部份中文罗氟司特处方资料（仅供参考） 【通用名】罗氟司特片/ Roflumilast Tablets 【商品名】Daxas（欧盟），DALIRESP（美国） 【国外进展】 由瑞士奈科明（Nycomed）公司及其美国合作伙伴Forest实验室公司共同开发。 2010年7月，欧洲EMA批准罗氟司特片上市； 2011年2月，FDA批准上市。 【剂型及规格】片剂，规格为0.5mg。 【适应症】 本品适用于有慢性支气管炎和急性加重史的重度慢性阻塞性肺疾病（COPD）患者的治疗，以降低COPD急性加重的风险。 【用法用量】口服。推荐剂量为每日1次，每次500μg。空腹或与食物同服均可。 2010年7月6日,欧盟已批准其罗氟司特Daxas（roflumilast）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。 DAXAS 500 micrograms film-coated tablets 1. Name of the medicinal product Daxas 500 micrograms film-coated tablets 2. Qualitative and quantitative composition Each tablet contains 500 micrograms of roflumilast. Excipient with known effect: Each film-coated tablet contains 188.72 mg lactose (as monohydrate). For the full list of excipients, see section 6.1. 3. Pharmaceutical form Film-coated tablet (tablet). Yellow, D-shaped film-coated tablet of 9 mm, embossed with “D” on one side. 4. Clinical particulars 4.1 Therapeutic indications Daxas is indicated for maintenance treatment of severe chronic obstructive pulmonary disease (COPD) (FEV1 post-bronchodilator less than 50% predicted) associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add on to bronchodilator treatment. 4.2 Posology and method of administration Posology The recommended dose is one tablet of 500 micrograms roflumilast once daily. Daxas may need to be taken for several weeks to achieve its effect (see section 5.1). Daxas has been studied in clinical trials for up to one year. Special populations Older people (65 years and older) No dose adjustment is necessary. Renal impairment No dose adjustment is necessary. Hepatic impairment The clinical data with Daxas in patients with mild hepatic impairment classified as Child-Pugh A are insufficient to recommend a dose adjustment (see section 5.2) and therefore Daxas should be used with caution in these patients. Patients with moderate or severe hepatic impairment classified as Child-Pugh B or C must not take Daxas (see section 4.3). Paediatric population There is no relevant use of Daxas in the paediatric population (under 18 years) in the indication COPD. Method of administration For oral use. The tablet should be swallowed with water and taken at the same time every day. The tablet can be taken with or without food. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Moderate or severe hepatic impairment (Child-Pugh B or C) (see section 4.2). 4.4 Special warnings and precautions for use All patients should be informed about the risks of Daxas and the precautions for safe use and should be given a patient card before starting Daxas. Rescue medicinal products Roflumilast is an anti-inflammatory substance indicated for maintenance treatment of severe COPD associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add on to bronchodilator treatment. It is not indicated as rescue medicinal product for the relief of acute bronchospasms. Weight decrease In 1-year studies (M2-124, M2-125), a decrease of body weight occurred more frequently in patients treated with Daxas compared to placebo-treated patients. After discontinuation of Daxas, the majority of patients had regained body weight after 3 months. Body weight of underweight patients should be checked at each visit. Patients should be advised to check their body weight on a regular basis. In the event of an unexplained and clinically concerning weight decrease, the intake of Daxas should be stopped and body weight should be further followed-up. Special clinical conditions Due to lack of relevant experience, treatment with Daxas should not be initiated or existing treatment with Daxas should be stopped in patients with severe immunological diseases (e.g. HIV infection, multiple sclerosis, lupus erythematosus, progressive multifocal leukoencephalopathy), severe acute infectious diseases, cancers (except basal cell carcinoma), or patients being treated with immunosuppressive medicinal products (i.e.: methotrexate, azathioprine, infliximab, etanercept, or oral corticosteroids to be taken long-term; except short-term systemic corticosteroids). Experience in patients with latent infections such as tuberculosis, viral hepatitis, herpes viral infection and herpes zoster is limited. Patients with congestive heart failure (NYHA grades 3 and 4) have not been studied and therefore treatment of these patients is not recommended. Psychiatric disorders Daxas is associated with an increased risk of psychiatric disorders such as insomnia, anxiety, nervousness and depression. Rare instances of suicidal ideation and behaviour, including completed suicide, have been observed in patients with or without history of depression, usually within in the first weeks of treatment (see section 4.8). The risks and benefits of starting or continuing treatment with Daxas should be carefully assessed if patients report previous or existing psychiatric symptoms or if concomitant treatment with other medicinal products likely to cause psychiatric events is intended. Daxas is not recommended in patients with a history of depression associated with suicidal ideation or behaviour. Patients and caregivers should be instructed to notify the prescriber of any changes in behaviour or mood and of any suicidal ideation. If patients suffered from new or worsening psychiatric symptoms, or suicidal ideation or suicidal attempt is identified, it is recommended to discontinue treatment with Daxas. Persistent intolerability While adverse reactions like diarrhoea, nausea, abdominal pain and headache mainly occur within the first weeks of therapy and mostly resolve on continued treatment, Daxas treatment should be reassessed in case of persistent intolerability. This might be the case in special populations that may have higher exposure, such as in black, non-smoking females (see section 5.2) or in patients concomitantly treated with CYP1A2/ 2C19/3A4 inhibitors (such as fluvoxamine and cimetidine) or the CYP1A2/3A4 inhibitor enoxacin (see section 4.5). Theophylline There are no clinical data to support the concomitant treatment with theophylline for maintenance therapy. Therefore, the concomitant treatment with theophylline is not recommended. Lactose Daxas tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 4.5 Interaction with other medicinal products and other forms of interaction Interaction studies have only been performed in adults. A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2. Both roflumilast and roflumilast N-oxide have intrinsic phosphodiesterase 4 (PDE4) inhibitory activity. Therefore, following administration of roflumilast, the total PDE4 inhibition is considered to be the combined effect of both roflumilast and roflumilast N-oxide. Interaction studies with CYP1A2/3A4 inhibitor enoxacin and the CYP1A2/2C19/3A4 inhibitors cimetidine and fluvoxamine, resulted in increases of the total PDE4 inhibitory activity of 25%, 47% and 59%, respectively. The tested dose of fluxoxamine was 50 mg. A combination of Daxas with these active substances might lead to an increase of exposure and persistent intolerability. In this case, Daxas treatment should be reassessed (see section 4.4). Administration of the cytochrome P450 enzyme inducer rifampicin resulted in a reduction in total PDE4 inhibitory activity by about 60%. Therefore, the use of strong cytochrome P450 enzyme inducers (e.g. phenobarbital, carbamazepine, phenytoin) may reduce the therapeutic efficacy of roflumilast. Thus, Daxas treatment is not recommended in patients receiving strong cytochrome P450 enzyme inducers. Clinical interaction studies with CYP3A4 inhibitors erythromycin and ketoconazole showed increases of 9% of the total PDE4 inhibitory activity. Co-administration with theophylline resulted in an increase of 8% of the total PDE4 inhibitory activity (see section 4.4). In an interaction study with an oral contraceptive containing gestodene and ethinyl oestradiol, the total PDE4 inhibitory activity was increased by 17%. No dose adjustment is necessary in patients receiving these active substances. No interactions were observed with inhaled salbutamol, formoterol, budesonide and oral montelukast, digoxin, warfarin, sildenafil and midazolam. Co-administration with an antacid (combination of aluminium hydroxide and magnesium hydroxide) did not alter the absorption or pharmacokinetics of roflumilast or its N-oxide. 