From 057834d36f24d6d2882b77c2983f93d6f92ad1b8 Mon Sep 17 00:00:00 2001 From: Bersella Date: Tue, 12 Sep 2023 22:10:23 +0800 Subject: [PATCH] Added leaflet of Trelstar (Triptorelin Pamoate) --- content/misc/trelstar/index.md | 654 ++++++++++++++++++++++++++ content/misc/trelstar/trelstar-0.png | Bin 0 -> 22922 bytes content/misc/trelstar/trelstar-1.png | Bin 0 -> 7524 bytes content/misc/trelstar/trelstar-10.png | Bin 0 -> 20607 bytes content/misc/trelstar/trelstar-11.jpg | Bin 0 -> 14633 bytes content/misc/trelstar/trelstar-2.png | Bin 0 -> 17112 bytes content/misc/trelstar/trelstar-3.png | Bin 0 -> 19520 bytes content/misc/trelstar/trelstar-4.png | Bin 0 -> 9414 bytes content/misc/trelstar/trelstar-5.png | Bin 0 -> 36017 bytes content/misc/trelstar/trelstar-6a.png | Bin 0 -> 17404 bytes content/misc/trelstar/trelstar-6b.png | Bin 0 -> 5011 bytes content/misc/trelstar/trelstar-7.png | Bin 0 -> 11696 bytes content/misc/trelstar/trelstar-8.png | Bin 0 -> 17554 bytes content/misc/trelstar/trelstar-9.png | Bin 0 -> 20688 bytes 14 files changed, 654 insertions(+) create mode 100644 content/misc/trelstar/index.md create mode 100644 content/misc/trelstar/trelstar-0.png create mode 100644 content/misc/trelstar/trelstar-1.png create mode 100644 content/misc/trelstar/trelstar-10.png create mode 100644 content/misc/trelstar/trelstar-11.jpg create mode 100644 content/misc/trelstar/trelstar-2.png create mode 100644 content/misc/trelstar/trelstar-3.png create mode 100644 content/misc/trelstar/trelstar-4.png create mode 100644 content/misc/trelstar/trelstar-5.png create mode 100644 content/misc/trelstar/trelstar-6a.png create mode 100644 content/misc/trelstar/trelstar-6b.png create mode 100644 content/misc/trelstar/trelstar-7.png create mode 100644 content/misc/trelstar/trelstar-8.png create mode 100644 content/misc/trelstar/trelstar-9.png diff --git a/content/misc/trelstar/index.md b/content/misc/trelstar/index.md new file mode 100644 index 0000000..fd3e8b5 --- /dev/null +++ b/content/misc/trelstar/index.md @@ -0,0 +1,654 @@ +--- +title: 帕莫酸曲普瑞林(美国 Trelstar)处方说明书 +weight: 1000 +description: 本文为美国 Verity 制药公司的帕莫酸曲普瑞林悬浮液注射剂(美国 Trelstar)处方说明书的中文翻译。 +keywords: [曲普瑞林, Trelstar, GnRH 类似物, GnRH 激动剂] +--- + +
+ +**译者按:** 本文为美国 Verity 制药公司的帕莫酸曲普瑞林悬浮液注射剂(美国 Trelstar)处方说明书的中文翻译。说明书原文:\ +**提示:** 曲普瑞林和亮丙瑞林作为 GnRH 激动剂,均已列入中国大陆多省集采目录,均为**醋酸盐**注射剂(详见 [Wiki 引用资料](https://mtf.wiki/zh-cn/docs/medicine/antiandrogen/gnrha/)),均仅有 3.75 mg 剂型。亮丙瑞林尚未被美国 FDA 批准。 + +初次批准日期:2000 年\ +修订日期:2023 年 3 月\ +**请仔细阅读说明书并在医师指导下使用** +
