适应症和用途

哮喘的治疗

Foradil AEROLIZER仅在与可逆性阻塞性呼吸道疾病的成人和5岁及以上的儿童和成人一起使用时，与长期哮喘控制药物（例如吸入皮质类固醇）同时治疗，用于治疗哮喘和预防支气管痉挛，包括有夜间哮喘症状的患者。

长效β2 -肾上腺素能激动剂（LABA）如福莫特罗，在Foradil AEROLIZER活性成分，增加哮喘有关的死亡风险。禁忌使用Foradil AEROLIZER治疗哮喘，而无需同时使用长期哮喘控制药物，例如吸入皮质类固醇。仅将Foradil AEROLIZER用作目前正在服用但长期控制哮喘药物（例如吸入皮质类固醇）控制不足的哮喘患者的其他治疗方法。一旦达到并保持了哮喘控制，就应定期评估患者并逐步降低治疗（例如，停止Foradil AEROLIZER），而不会失去哮喘控制，并维持患者长期服用哮喘控制药物，例如吸入皮质类固醇。对于吸入低剂量或中等剂量吸入糖皮质激素可充分控制哮喘的患者，请勿使用Foradil AEROLIZER [见禁忌症（4）和警告和注意事项（5.1） ]。

小儿和青少年患者

对照临床试验的可用数据表明，LABA增加了儿童和青少年患者哮喘相关住院的风险。 对于需要在吸入皮质类固醇中添加LABA的小儿和青少年哮喘患者，通常应同时使用含有吸入性皮质类固醇和LABA的固定剂量联合产品，以确保两种药物的依从性。如果临床上指示使用单独的长期哮喘控制药物（例如，吸入皮质类固醇）和LABA，则必须采取适当的步骤以确保两种治疗成分的依从性。如果不能确保依从性，则建议同时吸入皮质类固醇和LABA的固定剂量组合产品[参见警告和注意事项（5.1） ]。

重要使用限制

Foradil AEROLIZER不适用于缓解急性支气管痉挛。

预防运动引起的支气管痉挛

偶尔使用Foradil AEROLIZER还可用于成人和5岁及以上的儿童急性预防运动引起的支气管痉挛。在没有持续性哮喘的患者中，临床上可能建议使用Foradil AEROLIZER作为单一药物预防运动引起的支气管痉挛。对于患有持续性哮喘的患者，临床上可能需要使用Foradil AEROLIZER预防运动引起的支气管痉挛，但哮喘的治疗应包括长期哮喘控制药物，例如吸入皮质类固醇。

慢性阻塞性肺疾病的维持治疗

对于慢性阻塞性肺疾病（包括慢性支气管炎和肺气肿）的患者，支气管狭窄的维持治疗中，Foradil AEROLIZER可长期，每天两次（早晨和晚上）给药。

重要使用限制

不推荐使用Foradil AEROLIZER缓解急性支气管痉挛。

剂量和给药

Foradil胶囊只能通过口服吸入途径给药，并且只能使用AEROLIZER吸入剂给药（请参阅随附的药物指南）。不要吞咽Foradil胶囊。 Foradil胶囊应始终保存在水泡中，并且只能在使用前立即取出。

哮喘

长效β2 -肾上腺素能激动剂（LABA），如福莫特罗，在Foradil AEROLIZER的活性成分，增加哮喘相关死亡的风险[见警告和注意事项（5.1）]。由于这种风险，禁忌使用Foradil AEROLIZER来治疗哮喘，而不同时使用长期的哮喘控制药物，例如吸入皮质类固醇。仅将Foradil AEROLIZER用作目前正在服用但长期控制哮喘药物（例如吸入皮质类固醇）控制不足的哮喘患者的其他治疗方法。一旦达到并保持了哮喘控制，就应定期评估患者并逐步降低治疗（例如，停止Foradil AEROLIZER），而不会失去哮喘控制，并维持患者长期服用哮喘控制药物，例如吸入皮质类固醇。对于使用低剂量或中等剂量吸入皮质类固醇充分控制哮喘的患者，请勿使用Foradil AEROLIZER。

小儿和青少年患者

对于5岁及以上的成人和儿童，通常的剂量是使用AEROLIZER吸入器每12小时吸入1个12 mcg Foradil胶囊的内容物。患者不得呼入设备。 Foradil的每日总剂量不应超过每天两次两次的一个胶囊（每日总剂量为24 mcg）。不建议更频繁地给药或大量吸入给药。如果在两次剂量之间出现症状，应服用吸入的短效β2-激动剂以立即缓解。

对照临床试验的可用数据表明，LABA增加了儿童和青少年患者哮喘相关住院的风险。对于小于18岁的哮喘患者，需要在吸入皮质类固醇中添加LABA，通常应同时使用含有吸入性皮质类固醇和LABA的固定剂量组合产品，以确保两种药物的依从性。如果临床上指示使用单独的长期哮喘控制药物（例如，吸入皮质类固醇）和LABA，则必须采取适当的步骤以确保两种治疗成分的依从性。如果不能确保依从性，则建议同时吸入皮质类固醇和LABA的固定剂量组合产品。

