Approval date: March 12, 2018
Umedium bromide vilanterol inhalation powder instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Umethyllium bromide vilanterol inhalation powder nebulizer
Trade name: Oraxin/ANORO
English name: Umeclidinium Bromide and Vilanterol Trifenatate Powder for Inhalation
Hanyu Pinyin: Wumeixiu’an Weilanteluo Xirufenwuji
Ingredients
This product is a compound preparation, the active ingredients of which are Wumeixiu’an Weilanteluo and Vilanterol Trifenatate.
Active ingredient: Umethyllium bromide
Chemical name: 1-[2-(benzyloxy)ethyl]-4-(hydroxydiphenylmethyl)-1-nitrogen cationic bicyclo[2.2.2]bromooctane
Chemical structure formula.
Molecular formula: C29H34NO2-Br
Molecular weight: 508.5
Active ingredient: Vilanterol triphenylacetate
Chemical name: triphenylacetic acid-4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol
Chemical structure formula.
Molecular formula: C24H33Cl2NO5-C20H16O2
Molecular weight: 774.8
Excipients: lactose (C12H22O11-H2O), magnesium stearate.
Characteristic】
The product is a multi-dose powder inhaler, Umedium bromide and Villanterol triacetate are sealed in two aluminum foil strips in the form of vesicles and placed in the powder inhaler (ELLIPTA), the contents of the vesicles are white powder.
Indications
It is suitable for the long-term maintenance treatment of chronic obstructive pulmonary disease (COPD) and is used once a day to relieve the symptoms of COPD patients.
Specification
Umethyllium bromide (as Umethyllium) 62.5μg and Vilanterol triacetate (as Vilanterol) 25μg.
Dosage and Administration
Usage
This product is for oral inhalation only.
Dosage
Adults
The recommended dose is 62.5μg/25μg of this product per inhalation, once daily.
This product should be administered at the same time each day, once daily, to maintain the bronchodilator effect. The maximum dose is 62.5 μg/25 μg per inhalation, once daily.
Special Groups
Children and adolescents
This product is not indicated for use in children and adolescents.
Geriatric patients
No dose adjustment is required in patients older than 65 years of age (see [Pharmacokinetics]).
Patients with renal insufficiency
No dose adjustment is required in patients with renal insufficiency (see [Pharmacokinetics]).
Patients with hepatic insufficiency
No dose adjustment is required in patients with mild or moderate hepatic insufficiency. The dosing of this product has not been studied in patients with severe hepatic insufficiency and should be used with caution (see [Pharmacokinetics]).
[Adverse Reactions].
Safety Summary
The most frequently reported adverse reaction to umebramine/vilanterol was nasopharyngitis (9%).
Summary of the list of adverse reactions
Clinical trial data
The safety profile of this product is based on safety data from its clinical development program, a clinical research program including 6,855 COPD patients with umebramonium/vilanterol and individual active ingredients. The program included 2354 patients who received once-daily umebramonium/vilanterol in a 24-week or longer Phase III clinical study, of whom 1296 received a therapeutic dose of 62.5 μg/25 μg in the 24-week study, 832 received a higher dose of 125 μg/25 μg in the 24-week study, and 226 patients received 125 μg/25 μg in the 12-month study received 125 μg/25 μg.
The frequency of adverse reactions identified in the table below is derived from the crude incidence observed after pooling the five 24-week studies and one 12-month safety study.
Adverse reaction frequencies are defined as follows: 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) and unknown (not assessable from available data).
Systemic Organ Classification Adverse Reaction Frequency Infection and Infestation Urinary Tract Infection
Sinusitis
nasopharyngitis
pharyngitis
Upper respiratory tract infections common
Common
Common
Common
Common immune system disorders allergic reactions, including
Rash
Rapid onset allergic reactions, angioedema, urticaria
Uncommon
Rare neurological headache
Tremor
Taste disorders common
Uncommon
Uncommon Eye disorders Blurred vision
Glaucoma
Elevated intraocular pressure rare
Rare
Rare Cardiovascular system Atrial fibrillation
Supraventricular tachycardia
Ventricular autonomic rhythm
Tachycardia
Supraventricular extrasystoles
Palpitations uncommon
Uncommon
Uncommon
Uncommon
Uncommon
Uncommon Respiratory, thoracic and mediastinal
Cough
Oropharyngeal pain
Paradoxical bronchospasm common
Common
Rare Gastrointestinal constipation
Dry mouth common
Common Skin and subcutaneous tissue rash Uncommon Renal and urinary tract disorders Urinary retention
Difficulty in urination
Bladder outlet obstruction rare
Rare
Rare
Other adverse reactions in clinical trials listed in the instructions for other countries that are not exporters include: lower respiratory tract infection, neck pain, limb pain, back pain, chest pain, diarrhea, cough, dyspepsia, abdominal pain, gastroesophageal reflux disease, vomiting, musculoskeletal pain in the chest, chest discomfort, malaise, ventricular extrasystoles, myocardial infarction, pruritus and conjunctivitis; arthralgia, nausea, vertigo, pleuritic pain, viral respiratory tract infections, toothache and diabetes.
