Utibron Neohaler

Utibron Neohaler的适应症和用法

UTIBRON®NEOHALER®是慢性阻塞性肺疾病（COPD），包括慢性支气管炎和/或肺气肿的长期，维持治疗气流阻塞的茚达特罗和格隆溴铵的组合表示。

使用的重要限制：Utibron Neohaler不是急性支气管痉挛缓解或用于哮喘的治疗中[见警告和注意事项（ 5.1 ， 5.2 ）]。尚未确定UTIBRON在哮喘中的安全性和有效性。

Utibron Neohaler剂量和给药

仅用于口服吸入。不要吞下UTIBRON胶囊，因为不会对肺产生预期的影响。 UTIBRON胶囊只能与NEOHALER设备一起使用[请参阅过量（ 10 ）]。

Utibron Neohaler的推荐剂量是每天使用NEOHALER设备吸入一个UTIBRON胶囊的内容物两次。

每天应在同一时间（早晨1粒胶囊，晚上1粒胶囊）给药Utibron Neohaler。不建议更频繁地给予Utibron Neohaler或多次吸入（每天两次超过1粒胶囊）。

将UTIBRON胶囊存放在泡罩中，仅可在与NEOHALER设备一起使用之前立即取出。

老年患者，轻度和中度肝功能不全患者或轻度至中度肾功能不全患者无需调整剂量。

剂型和优势

吸入粉剂：Utibron Neohaler由UTIBRON胶囊组成，内含茚达特罗/格隆溴铵粉末和NEOHALER装置。 UTIBRON胶囊的羟丙甲纤维素胶囊含有27.5 mcg / 15.6 mcg茚达特罗/吡咯烷酸酯，带有黄色透明帽和无色透明体，黑色“ 帽子上的徽标”和机身黑条下方的黑色产品代码“ IGP27.5_15.6”。

禁忌症

哮喘患者禁忌使用LABA，包括Utibron Neohaler，不吸入皮质类固醇[参见警告和注意事项（ 5.1 ）] 。 Utibron Neohaler不适用于哮喘的治疗。

Utibron Neohaler禁用于对茚达特罗，格隆溴铵或任何成分过敏的患者[见警告和注意事项（ 5.5 ）] 。

警告和注意事项

5.1严重的哮喘相关事件–住院，插管，死亡

• 尚未确定Utibron Neohaler在哮喘患者中的安全性和有效性。没有将Utibron Neohaler用于哮喘的治疗[参见禁忌症（ 4 ） ]。
• 的长效β2 -肾上腺素能激动剂（LABA）单药使用[无吸入糖皮质激素（ICS）的哮喘与哮喘有关的死亡风险增加相关。对照临床试验的可用数据还表明，将LABA用作单药治疗会增加儿童和青少年患者哮喘相关住院的风险。这些发现被认为是LABA单一疗法的一种类效应。当将LABA与ICS固定剂量组合使用时，大型临床试验的数据表明，与单独的ICS相比，严重哮喘相关事件（住院，插管，死亡）的风险并未显着增加。
• 一项为期28周的美国安慰剂对照研究，比较了另一种LABA（沙美特罗）与安慰剂的安全性（均添加到常规哮喘治疗中），发现接受沙美特罗的患者与哮喘相关的死亡人数增加（沙美特罗治疗的患者为13 / 13,176）对比安慰剂治疗的患者为3 / 13,179； RR 4.37，95％CI 1.25，15.34）。与哮喘相关的死亡风险增加被认为是LABA的一种分类作用，包括indacaterol（Utibron Neohaler中的一种成分）。
• 尚未进行足以确定接受Utibron Neohaler治疗的患者中与哮喘相关的死亡率是否增加的研究。
• 现有数据并不表明在COPD患者中使用LABA会增加死亡风险。

疾病恶化和急性发作

患有COPD急性恶化或可能危及生命的发作的患者不应开始使用Utibron Neohaler。 Utibron Neohaler尚未在严重恶化的COPD患者中进行研究。在这种情况下启动Utibron Neohaler是不合适的。

Utibron Neohaler不应用于缓解急性症状，即，作为治疗急性支气管痉挛发作的急救疗法。尚未对Utibron Neohaler缓解急性症状进行研究，因此不应将额外剂量用于此目的。急性症状时，应与吸入短效β-激动剂2进行处理。

当开始Utibron Neohaler，病人谁一直在服用口服或吸入短效β定期2受体激动剂（例如，每日4次）应指示中止定期使用这些药物，只有对症使用它们缓解急性呼吸道症状。当处方Utibron Neohaler，医疗服务提供者也应该规定一个吸入短效β-激动剂2，指导它如何被使用的患者。增加吸入的β-激动剂2是使用疾病恶化的信号为哪些提示就医被指示。

COPD可能在几个小时内急剧恶化，或者在几天或更长时间内长期恶化。如果Utibron Neohaler不再控制支气管收缩症状；患者的吸入，短效β-激动剂2变得不太有效;或病人需要短效β2 -激动剂比平常的多个吸，这些可能是疾病的恶化的标记物。在这种情况下，应立即对患者和COPD治疗方案进行重新评估。在这种情况下，不宜将Utibron Neohaler的日剂量增加到建议剂量以上。

过度使用Utibron Neohaler以及与其他长效Beta2-肾上腺素能激动剂一起使用

与含有β2个-adrenergics其它吸入药物，Utibron Neohaler不应被更频繁地使用非推荐的，在较高剂量超过建议，或者与含有的LABAs其他药物结合，作为过量可能会导致。与过量使用吸入拟交感神经药有关的临床上显着的心血管影响和死亡已有报道。使用Utibron Neohaler的患者不得出于任何原因使用另一种含有LABA的药物[请参见药物相互作用（ 7.1 ）] 。

矛盾性支气管痉挛

与其他吸入药物一样，Utibron Neohaler可能产生反常的支气管痉挛，可能危及生命。如果在用Utibron Neohaler给药后发生反常的支气管痉挛，应立即用吸入的短效支气管扩张剂治疗；应立即停用Utibron Neohaler，并开始其他治疗。