4.6 Fertility, pregnancy and lactation Women of childbearing potential Women of childbearing age should be advised to use an effective method of contraception during treatment. Daxas is not recommended in women of childbearing potential not using contraception. Pregnancy There are limited amount of data from the use of roflumilast in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Daxas is not recommended during pregnancy. Roflumilast has been demonstrated to cross the placenta in pregnant rats. Breastfeeding Available pharmacokinetic data in animals have shown excretion of roflumilast or its metabolites in milk. A risk to the breastfed infant cannot be excluded. Daxas should not be used during breast-feeding. Fertility In a human spermatogenesis study, roflumilast 500 micrograms had no effects on semen parameters or reproductive hormones during the 3-month treatment period and the following 3-month off-treatment period. 4.7 Effects on ability to drive and use machines Daxas has no influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile In clinical COPD studies, approximately 16% of patients experienced adverse reactions with roflumilast (compared to 5% in placebo). The most commonly reported adverse reactions were diarrhoea (5.9%), weight decreased (3.4%), nausea (2.9%), abdominal pain (1.9%) and headache (1.7%). The majority of these adverse reactions were mild or moderate. These adverse reactions mainly occurred within the first weeks of therapy and mostly resolved on continued treatment. Tabulated list of adverse reactions Within the following table, adverse reactions are ranked under the MedDRA frequency classification: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1. Adverse reactions with roflumilast in clinical COPD studies and post-marketing experience Frequency Common Uncommon Rare System Organ Class Immune system disorders   Hypersensitivity Angioedema Endocrine disorders     Gynaecomastia Metabolism and nutrition disorders Weight decreased Decreased appetite     Psychiatric disorders Insomnia Anxiety Suicidal ideation and behaviour* Depression Nervousness Nervous system disorders Headache Tremor Vertigo Dizziness Dysgeusia Cardiac disorders   Palpitations   Respiratory, thoracic and mediastinal disorders     Respiratory tract infections (excluding Pneumonia) Gastrointestinal disorders Diarrhoea Nausea Abdominal pain Gastritis Vomiting Gastro-esophageal reflux disease Dyspepsia Haematochezia Constipation Hepatobiliary disorders     Gamma-GT increased Aspartate aminotransferase (AST) increased Skin and subcutaneous tissue disorders   Rash Urticaria Musculoskeletal and connective tissue disorders   Muscle spasms and weakness Myalgia Back pain Blood creatine phosphokinase (CPK) increased General disorders and administration site conditions   Malaise Asthenia Fatigue   Description of selected adverse reactions * In clinical studies and post-marketing experience, rare instances of suicidal ideation and behaviour, including completed suicide, were reported. Patients and caregivers should be instructed to notify the prescriber of any suicidal ideation (see also section 4.4). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. 4.9 Overdose Symptoms In Phase I studies, the following symptoms were observed at an increased rate after single oral doses of 2,500 micrograms and one single dose of 5,000 micrograms (ten times the recommended dose): headache, gastrointestinal disorders, dizziness, palpitations, light-headedness, clamminess and arterial hypotension. Management In case of overdose, it is recommended that the appropriate supportive medical care is provided. Since roflumilast is highly protein bound, haemodialysis is not likely to be an efficient method of its removal. It is not known whether roflumilast is dialysable by peritoneal dialysis. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Drugs for obstructive airway diseases, Other systemic drugs for obstructive airway diseases, ATC code: R03DX07 Mechanism of action Roflumilast is a PDE4 inhibitor, a non-steroid, anti-inflammatory agent designed to target both the systemic and pulmonary inflammation associated with COPD. The mechanism of action is the inhibition of PDE4, a major cyclic adenosine monophosphate (cAMP)-metabolizing enzyme found in structural and inflammatory cells important to the pathogenesis of COPD. Roflumilast targets the PDE4A, 4B and 4D splicing variants with similar potency in the nanomolar range. The affinity to the PDE4C splicing variants is 5 to 10-fold lower. This mechanism of action and the selectivity also apply to roflumilast N-oxide, which is the major active metabolite of roflumilast. Pharmacodynamic effects Inhibition of PDE4 leads to elevated intracellular cAMP levels and mitigates COPD-related malfunctions of leukocytes, airway and pulmonary vascular smooth muscle cells, endothelial and airway epithelial cells and fibroblasts in experimental models. Upon in vitro stimulation of human neutrophils, monocytes, macrophages or lymphocytes, roflumilast and roflumilast N-oxide suppress the release of inflammatory mediators e.g. leukotriene B4, reactive oxygen species, tumor necrosis factor α, interferon γ and granzyme B. In patients with COPD, roflumilast reduced sputum neutrophils. Furthermore, roflumilast attenuated influx of neutrophils and eosinophils into the airways of endotoxin challenged healthy volunteers. Clinical efficacy and safety In two confirmative replicate one-year studies (M2-124 and M2-125) and two supplementary six-month studies (M2-127 and M2-128), a total number of 4,768 patients were randomized and treated of whom 2,374 were treated with Daxas. The design of the studies was parallel-group, double-blind and placebo-controlled. The one-year studies included patients with a history of severe to very severe COPD [FEV1 (forced expiratory volume in one second) ≤50% of predicted] associated with chronic bronchitis, with at least one documented exacerbation in the previous year and with symptoms at baseline as determined by cough and sputum score. Long-acting beta-agonists (LABAs) were allowed in the studies and were used in approximately 50% of the study population. Short-acting anticholinergics (SAMAs) were allowed for those patients not taking LABAs. Rescue medicinal products (salbutamol or albuterol) were allowed on an as-needed basis. The use of inhaled corticosteroids and theophylline was prohibited during the studies. Patients with no history of exacerbations were excluded. In a pooled analysis of the one-year studies M2-124 and M2-125, Daxas 500 micrograms once daily significantly improved lung function compared to placebo, on average by 48 ml (pre-bronchodilator FEV1, primary endpoint, p<0.0001), and by 55 ml (post-bronchodilator FEV1, p<0.0001). The improvement in lung function was apparent at the first visit after 4 weeks and was maintained up to one year (end of treatment period). The rate (per patient per year) of moderate exacerbations (requiring intervention with systemic glucocorticosteroids) or severe exacerbations (resulting in hospitalisation and/or leading to death) after 1 year was 1.142 with roflumilast and 1.374 with placebo corresponding to a relative risk reduction of 16.9% (95%CI: 8.2% to 24.8%) (primary endpoint, p=0.0003). Effects were similar, independent of previous treatment with inhaled corticosteroids or