哮喘新型复方雾化吸入剂Dulera(mometasone furoate and formoterol fumarate dihydrate)获美国FDA批准用于治疗慢性阻塞性肺
2010年6月24日，美国食品药品管理局(FDA)已批准Dulera用于治疗12岁及12岁以上的哮喘患者。Dulera是一种含有皮质类固醇(糠酸莫米松)与长效β2受体激动剂(LABA)(富马酸福莫特罗)的雾化吸入剂。
Dulera作为处方药，仅用于经长期平喘药(如吸入性皮质类固醇)治疗后哮喘未获充分控制或因病情严重而应开始吸入性皮质类固醇与LABA联合治疗的患者。一旦哮喘得到控制、病情平稳，则应定期对患者进行评估，如病情允许，应停止此治疗方案(即停用Dulera)。此时，患者的哮喘在接受吸入性皮质类固醇等长期哮喘控制药物时应能保持平稳。
Dulera不应作为急救药物，也不能取代速效吸入剂用于急性发作的治疗。
Dulera以压力定量吸入器的形式包装分发，其内置一个数字计数器，可显示剩余的剂数。
两剂的复合制剂Duraler于2010年7月底出售。每剂含5μg富马酸福莫特罗和100μg或200μg糠酸莫米松。建议开始剂量是根据先前的哮喘治疗设定的。每日最大建议剂量为Dulera 200μg/5μg，每日早晚各吸入1次。
批准日期：2016年7月 公司：默克公司
DULERA（糠酸莫米松和富马酸福莫特罗二水合物[mometasone furoate and formoterol fumarate dihydrate]）吸入气雾剂，用于口服吸入使用
美国初步批准：2010年
警告：
哮喘相关死亡请参阅完整的处方信息以获取完整的盒装警告。
长效β2-肾上腺素能激动剂（LABA），例如福莫特罗，DULERA的活性成分之一，增加了哮喘相关死亡的风险。来自大型安慰剂对照的美国研究的数据比较了添加到常规哮喘治疗中的另一种LABA（沙美特罗）或安慰剂的安全性，显示在接受沙美特罗的患者中哮喘相关死亡的增加。使用沙美特罗的这一发现被认为是LABA的类效应，包括福莫特罗。目前可用的数据不足以确定是否同时使用吸入性皮质类固醇或其他长期哮喘控制药物减轻了LABA引起的哮喘相关死亡风险的增加。来自对照临床试验的可用数据表明LABA增加了儿科和青少年患者中与哮喘相关的住院的风险。
当治疗哮喘患者时，仅对于长期哮喘控制药物（例如吸入性皮质类固醇）没有充分控制的哮喘患者规定DULERA，或者其疾病严重程度显然需要开始用吸入性皮质类固醇和LABA治疗。一旦实现和维持哮喘控制，定期评估患者，并且如果可能的话，逐步降低治疗（例如，停止DULERA）而不失去哮喘控制，并且保持患者长期哮喘控制药物，例如吸入性皮质类固醇。对于低剂量或中剂量吸入性皮质类固醇控制哮喘的患者，不要使用DULERA。
作用机制
DULERA：DULERA含有糠酸莫米松和富马酸福莫特罗;因此，下面针对各个部件描述的动作机制适用于DULERA。这些药物代表对哮喘的临床，生理和炎症指数具有不同作用的两种不同类型的药物（合成皮质类固醇和选择性长效β2-肾上腺素能受体激动剂）。
莫米松糠酸酯：糠酸莫米松是一种皮质类固醇，表现出有效的抗炎活性。皮质类固醇对哮喘的作用的确切机制尚不清楚。炎症是哮喘发病机理中的重要组成部分。皮质类固醇已显示对涉及炎症的多种细胞类型（例如肥大细胞，嗜酸性粒细胞，嗜中性粒细胞，巨噬细胞和淋巴细胞）和介质（例如组胺，类二十烷酸，白三烯和细胞因子）具有广泛的抑制作用，哮喘反应。皮质类固醇的这些抗炎作用可能有助于它们在哮喘中的功效。
莫米松糠酸酯在体外显示出对人糖皮质激素受体的结合亲和力，其为地塞米松的约12倍，曲安奈德的7倍，布地奈德的5倍，和氟替卡松的1.5倍。这些发现的临床意义是未知的。
福莫特罗富马酸盐：福莫特罗富马酸盐是一种长效选择性β2-肾上腺素能受体激动剂（β2激动剂）。吸入的福莫特罗富马酸盐作为支气管扩张剂局部作用于肺部。体外研究表明福莫特罗在β2受体比在β1-受体具有超过200倍的激动剂活性。尽管β2受体是支气管平滑肌中主要的肾上腺素能受体，β1受体是心脏中的主要受体，但在人心脏中也有β2受体，其包含总β-肾上腺素能受体的10％至5​​0％。这些受体的精确功能尚未确定，但它们提高了甚至高选择性β2-激动剂可能具有心脏作用的可能性。
β2-肾上腺素受体激动剂药物（包括福莫特罗）的药理学作用至少部分地归因于刺激胞内腺苷酸环化酶，所述腺苷环化酶催化三磷酸腺苷（ATP）转化为环状-3'，5'-腺苷一磷酸环AMP）。增加的环AMP水平引起支气管平滑肌松弛和抑制从细胞，特别是来自肥大细胞的即时过敏反应的介质的释放。
