Approval date: December 28, 2017
Indatrol Grononium Bromide Inhalation Powder for Capsules Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Indatrololone Ammonium Bromide Inhalation Powder Nebulizer Capsules
Trade name: Jelun®, Ultibro®
English name: Indacaterol Maleate and Glycopyrronium Bromide Powder for Inhalation, Hard Capsules
Hanyu Pinyin: Yindateluo Gelongxiu’an Xirufenwujiyong Jiaonang
Ingredients
This product is a compound preparation, the active ingredients of which are indateluo maleate and geranium bromide.
Active ingredient: Indaterol maleate.
Chemical name: (R)-5-[2-(5,6-diethyldihydroinden-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one maleate.
Chemical structure formula.
Molecular formula: C24H28N2O3-C4H4O4
Molecular weight: 508.56
Active ingredient: Gronium bromide.
Chemical name: Gronium bromide 3-hydroxy-1,1-dimethylpyrrolidinyl-α-cyclopentyl mandelic acid ester.
Chemical structure formula.
Molecular Formula: C19H28BrNO3
Molecular weight: 398.34
Excipients are.
Lactose monohydrate, magnesium stearate, hydroxypropyl methylcellulose capsule shell, printing ink.
Properties
This product is a transparent hard capsule, the contents of white to off-white powder, no visible foreign matter.
Indications
This product is indicated for maintenance bronchodilator therapy for symptom relief in adults with chronic obstructive pulmonary disease (COPD) (including chronic bronchitis and emphysema).
Specification
Each capsule contains 110µg (C24H28N2O3) of indantaterol maleate and 50µg (C19H28NO3) of grononium bromide.
Dosage]
Dosage
The recommended dose is one capsule of the drug inhaled once a day, administered by the accompanying powder inhaler.
It is recommended to inhale this product at the same time every day. If a dose of medication is missed, make up the inhalation on the same day as soon as possible. Patients should be instructed not to administer more than one dose of medication in a day.
Dosage
This product is intended for oral inhalation administration only; this capsule should not be taken orally.
Capsules should only be administered by the accompanying powder inhaler. Patients should be instructed in the proper use of this product. Patients who do not see improvement in respiratory symptoms should be asked if they swallowed the medication, not inhaled it. Please refer to the instructions for the installation and use of the powder inhaler in this manual.
Special Populations
Renal Impairment
Patients with mild to moderate renal impairment may use this product at the recommended dose. Patients with severe renal impairment or end-stage renal disease requiring dialysis should use this product only if the expected benefit outweighs the potential risk (see [Precautions] and [Pharmacokinetics]).
Hepatic Impairment
This product may be used at the recommended dose in patients with mild to moderate hepatic impairment. No data are available for patients with severe hepatic impairment, therefore, this product should be used with caution in these patients (see [Pharmacokinetics]).
Pediatric Population
See [Pediatric Population] section.
Geriatric population
See [Geriatric Population] section.
Adverse reactions]
Safety characteristics are derived from experience with the application of this product in compound formulations as well as each single ingredient.
Safety Summary
The safety profile of this product is based on data from up to 15 months of use at the recommended therapeutic dose.
The product showed similar adverse reactions to the individual components. Because this product contains indantaterol and grononium, the type and severity of adverse reactions expected for the combination formulation are related to those of the single ingredient.
The safety profile of this product is characterized by typical anticholinergic and β-adrenergic symptoms associated with its individual components. The other most common adverse reactions associated with this product (occurring in at least 3% of patients using this product and higher than in the placebo group) were cough, nasopharyngitis, and headache.
Summary of the Adverse Reaction List
Adverse reactions detected during clinical studies and post-marketing sources were summarized and tabulated according to MedDRA system organ classification (Table 1). Adverse reactions were ranked by frequency of occurrence within each system organ classification, with the most common reactions listed first. Within each same frequency group, adverse reactions were ranked in decreasing order of severity. In addition, the corresponding frequency classification for each adverse reaction was based on the following: very common (≥1/10); common (≥1/100 to <1/10); occasional (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); unknown (based on available data, it is not possible to estimate).
