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Lotronex的适应症和用法

Lotronex仅适用于患有以下疾病的严重腹泻为主的肠易激综合征（IBS）的女性：

• 慢性IBS症状（通常持续6个月或更长时间），
• 排除了胃肠道的解剖或生化异常，并且
• 对传统疗法没有足够的反应。

如果腹泻为主的IBS包括腹泻和下列一项或多项，则表示腹泻严重：

• 频繁且严重的腹痛/不适，
• 尿频或大便失禁
• 因IBS而导致的残疾或日常活动受限。

由于与Lotronex相关的罕见但严重的胃肠道不良反应，因此适应症仅限于那些受益于风险平衡最有利的患者。

尚未进行临床研究以充分证实Lotronex对男性的益处。

Lotronex剂量和用法

成年病人

为了降低便秘的风险，Lotronex应该以每天两次0.5 mg的剂量开始服用。以此剂量便秘的患者应停止服用Lotronex，直到便秘消退。它们可以每天一次以0.5 mg重新开始。如果便秘以较低剂量再次出现，应立即停用Lotronex。

每天一次或两次良好控制0.5 mg的患者可以维持该方案。如果4周后剂量耐受性良好，但不能充分控制IBS症状，则可以每天两次将剂量增加至1 mg 。在每天两次1 mg的治疗4周后，如果IBS症状得不到充分控制，则应停用Lotronex。

Lotronex可以与食物一起或不与食物一起服用[参见临床药理学（ 12.3 ）] 。

出现便秘或缺血性结肠炎体征的患者应立即停用Lotronex。发生缺血性结肠炎的患者不应重新使用Lotronex。

临床试验和上市后的经验表明，虚弱的患者或服用减少胃肠蠕动的其他药物的患者，发生便秘严重并发症的风险更大。因此，如果为这些患者开了Lotronex，则应采取适当的谨慎措施并采取后续行动。

上市后的经验表明，老年患者发生便秘并发症的风险更高；因此，如果为这些患者开具Lotronex处方，则应采取适当的谨慎措施并采取后续行动[见警告和注意事项（ 5.1 ）] 。

肝功能不全患者

Lotronex被肝脏广泛代谢，肝功能不全的患者可能会增加Lotronex的暴露量。增加药物暴露可能会增加发生严重不良反应的风险。轻度或中度肝功能不全的患者应谨慎使用Lotronex，严重肝功能不全的患者应禁用Lotronex [见禁忌症（ 4 ），在特定人群中使用（ 8.6 ）]。

剂型和优势

0.5毫克和1毫克片剂

Lotronex片剂0.5毫克（0.562毫克阿洛司琼HCl相当于0.5毫克阿洛司琼）是白色，椭圆形，薄膜包衣的片剂，在其一面上凹陷有GX EX1。

Lotronex片剂1毫克（1.124毫克盐酸阿洛司琼相当于1毫克阿洛司琼）是一种蓝色，椭圆形，薄膜包衣的片剂，表面压制有GX CT1。

禁忌症

便秘

便秘患者不应开始使用Lotronex [请参阅警告和注意事项（ 5.1 ）] 。

严重肠病或肝病的病史

具有以下病史的患者禁用Lotronex：

• 便秘的慢性或严重便秘或后遗症
• 肠梗阻，狭窄，中毒性巨结肠，胃肠道穿孔和/或粘连
• 缺血性结肠炎，肠循环障碍，血栓性静脉炎或高凝状态
• 克罗恩氏病或溃疡性结肠炎
• 憩室炎
• 严重肝功能不全

氟伏沙明的同时使用

禁止同时使用Lotronex和氟伏沙明。氟伏沙明是一种已知的CYP1A2强抑制剂，已显示可将阿洛司琼的平均血浆浓度（AUC）增加约6倍，并将半衰期延长约3倍[见药物相互作用（ 7.1 ）] 。

警告和注意事项

便秘的严重并发症

一些患者在没有警告的情况下经历了严重的便秘并发症。

据报道，在临床试验中，使用Lotronex会导致便秘的严重并发症，包括阻塞，肠梗阻，撞击，中毒性巨结肠和继发性肠缺血。据报道，便秘的并发症是每天两次使用1 mg，剂量较低。对于便秘的严重并发症，尚未建立剂量反应关系。在接受Lotronex或安慰剂治疗的女性中，便秘严重并发症的发生率约为0.1％（每1000名患者中有1名）。此外，售后临床实践还报告了极少的穿孔和死亡病例。在某些情况下，便秘并发症需要肠道手术，包括结肠切除术。老年人，虚弱的人或服用其他降低胃肠蠕动的药物的患者，便秘并发症的风险可能更高。

出现便秘的患者应立即停用Lotronex [见盒装警告]。

缺血性结肠炎

一些患者在没有预警的情况下经历了缺血性结肠炎。

在临床试验以及该药物的市场使用期间，已经报道了接受Lotronex的患者发生缺血性结肠炎。在IBS临床试验中，接受Lotronex的女性在3个月内缺血性结肠炎的累积发生率为0.2％（每千名患者2例，95％置信区间1至3），为0.3％（每千名患者3例，置信区间95％1）。至4）到6个月。据报道缺血性结肠炎每天两次使用1 mg，剂量较低。尚未建立剂量反应关系。据报道一名接受安慰剂的患者发生缺血性结肠炎。对照临床试验中的患者经验不足以估计服用Lotronex超过6个月的患者缺血性结肠炎的发生率。

有缺血性结肠炎迹象的患者应立即停用Lotronex，例如直肠出血，血性腹泻或新的或加剧的腹痛。由于缺血性结肠炎可能危及生命，因此应迅速评估患有缺血性结肠炎的体征或症状的患者，并进行适当的诊断测试。发生缺血性结肠炎的患者不应恢复用Lotronex治疗。