体外试验显示福莫特罗是从人肺释放肥大细胞介质（例如组胺和白三烯）的抑制剂。福莫特罗还抑制麻醉的豚鼠中组胺诱导的血浆白蛋白外渗，并抑制具有气道高反应性的狗中的过敏原诱导的嗜酸性粒细胞流入。这些体外和动物发现对人类的相关性是未知的。
适应症和用法
DULERA是一种含有皮质类固醇和长效β2-肾上腺素能激动剂的组合产品，适用于：
治疗12岁及以上患者的哮喘。
重要限制：
不适用于缓解急性支气管痉挛。
剂量和给药
仅用于口服吸入。
治疗哮喘患者≥12年：每天2次吸入DULERA 10mcg/5mcg或200mcg/5mcg。起始剂量基于先前的哮喘治疗。
剂量形式和强度
每次致动含有糠酸莫米松（100或200mcg）和福莫特罗富马酸盐二水合物（5mcg）的组合的吸入气雾剂。
禁忌症
主要治疗哮喘状态或急性哮喘发作需要强化措施。对DULERA.WARNINGS和PRECAUTIONS的任何成分超敏反应
哮喘相关死亡：长效β2-肾上腺素能激动剂增加风险。仅为推荐的患者群体规定。
疾病和急性发作的恶化：不要在急性恶化的哮喘中引发或治疗急性症状。
与其他长效β2激动剂一起使用：不要组合使用，因为过量的风险。
局部感染：白色念珠菌可能发生口腔和咽喉感染。定期监测患者对口腔有不良影响的迹象。建议患者在吸入后冲洗口腔。
免疫抑制：现有结核病，真菌，细菌，病毒或寄生虫感染的潜在恶化;或眼部单纯疱疹感染。在易感患者中可能发生更严重甚至致命的水痘或麻疹病程。在这些感染的患者中谨慎使用，因为这些感染恶化的可能性。
转移患者从系统性皮质类固醇：从口服类固醇转移时肾上腺功能受损的风险。如果转移到DULERA，使患者缓慢地从全身性皮质类固醇。
高血压和肾上腺抑制：可能发生在非常高的剂量或常规剂量的敏感个体。如果发生这种变化，缓慢停止DULERA。
强细胞色素P450 3A4抑制剂（例如，利托那韦）：全身皮质类固醇效应增加的风险。使用DULERA时请小心。
矛盾的支气管痉挛：如果发生支气管痉挛矛盾，停止DULERA并建立替代疗法。
心血管疾病患者：由于β-肾上腺素能刺激，谨慎使用。
骨矿物质密度降低：监测具有骨矿物质含量降低的主要危险因素的患者。
对生长的影响：监测儿科患者的生长。青光眼和白内障：监测具有视力变化或具有眼压升高，青光眼和/或白内障的病史的患者。
共存病症：在动脉瘤，嗜铬细胞瘤，惊厥性疾病，甲状腺毒症，糖尿病和酮症酸中毒患者中谨慎使用。低钾血症和高血糖：警惕低钾血症和高血糖。
不良反应
最常见的不良反应（报告≥3％的患者）包括：
鼻咽炎，鼻窦炎和头痛。
药物相互作用
强细胞色素P450 3A4抑制剂（例如，利托那韦）：谨慎使用。可能引起全身性皮质类固醇效应增加。
肾上腺素能代谢：谨慎使用。另外的肾上腺素能药物可以增强交感神经效应。黄嘌呤衍生物和利尿剂：谨慎使用。可能加强ECG变化和/或低钾血症。 MAO抑制剂，三环抗抑郁药，大环内酯和延长QTc间期的药物：非常小心使用。可能加强对心血管系统的影响。
β-受体阻滞剂：谨慎使用，并且仅在有医疗必要时使用。可能降低有效性并产生严重的支气管痉挛。
卤化烃：在接受伴随卤代烃麻醉的患者中，心律失常风险增加。
在特定人群中使用
肝脏损害：监测患者的药物暴露增加的迹象。

完整处方资料附件：
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=116464ce-cfd8-4b9f-8b5a-3a114b6ff2b1
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产地国家：美国 
原产地英文商品名:
Dulera(100mcg/5mcg) Inhaler 120Inhalation. Pack Size: 1Unit HFA Aerosol AD.
原产地英文药品名:
mometasone furoate/formoterol fumarate dihydrate
中文参考商品译名:
Dulera(100微克/5微克)/吸入剂 120吸入剂/HFA气雾剂
中文参考药品译名:
糠酸莫米松/富马酸福莫特罗
生产厂家中文参考译名:
默克公司
生产厂家英文名:
Merck＆Co.Inc

DULERA® (mometasone furoate and formoterol fumarate)
WARNING:
ASTHMA-RELATED DEATH
