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。

警告：QT延长，毁伤点和突然死亡

CAPRELSA可以延长QT间隔。接受CAPRELSA的患者发生尖锐湿疣和猝死。低钙血症，低钾血症，低镁血症或长QT综合征患者请勿使用CAPRELSA。在服用CAPRELSA之前纠正低钙血症，低钾血症和/或低镁血症。定期监测电解质。避免使用已知会延长QT间隔的药物。只有开处方者和与所述受限分发程序认证的药房能够处方和分发CAPRELSA [ 见警告和注意事项（5.1，5.15） ]。

1适应症和用途

CAPRELSA适用于无法切除的局部晚期或转移性疾病患者的症状性或进行性甲状腺髓样癌的治疗。

仅在仔细考虑与CAPRELSA治疗相关的风险后，才可将CAPRELSA用于患有惰性，无症状或进展缓慢的疾病的患者。

2用法用量

CAPRELSA的推荐剂量是每天口服300 mg，直至疾病进展或出现不可接受的毒性。

CAPRELSA可以带或不带食物一起服用。

不要在下一次服药后的12小时内服药。

请勿粉碎CAPRELSA片剂。通过搅拌约10分钟，片剂可以分散在2盎司的水中（不会完全溶解）。请勿使用其他液体进行分散。分散后立即吞下。将所有剩余的残留物与4盎司额外的水混合并吞下。

分散体也可以通过鼻胃或胃造口术管给药。

2.1剂量调整

对于不良反应

每天300 mg的剂量可以降低至200 mg（两片100 mg片剂），然后针对3级或更常见的不良事件通用术语标准（CTCAE）降低至100 mg。

为以下中断CAPRELSA：

• 校正后的QT间隔，Fridericia（QTcF）大于500毫秒：当QTcF返回小于450毫秒时，以减少的剂量恢复。
• CTCAE 3级或更高毒性：当毒性分解或改善为CTCAE 1级时，以减少的剂量恢复。

对于复发毒性，如果需要继续治疗，则在解决或改善CTCAE 1级严重程度后，将CAPRELSA的剂量减少至100 mg。

由于具有19天的半衰期，因此不良反应（包括延长的QT间隔）可能无法迅速解决。适当监视[ 请参阅警告和注意事项（5.1），（5.2），（5.3），（5.4），（5.5），（5.6），（5.7）和（5.9） ]。

对于肾功能不全的患者

将中度（肌酐清除率≥30至<50 mL / min）和严重（肌酐清除率<30 mL / min）肾功能不全的患者的起始剂量降低至200 mg [ 请参阅警告和注意事项（5.12）和在特定人群中的使用（ 8.6） ]。

对于肝功能不全的患者

不建议将CAPRELSA用于中度和重度肝功能不全的患者[ 参见在特定人群中的使用（8.7） ]。

3剂型和强度

CAPRELSA 100毫克片剂为白色，圆形，双凸，薄膜包衣，在一侧凹有“ Z 100”，在背面凹有平纹。

CAPRELSA 300 mg片剂为白色，椭圆形，双凸，薄膜包衣，在一侧凹有“ Z 300”，在背面凹有平纹。

4禁忌症

先天性长QT综合征患者请勿使用[ 见盒装警告 ]。

5警告和注意事项

5.1 QT延长和尖尖的十字军

CAPRELSA可以以浓度依赖性的方式延长QT间隔[ 参见临床药理学（12.2） ]。CAPRELSA治疗的患者发生尖锐湿疣，室性心动过速和猝死。

QTcF间隔大于450 ms的患者不要开始CAPRELSA治疗。患有尖锐湿疣，先天性长QT综合征，缓慢性心律失常或无代偿性心力衰竭的患者，请勿服用CAPRELSA。CAPRELSA尚未在室性心律不齐或近期心肌梗死的患者中进行过研究。肾功能不全患者的Vandetanib暴露量增加。将中至重度肾功能不全患者的起始剂量降低至200 mg，并经常监测QT间隔。

在开始使用CAPRELSA治疗后2-4周和8-12周，以及之后每3个月，获取ECG和血清钾，钙，镁和TSH。腹泻患者应更频繁地监测电解质和心电图。为延长QT剂量而进行的任何剂量减少或超过2周的任何剂量中断后，均应按照上述方法进行QT评估。将血清钾水平维持在4 mEq / L或更高（在正常范围内），并将血清镁和钙水平维持在正常范围内，以降低QT延长的风险。

避免将CAPRELSA与已知会延长QT间隔的药物一起使用[ 参见警告和注意事项（5.11）和药物相互作用（7.4） ]。如果将此类药物给予已经接受CAPRELSA的患者，并且没有替代疗法，则应更频繁地对QT间隔进行ECG监测。

在QTcF大于500 ms的患者中停止CAPRELSA，直到QTcF恢复至小于450 ms。然后可以以减少的剂量重新开始CAPRELSA的给药[ 参见剂量和用法（2.1） ]。

5.2严重的皮肤反应

CAPRELSA治疗的患者发生了严重的，有时甚至是致命的皮肤反应，包括中毒性表皮坏死症（TEN）和史蒂文斯-约翰逊综合症。永久停用CAPRELSA以引起严重的皮肤反应，并请患者进行紧急医疗评估。可能需要全身性治疗，例如皮质类固醇。

在CAPRELSA治疗期间以及治疗终止后最多4个月内可能会发生光敏反应。

5.3间质性肺疾病

CAPRELSA治疗的患者发生了间质性肺疾病（ILD）或肺炎，包括死亡。考虑出现非特异性呼吸道体征和症状的患者的ILD诊断。

中断CAPRELSA治疗急性或恶化的肺部症状。如果确认了ILD，请中止CAPRELSA。

5.4缺血性脑血管事件

CAPRELSA治疗的患者发生了包括死亡在内的缺血性脑血管事件。在随机甲状腺髓样癌（MTC）研究中，与安慰剂相比，CAPRELSA发生缺血性脑血管事件的频率更高（1.3％比0％）。尚未研究解决缺血性脑血管事件后恢复CAPRELSA治疗的安全性。在发生严重缺血性脑血管事件的患者中停用CAPRELSA。

5.5出血

CAPRELSA治疗的患者发生了严重的出血事件，包括死亡。对于近期有咯血≥1/ 2茶匙红血病史的患者，请勿服用CAPRELSA。严重出血患者应停用CAPRELSA。

5.6心力衰竭

CAPRELSA治疗的患者发生心力衰竭，包括死亡。监测心力衰竭的体征和症状。考虑对心力衰竭患者停用CAPRELSA。停止使用CAPRELSA后，心力衰竭可能无法逆转。

5.7腹泻

在随机MTC研究中，接受CAPRELSA的患者中有11％发生3级或更高级别的腹泻。如果发生腹泻，请仔细监测血清电解质和心电图，以降低风险，并能及早发现因脱水而导致的QT延长[ 见警告和注意事项（5.1） ]。中断CAPRELSA治疗严重腹泻。改善后，以减少的剂量恢复CAPRELSA [ 参见剂量和用法（2.1） ]。

5.8甲状腺功能减退

在一项随机的MTC研究中，其中90％的患者曾接受过甲状腺切除术，与安慰剂治疗的患者相比，CAPRELSA治疗的患者中49％的患者需要增加甲状腺替代疗法的剂量。在开始使用CAPRELSA治疗后的2-4周和8-12周，在基线时以及之后每3个月获取促甲状腺激素（TSH）。如果出现甲状腺功能减退的体征或症状，请检查甲状腺激素水平并相应调整甲状腺替代疗法。

5.9高血压

CAPRELSA治疗的患者发生了高血压，包括高血压危机。监视所有患者的高血压。可能需要减少剂量或中断高血压治疗。如果无法控制高血压，请勿恢复CAPRELSA [ 参见剂量和用法（2.1） ]。

5.10可逆性后脑白质脑病综合征

CAPRELSA治疗的患者发生了可逆性后脑白质脑病综合征（RPLS），这是通过脑部MRI确诊的皮层下血管性水肿综合征。任何出现癫痫，头痛，视力障碍，精神错乱或精神功能改变的患者均应考虑该综合征。在临床研究中，在服用CAPRELSA时发生RPLS的四名患者中有三名也患有高血压。RPLS患者停止CAPRELSA治疗。

5.11药物相互作用

避免将CAPRELSA与抗心律不齐药物（包括但不限于胺碘酮，二吡酰胺，普鲁卡因酰胺，索他洛尔，多非利特）及其他可能延长QT间隔的药物（包括但不限于氯喹，克拉霉素，多拉西酮，格拉尼司琼，氟哌啶醇，美沙酮，莫西沙星和匹莫齐特[ 参见药物相互作用（7.4）和临床药理学（12.2） ]。

5.12肾功能不全

肾功能不全患者的Vandetanib暴露量增加。将中度至重度肾功能不全患者的起始剂量降低至200 mg，并密切监测QT间隔。对于需要透析的终末期肾病患者，没有可用的信息[ 请参见盒装警告，剂量和用法（2.1），在特定人群中使用（8.6）和临床药理学（12.3） ]。

5.13肝功能不全

不建议将CAPRELSA用于中度和重度肝功能不全的患者，因为尚未确定其安全性和有效性[ 参见剂量和给药方法（2.1） ]。

5.14胚胎-胎儿毒性

根据其作用机理，CAPRELSA对孕妇服用可引起胎儿伤害。在大鼠中，vandetanib具有等于​​或低于300 mg临床剂量的预期暴露量的胚胎毒性，胎儿毒性和诱发的胎儿畸形，并对雌性生育能力，幼仔的胚胎胎儿发育和产后发育产生不利影响。

建议妇女注意对胎儿的潜在危害。劝告有生殖潜力的妇女在用CAPRELSA治疗期间以及最后一次用药后至少4个月内使用有效的避孕药[见在特定人群中使用（8.1），（8.3） ]。

5.15 CAPRELSA REMS（风险评估和缓解策略）计划

由于存在延长QT的风险，尖尖的Torsades和突然死亡，CAPRELSA仅可通过称为CAPRELSA REMS程序的受限制发行程序获得。只有获得该计划认证的处方者和药房才能开具和分配CAPRELSA。

要了解特定的REMS要求并注册CAPRELSA REMS计划，请致电1-800-817-2722或访问www.caprelsarems.com。

6不良反应

标签上其他地方讨论了以下严重不良反应：

• QT延长和尖尖扭转症[ 见盒装警告，警告和注意事项（5.1） ]
• 严重的皮肤反应[ 请参阅警告和注意事项（5.2） ]
• 间质性肺疾病[ 见警告和注意事项（5.3） ]
• 缺血性脑血管事件[ 请参阅警告和注意事项（5.4） ]
• 出血[ 请参阅警告和注意事项（5.5） ]
• 心力衰竭[ 请参阅警告和注意事项（5.6） ]
• 腹泻[ 请参阅警告和注意事项（5.7） ]
• 甲状腺功能低下[ 请参阅警告和注意事项（5.8） ]
• 高血压[ 请参阅警告和注意事项（5.9） ]
• 可逆性后脑白质脑病综合征[ 请参阅警告和注意事项（5.10） ]
• 胚胎-胎儿毒性[ 请参阅警告和注意事项（5.14） ]

