布罗瓦纳的适应症和用法

慢性阻塞性肺病的维持治疗

Brovana（酒石酸阿福特罗）吸入剂可用于慢性阻塞性肺疾病（COPD）（包括慢性支气管炎和肺气肿）患者的支气管狭窄长期，每日两次（早晨和晚上）维持治疗。 Brovana吸入溶液仅供雾化使用。

重要使用限制

没有建议使用Brovana吸入溶液来治疗慢性阻塞性肺疾病的急性恶化[见警告和注意事项（ 5.2 ） ]。

没有建议使用Brovana吸入溶液治疗哮喘。 Brovana吸入溶液在哮喘中的安全性和有效性尚未确定。

Brovana剂量和给药

Brovana（酒石酸阿福特罗酯）吸入溶液的推荐剂量是一个15 mcg单位剂量的小瓶，每天通过雾化两次（早晨和晚上）给药。不建议每日总剂量大于30 mcg（每天两次15 mcg）。

Brovana吸入溶液应通过与空气压缩机相连的标准射流雾化器以口服途径给药（请参阅随附的患者信息）。不应吞服Brovana吸入溶液。 Brovana吸入溶液应冷藏保存在铝箔袋中。打开小袋后，应将未使用的单位剂量小瓶放回小袋中，并存放在小袋中。应立即使用已打开的单位剂量小瓶。

如果推荐的维持治疗方案未能提供通常的反应，则应立即寻求医疗建议，因为这通常是COPD不稳定的迹象。在这种情况下，应重新评估治疗方案，并应考虑其他治疗选择。

肾或肝功能不全的患者无需调整剂量。但是，由于肝功能不全患者的Brovana吸入溶液的清除时间延长，因此应密切监测。

尚未确定在雾化器中与其他药物混合使用时，Brovana吸入溶液的药物相容性（物理和化学），功效和安全性。

当使用PARI LC®加雾化器（带口罩或口罩）和PARI DURA NEB™3000压缩机给予Brovana吸入溶液的安全性和有效性已经得到确认的临床试验。从基于非压缩机的雾化器系统提供的Brovana吸入溶液的安全性和有效性尚未确定。

剂型和优势

Brovana（酒石酸阿福特罗）吸入溶液以无菌溶液形式提供，用于在低密度聚乙烯单位剂量小瓶中雾化。每个2毫升的小瓶中含有15 mcg的阿福莫特相当于22 mcg的酒石酸阿福特罗。

禁忌症

Brovana吸入溶液禁用于对阿福特罗，外消旋福莫特罗或对该产品任何其他成分过敏的患者。

哮喘患者禁忌使用LABA，包括Brovana吸入溶液，但不吸入皮质类固醇[见警告和注意事项（ 5 ） ]。 Brovana吸入溶液未用于治疗哮喘。

警告和注意事项

严重的与哮喘有关的事件-住院，插管，死亡

• 尚无Brovana吸入溶液在哮喘患者中的安全性和有效性。 Brovana吸入溶液未用于治疗哮喘[参见禁忌症（ 4 ） ]。
• 的长效β2 -肾上腺素能激动剂（LABA）单药[无吸入糖皮质激素（ICS）的哮喘使用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小儿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，与单独的ICS相比，来自大型临床试验的数据并未显示出与哮喘相关的严重事件（住院，插管和死亡）的风险显着增加。
• 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）。哮喘相关死亡风险的增加被认为是LABA的一种类效应，包括Brovana吸入溶液。
• 尚无足以确定是否使用Brovana吸入溶液治疗的患者中与哮喘相关的死亡率增加的研究。外消旋福莫特罗的临床研究表明，接受外消旋福莫特罗的患者比接受安慰剂的患者发生严重哮喘恶化的几率更高。这些研究的规模不足以准确量化治疗组之间严重哮喘恶化率的差异。
• 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

对于严重恶化的COPD患者，不应开始使用Brovana吸入溶液。在这种情况下，不宜使用Brovana吸入溶液。

不建议将Brovana吸入溶液用于治疗支气管痉挛的急性发作，即急救疗法，不应为此目的使用额外剂量。急性症状时，应与吸入短效β激动剂2进行处理。

当开始Brovana吸入溶液，患者谁已采取吸入短效β定期2受体激动剂（例如，每天4次）应指示停止经常使用这些药物，并利用它们只对症状缓解急性呼吸道症状。当处方Brovana吸入溶液，医疗服务提供者也应该规定一个吸入短效β-激动剂2，并指导患者应该如何使用。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Brovana吸入溶液不再控制支气管收缩的症状，或患者的吸入，短效激动剂变得不太有效或患者需要短效β2 -激动剂比平常的多个吸的β2，这些可以是恶化的标记物疾病在这种情况下，应立即重新评估患者和COPD治疗方案。在这种情况下，不建议将Brovana吸入溶液的日剂量增加到建议的15 mcg日剂量两次以上。

过量使用Brovana吸入溶液以及与其他长效Beta2-激动剂一起使用

据报导，过量吸入吸入拟交感神经药可导致死亡。作为与其它吸入β2 -肾上腺素能药物，Brovana吸入溶液不应该被更经常超过建议，或者与含有长效β2 -激动剂的其它药物结合使用时，在更高的剂量。