+ +## 品名 {#name} + +**TRELSTAR® (帕莫酸曲普瑞林悬浮液注射剂),用于肌肉注射** *(以下简称“本品”)*\ +**美国初次批准日期:2000 年** + +## 说明书摘要 {#highlights} + +**以下摘要内容不足以确保本品使用的安全性与有效性。请参见[说明书详情]({{< ref "#full-info" >}})。** + +### 适应症 {#highlights-indications} + +本品为促性腺激素释放激素(GnRH)激动剂,用于治疗晚期前列腺癌。([1]({{< ref "#indications" >}})) + +### 用法用量 {#highlights-dosage} + +本品用于单侧臀部进行单次肌注。因释放特性不同,以下剂型不可混用,必须依所需注射间隔来选择剂型。([2.1]({{< ref "#dosing-info" >}})) + +- 3.75 mg,每四周一次。([2.1]({{< ref "#dosing-info" >}})) +- 11.25 mg,每 12 周一次。([2.1]({{< ref "#dosing-info" >}})) +- 22.5 mg,每 24 周一次。([2.1]({{< ref "#dosing-info" >}})) + +### 性状及成分含量 {#highlights-forms} + +本品为注射用悬浮液,每份含 3.75 mg、11.25 mg 或 22.5 mg。([3]({{< ref "#forms" >}})) + +### 禁忌症 {#highlights-contraindications} + +- 已知对曲普瑞林或本品其它成分过敏;对其它 GnRH 激动剂或 GnRH 过敏。([4]({{< ref "#contraindications" >}})) + +### 警告和注意事项 {#highlights-warnings} + +- **超敏反应**:已有因使用本品引起过敏性休克、超敏反应和血管性水肿的报告。如发生此类反应,应停用本品并对症治疗。([5.1]({{< ref "#hypersensitivity-reactions" >}})) +- **肿瘤暴发**:治疗开始后数周内会出现血清睾酮水平的短暂上升。这可能会使前列腺癌恶化,并导致脊髓压迫和尿道阻塞。对有相关风险的患者密切观察,并对症处置。([5.2]({{< ref "#transient-increase-t" >}}))([5.3]({{< ref "#metastatic-vertebral-lesions" >}})) +- **对 QT/QTc 间期的影响**:雄激素去除治疗可能会使 QT 间期延长。考虑风险和收益。([5.4]({{< ref "#effect-qt-interval" >}})) +- **高血糖和糖尿病**:已有男性给予 GnRH 类似物后引起高血糖,使糖尿病发生风险增加的报告。监测血糖,并依现有医学实践处置。([5.5]({{< ref "#hyperglycemia" >}})) +- **心血管疾病**:已有男性患心肌梗塞、心源性猝死和卒中的风险增加之报告。对心血管疾病进行监测,并依现有医学实践处置。([5.6]({{< ref "#cardiovascular-diseases" >}})) + +### 不良反应 {#highlights-adverse-reactions} + +- 以本品 3.75 mg 剂型治疗期间,最常见(≥5%)的不良反应有:潮热、骨痛、阳萎、头痛。([6.1]({{< ref "#clinical-trails" >}})) +- 以本品 11.25 mg 剂型治疗期间,最常见(≥5%)的不良反应有:潮热、骨痛、头痛、腿水肿、腿痛。([6.1]({{< ref "#clinical-trails" >}})) +- 以本品 22.5 mg 剂型治疗期间,最常见(≥5%)的不良反应有:潮热、勃起障碍、睾丸萎缩。([6.1]({{< ref "#clinical-trails" >}})) + +**如需报告任何疑似不良反应,请致电 Verity 制药公司:1-844-837-4891,或致电美国 FDA:1-800-FDA-1088。另可登录 。** + +### 特殊人群用药 {#highlights-specific-populations} + +- 妊娠妇女:本品可能对胎儿有害。([5.9]({{< ref "#embryofetal-toxicity" >}}))([8.1]({{< ref "#pregnancy" >}})) +- 有生育力的女性和男性:本品可损害生育力。([8.3]({{< ref "#reproductive-potential" >}})) + +### 药物相互作用 {#highlights-drug-interactions} + +无。([7]({{< ref "#drug-interactions" >}})) + +**对患者的劝告提示请参见[第十七章]({{< ref "#patient-counseling" >}})。** + +**修订日期:2023 年 3 月** + +-------- + +## 处方说明书详情 {#full-info} + +## 一、适应症 {#indications} + +本品用于治疗晚期前列腺癌。——参见“临床研究”([14]({{< ref "#clinical-studies" >}})) + + +## 二、用法用量 {#dosage} + +### 2.1 使用说明 {#dosing-info} + +本品*必须在医师指导下使用*。 + +本品用于单侧臀部进行单次肌注。用药排期取决于所用剂型(见表一)。本品所含冻干微粒仅可于***无菌水***中复溶;***不得使用其它溶剂***。 + +
+ +**「表一」本品建议用法** + +```csv +剂量,3.75 mg,11.25 mg,22.5 mg +建议用法,每四周注射一次,每 12 周注射一次,每 24 周注射一次 +``` + +
+ +因释放特性不同,以上剂型不可混用,必须依所需注射间隔来选择剂型。\ +复溶后形成的悬浮液应立即使用。\ +和其它用于肌注的药物类似,注射部位应定期轮换。\ +胃肠外给药前,在溶液和容器允许的情况下,应目视溶液是否存在颗粒物和变色。 + +### 2.2 采用 Mixject® 系统复溶本品的步骤说明 {#mixject} + +**重要提示:** 在启用 Mixject 和用药之前,请阅读以下全部说明,让患者准备好接受注射。 + +{{< figure src="trelstar-0.png" width="75%" >}} + +> **Mixject 准备和启用说明** + +启用 Mixject 之前,即以香皂和热水清洗双手,并戴上手套。将未启封的托盘置于覆盖无菌垫或无菌布的洁净、平整表面上。揭开托盘密封膜,取出 Mixject 组件和西林瓶。 + +| 步骤 | 详解 | +|-|-| +| **步骤一:准备西林瓶** {{< figure src="trelstar-1.png" width="30%" >}} | 揭开西林瓶上的翻盖,露出橡胶塞。
