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舒马曲坦琥珀酸酯

舒马曲坦琥珀酸酯

描述

舒马曲坦琥珀酸盐片剂包含舒马曲坦（作为琥珀酸盐），这是一种选择性的5-羟色胺1受体亚型激动剂。舒马曲坦琥珀酸酯的化学名称为3- [2-（二甲基氨基）乙基] -N-甲基-吲哚-5-甲磺酰胺琥珀酸酯（1：1），它具有以下结构：

分子式为C14H21N3O2S·C4H6O4，分子量为413.5。舒马曲坦琥珀酸酯是白色至类白色粉末，易溶于水和盐水。每种口服舒马曲坦琥珀酸盐片剂包含35、70或140 mg舒马曲坦琥珀酸盐，USP分别相当于25、50或100 mg舒马曲坦。每片还含有非活性成分胶体二氧化硅，交联羧甲基纤维素钠，D＆C Red＃27铝色淀（仅100毫克），磷酸氢钙，羟丙甲纤维素，氧化铁红（仅100毫克），硬脂酸镁，微晶纤维素，聚乙二醇（仅25和50毫克），聚山梨酯80（仅25和50毫克）丙二醇（仅100毫克），滑石粉，二氧化钛。

临床药理学

作用机理：舒马曲坦是对5-羟色胺1受体亚型（可能是5-HT1D家族成员）的激动剂，对5-HT1A，5-HT5A和5-HT7受体的亲和力很弱，而没有明显的亲和力（使用标准放射性配体结合测定法测量）或对5-HT2、5-HT3或5-HT4受体亚型或1-、, 2-或ß-肾上腺素能的药理活性;多巴胺1;多巴胺2;毒蕈碱或苯二氮卓类受体。

舒马曲坦激活的血管5-HT1受体亚型存在于狗和灵长类动物的颅内动脉，人基底动脉以及人硬脑膜的脉管系统中，并介导血管收缩。人类的这种行为与偏头痛的缓解有关。动物研究的实验数据表明，除了引起血管收缩外，舒马普坦还可以激活支配颅骨血管的三叉神经周围末端的5-HT1受体。这种作用也可能有助于舒马曲坦对人的抗偏头痛作用。

在麻醉的狗中，舒马曲坦选择性降低颈动脉血流，而对动脉血压或总外周阻力几乎没有影响。在猫中，舒马曲坦选择性收缩颈动脉动静脉吻合术，而对脑或脑外组织的血流或抵抗力影响很小。

药代动力学：口服舒马普坦100 mg后口服25 mg的平均最大浓度为18 ng / mL（范围7至47 ng / mL）和51 ng / mL（范围28至100 ng / mL）。 。这与分别以5和20mg鼻内剂量给药后的Cmax为5和16ng / mL相比。皮下注射6 mg后的平均Cmax为71 ng / mL（范围为49至110 ng / mL）。生物利用度约为15％，主要是由于系统前代谢，部分是由于吸收不完全。在偏头痛发作和无偏头痛期间，Cmax相似，但是在发作期间，Tmax稍晚一些，大约为2小时，而2小时为2.5小时。当以单剂量形式给药时，舒马曲坦在25到200 mg的剂量范围内在其吸收程度（曲线下的面积[AUC]下）显示出剂量比例，但是100 mg后的Cmax大约比预期的低25％（基于在25mg剂量上）。

一项食品效果研究涉及在空腹情况下以高脂餐食向健康志愿者服用100毫克舒马曲坦琥珀酸盐片剂，并显示在进食状态下Cmax和AUC分别增加了15％和12％。

血浆蛋白结合率低（14％至21％）。尚未评估舒马曲坦对其他药物的蛋白质结合的影响，但鉴于蛋白质结合率低，预计这种影响很小。表观分布体积为2.4 L / kg。

舒马曲坦的消除半衰期约为2.5小时。口服放射性标记的14C-苏门曲普坦主要经肾脏排泄（约60％），粪便中约40％。尿液中排泄的大多数放射性标记化合物是主要代谢物，即惰性的吲哚乙酸（IAA）或IAA葡糖醛酸。只有3％的剂量可以恢复为不变的舒马曲坦。

对人体微粒体的体外研究表明，舒马曲坦被单胺氧化酶（MAO）代谢，主要是A同工酶，该酶的抑制剂可能会改变舒马曲坦的药代动力学，从而增加全身暴露。用MAO-B抑制剂未见明显作用（见禁忌症，警告和注意事项：药物相互作用）。

特殊人群：肾功能不全：尚未检查肾功能不全对舒马曲坦药代动力学的影响，但由于舒马曲坦主要代谢成非活性物质，因此临床预期效果不大。

肝功能不全：肝脏在口服舒马普坦的系统性清除中起重要作用。因此，在患有肝病的患者中，舒马曲坦口服后的生物利用度可能显着增加。在一项针对性别，年龄和体重与健康受试者匹配的肝功能受损患者（N = 8）的小型研究中，与健康受试者相比，肝功能受损患者的AUC和Cmax和Tmax升高了约70％ （请参阅剂量和管理）。

年龄：老年人（平均年龄72岁；男性2名，女性4名）和偏头痛患者（平均年龄38岁； 25名男性和155名女性）中口服舒马曲坦的药代动力学与健康男性相似（平均年龄30岁）（请参阅预防措施：老人用药）。

性别：在一项将女性与男性进行比较的研究中，未观察到性别之间AUC，Cmax，Tmax和半衰期之间的药代动力学差异。

种族：舒马曲坦的全身清除率和Cmax在黑人（N = 34）和白种人（N = 38）健康男性受试者中相似。
药物相互作用：单胺氧化酶抑制剂：用MAO-A抑制剂治疗通常会导致舒马曲坦血浆水平增加（请参阅禁忌症和注意事项）。