6.1临床试验经验

由于临床试验是在广泛不同的条件下进行的，因此无法将在某种药物的临床试验中观察到的不良反应率直接与另一种药物的临床试验中观察到的不良反应率进行比较，并且可能无法反映实际中观察到的不良反应率。

不可切除的局部晚期或转移性甲状腺髓样癌患者接受CAPRELSA 300 mg（n = 231）或安慰剂（n = 99）治疗。接触CAPRELSA的人口是58％的男性，94％的白人，中位年龄为50岁。下述数据反映了CAPRELSA暴露607天的中位数。

据报道，最常见的药物不良反应发生在> 20％的CAPRELSA治疗患者中，且臂间差异≥5％，按发生频率递减的顺序出现：腹泻/结肠炎，皮疹，痤疮样皮炎，高血压，恶心，头痛，上呼吸道感染，食欲下降和腹痛。

在接受CAPRELSA治疗的患者中，有109例（47％）发生剂量中断，有83例（36％）发生剂量减少。不良反应导致231例接受CAPRELSA的患者中有28例（12％）停止研究治疗，而接受安慰剂的99例患者中有3例（3.0％）导致研究治疗中断。CAPRELSA治疗导致2个或更多（≥0.9％）患者永久停药的不良反应为：乏力（1.7％），皮疹（1.7％），腹泻（0.9％），疲劳（0.9％），发热（0.9％） ，肌酐升高（0.9％），QT延长（0.9％）和高血压（0.9％）。

表1：在CAPRELSA治疗的患者中，随机治疗期间发生较高发生率的某些不良反应的患者平均发生率（臂间差异≥5％[所有等级] *）

在接受CAPRELSA治疗的患者与接受安慰剂治疗的患者中，临床上重要的罕见药物不良反应包括胰腺炎（0.4％vs. 0％）和心力衰竭（0.9％vs. 0％）。

与接受甲状腺髓样癌的安慰剂患者相比，接受CAPRELSA的患者视力模糊更常见（分别为9％和1％）。预定的裂隙灯检查显示接受治疗的患者的角膜混浊（涡状角膜病），可能导致光晕和视力下降。对报告视觉改变的患者进行眼科检查，包括裂隙灯检查。

类效果

CAPRELSA是血管内皮生长因子受体（VEGFR）信号的抑制剂。抑制VEGFR信号传导可导致肠穿孔。0.4％CAPRELSA治疗的患者发生肠穿孔，而安慰剂治疗患者为0％。

接受CAPRELSA治疗的患者发生1-2级出血事件的发生率为14％，而甲状腺髓样癌（MTC）研究的随机部分中安慰剂为7％。

表2：经CAPRELSA治疗的患者中发生率较高的MTC患者中某些实验室异常的平均患者发生率（臂间差异≥5％[所有等级] *）

在MTC研究中，没有ALT升高3至4级的患者伴随胆红素升高。

7药物相互作用

7.1 CYP3A4诱导剂对CAPRELSA的影响

利福平，一种强CYP3A4诱导剂，降低vandetanib的血浆浓度。在CAPRELSA治疗期间避免同时使用已知的强CYP3A4强诱导剂。避免同时使用圣约翰草，因为它会不可预测地减少vandetanib的暴露[ 见临床药理学（12.3） ]。

7.2 CAPRELSA对OCT2转运蛋白的影响

CAPRELSA增加了由2型有机阳离子转运蛋白（OCT2）转运的二甲双胍的血浆浓度。与OCREL2一起运输的药物一起使用CAPRELSA时，请务必谨慎并密切监测其毒性[ 参见临床药理学（12.3） ]。

7.3 CAPRELSA对地高辛的作用

CAPRELSA增加了地高辛的血浆浓度。与地高辛一起使用CAPRELSA时要谨慎并密切监测其毒性[ 参见临床药理学（12.3） ]。

7.4延长QT间隔的药物

避免将CAPRELSA与可能延长QT间隔的药物同时使用[ 请参阅警告和注意事项（5.11） ]。

8在特定人群中的使用

8.1怀孕

风险摘要

根据其作用机理，CAPRELSA对孕妇服用可引起胎儿伤害。Vandetanib对大鼠的胚胎毒性，胎儿毒性和诱发的胎儿畸形，其暴露量小于或等于建议的人类300 mg /天的预期暴露量。建议孕妇注意胎儿的潜在危险。

在美国普通人群中，临床公认的怀孕中主要先天缺陷和流产的估计背景风险分别为2％至4％和15％至20％。

动物数据

在生殖毒性研究中，凡德他尼在交配前和妊娠第一周以25 mg / kg /天的剂量（根据C max大约等于人体在300 mg临床剂量下的暴露量）向雌性大鼠给药，植入前和植入后的损失增加，导致活胚数量减少。

在器官发生过程中，vandetanib导致植入后损失增加，包括偶尔以25 mg / kg / day的剂量产生总的凋落物损失。凡德他尼以大于10 mg / kg /天的剂量（约为300 mg临床剂量的人C max的 0.4倍）治疗导致晚期胚胎胎儿死亡增加和胎儿出生体重减少。这项研究未发现畸形的无效水平。的给药凡德他尼的人C在剂量大于或等于1毫克/公斤/天（约0.03倍最大 在300毫克的临床剂量下）导致血管畸形和骨骼变化的剂量依赖性增加，包括颅骨，椎骨和胸骨的骨化延迟，表明胎儿发育延迟。

在一项大鼠产前和产后发育研究中，凡德他尼在妊娠和/或哺乳期间产生轻度母体毒性的剂量（1和10 mg / kg /天），降低了幼鼠的存活率并降低了产后幼鼠的生长。出生后幼崽生长的减少与身体发育的延迟有关。

8.2哺乳

没有关于人乳中存在vandetanib或其代谢产物或vandetanib对母乳喂养的孩子或产奶量的影响的数据。Vandetanib存在于哺乳期大鼠的乳汁中（见数据）。由于在母乳喂养的儿童中CAPRELSA可能引起严重的不良反应，因此建议女性在CAPRELSA治疗期间和最终剂量后的4个月内不要母乳喂养。

数据

动物数据

在非临床研究中，vandetanib在给哺乳大鼠给药后从大鼠乳汁中排出，并在幼犬血浆中发现。由于该药物的半衰期较长，因此将Vandetanib转移至母乳中可导致幼仔相对恒定的暴露。

8.3生殖潜力的男性和女性

验孕

在开始使用CAPRELSA治疗之前，请验证具有生殖潜能的女性的妊娠状况[请参见在特定人群中使用（8.1） ]。

避孕

对孕妇服用CAPRELSA可能会造成胎儿伤害[见在特定人群中使用（8.1） ]。

女性

劝告有生殖潜力的女性在用CAPRELSA治疗期间和最终剂量后4个月内使用有效的避孕方法。

不孕症

没有关于CAPRELSA对人类生育力影响的数据。动物研究结果表明，凡德他尼可损害男性和女性的生育能力[见非临床毒理学（13.1） ]。

8.4小儿使用

CAPRELSA在儿科患者中的安全性和有效性尚未确定。

8.5老年人使用

CAPRELSA的MTC研究没有包括足够多的65岁及以上的患者，以确定他们与年轻患者相比是否有不同的反应。

8.6肾功能不全

肾功能不全患者的Vandetanib暴露量增加。将中度（肌酐清除率≥30至<50 mL / min）和严重（肌酐清除率<30 mL / min）肾功能不全的患者的起始剂量降低至200 mg [ 参见剂量和用法（2.1），警告和注意事项（5.12））和临床药理学（12.3） ]。

8.7肝功能不全

在轻度（n = 8），中度（n = 7）和重度（n = 6）肝功能不全（n = 5）的受试者中，单次服用800 mg后评估CAPRELSA的药代动力学。轻度（Child-Pugh A级），中度（Child-Pugh B级）和重度（Child-Pugh C级）肝功能不全的受试者的平均AUC和清除率值与正常肝功能的受试者相当。

肝功能不全患者（血清胆红素大于正常上限的1.5倍）的数据有限。不建议将CAPRELSA用于中度和重度肝功能不全的患者，因为尚未确定其安全性和有效性[ 参见剂量和用法（2.1）和警告和注意事项（5.13） ]。

10过量

如果用药过量，请密切监测患者的QTc延长时间。由于有19天的半衰期，因此不良反应可能无法迅速解决。

11说明

Vandetanib的化学名称为N-（4-溴-2-氟苯基）-6-甲氧基-7-[（1-甲基哌啶-4-基）甲氧基]喹唑啉-4-胺。

结构和分子式为：

C 22 H 24 BrFN 4 O 2

Vandetanib的分子量为475.36。Vandetanib表现出pH依赖性溶解度，在较低pH值下溶解度增加。Vandetanib实际上在25°C（77°F）下不溶于水，其值为0.008 mg / mL。

每日口服的CAPRELSA片剂有两种剂量强度，分别含有100 mg或300 mg vandetanib。片剂芯包含以下非活性成分：磷酸氢钙二水合物，微晶纤维素，交聚维酮，聚维酮和硬脂酸镁。片剂薄膜衣包含以下非活性成分：羟丙甲纤维素2910，聚乙二醇300和二氧化钛E171。

12临床药理学

12.1行动机制

体外研究表明，vandetanib可抑制EGFR和VEGFR家族，RET，BRK，TIE2以及EPH受体和Src激酶家族成员的酪氨酸激酶活性。这些受体酪氨酸激酶参与正常的细胞功能和病理过程，例如肿瘤发生，转移，肿瘤血管生成和肿瘤微环境的维持。此外，该药物的N-去甲基代谢产物占vandetanib暴露的7-17％，对母体化合物的VEGF受体（KDR和Flt-1）和EGFR具有相似的抑制活性。

在体外，vandetanib抑制肿瘤细胞和内皮细胞中表皮生长因子（EGF）刺激的受体酪氨酸激酶磷酸化以及内皮细胞中VEGF刺激的酪氨酸激酶磷酸化。

在体内，vandetanib给药可减少肿瘤细胞诱导的血管生成，肿瘤血管通透性并抑制肿瘤小鼠模型中的肿瘤生长和转移。

12.2药效学

心脏电生理学

在3期临床试验中，在231例甲状腺髓样癌患者中随机接受CAPRELSA 300 mg每天一次。CAPRELSA与持续血浆浓度依赖性QT延长有关。根据暴露-反应关系，对于300 mg剂量，相对于基线（ΔQTcF）的平均（90％CI）QTcF变化为35（33-36）ms。在试验期间（长达2年），ΔQTcF保持在30 ms以上。另外，36％的患者的ΔQTcF升高超过60 ms，而4.3％的患者的QTcF大于500 ms。曾发生过尖尖的扭转性反倾销案件和猝死[ 见盒装警告和警告与注意事项（5.1），（5.11） ]。

12.3药代动力学

每天口服300 mg后，对231名MTC患者进行了CAPRELSA的群体药代动力学分析。CAPRELSA在300 mg剂量下在MTC患者中的药代动力学的特征是平均清除率约为13.2 L / h，平均分布体积约为7450 L，平均血浆半衰期为19天。

吸收性

口服CAPRELSA后，吸收缓慢，在给药后通常在6小时的中值达到峰值血浆浓度，范围为4-10小时。Vandetanib多次给药累积约8倍，并在约3个月内达到稳定状态。

凡德他尼暴露不受食物影响

分配

Vandetanib结合人血清白蛋白和α1-酸-糖蛋白，体外蛋白结合率约为90％。在每天一次300 mg的稳态暴露下，来自结直肠癌患者的离体血浆样品中，蛋白质结合的平均百分比为94％。

代谢

以下的口服给药14 C- 凡德他尼，不变凡德他尼和代谢物凡德他尼 N-氧化物和N-去甲基凡德他尼在血浆，尿和粪便中检测到。葡糖醛酸苷共轭物仅在排泄物中被视为次要代谢物。N-去甲基vandetanib主要由CYP3A4和vandetanib -N-氧化物通过含有黄素的单加氧酶FMO1和FMO3产生。的N- desmethyl- 凡德他尼和凡德他尼 -N -氧化物循环分别约为7-17％和1.4-2.2％的浓度，这些的凡德他尼。

排泄

在单剂14 C- vandetanib后的21天收集期内，大约回收了69％，粪便中回收了44％，尿液中回收了25％。剂量的排泄很慢，基于血浆半衰期，预计将排泄超过21天。

Vandetanib不是在HEK293细胞中表达的hOCT2的底物。Vandetanib抑制HEK-OCT2细胞摄取选择性OCT2标记底物14 C-肌酸酐，平均IC 50为2.1μg / mL。这高于在300 mg多次给药后观察到的vandetanib血浆浓度（0.81μg/ mL）。vandetanib抑制肌酐的肾脏排泄，为接受vandetanib的人类受试者血浆肌酐增加提供了解释。

特定人群

年龄和性别的影响

在癌症患者的群体药代动力学评估中，vandetanib的口服清除率与患者年龄或性别之间没有明显的关系。

种族

根据有限数量患者的交叉研究比较，日本人（N = 3）和中国人（N = 7）患者接受相同剂量CAPRELSA 的vandetanib平均暴露量高于白种人（N = 7）患者。

小儿科

Vandetanib的药代动力学尚未在儿科患者中进行评估。

肾功能不全的影响

在六个轻度（肌酐清除率= 50至<80 mL / min）受试者，八个中度（肌酐清除率≥30至<50 mL / min）受试者，800名单剂量CAPRELSA剂量后，评估了vandetanib的药代动力学患有严重（肌酐清除率<30 mL / min）肾功能不全的受试者和十名肾功能正常（肌酐清除率> 80 mL / min）的受试者。轻度肾功能不全的受试者的vandetanib平均AUC 与肾功能正常的受试者相当。与肾功能正常的患者相比，在中度或重度肾功能不全的受试者中，vandetanib的平均AUC分别增加了39％和41％[ 参见剂量和给药方法（2.1），警告和注意事项（5.12）和在特定人群中的使用（8.6） ]。

药物相互作用

其他药物对CAPRELSA的影响

强大的CYP3A4诱导剂：在一项针对12名健康志愿者的交叉研究中，在第1天和第10天单独口服300 mg CAPRELSA口服，并与每日剂量的600 mg利福平（一种强CYP3A4诱导剂）合用在第1至31天。与CAPRELSA利福平的联合给药减少几何平均AUC 0-504h的凡德他尼相比：40％（56％，63％90％置信区间（CI））凡德他尼单独。没有观察到vandetanib的平均C max有临床意义的变化。N-去甲基vandetanib的几何平均AUC 0–504h和C max与单独使用vandetanib相比，在存在利福平的情况下分别增加了266％和414％[ 参见药物相互作用（7.1） ]。

强效CYP3A4抑制剂：在一项针对14位健康志愿者的交叉研究中，在第1天单独口服口服300 mg剂量的CAPRELSA，并在第4天与第1天每天联合服用200 mg的伊曲康唑（一种强CYP3A4抑制剂）。 –24。将伊曲康唑与CAPRELSA并用时，vandetanib的几何平均AUC 0-504h或C max无变化。

胃pH升高剂：在一项针对14位健康志愿者的交叉研究中，单独口服一次口服300 mg CAPRELSA，并与五种每日剂量的40 mg奥美拉唑（质子泵抑制剂）联用。奥美拉唑与CAPRELSA并用时，vandetanib的几何平均AUC 0–504h和C max没有观察到临床意义的变化。

在对16位健康志愿者的交叉研究中，单独口服300 mg CAPRELSA口服，两次口服150 mg雷尼替丁（H 2受体拮抗剂）约间隔12小时。雷尼替丁与CAPRELSA并用时，vandetanib的几何平均AUC 0-504h和C max无变化。

CAPRELSA对其他药物的影响

敏感的CYP3A4底物：在对16位健康志愿者的交叉研究中，单独口服一次7.5毫克剂量的咪达唑仑（作为2毫克/毫升口服糖浆），一种敏感的CYP3A4底物，在接受单次800毫克后8天CAPRELSA的口服剂量。当CAPRELSA与咪达唑仑同时使用时，咪达唑仑的几何平均C max和AUC inf没有变化。

OCT2转运蛋白的底物：在一项针对13名健康志愿者的交叉研究中，口服1000毫克二甲双胍（OCT2的底物）单次口服，口服800 mg CAPRELSA后3小时。CAPRELSA与二甲双胍的共同给药使二甲双胍的几何平均AUC inf增加了74％（90％CI：58％，92％）和二甲双胍的几何平均C max增加了50％（90％CI：34％，67％）单独使用二甲双胍[ 参见药物相互作用（7.2） ]。

P-糖蛋白转运蛋白的底物：在一项针对14位健康志愿者的交叉研究中，单独口服0.25 mg的地高辛（一种P-糖蛋白的底物）与300 mg CAPRELSA口服一起服用。CAPRELSA的共同给药可使地高辛的几何平均C max增加29％（90％CI：10％，52％），地高辛的AUC 0–t几何平均增加23％（90％CI：12％，34％）与单独使用地高辛相比[ 见药物相互作用（7.3） ]。

13毒理学

13.1致癌，诱变，生育力受损

在一项为期2年的大鼠Vandetanib研究中，当每天以高达10 mg / kg的剂量（在300 mg临床剂量下的人C max的 0.7倍）进行口服灌胃给药时，或在Tg∙RasH2小鼠中给药时，则不会致癌通过每日口服管饲以最大30 mg / kg 的剂量（在300 mg的临床剂量下为人C max的 5倍）给药26周。Vandetanib在细菌反向突变（Ames）分析中在体外没有致突变性，在使用人淋巴细胞的体外细胞遗传学分析中或在体内大鼠微核试验中均无致突变性。

根据非临床发现，CAPRELSA治疗可能会损害男性和女性的生育能力。在雄性大鼠的生育力研究中，当未治疗的雌性与雄性每天，分别接受1、5、20 mg / kg / day的vandetanib交配时，vandetanib对交配或生育率没有影响（分别约为0.03、0.22或0.40倍，根据300 mg临床剂量的癌症患者的曲线下面积（AUC）计算的人体暴露量）; 但是，在同一项研究中，以20 mg / kg /天的剂量水平与雄性交配的雌性与雄性交配的雌性活胚数略有减少，而与雄性交配Vandetanib的雌性则在植入前损失增加剂量≥5mg / kg /天。在一项女性生育力研究中，有发情周期不规则性增加，妊娠率略有下降和着床率增加的趋势。在一项为期一个月的大鼠重复剂量毒性研究中，凡德他尼剂量为75 mg / kg /天的大鼠卵巢中的黄体数量减少了（约为300 mg临床上基于AUC的人暴露量的1.8倍）剂量）。

13.2动物毒理学和/或药理学

在伤口愈合的动物模型中，与对照组相比，服用vandetanib的小鼠的皮肤断裂强度降低。这表明CAPRELSA减慢但不能阻止伤口愈合。为避免伤口愈合不良的风险，CAPRELSA停药与随后的择期手术之间的适当间隔尚未确定。

14临床研究

一项双盲，安慰剂对照研究（研究D4200C00058，NCT00410761）将不可切除的局部晚期或转移性甲状腺髓样癌患者随机分为CAPRELSA 300 mg（n = 231）和安慰剂（n = 100）。

与安慰剂相比，CAPRELSA的主要疗效结局指标是无进展生存期（PFS）。其他功效结局指标包括总体生存率（OS）和总体客观反应率（ORR）评估。对PFS和ORR的评估使用了集中的，独立的成像数据盲检查。根据研究者的评估得出的客观疾病进展后，患者不再接受盲法研究治疗，可以选择接受开放标签的CAPRELSA。最初随机分配至CAPRELSA的患者中有47％（109/231）在疾病进展后选择接受开放标签的CAPRELSA，而最初随机分配给安慰剂的患者中有79％（79/100）的患者选择了在疾病进展后接受开放标签的CAPRELSA疾病进展。

基于中央回顾RECIST评估的PFS分析结果显示，随机分组至CAPRELSA的患者的PFS有统计学显着改善（危险比（HR）= 0.35; 95％可信区间（CI）= 0.24-0.53; p < 0.001）。有症状或入组前6个月内进展的患者亚组的PFS结果相似（有症状的患者HR = 0.31 95％CI：0.19，0.53;有症状的HR = 0.41 95％CI：0.25，0.66在注册之前的6个月内取得了进步的人）。两个治疗组的最终OS中位数相似。

随机分配给CAPRELSA的患者的总体客观缓解率（ORR）为44％，而随机分配给安慰剂的患者为1％。所有客观回应均为部分回应。

图1：研究D4200C00058中无进展生存的Kaplan-Meier曲线

表3：研究D4200C00058中的功效结果

15参考

1. OSHA危险药物（OSHA技术手册）。OSHA。

16供应/存储和处理方式

100 mg片剂装在装有30片的瓶子中（NDC 58468-7820-3）。

300毫克片剂装在装有30片的瓶子中（NDC 58468-7840-3）。

16.1储存和处理

CAPRELSA片剂应存储在25°C（77°F）下；允许在15°C–30°C（59°F–86°F）范围内进行偏移[请参阅USP控制的室温]。

应考虑正确处理和处置抗癌药物的程序。有关此主题的指南已发布。1不要压碎CAPRELSA片剂。

17患者咨询信息

建议患者阅读FDA批准的患者标签（用药指南）。

QT延长和尖尖的十字军

建议患者出现晕厥，晕厥前症状和心时联系其医疗保健提供者。告知患者，他们的医护人员应在治疗过程中监测其电解质和心电图[ 见警告和注意事项（5.1） ]。

严重的皮肤反应

建议患者在发生皮肤反应或出疹子时联系其医疗保健提供者[ 请参阅警告和注意事项（5.2） ]。

间质性肺疾病（ILD）

建议患者在突然发作或呼吸困难，持续咳嗽或发烧加剧时联系其医疗保健提供者[ 见警告和注意事项（5.3） ]。

腹泻

建议患者出现腹泻时联系其医疗保健提供者[ 请参阅警告和注意事项（5.7） ]。

可逆性后脑白质脑病综合征（RPLS）

建议患者发生癫痫，头痛，视力障碍，意识模糊或思维困难时与他们的医护人员联系[ 请参阅警告和注意事项（5.10） ]。

胚胎-胎儿毒性

劝告有生殖潜力的女性在使用CAPRELSA治疗期间以及最后一次用药后4个月内使用有效的避孕方法。建议女性在使用CAPRELSA治疗期间怀孕或怀疑怀孕时联系其医疗保健提供者[请参见在特定人群中使用（8.1），（8.3） ]。

哺乳期

劝告妇女在用CAPRELSA治疗期间以及末次给药后4个月内不要母乳喂养[见在特定人群中使用（8.2） ]。

光敏性

由于服用CAPRELSA期间和停药后至少4个月对日晒的敏感性增加，建议患者使用适当的防晒措施[见警告和注意事项（5.2） ]。

管理

告知患者CAPRELSA可以带或不带食物一起服用，并且不要压碎CAPRELSA片剂[见临床药理学（12.3） ]。

发行：
Genzyme Corporation
剑桥，马萨诸塞州02142

CAPRELSA是Genzyme Corporation的注册商标
©2018 Genzyme Corporation。

用药指南

CAPRELSA ®（KAP-REL-SAH）
（凡德他尼）
片

在开始服用CAPRELSA之前以及每次补充时，请阅读本《用药指南》。可能有新的信息。本用药指南不能代替您的医疗保健提供者谈论您的医疗状况或治疗。

关于CAPRELSA，我应该了解的最重要信息是什么？

CAPRELSA会导致心脏电活动的改变，称为QT延长，这可能会导致心律不齐，甚至导致死亡。如果您自出生以来就患有长期QT综合征，就不应服用CAPRELSA。

您的医疗服务提供者应执行一项检查，以检查您的血钾，钙，镁和促甲状腺激素（TSH）的水平，以及通过称为心电图（ECG）的检查来检查心脏的电活动。您应该进行以下测试：

• 在开始CAPRELSA之前
• 在CAPRELSA治疗期间定期进行：
• 开始CAPRELSA后2至4周
• 开始CAPRELSA后8到12周
• 此后每3个月
• 如果您的医疗保健提供者更改了您的CAPRELSA剂量
• 如果您开始服用会导致QT延长的药物
• 按照您的医疗保健提供者的指示

如果您的QT延长，您的医疗服务提供者可能会暂停您的CAPRELSA治疗一段时间，然后以较低的剂量重新开始。

如果在服用CAPRELSA时感到头晕，晕眩或心脏不规则跳动，请立即致电您的医疗保健提供者。这些可能是与QT延长有关的症状。

什么是CAPRELSA？

CAPRELSA是用于治疗甲状腺髓样癌的处方药，该甲状腺癌无法通过手术切除或已经扩散到身体的其他部位。从体内清除CAPRELSA需要很长时间，停止治疗后，您可能有与CAPRELSA相关的副作用的风险。

尚不知道CAPRELSA在儿童中是否安全有效。

谁不应该服用CAPRELSA？

如果您有QT延长期，请勿服用CAPRELSA。

在服用CAPRELSA之前，我应该告诉我的医疗保健提供者什么？

在服用CAPRELSA之前，请告知您的医疗保健提供者是否：

• 有任何心脏问题，包括先天性长QT综合征
• 心律不齐
• 服用或已经停止服用导致QT延长的药物
• 血液中钾，钙或镁含量低
• 血液中的促甲状腺激素水平高
• 有高血压
• 有皮肤问题
• 有呼吸困难的病史
• 最近有咳嗽或出血的病史
• 腹泻
• 有肝脏问题
• 有肾脏问题
• 癫痫发作或正在接受癫痫治疗
• 正在怀孕或打算怀孕。CAPRELSA可能会对未出生的婴儿造成伤害。如果您怀孕或计划怀孕，请与您的医疗保健提供者联系。
• 如果您能够怀孕，则应在使用CAPRELSA治疗期间以及最后一次服用CAPRELSA后至少4个月内使用有效的节育措施。
• 与您的医疗保健提供者谈谈在服用CAPRELSA时采取避孕措施以防止怀孕的方法。
• 正在母乳喂养或计划母乳喂养。不知道CAPRELSA是否会进入母乳。您和您的医疗保健提供者应决定是否要服用CAPRELSA或母乳喂养。您不应该两者都做。

告知您的医疗保健提供者您所服用的所有药物，包括处方药和非处方药，维生素和草药补品。CAPRELSA和其他药物可能互相影响，引起副作用。

尤其要告诉您的医疗保健提供者是否服用：

• 圣约翰草。服用CAPRELSA时，请勿服用圣约翰草
• 某些会影响肝脏分解药物的药物
• 心脏药

询问您的医疗保健提供者，如果您不确定您的药物是否上面列出的一种。

除非您已与医疗保健提供者或药剂师进行过交谈，否则在服用CAPRELSA时请勿服用其他药物。

知道你吃的药。保留一份清单，以在您购买新药时向您的医疗保健提供者和药剂师显示。

我应该如何服用CAPRELSA？

• 完全按照医护人员的指示服用CAPRELSA。除非您的医疗保健提供者告诉您，否则请勿更改剂量或停止服用CAPRELSA。
• CAPRELSA可以带或不带食物一起服用。
• 用水吞服CAPRELSA片剂。
• 请勿压碎或咀嚼CAPRELSA片剂。如果CAPRELSA片剂不小心被压碎，则应避免与皮肤接触。如果发生接触，请用水冲洗受影响的区域。
• 如果您不能完全吞服CAPRELSA片剂：
• 将您的CAPRELSA剂量放在装有2盎司非碳酸水的玻璃杯中（不要使用其他液体）。
• 将CAPRELSA片剂和水的混合物搅拌约10分钟，或者直到片剂非常细小为止（片剂不会完全溶解）。
• 立即吞下CAPRELSA和水的混合物。
• 如果玻璃杯中残留有CAPRELSA和水的混合物，请再与4盎司的非碳酸水混合，然后吞下混合物，以确保您服用了全部剂量的CAPRELSA。
• 如果您错过剂量而您的下一个剂量是：
• 少于12小时，请在正常时间服用下一剂。不要弥补错过的剂量。
• 12小时或更长时间，请记住就立即服用错过的剂量。在正常时间服用下一剂。

如果您服用过多的CAPRELSA，请立即致电您的医疗保健提供者。

• 在使用CAPRELSA治疗期间，您的医疗保健提供者应检查您的血液和心脏是否有副作用。请参阅“ 关于CAPRELSA，我应该了解的最重要的信息是什么？ ”
• 您的医疗服务提供者应在使用CAPRELSA治疗期间定期检查您的血压。

服用CAPRELSA时应避免什么？

• 限制暴露在阳光下。CAPRELSA可以使您的皮肤对阳光敏感。在服用CAPRELSA的同时，以及停止CAPRELSA治疗后的4个月，请使用防晒霜，并在户外穿覆盖皮肤的衣服，包括头部，手臂和腿。
• 驾驶或使用机械之前，请务必小心。请记住，CAPRELSA可能会使您感到疲倦，虚弱或导致视力模糊。

CAPRELSA可能有哪些副作用？

CAPRELSA可能引起严重的副作用，包括：

• 请参阅“ 关于CAPRELSA，我应该了解的最重要的信息是什么？ ”
• 严重的皮肤反应。CAPRELSA可能引起严重的皮肤反应，例如中毒性表皮坏死溶解和史蒂文斯-约翰逊综合症，或其他可能影响身体任何部位的严重皮肤反应。这些严重的皮肤反应可能会危及生命，您可能需要在医院接受治疗。如果您遇到任何这些症状，请立即致电您的医疗保健提供者。
• 皮疹或痤疮
• 皮肤干燥
• 发痒
• 皮肤上出现水泡
• 口腔有水泡或疮
• 皮肤脱皮
• 发热
• 肌肉或关节疼痛
• 脸，手或脚底发红或肿胀
• 呼吸问题（间质性肺疾病）。CAPRELSA可能引起称为间质性肺病的呼吸问题，并可能导致死亡。如果您遇到呼吸急促或咳嗽突然或恶化的情况，请立即告知您的医疗保健提供者。
• 行程。据报道，一些服用CAPRELSA的人发生中风，并在某些情况下导致死亡。如果您患有中风症状，请停止服用CAPRELSA，并立即致电您的医疗保健提供者，包括：
• 面部，手臂或腿部麻木或虚弱，尤其是身体的一侧
• 突然的混乱，说话或理解上的麻烦
• 一只或两只眼睛突然出现麻烦
• 突然的行走困难，头晕，失去平衡或失去协调
• 突然严重头痛
• 流血的。使用CAPRELSA治疗期间可能会流血。如果您服用CAPRELSA时有严重出血，请立即告知您的医疗服务提供者。
• 心脏衰竭。CAPRELSA可能导致心力衰竭，甚至导致死亡。如果您患有心力衰竭，可能必须停止服用CAPRELSA。停止CAPRELSA后，心力衰竭可能无法逆转。您的医疗保健提供者应监视您是否有心力衰竭的体征和症状。
• 腹泻。腹泻通常是甲状腺髓样癌的症状。CAPRELSA也可能引起腹泻或使腹泻恶化。如果腹泻，您的医疗保健提供者应检查您的血液水平以更频繁地监测电解质。
• 甲状腺激素。服用CAPRELSA可能会改变甲状腺激素。您的医疗保健提供者应在服用CAPRELSA时监测您的甲状腺激素水平。
• 高血压（高血压）。如果您出现高血压或高血压恶化，您的医疗保健提供者可能会降低您的CAPRELSA剂量或告诉您停止服用CAPRELSA，直到您的血压得到控制。您的医疗保健提供者可能开了另一种药物来控制您的高血压。
• 可逆性后脑白质脑病综合征（RPLS）。服用CAPRELSA可能会发生一种称为可逆性后脑白质脑病综合征的疾病。如果您有以下情况，请立即致电您的医疗保健提供者：
• 头疼
• 癫痫发作
• 混乱
• 视力改变
• 问题思考

CAPRELSA最常见的副作用包括：

• 腹泻
• 皮疹
• 粉刺
• 恶心
• 高血压
• 头痛
• 感觉累了
• 食欲不振
• 上呼吸道感染
• 胃（腹部）疼痛

告诉您的医疗保健提供者，如果您有任何困扰您或不会消失的副作用。

这些并非CAPRELSA的所有可能的副作用。有关更多信息，请咨询您的医疗保健提供者或药剂师。

打电话给您的医生，征求有关副作用的医疗建议。您可以通过1-800-FDA-1088向FDA报告副作用。

我应该如何存储CAPRELSA？

• 将CAPRELSA片剂存放在59°F至86°F（15°C至30°C）下。
• 安全地丢弃过期或不再需要的药物。询问您的药剂师如何安全丢弃CAPRELSA片剂。

将CAPRELSA和所有药物放在儿童接触不到的地方。

有关CAPRELSA的一般信息。

有时出于药物指南中列出的目的以外的目的开出药物。请勿在没有规定的条件下使用CAPRELSA。即使他人有与您相同的症状，也请勿将CAPRELSA给予他人。可能会伤害他们。

本药物指南总结了有关CAPRELSA的重要信息。如果您需要更多信息，请与您的医疗保健提供者联系。您可以询问您的医疗保健提供者或药剂师以了解有关为医疗专业人员编写的CAPRELSA的信息。

有关更多信息，请访问www.caprelsa.com或致电1-800-817-2722。

CAPRELSA中的成分是什么？

有效成分：vandetanib

非活性成分：

• 片剂核心：磷酸氢钙二水合物，微晶纤维素，交聚维酮，聚维酮和硬脂酸镁
• 平板电脑薄膜衣：羟丙甲纤维素2910，聚乙二醇300和二氧化钛E171

本药物指南已获得美国食品和药物管理局的批准。

分配者：

Sanofi Genzyme
剑桥，MA 02142

发行12/2016
CAPRELSA是Genzyme Corporation的注册商标
©Genzyme Corporation2016。保留所有权利。

主要显示面板-100毫克片剂瓶纸箱

NDC 58468-7820-3

Caprelsa ®
（凡德他尼）片剂

100毫克

仅Rx

无需
为每位患者提供随附的用药指南。

30片

主要显示面板-300毫克片剂瓶纸箱

NDC 58468-7840-3

Caprelsa ®
（凡德他尼）片剂

300毫克

仅Rx

无需
为每位患者提供随附的用药指南。

30片

【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/e5721cb8-4185-47b9-bbb3-1c587e558a03/spl-doc?hl=Vandetanib

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。

WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH

CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients receiving CAPRELSA. Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to CAPRELSA administration. Monitor electrolytes periodically. Avoid drugs known to prolong the QT interval. Only prescribers and pharmacies certified with the restricted distribution program are able to prescribe and dispense CAPRELSA [see Warnings and Precautions (5.1, 5.15)].

1 INDICATIONS AND USAGE

CAPRELSA is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

Use CAPRELSA in patients with indolent, asymptomatic or slowly progressing disease only after careful consideration of the treatment related risks of CAPRELSA.

2 DOSAGE AND ADMINISTRATION

The recommended dose of CAPRELSA is 300 mg taken orally once daily until disease progression or unacceptable toxicity occurs.

CAPRELSA may be taken with or without food.

Do not take a missed dose within 12 hours of the next dose.

Do not crush CAPRELSA tablets. The tablets can be dispersed in 2 ounces of water by stirring for approximately 10 minutes (will not completely dissolve). Do not use other liquids for dispersion. Swallow immediately after dispersion. Mix any remaining residue with 4 additional ounces of water and swallow.

The dispersion can also be administered through nasogastric or gastrostomy tubes.

2.1 Dosage Adjustment

For Adverse Reactions

The 300 mg daily dose can be reduced to 200 mg (two 100 mg tablets) and then to 100 mg for Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or greater toxicities.

Interrupt CAPRELSA for the following:

• Corrected QT interval, Fridericia (QTcF) greater than 500 ms: Resume at a reduced dose when the QTcF returns to less than 450 ms.
• CTCAE Grade 3 or greater toxicity: Resume at a reduced dose when the toxicity resolves or improves to CTCAE Grade 1.

For recurrent toxicities, reduce the dose of CAPRELSA to 100 mg after resolution or improvement to CTCAE Grade 1 severity, if continued treatment is warranted.

Because of the 19-day half-life, adverse reactions including a prolonged QT interval may not resolve quickly. Monitor appropriately [see Warnings and Precautions (5.1), (5.2), (5.3), (5.4), (5.5), (5.6), (5.7), and (5.9)].

For Patients with Renal Impairment

Reduce the starting dose to 200 mg in patients with moderate (creatinine clearance ≥30 to <50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment [see Warnings and Precautions (5.12) and Use in Specific Populations (8.6)].

For Patients with Hepatic Impairment

CAPRELSA is not recommended for use in patients with moderate and severe hepatic impairment [see Use in Specific Populations (8.7)].

3 DOSAGE FORMS AND STRENGTHS

CAPRELSA 100 mg tablets are white, round, biconvex, film-coated, and intagliated with 'Z 100' on one side and plain on the reverse side.

CAPRELSA 300 mg tablets are white, oval, biconvex, film-coated, and intagliated with 'Z 300' on one side and plain on the reverse side.

4 CONTRAINDICATIONS

Do not use in patients with congenital long QT syndrome [see Boxed Warning].

5 WARNINGS AND PRECAUTIONS

5.1 QT Prolongation and Torsades de Pointes

CAPRELSA can prolong the QT interval in a concentration-dependent manner [see Clinical Pharmacology (12.2)]. Torsades de pointes, ventricular tachycardia and sudden deaths have occurred in patients treated with CAPRELSA.

Do not start CAPRELSA treatment in patients whose QTcF interval is greater than 450 ms. Do not administer CAPRELSA to patients who have a history of Torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure. CAPRELSA has not been studied in patients with ventricular arrhythmias or recent myocardial infarction. Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate to severe renal impairment and monitor QT interval frequently.

Obtain an ECG and serum potassium, calcium, magnesium and TSH at baseline, 2–4 weeks and 8–12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. Monitor electrolytes and ECGs more frequently in patients who experience diarrhea. Following any dose reduction for QT prolongation or any dose interruption greater than 2 weeks, conduct QT assessments as described above. Maintain serum potassium levels of 4 mEq/L or higher (within normal range) and maintain serum magnesium and calcium levels within normal ranges to reduce the risk of QT prolongation.

Avoid using CAPRELSA with drugs known to prolong the QT interval [see Warnings and Precautions (5.11) and Drug Interactions (7.4)]. If such drugs are given to patients already receiving CAPRELSA and no alternative therapy exists, perform ECG monitoring of the QT interval more frequently.

Stop CAPRELSA in patients who develop a QTcF greater than 500 ms until the QTcF returns to less than 450 ms. Dosing of CAPRELSA can then be resumed at a reduced dose [see Dosage and Administration (2.1)].

5.2 Severe Skin Reactions

Severe and sometimes fatal skin reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome, have occurred in patients treated with CAPRELSA. Permanently discontinue CAPRELSA for severe skin reactions and refer the patient for urgent medical evaluation. Systemic therapies such as corticosteroids may be required.

Photosensitivity reactions can occur during CAPRELSA treatment and up to 4 months after treatment discontinuation.

5.3 Interstitial Lung Disease

Interstitial Lung Disease (ILD) or pneumonitis, including fatalities, has occurred in patients treated with CAPRELSA. Consider a diagnosis of ILD in patients presenting with non-specific respiratory signs and symptoms.

Interrupt CAPRELSA for acute or worsening pulmonary symptoms. Discontinue CAPRELSA if ILD is confirmed.

5.4 Ischemic Cerebrovascular Events

Ischemic cerebrovascular events, including fatalities, occurred in patients treated with CAPRELSA. In the randomized medullary thyroid cancer (MTC) study, ischemic cerebrovascular events occurred more frequently with CAPRELSA compared to placebo (1.3% compared to 0%). The safety of resumption of CAPRELSA therapy after resolution of an ischemic cerebrovascular event has not been studied. Discontinue CAPRELSA in patients who experience a severe ischemic cerebrovascular event.

5.5 Hemorrhage

Serious hemorrhagic events, including fatalities, occurred in patients treated with CAPRELSA. Do not administer CAPRELSA to patients with a recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue CAPRELSA in patients with severe hemorrhage.

5.6 Heart Failure

Heart failure, including fatalities, occurred in patients treated with CAPRELSA. Monitor for signs and symptoms of heart failure. Consider discontinuation of CAPRELSA in patients with heart failure. Heart failure may not be reversible upon stopping CAPRELSA.

5.7 Diarrhea

Diarrhea of Grade 3 or greater severity occurred in 11% of patients receiving CAPRELSA in the randomized MTC study. If diarrhea occurs, carefully monitor serum electrolytes and ECGs to reduce the risk and enable early detection of QT prolongation resulting from dehydration [see Warnings and Precautions (5.1)]. Interrupt CAPRELSA for severe diarrhea. Upon improvement, resume CAPRELSA at a reduced dose [see Dosage and Administration (2.1)].

5.8 Hypothyroidism

In the randomized MTC study in which 90% of the patients enrolled had prior thyroidectomy, increased dosing of thyroid replacement therapy was required in 49% of CAPRELSA-treated patients compared to 17% of placebo-treated patients. Obtain Thyroid-stimulating hormone (TSH) at baseline, at 2–4 weeks and 8–12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. If signs or symptoms of hypothyroidism occur, examine thyroid hormone levels and adjust thyroid replacement therapy accordingly.

5.9 Hypertension

Hypertension, including hypertensive crisis, has occurred in patients treated with CAPRELSA. Monitor all patients for hypertension. Dose reduction or interruption for hypertension may be necessary. If hypertension cannot be controlled, do not resume CAPRELSA [see Dosage and Administration (2.1)].

5.10 Reversible Posterior Leukoencephalopathy Syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by an MRI of the brain, has occurred in patients treated with CAPRELSA. Consider this syndrome in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical studies, three of four patients who developed RPLS while taking CAPRELSA also had hypertension. Discontinue CAPRELSA treatment in patients with RPLS.

5.11 Drug Interactions

Avoid administration of CAPRELSA with anti-arrhythmic drugs (including but not limited to amiodarone, disopyramide, procainamide, sotalol, dofetilide) and other drugs that may prolong the QT interval (including but not limited to chloroquine, clarithromycin, dolasetron, granisetron, haloperidol, methadone, moxifloxacin, and pimozide) [see Drug Interactions (7.4) and Clinical Pharmacology (12.2)].

5.12 Renal Impairment

Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate to severe renal impairment and monitor the QT interval closely. There is no information available for patients with end-stage renal disease requiring dialysis [see Boxed Warning, Dosage and Administration (2.1), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

5.13 Hepatic Impairment

CAPRELSA is not recommended for use in patients with moderate and severe hepatic impairment, as safety and efficacy have not been established [see Dosage and Administration (2.1)].

5.14 Embryo-Fetal Toxicity

Based on its mechanism of action, CAPRELSA can cause fetal harm when administered to a pregnant woman. In rats, vandetanib was embryotoxic, fetotoxic, and induced fetal malformations at exposures equivalent to or lower than those expected at the 300 mg clinical dose and had adverse effects on female fertility, embryofetal development, and postnatal development of pups.

Advise women of the potential hazard to a fetus. Advise women of reproductive potential to use effective contraception during treatment with CAPRELSA and for at least 4 months following the last dose [see Use in Specific Populations (8.1), (8.3)].

5.15 CAPRELSA REMS (Risk Evaluation and Mitigation Strategy) Program

Because of the risk of QT prolongation, Torsades de pointes, and sudden death, CAPRELSA is available only through a restricted distribution program called the CAPRELSA REMS Program. Only prescribers and pharmacies certified with the program are able to prescribe and dispense CAPRELSA.

To learn about the specific REMS requirements and to enroll in the CAPRELSA REMS Program, call 1-800-817-2722 or visit www.caprelsarems.com.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the label:

• QT Prolongation and Torsades de Pointes [see Boxed Warning, Warnings and Precautions (5.1)]
• Severe Skin Reactions [see Warnings and Precautions (5.2)]
• Interstitial Lung Disease [see Warnings and Precautions (5.3)]
• Ischemic Cerebrovascular Events [see Warnings and Precautions (5.4)]
• Hemorrhage [see Warnings and Precautions (5.5)]
• Heart Failure [see Warnings and Precautions (5.6)]
• Diarrhea [see Warnings and Precautions (5.7)]
• Hypothyroidism [see Warnings and Precautions (5.8)]
• Hypertension [see Warnings and Precautions (5.9)]
• Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.10)]
• Embryo-Fetal Toxicity [see Warnings and Precautions (5.14)]

6.1 Clinical Trials Experience

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

Patients with unresectable locally advanced or metastatic medullary thyroid cancer were treated with CAPRELSA 300 mg (n=231) or Placebo (n=99). The population exposed to CAPRELSA was 58% male, 94% white, and had a median age of 50 years. The data described below reflect a median exposure to CAPRELSA for 607 days.

The most commonly reported adverse drug reactions which occurred in >20% of CAPRELSA-treated patients and with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea/colitis, rash, acneiform dermatitis, hypertension, nausea, headache, upper respiratory tract infection, decreased appetite, and abdominal pain.

Among CAPRELSA-treated patients, dose interruption occurred in 109 (47%) and dose reduction occurred in 83 (36%). Adverse reactions led to study treatment discontinuation in 28 of 231 patients (12%) receiving CAPRELSA and in 3 of 99 patients (3.0%) receiving placebo. Adverse reactions leading to permanent discontinuation in 2 or more (≥0.9%) patients treated with CAPRELSA were: asthenia (1.7%), rash (1.7%), diarrhea (0.9%), fatigue (0.9%), pyrexia (0.9%), elevated creatinine (0.9%), QT prolongation (0.9%), and hypertension (0.9%).

Table 1: Per-Patient Incidence of Selected Adverse Reactions Occurring at a Higher Incidence in CAPRELSA-Treated Patients During Randomized Treatment (Between-Arm Difference of ≥5% [All Grades]*)

Clinically important uncommon adverse drug reactions in patients who received CAPRELSA versus patients who received placebo included pancreatitis (0.4% vs. 0%) and heart failure (0.9% vs. 0%).

Blurred vision was more common in patients who received CAPRELSA versus patients who received placebo for medullary thyroid cancer (9% vs. 1%, respectively). Scheduled slit lamp examinations revealed corneal opacities (vortex keratopathies) in treated patients, which can lead to halos and decreased visual acuity. Perform ophthalmologic examination, including slit lamp examination, in patients who report visual changes.

Class Effects

CAPRELSA is an inhibitor of vascular endothelial growth factor receptor (VEGFR) signaling. Inhibition of VEGFR signaling can result in intestinal perforation. Intestinal perforation occurred in 0.4% of CAPRELSA treated patients versus 0% of placebo treated patients.

The incidence of Grade 1–2 bleeding events was 14% in patients receiving CAPRELSA compared with 7% on placebo in the randomized portion of the medullary thyroid cancer (MTC) study.

Table 2: Per-Patient Incidence of Selected Laboratory Abnormalities in Patients with MTC Occurring at a Higher Incidence in CAPRELSA-Treated Patients (Between-Arm Difference of ≥5% [All Grades]*)

No patient with a Grade 3–4 ALT elevation had a concomitant increase in bilirubin in the MTC study.

7 DRUG INTERACTIONS

7.1 Effect of CYP3A4 Inducers on CAPRELSA

Rifampicin, a strong CYP3A4 inducer, decreased vandetanib plasma concentrations. Avoid concomitant use of known strong CYP3A4 inducers during CAPRELSA therapy. Avoid concomitant use of St. John's wort because it can decrease vandetanib exposure unpredictably [see Clinical Pharmacology (12.3)].

7.2 Effect of CAPRELSA on OCT2 Transporter

CAPRELSA increased plasma concentrations of metformin that is transported by the organic cation transporter type 2 (OCT2). Use caution and closely monitor for toxicities when administering CAPRELSA with drugs that are transported by OCT2 [see Clinical Pharmacology (12.3)].

7.3 Effect of CAPRELSA on Digoxin

CAPRELSA increased plasma concentrations of digoxin. Use caution and closely monitor for toxicities when administering CAPRELSA with digoxin [see Clinical Pharmacology (12.3)].

7.4 Drugs that Prolong the QT Interval

Avoid concomitant use of CAPRELSA with agents that may prolong the QT interval [see Warnings and Precautions (5.11)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on its mechanism of action, CAPRELSA can cause fetal harm when administered to a pregnant woman. Vandetanib is embryotoxic, fetotoxic, and induced fetal malformations in rats at exposures less than or equal to those expected at the recommended human dose of 300 mg/day. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Animal data

In reproductive toxicity studies, administration of vandetanib to female rats prior to mating and through the first week of pregnancy at a dose of 25 mg/kg/day (approximately equal to the human exposure at the 300 mg clinical dose based on Cmax), there were increases in pre-implantation loss and post-implantation loss resulting in a reduction in the number of live embryos.

During organogenesis, vandetanib caused an increase in post-implantation loss, including occasional total litter loss at a dose of 25 mg/kg/day. At doses greater than 10 mg/kg/day (approximately 0.4 times the human Cmax at the 300 mg clinical dose) treatment with vandetanib resulted in increases in late embryofetal death and decreases in fetal birth weight. A no-effect level for malformations was not identified in this study. Administration of vandetanib at doses greater than or equal to 1 mg/kg/day (approximately 0.03 times the human Cmax at the 300 mg clinical dose) resulted in dose dependent increases in both malformations of the heart vessels and skeletal variations including delayed ossification of the skull, vertebrae, and sternum, indicating delayed fetal development.

In a rat pre- and postnatal development study, at doses (1 and 10 mg/kg/day) producing mild maternal toxicity during gestation and/or lactation, vandetanib decreased pup survival and reduced postnatal pup growth. Reduced postnatal pup growth was associated with a delay in physical development.

8.2 Lactation

There are no data on the presence of vandetanib or its metabolites in human milk or the effects of vandetanib on the breastfed child or on milk production. Vandetanib was present in the milk of lactating rats (see Data). Because of the potential for serious adverse reactions from CAPRELSA in breastfed children, advise women not to breastfeed during treatment with CAPRELSA and for 4 months after the final dose.

Data

Animal data

In nonclinical studies, vandetanib was excreted in rat milk and found in plasma of pups following dosing to lactating rats. Vandetanib transfer in breast milk resulted in relatively constant exposure in pups due to the long half-life of the drug.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating treatment with CAPRELSA [see Use in Specific Populations (8.1)].

Contraception

CAPRELSA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Advise females of reproductive potential to use effective contraception during treatment with CAPRELSA and for 4 months after the final dose.

Infertility

There are no data on the effect of CAPRELSA on human fertility. Results from animal studies indicate that vandetanib can impair male and female fertility [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and efficacy of CAPRELSA in pediatric patients have not been established.

8.5 Geriatric Use

The MTC study of CAPRELSA did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently compared to younger patients.

8.6 Renal Impairment

Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate (creatinine clearance ≥30 to <50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment [see Dosage and Administration (2.1), Warnings and Precautions (5.12) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

The pharmacokinetics of CAPRELSA were evaluated after a single dose of 800 mg in subjects with mild (n=8), moderate (n=7), and severe (n=6) hepatic impairment and normal hepatic function (n=5). Subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment had comparable mean AUC and clearance values to those with normal hepatic function.

There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). CAPRELSA is not recommended for use in patients with moderate and severe hepatic impairment, as safety and efficacy have not been established [see Dosage and Administration (2.1) and Warnings and Precautions (5.13)].

10 OVERDOSAGE

In the event of an overdose, monitor patients closely for QTc prolongation. Because of the 19-day half-life, adverse reactions may not resolve quickly.

11 DESCRIPTION

Vandetanib has the chemical name N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl) methoxy]quinazolin-4-amine.

The structural and molecular formulas are:

C22H24BrFN4O2

Vandetanib has a molecular weight of 475.36. Vandetanib exhibits pH-dependent solubility, with increased solubility at lower pH. Vandetanib is practically insoluble in water with a value of 0.008 mg/mL at 25°C (77°F).

CAPRELSA tablets for daily oral administration are available in two dosage strengths containing either 100 mg or 300 mg of vandetanib. The tablet cores contain the following inactive ingredients: calcium hydrogen phosphate dihydrate, microcrystalline cellulose, crospovidone, povidone, and magnesium stearate. The tablet film-coat contains the following inactive ingredients: hypromellose 2910, macrogol 300, and titanium dioxide E171.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

In vitro studies have shown that vandetanib inhibits the tyrosine kinase activity of the EGFR and VEGFR families, RET, BRK, TIE2, and members of the EPH receptor and Src kinase families. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment. In addition, the N-desmethyl metabolite of the drug, representing 7 to 17.1% of vandetanib exposure, has similar inhibitory activity to the parent compound for VEGF receptors (KDR and Flt-1) and EGFR.

In vitro, vandetanib inhibited epidermal growth factor (EGF)-stimulated receptor tyrosine kinase phosphorylation in tumor cells and endothelial cells and VEGF-stimulated tyrosine kinase phosphorylation in endothelial cells.

In vivo, vandetanib administration reduced tumor cell-induced angiogenesis, tumor vessel permeability, and inhibited tumor growth and metastasis in mouse models of cancer.

12.2 Pharmacodynamics

Cardiac Electrophysiology

In 231 patients with medullary thyroid cancer randomized to receive CAPRELSA 300 mg once daily in the phase 3 clinical trial. CAPRELSA was associated with sustained plasma concentration-dependent QT prolongation. Based on the exposure-response relationship, the mean (90% CI) QTcF change from baseline (ΔQTcF) was 35 (33–36) ms for the 300 mg dose. The ΔQTcF remained above 30 ms for the duration of the trial (up to 2 years). In addition, 36% of patients experienced greater than 60 ms increase in ΔQTcF and 4.3% of patients had QTcF greater than 500 ms. Cases of Torsades de pointes and sudden death have occurred [see Boxed Warning and Warnings and Precautions (5.1), (5.11)].

12.3 Pharmacokinetics

A population pharmacokinetic analysis of CAPRELSA was conducted in 231 patients with MTC following oral administration of 300 mg daily doses. The pharmacokinetics of CAPRELSA at the 300 mg dose in MTC patients are characterized by a mean clearance of approximately 13.2 L/h, a mean volume of distribution of approximately 7450 L, and a median plasma half-life of 19 days.

Absorption

Following oral administration of CAPRELSA, absorption is slow with peak plasma concentrations typically achieved at a median of 6 hours, range 4-10 hours, after dosing. Vandetanib accumulates approximately 8-fold on multiple dosing with steady state achieved in approximately 3 months.

Exposure to vandetanib is unaffected by food

Distribution

Vandetanib binds to human serum albumin and α1-acid-glycoprotein with in vitro protein binding being approximately 90%. In ex vivo plasma samples from colorectal cancer patients at steady state exposure after 300 mg once daily, the mean percentage protein binding was 94%.

Metabolism

Following oral dosing of 14C-vandetanib, unchanged vandetanib and metabolites vandetanib N-oxide and N-desmethyl vandetanib were detected in plasma, urine and feces. A glucuronide conjugate was seen as a minor metabolite in excreta only. N-desmethyl-vandetanib is primarily produced by CYP3A4 and vandetanib-N-oxide by flavin-containing monooxygenase enzymes FMO1 and FMO3. N-desmethyl-vandetanib and vandetanib-N-oxide circulate at concentrations of approximately 7–17% and 1.4–2.2%, respectively, of those of vandetanib.

Excretion

Within a 21-day collection period after a single dose of 14C-vandetanib, approximately 69% was recovered with 44% in feces and 25% in urine. Excretion of the dose was slow and further excretion beyond 21 days would be expected based on the plasma half-life.

Vandetanib was not a substrate of hOCT2 expressed in HEK293 cells. Vandetanib inhibits the uptake of the selective OCT2 marker substrate 14C-creatinine by HEK-OCT2 cells, with a mean IC50 of 2.1 μg/mL. This is higher than vandetanib plasma concentrations (0.81 μg/mL) observed after multiple dosing at 300 mg. Inhibition of renal excretion of creatinine by vandetanib provides an explanation for increases in plasma creatinine seen in human subjects receiving vandetanib.

Specific Populations

Effects of age and gender

In a population pharmacokinetic evaluation in cancer patients, no relationship was apparent between oral clearance of vandetanib and patient age or gender.

Ethnicity

Based on a cross-study comparison in a limited number of patients, Japanese (N=3) and Chinese (N=7) patients had average exposures of vandetanib that were higher than Caucasian (N=7) patients receiving the same dose of CAPRELSA.

Pediatric

The pharmacokinetics of vandetanib has not been evaluated in pediatric patients.

Effect of renal impairment

The pharmacokinetics of vandetanib were evaluated after a single CAPRELSA dose of 800 mg in six subjects with mild (creatinine clearance = 50 to <80 mL/min), eight subjects with moderate (creatinine clearance ≥30 to <50 mL/min), six subjects with severe (creatinine clearance <30 mL/min) renal impairment and ten subjects with normal (creatinine clearance >80 mL/min) renal function. Subjects with mild renal impairment had a comparable mean AUC of vandetanib to that with normal renal function. In subjects with moderate or severe renal impairment, the average AUC of vandetanib increased by 39% and 41%, respectively, compared to patients with normal renal function [see Dosage and Administration (2.1), Warnings and Precautions (5.12) and Use in Specific Populations (8.6)].

Drug Interactions

Effect of other drugs on CAPRELSA

Strong CYP3A4 inducers: In a cross-over study in 12 healthy volunteers, a single oral 300 mg dose of CAPRELSA was administered alone on day 1 and on day 10 in combination with daily doses of 600 mg of rifampicin (a strong CYP3A4 inducer) given on days 1–31. The coadministration of rifampicin with CAPRELSA decreased the geometric mean AUC0–504h of vandetanib by 40% (90% confidence interval (CI): 56%, 63%) compared to vandetanib alone. No clinically meaningful change in the mean Cmax of vandetanib was observed. The geometric mean AUC0–504h and Cmax of N-desmethylvandetanib increased by 266% and 414%, respectively, in the presence of rifampicin compared with vandetanib alone [see Drug Interactions (7.1)].

Strong CYP3A4 inhibitors: In a cross-over study in 14 healthy volunteers, a single oral 300 mg dose of CAPRELSA was administered alone and on day 4 in combination with daily doses of 200 mg of itraconazole (a strong CYP3A4 inhibitor) given on days 1–24. No change was observed in the geometric mean AUC0–504h or Cmax of vandetanib when itraconazole was coadministered with CAPRELSA.

Gastric pH elevating agents: In a cross-over study of 14 healthy volunteers, a single oral 300 mg dose of CAPRELSA was administered alone and in combination with five daily doses of 40 mg omeprazole (a proton pump inhibitor). No clinically meaningful change was observed in the geometric mean AUC0–504h and Cmax of vandetanib when omeprazole was coadministered with CAPRELSA.

In a cross-over study of 16 healthy volunteers, a single 300 mg oral dose of CAPRELSA was administered alone and after two oral doses of 150 mg of ranitidine (a H2 receptor antagonist) administered about 12 hours apart. No change was observed in the geometric mean AUC0–504h and Cmax of vandetanib when ranitidine was coadministered with CAPRELSA.

Effect of CAPRELSA on other drugs

Sensitive CYP3A4 substrates: In a cross-over study of 16 healthy volunteers, a single oral 7.5 mg dose of midazolam (as 2 mg/mL oral syrup), a sensitive CYP3A4 substrate, was administered alone and 8 days after receiving a single 800 mg oral dose of CAPRELSA. No change was observed in the geometric mean Cmax and AUCinf of midazolam when CAPRELSA was coadministered with midazolam.

Substrates of OCT2 transporter: In a cross-over study of 13 healthy volunteers, a single 1000 mg oral dose of metformin, a substrate of OCT2, was administered alone and 3 hours after receiving a single 800 mg oral dose of CAPRELSA. The coadministration of CAPRELSA with metformin increased the geometric mean AUCinf of metformin by 74% (90% CI: 58%, 92%) and geometric mean Cmax of metformin by 50% (90% CI: 34%, 67%) compared to metformin alone [see Drug Interactions (7.2)].

Substrates of P-glycoprotein transporter: In a cross-over study of 14 healthy volunteers, a single oral 0.25 mg dose of digoxin, a substrate of P-glycoprotein, was administered alone and in combination with a single 300 mg oral dose of CAPRELSA. The coadministration of CAPRELSA increased the geometric mean Cmax digoxin by 29% (90% CI: 10%, 52%) and the geometric mean of AUC0–t of digoxin by 23% (90% CI: 12%, 34%) compared to digoxin alone [see Drug Interactions (7.3)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Vandetanib was not carcinogenic in a 2-year study in rats when administered by daily oral gavage at doses of up to 10 mg/kg (0.7 times the human Cmax at the 300 mg clinical dose), or in the Tg∙RasH2 mouse when administered by daily oral gavage at doses of up to 30 mg/kg (~5 times the human Cmax at the clinical dose of 300 mg) for 26 weeks. Vandetanib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in either the in vitro cytogenetic assay using human lymphocytes or in the in vivo rat micronucleus assay.

Based on nonclinical findings, male and female fertility may be impaired by treatment with CAPRELSA. In a fertility study of male rats, vandetanib had no effect on copulation or fertility rate when untreated females were mated with males administered 1, 5, or 20 mg/kg/day of vandetanib (approximately 0.03, 0.22, or 0.40 times, respectively, the human exposure based on area under the curve (AUC) in patients with cancer at the 300 mg clinical dose); however, in the same study there was a slight decrease in the number of live embryos in females mated with males treated at the 20 mg/kg/day dose level and an increase in preimplantation loss in females mated with males administered vandetanib at doses of ≥5 mg/kg/day. In a female fertility study, there was a trend towards increased estrus cycle irregularity, a slight reduction in pregnancy incidence and an increase in implantation loss. In a one month repeat-dose toxicity study in rats, there was a decrease in the number of corpora lutea in the ovaries of rats administered 75 mg/kg/day vandetanib (approximately 1.8 times the human exposure based on AUC at the 300 mg clinical dose).

13.2 Animal Toxicology and/or Pharmacology

In an animal model of wound-healing, mice dosed with vandetanib had reduced skin-breaking strength compared with controls. This suggests that CAPRELSA slows but does not prevent wound healing. The appropriate interval between discontinuation of CAPRELSA and subsequent elective surgery required to avoid the risks of impaired wound healing has not been determined.

14 CLINICAL STUDIES

A double-blind, placebo-controlled study (Study D4200C00058, NCT00410761) randomized patients with unresectable locally advanced or metastatic medullary thyroid cancer to CAPRELSA 300 mg (n=231) versus placebo (n=100).

The major efficacy outcome measure was progression-free survival (PFS) with CAPRELSA compared to placebo. Other efficacy outcome measures included evaluation of overall survival (OS) and overall objective response rate (ORR). Centralized, independent blinded review of the imaging data was used in the assessment of PFS and ORR. Upon objective disease progression based on the investigator's assessment, patients were discontinued from blinded study treatment and given the option to receive open-label CAPRELSA. Forty-seven percent (109/231) of the patients initially randomized to CAPRELSA opted to receive open-label CAPRELSA after disease progression, and 79% (79/100) of the patients initially randomized to placebo opted to receive open-label CAPRELSA after disease progression.

The result of the PFS analysis, based on the central review RECIST assessment, showed a statistically significant improvement in PFS for patients randomized to CAPRELSA (Hazard Ratio (HR) = 0.35; 95% Confidence Interval (CI) = 0.24-0.53; p<0.001). Analyses in the subgroups of patients who were symptomatic or had progressed within 6 months prior to their enrollment showed similar PFS results (HR = 0.31 95% CI: 0.19, 0.53 for symptomatic patients; HR = 0.41 95% CI: 0.25, 0.66 for patients who had progressed within 6 months prior to enrollment). Median final OS were similar across both treatment arms.

The overall objective response rate (ORR) for patients randomized to CAPRELSA was 44% compared to 1% for patients randomized to placebo. All objective responses were partial responses.

Figure 1: Kaplan-Meier Curves for Progression Free Survival in Study D4200C00058

Table 3: Efficacy Results in Study D4200C00058

15 REFERENCES

1. OSHA Hazardous Drugs (OSHA Technical Manual). OSHA.

16 HOW SUPPLIED/STORAGE AND HANDLING

100 mg Tablets Available in bottles containing 30 tablets (NDC 58468-7820-3).

300 mg Tablets Available in bottles containing 30 tablets (NDC 58468-7840-3).

16.1 Storage and Handling

CAPRELSA tablets should be stored at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F) [See USP controlled room temperature].

Procedures for proper handling and disposal of anticancer drugs should be considered. A guideline on this subject has been published.1 Do not crush CAPRELSA tablets.