不良反应

标签的其他部分详细说明了以下不良反应：

• 便秘的并发症[请参阅盒装警告，警告和注意事项（ 5.1 ）]
• 缺血性结肠炎[请参阅盒装警告，警告和注意事项（ 5.2 ）]

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在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。

肠易激综合征的患者：表1总结了22次重复剂量研究对IBS患者的不良反应，这些患者每天两次接受1 mg Lotronex治疗8至24周。表1中的不良反应报道在接受Lotronex的患者中占1％或更多，并且在Lotronex上发生的频率高于在安慰剂上。与安慰剂相比，在用Lotronex治疗的患者中观察到便秘的统计学差异显着（p <0.0001）。

胃肠道：便秘是Lotronex治疗的常见且与剂量有关的副作用[请参阅警告和注意事项（ 5.1 ）] 。在临床研究中，据报道，约有29％的IBS患者接受Lotronex 1 mg每天两次治疗（n = 9,316）。与安慰剂相比，该作用具有统计学意义（p <0.0001）。每天两次接受Lotronex 1 mg治疗的患者中有11％（11％）由于便秘而退出研究。尽管每天用Lotronex 0.5 mg两次治疗的IBS患者人数相对较少（n = 243），但只有11％的患者报告便秘，而4％的患者因便秘而退出临床研究。在接受每日两次便秘的Lotronex 1 mg治疗的患者中，报告便秘的患者中，有75％报告单发发作，大多数报告便秘（70％）在治疗的第一个月内发生，至首次报告便秘发作的中位时间为8天。在临床试验中，便秘的发生强度一般为轻度至中度，本质上是短暂的，并且在继续治疗或中断治疗后自发缓解。然而，在临床研究和上市后的经验中已报告了便秘的严重并发症[见盒装警告和警告及注意事项（ 5.1 ）] 。在研究1和2中，有9％的接受Lotronex治疗的患者报告便秘，连续4天没有排便[见临床研究（ 14.2 ）] 。中断治疗后，有78％的受影响患者在2天之内恢复了排便，并能够重新开始使用Lotronex治疗。

肝脏：接受Lotronex或安慰剂的患者中ALT升高的相似发生率（> 2倍）（1.0％对1.2％）。在一项为期12周的研究中，报告了一名接受Lotronex的患者中没有黄疸的一例肝炎（ALT，AST，碱性磷酸酶和胆红素升高）。与Lotronex的因果关系尚未建立。

长期安全性：对照临床试验中的患者经验不足以估计服用Lotronex超过6个月的患者缺血性结肠炎的发生率。

重度腹泻型肠易激综合症的女性：表2汇总了1次重复剂量研究对12周重度腹泻型IBS严重的女性患者的胃肠道不良反应。在接受Lotronex的患者中，有3％或更多的患者报告了表2中的不良反应，并且与安慰剂相比，Lotronex的发生率更高。在接受Lotronex的患者中，有3％或更多的患者报告了其他事件，并且与安慰剂相比，Lotronex的发生频率更高，包括上呼吸道感染，病毒性胃肠炎，肌肉痉挛，头痛和疲劳。

另一项针对701名严重腹泻为主的IBS妇女的研究报告的不良反应与表2相似。据报道，在接受Lotronex的患者中有3％或更多的患者发生胃肠道不良反应，并且与安慰剂相比，使用Lotronex的频率更高，其中包括便秘（分别服用Lotronex 1 mg，每天两次或0.5 mg的患者分别有14％和10％，而2 ％服用安慰剂），腹痛，恶心，呕吐和肠胃气胀。在接受Lotronex的患者中，有3％或更多的患者报告了其他事件，并且与安慰剂相比，Lotronex发生的频率更高，包括鼻咽炎，鼻窦炎，上呼吸道感染，尿路感染，病毒性胃肠炎和咳嗽。

便秘：便秘是严重腹泻为主的IBS妇女中最常见的不良反应，见表2 。在因便秘而退出的患者中，用Lotronex治疗的组有剂量反应（安慰剂为2％，每天0.5 mg一次为5％，每天1mg一次为8％，每天两次1mg为11％） ）。在这些用Lotronex治疗的以腹泻为主的严重IBS的患者中，报告便秘最多（75％）的患者报告说有一次发作发生在治疗的前15天内，并持续4到5天。

Lotronex临床评估期间观察到的其他事件：在临床试验评估期间，多次和单次剂量的Lotronex给药，导致86项完成的临床研究中有11874名受试者暴露。在试验之间，Lotronex的暴露条件，剂量和持续时间各不相同，这些研究包括健康的男性和女性志愿者以及患有IBS和其他适应症的男性和女性患者。

在下面的清单中，使用标准化编码字典对报告的不良反应进行了分类。仅提出研究者认为可能与Lotronex有关的事件，至少在2例患者中发生，并且在Lotronex治疗期间发生的频率高于安慰剂给药期间。研究人员认为，至少有1名患者发生了严重的不良反应，研究人员认为该事件与Lotronex的治疗有关，并且与安慰剂治疗的患者相比，发生在Lotronex的患者中的发生频率更高。

在下面的清单中，事件是按正文系统分类的。在每个身体系统内，事件以频率降序显示。使用以下定义：罕见不良反应是指在1/100至1 / 1,000患者中一次或多次发生的不良反应；罕见的不良反应是少于1 / 1,000的患者一次或多次发生的不良反应。