将西林瓶直立放置于操作面的右上方。
用酒精棉签给橡胶塞消毒。
弃置酒精棉签,待橡胶塞表面干燥。 | +| **步骤二:安装 Mixject 药瓶连接器** {{< figure src="trelstar-2.png" >}} | 从装有西林瓶连接器的泡罩包装上揭去密封膜。***请勿移除泡罩包装。***
在水平面上,将装有西林瓶连接器的泡罩包装轻轻放置于西林瓶之上;
***刺穿西林瓶时,确保刺针处于中心且垂直***。
缓慢按下,直至连接器到位并发出“咔嗒”声。

移除泡罩包装。确认连接器与西林瓶锁定紧密。 | +| **步骤三:安装注射器** {{< figure src="trelstar-3.png" >}} | (a) 将活塞杆旋进注射器针管末端的灰色活塞。
用拇指和食指握住针管口的塑料锁钮,将针管的灰色橡胶盖旋出并弃置。

(b) 继续握住锁钮,确保时刻观察到连接过程。
将注射器对准西林瓶连接器侧面的开孔,顺时针旋转锁钮,使二者连通。
***缓慢旋转,直至无法继续旋转,以确保连接紧密。***
(用力过度可导致连接松弛,出现漏液) | +| **步骤四:将溶剂推入西林瓶** {{< figure src="trelstar-4.png" >}} | 将组合体安全持于右上方,同时缓慢推入活塞,使***所有溶剂***推入西林瓶。
确保溶剂冲到西林瓶边缘。
保持活塞杆于低位,切勿拉伸。 | +| **步骤五:将本品混合成悬浮液** {{< figure src="trelstar-5.png" >}} | 保持活塞杆于低位,轻轻抓住西林瓶和西林瓶连接器;
***用力摇动 30 秒,使瓶中成分充分混合***。

悬浮液应是均匀且浑浊的。为避免沉积,***应立即执行步骤六***。
本品复溶后须在***两分钟内***注射完毕。

**注:** 如西林瓶中出现沉积,应再次摇动之。 | +| **步骤六:将本品装入注射器** {{< figure src="trelstar-6a.png" >}} {{< figure src="trelstar-6b.png" width="70%" >}} | (a) 翻转组合体,使西林瓶倒置。
从针管和针管锁钮处轻轻握住组合体;
缓慢拉伸活塞杆,使复溶药剂吸入注射器,***同时保持活塞压力恒定***。

(b) 旋转组合体,使注射器垂直向上。
将气泡从注射器排出,但切勿使液面高于锁钮。 | +| **步骤七:分离西林瓶连接器**
{{< figure src="trelstar-7.png" >}} | 将西林瓶举到右上方。
**轻轻抓住针管和针管锁钮。**
用另一只手抓住西林瓶连接器的塑料盖,顺时针旋转,使其与注射器分离。
操作时***仅可抓住连接器盖子***。 | +| **步骤八:针头准备**
{{< figure src="trelstar-8.png" >}} | 先确认患者已准备好接受注射。
注射前,将注射器翻转至少五次,使颗粒均匀分布。
提起安全盖,移除针头外的透明塑料壳。
安全盖应与针头垂直;针头应背对您的视线。
***切勿举起针头。***

至此,注射器已准备完毕。
***复溶后的悬浮液应立即注射(两分钟内)***,以免过度增稠。 | +| **步骤九:注射**
{{< figure src="trelstar-9.png" >}} | 将针头对准臀大肌,垂直刺入,进行注射。
确保所有药液于十秒内不间断注射完毕。

注射部位应轮换。| +| **步骤十:安全处置注射器**
{{< figure src="trelstar-10.png" >}} | 注射后,立即用拇指或食指对准安全盖上的防滑纹理处中央;
按压安全盖直至到位(听到声音或感到被锁定),盖住针头,以策安全。
单手操作时,应使注射器远离您和其他人。
注射器单次使用后需立即弃置到尖锐物废弃桶中。 | + + +## 三、性状与成分含量 {#forms} + +本品为注射用悬浮液,每份 3.75 mg、11.25 mg 或 22.5 mg。 + + +## 四、禁忌症 {#contraindications} + +### 4.1 超敏反应 {#hypersensitivity} + +已知对曲普瑞林或本品其它成分过敏者,以及对其它 GnRH 激动剂或 GnRH 过敏者,禁用本品。——参见“警告和注意事项”([5.1]({{< ref "#hypersensitivity-reactions" >}})) + + +## 五、警告和注意事项 {#warnings-precautions} + +### 5.1 超敏反应 {#hypersensitivity-reactions} + +已有与使用曲普瑞林相关的过敏性休克、超敏反应和血管性水肿报告。如出现超敏反应,应立即停用本品,并予以适当支持和对症治疗。 + +### 5.2 血清睾酮的短暂升高 {#transient-increase-t} + +和其它 GnRH 激动剂相似,曲普瑞林在用药初期会引起血清睾酮水平的短暂升高。已有使用 GnRH 激动剂前期的数周内因此出现前列腺癌征兆和症状恶化的散发病例报告。可能恶化或新发的症状有:骨痛、神经病变、血尿、尿道或膀胱口阻塞等。——参见“药理毒理”([12.2]({{< ref "#pharmacodynamics" >}})) + +### 5.3 转移性脊椎损伤和尿道阻塞 {#metastatic-vertebral-lesions} + +已有使用 GnRH 激动剂引起脊椎压迫的病例报告;其中有的可导致无力或瘫痪,甚至致命性并发症。如出现脊椎压迫或肾功能损害,应就此采取标准治疗;严重者考虑立即行睾丸切除术。 + +对于患有转移性脊椎损伤和/或上、下尿道阻塞的患者,应在治疗开始后数周内密切观察。 + +### 5.4 对 QT/QTc 间期的影响 {#effect-qt-interval} + +雄激素去除治疗可使得 QT/QTc 间期延长。对于患有先天性长 QT 综合征、先天性心衰竭、频发性电解质紊乱的患者,以及正服用已知可延长 QT 间期之药物的患者,医师应考虑雄激素去除治疗的收益是否大于其潜在风险。