矛盾性支气管痉挛

作为与其它吸入β2 -激动剂，Brovana吸入溶液可产生矛盾性支气管痉挛，可能是危及生命的。如果发生自相矛盾的支气管痉挛，应立即停用Brovana吸入溶液，并采取替代疗法。

心血管作用

Brovana吸入溶液，如其它β-2 -激动剂，如由脉冲速率的增加，收缩和/或舒张期血压，和/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，则可能需要停药。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。这些发现的临床意义尚不清楚。对于患有心血管疾病，尤其是冠状动脉供血不足，心律不齐和高血压的患者，应谨慎使用Brovana吸入溶液和其他拟交感神经胺。

共存条件

与其他拟交感神经胺类药物一样，Brovana吸入溶液应在患有心血管疾病，尤其是冠状动脉供血不足，心律不齐和高血压的患者中谨慎使用；患有抽搐障碍或甲状腺毒症的患者，以及对拟交感神经胺反应异常的患者。在两项汇总的，为期12周的安慰剂对照试验中，研究了Brovana吸入溶液剂量为15μgBID，25μgBID和50μgQD的情况，观察到平均给药前和给药后2小时收缩压和/或舒张压的变化一般下降2-4毫米/汞柱;对于脉搏率，最大增加的平均值为8.8-12.0次/分钟。在一项为期一年的研究过程中，测量连续心电图，同时每天接受50 mcg的Brovana吸入溶液，与活性比较剂沙美特罗相比，QT CF升高了约3.0毫秒。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。

低钾血症和高血糖症

β激动剂可能会通过细胞内分流在某些患者中产生严重的低钾血症，这可能会产生不利的心血管作用[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。 β-激动剂药物可能会在某些患者中产生短暂的高血糖症。

在临床试验中，长期建议剂量的Brovana吸入溶液长期给药，血清钾和血糖的临床显着变化与剂量相关。

立即超敏反应

过敏反应，荨麻疹，血管性水肿，皮疹和支气管痉挛的病例表明，服用Brovana吸入溶液后可能立即发生超敏反应。

不良反应

长效β2 -肾上腺素能激动剂，如Brovana，如单药治疗（无吸入糖皮质激素）治疗哮喘增加哮喘相关事件的风险。没有建议使用Brovana吸入溶液治疗哮喘[请参阅警告和注意事项（ 5.1 ）]。

Beta2-激动剂不良反应概况

到Brovana吸入溶液的不良反应预计将在性质上其它β2 -肾上腺素能受体激动剂，包括类似：心绞痛，高血压或低血压，心动过速，心律失常，紧张，头痛，震颤，口干，心悸，肌肉痉挛，恶心，头晕，疲劳，不适，低血钾，高血糖，代谢性酸中毒和失眠。

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，因此不能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，并且可能无法反映在临床实践中观察到的不良反应率。

在短期试验中患有COPD的成年人（12周）

以下针对35岁以上成年人的安全性数据基于12周的两项临床试验。在为期12周的2项试验中，使用Brovana吸入溶液治疗1456例COPD患者（男性860例，女性596例，女性34至89岁），每天两次15 mcg，每天两次25 mcg，每天一次50 mcg，沙美特罗42每天两次mcg，或安慰剂。这两项试验中的种族/种族分布包括1383名白种人，49名黑人，10名亚洲人和10名西班牙裔，以及4名分类为“其他”的患者。

在两个为期12周的安慰剂对照试验中，共1,456名COPD患者中，有288人每天两次接受15 mcg Brovana吸入溶液治疗，而293人接受安慰剂治疗。还评估了每天两次25 mcg和每天一次50 mcg的剂量。

表1显示了这两项试验中患者的不良反应发生率，其中Brovana吸入溶液15 mcg每天两次的频率大于或等于2％，Brovana吸入溶液15 mcg每天两次的频率超过或等于2％在安慰剂组中。每天两次发生15 mcg不良反应的患者总数和百分比为202（70％），而安慰剂组为219（75％）。十种不良事件显示出剂量关系：虚弱，发烧，支气管炎，COPD，头痛，呕吐，高钾血症，白细胞增多，神经质和震颤。

每天两次用Brovana吸入溶液15 mcg进行治疗的患者发生的不良事件发生率低于2％，但高于安慰剂，如下：

全身：脓肿，过敏反应，洋地黄中毒，发烧，疝气，注射部位疼痛，颈部僵硬，赘生物，骨盆痛，腹膜后出血

心血管疾病：动脉硬化，房扑，房室传导阻滞，充血性心力衰竭，心脏传导阻滞，心肌梗塞，QT间隔延长，室上性心动过速，倒置T波

消化系统：便秘，胃炎，黑便，口腔念珠菌病，牙周脓肿，直肠出血

代谢和营养失调：脱水，水肿，葡萄糖耐量降低，痛风，高血糖症，高脂血症，低血糖症，低钾血症

肌肉骨骼：关节痛，关节炎，骨骼疾病，类风湿关节炎，肌腱挛缩

神经：躁动，脑梗塞，周围感觉异常，运动减退，瘫痪，嗜睡，震颤

呼吸系统：肺癌，呼吸系统疾病，声音改变

皮肤和附属物：皮肤干燥，单纯疱疹，带状疱疹，皮肤变色，皮肤肥大

特殊感觉：视力异常，青光眼

泌尿生殖器：乳腺肿瘤，钙结晶尿，膀胱炎，糖尿，血尿，肾结石，夜尿症，PSA增加，脓尿，尿路疾病，尿液异常。

在这些试验中，Brovana吸入溶液15 mcg每天两次，所有心血管不良事件的总发生率为6.9％，而安慰剂组为13.3％。 Brovana吸入溶液没有频繁发生的特定心血管不良事件（频率≥1％，大于安慰剂）。 Brovana吸入溶液每天两次15 mcg与安慰剂组之间的COPD恶化率也相当，分别为12.2％和15.1％。