运动诱发的支气管痉挛（EIB）

在没有持续性哮喘的患者中，临床上可能建议使用Foradil AEROLIZER作为预防运动引起的支气管痉挛的单一药物。在患有持续性哮喘的患者中，临床上可能指示使用Foradil AEROLIZER预防运动引起的支气管痉挛，但哮喘的治疗应包括长期哮喘控制药物，例如吸入皮质类固醇。对于5岁或以上的成人和儿童，通常的剂量是在锻炼前至少15分钟吸入一粒12 mcg的Foradil胶囊中的内容物，偶尔根据需要服用。如果根据需要间歇使用预防措施，保护可能会持续长达12个小时。

服用该药物后12小时内不得再使用Foradil AEROLIZER。对于预防EIB的定期，每日两次给药尚未进行研究。每天两次接受Foradil AEROLIZER治疗哮喘的患者不应使用额外剂量来预防EIB，而可能需要短效支气管扩张剂。

慢性阻塞性肺疾病（COPD）

对于COPD患者（包括慢性支气管炎和肺气肿）的支气管狭窄治疗，通常的剂量是使用AEROLIZER吸入器每12小时吸入1 mcg Foradil胶囊中的内容物。

不建议每日总剂量大于24 mcg。

剂量形式和强度

Foradil AEROLIZER由Foradil胶囊和AEROLIZER吸入器组成。 Foradil胶囊在透明硬质明胶胶囊中含有12 mcg富马酸福莫特罗干粉制剂，仅供AEROLIZER吸入器吸入使用。

禁忌症

• 由于存在与哮喘相关的死亡和住院风险，因此禁用Foradil AEROLIZER来治疗哮喘，而不同时使用长期的哮喘控制药物，例如吸入皮质类固醇，是禁忌的[见警告和注意事项（5.1） ] 。
• 禁止使用Foradil AEROLIZER作为哮喘状态或其他需要加强治疗的哮喘或COPD急性发作的主要治疗方法[见警告和注意事项（5.2） ]。
• 对富马酸福莫特罗或对该产品任何成分有过敏史的患者禁用Foradil（富马酸福莫特罗）[请参阅警告和注意事项（5.7） ]。

警告和注意事项

哮喘相关死亡

长效β2 -肾上腺素能激动剂，如福莫特罗，在Foradil AEROLIZER活性成分，增加哮喘有关的死亡风险。目前可获得的数据不足以确定并用吸入皮质类固醇或其他长期哮喘控制药物是否可以缓解由LABA引起的与哮喘相关的死亡风险的增加。

由于这种风险，禁忌使用Foradil AEROLIZER来治疗哮喘，而不同时使用长期的哮喘控制药物，例如吸入皮质类固醇。一旦达到并保持了哮喘控制，就应定期评估患者并逐步降低治疗（例如，停止Foradil AEROLIZER），而不会失去哮喘控制，并维持患者长期服用哮喘控制药物，例如吸入皮质类固醇。对于使用低剂量或中等剂量吸入皮质类固醇充分控制哮喘的患者，请勿使用Foradil AEROLIZER。

小儿和青少年患者

对照临床试验的可用数据表明，LABA增加了儿童和青少年患者哮喘相关住院的风险。对于需要在吸入皮质类固醇中添加LABA的小儿和青少年哮喘患者，通常应考虑同时包含吸入性皮质类固醇和LABA的固定剂量联合产品，以确保两种药物的依从性。如果临床上指示使用单独的长期哮喘控制药物（例如，吸入皮质类固醇）和LABA，则必须采取适当的步骤以确保两种治疗成分的依从性。如果不能确保依从性，则建议同时吸入皮质类固醇和LABA的固定剂量组合产品。

一项为期28周的美国安慰剂对照研究比较了沙美特罗和安慰剂的安全性（均添加到常规哮喘治疗中），结果显示接受沙美特罗治疗的患者与哮喘相关的死亡增加（沙美特罗治疗的患者为13 / 13,176 vs 3 /接受安慰剂治疗的患者为13,179； RR 4.37，95％CI 1.25，15.34）。哮喘相关死亡的风险增加被认为是长效β2-肾上腺素能激动剂（包括福莫特罗）的一种类效应。尚无足以确定Foradil AEROLIZER是否增加哮喘相关死亡率的研究。

用Foradil AEROLIZER进行的临床研究表明，与接受安慰剂的患者相比，接受Foradil AEROLIZER的患者发生严重哮喘恶化的几率更高[见不良反应（6.2，6.3） ]。这些研究的规模不足以精确地量化治疗组之间严重哮喘急性发作率的差异。

上述研究招募了哮喘患者。没有研究已进行了那名充足，以确定死亡的COPD患者的速率是否增加长效β2 -肾上腺素能激动剂。

疾病恶化和急性发作

哮喘或COPD严重恶化，严重恶化或可能危及生命的患者，不应开始使用Foradil AEROLIZER。在此设置中不适合使用Foradil AEROLIZER [请参阅适应症和用法（ 1.1，1.3 ） ]。

哮喘可能在数小时内急剧恶化，或在数天或更长时间内长期恶化。它以观察哮喘恶化的迹象，如使用吸入短效β2 -肾上腺素能激动剂或呼气峰流速（PEF）或肺功能下降显著上升是非常重要的。这些发现需要立即评估。如果病情恶化，应建议患者立即就医。在这种情况下，不建议将Foradil AEROLIZER的每日剂量增加到建议剂量以上。 Foradil AEROLIZER的使用剂量不应超过每日两次（早晨和晚上），建议剂量为每天两次。