由于肠道和肝脏代谢的首过效应，MAO-A抑制剂与口服舒马曲坦共同给药后全身暴露的增加大于单胺氧化酶抑制剂（MAOI）与皮下舒马曲坦共同给药后的全身暴露增加。在一项针对14位健康女性的研究中，使用MAO-A抑制剂预处理可降低皮下舒马曲坦的清除率。在该实验的条件下，结果是舒马曲坦血浆浓度×时间曲线（AUC）下面积增加了2倍，相当于消除半衰期增加了40％。对于MAO-B抑制剂，这种相互作用不明显。

一项小型研究评估了用MAO-A抑制剂预处理对25 mg口服舒马曲坦片剂的生物利用度的影响，导致全身暴露量增加了约7倍。

酒精：舒马曲坦摄入前30分钟摄入的酒精对舒马曲坦的药代动力学没有影响。

临床研究

3项随机，双盲，安慰剂对照研究证明了舒马曲坦琥珀酸酯片在急性偏头痛治疗中的功效。参加这3项研究的患者主要是女性（87％）和白种人（97％），平均年龄为40岁（18至65岁）。指导患者治疗中度至重度头痛。头痛反应定义为在给药后4小时内头痛程度从中度或重度疼痛减轻至轻度或无痛。还评估了相关的症状，例如恶心，畏光和恐惧心理。给药后24小时内评估反应的维持。初次治疗后4到24小时再给予第二剂量的舒马曲坦琥珀酸盐片剂或其他药物治疗复发性头痛。如果偏头痛疼痛没有改善或恶化，则在初始治疗后2小时开始向研究2和3中的患者提供对乙酰氨基酚。在初次治疗后4到24小时内允许使用其他药物治疗复发性头痛或所有3项研究中的抢救药物。还确定了使用这些额外治疗的频率和时间。在所有研究中，将25、50和100毫克的剂量与治疗偏头痛的安慰剂进行了比较。在一项研究中，还分别比较了25、50和100 mg的剂量。

在所有3个试验中，在接受所有剂量的舒马普坦琥珀酸盐片剂治疗的患者中，治疗2、4小时后达到头痛反应的患者比例明显高于接受安慰剂的患者。在3项研究中的1项中，与25毫克剂量组相比，在50或100毫克组中，在2和4小时出现头痛反应的患者在统计学上显着更高。在任何研究中，50和100 mg剂量组之间在统计学上没有显着差异。表1总结了这3项对照临床试验的结果。

基于在不同临床试验中获得的结果进行的药物性能比较从来都不可靠。因为研究是由不同的研究者在不同的时间，不同的患者样本下进行的，采用不同的标准和/或对同一标准的不同解释，在不同条件下（剂量，给药方案等），治疗反应的定量估计和预计响应时间因研究而异。

表1.治疗后2小时和4小时头痛反应（无或轻度疼痛）患者的百分比

*与安慰剂相比，p <0.05。
与25 mg相比，†P <0.05。
在图1中描述了在治疗后4小时内达到初始头痛反应的估计概率。

图1.在240分钟内实现初始头痛反应的估计概率*

*该图显示了舒马曲坦治疗后随时间推移出现头痛反应（无或轻度疼痛）的可能性。显示的平均值基于3个临床对照试验的合并数据，提供了疗效证据。患者在240分钟内未达到响应和/或无法抢救的Kaplan-Meier图被审查为240分钟。
对于基线时有偏头痛相关的恶心，畏光和/或恐惧症的患者，在服用舒马普坦琥珀酸酯后2小时（研究1）和4小时（研究1、2和3）时，这些症状的发生率较低片剂与安慰剂相比。
最早在研究2的2小时和研究1的3或4个小时，直到研究治疗的初始剂量后的24个小时，患者可以以第二次研究治疗或其他剂量的形式使用其他缓解疼痛的方法药物。图2总结了在研究治疗的初始剂量后的24小时内，患者服用第二剂或其他药物治疗偏头痛的估计概率。

图2.初始剂量的研究治疗药物后24小时内服用第二剂量或其他药物治疗偏头痛的患者估计概率*

* Kaplan-Meier图基于在3项临床对照试验中获得的数据，提供了在不检查24小时的情况下未使用其他治疗方法的患者的疗效证据。该图还包括对初始剂量无反应的患者。服药后2小时内不得采取任何补救措施。

有证据表明，高于50毫克的剂量不能提供比50毫克更大的效果。没有证据表明舒马曲坦治疗与复发性头痛的严重程度增加有关。舒马曲坦琥珀酸酯片的疗效不受先兆的影响。治疗前头痛的持续时间；患者的性别，年龄或体重；与月经的关系；或同时使用常见的偏头痛预防药物（例如，β受体阻滞剂，钙通道阻滞剂，三环类抗抑郁药）。没有足够的数据来评估种族对功效的影响。

适应症和用途

舒马曲坦琥珀酸盐片剂适用于成人有或没有先兆的偏头痛发作的急性治疗。

舒马曲坦琥珀酸盐片剂不用于偏头痛的预防性治疗或用于偏瘫或基底偏头痛的治疗（请参见禁忌症）。尚无舒马曲坦琥珀酸酯片用于丛集性头痛的安全性和有效性，丛集性头痛目前存在于年龄较大的男性人群中。

禁忌症

舒马曲坦琥珀酸盐片剂不应给予有缺血性心脏，脑血管或周围血管综合征的病史，症状或体征的患者。此外，患有其他重要的潜在心血管疾病的患者不应接受舒马曲坦琥珀酸盐片剂。缺血性心脏综合征包括但不限于任何类型的心绞痛（例如，稳定的心绞痛和血管痉挛性心绞痛，如Prinzmetal变体），所有形式的心肌梗塞和无症状的心肌缺血。脑血管综合症包括但不限于任何类型的中风以及短暂性脑缺血发作。周围血管疾病包括但不限于缺血性肠病（请参阅警告）。