尽管报道的事件发生在用Lotronex治疗期间，但不一定是由它引起的。

• 血液和淋巴管炎：稀有：红细胞或血红蛋白定量缺陷和出血。
• 心血管：不常见：快速性心律失常。罕见：心律不齐，血压升高和心脏收缩期。
• 药物相互作用，药物过量和创伤：稀有：挫伤和血肿。
• 耳，鼻和喉咙：罕见：耳，鼻和喉咙感染；病毒性耳，鼻和喉咙感染；和喉炎。
• 内分泌和代谢：罕见：钙和磷酸盐代谢紊乱，高血糖症，下丘脑/垂体功能低下，低血糖症和体液紊乱。
• 眼睛：稀有：眼睛对光的敏感性。
• 胃肠道：不常见：低唾液酸化，消化不良症状，胃肠道痉挛，缺血性结肠炎[请参阅警告和注意事项（ 5.2 ）]和胃肠道病变。稀有：异常压痛，结肠炎，胃肠道症状和体征，直肠炎，憩室炎，粪便潜血阳性，胃酸过多，胃肠道蠕动和肠梗阻减少，胃肠道阻塞，口腔症状，胃肠道肠套叠，胃炎，胃十二指肠炎，肠胃炎和肠胃炎。
• 肝胆道和胰腺：罕见：胆红素水平异常和胆囊炎。
• 下呼吸道：不常见：呼吸障碍。
• 肌肉骨骼：罕见：肌肉疼痛；肌肉僵硬，紧绷和僵硬；以及骨骼和骨骼疼痛。
• 神经系统：不常见：催眠作用。稀有：记忆效应，震颤，梦想，认知功能障碍，味觉障碍，平衡障碍，意识错乱，镇静和感觉不足。
• 非特定地点：不常见：不适和疲劳，抽筋，疼痛，温度调节障碍。稀有：灼热感，冷热感，冷感和真菌感染。
• 精神病学：不常见：焦虑症。稀有：情绪低落。
• 生殖：罕见：性功能障碍，女性生殖道出血和出血，生殖感染和真菌生殖感染。
• 皮肤：不常见：出汗和荨麻疹。罕见：脱发和脱发；痤疮和毛囊炎；汗水和皮脂异常；皮肤过敏反应湿疹;皮肤感染；皮炎和皮肤病;和指甲疾病。
• 泌尿科：不常见：尿频。罕见：膀胱发炎；多尿和利尿;和尿路出血。

上市后经验

除了临床试验中报道的事件外，在临床实践中使用Lotronex期间还发现了以下事件。由于是自愿报告的，来自未知大小的人群，因此无法估算频率。由于这些事件的严重性，报告频率或与Lotronex的潜在因果关系，因此已选择将这些事件包括在内。

• 胃肠道：撞击，穿孔，溃疡，肠小肠系膜缺血。
• 神经系统：头痛。
• 皮肤：皮疹。

药物相互作用

体内数据表明，阿洛司琼主要被细胞色素P450（CYP）1A2代谢，而CYP3A4和CYP2C9的贡献较小。因此，这些酶的诱导剂或抑制剂可能会改变阿洛司琼的清除率。

CYP1A2抑制剂

Fluvoxamine是已知的CYP1A2的强抑制剂，并且还抑制CYP3A4，CYP2C9和CYP2C19。在药代动力学研究中，40名健康女性受试者接受氟伏沙明的剂量从每天50毫克增加到200毫克，持续16天，最后一天与阿洛司琼合用1毫克。氟伏沙明将阿洛司琼的平均血浆浓度（AUC）提高了约6倍，半衰期延长了约3倍。禁忌同时服用阿洛司琼和氟伏沙明[见禁忌症（ 4.3 ）] 。

尚未评估阿洛司琼与中度CYP1A2抑制剂（包括喹诺酮类抗生素和西咪替丁）的同时给药，但除非有临床需要，否则应避免使用，因为相似的潜在药物相互作用。

CYP3A4抑制剂

酮康唑是已知的CYP3A4强抑制剂。在一项药代动力学研究中，有38位健康的女性受试者每天两次接受酮康唑200 mg，共7天，并在最后一天共同服用阿洛司琼1 mg。酮康唑使阿洛司琼的平均血浆浓度（AUC）增加了29％。同时使用阿洛司琼和酮康唑时应谨慎。阿洛司琼和强CYP3A4抑制剂如克拉霉素，替利洛霉素，蛋白酶抑制剂，伏立康唑和伊曲康唑的共同给药尚未得到评估，但由于相似的潜在药物相互作用，应谨慎行事。诱导或抑制其他途径对暴露于阿洛司琼及其代谢产物的影响尚不清楚。

其他CYP酶

体外人肝微粒体研究和体内代谢探针研究表明alosetron不会抑制CYP酶3A4、2C9或2C19。在体外，总药物浓度比1 mg剂量时观察到的峰值血浆浓度高27倍，阿洛司琼抑制CYP酶1A2（60％）和2E1（50％）。在体内代谢探针研究中，alosetron不会抑制CYP2E1，但会产生30％的CYP1A2和N-乙酰转移酶抑制作用。尽管未使用阿洛司琼进行研究，但抑制N-乙酰基转移酶可能对异烟肼，普鲁卡因胺和肼苯哒嗪等药物产生临床相关影响。在与茶碱的临床相互作用研究中进一步探讨了对CYP1A2的影响，未观察到对代谢的影响。另一项研究表明，阿洛司琼对口服避孕药乙炔雌二醇和左炔诺孕酮（CYP3A4底物）的血浆浓度没有临床意义。还使用阿洛司琼和CYP3A4底物西沙必利进行了临床相互作用研究。没有观察到对西沙必利代谢或QT间隔有显着影响。尚未检查阿洛司琼对单胺氧化酶和继高腔内浓度继发的肠道首过的影响。根据来自体外和体内研究的上述数据，阿洛司琼不太可能抑制经CYP酶2C9、2C19或2E1代谢的药物的肝代谢清除率。

Alosetron似乎没有诱导主要的细胞色素P450药物代谢酶3A。 Alosetron似乎也不会诱导CYP酶2E1或2C19。未知阿洛司琼是否会诱导其他酶。

在特定人群中的使用

怀孕

孕妇使用Lotronex的现有数据不足以得出有关与药物相关的重大先天缺陷，流产或不良母婴后果的风险的结论。在动物生殖研究中，在器官形成过程中，大鼠和兔子口服阿洛司琼的剂量分别为建议的人用剂量的160至240倍，未观察到不利的发育影响（见数据）。