长期（52周）安全性试验中患有COPD的成年人

在一项针对中度至重度COPD患者的52周双盲，随机，安慰剂对照的安全性试验中对Brovana吸入溶液进行了评估。主要终点是呼吸死亡或首次COPD急性发作相关住院的时间，以先发生者为准。根据临床研究者的判断，该事件必须是死亡或住院，患者的呼吸状况占主要地位和/或具有煽动性。该试验的目的是证明接受Brovana吸入溶液治疗的患者发生呼吸道疾病或与COPD恶化相关的住院风险不比接受安慰剂治疗的患者高40％。随机将总共841例COPD患者（男性479例，女性361例，年龄41至94岁）：420例Brovana吸入溶液15 mcg，每天两次，安慰剂421例。在随机分组的患者中，Brovana吸入溶液组中的255名患者（61％）和安慰剂组中的211名患者（50％）完成了一年的治疗。达到该试验目标的事实表明，与安慰剂相比，用Brovana吸入溶液治疗的COPD患者的呼吸死亡或COPD恶化相关住院风险没有增加。

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，因为阿福特罗的交感神经作用可能强化[见警告和注意事项（ 5.3 ， 5.5 ， 5.6 ， 5.7 ）]。

黄嘌呤衍生物，类固醇或利尿剂

与甲基黄嘌呤（氨茶碱，茶碱），类固醇或利尿剂同时治疗可能会增强肾上腺素能激动剂（包括Brovana吸入溶液）的任何低钾血症作用[见警告和注意事项（ 5.7 ） ]。

尚未接受接受Brovana吸入溶液的患者同时使用静脉或口服甲基黄嘌呤（例如氨茶碱，茶碱）的评估。在两项合并的，为期12周，安慰剂对照的试验中，包括每天两次两次15 mcg，每天两次25 mcg和每天一次50 mcg的Brovana吸入溶液剂量，在873名Brovana吸入溶液治疗的受试者中，有54名患者在研究开始时接受了茶碱。在一项为期12个月的对照试验中，该试验包括每日一次50 mcg的布罗瓦那吸入溶液剂量，在528名布罗瓦那吸入溶液治疗的受试者中，有30位在研究开始时接受了茶碱治疗。在这些试验中，与茶碱相比，同时服用茶碱的受试者的心率和收缩压分别高约2-3 bpm和6-8 mm Hg。

非钾利尿剂

使用非激动钾的利尿剂（例如loop或噻嗪类利尿剂）可能会导致ECG变化和/或低钾血症，β-激动剂会严重恶化，尤其是当超过推荐剂量的β-激动剂时。尽管尚不清楚这些作用的临床意义，但建议同时使用β-激动剂（包括Brovana吸入溶液）与不留钾的利尿剂。

MAO抑制剂，三环类抗抑郁药，QTc延长药物

与其他β-受体激动剂一样，Brovana吸入溶液应特别谨慎地用单胺氧化酶抑制剂，三环抗抑郁药或已知因肾上腺素能激动剂对心血管系统有作用而延长QTc间隔的药物治疗的患者。被这些药剂增强。已知延长QTc间隔的药物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Brovana吸入溶液可能会互相抑制彼此的作用。 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。

在特定人群中的使用

怀孕

风险摘要

没有针对孕妇的充分且对照良好的研究。只有在对患者的预期收益超过对胎儿的潜在风险时，才应在怀孕期间使用Brovana。如果妇女在服用Brovana时怀孕，应建议其联系医生。在动物生殖研究中，通过口服途径向大鼠和兔子口服阿福特罗，分别以每12小时15 mcg的建议最大人类每日吸入剂量（MRHDID），分别为成人暴露量的370倍和8400倍，发现存在结构性异常，胚胎胎儿和婴儿死亡率以及生长变化。当通过口服途径给予阿福特罗以实现高全身暴露时，这些不良反应通常发生在MRHDID的大数倍处。在暴露于MRHDID约4,900倍的兔子中，没有观察到胎儿受到伤害的证据。

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。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2-4％和15-20％。

临床注意事项

人工或分娩：

Brovana对人工和分娩的潜在影响尚不清楚。由于β-激动剂可能会干扰子宫收缩力，因此应限制在分娩过程中使用Brovana吸入溶液，以使获益明显超过风险。

数据

动物资料

在一项胚胎胎儿发育研究中，怀孕的大鼠从妊娠第6天到第17天每天接受1,000、5,000或10,000 mcg / kg / kg的剂量，根据发现畸形的脐静脉（脐疝）的结果，阿福特罗被证明具有致畸性。胎儿在​​MRHDID暴露量下约为成人暴露量的370倍（以AUC为基础，母体口服剂量为1,000 mcg / kg /天或更高）。在MRHDID暴露量高达MRHDID的2400倍（以AUC为基础上）的大鼠中未观察到母体毒性母体口服剂量不超过10,000 mcg / kg /天），未发现大鼠胎儿的未观察到的不良反应水平（NOAEL）。