Postmarketing Safety Information
MedDRA
Systemic Organ Classification Adverse Reaction Frequency Immune System Disorders Allergic reactions include:
Skin rash
Rapid onset allergic reactions, angioedema, urticaria
Uncommon
Rare psychiatric disorders anxiety uncommon neurological disorders tremor
Taste disorders uncommon
Uncommon eye disorders blurred vision
Glaucoma
Elevated intraocular pressure rare
Rare
Rare heart disease Palpitations
Uncommon respiratory, thoracic and mediastinal disorders Paradoxical bronchospasm
Vocal difficulties rare
Rare skeletal and connective tissue muscle spasms Uncommon renal and urinary disorders urinary retention
Difficulty in urination rare
Rare
Contraindications
Contraindicated in patients with hypersensitivity to the active ingredient in this product or to any of the excipients.
Contraindicated in patients with severe milk protein hypersensitivity.
Precautions]
Asthma
The safety and efficacy of this product have not been established in patients with asthma. This product is contraindicated in the treatment of asthma.
Disease progression and acute exacerbations
This product should not be used during acute deterioration of COPD or during potentially life-threatening exacerbations. This product has not been studied in subjects with rapidly deteriorating COPD and is not indicated for use in such patients.
This product is contraindicated for the relief of acute symptoms, i.e., as remedial therapy for an acute attack of bronchospasm. It has not been studied for the relief of acute symptoms and additional doses should not be administered in this setting. Inhaled short-acting beta2-agonists should be administered for treatment of acute symptoms if they occur.
Patients who have been receiving oral or inhaled short-acting beta2-agonists on a regular basis (e.g., four times a day) should discontinue these medications when starting treatment with this product and use them only when needed to relieve acute respiratory symptoms. When prescribing this product, the healthcare provider should also prescribe and instruct the patient on the use of an inhaled short-acting beta2-agonist. An increase in the frequency of inhaled short-acting beta2-agonist use may indicate worsening disease and require prompt medical treatment.
COPD can deteriorate rapidly over a few hours or slowly over several days or even longer. If the product does not continue to control the symptoms of bronchial stenosis; if the patient’s inhaled short-acting beta2-agonist fails; or if the patient is using short-acting beta2-agonists more often than before, this may indicate disease progression. In this case, the patient should be immediately re-evaluated and COPD therapy should be initiated. Increasing the daily dose of this product above the recommended dose is not appropriate in this situation.
Overdose and combination with other long-acting beta2 agonists
The frequency and dose of this product should not exceed the recommended values, and it should not be combined with other LABA-containing drugs (which may lead to overdose). There have been reports of clinically significant cardiovascular effects and death due to overuse of inhaled sympathomimetic drugs. Patients using this product should not be co-administered with another LABA-containing drug (e.g., salmeterol, formoterol fumarate, albuterol tartrate, indacaterol) for any reason.
Interaction with potent cytochrome P450 3A4 inhibitors
Caution is required when combining this product with long-term ketoconazole and other known potent cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, vinblastomycin, voriconazole) because of the potential for increased cardiovascular adverse effects (see [ Drug Interactions]).
Paradoxical bronchospasm
As with other inhaled drugs, this product can cause paradoxical bronchospasm, which can be life-threatening. If paradoxical bronchospasm develops after inhalation of this product, it should be treated immediately with an inhaled short-acting bronchodilator; discontinue the product immediately and take alternative therapy.
Allergic reactions
Allergic reactions, such as tachyphylaxis, angioedema, rash and urticaria, may occur after inhalation of this product. If these symptoms occur, the product should be discontinued. Allergic reactions have been reported in patients with severe milk protein allergy after inhalation of other lactose-containing powders; therefore, this product is contraindicated in patients with severe milk protein allergy.
Cardiovascular effects
As with other beta2-agonists, vilanterol may cause clinically significant cardiovascular effects in some patients, as measured by increased pulse rate, diastolic and systolic blood pressure, or increased symptoms. If such effects occur, the product should be discontinued. In addition, electrocardiographic changes (e.g., flattening of the T wave, prolongation of the QTc interval, and downward shift of the ST segment) have been reported with β-agonists, but the clinical significance of these effects is not known.
Therefore, this product should be used with caution in patients with cardiovascular disease (especially with coronary insufficiency, arrhythmias and hypertension).
Comorbidities
This product has sympathomimetic amine-like effects and should be used with caution in patients with convulsive disorders, hyperthyroidism, and sensitivity to sympathomimetic amines. Exacerbation of preexisting diabetes mellitus and ketoacidosis has been reported after intravenous administration of the related beta2-adrenoceptor agonist salbutamol.
Exacerbation of closed-angle glaucoma
This product should be used with caution in patients with closed-angle glaucoma. Both physicians and patients should be alert for signs and symptoms of acute closed-angle glaucoma (e.g., ocular pain or discomfort, blurred vision, visual halos or colored images associated with red eye due to conjunctival congestion, corneal edema). If a patient develops any of these signs or symptoms, he or she should consult a physician immediately.
Worsening of urinary retention
This product should be used with caution in patients with urinary retention. Both physicians and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty urinating, painful urination), especially in patients with an enlarged prostate or bladder neck obstruction. If a patient develops any of these signs or symptoms, he or she should consult a physician immediately.
Hypokalemia and hyperglycemia
Beta-adrenergic agonists may cause significant hypokalemia in some patients via intracellular shunts, which can have potentially adverse cardiovascular effects. The reduction in serum potassium is usually transient and does not require supplementation. beta-Agonists may cause transient hyperglycemia in some patients. This product was evaluated in four 6-month clinical trials and no therapeutic effects on blood glucose or blood potassium were found in subjects with COPD.