立即超敏反应

据报道，在使用茚达特罗或格隆溴铵（Utibron Neohaler的成分）后立即发生超敏反应。如果出现迹象表明有过敏反应，特别是血管性水肿（包括呼吸困难或吞咽，舌头，嘴唇和面部肿胀），荨麻疹或皮疹，应立即停用Utibron Neohaler并采取替代疗法。对牛奶蛋白严重过敏的患者应谨慎使用Utibron Neohaler。

心血管作用

茚达特罗，像其它β2 -激动剂，如由脉冲速率的增加，收缩压或舒张压，或症状测量可产生在一些患者中的临床上显著心血管效果。如果发生此类影响，则可能需要停用Utibron Neohaler。此外，据报道，β-激动剂会产生ECG变化，例如T波变平，QTc间隔延长和ST段抑制，尽管这些发现的临床意义尚不清楚。

因此，在患有心血管疾病，尤其是冠状动脉供血不足，心律不齐和高血压的患者中，应谨慎使用Utibron Neohaler。

共存条件

与所有含有拟交感神经胺的药物一样，Utibron Neohaler在惊厥性疾病或甲状腺毒症患者以及对拟交感神经胺反应异常的患者中应谨慎使用。在相关的β-激动剂2沙丁胺醇，当静脉给药的剂量，据报道，会加重现有的糖尿病酮症酸中毒和。

窄角型青光眼恶化

窄角型青光眼患者应谨慎使用Utibron Neohaler。处方者和患者应警惕急性窄角型青光眼的体征和症状（例如眼痛或不适，视力模糊，视觉晕圈或彩色图像以及结膜充血和角膜水肿引起的红眼）。如果出现任何这些体征或症状，请指导患者立即就医。

尿Re留的恶化

尿retention留患者应谨慎使用Utibron Neohaler。处方者和患者应警惕尿retention留的体征和症状（例如，排尿困难，排尿疼痛），尤其是在前列腺增生或膀胱颈阻塞的患者中。如果出现任何这些体征或症状，请指导患者立即就医。

低钾血症和高血糖症

贝塔2 -肾上腺素能激动剂可在一些患者中产生显著低钾血症，具有生产不良心血管作用的潜力[见临床药理学（ 12.2 ）]。血清钾的减少通常是短暂的，不需要补充。高剂量的β2 -肾上腺素能激动剂的吸入可能产生在血浆葡萄糖增加。

在患有严重COPD的患者中，低氧血症可通过低氧和同时进行的治疗来加强[见药物相互作用（ 7.2 ）] ，这可能会增加对心律不齐的敏感性。

在两项为期12周的临床试验中，评估Utibron Neohaler在患有COPD的受试者中，没有证据表明对血清葡萄糖或钾有治疗作用。

不良反应

LABA，例如茚达特罗（Udabron Neohaler中的有效成分之一），作为哮喘的单一疗法（不吸入皮质类固醇），增加了发生哮喘相关事件的风险。 Utibron Neohaler不适用于哮喘的治疗[请参阅警告和注意事项（ 5.1 ）]。

其他部分将详细描述以下不良反应：

• 矛盾性支气管痉挛[见警告和注意事项（ 5.4 ）]。
• 立即发生超敏反应[请参阅警告和注意事项（ 5.5 ）]。
• 心血管效应[见警告和注意事项（ 5.6 ）] 。
• 窄角型青光眼恶化[见警告和注意事项（ 5.8 ）] 。
• 尿retention留的恶化[见警告和注意事项（ 5.9 ）] 。

临床试验经验

由于临床试验是在宽泛的条件下进行的，因此不能将药物在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，并且可能无法反映在临床实践中观察到的不良反应率。

Utibron Neohaler安全性数据库在两项12周的肺功能试验和一项52周的长期安全性研究中纳入了2654名COPD患者。总共712名受试者每天两次接受27.5 mcg / 15.6 mcg的Utibron Neohaler治疗（BID）。下文所述的安全性数据基于两项12周的试验和一项52周的试验。

12周试用

表1中与Utibron Neohaler相关的不良反应发生率基于两项为期12周的安慰剂对照试验（试验1和2；分别为N = 1,001和N = 1,042）。在2040名受试者中，男性占63％，白人占91％。他们的平均年龄为63岁，平均吸烟史为47包年，其中52％被确定为当前吸烟者。筛查时，平均1秒支气管扩张剂后预测的强制呼气量（FEV 1 ）为55％（范围：29％至79％），平均支气管扩张剂后FEV 1 /强迫肺活量（FVC）的比率为50 ％（范围：19％至71％），平均可逆性百分比为23％（范围：0％至144％）。

最常见的不良反应（发生率大于或等于2％且高于安慰剂）是鼻咽炎和高血压。

Utibron Neohaler治疗的患者因不良反应而中止治疗的比例为2.95％，安慰剂治疗的患者为4.13％。

受试者每天两次以下两次接受1剂剂量：Utibron Neohaler 27.5 mcg / 15.6 mcg，茚达特罗27.5 mcg，格隆溴铵15.6 mcg或安慰剂。

与安慰剂相比，Utibron Neohaler发生的其他不良反应更为频繁，但发生率低于1％，包括消化不良，胃肠炎，胸痛，疲劳，周围水肿，皮疹/瘙痒，失眠，头晕，膀胱阻塞/尿retention留，心房颤动，心，心动过速。

52周试用

在一项长期安全性试验中，对614位受试者进行了长达52周的治疗，每天两次使用茚达特罗/格隆溴铵27.5 mcg / 15.6 mcg，每天两次使用茚达特罗/格隆溴铵27.5 / 31.2 mcg，每天一次使用茚达特罗/ 75yr 3mg。长期安全性试验的人口统计学和基线特征与上述安慰剂对照的功效试验相似。在长期安全性试验中报告的不良反应与在12周的安慰剂对照试验中观察到的不良反应一致。在该试验中，每天两次接受茚达特罗/吡咯烷酸盐27.5 mcg / 15.6 mcg的组中，发生频率大于或等于2％的其他不良反应超过了每天一次的茚达特罗75 mcg的发生频率，分别是上呼吸道和下呼吸道感染，肺炎，腹泻，头痛，胃食管反流疾病，高血糖症，鼻炎。