Foradil AEROLIZER不应用于治疗急性症状。尚未研究过Foradil AEROLIZER缓解急性症状的情况，因此不应使用额外剂量。当处方Foradil AEROLIZER，医生也应该提供一个吸入短效β-激动剂2治疗急性即出现症状的病人，尽管经常每天两次（早晚）使用Foradil AEROLIZER的。患者还应当提醒，增加吸入的β-激动剂2使用是哮喘恶化[参见患者（17）的信息和附带的用药指南的信号。 ]

当与Foradil AEROLIZER开始治疗，谁一直在服用吸入患者，短效定期测试2激动剂（例如，每天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症状。

Foradil AEROLIZER不能替代皮质类固醇

没有数据表明Foradil具有任何临床抗炎作用，因此不能期望它代替皮质类固醇。在开始Foradil AEROLIZER时，不应停止或减少皮质类固醇激素。已经需要口服或吸入皮质类固醇治疗哮喘的患者，即使因服用Foradil AEROLIZER而感觉好转，也应继续接受此类治疗。皮质类固醇剂量的任何变化，尤其是减少剂量，都应在临床评估后才进行[参见患者咨询信息（17.2） ]。

过度使用以及与其他长效Beta2-激动剂一起使用

Foradil AEROLIZER不应更频繁地使用或以高于建议的剂量使用，或与其他含有LABA的药物联合使用，因为这可能导致过量。由于任何原因，使用Foradil AEROLIZER的患者均不应使用其他LABA（例如沙美特罗西那福酯，酒石酸阿福特罗）。据报导，在哮喘患者中过度使用吸入拟交感神经药可导致死亡。确切的死亡原因尚不清楚，但怀疑有严重的急性哮喘危机的意外发展和随后的低氧引起的心脏骤停。此外，来自Foradil AEROLIZER的临床试验数据表明，使用比推荐剂量高的剂量会导致严重的哮喘急性发作风险增加[见不良反应（6.2，6.3） ]。

矛盾性支气管痉挛

作为与其它吸入β2 -激动剂，福莫特罗能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Foradil AEROLIZER并采取替代疗法。

心血管和中枢神经系统的影响

过度的β-肾上腺素刺激与癫痫发作，心绞痛，高血压或低血压，心动过速（最高200次/分钟），心律不齐，神经质，头痛，震颤，心慌，恶心，头晕，疲劳，不适和失眠有关。据报导，过量吸入吸入拟交感神经药可导致死亡[见剂量过量（10） ]。

富马酸福莫特罗，像其它β2 -激动剂，可以通过在脉冲速率增加，血压，和/或症状测量产生在一些患者中的临床上显著心血管效果。尽管以推荐剂量服用Foradil AEROLIZER后这种作用并不常见，但如果发生，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。因此，富马酸福莫特罗与其他拟交感神经胺类药物一样，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。

立即超敏反应

如出现过敏反应，荨麻疹，血管性水肿，皮疹和支气管痉挛，则可在服用Foradil AEROLIZER后立即发生超敏反应。

Foradil AEROLIZER含有乳糖，其中含有微量的牛奶蛋白。患有严重乳蛋白过敏的患者可能会对含乳蛋白的产品产生过敏反应。

共存条件

与其他拟交感神经胺类药物一样，富马酸福莫特罗在患有心血管疾病，尤其是冠状动脉供血不足，心律不齐，高血压，动脉瘤和嗜铬细胞瘤的患者中应谨慎使用；患有抽搐障碍或甲状腺毒症的患者；对拟交感神经胺反应异常的患者。据报道，相关的β2-激动剂沙丁胺醇的剂量在静脉内给药时会加重先前存在的糖尿病和酮症酸中毒。

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影响。血清钾的减少通常是短暂的，不需要补充。

在临床研究期间，以推荐剂量长期服用Foradil AEROLIZER时，血糖和/或血清钾的临床改变很少见。

行政路线不当

Foradil胶囊只能与AEROLIZER吸入器一起使用，不应吞咽。

Foradil胶囊应始终保存在水泡中，使用前请立即取出。

不良反应

长效β2 -肾上腺素能激动剂（LABA），包括福莫特罗，在Foradil AEROLIZER活性成分，增加哮喘相关死亡的风险，并可能增加儿童和青少年患者哮喘相关的住院治疗的风险。使用Foradil AEROLIZER的临床试验表明，接受Foradil AEROLIZER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[请参阅警告和注意事项（5.1） ]。

LABA药物常见的不良反应包括：心绞痛，高血压或低血压，心动过速，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，低血钾症，高血糖症，代谢性酸中毒和失眠。

由于临床试验是在广泛不同的条件下进行的，因此不能将在一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试验中观察到的不良反应率。

哮喘

在多剂量对照临床试验的5824名患者中，1985年接受Foradil AEROLIZER的推荐剂量为12 mcg，每天两次。下表显示了出现紧急治疗的不良反应，每天两次Foradil组的发生频率大于或等于1％，并且Foradil组的发生率超过安慰剂。三种治疗突发性不良反应显示每天两次两次分别以6、12和24 mcg的测试剂量进行剂量排序；震颤，头晕和说话困难。