Long-acting beta2-adrenergic agonists (LABA), such as formoterol, one of the active ingredients in DULERA, increase the risk of asthma-related death. Data from a large placebo-controlled U.S. study that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of the LABA, including formoterol. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, DULERA should only be used for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue DULERA) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use DULERA for patients whose asthma is adequately
(DESCRIPTION)
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use DULERA safely and effectively. See full prescribing information for DULERA.
DULERA® 100 mcg/5 mcg (mometasone furoate 100 mcg and formoterol fumarate dihydrate 5 mcg) Inhalation Aerosol
DULERA® 200 mcg/5 mcg (mometasone furoate 200 mcg and formoterol fumarate dihydrate 5 mcg) Inhalation Aerosol
FOR ORAL INHALATION
Initial U.S. Approval: 2010
CLINICAL PHARMACOLOGY:
Mechanism of Action
DULERA: DULERA contains both mometasone furoate and formoterol fumarate; therefore, the mechanisms of actions described below for the individual components apply to DULERA. These drugs represent two different classes of medications (a synthetic corticosteroid and a selective long-acting beta2-adrenergic receptor agonist) that have different effects on clinical, physiological, and inflammatory indices of asthma.
Mometasone furoate: Mometasone furoate is a corticosteroid demonstrating potent anti-inflammatory activity. The precise mechanism of corticosteroid action on asthma is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of inhibitory effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation and in the asthmatic response. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.
Mometasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor, which is approximately 12 times that of dexamethasone, 7 times that of triamcinolone acetonide, 5 times that of budesonide, and 1.5 times that of fluticasone. The clinical significance of these findings is unknown.
