英文药名: Daxas (Roflumilast Tablets) 中文药名: 罗氟司特片 药品简介 Daxas(roflumilast, 罗氟司特)用于治疗慢性阻塞性肺疾病(COPD) 。 慢性阻塞性肺疾病(COPD)是一种进行性呼吸道疾病。在气流受限影响下，COPD患者呼气期间气体过度滞留肺中，进而导致患者出现呼吸困难、运动耐量下降、生活质量恶化、死亡风险增高等危害。男性40岁以上群体中，慢性阻塞性肺疾病的发病率较高，吸烟成为主要危险因素。COPD在临床上的漏诊和误诊比例已高达70%，是当前人类的五大死因之一。 该药是一种新型的选择性磷酸二酯酶-4（PDE－4）抑制剂，每日口服1次。 罗氟司特（Roflumilast）属于磷酸二酯酶-4抑制剂，适用于慢性阻塞性肺病，商品名为Daxas。最先由德国安达（Altana）公司研制，目前已是瑞士奈科明公司（NycomedGmbH）旗下的产品。2005年，已在欧洲和美国进行了罗氟司特的临床试验。 罗氟司特为口服制剂，主要表达于与哮喘有关的炎症细胞，包括嗜酸粒细胞、中性粒细胞和肥大细胞。该药能特异地作用于参与平滑肌收缩的某种酶，从而阻断促炎症反应信号传递，具有抗炎活性，在气喘和慢阻肺的临床治疗上获得了较好的疗效。平滑肌收缩是支气管痉挛的特征之一，支气管痉挛时，气道突然狭窄，从而引起呼吸困难和呼吸系统疾病。罗氟司特还明显地延缓了呼吸系统症状的恶化，同时极大地提高患者的生活质量。 2009年，瑞士奈科明制药公司完成了罗氟司特的Ⅲ期临床试验后，取得了良好的结果。并在欧洲递交了上市申请，公司也计划尽快在美国申请这种药物。奈科明已与ForestLab签订合作协议，ForestLab付出6亿美元的代价，获得了在美国销售Daxas的权益，并负责罗氟司特在美国FDA审报的申请与推广销售。而奈科明将保留药物在欧洲和全球其他地区的销售权。罗氟司特作为首只磷酸二酯酶IV抑制剂，其上市将成为该类药物创新上的一大突破。 Nycomed公司2010年7月6日宣布，欧盟已批准其罗氟司特（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。 本品为一日1次用药的口服片剂，须与其他支气管扩张药合用，适用于有频繁加重病史的成人患者慢性支气管炎相关严重COPD（舒张后FEV1小于预计值的50%）的维持治疗。本品作为新一类COPD治疗药物，预计将很快投放欧洲市场，首先上市的国家为德国和英国。 4项Ⅲ期临床研究为本品获批奠定了基础。在两项关键性安慰剂对照临床研究中，共纳入超过3000例COPD患者。研究证明，本品可显著改善患者中至重度加重发作和舒张前FEV1，不管是否与长效β2激动剂联用。研究还证明，与安慰剂相比，本品可显著改善患者肺功能。 美国初始批准：2011  公司：Forest Pharmaceuticals, Inc. 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：500 μg 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。 包装规格： 注：以下产品不同各和不同价格，购买时请以电话咨询为准！ ■ 500mcg*30片(Merck Sharp & Dohme 生产） ■ 500mcg*30片(Nycomed 生产） Daxas® roflumilast Daxas is has been approved in the EUROPEAN union. Daxas' ® EUROPEAN approved indication is for the maintenance treatment of severe chronic obstructive pulmonary disease (COPD) (FEV1 post-brochodilator less then 50% predicted) associated with chronic bronchitis in patients with a history of frequent exacerbations as add on to bronchodilator treatment Update July 2010 On July 28th 2010 the EUROPEAN MEDICINES AGENCY has published the marketing autorisation for DAXAS: The use is strictly limited  tot the approved indication: Daxas' ® EUROPEAN approved indication is for the maintenance treatment of severe chronic obstructive pulmonary disease (COPD) (FEV1 post-brochodilator less then 50% predicted) associated with chronic bronchitis in patients with a history of frequent exacerbations as add on to bronchodilator treatment Update June 2010 On September 6th 2009: Nycomed announced the submission of a New Drug Application (NDA) to the US Food and Drug Administration (FDA) for Daxas® as a once-daily oral treatment for patients with symptomatic COPD. In June 2009 an application for European Registration has been filed. On April 7, 2010: A FDA Pulmonary-Allergy Drugs Advisory Committee Meeting. The panel voted 5 to 10 against a question that asked if the data submitted by Forest provided "substantial evidence" to support approval of Daxas® , to treat certain patients with chronic obstructive pulmonary disease, or COPD The decision came after two previous votes on Daxas® on safety and effectiveness. The panel voted 9 to 6 on each vote that Daxas was effective and safe. The FDA usually follows the advice of its panels but isn't required to do so. On April 23, 2010, the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) published a positive opinion, recommending the approval of Daxas in the European Union. On May 18, 2010 Nycomed and Forest Laboratories received a complete response letter asking for certain additional information and analysis, and although no new trials are ordered, launch of the COPD treatment will in the USA now be delayed.   Four Studies Published in The Lancet Show Roflumilast (Daxas®), a New Oral Approach to COPD, Improves Lung Function and Reduces Exacerbations NEW YORK - (Business Wire) Forest Laboratories, Inc. (NYSE: FRX), an international pharmaceutical manufacturer and marketer and Nycomed, a privately owned pharmaceutical company, today announced that results of four phase III trials have been published in the prestigious peer-reviewed medical journal The Lancet showing that roflumilast, a phosphodiesterase 4 (PDE4) inhibitor, improved lung function and reduced exacerbations in patients with moderate to severe COPD. COPD is an under-diagnosed progressive lung disease that may lead to death. Worldwide, COPD kills four people every minute and the World Health Organization (WHO) predicts that it will be the third leading cause of death by 2030. WHO estimates that 80 million people have moderate to severe COPD. Roflumilast, a once-a-day oral tablet, would be the first in an entirely new class of treatment for COPD if it receives regulatory approval from the authorities in Europe (EMEA) and the US (FDA). The phase III placebo-controlled trials of roflumilast evaluated the treatment in two 12-month (Lancet 2009; 374: 685–694) and two six-month studies (Lancet 2009; 374: 695–703), involving 4,500 patients in ten countries. Details of the results of the four studies will be published in The Lancet on August 29 (data and information under embargo until Friday, August 28 at 00:01am GMT). The two 12-month studies published in The Lancet demonstrated that roflumilast produced a statistically significant and clinically relevant reduction in exacerbations (lung attacks that need treatment with systemic steroids or lead to hospitalisation), even for patients who were also taking long-acting bronchodilators. The studies showed a reduction in moderate to severe exacerbations by 17 percent per patient per year (rate of 1.14 events per year with roflumilast vs. 1.37 per year with placebo, p<0.001). The reduction in exacerbations was irrespective of concomitant treatment with long-acting beta-2 agonists, a standard bronchodilator therapy. When added to standard bronchodilator therapies in the two six-month studies, a clear trend for the reduction of exacerbations was observed with roflumilast, over and above what was achieved with these therapies alone. There was also a statistically significant difference with roflumilast in other prespecified endpoints, including median time to first exacerbation (moderate to severe in the salmeterol study, and mild, moderate and severe in the tiotropium study) and in the proportion of patients in both studies experiencing a mild, moderate, or severe exacerbation. Lung function, as measured by FEV1 (how much volume can be exhaled in one second), was the primary or co-primary endpoint in all four studies. Across the studies, roflumilast demonstrated a statistically significant improvement in pre-bronchodilator FEV1, in the range of 48 to 80 mL (p<0.001). Nausea, diarrhea and weight loss were the most common adverse events recorded in patients in the four trials, but they were generally mild to moderate in intensity and generally occurred in the first weeks of treatment. Professor Peter Calverley, Professor of Respiratory Medicine, University of Liverpool, UK, and the lead author of the 12-month studies, said: “COPD can devastate people’s lives and exacerbations can be extremely frightening, so a novel tablet like roflumilast is really exciting for those of us treating patients. Roflumilast acts differently to bronchodilators as it acts on the underlying condition, not primarily impacting on everyday symptoms. It acts slowly and the effects, as we saw in our studies, are gradual and sustained.” “Roflumilast could be an important new treatment for COPD,” added Professor Fernando Martinez, University of Michigan, also a lead author of the 12-month studies. “We clearly need new options for patients with COPD and the results of these studies, published in The Lancet, confirm that roflumilast is beneficial. It reduced exacerbations, or lung attacks, and significantly improved lung function, in a patient population whose lung function is very poor.” Professor Leonardo Fabbri, Professor of Respiratory Medicine, University of Modena and Reggio Emilia, Italy, and lead author of the six-month studies, said: “Roflumilast has a novel mode of action and has the potential to become the first of a new class of drugs and potentially the only completely new treatment option for COPD in the next several years. These eagerly awaited results, published this week in The Lancet, show that in addition to confirming the sustained statistically significant improvements in lung function, roflumilast also showed a trend to reducing exacerbations when given in addition to long acting inhaled bronchodilators. The results of the two six-months trials examining the additive effect of roflumilast on top of salmeterol or tiotropium support and extend the findings of the 12-month trials, by showing a clinically relevant lung function improvement in patients with impaired lung function on top of maximum