由于舒马曲坦琥珀酸盐片剂可能会导致血压升高，因此不应将其用于高血压患者。

禁止同时使用MAO-A抑制剂或在停用MAO-A抑制剂的2周内使用（请参阅临床药理学：药物相互作用和注意事项：药物相互作用）。

偏瘫或基底性偏头痛患者不应服用舒马曲坦琥珀酸酯片。

舒马曲坦琥珀酸盐片剂和任何含麦角胺或麦角类药物（如二氢麦角胺或甲基麦角胺）均不得在24小时之内使用，舒马普坦琥珀酸盐和另一种5-HT1激动剂也不应使用。

对舒马曲坦或其任何成分过敏的患者禁用舒马曲坦琥珀酸盐片剂。

舒马曲坦琥珀酸盐片剂对严重肝功能不全的患者禁用。

警告

舒马曲坦琥珀酸盐片剂应仅在明确诊断出偏头痛的情况下使用。
心肌缺血和/或梗塞及其他不良心脏事件的风险：舒马普坦不宜用于已证明有缺血性或血管痉挛性冠心病（CAD）的患者（请参阅禁忌证）。强烈建议对于存在以下危险因素（例如高血压，高胆固醇血症，吸烟者，肥胖，糖尿病，CAD家族史牢固，患有外科或生理性更年期的女性，年龄在40岁以上的男性），除非心血管评估提供令人满意的临床证据表明该患者合理地没有冠状动脉和缺血性心肌病或其他重要的潜在心血管疾病。心脏诊断程序检测心血管疾病或易患冠状动脉血管痉挛的敏感性充其量只是充其量。如果在心血管评估过程中，患者的病史或心电图检查发现发现指示或与冠状动脉痉挛或心肌缺血相一致的结果，则不应给予舒马普坦治疗（请参阅禁忌证）。

对于确定具有可预测的心血管疾病评估结果的可预测CAD的危险因素的患者，强烈建议在医生办公室或类似的医务人员和配备完善的设施中进行舒马曲坦片的首剂给药，除非患者先前已接受舒马曲坦。因为在没有临床症状的情况下可能会发生心脏缺血，所以对于这些有危险因素的患者，应考虑在舒马曲坦琥珀酸盐片剂紧接后的间隔内首次使用心电图（ECG）。

建议间歇性长期使用舒马曲坦的患者，并且如上所述具有或获得可预测CAD的危险因素的患者，在继续使用舒马曲坦的同时进行定期的心血管评估。
上述系统性方法旨在降低患有无法识别的心血管疾病患者意外接触舒马曲坦的可能性。

药物相关的心脏事件和死亡：在服用舒马普坦琥珀酸盐注射剂或舒马普坦琥珀酸盐片剂后数小时内，就出现了严重的不良心脏事件，包括急性心肌梗塞，危及生命的心律紊乱和死亡。考虑到舒马曲坦在偏头痛患者中的使用程度，这些事件的发生率极低。

舒马普坦可引起冠脉血管痉挛的事实，其中一些事件发生在既往没有心脏病史且没有CAD记录的患者中，并且这些事件与舒马普坦的使用非常接近，这支持以下结论：由药物引起的。但是，在许多情况下，如果已经知道潜在的冠状动脉疾病，则这种关系是不确定的。

舒马曲坦的上市前经验：在6,348例偏头痛患者中，他们参加了口服舒马曲坦的上市前对照和非对照临床试验，其中2例在接受口服舒马曲坦后不久就发生了临床不良事件，这些反应可能反映了冠脉血管痉挛。这些不良事件均与严重的临床结果无关。

在超过1,900例偏头痛患者参加了皮下舒马普坦的上市前对照临床试验，其中8例患者在接受舒马普坦期间或之后持续发生临床事件，可能反映了冠状动脉血管痉挛。这8例患者中有6例的ECG改变与短暂性脑缺血一致，但没有伴随的临床症状或体征。在这8例患者中，有4例在研究入选之前就具有提示CAD的发现或预测CAD的危险因素。
在大约4,000名参加舒马曲坦鼻喷剂上市前对照和非对照临床试验的偏头痛患者中，有1名患者可能在冠状动脉痉挛事件后发生了无症状的心内膜下梗死。

舒马曲坦的上市后经验：与舒马普坦琥珀酸盐注射液或舒马曲坦琥珀酸盐片剂一起使用已报道了严重的心血管事件，其中一些导致死亡。但是，售后监督的不受控制的性质使得无法确切确定舒马曲坦实际引起的报告病例比例，也无法可靠地评估个别病例的因果关系。从临床的角度来看，舒马曲坦琥珀酸酯给药与临床事件发作之间的潜伏期越长，引起这种关联的可能性就越小。因此，人们的兴趣集中在琥珀酸舒马曲坦给药后1小时内开始的事件。

舒马普坦给药后1小时内已观察到心脏事件，包括：冠状动脉血管痉挛，短暂性缺血，心肌梗塞，室性心动过速和室颤，心脏骤停和死亡。
其中一些事件发生在没有CAD征象的患者中，似乎代表了冠状动脉血管痉挛的后果。但是，在舒马曲坦给药后1小时内发生的严重心脏事件的国内报道中，几乎所有患者都有可预测CAD的危险因素，并且在大多数情况下已确定存在明显的基础CAD（参见禁忌症）。

药物相关的脑血管事件和死亡：口服或皮下舒马普坦治疗的患者有脑出血，蛛网膜下腔出血，中风和其他脑血管事件的报道，其中一些死亡。舒马曲坦与这些事件的关系尚不确定。在许多情况下，似乎有可能是脑血管事件是原发性的，舒马普坦是在不正确地认为所经历的症状是由偏头痛引起的情况下才服用的。与其他急性偏头痛治疗一样，在以前没有被诊断为偏头痛的患者以及表现出非典型症状的偏头痛中，治疗头痛之前，应注意排除其他可能出现的严重神经系统疾病。还应注意，偏头痛患者可能发生某些脑血管事件（例如，脑血管意外，短暂性脑缺血发作）的风险增加。