Table 1 Adverse reactions
Frequency classification of adverse reactions Infections and infestations Upper respiratory tract infections very common Nasopharyngitis common Urinary tract infections common Sinusitis common Rhinitis common Immune system disorders Hypersensitivity reactions common Angioneurotic edema2 Occasional metabolic and nutritional disorders Hyperglycemia and diabetes common Psychiatric disorders Insomnia occasional neurologic disorders Dizziness common Headache common Sensory abnormalities rare Ocular disorders Glaucoma1 Occasional cardiac disorders Ischemic heart disease Occasional atrial fibrillation Occasional tachycardia Occasional palpitations Occasional respiratory, thoracic, and mediastinal disorders Cough Common oropharyngeal pain including laryngeal irritation Common paradoxical bronchospasm Occasional vocal difficulties2 Occasional epistaxis Occasional gastrointestinal disorders Indigestion Common dental caries Common gastroenteritis Occasional dry mouth Occasional skin and subcutaneous tissue disorders Pruritus/rash Occasional skeletal muscle and connective tissue disorders Musculoskeletal pain Occasional muscle spasms Occasional myalgia Occasional extremity pain Occasional renal and urinary disorders Bladder obstruction and urinary retention Common general disorders and abnormalities at the site of administration Fever1 Common chest pain Common peripheral edema Occasional fatigue Occasional 1 Adverse reactions observed during application of the compounded formulation of the product, not the application of the individual ingredients.
2 Reported from post-marketing experience; however, frequency calculations are based on clinical trial data.
Description of Adverse Reactions of Concern
The most common adverse event for anticholinergic drugs was dry mouth (0.64% vs 0.45% for placebo); however, the incidence of this adverse event was lower in the group administered with this product than with grononium alone. Most dry mouth events were suspected to be drug-related and mild (no severe). Cough was common, but usually mild.
Certain serious adverse events, including hypersensitivity reactions and ischemic heart disease, have been reported as adverse drug reactions to indacaterol alone. The incidence of hypersensitivity reactions and ischemic heart disease reported for this product was 2.06% versus 1.9% for placebo and 0.67% versus 0.78% for placebo, respectively.
[Contraindications].
Contraindicated in patients with hypersensitivity reactions to the active ingredient or any of the excipients.
Precautions]
This product should not be used in combination with drugs containing other long-acting beta-adrenergic agonists or long-acting muscarinic receptor antagonists (see [Drug Interactions]).
Asthma
This product is not indicated for the treatment of asthma due to the lack of data on the indication for asthma.
Long-acting beta2-adrenergic agonists may increase the risk of serious adverse events associated with asthma (including asthma-related death) when used in the treatment of asthma.
Not for use as an emergency medicine
This product is not indicated for the treatment of acute attacks of bronchospasm.
Hypersensitivity reactions
Rapid hypersensitivity reactions have been reported following the use of indantaterol or grononium (components of this combination). If signs suggestive of a paradoxical reaction occur, particularly angioedema (including difficulty in breathing or swallowing, swelling of the tongue, lips and face), urticaria or rash, treatment should be discontinued immediately and alternative therapy initiated.
Paradoxical bronchospasm
As with other inhaled drug delivery treatments, treatment with this product may result in paradoxical bronchospasm and may be life-threatening. If this occurs, the product should be discontinued immediately and alternative therapy should be initiated.
Anticholinergic effects associated with grononium
Narrow-angle glaucoma
There are no data on the use of this product in patients with narrow-angle glaucoma; therefore, it should be used with caution in these patients.
Patients should be informed about the signs and symptoms of acute narrow-angle glaucoma and advised to discontinue the product and contact their physician immediately if any of these signs or symptoms develop.
Urinary retention
There are no data on its use in patients with urinary retention; therefore, this product should be used with caution in these patients.
Patients with severe renal impairment
A mean moderate 1.4-fold increase in total systemic exposure (AUClast) of grononium was observed in subjects with mild and moderate renal impairment and a mean 2.2-fold increase in patients with severe renal impairment and end-stage renal disease. In patients with severe renal impairment (estimated glomerular filtration rate less than 30 ml/min/1.73 m2), including patients with end-stage renal disease requiring dialysis, this product should be administered only if the expected benefit outweighs the potential risk (see [Pharmacokinetics]). These patients should be closely monitored for potential adverse reactions.
