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新复方药Anoro Ellipta（umeclidinium/vilanterol，UMEC/VI，55mcg/22mcg）获欧盟委员会（EC）批准，作为每日一次的维持治疗用支气管扩张剂，用于缓解慢性阻塞性肺病（COPD）患者的症状。
Anoro Ellipta 55 micrograms/22 micrograms inhalation powder, pre-dispensed
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: Ireland IMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.imb.ie; e-mail: imbpharmacovigilance@imb.ie United Kingdom the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. 4.9 Overdose An overdose of umeclidinium/vilanterol will likely produce signs and symptoms due to the individual components' actions, consistent with the known inhaled muscarinic antagonist adverse reactions (e.g. dry mouth, visual accommodation disturbances and tachycardia) or those with overdose of other beta2-adrenergic agonists (e.g. arrhythmias, tremor, headache, palpitations, nausea, hyperglycaemia and hypokalaemia). If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination with anticholinergics, ATC code: R03AL03 Mechanism of action Umeclidinium/vilanterol is a combination inhaled long-acting muscarinic receptor antagonist/long-acting beta2-adrenergic agonist (LAMA/LABA). Following oral inhalation both compounds act locally on airways to produce bronchodilation by separate mechanisms. Umeclidinium Umeclidinium is a long acting muscarinic receptor antagonist (also referred to as an anticholinergic). It is a quinuclidine derivative with activity across multiple muscarinic receptor subtypes. Umeclidinium exerts its bronchodilatory activity by competitively inhibiting the binding of acetylcholine with muscarinic receptors on airway smooth muscle. It demonstrates slow reversibility at the human M3 muscarinic receptor subtype in vitro and a long duration of action in vivo when administered directly to the lungs in pre-clinical models. Vilanterol Vilanterol is a selective long-acting, beta2-adrenergic receptor agonist (beta2-adrenergic agonist). The pharmacologic effects of beta2-adrenergic agonists, including vilanterol, are at least in part attributable to stimulation of intracellular adenylate 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. Pharmacodynamic effects In Phase III, 6-month studies umeclidinium/vilanterol provided clinically meaningful improvements over placebo in lung function (as measured by forced expiratory volume in 1 second [FEV1]) over 24 hours following once daily administration, which were evident at 15 minutes following administration of the first dose (improvement over placebo by 112 ml (p <0.001*). Mean peak improvements in FEV1 within the first 6 hours following dosing relative to placebo was 224 ml (p<0.001* ) at Week 24. There was no evidence for tachyphylaxis in the effect of ANORO over time. Cardiac electrophysiology The effect of umeclidinium/vilanterol on the QT interval was evaluated in a placebo and active (moxifloxacin) controlled QT study involving once daily administration of umeclidinium/vilanterol 113/22 micrograms or 500/100 micrograms (pre-dispensed dose with umeclidinium at eight times the recommended dose and vilanterol at four times the recommended dose) for 10 days in 103 healthy volunteers. The maximum mean difference in prolongations of QT interval (corrected using the Fridericia method, QTcF) from placebo after baseline-correction was 4.3 (90% CI=2.2 to 6.4) milliseconds seen 10 minutes after administration with umeclidinium/vilanterol 113/22 micrograms and 8.2 (90% CI=6.2 to 10.2) milliseconds seen 30 minutes after administration with umeclidinium/vilanterol 500/100 micrograms. Therefore, no clinically relevant pro-arrhythmic potential related to QT-interval prolongations was observed with umeclidinium/vilanterol 113/22 micrograms. A dose-dependent increase in heart rate was also observed. The maximum mean difference in heart rate from placebo after baseline-correction was 8.4 (90% CI=7.0 to 9.8) beats/minute and 20.3 (90% CI=18.9 to 21.7) beats/minute seen 10 minutes after administration of umeclidinium/vilanterol 113/22 micrograms and 500/100 micrograms respectively. In addition, no clinically significant effects on cardiac rhythm were observed on 24-hour Holter monitoring in 53 patients with COPD who were treated with umeclidinium/vilanterol 55/22 micrograms once daily in one 6-month study, or in a further 55 patients who received umeclidinium/vilanterol 113/22 micrograms once daily in another 6-month study and 226 patients who received 113/22 micrograms once daily in the 12-month study. Clinical efficacy The clinical efficacy of umeclidinium/vilanterol administered once daily was evaluated in eight Phase III clinical studies in 6,835 adult patients with a clinical diagnosis of COPD; 5,618 patients from five 6-month studies (two placebo-controlled and three active [tiotropium]-comparator controlled), 655 patients from two 3-month exercise endurance/lung function studies and 562 patients from a 12-month supportive study. Effects on lung function ANORO demonstrated improvements in lung function (as defined by change from baseline in trough FEV1) in several studies. In one 6-month Phase III study, ANORO demonstrated statistically significant improvements in trough FEV1 (primary endpoint) at Week 24 compared with placebo and each monotherapy component treatment arm. In addition, ANORO demonstrated clinically meaningful and statistically significant improvements in trough FEV1 compared with tiotropium in two of the three 6-month active-comparator studies and numerically greater improvements from tiotropium in the third active-comparator study (see Table 1). There was no attenuation of the bronchodilator effect over time. Symptomatic outcomes Breathlessness: ANORO demonstrated a statistically significant and clinically meaningful reduction in breathlessness as evaluated by an increase in TDI focal score at Week 24 (key secondary end-point) compared with placebo (see Table 1). Improvements in TDI focal score compared with each monotherapy component and tiotropium were not statistically significant (see Table 1). The proportion of patients who responded with at least the minimum clinically important difference (MCID) of 1 unit TDI focal score at Week 24 was greater for ANORO (58%) compared with placebo (41%) and each monotherapy component (53% for umeclidinium and 51% for vilanterol). Health-related quality of life: ANORO has also shown an improvement in health-related quality of life measured using the St. George's Respiratory Questionnaire (SGRQ) as indicated by a reduction in SGRQ total score at Week 24 compared with placebo and each monotherapy component (see Table 1). ANORO showed a statistically significant reduction in SGRQ total score compared with tiotropium in one of the three active-comparator studies (see Table 1). The proportion of patients who responded with at least the MCID in SGRQ score (defined as a decrease of 4 units from baseline) at Week 24 was greater for ANORO (49%) compared with placebo (34%) and each monotherapy component (44% for umeclidinium and 48% for vilanterol). In one active-comparator study, a higher percentage of patients receiving ANORO responded with a clinically meaningful improvement in SGRQ score at Week 24 (53%) compared to tiotropium (46%). In the other two active-comparator studies, a similar proportion of patients achieved at least the MCID with ANORO and tiotropium; 49% and 54% for ANORO 55/22 micrograms and 52% and 55% for tiotropium. Use of rescue medication ANORO reduced the use of rescue medication with salbutamol compared with placebo and umeclidinium (see Table 1) and demonstrated a higher percentage of days when no rescue medication was needed (on average 36.1%) compared with placebo (on average 21.7%). In the three 6-month active-comparator-controlled studies, ANORO reduced the use of rescue medication with salbutamol compared with tiotropium, with statistically significant reductions observed in two of the studies (see Table 1). ANORO also demonstrated a higher percentage of days when no rescue medication was needed in all three studies (average within the range 17.6% to 21.5%) compared with tiotropium (average within the range 11.7% to 13.4%). Table 1. Lung function, symptomatic and health related quality of life outcomes at Week 24
mcg = micrograms n/e = not evaluated 1. Least squares mean 2. Pooled data from Study DB2113360 and Study DB2113374 3. Difference in the mean number of puffs per day over Weeks 1-24 A higher dose of umeclidinium/vilanterol (113/22 micrograms) was also studied in a 24-week placebo controlled clinical study and in two of the three 24-week active-controlled studies. The results were similar to those for the ANORO dose and provided additional supportive evidence for the efficacy of ANORO. COPD exacerbations ANORO reduced the risk of a COPD exacerbation by 50% compared with placebo (based analysis of time to first exacerbation: Hazard Ratio (HR) 0.5, p=0.004*); by 20% compared with umeclidinium (HR 0.8, p=0.391); and by 30% compared with vilanterol (HR 0.7, p=0.121). From the three active-comparator studies, the risk of a COPD exacerbation compared with tiotropium was reduced by 50% in one study (HR 0.5, p=0.044) and was increased by 20% and 90% in two studies (HR 1.2, p=0.709 and HR 1.9, p=0.062 respectively). These studies were not specifically designed to evaluate the effect of treatments on COPD exacerbations and patients were withdrawn from the study if an exacerbation occurred. Exercise endurance and lung volumes ANORO 55/22 micrograms improved exercise endurance time compared with placebo, as evaluated with the endurance shuttle walk test (ESWT), in one study but not the second and improved lung volume measures compared with placebo in both studies in adult COPD patients with hyperinflation (functional residual capacity [FRC] >120%). In the first study, ANORO 55/22 micrograms demonstrated a statistically significant and clinically relevant improvement (based on a minimal clinically important difference (MCID) between 45 to 85 seconds) over placebo in exercise endurance time (EET) obtained 3 hours after dosing at Week 12 (69.4 seconds [p=0.003]). Improvement in EET compared with placebo was seen at Day 2 and was sustained at Week 6 and Week 12. In the second study, the treatment difference in EET between ANORO 55/22 micrograms and placebo was 21.9 seconds (p=0.234) at Week 12. ANORO 55/22 micrograms also showed statistically significant improvements compared with placebo in change from baseline in lung volume measures at trough and at 3 hours post dose at Week 12 in the first study (inspiratory capacity: 237 ml and 316 ml respectively, residual volume: -466 ml and -643 ml respectively and functional residual capacity: -351 ml and -522 ml respectively; all p<0.001). In the second study, ANORO 55/22 micrograms showed improvements compared with placebo in change from baseline in lung volume measures at trough and at 3 hours post dose at Week 12 (inspiratory capacity: 198 ml and 238 ml respectively, residual volume: -295 ml and -351 ml respectively and functional residual capacity: -238 ml and -302 ml respectively); all p<0.001*). Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with ANORO in all subsets of the paediatric population in COPD (see section 4.2 for information on paediatric use). * A step-down statistical testing procedure was used in this study and this comparison was below a comparison that did not achieve statistical significance. Therefore, statistical significance on this comparison cannot be inferred. 5.2 Pharmacokinetic properties When umeclidinium and vilanterol were administered in combination by the inhaled route, the pharmacokinetics of each component was similar to those observed when each active substance was administered separately. For pharmacokinetic purposes each component can therefore be considered separately. Absorption Umeclidinium Following inhaled administration of umeclidinium in healthy volunteers, Cmax occurred at 5 to 15 minutes. The absolute bioavailability of inhaled umeclidinium was on average 13% of the dose, with negligible contribution from oral absorption. Following repeat dosing of inhaled umeclidinium, steady state was achieved within 7 to 10 days with 1.5 to 1.8-fold accumulation. Vilanterol Following inhaled administration of vilanterol in healthy volunteers, Cmax occurred at 5 to 15 minutes. The absolute bioavailability of inhaled vilanterol was 27%, with negligible contribution from oral absorption. Following repeat dosing of inhaled vilanterol, steady state was achieved within 6 days with up to 2.4-fold accumulation. Distribution Umeclidinium Following intravenous administration to healthy volunteers, the mean volume of distribution was 86 litres. In vitro plasma protein binding in human plasma was on average 89%. Vilanterol Following intravenous administration to healthy volunteers, the mean volume of distribution at steady state was 165 litres. In vitro plasma protein binding in human plasma was on average 94%. Biotransformation Umeclidinium In vitro studies showed that umeclidinium is primarily metabolised by cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (glucuronidation, etc), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low. Vilanterol In vitro studies showed that vilanterol is primarily metabolised by cytochrome P450 3A4 (CYP3A4) and is a substrate for the P-gp transporter. The primary metabolic routes for vilanterol are O-dealkylation to a range of metabolites with significantly reduced beta1- and beta2-adrenergic agonist activity. Plasma metabolic profiles following oral administration of vilanterol in a human radiolabel study were consistent with high first-pass metabolism. Systemic exposure to the metabolites is low. Elimination Umeclidinium Plasma clearance following intravenous administration was 151 litres/hour. Following intravenous administration, approximately 58% of the administered radiolabelled dose (or 73% of the recovered radioactivity) was excreted in faeces by 192 hours post-dose. Urinary elimination accounted for 22% of the administered radiolabelled dose by 168 hours (27% of recovered radioactivity). The excretion of the drug-related material in the faeces following intravenous dosing indicated secretion into the bile. Following oral administration to healthy male volunteers, total radioactivity was excreted primarily in faeces (92% of the administered radiolabelled dose or 99% of the recovered radioactivity) by 168 hours post-dose. Less than 1% of the orally administered dose (1% of recovered radioactivity) was excreted in urine, suggesting negligible absorption following oral administration. Umeclidinium plasma elimination half-life following inhaled dosing for 10 days averaged 19 hours in healthy volunteers, with 3% to 4% excreted unchanged in urine at steady-state. Vilanterol Plasma clearance of vilanterol following intravenous administration was 108 litres/hour. Following oral administration of radiolabelled vilanterol, mass balance showed 70% of the radiolabel in urine and 30% in faeces. Primary elimination of vilanterol was by metabolism followed by excretion of metabolites in urine and faeces. Vilanterol plasma elimination half-life following inhaled dosing for 10 days averaged 11 hours. Characteristics in specific groups of healthy volunteers or patients Elderly A population pharmacokinetic analysis showed that pharmacokinetics of umeclidinium and vilanterol were similar between COPD patients 65 years and older and those younger than 65 years of age. Renal impairment Patients with severe renal impairment showed no evidence of an increase in systemic exposure to either umeclidinium or vilanterol (Cmax and AUC) following administration of umeclidinium/vilanterol with umeclidinium at twice the recommended dose and vilanterol at the recommended dose and no evidence of altered protein binding between patients with severe renal impairment and healthy volunteers. Hepatic impairment Patients with moderate hepatic impairment (Child-Pugh Class B) showed no evidence of an increase in systemic exposure to either umeclidinium or vilanterol (Cmax and AUC) following administration of umeclidinium/vilanterol with umeclidinium at twice the recommended dose and vilanterol at the recommended dose and no evidence of altered protein binding between patients with moderate hepatic impairment and healthy volunteers. Umeclidinium/vilanterol has not been evaluated in patients with severe hepatic impairment. Other special populations A population pharmacokinetic analysis showed that no dose adjustment is required for umeclidinium or vilanterol based on the effect of age, race, gender, inhaled corticosteroid use, or weight. A study in CYP2D6 poor metabolisers showed no evidence of a clinically significant effect of CYP2D6 genetic polymorphism on systemic exposure to umeclidinium. 5.3 Preclinical safety data In nonclinical studies with umeclidinium and vilanterol, alone and in combination, findings were those typically associated with the primary pharmacology of either muscarinic receptor antagonists or beta2-adrenergic agonists respectively and/or local irritancy. The following statements reflect studies conducted on the individual components. Genotoxicity and carcinogenicity Umeclidinium was not genotoxic in a standard battery of studies and was not carcinogenic in lifetime inhalation studies in mice or rats at exposures ≥ 26 or ≥ 22-fold, times the human clinical exposure of umeclidinium 55 micrograms, based on AUC, respectively. In genetic toxicity studies, vilanterol (as alpha-phenylcinnamate) and triphenylacetic acid were not genotoxic indicating that vilanterol (as trifenatate) does not represent a genotoxic hazard to humans. Consistent with findings for other beta2-adrenergic agonists, in lifetime inhalation studies, vilanterol trifenatate caused proliferative effects in the female rat and mouse reproductive tract and in the rat pituitary gland. There was no increase in tumour incidence in rats or mice at exposures 0.5- or 13-fold, times the human clinical exposure of vilanterol 22 micrograms based on AUC, respectively. Reproductive toxicity Umeclidinium was not teratogenic in rats or rabbits. In a pre- and post-natal study, subcutaneous administration of umeclidinium to rats resulted in lower maternal body weight gain and food consumption and slightly decreased pre-weaning pup body weights in dams given 180 micrograms/kg/day dose (approximately 80-times the human clinical exposure of umeclidinium 55 micrograms, based on AUC). Vilanterol was not teratogenic in rats. In inhalation studies in rabbits, vilanterol caused effects similar to those seen with other beta2-adrenergic agonists (cleft palate, open eyelids, sternebral fusion and limb flexure/malrotation) at 6-times the human clinical exposure based on AUC. When given subcutaneously there were no effects at 36-times the human clinical exposure of vilanterol 22 micrograms, based on AUC. 6. Pharmaceutical particulars 6.1 List of excipients Lactose monohydrate, Magnesium stearate. 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years In-use shelf-life: 6 weeks 6.4 Special precautions for storage Do not store above 30°C. If stored in a refrigerator allow the inhaler to return to room temperature for at least an hour before use. Keep the inhaler inside the sealed tray to protect from moisture and only remove immediately before first use. 6.5 Nature and contents of container The ELLIPTA inhaler consists of a light grey body, red mouthpiece cover and a dose counter, packed into a foil laminate tray containing a desiccant packet. The tray is sealed with a peelable foil lid. The inhaler contains two aluminium foil laminate blisters of 7 or 30 doses. The inhaler is a multi-component device composed of polypropylene, high density polyethylene, polyoxymethylene, polybutylene terephthalate, acrylonitrile butadiene styrene, polycarbonate and stainless steel. Pack sizes of 7 or 30 dose inhalers. Multipack of 3 x 30 dose inhalers. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements. For instructions for handling, see section 4.2. 7. Marketing authorisation holder Glaxo Group Limited 980 Great West Road Brentford Middlesex TW8 9GS United Kingdom 8. Marketing authorisation number(s) EU/1/14/898/001 EU/1/14/898/002 EU/1/14/898/003 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 8 May 2014 10. Date of revision of the text Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 慢性阻塞性肺病新复方药Anoro获欧盟批准 2014年5月9日，葛兰素史克（GSK）新复方药Anoro Ellipta（umeclidinium/vilanterol，UMEC/VI，55mcg/22mcg）获欧盟委员会（EC）批准，作为每日一次的维持治疗用支气管扩张剂，用于缓解慢性阻塞性肺病（COPD）患者的症状。GSK预计将于2014年第二至第三季度在欧洲推出Anoro Ellipta。 Anoro Ellipta的获批，是基于UMEC/VI 关键性III期项目的数据，该项目包括7项III期临床试验，涉及近6000例COPD患者。 Anoro Ellipta结合了2种长效支气管扩张剂，是长效毒蕈碱受体拮抗剂（LAMA）UMEC（umeclidinium）和长效β2受体激动剂（LABA）维兰特罗(VI，vilanterol)的复方药，通过新型干粉吸入器Ellipta给药。 UMEC/VI是葛兰素史克的一个独特产品，于2013年12月获FDA批准以商品名Anoro Ellipta上市，作为每日一次的吸入性疗法，用于慢性阻塞性肺病（COPD）患者的长期维持治疗，包括慢性支气管炎和肺气肿。Anoro Ellipta不适用于急性支气管痉挛（acute bronchospasm）的缓解或哮喘（asthma）的治疗。 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