对于指定人群，估计的主要先天缺陷和流产的背景风险尚不清楚。所有怀孕都有出生缺陷，流产或其他不良后果的背景风险。在美国普通人群中，在临床公认的怀孕中，主要先天缺陷和流产的估计背景风险分别为2％至4％和流产15％至20％。

动物资料

在器官发生期间口服阿洛司琼对怀孕大鼠的最高剂量为40 mg / kg /天（基于体表面积的推荐人剂量的约160倍）或对怀孕兔子的最大剂量，均未观察到不利的发育影响到30 mg / kg /天（约为人体表面积的每日推荐剂量的240倍）。

哺乳期

阿洛司琼和/或阿洛司琼的代谢产物从泌乳大鼠的母乳中排出。尚不知道阿洛司琼是否会从人乳中排出。由于许多药物是从人乳中排泄的，因此当对哺乳期妇女服用Lotronex时应格外小心。

没有关于牛奶中阿洛司琼的存在，对母乳喂养婴儿的影响或对牛奶产量的影响的数据。

哺乳期大鼠的母乳中存在阿洛司琼和/或阿洛司琼的代谢产物。当动物乳中存在某种药物时，该药物可能存在于人乳中。应当考虑母乳喂养的发育和健康益处，以及母亲对Lotronex的临床需求以及Lotronex或潜在母体疾病对母乳喂养婴儿的任何潜在不利影响。

监测通过母乳暴露于Lotronex的婴儿的严重便秘和便血。

儿科用

儿科患者的安全性和有效性尚未确定。根据成人便秘和缺血性结肠炎严重并发症的风险，不建议在儿童人群中使用Lotronex。

老人用

在一些针对健康男性或女性的研究中，与年轻人相比，65岁及65岁以上的人群血浆浓度升高了约40％ [请参阅警告和注意事项（ 5.1 ）] 。但是，这种作用在男性中并未得到一致观察。

上市后的经验表明，老年患者发生便秘并发症的风险更高，因此，如果为这些患者开具Lotronex处方，则应进行适当的谨慎和随访[见警告和注意事项（ 5.1 ）] 。

肝功能不全

由于阿洛司琼的广泛肝代谢，肝功能不全的患者可能会增加对阿洛司琼和/或其代谢产物的暴露。严重肝功能不全的患者不应使用Alosetron，轻度或中度肝功能不全的患者应谨慎使用Alosetron。

对1位女性和5位男性中度肝功能不全（Child-Pugh评分为7至9）和1位女性和2位男性肝功能严重（Child-Pugh评分> 9）。与健康受试者的历史数据相比，患有严重肝功能不全的患者对阿洛司琼的全身暴露量更高。患有严重肝功能不全的女性的暴露量约为健康女性的14倍，而患有中度肝功能不全的女性的暴露量约为健康的女性的1.6倍。由于受试对象的人数少且药代动力学结果之间存在较高的受试者间差异，因此无法得出明确的定量结论。然而，由于患有严重肝功能不全的女性对阿洛司琼的暴露量更大，因此不建议在患有严重肝功能不全的女性中使用阿洛司琼[参见剂量和给药方法（ 2.2 ），禁忌症（ 4 ）] 。

肾功能不全

肾功能不全（肌酐清除率4至56 mL / min）对阿洛司琼的肾脏消除没有影响，因为该途径对消除阿洛司琼的贡献很小。尚未评估肾脏损害对代谢物药代动力学的影响以及终末期肾脏疾病的影响。

过量

没有过量的Lotronex特效解毒剂。患者应接受适当的支持治疗。在临床研究中，口服剂量高达16毫克，无明显不良反应。该剂量比建议的每日总剂量高8倍。过量的Lotronex可能会抑制代谢消除并降低其他药物的首过通过时间[请参见药物相互作用（ 7 ）]。

Lotronex说明

Lotronex片剂中的活性成分是盐酸阿洛司琼（HCl），它是5-羟色胺5-HT 3受体类型的有效和选择性拮抗剂。化学上，阿洛司琼被指定为2,3,4,5-四氢-5-甲基-2-[（（5-甲基-1H-咪唑-4-基）甲基] -1H-吡啶并[4,3-b]吲哚-1-一，一盐酸盐。 Alosetron是非手性的，经验式为C 17 H 18 N 4 O•HCl，分子量为330.8。 Alosetron是白色至米色的固体，在水中的溶解度为61 mg / mL，在0.1M盐酸中的溶解度为42 mg / mL，在pH 6磷酸盐缓冲液中的溶解度为0.3 mg / mL，在pH 8磷酸盐缓冲液中的溶解度为<0.1 mg / mL 。阿洛司琼的化学结构为：

Lotronex片剂以0.5毫克（白色）和1毫克（蓝色）片剂口服给药。 0.5毫克片剂含有0.562毫克盐酸阿洛司琼，相当于0.5毫克阿洛司琼； 1毫克片剂含有1.124毫克盐酸阿洛司琼，相当于1毫克阿洛司琼。每片还含有非活性成分乳糖（无水），硬脂酸镁，微晶纤维素和预糊化淀粉。 0.5毫克片剂的白色薄膜衣包含羟丙甲纤维素，二氧化钛和三醋精。 1毫克片剂的蓝色薄膜衣包含羟丙甲纤维素，二氧化钛，三醋精和靛蓝胭脂红。

Lotronex-临床药理学

作用机理

Alosetron是一种有效的选择性5-HT 3受体拮抗剂。 5-HT 3受体是配体门控的阳离子通道，广泛分布在人胃肠道的肠神经元以及其他周围和中央位置。这些通道的激活和导致的神经元去极化影响内脏疼痛，结肠转运和胃肠道分泌物的调节，这些过程与IBS的病理生理学有关。 5-HT 3受体拮抗剂（如阿洛司琼）可抑制非选择性阳离子通道的激活，从而导致肠道神经系统的调节。