对于电解质紊乱应予以纠正。考虑定期监测心电图和电解质。 + +### 5.5 高血糖和糖尿病 {#hyperglycemia} + +已有男性使用 GnRH 激动剂后引起高血糖,且糖尿病发生风险升高的报告。高血糖可能意味着糖尿病发展;对于糖尿病患者,这意味着血糖控制作用减弱。\ +对于使用 GnRH 激动剂的患者,要定期监测血糖和/或糖化血红蛋白(HbA1c);对于高血糖或糖尿病的治疗,依现有实践进行处置。 + +### 5.6 心血管疾病 {#cardiovascular-diseases} + +男性中已有与使用 GnRH 激动剂相关的心肌梗塞、心源性猝死和卒中风险升高的报告。由于报告率很低,以上风险应该较低;在为前列腺癌患者制订治疗方案时,应综合其心血管风险因素对该风险进行研判。\ +对于使用 GnRH 激动剂的患者,应监测其是否出现心血管疾病相关症状或体征,并依现有医学实践处置。 + +### 5.7 实验室检测事项 {#laboratory-tests} + +应定期或按需测量血清睾酮水平,以监测对本品的反馈效果。 + +### 5.8 与实验室检测结果的相互作用 {#laboratory-test-interactions} + +长期或连续使用曲普瑞林,会抑制脑垂体—性腺轴功能。如在治疗期间和治疗停止时对脑垂体—性腺轴功能进行诊断测试,则结果可能有误导之嫌。 + +### 5.9 胚胎/胎儿毒性 {#embryofetal-toxicity} + +从动物研究结果和本品的作用机理看,本品用于妊娠妇女可能对胎儿有害。——参见“药理毒理”([12.1]({{< ref "#mechanism-action" >}}))\ +在动物发育和生殖毒理研究中,妊娠大鼠在器官形成期每日给予曲普瑞林(剂量以体表面积计,相当于人体每日大致剂量的 0.2 倍、0.8 倍和 8 倍),对母亲和胚胎/胎儿均造成毒性,后果包括流产。\ +告诫妊娠患者和有生育力的妇女,本品可能对胎儿有害。——参见“特殊人群用药”([8.1]({{< ref "#pregnancy" >}})) + + +## 六、不良反应 {#adverse-reactions} + +### 6.1 来自临床试验的报告 {#clinical-trails} + +因各临床试验的条件不同,无法将一种药物在临床试验中的不良反应发生率,与另一种药物的不良反应发生率进行直接比较;其也并非反映实际发生率。 + +已有临床试验就本品三种剂型用于晚期前列腺癌患者的安全性进行评价。初次注射后的第一周,睾酮平均水平较基线有所上升;此后,在第二周末降至基线或基线以下。睾酮水平的短暂上升可能与一系列症状或体征的短暂性恶化有关,包括骨痛、神经病变、血尿、尿道或膀胱口阻塞等。已有脊椎压迫并发下肢无力或瘫痪的散发病例报告。——参见“警告和注意事项”([5.3]({{< ref "#metastatic-vertebral-lesions" >}})) + +临床试验中所报告的本品三种剂型的不良反应,见表二、表三和表四。通常对于转移性前列腺癌患者,难以确立本品与不良反应之间的因果关系。\ +在与曲普瑞林相关的不良反应中,绝大部分是出于其药理作用——即促使血清睾酮水平发生变化,在治疗初期增加,或在去势效果达成后睾酮减少——之缘故。还可能会发生注射部位局部反应或过敏反应。 + +以下不良反应在使用本品 3.75 mg 剂型的患者中报告率达 1% 以上,被医师认为可能与本品的治疗存在关联: + +
+ +**「表二」Trelstar 3.75 mg:与治疗相关的,患者治疗期间报告率达 1% 以上的不良反应** + +```csv +不良反应 \*,人数\n(共 140 人),% +**给药部位症状**,, +注射部位疼痛,5,3.6 +**全身性症状**,, +潮热,82,58.6 +疼痛,3,2.1 +腿痛,3,2.1 +疲乏,3,2.1 +**心血管疾病**,, +高血压,5,3.6 +**中枢和外围神经系统症状**,, +头痛,7,5.0 +眩晕,2,1.4 +**胃肠道疾病**,, +腹泻,2,1.4 +呕吐,3,2.1 +**肌肉骨骼疾病**,, +骨痛,17,12.1 +**精神疾病**,, +失眠,3,2.1 +阳萎,10,7.1 +情绪不稳,2,1.4 +**红细胞疾病**,, +贫血,2,1.4 +**皮肤和附肢疾病**,, +瘙痒,2,1.4 +**泌尿系统疾病**,, +尿道感染,2,1.4 +尿潴留,2,1.4 +``` + +\* 注:Trelstar 3.75 mg 之不良反应依 WHO 不良反应术语表(WHOART)进行分类 + +
+ +以下不良反应在使用本品 11.25 mg 剂型的患者中报告率达 1% 以上,被医师认为可能与本品的治疗存在关联: + +
+ +**「表三」Trelstar 11.25 mg:与治疗相关的,患者治疗期间报告率达 1% 以上的不良反应** + +```csv +不良反应 \*,人数\n(共 174 人),% +**给药部位症状**,, +注射部位疼痛,7,4.0 +**全身性症状**,, +潮热,127,73.0 +腿痛,9,5.2 +疼痛,6,3.4 +背痛,5,2.9 +疲乏,4,2.3 +胸痛,3,1.7 +无力,2,1.1 +外周性水肿,2,1.1 +**心血管疾病**,, +高血压,7,4.0 +坠积性水肿,4,2.3 +**中枢和外围神经系统症状**,, +头痛,12,6.9 +眩晕,5,2.9 +腿绞痛,3,1.7 +**内分泌疾病**,, +乳房疼痛,4,2.3 +男性乳房发育,3,1.7 +**胃肠道疾病**,, +恶心,5,2.9 +便秘,3,1.7 +食欲不振,3,1.7 +腹泻,2,1.4 +腹痛,2,1.1 +**肝胆疾病**,, +肝功能异常,2,1.1 +**代谢与营养类疾病**,, +腿水肿,11,6.3 +碱性磷酸酶升高,3,1.7 +**肌肉骨骼疾病**,, +骨痛,23,13.2 +关节痛,4,2.3 +肌痛,2,1.1 +**精神类疾病**,, +性欲降低,4,2.3 +阳萎,4,2.3 +失眠,3,1.7 +厌食,3,1.7 +**呼吸系统疾病**,, +咳嗽,3,1.7 +呼吸急促,2,1.1 +咽炎,2,1.1 +**皮肤和附肢疾病**,, +皮疹,3,1.7 +**泌尿系统疾病**,, +尿痛,8,4.6 +尿潴留,2,1.1 +**视力疾病**,, +眼痛,2,1.1 +结膜炎,2,1.1 +``` + +\* 注:Trelstar 11.25 mg 之不良反应依 WHO 不良反应术语表(WHOART)进行分类 + +