在一项胚胎胎儿发育研究中，怀孕的兔子从妊娠第7天到第20天每天分别接受20,000、40,000或80,000 mcg / kg / kg的剂量，根据兔子胎儿胎儿右肾畸形（畸形）的发现，阿福特罗被证明具有致畸性。 MRHDID的暴露量约为成人暴露量的8400倍以上（基于AUC，母亲口服剂量为20,000 mcg / kg /天及更高）。在成年兔的胎儿中，观察到的畸形包括近动畸形，球状主动脉和肝囊肿，以及体重下降，约为成人的MRHDID的26,000倍以上，且高于MRHDID（以mcg / m 2为基础，母亲口服剂量为40,000 mcg / kg /天及更高）。在成人中，以成人MRHDID约52,000倍的剂量（以mcg / m 2为基础，母体口服剂量为80,000 mcg /时），在兔胎儿中观察到畸形包括畸形，肺小叶发育不全和室间隔缺损以及胚胎致死性。公斤/天）。在成人中，观察到的母体毒性约为MRHDID的26,000倍以上，并且高于MRHDID（以mcg / m 2为基础，母体口服剂量为40,000 mcg / kg /天或更高）。没有证据表明在MRHDID暴露下，兔子受到的胎儿伤害约为4,900倍，并且低于成年暴露（以母体口服剂量为10,000 mcg / kg /天和更低的AUC为基础）。

在一项产前和产后发育研究中，从妊娠第6天到哺乳期20天，雌性大鼠接受阿莫特罗的口服剂量分别为0、1,000、5,000和10,000 mcg / kg /天，每天接受325的雌性大鼠的妊娠时长β-肾上腺素能激动剂的药理作用延长了分娩或难产的时间，延长了MRHDID的时间并高于MRHDID（以mcg / m 2为基础，孕妇口服剂量为1,000 mcg / kg /天及更高）。如阿福特罗，以放松子宫肌肉。由于分娩过程中的并发症，对一名接受MRHDID剂量3200倍（以mcg / m 2为基础，孕妇口服剂量为10,000 mcg / kg /天）的女性安乐死。在出生时和哺乳期，幼仔的存活率和体重降低了1600倍，并高于MRHDID（以mcg / m 2为基础，母体口服剂量为5,000 mcg / kg /天和更高）。在MRHDID剂量的3200倍（以mcg / m 2为基础，母体口服剂量为10,000 mcg / kg /天）的情况下，观察到1个幼崽的脐疝畸形。在MRHDID的3200倍剂量下（以mcg / m 2为基础，母体口服剂量为10,000 mcg / kg /天），观察到了幼鼠的潜在发育延迟。然而，剂量是MRHDID的1600倍（以mcg / m 2为基础，母体口服剂量为5,000 mcg / kg /天）时，没有发育延迟。

哺乳期

风险摘要

没有关于母乳中阿福特罗或其代谢物的存在，对母乳喂养婴儿的影响或对牛奶产量的影响的数据。但是，阿福特罗在泌乳大鼠的乳汁中排泄。应当考虑母乳喂养的发育和健康益处，以及母亲对Brovana的临床需求以及Brovana或潜在母体疾病对母乳喂养婴儿的任何潜在不利影响。

数据

口服10,000 mcg / kg剂量的放射性标记的酒石酸阿福特罗后，在哺乳期大鼠的牛奶中检测到阿福特罗及其代谢产物。

儿科用

Brovana吸入溶液被批准用于与慢性阻塞性肺疾病（包括慢性支气管炎和肺气肿）相关的支气管狭窄的长期维持治疗。这种疾病不会在儿童中发生。尚未确定Brovana吸入溶液在小儿患者中的安全性和有效性。

老人用

在两项针对成年人COPD的安慰剂对照临床研究中，接受Brovana吸入溶液治疗的873名患者中，有391名（45％）年龄在65岁或以上，而96名（11％）年龄在75岁或以上。在这些受试者和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。在65岁及65岁以上的受试者中，有129名（33％）每天两次以15 mcg的建议剂量接受Brovana吸入溶液，其余的则接受更高的剂量。在每天接受两次15 mcg，每天两次两次25 mcg和安慰剂的患者中，年龄在65至≤75岁的患者的心电图异常ECG警报具有可比性（分别为3.9％，5.2％和7.1％）。每天一次以50 mcg的剂量服用Brovana吸入溶液时，观察到较高的频率（12.4％）。这一发现的临床意义尚不清楚。其他报告的临床经验尚未发现老年患者和年轻患者之间反应的差异，但是不能排除某些老年患者的敏感性更高。

