近日，美国塞Seoracor公司开发的酒石酸阿福特罗afromoterol tartrate吸入液(商品名:Brovana)在美国获准上市,用于长期维持治疗慢性阻塞性肺病(COPD)引起的支气管收缩症状,包括慢性支气管炎和肺气肿. 批准日期：2006年10月 公司：Sunovion制药 BROVANA（阿福特罗酒石酸盐[Arformoterol tartrate]）吸入溶液 美国首次批准：2006 适应症 与USAGEBROVANA吸入溶液是一种长效β2-肾上腺素受体激动剂（β2-受体激动剂）表示： 从长期来看，在维持治疗慢性阻塞性肺疾病（COPD），包括慢性支气管炎和肺气肿患者的支气管收缩，每天两次（早上和晚上）管理。 使用的重要限制： 解决方案是不是表示BROVANA吸入治疗慢性阻塞性肺疾病急性恶化。 解决方案是不是表示BROVANA吸入治疗哮喘。 用法用量 ADMINISTRATIONFor口腔吸入。 不推荐甲每日总剂量大于30微克 一个15mcg/2mL瓶，每12小时。 对于使用一个标准的喷射喷雾器（与面罩或口片）连接到一个空气压缩机。 的剂型和STRENGTHSInhalation解决方案（单位剂量小瓶雾化）：15 mcg/2mL。 解决方案 CONTRAINDICATIONSBROVANA的吸入溶液中的禁忌与过敏病史的患者阿福特罗，外消旋福莫特罗或该产品的任何其他组件。 所有LABA，包括BROVANA吸入解决方案，在不使用的长期哮喘控制药物哮喘患者是禁忌。 在急性恶化的患者，警告和PRECAUTIONSDo无法启动BROVANA吸入的解决方案。 不要用于缓解急性症状。随之而来的短效β2-受体激动剂，可用于需要急性救灾。 不要超过推荐剂量。过度使用BROVANA吸入溶液，或在含有长效β2-激动剂与其他药物一起使用，可导致临床上显着的心血管效应，并可能是致命的。 可能会出现危及生命的矛盾性支气管痉挛。立即停止BROVANA吸入解决方案。 请谨慎使用患者的心血管疾病或惊厥性疾病，甲状腺功能亢进，或与拟交感神经药物的敏感性。 不利REACTIONSMost常见的不良反应（≥2％的发病率比安慰剂更常见）是疼痛，胸部疼痛，背部疼痛，腹泻，鼻窦炎，腿抽筋，呼吸困难，皮疹，感冒综合征，血管神经性水肿和肺部疾病。 药物的INTERACTIONSOther肾上腺素能药物可能会增强效果。请谨慎使用。 黄嘌呤衍生物，类固醇，利尿药，非保钾利尿剂可能会增强低血钾或心电图改变。请谨慎使用。 MAO抑制剂，三环类抗抑郁药和QT间期延长的药物，可能会增强对心血管系统的影响。使用非常谨慎。 β-受体阻滞剂可能会降低效益。可能会阻止β-受体激动剂的支气管扩张作用。请谨慎使用，只有当医疗上必要的。 使用在特定POPULATIONSHepatic减值 使用与肝功能损害患者慎用。 日期：07/2011 -------------------------------------------------------------------- BROVANA SOL INH 15MCG/2ML UD30  ARFORMOTEROL TARTRATE  SUNOVION PHARMACEUTICALS  63402-0911-30             BROVANA SOL INH 15MCG/2ML UD60  ARFORMOTEROL TARTRATE  SUNOVION PHARMACEUTICALS  63402-0911-64             -------------------------------------------------------------------- CLINICAL PHARMACOLOGY Mechanism of Action Arformoterol, the (R,R)-enantiomer of formoterol, is a selective long-acting beta2-adrenergic receptor agonist (beta2-agonist) that has two-fold greater potency than racemic formoterol (which contains both the (S,S) and (R,R)-enantiomers). The (S,S)-enantiomer is about 1,000-fold less potent as a beta2-agonist than the (R,R)-enantiomer. While it is recognized that beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, data indicate that 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 arformoterol, 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 intracellular 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 arformoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Arformoterol 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. 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. Pharmacokinetics The pharmacokinetics (PK) of arformoterol have been investigated in healthy subjects, elderly subjects, renally and hepatically impaired subjects, and chronic obstructive pulmonary disease (COPD) patients following the nebulization of the recommended therapeutic dose and doses up to 96 mcg. Absorption In COPD patients administered 15 mcg arformoterol every 12 hours for 14 days, the mean steady-state peak (R,R)-formoterol plasma concentration (Cmax) and systemic exposure (AUC0-12h) were 4.3 pg/mL and 34.5 pg*hr/mL, respectively. The median steady-state peak (R,R)-formoterol plasma concentration time (tmax) 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 (AUC0-12h) 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 Cmax 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 AUC0-6h by 27% and Cmax 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. Distribution 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. Generic Name for BROVANA Arformoterol 15micrograms/2mL; soln for inh. Legal Classification: Rx Pharmacological Class for BROVANA Long-acting β2-agonist. Manufacturer of BROVANA Sunovion Indications for BROVANA Long-term maintenance treatment of bronchoconstriction due to COPD. Adult dose for BROVANA By nebulizer: 15micrograms by inhalation twice daily (AM & PM). Use standard jet (eg, PARI LC PLUS) nebulizer with air compressor (eg, PARI DURA-NEB 3000). Reevaluate periodically. Children's dosing for BROVANA Not recommended. Contraindications for BROVANA Not for treatment of acute attacks. Do not initiate in significantly or acutely deteriorating COPD. Concomitant other long-acting β2-agonists. Warnings/Precautions for BROVANA Do not exceed recommended dose. Cardiovascular disease (esp. coronary insufficiency, arrhythmias, hypertension). Convulsive disorders. Hepatic impairment. Hyperthyroidism. Hypokalemia. Hyperresponsiveness to sympathomimetics. Diabetes. Ketoacidosis. Monitor potassium. Prescribe a short-acting β2-agonist for acute symptoms; monitor for increased need. Pregnancy (Cat.C). Labor & delivery. Nursing mothers. Interactions for BROVANA See Contraindications. Avoid other sympathomimetics (except short-acting bronchodilators). Avoid use during or within 2 weeks of MAOIs, tricyclics, others that prolong QTc interval. Antagonized by β-blockers. K+-depleting diuretics, theophylline, aminophylline, steroids may potentiate hypokalemia. Adverse Reactions for BROVANA Asthenia, fever, bronchitis, headache, GI upset, serum K+ changes, leukocytosis, nervousness, pain, tremor, flu syndrome; cardiovascular effects (eg, increased pulse rate or BP; consider discontinuing if occurs); rarely: paradoxical bronchospasm, hypersensitivity reactions; increased risk of asthma-related death. How is BROVANA supplied? Vials (2mL)—30