Systemic effects of beta-agonists
Although there are usually no clinically significant effects on the cardiovascular system with application of the recommended dose of this product, as with other beta2-adrenergic agonist-containing drugs, in patients with cardiovascular disease (coronary artery disease, acute myocardial infarction, arrhythmias, hypertension), in patients with convulsive disease or hyperthyroidism, and in patients with abnormal sensitivity to beta2-adrenergic agonists This product should be used with caution.
As with other drugs containing inhaled beta2-adrenergic agonists, this product should not be used more frequently or at higher doses than recommended.
Cardiovascular effects
In some patients, beta2-adrenergic agonists may produce clinically significant cardiovascular effects (including increased pulse rate, increased blood pressure, and/or symptoms). Once such effects occur during drug application, treatment may need to be discontinued. In addition, β-adrenergic agonists have been reported to cause electrocardiographic (ECG) changes, although the clinical significance of these changes, such as T-wave depression, QT interval prolongation, and ST-segment depression, is not known. Thus, long-acting β2-adrenergic agonists should be used with caution in patients with known or suspected QT interval prolongation or who are on medications that affect the QT interval.
In clinical studies, patients with unstable ischemic heart disease, left ventricular failure, a history of myocardial infarction, arrhythmias (other than chronic stable atrial fibrillation), a history of QT prolongation syndrome, or a prolonged QTc (Fridericia method) (>450 ms) were excluded, and therefore there is no experience with its use in these patients. This product should be used with caution in these patients.
No clinically significant QTc interval prolongation effects were observed at the recommended therapeutic dose levels in clinical studies of this product (see [Pharmacology and Toxicology]).
Hypokalemia
The application of beta2-adrenergic agonists may produce significant hypokalemia in some patients. Hypokalemia may cause adverse cardiovascular effects. The decrease in serum potassium is usually transient and does not require potassium supplementation. In patients with severe COPD, hypoxia and coadministration may exacerbate hypokalemia and may increase susceptibility to arrhythmias (see [Drug Interactions]).
In clinical studies of this product, no clinically significant hypokalemic effects were observed at the recommended therapeutic dose levels (see [Pharmacologic Toxicology]).
Hyperglycemia
Inhalation of high doses of beta2-adrenergic agonists may result in elevated blood glucose. Once treatment with this product is initiated, blood glucose should be monitored more closely in patients with diabetes.
In long-term clinical studies, a higher proportion of patients (4.9%) than in the placebo group (2.7%) experienced clinically significant changes in blood glucose after application of the recommended dose of this product. This product has not been studied in diabetic patients with poor glycemic control.
Excipients
This product should not be used in patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or impaired glucose-galactose absorption.
Effects on driving and operation of machinery
This product has no or only negligible effect on the ability to drive and operate machinery. However, the occurrence of dizziness may affect the ability to drive and operate machinery. See [Adverse Reactions].
Use with caution in athletes
For pregnant and lactating women
Pregnancy
There are no data on the use of this product in pregnant women. Animal studies have not suggested direct or indirect deleterious effects related to reproductive toxicity at clinically relevant exposures (see [Pharmacology and Toxicology]).
Indataterol may have a delivery-inhibiting effect because it relaxes uterine smooth muscle. The potential human risks are not known and therefore the product should be administered during pregnancy only if the expected benefit to the patient outweighs the potential risk to the fetus.
Lactation
It is not known whether indantatrole, grononium, and their metabolites are secreted into human breast milk. Data from pharmacokinetic/toxicological studies are available indicating that indantaterol, grononium, and their metabolites can be secreted into the milk of lactating rats. It should be considered for use in nursing females only if the expected benefit to the patient outweighs any potential risk to the infant (see [Pharmacology and Toxicology]).
Fertility
Reproductive studies and other animal data have not shown effects on fertility in females or males.
Pediatric Use]
For COPD indications, there is no indication for this product in the pediatric population (under 18 years of age). The safety and efficacy of this product in children have not been confirmed. No relevant data are available.
Geriatric use]
Geriatric patients (75 years and older) can take this product at the recommended dose.
Drug Interactions]
Indataterol and grononium are administered simultaneously by oral inhalation and the two active ingredients do not affect their respective pharmacokinetics at steady state.
No specific drug interaction studies have been conducted for this product. Information on potential drug interactions was derived from information on the respective possible interactions of the two ingredients.
In vitro studies indicate little potential for metabolism-related drug interactions with indantaterol at exposure levels of clinical doses. (See [Pharmacokinetics]).