Effects on driving and mechanical handling ability
Umedium/Vilanterol had no or negligible effects on driving or mechanical handling.
Pregnant women and nursing mothers
Pregnant women
There are no data on the use of Umethrin/Vilanterol in pregnant women. Animal studies have shown no clinical relevance for reproductive toxicity after administration of vilanterol exposure (see [Pharmacologic Toxicology]).
Umethrin/Vilanterol should not be used during pregnancy unless the expected benefit of the drug to the mother outweighs the potential risk to the fetus.
Lactation
It is not known whether umebramonium or vilanterol is secreted in human breast milk. However, other beta2-adrenoceptor agonists can be detected in human breast milk. The risk to the newborn/infant cannot be excluded. The benefit of breastfeeding to the infant and the benefit of treatment to the mother must be considered when deciding whether to discontinue breastfeeding or to discontinue treatment with umebramonium/vilanterol.
Fertility
There are no data on the effects of umebramonium/vilanterol on human fertility. Animal studies have shown no effect of umebramonium or vilanterol on fertility.
Pediatric Use]
This product is contraindicated in children. The safety and efficacy of this product have not been established in pediatric patients.
Geriatric Use]
See [Dosage].
Drug Interactions
Beta-adrenergic receptor blockers
Drugs containing β-adrenoceptor blockers may attenuate or antagonize the effects of β2-adrenoceptor agonists (e.g., vilanterol). Concomitant use of non-selective or selective beta-adrenoceptor blockers should be avoided unless there is a strong rationale for their combined use.
Metabolic and transporter-based interactions
Vilanterol is a substrate for cytochrome P450 3A4 (CYP3A4). The combination of potent CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, itraconazole, ritonavir, telithromycin) may inhibit the metabolism of vilanterol and increase its systemic exposure. Co-administration of ketoconazole (400 mg) in healthy subjects increased the mean AUC (0-t) and Cmax of vilanterol by 65% and 22%, respectively. The increase in vilanterol exposure was not associated with increased systemic effects on heart rate, potassium, or QT interval (corrected by the Fridericia method) associated with β-adrenoceptor agonists. Caution should be exercised when combining umebramine/verantelor with ketoconazole or other known potent CYP3A4 inhibitors because of the potential to increase systemic exposure to verantelor, making the potential for adverse reactions increased. Verapamil (an intermediate-acting CYP3A4 inhibitor) has no significant effect on the pharmacokinetics of vilanterol.
Umetabromine is a substrate for cytochrome P450 2D6 (CYP2D6). The steady-state pharmacokinetics of umebramine was evaluated in healthy subjects lacking CYP2D6 (weak metabolizers). At the 4-fold dose level, no effect on umebramine AUC or Cmax was seen. At the 8-fold dose level, an approximately 1.3-fold increase in umebramine AUC was observed, with no effect on umebramine Cmax. Based on the degree of variability in these data, there were no clinically relevant drug interactions expected when umebramonium/vilanterol was given in combination with CYP2D6 inhibitors or in patients genetically deficient in CYP2D6 activity (weak metabolizers).
Both umebramonium and vilanterol are substrates of the P-glycoprotein transporter (Pgp). The effect of the intermediate-acting P-gp inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics of umebramonium and vilanterol was evaluated in healthy subjects. No effect of verapamil on the Cmax of umebramide or verantelor was observed. An approximately 1.4-fold increase in the AUC of umebramine was observed, with no effect on the AUC of vilanterol. Based on the extent of change in these data, there were no clinically relevant drug interactions expected with the combination of umebramonium/vilanterol and Pgp inhibitors.
Other antimuscarinic or sympathomimetic agents
Umedium bromide/vilanterol has not been studied and is not recommended in combination with other long-acting muscarinic antagonists, long-acting beta2-adrenergic agonists, or preparations containing either because of the potential for increased adverse reactions to known inhaled muscarinic receptor antagonists or beta2-adrenergic agonists (see [Precautions] and [Overdose]).
Hypokalemia
Combination with methylxanthine derivatives, steroids, or non-potassium-protective diuretics for hypokalemia may enhance the possible hypokalemic effects of beta2-adrenoceptor agonists and should therefore be used with caution (see [Precautions]).
Other therapeutic agents for COPD
Although formal in vivo drug interaction studies have not been performed, umebramine/vilanterol has been used in combination with other COPD medications (including short-acting sympathomimetic bronchodilators) and inhaled glucocorticoids without clinical evidence of drug interactions.
[Drug overdose].
Overdose with umeclidinium/vilanterol may produce signs and symptoms caused by single-component effects consistent with known adverse reactions to inhaled muscarinic receptor antagonists (e.g., dry mouth, visual dysregulation, and tachycardia) or to other beta2-adrenergic agonists (e.g., arrhythmia, tremor, headache, palpitations, nausea, hyperglycemia, and hypokalemia).
If an overdose occurs, the patient should be treated with supportive care and appropriate monitoring if necessary.
Clinical trials]
The safety and efficacy of once-daily administration of umebramine/vilanterol were evaluated in eight phase III clinical studies in adult patients with clinically confirmed COPD; these included five 6-month efficacy studies (DB2113361, DB2113373, DB2113360, DB2113374, and ZEP117115), two 12-week exercise tolerance studies (DB2114417 and DB2114418) and 1 study of the safety of umebramine/vilanterol given during 12 months of treatment (DB2113359). The studies evaluated oral inhalation of umebramonium/vilanterol at 62.5 μg/25 μg and/or 125 μg/25 μg, both once a day. The efficacy results of umebramonium/vilanterol 62.5 μg/25 μg are reported below.
Placebo-controlled study
In a 6-month study (DB2113373), the 62.5 μg/25 μg dose of umebramonium/vilanterol resulted in a statistically significant improvement in lung function (defined as the difference in change from baseline in FEV1 trough values at 24 weeks) compared with placebo, as shown in Table 1. compared with placebo, umebramonium/vilanterol demonstrated a significant bronchodilator effect and was maintained throughout the 24-week treatment period.
Table 1. primary efficacy endpoints at 24 weeks of treatment (study DB2113373)
FEV1 trough (L) Difference from placebo Baseline
(SD) Change from Baseline (SE) Treatment Difference
(95% CI) p-value Study DB2113373 Umetabromine/Vilanterol
62.5 μg /25 μg OD
(n= 413)1.28
(0.56)0.17
(0.01)0.17(0.13,0.21)
<0.001 placebo
(n=280)1.20
(0.47)0.00
(0.02)-Abbreviations: CI = confidence interval; FEV1 = exertional expiratory volume in 1 second; L = liters; µg = micrograms; n = number of patients treated; OD = once daily; SD = standard deviation; SE = standard error.
Umedium bromide/vilanterol showed a statistically significant (0.24 L; p < 0.001) improvement from baseline values in weighted mean FEV1 at 0-6 hours after administration at 24 weeks of treatment compared to placebo.
Improvement in Transitional Dyspnea Index (TDI) scores at 24 weeks of treatment was statistically significant for both umebramine/vilanterol compared to placebo (1.2 units; p < 0.001). The minimum clinically important difference (MCID) response rate regarding the ³1-unit TDI score at week 24 was 58% (226/389) in patients treated with umebramine/vilanterol and 41% (106/260) in the placebo group.
The study also showed that compared with placebo, the response rate at 24 weeks of treatment with umebramonium/vilanterol was higher than that with the St. George’s Respiratory Questionnaire (SGRQ) total score, a disease-specific health status assessment tool, showed a statistically significant improvement (-5.51 units, p£0.001) from baseline values. Regarding the reduction of ³4 units (MCID) response rate in the total SGRQ score, it was 49% (188/381) in patients treated with umebramonium/vilanterol and 34% (86/254) in the placebo group.
In addition, patients treated with umebramonium/vilanterol required fewer emergency salbutamol treatments than those treated with placebo (mean statistically significant reduction of 0.8 sprays/day; p=0.001). Over the course of the 24-week study, the percentage of patients treated with umebramonium/vilanterol (mean 36.1%) was higher than placebo (mean 21.7%, respectively; no formal statistical analysis was performed for this endpoint) for those who did not require emergency drug therapy.
Umedium bromide/vilanterol 62.5 μg/25 μg treatment resulted in a lower risk of developing an acute exacerbation of COPD than placebo (analysis of time to first acute exacerbation; risk ratio (HR) 0.5, 95% CI=0.3 to 0.8, a 50% risk reduction, p=0.004).
Tiotropium control drug study
In studies ZEP117115 and DB2113360, patients treated with 62.5 μg/25 μg of umebramonium/vilanterol showed a statistically significant and clinically meaningful improvement in FEV1 trough to baseline ratio compared with tiotropium at week 24 (see Table 2). In study DB2113374, treatment with umebramonium/vilanterol 62.5 μg/25 μg showed a clinically significant improvement in the FEV1 trough to baseline ratio compared to tiotropium at 24 weeks (see Table 2).
Table 2. primary efficacy endpoints at 24 weeks (studies ZEP117115, DB2113360 and DB2113374)
FEV1 trough (L) Difference from baseline compared to tiotropium
(SD) difference from baseline (SE) treatment difference
(95% CI)
p-value study ZEP117115 Umetropium/Vilanterol 62.5µg /25µg OD (n=454)1.25(0.49)0.21(0.01)0.11 (0.08,0.14)
<0.001 Tiotropium 18µg OD (n=451)1.25(0.49)0.09(0.01)-Study DB2113360 Umetropium/Vilanterol 62.5µg /25µg OD (n=207)1.32(0.53)0.21(0.02)0.09 (0.04,0.14)
<0.001 Tiotropium bromide 18µg OD (n=203)1.29(0.53)0.12(0.02)-Study DB2113374 Umetropium/Vilanterol 62.5µg /25µg OD (n=217)1.16 (0.48)0.21 (0.02)0.06 (0.01, 0.11)0.018* Tiotropium Ammonium bromide 18µg OD (n=215) 1.16 (0.45) 0.15 (0.02) – Abbreviations: CI = confidence interval; FEV1 = exertional expiratory volume in 1 second; L = liters; µg = micrograms; n = number of patients treated; OD = once daily; SD = standard deviation; SE = standard error. * This comparative analysis cannot conclude a statistically significant difference because the pretest results in the specified stratification test did not reach a statistically significant difference.
In studies ZEP117115 and DB2113360, umeclidinium/vilanterol showed a statistically significant improvement of 0-6 hour weighted mean FEV1 over baseline values of 0.11 L and 0.07 L after administration at 24 weeks compared to tiotropium (p≤0.005), respectively. In study DB2113374, umeclidinium/vilanterol demonstrated a statistically significant improvement in 0-6 hour weighted mean FEV1 over baseline values (of 0.10 L) after administration at 24 weeks compared to tiotropium.
In studies DB2113360 and DB2113374, both umebramonium/vilanterol and tiotropium resulted in improvements in dyspnea (TDI time point score) and health-related quality of life (SGRQ) from baseline. In the 3rd positive control study (ZEP117115), the improvement in total SGRQ score from baseline at week 24 was more pronounced in the umebramonium/vilanterol treatment group compared with tiotropium, which was statistically different (2.10 units; p=0.006). In this study, the proportion of patients treated with umebramonium/vilanterol who had an effective ³4-unit reduction in total SGRQ score from baseline (MCID) was 53% (237/445) compared with 46% (196/430) in the tiotropium-treated group.
In study ZEP117115 and study DB2113360, there was a statistically significant reduction in the amount of salbutamol, the emergency drug required during weeks 1-24 of treatment with umebramonium/vilanterol, compared to tiotropium [0.5 sprays/day (p<0.001) and 0.7 sprays/day (p=0.022), respectively].
During the studies of ZEP117115, DB2113360 and DB2113374, the mean proportion of days without emergency medication decreased by 13.3%, 11.7% and 13.4% from baseline in patients treated with tiotropium, respectively; in contrast, the mean proportion of days without emergency medication decreased more significantly from baseline in patients treated with umebramonium/vilanterol. The mean percentage of days without emergency medication decreased more significantly than at baseline for patients treated with umebramonium/vilanterol (21.5%, 18.6%, and 17.6% in the three studies). However, no formal statistical analysis was performed for this endpoint.
In study ZEP117115, treatment with umebramine/vilanterol 62.5 μg/25 μg resulted in a reduced risk of acute exacerbation of COPD compared to tiotropium (analysis to time to first acute exacerbation: hazard ratio (HR) 0.5, 95% CI 0.3 to 1.0, 50% risk reduction, p=0.044).
Supportive 3-month exercise tolerance study
In two identical 12-week clinical studies, adult patients with COPD with pulmonary hyperinflation (functional residual air volume [FRC] >120% of predicted value) were evaluated for exercise tolerance with the Endurance Round Trip Walk Test (ESWT).
In study DB2114418, patients received 62.5 μg/25 μg of this product for 12 weeks and showed a statistically significant improvement in exercise tolerance time (EET) compared to placebo of 69.4 seconds at 3 hours after dosing in week 12 (p=0.003), respectively. An improvement in EET (compared to placebo) occurred the day after administration and was maintained at weeks 6 and 12. In the second study (DB2114417), no statistically significant improvement in EET was seen after treatment with 62.5 μg/25 μg of this product (21.9 seconds; p > 0.05).
In study DB2114418, the results showed that the change in FEV1 trough value relative to baseline at week 12 was a statistically significant improvement for this product over placebo (change of 0.24 L; p < 0.001); and the change in lung volume relative to baseline at week 12 was a statistically significant improvement for pre-dose and 3 hours post-dose compared to placebo (deep inspiratory volume: 0.24 L and 0.32 L, respectively). 0.24 L and 0.32 L, residual air volume: -0.47 L and 0.64 L, respectively, and functional residual air volume: -0.35 L and -0.52 L, respectively; p < 0.001 for all indices). In study DB2114417, the results showed that the change in FEV1 trough values relative to baseline at week 12 showed a clinically meaningful improvement over placebo (change of 0.21 L); at week 12, the change in lung volumes relative to baseline after and 3 hours after dosing improved over placebo (deep inspiratory volume: 0.20 L and 0.24 L, respectively, and residual air volume: 0.29 L and 0.35 L, respectively, and functional residual air volume: 0.24 L and 0.30 L, respectively).
Safety
Cardiac electrophysiology
In three clinical studies in which 53 patients were treated with umebramine/vilanterol 62.5 μg/25 μg and 281 patients were treated with umebramine/vilanterol 125 μg /25 μg, 24-hour Holter monitoring did not show clinically significant effects on cardiac rhythm. The three clinical studies included 53 patients with COPD in a 6-month clinical study treated with once-daily ubirome/vilanterol 62.5 μg/25 μg; 55 patients in another 6-month clinical study treated with once-daily ubirome/vilanterol 125 μg/25 μg; and 226 patients in a 12-month clinical study received once-daily treatment with umebramonium/vilanterol 125 μg /25 μg.
In a QT study with placebo and positive control (moxifloxacin), the effect of umebramonium/vilanterol 125 μg /25 μg on the QT interval was evaluated and no clinically relevant arrhythmogenic responses that might be associated with QT interval prolongation were seen.
A dose-dependent increase in heart rate was also observed. The maximum mean difference in baseline-corrected heart rate over placebo was seen at 8.4 beats/min (90% CI=7.0 to 9.8) and 20.3 beats/min (90% CI=18.9 to 21.7) 10 minutes after administration of 125 μg/25 μg and 500 μg/100 μg of umeclidinium/vilanterol, respectively.
Clinical trial data from China
DB2114634 was an international multicenter, randomized, double-blind, placebo-controlled, parallel-group study that enrolled 580 adult patients with clinically confirmed COPD, including 385 Chinese COPD patients. The study evaluated the efficacy and safety of 62.5 μg/25 μg and 125 μg/25 μg once daily for COPD treatment for 24 weeks. The efficacy results of 62.5 μg/25 μg of this product are as follows.
Pulmonary function (defined as the change from baseline in FEV1 trough values at 24 weeks of treatment) was significantly improved by 62.5 μg/25 μg of umebramine/vilanterol compared to placebo, with statistically significant improvements as shown in Table 3. The improvement in pulmonary function occurred earlier (day 2 of treatment) and persisted throughout the treatment period in patients treated with this product compared to placebo.
Table 3. primary efficacy endpoints at 24 weeks (study DB2114634, Chinese ITT population)
FEV1 trough (L) Difference from placebo Baseline
(SD) Change from baseline (SE) Treatment difference (95% CI)
P-value Umetabromine/Vilanterol 62.5 μg/25 μg OD
(n= 128) 0.99 (0.38) 0.20 (0.02) 0.17 (0.12,0.22)
<0.001 Placebo
(n=129)0.98 (0.32)0.03 (0.02) Abbreviations: CI = confidence interval; FEV1 = exertional expiratory volume in 1 second; L = liters; μg = micrograms; n = number of patients treated; OD = once daily; SD = standard deviation; SE = standard error.
Analysis of the TDI score (secondary endpoint) at week 24 showed a statistically significant improvement (1.1 units) observed with 62.5 μg/25 μg of this product compared to placebo. At all visits assessing TDI (weeks 4, 12 and 24), improvement in TDI score compared to placebo was at or above 1 unit of MCID. analysis of the proportion of those with validated TDI scores showed that the proportion of subjects with ≥1 unit of improvement was higher in the Benadryl-treated group than in the placebo group.
Analysis of the 0-6 hour weighted mean FEV1 (secondary endpoint) on day 1 confirmed that a statistically significant improvement was obtained with 62.5 μg/25 μg of this product compared to placebo.
In addition, a reduction in the use of the emergency drug salbutamol provided evidence of patient benefit. During weeks 1 to 24, 62.5 μg/25 μg of this product resulted in a 0.8 snap/day reduction in emergency medication use compared with placebo and an increase in the percentage of days without emergency medication use.
Treatment with this product also demonstrated a favorable effect in health-related quality of life compared to placebo. At weeks 4, 12, and 24, there was a clinically meaningful reduction in total SGRQ score from baseline (i.e., ≥4 units).
[Pharmacology and Toxicology].
Pharmacological effects
This product is a combination of Umethyllium bromide and Verantel. Umedium bromide is a long-acting muscarinic receptor antagonist, which exerts bronchodilator effects mainly by competitively inhibiting the binding of acetylcholine to M3-type muscarinic receptors on the smooth muscle of the respiratory tract.
Vilanterol is a selective long-acting β2-adrenergic receptor agonist that has an activating effect on intracellular adenylate cyclase, which catalyzes the conversion of ATP to cyclic-3′,5′-phosphate adenosine (cAMP), thereby increasing cAMP levels, relaxing bronchial smooth muscle and inhibiting the release of tachyphylaxis mediators from cells (especially mast cells).
Toxicological studies
Umetabromine
Genotoxicity: Ames test, in vitro mouse lymphoma test, in vivo rat micronucleus test were all negative.
Reproductive toxicity: No adverse effects of umebramonium bromide on fertility in rats were observed at the doses tested. Subcutaneous administration of umebramonium bromide to rats at 180 μg/kg/day (approximately 80 times the human exposure at the clinically recommended dose of 62.5 μg) resulted in increased maternal body weight, decreased food intake, and a slight decrease in fetal pre-weaning weight, with no perinatal toxicity associated with the administration. Umethrin may be secreted into rat milk, but whether it is secreted into human milk is unknown.
Carcinogenicity: In a 2-year carcinogenicity study, no treatment-related increase in tumor incidence was observed in rats and mice given ursodiol 137 and 295/200 μg/kg/day (male/female), respectively, by inhalation (exposure approximately 20 and 25/20 times the exposure at the maximum recommended adult clinical inhalation dose).
Vilanterol
Genotoxicity: Results of the Ames test, in vitro Syrian hamster embryonic cell transformation assay, in vitro DNA synthesis assay, and in vivo rat bone marrow micronucleus assay were negative, and results of the in vitro mouse lymphoma assay were inconclusive.
Reproductive toxicity: No significant effects on fertility were observed in male and female rats given vilanterol by inhalation at maximum doses of 31,500 and 37,100 μg/kg/day (approximately 12,000 and 14,500 times the clinically recommended dose based on adult body surface area). Inhalation administration of vilanterol to rabbits (at doses administered at exposures approximately 6 times the human clinical exposure) can cause embryo-fetal toxic effects similar to other β2 agonists, such as cleft palate, cleft eyelids, sternal fusion, and impaired limb flexion/rotation. Vilanterol given by inhalation or subcutaneous injection to female rabbits at doses of 5740 or 300 μg/kg/day, respectively (exposure approximately 450 times the clinically recommended inhalation dose for human exposure) can cause embryonic vertebral vertebral and metacarpal ossification insufficiency. No administration-related abnormalities were observed in rabbits given vilanterol by subcutaneous injection (exposure approximately 36 times the human exposure at the clinical dose of 22 μg). No embryo-fetal reproductive toxicity of vilanterol was observed in rats. No significant perinatal or postnatal developmental effects were observed in rats given vilanterol orally at 10,000 μg/kg/day (approximately 3900 times the maximum recommended human clinical dose based on body surface area). It is not known whether vilanterol is secreted into human milk, but other β2 agonists have been detected in human milk.
Carcinogenicity.
In a 2-year carcinogenicity test in mice, inhalation administration of vilanterol to females at 29500 μg/kg/day (7800 times the exposure at the maximum recommended human inhalation dose) caused an increase in the incidence of ovarian mesenchymal tubular adenomas, and no carcinogenicity was seen at a dose of 615 μg/kg/day (210 times the exposure at the maximum recommended human inhalation dose). In a 2-year carcinogenicity test in rats, inhalation administration of vilanterol to females at doses greater than or equal to 84.4 μg/kg/day (exposure greater than or equal to 20 times the maximum recommended human inhalation dose) caused a significant increase in ovarian tract smooth muscle tumors and shortened the latency period of pituitary tumors. No carcinogenicity was observed at an inhalation dose of 10.5 μg/kg/day (exposure approximately 1 times the maximum recommended human inhalation dose). The carcinogenicity of vilanterol in rodents is similar to that previously reported for other beta-adrenergic agonist drugs.
Compounding studies
Single-drug systemic exposures (AUC and Cmax) were similar or lower for the combined inhalation administration of umeclidinium and vilanterol compared to those administered alone. No incremental effect of the single drug in the combination on exposure to the other components was observed.
Combined administration toxicity tests of umebramine and vilanterol included 4-week inhalation toxicity in rats and dogs, 13-week repeat inhalation toxicity in dogs, and intravenous cardiovascular toxicity tests. No new toxicity was observed in the 4-week toxicity test in rats and dogs compared to the single agent, and a moderate irritation exacerbation effect was observed in the upper respiratory tract of rats. 13-week co-administration had similar cardiovascular effects to vilanterol alone in dogs, with reflex tachycardia and peripheral vasodilation associated with the pharmacological effects of the β2-agonist. Microscopically, mixed inflammatory cell infiltration of the canine laryngeal mucosa was observed, presumably related to the local irritability of the administered drug. In the above repeated administration toxicity test, no increase in systemic exposure was observed with co-administration compared to single drug.
Pharmacokinetics]
The pharmacokinetics of each component were similar to those observed when each active substance was administered alone when umebramine and vilanterol were administered in combination by the inhalation route. Therefore, the pharmacokinetics of each component can be considered separately.
Absorption
Umetabromine
After inhalation of umebramonium in healthy subjects, Cmax was reached at 5-15 min. the absolute bioavailability of inhaled umebramonium averaged 13% of the dose, with negligible absorption via the oral cavity. Steady state was reached within 7 to 10 days after multiple inhalations of umebramine, with a 1.5 to 1.8-fold accumulation.
Vilanterol
After inhalation administration of vilanterol to healthy subjects, Cmax occurs at 5-15 min. the absolute bioavailability of inhaled vilanterol is 27%, with negligible absorption via the oral cavity. After multiple inhalations of vilanterol, steady state was reached within 6 days, with a maximum accumulation of 2.4-fold.
Distribution
Umetabromine
After intravenous administration to healthy subjects, the mean volume of distribution was 86 liters. The mean in vitro human plasma protein binding was 89%.
Vilanterol
After intravenous administration to healthy subjects, the mean volume of distribution at steady state was 165 liters. In vitro human plasma protein binding averaged 94%.
Biotransformation
Umetabromine
In vitro studies have shown that umebramonium is primarily metabolized by cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The main metabolic pathway of umebramine is oxidation (hydroxylation, O-dealkylation) followed by conjugation (glucosylation, etc.), resulting in a series of metabolites with reduced pharmacological activity or undetermined pharmacological activity. Systemic exposure of metabolites is low.
Vilanterol
In vitro studies have shown that vilanterol is primarily metabolized by cytochrome P450 3A4 (CYP3A4) and is a substrate for the P-gp transporter. The major metabolic pathway of vilanterol is O dealkylation to produce a series of metabolites with markedly reduced β1 and β2 adrenoceptor agonist activity. In a radiolabeled human study, plasma metabolism following oral administration of vilanterol was characterized as consistent with a high first-pass effect. Systemic exposure of metabolites was low.
Elimination
Umetabromine.
The plasma clearance after intravenous administration was 151 L/h. Following intravenous administration, approximately 58% of the administered radiolabeled dose (or 73% of the recovered radioactivity) was excreted in the feces at 192 hours post-dose. Urinary excretion was 22% of the administered radiolabeled dose (27% of the recovered radioactivity) at 168 hours post-dose. Drug-related substances were excreted in the feces after intravenous administration, indicating that umebramine can be secreted into the bile. After oral administration in healthy male volunteers, total radioactivity was excreted mainly in the feces up to 168 hours after administration (92% of the administered radiolabeled dose or 99% of the recovered radioactivity). Less than 1% of the orally administered dose (1% of the recovered radioactivity) was excreted in the urine, indicating negligible absorption after oral administration. After 10 days of inhalation administration in healthy subjects, the plasma elimination half-life of vilanterol averaged 19 hours, with 3% to 4% of the prototype excreted in the urine at steady state.
Vilanterol
After intravenous administration, the plasma clearance of vilanterol was 108 L/h. After oral administration of radiolabeled vilanterol, mass balance showed 70% of the radiolabel in the urine and 30% in the feces. Elimination of vilanterol is primarily by metabolism, followed by excretion of metabolites in the urine and feces. The mean plasma elimination half-life of vilanterol after 10 days of inhalation administration was 11 hours.
Characteristics in Specific Healthy Subjects or Patients
Elderly
Population pharmacokinetic analysis showed that the pharmacokinetics of umebramine and vilanterol were similar in COPD patients 65 years of age and older compared to COPD patients younger than 65 years of age.
Renal insufficiency
There was no evidence of increased systemic exposure (Cmax and AUC) to umebramonium or vilanterol in patients with severe renal insufficiency following administration of umebramonium/vilanterol (twice the recommended dose for umebramonium and twice the recommended dose for vilanterol) and no evidence of altered protein binding in patients with severe renal insufficiency compared to healthy subjects.
Hepatic insufficiency
There was no evidence of increased systemic exposure (Cmax and AUC) to eumetronium or vilanterol in patients with moderate hepatic insufficiency (Child-Pugh category B) following administration of eumetronium/vilanterol (twice the recommended dose of eumetronium and the recommended dose of vilanterol) and no evidence of altered protein binding in patients with moderate hepatic insufficiency compared to healthy subjects. Umedium/vilanterol has not been evaluated in patients with severe hepatic insufficiency.
Other Special Populations
Population pharmacokinetic analysis indicates that no dose adjustment of umebramonium or vilanterol based on age, race, sex, inhaled glucocorticoid use, or body weight is required. A study in CYP2D6 weak metabolizers showed no evidence of a clinically significant effect of CYP2D6 genetic polymorphisms on systemic exposure to umebramine.
[Storage].
Seal and store in a dry place not exceeding 30°C. Store the inhaler in a sealed box to avoid moisture and remove only before starting use.
If refrigerated, bring the inhaler back to room temperature at least 1 hour before first use and store in a dry place not exceeding 30°C after use.
Package】
Each box contains 1 ELLIPTA, sealed in a composite aluminum foil box with a silica gel desiccant bag inside.
ELLIPTA has 2 built-in aluminum foil blister strips, each strip is arranged with 7 or 30 blisters, one strip contains Umetanium bromide (by Umetanium) 62.5 μg/blister, the other strip contains Vilanterol triacetate (by Vilanterol) 25 μg/blister.
7 syringes/box, 30 syringes/box.
【Expiration date】.
24 months.
Discard this product 6 weeks after opening the sealed box or when the counter reads “0” (all blisters have been used), whichever is earlier. The easy-to-use device must not be reused and disassembled.
Execution standard
Imported drug registration standard JX20160112.
Imported drug registration number
Imported drug registration certificate number: H20180005
【Manufacturing Company
Company Name: Glaxo Group Limited.
Company Address: 980 Great West Road, Brentford, Middlesex TW8 9GS, United Kingdom (UK)
Production
Production
Plant: Glaxo Operations UK Ltd.
Production Address: Priory Street, Ware, Hertfordshire, SG12 0DJ, United Kingdom (UK)
Address of office in China: 6th Floor, Metropolitan Headquarters Building, 168 Middle Xizang Road, Shanghai.
Postal Code: 200001
Telephone number: (86 21) 23019800
Fax number: (86 21) 23019801
GSK service hotline: 400-183-3383/800-820-3383
Trademarks are owned by or used under license by GlaxoSmithKline Group.
©[2017] GlaxoSmithKline Group or its licensors
[Guidance for use].
When using Enactor for the first time, no prior inspection or any special way of preparation is required. The easy-access device can be used immediately and directly. Just follow the instructions step by step.
The parts contained in the outer box of the easy-access device are shown in the figure below.
The easy-to-use device comes in a foil box. Open the foil box only when you are ready to inhale a dose of medication. When you are ready to use the device, remove the lid and open the foil box. The aluminum foil box contains a desiccant sachet for dehumidification. Discard this desiccant sachet – do not open, consume or inhale the desiccant.
When you remove the Enactor from the cassette, it is in the ‘off’ state. Only open the Enactor when you are ready to inhale a dose of medication.
Write down the “discard” date on the label space of the device. The “discard” date is 6 weeks after the date the foil cartridge is first opened. After this date, the inhaler should not be used again.
The following instructions for each step of the 30-dose epidural (30-day dose) are also applicable to the 7-dose inhaler (7-day dose).
Please read the following instructions before use
If you open and close the easy-access lid when you are not inhaling medication, a dose will be lost.
The lost dose will be safely stored in the epidural, but cannot be used again.
The Enactor is designed to prevent accidental inhalation of additional medication or double doses in 1 inhalation.
Preparing to administer medication
Open the lid when you are ready to inhale the medication. Do not shake the device.
Slide the cap down until you hear a “click” sound.
The medication is ready for inhalation. Confirm that the medication has been released by decreasing the dose counter by 1.
If you hear a click but the dose counter does not decrement, the inhaler is not releasing 1 inhaled medication and should be returned to your physician for consultation.
The inhaler should not be shaken at any time.
Inhalation of medication
Exhale as far as possible when the inhaler should be held away from the mouth and nose. However, do not exhale into the epidural.
The nozzle should be placed between the upper and lower lips with the lips wrapped tightly around the nozzle. Do not block the ventilation holes with your fingers during use.
Take a long, deep, steady breath and hold it for as long as possible (at least 3-4 seconds).
Withdraw the easy-access device from the mouth.
Exhale slowly and gently.
You should not be able to taste or feel the medication, especially if you are using the epidural correctly.
Close the epidural
If you want to clean the mouthpiece, use a dry paper towel to wipe it clean before closing the easy-access lid.
Slide the lid up as far as it will go until it covers the nozzle.
Slide the cover up until it covers the nozzle.