肝功能不全

肝功能不全的患者应谨慎使用Brovana吸入溶液，因为这些患者的全身暴露量增加[参见临床药理学（ 12.3 ） ]。

肾功能不全

与人口统计学匹配的健康对照组相比，阿福特罗的全身暴露与肾功能受损的患者相似[见临床药理学（ 12.3 ） ]。

药物滥用和依赖性

在临床试验中，没有使用布罗瓦那吸入溶液滥用或药物依赖的证据。

过量

过量服用Brovana（酒石酸阿福特罗）吸入溶液相关的预期症状和体征是过度的β-肾上腺素刺激和/或不良反应中列出的任何症状和体征的出现或夸大。体征和症状可能包括心绞痛，高血压或低血压，心动过速，速率高达200次/分钟，心律不齐，神经质，头痛，震颤，口干，心lp，肌肉痉挛，恶心，头晕，疲劳，不适，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过量服用Brovana吸入溶液有关。

药物过量的治疗包括停用Brovana吸入溶液以及适当的对症和/或支持疗法。考虑到此类药物可产生支气管痉挛，可以考虑明智地使用心脏选择性β受体阻滞剂。没有足够的证据来确定透析是否对过量服用Brovana吸入溶液有益。如果过量，建议进行心脏监护。

Brovana说明

Brovana（酒石酸阿福特罗）吸入溶液是阿福特罗（福莫特罗的（R，R）-对映体）的酒石酸盐的无菌，透明，无色水溶液。

阿福特罗是选择性β2 -肾上腺素能支气管扩张药。酒石酸阿福特罗的化学名称为甲酰胺，N- [2-羟基-5-[（1R）-1-羟基-2-[[（1R）-2-（4-甲氧基苯基）-1-甲基乙基]氨基]乙基]苯基]-，（2R，3R）-2,3-二羟基丁二酸酯（1：1盐），其确定的结构式如下：

酒石酸阿福特罗的分子量为494.5 g / mol，其经验式为C 19 H 24 N 2 O 4 •C 4 H 6 O 6 （1：1盐）。它是白色至类白色固体，微溶于水。

酒石酸阿福特罗是（R，R）-福莫特罗L-酒石酸酯的美国采用名称（USAN）。

Brovana（酒石酸阿福特罗）吸入溶液以2 mL酒石酸阿福特罗溶液形式提供，包装在2.1 mL单位剂量，低密度聚乙烯（LDPE）单位剂量小瓶中。每个单位剂量的药瓶在无菌的等渗盐溶液中均含有15 mcg阿福特罗（相当于22 mcg酒石酸阿福特罗），用柠檬酸和柠檬酸钠将pH调节至5.0。

Brovana吸入溶液在通过雾化给药前无需稀释。像所有其他雾化治疗一样，输送到肺部的量将取决于患者因素，使用的雾化器和压缩机的性能。在的平均流动速率使用PARI LC®加喷雾器（与吹口）在体外条件下连接到PARI DURA NEB™3000压缩机，从嘴件（标称％）的平均递送剂量为约4.1微克（27.6％） 3.3升/分钟平均雾化时间为6分钟或更短。 Brovana吸入溶液应以标准流量通过面罩或口罩从标准喷雾器中施用。

应仔细指导患者正确使用该药物的方法（请参阅随附的患者信息）。

Brovana-临床药理学

作用机理

阿福特罗中，（R，R）福莫特罗的对映异构体，是一种选择性长效β具有比外消旋福莫特罗两倍更大的效力（其既包含（S，S 2 -肾上腺素能受体激动剂（测试版2激动剂） ）和（R，R）-对映体）。作为一个beta 2激动剂比（R，R） -对映体的（S，S） -对映体为约1,000倍效力较低。虽然人们认识到的β2 -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，数据表明，也存在的β2 -受体在人的心脏包括10％至50占总β-肾上腺素受体的百分比。这些受体的确切功能尚未确定，但他们提出，即使是高选择性β2受体激动剂可能有强心作用的可能性。

的β2肾上腺素能受体兴奋剂药物，包括阿福特罗的药理作用，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（循环AMP）。细胞内环AMP含量的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。

体外试验表明，阿福莫特罗是人肺中肥大细胞介质（例如组胺和白三烯）释放的抑制剂。阿福特罗还抑制麻醉的豚鼠中组胺诱导的血浆白蛋白外渗，并抑制气道高反应性犬的变应原诱导的嗜酸性粒细胞流入。这些体外和动物发现与人类的相关性未知。

药效学

系统安全性与药代动力学/药效动力学关系

吸入的β-激动剂2的主要不利影响发生全身β-肾上腺素能受体的过度活化的结果。最常见的不良反应可能包括骨骼肌震颤和抽筋，失眠，心动过速，血浆钾减少和血浆葡萄糖增加。

对血清钾和血清葡萄糖水平的影响

在每天两次（5 mcg，15 mcg或25 mcg； 215例COPD患者）和每天一次（15 mcg，25 mcg或50 mcg； 191例患者）的剂量范围研究中评估血清钾和血清葡萄糖的变化COPD患者的Brovana吸入溶液。在给药后第0周的第2和6小时（首次给药后），在Brovana吸入溶液组中观察到的血清钾平均变化范围为0至-0.3 mEq / L，在治疗2周后观察到相似的变化。服用Brovana Inhalation Solution剂量组在给药后第2天和第6天均观察到平均血清葡萄糖水平的变化，从降低1.2 mg / dL到增加32.8 mg / dL。日常治疗。

电生理学

The effect of Brovana Inhalation Solution on QT interval was evaluated in a dose-ranging study following multiple doses of Brovana Inhalation Solution 5 mcg, 15 mcg, or 25 mcg twice daily or 15 mcg, 25 mcg, or 50 mcg once daily for 2 weeks in patients with COPD. ECG assessments were performed at baseline, time of peak plasma concentration and throughout the dosing interval. Different methods of correcting for heart rate were employed, including a subject-specific method and the Fridericia method.

