温馨提醒：本说明书仅供参考，最新的说明书详见药品附带的说明书。

1 适应症和用法

1.1 早期乳腺癌的辅助治疗

Femara（来曲唑）适用于绝经后妇女激素受体阳性早期乳腺癌的辅助治疗。  

1.2 早期乳腺癌的延长辅助治疗

Femara 适用于已接受 5 年他莫昔芬辅助治疗的绝经后妇女早期乳腺癌的延长辅助治疗。Femara 在早期乳腺癌的延长辅助治疗中的有效性基于对接受 Femara 治疗的患者的无病生存期 (DFS) 的中位 60 个月分析 [见临床研究 (14.2, 14.3) ]。  

1.3 晚期乳腺癌的一线和二线治疗

Femara 适用于激素受体阳性或未知、局部晚期或转移性乳腺癌的绝经后妇女的一线治疗。Femara 也适用于治疗抗雌激素治疗后疾病进展的绝经后妇女的晚期乳腺癌 [见临床研究 (14.4, 14.5)]。 

2 剂量和给药方法

2.1 推荐剂量

Femara 的推荐剂量是每天服用一次 2.5 毫克片剂，与进餐无关。

2.2 用于早期乳腺癌的辅助治疗

在辅助治疗中，来曲唑治疗的最佳持续时间尚不清楚。在辅助研究和批准后辅助研究中，中位治疗持续时间为 5 年。复发时应停止治疗 [见临床研究(14.1) ] 。

2.3 用于早期乳腺癌的延长辅助治疗

在延长的辅助设置中，Femara 的最佳治疗持续时间尚不清楚。研究中的计划治疗持续时间为 5 年。在中位随访 62 个月进行的最终更新分析中，Femara 的中位治疗持续时间为 60 个月。百分之七十一 (71%) 的患者接受了至少 3 年的治疗，58% 的患者完成了至少 4.5 年的延长辅助治疗。肿瘤复发时应终止治疗[见临床研究(14.2)]。

2.4 用于晚期乳腺癌的一线和二线治疗

在患有晚期疾病的患者中，应继续用 Femara 治疗直至肿瘤进展明显 [见临床研究 (14.4, 14.5)]。

2.5 在肝受损中使用

对于轻度至中度肝功能不全的患者，不建议调整剂量，尽管由于肝硬化导致的中度肝功能不全受试者的 Femara 血液浓度适度增加。肝硬化和严重肝功能不全患者的 Femara 剂量应减少 50% [见警告和注意事项 (5. 3 ) ] 。此类患者的 Femara 推荐剂量为 2.5 mg，每隔一天给药一次。尚未确定肝损伤对胆红素水平升高的非肝硬化癌症患者 Femara 暴露的影响。  

2.6 在肾受损中使用

有肾受损患者如肌酐清除率大于或等于 10 mL/min 无需调整剂量 [见临床药理学( 12.3) ]。

3 剂型和规格

2.5 mg 片剂：深黄色，​​薄膜包衣，圆形，略微双凸，斜边（一侧印有字母 FV，另一侧印有 CG）。

4 禁忌症

妊娠：来曲唑可能致胎儿危害[见特殊人群中使用(8.1)]。

已知对活性物质或任何赋形剂过敏[见不良反应 (6)]。

5 警告和注意事项

5.1 骨骼效果  

使用 Femara 可能会导致骨矿物质密度 (BMD) 降低。应考虑监测 BMD。一项评估辅助治疗安全性的安全性研究的结果比较了来曲唑辅助治疗与他莫昔芬对腰椎 (L2-L4) BMD 的影响，结果显示在 24 个月时，来曲唑的腰椎 BMD 中位数降低了4.1 %手臂与他莫昔芬手臂的中位数增加 0.3% 相比（差异 = 4.4%）（P  < 0.0001）[参见不良反应(6)]。BMD 子研究 (MA-17B) 在扩展辅助设置中的更新结果表明，在 2 年时接受来曲唑治疗的患者  与安慰剂组的中位数下降 2.0% 相比，髋部骨密度从基线的中位数下降了 3.8%。来曲唑和安慰剂治疗组腰椎 BMD 从基线的变化没有显着差异 [见不良反应(6)]。  

在辅助试验 (BIG 1-98) 中，随机分组后任何时间的骨折发生率在中位随访 96 个月时，来曲唑组为 14.7%，他莫昔芬组为 11.4%。来曲唑的骨质疏松症发生率为 5.1% ，他莫昔芬为 2.7% [参见不良反应(6)]。在扩展辅助试验 (MA-17) 中，在中位随访 62 个月时，随机分组后任何时间的骨折发生率对于来曲唑为 13.3%，对于安慰剂为 7.8%。来曲唑新发骨质疏松症的发生率为 14.5% ，安慰剂为 7.8% [参见不良反应 (6) ] 。

5.2 胆固醇

应考虑监测血清胆固醇。在辅助试验 (BIG 1-98) 中，52.3% 的来曲唑患者和 28.6% 的他莫昔芬患者报告了高胆固醇血症。0.4% 的来曲唑患者和 0.1% 的他莫昔芬患者报告了 3-4 级高胆固醇血症。同样在辅助设置中，在基线总血清胆固醇在正常范围内（即，较少155/1843 (8.4%) 的来曲唑患者比 =1.5 x ULN) vs 71/1840 (3.9%) 的他莫昔芬患者 29% 的来曲唑患者需要降脂药物 和 20% 服用他莫昔芬 [见不良反应 (6)]。

5.3 肝损伤

服用 2.5 mg Femara 的肝硬化和严重肝损伤受试者经历的 Femara 暴露是肝功能正常的健康志愿者的大约两倍 [见临床药理学( 12.3 ) ]。因此，建议该患者群体减少剂量。尚未确定肝受损对胆红素水平升高癌症患者 Femara 暴露的影响 [见剂量和给药方法 (2. 5 ) ] 。  

5.4 疲劳和头晕

由于使用 Femara 会导致疲劳、头晕和嗜睡，因此在了解患者对使用 Femara 的反应之前，建议在驾驶或使用机械时谨慎行事。

5.5 实验室检查异常

Femara 对任何血液学或临床化学参数的剂量相关效应均不明显。在一些接受 Femara 2.5 mg 的患者中观察到淋巴细胞计数中度下降，临床意义不确定。这种抑郁在大约一半受影响的人中是短暂的。两名服用 Femara 的患者出现了血小板减少症；与研究药物的关系尚不清楚。患者因实验室异常而退出，无论是否与研究治疗有关，都很少见。  

5.6 胚胎-胎儿毒性

根据上市后报告、动物研究结果和作用机制，Femara 可对胎儿造成伤害，孕妇禁用。在上市后报告中，怀孕期间使用来曲唑导致自然流产和先天性出生缺陷。以 mg/m 2为基础，母体暴露低于最大推荐人用剂量 (MHRD) 时，来曲唑在大鼠和兔中引起胚胎-胎儿毒性。告知孕妇对胎儿的潜在风险。建议有生育能力的女性在 Femara 治疗期间和最后一次给药后至少 3 周内使用有效的避孕措施[参见不良反应 (6.2)、在特定人群中的使用 (8.1、8.3) 和临床药理学 (12.1)]。

6 不良反应

在说明书的其他部分更详细地讨论了以下不良反应。

• 骨骼效应[见警告和注意事项 (5.1)]
• 胆固醇增加 [见警告和注意事项 (5.2)]
• 疲劳和头晕[见警告和注意事项 (5.4)]

6.1 临床试验经验

因为临床试验是在广泛不同条件下进行的，一种药物临床试验中观察到的不良反应率不能与另一种药物临床试验中的发生率直接比较并且可能不反映实践中观察到的发生率。

早期乳腺癌的辅助治疗

在 BIG 1-98 研究中，对于接受 Femara 和他莫昔芬治疗的患者，辅助治疗的中位治疗持续时间为 60 个月，安全性随访的中位持续时间为 96 个月。

根据两种药物已知的药理特性和副作用特征，某些不良反应被前瞻性地指定用于分析（见表 1）。

无论基线时是否存在症状，均对不良反应进行了分析。根据通用毒性标准（CTC）2.0 版/不良事件通用术语标准（CTCAE）3.0 版，报告的大多数不良反应（约 75% 的报告 AE 患者）为 1 级或 2 级。表 1 描述了不良反应（1-4 级和 3-4 级），与单药治疗组分析（安全人群）的辅助试验中的研究治疗无关。

表 1：辅助研究中出现不良反应（CTC 1-4 级）的患者——单药治疗组分析（中位随访 96 个月；中位治疗 60 个月）

在研究治疗期间考虑所有等级时，Femara 的骨折（10.1% 对 7.1%）、心肌梗塞（1.0% 对 0.5%）和关节痛（25.2% 对 20.4%）事件发生率更高（Femara 对他莫昔芬）分别）。他莫昔芬在血栓栓塞事件（2.1% 对 3.6%）、子宫内膜增生/癌（0.3% 对 2.9%）和子宫内膜增生障碍（0.3% 对 1.8%）方面的发生率更高（分别为 Femara 对他莫昔芬）。

在中位随访 96 个月时，Femara (14.7%) 的骨折事件发生率高于他莫昔芬 (11.4%)。与 Femara 相比，他莫昔芬在血栓栓塞事件（4.6% 对 3.2%）和子宫内膜增生或癌症（2.9% 对 0.4%）方面的发生率更高（分别为他莫昔芬和 Femara）。

骨骼研究：263 名接受辅助治疗的受体阳性早期乳腺癌绝经后妇女的安全性试验结果比较来曲唑辅助治疗与他莫昔芬辅助治疗对腰椎 (L2-L4) BMD 的影响显示为 24 个月的中位值来曲唑组腰椎 BMD 降低 4.1%，而他莫昔芬组腰椎 BMD 中位数增加 0.3%（差异 = 4.4%）（P < 0.0001）。基线 BMD 正常的患者在 2 年内没有发生骨质疏松症，只有 1 名基线时骨质减少（T 评分为 -1.9）的患者在治疗期间发生骨质疏松症（通过中央审查评估）。全髋 BMD 的结果相似，尽管两种治疗之间的差异不太明显。在 2 年期间，来曲唑组 103 名患者中的 4 名 (4%) 和他莫昔芬组 97 名患者中的 6 名 (6%) 报告了骨折。  

脂质研究：在一项安全性试验中，263 名切除受体阳性早期乳腺癌的绝经后妇女在 24 个月时比较了辅助来曲唑和他莫昔芬对脂质分布的影响，来曲唑患者中有 12% 的总胆固醇值至少有一个较高的 CTCAE级高于基线，而服用他莫昔芬的患者为 4%。在另一项批准后随机、多中心、开放标签的来曲唑研究中 与阿那曲唑相比，在激素受体和淋巴结阳性乳腺癌绝经后妇女的辅助治疗中（FACE，NCT00248170），两个治疗组的中位治疗持续时间均为 60 个月。表 2 描述了不良反应（1-4 级和 3-4 级），与辅助研究（安全人群）中的研究治疗无关。

表 2：不良反应（CTC 1-4 级），发生在任一治疗组至少 5% 的患者中，按首选术语（安全设置）

在 2049 名接受来曲唑治疗且未包括在表中的患者中，不到 5% 的患者还发现了以下不良反应：跌倒、眩晕、高胆红素血症、黄疸和胸痛。

早期乳腺癌的延长辅助治疗，中位治疗持续时间为24个月    

在研究 MA-17 中，对于接受 Femara 和安慰剂的患者，延长辅助治疗的中位持续时间为 24 个月，安全性随访的中位持续时间为 28 个月。

表 3 描述了在治疗期间任何治疗组中发生频率至少为 5% 的不良反应。根据 CTC 2.0 版，报告的大多数不良反应为 1 级和 2 级。在延长的辅助设置中，报告的与安慰剂显着不同的药物相关不良反应是潮热、关节痛/关节炎和肌痛。

表 3：任一治疗组中至少 5% 的患者发生不良反应

根据对患者的中位随访 28 个月，核心随机研究中接受 Femara 治疗的患者的临床骨折发生率为 5.9% (152)，安慰剂为 5.5% (142)。接受 Femara 治疗的患者自我报告骨质疏松症的发生率为 6.9% (176)，高于接受安慰剂治疗的患者的 5.5% (141)。21.1% 接受 Femara 治疗的患者和 18.7% 接受安慰剂治疗的患者接受了双膦酸盐治疗。

核心随机研究的心血管缺血事件发生率在接受 Femara 6.8% (175) 和安慰剂 6.5% (167) 的患者之间具有可比性。

一项患者报告的衡量治疗对与雌激素缺乏相关的重要症状影响的措施表明，在血管舒缩和性症状领域，安慰剂有利于差异。

骨亚研究： [见警告和注意事项( 5. 1 ) ] 

脂质子研究：在延长的辅助设置中，基于 62 个月的中位随访时间，在 5 年以上的任何时间，Femara 和安慰剂在总胆固醇或任何脂质部分方面没有显着差异。允许使用降脂药物或升高脂质的饮食管理 [见警告和注意事项(5.2)]。

更新的分析是，早期乳腺癌的延长辅助治疗，中位治疗持续时间为60个月

延长辅助治疗试验 (MA-17) 早期揭盲 [见不良反应 (6)]。在更新（最终分析）时，总体上看到的副作用与中位治疗持续时间为 24 个月时看到的副作用一致。  

在治疗期间或停止治疗后 30 天内（中位治疗持续时间 60 个月），与安慰剂组（5.8%）相比，Femara 组的骨折发生率更高（10.4%），骨质疏松症的发生率也更高（Femara 组为 12.2% vs.安慰剂 6.4%）。

根据安全人群随机化来曲唑组62 个月的中位随访时间，随机化后任何时间新发骨折的发生率来曲唑组为 13.3% ，安慰剂组为 7.8%。来曲唑组新发骨质疏松症的发生率为 14.5% ，安慰剂组为 7.8%。

在治疗期间或停止治疗后 30 天内（中位治疗持续时间 60 个月），Femara 的心血管事件发生率为 9.8%，安慰剂为 7.0%。

根据安全人群随机化来曲唑组的 62 个月中位随访时间，随机化后任何时间的心血管疾病发生率对于来曲唑为 14.4% ，对于安慰剂为 9.8%。

脂质子研究：在扩展辅助设置 (MA-17) 中，基于 62 个月的中位随访时间，Femara 和安慰剂在 5 年内的总胆固醇或任何脂质部分方面没有显着差异。允许使用降脂药物或对升高的脂质进行饮食管理[见警告和注意事项(5.2 )] 。 

晚期乳腺癌的一线治疗

在研究 P025 中，共有 455 名患者在 Femara 臂中接受了 11 个月的中位暴露时间（他莫昔芬臂中位暴露时间为 6 个月）。Femara 和他莫昔芬的不良反应发生率相似。最常报告的不良反应是骨痛、潮热、背痛、恶心、关节痛和呼吸困难。10/455 (2%) 的 Femara 患者和 15/455 (3%) 的他莫昔芬患者因肿瘤进展以外的不良反应而停药。

在一线治疗研究中，至少 5% 接受 Femara 2.5 mg 或他莫昔芬 20 mg 治疗的患者报告的不良反应如表 4 所示。

表 4：任一治疗组中至少 5% 的患者发生不良反应

其他不太频繁（小于或等于 2%）的不良反应被认为是两个治疗组的结果，包括外周血栓栓塞事件、心血管事件和脑血管事件。外周血栓栓塞事件包括静脉血栓形成、血栓性静脉炎、门静脉血栓形成和肺栓塞。心血管事件包括心绞痛、心肌梗塞、心肌缺血和冠心病。脑血管事件包括短暂性脑缺血发作、血栓性或出血性中风以及偏瘫的发展。

晚期乳腺癌的二线治疗

在醋酸甲地孕酮比较研究 (AR/BC2) 中，因除肿瘤进展以外的不良反应而停药的人数在服用 Femara 0.5 mg 时为 5/188 (2.7%)，在服用 Femara 2.5 mg 时为 4/174 (2.3%)，在服用 Femara 时为 15 /190 (7.9%) 醋酸甲地孕酮。两种 Femara 剂量组的血栓栓塞事件均少于醋酸甲地孕酮组（0.6% 对 4.7%）。与醋酸甲地孕酮相比，使用 Femara 的阴道出血也较少（0.3% 对 3.2%）。在氨基鲁米特比较研究 (AR/BC3) 中，0.5 mg Femara 组因进展以外的原因停药的发生率为 6/193 (3.1%)，2.5 mg Femara 组为 7/185 (3.8%)，7/178 (3.9%) ) 服用氨基鲁米特的患者。

不良反应发生率的比较表明，在这两项研究中，高剂量和低剂量 Femara 组之间没有显着差异。在所有治疗组中观察到的大多数不良反应的严重程度为轻度至中度，通常无法区分治疗引起的不良反应与患者转移性乳腺癌的后果、雌激素剥夺的影响或并发疾病。

在两项对照试验 AR/BC2 和 AR/BC3 中，用 Femara 0.5 mg、Femara 2.5 mg、醋酸甲地孕酮或氨基鲁米特治疗的患者中至少 5% 报告的不良反应见表 5。

表 5：任一治疗组中至少 5% 的患者发生不良反应

1包括外周性水肿、腿部水肿、依赖性水肿、水肿。

2包括肌肉骨骼痛、骨骼痛、背痛、手臂痛、腿痛。

3包括皮疹、红斑性皮疹、斑丘疹、牛皮癣样皮疹、水泡性皮疹。

至少有 3 名接受 Femara 治疗的患者报告了其他不太常见（低于 5%）的不良反应，这些不良反应被认为是必然的，包括高钙血症、骨折、抑郁、焦虑、胸腔积液、脱发、出汗增加和眩晕。

晚期乳腺癌的一线和二线治疗

在一线和二线转移试验和上市后经验的综合分析中，报告的其他不良反应包括白内障、眼睛刺激、心悸、心力衰竭、心动过速、感觉迟钝（包括感觉迟钝/感觉异常）、动脉血栓形成、记忆障碍、烦躁、紧张、荨麻疹、尿频增加、白细胞减少、口腔炎癌痛、发热、白带、食欲增加、皮肤和粘膜干燥（包括口干）、味觉障碍和口渴。

6.2 上市后经验

在批准后使用 Femara 期间，已确定以下不良反应。因为这些反应是从不确定规模的人群中自愿报告的，所以并不总是能够可靠地估计它们的频率或建立与药物暴露的因果关系。

• 眼部疾病：视力模糊
• 肝胆疾病：肝酶升高、肝炎
• 免疫系统疾病：过敏反应、超敏反应
• 神经系统疾病：腕管综合症、扳机指
• 怀孕：自然流产、先天性出生缺陷
• 皮肤和皮下疾病：血管性水肿、中毒性表皮坏死松解症、多形性红斑

7 药物相互作用

他莫昔芬

Femara 和他莫昔芬每天 20 mg 的共同给药导致来曲唑血浆水平平均降低38%（研究 P015）。二线乳腺癌试验（AR/BC2 和 AR/BC3）的临床经验表明，如果在他莫昔芬后立即给予 Femara，Femara 治疗的疗效不会受损。

西咪替丁

与西咪替丁的药代动力学相互作用研究（研究 P004）显示对来曲唑药代动力学没有临床显着影响。

华法林

与华法林的相互作用研究 (P017) 显示来曲唑对华法林药代动力学没有临床显着影响。

其他抗癌药

迄今为止，尚无将 Femara 与其他抗癌药物联合使用的临床经验。

8 在特定人群中的使用

8.1 怀孕

风险总结

根据上市后报告、动物研究结果和作用机制，Femara 可对胎儿造成伤害，孕妇禁用。在上市后报告中，怀孕期间使用来曲唑导致自然流产和先天性出生缺陷；然而，数据不足以告知药物相关风险 [见禁忌症(4)、警告和注意事项(5.6)、不良反应(6.2)和临床药理学(12.1)]。

在动物生殖研究中，在器官形成期间给怀孕动物服用来曲唑导致植入后妊娠丢失和再吸收增加、活胎减少和胎儿畸形影响大鼠和兔子的肾脏和骨骼系统，剂量约为每日最大推荐剂量的 0.1 倍以 mg/m 2为基础的人体剂量 (MRHD) （见数据）。

对指定人群来说，重大出生缺陷和流产的背景风险未知。然而，在美国一般人群中，重大出生缺陷的背景风险为 2%-4%，流产为临床认可的妊娠的 15%-20%。

数据

动物资料

在雌性大鼠的生育力和早期胚胎发育毒性研究中，从交配前 2 周开始直至怀孕第 6 天口服来曲唑剂量 ≥ 0.003 mg/kg/天（约为最大剂量的 0.01 倍）导致着床前损失增加以 mg/m 2为基础的推荐人体剂量）。

在一项大鼠胚胎-胎儿发育毒性研究中，在器官形成期间每日口服来曲唑剂量 ≥ 0.003 mg/kg（按 mg/m 2计算，约为人类最大推荐剂量的 0.01 倍）导致胚胎-胎儿毒性包括宫内死亡率、吸收增加和着床后丢失、活胎数量减少和胎儿异常，包括肾乳头缺失和缩短、输尿管扩张、水肿以及额骨和跖骨骨化不完全。来曲唑在 0.03 mg/kg 的剂量下（大约是 mg/m 2人体最大推荐剂量的 0.01 倍）对大鼠有致畸作用基础）并导致胎儿半球形头部和颈椎/椎体椎体融合。

在家兔胚胎-胎儿发育毒性研究中，在器官形成期间每日口服来曲唑剂量 ≥ 0.002 mg/kg（按 mg/m 2计算，约为人类最大推荐剂量的 0.01 倍）导致胚胎-胎儿毒性，包括宫内死亡率、再吸收增加、着床后丢失增加和活胎数量减少。胎儿异常包括头骨、胸骨和前后腿的不完全骨化。

8.2 哺乳期

风险总结

尚不清楚来曲唑是否存在于人乳中。没有关于来曲唑对母乳喂养婴儿或产奶量影响的数据。哺乳期大鼠接触来曲唑与雄性后代的生殖性能受损有关（见数据）。由于 Femara 对母乳喂养婴儿的严重不良反应的可能性，建议哺乳期妇女在服用 Femara 期间和最后一次给药后至少 3 周内不要进行母乳喂养。

数据

动物资料

在哺乳期大鼠的出生后发育毒性研究中，在哺乳期第 0 天至第 20 天口服来曲唑，剂量为 1、0.003、0.03 或 0.3 mg/kg/天。来曲唑剂量低至 0.003 mg/kg/day（以 mg/m 2为基础，约为人类最大推荐剂量的 0.01 倍）时，雄性后代的生殖性能受损，这反映在交配率和妊娠率下降上。对雌性后代的生殖性能没有影响。

8.3 具有生殖潜能的女性和男性

妊娠试验

根据动物研究，当给予孕妇 Femara 可能致胎儿伤害[见在特殊人群中使用 (8.1)]。具有生育潜力的女性在开始 Femara 治疗前应进行妊娠试验。

避孕

女性

根据动物研究，当给予孕妇 Femara 可能致胎儿伤害[见在特殊人群中使用 (8.1)]。忠告有生殖潜能的女性在用 Femara 治疗期间和末次给药后共至少 3 周使用有效避孕。

不育症

女性

根据在雌性动物中的研究，Femara 可能损害具有生殖潜能的雌性的生育力[见非临床毒理学 (13.1)]。

男性

根据在雄性动物中的研究，Femara 可能损害具有生殖潜能的雄性的生育力[见非临床毒理学 (13.1)]。

8.4 儿科使用

儿科患者的安全性和有效性尚未确定。

通过口服强饲法以 0.003、0.03、0.3 mg/kg/天的剂量对幼鼠（产后第 7 天）给予来曲唑 12 周，导致骨骼/生长不良效应（骨成熟、骨矿物质密度）以及神经内分泌和生殖发育扰动下丘脑-垂体轴。给予 0.3 mg/kg/day 导致 AUC 值与接受推荐剂量 2.5 mg/day 成年患者的 AUC 相似。生育力下降伴随着垂体肥大和睾丸变化，包括曲细精管上皮细胞退化和女性生殖道萎缩。本研究中的幼鼠在停用来曲唑后被允许恢复治疗42天。在临床相关暴露条件下，组织病理学变化是不可逆的。