上市后经验

在全球范围内以高于推荐剂量的茚达特罗/格隆溴铵的批准后使用中，已经确定了以下血管性水肿和声音障碍的其他不良反应。由于该反应是从不确定大小的人群中自愿报告的，因此并非总是可能可靠地估计频率或建立与药物暴露的因果关系。

药物相互作用

肾上腺素药物

如果附加肾上腺素药是通过任何途径施用，但是它们应谨慎使用，因为茚达特罗的交感神经影响，Utibron Neohaler的组分，可以强化[见警告和注意事项（ 5.3 ， 5.6 ， 5.7 ， 5.10 ）]。

黄嘌呤衍生物，类固醇或利尿剂

用黄嘌呤衍生物，类固醇，利尿剂或伴随治疗，会增强的β2 -肾上腺素能激动剂，例如茚达特罗，Utibron Neohaler的组件的任何低钾效应[见警告和注意事项（ 5.10 ）]。

非钾利尿剂

服用非钾保留性利尿剂（例如loop或噻嗪类利尿剂）可能引起的心电图变化和/或低钾血症，可被β-激动剂（如Udabron Neohaler的成分茚达特罗）急剧恶化。尤其是当超过建议剂量的β-激动剂时。尽管尚不清楚这些作用的临床相关性，但在联合使用Utibron Neohaler和不留钾的利尿剂时建议谨慎。

单胺氧化酶抑制剂，三环抗抑郁药，延长QTc的药物

茚达特罗，Utibron Neohaler的部件中的一个，与其它β2 -激动剂，应当格外小心，以患者被单胺氧化酶抑制剂，三环抗抑郁药，或已知延长QT间期的其他药物治疗的施用，因为肾上腺素的作用这些药物可能会增强心血管系统的激动剂。已知延长QTc间隔的药物可能会增加室性心律失常的风险。

Beta-Blockers

当同时给药时，β-肾上腺素能受体拮抗剂（β-受体阻滞剂）和Utibron Neohaler可能相互干扰。 β受体阻滞剂不仅会阻断β激动剂的治疗作用，而且可能在COPD患者中产生严重的支气管痉挛。因此，患有COPD的患者通常不应使用β受体阻滞剂治疗。但是，在某些情况下，例如预防心肌梗塞后，对于COPD患者，使用β受体阻滞剂可能没有可接受的替代方法。在这种情况下，可以考虑使用心脏选择性β受体阻滞剂，尽管应谨慎使用。

抗胆碱药

与伴随使用的抗胆碱能药物可能发生加性相互作用。因此，与其它抗胆碱能含有的药物，因为这Utibron Neohaler的共同给药避免可能导致增加的抗胆碱能的不利影响[见警告和注意事项（ 5.8 ， 5.9 ），不良反应（ 6 ）]。

细胞色素P450 3A4和P-gp外排转运蛋白的抑制剂

使用有效和特定的CYP3A4和P-gp抑制剂（即酮康唑，红霉素，维拉帕米和利托那韦），与茚达特罗（Utibron Neohaler的一种成分）进行药物相互作用研究。数据表明茚达特罗的全身清除率受P-gp和CYP3A4活性的调节影响，并且由强双重抑制剂酮康康唑引起的曲线下面积增加2倍（AUC）反映了最大联合抑制作用。在临床试验中对茚达特罗进行了长达一年的评估，剂量高达600 mcg。抑制茚达特罗清除率的主要因素，CYP3A4和P-gp，对茚达特罗治疗剂量的安全性没有影响。因此，当与CYP3A4和P-gp抑制剂同时给药时，对于Utibron Neohaler，建议的每日两次剂量为27.5 / 15.6 mcg，无需调整剂量[见临床药理学（ 12.3 ）] 。

在特定人群中的使用

怀孕

致畸作用：妊娠C类

没有Utibron Neohaler或其单独成分茚达特罗和格隆溴铵在孕妇中进行的充分对照研究。用茚达特罗和格隆溴铵的各个成分进行了动物繁殖研究。由于动物繁殖研究并不总是能够预测人类的反应，因此只有在潜在益处证明对胎儿具有潜在风险的情况下，才应在妊娠期间使用Utibron Neohaler。如果妇女在服用Utibron Neohaler时怀孕，应建议其联系医生。

茚达特罗：茚达特罗在Wistar大鼠和新西兰兔中的致畸性分别约为成年MRHD的340倍和770倍（以大鼠和兔子中母体皮下剂量最高1 mg / kg /天的AUC为基础）。

格隆溴铵：格隆溴铵在Wistar大鼠或新西兰白兔中不致畸变，分别是成年MRHD的1400倍和530倍（以母体吸入剂量在大鼠中最高每日3.83 mg / kg /天和最高4.4时的AUC基础）毫克/公斤/天）。

非致畸作用：

茚达特罗：对成年小鼠的MRHD大约110倍时，对大鼠的围产期和产后发育没有影响（母体皮下剂量最高为0.3 mg / kg /天时，以AUC为基础）。

格隆溴铵：对成年小鼠MRHD约1100倍时，其对围产期和产后发育没有影响（在母体皮下剂量高达1.88 mg / kg /天的情况下，以AUC为基础）。

人工与分娩

没有足够的，经过良好控制的人体试验来研究Utibron Neohaler在分娩和生产期间的作用。因为β激动剂可能会干扰子宫收缩，所以只有在潜在益处证明潜在风险合理的情况下，才应在分娩时使用Utibron Neohaler。