17 PATIENT COUNSELING INFORMATION

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

QT Prolongation and Torsades de Pointes

Advise patients to contact their healthcare provider in the event of syncope, pre-syncopal symptoms, and cardiac palpitations. Advise patients that their healthcare provider will monitor their electrolytes and ECGs during treatment [see Warnings and Precautions (5.1)].

Severe Skin Reactions

Advise patients to contact their healthcare provider in the event of skin reactions or rash [see Warnings and Precautions (5.2)].

Interstitial Lung Disease (ILD)

Advise patients to contact their health care provider in the event of sudden onset or worsening of breathlessness, persistent cough or fever [see Warnings and Precautions (5.3)].

Diarrhea

Advise patients to contact their healthcare provider in the event of diarrhea [see Warnings and Precautions (5.7)].

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Advise patients to contact their healthcare provider in the event of seizures, headaches, visual disturbances, confusion or difficulty thinking [see Warnings and Precautions (5.10)].

Embryo-Fetal Toxicity

Advise females of reproductive potential to use effective contraception during treatment with CAPRELSA and for 4 months following the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with CAPRELSA [see Use in Specific Populations (8.1), (8.3)].

Lactation

Advise women not to breastfeed during treatment with CAPRELSA and for 4 months after the last dose [see Use in Specific Populations (8.2)].

Photosensitivity

Advise patients to use appropriate sun protection due to the increased susceptibility to sunburn while taking CAPRELSA and for at least 4 months after drug discontinuation [see Warnings and Precautions (5.2)].

Administration

Advise patients that CAPRELSA can be taken with or without food and not to crush CAPRELSA tablets [see Clinical Pharmacology (12.3)].

Distributed by:
Genzyme Corporation
Cambridge, MA 02142

CAPRELSA is a registered trademark of Genzyme Corporation
©2018 Genzyme Corporation.

MEDICATION GUIDE

CAPRELSA® (kap-rel-sah)
(vandetanib)
Tablets

Read this Medication Guide before you start taking CAPRELSA and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment.

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

CAPRELSA can cause a change in the electrical activity of your heart called QT prolongation, which can cause irregular heartbeats and that may lead to death. You should not take CAPRELSA if you have had a condition called long QT syndrome since birth.

Your healthcare provider should perform tests to check the levels of your blood potassium, calcium, magnesium, and thyroid-stimulating hormone (TSH) as well as the electrical activity of your heart with a test called an electrocardiogram (ECG). You should have these tests:

• Before starting CAPRELSA
• Regularly during CAPRELSA treatment:
• 2 to 4 weeks after starting CAPRELSA
• 8 to 12 weeks after starting CAPRELSA
• Every 3 months thereafter
• If your healthcare provider changes your dose of CAPRELSA
• If you start taking medicine that causes QT prolongation
• As instructed by your healthcare provider

Your healthcare provider may stop your CAPRELSA treatment for a while and restart you at a lower dose if you have QT prolongation.

Call your healthcare provider right away if you feel faint, light-headed, or feel your heart beating irregularly while taking CAPRELSA. These may be symptoms related to QT prolongation.

What is CAPRELSA?

CAPRELSA is a prescription medicine used to treat medullary thyroid cancer that cannot be removed by surgery or that has spread to other parts of the body. It takes a long time to get rid of CAPRELSA from your body and you may be at risk for side effects related to CAPRELSA after you have stopped your treatment.

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

Who should not take CAPRELSA?

Do not take CAPRELSA if you have had QT prolongation.

What should I tell my healthcare provider before taking CAPRELSA?

Before you take CAPRELSA, tell your healthcare provider if you:

• have any heart problems, including a condition called congenital long QT syndrome
• have an irregular heartbeat
• take or have stopped taking a medicine that causes QT prolongation
• have low blood levels of potassium, calcium, or magnesium
• have high blood levels of thyroid-stimulating hormone
• have high blood pressure
• have skin problems
• have a history of breathing problems
• have a recent history of coughing up blood or bleeding
• have diarrhea
• have liver problems
• have kidney problems
• have seizures or are being treated for seizures
• are pregnant or plan to become pregnant. CAPRELSA can cause harm to your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
• If you are able to become pregnant, you should use effective birth control during your treatment with CAPRELSA and for at least 4 months after your last dose of CAPRELSA.
• Talk to your healthcare provider about birth control methods to prevent pregnancy while you are taking CAPRELSA.
• are breastfeeding or plan to breastfeed. It is not known if CAPRELSA passes into your breast milk. You and your healthcare provider should decide if you will take CAPRELSA or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. CAPRELSA and other medicines may affect each other causing side effects.

Especially tell your healthcare provider if you take:

• St. John's Wort. You should not take St. John's Wort while taking CAPRELSA
• certain medicines that can affect how your liver breaks down medicine
• a medicine for your heart

Ask your healthcare provider if you are not sure if your medicine is one listed above.

Do not take other medicines while taking CAPRELSA until you have talked with your healthcare provider or pharmacist.

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

How should I take CAPRELSA?

• Take CAPRELSA exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking CAPRELSA unless your healthcare provider tells you to.
• CAPRELSA may be taken with or without food.
• Swallow CAPRELSA tablets whole with water.
• Do not crush or chew CAPRELSA tablets. If CAPRELSA tablets are accidentally crushed, contact with skin should be avoided. If contact occurs, wash affected areas well with water.
• If you cannot swallow CAPRELSA tablets whole:
• place your dose of CAPRELSA in a glass that contains 2 ounces of noncarbonated water (no other liquids should be used).
• stir the CAPRELSA tablet(s) and water mixture for about 10 minutes or until the tablet(s) are in very small pieces (the tablets will not completely dissolve).
• swallow CAPRELSA and water mixture right away.
• if any CAPRELSA and water mixture remains in the glass, mix with an additional 4 ounces of noncarbonated water and swallow the mixture to make sure that you take your full dose of CAPRELSA.
• If you miss a dose and your next dose is in:
• less than 12 hours, take your next dose at the normal time. Do not make up for the missed dose.
• 12 hours or more, take the missed dose as soon as you remember. Take the next dose at the normal time.

Call your healthcare provider right away if you take too much CAPRELSA.

• During treatment with CAPRELSA, your healthcare provider should check your blood and heart for side effects. See "What is the most important information I should know about CAPRELSA?"
• Your healthcare provider should check your blood pressure regularly during your treatment with CAPRELSA.

What should I avoid while taking CAPRELSA?

• Limit exposure to the sun. CAPRELSA can make your skin sensitive to the sun. While taking CAPRELSA and for 4 months after stopping your CAPRELSA treatment, use sun block and wear clothes that cover your skin, including your head, arms and legs when you go outdoors.
• Use caution before driving or using machinery. Keep in mind CAPRELSA may make you feel tired, weak, or cause blurred vision.

What are the possible side effects of CAPRELSA?

CAPRELSA may cause serious side effects, including:

• See "What is the most important information I should know about CAPRELSA?"
• Serious skin reactions. CAPRELSA can cause serious skin reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome, or other serious skin reactions that may affect any part of your body. These serious skin reactions may be life threatening and you may need to be treated in a hospital. Call your healthcare provider right away if you experience any of these symptoms.
• Skin rash or acne
• Dry skin
• Itching
• Blisters on your skin
• Blisters or sores in your mouth
• Peeling of your skin
• Fever
• Muscle or joint aches
• Redness or swelling of your face, hands, or soles of your feet
• Breathing problems (interstitial lung disease). CAPRELSA may cause a breathing problem called interstitial lung disease that can lead to death. Tell your healthcare provider right away if you experience sudden or worsening shortness of breath or cough.
• Stroke. Strokes have been reported in some people who have taken CAPRELSA and in some cases have caused death. Stop taking CAPRELSA and call your healthcare provider right away if you have symptoms of a stroke which may include:
• numbness or weakness of the face, arm or leg, especially on one side of the body
• sudden confusion, trouble speaking or understanding
• sudden trouble seeing in one or both eyes
• sudden trouble walking, dizziness, loss of balance or coordination
• sudden, severe headache
• Bleeding. Bleeding can happen during your treatment with CAPRELSA. Tell your healthcare provider right away if you have severe bleeding while you are taking CAPRELSA.
• Heart failure. CAPRELSA can cause heart failure that can lead to death. You may have to stop taking CAPRELSA if you have heart failure. Heart failure may not be reversible after stopping CAPRELSA. Your healthcare provider should monitor you for signs and symptoms of heart failure.
• Diarrhea. Diarrhea is often a symptom of medullary thyroid cancer. CAPRELSA can also cause diarrhea or make diarrhea worse. Your healthcare provider should check your blood levels to monitor your electrolytes more frequently if you have diarrhea.
• Thyroid hormones. You can have changes in your thyroid hormone when taking CAPRELSA. Your healthcare provider should monitor your thyroid hormone levels while taking CAPRELSA.
• High blood pressure (hypertension). If you develop high blood pressure or your high blood pressure gets worse, your healthcare provider may lower your dose of CAPRELSA or tell you to stop taking CAPRELSA until your blood pressure is under control. Your healthcare provider may prescribe another medicine to control your high blood pressure.
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS). A condition called reversible posterior leukoencephalopathy syndrome can happen while taking CAPRELSA. Call your healthcare provider right away if you have:
• headaches
• seizures
• confusion
• changes in vision
• problems thinking

The most common side effects of CAPRELSA include:

• diarrhea
• rash
• acne
• nausea
• high blood pressure
• headache
• feeling tired
• loss of appetite
• upper respiratory tract infections
• stomach (abdominal) pain

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of CAPRELSA. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store CAPRELSA?

• Store CAPRELSA tablets at 59°F to 86°F (15°C to 30°C).
• Safely throw away medicine that is out of date or that you no longer need. Ask your pharmacist how to safely throw away CAPRELSA tablets.

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

General information about CAPRELSA.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use CAPRELSA for a condition for which it was not prescribed. Do not give CAPRELSA to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes important information about CAPRELSA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about CAPRELSA that is written for health professionals.

For more information, go to www.caprelsa.com or call 1-800-817-2722.

What are the ingredients in CAPRELSA?

Active ingredient: vandetanib

Inactive ingredients:

• Tablet core: calcium hydrogen phosphate dihydrate, microcrystalline cellulose, crospovidone, povidone, and magnesium stearate
• Tablet film-coat: hypromellose 2910, macrogol 300, and titanium dioxide E171

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distributed by:

Sanofi Genzyme
Cambridge, MA 02142

Issued 12/2016
CAPRELSA is a registered trademark of Genzyme Corporation
©Genzyme Corporation 2016. All Rights Reserved.

PRINCIPAL DISPLAY PANEL - 100 mg Tablet Bottle Carton

NDC 58468-7820-3

Caprelsa®
(vandetanib) tablets

100 mg

Rx only

Dispense with enclosed medication
guide to each patient.

30 Tablets

PRINCIPAL DISPLAY PANEL - 300 mg Tablet Bottle Carton

NDC 58468-7840-3

Caprelsa®
(vandetanib) tablets

300 mg

Rx only

Dispense with enclosed medication
guide to each patient.

30 Tablets

【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。