8.5 老年人使用

所有转移性乳腺癌一线和二线治疗研究中患者的中位年龄为 64-65 岁。大约 1/3 的患者年龄大于或等于 70 岁。在一线研究中，年龄大于或等于 70 岁的患者比小于 70 岁的患者经历了更长的肿瘤进展时间和更高的缓解率。

对于扩展辅助设置 (MA-17)，超过 5,100 名绝经后妇女参加了临床研究。总共有 41% 的患者在入组时年龄在 65 岁或以上，而 12% 的患者年龄在 75 岁或以上。在扩展辅助设置中，未观察到这些老年患者和年轻患者之间在安全性或有效性方面的总体差异，并且其他报告的临床经验尚未确定老年患者和年轻患者之间的反应差异，但不能确定某些老年个体的敏感性更高排除。

在辅助设置 (BIG 1-98) 中，超过 8,000 名绝经后妇女参加了临床研究。总共有 36% 的患者在入组时年龄在 65 岁或以上，而 12% 的患者年龄在 75 岁或以上。无论研究治疗分配如何，老年患者普遍报告了更多的不良反应。然而，与他莫昔芬相比，在老年患者和年轻患者之间没有观察到安全性和有效性方面的总体差异。

10 过量_

已报告Femara 过量的孤立病例。在这些情况下，最高单次摄入剂量为 62.5 毫克或 25 片。虽然在这些病例中没有报告严重的不良反应，但由于可用数据有限，无法提出明确的治疗建议。但是，如果患者警觉，可能会引起呕吐。一般来说，支持治疗和经常监测生命体征也是合适的。在单剂量研究中，使用的最高剂量为 30 毫克，耐受性良好；在多剂量试验中，最大剂量 10 毫克的耐受性良好。

在小鼠和大鼠单次口服剂量等于或大于 2,000 mg/kg（按 mg/m 2 计算，约为人类每日最大推荐剂量的 4,000 至 8,000 倍）后观察到致死率；死亡与运动活动减少、共济失调和呼吸困难有关。在单次静脉注射剂量等于或大于 10 mg/kg（按 mg/m 2 计算，约为人类每日最大推荐剂量的 50 倍）后，观察到猫的致死率；死亡之前出现血压下降和心律失常。

11 说明

口服 Femara 片剂含有 2.5 毫克来曲唑，一种非甾体芳香酶抑制剂（雌激素合成抑制剂）。化学描述为4,4'-(1H-1,2,4-Triazol-1-ylmethylene) dibenzonitrile，结构式为

来曲唑是一种白色至淡黄色结晶粉末，几乎无味，易溶于二氯甲烷，微溶于乙醇，几乎不溶于水。它的分子量为 285.31 g/mol，经验式为 C 17 H 11 N 5，熔程为 184°C 至 185°C。

Femara 可作为口服给药的 2.5 毫克片剂使用。

非活性成分： 胶体二氧化硅、氧化铁、羟丙基甲基纤维素、乳糖一水合物、硬脂酸镁、玉米淀粉、微晶纤维素、聚乙二醇、羟基乙酸淀粉钠、滑石粉和二氧化钛。 

12 临床药理学

12.1 作用机制

一些乳腺癌的生长是由雌激素刺激或维持的。被认为对激素有反应（即雌激素和/或孕激素受体阳性或受体未知）的乳腺癌治疗包括降低雌激素水平（卵巢切除术、肾上腺切除术、垂体切除术）或抑制雌激素作用（抗雌激素和促孕药物）的各种努力. 这些干预措施导致一些女性的肿瘤质量减少或肿瘤生长的进展延迟。

在绝经后妇女中，雌激素主要来自芳香酶的作用，芳香酶将肾上腺雄激素（主要是雄烯二酮和睾酮）转化为雌酮和雌二醇。因此，可以通过特异性抑制芳香酶来抑制外周组织和癌组织本身的雌激素生物合成。

Letrozole是芳香酶系统的非甾体竞争性抑制剂；它抑制雄激素向雌激素的转化。在成年非肿瘤和肿瘤雌性动物中，来曲唑在减轻子宫重量、升高血清 LH 和引起雌激素依赖性肿瘤消退方面与卵巢切除术一样有效。与卵巢切除术相反，来曲唑治疗不会导致血清 FSH 升高。来曲唑选择性地抑制性腺类固醇生成，但对肾上腺盐皮质激素或糖皮质激素合成没有显着影响。

来曲唑通过竞争性结合酶的细胞色素 P450 亚基的血红素来抑制芳香酶，导致所有组织中雌激素生物合成的减少。用来曲唑治疗女性可显着降低血清雌酮、雌二醇和硫酸雌酮，并且未显示显着影响肾上腺皮质类固醇合成、醛固酮合成或甲状腺激素合成。

12.2 药效学

在患有晚期乳腺癌的绝经后患者中，每日剂量为 0.1 mg 至 5 mg Femara（来曲唑）可将雌二醇、雌酮和硫酸雌酮的血浆浓度从基线水平抑制 75% 至 95%，并在两到三天内达到最大抑制。抑制与剂量相关，剂量为 0.5 mg 或更高时，雌酮和硫酸雌酮的许多值都低于测定中的检测限。在接受 0.5 mg 或更高剂量治疗的所有患者中，雌激素抑制在整个治疗过程中得以维持。

来曲唑在抑制芳香酶活性方面具有高度特异性。肾上腺类固醇生成没有损害。在接受每日剂量 Femara 0.1 mg 至 5 mg 治疗的绝经后患者中，皮质醇、醛固酮、11-脱氧皮质醇、17-羟基-孕酮、ACTH 的血浆浓度或血浆肾素活性未发现临床相关变化。在每天服用 0.1、0.25、0.5、1、2.5 和 5 mg 的药物治疗 6 周和 12 周后进行的 ACTH 刺激试验未表明醛固酮或皮质醇产生有任何减弱。因此，没有必要补充糖皮质激素或盐皮质激素。

健康绝经后妇女单次服用 0.1、0.5 和 2.5 毫克 Femara 后雄激素（雄烯二酮和睾酮）血浆浓度未见变化，绝经后患者每日服用 0.1 毫克至 5 毫克剂量后雄烯二酮血浆浓度未见变化。这表明雌激素生物合成的阻断不会导致雄激素前体的积累。LH 和 FSH 的血浆水平不受患者来曲唑的影响，甲状腺功能也不受 TSH 水平、T3 摄取和 T4 水平的评估。

12.3 药代动力学

吸收与分布： 来曲唑在胃肠道吸收迅速、完全，吸收不受食物影响。它被缓慢代谢成一种无活性的代谢物，其葡萄糖醛酸结合物经肾脏排泄，代表主要的清除途径。大约 90% 的放射性标记来曲唑在尿液中回收。来曲唑的终末消除半衰期约为 2 天，每天 2.5 mg 给药后 2-6 周可达到稳态血浆浓度。稳态血浆浓度比单次给药后测得的浓度预测值高 1.5 至 2 倍，表明来曲唑的药代动力学存在轻微的非线性每天服用 2.5 毫克。然而，这些稳态水平会维持很长时间，并且不会发生来曲唑的连续蓄积。来曲唑与蛋白质的结合很弱，分布容积很大（大约 1.9 L/kg）。

消除

代谢和排泄： 代谢为无药理活性的甲醇代谢物（4,4'-甲醇-双苯甲腈）和该代谢物的葡萄糖醛酸结合物的肾脏排泄是来曲唑清除的主要途径。在尿液中回收的放射性标记中，至少 75% 是甲醇代谢物的葡萄糖醛酸苷，约 9% 是两种未鉴定的代谢物，6% 是原形来曲唑。

在具有特定 CYP 同工酶活性的人微粒体中，CYP3A4 将来曲唑代谢为甲醇代谢物，而 CYP2A6 则形成该代谢物及其酮类似物。在人肝微粒体中，来曲唑抑制 CYP2A6 和 CYP2C19，但这些发现的临床意义尚不清楚。  

特定人群

儿科、老年和种族： 在研究人群（年龄从 35 岁到 80 岁以上的成人）中，未观察到药代动力学参数随年龄增加而发生变化。尚未研究成人和儿童人群之间来曲唑药代动力学的差异。尚未研究因种族引起的来曲唑药代动力学差异。

肾功能不全：在一项针对肾功能不同的志愿者（24 小时肌酐清除率：9 至 116 mL/min）的研究中，未发现肾功能对单剂量 2.5 mg Femara 的药代动力学有影响。此外，在一项针对 347 名晚期乳腺癌患者的研究 (AR/BC2) 中，大约一半接受 2.5 mg Femara，另一半接受 0.5 mg Femara，肾功能损害（计算的肌酐清除率：20 至 50 mL/min）不会影响稳态血浆来曲唑浓度。

肝损伤：在一项针对轻度至中度非转移性肝功能障碍（如肝硬化、Child-Pugh 分级 A 和 B）受试者的研究中，中度肝损伤志愿者的平均曲线下面积 (AUC) 值为 37%高于正常受试者，但仍在未受损受试者的范围内。  

在一项药代动力学研究中，患有肝硬化和严重肝功能损害（Child-Pugh 分类 C，其中包括胆红素约为 ULN 的 2-11 倍，伴有少量至重度腹水）的受试者的暴露量 (AUC) 增加了两倍并且减少了 47%系统清除。因此预计有严重肝损伤的乳腺癌患者比接受类似剂量这种药物的正常肝功能患者暴露于更高水平的来曲唑[见剂量和给药方法(2. 5 )] 。

13 非临床毒理学

13.1 癌发生、突变发生、生育力受损

在小鼠中进行的一项常规致癌研究以 0.6 至 60 mg/kg/天的剂量（按 mg/m 2 计算，约为每日最大推荐人体剂量的 1 至 100 倍）给药长达 2 年，结果显示剂量-良性卵巢间质瘤发病率的相关增加。当因生存率低而排除高剂量组时，合并肝细胞腺瘤和肝癌的发病率在女性中表现出显着趋势。在另一项研究中，60 mg/kg/天的小鼠血浆 AUC 0-12 小时水平比推荐剂量的乳腺癌患者的AUC 0-24 小时水平高 55 倍。大鼠口服剂量为 0.1 至 10 mg/kg/天（按 mg/m 计算，约为每日最大推荐人体剂量的 0.4 至 40 倍）的致癌性研究2基础）长达 2 年，在 10 mg/kg/天的剂量下，良性卵巢间质瘤的发病率也有所增加。在剂量等于或大于 0.1 mg/kg/day 时在雌性中观察到卵巢增生。在 10 mg/kg/天时，大鼠的血浆 AUC 0-24 小时水平比推荐剂量的乳腺癌患者的水平高 80 倍。在小鼠和大鼠中观察到的良性卵巢间质瘤被认为与雌激素合成的药理学抑制有关，可能是由于循环雌激素减少导致黄体生成素增加所致。

Femara（来曲唑）在体外试验（Ames 和大肠杆菌细菌试验）中没有致突变性，但在体外试验（CHO K1 和 CCL 61 中国仓鼠卵巢细胞）中被观察到是一种潜在的染色体断裂剂。来曲唑在体内不致染色体断裂（大鼠微核试验）。

在雌性大鼠的生育力和早期胚胎发育毒性研究中，从交配前 2 周开始直至怀孕第 6 天口服来曲唑剂量 ≥ 0.03 mg/kg/天（约为最大剂量的 0.1 倍）导致着床前损失增加以 mg/m 2为基础的推荐人体剂量）。在重复剂量毒性研究中，在小鼠、大鼠和犬中分别以 0.6、0.1 和 0.03 mg/kg 的剂量给予来曲唑导致雌性性行为不活跃和雄性和雌性生殖道萎缩（约 1、0.4 、和 0.4 倍每日最大推荐人体剂量（以 mg/m 2为基础）。

14 项 临床研究

14.1 更新早期乳腺癌的辅助治疗  

在一项多中心研究（BIG 1-98，NCT00004205）中，招募了超过 8,000 名患有切除的受体阳性早期乳腺癌的绝经后妇女，以下治疗之一以双盲方式随机分配：

选项1：

1. 他莫昔芬5年
2. Femara 5 年
3. 他莫昔芬 2 年，随后 Femara 3 年
4. Femara 2 年，然后他莫昔芬 3 年

选项 2：

1. 他莫昔芬 5 年
2. Femara 5年

BIG 1-98 辅助研究旨在回答两个主要问题：5 年 Femara 是否优于 5 年他莫昔芬（主要核心分析）以及 2 年时转换内分泌治疗是否优于继续相同治疗总代理5年（序贯处理分析）。表 6 显示了研究人群的选定基线特征。

该试验的主要终点是 DFS（即随机分组与最早出现局部、区域或远处复发、浸润性对侧乳腺癌或任何原因死亡之间的间隔）。次要终点是总生存期（OS）、全身无病生存期（SDFS）、浸润性对侧乳腺癌、乳腺癌复发时间（TBR）和远处转移时间（TDM）。

主要核心分析 (PCA) 包括所有患者和两种随机化选项中单药治疗组的所有随访，但两个序贯治疗组的随访在转换治疗后 30 天被截断。PCA 的中位治疗持续时间为 24 个月，中位随访时间为 26 个月。除了总生存期和对侧乳腺癌外，Femara 在所有终点均优于他莫昔芬 [例如，DFS：风险比 (HR) 0.79；95% 置信区间 (0.68, 0.92)； P  = 0.002；SDFS：HR 0.83；95% 置信区间 (0.70, 0.97)；TDM：HR 0.73；95% 置信区间 (0.60, 0.88)；操作系统：HR 0.86；95% 置信区间 (0.70, 1.06)。  

2005 年，根据独立数据监测委员会的建议，对他莫昔芬组进行了揭盲，允许患者完成 Femara 的初始辅助治疗（如果他们接受他莫昔芬至少 2 年）或开始使用 Femara 的延长辅助治疗（如果他们接受他莫昔芬治疗至少 4.5 年）如果他们仍然活着并且没有疾病。总共有 632 名患者交叉使用 Femara 或另一种芳香化酶抑制剂。在这 632 名患者中，大约 70% (448) 交叉接受 Femara 以完成初始辅助治疗，其中大部分在第 3 年至第 4 年交叉。所有这些患者都在选项 1 中。共有 184 名患者开始使用 Femara 进行延长辅助治疗（ 172 名患者）或另一种芳香化酶抑制剂（12 名患者）。为了探索这种选择性交叉的影响，

PCA 允许在 2005 年仅 26 个月的中位随访后报告 Femara 5 年与他莫昔芬 5 年的结果。PCA 的设计对于在较长时间后评估 Femara 的效果并不是最佳的（因为随访在大约 25 个月时被截断为两组）。MAA（忽略两个连续治疗组）在每次治疗中提供了同样长的随访时间，并且没有像 PCA 那样过分强调早期复发。因此，MAA 提供了临床上适当的更新疗效结果来回答第一个主要问题，尽管选择性交叉到 Femara 混淆了他莫昔芬参考组。表 7 总结了 MAA 的更新结果。该分析的中位随访时间为 73 个月。

序贯治疗分析 (STA) 解决了研究的第二个主要问题。STA 的主要分析是从转换（或单药治疗组的等效时间点）+ 30 天（STA-S）开始，在 2.5% 的水平上对每个成对比较应用双侧测试。额外的分析是根据随机化 (STA-R) 进行的，但这些比较（根据不断变化的医疗实践添加）的功效不足。

表 6：辅助研究——患者和疾病特征（ITT 人群）

表 7：更新的辅助研究结果 - 单药治疗组分析（中位随访 73 个月）

图 1 显示了无病生存单药治疗分析的 Kaplan-Meier 曲线。

DFS 事件定义为局部区域复发、远处转移、侵袭性对侧乳腺癌或任何原因导致的死亡（即，定义不包括第二个非乳腺癌原发性癌症）。

MAA 未达到两组总生存期的中位数。总体生存率无统计学差异。与他莫昔芬组相比，Femara 组的生存风险比为 0.87，95% CI (0.75, 1.02)（见表 7）。

在序贯治疗分析中，与任一单一疗法相比，DFS、OS、SDFS 和远距离 DFS 没有显着差异（例如，[他莫昔芬 2 年之后] Femara 3 年与他莫昔芬超过 2 年，DFS HR 0.89； 97.5% CI 0.68, 1.15 和 [Femara 2 年之后]他莫昔芬 3 年对比 Femara 超过 2 年，DFS HR 0.93；97.5% CI 0.71, 1.22)。

在序贯治疗分析中，随机化的 DFS、OS、SDFS 和远期 DFS 没有显着差异。

14.2 早期乳腺癌的延长辅助治疗，中位治疗持续时间为 24 个月

Femara 的双盲、随机、安慰剂对照试验（MA-17，NCT00003140） 在超过 5,100 名患有受体阳性或未知原发性乳腺癌的绝经后妇女中进行，这些妇女在接受他莫昔芬辅助治疗 5 年后无病。

研究中患者的计划治疗持续时间为 5 年，但由于中期分析显示 Femara 对时间没有复发或对侧乳腺癌的有利影响，该试验提前终止。在揭盲时，女性的随访时间中位数为 28 个月，30% 的患者完成了 3 年或更长时间的随访，不到 1% 的患者完成了 5 年的随访。

表 8 显示了研究人群的选定基线特征。

表 8：选定的研究人群人口统计（修改后的 ITT 人群）

表 9 显示了研究结果。无病生存期是指从随机分组到原发疾病局部或远处复发或对侧乳腺癌发展或死亡的最早事件的时间。激素受体状态、淋巴结状态和辅助化疗的无病生存率与总体结果相似。生存分析的数据还为时过早。

表 9：扩展辅助研究结果

CI = 风险比的置信区间。风险比小于 1.0 表示有利于 Femara 的差异（复发风险较小）；风险比大于 1.0 表示有利于安慰剂的差异（Femara 的复发风险更高）。

1局部区域复发、远处复发、对侧乳腺癌或任何原因死亡的首次事件。  

2按受体状态、淋巴结状态和既往辅助化疗分层的分析（随机化时的分层因素）。P值基于分层对数秩检验。

14.3 早期乳腺癌延长辅助治疗的更新分析，中位治疗持续时间为 60 个月

表 10：扩展辅助研究结果的更新

1根据受体状态、淋巴结状态和既往化疗进行调整。

2分层对数秩检验，按受体状态、淋巴结状态和既往化疗进行分层。

3 DFS 事件定义为最早的局部区域复发、远处转移、对侧乳腺癌或任何原因导致的死亡，并且忽略了 60% 的安慰剂组转用 Femara。

4协议定义不包括任何原因导致的死亡。

更新分析是在中位随访 62 个月时进行的。在 Femara 组中，71% 的患者接受了至少 3 年的治疗，58% 的患者完成了至少 4.5 年的延长辅助治疗。在中位随访 28 个月的研究揭盲后，安慰剂组中约 60% 的选定患者选择改用 Femara。  

在表 10 所示的更新分析中，与安慰剂相比，Femara 显着降低了乳腺癌复发或对侧乳腺癌的风险（HR 0.75；95% CI 0.63，0.89；P = 0.001 ）  。然而，在更新的 DFS 分析（随机化与局部区域复发、远处转移、对侧乳腺癌或任何原因死亡的最早事件之间的间隔）中，治疗差异被安慰剂组转换中 60% 的患者严重稀释到 Femara，占随访总安慰剂患者年数的 64%。忽略这些转换，DFS 事件的风险降低了 11%（HR 0.89；95% CI 0.77，1.03），但并不显着。远距离 DFS 或总生存率没有显着差异。

14.4 晚期乳腺癌的一线治疗

一项随机、双盲、多国试验 (P025) 在 916 名绝经后局部晚期（IIIB 期或局部区域复发不适合手术或放疗）或转移性乳腺癌患者中比较了 Femara 2.5 mg 和他莫昔芬 20 mg。进展时间 (TTP) 是试验的主要终点。本研究的选定基线特征如表 11 所示。

表 11：选定的研究人口统计数据

Femara 在 TTP 和客观肿瘤反应率方面优于他莫昔芬（见表 12）。

表 12 总结了试验结果，总中位随访时间约为 32 个月。（所有分析均未经调整并使用双侧P值。）

表 12：晚期乳腺癌一线治疗结果

1风险比。

2优势比。

3总体对数秩检验。

图 2 显示了 TTP 的 Kaplan-Meier 曲线。

图 2：Kaplan-Meier 估计的进展时间（研究 P025）

表 13 显示了先前接受过抗雌激素辅助治疗的女性亚组的结果，表 14 显示了疾病部位的结果，表 15 显示了受体状态的结果。

表 13：接受过抗雌激素治疗的患者的疗效

风险比小于 1 或优势比大于 1 有利于 Femara；风险比大于 1 或比值比小于 1 有利于他莫昔芬。

表 14：疾病部位的疗效

表 15：不同受体状态的功效

风险比小于 1 或优势比大于 1 有利于 Femara；风险比大于 1 或比值比小于 1 有利于他莫昔芬。

图 3 显示了生存的 Kaplan-Meier 曲线。

图 3：随机治疗组的生存率

图例： 随机 Femara：n = 458，事件 57%，中位总生存期 35 个月（95% CI 32 至 38 个月）

随机化他莫昔芬：n = 458，事件 57%，中位总生存期 32 个月（95% CI 28 至 37 个月）

总体对数秩P  = 0.5136（即，治疗组之间的总体生存率没有显着差异）。

Femara 组的中位总生存期为 35 个月，他莫昔芬组为 32 个月，P值为 0.5136。研究设计允许患者在进展到其他疗法时交叉。大约 50% 的患者转入了相反的治疗组，几乎所有转入治疗组的患者都在 36 个月时转入了治疗组。中位交叉时间为 17 个月（Femara 至他莫昔芬）和 13 个月（他莫昔芬至 Femara）。在未转到相反治疗组的患者中，Femara 组的中位生存期为 35 个月（n = 219，95% CI，29 至 43 个月），他莫昔芬组为 20 个月（n = 229，95% CI，16 至 43 个月） 26 个月）。

14.5 晚期乳腺癌的二线治疗

Femara 最初在 181 名绝经后雌激素/孕激素受体阳性或以前至少接受过抗雌激素治疗的未知晚期乳腺癌患者。患者接受过其他激素治疗，也可能接受过细胞毒性治疗。在试验中，每天接受 Femara 2.5 mg 治疗的 40 名患者中有 8 名 (20%) 达到了客观的肿瘤反应（完全或部分反应）。

两项大型随机、对照、多国（主要是欧洲）试验（AR/BC2、AR/BC3）在抗雌激素治疗后仍进展的晚期乳腺癌患者中进行。患者被随机分为每天 0.5 毫克 Femara、每天 2.5 毫克 Femara 或比较剂 [一项研究中每天 160 毫克醋酸甲地孕酮 (AR/BC2)；在另一项研究 (AR/BC3) 中，氨基鲁米特 250 mg 每天两次并补充皮质类固醇。在每项研究中，超过 60% 的患者接受了治疗性抗雌激素治疗，其中约五分之一的患者有客观反应。醋酸甲地孕酮对照研究是双盲的；另一项研究是开放标签的。表 16 显示了每项研究的选定基线特征。

表 16：选定的研究人口统计数据

确认的客观肿瘤反应（完全反应加部分反应）是试验的主要终点。根据国际抗癌联盟 (UICC) 标准测量反应，并通过独立的盲法审查进行验证。在初始响应记录后 4 至 12 周，所有响应均由第二次评估确认。

表 17 显示了第一个试验 (AR/BC2) 的结果，至少随访 15 个月，比较 Femara 0.5 mg、Femara 2.5 mg 和醋酸甲地孕酮 160 mg（所有分析均未调整）。

表 17：醋酸甲地孕酮研究结果

*双边P值。

醋酸甲地孕酮研究进展的 Kaplan-Meier 曲线如图 4 所示。

图 4：Kaplan-Meier 估计的进展时间（醋酸甲地孕酮研究）

比较 Femara 与氨基鲁米特 (AR/BC3) 的研究结果，最少随访 9 个月，如表 18 所示（使用未经调整的分析）。

表 18：氨基鲁米特研究结果

*双边P值。

氨基鲁米特研究进展的 Kaplan-Meier 曲线如图 5 所示。

图 5：Kaplan-Meier 估计的进展时间（氨鲁米特研究）

16 如何供应/储存和处理

包装在带有安全螺帽的 HDPE 瓶中。

2.5 毫克片剂

     瓶装 30 片................................................ ...................................国家数据中心 0078-0249-15

储存温度为 20°C 至 25°C（68°F 至 77°F）；允许在 15°C 和 30°C（59°F 和 86°F）之间进行短途旅行 [参见 USP 受控室温]。

17 患者咨询信息

胚胎-胎儿毒性

忠告生殖潜能女性对胎儿的潜在风险和在 Femara 治疗期间和最后一次给药后共至少 3 周使用有效避孕。建议女性在用 Femara 治疗期间如果怀孕或怀疑怀孕联系她们的医疗保健提供者[见警告和注意事项 (5.6 ) 和在特定人群中使用 (8.1, 8.3)]。

哺乳期

建议妇女在 Femara 治疗期间和末次给药后至少 3 周内不要哺乳[见特殊人群中使用(8.2)]。

不育症

忠告生殖潜能的雌性和雄性来自 Femara 降低生育力的潜能 [见特殊人群中使用(8.3)]。

疲劳和头晕

由于使用 Femara 曾观察到疲劳和头晕，并且嗜睡的报道不常见，因此建议在驾驶或使用机械时小心[见警告和注意事项 (5.4)]。

骨骼效果

应考虑监测骨矿物质密度[见警告和注意事项(5.1)]。

分销商：

Novartis Pharmaceuticals Corporation

East Hanover, New Jersey, 07936

© 诺华

T2020-51

主要显示面板

国家数据中心 0078-0249-15

Femara® 

（来曲唑片）

每片 2.5 毫克

仅限处方药

30 片

诺华

【备注】以上内容仅供参考，不作为用药依据，详情请参照药品附带说明书。

本说明书来源于：美国FDA

https://nctr-crs.fda.gov/fdalabel/services/spl/set-ids/82b77d74-085f-45ac-a7dd-1f5c038bf406/spl-doc?hl=Letrozole

温馨提醒：

①建议您用 谷歌浏览器  在电脑上或手机  打开以上链接，就可以自动翻译成简体中文，而且翻译的还比较准确。

②本说明书仅供参考，最新的说明书详见药品附带的说明书。

1 INDICATIONS AND USAGE

1.1 Adjuvant Treatment of Early Breast Cancer

Femara (letrozole) is indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. 

1.2 Extended Adjuvant Treatment of Early Breast Cancer

Femara is indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women, who have received 5 years of adjuvant tamoxifen therapy. The effectiveness of Femara in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival (DFS) in patients treated with Femara for a median of 60 months [see Clinical Studies (14.2, 14.3)]. 

1.3 First and Second-Line Treatment of Advanced Breast Cancer

Femara is indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer. Femara is also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy [see Clinical Studies (14.4, 14.5)]. 

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

The recommended dose of Femara is one 2.5 mg tablet administered once a day, without regard to meals.

2.2 Use in Adjuvant Treatment of Early Breast Cancer

In the adjuvant setting, the optimal duration of treatment with letrozole is unknown. In both the adjuvant study and the post approval adjuvant study, median treatment duration was 5 years. Treatment should be discontinued at relapse [see Clinical Studies (14.1)].

2.3 Use in Extended Adjuvant Treatment of Early Breast Cancer

In the extended adjuvant setting, the optimal treatment duration with Femara is not known. The planned duration of treatment in the study was 5 years. In the final updated analysis, conducted at a median follow-up of 62 months, the median treatment duration for Femara was 60 months. Seventy-one percent (71%) of patients were treated for at least 3 years and 58% of patients completed at least 4.5 years of extended adjuvant treatment. The treatment should be discontinued at tumor relapse [see Clinical Studies (14.2)].

2.4 Use in First and Second-Line Treatment of Advanced Breast Cancer

In patients with advanced disease, treatment with Femara should continue until tumor progression is evident [see Clinical Studies (14.4, 14.5)].

2.5 Use in Hepatic Impairment

No dosage adjustment is recommended for patients with mild to moderate hepatic impairment, although Femara blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis. The dose of Femara in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% [see Warnings and Precautions (5.3)]. The recommended dose of Femara for such patients is 2.5 mg administered every other day. The effect of hepatic impairment on Femara exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been determined.

2.6 Use in Renal Impairment

No dosage adjustment is required for patients with renal impairment if creatinine clearance is greater than or equal to 10 mL/min [see Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

2.5 mg tablets: dark yellow, film-coated, round, slightly biconvex, with beveled edges (imprinted with the letters FV on one side and CG on the other side).

4 CONTRAINDICATIONS

• Pregnancy: Letrozole can cause fetal harm [see Use in Specific Populations (8.1)].
• Known hypersensitivity to the active substance, or to any of the excipients [see Adverse Reactions (6)].

5 WARNINGS AND PRECAUTIONS

5.1 Bone Effects  

Use of Femara may cause decreases in bone mineral density (BMD). Consideration should be given to monitoring BMD. Results of a safety study to evaluate safety in the adjuvant setting comparing the effect on lumbar spine (L2-L4) BMD of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months a median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%) (P < 0.0001) [see Adverse Reactions (6)]. Updated results from the BMD substudy (MA-17B) in the extended adjuvant setting demonstrated that at 2 years patients receiving letrozole had a median decrease from baseline of 3.8% in hip BMD compared to a median decrease of 2.0% in the placebo group. The changes from baseline in lumbar spine BMD in letrozole and placebo treated groups were not significantly different [see Adverse Reactions (6)].  

In the adjuvant trial (BIG 1-98) the incidence of bone fractures at any time after randomization was 14.7% for letrozole and 11.4% for tamoxifen at a median follow-up of 96 months. The incidence of osteoporosis was 5.1% for letrozole and 2.7% for tamoxifen [see Adverse Reactions (6)]. In the extended adjuvant trial (MA-17), the incidence of bone fractures at any time after randomization was 13.3% for letrozole and 7.8% for placebo at a median follow-up of 62 months. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo [see Adverse Reactions (6)].

5.2 Cholesterol

Consideration should be given to monitoring serum cholesterol. In the adjuvant trial (BIG 1-98), hypercholesterolemia was reported in 52.3% of letrozole patients and 28.6% of tamoxifen patients. Grade 3-4 hypercholesterolemia was reported in 0.4% of letrozole patients and 0.1% of tamoxifen patients. Also in the adjuvant setting, an increase of greater than or equal to 1.5 x upper limit of normal (ULN) in total cholesterol (generally nonfasting) was observed in patients on monotherapy who had baseline total serum cholesterol within the normal range (i.e., less than =1.5 x ULN) in 155/1843 (8.4%) patients on letrozole vs 71/1840 (3.9%) patients on tamoxifen Lipid lowering medications were required for 29% of patients on letrozole and 20% on tamoxifen [see Adverse Reactions (6)].

5.3 Hepatic Impairment

Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of Femara experienced approximately twice the exposure to Femara as healthy volunteers with normal liver function [see Clinical Pharmacology (12.3)]. Therefore, a dose reduction is recommended for this patient population. The effect of hepatic impairment on Femara exposure in cancer patients with elevated bilirubin levels has not been determined [see Dosage and Administration (2.5)].

5.4 Fatigue and Dizziness

Because fatigue, dizziness, and somnolence have been reported with the use of Femara, caution is advised when driving or using machinery until it is known how the patient reacts to Femara use.

5.5 Laboratory Test Abnormalities

No dose-related effect of Femara on any hematologic or clinical chemistry parameter was evident. Moderate decreases in lymphocyte counts, of uncertain clinical significance, were observed in some patients receiving Femara 2.5 mg. This depression was transient in about half of those affected. Two patients on Femara developed thrombocytopenia; relationship to the study drug was unclear. Patient withdrawal due to laboratory abnormalities, whether related to study treatment or not was infrequent.  

5.6 Embryo-Fetal Toxicity

Based on post-marketing reports, findings from animal studies and the mechanism of action, Femara can cause fetal harm and is contraindicated for use in pregnant women. In post-marketing reports, use of letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects. Letrozole caused embryo-fetal toxicities in rats and rabbits at maternal exposures that were below the maximum recommended human dose (MHRD) on a mg/m2 basis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during therapy with Femara and for at least 3 weeks after the last dose [see Adverse Reactions (6.2), Use in Specific Populations (8.1, 8.3), and Clinical Pharmacology (12.1)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling.

• Bone effects [see Warnings and Precautions (5.1)]
• Increases in cholesterol [see Warnings and Precautions (5.2)]
• Fatigue and Dizziness [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

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.

Adjuvant Treatment of Early Breast Cancer

In study, BIG 1-98, the median treatment duration of adjuvant treatment was 60 months and the median duration of follow-up for safety was 96 months for patients receiving Femara and tamoxifen.

Certain adverse reactions were prospectively specified for analysis (see Table 1), based on the known pharmacologic properties and side effect profiles of the two drugs.

Adverse reactions were analyzed irrespective of whether a symptom was present or absent at baseline. Most adverse reactions reported (approximately 75% of patients who reported AEs) were Grade 1 or Grade 2 applying the Common Toxicity Criteria (CTC) Version 2.0/Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0. Table 1 describes adverse reactions (Grades 1-4 and Grades 3-4) irrespective of relationship to study treatment in the adjuvant trial for the monotherapy arms analysis (safety population).

Table 1: Patients With Adverse Reactions (CTC Grades 1-4) in the Adjuvant Study – Monotherapy Arms Analysis (Median Follow-up 96 Months; Median Treatment 60 Months)

When considering all grades during study treatment, a higher incidence of events was seen for Femara regarding fractures (10.1% vs 7.1%), myocardial infarctions (1.0% vs 0.5%), and arthralgia (25.2% vs 20.4%) (Femara vs tamoxifen respectively). A higher incidence was seen for tamoxifen regarding thromboembolic events (2.1% vs 3.6%), endometrial hyperplasia/cancer (0.3% vs 2.9%), and endometrial proliferation disorders (0.3% vs 1.8%) (Femara vs tamoxifen respectively).

At a median follow-up of 96 months, a higher incidence of events was seen for Femara (14.7%) than for tamoxifen (11.4%) regarding fractures. A higher incidence was seen for tamoxifen compared to Femara regarding thromboembolic events (4.6% vs 3.2%), and endometrial hyperplasia or cancer (2.9% vs 0.4%) (tamoxifen vs Femara, respectively).  

Bone Study: Results of a safety trial in 263 postmenopausal women with resected receptor positive early breast cancer in the adjuvant setting comparing the effect on lumbar spine (L2-L4) BMD of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months a median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%) (P < 0.0001). No patients with a normal BMD at baseline became osteoporotic over the 2 years and only 1 patient with osteopenia at baseline (T score of -1.9) developed osteoporosis during the treatment period (assessment by central review). The results for total hip BMD were similar, although the differences between the two treatments were less pronounced. During the 2 year period, fractures were reported by 4 of 103 patients (4%) in the letrozole arm, and 6 of 97 patients (6%) in the tamoxifen arm.  

Lipid Study: In a safety trial in 263 postmenopausal women with resected receptor positive early breast cancer at 24 months comparing the effects on lipid profiles of adjuvant letrozole to tamoxifen, 12% of patients on letrozole had at least one total cholesterol value of a higher CTCAE grade than at baseline compared with 4% of patients on tamoxifen. In another postapproval randomized, multicenter, open label, study of letrozole vs anastrozole in the adjuvant treatment of postmenopausal women with hormone receptor and node positive breast cancer (FACE, NCT00248170), the median duration of treatment was 60 months for both treatment arms. Table 2 describes adverse reactions (Grades 1-4 and Grades 3-4) irrespective of relationship to study treatment in the adjuvant study (safety population).

Table 2: Adverse Reactions (CTC Grades 1-4), Occurring in at Least 5% of Patients in Either Treatment Arm, by Preferred Term (Safety set)

The following adverse reactions were also identified in less than 5% of the 2049 patients treated with letrozole and not included in the table: fall, vertigo, hyperbilirubinemia, jaundice, and chest pain.

Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months

In study MA-17, the median duration of extended adjuvant treatment was 24 months and the median duration of follow-up for safety was 28 months for patients receiving Femara and placebo.

Table 3 describes the adverse reactions occurring at a frequency of at least 5% in any treatment group during treatment. Most adverse reactions reported were Grade 1 and Grade 2 based on the CTC Version 2.0. In the extended adjuvant setting, the reported drug-related adverse reactions that were significantly different from placebo were hot flashes, arthralgia/arthritis, and myalgia.

Table 3: Adverse Reactions Occurring in at Least 5% of Patients in Either Treatment Arm

Based on a median follow-up of patients for 28 months, the incidence of clinical fractures from the core randomized study in patients who received Femara was 5.9% (152) and placebo was 5.5% (142). The incidence of self-reported osteoporosis was higher in patients who received Femara 6.9% (176) than in patients who received placebo 5.5% (141). Bisphosphonates were administered to 21.1% of the patients who received Femara and 18.7% of the patients who received placebo.

The incidence of cardiovascular ischemic events from the core randomized study was comparable between patients who received Femara 6.8% (175) and placebo 6.5% (167).

A patient-reported measure that captures treatment impact on important symptoms associated with estrogen deficiency demonstrated a difference in favor of placebo for vasomotor and sexual symptom domains.

Bone Substudy: [see Warnings and Precautions (5.1)]

Lipid Substudy: In the extended adjuvant setting, based on a median duration of follow-up of 62 months, there was no significant difference between Femara and placebo in total cholesterol or in any lipid fraction at any time over 5 years. Use of lipid lowering drugs or dietary management of elevated lipids was allowed [see Warnings and Precautions (5.2)].

Updated Analysis, Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months

The extended adjuvant treatment trial (MA-17) was unblinded early [see Adverse Reactions (6)]. At the updated (final analysis), overall the side effects seen were consistent to those seen at a median treatment duration of 24 months.  

During treatment or within 30 days of stopping treatment (median duration of treatment 60 months) a higher rate of fractures was observed for Femara (10.4%) compared to placebo (5.8%), as also a higher rate of osteoporosis (Femara 12.2% vs placebo 6.4%).

Based on 62 months median duration of follow-up in the randomized letrozole arm in the safety population the incidence of new fractures at any time after randomization was 13.3% for letrozole and 7.8% for placebo. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo.

During treatment or within 30 days of stopping treatment (median duration of treatment 60 months), the incidence of cardiovascular events was 9.8% for Femara and 7.0% for placebo.

Based on 62 months median duration of follow-up in the randomized letrozole arm in the safety population the incidence of cardiovascular disease at any time after randomization was 14.4% for letrozole and 9.8% for placebo.

Lipid Substudy: In the extended adjuvant setting (MA-17), based on a median duration of follow-up of 62 months, there was no significant difference between Femara and placebo in total cholesterol or in any lipid fraction over 5 years. Use of lipid lowering drugs or dietary management of elevated lipids was allowed [see Warnings and Precautions (5.2)].

First-Line Treatment of Advanced Breast Cancer

In study P025 a total of 455 patients were treated for a median time of exposure of 11 months in the Femara arm (median 6 months in the tamoxifen arm). The incidence of adverse reactions was similar for Femara and tamoxifen. The most frequently reported adverse reactions were bone pain, hot flushes, back pain, nausea, arthralgia, and dyspnea. Discontinuations for adverse reactions other than progression of tumor occurred in 10/455 (2%) of patients on Femara and in 15/455 (3%) of patients on tamoxifen.

Adverse reactions that were reported in at least 5% of the patients treated with Femara 2.5 mg or tamoxifen 20 mg in the first-line treatment study are shown in Table 4.

Table 4: Adverse Reactions Occurring in at Least 5% of Patients in Either Treatment Ar

Other less frequent (less than or equal to 2%) adverse reactions considered consequential for both treatment groups, included peripheral thromboembolic events, cardiovascular events, and cerebrovascular events. Peripheral thromboembolic events included venous thrombosis, thrombophlebitis, portal vein thrombosis, and pulmonary embolism. Cardiovascular events included angina, myocardial infarction, myocardial ischemia, and coronary heart disease. Cerebrovascular events included transient ischemic attacks, thrombotic or hemorrhagic strokes, and development of hemiparesis.

Second-Line Treatment of Advanced Breast Cancer

Study discontinuations in the megestrol acetate comparison study (AR/BC2) for adverse reactions other than progression of tumor were 5/188 (2.7%) on Femara 0.5 mg, in 4/174 (2.3%) on Femara 2.5 mg, and in 15/190 (7.9%) on megestrol acetate. There were fewer thromboembolic events at both Femara doses than on the megestrol acetate arm (0.6% vs 4.7%). There was also less vaginal bleeding (0.3% vs 3.2%) on Femara than on megestrol acetate. In the aminoglutethimide comparison study (AR/BC3), discontinuations for reasons other than progression occurred in 6/193 (3.1%) on 0.5 mg Femara, 7/185 (3.8%) on 2.5 mg Femara, and 7/178 (3.9%) of patients on aminoglutethimide.

Comparisons of the incidence of adverse reactions revealed no significant differences between the high and low dose Femara groups in either study. Most of the adverse reactions observed in all treatment groups were mild to moderate in severity and it was generally not possible to distinguish adverse reactions due to treatment from the consequences of the patient’s metastatic breast cancer, the effects of estrogen deprivation, or intercurrent illness.

Adverse reactions that were reported in at least 5% of the patients treated with Femara 0.5 mg, Femara 2.5 mg, megestrol acetate, or aminoglutethimide in the two controlled trials AR/BC2 and AR/BC3 are shown in Table 5.

Table 5: Adverse Reactions Occurring at a Frequency of at Least 5% of Patients in Either Treatment Arm

1Includes peripheral edema, leg edema, dependent edema, edema.

2Includes musculoskeletal pain, skeletal pain, back pain, arm pain, leg pain.

3Includes rash, erythematous rash, maculopapular rash, psoriasiform rash, vesicular rash.

Other less frequent (less than 5%) adverse reactions considered consequential and reported in at least 3 patients treated with Femara, included hypercalcemia, fracture, depression, anxiety, pleural effusion, alopecia, increased sweating, and vertigo.

First and Second-Line Treatment of Advanced Breast Cancer

In the combined analysis of the first- and second-line metastatic trials and postmarketing experiences other adverse reactions that were reported were cataract, eye irritation, palpitations, cardiac failure, tachycardia, dysesthesia (including hypesthesia/paresthesia), arterial thrombosis, memory impairment, irritability, nervousness, urticaria, increased urinary frequency, leukopenia, stomatitis cancer pain, pyrexia, vaginal discharge, appetite increase, dryness of skin and mucosa (including dry mouth), and disturbances of taste and thirst.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Femara. 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.

• Eye Disorders: blurred vision
• Hepatobiliary Disorders: increased hepatic enzymes, hepatitis
• Immune System Disorders: anaphylactic reactions, hypersensitivity reactions
• Nervous System Disorders: carpal tunnel syndrome, trigger finger
• Pregnancy: spontaneous abortions, congenital birth defects
• Skin and subcutaneous disorders: angioedema, toxic epidermal necrolysis, erythema multiforme

7 DRUG INTERACTIONS

Tamoxifen

Coadministration of Femara and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels of 38% on average (Study P015). Clinical experience in the second-line breast cancer trials (AR/BC2 and AR/BC3) indicates that the therapeutic effect of Femara therapy is not impaired if Femara is administered immediately after tamoxifen.

Cimetidine

A pharmacokinetic interaction study with cimetidine (Study P004) showed no clinically significant effect on letrozole pharmacokinetics.

Warfarin

An interaction study (P017) with warfarin showed no clinically significant effect of letrozole on warfarin pharmacokinetics.

Other Anticancer Agents

There is no clinical experience to date on the use of Femara in combination with other anticancer agents.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on postmarketing reports, findings from animal studies and the mechanism of action, Femara can cause fetal harm and is contraindicated for use in pregnant women. In post-marketing reports, use of letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects; however, the data are insufficient to inform a drug-associated risk [see Contraindications (4), Warnings and Precautions (5.6), Adverse Reactions (6.2), and Clinical Pharmacology (12.1)].

In animal reproduction studies, administration of letrozole to pregnant animals during organogenesis resulted in increased post-implantation pregnancy loss and resorption, fewer live fetuses, and fetal malformation affecting the renal and skeletal systems in rats and rabbits at doses approximately 0.1 times the daily maximum recommended human dose (MRHD) on a mg/m2 basis (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.

Data

Animal Data

In a fertility and early embryonic development toxicity study in female rats, oral administration of letrozole starting 2 weeks before mating until pregnancy day 6 resulted in an increase in pre-implantation loss at doses ≥ 0.003 mg/kg/day (approximately 0.01 times the maximum recommended human dose on a mg/m2 basis).

In an embryo-fetal developmental toxicity study in rats, daily administration of oral letrozole during the period of organogenesis at doses ≥ 0.003 mg/kg (approximately 0.01 time the maximum recommended human dose on a mg/m2 basis) resulted in embryo-fetal toxicity including intrauterine mortality, increased resorptions and postimplantation loss, decreased numbers of live fetuses and fetal anomalies, including absence and shortening of renal papilla, dilation of ureter, edema, and incomplete ossification of frontal skull and metatarsals. Letrozole was teratogenic to rats at a dose of 0.03 mg/kg (approximately 0.01 times the maximum recommended human dose on a mg/m2 basis) and caused fetal domed head and cervical/centrum vertebral fusion.

In the embryo-fetal development toxicity study in rabbits, daily administration of oral letrozole during the period of organogenesis at doses ≥ 0.002 mg/kg (approximately 0.01 times the maximum recommended human dose on a mg/m2 basis) resulted in embryo-fetal toxicity, including intrauterine mortality, increased resorption, increased postimplantation loss and decreased numbers of live fetuses. Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs.

8.2 Lactation

Risk Summary

It is not known if letrozole is present in human milk. There are no data on the effects of letrozole on the breastfed infant or milk production. Exposure of lactating rats to letrozole was associated with impaired reproductive performance of the male offspring (see Data). Because of the potential for serious adverse reactions in breastfed infants from Femara, advise lactating women not to breastfeed while taking Femara and for at least 3 weeks after the last dose.

Data

Animal Data

In a postnatal developmental toxicity study in lactating rats, letrozole was administered orally at doses of 1, 0.003, 0.03, or 0.3 mg/kg/day on Day 0 through Day 20 of lactation. The reproductive performance of the male offspring was impaired at letrozole dose as low as 0.003 mg/kg/day (approximately 0.01 times the maximum recommended human dose on a mg/m2 basis), as reflected by decreased mating and pregnancy ratios. There were no effects on the reproductive performance of female offspring.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Based on animal studies, Femara can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Females of reproductive potential should have a pregnancy test prior to starting treatment with Femara.

Contraception

Females

Based on animal studies, Femara can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Femara and for at least 3 weeks after the last dose.

Infertility

Females

Based on studies in female animals, Femara may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)].

Males

Based on studies in male animals, Femara may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

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

Letrozole administration to young (postnatal day 7) rats for 12 weeks duration at 0.003, 0.03, 0.3 mg/kg/day by oral gavage resulted in adverse skeletal/growth effects (bone maturation, bone mineral density) and neuroendocrine and reproductive developmental perturbations of the hypothalamic-pituitary axis. Administration of 0.3 mg/kg/day resulted in AUC values that were similar to the AUC in adult patients receiving the recommended dose of 2.5 mg/day. Decreased fertility was accompanied by hypertrophy of the hypophysis and testicular changes that included degeneration of the seminiferous tubular epithelium and atrophy of the female reproductive tract. Young rats in this study were allowed to recover following discontinuation of letrozole treatment for 42 days. Histopathological changes were not reversible at clinically relevant exposures.

8.5  Geriatric Use

The median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 64-65 years. About 1/3 of the patients were greater than or equal to 70 years old. In the first-line study, patients greater than or equal to 70 years of age experienced longer time to tumor progression and higher response rates than patients less than 70.

For the extended adjuvant setting (MA-17), more than 5,100 postmenopausal women were enrolled in the clinical study. In total, 41% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. In the extended adjuvant setting, no overall differences in safety or efficacy were observed between these older patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

In the adjuvant setting (BIG 1-98), more than 8,000 postmenopausal women were enrolled in the clinical study. In total, 36% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. More adverse reactions were generally reported in elderly patients irrespective of study treatment allocation. However, in comparison to tamoxifen, no overall differences with regards to the safety and efficacy profiles were observed between elderly patients and younger patients.

10 OVERDOSAGE

Isolated cases of Femara overdose have been reported. In these instances, the highest single dose ingested was 62.5 mg or 25 tablets. While no serious adverse reactions were reported in these cases, because of the limited data available, no firm recommendations for treatment can be made. However, emesis could be induced if the patient is alert. In general, supportive care and frequent monitoring of vital signs are also appropriate. In single-dose studies, the highest dose used was 30 mg, which was well tolerated; in multiple-dose trials, the largest dose of 10 mg was well tolerated.

Lethality was observed in mice and rats following single oral doses that were equal to or greater than 2,000 mg/kg (about 4,000 to 8,000 times the daily maximum recommended human dose on a mg/m2 basis); death was associated with reduced motor activity, ataxia and dyspnea. Lethality was observed in cats following single IV doses that were equal to or greater than 10 mg/kg (about 50 times the daily maximum recommended human dose on a mg/m2 basis); death was preceded by depressed blood pressure and arrhythmias.

11 DESCRIPTION

Femara tablets for oral administration contains 2.5 mg of letrozole, a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis). It is chemically described as 4,4'-(1H-1,2,4-Triazol-1-ylmethylene) dibenzonitrile, and its structural formula is

Letrozole is a white to yellowish crystalline powder, practically odorless, freely soluble in dichloromethane, slightly soluble in ethanol, and practically insoluble in water. It has a molecular weight of 285.31 g/mol, empirical formula C17H11N5, and a melting range of 184°C to 185°C.

Femara is available as 2.5 mg tablets for oral administration.

Inactive Ingredients: Colloidal silicon dioxide, ferric oxide, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, maize starch, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, talc, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The growth of some cancers of the breast is stimulated or maintained by estrogens. Treatment of breast cancer thought to be hormonally responsive (i.e., estrogen and/or progesterone receptor positive or receptor unknown) has included a variety of efforts to decrease estrogen levels (ovariectomy, adrenalectomy, hypophysectomy) or inhibit estrogen effects (antiestrogens and progestational agents). These interventions lead to decreased tumor mass or delayed progression of tumor growth in some women.

In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.

Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH, and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.

Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones.

12.2 Pharmacodynamics

In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg Femara (letrozole) suppress plasma concentrations of estradiol, estrone, and estrone sulfate by 75% to 95% from baseline with maximal suppression achieved within two-three days. Suppression is dose-related, with doses of 0.5 mg and higher giving many values of estrone and estrone sulfate that were below the limit of detection in the assays. Estrogen suppression was maintained throughout treatment in all patients treated at 0.5 mg or higher.

Letrozole is highly specific in inhibiting aromatase activity. There is no impairment of adrenal steroidogenesis. No clinically-relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH or in plasma renin activity among postmenopausal patients treated with a daily dose of Femara 0.1 mg to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1, 0.25, 0.5, 1, 2.5, and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Glucocorticoid or mineralocorticoid supplementation is, therefore, not necessary.

No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1, 0.5, and 2.5 mg single doses of Femara or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 mg to 5 mg. This indicates that the blockade of estrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH were not affected by letrozole in patients, nor was thyroid function as evaluated by TSH levels, T3 uptake, and T4 levels.

12.3 Pharmacokinetics

Absorption and Distribution: Letrozole is rapidly and completely absorbed from the gastrointestinal tract and absorption is not affected by food. It is metabolized slowly to an inactive metabolite whose glucuronide conjugate is excreted renally, representing the major clearance pathway. About 90% of radiolabeled letrozole is recovered in urine. Letrozole’s terminal elimination half-life is about 2 days and steady-state plasma concentration after daily 2.5 mg dosing is reached in 2-6 weeks. Plasma concentrations at steady state are 1.5 to 2 times higher than predicted from the concentrations measured after a single dose, indicating a slight non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. These steady-state levels are maintained over extended periods, however, and continuous accumulation of letrozole does not occur. Letrozole is weakly protein bound and has a large volume of distribution (approximately 1.9 L/kg).

Elimination

Metabolism and Excretion: Metabolism to a pharmacologically-inactive carbinol metabolite (4,4'-methanol-bisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the major pathway of letrozole clearance. Of the radiolabel recovered in urine, at least 75% was the glucuronide of the carbinol metabolite, about 9% was two unidentified metabolites, and 6% was unchanged letrozole.

In human microsomes with specific CYP isozyme activity, CYP3A4 metabolized letrozole to the carbinol metabolite while CYP2A6 formed both this metabolite and its ketone analog. In human liver microsomes, letrozole inhibited CYP2A6 and CYP2C19, however, the clinical significance of these findings is unknown.  

Specific Populations

Pediatric, Geriatric and Race: In the study populations (adults ranging in age from 35 to greater than 80 years), no change in pharmacokinetic parameters was observed with increasing age. Differences in letrozole pharmacokinetics between adult and pediatric populations have not been studied. Differences in letrozole pharmacokinetics due to race have not been studied.

Renal Impairment: In a study of volunteers with varying renal function (24-hour creatinine clearance: 9 to 116 mL/min), no effect of renal function on the pharmacokinetics of single doses of 2.5 mg of Femara was found. In addition, in a study (AR/BC2) of 347 patients with advanced breast cancer, about half of whom received 2.5 mg Femara and half 0.5 mg Femara, renal impairment (calculated creatinine clearance: 20 to 50 mL/min) did not affect steady-state plasma letrozole concentrations.

Hepatic Impairment: In a study of subjects with mild to moderate non-metastatic hepatic dysfunction (e.g., cirrhosis, Child-Pugh classification A and B), the mean area under curve (AUC) values of the volunteers with moderate hepatic impairment were 37% higher than in normal subjects, but still within the range seen in subjects without impaired function.

In a pharmacokinetic study, subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh classification C, which included bilirubins about 2-11 times ULN with minimal to severe ascites) had two-fold increase in exposure (AUC) and 47% reduction in systemic clearance. Breast cancer patients with severe hepatic impairment are thus expected to be exposed to higher levels of letrozole than patients with normal liver function receiving similar doses of this drug [see Dosage and Administration (2.5)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A conventional carcinogenesis study in mice at doses of 0.6 to 60 mg/kg/day (about 1 to 100 times the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years revealed a dose-related increase in the incidence of benign ovarian stromal tumors. The incidence of combined hepatocellular adenoma and carcinoma showed a significant trend in females when the high dose group was excluded due to low survival. In a separate study, plasma AUC0-12hr levels in mice at 60 mg/kg/day were 55 times higher than the AUC0-24hr level in breast cancer patients at the recommended dose. The carcinogenicity study in rats at oral doses of 0.1 to 10 mg/kg/day (about 0.4 to 40 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years also produced an increase in the incidence of benign ovarian stromal tumors at 10 mg/kg/day. Ovarian hyperplasia was observed in females at doses equal to or greater than 0.1 mg/kg/day. At 10 mg/kg/day, plasma AUC0-24hr levels in rats were 80 times higher than the level in breast cancer patients at the recommended dose. The benign ovarian stromal tumors observed in mice and rats were considered to be related to the pharmacological inhibition of estrogen synthesis and may be due to increased luteinizing hormone resulting from the decrease in circulating estrogen.

Femara (letrozole) was not mutagenic in in vitro tests (Ames and E.coli bacterial tests) but was observed to be a potential clastogen in in vitro assays (CHO K1 and CCL 61 Chinese hamster ovary cells). Letrozole was not clastogenic in vivo (micronucleus test in rats).

In a fertility and early embryonic development toxicity study in female rats, oral administration of letrozole starting 2 weeks before mating until pregnancy day 6 resulted in an increase in pre-implantation loss at doses ≥ 0.03 mg/kg/day (approximately 0.1 times the maximum recommended human dose on a mg/m2 basis). In repeat-dose toxicity studies, administration of letrozole caused sexual inactivity in females and atrophy of the reproductive tract in males and females at doses of 0.6, 0.1 and 0.03 mg/kg in mice, rats and dogs, respectively (approximately 1, 0.4, and 0.4 times the daily maximum recommended human dose on a mg/m2 basis, respectively).

14 CLINICAL STUDIES

14.1 Updated Adjuvant Treatment of Early Breast Cancer  

In a multicenter study (BIG 1-98, NCT00004205) enrolling over 8,000 postmenopausal women with resected, receptor-positive early breast cancer, one of the following treatments was randomized in a double-blind manner:

Option 1:

1. Tamoxifen for 5 years
2. Femara for 5 years
3. Tamoxifen for 2 years followed by Femara for 3 years
4. Femara for 2 years followed by tamoxifen for 3 years

Option 2:

1. Tamoxifen for 5 years
2. Femara for 5 years

The study in the adjuvant setting, BIG 1-98 was designed to answer two primary questions: whether Femara for 5 years was superior to Tamoxifen for 5 years (Primary Core Analysis) and whether switching endocrine treatments at 2 years was superior to continuing the same agent for a total of 5 years (Sequential Treatments Analysis). Selected baseline characteristics for the study population are shown in Table 6.

The primary endpoint of this trial was DFS (i.e., interval between randomization and earliest occurrence of a local, regional, or distant recurrence, or invasive contralateral breast cancer, or death from any cause). The secondary endpoints were overall survival (OS), systemic disease-free survival (SDFS), invasive contralateral breast cancer, time to breast cancer recurrence (TBR) and time to distant metastasis (TDM).

The Primary Core Analysis (PCA) included all patients and all follow-up in the monotherapy arms in both randomization options, but follow-up in the two sequential treatments arms was truncated 30 days after switching treatments. The PCA was conducted at a median treatment duration of 24 months and a median follow-up of 26 months. Femara was superior to tamoxifen in all endpoints except overall survival and contralateral breast cancer [e.g., DFS: hazard ratio (HR) 0.79; 95% CI (0.68, 0.92); P = 0.002; SDFS: HR 0.83; 95% CI (0.70, 0.97); TDM: HR 0.73; 95% CI (0.60, 0.88); OS: HR 0.86; 95% CI (0.70, 1.06).  

In 2005, based on recommendations by the independent Data Monitoring Committee, the tamoxifen arms were unblinded and patients were allowed to complete initial adjuvant therapy with Femara (if they had received tamoxifen for at least 2 years) or to start extended adjuvant treatment with Femara (if they had received tamoxifen for at least 4.5 years) if they remained alive and disease-free. In total, 632 patients crossed to Femara or another aromatase inhibitor. Approximately 70% (448) of these 632 patients crossed to Femara to complete initial adjuvant therapy and most of these crossed in years 3 to 4. All of these patients were in Option 1. A total of 184 patients started extended adjuvant therapy with Femara (172 patients) or with another aromatase inhibitor (12 patients). To explore the impact of this selective crossover, results from analyses censoring follow-up at the date of the selective crossover (in the tamoxifen arm) are presented for the MAA.

The PCA allowed the results of Femara for 5 years compared with tamoxifen for 5 years to be reported in 2005 after a median follow-up of only 26 months. The design of the PCA is not optimal to evaluate the effect of Femara after a longer time (because follow-up was truncated in two arms at around 25 months). The MAA (ignoring the two sequential treatment arms) provided follow-up equally as long in each treatment and did not over-emphasize early recurrences as the PCA did. The MAA thus provides the clinically appropriate updated efficacy results in answer to the first primary question, despite the confounding of the tamoxifen reference arm by the selective crossover to Femara. The updated results for the MAA are summarized in Table 7. Median follow-up for this analysis is 73 months.

The Sequential Treatments Analysis (STA) addresses the second primary question of the study. The primary analysis for the STA was from switch (or equivalent time-point in monotherapy arms) + 30 days (STA-S) with a two-sided test applied to each pair-wise comparison at the 2.5% level. Additional analyses were conducted from randomization (STA-R) but these comparisons (added in light of changing medical practice) were under-powered for efficacy.

Table 6: Adjuvant Study - Patient and Disease Characteristics (ITT Population)

Table 7: Updated Adjuvant Study Results - Monotherapy Arms Analysis (Median Follow-up 73 Months)

Definition of:

1Disease-free survival: Interval from randomization to earliest event of invasive loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death without a prior event.

2Systemic disease-free survival: Interval from randomization to invasive regional recurrence, distant metastasis, or death without a prior cancer event.

3Time to distant metastasis: Interval from randomization to distant metastasis.

4Distant disease-free survival: Interval from randomization to earlier event of relapse in a distant site or death from any cause.

ITT analysis ignores selective crossover in tamoxifen arms.

Censored analysis censors follow-up at the date of selective crossover in 632 patients who crossed to Femara or another aromatase inhibitor after the tamoxifen arms were unblinded in 2005.

Figure 1 shows the Kaplan-Meier curves for Disease-Free Survival Monotherapy Analysis.

Figure 1: Disease-Free Survival (Median follow-up 73 months, ITT Approach)

DFS events defined as loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death from any cause (i.e., definition excludes second non-breast primary cancers).

The medians of overall survival for both arms were not reached for the MAA. There was no statistically significant difference in overall survival. The hazard ratio for survival in the Femara arm compared to the tamoxifen arm was 0.87, with 95% CI (0.75, 1.02) (see Table 7).

There were no significant differences in DFS, OS, SDFS, and Distant DFS from switch in the Sequential Treatments Analysis with respect to either monotherapy (e.g., [tamoxifen 2 years followed by] Femara 3 years versus tamoxifen beyond 2 years, DFS HR 0.89; 97.5% CI 0.68, 1.15 and [Femara 2 years followed by] tamoxifen 3 years versus Femara beyond 2 years, DFS HR 0.93; 97.5% CI 0.71, 1.22).

There were no significant differences in DFS, OS, SDFS, and Distant DFS from randomization in the Sequential Treatments Analyses.

14.2 Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months

A double-blind, randomized, placebo-controlled trial (MA-17, NCT00003140) of Femara was performed in over 5,100 postmenopausal women with receptor-positive or unknown primary breast cancer who were disease free after 5 years of adjuvant treatment with tamoxifen.

The planned duration of treatment for patients in the study was 5 years, but the trial was terminated early because of an interim analysis showing a favorable Femara effect on time without recurrence or contralateral breast cancer. At the time of unblinding, women had been followed for a median of 28 months, 30% of patients had completed 3 or more years of follow-up and less than 1% of patients had completed 5 years of follow-up.

Selected baseline characteristics for the study population are shown in Table 8.

Table 8: Selected Study Population Demographics (Modified ITT Population)

Table 9 shows the study results. Disease-free survival was measured as the time from randomization to the earliest event of loco-regional or distant recurrence of the primary disease or development of contralateral breast cancer or death. Disease-free survival by hormone receptor status, nodal status and adjuvant chemotherapy were similar to the overall results. Data were premature for an analysis of survival.

Table 9: Extended Adjuvant Study Results

CI = confidence interval for hazard ratio. Hazard ratio of less than 1.0 indicates difference in favor of Femara (lesser risk of recurrence); hazard ratio greater than 1.0 indicates difference in favor of placebo (higher risk of recurrence with Femara).

1First event of loco-regional recurrence, distant relapse, contralateral breast cancer or death from any cause.  

2Analysis stratified by receptor status, nodal status and prior adjuvant chemotherapy (stratification factors as at randomization). P-value based on stratified log-rank test.

14.3 Updated Analyses of Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months

Table 10: Update of Extended Adjuvant Study Results

1Adjusted by receptor status, nodal status and prior chemotherapy.

2Stratified log-rank test, stratified by receptor status, nodal status and prior chemotherapy.

3DFS events defined as earliest of loco-regional recurrence, distant metastasis, contralateral breast cancer or death from any cause, and ignoring switches to Femara in 60% of the placebo arm.

4Protocol definition does not include deaths from any cause.

Updated analyses were conducted at a median follow-up of 62 months. In the Femara arm, 71% of the patients were treated for a least 3 years and 58% of patients completed at least 4.5 years of extended adjuvant treatment. After the unblinding of the study at a median follow-up of 28 months, approximately 60% of the selected patients in the placebo arm opted to switch to Femara.  

In this updated analysis shown in Table 10 Femara significantly reduced the risk of breast cancer recurrence or contralateral breast cancer compared with placebo (HR 0.75; 95% CI 0.63, 0.89; P = 0.001). However, in the updated DFS analysis (interval between randomization and earliest event of loco-regional recurrence, distant metastasis, contralateral breast cancer, or death from any cause) the treatment difference was heavily diluted by 60% of the patients in the placebo arm switching to Femara and accounting for 64% of the total placebo patient-years of follow-up. Ignoring these switches, the risk of DFS event was reduced by a non-significant 11% (HR 0.89; 95% CI 0.77, 1.03). There was no significant difference in distant DFS or overall survival.

14.4 First-Line Treatment of Advanced Breast Cancer

A randomized, double-blind, multinational trial (P025) compared Femara 2.5 mg with tamoxifen 20 mg in 916 postmenopausal patients with locally advanced (Stage IIIB or loco-regional recurrence not amenable to treatment with surgery or radiation) or metastatic breast cancer. Time to progression (TTP) was the primary endpoint of the trial. Selected baseline characteristics for this study are shown in Table 11.

Table 11: Selected Study Population Demographics

Femara was superior to tamoxifen in TTP and rate of objective tumor response (see Table 12).

Table 12 summarizes the results of the trial, with a total median follow-up of approximately 32 months. (All analyses are unadjusted and use 2-sided P-values.)

Table 12: Results of First-Line Treatment of Advanced Breast Cancer

1Hazard ratio.

2Odds ratio.

3Overall log-rank test.

Figure 2 shows the Kaplan-Meier curves for TTP.

Figure 2: Kaplan-Meier Estimates of Time to Progression (Study P025)

Table 13 shows results in the subgroup of women who had received prior antiestrogen adjuvant therapy, Table 14, results by disease site and Table 15, the results by receptor status.

Table 13: Efficacy in Patients Who Received Prior Antiestrogen Therapy

Hazard ratio less than 1 or odds ratio greater than 1 favors Femara; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen.

Table 14: Efficacy by Disease Site

Table 15: Efficacy by Receptor Status

Hazard ratio less than 1 or odds ratio greater than 1 favors Femara; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen.

Figure 3 shows the Kaplan-Meier curves for survival.

Figure 3: Survival by Randomized Treatment Arm

Legend: Randomized Femara: n = 458, events 57%, median overall survival 35 months (95% CI 32 to 38 months)

Randomized tamoxifen: n = 458, events 57%, median overall survival 32 months (95% CI 28 to 37 months)

Overall log-rank P = 0.5136 (i.e., there was no significant difference between treatment arms in overall survival).

The median overall survival was 35 months for the Femara group and 32 months for the tamoxifen group, with a P-value 0.5136. Study design allowed patients to cross over upon progression to the other therapy. Approximately 50% of patients crossed over to the opposite treatment arm and almost all patients who crossed over had done so by 36 months. The median time to crossover was 17 months (Femara to tamoxifen) and 13 months (tamoxifen to Femara). In patients who did not cross over to the opposite treatment arm, median survival was 35 months with Femara (n = 219, 95% CI, 29 to 43 months) vs 20 months with tamoxifen (n = 229, 95% CI, 16 to 26 months).

14.5 Second-Line Treatment of Advanced Breast Cancer

Femara was initially studied at doses of 0.1 mg to 5.0 mg daily in six noncomparative trials (AR/BC1, P01, AR/ST1, AR/PS1, AR/ES1, and NJO-03) in 181 postmenopausal estrogen/progesterone receptor positive or unknown advanced breast cancer patients previously treated with at least antiestrogen therapy. Patients had received other hormonal therapies and also may have received cytotoxic therapy. Eight (20%) of forty patients treated with Femara 2.5 mg daily in trials achieved an objective tumor response (complete or partial response).

Two large randomized, controlled, multinational (predominantly European) trials (AR/BC2, AR/BC3) were conducted in patients with advanced breast cancer who had progressed despite antiestrogen therapy. Patients were randomized to Femara 0.5 mg daily, Femara 2.5 mg daily, or a comparator [megestrol acetate 160 mg daily in one study (AR/BC2); and aminoglutethimide 250 mg twice a day with corticosteroid supplementation in the other study (AR/BC3)]. In each study over 60% of the patients had received therapeutic antiestrogens, and about one-fifth of these patients had an objective response. The megestrol acetate controlled study was double-blind; the other study was open label. Selected baseline characteristics for each study are shown in Table 16.

Table 16: Selected Study Population Demographics

Confirmed objective tumor response (complete response plus partial response) was the primary endpoint of the trials. Responses were measured according to the Union Internationale Contre le Cancer (UICC) criteria and verified by independent, blinded review. All responses were confirmed by a second evaluation 4 to 12 weeks after the documentation of the initial response.

Table 17 shows the results for the first trial (AR/BC2), with a minimum follow-up of 15 months that compared Femara 0.5 mg, Femara 2.5 mg, and megestrol acetate 160 mg daily (All analyses are unadjusted).

Table 17: Megestrol Acetate Study Results

*Two-sided P-value.

The Kaplan-Meier curves for progression for the megestrol acetate study are shown in Figure 4.

Figure 4: Kaplan-Meier Estimates of Time to Progression (Megestrol Acetate Study)

The results for the study comparing Femara to aminoglutethimide (AR/BC3), with a minimum follow-up of 9 months, are shown in Table 18 (Unadjusted analyses are used).

Table 18: Aminoglutethimide Study Results

*Two-sided P-value.

The Kaplan-Meier curves for progression for the aminoglutethimide study is shown in Figure 5.

Figure 5: Kaplan-Meier Estimates of Time to Progression (Aminoglutethimide Study)

16 HOW SUPPLIED/STORAGE AND HANDLING

Packaged in HDPE bottles with a safety screw cap.

2.5 mg tablets

     Bottles of 30 tablets...................................................................................NDC 0078-0249-15

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during Femara therapy and for at least 3 weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with Femara [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1, 8.3)].

Lactation

Advise women not to breastfeed during Femara treatment and for at least 3 weeks after the last dose [see Use in Specific Populations (8.2)].

Infertility

Advise females and males of reproductive potential of the potential for reduced fertility from Femara [see Use in Specific Populations (8.3)].

Fatigue and Dizziness

Since fatigue and dizziness have been observed with the use of Femara and somnolence was uncommonly reported, caution is advised when driving or using machinery [see Warnings and Precautions (5.4)].

Bone Effects

Consideration should be given to monitoring bone mineral density [see Warnings and Precautions (5.1)].

Distributed by:

Novartis Pharmaceuticals Corporation

East Hanover, New Jersey, 07936

© Novartis

T2020-51

PRINCIPAL DISPLAY PANEL

NDC 0078-0249-15

Femara®

(letrozole tablets)

2.5 mg per tablet

Rx only

30 Tablets

NOVARTIS

【备注】以上内容仅供参考，不作为用药依据，详情请参照药品附带说明书。