bronchodilation.” “The lung function improvements on top of current bronchodilation clearly indicates that roflumilast improves lung function over and above what can be achieved with other COPD treatments alone. It also demonstrates that roflumilast works in a different way to current treatments and supports roflumilast’s potential to change how COPD is managed,” added Professor Klaus Rabe, Professor of Medicine at Leiden University Medical Center, also a lead author of the six-month studies. Nycomed’s Executive Vice President R&D, Anders Ullman, said: “We are very pleased with the results published in The Lancet this week. In four studies, two 12-month studies and two six-month studies, roflumilast showed clear therapeutic potential, decreasing exacerbations and improving lung function. The uniformity of the results is really encouraging and gives us great hope that our faith in roflumilast has been confirmed. We are now undergoing the regulatory review process with the European and US authorities.” “Based on the results from the pivotal studies published this week, it appears that roflumilast provides added activity on top of other commonly used treatments for COPD,” said Lawrence S. Olanoff, President and Chief Operating Officer of Forest Laboratories. “Roflumilast represents the first in a new class of agents to treat COPD and, if approved, would be the first oral anti-inflammatory maintenance treatment for the disease.”   Further details for the four trials have been presented at the European Respiratory Society Annual Congress 2009, in Vienna, Austria, September 12 to 16, 2009. 12-Month Trials The two replicate, 12-month trials were randomised, placebo controlled and double blind. One 12 month study was conducted in 246 centres in 10 countries and the second was conducted in 221 centres in eight countries. COPD patients were over 40, and either former or current smokers with a smoking history of at least 20 pack-years. The patients had symptoms of chronic cough and sputum, their post-bronchodilator FEV1 was ≤ 50% of the predicted value and they had at least one documented moderate to severe exacerbation in the previous year. Approximately 50% of the patients were concomitantly using long acting beta agonists. Patients were permitted to use short-acting bronchodilators to relieve their symptoms as needed. Compared with placebo, roflumilast significantly reduced the rate of exacerbations and improved lung function in treated patients. The rate of moderate to severe exacerbations in the study period (pooled data) was 1.14 per year in the patients treated with roflumilast compared with 1.37 per year, in the placebo group. This represents an improvement of 17 per cent (RR 0.83; CI 0.75-0.92, p<0.001). The pooled data for lung function using the pre-bronchodilator FEV1 measurement (forced expiratory volume in one second) showed an average increase of 48mL (p<0.001) in roflumilast treated patients compared with the placebo group. The improvement in post-bronchodilator FEV1 was 55mL (p<0.001) with roflumilast. The differences found in exacerbation rates and lung function were similar irrespective of whether roflumilast was used with or without a long-acting beta-agonist. Using another measurement, FVC (forced vital capacity, the lung capacity measured when the patient is exhaling for as hard and as long as possible) roflumilast patients also scored higher with an average increased FVC of 98 mL (p<0.001) compared with the placebo group. These patients had not used a bronchodilator prior to testing. The improvement in post-bronchodilator FVC was 101 mL (p<0.001). Roflumilast was well tolerated by most patients. Slightly more patients discontinued the trial in the roflumilast group than those taking placebo (14 percent vs 11 percent). Diarrhea, nausea and headache were the commonest reasons for discontinuation. A reduction in weight, around 2kg, was seen consistently across all the studies published in The Lancet. When patients stopped taking roflumilast the majority regained weight. In addition, in the 12- month studies, only four patients out of 1,547 dropped out because of weight loss. Six-month trials In the six-month trial patients used roflumilast or a placebo in conjunction with commonly used long acting bronchodilators (inhalers). In one trial, patients used salmeterol with roflumilast or placebo. In the second trial, patients used tiotropium, a long-acting bronchodilator which also reduces the production of mucus, with roflumilast or placebo. Patients used “rescue mediation” short-acting bronchodilators, as needed. There were 933 patients in the salmeterol trial and 743 patients in the tiotropium trial. Overall patients had moderate to severe COPD; were over 40, current or former smokers with a history of smoking at least a pack a day for 10 years. In contrast to the 12-month trials, patients in the six-months trials did not require a history of exacerbations. Patients recruited to the tiotropium study were more symptomatic than those in the salmeterol study as they were required to have daily chronic cough and sputum production and a documented use of rescue medication. Patients were seen and measured once a month for the first three months and every six weeks for the last three months of the trial. Compared with placebo, patients taking roflumilast in addition to salmeterol, had an average increased pre-bronchodilator FEV1 (forced expiratory volume in one second) of 49mL (p<0.001). Compared with placebo, patients taking roflumilast in addition to tiotropium had an average increased pre-bronchodilator FEV1 of 80mL (p<0.001). There was a similar FEV1 advantage in both trials when measurements were taken after using a short-acting bronchodilator, an increase of 60mL (p<0.001) in the salmeterol study and 81mL (p<0.001) in the tiotropium study. Roflumilast was well tolerated by most patients. Slightly more patients discontinued the trials in the roflumilast group than those taking placebo (13 percent vs 8 percent). Diarrhea, nausea and headache were the most commonly reported adverse events. About Roflumilast (Daxas®) Roflumilast is an orally administered phosphodiesterase 4 (PDE4) enzyme inhibitor targeting cells and mediators in the body believed to be important in the COPD disease process. Roflumilast is expected to act on the underlying mechanism of COPD and related inflammatory diseases. If approved, roflumilast, a once-a-day oral tablet, will be the first in an entirely new class of treatment for COPD. It will also be the first oral anti-inflammatory treatment for COPD patients. Current treatment for COPD patients includes the use of inhaled bronchodilators and inhaled corticosteroids.   About COPD COPD is an under-diagnosed progressive lung disease that may lead to death. Worldwide, COPD kills four people every minute and the World Health Organization (WHO) predicts that it will be the third leading cause of death by 2030. WHO estimates that 80 million people have moderate to severe COPD. Symptoms of COPD include breathlessness, chronic cough and excessive production of phlegm. A significant worsening of symptoms called an exacerbation or lung attack can last several weeks. Breathing becomes severely compromised and patients may need to be admitted to hospital. Exacerbations are frightening events resulting in increased patient anxiety, worsening health status, lung function decline and increased risk of death. Smoking is a major contributory factor in western countries, and pollution from fires for cooking and heating is an additional contributory factor in less developed countries. Industrial and chemical pollutants can also cause COPD. Chronic inflammation in the lungs plays a significant role in COPD. Current medications used to treat the condition deal mainly with symptoms rather than the underlying disease. Roflumilast is a new PDE4 inhibitor being developed specifically to target the chronic inflammation which is COPD-related.. About Nycomed Nycomed is a privately owned global pharmaceutical company with a differentiated portfolio focused on branded medicines in gastroenterology, respiratory and inflammatory diseases, pain, osteoporosis and tissue management. An extensive range of OTC products completes the portfolio. Daxas(R)（罗氟司特）是一种治疗慢性阻塞性肺病 (COPD) 特药 Daxas(R)（罗氟司特）是一种口服的选择性磷酸二酯酶4 (PDE4) 抑制剂，该药品已经证明能够以一种崭新的作用方式抑制与慢性阻塞性肺病 (COPD) 有关的炎症[5]。作为一天口服一次的药片，Daxas(R)（罗氟司特）不仅是严重 COPD 新疗法中的第一种药品，而且是第一种面向 COPD 患者的口服抗炎药。 四项大型随机安慰剂对照试验已经证明，在和第一线维持性疗法共同使用时，罗氟司特能够极大地抑制病情的恶化，而且可以改进肺功能。 Daxas(R)（罗氟司特）的药物耐受性普遍良好。在涉及12,000名患者的临床 COPD 试验中，最常见的副作用是腹泻（5.9%）、体重下降（3.4%）、呕吐（2.9%）、腹痛（1.9%）和头痛（1.7%）。大部分副作用都很温和或适中。这些反应主要发生在治疗开始后的第一周，且大部分随着持续治疗而消失