在单次肌内注射0.006 mg / kg格隆溴铵后的86分钟内，进行剖腹产的人类产妇的脐血血浆浓度较低。

护理母亲

Utibron Neohaler：尚不清楚Utibron Neohaler是否从人母乳中排出。由于许多药物是从人乳中排出的，因此当对哺乳妇女使用Utibron Neohaler时应格外小心。由于没有经过良好控制的人类研究有关哺乳母亲使用Utibron Neohaler的数据，因此，根据各个组成部分的数据，应考虑到重要性，决定是否停止护理或停止使用Utibron Neohaler。 Utibron Neohaler的母亲。

茚达特罗：尚不知道茚达特罗是否会从人乳中排出。在哺乳期大鼠的牛奶中检测到茚达特罗（包括其代谢产物）。

格隆溴铵：格隆溴铵是否会从人乳中排泄。在哺乳期大鼠的乳汁中发现了甘草次膦酸盐（包括其代谢产物），并且其乳汁中的浓度高达大坝血液中的十倍。

儿科用

Utibron Neohaler不适用于儿童。尚未确定Utibron Neohaler在儿科患者中的安全性和有效性。

老人用

根据现有数据，不需调整老年患者的Utibron Neohaler剂量。 Utibron Neohaler可按建议剂量用于75岁及以上的老年患者。

在Utibron Neohaler临床研究的受试者总数中，有45％的年龄为65岁及以上，而11％的年龄为75岁及以上。在这些受试者与较年轻的受试者之间未观察到安全性或有效性的总体差异，其他报告的临床经验也未发现老年与较年轻患者之间的反应差异，但是不能排除某些老年患者的敏感性更高。

肾功能不全

根据其单一疗法成分的药代动力学特征，Utibron Neohaler可以按推荐剂量用于轻至中度肾功能不全的患者。对于严重肾功能不全（估计GFR低于30 mL / min / 1.73 m 2 ）或需要透析的终末期肾脏疾病的患者，如果预期获益超过潜在风险，则应使用Utibron Neohaler，因为可能全身性暴露于格隆溴铵在这个人群中增加[见临床药理学（ 12.3 ）] 。

肝功能不全

根据其单一疗法成分的药代动力学特征，Utibron Neohaler可以按推荐剂量用于轻度和中度肝功能不全的患者。尚未对严重肝功能不全的受试者进行研究[见临床药理学（ 12.3 ）] 。

过量

在COPD患者中，在2周内吸入了高达600 / 124.8 mcg的Utibron Neohaler剂量，并且对心率，QTc间隔，血糖或血钾没有相关影响。用Utibron Neohaler给药300 / 124.8 mcg和600 / 124.8 mcg后14天，室性异常增加，但患病率低且患者人数少（600 / 124.8 mcg和300 / 124.8 mcg的N = 49和N = 51 Utibron Neohaler分别排除了进行精确分析的可能性。在总共四名患者中，记录到非持续性室性心动过速，最长记录为9次（4秒）。

在健康志愿者中，Utibron Neohaler的单剂量给药剂量高达440 / 499.2 mcg茚达特罗/格隆溴铵的耐受性良好，对ECG，血清钾或血糖无临床显着影响。

Utibron Neohaler含有茚达特罗和格隆溴铵；因此，与下述单个成分过量相关的风险适用于Utibron Neohaler。药物过量的治疗包括停用Utibron Neohaler以及适当的对症和/或支持疗法。考虑到这种药物会产生支气管痉挛，可以考虑明智地使用心脏选择性β受体阻滞剂。如果过量，建议进行心脏监护。

茚达特罗

与茚达特罗过量相关的潜在体征和症状是过度的β-肾上腺素刺激以及任何体征和症状的发生或夸大的症状和症状，例如心绞痛，高血压或低血压，心动过速（最高200 bpm），心律不齐，神经质，头痛，震颤，口干，心慌，肌肉痉挛，恶心，呕吐，嗜睡，头晕，疲劳，全身乏力，低钾血症，高血糖症，代谢性酸中毒和失眠。与所有吸入拟交感神经药一样，心脏骤停甚至死亡可能与茚达特罗过量有关。

在COPD患者中，单剂量茚达特罗3000 mcg与脉搏率，收缩压和QTc间隔的适度增加有关。

甘草酸

过量的格隆溴铵可能会导致抗胆碱能的体征和症状，例如恶心，呕吐，头晕，头昏眼花，视力模糊，眼内压升高（引起疼痛，视力障碍或眼睛变红），便秘或排尿困难。

在COPD患者中，耐受性良好的口服28天每天一次总剂量为124.8 mcg和249.6 mcg的格隆溴铵反复吸入。

在健康志愿者中静脉内注射150 mcg格隆溴铵（相当于120 mcg活性部分）后，血浆峰值水平和总全身暴露分别比稳定状态下的峰值和总全身暴露高约270倍和13倍。建议的每日剂量为31.2 mcg的格隆溴铵（即每天两次15.6 mcg的格隆溴铵），并且耐受性良好。

Utibron Neohaler说明

Utibron Neohaler由干粉制剂组成，仅通过NEOHALER设备即可通过口服吸入将茚达特罗和格隆溴铵的组合递送给患者。吸入性粉末包装在具有黄色透明盖和无色透明体的羟丙甲纤维素（HPMC）胶囊中。

每个胶囊包含27.5 mcg / 15.6 mcg茚达特罗/格隆溴铵与约24.9 mg乳糖一水合物（含痕量牛奶蛋白）和0.03 mg硬脂酸镁的干粉混合物。

Utibron Neohaler的一种活性成分是马来酸茚达特罗（一种对映异构体）。茚达特罗马来酸盐是选择性β2 -肾上腺素能激动剂。它的化学名称是（R）-5- [2-（5,6-二乙基茚满-2-基氨基）-1-羟乙基] -8-羟基-1H-喹啉-2-一马来酸酯；其结构式为：

马来酸茚达特罗的分子量为508.56，其经验公式为C24H28N2O3•C4H4O4。马来酸茚达特罗是白色至非常浅灰色或非常浅黄色的粉末。马来酸茚达特罗微溶于乙醇，微溶于水。