5岁及以上多剂量对照临床试验中出现治疗不良反应的次数和频率

在5至12岁的患者中，每天两次两次服用12 mcg的安慰剂组的患者报告急诊不良反应的数量和百分比相当。通常，在儿童中观察到的紧急治疗不良反应的模式与在成年人中观察到的通常模式不同。福莫特罗组比安慰剂组更频繁出现治疗反应不良反应，反映出感染/发炎（病毒感染，鼻炎，扁桃体炎，胃肠炎）或腹部不适（腹部疼痛，恶心，消化不良）。

12岁及以上的青少年和成年人的严重哮喘恶化

在两项为期12周的对照试验中，共有1095名12岁及12岁以上的患者入组，将Foradil AEROLIZER每天两次12 mcg，Foradil AEROLIZER每天两次24 mcg，沙丁胺醇180 mcg每天四次和安慰剂进行比较。每天两次两次服用Foradil AEROLIZER 24 mcg，比每天两次，沙丁胺醇或安慰剂的推荐剂量的Foradil AEROLIZER 12 mcg发生更严重的哮喘恶化（导致住院的急性哮喘恶化）。结果如下表所示。

在一项为期16周的随机，多中心，双盲，平行组试验中，每天两次服用24 mcg或每天两次服用12 mcg Foradil AEROLIZER的患者比接受安慰剂的患者出现更严重的哮喘加重[参见临床试验（14.1） ]。结果如下表所示。

5-11岁儿童的严重哮喘恶化

在一项大型，多中心，随机，双盲，52周临床试验中，对518名哮喘儿童（5至12岁）进行了每日两次Foradil AEROLIZER 12 mcg与每日两次Foradil AEROLIZER 24 mcg和安慰剂的安全性比较。需要日常支气管扩张药和抗炎治疗。如下表所示，每天两次两次服用Foradil AEROLIZER 24 mcg的孩子比每天两次服用Foradil AEROLIZER 12 mcg或安慰剂的孩子有严重的哮喘发作。

慢性阻塞性肺病

在两项关键性多剂量慢性阻塞性肺疾病（COPD）对照试验中的1634名患者中，有405人每天两次接受Foradil AEROLIZER 12 mcg治疗。报告的治疗紧急不良反应与哮喘患者相似，但安慰剂和福莫特罗治疗的患者发生COPD相关事件的发生率更高。

下表显示了出现紧急治疗的不良反应，其中Foradil AEROLIZER组的发生频率大于或等于1％，并且Foradil AEROLIZER组的发生率超过安慰剂。两项临床试验包括每日两次两次的12 mcg和24 mcg剂量。七种紧急治疗不良反应显示，每天两次两次接受试验的12和24 mcg剂量之间的剂量顺序；咽炎，发烧，肌肉痉挛，痰液增加，发声困难，肌痛和震颤。

在多剂量对照临床试验中治疗的成人COPD患者中出现治疗不良反应的次数和频率

总体而言，在两项关键性研究中，所有Foradil AEROLIZER 12 mcg每天两次的所有心血管治疗不良反应发生频率为6.4％，而安慰剂为6.0％。没有对Foradil AEROLIZER频繁发生的特定的心血管治疗紧急反应（频率大于或等于1％且大于安慰剂）。

上市后经验

在Foradil的批准后使用过程中，已经确认了以下不良反应。由于这些反应是从不确定大小的人群中自愿报告的，因此并非总是能够可靠地估计其发生频率或建立与药物暴露的因果关系。

在使用Foradil的广泛的全球营销经验中，已经报道了哮喘的严重加重，包括一些致命的哮喘。尽管这些病例大多数发生在患有严重或急性恶化的哮喘的患者中[见警告和注意事项（5.1，5.2） ]，但少数病例发生在哮喘较轻的患者中。从这些个案报告中无法确定Foradil AEROLIZER是否促成了事件。

免疫系统疾病：罕见的过敏反应报告，包括严重的低血压和血管性水肿

代谢和营养失调：低钾血症，高血糖症

呼吸，胸和纵隔疾病：咳嗽

皮肤和皮下组织疾病：皮疹

心脏疾病：心绞痛，心律不齐，例如房颤，室性前收缩，心律失常

检查：心电图QT延长，血压升高（包括高血压）

药物相互作用

肾上腺素药物

如果要通过任何途径使用其他肾上腺素能药物，则应谨慎使用，因为福莫特罗的药理学可预测的交感作用可能会增强。

黄嘌呤衍生物或全身性皮质类固醇

黄嘌呤衍生物或全身性皮质类固醇的同时治疗可能会增强肾上腺素能激动剂的任何低钾血症作用。

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改变或低钾血症，β激动剂会严重加剧这种情况，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-激动剂和不使用钾的利尿剂。

单胺氧化酶抑制剂和三环抗抑郁药，QTc延长药物

福莫特罗，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，大环内酯或已知延长QT间期的药物治疗，因为肾上腺素受体激动剂的对心血管系统的作用，可以强化给药由这些代理商。已知延长QTc间隔的药物会增加室性心律失常的风险。

Beta阻滞剂

当同时给药时，β-肾上腺素能受体拮抗剂（β-受体阻滞剂）和福莫特罗可能彼此抑制作用。 β-阻断剂不仅阻止的β2 -激动剂，如福莫特罗的治疗效果，但在哮喘患者可能会产生严重的支气管痉挛。因此，哮喘患者通常不应使用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，对于哮喘患者，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。