+ +以下不良反应在使用本品 22.5 mg 剂型的患者中报告率达 5% 以上;并非所有不良反应均被医师认为与本品存在关联。下表还列出了被医师认为存在合理关系、或无法建立因果关系的不良反应之发生率。 + +
+ +**「表四」Trelstar 22.5 mg:患者(120 人)治疗期间报告率达 5% 以上的不良反应** + +```csv +不良反应 \*,治疗中突发\n(例),%,与治疗相关\n(例),% +**全身性和给药部位症状**,,,, +外周性水肿,6,5.0,0,0 +**传染病和感染性疾病**,,,, +流感,19,15.8,0,0 +支气管炎,6,5.0,0,0 +**内分泌疾病**,,,, +糖尿病/高血糖,6,5.0,0,0 +**肌肉骨骼和结缔组织疾病**,,,, +背痛,13,10.8,1,0.8 +关节痛,9,7.5,1,0.8 +四肢痛,9,7.5,1,0.8 +**神经系统疾病**,,,, +头痛,9,7.5,2,1.7 +**精神类疾病**,,,, +失眠,6,5.0,1,0.8 +**肾脏和泌尿系统疾病**,,,, +尿道感染,14,11.6,0,0 +尿潴留,6,5.0,0,0 +**生殖系统和乳房疾病**,,,, +勃起障碍,12,10.0,12,10.0 +睾丸萎缩,9,7.5,9,7.5 +**血管疾病**,,,, +潮热,87,72.5,86,71.7 +高血压,17,14.2,1,0.8 +``` + +\* 注:Trelstar 22.5 mg 之不良反应依《监管活动医学词典》(MedDRA)进行分类 + +
+ +> **治疗期间实验室检测结果的变化** + +有 10% 以上患者结果异常(未见于基线)的实验室检测项目如下。 + +- *Trelstar 3.75 mg*:治疗期间未见任何有临床意义的检测结果变化。 +- *Trelstar 11.25 mg*:在第 253 天的随访中,血红蛋白和红细胞计数(RBC)降低;血糖、胆红素(BUN)、谷草转氨酶(SGOT)、谷丙转氨酶(SGPT)和碱性磷酸酶升高。 +- *Trelstar 22.5 mg*:研究中发现血红蛋白减少;血糖和肝转氨酶升高。大多数变幅均为轻至中度。 + +### 6.2 上市后的不良反应报告 {#postmarketing-experience} + +自促性腺激素释放激素激动剂被批准使用以来,已识别到以下不良反应。这些不良反应来自使用者自发报告,规模不明,故无法准确估计其发生率、或建立与药物暴露的因果关系。 + +上市后监测中,已有罕见的、使用促性腺激素释放激素激动剂之后出现垂体卒中(严重性仅次于垂体梗死的临床症状)的病例报告。其中,多数病例在初次用药后两周内、甚至一小时内即被确诊;多数病例被确诊为垂体腺瘤;垂体卒中表现为急性头痛、呕吐、视力改变、眼肌瘫痪、意识改变,有的还发生心血管闭塞。这种情况下需立即就医。 + +上市以来,以下不良反应已被报告:惊厥、间质性肺病和血栓栓塞事件(包括但不限于肺栓塞、脑梗、心肌梗塞、深静脉血栓、短暂性脑缺血和血栓性静脉炎等)。 + + +## 七、药物相互作用 {#drug-interactions} + +尚未对曲普瑞林与任意一种药品之间的相互作用进行研究。 + +人体内曲普瑞林的药代动力学资料表明,由组织降解产生的 C-末端片段在组织内被完全降解,或在血浆中被迅速降解,或被肾脏清除。因此,肝微粒体酶不大可能参与曲普瑞林之代谢。\ +然而,对于可诱发高泌乳素水平的药物,尽管尚缺乏相关资料,但考虑到高泌乳素血症可使得垂体 GnRH 受体数量减少,应注意不将其与曲普瑞林并用。 + + +## 八、特殊人群用药提示 {#specific-populations} + +### 8.1 妊娠妇女用药 {#pregnancy} + +> **风险概述** + +从动物试验结果和本品的作用机理看,本品用于妊娠妇女时可能对胎儿有害。——参见“药理毒理”([12.1]({{< ref "#mechanism-action" >}}))\ +以本品治疗后可预见的激素变化,会增加流产风险。在动物发育和生殖毒理研究中,妊娠大鼠在器官分化期每日给予曲普瑞林(剂量以体表面积计,相当于人体每日大致剂量的 0.2 倍、0.8 倍和 8 倍),对母亲和胚胎/胎儿均造成毒性,后果包括流产。\ +告诫妊娠患者和有生育力的妇女,本品可能对胎儿有害。 + +> **研究资料** + +*动物试验资料:*\ +研究中,妊娠大鼠在器官分化期每日给予曲普瑞林 2、10 和 100 μg/kg/天(按体表面积计,相当于人体日均剂量的约 0.2 倍、0.8 倍和 8 倍),结果母亲和胚胎/胎儿均产生毒性反应。其中,高剂量下的胚胎/胎儿毒性表现为着床前流产、再吸收增加,以及平均活胎数减少等。\ +未观察到曲普瑞林对大鼠或小鼠活胎存在致畸作用。小鼠给予的剂量为 2、20 和 200 μg/kg/天(按体表面积计,相当于人体日均剂量的约 0.1 倍、0.7 倍和 7 倍)。 + +### 8.2 哺乳期妇女用药 {#lactation} + +本品用于女性的安全性和有效性尚未确立。尚无资料表明曲普瑞林是否会分泌到人乳汁、对乳汁分泌有何作用、或对母乳喂养的婴儿有何影响。由于本品对母乳喂养的婴儿可能会引起严重不良反应,故应综合考虑本品对母亲的重要性,选择以下其中一项:1) 停止母乳喂养;2) 停用本品。 + +### 8.3 有生育力的女性和男性用药 {#reproductive-potential} + +> **致不育性** + +*男性:*\ +从本品的作用机理看,本品可能损害可生育男性的生育力。——参见“药理毒理”([12.1]({{< ref "#mechanism-action" >}})) + +### 8.4 儿童用药 {#pediatric-use} + +本品对儿童患者的安全性和有效性尚未确立。 + +### 8.5 老年用药 {#geriatric-use} + +前列腺癌多见于老年群体。有关本品的临床研究大多都针对 65 岁以上患者进行。——参见“药理毒理”([12.3]({{< ref "#pharmacokinetics" >}}))和“临床研究资料”([14]({{< ref "#clinical-studies" >}})) + +### 8.6 肾功能不全者用药 {#renal-impairment} + +肾功能不全群体的药物暴露量高于健康年轻男性。