In vitro studies indicate that grononium is unlikely to inhibit or induce the metabolism of other drugs and does not affect processes involving drug transporters. A variety of enzymes are involved in the metabolism of grononium and play a minor role in its clearance. Inhibition or induction of grononium metabolism is unlikely to result in meaningful changes in the systemic exposure of the drug. (See [Pharmacokinetics]).
Drugs not recommended for combination
Beta-adrenergic blockers
Beta-adrenergic blockers have attenuating or antagonistic effects on beta2-adrenergic agonists; therefore, this product should not be used in combination with beta-adrenergic blockers (including eye drops) unless there is a compelling reason for their use. If needed, cardiovascular selective beta-adrenergic blockers may be preferred, but should be used with caution.
Anticholinergic drugs
No studies have been performed combining this product with other anticholinergic-containing drugs; therefore, combining this product with other anticholinergic-containing drugs is not recommended. (See [Precautions])
Sympathomimetic drugs
Combination with other sympathomimetic drugs (alone or as part of a combination) may have the potential to increase the risk of adverse events with indantatrole. (See [Precautions])
Drugs that should be used with caution in combination
Treatment of hypokalemia
When combined with methylated xanthine derivatives, steroids, or non-potassium preserving diuretics, they may increase the potential hypokalemic effects of beta2-adrenergic agonists and should therefore be used with caution. (See [Precautions])
Drugs known to prolong the QTc interval
As with other beta2-adrenergic agonist-containing drugs, this product should be used with caution in patients receiving monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QT interval, due to the potential for enhanced effects on the QT interval. Drugs known to prolong the QT interval may increase the risk of ventricular arrhythmias. (See [Precautions])
Factors to consider when combining drugs
Drug interactions based on metabolism and transporters
Inhibition of CYP3A4 and P-glycoprotein (P-gp), which play a major role in the clearance of indinaterol, can increase systemic exposure to indinaterol by up to 2-fold. Clinical safety data are available for 1 year of dosing at 2 times the maximum recommended dose of indinaterol, so the magnitude of the increased exposure due to interaction is not considered to increase any safety risk.
Cimetidine and other organic cation transport inhibitors
In clinical studies in healthy volunteers, cimetidine (an organic cation-transport inhibitor) affected renal excretion of grononium, increasing overall grononium exposure (AUC) by 22% and decreasing renal excretion by 23%. Based on the extent of this change in exposure, no clinically significant drug interactions are expected when grononium is combined with cimetidine or other organic cation-transporting inhibitors.
Drug Overdose]
Information related to this product
In single-dose studies in healthy volunteers, this product was well tolerated at 4 times the recommended dose (4 doses of 110/50 µg each, 1 hour apart), and there were no meaningful effects on heart rate, QTc interval, serum potassium, or blood glucose.
In COPD patients, inhaled doses of up to 600/100 µg for 2 weeks did not produce meaningful effects on heart rate, QTc interval, blood glucose, or serum potassium. Ventricular ectopic beats increased after 14 days of 300/100 and 600/100 µg administration, but the low incidence and small number of patients (N=49 and N=51 for 600/100 µg and 300/100 µg, respectively) did not allow for precise analysis. A total of 4 patients with nonsustained ventricular tachycardia were recorded with the longest episode recorded at 9 beats (4 seconds).
Overdose may lead to the typical manifestations of β2-adrenergic overstimulation, i.e., tachycardia, tremor, palpitations, headache, nausea, vomiting, drowsiness, ventricular arrhythmias, metabolic acidosis, hypokalemia, and hyperglycemia, or may induce anticholinergic effects, e.g., increased intraocular pressure (causing eye pain, abnormal vision, or redness of the eyes), constipation, or difficulty urinating. Supportive therapy and symptomatic treatment may be used. Severe cases should be treated with hospitalization. For beta2-adrenergic effects, cardioselective beta-blockers may be considered, but they need to be supervised by a physician and with great caution, as beta-adrenergic blockers may provoke bronchospasm.
Information related to indacaterol
Moderate pulse rate acceleration, increased systolic blood pressure, and prolonged QTc interval have been observed with a single application of 3000 µg in patients with COPD.
Information related to grononium
In COPD patients, multiple oral inhalations of grononium totaling 100 and 200 µg once daily were well tolerated for 28 days.
Accidental oral administration of grononium capsules is unlikely to cause acute toxicity due to the low oral bioavailability (~5%).
In healthy volunteers, peak plasma concentrations and systemic exposure following intravenous infusion of grononium bromide 150 µg (equivalent to 120 µg grononium) were 50 and 6 times higher than the steady-state peak concentration and total exposure, respectively, of the recommended therapeutic dose of grononium (50 µg once daily) and were well tolerated.
Clinical trials]
The Phase III clinical development program includes six clinical studies (enrolling more than 8,000 patients): 1) a 26-week placebo and positive control study (positive control of indantaterol once daily, grononium once daily, and open-label tiotropium once daily); 2) a 26-week positive control study (positive control of inhaled glucocorticoid/long-acting beta2 agonist twice daily); and 3) a 64-week positive control study (positive control of inhaled glucocorticoid/long-acting beta2 agonist twice daily). twice daily); 3) a 64-week positive-controlled study (positive control was grononium once daily, open-label tiotropium once daily); 4) a 52-week placebo-controlled study; 5) a 3-week placebo and positive-control (positive control was tiotropium once daily) exercise tolerance study and 6) a 52-week positive-controlled (positive control was inhaled glucocorticoid/long-acting beta2 receptor agonist twice daily) study.
Four of these studies enrolled patients with moderate to severe COPD. 64-week studies enrolled patients with severe to very severe COPD and a history of at least 1 acute exacerbation of moderate or severe COPD in the past 1 year.
In the 52-week positive control study, patients with moderate to very severe COPD and a history of at least 1 acute exacerbation of moderate or severe COPD in the past 1 year were enrolled.
Effects on lung function
In several clinical studies, this product resulted in clinically meaningful improvements in lung function (measurement of exertional expiratory volume in the first second, FEV1). A bronchodilator effect was observed within 5 minutes of the first dose in the phase III study and was maintained for 24 hours from the first dose. The bronchodilator effect did not diminish over time.
The magnitude of the effect was dependent on the degree of reversibility of baseline airway restriction (as tested by short-acting muscarinic receptor antagonist bronchodilators and short-acting β2-agonist bronchodilators): patients with low baseline reversibility (<5%) usually had a lower bronchodilator effect than patients with higher baseline reversibility (≥5%). At 26 weeks (primary endpoint), the product increased FEV1 trough by 80 ml in patients with low reversibility (<5%) (n=82 in the product group and n=42 in the placebo group; p=0.053) and by 220 ml in patients with higher reversibility (≥5%) (n=392 in the product group and n=190 in the placebo group; p<0.001).
FEV1 trough and peak values
As listed in the table below, at week 26 (primary endpoint), this product resulted in a 200 ml increase in FEV1 trough values after administration compared to placebo (p<0.001), which was statistically significant compared to the single-ingredient treatment group (indantaterol and gronadion) and the tiotropium treatment group.
Post-administration FEV1 troughs (least squares means) at study day 1 and week 26 (primary endpoint)
Treatment difference Study day 1 Study week 26 Benzo – placebo 190 ml (p<0.001) 200 ml (p<0.001) Benzo – indantatrol 80 ml (p<0.001) 70 ml (p<0.001) Benzo -Grononium 80 ml (p<0.001) 90 ml (p<0.001) This product -Tiotropium 80 ml (p<0.001) 80 ml (p<0.001) Mean pre-dose FEV1 in this product group (early morning before -45 min and before -15 min of dosing collected mean) was statistically significantly better than positive control at 26 weeks (treatment difference least squares mean of 100 ml, p<0.001); significantly better than placebo at 52 weeks (treatment difference least squares mean of 189 ml, p<0.001); and significantly better than grononium at all visits up to 64 weeks (treatment difference least squares mean of 70- 80 ml, p<0.001) and tiotropium (least squares mean treatment difference of 60-80 ml, p<0.001). In the 52-week positive control study, the mean pre-dose FEV1 was statistically significantly better in the Benadryl group than in the positive control group at all visits up to 52 weeks (treatment difference least squares mean 62-86 mL, p<0.001). At 26 weeks, the improvement in peak FEV1 in the first 4 hours after dosing (treatment difference least squares mean value of 330 ml) was statistically significantly better in the Benzedrine group than in the placebo group (p<0.001).