Relative to placebo, the mean change in subject-specific QTc averaged over the dosing interval ranged from -1.8 to 2.7 msec, indicating little effect of Brovana Inhalation Solution on cardiac repolarization after 2 weeks of treatment. The maximum mean change in subject-specific QTc for the Brovana Inhalation Solution 15 mcg twice daily dose was 17.3 msec, compared with 15.4 msec in the placebo group. No apparent correlation of QTc with arformoterol plasma concentration was observed.

Electrocardiographic Monitoring in Patients with COPD

The effect of different doses of Brovana Inhalation Solution on cardiac rhythm was assessed using 24-hour Holter monitoring in two 12-week, double-blind, placebo-controlled studies of 1,456 patients with COPD (873 received Brovana Inhalation Solution at 15 or 25 mcg twice daily or 50 mcg once daily doses; 293 received placebo; 290 received salmeterol). The 24-hour Holter monitoring occurred once at baseline, and up to 3 times during the 12-week treatment period. The rates of new-onset cardiac arrhythmias not present at baseline over the double-blind 12-week treatment period were similar (approximately 33-34%) for patients who received Brovana Inhalation Solution 15 mcg twice daily to those who received placebo. There was a dose-related increase in new, treatment-emergent arrhythmias seen in patients who received Brovana Inhalation Solution 25 mcg twice daily and 50 mcg once daily, 37.6% and 40.1%, respectively. The frequencies of new treatment-emergent events of non-sustained (3-10 beat run) and sustained (>10 beat run) ventricular tachycardia were 7.4% and 1.1% in Brovana Inhalation Solution 15 mcg twice daily and 6.9% and 1.0% in placebo. In patients who received Brovana Inhalation Solution 25 mcg twice daily and 50 mcg once daily, the frequencies of non-sustained (6.2% and 8.2%, respectively) and sustained ventricular tachycardia (1.0% and 1.0%, respectively) were similar. Five cases of ventricular tachycardia were reported as adverse events (1 in Brovana Inhalation Solution 15 mcg twice daily and 4 in placebo), with two of these events leading to discontinuation of treatment (2 in placebo).

There were no baseline occurrences of atrial fibrillation/flutter observed on 24-hour Holter monitoring in patients treated with Brovana Inhalation Solution 15 mcg twice daily or placebo. New, treatment-emergent atrial fibrillation/flutter occurred in 0.4% of patients who received Brovana Inhalation Solution 15 mcg twice daily and 0.3% of patients who received placebo. There was a dose-related increase in the frequency of atrial fibrillation/flutter reported in the Brovana Inhalation Solution 25 mcg twice daily and 50 mcg once daily dose groups of 0.7% and 1.4%, respectively. Two cases of atrial fibrillation/flutter were reported as adverse events (1 in Brovana Inhalation Solution 15 mcg twice daily and 1 in placebo).

Dose-related increases in mean maximum change in heart rate in the 12 hours after dosing were also observed following 12 weeks of dosing with Brovana Inhalation Solution 15 mcg twice daily (8.8 bpm), 25 mcg twice daily (9.9 bpm) and 50 mcg once daily (12 bpm) versus placebo (8.5 bpm).

Tachyphylaxis/Tolerance

Tolerance to the effects of inhaled beta-agonists can occur with regularly-scheduled, chronic use.

In two placebo-controlled clinical trials in patients with COPD involving approximately 725 patients in each, the overall efficacy of Brovana Inhalation Solution was maintained throughout the 12-week trial duration. However, tolerance to the bronchodilator effect of Brovana Inhalation Solution was observed after 6 weeks of dosing, as measured by a decrease in trough FEV 1 . FEV 1 improvement at the end of the 12-hour dosing interval decreased by approximately one-third (22.1% mean improvement after the first dose compared to 14.6% at week 12). Tolerance to the trough FEV 1 bronchodilator effect of Brovana Inhalation Solution was not accompanied by other clinical manifestations of tolerance in these trials.

药代动力学

The pharmacokinetics (PK) of arformoterol have been investigated in healthy subjects, elderly subjects, renally and hepatically impaired subjects, and COPD patients following the nebulization of the recommended therapeutic dose and doses up to 96 mcg.

吸收性

In COPD patients administered 15 mcg arformoterol every 12 hours for 14 days, the mean steady-state peak (R,R)-formoterol plasma concentration (C max ) and systemic exposure (AUC 0-12h ) were 4.3 pg/mL and 34.5 pg • hr/mL, respectively. The median steady-state peak (R,R)-formoterol plasma concentration time (t max ) was observed approximately one-half hour after drug administration.

Systemic exposure to (R,R)-formoterol increased linearly with dose in COPD patients following arformoterol doses of 5 mcg, 15 mcg, or 25 mcg twice daily for 2 weeks or 15 mcg, 25 mcg, or 50 mcg once daily for 2 weeks.

In a crossover study in patients with COPD, when arformoterol 15 mcg inhalation solution and 12 and 24 mcg formoterol fumarate inhalation powder (Foradil ® Aerolizer ® ) was administered twice daily for 2 weeks, the accumulation index was approximately 2.5 based on the plasma (R,R)-formoterol concentrations in all three treatments. At steady- state, geometric means of systemic exposure (AUC 0-12h ) to (R,R)-formoterol following 15 mcg of arformoterol inhalation solution and 12 mcg of formoterol fumarate inhalation powder were 39.33 pg • hr/mL and 33.93 pg • hr/mL, respectively (ratio 1.16; 90% CI 1.00, 1.35), while the geometric means of the C max were 4.30 pg/mL and 4.75 pg/mL, respectively (ratio 0.91; 90% CI 0.76, 1.09).

In a study in patients with asthma, treatment with arformoterol 50 mcg with pre- and post-treatment with activated charcoal resulted in a geometric mean decrease in (R,R)-formoterol AUC 0-6h by 27% and C max by 23% as compared to treatment with arformoterol 50 mcg alone. This suggests that a substantial portion of systemic drug exposure is due to pulmonary absorption.

分配

The binding of arformoterol to human plasma proteins in vitro was 52-65% at concentrations of 0.25, 0.5 and 1.0 ng/mL of radiolabeled arformoterol. The concentrations of arformoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of multiple doses of 50 mcg arformoterol.

代谢

In vitro profiling studies in hepatocytes and liver microsomes have shown that arformoterol is primarily metabolized by direct conjugation (glucuronidation) and secondarily by O-demethylation. At least five human uridine diphosphoglucuronosyltransferase (UGT) isozymes catalyze arformoterol glucuronidation in vitro . Two cytochrome P450 isozymes (CYP2D6 and secondarily CYP2C19) catalyze the O-demethylation of arformoterol.

Arformoterol was almost entirely metabolized following oral administration of 35 mcg of radiolabeled arformoterol in eight healthy subjects. Direct conjugation of arformoterol with glucuronic acid was the major metabolic pathway. Most of the drug-related material in plasma and urine was in the form of glucuronide or sulfate conjugates of arformoterol. O-Desmethylation and conjugates of the O-desmethyl metabolite were relatively minor metabolites accounting for less than 17% of the dose recovered in urine and feces.

消除

After administration of a single oral dose of radiolabeled arformoterol to eight healthy male subjects, 63% of the total radioactive dose was recovered in urine and 11% in feces within 48 hours. A total of 89% of the total radioactive dose was recovered within 14 days, with 67% in urine and 22% in feces. Approximately 1% of the dose was recovered as unchanged arformoterol in urine over 14 days. Renal clearance was 8.9 L/hr for unchanged arformoterol in these subjects.

In COPD patients given 15 mcg inhaled arformoterol twice a day for 14 days, the mean terminal half-life of arformoterol was 26 hours.

Special Populations:

性别

A population PK analysis indicated that there was no effect of gender upon the pharmacokinetics of arformoterol.

种族

The influence of race on arformoterol pharmacokinetics was assessed using a population PK analysis and data from healthy subjects. There was no clinically significant impact of race upon the pharmacokinetic profile of arformoterol.

老年医学

The pharmacokinetic profile of arformoterol in 24 elderly subjects (aged 65 years or older) was compared to a younger cohort of 24 subjects (18-45 years) that were matched for body weight and gender. No significant differences in systemic exposure (AUC and C max ) were observed when the two groups were compared.

小儿科

The pharmacokinetics of arformoterol have not been studied in pediatric subjects.

肝功能不全

The pharmacokinetic profile of arformoterol was assessed in 24 subjects with mild, moderate, and severe hepatic impairment. The systemic exposure (C max and AUC) to arformoterol increased 1.3 to 2.4-fold in subjects with hepatic impairment compared to 16 demographically matched healthy control subjects. No clear relationship between drug exposure and the severity of hepatic impairment was observed. Brovana Inhalation Solution should be used cautiously in patients with hepatic impairment.

肾功能不全

The impact of renal disease upon the pharmacokinetics of arformoterol was studied in 24 subjects with mild, moderate, or severe renal impairment. Systemic exposure (AUC and C max ) to arformoterol was similar in renally impaired patients compared with demographically matched healthy control subjects.

Drug-Drug Interaction

When paroxetine, a potent inhibitor of CYP2D6, was co-administered with Brovana Inhalation Solution at steady-state, exposure to either drug was not altered. Dosage adjustments of Brovana Inhalation Solution are not necessary when the drug is given concomitantly with potent CYP2D6 inhibitors.

Arformoterol did not inhibit CYP1A2, CYP2A6, CYP2C9/10, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or CYP4A9/11 enzymes at >1,000-fold higher concentrations than the expected peak plasma concentrations following a therapeutic dose.

药物基因组学

Arformoterol is eliminated through the action of multiple drug metabolizing enzymes. Direct glucuronidation of arformoterol is mediated by several UGT enzymes and is the primary elimination route. O-Desmethylation is a secondary route catalyzed by the CYP enzymes CYP2D6 and CYP2C19. In otherwise healthy subjects with reduced CYP2D6 and/or UGT1A1 enzyme activity, there was no impact on systemic exposure to arformoterol compared to subjects with normal CYP2D6 and/or UGT1A1 enzyme activities.

非临床毒理学

致癌，诱变，生育力受损

Long-term studies were conducted in mice using oral administration and rats using inhalation administration to evaluate the carcinogenic potential of arformoterol.

