2010年7月欧盟已批准Nycomed公司的罗氟司特(roflumilast，Daxas)上市用于慢性阻塞性肺疾病(COPD)的治疗。本品为选择性磷酸二酯酶4(PDE4)抑制剂，是十多年来首次获得欧盟批准的新一类COPD治疗药物。美国FDA于2011年3月1日批准罗氟司特(roflumilast，Daliresp)用于治疗重性慢性阻塞性肺病(COPD)，可每日服用，用于减少COPD发病频率及减缓症状。 作用机制 Roflumilast及其活性代谢物(roflumilast氮氧化物)是磷酸二酯酶4(PDE4)的选择性抑制剂。Roflumilast和roflumilast氮氧化物抑制PDE4(在肺组织中一种主要的环-3’,5’-磷酸腺苷(环AMP)-代谢酶)活性导致细胞内环AMP的蓄积。而通过这种特殊机制DALIRESP在COPD患者中发挥其治疗作用未充分确定，被认为是增加肺细胞细胞内环AMP的作用有关。 适应证和用途 DALIRESP是适用于治疗有严重COPD伴有慢性支气管炎和加重史的患者中以减低COPD加重的风险. 使用的限制：DALIRESP不是一种支气管扩张剂而且不适用于为缓解急性支气管扩张。 剂量和给药方法 对有COPD患者的推荐剂量为每天一片500 μg，有或无食物。 剂型和规格 片：500μg 禁忌证 （1）中度至严重肝受损(Child-Pugh类别B或C)。 警告和注意事项 （1）急性支气管痉挛：不要用予缓解急性支气管痉挛。 （2）精神事件包括自杀行为：建议患者，他们的护理人员，和家庭警惕失眠，焦虑， 抑郁, 自杀念头或其他情绪变化出现或恶化，和如发生这类变化联系他们的医疗卫生提供者。在有抑郁和/或自杀念头或行为史患者中仔细权衡用DALIRESP治疗的风险和获益。 （3）体重减轻：常规监查体重。如发生不能解释或有临床意义的体重减轻，评价体重减轻和考虑停止DALIRESP。 （4）药物相互作用：建议不要与强细胞色素P450酶诱导剂使用(如利福平[rifampicin]，苯巴比妥[Phenobarbital]，卡马西平[carbamazepine]，苯妥英[phenytoin])。 不良反应 最常见不良反应(≥ 2%)是腹泻，体重减轻，恶心，头痛，背痛，流感，失眠，头晕和食欲减退。 为报告不良反应联系Forest Laboratories, Inc.改善电话1-800-678-1605或FDA电话1-800-FDA-1088或www.fda.gov/medwatch. 药物相互作用 （1）与CYP3A4抑制剂或CYP3A4和CYP1A2双重抑制剂使用(如，红霉素[erythromycin], 酮康唑ketoconazole]，氟伏沙明[fluvoxamine]，依诺沙星[enoxacin]，西咪替丁[cimetidine])将增加roflumilast全身暴露和可能导致增加不良反应。这类同时使用的风险应仔细对效益权衡。 特殊人群中使用 （1）哺乳母亲：因为roflumilast和/或其代谢物可能排泄至人乳和尚无DALIRESP对母乳唯有婴儿的研究，正在哺乳的妇女不应使用DALIRESP。 如何供应/贮存/处置 1)如何供应 DALIRESP以白色至灰白色圆片供应，一侧凹有“D”和另一侧“500”。每片含500 μg roflumilast。 DALIRESP片 可得到在瓶中s含30片 - NDC 0456-0095-30或90片 - NDC 0456-0095-90. 2 )贮存和处置 贮藏DALIRESP 500 μg片在20° - 25°C (68° - 77°F)‘外出时允许至15° - 30°C(59° - 86°F)。[见USP控制室温]。 Daliresp (500 mcg) is a selective PDE4 inhibitor that is indicated as a treatment to reduce the risk of exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. Daliresp is a once-daily oral tablet and is the first and only selective PDE4 inhibitor approved by the FDA. While the specific mechanism by which Daliresp exerts its therapeutic action in COPD patients is not well defined, it is thought to be related to the effects of increased intracellular cyclic AMP in lung cells. Daliresp is not a steroid, is not a bronchodilator, and is not indicated for the relief of acute bronchospasm. Daliresp will be available nationwide in the second calendar quarter of 2011. In August 2009 Forest Laboratories and Nycomed entered into a definitive collaboration and distribution agreement pursuant to which Forest acquired an exclusive license for Daliresp in the United States. Indication Daliresp is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. Limitations of use: Daliresp is not a bronchodilator and is not indicated for the relief of acute bronchospasm. About COPD COPD is an under-diagnosed, progressive, irreversible lung disease and is the third leading cause of death in the U.S. Approximately 12 million people in the U.S. are currently diagnosed with COPD and an additional 12 million are likely to have the disease and not know. Approximately half of COPD patients treated by a physician with controller medications have severe COPD. Of the patients diagnosed with severe COPD, almost three quarters, or 2.8 million, have chronic bronchitis. Symptoms of COPD include breathlessness, chronic cough and excessive production of phlegm. A significant worsening of symptoms called an exacerbation can last several weeks and often requires substantial medical