Utibron Neohaler的另一个活性成分是格隆溴铵，在化学上被描述为（3RS）-3-[（2SR）-（2-环戊基-2-羟基-2-苯基乙酰基）氧基] -1,1-二甲基吡咯烷溴化物。这种合成的季铵化合物在毒蕈碱乙酰胆碱受体上也起竞争性拮抗剂的作用，也称为抗胆碱能药。格隆溴铵，C 19 H 28 BrNO 3 ，是一种白色粉末，易溶于水，微溶于无水乙醇。它的分子量为398.33。结构式为：

NEOHALER设备是一种塑料吸入设备，用于吸入UTIBRON胶囊内的干粉。输送到肺部的药物量将取决于患者因素，例如吸气流速和吸气时间。

在以90 L / min的固定流速进行1.3秒的标准化体外测试下，NEOHALER吸入器递送了20.8 mcg / 15.6 mcg剂量强度的20.8 mcg茚达特罗和12.8 mcg格隆溴铵（相当于27.5 mcg / 12.5 mcg茚达特罗） / glycopyrronium）。该体外测试显示，NEOHALER装置的电阻率为0.059 cm H 2 O 1/2 / L / min。通过NEOHALER设备可达到的峰值吸气流速（PIFR）在26位严重程度不同的COPD成人患者中进行了评估。成人患者的平均PIFR为95 L / min（52至133 L / min）。在这项研究中，有26名患者中有25名（96％）通过该装置产生的PIFR超过60 L / min。

Utibron Neohaler-临床药理学

作用机理

Utibron Neohaler包含茚达特罗和格隆溴铵。以下针对各个组件所述的作用机制适用于Utibron Neohaler。这些药物代表2种不同类别的药物（LABA和抗胆碱能药物），它们对临床和生理指标具有不同的累加作用。

茚达特罗：茚达特罗是长效β2 -肾上腺素能激动剂（LABA）。吸入时，茚达特罗在肺中局部起支气管扩张剂的作用。虽然测试2 -受体是在支气管平滑肌和β的主要肾上腺素能受体-1受体是在心脏中的主要受体，也存在的β2 -肾上腺素能受体在人的心脏包括总肾上腺素能受体的10％至50％ 。这些受体的精确功能是未知的，但它们的存在引起，即使高度选择性β2 -肾上腺素能受体激动剂可具有强心作用的可能性。

的β2肾上腺素能受体兴奋剂药物，包括茚达特罗的药理作用，至少部分归因于细胞内腺苷酸环化酶的刺激作用，催化三磷酸腺苷（ATP）的，以环状3' ，5'-单磷酸腺苷转化的酶（环状单磷酸盐）。循环AMP含量增加会导致支气管平滑肌松弛，并抑制细胞（尤其是肥大细胞）立即超敏反应的介质释放。体外研究已经表明，茚达特罗具有多于于β-2 -受体相比对β相比对β3 -受体24倍的激动剂活性1 -受体和20倍更高的激动剂活性。这些发现的临床意义尚不清楚。

格隆溴铵：格隆溴铵是一种长效毒蕈碱拮抗剂，通常被称为抗胆碱能药。它与毒蕈碱受体M1至M5的亚型具有相似的亲和力。在气道中，它通过抑制平滑肌M3受体导致支气管扩张而表现出药理作用。人类和动物起源的受体和分离的器官制剂显示出拮抗作用的竞争性和可逆性。在临床前的体外和体内研究中，预防乙酰甲胆碱诱导的支气管收缩作用是剂量依赖性的，持续时间超过24小时。这些发现的临床相关性未知。吸入格隆溴铵后的支气管扩张主要是部位特异性作用。

药效学

心脏电生理学

QTc间隔是在Utibron Neohaler和每种单一疗法成分的TQT研究中进行的。用茚达特罗和格隆溴铵的TQT研究表明，在超剂量和治疗剂量下，这两种化合物均未对校正的QT间隔产生相关影响（对于格隆溴铵，仅测试了超剂量）。

In a randomized, partially-blinded, placebo- and positive-controlled, crossover TQT study in 84 healthy subjects a supratherapeutic dose of Utibron Neohaler (indacaterol/glycopyrrolate 440/499.2 mcg) was administered. This is a 16/32 dose multiple compared to a single dose of the recommended 27.5/15.6 mcg twice-daily dosage of Utibron Neohaler, which resulted in exposure multiples for mean C max of 9.3 for indacaterol and 35.2 for glycopyrrolate compared to steady-state pharmacokinetics of Utibron Neohaler 27.5/15.6 mcg twice-daily. The mean maximal change from baseline in QTcI compared to placebo was 8.70 msec (2-sided 90% CI 7.3, 10.1) at 30 minutes after dosing. Although a marginal QT effect of Utibron Neohaler was observed at the supratherapeutic dose, it is unlikely there will be a clinically relevant effect at the therapeutic exposure.

药代动力学

吸收性

Following inhalation of Utibron Neohaler, the median time to reach peak plasma concentrations of indacaterol and glycopyrrolate was achieved rapidly at approximately 15 minutes and 5 minutes, respectively.

The steady-state systemic exposure (AUC 0-12h,ss ; C max,ss ) to indacaterol and glycopyrrolate is similar after the twice-daily inhalation of 2 (times 2) capsules of Utibron Neohaler 27.5 mcg/15.6 mcg as compared to the twice-daily inhalation of the monotherapy products indacaterol 27.5 mcg (times 2) alone or glycopyrrolate 15.6 mcg (times 2) alone, respectively.

Indacaterol: Absolute bioavailability of indacaterol after an inhalation dose was on average 43% to 45%. Systemic exposure results from a composite of pulmonary and intestine absorption. Indacaterol serum concentrations increased with repeated once-daily administration. Steady-state was achieved within 12 to 15 days. The mean accumulation ratio of indacaterol, ie, AUC over the 24-hour dosing interval on Day 14 or Day 15 compared to Day 1, was in the range of 2.9 to 3.8 for once-daily inhaled doses between 75 mcg and 600 mcg.

