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Eklira Genuair(aclidinium bromide)-阿地溴铵吸入性粉剂
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 (see details below). United Kingdom Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard. 4.9 Overdose High doses of aclidinium bromide may lead to anticholinergic signs and symptoms. However, single inhaled doses up to 6,000 µg aclidinium bromide have been administered to healthy subjects without systemic anticholinergic adverse effects. Additionally, no clinically relevant adverse effects were observed following 7-day twice daily dosing of up to 800 µg aclidinium bromide in healthy subjects. Acute intoxication by inadvertent medicinal product ingestion of aclidinium bromide is unlikely due to its low oral bioavailability and the breath-actuated dosing mechanism of the Genuair inhaler. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Anticholinergics; ATC Code: R03BB05. Aclidinium bromide is a competitive, selective muscarinic receptor antagonist (also known as an anticholinergic), with a longer residence time at the M3 receptors than the M2 receptors. M3 receptors mediate contraction of airway smooth muscle. Inhaled aclidinium bromide acts locally in the lungs to antagonise M3 receptors of airway smooth muscle and induce bronchodilation. Nonclinical in vitro and in vivo studies showed rapid, dose-dependent and long-lasting inhibition by aclidinium of acetylcholine-induced bronchoconstriction. Aclidinium bromide is quickly broken down in plasma, the level of systemic anticholinergic side effects is therefore low. Pharmacodynamic effects Clinical efficacy studies showed that Eklira Genuair provided clinically meaningful improvements in lung function (as measured by the forced expiratory volume in 1 second [FEV1]) over 12 hours following morning and evening administration, which were evident within 30 minutes of the first dose (increases from baseline of 124-133 mL). Maximal bronchodilation was achieved within 1-3 hours after dosing with mean peak improvements in FEV1 relative to baseline of 227-268 mL at steady-state. Cardiac electrophysiology No effects on QT interval (corrected using either the Fridericia or Bazett method or individually-corrected) were observed when aclidinium bromide (200 µg or 800 µg) was administered once daily for 3 days to healthy subjects in a thorough QT study. In addition, no clinically significant effects of Eklira Genuair on cardiac rhythm were observed on 24-hour Holter monitoring after 3 months treatment of 336 patients (of whom 164 received Eklira Genuair 322 µg twice daily). Clinical Efficacy The Eklira Genuair Phase III clinical development programme included 269 patients treated with Eklira Genuair 322 µg twice daily in one 6-month randomised, placebo-controlled study and 190 patients treated with Eklira Genuair 322 µg twice daily in one 3-month randomised, placebo-controlled study. Efficacy was assessed by measures of lung function and symptomatic outcomes such as breathlessness, disease-specific health status, use of rescue medication and occurrence of exacerbations. In the long-term safety studies, Eklira Genuair was associated with bronchodilatory efficacy when administered over a 1-year treatment period. Bronchodilation In the 6-month study, patients receiving Eklira Genuair 322 µg twice daily experienced a clinically meaningful improvement in their lung function (as measured by FEV1). Maximal bronchodilatory effects were evident from day one and were maintained over the 6-month treatment period. After 6 months treatment, the mean improvement in morning pre-dose (trough) FEV1 compared to placebo was 128 mL (95% CI=85-170; p<0.0001). Similar observations were made with Eklira Genuair in the 3 month study. Disease-Specific Health Status and Symptomatic Benefits Eklira Genuair provided clinically meaningful improvements in breathlessness (assessed using the Transition Dyspnoea Index [TDI]) and disease-specific health status (assessed using the St. George's Respiratory Questionnaire [SGRQ]). The Table below shows symptom relief obtained after 6 months treatment with Eklira Genuair.
Pooled efficacy analysis of the 6-month and 3-month placebo controlled studies demonstrated a statistically significant reduction in the rate of moderate to severe exacerbations (requiring treatment with antibiotics or corticosteroids or resulting in hospitalisations) with aclidinium 322 µg twice daily compared to placebo (rate per patient per year: 0.31 vs 0.44 respectively; p=0.0149). Exercise tolerance In a 3-week crossover, randomised, placebo-controlled clinical study Eklira Genuair was associated with a statistically significant improvement in exercise endurance time in comparison to placebo of 58 seconds (95% CI=9-108; p=0.021; pre-treatment value: 486 seconds). Eklira Genuair statistically significantly reduced lung hyperinflation at rest (functional residual capacity [FRC]=0.197 L [95% CI=0.321, 0.072; p=0.002]; residual volume [RV]=0.238 L [95% CI=0.396, 0.079; p=0.004]) and also improved trough inspiratory capacity (by 0.078 L; 95% CI=0.01, 0.145; p=0.025) and reduced dyspnoea during exercise (Borg scale) (by 0.63 Borg units; 95% CI=1.11, 0.14; p=0.012). Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Eklira Genuair in all subsets of the paediatric population in COPD (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Absorption Aclidinium bromide is rapidly absorbed from the lung, achieving maximum plasma concentrations within 5 minutes of inhalation in healthy subjects, and normally within the first 15 minutes in COPD patients. The fraction of the inhaled dose that reaches the systemic circulation as unchanged aclidinium is very low at less than 5%. Peak plasma concentrations achieved after dry powder inhalation by COPD patients of single doses of 400 µg aclidinium bromide were approximately 80 pg/mL. Steady-state plasma levels were attained within seven days of twice daily dosing and considering the short half life, steady-state may be reached soon after the first dose. No accumulation on repeat dosing was observed at steady-state. Distribution Whole lung deposition of inhaled aclidinium bromide via the Genuair inhaler averaged approximately 30% of the metered dose. The plasma protein binding of aclidinium bromide determined in vitro most likely corresponded to the protein binding of the metabolites due to the rapid hydrolysis of aclidinium bromide in plasma; plasma protein binding was 87% for the carboxylic acid metabolite and 15% for the alcohol metabolite. The main plasma protein that binds aclidinium bromide is albumin. Biotransformation Aclidinium bromide is rapidly and extensively hydrolysed to its pharmacologically inactive alcohol- and carboxylic acid-derivatives. The hydrolysis occurs both chemically (non-enzymatically) and enzymatically by esterases, butyrylcholinesterase being the main human esterase involved in the hydrolysis. Plasma levels of the acid metabolite are approximately 100-fold greater than those of the alcohol metabolite and the unchanged active substance following inhalation. The low absolute bioavailability of inhaled aclidinium bromide (<5%) is because aclidinium bromide undergoes extensive systemic and pre-systemic hydrolysis whether deposited in the lung or swallowed. Biotransformation via CYP450 enzymes plays a minor role in the total metabolic clearance of aclidinium bromide. In vitro studies have shown that aclidinium bromide at the therapeutic dose or its metabolites do not inhibit or induce any of the cytochrome P450 (CYP450) enzymes and do not inhibit esterases (carboxylesterase, acetylcholinesterase and butyrylcholinesterase). In vitro studies have shown that aclidinium bromide or the metabolites of aclidinium bromide are not substrates or inhibitors of P-glycoprotein. Elimination The terminal elimination half-life of aclidinium bromide is approximately 2 to 3 hours. Following intravenous administration of 400 µg radiolabelled aclidinium bromide to healthy subjects, approximately 1% of the dose was excreted as unchanged aclidinium bromide in the urine. Up to 65% of the dose was eliminated as metabolites in the urine and up to 33% as metabolites in the faeces. Following inhalation of 200 µg and 400 µg of aclidinium bromide by healthy subjects or COPD patients, the urinary excretion of unchanged aclidinium was very low at about 0.1% of the administered dose, indicating that renal clearance plays a minor role in the total aclidinium clearance from plasma. Linearity/non-linearity Aclidinium bromide demonstrated kinetic linearity and a time-independent pharmacokinetic behaviour in the therapeutic range. Pharmacokinetic/pharmacodynamic relationship Because aclidinium bromide acts locally in the lungs and is quickly broken down in plasma there is no direct relationship between pharmacokinetics and pharmacodynamics. Special populations Elderly patients The pharmacokinetic properties of aclidinium bromide in patients with moderate to severe COPD appear to be similar in patients aged 40–59 years and in patients aged ≥70 years. Therefore, no dose adjustment is required for elderly COPD patients. Hepatically-impaired patients No studies have been performed on hepatically-impaired patients. As aclidinium bromide is metabolised mainly by chemical and enzymatic cleavage in the plasma, hepatic dysfunction is very unlikely to alter its systemic exposure. No dose adjustment is required for hepatically-impaired COPD patients. Renally-impaired patients No significant pharmacokinetic differences were observed between subjects with normal renal function and subjects with renal impairment. Therefore, no dose adjustment and no additional monitoring are required for renally-impaired COPD patients. 5.3 Preclinical safety data Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential and toxicity to reproduction and development. Effects in nonclinical studies with respect to cardiovascular parameters (increased heart rates in dogs), reproductive toxicity (fetotoxic effects), and fertility (slight decreases in conception rate, number of corpora lutea, and pre- and post-implantation losses) were observed only at exposures considered sufficiently in excess of the maximum human exposure indication to be of little relevance to clinical use. The low toxicity observed in nonclinical toxicity studies is in part due to rapid metabolism of aclidinium bromide in plasma and the lack of significant pharmacological activity of the major metabolites. The safety margins for human systemic exposure with 400 µg twice daily over the no observed adverse effect levels in these studies ranged from 17- to 187-fold. 6. Pharmaceutical particulars 6.1 List of excipients Lactose monohydrate. 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. To be used within 90 days of opening the pouch. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. Keep the Genuair inhaler inside the pouch until the administration period starts. 6.5 Nature and contents of container The inhaler device is a multicomponent device made of polycarbonate, acrylonitrile-butadiene-styrene, polyoxymethylene, polyester-butylene-terephthalate, polypropylene, polystyrene and stainless steel. It is white-coloured with an integral dose indicator and a green dosage button. The mouthpiece is covered with a removable green protective cap. The inhaler is supplied in a plastic laminate pouch, placed in a cardboard carton. Carton containing 1 inhaler with 30 unit doses. Carton containing 1 inhaler with 60 unit doses. Carton containing 3 inhalers each with 60 unit doses. 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 use please see section 4.2. 7. Marketing authorisation holder AstraZeneca AB SE-151 85 Södertälje Sweden 8. Marketing authorisation number(s) EU/1/12/778/001 EU/1/12/778/002 EU/1/12/778/003 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 20 July 2012 10. Date of revision of the text 28th April 2015 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu Eklira Genuair (aclidinium bromide) is the second inhaled long-acting anticholinergic to be licensed for the maintenance treatment of COPD PHARMACOLOGY Aclidinium bromide is a competitive, selective muscarinic receptor antagonist, with a longer residence time at M3 receptors than M2 receptors. M3 receptors mediate contraction of smooth muscle in the airways; thus, the activity of inhaled aclidinium bromide at these receptors induces bronchodilation. Once absorbed, aclidinium bromide is rapidly broken down in the plasma, resulting in minimal systemic anticholinergic side-effects. CLINICAL STUDIES The efficacy and safety of aclidinium bromide in the maintenance treatment of COPD was investigated in two randomised, placebo-controlled, double-blind phase III studies of similar design: the ACCORD COPD I study (n=561) assessed patients over 12 weeks and the ATTAIN study (n=828) evaluated patients over 24 weeks.2,3 In both studies, patients with moderate to severe COPD were randomised (1:1:1) to receive twice-daily doses of aclidinium bromide 200 microgram, 400 microgram or placebo, all administered using a proprietary dry powder inhaler (Genuair).2,3 Investigators used the change from baseline in trough forced expiratory volume in one second (FEV1) as the primary efficacy endpoint. Peak FEV1 at trial end was the secondary endpoint. To evaluate the effect of treatment on quality of life, investigators measured health status using the St George’s Respiratory Questionnaire (SGRQ). In addition, clinical COPD symptoms were assessed using the Transitional Dyspnoea Index (TDI).2,3 At trial end, the 400 microgram twice-daily metered dose of aclidinium bromide (which corresponds to a delivered dose of 322 microgram aclidinium) provided a significant improvement from baseline in mean trough FEV1 compared with placebo: 124ml in the ACCORD COPD I study and 128ml in the ATTAIN study (p<0.0001 for both). Peak FEV1 was also significantly increased: by 192ml and 209ml, respectively (p<0.0001 for both). Clinically meaningful improvements in SGRQ score (≥4 point decrease from baseline) and TDI (≥1 unit increase from baseline) were observed for both doses in both studies (p<0.001 for all comparisons). Also, patients in both studies treated with the 400 microgram twice-daily dose had a reduced need for rescue medication by an average of around one inhalation per day over the treatment period.2,3 In a pooled analysis of the two trials, the 400 microgram twice-daily dose significantly reduced the rate of moderate to severe exacerbations (ie, those requiring hospitalisation or treatment with antibiotics or corticosteroids) compared with placebo (0.31 vs 0.44 per patient per year; p=0.0149).1 Aclidinium bromide was well tolerated in both studies, with most adverse events being mild to moderate in severity. The most commonly observed side-effect in all groups was exacerbation of COPD symptoms. The incidence of anticholinergic side-effects was similar across all treatment arms. Other effects reported more commonly in patients who received aclidinium bromide included headache, diarrhoea, cough, rhinitis and nasopharyngitis. In a study in healthy individuals, inhalation of aclidinium bromide 200 or 800 microgram once daily for 3 days had no clinically significant effects on QT interval. Additionally, no effects on cardiac rhythm were seen in a 3-month study using a dose of 400 microgram twice daily. As with other inhaled therapies, aclidinium bromide can cause paradoxical bronchospasm; if this occurs, treatment should be stopped and alternative therapy considered. Owing to its anticholinergic properties, aclidinium bromide should be used with caution in patients with BPH, bladder-neck obstruction or narrow-angle glaucoma.1 Aclidinium bromide is presented in the Genuair device, which provides confirmation to the patient of successful inhalation. It also includes a dose indicator, a safety mechanism to prevent double dosing and an end-of-dose lockout mechanism to prevent。 英国上市和德国上市
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