卤代烃

伴有卤代烃麻醉的患者出现心律不齐的风险增加。

在特定人群中的使用

怀孕

怀孕类别C。

致畸作用：尚无对孕妇Foradil AEROLIZER进行充分且对照良好的研究。富马酸福莫特罗在大鼠和兔子中的动物繁殖研究显示出致畸性和其他发育毒性作用的证据。由于没有对孕妇进行充分且对照良好的研究，因此仅在潜在益处证明对胎儿具有潜在风险的情况下，才应在怀孕期间使用Foradil AEROLIZER。

整个器官发生过程中服用的富马酸福莫特罗在口服后未在大鼠或兔子中引起畸形。当在整个器官发生过程中给大鼠服用时，口服剂量等于或大于成人最大推荐人类剂量（MRHD）的80倍（母体剂量为0.2 mg / kg及以上，以mcg / m 2为基础）会延迟胎儿的骨化成人的MRHD等于或大于MRHD的2400倍（对于mcg / m 2为6 mg / kg或更高的孕产妇剂量）降低了胎儿体重。已经证明富马酸福莫特罗在口服剂量等于或大于成年MRHD 2400倍的成人时（以mcg / m 2为基础的母体剂量为6 mg / kg及以上）会导致死产和新生儿死亡。怀孕后期。但是，这些作用并非以成人MRHD的80倍的剂量产生的（以mcg / m 2为基础，母体剂量为0.2 mg / kg）。

在另一个测试实验室中，富马酸福莫特罗被证明对大鼠和兔子具有致畸性。在成年大鼠胎儿口服剂量等于或大于成人MRHD的1200倍（以mcg / m 2为基础，母体剂量3 mg / kg /天及以上）时，观察到脐疝畸形。对于大鼠胎儿，观察到的Brachygnathia是骨骼畸形，其口服剂量等于成人MRHD的6100倍（以mcg / m 2为基础，母体剂量为15 mg / kg /天）。在另一项大鼠研究中，成人吸入剂量最高为MRHD的500倍（母体剂量最高为1.2 mg / kg /天，以mcg / m 2为基础），未观察到致畸作用。 Subcapsular cysts on the liver were observed for rabbit fetuses at an oral dose equal to 49000 times the MRHD for adults (on a mcg/m 2 basis for a maternal dose of 60 mg/kg). No teratogenic effects were observed at oral doses up to 3000 times the MRHD for adults (on a mcg/m 2 basis for maternal doses up to 3.5 mg/kg).

人工与分娩

There are no adequate and well-controlled human studies that have investigated the effects of Foradil AEROLIZER during labor and delivery.

Because beta-agonists may potentially interfere with uterine contractility, Foradil AEROLIZER should be used during labor only if the potential benefit justifies the potential risk.

Formoterol fumarate has been shown to cause stillbirth and neonatal mortality at oral doses equal to or greater than 2400 times the MRHD for adults (on a mcg/m 2 basis for maternal doses of 6 mg/kg and above) in rats receiving the drug for several days at the end of pregnancy. These effects were not produced at a dose 80 times the MRHD for adults (on a mcg/m 2 basis for a maternal dose of 0.2 mg/kg).

护理母亲

In reproductive studies in rats, formoterol was excreted in the milk. It is not known whether formoterol is excreted in human milk, but because many drugs are excreted in human milk, caution should be exercised if Foradil AEROLIZER is administered to nursing women. There are no well-controlled human studies of the use of Foradil AEROLIZER in nursing mothers.

儿科用

哮喘

对照临床试验的可用数据表明，LABA增加了儿童和青少年患者哮喘相关住院的风险。 For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be used to ensure adherence with both drugs [ see Indications and Usage (1.1) and Warnings and Precautions (5.1) ].

A total of 776 children 5 years of age and older with asthma were studied in three multiple-dose controlled clinical trials. Of the 512 children who received formoterol, 508 were 5-12 years of age, and approximately one third were 5-8 years of age [ see Adverse Reactions (6.2, 6.3) ].

Exercise-Induced Bronchospasm

A total of 25 pediatric patients, 4-11 years of age, were studied in two well-controlled single-dose clinical trials.

The safety and effectiveness of Foradil AEROLIZER in pediatric patients below 5 years of age has not been established [ see Clinical Trials (14.3), and Adverse Reaction (6.2) ].

老人用

Of the total number of patients who received Foradil AEROLIZER in adolescent and adult chronic dosing asthma clinical trials, 318 were 65 years of age or older and 39 were 75 years of age and older. Of the 811 patients who received Foradil AEROLIZER in two pivotal multiple-dose controlled clinical studies in patients with COPD, 395 (48.7%) were 65 years of age or older while 62 (7.6%) were 75 years of age or older.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。 A slightly higher frequency of chest infection was reported in the 39 asthma patients 75 years of age and older, although a causal relationship with Foradil has not been established. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

过量

The expected signs and symptoms with overdosage of Foradil AEROLIZER are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms listed under ADVERSE REACTIONS, eg, angina, hypertension or hypotension, tachycardia, with rates up to 200 beats/min., arrhythmias, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, and insomnia. Metabolic acidosis may also occur. Cardiac arrest and even death may be associated with an overdose of Foradil AEROLIZER.

Treatment of overdosage consists of discontinuation of Foradil AEROLIZER together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of Foradil AEROLIZER. Cardiac monitoring is recommended in cases of overdosage.