intervention, including hospitalization. Exacerbations can result in worsening health status, lung function decline, and increased risk of death. Important Safety Information Contraindications Daliresp is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C). Warnings and Precautions Acute Bronchospasm Daliresp is not a bronchodilator and should not be used for the relief of acute bronchospasm. Psychiatric Events including Suicidality Treatment with Daliresp is associated with an increase in psychiatric adverse reactions (5.9% of patients treated with Daliresp versus 3.3% treated with placebo). Instances of suicidal ideation and behavior, including completed suicide, have been observed in clinical trials. Three patients treated with Daliresp experienced suicide-related adverse reactions (one completed suicide and two suicide attempts) compared to one patient (suicidal ideation) treated with placebo. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully weigh the risks and benefits of treatment with Daliresp in patients with a history of depression and/or suicidal thoughts or behavior and evaluate the risks and benefits of continuing treatment if such events occur. Weight Decrease Weight loss was a common adverse reaction in Daliresp clinical trials (7.5% of patients treated with Daliresp vs 2.1% treated with placebo). In addition to being reported as adverse reactions, weight was prospectively assessed in two 1-year trials. In these studies, 20% of patients receiving Daliresp experienced moderate weight loss (5-10% of body weight) vs 7% receiving placebo and 7% receiving Daliresp vs 2% receiving placebo experienced severe weight loss (>10% body weight). During follow-up after treatment discontinuation, the majority of patients with weight loss regained some of the weight they had lost while receiving Daliresp. Patients treated with Daliresp should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of Daliresp should be considered. Drug Interactions Use of Daliresp with strong cytochrome P450 enzyme inducers (eg, rifampicin, phenobarbital, carbamazepine, phenytoin) is not recommended. The risk of using Daliresp with inhibitors of CYP3A4 and/or CYP1A2 enzymes should be weighed carefully against benefit. Adverse Reactions The most common adverse reactions observed with Daliresp (incidence greater-than or equal to 2% and greater than placebo) were diarrhea(10% vs 3%), weight decreased (8% vs 2%), nausea (5% vs 1%), headache (4% vs 2%), back pain (3% vs 2%), influenza (3% vs 3%), insomnia (2% vs 1%), dizziness (2% vs 1%), decreased appetite (2% vs 0%). Use in Specific Populations 2011年3月1日，美国食品药品监督管理局批准了慢性阻塞性肺炎新药罗氟司特 (roflumilast，Daliresp)。本品每日使用，可降低哮喘发作频率或者减轻严重的慢性阻塞性肺炎(COPD)的症状。 COPD是一种使呼吸困难的严重肺部疾病，症状有：呼吸急促、慢性咳嗽、痰多等，病情可在数周内恶化导致肾功能衰竭，死亡风险提高并可能产生严重的焦虑症。吸烟是发生COPD的首要原因，根据美国国立心脏、肺和血液研究所的报告显示，COPD是美国第四大致死原因。 本品是新一类的COPD药物，是磷酸二酯酶-4(PDE-4)抑制剂。可用于严重COPD患者的咳嗽及支气管相关的痰多等症状，不适用于轻度肺气肿等。 FDA药品评价及研究中心药品评估二部的负责人Curtis Rosebraugh表示：COPD是一种严重的疾病，并持续恶化，新的治疗选择能减少复发频率，对慢性支气管疾病的COPD患者十分重要，防止在治疗过程中病情恶化。 通过对1500例40岁及以上的患者对Roflumilast的安全性及有效性进行了两项临床III期试验，这些有慢性支气管炎的COPD患者在接受治疗前的12个月内有病情恶化的现象。 FDA批准Roflumilast时同时发布了用药指南，提醒患者可能发生的精神健康风险，包括情绪、思想、行为的变化以及体重意外减轻等。Roflumilast不可用于突发性的呼吸系统疾病，如急性支气管痉挛等，不建议18岁以下未成年人使用，常见的毒副作用有：腹泻、呕吐、头疼、背疼、失眠、厌食及嗜睡等。 Roflumilast是由Forest Lab的子公司Forest PHarmaceuticals生产上市。