其他与血管痉挛有关的事件：除冠状动脉血管痉挛外，舒马曲坦还可能引起血管痉挛反应。外周血管缺血和结肠缺血伴腹痛和血性腹泻都有报道。

5-羟色胺综合症：曲坦类药物可能会导致潜在的威胁生命的5-羟色胺综合症的发展，包括使用舒马曲坦琥珀酸酯治疗，尤其是在与选择性5-羟色胺再摄取抑制剂（SSRIs）或5-羟色胺去甲肾上腺素再摄取抑制剂（SNRIs）联合使用时。如果临床上保证舒马曲坦和SSRI（例如氟西汀，帕罗西汀，舍曲林，氟伏沙明，西酞普兰，依西酞普兰）或SNRI（例如文拉法辛，度洛西汀）同时治疗，建议对患者进行仔细观察，尤其是在治疗开始和给药期间增加。 5-羟色胺综合征的症状可能包括精神状态变化（例如，躁动，幻觉，昏迷），自主神经不稳定（例如，心动过速，不稳定的血压，体温过高），神经肌肉畸变（例如，反射亢进，不协调）和/或胃肠道症状（例如，恶心，呕吐，腹泻）。

血压升高：在有高血压病史和无高血压病史的患者中，罕见地出现了血压的大幅升高，包括高血压危机。舒马曲坦是高血压患者的禁忌症（见禁忌症）。对于控制性高血压的患者，应谨慎服用舒马普坦，因为在少数患者中观察到血压和周围血管阻力暂时升高。

伴随药物使用：在服用MAO-A抑制剂的患者中，口服后推荐剂量的舒马普坦血浆水平比在其他情况下获得的舒马曲坦血浆水平高7倍。因此，禁忌舒马曲坦琥珀酸酯片和MAO-A抑制剂的共同给药（见临床药理和禁忌症）。

超敏反应：接受舒马曲坦的患者极少发生超敏反应（过敏反应/类过敏反应）。这种反应可能危及生命或致命。通常，对多种过敏原有敏感史的人更容易发生对药物的超敏反应（参见禁忌症）。

预防措施

概述：使用舒马普坦琥珀酸盐片剂后有胸部不适和下颌或颈部紧绷的报道，使用舒马普坦琥珀酸盐鼻腔喷雾剂后很少见。舒马普坦琥珀酸盐注射液给药后，胸部，下颌或颈部紧绷相对常见。这些症状很少与缺血性ECG改变有关。但是，由于舒马普坦可能引起冠状动脉血管痉挛，因此在接受其他剂量的舒马曲坦之前，应评估舒马普坦后出现心绞痛征兆或症状的患者是否存在CAD或普林兹金属变型心绞痛的易感性，并应进行心电图监护恢复，类似症状再次出现。同样，舒马普坦后出现其他症状或体征提示动脉血流减少的患者，例如缺血性肠综合症或雷诺氏综合症，应进行动脉粥样硬化或血管痉挛的易感性评估（请参阅警告）。

对于可能会改变药物吸收，代谢或排泄的疾病（例如肝或肾功能受损）的患者，也应谨慎服用舒马曲坦琥珀酸盐片剂。

舒马曲坦给药后有癫痫发作的报道极少。有癫痫病史或癫痫发作阈值降低的患者应谨慎使用舒马曲坦。

对于以前未诊断为偏头痛或非典型头痛的患者，在治疗头痛之前应注意排除其他潜在的严重神经系统疾病。很少有报道称患者接受舒马普坦治疗后因严重头痛而继发于继发于神经病变的继发性头痛（请参阅警告）。
对于给定的发作，如果患者对舒马曲坦的第一剂无反应，则应在给予第二剂之前重新考虑偏头痛的诊断。

急性偏头痛治疗的过度使用与易感患者头痛的加剧（药物过度使用性头痛）有关。可能需要中止治疗。

与含黑色素的组织结合：在接受单次皮下注射剂量（0.5 mg / kg）或口服剂量（2 mg / kg）放射性标记的舒马曲坦治疗的大鼠中，从眼睛消除放射性的半衰期为15天和23天，分别表明舒马曲坦和/或其代谢产物与眼睛的黑色素结合。由于随着时间的流逝，富含黑色素的组织中可能会积累，这增加了舒马曲坦在长期使用后可能在这些组织中引起毒性的可能性。但是，在任何口服或皮下毒性研究中，均未发现与舒马普坦治疗相关的对视网膜的影响。尽管在临床试验中未对眼科功能进行系统的监测，也未提供有关眼科监测的具体建议，但开药者应意识到长期眼科作用的可能性。

角膜混浊：舒马普坦可引起犬的角膜混浊和角膜上皮缺损。这增加了这些变化可能在人类中发生的可能性。尽管在临床试验中未对患者的这些变化进行系统的评估，并且未提供监测的具体建议，但开药者应意识到这些变化的可能性（请参见动物毒理学）。

给患者的信息：有关提供给患者的单独传单的文本，请参见本标签末尾的患者信息。
使用舒马普坦或其他曲普坦时，应特别提醒患者有关血清素综合征的风险，尤其是在与SSRI或SNRI并用时。

实验室检查：不建议使用特定的实验室检查来监测舒马曲坦治疗前后的患者。

药物相互作用：选择性5-羟色胺再摄取抑制剂/ 5-羟色胺
去甲肾上腺素再摄取抑制剂和5-羟色胺综合征：据报道，在同时使用SSRI或SNRI和曲普坦期间，存在危及生命的5-羟色胺综合征（见警告）。

含麦角酮的药物：据报道含麦角酮的药物可引起长时间的血管痉挛反应。因为从理论上讲，这些作用可能是累加的，所以应避免在彼此之间的24小时之内使用含麦角胺或麦角类药物（如二氢麦角胺或甲基麦角胺）和舒马曲坦（请参阅禁忌证）。

单胺氧化酶-A抑制剂： MAO-A抑制剂可降低舒马普坦清除率，显着增加全身暴露。因此，禁止在接受MAO-A抑制剂的患者中使用舒马曲坦琥珀酸盐片剂（请参阅临床药理和禁忌症）。