Formoterol fumarate: Formoterol fumarate is a long-acting selective beta2-adrenergic receptor agonist (beta2-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 beta2-receptors than at beta1-receptors. Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-receptors in the human heart comprising 10% to 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 beta2-agonists may have cardiac effects.
The pharmacologic effects of beta2-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
INDICATIONS AND USAGE
DULERA is a combination product containing a corticosteroid and a long-acting beta2-adrenergic agonist indicated for:
Treatment of asthma in patients 12 years of age and older.
Important limitations:
Not indicated for the relief of acute bronchospasm.
USE IN SPECIFIC POPULATIONS
Hepatic impairment: Monitor patients for signs of increased drug exposure
CONTRAINDICATIONS
Primary treatment of status asthmaticus or acute episodes of asthma requiring intensive measures.
Hypersensitivity to any of the ingredients of DULERA
PRECAUTIONS
WARNINGS AND PRECAUTIONS
Asthma-related death: Long-acting beta2-adrenergic agonists increase the risk. Prescribe only for recommended patient populations.
Deterioration of disease and acute episodes: Do not initiate in acutely deteriorating asthma or to treat acute symptoms.
Use with additional long-acting beta2-agonist: Do not use in combination because of risk of overdose.
Localized infections: Candida albicans infection of the mouth and throat may occur. Monitor patients periodically for signs of adverse effects on the oral cavity. Advise patients to rinse the mouth following inhalation.
Immunosuppression: Potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infection; or ocular herpes simplex infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. Use with caution in patients with these infections because of the potential for worsening of these infections.
Transferring patients from systemic corticosteroids: Risk of impaired adrenal function when transferring from oral steroids. Taper patients slowly from systemic corticosteroids if transferring to DULERA.
Hypercorticism and adrenal suppression: May occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue DULERA slowly.
Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Risk of increased systemic corticosteroid effects. Exercise caution when used with DULERA.
Paradoxical bronchospasm: Discontinue DULERA and institute alternative therapy if paradoxical bronchospasm occurs.
Patients with cardiovascular disorders: Use with caution because of beta-adrenergic stimulation.
Decreases in bone mineral density: Monitor patients with major risk factors for decreased bone mineral content.
Effects on growth: Monitor growth of pediatric patients.
Glaucoma and cataracts: Monitor patients with change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts closely.
Coexisting conditions: Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis.
Hypokalemia and hyperglycemia: Be alert to hypokalemia and hyperglycemia.
DRUG INTERACTIONS
Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Use with caution. May cause increased systemic corticosteroid effects.
Adrenergic agents: Use with caution. Additional adrenergic drugs may potentiate sympathetic effects.
Xanthine derivatives and diuretics: Use with caution. May potentiate ECG changes and/or hypokalemia.
MAO inhibitors, tricyclic antidepressants, and drugs that prolong QTc interval: Use with extreme caution. May potentiate effect on the cardiovascular system.
Beta-blockers: Use with caution and only when medically necessary. May decrease effectiveness and produce severe bronchospasm.
ADVERSE REACTIONS
Most common adverse reactions (reported in 3% of patients) included:
Nasopharyngitis, sinusitis and headache. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Schering Corporation, a subsidiary of Merck & Co., Inc., at 1-800-526-4099 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
DOSAGE AND ADMINISTRATION
DOSAGE AND ADMINISTRATION (summary)
For oral inhalation only.
Treatment of asthma in patients 12 years: 2 inhalations twice daily of DULERA 100 mcg/5 mcg or 200 mcg/5 mcg. Starting dosage is based on prior asthma therapy.
DOSAGE AND ADMINISTRATION
2.1 General
DULERA should be administered only by the orally inhaled route (see Instructions for Using DULERA in the Medication Guide). After each dose, the patient should be advised to rinse his/her mouth with water without swallowing.