Glycopyrrolate: Following repeated once-daily inhalation in patients with COPD, pharmacokinetic steady-state of glycopyrrolate was reached within 1 week of treatment. There was no indication that the glycopyrrolate pharmacokinetics changes over time. With once-daily doses of 124.8 mcg and 249.6 mcg, steady-state exposure to glycopyrrolate (AUC over the dosing interval) was about 1.4- to 1.7-fold higher than after the first dose.

分配

Indacaterol: After intravenous infusion, the volume of distribution (V z ) of indacaterol was 2,361 to 2,557 L, indicating an extensive distribution. The in vitro human serum and plasma protein binding was 94.1% to 95.3% and 95.1% to 96.2%, respectively.

Glycopyrrolate: After intravenous administration, the steady-state volume of distribution (V ss ) of glycopyrrolate was 83 L and the volume of distribution in the terminal phase (V z ) was 376 L. The in vitro human plasma protein binding of glycopyrrolate was 38% to 41% at concentrations of 1 to 10 ng/mL.

代谢

Indacaterol: In vitro investigations indicated that UGT1A1 is the only UGT isoform that metabolized indacaterol to the phenolic O-glucuronide. The oxidative metabolites were found in incubations with recombinant CYP1A1, CYP2D6, and CYP3A4. CYP3A4 is concluded to be the predominant isoenzyme responsible for hydroxylation of indacaterol. In vitro investigations further indicated that indacaterol is a low affinity substrate for the efflux pump P-gp.

After oral administration of radiolabelled indacaterol in a human ADME (absorption, distribution, metabolism, excretion) study, unchanged indacaterol was the main component in serum, accounting for about one-third of total drug-related AUC over 24 hours. A hydroxylated derivative was the most prominent metabolite in serum. Phenolic O-glucuronides of indacaterol and hydroxylated indacaterol were further prominent metabolites. A diastereomer of the hydroxylated derivative, a N-glucuronide of indacaterol, and C- and N-dealkylated products were further metabolites identified.

Glycopyrrolate: In vitro metabolism studies show glycopyrrolate hydroxylation resulting in a variety of mono- and bis-hydroxylated metabolites and direct hydrolysis resulting in the formation of a carboxylic acid derivative (M9). Further in vitro investigations showed that multiple CYP isoenzymes contribute to the oxidative biotransformation of glycopyrrolate and the hydrolysis to M9 is likely to be catalyzed by members from the cholinesterase family pre-systemically and/or via first pass metabolism from the swallowed dose fraction of orally inhaled glycopyrrolate. Glucuronide and/or sulfate conjugates of glycopyrrolate were found in urine of humans after repeated inhalation, accounting for about 3% of the dose.

消除

Indacaterol: In clinical studies which included urine collection, the amount of indacaterol excreted unchanged via urine was generally lower than 2% of the dose. Renal clearance of indacaterol was, on average, between 0.46 L/h and 1.20 L/h. When compared with the serum clearance of indacaterol of 18.8 L/h to 23.3 L/h, it is evident that renal clearance plays a minor role (about 2% to 6% of systemic clearance) in the elimination of systemically available indacaterol.

In a human ADME study where indacaterol was given orally, the fecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human feces primarily as unchanged parent drug (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose). Mass balance was complete with greater than or equal to 90% of the dose recovered in the excreta.

Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life ranging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing, ranged from 40 to 56 hours, which is consistent with the observed time to steady-state of approximately 12 to 15 days.

Glycopyrrolate: Renal elimination of parent drug accounts for about 60% to 70% of total clearance of systemically available glycopyrrolate whereas non-renal clearance processes account for about 30% to 40%. Biliary clearance contributes to the non-renal clearance, but the majority of non-renal clearance is thought to be due to metabolism.

Following inhalation of single and repeated once-daily doses between 62.4 mcg and 249.6 mcg glycopyrrolate by healthy volunteers and patients with COPD, mean renal clearance of glycopyrrolate was in the range of 17.4 L/h and 24.4 L/h. Active tubular secretion contributes to the renal elimination of glycopyrrolate.

Glycopyrrolate plasma concentrations declined in a multi-phasic manner. The mean terminal elimination half-life of glycopyrrolate was much longer after inhalation (33 to 53 hours) than after intravenous (6.2 hours) and oral (2.8 hours) administration.

药物相互作用

There is no pharmacokinetic drug-drug interaction resulting from the concomitant administration of inhaled glycopyrrolate and inhaled indacaterol based on steady-state exposure data.

No specific drug-drug interaction studies were conducted with Utibron Neohaler. Information on the potential for interactions for Utibron Neohaler is based on the potential for each of its 2 monotherapy components.

Effect of co-administered drugs on indacaterol and glycopyrrolate exposure

Indacaterol:

Inhibitors of Cytochrome P450 3A4 and P-gp Efflux Transporter : Drug interaction studies were carried out using potent and specific inhibitors of CYP3A4 and P-gp (ie, ketoconazole, erythromycin, verapamil and ritonavir). Coadministration of indacaterol 300 mcg (single dose) with verapamil (80 mg 3 times a day for 4 days) showed 2-fold increase in indacaterol AUC 0-24h , and 1.5-fold increase in indacaterol C max . Coadministration of indacaterol inhalation powder 300 mcg (single dose) with erythromycin (400 mg 4 times a day for 7 days) showed a 1.4-fold increase in indacaterol AUC 0-24h , and 1.2-fold increase in indacaterol C max . Coadministration of indacaterol inhalation powder 300 mcg (single dose) with ketoconazole (200 mg twice-daily for 7 days) caused a 1.9-fold increase in indacaterol AUC 0-24h , and 1.3-fold increase in indacaterol C max . Coadministration of indacaterol 300 mcg (single dose) with ritonavir (300 mg twice-daily for 7.5 days) resulted in a 1.7-fold increase in indacaterol AUC 0-24h whereas indacaterol C max was unaffected [see Drug Interactions ( 7.7 )] .

Glycopyrrolate:

Cimetidine or Other Inhibitors of Organic Cationic Transport : In a clinical study in healthy volunteers, cimetidine, an inhibitor of organic cation transport that is thought to contribute to the renal excretion of glycopyrrolate, increased total exposure (AUC) to glycopyrrolate by 22% and decreased renal clearance by 23%.

Effect of UTIBRON on co-administered drugs exposure

In vitro studies show that Utibron Neohaler is not likely to inhibit or induce the metabolism of other drugs, nor processes involving drug transporters.

Indacaterol: In vitro investigations indicated that indacaterol has negligible potential to cause metabolic interactions with medications (by inhibition or induction of cytochrome P450 enzymes, or induction of UGT1A1) at the systemic exposure levels achieved in clinical practice. In vitro investigation furthermore indicated that, in vivo , indacaterol is unlikely to significantly inhibit transporter proteins such as P-gp, MRP2, BCRP, the cationic substrate transporters hOCT1 and hOCT2, and the human multidrug and toxin extrusion transporters hMATE1 and hMATE2K, and that indacaterol has negligible potential to induce P-gp or MRP2.

Glycopyrrolate: In vitro inhibition studies demonstrated that glycopyrrolate has no relevant capacity to inhibit CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5, the efflux transporters MDR1, MRP2 or MXR, and the uptake transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2. In vitro enzyme induction studies did not indicate a clinically relevant induction by glycopyrrolate for any of the cytochrome P450 isoenzymes tested as well as for UGT1A1 and the transporters MDR1 and MRP2.

特定人群

Population pharmacokinetic analysis showed no evidence of a clinically significant effect of age (40 to 85 years), body weight (45 to 120 kg), gender, smoking status, and baseline FEV 1 on systemic exposure of either indacaterol or glycopyrrolate following inhalation of Utibron Neohaler.

Similarly no relevant covariate effect (of age, body weight, gender, smoking status, and baseline FEV 1 ) was observed following the inhalation of the 2 components indacaterol and glycopyrrolate separately.

肾功能不全的患者

Indacaterol: Due to the very low contribution of the urinary pathway to total body elimination of indacaterol, a study in renally impaired subjects was not performed.

Glycopyrrolate: Renal impairment has an impact on the systemic exposure to glycopyrrolate. A moderate mean increase in total systemic exposure (AUC last) of up to 1.4-fold was seen in subjects with mild and moderate renal impairment [estimated GFR greater than or equal to 30 mL/min/1.73m 2 ] and up to 2.2-fold in subjects with severe renal impairment and end stage renal disease [estimated GFR less than 30 mL/min/1.73m 2 ] [see Use in Specific Populations ( 8.6 )] .

肝功能不全患者

Based on the clinical pharmacokinetic characteristics of its monotherapy components, Utibron Neohaler can be used at the recommended dose in patients with mild and moderate hepatic impairment. Utibron Neohaler has not been evaluated in subjects with severe hepatic impairment.

Indacaterol: Patients with mild and moderate hepatic impairment showed no relevant changes in C max or AUC of indacaterol, nor did protein binding differ between mild and moderate hepatic impaired subjects and their healthy controls. Studies in subjects with severe hepatic impairment were not performed [see Use in Specific Populations ( 8.7 )] .

Glycopyrrolate: Clinical studies in patients with hepatic impairment have not been conducted. Glycopyrrolate is cleared predominantly from the systemic circulation by renal excretion.

Ethnicity

There was no evidence of a clinically significant ethnic/race effect (across Caucasian, Chinese, and Japanese subjects) on the systemic exposure to indacaterol and glycopyrrolate following inhalation of Utibron Neohaler.

Similarly, no relevant ethnic effect was observed following the inhalation of the 2 components indacaterol and glycopyrrolate separately.

药物基因组学

Indacaterol: The pharmacokinetics of indacaterol were prospectively investigated in subjects with the UGT1A1 (TA)7/(TA)7 genotype (low UGT1A1 expression; also referred to as *28) and the (TA)6, (TA)6 genotype. Steady-state AUC and C max of indacaterol were 1.2-fold higher in the [(TA)7, (TA)7] genotype, suggesting no relevant effect of UGT1A1 genotype of indacaterol exposure.

Glycopyrrolate: The effects of pharmacogenomic variants on the pharmacokinetics of glycopyrrolate have not been investigated.

非临床毒理学

致癌，诱变，生育力受损

No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with Utibron Neohaler; however, studies are available for the individual components, indacaterol and glycopyrrolate, as described below.

Indacaterol: Indacaterol produced no treatment-related increases in the incidence of tumors in a 2-year inhalation study in Wistar rats at inhaled doses up to 2.09 mg/kg/day (approximately 110 times the MRHD in adults on an AUC basis, respectively). A 26-week oral (gavage) study in CB6F1/TgrasH2 hemizygous mice with indacaterol at doses up to 600 mg/kg/day did not show any evidence of tumorigenicity.

Indacaterol tested negative in the following genotoxicity assays: the in vitro Ames test, in vitro chromosome aberration test in V79 Chinese hamster cells, and in vivo rat bone marrow micronucleus test.

Indacaterol had no effects on fertility and reproductive performance in male and female rats at subcutaneous doses up to 2 mg/kg/day (approximately 890 and 670 times in males and females, respectively, the MRHD in adults on an AUC basis).

Glycopyrrolate: Glycopyrrolate produced no treatment-related increases in the incidence of tumors in a 2-year inhalation study in Wistar rats at inhaled doses up to 0.56 mg/kg/day (approximately 170 times the MRHD in adults on an AUC basis). A 26-week oral (gavage) study in male and female TgrasH2 mice that received glycopyrrolate at doses up to 93.8 and 125.1 mg/kg/day, respectively, did not show any evidence of tumorigenicity.

Glycopyrrolate tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro human lymphocyte chromosomal aberration assay, and in vivo rat bone marrow micronucleus assay.

Impairment of fertility was observed in male and female rats at a subcutaneous dose of 1.88 mg/kg/day (approximately 1900 and 1100 times the MRHD in adults on an AUC basis, respectively) based upon findings of decreased corpora lutea, implantation sites and live fetuses. No effects on fertility and reproductive performance in male and female rats were observed at a subcutaneous dose of 0.63 mg/kg/day (approximately 350 times the MRHD in adults on an AUC basis).

Animal Toxicology

Eye findings were seen for glycopyrrolate and were observed in Wistar rats at inhaled doses of 0.67 mg/kg/day and higher (approximately 280 times the MRHD in adults on an AUC basis) based upon findings of anterior capsule opacity, prominent anterior suture line, and anterior cataract. No eye findings in Wistar rats were observed at an inhaled dose of 0.09 mg/kg/day (approximately 60 times the MRHD in adults on an AUC basis). Eye findings were observed in beagle dogs at an inhaled dose of 0.33 mg/kg/day (approximately 150 times the MRHD in adults on an AUC basis) based upon findings of conjunctival hyperemia and corneal opacity. No eye findings in beagle dogs were observed at an inhaled dose of 0.12 mg/kg/day (approximately 100 times the MRHD in adults on an AUC basis).

临床研究

The safety and efficacy of Utibron Neohaler were evaluated in a clinical development program that included 3 dose-ranging trials, 2 lung function trials of 12 weeks duration (placebo-controlled and active-controlled) and a 12-month long-term safety trial. The efficacy of Utibron Neohaler is based primarily on the dose-ranging trials in 562 subjects with COPD or asthma and the 2 placebo- and active-controlled confirmatory trials in 2043 subjects with additional support from one active-controlled 12-month trial in 615 subjects with COPD.

Dose-Ranging Trials

Dose selection for Utibron Neohaler for COPD was based on data for the individual components, indacaterol and glycopyrrolate.

Indacaterol: Indacaterol dose selection in Utibron Neohaler is based on the registered dose of 75 mcg once-daily and is also supported by a single-dose, multicenter, randomized, double-blind, placebo-controlled, crossover study in asthma evaluating 5 doses of indacaterol in 91 subjects, (37.5 mcg, 55 mcg, 75 mcg, and 150 mcg once-daily (QD), and 27.5 mcg twice-daily (BID)). A dose-related increase in FEV 1 AUC 0-24h compared with placebo was observed. The differences in change from baseline in FEV 1 AUC 0-24h Rafter single dosing for the indacaterol 37.5 mcg, 55 mcg, 75 mcg, and 150 mcg once-daily and the 27.5 mcg twice-daily doses compared to placebo were 0.099 L (95% CI: 0.069, 0.128), 0.132 L (0.103, 0.162), 0.143 L (0.114, 0.171), 0.187 L (0.157, 0.216), and 0.121 L (0.092, 0.151), respectively. These results supported the evaluation of indacaterol 27.5 mcg twice-daily in the confirmatory COPD trials. Utibron Neohaler is not indicated for asthma.

Figure 1. Adjusted mean change from baseline in FEV 1 (L) over 24 hours on Day 1

Glycopyrrolate: Dose selection for glycopyrrolate in Utibron Neohaler in COPD was supported by a 28-day, randomized, double-blind, placebo-controlled, 2-period, crossover study evaluating 7 doses of glycopyrrolate (15.6 mcg, 31.2 mcg, 62.4 mcg, and 124.8 mcg once-daily and 15.6 mcg, 31.2 mcg, and 62.4 mcg twice-daily) or placebo in 388 subjects with COPD. The differences in trough FEV 1 from baseline after 28 days compared to placebo for the 15.6 mcg, 31.2 mcg, 62.4 mcg, and 124.8 mcg once-daily and for 15.6 mcg, 31.2 mcg, and 62.4 mcg twice-daily doses were 0.083 L (95% CI: 0.030, 0.136), 0.098 L (0.048, 0.148), 0.090 L (0.038, 0.142), 0.176 L (0.132, 0.220), 0.139 L (0.089, 0.189), 0.167 L (0.115, 0.219), and 0.177 L (0.132, 0.222), respectively. The dose-ranging results supported the evaluation of glycopyrrolate 15.6 mcg twice-daily in the confirmatory COPD trials.

Figure 2. Adjusted mean change from baseline in FEV 1 (L) over 24 hours on Days 1 and 28

Based on the findings from dose-ranging studies of the individual components, a twice-daily dose of

indacaterol/glycopyrrolate 27.5 mcg/15.6 mcg was evaluated in the confirmatory COPD trials.

Confirmatory Trials

The clinical development program for Utibron Neohaler included two (Trial 1 and Trial 2) 12-week, randomized, double-blinded, placebo- and active-controlled, parallel-group trials in subjects with COPD designed to evaluate the efficacy and safety of Utibron Neohaler; and one 12-month, randomized, double-blind, active-controlled trial (Trial 3) that evaluated bronchodilation and effects on long-term safety.

The 12-week trials evaluated the efficacy of 2038 subjects that had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking greater than 10 pack-years, had a post-albuterol FEV 1 greater than or equal to 30% and less than 80% of predicted normal values, had a ratio of FEV 1 /FVC of less than 0.7, and were symptomatic as determined by a Modified Medical Research Council (mMRC) score greater than or equal to 2. Of the 2038 subjects included in the efficacy analysis, 63% were male and 91% were Caucasian. They had a mean age of 63 years and an average smoking history of 47 pack-years, with 52% identified as current smokers, and 46% used concomitant inhaled corticosteroids. At screening, the mean post-bronchodilator percent predicted FEV 1 was 55% (range: 29% to 79%), the mean post-bronchodilator FEV 1 /FVC ratio was 50% (range: 19% to 71%), and the mean percent reversibility was 23% (range: 0% to 144%).

Trial 1 and Trial 2 evaluated Utibron Neohaler (indacaterol/glycopyrrolate) 27.5 mcg/15.6 mcg twice-daily (BID), indacaterol 27.5 mcg BID, glycopyrrolate 15.6 mcg BID, and placebo BID. The primary endpoint was the change from baseline in FEV 1 AUC 0-12h Rfollowing the morn