underlying treatment with LABAs. In the subgroup of patients with history of frequent exacerbations (at least 2 exacerbations during the last year), the rate of exacerbations was 1.526 with roflumilast and 1.941 with placebo corresponding to a relative risk reduction of 21.3% (95%CI: 7.5% to 33.1%). Roflumilast did not significantly reduce the rate of exacerbations compared with placebo in the subgroup of patients with moderate COPD. The reduction of moderate or severe exacerbations with Daxas and LABA compared to placebo and LABA was on average 21% (p=0.0011). The respective reduction in exacerbations seen in patients without concomitant LABAs was on average 15% (p=0.0387). The numbers of patients who died due to any reason were equal for those treated with placebo or roflumilast (42 deaths each group; 2.7% each group; pooled analysis). A total of 2,690 patients were included and randomized in two supportive 1-year studies (M2-111 and M2-112). In contrast to the two confirmative studies, a history of chronic bronchitis and of COPD exacerbations was not requested for patients' inclusion. Inhaled corticosteroids were used in 809 (61%) of the roflumilast treated patients, whereas the use of LABAs and theophylline was prohibited. Daxas 500 micrograms once daily significantly improved lung function compared to placebo, on average by 51 ml (pre-bronchodilator FEV1, p<0.0001), and by 53 ml (post-bronchodilator FEV1, p<0.0001). The rate of exacerbations (as defined in the protocols) were not significantly reduced by roflumilast in the individual studies (relative risk reduction: 13.5% in study M2-111 and 6.6% in study M2-112; p= not significant). Adverse events rates were independent of concomitant treatment with inhaled corticosteroids. Two six-month supportive studies (M2-127 and M2-128) included patients with a history of COPD for at least 12 months prior to baseline. Both studies included moderate to severe patients with a non-reversible airway obstruction and a FEV1 of 40% to 70% of predicted. Roflumilast or placebo treatment was added to continuous treatment with a long-acting bronchodilator, in particular salmeterol in study M2-127 or tiotropium in study M2-128. In the two six-month studies, pre-bronchodilator FEV1 was significantly improved by 49 ml (primary endpoint, p<0.0001) beyond the bronchodilator effect of concomitant treatment with salmeterol in study M2-127 and by 80 ml (primary endpoint, p<0.0001) incremental to concomitant treatment with tiotropium in study M2-128. No study has been conducted to compare Daxas to the combination of LABA plus inhaled corticosteroids or on top of the combination of LABA plus inhaled corticosteroids. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Daxas in all subsets of the paediatric population in chronic obstructive pulmonary disease (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Roflumilast is extensively metabolised in humans, with the formation of a major pharmacodynamically active metabolite, roflumilast N-oxide. Since both roflumilast and roflumilast N-oxide contribute to PDE4 inhibitory activity in vivo, pharmacokinetic considerations are based on total PDE4 inhibitory activity (i.e. total exposure to roflumilast and roflumilast N-oxide). Absorption The absolute bioavailability of roflumilast following a 500 micrograms oral dose is approximately 80%. Maximum plasma concentrations of roflumilast typically occur approximately one hour after dosing (ranging from 0.5 to 2 hours) in the fasted state. Maximum concentrations of the N-oxide metabolite are reached after about eight hours (ranging from 4 to 13 hours). Food intake does not affect the total PDE4 inhibitory activity, but delays time to maximum concentration (tmax) of roflumilast by one hour and reduces Cmax by approximately 40%. However, Cmax and tmax of roflumilast N-oxide are unaffected. Distribution Plasma protein binding of roflumilast and its N-oxide metabolite is approximately 99% and 97%, respectively. Volume of distribution for single dose of 500 micrograms roflumilast is about 2.9 l/kg. Due to the physico-chemical properties, roflumilast is readily distributed to organs and tissues including fatty tissue of mice, hamster and rat. An early distribution phase with marked penetration into tissues is followed by a marked elimination phase out of fatty tissue most probably due to pronounced break-down of parent compound to roflumilast N-oxide. These studies in rats with radiolabeled roflumilast also indicate low penetration across the blood-brain barrier. There is no evidence for a specific accumulation or retention of roflumilast or its metabolites in organs and fatty tissue. Biotransformation Roflumilast is extensively metabolised via Phase I (cytochrome P450) and Phase II (conjugation) reactions. The N-oxide metabolite is the major metabolite observed in the plasma of humans. The plasma AUC of the N-oxide metabolite on average is about 10-fold greater than the plasma AUC of roflumilast. Thus, the N-oxide metabolite is considered to be the main contributor to the total PDE4 inhibitory activity in vivo. In vitro studies and clinical interaction studies suggest that the metabolism of roflumilast to its N-oxide metabolite is mediated by CYP1A2 and 3A4. Based on further in vitro results in human hepatic microsomes, therapeutic plasma concentrations of roflumilast and roflumilast N-oxide do not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11. Therefore, there is a low probability of relevant interactions with substances metabolised by these P450 enzymes. In addition, in vitro studies demonstrated no induction of the CYP1A2, 2A6, 2C9, 2C19, or 3A4/5 and only a weak induction of CYP2B6 by roflumilast. Elimination The plasma clearance after short-term intravenous infusion of roflumilast is about 9.6 l/h. Following an oral dose, the median plasma effective half-life of roflumilast and its N-oxide metabolite are approximately 17 and 30 hours, respectively. Steady state plasma concentrations of roflumilast and its N-oxide metabolite are reached after approximately 4 days for roflumilast and 6 days for roflumilast N-oxide following once-daily dosing. Following intravenous or oral administration of radiolabeled roflumilast, about 20% of the radioactivity was recovered in the faeces and 70% in urine as inactive metabolites. Linearity/Non-linearity The pharmacokinetics of roflumilast and its N-oxide metabolite are dose-proportional over a range of doses from 250 micrograms to 1,000 micrograms. Special populations In older people, females and in non-Caucasians, total PDE4 inhibitory activity was increased. Total PDE4 inhibitory activity was slightly decreased in smokers. None of these changes were considered to be clinically meaningful. No dose adjustment is recommended in these patients. A combination of factors, such as in black, non-smoking females, might lead to an increase of exposure and persistent intolerability. In this case, Daxas treatment should be reassessed (see section 4.4). Renal impairment Total PDE4 inhibitory activity decreased by 9% in patients with severe renal impairment (creatinine clearance 10-30 ml/min). No dose adjustment is necessary. Hepatic impairment The pharmacokinetics of Daxas 250 micrograms once-daily was tested in 8 patients with mild to moderate hepatic impairment classified as Child-Pugh A and B. In these patients, the total PDE4 inhibitory activity was increased by about 20% in patients with Child-Pugh A and about 90% in patients with Child-Pugh B. Simulations suggest dose proportionality between Daxas 250 and 500 micrograms in patients with mild and moderate hepatic impairment. Caution is necessary in Child-Pugh A patients (see section 4.2). Patients with moderate or severe hepatic impairment classified as Child-Pugh B or C should not take Daxas (see section 4.3). 5.3 Preclinical safety data There is no evidence for an immunotoxic, skin sensitising or phototoxic potential. A slight reduction in male fertility was seen in conjunction with epididymal toxicity in rats. No epididymal toxicity or changes in semen parameters were present in any other rodent or non-rodent species including monkeys in spite of higher exposures. In one of two rat embryofetal development studies, a higher incidence of incomplete skull bone ossification was seen at a dose producing maternal toxicity. In one of three rat studies on fertility and embryofetal development, post-implantation losses were observed. Post-implantation losses were not seen in rabbits. Prolongation of gestation was seen in mice. The relevance of these findings to humans is unknown. Most relevant findings in safety pharmacology and toxicology studies occurred at higher doses and exposure than that intended for clinical use. These findings consisted mainly of gastrointestinal findings (i.e. vomiting, increased gastric secretion, gastric erosions, intestine inflammation) and cardiac findings (i.e. focal haemorrhages, haemosiderin deposits and lympho-histiocytic cell infiltration in the right atria in dogs, and decreased blood pressure and increased heart rate in rats, guinea pigs and dogs). Rodent-specific toxicity in the nasal mucosa was observed in repeat-dose toxicity and carcinogenicity studies. This effect seems to be due to an ADCP (4-Amino-3,5-dichloro-pyridine) N-oxide intermediate specifically formed in rodent olfactory mucosa, with special binding affinity in these species (i.e. mouse, rat and hamster). 6. Pharmaceutical particulars 6.1 List of excipients Core Lactose monohydrate Maize starch Povidone (K90) Magnesium stearate Coating Hypromellose 2910 Macrogol 4000 Titanium dioxide (E171) Iron oxide yellow (E172) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container PVC/PVDC aluminium blisters in packs of 10, 14, 28, 30, 84, 90 or 98 film-coated tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling No special requirements. 7. Marketing authorisation holder Takeda GmbH Byk-Gulden-Straße 2 D-78467 Konstanz Germany 8. Marketing authorisation number(s) EU/1/10/636/001-007 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 05 July 2010 10. Date of revision of the text 30th August 2013 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. *罗氟司特治疗COPD --摘自《慢性阻塞性肺疾病新药：罗氟司特》 慢性阻塞性肺疾病（COPD）是发生在气道和肺部的慢性炎症性疾病，以气道进行性受限为特征，不能完全逆转。主要发病原因是吸烟，职业和环境污染也有一定的作用。COPD有一些慢性共患病，比如心力衰竭和代谢综合征，对COPD的临床表现和进展也有一定的影响。 到目前为止，市场上还没有一种药物能够延缓或阻止COPD的进展。现有的治疗主要是通过支气管扩张剂缓解症状，包括吸入性β2受体激动剂，比如沙美特罗（Serevent）、福莫特罗（Foradil）和茚达特罗（Onbrez）；以及抗胆碱能药物，比如噻托溴铵（Spiriva）。重症以及有急性发作史的患者通常给予吸入性激素联合长效β2受体激动剂（LABAs）治疗，以减少急性发作的频率。茶碱是一种弱效的支气管扩张剂，也已用于COPD的治疗，但是其治疗窗比较窄，而且与其他药物有相互作用，因此限制了其在临床上的应用。 磷酸二酯酶4（PDE4）是炎症和免疫细胞中一种主要的cAMP代谢酶，因此PDE4抑制剂具有广泛的抗炎作用。目前已有几种PDE4抑制剂正在开展针对气道炎症性疾病（包括COPD和哮喘）的研究，而罗氟司特（roflumilast，Daxas）是第一个获批的此类药物。 罗氟司特（500μg口服，每天一次）治疗COPD的有效性和安全性通过了几项随机双盲安慰剂对照试验的验证。 两项为期一年的研究共入组3 091例重度到极重度的COPD患者（支气管扩张治疗后FEV1≤50%），伴有慢性咳嗽和咳痰，一年内至少有一次记录在病历的急性发作。可给予LABAs或短效抗胆碱能药物，必要时给予补救药物（沙美特罗或沙丁胺醇）。禁用吸入性糖皮质激素、噻托溴铵以及茶碱。主要观察终点为支气管扩张剂使用前FEV1的改变以及中到重度急性发作的频率。 对两项研究的结果进行分析发现，罗氟司特与安慰剂相比，可显著改善肺功能，增加支气管扩张剂使用前的平均FEV1达48 mL。1年后，中度（需要全身使用糖皮质激素）或重度（导致住院和或死亡）急性发作的发生率（每患者每年），罗氟司特组为1.14，安慰剂组为1.37，相对风险降低了16.9%。 在此之前还有一项为期1年左右的研究，共入组1513例重症COPD患者（使用支气管扩张剂后FEV1≤50%），但不一定有慢性支气管炎以及COPD急性发作史。 允许给予吸入性糖皮质激素治疗，但不允许使用LABAs和茶碱。与安慰剂相比，罗氟司特可显著改善肺功能，增加平均支气管扩张剂使用后FEV1达39 mL，但并未降低急性发作率。 鉴于多项研究的结果，罗氟司特被欧盟EMEA批准作为支气管扩张剂的辅助药物，用于有频繁急性发作的成人重症COPD（支气管扩张剂使用后FEV1＜50%）患者的维持治疗。 具有新型作用机制的口服PDE4抑制剂罗氟司特的上市将会有效的改善COPD的治疗现状。与现有的治疗药物联合，罗氟司特能够进一步缓解症状，减少急性发作，但只对大多数重症患者有效，也就是说，有慢性咳嗽以及反复急性发作，气道严重受限的COPD患者，将会受益于罗氟司特的上市。由于COPD急性发作将会加快疾病进展，增加死亡率，因此，罗氟司特减少疾病发作的这一疗效非常重要。此外，罗氟司特可减轻肺部炎症反应，对吸入性糖皮质激素的疗效会有所辅助。而且，其口服给药的途径也会大大改善患者的依从性。有趣的是，罗氟司特治疗糖尿病患者，还可以稍微减轻体重，降低血糖以及糖化血红蛋白水平，表明该药还有全身代谢效应。但是，罗氟司特对全身炎症标记物却无作用，比如C反应蛋白，因此，其对全身炎症反应以及共病的作用机制还有待进一步探讨。不过，罗氟司特也有一些不良反应，包括腹泻、头痛和呕吐，临床治疗时应予以关注。