In a 24-month carcinogenicity study in CD-1 mice, arformoterol caused a dose-related increase in the incidence of uterine and cervical endometrial stromal polyps and stromal cell sarcoma in female mice at oral doses of 1,000 mcg/kg and above (AUC exposure approximately 70 times adult exposure at the MRHDID).

In a 24-month carcinogenicity study in Sprague-Dawley rats, arformoterol caused a statistically significant increase in the incidence of thyroid gland c-cell adenoma and carcinoma in female rats at an inhalation dose of 200 mcg/kg (AUC exposure approximately 130 times adult exposure at the MRHDID). There were no tumor findings with an inhalation dose of 40 mcg/kg (AUC exposure approximately 55 times adult exposure at the MRHDID).

Arformoterol was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacteria, chromosome aberration analyses in mammalian cells, and micronucleus test in mice.

Arformoterol had no effects on fertility and reproductive performance in rats at oral doses up to 10,000 mcg/kg (approximately 3,200 times the MRHDID in adults on a mcg/m 2 basis).

动物毒理学和/或药理学

Animal Pharmacology

In animal studies investigating its cardiovascular effects, arformoterol induced dose-dependent increases in heart rate and decreases in blood pressure consistent with its pharmacology as a beta-adrenergic agonist. In dogs, at systemic exposures higher than anticipated clinically, arformoterol also induced exaggerated pharmacologic effects of a beta-adrenergic agonist on cardiac function as measured by electrocardiogram (sinus tachycardia, atrial premature beats, ventricular escape beats, PVCs).

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings is unknown.

临床研究

Adult COPD Trials

Brovana (arformoterol tartrate) Inhalation Solution was studied in two identical, 12-week, double-blind, placebo- and active-controlled, randomized, multi-center, parallel group trials conducted in the United States (Clinical Trial A and Clinical Trial B). A total of 1,456 adult patients (age range: 34 to 89 years; mean age: 63 years; gender: 860 males and 596 females) with COPD who had a mean FEV 1 of 1.3 L (42% of predicted) were enrolled in the two clinical trials. The racial/ethnic distribution in these two trials included 1383 Caucasians, 49 Blacks, 10 Asians, and 10 Hispanics, and 4 patients classified as Other. The diagnosis of COPD was based on a prior clinical diagnosis of COPD, a smoking history (greater than 15 pack-years), age (at least 35 years), spirometry results (baseline FEV 1 ≤65% of predicted value and >0.70 L, and a FEV 1 /forced vital capacity (FVC) ratio ≤70%). About 80% of patients in these studies had bronchodilator reversibility, defined as a 10% or greater increase in FEV 1 after inhalation of 2 actuations (180 mcg racemic albuterol from a metered dose inhaler). Both trials compared Brovana Inhalation Solution 15 mcg twice daily (288 patients), 25 mcg twice daily (292 patients), 50 mcg once daily (293 patients) with placebo (293 subjects). Both trials included salmeterol inhalation aerosol, 42 mcg twice daily as an active comparator (290 patients).

In both 12-week trials, Brovana Inhalation Solution 15 mcg twice daily resulted in a statistically significant change of approximately 11% in mean FEV 1 (as measured by percent change from study baseline FEV 1 at the end of the dosing interval over the 12 weeks of treatment, the primary efficacy endpoint) compared to placebo. Compared to Brovana Inhalation Solution 15 mcg twice daily, Brovana Inhalation Solution 25 mcg twice daily and 50 mcg once daily did not provide sufficient additional benefit on a variety of endpoints, including FEV 1 , to support the use of higher doses. Plots of the mean change in FEV 1 values obtained over the 12 hours after dosing for the Brovana Inhalation Solution 15 mcg twice daily dose group and for the placebo group are provided in Figures 1 and 2 for Clinical Trial A, below. The plots include mean FEV 1 change observed after the first dose and after 12 weeks of treatment. The results from Clinical Trial B were similar.

Figure 1 Mean Change in FEV 1 Over Time for Clinical Trial A at Week 0 (Day 1)

Figure 2 Mean Change in FEV 1 Over Time for Clinical Trial A at Week 12

Brovana Inhalation Solution 15 mcg twice daily significantly improved bronchodilation compared to placebo over the 12 hours after dosing (FEV 1 AUC 0-12h ). This improvement was maintained over the 12-week study period.

Following the first dose of Brovana Inhalation Solution 15 mcg, the median time to onset of bronchodilation, defined by an FEV 1 increase of 15%, occurred at 6.7 min. When defined as an increase in FEV 1 of 12% and 200 mL, the time to onset of bronchodilation was 20 min after dosing. Peak bronchodilator effect was generally seen within 1-3 hours of dosing.

In both clinical trials, compared to placebo, patients treated with Brovana Inhalation Solution demonstrated improvements in peak expiratory flow rates, supplemental ipratropium and rescue albuterol use.

供应/存储和处理方式

Brovana (arformoterol tartrate) Inhalation Solution is supplied in a single strength (15 mcg of arformoterol, equivalent to 22 mcg of arformoterol tartrate) as 2 mL of a sterile solution in low-density polyethylene (LDPE) unit-dose vials overwrapped in foil. Brovana Inhalation Soluti