药物/实验室测试的相互作用：未知舒马曲坦琥珀酸酯片会干扰常用的临床实验室测试。

致癌，诱变，生育力受损：致癌：在致癌性研究中，通过强饲法（大鼠104周）或饮用水（小鼠78周）给大鼠和小鼠给予舒马普坦。接受最高剂量（160 mg / kg /天的目标剂量）的小鼠所达到的平均暴露量约为最大推荐单次口服剂量100 mg后人类所达到暴露量的40倍。给予大鼠的最高剂量（160 mg / kg /天，从第21周的360 mg / kg /天减少）约为最大建议单人口服剂量100 mg（基于mg / m2）的15倍。没有证据表明与舒马普坦给药有关的任何一种肿瘤的增加。

诱变：在2种基因突变试验（Ames试验和体外哺乳动物中国仓鼠V79 / HGPRT试验）中进行测试时，无论是否存在代谢活化，苏门曲普坦均不致突变。在2种细胞遗传学测定中（体外人淋巴细胞测定和体内大鼠微核测定），舒马曲坦与致癌活性无关。

生育能力的损害：在一项研究中，在交配之前和整个交配期间每天给雄性和雌性大鼠口服口服舒马曲坦，在用50和500 mg的动物进行交配后，其生育能力下降与治疗相关/公斤/天。此发现的最高无效应剂量为5 mg / kg /天，或以mg / m2为基础的最大建议单人口服剂量100 mg的一半左右。目前尚不清楚该问题与男性或女性的治疗有关，还是与两者的治疗有关。在一项通过皮下途径进行的类似研究中，没有证据表明最大测试剂量60 mg / kg /天会导致生育力受损，这大约相当于每毫克/平方米2推荐的最大单人口服剂量100毫克的6倍基础。

怀孕：致畸作用：怀孕C类：在大鼠和兔子的生殖毒性研究中，舒马曲坦口服治疗与胚胎致死率，胎儿异常和幼仔死亡率有关。 When administered by the intravenous route to rabbits, sumatriptan has been shown to be embryolethal.没有针对孕妇的充分且对照良好的研究。 Therefore, sumatriptan succinate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In assessing this information, the following findings should be considered.

Embryolethality: When given orally or intravenously to pregnant rabbits daily throughout the period of organogenesis, sumatriptan caused embryolethality at doses at or close to those producing maternal toxicity. In the oral studies this dose was 100 mg/kg/day, and in the intravenous studies this dose was 2 mg/kg/day. The mechanism of the embryolethality is not known. The highest no-effect dose for embryolethality by the oral route was 50 mg/kg/day, which is approximately 9 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis. By the intravenous route, the highest no-effect dose was 0.75 mg/kg/day, or approximately one tenth of the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

The intravenous administration of sumatriptan to pregnant rats throughout organogenesis at 12.5 mg/kg/day, the maximum dose tested, did not cause embryolethality. This dose is equivalent to the maximum single recommended human oral dose of 100 mg on a mg/m2 basis. Additionally, in a study in rats given subcutaneous sumatriptan daily prior to and throughout pregnancy at 60 mg/kg/day, the maximum dose tested, there was no evidence of increased embryo/fetal lethality. This dose is equivalent to approximately 6 times the maximum recommended single human oral dose of 100 mg on a mg/m2 basis.

Teratogenicity: Oral treatment of pregnant rats with sumatriptan during the period of organogenesis resulted in an increased incidence of blood vessel abnormalities (cervicothoracic and umbilical) at doses of approximately 250 mg/kg/day or higher. The highest no-effect dose was approximately 60 mg/kg/day, which is approximately 6 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis. Oral treatment of pregnant rabbits with sumatriptan during the period of organogenesis resulted in an increased incidence of cervicothoracic vascular and skeletal abnormalities. The highest no-effect dose for these effects was 15 mg/kg/day, or approximately 3 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

A study in which rats were dosed daily with oral sumatriptan prior to and throughout gestation demonstrated embryo/fetal toxicity (decreased body weight, decreased ossification, increased incidence of rib variations) and an increased incidence of a syndrome of malformations (short tail/short body and vertebral disorganization) at 500 mg/kg/day. The highest no-effect dose was 50 mg/kg/day, or approximately 5 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis. In a study in rats dosed daily with subcutaneous sumatriptan prior to and throughout pregnancy, at a dose of 60 mg/kg/day, the maximum dose tested, there was no evidence of teratogenicity. This dose is equivalent to approximately 6 times the maximum recommended single human oral dose of 100 mg on a mg/m2 basis.

Pup Deaths: Oral treatment of pregnant rats with sumatriptan during the period of organogenesis resulted in a decrease in pup survival between birth and postnatal day 4 at doses of approximately 250 mg/kg/day or higher. The highest no-effect dose for this effect was approximately 60 mg/kg/day, or 6 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

Oral treatment of pregnant rats with sumatriptan from gestational day 17 through postnatal day 21 demonstrated a decrease in pup survival measured at postnatal days 2, 4, and 20 at the dose of 1,000 mg/kg/day. The highest no-effect dose for this finding was 100 mg/kg/day, approximately 10 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis. In a similar study in rats by the subcutaneous route there was no increase in pup death at 81 mg/kg/day, the highest dose tested, which is equivalent to 8 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

Nursing Mothers: Sumatriptan is excreted in human breast milk following subcutaneous administration. Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with sumatriptan succinate tablets.

Pediatric Use: Safety and effectiveness of sumatriptan succinate tablets in pediatric patients have not been established. Completed placebo-controlled clinical trials evaluating oral sumatriptan (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent migraineurs. These studies did not establish the efficacy of oral sumatriptan compared to placebo in the treatment of migraine in adolescents. Adverse events observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse events in these patients appeared to be both doseand age-dependent, with younger patients reporting events more commonly than older adolescents.

Postmarketing experience includes a limited number of reports that describe pediatric patients who have experienced adverse events, some clinically serious, after use of subcutaneous sumatriptan and/or oral sumatriptan. These reports include events similar in nature to those reported rarely in adults. A myocardial infarction has been reported in a 14-year-old male following the use of oral sumatriptan; clinical signs occurred within 1 day of drug administration. Since clinical data to determine the frequency of serious adverse events in pediatric patients who might receive injectable, oral, or intranasal sumatriptan are not presently available, the use of sumatriptan in patients aged younger than 18 years is not recommended.

Geriatric Use: The use of sumatriptan in elderly patients is not recommended because elderly patients are more likely to have decreased hepatic function, they are at higher risk for CAD, and blood pressure increases may be more pronounced in the elderly (see WARNINGS).

不良事件

Serious cardiac events, including some that have been fatal, have occurred following the use of sumatriptan succinate injection or tablets. These events are extremely rare and most have been reported in patients with risk factors predictive of CAD. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS).
Significant hypertensive episodes, including hypertensive crises, have been reported on rare occasions in patients with or without a history of hypertension (see WARNINGS).
Incidence in Controlled Clinical Trials: Table 2 lists adverse events that occurred in placebo-controlled clinical trials in patients who took at least 1 dose of study drug. Only events that occurred at a frequency of 2% or more in any group treated with sumatriptan succinate tablets and were more frequent in that group than in the placebo group are included in Table 2. The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ.

Table 2. Treatment - Emergent Adverse Events Reported by at Least 2% of Patients in Controlled Migraine Trials*

*Events that occurred at a frequency of 2% or more in the group treated with sumatriptan succinate tablets and that occurred more frequently in that group than the placebo group.

Other events that occurred in more than 1% of patients receiving sumatriptan succinate tablets and at least as often on placebo included nausea and/or vomiting, migraine, headache, hyposalivation, dizziness, and drowsiness/sleepiness.

Sumatriptan succinate tablets are generally well tolerated. Across all doses, most adverse reactions were mild and transient and did not lead to long-lasting effects. The incidence of adverse events in controlled clinical trials was not affected by gender or age of the patients. There were insufficient data to assess the impact of race on the incidence of adverse events.

Other Events Observed in Association With the Administration of Sumatriptan Succinate Tablets: In the paragraphs that follow, the frequencies of less commonly reported adverse clinical events are presented. Because the reports include events observed in open and uncontrolled studies, the role of sumatriptan succinate tablets in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, etc., limit the value of quantitative frequency estimates provided. Event frequencies are calculated as the number of patients who used sumatriptan succinate tablets (25, 50, or 100 mg) and reported an event divided by the total number of patients (N = 6,348) exposed to sumatriptan succinate tablets. All reported events are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients, infrequent adverse events are those occurring in 1/100 to 1/1,000 patients, and rare adverse events are those occurring in fewer than 1/1,000 patients.

Atypical Sensations: Frequent were burning sensation and numbness. Infrequent was tight feeling in head. Rare were dysesthesia.

Cardiovascular: Frequent were palpitations, syncope, decreased blood pressure, and increased blood pressure. Infrequent were arrhythmia, changes in ECG, hypertension, hypotension, pallor, pulsating sensations, and tachycardia. Rare were angina, atherosclerosis, bradycardia, cerebral ischemia, cerebrovascular lesion, heart block, peripheral cyanosis, thrombosis, transient myocardial ischemia, and vasodilation.

Ear, Nose, and Throat: Frequent were sinusitis, tinnitus; allergic rhinitis; upper respiratory inflammation; ear, nose, and throat hemorrhage; external otitis; hearing loss; nasal inflammation; and sensitivity to noise. Infrequent were hearing disturbances and otalgia. Rare was feeling of fullness in the ear(s).

Endocrine and Metabolic : Infrequent was thirst. Rare were elevated thyrotropin stimulating hormone (TSH) levels; galactorrhea; hyperglycemia; hypoglycemia; hypothyroidism;烦恼体重增加;减肥endocrine cysts, lumps, and masses; and fluid disturbances.

Eye: Rare were disorders of sclera, mydriasis, blindness and low vision, visual disturbances, eye edema and swelling, eye irritation and itching, accommodation disorders, external ocular muscle disorders, eye hemorrhage, eye pain, and keratitis and conjunctivitis.

Gastrointestinal: Frequent were diarrhea and gastric symptoms. Infrequent were constipation, dysphagia, and gastroesophageal reflux. Rare were gastrointestinal bleeding, hematemesis, melena, peptic ulcer, gastrointestinal pain, dyspeptic symptoms, dental pain, feelings of gastrointestinal pressure, gastritis, gastroenteritis, hypersalivation, abdominal distention, oral itching and irritation, salivary gland swelling, and swallowing disorders.

Hematological Disorders: Rare was anemia.

Musculoskeletal: Frequent was myalgia. Infrequent was muscle cramps. Rare were tetany; muscle atrophy, weakness, and tiredness; arthralgia and articular rheumatitis; acquired musculoskeletal deformity; muscle stiffness, tightness, and rigidity; and musculoskeletal inflammation.

Neurological: Frequent were phonophobia and photophobia. Infrequent were confusion, depression, difficulty concentrating, disturbance of smell, dysarthria, euphoria, facial pain, heat sensitivity, incoordination, lacrimation, monoplegia, sleep disturbance, shivering, syncope, and tremor. Rare were aggressiveness, apathy, bradylogia, cluster headache, convulsions, decreased appetite, drug abuse, dystonic reaction, facial paralysis, hallucinations, hunger, hyperesthesia, hysteria, increased alertness, memory disturbance, neuralgia, paralysis, personality change, phobia, radiculopathy, rigidity, suicide, twitching, agitation, anxiety, depressive disorders, detachment, motor dysfunction, neurotic disorders, psychomotor disorders, taste disturbances, and raised intracranial pressure.

Respiratory: Frequent was dyspnea. Infrequent was asthma. Rare were hiccoughs, breathing disorders, cough, and bronchitis.

Skin: Frequent was sweating. Infrequent were erythema, pruritus, rash, and skin tenderness. Rare were dry/scaly skin, tightness of skin, wrinkling of skin, eczema, seborrheic dermatitis, and skin nodules.

Breasts: Infrequent was tenderness. Rare were nipple discharge; breast swelling; cysts, lumps, and masses of breasts; and primary malignant breast neoplasm.

Urogenital: Infrequent were dysmenorrhea, increased urination, and intermenstrual bleeding. Rare were abortion and hematuria, urinary frequency, bladder inflammation, micturition disorders, urethritis, urinary infections, menstruation symptoms, abnormal menstrual cycle, inflammation of fallopian tubes, and menstrual cycle symptoms.

Miscellaneous: Frequent was hypersensitivity. Infrequent were fever, fluid retention, and overdose. Rare were edema, hematoma, lymphadenopathy, speech disturbance, voice disturbances, contusions.

Other Events Observed in the Clinical Development of Sumatriptan Succinate: The following adverse events occurred in clinical trials with sumatriptan succinate injection and sumatriptan succinate nasal spray. Because the reports include events observed in open and uncontrolled studies, the role of sumatriptan succinate in their causation cannot be reliably determined. All reported events are included except those already listed, those too general to be informative, and those not reasonably associated with the use of the drug.
Atypical Sensations: Feeling strange, prickling sensation, tingling, and hot sensation.
Cardiovascular: Abdominal aortic aneurysm, abnormal pulse, flushing, phlebitis, Raynaud syndrome, and various transient ECG changes (nonspecific ST or T wave changes, prolongation of PR or QTc intervals, sinus arrhythmia, nonsustained ventricular premature beats, isolated junctional ectopic beats, atrial ectopic beats, delayed activation of the right ventricle).
Chest Symptoms: Chest discomfort.
Endocrine and Metabolic: Dehydration.
Ear, Nose, and Throat: Disorder/discomfort nasal cavity and sinuses, ear infection, Meniere disease, and throat discomfort.
Eye: Vision alterations.
Gastrointestinal: Abdominal discomfor t, colitis, disturbance of liver function tests, flatulence/eructation, gallstones, intestinal obstruction, pancreatitis, and retching.
Injection Site Reaction
Miscellaneous : Difficulty in walking, hypersensitivity to various agents, jaw discomfort, miscellaneous laboratory abnormalities, "serotonin agonist effect," swelling of the extremities, and swelling of the face.
Mouth and Teeth: Disorder of mouth and tongue (eg, burning of tongue, numbness of tongue, dry mouth).
Musculoskeletal: Arthritis, backache, intervertebral disc disorder, neck pain/stiffness, need to flex calf muscles, and various joint disturbances (pain, stiffness, swelling, ache).

Neurological: Bad/unusual taste, chills, diplegia, disturbance of emotions, sedation, globus hystericus, intoxication, myoclonia, neoplasm of pituitary, relaxation, sensation of lightness, simultaneous hot and cold sensations, stinging sensations, stress, tickling sensations, transient hemiplegia, and yawning.
Respiratory: Influenza and diseases of the lower respiratory tract and lower respiratory tract infection.
Skin: Skin eruption, herpes, and peeling of the skin.
Urogenital: Disorder of breasts, endometriosis, and renal calculus.

Postmarketing Experience (Reports for Subcutaneous or Oral Sumatriptan): The following section enumerates potentially important adverse events that have occurred in clinical practice and that have been reported spontaneously to various surveillance systems. The events enumerated represent reports arising from both domestic and nondomestic use of oral or subcutaneous dosage forms of sumatriptan. The events enumerated include all except those already listed in the ADVERSE REACTIONS section above or those too general to be informative. Because the reports cite events reported spontaneously from worldwide postmarketing experience, frequency of events and the role of sumatriptan in their causation cannot be reliably determined. It is assumed, however, that systemic reactions following sumatriptan use are likely to be similar regardless of route of administration.
Blood: Hemolytic anemia, pancytopenia, thrombocytopenia.
Cardiovascular: Atrial fibrillation, cardiomyopathy, colonic ischemia (see WARNINGS), Prinzmetal variant angina, pulmonary embolism, shock, thrombophlebitis.
Ear, Nose, and Throat : Deafness.
Eye: Ischemic optic neuropathy, retinal artery occlusion, retinal vein thrombosis, loss of vision.
Gastrointestinal : Ischemic colitis with rectal bleeding (see WARNINGS), xerostomia.
Hepatic: Elevated liver function tests.
Neurological: Central nervous system vasculitis, cerebrovascular accident, dysphasia, serotonin syndrome, subarachnoid hemorrhage.
Non-Site Specific: Angioneurotic edema, cyanosis, death (see WARNINGS), temporal arteritis.
Psychiatry: Panic disorder.
Respiratory: Bronchospasm in patients with and without a history of asthma.
Skin: Exacerbation of sunburn, hypersensitivity reactions (allergic vasculitis, erythema, pruritus, rash, shortness of breath, urticaria; in addition, severe anaphylaxis/anaphylactoid reactions have been reported [see WARNINGS]), photosensitivity.
Urogenital: Acute renal failure.

药物滥用与依赖

One clinical study with sumatriptan succinate injection enrolling 12 patients with a history of substance abuse failed to induce subjective behavior and/or physiologic response ordinarily associated with drugs that have an established potential for abuse.

过量

Patients (N = 670) have received single oral doses of 140 to 300 mg without significant adverse effects. Volunteers (N = 174) have received single oral doses of 140 to 400 mg without serious adverse events.

Overdose in animals has been fatal and has been heralded by convulsions, tremor, paralysis, inactivity, ptosis, erythema of the extremities, abnormal respiration, cyanosis, ataxia, mydriasis, salivation, and lacrimation. The elimination half-life of sumatriptan is approximately 2.5 hours (see CLINICAL PHARMACOLOGY), and therefore monitoring of patients after overdose with sumatriptan succinate tablets should continue for at least 12 hours or while symptoms or signs persist.

It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan.

剂量和给药

In controlled clinical trials, single doses of 25, 50, or 100 mg of sumatriptan succinate tablets were effective for the acute treatment of migraine in adults. There is evidence that doses of 50 and 100 mg may provide a greater effect than 25 mg (see CLINICAL TRIALS). There is also evidence that doses of 100 mg do not provide a greater effect than 50 mg. Individuals may vary in response to doses of sumatriptan succinate tablets. The choice of dose should therefore be made on an individual basis, weighing the possible benefit of a higher dose with the potential for a greater risk of adverse events.

If the headache returns or the patient has a partial response to the initial dose, the dose may be repeated after 2 hours, not to exceed a total daily dose of 200 mg. If a headache returns following an initial treatment with sumatriptan succinate injection, additional single sumatriptan succinate tablets (up to 100 mg/day) may be given with an interval of at least 2 hours between tablet doses. The safety of treating an average of more than 4 headaches in a 30-day period has not been established.
Because of the potential of MAO-A inhibitors to cause unpredictable elevations in the bioavailability of oral sumatriptan, their combined use is contraindicated (see CONTRAINDICATIONS).

Hepatic disease/functional impairment may also cause unpredictable elevations in the bioavailability of orally administered sumatriptan. Consequently, if treatment is deemed advisable in the presence of liver disease, the maximum single dose should in general not exceed 50 mg (see CLINICAL PHARMACOLOGY for the basis of this recommendation).

供应方式

Sumatriptan succinate tablets 100 mg of sumatriptan (base) as the succinate. Sumatriptan succinate tablets, 100 mg are pink, triangular-shaped, film-coated tablets debossed with "S" on one side and "100" on the other.

Unit-of-use blister pack of 9 (1x9) tablets.....NDC 62756-521-69
Unit-of-use blister pack of 9 (3x3) tablets.....NDC 62756-521-93

Store at 20° - 25°C (68° - 77°F); excursions permitted to 15° - 30°C (59° - 86°F) [See USP controlled Room Temperature.]

动物毒理学

Corneal Opacities: Dogs receiving oral sumatriptan developed corneal opacities and defects in the corneal epithelium. Corneal opacities were seen at the lowest dosage tested, 2 mg/kg/day, and were present after 1 month of treatment. Defects in the corneal epithelium were noted in a 60-week study. Earlier examinations for these toxicities were not conducted and no-effect doses were not established; however, the relative exposure at the lowest dose tested was approximately 5 times the human exposure after a 100 mg oral dose. There is evidence of alterations in corneal appearance on the first day of intranasal dosing to dogs. Changes were noted at the lowest dose tested, which was approximately one half the maximum single human oral dose of 100 mg on a mg/m2 basis.

患者信息

The following wording is contained in a separate leaflet provided for patients.

Information for the Patient
Sumatriptan Succinate Tablets

Read this leaflet carefully before you start to take sumatriptan succinate tablets. Keep the leaflet for reference because it gives you a summary of important information about sumatriptan succinate tablets.
Read the leaflet that comes with each refill of your prescription because there may be new information.
This leaflet does not have all the information about sumatriptan succinate tablets. Ask your healthcare provider for more information or advice.

What are sumatriptan succinate tablets?

Sumatriptan succinate tablets are a kind of medicine called a triptan. You should take it only if you have a prescription.
Sumatriptan succinate tablets are used to relieve your migraine. They are not used to prevent attacks or reduce the number of attacks you have. Use sumatriptan succinate tablets only to treat an actual migraine attack.

The decision to use sumatriptan succinate tablets is one that you and your healthcare provider should make together, based on your personal needs and health.

Talk with your healthcare provider before taking sumatriptan succinate tablets
1. Risk factors for heart disease to tell your healthcare provider:
Tell your healthcare provider if you have risk factors for heart disease such as:

• 高血压
• high cholesterol
• being overweight
• 糖尿病
• smoking
• strong family history of heart disease
• you are postmenopausal
• you are a male over 40 years of age

If you do have risk factors for heart disease, your healthcare provider should check you for heart disease to see if sumatriptan succinate tablets are right for you.
Although most of the people who have taken sumatriptan succinate tablets have not had any serious side effects, some have had serious heart problems. Deaths have been reported, but these were rare considering the extensive worldwide use of sumatriptan succinate tablets. Usually, serious problems happened in people with known heart disease. It was not clear whether sumatriptan succinate tablets had anything to do with these deaths.

2. Important questions to ask yourself before you take sumatriptan succinate tablets:
If the answer to any of the following questions is YES or if you do not know the answer, then please talk with your healthcare provider before you take sumatriptan succinate tablets:

• Are you pregnant? Do you think you might be pregnant? Are you trying to become pregnant? Are you not using adequate contraception? Are you breastfeeding?
• Do you have any chest pain, heart disease, shortness of breath, or irregular heartbeats? Have you had a heart attack?
• Do you have risk factors for heart disease (see list above)?
• Have you had a stroke, a mini-stroke (also called a transient ischemic attack or TIA), or Raynaud syndrome?
• Do you have high blood pressure?
• Have you ever had to stop taking this or any other medicine because of an allergy or other problems?
• Are you taking any other migraine medicines, including other triptans? Are you taking any medicines containing ergotamine, dihydroergotamine, or methysergide?
• Are you taking any medicine for depression or other health problems such as a monoamine oxidase inhibitor, selective serotonin reuptake inhibitor (SSRI), or serotonin norepinephrine reuptake inhibitor (SNRI)? Common SSRIs are citalopram HBr (CELEXA ® *), escitalopram oxalate (LEXAPRO®*), paroxetine (PAXIL*), fluoxetine (PROZAC®*/SARAFEM®*), olanzapine/fluoxetine (SYMBYAX®*), sertraline (ZOLOFT®*), and fluvoxamine. Common SNRIs are duloxetine (CYMBALTA®*) and venlafaxine (EFFEXOR®*).
• Have you had, or do you have, any disease of the liver or kidney?
• Have you had, or do you have, epilepsy or seizures?
• Is this headache different from your usual migraine attacks?

Remember, if you answered YES to any of the above questions, then talk with your healthcare provider about it.

Important points about sumatriptan succinate tablets
1. The use of sumatriptan succinate tablets during pregnancy: