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盐酸厄洛替尼片说明书 

美国FDA首次批准：2004

请仔细阅读说明书并在医师指导下使用

 

【药品名称】 

通用名称：盐酸厄洛替尼片 

商品名称：Tarceva

通用英文名称：Erlotinib Hydrochloride Tablets

其他名称：特罗凯 

 

[成份】 

 

本品主要成份为盐酸厄洛替尼。 

化学名称： N-(3-乙炔苯基)-6,7-双(2-甲氧乙氧基)-4-喹唑啉胺盐酸盐

分子式：C22H23N3O4·HCl 

分子量：429.90

 

【适应症/功能主治】 

 

厄洛替尼单药适用于表皮生长因子受体（EGFR）基因具有敏感突变的局部晚期或转移 性非小细胞肺癌（NSCLC）患者的治疗，包括一线治疗、维持治疗，或既往接受过至少一 次化疗进展后的二线及以上治疗。

 

（见【临床试验】） 两项多中心、随机、安慰剂对照的Ⅲ期试验结果显示，厄洛替尼联合含铂化疗方案（卡 铂+紫杉醇；或者吉西他滨+顺铂）作为局部晚期或转移的 NSCLC 患者一线治疗，相对单用 含铂化疗未增加临床获益，因此不推荐用于上述情况的一线治疗。

 

【规格型号】150mg*30

 

 

【用法用量】 

 在考虑本品用于局部晚期或转移性 NSCLC 患者治疗前，应对患者进行 EGFR 突变状态 检测。 

 

厄洛替尼单药用于非小细胞肺癌的推荐剂量为 150mg/日，至少在饭前 1 小时或饭后 2 小时服用。持续用药直到疾病进展或出现不能耐受的毒性反应。目前无证据表明进展后继续 使用本品治疗能使患者受益。

 

剂量调整 

患者出现新的急性发作或进行性的肺部症状，如呼吸困难、咳嗽和发热，应暂停厄洛替 尼治疗进行诊断评估。如果确诊是 ILD（间质性肺病），则应停用厄洛替尼，并给予适当的 治疗（参见【注意事项】警告-肺毒性）。

 

肝功能衰竭或胃肠穿孔的患者应停止使用厄洛替 尼。脱水且有肾衰竭风险的患者、患严重大疱、水泡或剥脱性皮肤病的患者、患急性/正在 加重眼疾的患者，应中断或停止使用厄洛替尼（参见【注意事项】）。 

 

腹泻通常可用洛哌丁胺控制。严重腹泻使用洛哌丁胺无效或出现脱水的患者需要剂量减 量和暂时停止治疗。严重皮肤反应的患者也需要剂量减量和暂时停止治疗。 如果必须减量，厄洛替尼应该每次减少 50mg。 同时使用 CYP3A4 强抑制剂如阿扎那韦、克拉霉素、印地那韦、伊曲康唑、酮康唑、 奈法唑酮、奈非那韦、利托那韦、沙奎那韦、泰利霉素、醋竹桃霉素（TAO）、伏立康唑等 药物或者葡萄柚、葡萄柚汁时应考虑减量，否则可出现严重的不良反应。同样，同时使用 CYP3A4 与CYP1A2 共同抑制剂（如环丙沙星）的患者，若出现严重不良反应，应减少厄洛替 尼用量（参见【药物相互作用】）。

 

 治疗前使用 CYP3A4 诱导剂利福平可减少厄洛替尼 AUC 的 2/3-4/5。应考虑使用无 CYP3A4 诱导活性的其它可替代药物。如果没有可替代药物，厄洛替尼的剂量可考虑高于 150mg，但需密切监测安全性。与利福平合用时厄洛替尼最大研究剂量为450mg。如果增加 厄洛替尼的剂量，则当停止利福平或其它诱导剂时应迅速将厄洛替尼再减少到初始剂量。其 它 CYP3A4 诱导剂包括但不限于利福布汀、利福喷丁、苯妥英、卡马西平、苯巴比妥和圣 约翰草（St. John’s Wort），如果可能也应避免使用这些药物（参见【注意事项】和【药物相 互作用】）。

 

 厄洛替尼经肝脏代谢和胆道分泌。虽然中度肝功能损伤患者（Child-Pugh 分级 7-9）的 厄洛替尼暴露量与肝功能正常患者类似，厄洛替尼应慎用于肝脏功能损伤的患者。总胆红素> 3 x ULN 的患者应慎用厄洛替尼。治疗前检查异常的情况下，若肝功能出现严重变化，例如 总胆红素翻倍和/或转氨酶升高三倍，则应中断或停止使用厄洛替尼。检查发现肝功能异常 持续加重时，应在达到重度异常前就考虑中断和/或降低剂量并同时增加肝功能检查监测频 率。治疗前检查正常的情况下，如果总胆红素>3 x ULN 和/或转氨酶>5 x ULN ，则应中断 或停止使用厄洛替尼（参见【注意事项】和【不良反应】）。

 

尚未进行肾损伤患者（血清肌酐浓度>1.5 x ULN）的疗效和安全性研究。

基于药代动力 学数据，轻度或中度肾损伤患者不需要剂量调整（参见【药代动力学】）。不推荐严重肾损 伤患者使用厄洛替尼。 已证实吸烟会导致厄洛替尼暴露量降低 50-60%。正在吸烟 NSCLC 患者的厄洛替尼最 大耐受剂量为 300mg。在持续吸烟的患者中，与建议的 150 mg 剂量相比，300 mg 剂量在化 疗失败后的二线治疗中未显示出疗效提高。（参见【药物相互作用】和【药代动力学】特殊 人群）。 

 

【不良反应】 

由于临床试验进行的条件有很大不同，因此无法直接将一个药物临床试验与另一个药物 临床试验中的不良反应发生率进行比较，也可能无法反映临床实践中观察到的发生率。 

 

厄洛替尼的安全性评估是基于 1500 多例至少接受过一次 150mg厄洛替尼单药治疗患者 的数据和300多例接受过厄洛替尼100mg或150mg联合吉西他滨治疗患者的数据，以及1228 例接受厄洛替尼联合化疗患者的数据。 来自于临床试验中厄洛替尼单药或联合化疗报告的不良反应 （ADR） 总结如下。

 

ADR 是发生率至少 10%（厄洛替尼组）且较对照组高（³3%）的不良反应。 服用厄洛替尼治疗 NSCLC 和其它晚期实体肿瘤的患者中有报告严重的不良反应，包括 致命的事件（参见【注意事项】警告-肺毒性和【用法用量】剂量调整）。 

 

厄洛替尼单药治疗 

具有 EGFR 基因敏感突变的 NSCLC 一线治疗

 在一项 153 名高加索患者参加的开放性随机对照的 III 期研究 ML20650 (EURTAC)中， 对 75 名 EGFR 突变的 NSCLC 患者使用本品一线治疗的安全性进行了评估，未发现新的安 全性信号。 在研究 ML20650 中，使用本品治疗的患者最常见的不良反应为皮疹和腹泻（分别为 80% 和 57%，所有分级），大部分为 1 级或 2 级，不需干预即可控制。3 级皮疹和腹泻的发生率 分别为 9%和 4%。未见 4 级皮疹或腹泻。分别有 1%的患者因皮疹或腹泻而停止使用本品。 发生皮疹或腹泻的患者分别有11%和 7%需要进行剂量调整（暂停或减量）。

 

 YO25121(ENSURE)是在亚洲患者中进行的一项多中心、开放、随机、对照III期临床研 究，比较厄洛替尼与吉西他滨/顺铂作为一线治疗具有EGFR基因敏感突变的晚期(IIIB/IV 期)NSCLC的疗效和安全性，对110例厄洛替尼治疗患者进行安全性评价，与厄洛替尼的已知 安全性特征一致，未发现新的安全信号。 该研究中厄洛替尼组中最常见AE为皮疹（67.3%）、腹泻（40.9%）和甲沟炎（10.9%）， 大多数皮疹为1级或2级，7例患者（6.4%）出现3级皮疹。多数腹泻为1级或2级，2例患者为 3级腹泻，无4级或5级腹泻。厄洛替尼治疗组中观察到1例（0.9%）间质性肺炎。厄洛替尼 组中报告丙氨酸氨基转移酶（ALT）升高为9.1% ，天冬氨酸氨基转移酶（AST）升高为5.5%， 血胆红素升高6.4%，多数为1级或2级。

 

厄洛替尼组（至少 2 例患者）中最常见严重不良事件（SAE）为呼吸困难（3 例患者； 2.7%）、胸腔积液、上消化道出血和骨痛（各有 2 例患者[1.8%]发生）。 另一项在中国23个中心进行的随机、对照、开放性的III期试验（MO20981，OPTIMAL） 中,在不可切除的ⅢB期（T4胸水）或Ⅳ期、伴有EGFR突变的NSCLC初治患者中比较厄洛替 尼单药与吉西他滨+卡铂联合化疗的疗效。对83例接受厄洛替尼治疗患者进行安全性评价， 与厄洛替尼的已知安全性特征一致，未发现新的安全信号。 该研究中厄洛替尼组不良反应发生率为 88.0%（73/83），化疗组为 98.6%（71/72）。 其 中厄罗替尼组绝大部分为1～2 级不良反应，3～4 级的不良反应少，占 12.0%（10/83），其 中皮疹 2 例（占 2.4％），其他包括肝功能检查异常（ALT/AST 升高，肝酶增加，转氨酶升 高，血胆红素升高），白细胞计数升高，腹泻，血尿和口腔溃疡各 1 例（各占1.2％）。化疗 组 3～4 级的不良反应占 65.3%（47/72），最常见的为实验室检查异常，如中性粒细胞计数 下降，血小板计数下降，白细胞计数下降和血红蛋白减低（11.1~41.7%）。 厄洛替尼组严重不良反应2例（2.4%），均为肝功能异常。吉西他滨+卡铂组严重不良反 应有10例（13.9%），分别为血小板下降7例，中性粒细胞减少、死亡和肝功能异常各1例。 

 

NSCLC 维持治疗

 

两项双盲、随机、安慰剂对照的 III 期研究 BO18192（SATURN）和 BO25460（IUNO） 中，共 1532 例复发或转移的晚期NSCLC 患者接受一线标准铂类为基础的化疗后接受厄洛 替尼 150mg 每天一次或安慰剂治疗，持续直至出现疾病进展、不可接受的毒性或死亡事件 为止。厄洛替尼治疗组报告的最频繁的不良反应为皮疹和腹泻（见表 2.）在任一研究中均未 观察到 IV 级的皮疹或腹泻。在研究 BO18192 中，因为皮疹和腹泻导致厄洛替尼停药的患者 百分比分别为 1% 和<1%，而在研究BO25460 中，没有患者因皮疹或腹泻而中止治疗。在 研究 BO18192 中，因为皮疹和腹泻需要进行剂量调整（中断或减量）的患者百分比 8.3%和 3%，在研究 BO25460 中，这一比例分别为 5.6%和 2.8%。

 

在维持治疗研究中，接受厄洛替尼单药治疗的患者出现了肝功能检查异常（包括 ALT、 AST 和胆红素升高）。厄洛替尼组和安慰剂组治疗患者发生 2 级(>2.5 – 5.0 x ULN) ALT 升高 的患者分别占 2%和 1%，3 级(>5.0 – 20.0 x ULN) ALT 升高的患者分别占 1%和 0%。厄洛替 尼治疗组出现 2 级(>1.5-3.0 x ULN)和 3 级 (>3.0-10.0 x ULN)胆红素升高的患者分别占 4%和<1%，与之相比，这两事件在安慰剂组均<1%。若肝功能出现严重变化，则应中断或停止厄 洛替尼给药（参见【用法用量】）。 NSCLC 二/三线治疗 一项随机、双盲、安慰剂对照的 III 期研究（BR.21）中，731 例既往至少一个化疗方案 失败的局部晚期或转移性 NSCLC 患者按 2:1 的比例随机接受每日一次口服厄洛替尼 150mg 或者安慰剂治疗，直到疾病进展或有不能接受的毒性反应。该研究中报告的不良反应见表 3。 最常见的不良反应是皮疹（75%）和腹泻（54%）。程度多为 I 级或 II 级，无需干预即 可获得控制。厄洛替尼治疗的患者 III/IV 级皮疹和腹泻发生率分别为 9%和 6%。厄洛替尼治 疗的患者因皮疹或腹泻而终止试验的比例均为 1%。分别有 6%和 1%的患者因皮疹和腹泻需 要减量。BR.21 研究中出现皮疹的中位时间为 8 天，出现腹泻的中位时间为 12 天。

 

厄洛替尼 150mg 单药治疗的 NSCLC 患者中可观察到肝功能检查异常（包括 ALT、AST 和胆红素升高）。升高主要为一过性或与肝脏转移有关。厄洛替尼和安慰剂治疗患者出现 II 级 ALT 升高（>2.5-5.0 倍正常上限）分别为 4%和<1%。厄洛替尼治疗患者中未出现 III 级 ALT 升高（>5.0-20.0 倍正常上限）。肝功能异常严重时要考虑剂量减量或暂停治疗（参见【用 法用量】剂量调整）。 在一项厄洛替尼单药治疗晚期 NSCLC 的单组、非对照国际多中心临床研究（TRUST） 的中期分析中，总结了 6578 例患者的安全性数据，结果没有发现新的安全性信号。厄洛替尼治疗相关的皮疹发生率为 71%,其中 III/IV 级皮疹为 12%。厄洛替尼严重不良反应的发生 率为 4%。有 5%的患者因不能耐受不良反应而提前终止厄洛替尼治疗；在 509 例入选的中 国患者中，皮疹发生率为 84%，III/IV 级皮疹的发生率为 4%。仅 3 例（<1%）患者出现厄 洛替尼治疗治疗相关的严重不良反应。6 例（1%）患者因不良反应提前了终止厄洛替尼治 疗。 

 

厄洛替尼联合化疗 一项对照临床试验（PA.3）中，569 例局部晚期不可手术切除的或转移性胰腺癌患者按 1:1 比例随机接受厄洛替尼（100 mg 或 150 mg）或安慰剂联合吉西他滨 IV（1000 mg/m2 ， 周期 1——第 1, 8, 15, 22, 29, 36 和 43 天给药，8 周为一周期；周期 2 及以后周期中，第 1, 8 和 15 天给药，4 周为一周期）。厄洛替尼每日口服直至疾病进展或不可接受的毒性。主要终 点是生存期，次要终点是缓解率和无进展生存期。缓解时间也予以观察。共 285 例患者接受 厄洛替尼联合吉西他滨治疗（261 例患者在 100mg 组，24 例患者在 150mg 组），284 例患者 接受吉西他滨加安慰剂治疗（260 例患者在 100mg 组，24 例患者在 150mg 组）。接受 150mg 厄洛替尼治疗的患者过少，不足以得出任何结论。 接受100mg厄洛替尼＋吉西他滨治疗的胰腺癌患者中最常见的不良反应是乏力、皮疹、 恶心、食欲不振和腹泻。在厄洛替尼＋吉西他滨治疗组中，接受治疗患者 III/IV 级皮疹和腹 泻的发生率各为 5%，中位发生时间分别为 10 天和 15 天，各导致 2%的患者进行减量治疗， 不超过 1%的患者停药。 150mg 组（23 例）中特定的一些不良反应，包括皮疹的发生率更高，以至减量或者停 药更加频繁。

 

在胰腺癌临床试验中，在厄洛替尼/吉西他滨组中 10 例患者发生深静脉血栓（发生率为 3.9%）。相比之下，在安慰剂/吉西他滨组中 3 例患者发生深静脉血栓（发生率为 1.2%）。III 级或 IV 级血栓事件，包括深静脉血栓的总体发生率在两个治疗组中类似：厄洛替尼＋吉西 他滨组为 11%，安慰剂＋吉西他滨组为 9%。 厄洛替尼＋吉西他滨组与安慰剂＋吉西他滨组相比，III 级或 IV 级血液学实验室毒性未 见差异。 在厄洛替尼＋吉西他滨组中发生率在 5%以下的严重不良反应（≥ NCI-CTC III 级）包括 昏厥、心律不齐、肠梗阻、胰腺炎、溶血性贫血包括血小板减少引起的微血管溶血性贫血、 心肌梗塞/心肌缺血、脑血管意外包括脑出血以及肾功能不全（见【注意事项】警告）。 接受厄洛替尼＋吉西他滨治疗的胰腺癌患者中观察到肝功能检查异常（包括 ALT、AST 和胆红素升高）。如果肝功能变化 严重的话，应该考虑减少厄洛替尼的用量或者停药（见【用法用量】剂量调整部分）。

 

其他的观察资料（基于所有的临床研究数据） 以下的不良反应是在接受厄洛替尼 150mg 单药治疗或者厄洛替尼 100mg 或150mg 与 吉西他滨联合治疗的患者中观察到的。 以下的术语用于对不良反应的发生率进行分级：非常常见（≥1/10）；常见（≥1/100, <1/10）； 不常见（≥1/1,000, <1/100）；罕见（≥1/10,000, <1/1000）；非常罕见（<1/10,000），包括单个 报告。 非常常见的不良反应见表 1、表 2、表 3 和表 4，其他频率的不良反应分类总结如下。 胃肠道异常： 厄洛替尼治疗组有胃肠道穿孔报告，但不常见（少于 1%），部分病例产生致命的后果.

 

消化道出血的病例报道常见（包括部分死亡病例），一些与同时服用华法林有关（参见 【注意事项】国际标准化比值（INR）升高和出血可能部分）。

这些报道包括消化器官溃疡 出血（胃炎、胃与十二指肠溃疡）、呕血、便血、黑粪症以及可能的结肠炎出血（见【注意 事项】）。 

肾功能异常 

有报告急性肾衰竭或肾功能不全，包括死亡，伴有或不伴有低血钾症（见【注意事项】）。 

 

肝功能异常 

厄洛替尼的临床试验中经常观察到肝功能检查异常（包括 ALT、AST、胆红素升高）， 联合化疗的 PA3 研究中尤其常见。大部分为轻到中度，呈一过性或与肝转移有关。厄洛替 尼使用期间报告了肝功能衰竭（包括死亡）的罕见病例。混杂因素包括先前存在的肝脏疾病 或合用肝毒性药物。 

 

眼疾 

接受厄洛替尼治疗的患者有非常罕见的角膜溃疡或穿孔的报告。 角膜炎和结膜炎在厄洛替尼治疗中经常发生。睫毛生长异常包括：睫毛向内生长、过度 生长和睫毛变粗等（见【注意事项】）。 

呼吸道、胸部和纵隔异常 

厄洛替尼治疗 NSCLC 和其他进展性实体瘤时，有报道患者发生严重的间质性肺病 （ILD 样事件包括死亡）（见【注意事项】）。 

鼻衄在 NSCLC 和其它实体瘤试验中均有报道。 

皮肤和皮下组织异常 接受厄洛替尼治疗患者最常报告的不良反应为皮疹，一般表现为轻到中度的红斑和脓疱 性丘疹，多发生或加重于身体阳光暴露部位。对于要暴露在阳光下的患者，建议穿上保护性 的衣服，和/或使用防晒霜（例如含矿物质）。常见痤疮、痤疮样皮炎和毛囊炎，大部分为轻 中度，非严重性。皮肤开裂报道常见，多不严重，大部分与皮疹和皮肤干燥有关。其它轻度 的皮肤反应如色素沉着也有观察到，但不常见（少于 1%）。 已有大疱性，水泡性和剥脱性皮肤改变的报告，包括非常罕见的 Stevens-Johnson 综合 征/中毒性表皮坏死松解症，有些情况下是致命的（见【注意事项】）。 

临床试验中有报道其它头发和指甲变化，通常不严重，例如，常见甲沟炎，罕见睫毛/ 眉毛变化以及脆甲和松甲。

 

 总体上，无论是单药治疗还是与吉西他滨联合使用，厄洛替尼的安全性在女性与男性之 间以及年轻人与 65 岁以上老年人之间无显著差别，在白种人和亚洲患者之间也无差别（参 见【注意事项】和【老年用药】）。 

 

上市后经验 

在厄洛替尼上市后观察到以下不良反应。因为这些不良反应来自不确定的样本量的自发 报告，故不能可靠的估计其发生频率和药物的因果关系。 皮肤和皮下组织异常: 头发和指甲变化，通常不严重，上市后监测中罕有报告，例如，多毛症、睫毛/眉毛变 化、甲沟炎以及脆甲和松甲。 大疱、起泡、表皮剥落等皮肤情况也有报告，提示 Stevens-Johnson 综合症/表皮坏死性 松解。 胃肠道异常 胃肠穿孔 肝脏异常 在用厄洛替尼单药治疗或联合化疗的患者中有报告肝衰竭。 肌肉骨骼与结缔组织异常 与他汀类药物治疗联用时发生肌病，包括横纹肌溶解症。 眼科异常 在上市后的监测中有葡萄膜炎的报告。 

 

【禁忌】 对本品及成份过敏者禁用。 

 

【注意事项】 

当考虑本品用于晚期或转移性 NSCLC 患者的治疗时，建议对所有患者的 EGFR 突变进 行评估，应选用经过良好验证的可靠方法，以避免出现假阴性或假阳性的检测结果。需要注 意的是，在肿瘤具有外显子 19 缺失或外显子 21（L858R）置换之外其他 EGFR 突变的转移性 NSCLC 患者中，尚未评价厄洛替尼作为一线治疗的安全性和有效性（见【临床试验】）。 

警告 

肺毒性 

在 NSCLC 或其它实体瘤接受厄洛替尼治疗的患者偶有报道严重间质性肺病样事件，包 括致命的情况。在厄洛替尼单药治疗NSCLC 试验中（参见【临床试验】），维持治疗研究中 间质性肺病样事件在厄洛替尼组和安慰剂组的发生率分别为 0.7%和0%，二/三线治疗研究中 间质性肺病样事件的发生率（0.8%）在厄洛替尼组和安慰剂组一样。在治疗胰腺癌试验中 －联合吉西他滨（参见【临床试验】），间质性肺病样事件的发生率在厄洛替尼＋吉西他滨组 为 2.5%，在安慰剂＋吉西他滨组为0.4%。 所有试验中（包括无对照组试验和联合化疗的试验）共 32000 例接受厄洛替尼治疗患者 总的间质性肺病样事件发生率约为 0.6%。 怀疑为间质性肺病样事件的患者的诊断报告包括肺炎、放射性肺炎、过敏性肺炎、间质 性肺炎、间质性肺病、闭塞性细支气管炎、肺纤维化、急性呼吸窘迫综合征、肺浸润和肺泡 炎。症状在服用厄洛替尼后 5 天至 9 个月（中位时间 39 天）出现。大多数病例合并有其它 引起间质性肺病的因素，如同时或既往的化疗、既往放疗、之前存在的肺实质病变、转移性 肺疾病或肺部感染。 一旦出现新的急性发作或进行性的不能解释的肺部症状如呼吸困难、咳嗽和发热时，在 诊断评价时要暂时停止厄洛替尼治疗。一旦确诊是 ILD（间质性肺病），则应停止厄洛替尼 治疗，必要时给予适当的治疗（参见【不良反应】和【用法用量】）。 

 

腹泻、脱水、电解质失衡和肾衰

接受厄洛替尼治疗的患者可能发生腹泻，中度或重度腹泻应给予洛哌丁胺治疗。部分患 者可能需要减量。对严重或持续的脱水相关腹泻、恶心、厌食或者呕吐，患者需停药并对脱 水采取适当的治疗措施（见【不良反应】）。接受厄洛替尼治疗的患者有肝肾综合症、急性肾 衰（包括死亡）和肾功能不全报告。有些由基线肝损伤引起，有些与腹泻、呕吐和/或厌食 症引起的脱水或联合化疗有关。 罕有低钾血症和肾衰竭（包括致命的情况）报道，一些报道继发于腹泻、呕吐和/或厌食 导致的脱水，也有些报道有合并化疗药物。 在 3 项单药治疗肺癌研究中，厄洛替尼组重度肾损害的总发生率为 0.5%，对照组为 0.8%。 在胰腺癌研究中，厄洛替尼加吉西他滨组肾损害的发病率为 1.4%，对照组为 0.4%。在出现重度肾损害患者中暂停服用厄洛替尼直至肾毒性消退。 对发生严重性腹泻或持续性腹泻、甚至脱水的患者，特别是存在高危险因素的患者群（例 如接受同步化疗、有其它症状或疾病、或有包括年龄偏大等其它基础因素的患者群），应中 断厄洛替尼治疗，并采取适当措施对患者进行静脉补液。对脱水患者应在补液的同时进行肾 功能及血电解质包括血钾的监测，建议定期监测有脱水风险患者的肾功能和血清电解质（见 【不良反应】）。 

 

心肌梗塞/心肌缺血 

在胰腺癌临床试验中，在厄洛替尼/吉西他滨组中 6 例患者（发生率 2.3%）发生心肌梗 塞/心肌缺血，其中 1 例患者由于心肌梗塞死亡。相比之下，在安慰剂/吉西他滨组中 3 例患 者发生心肌梗塞（发生率 1.2%），其中 1 例由于心肌梗塞死亡。 脑血管意外 在胰腺癌临床试验中，在厄洛替尼/吉西他滨组中 6 例患者（发生率 2.3%）发生脑血管 意外，其中出血 1 次，是唯一的致命事件。相比之下，在安慰剂/吉西他滨组中没有脑血管 意外。 血小板减少引起的微血管溶血性贫血 在胰腺癌临床试验中，在厄洛替尼/吉西他滨组中 2 例患者（发生率 0.8%）发生血小板 减少引起的微血管溶血性贫血。两位患者均为同时使用了厄洛替尼和吉西他滨。相比之下， 在安慰剂/吉西他滨组中没有发生血小板减少引起的微血管溶血性贫血。 

 

肝炎、肝衰竭 

厄洛替尼使用期间报告了肝功能衰竭（包括死亡）的罕见病例。混杂因素包括既往肝脏 疾病或合用肝毒性药物。因此，这类患者应定期进行肝功能检查。出现严重肝功能异常者应 停止服用厄洛替尼。在检查发现肝功能异常持续加重时，应考虑中断和/或降低剂量同时增 加肝功能检查监测频率。治疗前检查正常的情况下，如果总胆红素>3 × ULN 和/或转氨酶>5 × ULN ，则应中断或停止使用厄洛替尼（参见【不良反应】和【用法用量】）。 肝功能异常和肝损伤患者 离体和在体实验均证明厄洛替尼主要在肝脏清除。因此肝功能异常的患者厄洛替尼的暴 露量增加（参见【药代动力学】特殊人群-肝脏功能异常患者和【用法用量】剂量调整）。 在中度肝损伤（Child-Pugh B）患者（与显著肝肿瘤负荷有关）的药代动力学研究中， 15 例患者中有 10 例在治疗期间或厄洛替尼末次给药 30 天内死亡。1 例患者死于肝肾综合征， 1 例患者死于快速进展的肝功能衰竭，其余 8 例死于进展性疾病。10 例死亡患者中有 8 例基 线总胆红素> 3 × ULN，这表明患有重度肝损伤，因此总胆红素> 3 × ULN 的患者应慎用厄 洛替尼。在厄洛替尼治疗期间应对肝损伤（总胆红素> ULN 或 Child-Pugh A, B 和 C）患者 进行密切监测。治疗前检查异常的情况下，若肝功能出现重度变化，总胆红素翻倍和/或转 氨酶升高三倍，则应中断或停止使用厄洛替尼（参见【用法用量】）。

 

 胃肠道穿孔 

接受厄洛替尼治疗的患者出现胃肠道穿孔的风险增加，但不常见（部分病例发生致命的 后果）。同时合并使用抗血管生成药、皮质激素类药物、非甾体类抗炎药（NSAIDs）、和/ 或紫杉类药物为基础的化疗，或者既往有消化性溃疡或憩室疾病病史的患者风险更高。出现 胃肠道穿孔的患者应永久停用厄洛替尼（见【不良反应】）。 

 

大疱性或剥脱性皮肤改变 

有报道大疱性，水泡性和剥脱性皮肤症状,包括非常罕见的 Stevens-Johnson 综合征/中毒 性表皮坏死松解症, 有些情况下是致命的（见【不良反应】）。如患者出现严重的大疱性，水 泡性和剥脱性皮肤症状，应中断或停用厄洛替尼。 

 

眼部疾病 

使用厄洛替尼治疗有非常罕见的角膜穿孔或角膜溃疡的报道。还观察到的其他眼部异常 包括异常睫毛生长、干燥性角膜结膜炎或疱疹性角膜炎，这些也是发生角膜穿孔/溃疡的危 险因子。如患者出现急性眼科异常或加重例如眼睛疼痛，应中断或停用厄洛替尼 （见【不 良反应】）。 

 

相互作用 

厄洛替尼可能存在有临床意义的药物-药物相互作用（见【药物相互作用】）。 国际标准化比值升高和出血可能 在接受本品治疗的患者中有报道表明，与香豆素类抗凝药包括华法林的相互作用导致国 际标准化比值（INR）升高和出血事件增加，部分病例产生致命后果。应对使用香豆素类抗 凝药的患者的凝血时间和 INR 变化进行定期监测。 该片剂中含有乳糖，因此患有罕见遗传病半乳糖不耐受、Lapp乳糖酶缺乏症或葡萄糖- 半乳糖吸收不良的患者不应使用本品。 对驾驶和机械操作能力的影响 第15 页 共 34 页 尚未进行本品对驾驶和机械操作能力影响的研究，但厄洛替尼对精神能力无影响。 

 

【孕妇及哺乳期妇女用药】 

尚未在妊娠妇女中进行厄洛替尼的充分的、对照性研究。

在器官形成期，当家兔血浆中 厄洛替尼药物浓度达到每日 150mg 给药时人血浆浓度的 3 倍时出现母体毒性导致胚胎/胎儿 死亡和流产。雌性大鼠在交配前到妊娠第一周接受相当于 150mg 临床剂量的 0.3 或 0.7 倍剂 量（根据 mg/m2 计算）的厄洛替尼可以引起早期吸收而导致成活胎儿数量下降。对人类的潜 在危险性未知。生育期妇女服用厄洛替尼期间应避免妊娠。在治疗期间和治疗完成后至少 2 周应充分避孕。只有认为母亲的受益大于对胎儿的危害时妊娠女性才能继续治疗。如果妊娠 期间使用厄洛替尼，患者应了解对胎儿的潜在危害和可能导致流产。 不清楚人乳汁中是否分泌有厄洛替尼。因为许多药物可分泌到人乳汁中而且厄洛替尼对 婴儿的影响尚未研究，建议妇女使用厄洛替尼时避免哺乳。 

 

【儿童用药】 

未在 18 岁以下患者中确立厄洛替尼获批适应症的有效性和安全性。 

 

【老年用药】 

NSCLC 维持治疗 参加随机 NSCLC 维持治疗试验的所有患者中，约 66%的患者小于 65 岁，34%的患者 等于或大于 65 岁。65 岁以下患者总生存期的风险比为 0.78（95% CI: 0.65, 0.95），65 岁或 以上患者总生存期的风险比为 0.88（95% CI: 0.68, 1.15）。 NSCLC 二/三线治疗 参加 NSCLC 随机试验的总人群中，62%的患者小于 65 岁，而 38%的患者为 65 岁以上。 在两个年龄组中都可获得生存受益（参见【临床试验】）。 

 

【药物相互作用】 

仅在成人中进行了相互作用研究。 

体外研究发现，厄洛替尼是 CYP1A1 的强效抑制剂、CYP3A4 和 CYP2C8 的中度抑制 剂、UGT1A1 诱导的葡萄苷酸化的强抑制剂。 由于 CYP1A1 在人体组织中的表达十分有限，无从获得 CYP 1Al 强抑制剂的生理学相 关性。 对葡萄苷酸化的抑制作用可能会导致与一些仅能通过该途径清除的 UGT1Al 底物类药 物发生相互作用。对于 UGT1A1 表达水平较低或患有遗传葡萄苷酸化疾病（如 Gilbert 疾病） 的患者，其血清胆红素浓度可能升高，必须慎用。 

 

厄洛替尼经肝脏代谢，主要通过 CYP3A4，少量通过 CYP1A2 和肺同工酶 CYP1A1。任 何通过这些酶代谢的药物或者酶的抑制剂或诱导剂均有可能与厄洛替尼发生相互作用。 CYP3A4 强抑制剂可以降低厄洛替尼代谢，使其血药浓度升高。与单独使用厄洛替尼相 比，酮康唑（200mg 每天 2 次服用 5 天）通过抑制 CYP3A4 代谢活性导致厄洛替尼的 AUC 增加（平均 AUC 增加 86%），Cmax增加 69%。厄洛替尼与 CYP3A4 和 CYP1A2 抑制剂环丙 沙星合用时，厄洛替尼的 AUC 及 Cmax 分别增加 39%和 17%，活性代谢产物的 AUC 和 Cmax 分别约增加了 60%和 48%，目前还未明确该暴露增加的临床相关性。

 

厄洛替尼慎与环丙沙 星或强效 CYP1A2 抑制剂（如氟伏沙明）联用。因此，厄洛替尼与 CYP3A4 强抑制剂或结 合的CYP3A4 /CYP1A2 抑制剂合用时应注意，一旦发现毒性作用，应当降低厄洛替尼剂量。 CYP3A4 强诱导剂可提高厄洛替尼的代谢，显著降低厄洛替尼的血药浓度。

 

与单独使用 厄洛替尼相比，给予150mg厄洛替尼后，利福平（600mg每天1次服用7天）通过诱导CYP3A4 代谢活性导致厄洛替尼的平均 AUC 降低 69%。 若治疗前已使用或治疗中并用利福平，单剂给药 450 mg 后厄洛替尼的平均 AUC 是未 经利福平治疗时单剂给药 150 mg 厄洛替尼后的 57.5%。如可能，应选择其他不具强 CYP3A4 诱导性的药物治疗。对于需要采用厄洛替尼 + 强 CYP3A4 诱导剂（如利福平）治疗的患者， 应在密切监控药物安全性情况下（见【注意事项】）考虑将剂量增至300 mg，如能良好耐受 2 周以上，可考虑将剂量进一步增至 450 mg，同时密切监控药物安全性。

 

此条件下未对更高 的剂量进行研究。在与其它诱导剂，如苯妥英、卡马西平、巴比妥类或圣约翰草（St. Johns Wort）合用时，暴露量可能也会降低，厄洛替尼与这些活性药物合用时应特别小心。可能的 情况下，可以考虑使用其它无强效 CYP3A4 诱导活性的治疗药物。 厄洛替尼预治疗或合用对典型的 CYP3A4 底物咪达唑仑和红霉素的清除率没有影响。 因此，与其他CYP3A4 底物清除间的显著相互作用也不可能发生。咪达唑仑口服利用度似 乎降低了 24%，但这并非 CYP3A4 活性的影响所致。

 

在另一项临床试验中，厄洛替尼与 CYP3A4/2C8 底物紫杉醇合用，对其药代动力学无影响。因此与其它 CYP3A4 底物的清除可 能也无显著相互作用。 厄洛替尼的溶解度与 pH 值相关。pH 值升高时，厄洛替尼的溶解度降低。改变上消化道 pH 值的药物可能会改变厄洛替尼的溶解度，进而影响其生物利用度。厄洛替尼与质子泵 抑制剂奥美拉唑合用，厄洛替尼的 AUC 和Cmax分别降低了 46%和 61%。Tmax或半衰期无变 化。厄洛替尼与 300mg H2受体阻断药雷尼替丁合用时，厄洛替尼的AUC 和 Cmax分别降低 33%和 54%。因此，可能的情况下应当避免厄洛替尼与减少胃酸产生的药物合用。在与这些 药物合用时增加厄洛替尼的剂量不太可能补偿暴露量的减少。然而，厄洛替尼与雷尼替丁间 隔给药时（雷尼替丁 150mg 每日两次，给药前 2 小时或给药后 10 小时给予厄洛替尼），厄 洛替尼的 AUC 和 Cmax分别只减少 15%和 17%。如果患者需要接受此类药物治疗，H2受体 阻断药如雷尼替丁应当考虑并采取间隔给药。须在 H2受体阻断药给药前 2 小时或给药后 10 小时给予厄洛替尼。 

 

厄洛替尼为 P-糖蛋白活性底物转运体的底物，与 Pgp 抑制剂（如环孢菌素和维拉帕米） 合用可能会改变厄洛替尼的分布和/或消除，目前尚不清楚该相互作用结果对毒性（如 CNS） 的影响，所以在此情况下应慎用。

 

 厄洛替尼会增加铂浓度。在一项临床研究中，厄洛替尼与卡铂和紫杉醇合并用药使总铂 AUC0-48增加了 10.6%。虽然该差异具有统计学显著意义，但认为该差异程度不具有临床相 关性。在临床实践中，可能还存在一些其它导致卡铂暴露量增加的共同因素，如肾损伤。卡 铂和紫杉醇对厄洛替尼的药代动力学无显著影响。 

 

卡培他滨可能会增加厄洛替尼的浓度。厄洛替尼与卡培他滨合用时，与另外一项厄洛替 尼单药研究中的数据相比，厄洛替尼 AUC 出现统计学显著增加，Cmax值也出现临界意义的 增加。厄洛替尼对卡培他滨的药代动力学无显著影响。 本品与他汀类药物合用可能增加他汀类药物引起的肌病包括罕见的横纹肌溶解症的发 生率。 已知吸烟会诱导 CYP1A1 和 CYP1A2，导致厄洛替尼暴露量减少 50-60%，建议吸烟者 戒烟（见【用法用量】和【药代动力学】特殊人群）。 

 

【药物过量】 

 

健康受试者中单次口服剂量 1000mg 和癌症患者每周单次口服 1600mg 能够耐受。健康 受试者每天两次 200mg 剂量仅数天的耐受性很差。根据这些试验的资料，超过每天 150mg 的推荐剂量时可能发生不能接受的严重不良反应（如腹泻、皮疹和肝脏转氨酶升高，见【用 法用量】）。怀疑过量时应停止厄洛替尼和给予对症治疗。

 

【药理毒理】 

 

药理作用： 

 

厄洛替尼是表皮生长因子受体（EGFR）/人表皮生长因子受体 I（也称为 HER1）的酪氨酸激酶抑制剂。厄洛替尼可有效抑制细胞内的 EGFR 磷酸化，EGFR 通常表达于正常细胞和肿瘤细胞的表面。

 

在非临床试验模型中，EGFR 磷酸化的抑制可引起细胞生长停滞和/或 细胞死亡。 EGFR 突变可导致构成抗细胞凋亡和增殖信号传导通路激活，厄洛替尼在 EGFR 敏感突变阳性肿瘤中有效阻断 EGFR 介导的信号通路的作用主要是由厄洛替尼与 EGFR 突变激酶 构域中 ATP 结合位点发生紧密结合所致。由于下游信号通路阻断，因此细胞增殖发生中止，并通过内在的细胞凋亡途径诱导细胞死亡。

 

毒理研究： 长期毒性实验研究显示，至少在一种动物种属中出现了角膜病变（萎缩，溃疡），皮肤 病变（滤泡变性、炎症、红肿和脱毛），卵巢萎缩，肝组织坏死，肾乳头坏死和肾小管扩张， 和胃肠道反应（延迟的胃排空和腹泻）。红细胞参数下降，白细胞参数（主要为嗜中性粒细 胞）增加。出现了用药相关的 ALT、AST 和胆红素升高。上述反应均发生在临床的药物暴 露水平之下。 

厄洛替尼在 UV 照射下有轻微光毒性。在一系列体外实验（细菌突变、人淋巴细胞染色 体畸变和哺乳细胞突变）和体内小鼠骨髓微核实验中分析了厄洛替尼的遗传毒性，结果未发 现有遗传毒性。 根

据厄洛替尼的作用模式认为它具有潜在的致癌性。在临床前研究中没有观察到潜在致 癌性的证据。

在遗传毒性研究中，厄洛替尼既无遗传毒性，也无致畸变作用。

已经开始在大 鼠和小鼠中开展长期致癌性研究，6 个月的慢性毒性研究中尚未观察到癌前增生性病变。 生殖毒性试验结果显示出现了生殖发育毒性（如大鼠的胚胎毒性、胚胎再吸收和家兔的 胎仔毒性；大鼠胎仔生长减缓和存活下降），但未见致畸性和对生育力有影响。这些反应均 发生在临床治疗的有关浓度。 

当家兔厄洛替尼血浆药物浓度达到大约人的血浆浓度（每日 150mg 的 AUC）3 倍时可 以出现母体毒性导致胚胎/胎儿死亡和流产。器官形成期间给药血浆药物浓度达到大约人的 血浆浓度（根据 AUC）时在家兔和大鼠中不会增加胚胎/胎儿死亡和流产。但是雌性大鼠在 交配前到妊娠第一周接受 30mg/m2 /d 到 60mg/m2 /d 的厄洛替尼（根据 mg/m2 计算相当于临床 剂量的 0.3-0.7 倍）可以引起早期吸收而导致成活胎儿数量下降。 

 

【药代动力学】 

尚缺乏在中国人中进行药代动力学研究的数据。以下资料来自国外临床研究。 

 

吸收和分布 

厄洛替尼口服 150mg 剂量时厄洛替尼的生物利用度大约为 60%，用药后 4 小时达到血 浆峰浓度。食物可显著提高生物利用度，达到几乎 100%。吸收后大约 93%厄洛替尼与白蛋 白和 α1 酸性糖蛋白（AAG）结合。厄洛替尼的表观分布容积为 232 升。

一项研究考察了厄 洛替尼在人体肿瘤组织中的分布情况，4 名患者（3 例 NSCLC, 1 例喉癌）接受厄洛替尼 150 mg 每天一次口服，在治疗第 9 天手术切除肿瘤样本显示肿瘤组织中厄洛替尼浓度平均 为 1,185 ng/g 组织。相当于稳态峰浓度的 63%（5-161%）的总体平均值。肿瘤组织中主要 活性代谢物平均浓度为 160 ng/g 组织，相当于稳态血浆峰浓度的 113%（88-130%）的总体 平均值。血浆蛋白结合近 95%。厄洛替尼与血清肌酐和 alpha-1 酸性糖蛋白（AAG）结合。

 

 代谢和清除

 体外细胞色素酶 P450 分析表明厄洛替尼主要通过 CYP3A4 代谢，少量通过 CYP1A2 和 第 30 页/共 34 页 肝外同工酶CYP1A1 代谢。肝外代谢包括小肠内 CYP3A4 代谢、肺内 CYP1A1 代谢以及肿 瘤组织内 1B1 代谢，可能对厄洛替尼的代谢清除有一定作用。 

已经证实的 3 种代谢途径有：1）单侧链或双侧链的 O-脱甲基化，再进一步氧化成羧酸； 2）乙炔基的氧化，再进一步水解成芳香羧酸；3）苯乙炔基的芳香环羟化。厄洛替尼两个侧 链中的任一个经 O-脱甲基后产生了主要代谢产物 OSI-420 和 OSI-413，在非临床体外测定与 体内肿瘤模型中，显示这两个代谢产物的效价与厄洛替尼相当， 其在血浆中的水平<10 % 的厄洛替尼，但药代动力学特征与厄洛替尼相似。 

 

口服 100mg 剂量后，可以回收到 91%的药物，其中在粪便中为 83%（原形药占给予剂 量 1%），尿液中为 8%（原形药占给予剂量 0.3%）。

 591 例服用单剂厄洛替尼的群体药代动力学分析表明中位半衰期为 36.2 小时。因此达到 稳态血浆浓度需要 7-8 天。清除率与年龄之间无明显相关性。吸烟者厄洛替尼的清除率增高 24%。 在 291 例 NSCLC 患者中进行了一项补充的群体药代动力学研究，厄洛替尼单药用于维 持治疗。分析结果表明，在此患者人群中影响厄洛替尼清除率的协变量与先前的单药药代动 力学分析结果相似，未发现新的协变量效应。 另外一项204例接受厄洛替尼＋吉西他滨联合用药的胰腺癌患者的药代动力学分析结果 表明，胰腺癌试验中影响厄洛替尼清除率的因素与先前单药的药代动力学分析类似。没有观 察到新的影响因素。与吉西他滨联合用药对厄洛替尼的血浆清除率无影响。 

 

特殊人群 

群体药代动力学分析显示，预测的表观清除率与患者年龄、体重、性别和种族之间不存 在临床意义的关系。

与厄洛替尼药代动力学相关的患者因素有血清总胆红素、AAG和当前吸 烟状况，血清总胆红素浓度和AAG浓度的增加与厄洛替尼清除率的下降有关，这些差异的 临床相关性尚不清楚。 

尚未对儿童和老年患者进行专门研究。 肝功能异常患者 厄洛替尼主要在肝脏清除。

中度肝功能损伤患者（Child-Pugh 分级 7-9）与肝功能正常患者的厄洛替尼暴露量类似，包括原发性肝癌和肝转移患者。在中度肝功能不全（Child-Pugh 分级 7-9）的实体瘤患者中，厄洛替尼 AUC 0-t和 Cmax的几何平均数分别为 27000 ng•h/mL 和 805 ng/mL，与之相比，在重度肝功能不全的患者（包括原发性肝癌或肝转移患者）中， 这两个值分别为29300 ng•h/mL 和 1090 ng/mL。虽然在中度肝功能损害患者中 Cmax较低， 且差异具有统计学意义，但不认为该差异具有临床显著意义。

目前尚无有关重度肝功能损伤 对厄洛替尼药代动力学的影响的数据。在群体药代动力学分析中发现，总胆红素血清浓度的 增加与厄洛替尼清除率的速率变慢有关。 

 

肾功能异常患者 

单剂给药后尿中分泌少于 9%。在肾功能异常的患者中未进行临床试验。 

 

吸烟患者 

不吸烟和正在吸烟的健康志愿者的药代动力学研究显示吸烟会导致厄洛替尼清除增加、 暴露减少。一项在不吸烟和当前吸烟健康志愿者中进行的每日口服厄洛替尼 150mg 药代动 力学研究证实了这一点。非吸烟者 Cmax几何平均数为 1056 ng/mL，吸烟者为 689 ng/mL，吸 烟者与非吸烟者的平均比值为 65.2%（95% CI: 44.3-95.9, p=0.031）。非吸烟者AUC0-inf几何 平均数为 18726 ng•h/mL，吸烟者为 6718 ng•h/mL，吸烟者与非吸烟者的平均比值为 35.9% （95% CI: 23.7-54.3, p<0.0001）。非吸烟者C24h几何平均数为288 ng/mL，吸烟者为34.8 ng/mL， 吸烟者与非吸烟者的平均比值为12.1%（95% CI: 4.82-30.2, p=0.0001）（吸烟组和从不吸烟/ 既往吸烟组各 16 位受试者）。正在吸烟者暴露量的减少可能是由于对肺 CYP1A1 和肝脏 CYP1A2 的诱导作用。 关键 III 期 NSCLC 临床试验（BR.21）中，正在吸烟者的厄洛替尼稳态血浆谷浓度为 0.65 µg/mL（n=16），约为既往吸烟者或从不吸烟者的 1/2（1.28 µg/mL，n=108），厄洛替尼 表观血浆清除率增加 24%。 正在吸烟的 NSCLC 患者的 I 期剂量爬坡研究中，稳态药代动力学分析显示厄洛替尼从 150mg 增加到最大耐受剂量 300mg 过程中，厄洛替尼暴露量随剂量成比例增加。300mg 剂 量水平下，正在吸烟患者的稳态血浆谷浓度为 1.22 µg/mL（n=17）（见【用法用量】和【药物相互作用】）。 

 

相互作用 

 

厄洛替尼主要通过 CYP3A4 代谢，因此推测 CYP3A4 的抑制剂会使其暴露增加。与 CYP3A4 的强抑制剂酮康唑联合使用时厄洛替尼的 AUC 提高了 2/3（见【药物相互作用】、 【用法用量】中的剂量调整部分）。 治疗前使用或者同时使用 CYP3A4 诱导剂利福平可以使厄洛替尼的清除提高 3 倍，同 时使厄洛替尼 的 AUC 下降 2/3（见【药物相互作用】和【用法用量】中的剂量调整部分）。 在一项 Ib 期临床试验中，吉西他滨和厄洛替尼的药代动力学没有发生显著的相互影响。 群体药代动力学分析显示，阿片类药物可使厄洛替尼暴露量约增加11%。 

 

【贮藏】 

25 ℃保存。15-30 ℃之间亦可接受。 

 

 

 

 

 

 

 

 

 

 

                                                                                                                                        文案整理：Dr. Jasmine Ding

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use TARCEVA safely and effectively. See full prescribing information for TARCEVA.

TARCEVA® (erlotinib) tablets, oral

Initial U.S. Approval: 2004

----------------------------RECENT MAJOR CHANGES-------------------------- Indications and Usage (1.1) 04/2010 Warnings and Precautions, Gastrointestinal Perforation (5.5) 04/2009 Warnings and Precautions, Bullous Skin Disorders (5.6) 04/2009 Warnings and Precautions, Ocular Disorders (5.10) 04/2009

----------------------------INDICATIONS AND USAGE---------------------------

TARCEVA is a kinase inhibitor indicated for: • Maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. (1.1) • Treatment of locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. (1.1) • First-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer, in combination with gemcitabine. (1.2)

 ----------------------DOSAGE AND ADMINISTRATION-----------------------

• The dose for NSCLC is 150 mg/day. (2.1) • The dose for pancreatic cancer is 100 mg/day. (2.2)

• All doses of TARCEVA should be taken on an empty stomach at least one hour before or two hours after food. (2.1, 2.2) • Reduce in 50 mg decrements, when necessary. (2.3)

---------------------DOSAGE FORMS AND STRENGTHS----------------------

• Tablets: 25 mg, 100 mg and 150 mg. (3)

-------------------------------CONTRAINDICATIONS------------------------------

• None. (4)

----------------------WARNINGS AND PRECAUTIONS-----------------------­

 • Interstitial Lung Disease (ILD)-like events, including fatalities have been infrequently reported. Interrupt TARCEVA if acute onset of new or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever occur. Discontinue TARCEVA if ILD is diagnosed. (5.1)

• Cases of acute renal failure (including fatalities), and renal insufficiency have been reported. Interrupt TARCEVA in the event of dehydration. Monitor renal function and electrolytes in patients at risk of dehydration. (5.2)

• Cases of hepatic failure and hepatorenal syndrome (including fatalities) have been reported. Monitor periodic liver function testing. Interrupt or discontinue TARCEVA if liver function changes are severe. (5.3)

• Monitor patients with hepatic impairment closely. Interrupt or discontinue TARCEVA if changes in liver function are severe (5.4)

• Gastrointestinal perforations, including fatalities, have been reported. Discontinue TARCEVA. (5.5)

• Bullous and exfoliative skin disorders, including fatalities, have been reported. Interrupt or discontinue TARCEVA (5.6)

 • Myocardial infarction/ischemia has been reported, including fatalities, in patients with pancreatic cancer. (5.7)

• Cerebrovascular accidents, including a fatality, have been reported in patients with pancreatic cancer. (5.8) • Microangiopathic Hemolytic Anemia with thrombocytopenia has been reported in patients with pancreatic cancer. (5.9)

• Corneal perforation and ulceration have been reported. Interrupt or discontinue TARCEVA (5.10)

• International Normalized Ratio (INR) elevations and bleeding events, some associated with concomitant warfarin administration have been reported. Monitor patients taking warfarin or other coumarin-derivative anticoagulants. (5.11)

• TARCEVA can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid pregnancy while on TARCEVA. (5.12)

------------------------------ADVERSE REACTIONS-------------------------------

• The most common adverse reactions (>20%) in maintenance treatment are rash-like events and diarrhea. (6)

• The most common adverse reactions (>20%) in 2nd line NSCLC are rash, diarrhea, anorexia, fatigue, dyspnea, cough, nausea, infection and vomiting. (6)

 • The most common adverse reactions (>20%) in pancreatic cancer are fatigue, rash, nausea, anorexia, diarrhea, abdominal pain, vomiting, weight decrease, infection, edema, pyrexia, constipation, bone pain, dyspnea, stomatitis and myalgia. (6) To report SUSPECTED ADVERSE REACTIONS, contact OSI Pharmaceuticals Inc. at 1-800-572-1932 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

------------------------------DRUG INTERACTIONS-------------------------------

• CYP3A4 inhibitors may increase erlotinib plasma concentrations. (7)

• CYP3A4 inducers may decrease erlotinib plasma concentrations. (7)

• CYP1A2 inducers may decrease erlotinib plasma concentrations. (7)

• Erlotinib solubility is pH dependent. Drugs that alter the pH of the upper GI tract may alter the solubility of erlotinib and hence its absorption. (7)

 • Cigarette smoking decreases erlotinib plasma concentrations (7) See 17 for PATIENT COUNSELING INFORMATION. Revised: [4/2010]

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1     Non-Small Cell Lung Cancer (NSCLC)

1.2     TARCEVA monotherapy is indicated for the maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy [see Clinical Studies (14.1)]. TARCEVA monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen [see Clinical Studies (14.2)]. Results from two, multicenter, placebo-controlled, randomized, Phase 3 trials conducted in first-line patients with locally advanced or metastatic NSCLC showed no clinical benefit with the concurrent administration of TARCEVA with platinum-based chemotherapy [carboplatin and paclitaxel or gemcitabine and cisplatin] and its use is not recommended in that setting [see Clinical Studies (14.3)].

1.3     1.2 Pancreatic Cancer TARCEVA in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer [see Clinical Studies (14.4)].

2 DOSAGE AND ADMINISTRATION

2.1 NSCLC The recommended daily dose of TARCEVA for NSCLC is 150 mg taken on an empty stomach at least one hour before or two hours after the ingestion of food. Treatment should continue until disease progression or unacceptable toxicity occurs. There is no evidence that treatment beyond progression is beneficial.

2.2 Pancreatic Cancer The recommended daily dose of TARCEVA for pancreatic cancer is 100 mg taken on an empty stomach at least one hour before or two hours after the ingestion of food, in combination with gemcitabine [see Clinical Studies (14.4) or the gemcitabine package insert]. Treatment should continue until disease progression or unacceptable toxicity occurs.

2.3 Dose Modifications In patients who develop an acute onset of new or progressive pulmonary symptoms, such as dyspnea, cough or fever, treatment with TARCEVA should be interrupted pending diagnostic evaluation. If Interstitial Lung Disease (ILD) is diagnosed, TARCEVA should be discontinued and appropriate treatment instituted as necessary [see Warnings and Precautions (5.1)]. Discontinue TARCEVA for hepatic failure or gastrointestinal perforation. Interrupt or discontinue TARCEVA in patients with dehydration who are at risk for renal failure, in patients with severe bullous, blistering or exfoliative skin conditions, or in patients with acute /worsening ocular disorders [see Warnings and Precautions (5.3, 5.4, 5.5, 5.6, 5.10)].

 Diarrhea can usually be managed with loperamide. Patients with severe diarrhea who are unresponsive to loperamide or who become dehydrated may require dose reduction or temporary interruption of therapy. Patients with severe skin reactions may also require dose reduction or temporary interruption of therapy. When dose reduction is necessary, the TARCEVA dose should be reduced in 50 mg decrements. In patients who are taking TARCEVA with a strong CYP3A4 inhibitor such as, but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole, or grapefruit or grapefruit juice, a dose reduction should be considered if severe adverse reactions occur. Similarly, in patients who are taking TARCEVA with an inhibitor of both CYP3A4 and CYP1A2 like ciprofloxacin, a dose reduction of TARCEVA should be considered if severe adverse reactions occur [see Drug Interactions (7)]. 3 4 5 5.1 Pre-treatment with the CYP3A4 inducer rifampicin decreased erlotinib AUC by about 2/3 to 4/5. Use of alternative treatments lacking CYP3A4 inducing activity is strongly recommended. If an alternative treatment is unavailable, an increase in the dose of TARCEVA should be considered as tolerated at two week intervals while monitoring the patient’s safety. The maximum dose of TARCEVA studied in combination with rifampicin is 450 mg. If the TARCEVA dose is adjusted upward, the dose will need to be reduced immediately to the indicated starting dose upon discontinuation of rifampicin or other inducers. Other CYP3A4 inducers include, but are not limited to rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital and St. John's Wort. These too should be avoided if possible [see Drug Interactions (7)]. Cigarette smoking has been shown to reduce erlotinib exposure. Patients should be advised to stop smoking. If a patient continues to smoke, a cautious increase in the dose of TARCEVA, not exceeding 300 mg may be considered, while monitoring the patient’s safety. However, efficacy and long-term safety (> 14 days) of a dose higher than the recommended starting doses have not been established in patients who continue to smoke cigarettes. If the TARCEVA dose is adjusted upward, the dose should be reduced immediately to the indicated starting dose upon cessation of smoking [see Clinical Pharmacology (12.3)]. Erlotinib is eliminated by hepatic metabolism and biliary excretion. Although erlotinib exposure was similar in patients with moderately impaired hepatic function (Child-Pugh B), patients with hepatic impairment (total bilirubin > ULN or Child-Pugh A, B and C) should be closely monitored during therapy with TARCEVA [see Warnings and Precautions (5.4)]. Treatment with TARCEVA should be used with extra caution in patients with total bilirubin > 3 x ULN. TARCEVA dosing should be interrupted or discontinued if changes in liver function are severe such as doubling of total bilirubin and/or tripling of transaminases in the setting of pretreatment values outside normal range. In the setting of worsening liver function tests, before they become severe, dose interruption and/or dose reduction with frequent liver function test monitoring should be considered. TARCEVA dosing should be interrupted or discontinued if total bilirubin is >3 x ULN and/or transaminases are >5 x ULN in the setting of normal pretreatment values [see Warnings and Precautions (5.3, 5.4), Adverse Reactions (6.1, 6.2) and Use in Specific Populations (8.8].

DOSAGE FORMS AND STRENGTHS

25 mg tablets White film-coated tablets for daily oral administration. Round, biconvex face and straight sides, white film-coated, printed in orange with a “T” and “25” on one side and plain on the other side. 100 mg tablets White film-coated tablets for daily oral administration. Round, biconvex face and straight sides, white film-coated, printed in gray with “T” and “100” on one side and plain on the other side. 150 mg tablets White film-coated tablets for daily oral administration. Round, biconvex face and straight sides, white film-coated, printed in maroon with “T” and “150” on one side and plain on the other side.

CONTRAINDICATIONS

None

WARNINGS AND PRECAUTIONS

Pulmonary Toxicity

There have been reports of serious Interstitial Lung Disease (ILD)-like events, including fatalities, in patients receiving TARCEVA for treatment of NSCLC, pancreatic cancer or other advanced solid tumors. In the randomized single-agent NSCLC studies [see Clinical Studies (14.1, 14.2)], the incidence of serious ILD-like events in the TARCEVA treated patients versus placebo treated patients was 0.7% versus 0% in the maintenance study and 0.8% for both groups in the 2nd and 3rd line study. In the pancreatic cancer study - in combination with gemcitabine – [see Clinical Studies (14.4)], the incidence of ILD-like events was 2.5% in the TARCEVA plus gemcitabine group vs. 0.4% in the placebo plus gemcitabine group. The overall incidence of ILD-like events in approximately 32,000 TARCEVA-treated patients from all studies (including uncontrolled studies and studies with concurrent chemotherapy) was approximately 1.1%. Reported diagnoses in patients suspected of having ILD-like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, Acute Respiratory Distress Syndrome and lung infiltration. Symptoms started from 5 days to more than 9 months (median 39 days) after initiating TARCEVA therapy. In the lung cancer trials most of the cases were associated with confounding or contributing factors such as concomitant/prior chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease, or pulmonary infections. In the event of an acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever, TARCEVA therapy should be interrupted pending diagnostic evaluation. If ILD is diagnosed, TARCEVA should be discontinued and appropriate treatment instituted as needed [see Dosage and Administration (2.3)].

5.2 Renal Failure

Cases of hepatorenal syndrome, acute renal failure (including fatalities), and renal insufficiency have been reported. Some were secondary to baseline hepatic impairment while others were associated with severe dehydration due to diarrhea, vomiting, and/or anorexia or concurrent chemotherapy use. In the event of dehydration, particularly in patients with contributing risk factors for renal failure (eg, pre-existing renal disease, medical conditions or medications that may lead to renal disease, or other predisposing conditions including advanced age), TARCEVA therapy should be interrupted and appropriate measures should be taken to intensively rehydrate the patient. Periodic monitoring of renal function and serum electrolytes is recommended in patients at risk of dehydration [see Adverse Reactions (6.1) and Dosage and Administration (2.3)].

5.3 Hepatotoxicity

Cases of hepatic failure and hepatorenal syndrome (including fatalities) have been reported during use of TARCEVA, particularly in patients with baseline hepatic impairment. Therefore, periodic liver function testing (transaminases, bilirubin, and alkaline phosphatase) is recommended. In the setting of worsening liver function tests, dose interruption and/or dose reduction with frequent liver function test monitoring should be considered. TARCEVA dosing should be interrupted or discontinued if total bilirubin is >3 x ULN and/or transaminases are >5 x ULN in the setting of normal pretreatment values [see Adverse Reactions (6.1, 6.2) and Dosage and Administration (2.3)].

5.4 Patients with Hepatic Impairment In a pharmacokinetic study in patients with moderate hepatic impairment (Child-Pugh B) associated with significant liver tumor burden, 10 out of 15 patients died on treatment or within 30 days of the last TARCEVA dose. One patient died from hepatorenal syndrome, 1 patient died from rapidly progressing liver failure and the remaining 8 patients died from progressive disease. Six out of the 10 patients who died had baseline total bilirubin > 3 x ULN suggesting severe hepatic impairment. Treatment with TARCEVA should be used with extra caution in patients with total bilirubin > 3 x ULN. Patients with hepatic impairment (total bilirubin > ULN or Child-Pugh A, B and C) should be closely monitored during therapy with TARCEVA. TARCEVA dosing should be interrupted or discontinued if changes in liver function are severe such as doubling of total bilirubin and/or tripling of transaminases in the setting of pretreatment values outside normal range [see Clinical Pharmacology (12.3) and Dosage and Administration (2.3)].

5.5 Gastrointestinal Perforation Gastrointestinal perforation (including fatalities) have been reported in patients receiving TARCEVA. Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular disease are at increased risk. [see Adverse Reactions (6.1, 6.2)]. Permanently discontinue TARCEVA in patients who develop gastrointestinal perforation.

5.6 Bullous and Exfoliative Skin Disorders Bullous, blistering and exfoliative skin conditions have been reported including cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis, which in some cases were fatal [see Adverse Reactions (6.1, 6.2)]. Interrupt or discontinue TARCEVA treatment if the patient develops severe bullous, blistering or exfoliating conditions.

5.7 Myocardial Infarction/Ischemia In the pancreatic carcinoma trial, six patients (incidence of 2.3%) in the TARCEVA/gemcitabine group developed myocardial infarction/ischemia. One of these patients died due to myocardial infarction. In comparison, 3 patients in the placebo/gemcitabine group developed myocardial infarction (incidence 1.2%) and one died due to myocardial infarction.

 5.8 Cerebrovascular Accident In the pancreatic carcinoma trial, six patients in the TARCEVA/gemcitabine group developed cerebrovascular accidents (incidence: 2.3%). One of these was hemorrhagic and was the only fatal event. In comparison, in the placebo/gemcitabine group there were no cerebrovascular accidents.

5.9 Microangiopathic Hemolytic Anemia with Thrombocytopenia In the pancreatic carcinoma trial, two patients in the TARCEVA/gemcitabine group developed microangiopathic hemolytic anemia with thrombocytopenia (incidence: 0.8%). Both patients received TARCEVA and gemcitabine concurrently. In comparison, in the placebo/gemcitabine group there were no cases of microangiopathic hemolytic anemia with thrombocytopenia.

5.10 Ocular Disorders

 Corneal perforation or ulceration have been reported during use of TARCEVA. Other ocular disorders including abnormal eyelash growth, keratoconjunctivitis sicca or keratitis have been observed with TARCEVA treatment and are known risk factors for corneal ulceration/perforation [see Adverse Reactions (6.1)]. Interrupt or discontinue TARCEVA therapy if patients present with acute/worsening ocular disorders such as eye pain.

5.11 Elevated International Normalized Ratio and Potential Bleeding

International Normalized Ratio (INR) elevations and infrequent reports of bleeding events, including gastrointestinal and non-gastrointestinal bleeding, have been reported in clinical studies, some associated with concomitant warfarin administration. Patients taking warfarin or other coumarin-derivative anticoagulants should be monitored regularly for changes in prothrombin time or INR [see Adverse Reactions (6.1)].

5.12 Use in Pregnancy

TARCEVA can cause fetal harm when administered to a pregnant woman. Erlotinib administered to rabbits during organogenesis at doses that result in plasma drug concentrations of approximately 3 times those in humans at the recommended dose of 150 mg daily, was associated with embryofetal lethality and abortion. When erlotinib was administered to female rats prior to mating and through the first week of pregnancy, at doses 0.3 or 0.7 times the clinical dose of 150 mg, on a mg/m2 basis, there was an increase in early resorptions that resulted in a decrease in the number of live fetuses [see Use in Specific Populations (8.1)]. There are no adequate and well-controlled studies in pregnant women using TARCEVA. Women of childbearing potential should be advised to avoid pregnancy while on TARCEVA. Adequate contraceptive methods should be used during therapy, and for at least 2 weeks after completing therapy. If TARCEVA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

6 ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Safety evaluation of TARCEVA is based on more than 1200 cancer patients who received TARCEVA as monotherapy, more than 300 patients who received TARCEVA 100 or 150 mg plus gemcitabine, and 1228 patients who received TARCEVA concurrently with other chemotherapies. There have been reports of serious events, including fatalities, in patients receiving TARCEVA for treatment of NSCLC, pancreatic cancer or other advanced solid tumors [see Warnings and Precautions (5) and Dosage and Administration (2.3)].

6.1 Clinical Trial Experience Non-Small Cell Lung Cancer Maintenance Study Adverse reactions, regardless of causality, that occurred in at least 3% of patients treated with single-agent TARCEVA at 150 mg and at least 3% more often than in the placebo group in the randomized maintenance trial are summarized by NCI-CTC (version 3.0) Grade in Table 1. The most common adverse reactions in patients receiving single-agent TARCEVA 150 mg were rash and diarrhea. Grade 3/4 rash and diarrhea occurred in 6.0% and 1.8%, respectively, in TARCEVA-treated patients. Rash and diarrhea resulted in study discontinuation in 1.2% and 0.5% of TARCEVA-treated patients, respectively. Dose reduction or interruption for rash and diarrhea was needed in 5.1% and 2.8% of patients, respectively. In TARCEVA-treated patients who developed rash, the onset was within two weeks in 66% and within one month in 81%. Table 1: NSCLC Maintenance Study: Adverse Reactions Occurring More Frequently (≥ 3%) in the Single-Agent TARCEVA Group than in the Placebo Group and in ≥ 3% of Patients in the TARCEVA Group.

Table 1: NSCLC Maintenance Study: Adverse Reactions Occurring More Frequently (≥ 3%) in the Single-Agent TARCEVA Group than in the Placebo Group and in ≥ 3% of Patients in the TARCEVA Group.

                                                  TARCEVA N = 433                   PLACEBO              N = 445

NCI-CTC Grade                     Any  Grade     Grade 3      Grade 4        Any Grade   Grade 3 Grade 4

MedDRA Preferred Term          %              %            %             %               %        %

Rash                                            49.2           6.0            0             5.8             0         0

Diarrhea                                     20.3           1.8            0             4.5              0         0

Fatigue                                        9.0             1.8            0             5.8             1.1       0

Anorexia                                     9.2              <1            0               4.9              <1       0

Pruritus                                       7.4              <1            0               2.7              0          0

Acne                                              6.2            <1            0                0                 0       0

Dermatitis Acneiform                 4.6            <1            0                1.1             0         0

Dry Skin                                         4.4             0             0                <1               0          0

Weight Decreased                        3.9           <1            0                <1               0          0

Paronychia                                   3.9              <1            0                 0                0         0

Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) were observed in

patients receiving single-agent TARCEVA 150 mg in the Maintenance study. Grade 2 (>2.5 – 5.0 x ULN) ALT elevations occurred in 2% and 1%, and

Grade 3 (>5.0 – 20.0 x ULN) ALT elevations were observed in 1% and 0% of TARCEVA and placebo treated patients, respectively. The TARCEVA

treatment group had Grade 2 (>1.5-3.0 x ULN) bilirubin elevations in 4% and Grade 3 (>3.0-10.0 x ULN) in <1% compared with <1% for both Grades 2 and

3 in the placebo group. TARCEVA dosing should be interrupted or discontinued if changes in liver function are severe [see Dosage and Administration

(2.3)].

Second/Third Line Study

Adverse reactions, regardless of causality, that occurred in at least 10% of patients treated with single-agent TARCEVA at 150 mg and at least 3% more

often than in the placebo group in the randomized trial of patients with NSCLC are summarized by NCI-CTC (version 2.0) Grade in Table 2.

The most common adverse reactions in this patient population were rash and diarrhea. Grade 3/4 rash and diarrhea occurred in 9% and 6%, respectively, in

TARCEVA-treated patients. Rash and diarrhea each resulted in study discontinuation in 1% of TARCEVA-treated patients. Six percent and 1% of patients

needed dose reduction for rash and diarrhea, respectively. The median time to onset of rash was 8 days, and the median time to onset of diarrhea was 12

days.

Table 2: NSCLC 2nd/3rd Line Study: Adverse Reactions Occurring More Frequently (≥ 3%) in the Single-agent TARCEVA 150 mg Group than in the

Placebo Group and in ≥10% of Patients in the TARCEVA Group.

TARCEVA 150 mg

N = 485

Placebo

N = 242

NCI-CTC Grade

Any

Grade Grade 3 Grade 4

Any

Grade Grade 3 Grade 4

MedDRA Preferred Term % % % % % %

Rash 75 8 <1 17 0 0

Diarrhea 54 6 <1 18 <1 0

Anorexia 52 8 1 38 5 <1

Fatigue 52 14 4 45 16 4

Dyspnea 41 17 11 35 15 11

Cough 33 4 0 29 2 0

Nausea 33 3 0 24 2 0

Infection 24 4 0 15 2 0

Vomiting 23 2 <1 19 2 0

Stomatitis 17 <1 0 3 0 0

Pruritus 13 <1 0 5 0 0

Dry skin 12 0 0 4 0 0

Conjunctivitis 12 <1 0 2 <1 0

Keratoconjunctivitis sicca 12 0 0 3 0 0

Abdominal pain 11 2 <1 7 1 <1

Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) were observed in

patients receiving single-agent TARCEVA 150 mg. These elevations were mainly transient or associated with liver metastases. Grade 2 (>2.5 – 5.0 x ULN)

ALT elevations occurred in 4% and <1% of TARCEVA and placebo treated patients, respectively. Grade 3 (>5.0 – 20.0 x ULN) elevations were not

observed in TARCEVA-treated patients. TARCEVA dosing should be interrupted or discontinued if changes in liver function are severe [see Dosage and

Administration (2.3)].

 Pancreatic Cancer

Adverse reactions, regardless of causality, that occurred in at least 10% of patients treated with TARCEVA 100 mg plus gemcitabine in the randomized trial

of patients with pancreatic cancer are summarized by NCI-CTC (version 2.0) Grade in Table 3.

The most common adverse reactions in pancreatic cancer patients receiving TARCEVA 100 mg plus gemcitabine were fatigue, rash, nausea, anorexia and

diarrhea. In the TARCEVA plus gemcitabine arm, Grade 3/4 rash and diarrhea were each reported in 5% of TARCEVA plus gemcitabine-treated patients.

The median time to onset of rash and diarrhea was 10 days and 15 days, respectively. Rash and diarrhea each resulted in dose reductions in 2% of patients,

and resulted in study discontinuation in up to 1% of patients receiving TARCEVA plus gemcitabine. The 150 mg cohort was associated with a higher rate of

certain class-specific adverse reactions including rash and required more frequent dose reduction or interruption.

Table 3: Adverse Reactions Occurring in ≥ 10% of TARCEVA-treated Pancreatic Cancer Patients: 100 mg cohort

TARCEVA + Gemcitabine

1000 mg/m2

 IV

N=259

Placebo + Gemcitabine

1000 mg/m2

 IV

N=256

NCI-CTC Grade

Any

Grade Grade 3 Grade 4

Any

Grade Grade 3 Grade 4

MedDRA Preferred Term

% % % % % %

Fatigue 73 14 2 70 13 2

Rash 69 5 0 30 1 0

Nausea 60 7 0 58 7 0

Anorexia 52 6 <1 52 5 <1

Diarrhea 48 5 <1 36 2 0

Abdominal pain 46 9 <1 45 12 <1

Vomiting 42 7 <1 41 4 <1

Weight decreased 39 2 0 29 <1 0

Infection* 39 13 3 30 9 2

Edema 37 3 <1 36 2 <1

Pyrexia 36 3 0 30 4 0

Constipation 31 3 1 34 5 1

Bone pain 25 4 <1 23 2 0

Dyspnea 24 5 <1 23 5 0

Stomatitis 22 <1 0 12 0 0

Myalgia 21 1 0 20 <1 0

TARCEVA + Gemcitabine

1000 mg/m2

 IV

N=259

Placebo + Gemcitabine

1000 mg/m2

 IV

N=256

NCI-CTC Grade

Any

Grade Grade 3 Grade 4

Any

Grade Grade 3 Grade 4

Depression 19 2 0 14 <1 0

Dyspepsia 17 <1 0 13 <1 0

Cough 16 0 0 11 0 0

Dizziness 15 <1 0 13 0 <1

Headache 15 <1 0 10 0 0

Insomnia 15 <1 0 16 <1 0

Alopecia 14 0 0 11 0 0

Anxiety 13 1 0 11 <1 0

Neuropathy 13 1 <1 10 <1 0

Flatulence 13 0 0 9 <1 0

Rigors 12 0 0 9 0 0

*Includes all MedDRA preferred terms in the Infections and Infestations System Organ Class

In the pancreatic carcinoma trial, 10 patients in the TARCEVA/gemcitabine group developed deep venous thrombosis (incidence: 3.9%). In comparison, 3

patients in the placebo/gemcitabine group developed deep venous thrombosis (incidence 1.2%). The overall incidence of grade 3 or 4 thrombotic events,

including deep venous thrombosis, was similar in the two treatment arms: 11% for TARCEVA plus gemcitabine and 9% for placebo plus gemcitabine.

No differences in Grade 3 or Grade 4 hematologic laboratory toxicities were detected between the TARCEVA plus gemcitabine group compared to the

placebo plus gemcitabine group.

Severe adverse reactions (≥grade 3 NCI-CTC) in the TARCEVA plus gemcitabine group with incidences < 5% included syncope, arrhythmias, ileus,

pancreatitis, hemolytic anemia including microangiopathic hemolytic anemia with thrombocytopenia, myocardial infarction/ischemia, cerebrovascular

accidents including cerebral hemorrhage, and renal insufficiency [see Warnings and Precautions (5)].

Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) have been observed

following the administration of TARCEVA plus gemcitabine in patients with pancreatic cancer. Table 4 displays the most severe NCI-CTC grade of liver

function abnormalities that developed. TARCEVA dosing should be interrupted or discontinued if changes in liver function are severe [see Dosage and

Administration (2.3)].

Table 4 Liver Function Test Abnormalities (most severe NCI-CTC grade) in Pancreatic Cancer Patients: 100 mg Cohort

TARCEVA + Gemcitabine 1000 mg/m2

 IV

N = 259

Placebo + Gemcitabine 1000 mg/m2

 IV

N = 256

NCI-CTC

Grade Grade 2 Grade 3 Grade 4 Grade 2 Grade 3 Grade 4

Bilirubin 17 % 10% <1% 11% 10% 3%

ALT 31% 13% <1% 22% 9% 0%

TARCEVA + Gemcitabine 1000 mg/m2

 IV

N = 259

Placebo + Gemcitabine 1000 mg/m2

 IV

N = 256

NCI-CTC

Grade Grade 2 Grade 3 Grade 4 Grade 2 Grade 3 Grade 4

AST 24% 10% <1% 19% 9% 0%

NSCLC and Pancreatic Indications: Low Frequency Adverse Reactions

Gastrointestinal Disorders

Gastrointestinal perforations have been reported [see Warnings and Precautions (5.5)].

During the NSCLC and the combination pancreatic cancer trials, infrequent cases of gastrointestinal bleeding have been reported, some associated with

concomitant warfarin or NSAID administration [see Warnings and Precautions (5.11)]. These adverse reactions were reported as peptic ulcer bleeding

(gastritis, gastroduodenal ulcers), hematemesis, hematochezia, melena and hemorrhage from possible colitis.

Renal Disorders

Cases of acute renal failure or renal insufficiency, including fatalities, with or without hypokalemia have been reported [see Warnings and Precautions (5.2)].

Hepatic Disorders

Hepatic failure has been reported in patients treated with single-agent TARCEVA or TARCEVA combined with chemotherapy [see Warnings and Precautions

(5.3)].

Ocular Disorders

Corneal ulcerations or perforations have been reported in patients receiving TARCEVA treatment. Abnormal eyelash growth including in-growing eyelashes,

excessive growth and thickening of the eyelashes have been reported [see Warnings and Precautions (5.10)] and are risk factors for corneal

ulceration/perforation.

NCI-CTC Grade 3 conjunctivitis and keratitis have been reported infrequently in patients receiving TARCEVA therapy in the NSCLC and pancreatic cancer

clinical trials. [see Patient Counseling Information (17)].

Skin, Hair, and Nail Disorders

Bullous, blistering and exfoliative skin conditions have been reported including cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis [see

Warnings and Precautions (5.6)].

In patients who develop skin rash, the appearance of the rash is typically erythematous and maculopapular and it may resemble acne with follicular pustules, but

is histopathologically different. This skin reaction commonly occurs on the face, upper chest and back, but may be more generalized or severe (NCI-CTC Grade

3 or 4) with desquamation. Skin reactions may occur or worsen in sun exposed areas; therefore, the use of sunscreen or avoidance of sun exposure is

recommended. Associated symptoms may include itching, tenderness and/or burning. Also, hyperpigmentation or dry skin with or without digital skin fissures

may occur.

Hair and nail disorders including alopecia, hirsutism, eyelash/eyebrow (see above) changes, paronychia and brittle and loose nails have been reported.

Other Disorders

Epistaxis was also reported in both the single-agent NSCLC and the pancreatic cancer clinical trials.

In general, no notable differences in the safety of TARCEVA monotherapy or in combination with gemcitabine could be discerned between females or males

and between patients younger or older than the age of 65 years [see Use in Specific Populations (8.5 and 8.6)]. The safety of TARCEVA appears similar in

Caucasian and Asian patients.

6.2 Post-marketing Experience

The following adverse reactions have been identified during post approval use of TARCEVA. Because these reactions are reported voluntarily from a

population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and subcutaneous tissue disorders

Hair and nail changes, mostly non-serious e.g. hirsutism, eyelash/eyebrow changes, paronychia and brittle and loose nails. Bullous, blistering and exfoliative

skin conditions have been reported including cases suggested of Stevens-Johnson syndrome/Toxic epidermal necrolysis [see Warnings and Precautions (5.6)].

Gastrointestinal Disorders

Gastrointestinal perforations [see Warnings and Precautions (5.5)].

Hepatic Disorders

Hepatic failure has been reported in patients treated with single-agent TARCEVA or TARCEVA combined with chemotherapy [see Warnings and Precautions

(5.3)].

7 DRUG INTERACTIONS

Erlotinib is metabolized predominantly by CYP3A4, and inhibitors of CYP3A4 would be expected to increase exposure. Co-treatment with the potent CYP3A4

inhibitor ketoconazole increases erlotinib AUC by 2/3. When TARCEVA was co-administered with ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2,

the erlotinib exposure [AUC] and maximum concentration [Cmax] increased by 39% and 17% respectively. Caution should be used when administering or taking

TARCEVA with ketoconazole and other strong CYP3A4 inhibitors such as, but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone,

nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole and grapefruit or grapefruit juice [see Dosage and Administration (2.3)].

Pre-treatment with the CYP3A4 inducer rifampicin for 7 days prior to TARCEVA decreased erlotinib AUC by about 2/3 to 4/5, which is equivalent to a dose of

about 30 to 50 mg in NSCLC patients. In a separate study, treatment with rifampicin for 11 days, with co-administration of a single 450 mg dose of TARCEVA

on day 8 resulted in a mean erlotinib exposure (AUC) that was 57.6% of that observed following a single 150 mg TARCEVA dose in the absence of rifampicin

treatment [see Dose Modifications (2.3)]. Use of alternative treatments lacking CYP3A4 inducing activity is strongly recommended. If an alternative treatment

is unavailable, adjusting the starting dose should be considered. If the TARCEVA dose is adjusted upward, the dose will need to be reduced immediately to the

indicated starting dose upon discontinuation of rifampicin or other inducers. Other CYP3A4 inducers include, but are not limited to, rifabutin, rifapentine,

phenytoin, carbamazepine, phenobarbital and St. John's Wort [see Dosage and Administration (2.3)].

Cigarette smoking has been shown to reduce erlotinib AUC. Patients should be advised to stop smoking; however, if they continue to smoke, a cautious

increase in the dose of TARCEVA may be considered, while monitoring the patient’s safety. If the TARCEVA dose is adjusted upward, the dose should be

reduced immediately to the indicated starting dose upon cessation of smoking [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Pretreatment and co-administration of TARCEVA decreased the AUC of CYP3A4 substrate, midazolam, by 24%. The mechanism is not clear.

In a study, there were no significant effects of gemcitabine on the pharmacokinetics of erlotinib nor were there significant effects of erlotinib on the

pharmacokinetics of gemcitabine.

Drugs that alter the pH of the upper GI tract may alter the solubility of erlotinib and reduce its bioavailability. Increasing the dose of TARCEVA when coadministered

with such agents is not likely to compensate for the loss of exposure. Co-administration of TARCEVA with omeprazole, a proton pump inhibitor,

decreased the erlotinib AUC by 46%. Since proton pump inhibitors affect pH of the upper GI tract for an extended period, separation of doses may not eliminate

the interaction. The concomitant use of proton pump inhibitors with TARCEVA should be avoided if possible. Co-administration of TARCEVA with 300 mg

ranitidine, an H2 receptor antagonist, decreased erlotinib AUC by 33%. When TARCEVA was administered with ranitidine 150 mg twice daily (at least 10 h

after the previous ranitidine evening dose and 2 h before the ranitidine morning dose), the erlotinib AUC decreased by 15%. If patients need to be treated with

an H2-receptor antagonist such as ranitidine, it should be used in a staggered manner. TARCEVA must be taken once a day, 10 hours after the H2-receptor

antagonist dosing and at least 2 hours before the next dose of H2-receptor antagonist. Although the effect of antacids on erlotinib pharmacokinetics has not been

evaluated, the antacid dose and the TARCEVA dose should be separated by several hours, if an antacid is necessary. [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D [See ‘Warnings and Precautions’ section]

TARCEVA can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant while

being treated with TARCEVA.

Erlotinib has been shown to cause maternal toxicity with associated embryofetal lethality and abortion in rabbits when given at doses that result in plasma drug

concentrations of approximately 3 times those in humans (AUCs at 150 mg daily dose). When given during the period of organogenesis to achieve plasma drug

concentrations approximately equal to those in humans, based on AUC, there was no increased incidence of embryofetal lethality or abortion in rabbits or rats.

However, female rats treated with 30 mg/m2

/day or 60 mg/m2

/day (0.3 or 0.7 times the clinical dose, on a mg/m2

 basis) of erlotinib prior to mating through the

first week of pregnancy had an increase in early resorptions that resulted in a decrease in the number of live fetuses.

No teratogenic effects were observed in rabbits or rats dosed with erlotinib during organogenesis at doses up to 600 mg/m2

/day in the rabbit (3 times the plasma

drug concentration seen in humans at 150 mg/day) and up to 60 mg/m2

/day in the rat (0.7 times the clinical dose of 150 mg/day on a mg/m2

 basis).

8.3 Nursing Mothers

It is not known whether erlotinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse

reactions in nursing infants from TARCEVA, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the

importance of the drug to the mother.

8.4 Pediatric Use

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

8.5 Geriatric Use

Maintenance Study

Of the total number of patients participating in the randomized NSCLC Maintenance trial, 66% were less than 65 years of age, and 34% of patients were aged 65

years or older. The hazard ratio for overall survival was 0.78 (95% CI: 0.65, 0.95) in patients less than 65 years of age and 0.88 (95% CI: 0.68, 1.15) in patients

who were 65 years or older.

Second/Third Line Study

Of the total number of patients participating in the randomized 2nd/3rd line NSCLC trial, 61% were less than 65 years of age, and 39% of patients were aged 65

years or older. The survival benefit was maintained across both age groups [OS HR = 0.75 (95% CI: 0.6, 0.9) in patients less than 65 years of age, and OS HR =

0.79 (95% CI: 0.6, 1.0) in patients who were 65 years or older].

First-Line Pancreatic Cancer

In the pancreatic cancer study, 52 % of patients were younger than 65 years of age and 48 % were 65 years of age or older. There were no clinically relevant

survival differences between the age groups [OS HR = 0.78 (95% CI: 0.6, 1.0) in patients less than 65 years of age, and OS HR = 0.94 (95% CI: 0.7, 1.2) in

patients who were 65 years or older]. No meaningful differences in safety or pharmacokinetics were observed between younger and older patients in these

studies. Therefore, no dosage adjustments are recommended in elderly patients.

8.6 Gender

Maintenance Study

Of the total number of patients participating in the randomized Maintenance trial, 73% were males and 27% females. There were no clinically relevant

differences in safety and efficacy based on gender [OS HR = 0.88 (96% CI: 0.74, 1.05) in males and OS HR = 0.64 (95% CI: 0.46, 0.91) in females].

Second/Third Line Study

Of the total number of patients participating in the randomized 2nd/3rd line NSCLC trial, 65% were males and 35% females. There were no clinically relevant

differences in safety and efficacy based on gender [OS HR = 0.76 (95% CI: 0.6, 0.9) in males and OS HR = 0.80 (95% CI: 0.6, 1.1) in females].

First Line Pancreatic Cancer

In the pancreatic cancer study, 51% of patients were males and 49% females. There were no clinically relevant differences in safety and efficacy based on

gender [OS HR = 0.74 (95% CI: 0.6, 0.9) in males and OS HR = 1.0 (95% CI: 0.8, 1.3) in females].

8.7 Race

Maintenance Study

In the randomized Maintenance trial, 84% of all patients were Caucasian and 15% were Asian. There were no clinically relevant differences in safety and

efficacy based on race [OS HR = 0.86 (95% CI: 0.73, 1.01) in Caucasians and OS HR = 0.66 (95% CI: 0.42, 1.05) in Asians].

Second/Third Line Study

In the randomized 2nd/3rd line NSCLC trial, 78% of all patients were Caucasian and 13% were Asian. There were no clinically relevant differences in safety and

efficacy based on race [OS HR = 0.79 (95% CI: 0.6, 1.0) in Caucasians and OS HR = 0.61 (95% CI: 0.4, 1.0) in Asians].

First-Line Pancreatic Cancer

In the pancreatic cancer study, 86% of all patients were Caucasian and 8% were Asian. There were no clinically relevant differences in safety and efficacy

based on race [OS HR = 0.88 (95% CI: 0.7, 1.1) in Caucasians and OS HR = 0.61 (95% CI: 0.3, 1.3) in Asians].

8.8 Patients with Hepatic Impairment

Patients with hepatic impairment (total bilirubin > ULN or Child Pugh A, B and C) should be closely monitored during therapy with TARCEVA. Treatment

with TARCEVA should be used with extra caution in patients with total bilirubin > 3 x ULN [see Warnings (5.4), Adverse Reactions (6.1, 6.2), and Dosage and

Administration (2.3)].

In vitro and in vivo evidence suggest that erlotinib is cleared primarily by the liver. However, erlotinib exposure was similar in patients with moderately

impaired hepatic function (Child-Pugh B) compared with patients with adequate hepatic function including patients with primary liver cancer or hepatic

metastases [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

8.9 Patients with Renal Impairment

Less than 9% of a single dose is excreted in the urine. No clinical studies have been conducted in patients with compromised renal function.

10 OVERDOSAGE

Single oral doses of TARCEVA up to 1,000 mg in healthy subjects and weekly doses up to 1,600 mg in cancer patients have been tolerated. Repeated twicedaily

doses of 200 mg single-agent TARCEVA in healthy subjects were poorly tolerated after only a few days of dosing. Based on the data from these studies,

an unacceptable incidence of severe adverse reactions, such as diarrhea, rash, and liver transaminase elevation, may occur above the recommended dose [see

Dosage and Administration (2)]. In case of suspected overdose, TARCEVA should be withheld and symptomatic treatment instituted.

11 DESCRIPTION

TARCEVA (erlotinib), a kinase inhibitor, is a quinazolinamine with the chemical name N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine.

TARCEVA contains erlotinib as the hydrochloride salt that has the following structural formula:

N

N

HN

O

O

O O

• HCl

Erlotinib hydrochloride has the molecular formula C22H23N3O4.HCl and a molecular weight of 429.90. The molecule has a pKa of 5.42 at 25o

C. Erlotinib

hydrochloride is very slightly soluble in water, slightly soluble in methanol and practically insoluble in acetonitrile, acetone, ethyl acetate and hexane.

Aqueous solubility of erlotinib hydrochloride is dependent on pH with increased solubility at a pH of less than 5 due to protonation of the secondary amine.

Over the pH range of 1.4 to 9.6, maximal solubility of approximately 0.4 mg/mL occurs at a pH of approximately 2.

TARCEVA tablets for oral administration are available in three dosage strengths containing erlotinib hydrochloride (27.3 mg, 109.3 mg and 163.9 mg)

equivalent to 25 mg, 100 mg and 150 mg erlotinib and the following inactive ingredients: lactose monohydrate, hypromellose, hydroxypropyl cellulose,

magnesium stearate, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate and titanium dioxide. The tablets also contain trace amounts of

color additives, including FD&C Yellow #6 (25 mg only) for product identification.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of clinical antitumor action of erlotinib is not fully characterized. Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase

associated with the epidermal growth factor receptor (EGFR). Specificity of inhibition with regard to other tyrosine kinase receptors has not been fully

characterized. EGFR is expressed on the cell surface of normal cells and cancer cells.

12.3 Pharmacokinetics

Absorption and Distribution:

Erlotinib is about 60% absorbed after oral administration and its bioavailability is substantially increased by food to almost 100%. Peak plasma levels occur 4

hours after dosing. The solubility of erlotinib is pH dependent. Erlotinib solubility decreases as pH increases. Co-administration of TARCEVA with

omeprazole, a proton pump inhibitor, decreased the erlotinib exposure [AUC] and maximum concentration [Cmax] by 46% and 61% respectively. When

TARCEVA was administered 2 hours following a 300 mg dose of ranitidine, an H2 receptor antagonist, the erlotinib AUC was reduced by 33% and Cmax by

54%. When TARCEVA was administered with ranitidine 150 mg twice daily (at least 10 h after the previous ranitidine evening dose and 2 h before the

ranitidine morning dose), the erlotinib AUC and Cmax decreased by 15% and 17% respectively [see Drug Interactions (7)].

Following absorption, erlotinib is approximately 93% protein bound to plasma albumin and alpha-1 acid glycoprotein (AAG). Erlotinib has an apparent volume

of distribution of 232 liters.

Metabolism and Excretion:

A population pharmacokinetic analysis in 591 patients receiving the single-agent TARCEVA 2nd/3rd line regimen showed a median half-life of 36.2 hours. Time

to reach steady state plasma concentration would therefore be 7 – 8 days. No significant relationships of clearance to covariates of patient age, body weight or

gender were observed. Smokers had a 24% higher rate of erlotinib clearance.

An additional population pharmacokinetic analysis was conducted in 291 NSCLC patients administered single-agent erlotinib as maintenance treatment. This

analysis demonstrated that covariates affecting erlotinib clearance in this patient population were similar to those seen in the prior single-agent pharmacokinetic

analysis. No new covariate effects were identified.

A third population pharmacokinetic analysis was conducted that incorporated erlotinib data from 204 pancreatic cancer patients who received erlotinib plus

gemcitabine. Similar results were observed to those seen in the prior single-agent pharmacokinetic analysis. No new covariate effects were identified. Coadministration

of gemcitabine had no effect on erlotinib plasma clearance.

In vitro assays of cytochrome P450 metabolism showed that erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2, and the

extrahepatic isoform CYP1A1. Following a 100 mg oral dose, 91% of the dose was recovered: 83% in feces (1% of the dose as intact parent) and 8% in urine

(0.3% of the dose as intact parent).

Cigarette smoking reduces erlotinib exposure. In the Phase 3 NSCLC trial, current smokers achieved erlotinib steady-state trough plasma concentrations which

were approximately 2-fold less than the former smokers or patients who had never smoked. This effect was accompanied by a 24% increase in apparent erlotinib

plasma clearance. In a separate study which evaluated the single-dose pharmacokinetics of erlotinib in healthy volunteers, current smokers cleared the drug

faster than former smokers or volunteers who had never smoked. The AUC0-infinity in smokers was about 1/3 to 1/2 of that in never/former smokers. In another

study which was conducted in NSCLC patients (N=35) who were current smokers, pharmacokinetic analyses at steady-state indicated a dose-proportional

increase in erlotinib exposure when the TARCEVA dose was increased from 150 mg to 300 mg. However, the exact dose to be recommended for patients who

currently smoke is unknown [see Drug Interactions (7) and Patient Counseling Information (17)].

Special Populations:

Patients with Hepatic Impairment

Patients with hepatic impairment (total bilirubin > ULN or Child Pugh A, B and C) should be closely monitored during therapy with TARCEVA. Treatment

with TARCEVA should be used with extra caution in patients with total bilirubin > 3 x ULN [see Warnings and Precautions (5.4), Adverse Reactions (6.1, 6.2),

and Dosage and Administration (2.3)].

In vitro and in vivo evidence suggest that erlotinib is cleared primarily by the liver. However, erlotinib exposure was similar in patients with moderately

impaired hepatic function (Child-Pugh B) compared with patients with adequate hepatic function including patients with primary liver cancer or hepatic

metastases.

Patients with Renal Impairment

Less than 9% of a single dose is excreted in the urine. No clinical studies have been conducted in patients with compromised renal function.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Erlotinib has not been tested for carcinogenicity.

Erlotinib has been tested for genotoxicity in a series of in vitro assays (bacterial mutation, human lymphocyte chromosome aberration, and mammalian cell

mutation) and an in vivo mouse bone marrow micronucleus test and did not cause genetic damage.

Erlotinib did not impair fertility in either male or female rats.

14 CLINICAL STUDIES

14.1 NSCLC – Maintenance Study

The efficacy and safety of TARCEVA as maintenance treatment of NSCLC were demonstrated in a randomized, double-blind, placebo-controlled trial

conducted in 26 countries, in 889 patients with locally advanced or metastatic NSCLC whose disease did not progress during first line platinum-based

chemotherapy. Patients were randomized 1:1 to receive TARCEVA 150 mg or placebo orally once daily (438 TARCEVA, 451 placebo) until disease

progression or unacceptable toxicity. The primary objective of the study was to determine if the administration of TARCEVA after standard platinum-based

chemotherapy in the treatment of NSCLC resulted in improved progression free survival (PFS) when compared with placebo, in all patients or in patients with

EGFR immunohistochemistry (IHC) positive tumors.

Demographic characteristics were balanced between the two treatment groups (Table 5).

Table 5: Demographic and Disease Characteristics:

TARCEVA

N=438

PLACEBO

N=451

Characteristics N (%) N (%)

Gender

 Female 117 (27%) 113 (25%)

 Male 321 (73%) 338 (75%)

Age (years)

≥65 Years 148 (34%) 151 (33%)

< 65 Years 290 (66%) 300 (67%)

Stage of NSCLC

 Unresectable Stage IIIB 116 (26%) 109 (24%)

 Stage IV 322 (74%) 342 (76%)

Race

Caucasian 370 (84%) 376 (83%)

 Black 3 (<1%) 1 (<1%)

Asian 62 (14%) 69 (15%)

 Other 3 (<1%) 5 (1%)

ECOG Performance Status at Baseline

0 135 (31%) 145 (32%)

 1 303 (69%) 306 (68%)

EGFR IHC

Positive 308 (70%) 313 (69%)

Negative 62 (14%) 59 (13%)

 Indeterminate 16 (4%) 24 (5%)

 Missing 52 (12%) 55 (12%)

Histology

 Squamous 166 (38%) 194 (43%)

TARCEVA PLACEBO

N=438 N=451

 Adenocarcinoma including Bronchioloaveolar 205 (47%) 198 (44%)

 Large Cell 21 (5%) 24 (5%)

 Other 46 (11%) 35 (8%)

Smoking Status

 Current Smoker 239 (55%) 254 (56%)

 Never Smoked 77 (18%) 75 (17%)

 Past Smoker 122 (28%) 122 (27%)

Smoking status: Current smoker = smoker at time of randomization or stopped within 1 year prior to randomization.

Progression free survival (PFS) and overall survival (OS) were evaluated in the intent-to-treat (ITT) population. The results of the study are

shown in Table 6.

Table 6: Efficacy Results: (ITT Population)

Median in Months (95% CI) Hazard Ratio (1) p-value (2)

TARCEVA 150 mg (95% CI)

N = 438

Placebo

N=451

Progression-Free Survival based 2.8 (2.8, 3.1) 2.6 (1.9, 2.7) 0.71 (0.62, 0.82) p < 0.0001

on investigator’s assessment

Overall Survival 12.0 (10.6, 13.9) 11.0 (9.9,12.1) 0.81 (0.70, 0.95) 0.0088

(1) Univariate Cox regression model

(2) Unstratified log-rank test.

Figure 1 depicts the Kaplan Meier Curves for Overall Survival (ITT Population).

Note: HR is from a univariate Cox regression model.

The PFS and OS Hazard Ratios, respectively, in patients with EGFR IHC-positive tumors were 0.69 (95% CI: 0.58, 0.82) and 0.77 (95% CI: 0.64, 0.93). The

PFS and OS Hazard Ratios in patients with IHC-negative tumors were 0.77 (95% CI: 0.51, 1.14) and 0.91 (95% CI: 0.59, 1.38), respectively.

Patients with adenocarcinoma had an OS Hazard Ratio of 0.77 (95% CI: 0.61, 0.97) and patients with squamous histology had an OS Hazard Ratio of 0.86

(95% CI: 0.68, 1.10).

14.2 NSCLC – Second/Third Line Study

The efficacy and safety of single-agent TARCEVA was assessed in a randomized, double blind, placebo-controlled trial in 731 patients with locally advanced

or metastatic NSCLC after failure of at least one chemotherapy regimen. Patients were randomized 2:1 to receive TARCEVA 150 mg or placebo (488

Tarceva, 243 placebo) orally once daily until disease progression or unacceptable toxicity. Study endpoints included overall survival, response rate, and

progression-free survival (PFS). Duration of response was also examined. The primary endpoint was survival. The study was conducted in 17 countries.

Table 7 summarizes the demographic and disease characteristics of the study population. Demographic characteristics were well balanced between the two

treatment groups. About two-thirds of the patients were male. Approximately one-fourth had a baseline ECOG performance status (PS) of 2, and 9% had a

baseline ECOG PS of 3. Fifty percent of the patients had received only one prior regimen of chemotherapy. About three quarters of these patients were known

to have smoked at some time.

Table 7: Demographic and Disease Characteristics

TARCEVA

(N = 488)

Placebo

(N = 243)

Characteristics n (%) n (%)

Gender

 Female 173 (35) 83 (34)

 Male 315 (65) 160 (66)

Age (years)

< 65 299 (61) 153 (63)

≥ 65 189 (39) 90 (37)

Race

Caucasian 379 (78) 188 (77)

 Black 18 (4) 12 (5)

Asian 63 (13) 28 (12)

 Other 28 (6) 15 (6)

ECOG Performance Status at Baseline*

0 64 (13) 34 (14)

 1 256 (52) 132 (54)

 2 126 (26) 56 (23)

 3 42 (9) 21 (9)

Weight Loss in Previous 6 Months

< 5% 320 (66) 166 (68)

 5 – 10% 96 (20) 36 (15)

 > 10% 52 (11) 29 (12)

 Unknown 20 (4) 12 (5)

Smoking History

 Never Smoked 104 (21) 42 (17)

 Current or Ex-smoker 358 (73) 187 (77)

 Unknown 26 (5) 14 (6)

Histological Classification

 Adenocarcinoma 246 (50) 119 (49)

 Squamous 144 (30) 78 (32)

 Undifferentiated Large Cell 41 (8) 23 (9)

 Mixed Non-Small Cell 11 (2) 2 (<1)

 Other 46 (9) 21 (9)

Time from Initial Diagnosis to

Randomization (Months)

 < 6 63 (13) 34 (14)

 6 – 12 157 (32) 85 (35)

 > 12 268 (55) 124 (51)

Best Response to Prior Therapy at

Baseline*

CR/PR 196 (40) 96 (40)

 PD 101 (21) 51 (21)

 SD 191 (39) 96 (40)

Number of Prior Regimens at Baseline*

1 243 (50) 121 (50)

 2 238 (49) 119 (49)

 3 7 (1) 3 (1)

Exposure to Prior Platinum at Baseline*

 Yes 454 (93) 224 (92)

 No 34 (7) 19 (8)

* Stratification factor as documented at baseline; distribution differs slightly from values reported at time of randomization.

The results of the study are shown in Table 8.

Table 8: Efficacy Results

Hazard

 TARCEVA Placebo Ratio (1) 95% CI p-value

 Median Median

Survival 0.73 0.61 – 0.86 <0.001 (2)

1-year Survival

6.7 mo 4.7 mo

31.2% 21.5%

Progression-Free Median Median

Survival 9.9 wk 7.9 wk 0.59 0.50 – 0.70 <0.001 (2)

Tumor Response

(CR+PR) 8.9% 0.9% <0.001 (3)

Median Median

Response Duration 34.3 wk 15.9 wk

(1) Cox regression model with the following covariates: ECOG performance status, number of prior regimens, prior platinum, best response to prior

chemotherapy.

(2) Two-sided Log-Rank test stratified by ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy.

(3) Two-sided Fisher’s exact test

Survival was evaluated in the intent-to-treat population. Figure 2 depicts the Kaplan-Meier curves for overall survival. The primary survival and PFS

analyses were two-sided Log-Rank tests stratified by ECOG performance status, number of prior regimens, prior platinum, best response to prior

chemotherapy.

Note: HR is from Cox regression model with the following covariates: ECOG performance status, number of prior regimens, prior platinum, best

response to prior chemotherapy. P-value is from two-sided Log-Rank test stratified by ECOG performance status, number of prior regimens, prior

platinum, best response to prior chemotherapy.

14.3 NSCLC - TARCEVA Administered Concurrently with Chemotherapy

Results from two, multicenter, placebo-controlled, randomized, trials in over 1000 patients conducted in first-line patients with locally advanced or

metastatic NSCLC showed no clinical benefit with the concurrent administration of TARCEVA with platinum-based chemotherapy [carboplatin and

paclitaxel (TARCEVA, N = 526) or gemcitabine and cisplatin (TARCEVA, N = 580)].

14.4 Pancreatic Cancer - TARCEVA Administered Concurrently with Gemcitabine

The efficacy and safety of TARCEVA in combination with gemcitabine as a first-line treatment was assessed in a randomized, double blind, placebocontrolled

trial in 569 patients with locally advanced, unresectable or metastatic pancreatic cancer. Patients were randomized 1:1 to receive TARCEVA (100

mg or 150 mg) or placebo once daily on a continuous schedule plus gemcitabine IV (1000 mg/m2

, Cycle 1 - Days 1, 8, 15, 22, 29, 36 and 43 of an 8 week

cycle; Cycle 2 and subsequent cycles - Days 1, 8 and 15 of a 4 week cycle [the approved dose and schedule for pancreatic cancer, see the gemcitabine

package insert]). TARCEVA or placebo was taken orally once daily until disease progression or unacceptable toxicity. The primary endpoint was survival.

Secondary endpoints included response rate, and progression-free survival (PFS). Duration of response was also examined. The study was conducted in 18

countries. A total of 285 patients were randomized to receive gemcitabine plus TARCEVA (261 patients in the 100 mg cohort and 24 patients in the 150 mg

cohort) and 284 patients were randomized to receive gemcitabine plus placebo (260 patients in the 100 mg cohort and 24 patients in the 150 mg cohort). Too

few patients were treated in the 150 mg cohort to draw conclusions.

Table 9 summarizes the demographic and disease characteristics of the study population that was randomized to receive 100 mg of TARCEVA plus

gemcitabine or placebo plus gemcitabine. Baseline demographic and disease characteristics of the patients were similar between the 2 treatment groups,

except for a slightly larger proportion of females in the TARCEVA arm (51%) compared with the placebo arm (44%). The median time from initial

diagnosis to randomization was approximately 1.0 month. Most patients presented with metastatic disease at study entry as the initial manifestation of

pancreatic cancer.

Table 9: Demographic and Disease Characteristics: 100 mg Cohort

TARCEVA+

Gemcitabine

(N=261)

Placebo + Gemcitabine

(N=260)

Characteristics N (%) N (%)

Gender

 Female 134 (51) 114 (44)

 Male 127 (49) 146 (56)

Age (Years)

 <65 136 (52) 138 (53)

≥65 125 (48) 122 (47)

Race

 Caucasian 225 (86) 231 (89)

 Black 8 (3) 5 (2)

Asian 20 (8) 14 (5)

 Other 8 (3) 10 (3)

ECOG Performance Status*

0 82 (31) 83 (32)

TARCEVA+

Gemcitabine

(N=261)

Placebo + Gemcitabine

(N=260)

Characteristics N (%) N (%)

 1 134 (51) 132 (51)

 2 44 (17) 45 (17)

 Unknown* 1 (<1) 0 (0)

Disease Status at Baseline**

 Locally Advanced 61 (23) 63 (24)

 Distant Metastasis 200 (77) 197 (76)

*Unknown includes responses of 'Unknown' and missing.

**Stratification factor as documented at baseline; distribution differs slightly from values reported at time of randomization.

The results of the study are shown in Table 10.

Table 10: Efficacy Results: 100 mg Cohort

TARCEVA + Placebo+ Hazard 95% CI p-value

Gemcitabine Gemcitabine Ratio (1)

Median Median

6.4 mo 6.0 mo

Survival 250 deaths 254 deaths 0.81 0.68 – 0.97 0.028 (2)

1-year Survival 23.8% 19.4%

Median Median

Progression-Free 3.8 mo 3.5 mo

Survival 225 events 232 events 0.76 0.64 – 0.92 0.006 (2)

Tumor Response

(CR+PR) 8.6% 7.9% 0.87 (3)

Response Median Median

Duration 23.9 wk 23.3 wk

(1) Cox regression model with the following covariates: ECOG performance status, and extent of disease.

(2) Two-sided Log-Rank test stratified by ECOG performance status and extent of disease.

(3) Two-sided Fisher’s exact test.

Survival was evaluated in the intent-to-treat population. Figure 3 depicts the Kaplan-Meier curves for overall survival in the 100 mg cohort. The primary survival and

PFS analyses were two-sided Log-Rank tests stratified by ECOG performance status and extent of disease.

Note: HR is from Cox regression model with the following covariates: ECOG performance status and extent of disease. P-value is from two-sided Log-Rank test

stratified by ECOG performance status and extent of disease.

16 HOW SUPPLIED/STORAGE AND HANDLING

25 mg Tablets

Round, biconvex face and straight sides, white film-coated, printed in orange with a “T” and “25” on one side and plain on the other side; supplied in:

Bottles of 30: NDC 50242-062-01

100 mg Tablets

Round, biconvex face and straight sides, white film-coated, printed in gray with “T” and “100” on one side and plain on the other side; supplied in:

Bottles of 30: NDC 50242-063-01

150 mg Tablets

Round, biconvex face and straight sides, white film-coated, printed in maroon with “T” and “150” on one side and plain on the other side; supplied in:

Bottles of 30: NDC 50242-064-01

Store at 25°C (77°F); excursions permitted to 15° – 30°C (59° – 86°F). See USP Controlled Room Temperature.

17 PATIENT COUNSELING INFORMATION

If the following signs or symptoms occur, patients should be advised to seek medical advice promptly [see Warnings and Precautions (5), Adverse Reactions (6)

and Dosage and Administration (2.3)].

• Onset or worsening of skin rash

• Severe or persistent diarrhea, nausea, anorexia, or vomiting

• Onset or worsening of unexplained shortness of breath or cough

• Eye irritation

Given that skin reactions are anticipated when taking TARCEVA, proactive intervention may include alcohol-free emollient cream and use of sunscreen or

avoidance of sun exposure [see Adverse Reactions (6.1).] The management of rash should be discussed with the patient. This may include topical

corticosteroids or antibiotics with anti-inflammatory properties. These approaches were used in the NSCLC and pancreatic pivotal clinical trials. Acne

preparations with drying properties may aggravate the dry skin and erythema. Treatment of rash has not been formally studied and should be based on rash

severity.

Women of childbearing potential should be advised to avoid becoming pregnant while taking TARCEVA [see Warnings and Precautions (5.12) and Use in

Specific Populations (8.1)].

Smokers should be advised to stop smoking while taking TARCEVA as plasma concentrations of erlotinib are reduced due to the effect of cigarette smoking

[see Clinical Pharmacology (12.3)].

Manufactured for:

OSI Pharmaceuticals Inc., Melville, NY 11747

Manufactured by:

Schwarz Pharma Manufacturing, Seymour, IN 47274

Distributed by:

Genentech USA, Inc. 1 DNA Way, South San Francisco, CA 94080-4990

For further information please call 1-877-TARCEVA (1-877-827-2382).

TARCEVA and are trademarks of OSI Pharmaceuticals, Inc., Melville, NY, 11747, USA.