DULERA should be primed before using for the first time by releasing 4 test sprays into the air, away from the face, shaking well before each spray. In cases where the inhaler has not been used for more than 5 days, prime the inhaler again by releasing 4 test sprays into the air, away from the face, shaking well before each spray.
The DULERA canister should only be used with the DULERA actuator. The DULERA actuator should not be used with any other inhalation drug product. Actuators from other products should not be used with the DULERA canister.
2.2 Dosing
DULERA should be administered as two inhalations twice daily every day (morning and evening) by the orally inhaled route.
Shake well prior to each inhalation.
The recommended starting dosages for DULERA treatment are based on prior asthma therapy.
Table 1: Recommended Dosages for DULERA

Previous Therapy	Recommended Dose	Maximum Recommended Daily Dose
Inhaled medium dose corticosteroids	DULERA 100 mcg/5 mcg, 2 inhalations twice daily	400 mcg/20 mcg
Inhaled high dose corticosteroids	DULERA 200 mcg/5 mcg, 2 inhalations twice daily	800 mcg/20 mcg

The maximum daily recommended dose is two inhalations of DULERA 200 mcg/5 mcg twice daily. Do not use more than two inhalations twice daily of the prescribed strength of DULERA as some patients are more likely to experience adverse effects with higher doses of formoterol. If symptoms arise between doses, an inhaled short-acting beta2-agonist should be taken for immediate relief.
If a previously effective dosage regimen of DULERA fails to provide adequate control of asthma, the therapeutic regimen should be reevaluated and additional therapeutic options, e.g., replacing the current strength of DULERA with a higher strength, adding additional inhaled corticosteroid, or initiating oral corticosteroids, should be considered.
TThe maximum benefit may not be achieved for 1 week or longer after beginning treatment. Individual patients may experience a variable time to onset and degree of symptom relief. For patients 12 years of age who do not respond adequately after 2 weeks of therapy, higher strength may provide additional asthma control
HOW SUPPLIED
How Supplied
DULERA is available in two strengths and supplied in the following package sizes:
Package NDC
DULERA 100 mcg/5 mcg
120 inhalations 0085-7206-01
DULERA 100 mcg/5 mcg
60 inhalations (institutional pack) 0085-7206-07
DULERA 200 mcg/5 mcg
120 inhalations 0085-4610-01
DULERA 200 mcg/5 mcg
60 inhalations (institutional pack) 0085-4610-05
Each strength is supplied as a pressurized aluminum canister that has a blue plastic actuator integrated with a dose counter and a blue dust cap. Each 120-inhalation canister has a net fill weight of 13 grams and each 60-inhalation canister has a net fill weight of 8.8 grams. Each canister is placed into a carton. Each carton contains 1 canister and a Medication Guide.
Initially the dose counter will display "64" or "124" actuations. After the initial priming with 4 actuations, the dose counter will read "60" or "120" and the inhaler is now ready for use.
Storage and Handling
The DULERA canister should only be used with the DULERA actuator. The DULERA actuator should not be used with any other inhalation drug product. Actuators from other products should not be used with the DULERA canister.
The correct amount of medication in each inhalation cannot be ensured after the labeled number of actuations from the canister has been used, even though the inhaler may not feel completely empty and may continue to operate. The inhaler should be discarded when the labeled number of actuations has been used (the dose counter will read "0").
Store at controlled room temperature 20°–25°C (68°–77°F); excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature].
The 120-inhalation inhaler does not require specific storage orientation. For the 60-inhalation inhaler, after priming store the inhaler with the mouthpiece down or in a horizontal position.
For best results, the canister should be at room temperature before use. Shake well before using. Keep out of reach of children. Avoid spraying in eyes.
Contents Under Pressure: Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw container into fire or incinerator
REFERENCE
Package Insert data: 
Manufactured by: 3M Health Care Ltd., Loughborough, United Kingdom.
Distributed by: Schering Corporation, a subsidiary of
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA