exposure to trastuzumab during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception.

Warnings/Precautions

Concerns related to adverse effects:

• Cardiomyopathy: [US Boxed Warning]: Trastuzumab is associated with symptomatic and asymptomatic reductions in left ventricular ejection fraction (LVEF) and heart failure (HF); the incidence is highest in patients receiving trastuzumab with an anthracycline-containing chemotherapy regimen. Evaluate LVEF in all patients prior to and during treatment; discontinue for cardiomyopathy. Extreme caution should be used in patients with pre-existing cardiac disease or dysfunction. Prior or concurrent exposure to anthracyclines or radiation therapy significantly increases the risk of cardiomyopathy; other potential risk factors include advanced age, high or low body mass index, smoking, diabetes, hypertension, and hyper-/hypothyroidism. Patients who receive anthracyclines after completion or discontinuation of trastuzumab are at increased risk of cardiac dysfunction (anthracyclines should be avoided for at least 7 months after the last trastuzumab dose, and then monitor cardiac function closely if anthracyclines are used. Discontinuation should be strongly considered in patients who develop a clinically significant reduction in LVEF during therapy; treatment with HF medications (eg, ACE inhibitors, beta-blockers) should be initiated. Withhold treatment for ≥16% decrease from pretreatment levels or LVEF below normal limits and ≥10% decrease from baseline (see Dosage Adjustment for Cardiotoxicity). Cardiomyopathy due to trastuzumab is generally reversible over a period of 1 to 3 months after discontinuation. Long-term (8 years) follow-up in the adjuvant setting (trastuzumab for 1 or 2 years administered sequentially following chemotherapy and radiation therapy) has demonstrated a low incidence of cardiac events, which were generally reversible in most patients (de Azambuja 2014). Trastuzumab is also associated with arrhythmias, hypertension, mural thrombus formation, stroke, and even cardiac death.

• Infusion reactions: [US Boxed Warning]: Infusion reactions (including fatalities) have been associated with use; discontinue for anaphylaxis or angioedema. Most reactions occur during or within 24 hours of the first infusion; interrupt infusion for dyspnea or significant hypotension; monitor until symptoms resolve. Infusion reactions may consist of fever and chills, and may also include nausea, vomiting, pain, headache, dizziness, dyspnea, hypotension, rash, and weakness. Re-treatment of patients who experienced severe hypersensitivity reactions has been attempted (with premedication). Some patients tolerated re-treatment, while others experienced a second severe reaction.

• Pulmonary toxicity: [US Boxed Warning]: May cause serious pulmonary toxicity (dyspnea, hypoxia, interstitial pneumonitis, pulmonary infiltrates, pleural effusion, noncardiogenic pulmonary edema, pulmonary insufficiency, acute respiratory distress syndrome [ARDS], and/or pulmonary fibrosis); discontinue for ARDS or interstitial pneumonitis. Use caution in patients with pre-existing pulmonary disease or patients with extensive pulmonary tumor involvement; these patient populations may have more severe toxicity. Pulmonary events may occur during or within 24 hours of administration; delayed reactions have occurred.

• Renal toxicity: Rare cases of nephrotic syndrome with evidence of glomerulopathy have been reported, with an onset of 4 to 18 months from trastuzumab initiation; complications may include volume overload and HF. The incidence of renal impairment was increased in metastatic gastric cancer patients when trastuzumab is added to chemotherapy.

Concurrent drug therapy issues:

• Chemotherapy: When used in combination with myelosuppressive chemotherapy, trastuzumab may increase the incidence of neutropenia (moderate-to-severe) and febrile neutropenia. The incidence of anemia may be higher when trastuzumab is added to chemotherapy.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pregnancy: [US Boxed Warning]: Trastuzumab exposure during pregnancy may result in oligohydramnios and oligohydramnios sequence (pulmonary hypoplasia, skeletal malformations and neonatal death). Advise patients of these risks and the need for effective contraception. Effective contraception is recommended in women of childbearing potential during treatment and for at least 7 months after the last trastuzumab dose.

Dosage form specific issues:

• Do not interchange: Conventional trastuzumab and ado-trastuzumab emtansine are notinterchangeable. Verify product label prior to reconstitution and administration to prevent medication errors. Dosing and treatment schedules between conventional trastuzumab (Herceptin) and ado-trastuzumab emtansine (Kadcyla) are different; confusion between the products may potentially cause harm to the patient.

Other warnings/precautions:

• HER2 expression: Establish HER2 status prior to treatment with an approved test, either HER2 protein overexpression by validated immunohistochemistry (IHC) assay or gene amplification by fluorescence in situ hybridization (FISH) assay. Due to differences in disease histopathology (eg, incomplete membrane staining and more frequent heterogeneous HER2 expression in gastric cancer), tests appropriate for the specific tumor type (breast or gastric) should be used to assess HER2 status. Unreliable results may occur from improper assay performance, such as use of suboptimally fixed tissue, failure to utilize specified reagents or to include appropriate controls for assay validation, or incorrectly following specific assay instructions. Information regarding HER2 diagnostic testing may be found at http://www.fda.gov/CompanionDiagnostics.

Monitoring Parameters

Assessment for HER2 overexpression and HER2 gene amplification by validated immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) methodology (pretherapy); test should be specific for cancer type (breast vs gastric cancer). Pregnancy test (prior to treatment in women of reproductive potential). Monitor vital signs during infusion; signs and symptoms of cardiac dysfunction; LVEF (baseline, every 3 months during treatment, upon therapy completion and if component of adjuvant therapy, every 6 months for at least 2 years; if treatment is withheld for significant LVEF dysfunction, monitor LVEF at 4-week intervals); signs and symptoms of infusion reaction or pulmonary toxicity; if pregnancy inadvertently occurs during treatment, monitor amniotic fluid volume

Pregnancy Considerations

Trastuzumab inhibits HER2 protein, which has a role in embryonic development. [US Boxed Warning]: Trastuzumab exposure during pregnancy may result in oligohydramnios and oligohydramnios sequence (pulmonary hypoplasia, skeletal malformations and neonatal death). Advise patients of these risks and the need for effective contraception. Oligohydramnios (reversible in some cases) has been reported with trastuzumab use alone or with combination chemotherapy. Monitor for oligohydramnios if trastuzumab exposure occurs during pregnancy or within 7 months prior to conception; conduct appropriate fetal testing if oligohydramnios occurs. Verify pregnancy status in women of reproductive potential prior to initiation of therapy. Women of reproductive potential should use effective contraception during treatment and for at least 7 months after the last trastuzumab dose. If trastuzumab is administered during pregnancy, or if a patient becomes pregnant during or within 7 months after treatment, report exposure to Genentech Adverse Events at 1-888-835-2555. Women exposed to trastuzumab during pregnancy (or within 7 months prior to conception) are encouraged to enroll in MotHER (the Herceptin Pregnancy Registry; 1-800-690-6720 or http://www.motherpregnancyregistry.com).

European Society for Medical Oncology (ESMO) guidelines for cancer during pregnancy recommend delaying treatment with trastuzumab (and other HER-2 targeted agents) until after delivery in pregnant patients with HER-2 positive disease (Peccatori 2013).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience flu-like symptoms, lack of appetite, abdominal pain, weight loss, change in taste, bone pain, joint pain, back pain, insomnia, rhinitis, rhinorrhea, muscle pain, or pharyngitis. Have patient report immediately to prescriber infusion reaction, signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), signs of infection, abnormal heartbeat, angina, tachycardia, shortness of breath, excessive weight gain, swelling of arms or legs, severe dizziness, passing out, vision changes, severe headache, severe nausea, vomiting, severe diarrhea, bruising, bleeding, severe loss of strength and energy, burning or numbness feeling, or depression (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.