描述

Foradil AEROLIZER consists of a dry powder formulation of formoterol fumarate intended for oral inhalation only with the AEROLIZER Inhaler. The inhalation powder is packaged in clear hard gelatin capsules.

Each capsule contains a dry powder blend of 12 mcg of formoterol fumarate and 25 mg of lactose (which contains trace levels of milk proteins) as a carrier.

The active component of Foradil is formoterol fumarate, a racemate. Formoterol fumarate is a selective beta 2 -adrenergic agonist. Its chemical name is (±)-2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl)-1-methylethyl]-amino]ethyl]formanilide fumarate dihydrate;其结构式为：

Formoterol fumarate has a molecular weight of 840.9, and its empirical formula is (C 19 H 24 N 2 O 4 ) 2 •C 4 H 4 O 4 •2H 2 O. Formoterol fumarate is a white to yellowish crystalline powder, which is freely soluble in glacial acetic acid, soluble in methanol, sparingly soluble in ethanol and isopropanol, slightly soluble in water, and practically insoluble in acetone, ethyl acetate, and diethyl ether.

The AEROLIZER Inhaler is a plastic device used for inhaling Foradil. The amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow rate and inspiratory time. Under standardized in vitro testing at a fixed flow rate of 60 L/min for 2 seconds, the AEROLIZER Inhaler delivered 10 mcg of formoterol fumarate from the mouthpiece. Peak inspiratory flow rates (PIFR) achievable through the AEROLIZER Inhaler were evaluated in 33 adult and adolescent patients and 32 pediatric patients with mild-to-moderate asthma. Mean PIFR was 117.82 L/min (range 34-188 L/min) for adult and adolescent patients, and 99.66 L/min (range 43-187 L/min) for pediatric patients. Approximately ninety percent of each population studied generated a PIFR through the device exceeding 60 L/min.

To use the delivery system, a Foradil capsule is placed in the well of the AEROLIZER Inhaler, and the capsule is pierced by pressing and releasing the buttons on the side of the device. The formoterol fumarate formulation is dispersed into the air stream when the patient inhales rapidly and deeply through the mouthpiece.

临床药理学

作用机理

Formoterol fumarate is a long-acting beta 2 -adrenergic receptor agonist (beta 2 -agonist). Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta 2 -receptors than at beta 1 -receptors. Although beta 2 -receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -receptors are the predominant receptors in the heart, there are also beta 2 -receptors in the human heart comprising 10%-50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta 2 -agonists may have cardiac effects.

The pharmacologic effects of beta 2 -adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

In vitro tests show that formoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Formoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans is unknown.

药效学

Systemic Safety and Pharmacokinetic/ Pharmacodynamic Relationships

The major adverse effects of inhaled beta 2 -agonists occur as a result of excessive activation of the systemic beta-adrenergic receptors. The most common adverse effects in adults and adolescents include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in plasma potassium, and increases in plasma glucose.

Pharmacokinetic/pharmacodynamic (PK/PD) relationships between heart rate, ECG parameters, and serum potassium levels and the urinary excretion of formoterol were evaluated in 10 healthy male volunteers (25 to 45 years of age) following inhalation of single doses containing 12, 24, 48, or 96 mcg of formoterol fumarate. There was a linear relationship between urinary formoterol excretion and decreases in serum potassium, increases in plasma glucose, and increases in heart rate.

In a second study, PK/PD relationships between plasma formoterol levels and pulse rate, ECG parameters, and plasma potassium levels were evaluated in 12 healthy volunteers following inhalation of a single 120 mcg dose of formoterol fumarate (10 times the recommended clinical dose). Reductions of plasma potassium concentration were observed in all subjects. Maximum reductions from baseline ranged from 0.55 to 1.52 mmol/L with a median maximum reduction of 1.01 mmol/L. The formoterol plasma concentration was highly correlated with the reduction in plasma potassium concentration. Generally, the maximum effect on plasma potassium was noted 1 to 3 hours after peak formoterol plasma concentrations were achieved. A mean maximum increase of pulse rate of 26 bpm was observed 6 hours post dose. The maximum increase of mean corrected QT interval (QTc) was 25 msec when calculated using Bazett's correction and was 8 msec when calculated using Fridericia's correction. The QTc returned to baseline within 12-24 hours post-dose. Formoterol plasma concentrations were weakly correlated with pulse rate and increase of QTc duration. The effects on plasma potassium, pulse rate, and QTc interval are known pharmacological effects of this class of study drug and were not unexpected at the very high formoterol dose (120 mcg single dose, 10 times the recommended single dose) tested in this study. These effects were well-tolerated by the healthy volunteers.

The electrocardiographic and cardiovascular effects of Foradil AEROLIZER were compared with those of albuterol and placebo in two pivotal 12-week double-blind studies of patients with asthma. A subset of patients underwent continuous electrocardiographic monitoring during three 24-hour periods. No important differences in ventricular or supraventricular ectopy between treatment groups were observed. In these two studies, the total number of patients with asthma exposed to any dose of Foradil AEROLIZER who had continuous electrocardiographic monitoring was about 200.