IBS的原因尚不清楚。 IBS的特征是胃肠道内脏过度敏感和活动过度，从而导致疼痛和运动活动的异常感觉。直肠扩张后，IBS患者比健康志愿者的疼痛和不适量低。在这种膨胀之后，阿洛司琼减轻了疼痛并夸大了运动反应，这可能是由于5-HT 3受体的阻滞所致。

药效学

在健康志愿者和IBS患者中，阿洛司琼（口服2 mg，每天两次，共8天）增加了结肠的通过时间，而不会影响口经的时间。在健康志愿者中，阿洛司琼还可以在单​​次4 mg剂量后增加基础空肠水和钠的吸收。在患有IBS的患者中，多次口服阿洛司琼（4 mg，每天两次，共6.5天）可显着提高结肠顺应性。

皮内注射5-羟色胺后，健康男性单次口服阿洛司琼的剂量会导致耀斑反应的剂量依赖性降低。每天两次口服阿洛司琼2 mg 27.5天后，老年受试者的尿中6-β-羟基皮质醇排泄减少了52％。这种下降在统计上并不显着。在另一项使用阿洛司琼1 mg每天口服两次，共4天的研究中，尿中的6-β-羟基皮质醇排泄量显着减少。但是，6-β-羟基皮质醇与皮质醇的比例没有变化，表明皮质醇产量可能降低。这些发现的临床意义尚不清楚。

药代动力学

在健康男性中，单次口服剂量介于0.05到16 mg之间，已经研究了Alosetron的药代动力学。阿洛司琼的药代动力学也已经在健康的男女中和IBS患者中进行了评估，反复口服的剂量范围为每天两次从1 mg到每天两次为8 mg。

吸收： Alosetron口服后迅速吸收，平均绝对生物利用度约为50％至60％（大约30％至> 90％）。施用放射性标记的阿洛司琼后，粪便中仅有1％的剂量作为未改变的药物被回收。向年轻人口服给予1 mg阿洛司琼剂量后，在1小时内出现了约5 ng / mL的峰值血浆浓度。在年轻女性中，平均血浆峰值浓度约为9 ng / mL，达到峰值的时间相似。

与口服相同剂量的女性相比，男性的血浆浓度降低了30％至50％，并且变化较小。 IBS患者的群体药代动力学分析证实，阿洛司琼浓度受性别影响（男性降低27％）。

饮食影响：与食物合用时，阿洛司琼的吸收减少约25％，平均时间延迟到15分钟达到峰值浓度[见剂量和用法（ 2.1 ）] 。

分布： Alosetron的分布体积约为65至95L。在20至4,000 ng / mL的浓度范围内，血浆蛋白结合率为82％。

Metabolism and Elimination: Plasma concentrations of alosetron increase proportionately with increasing single oral doses up to 8 mg and more than proportionately at a single oral dose of 16 mg. Twice-daily oral dosing of alosetron does not result in accumulation. The terminal elimination half-life of alosetron is approximately 1.5 hours (plasma clearance is approximately 600 mL/min). Population pharmacokinetic analysis in patients with IBS confirmed that alosetron clearance is minimally influenced by doses up to 8 mg.

Renal elimination of unchanged alosetron accounts for only 13% of the dose. Renal clearance is approximately 112 mL/min.

A study with 14 C-labeled alosetron in Caucasian males (n = 3) and females (n = 3) and an Asian male (n = 1) showed similar serum metabolite profiles. Unchanged alosetron was the major component in serum, with other metabolites being present at low concentrations, none amounting to more than 15% of the unmetabolized alosetron concentration. The circulating metabolites were identified as 6-hydroxy glucuronide, 6-hydroxy sulphate, 7-hydroxy sulphate, hydroxymethyl imidazole, and mono- and bis-oxygenated imidazole derivatives of alosetron. The metabolites are unlikely to contribute to the biological activity of alosetron. Of the circulating Phase I metabolites, only the hydroxymethyl imidazole has weak pharmacological activity, around 10-fold less potent than alosetron. Total recovery of radioactivity in the excreta was 85 ± 6%. The majority of the radiolabeled dose is excreted in the urine (74 ± 5%). The major urinary metabolites were the 6-hydroxy glucuronide and the mono- and bis-oxygenated imidazole derivatives of alosetron. 11 ± 4% of the radiolabeled dose was excreted in the feces with less than 1% of the dose being excreted as the unchanged alosetron.

Alosetron is metabolized by human microsomal cytochrome P450 (CYP), shown in vitro to involve enzymes 2C9 (30%), 3A4 (18%), and 1A2 (10%). Non–CYP-mediated Phase I metabolic conversion also contributes to an extent of about 11%. However, in vivo data suggest that CYP1A2 plays a more prominent role in alosetron metabolism (62 to 97% of alosetron clearance) based on correlation of alosetron clearance with in vivo CYP1A2 activity measured by probe substrate, increased clearance induced by smoking, and inhibition of clearance by fluvoxamine [see Contraindications ( 4 ), Drug Interactions ( 7 )].

非临床毒理学

致癌，诱变，生育力受损

In 2-year oral studies, alosetron was not carcinogenic in mice at doses up to 30 mg/kg/day or in rats at doses up to 40 mg/kg/day. These doses are about 60 to 160 times, respectively, the recommended human dose of alosetron of 2 mg/day (1 mg twice daily) based on body surface area. Alosetron was not genotoxic in the Ames tests, the mouse lymphoma cell (L5178Y/TK ± ) forward gene mutation test, the human lymphocyte chromosome aberration test, the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, or the in vivo rat micronucleus test for mutagenicity. Alosetron at oral doses up to 40 mg/kg/day (about 160 times the recommended daily human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male or female rats.