——参见“药理毒理”([12.3]({{< ref "#pharmacokinetics" >}})) + +### 8.7 肝功能不全者用药 {#hepatic-impairment} + +肝功能不全群体的药物暴露量高于健康年轻男性。——参见“药理毒理”([12.3]({{< ref "#pharmacokinetics" >}})) + + +## 十、药物过量 {#overdosage} + +临床研究中未见有关药物过量的记录。\ +在大鼠、小鼠单次用药毒理研究中,曲普瑞林经皮下注射后,半数致死剂量(LD50)分别为 250 mg/kg 和 400 mg/kg;以体表面积计,此剂量分别相当于人体月均剂量的约 600 倍和 500 倍。\ +如出现药物过量,应立即停止治疗,并予以适当支持和对症治疗。 + + +## 十一、本品成分详情 {#description} + +本品为白色或淡黄色冻干块状物。复溶后,本品呈浑浊状。本品含曲普瑞林帕莫酸盐,曲普瑞林是促性腺激素释放激素(GnRH)的一种人工十肽激动剂类似物。 + +- **通用名**:帕莫酸曲普瑞林 +- **化学名称**:5-氧代-L-脯氨酰基-L-组氨酰基-L-色氨酰基-L-丝氨酰基-L-酪氨酰基-D-色氨酰基-L-亮氨酰基-L-精氨酰基-L-脯氨酰基甘氨酰胺(帕莫酸盐) +- **化学式**:C64H82N18O13·C23H16O6 +- **分子量**:1699.9 +- **化学结构式**:见下 +- *CAS:124508-66-3* + +{{< figure src="trelstar-11.jpg" >}} + +本品以装有无菌可降解冻干微粒的一次性西林瓶的形式提供。产品所含成分见表五。 + +
+ +**「表五」Trelstar 产品所含成分** + +```csv +成分,Trelstar\n3.75 mg,Trelstar\n11.25 mg,Trelstar\n22.5 mg +帕莫酸曲普瑞林(基本单位),3.75 mg,11.25 mg,22.5 mg +共聚酸,138 mg,120 mg,183 mg +甘露醇(USP),71 mg,74 mg,74 mg +羧甲基纤维素钠(USP),25 mg,26 mg,26 mg +聚山梨酯 80(NF),1.7 mg,1.7 mg,1.7 mg +``` + +
+ +向装有本品的西林瓶注入 2 mL 无菌水并摇匀后,可得用于肌注的悬浮液。本品以西林瓶、Mixject 西林瓶连接器和预灌封无菌水(USP)2 mL 的注射器组合之形式上市。 + + +## 十二、药理毒理 {#pharmacology} + +### 12.1 作用机理 {#mechanism-action} + +曲普瑞林是促性腺激素释放激素(GnRH)的一种人工十肽激动剂类似物。体外对比研究显示,在对分散单层培养的大鼠垂体细胞释放促黄体激素的刺激作用上,曲普瑞林的作用强度相当于原生 GnRH 的 100 倍;在对垂体受体结合点上以碘-125 标记的 GnRH 之置换作用上,曲普瑞林的作用强度相当于原生 GnRH 的 20 倍。动物研究中发现,帕莫酸曲普瑞林对促黄体激素、促卵泡激素之释放的刺激作用,分别相当于原生 GnRH 的 13 倍和 21 倍。 + +### 12.2 药效学特性 {#pharmacodynamics} + +初次用药后,循环促黄体激素(LH)、促卵泡激素(FSH)、睾酮和雌二醇水平会有短暂升高。——参见“不良反应”([6]({{< ref "#adverse-reactions" >}}))\ +长期连续用药后,从治疗第 2~4 周后起,观察到 LH 和 FSH 分泌量降低并维持,同时睾丸性激素合成大幅减少。最终,血清睾酮浓度降至与去势男性相当的水平。结果是,需要相关激素维持的组织和身体功能停止活动。以上效果通常在停药后可逆。 + +单次肌注本品之后: + +- *Trelstar 3.75 mg*:健康男性志愿者中,血清睾酮水平在初期升高,于第 4 日达峰,此后到第 4 周降至低水平。 +- *Trelstar 11.25 mg*:男性晚期前列腺癌患者中,血清睾酮水平在初期升高,于第 2~3 日达峰,此后到第 3~4 周降至低水平。 +- *Trelstar 22.5 mg*:男性晚期前列腺癌患者中,血清睾酮水平在初期升高,于第 3 日达峰,此后到第 3~4 周降至低水平。 + +### 12.3 药代动力学特性 {#pharmacokinetics} + +药代动力学研究结果显示,健康男性单次静脉推注曲普瑞林后,其分布和清除遵循三室模型,半衰期分别约为 6 分钟、45 分钟和 3 小时。 + +> **吸收** + +前列腺癌患者单次肌注本品 3.75 mg、11.25 mg 和 22.5 mg 剂型之后,血药浓度在 1~3 小时内达峰,平均峰值分别为 28.4 ng/mL、38.5 ng/mL 和 44.1 ng/mL。\ +在连续 9 个月(3.75 mg 和 11.25 mg 剂型)或 12 个月(22.5 mg)的治疗期间,曲普瑞林并未在体内蓄积。 + +> **分布** + +健康男性志愿者单次静脉推注曲普瑞林 0.5 mg 之后,其分布容积为 30~33 L。\ +无证据表明曲普瑞林在临床相关的浓度下会与血浆蛋白结合。 + +> **清除** + +*代谢:*\ +曲普瑞林在人体中的代谢机理尚不清楚,但已知肝微粒体酶(细胞色素 P-450)参与代谢的可能性不大。曲普瑞林对其它药物代谢酶之活性的影响也尚不清楚。目前为止,尚未发现曲普瑞林的任何代谢物。\ +曲普瑞林的药代动力学资料表明,由组织降解产生的 C-末端片段在组织内被完全降解,或在血浆中被迅速降解,或被肾脏清除。 + +*排泄:*\ +曲普瑞林被肝脏和肾脏清除。六名健康男性志愿者(肌酐清除率 149.9 mL/min)单次静脉推注曲普瑞林 0.5 mg 之后,摄入量的 41.7% 以原形经尿液排出;总清除率为 211.9 mL/min。对于肝病患者(肌酐清除率 89.9 mL/min),该比例增至 62.3%。\ +此外,还观察到曲普瑞林在无尿患者(肌酐清除率为零)当中的非肾脏清除率为 76.2 mL/min,提示曲普瑞林的非肾脏清除主要依赖于肝脏。 + +> **特殊人群的药代动力学** + +*年龄和人种:*\ +尚未就年龄和人种对曲普瑞林药代动力学的影响进行系统研究。但是,从曲普瑞林用于肌酐清除率较高(约 150 mL/min)的 20~22 岁健康年轻男性志愿者的药代动力学资料来看,该群体中曲普瑞林的清除率相当于中度肾功能不全患者的两倍。这印证了曲普瑞林清除率和总肌酐清除率存在一定联动关系的事实,而后者已知随年龄降低。——参见“特殊人群用药”([8.6]({{< ref "#renal-impairment" >}}))和([8.7]({{< ref "#hepatic-impairment" >}})) + +*儿童群体:*\ +尚未就本品用于 18 岁以下患者的情况进行评价。——参见“特殊人群用药”([8.4]({{< ref "#pediatric-use" >}})) + +*肝功能和肾功能不全群体:*\ +单次静脉推注曲普瑞林 0.5 mg 之后,分布半衰期未受肾功能或肝功能不全影响。然而,肾功能不全不仅导致肌酐清除率降低,还导致曲普瑞林总清除率等比例的下降,并使得分布容积增加、清除半衰期延长(见表六)。\ +在肝功能不全的受试者中,曲普瑞林清除率的降幅相较肾功能不全者更为显著。由于分布容积增加甚微,该药的清除半衰期在肝功能不全者和肾功能不全者当中基本相当。肝/肾功能不全者的总暴露剂量(AUC)相当于健康年轻男性的 2~4 倍。——参见“特殊人群用药”([8.6]({{< ref "#renal-impairment" >}}))和([8.7]({{< ref "#hepatic-impairment" >}})) + +
+ +**「表六」健康志愿者和特殊人群中,静脉推注曲普瑞林 0.5 mg 之后的药代动力学参数(平均值 ± 标准差)** + +```csv +组别,血药浓度峰值\nCmax\n(ng/mL),总暴露剂量\nAUCinf\n(h·ng/mL),总血浆清除率\nClp\n(mL/min),肾脏清除率\nClrenal\n(mL/min),清除半衰期\nt1/2\n(h),肌酐清除率\nClcreat\n(mL/min) +健康男性志愿者 6 人,48.2 ± 11.8,36.1 ± 5.8,211.9 ± 31.6,90.6 ± 35.3,2.81 ± 1.21,149.9 ± 7.3 +患中度肾功能不全的男性 6 人,45.6 ± 20.5,69.9 ± 24.6,120.0 ± 45.0,23.3 ± 17.6,6.56 ± 1.25,39.7 ± 22.5 +患重度肾功能不全的男性 6 人,46.5 ± 14.0,88.0 ± 18.4,88.6 ± 19.7,4.3 ± 2.9,7.65 ± 1.25,8.9 ± 6.0 +有肝脏疾病的男性 6 人,54.1 ± 5.3,131.9 ± 18.1,57.8 ± 8.0,35.9 ± 5.0,7.58 ± 1.17,89.9 ± 15.1 +``` + +
+ + +## 十三、非临床毒理资料 {#nonclinical-toxicology} + +### 13.1 致癌性、致突变性与不育作用 {#carcinogenesis} + +大鼠每 28 日给予曲普瑞林 120、600 和 3000 μg/kg(以体表面积计,相当于人体月均剂量的约 0.3 倍、2 倍和 8 倍),持续 13~19 个月;该药造成了死亡率升高,且良性和恶性垂体肿瘤和组织肉瘤发生率增加(与剂量相关)。\ +小鼠每 28 日给予曲普瑞林至多 6000 μg/kg(以体表面积计,相当于人体月均剂量的约 8 倍),持续 18 个月;未观察到任何致癌作用。 + +致突变性研究中,细菌和哺乳类细胞试验(体外 Ames 试验、CHO 细胞染色体畸变试验和体内小鼠微核试验)均未表明曲普瑞林存在致突变潜力。 + +雌性大鼠中,在经历至少四轮发情期并配偶之前,连续 60 日皮下注射曲普瑞林生理盐水溶液 2、20 和 200 μg/kg/天(以体表面积计,相当于人体日均剂量的 0.2 倍、2 倍和 16 倍),或者两个月内每月注射一次曲普瑞林缓释微粒(约 20 μg/kg/天),未对其生育力或一般生殖功能造成影响。 + +尚未就曲普瑞林对雄性个体生育力的影响进行研究。 + +## 十四、临床研究资料 {#clinical-studies} + +### *Trelstar 3.75 mg* {#studies-3.75} + +一项随机主动对照试验将本品 3.75 mg 剂型用于患有晚期前列腺癌的 277 名男性。受试群体中,白人占 59.9%,黑人占 39.3%,其余人种占 0.8%;未观察到不同人种对曲普瑞林之反馈有任何差异。受试者年龄介乎 47~89 岁,平均 71 岁。一部分患者(140 人)给予本品 3.75 mg 剂型,其余给予已批准的 GnRH 激动剂;九个月内每月用药一次。主要疗效终点为:1) 治疗第 29 日前达成去势效果;2) 治疗的第 57~253 日维持去势效果。 + +在第 29 日,接受本品 3.75 mg 治疗的 137 人中,有 125 人(91.2%)的血清睾酮达去势水平(≤ 1.735 nmol/L,即 50 ng/dL);在第 57 日,有 97.7% 的血清睾酮达去势水平。此后在第 57~253 日,有 96.2% 的血清睾酮维持于去势水平。 + +研究中还将慢性病急性加重现象作为次要疗效终点。\ +第 85 日和第 169 日,在注射本品 3.75 mg 之后两小时,对血清 LH 水平进行测定。第 85 日,在有可比数据的 126 名患者中,有 124 人(98.4%)用药后两小时的血清 LH 水平 ≤ 1.0 IU/L,提示垂体促性腺激素细胞受体被去敏化。 + +### *Trelstar 11.25 mg* {#studies-11.25} + +一项随机主动对照试验将本品 11.25 mg 剂型用于患有晚期前列腺癌的 346 名男性。受试群体中,白人占 48%,黑人占 38%,其余人种占 15%;未观察到不同人种对曲普瑞林之反馈有任何差异。受试者年龄介乎 45~96 岁,平均 71 岁。一部分患者(174 人)给予本品 11.25 mg 剂型,每 12 周用药一次,至多三次(最大治疗时长 253 日);其余(172 人)给予本品 3.75 mg,每 28 日用药一次,至多九次。主要疗效终点为:1) 治疗第 29 日前达成去势效果;2) 治疗的第 57~253 日维持去势效果。 + +在第 29 日,接受本品 11.25 mg 治疗的 171 人中,有 167 人(97.7%)的血清睾酮达去势水平(≤ 1.735 nmol/L,即 50 ng/dL);此后在第 57~253 日,有 94.4% 的血清睾酮维持于去势水平。 + +### *Trelstar 22.5 mg* {#studies-22.5} + +一项非对照试验将本品 22.5 mg 剂型用于患有晚期前列腺癌的 120 名男性。受试群体中,白人占 64%,黑人占 23%,其余人种占 13%;年龄介乎 51~93 岁,平均 71.1 岁。患者(120 人)给予本品 22.5 mg,每 24 周用药一次,至多两次(最大治疗时长 337 日)。主要疗效终点有:1) 治疗第 29 日前达成去势效果;2) 治疗的第 57~337 日维持去势效果。 + +在第 29 日,接受本品 22.5 mg 治疗的 120 人中,有 117 人(97.5%)的血清睾酮达去势水平(≤ 1.735 nmol/L,即 50 ng/dL);此后在第 57~337 日,有 93.3% 维持去势效果。 + +上述有关 Trelstar 的临床研究结果汇总于表七。 + +
+ +**「表七」Trelstar 临床试验概览** + +```csv +有效成分含量,3.75 mg,11.25 mg,22.5 mg +**受试患者人数**,137,171,120 +**用药间期**,四周,十二周,二十四周 +**研究时长**,253 日,253 日,337 日 +**第 29 日达成去势效果者占比**(1),125/137\n(91.2%),167/171\n(97.7%),117/120\n(97.5%) +**第 57~253 日维持去势效果者占比**(2),96.2%,94.4%,无数据 +**第 57~337 日维持去势效果者占比**,无数据,无数据,112/120\n(93.3%)(3) +``` + +(1) 此处采用频率分布法计算去势效果是否维持。\ +(2) 此处采用卡普兰-梅耶(Kaplan-Meier)生存曲线计算去势效果的累计维持率。\ +(3) 此处纳入 5 名提前退出研究,但退出前睾酮已达去势水平的患者。 + +
+ + +### 十六、本品性状,包装及贮藏事项 {#supplied-handling} + +本品以 Trelstar Mixject 一次性使用组合系统的形式提供,其中包含:一支有盖西林瓶,内有以可降解乳酸—羟基乙酸共聚物(共聚酸)包裹的帕莫酸曲普瑞林无菌冻干微粒;一只 Mixject 西林瓶连接器;一支预灌封注射用无菌水(USP)2 mL 的注射器。 + +*Trelstar 3.75 mg*——NDC 74676-5902-1(TRELSTAR 3.75 mg 和 Mixject 一次性使用组合系统)\ +*Trelstar 11.25 mg*——NDC 74676-5904-1(TRELSTAR 11.25 mg 和 Mixject 一次性使用组合系统)\ +*Trelstar 22.5 mg*——NDC 74676-5906-1(TRELSTAR 22.5 mg 和 Mixject 一次性使用组合系统) + +#### 贮藏事项 {#storage} + +20~25°C(68~77°F)保存。——参见《美国药典》(USP)“室内恒温”\ +切勿将本品和 Mixject 冷冻保存。 + + +## 十七、对患者的劝告提示 {#patient-counseling} + +> **超敏反应** + +提醒患者,如在早前使用其它类似于本品的 GnRH 激动剂时曾出现超敏反应,则不得使用本品。——参见“禁忌症”([4]({{< ref "#contraindications" >}})) + +> **肿瘤暴发** + +提醒患者,本品治疗初期的数周内可引起肿瘤暴发。\ +提醒患者,睾酮水平升高可导致泌尿系统出现疼痛等症状的几率升高。\ +告诫患者,如开始以本品治疗后出现尿道阻塞、脊椎压迫、瘫痪或其它新发症状,或症状恶化,应联系医师。——参见“警告和注意事项”([5.2]({{< ref "#transient-increase-t" >}})) + +> **高血糖和糖尿病** + +告诫患者,本品会使高血糖和糖尿病风险增大。\ +告知患者在以本品治疗期间需定期对高血糖和糖尿病进行监测。——参见“警告和注意事项”([5.5]({{< ref "#hyperglycemia" >}})) + +> **心血管疾病** + +提醒患者,本品可导致心肌梗塞、心源性猝死和卒中的风险增大。\ +告诫患者,当出现与上述事件相关的体征和症状时,需立即向医师报告以做进一步评估。——参见“警告和注意事项”([5.6]({{< ref "#cardiovascular-diseases" >}})) + +> **泌尿和生殖系统疾病** + +告诫患者,本品可导致阳萎。 + +> **不育作用** + +提醒患者,本品可导致不育。——参见“特殊人群用药”([8.3]({{< ref "#reproductive-potential" >}})) + +> **有关继续以本品治疗的事项** + +提醒患者,当出现转移性、不受去势影响的前列腺癌后,本品一般需连续使用,且常与其它药物并用。——参见“用法用量”([2.1]({{< ref "#dosing-info" >}})) + +-------- + +如需医疗方面的问询请联系:\ +Verity Pharma\ +Medical Affairs\ +1-844-VERITY-1 (1-844-837-4891) + +销售企业:\ +Verity Pharmaceuticals, Inc.\ +Ewing, NJ 08628 + +生产企业:\ +Debiopharm Research & Manufacturing SA\ +CH-1920 Martigny, Switzerland + +Mixject 生产企业:\ +West Pharma. Services IL, Ltd.\ +Ra'anana, Israel + +TRELSTAR® 及其设计元素是 Verity Pharmaceuticals Inc. 的注册商标。\ +MIXJECT® 是 West Pharma. 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