Continuous electrocardiographic monitoring was performed in an 8-week, randomized, double-blind, and placebo controlled trial in 204 COPD patients treated with Foradil AEROLIZER 12 mcg twice daily or placebo. Holter monitoring was used to evaluate predefined proarrhythmic events. Non-sustained ventricular tachycardia occurred in 2 (2.2%) of Foradil AEROLIZER treated patients compared to none in the placebo group. An increase in ventricular premature beats (VPB) occurred in 3 (3.3 %) of Foradil AEROLIZER treated patients compared to 2 (1.9%) in the placebo group. There were no events of sustained ventricular tachycardia, ventricular flutter or fibrillation, or symptomatic runs of VPB. One patient in the Foradil AEROLIZER group had a serious adverse event of atrial flutter.

The electrocardiographic effects of Foradil AEROLIZER were evaluated versus placebo in a 12-month pivotal double-blind study of patients with COPD. An analysis of ECG intervals was performed for patients who participated at study sites in the United States, including 46 patients treated with Foradil AEROLIZER 12 mcg twice daily, and 50 patients treated with Foradil AEROLIZER 24 mcg twice daily. ECGs were performed predose, and at 5-15 minutes and 2 hours post-dose at study baseline and after 3, 6, and 12 months of treatment. The results showed that there was no clinically meaningful acute or chronic effect on ECG intervals, including QTc, resulting from treatment with Foradil AEROLIZER.

Tachyphylaxis /Tolerance

In a clinical study in 19 adult patients with mild asthma, the bronchoprotective effect of formoterol, as assessed by methacholine challenge, was studied following an initial dose of 24 mcg (twice the recommended dose) and after 2 weeks of 24 mcg twice daily. Tolerance to the bronchoprotective effects of formoterol was observed as evidenced by a diminished bronchoprotective effect on FEV 1 after 2 weeks of dosing, with loss of protection at the end of the 12 hour dosing period.

Rebound bronchial hyper-responsiveness after cessation of chronic formoterol therapy has not been observed.

In three large clinical trials in patients with asthma, while efficacy of formoterol versus placebo was maintained, a slightly reduced bronchodilatory response (as measured by 12-hour FEV 1 AUC) was observed within the formoterol arms over time, particularly with the 24 mcg twice daily dose (twice the daily recommended dose). A similarly reduced FEV 1 AUC over time was also noted in the albuterol treatment arms (180 mcg four times daily by metered-dose inhaler).

药代动力学

Information on the pharmacokinetics of formoterol in plasma has been obtained in healthy subjects by oral inhalation of doses higher than the recommended range and in Chronic Obstructive Pulmonary Disease (COPD) patients after oral inhalation of doses at and above the therapeutic dose. Urinary excretion of unchanged formoterol was used as an indirect measure of systemic exposure. Plasma drug disposition data parallel urinary excretion, and the elimination half-lives calculated for urine and plasma are similar.

吸收性

Following inhalation of a single 120 mcg dose of formoterol fumarate by 12 healthy subjects, formoterol was rapidly absorbed into plasma, reaching a maximum drug concentration of 92 pg/mL within 5 minutes of dosing. In COPD patients treated for 12 weeks with formoterol fumarate 12 or 24 mcg twice daily, the mean plasma concentrations of formoterol obtained at 10 min, 2 h, and 6 h post inhalation ranged between 4.0 and 8.8 pg/mL and 8.0 and 17.3 pg/mL, respectively.

Following inhalation of 12 to 96 mcg of formoterol fumarate by 10 healthy males, urinary excretion of both (R,R)- and (S,S)-enantiomers of formoterol increased proportionally to the dose. Thus, absorption of formoterol following inhalation appeared linear over the dose range studied.

In a study in patients with asthma, when formoterol 12 or 24 mcg twice daily was given by oral inhalation for 4 weeks or 12 weeks, the accumulation index, based on the urinary excretion of unchanged formoterol ranged from 1.63 to 2.08 in comparison with the first dose. For COPD patients, when formoterol 12 or 24 mcg twice daily was given by oral inhalation for 12 weeks, the accumulation index, based on the urinary excretion of unchanged formoterol was 1.19 - 1.38. This suggests some accumulation of formoterol in plasma with multiple dosing. The excreted amounts of formoterol at steady-state were close to those predicted based on single-dose kinetics. As with many drug products for oral inhalation, it is likely that the majority of the inhaled formoterol fumarate delivered is swallowed and then absorbed from the gastrointestinal tract.

分配

The binding of formoterol to human plasma proteins in vitro was 61%-64% at concentrations from 0.1 to 100 ng/mL. Binding to human serum albumin in vitro was 31%-38% over a range of 5 to 500 ng/mL. The concentrations of formoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of a single 120 mcg dose.

代谢

Formoterol is metabolized primarily by direct glucuronidation at either the phenolic or aliphatic hydroxyl group and O-demethylation followed by glucuronide conjugation at either phenolic hydroxyl groups. Minor pathways involve sulfate conjugation of formoterol and deformylation followed by sulfate conjugation. The most prominent pathway involves direct conjugation at the phenolic hydroxyl group. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2'-hydroxyl group. Four cytochrome P450 isozymes (CYP2D6, CYP2C19, CYP2C9, and CYP2A6) are involved in the O-demethylation of formoterol. Formoterol did not inhibit CYP450 enzymes at therapeutically relevant concentrations. Some patients may be deficient in CYP2D6 or 2C19 or both. Whether a deficiency in one or both of these isozymes results in elevated systemic exposure to formoterol or systemic adverse effects has not been adequately explored.

排泄

Following oral administration of 80 mcg of radiolabeled formoterol fumarate to 2 healthy subjects, 59%-62% of the radioactivity was eliminated in the urine and 32%-34% in the feces over a period of 104 hours. Renal clearance of formoterol from blood in these subjects was about 150 mL/min. Following inhalation of a 12 mcg or 24 mcg dose by 16 patients with asthma, about 10% and 15%-18% of the total dose was excreted in the urine as unchanged formoterol and direct conjugates of formoterol, respectively. Following inhalation of 12 mcg or 24 mcg dose by 18 patients with COPD the corresponding values were 7% and 6-9% of the dose, respectively.

Based on plasma concentrations measured following inhalation of a single 120 mcg dose by 12 healthy subjects, the mean terminal elimination half-life was determined to be 10 hours. From urinary excretion rates measured in these subjects, the mean terminal elimination half-lives for the (R,R)- and (S,S)-enantiomers were determined to be 13.9 and 12.3 hours, respectively. The (R,R)- and (S,S)-enantiomers represented about 40% and 60% of unchanged drug excreted in the urine, respectively, following single inhaled doses between 12 and 120 mcg in healthy volunteers and single and repeated doses of 12 and 24 mcg in patients with asthma. Thus, the relative proportion of the two enantiomers remained constant over the dose range studied and there was no evidence of relative accumulation of one enantiomer over the other after repeated dosing.

Special Populations

Gender: After correction for body weight, formoterol pharmacokinetics did not differ significantly between males and females.

Geriatric and Pediatric: The pharmacokinetics of formoterol have not been studied in the elderly population, and limited data are available in pediatric patients.

In a study of children with asthma who were 5 to 12 years of age, when formoterol fumarate 12 or 24 mcg was given twice daily by oral inhalation for 12 weeks, the accumulation index ranged from 1.18 to 1.84 based on urinary excretion of unchanged formoterol. Hence, the accumulation in children did not exceed that in adults, where the accumulation index ranged from 1.63 to 2.08 (see above). Approximately 6% and 6.5% to 9% of the dose was recovered in the urine of the children as unchanged and conjugated formoterol, respectively.

Hepatic/Renal Impairment

The pharmacokinetics of formoterol have not been studied in subjects with hepatic or renal impairment.

非临床毒理学

致癌，诱变，生育力受损

The carcinogenic potential of formoterol fumarate has been evaluated in 2-year drinking water and dietary studies in both rats and mice. In rats, the incidence of ovarian leiomyomas was increased at doses of 15 mg/kg and above in the drinking water study and at 20 mg/kg in the dietary study, but not at dietary doses up to 5 mg/kg (AUC exposure approximately 450 times human exposure at the maximum recommended human dose [MRHD]). In the dietary study, the incidence of benign ovarian theca-cell tumors was increased at doses of 0.5 mg/kg and above (AUC exposure at the low dose of 0.5 mg/kg was approximately 45 times human exposure at the MRHD). This finding was not observed in the drinking water study, nor was it seen in mice (see below).

In mice, the incidence of adrenal subcapsular adenomas and carcinomas was increased in males at doses of 69 mg/kg and above in the drinking water study, but not at doses up to 50 mg/kg (AUC exposure approximately 590 times human exposure at the MRHD) in the dietary study. The incidence of hepatocarcinomas was increased in the dietary study at doses of 20 and 50 mg/kg in females and 50 mg/kg in males, but not at doses up to 5 mg/kg in either males or females (AUC exposure approximately 60 times human exposure at the MRHD). Also in the dietary study, the incidence of uterine leiomyomas and leiomyosarcomas was increased at doses of 2 mg/kg and above (AUC exposure at the low dose of 2 mg/kg was approximately 25 times human exposure at the MRHD). Increases in leiomyomas of the rodent female genital tract have been similarly demonstrated with other beta-agonist drugs.

Formoterol fumarate was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacterial and mammalian cells, chromosomal analyses in mammalian cells, unscheduled DNA synthesis repair tests in rat hepatocytes and human fibroblasts, transformation assay in mammalian fibroblasts and micronucleus tests in mice and rats.

Reproduction studies in rats revealed no impairment of fertility at oral doses up to 3 mg/kg (approximately 1200 times the MRHD on a mcg/m 2 basis).

Animal Toxicology and/or Pharmacology

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently.这些发现的临床意义尚不清楚。

临床研究

哮喘

Adults and Adolescents 12 Years of Age and Older

In a placebo-controlled, single-dose clinical trial, the onset of bronchodilation (defined as a 15% or greater increase from baseline in FEV 1 ) was similar for Foradil AEROLIZER and albuterol 180 mcg by metered-dose inhaler.

In single-dose and multiple-dose clinical trials, the maximum improvement in FEV 1 for Foradil AEROLIZER 12 mcg generally occurred within 1 to 3 hours, and an increase in FEV 1 above baseline was observed for 12 hours in most patients.

Foradil AEROLIZER 12 mcg twice daily was compared to Foradil AEROLIZER 24 mcg twice daily, albuterol 180 mcg four times daily by metered-dose inhaler, and placebo in a total of 1095 adult and adolescent patients 12 years of age and above with mild-to-moderate asthma (defined as FEV 1 40%-80% of the patient's predicted normal value) who participated in two pivotal, 12-week, multi-center, randomized, double-blind, parallel group trials.

The results of both clinical trials showed that Foradil AEROLIZER 12 mcg twice d