临床研究

Dose-Ranging Study

Data from a dose-ranging study of women (n = 85) who received Lotronex 0.5 mg twice daily indicated that the incidence of constipation (14%) was lower than that experienced by women receiving 1 mg twice daily (29%). Therefore, to lower the risk of constipation, Lotronex should be started at a dosage of 0.5 mg twice a day. The efficacy of the 0.5 mg twice-daily dosage in treating severe diarrhea-predominant IBS has not been adequately evaluated in clinical trials. [See Dosage and Administration ( 2.1 )]

Efficacy Studies

Lotronex has been studied in women with IBS in five 12-week US multicenter, randomized, double-blind, placebo-controlled clinical studies.

Studies in Non-Constipated Women with Irritable Bowel Syndrome: Studies 1 and 2 were conducted in non-constipated women with IBS meeting the Rome Criteria 1 for at least 6 months. Women with severe pain or a history of severe constipation were excluded. A 2-week run-in period established baseline IBS symptoms.

About two thirds of the women had diarrhea-predominant IBS. Compared with placebo, 10% to 19% more women with diarrhea-predominant IBS who received Lotronex had adequate relief of IBS abdominal pain and discomfort during each month of the study.

Studies in Women With Severe Diarrhea-Predominant Irritable Bowel Syndrome: Lotronex is indicated only for women with severe diarrhea-predominant IBS [see Indications and Usage ( 1 )] . The efficacy of Lotronex in this subset of the women studied in clinical trials is supported by prospective and retrospective analyses.

Prospective Analyses: Studies 3 and 4 were conducted in women with diarrhea-predominant IBS and bowel urgency on at least 50% of days at entry. Women receiving Lotronex had significant increases over placebo (13% to 16%) in the median percentage of days with urgency control.

The lower gastrointestinal functions of stool consistency, stool frequency, and sense of incomplete evacuation were also evaluated by patients' daily reports. Stool consistency was evaluated on a scale of 1 to 5 (1 = very hard, 2 = hard, 3 = formed, 4 = loose, and 5 = watery). At baseline, average stool consistency was approximately 4 (loose) for both treatment groups. During the 12 weeks of treatment, the average stool consistency decreased to approximately 3.0 (formed) for patients who received Lotronex and 3.5 for the patients who received placebo in the 2 studies.

At baseline, average stool frequency was approximately 3.2 per day for both treatment groups. During the 12 weeks of treatment, the average daily stool frequency decreased to approximately 2.1 and 2.2 for patients receiving Lotronex and 2.7 and 2.8 for patients receiving placebo in the 2 studies.

There was no consistent effect upon the sense of incomplete evacuation during the 12 weeks of treatment for patients receiving Lotronex as compared to patients receiving placebo in either study.

Study 5 was conducted in women with severe diarrhea-predominant IBS and 1 or more of the following: frequent and severe abdominal pain or discomfort, frequent bowel urgency or fecal incontinence, disability or restriction of daily activities due to IBS. To evaluate the proportion of patients who responded to treatment, patients were asked every 4 weeks to compare their IBS symptoms during the previous month of treatment with how they usually felt during the 3 months prior to the study using an ordered 7-point scale (substantially worse to substantially improved). A responder was defined as a subject who reported moderate or substantial improvement on this global improvement scale (GIS). At Week 12, all three groups receiving Lotronex had significantly greater percentages of GIS responders compared to the placebo group (43% to 51% vs. 31%) using a Last Observation Carried Forward (LOCF) analysis. It should be noted that approximately 4% of subjects in each Lotronex dose group who were classified as responders using this approach were observed only through week 4. At each of the 4 week intervals of the treatment phase, all three dosages of Lotronex provided improvement in the average adequate relief rate of IBS pain and discomfort, stool consistency, stool frequency, and sense of urgency compared with placebo.

Retrospective Analyses: In analyses of patients from Studies 1 and 2 who had diarrhea-predominant IBS and indicated their baseline run-in IBS symptoms were severe at the start of the trial, Lotronex provided greater adequate relief of IBS pain and discomfort than placebo. In further analyses of Studies 1 and 2, 57% of patients had urgency at baseline on 5 or more days per week. In this subset, 32% of patients on Lotronex had urgency no more than 1 day in the last week of the trial, compared with 19% of patients on placebo.

In Studies 3 and 4, 66% of patients had urgency at baseline on 5 or more days per week. In this subset, 50% of patients on Lotronex had urgency no more than 1 day in the last week of the trial, compared with 29% of patients on placebo. Moreover, in the same subset, 12% on Lotronex had urgency no more than 2 days per week in any of the 12 weeks on treatment compared with 1% of placebo patients.

In Studies 1 and 2, patient-reported subjective outcomes related to IBS were assessed by questionnaires obtained at baseline and week 12. Patients in the more severe subset who received Lotronex reported less difficulty sleeping, less tiredness, fewer eating problems, and less interference with social activities and work/main activities due to IBS symptoms or problems compared to those who received placebo. Change in the impact of IBS symptoms and problems on emotional and mental distress and on physical and sexual activity in women who received Lotronex were not statistically different from those reported by women who received placebo.

长期使用

In a 48-week multinational, double-blind, placebo-controlled study, Lotronex 1 mg twice daily was evaluated in 714 women with non-constipated IBS. A retrospective analysis of the subset of women with severe diarrhea-predominant IBS (urgency on at least 10 days during the 2-week baseline period) was performed. Of the 417 patients with severe diarrhea-predominant IBS, 62% completed the trial.

Lotronex (n = 198) provided a greater average rate of adequate relief of IBS pain and discomfort (52% vs. 41%) and a greater average rate of satisfactory control of bowel urgency (60% vs. 48%) compared with placebo (n = 219). Significant improvement of these symptoms occurred for most of the 48-week treatment period with no evidence of tachyphylaxis.

参考资料

1. Thompson WG, Creed F, Drossman DA, et al. Functional bowel disease and functional abdominal pain. Gastroenterol Int . 1992;5:75-91.

供应/存储和处理方式

Lotronex Tablets, 0.5 mg (0.562 mg alosetron HCl equivalent to 0.5 mg alosetron) are white, oval, film-coated tablets debossed with GX EX1 on one face.

Bottles of 30 (NDC 65483-894-03) with child-resistant closures.

Lotronex Tablets, 1 mg (1.124 mg alosetron HCl equivalent to 1 mg alosetron), are blue, oval, film-coated tablets debossed with GX CT1 on one face.

Bottles of 30 (NDC 65483-895-03) with child-resistant closures.

Store at 20-25°C (68-77°F) (USP Controlled Room Temperature). Protect from light and moisture.

病人咨询信息

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

Prescriber and Patient Responsibilities

Patients should be fully counseled on and understand the risks and benefits of Lotronex before an initial prescription is written. The patient may be educated by the prescriber or a healthcare provider under a prescriber's direction. Patients should be fully counseled on and understand the risks and benefits of Lotronex before an initial prescription is written. The patient may be educated by the prescriber or a healthcare provider under a prescriber's direction.

Prescribers must:

• counsel patients for whom Lotronex is appropriate about the benefits and risks of Lotronex and discuss the impact of IBS symptoms on the patient's life.counsel patients for whom Lotronex is appropriate about the benefits and risks of Lotronex and discuss the impact of IBS symptoms on the patient's life.
• review the Medication Guide, which outlines the benefits and risks of Lotronex, and instruct the patient to read it carefully. Answer all questions the patient may have about Lotronex. The complete text of the Medication Guide is printed at the end of this document.review the Medication Guide, which outlines the benefits and risks of Lotronex, and instruct the patient to read it carefully. Answer all questions the patient may have about Lotronex. The complete text of the Medication Guide is printed at the end of this document.
• provide each patient with appropriate instructions for taking Lotronex.provide each patient with appropriate instructions for taking Lotronex.

Additional copies of the Medication Guide are available by contacting Sebela at 1-844-732-3521 or visiting wwwLotronex.com.

Patients who are prescribed Lotronex should be instructed to:

• read the Medication Guide before starting Lotronex and each time they refill their prescription.read the Medication Guide before starting Lotronex and each time they refill their prescription.
• not start taking Lotronex if they are constipated.not start taking Lotronex if they are constipated.
• immediately discontinue Lotronex and contact their prescriber if they become constipated, or have symptoms of ischemic colitis such as new or worsening abdominal pain, bloody diarrhea, or blood in the stool. Contact their prescriber again if their constipation does not resolve after discontinuation of Lotronex. Resume Lotronex only if their constipation has resolved and after discussion with and the agreement of their treating prescriber.immediately discontinue Lotronex and contact their prescriber if they become constipated, or have symptoms of ischemic colitis such as new or worsening abdominal pain, bloody diarrhea, or blood in the stool. Contact their prescriber again if their constipation does not resolve after discontinuation of Lotronex. Resume Lotronex only if their constipation has resolved and after discussion with and the agreement of their treating prescriber.
• stop taking Lotronex and contact their prescriber if Lotronex does not adequately control IBS symptoms after 4 weeks of taking 1 mg twice a day.stop taking Lotronex and contact their prescriber if Lotronex does not adequately control IBS symptoms after 4 weeks of taking 1 mg twice a day.

用药指南

用药指南 Lotronex ® (LOW-trah-nex) (alosetron hydrochloride) 平板电脑

Read the Medication Guide you get with each refill for Lotronex.可能有新的信息。 This Medication Guide does not take the place of talking with your doctor.

What is the most important information I should know about Lotronex? Lotronex is a meeicine only for some women with severe chronic irritable bowel syndrome (IBS) whose: main problem is darrhea and IBS symptoms have not been helped enough by other treatments. Some people have developed serious bowel side effects while taking Lotronex. Serious bowel (intestine) side effects can happen suddenly, including the following: Serious complications of constipation: These complications may lead to a hospital stay and, in rare cases, blood transfusions, surgery, and death. People who are older, who are weak from illness, or who take other constipating medicines may be more likely to have serious complications of constipation with Lotronex. To lower your chances of getting serious complications of constipation , do the following: If you are constipated , do not start taking Lotronex. If you get constipated while taking Lotronex , stop taking it right away and call your doctor. If your constipation does not get better after stopping Lotronex , call your doctor again. If you stopped taking Lotronex, do not start taking Lotronex again unless your doctor tells you to do so. Inflammation and injury of the intestines caused by reduced blood flow (ischemic colitis) : Ischemic colitis is caused by reduced blood flow to parts of the large bowel. The chance of getting ischemic colitis when you take Lotronex for more than 6 months is not known. Ischemic colitis may lead to a hospital stay and, in rare cases, blood transfusions, surgery, and death. Stop taking Lotronex and call your doctor or get medical help if you have symptoms of ischemic colitis such as new or worsening stomach-area (abdominal) pain, bloody diarrhea or blood in the stool.

What is Lotronex? Lotronex is a prescription medicine used only for some women wih severe chronic IBS whose: main problem is diarrhea and IBS symptoms have not been helped enough by other treatments. Lotronex does not cure IBS, and it may not help every person who takes it. For those who are helped, Lotronex reduces lower stomach area (abdominal) pain and discomfort, the sudden need to have a bowel movement (bowel urgency), and diarrhea from IBS. If you stop taking Lotronex, your IBS symptoms may return within 1 or 2 weeks to what they were before you started taking Lotronex. It is not known if Lotronex is safe and effective in men with IBS. It is not known if Lotronex is safe and effective in children.

Who should not take Lotronex? Do not take Lotronex if you: have constipation or you are constipated most of the time. have had a serious problem from constipation. If you are constipated now, do not start taking Lotronex. have had serious bowel blockages. have had blood flow problems to your bowels, such as ischemic colitis. have had blood clots. have had Crohn's disease, ulcerative colitis, diverticulitis, or severe liver disease. are taking fluvoxamine (LUVOX).

What should I talk about with my doctor before taking Lotronex? Talk with your doctor: about the possible benefits and risks of Lotronex. about how much of a problem IBS is in your life and what treatments you have tried. about any other illnesses you have and medicines you take or plan to take. These include prescription and non-prescription medicines, supplements, and herbal remedies. Certain illnesses and medicines can increase your chance of getting serious side effects while taking Lotronex. Other medicines may interact with how the body handles Lotronex. any allergies that you have. See the end of the Medication Guide for a complete list of ingredients in Lotronex. if you have liver problems. if you are pregnant or planning to become pregnant. It is not known if Lotronex can harm your unborn baby. if you are breastfeeding or plan to breastfeed. It is not known if Lotronex can harm your baby. Talk to your doctor about the best way to feed your baby if you take Lotronex.

How should I take Lotronex? Take Lotronex exactly as your doctor prescribes it. You can take Lotronex with or without food. Begin with 0.5 mg two times a day for 4 weeks to see how Lotronex affects you. You and your doctor may decide that you should keep taking this dose if you are doing well. Check with your doctor 4 weeks after starting Lotronex: If you try 0.5 mg two times a day for 4 weeks, it may not control your symptoms. If you do not get constipation or other side effects from Lotronex, your doctor may increase your dose up to 1 mg two times a day. If 1 mg two times a day does not work after 4 weeks, Lotronex is not likely to help you. You should stop taking it and call your doctor. Follow the instructions in the section “What is the most important information I should know about Lotronex?” about when you must stop taking the medicine and when you should call your doctor.

What are the possible side effects of Lotronex? Lotronex may cause serious side effects, including: See "What is the most important information I should know about Lotronex?" The most common side effects of Lotronex include: 便秘 stomach (abdominal) discomfort and pain 恶心 intestinal discomfort and pain These are not all the possible side effects of Lotronex. 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。

How should I store Lotronex? Store Lotronex at room temperature between 68°F to 77°F (20°C to 25°C). Protect Lotronex from light and moisture. Keep Lotronex and all medicines out of 药物相互作用（61） 酒精/食物相互作用（1） 疾病相互作用（4） 已知共有61种药物与Lotronex（alosetron）相互作用。 2种主要药物相互作用 57种中等程度的药物相互作用 2次轻微的药物相互作用 在数据库中显示可能与Lotronex（alosetron）相互作用的所有药物。 检查互动 输入药物名称以检查与Lotronex（alosetron）的相互作用。 最常检查的互动 查看Lotronex（阿洛司琼）与以下药物的相互作用报告。 Benadryl（苯海拉明） 咖啡因 mb（度洛西汀） 加巴喷丁 碘（洛哌丁胺） Lexapro（依他普仑） Lomotil（阿托品/苯乙氧基化物） 多种维生素 Nexium（艾美拉唑） 奥美拉唑 恩丹西酮 Reclast（唑来膦酸） Singulair（孟鲁司特） 拟甲状腺素（左甲状腺素） 曲马多 曲唑酮 姜黄 Viberzi（eluxadoline） 维生素B12（氰钴胺） 维生素C（抗坏血酸） 维生素D2（麦角钙化醇） 维生素D3（胆钙化固醇） 泽尔诺姆（tegaserod） Lotronex（alosetron）酒精/食物相互作用 Lotronex（alosetron）与酒精/食物有1种相互作用 Lotronex（alosetron）疾病相互作用 与Lotronex（alosetron）有4种疾病相互作用，包括： 胃肠道并发症 肝功能不全 血栓性疾病 肾功能不全 药物相互作用分类 这些分类只是一个准则。特定药物相互作用与特定个体的相关性很难确定。在开始或停止任何药物治疗之前，请务必咨询您的医疗保健提供者。 重大的 具有高度临床意义。避免组合；互动的风险大于收益。 中等 具有中等临床意义。通常避免组合；仅在特殊情况下使用。 次要 临床意义最小。降低风险；评估风险并考虑使用替代药物，采取措施规避相互作用风险和/或制定监测计划。 未知 没有可用的互动信息。 药物状态 可用性 仅处方 怀孕和哺乳 现有风险数据 CSA时间表* 不是管制药物 审批历史 FDA批准2000 相关药物 双环胺 天秤座 阿米蒂扎 元胶 苯甲醚 美国日本医生 Saadah Alrajab MD 经验：11-20年 Jooby Babu MD 经验：11-20年 Judah Askew MD 经验：11-20年 Manoj Mathew MD 经验：11-20年 Andreas Kyprianou MD 经验：11-20年 渡邊剛 经验：21年以上 村上和成 教授 经验：21年以上 中山秀章 教授 经验：21年以上 村田朗 经验：21年以上 溝上裕士 医院教授 经验：21年以上 临床试验 SARS-CoV-2 幸存者的负担 COVID-19 期间和之后的 PR-VR 在家计划 右美托咪定对 ST 段抬高型心肌梗死患者的心脏保护作用（合作​​） Isatuximab、Velcade 和地塞米松治疗多发性骨髓瘤和重度肾病患者 HFNO 对比经鼻 CPAP 用于接受 ERCP 深度镇静的肥胖患者 盐皮质激素受体拮抗剂和 SARS-CoV-2 感染（SpiroCOVID19）中的肺纤维化 用于预防成人 COVID-19 的灭活 SARS-CoV-2 疫苗的安全性 慢性呼吸功能不全患者的三分钟阶梯测试和运动饱和度检测 (STEPSAT) 导管定向肺再灌注治疗肺栓塞患者 儿童疾病综合管理工具：初级保健中脉搏血氧饱和度和临床决策支持算法 (TIMCI) 的评估