FEV1 AUC
Compared with positive controls, this product resulted in a 140 ml increase in FEV1 AUC 0-12 h (primary endpoint) after dosing at 26 weeks (p<0.001).
Symptom outcomes
Dyspnea
The product significantly improved dyspnea (assessed using the Transitional Dyspnea Index (TDI)); demonstrating an improvement in TDI local scores at week 26 compared to placebo (treatment difference least squares mean value of 1.09, p<0.001), tiotropium (treatment difference least squares mean value of 0.51, p=0.007) and positive control (treatment difference least squares mean value of 0.76, p=0.003) were statistically significant. The improvement compared to indantaterol and griseofulvin was 0.26 and 0.21, respectively.
A statistically significant difference was observed in the percentage of patients with a 1 or more point improvement in TDI score at 26 weeks with this product compared to placebo (68.1% and 57.5%, respectively; p=0.004). the percentage of patients with clinically significant improvement at 26 weeks was higher in the product group than in the tiotropium group (68.1% with this product and 59.2% with tiotropium; p=0.016) and positive controls (65.1% for this product and 55.5% for positive controls; p=0.088).
Health-related quality of life
The product also produced a statistically significant improvement in health-related quality of life as assessed by the St. George’s Respiratory Questionnaire (SGRQ), as evidenced by a lower total SGRQ score than placebo (least squares mean treatment difference of -3.01, p=0.002) and tiotropium (least squares mean treatment difference of -2.13, p=0.009) at 26 weeks, compared to indantaterol and griseofulvin At 64 weeks, the total SGRQ score was significantly reduced compared to the tiotropium group (least squares mean treatment difference -2.69, p<0.001). at 52 weeks, the reduction was statistically significant compared to the positive control (least squares mean treatment difference -1.3, p=0.003).
The proportion of patients with improved SGRQ scores (defined as a reduction of at least 4 points from baseline) was higher in the product group than in the placebo group (63.7% and 56.6%, respectively, p=0.088) and the tiotropium group (63.7% and 56.4%, respectively, p=0.047) at week 26, and higher than in the grononium and tiotropium groups at week 64 (57.3% for the product; 51.8% for grononium , p=0.055; and 50.8% for tiotropium, p=0.051) and higher than positive control (49.2% for this product; 43.7% for positive control, ratio 1.30, p<0.001) at 52 weeks.
Daily activities
The percentage of “days able to perform daily activities” was statistically significantly better in the group after 26 weeks than in the tiotropium group (least squares mean treatment difference 8.45%, p<0.001). At 64 weeks, the group showed numerical superiority to the grononium group (least squares mean treatment difference 1.95%; p=0.175) and statistical superiority to the tiotropium group (least squares mean treatment difference 4.96%; p=0.001).
Acute exacerbation of COPD
In a 64-week comparative study of this combination (n=729), grononium (n=739) and tiotropium (n=737), the annual incidence of acute exacerbations of moderate or severe COPD was 12% lower (p=0.038) in the grononium group and 10% lower (p=0.096) than in the tiotropium group. The number of acute exacerbations/patient-year for moderate or severe COPD in each group: 0.94 (812 events) in the Benzedrine group, 1.07 (900 events) in the grononium group, and 1.06 (898 events) in the tiotropium group. The annual incidence of all acute exacerbations (mild, moderate or severe) of COPD in this group was statistically significantly lower by 15% (p=0.001) compared to grononium and 14% (p=0.002) compared to tiotropium. Acute exacerbations/patient-years of all COPD in each group: 3.34 (2,893 events) in the present product group, 3.92 (3,294 events) in the grononium group, and 3.89 (3,301 events) in the tiotropium group.
The 52-week study comparing this product (n=1,675) to the positive control (n=1,679) met the study’s primary endpoint of non-inferiority to the positive control for all acute exacerbation rates (mild, moderate or severe) in COPD. The number of all acute exacerbations was 3.59/patient-year (4,531 events) in the product group and 4.03/patient-year (4,969 events) in the positive control group. The product further demonstrated superiority in reducing the annual incidence of all COPD acute exacerbations compared to positive controls (11%, p=0.003).
The product group reduced the annual incidence of moderate or severe acute exacerbations by 17% (p<0.001) and the annual incidence of severe acute exacerbations (requiring hospitalization) by 13% (not statistically significant, p=0.231) compared to positive controls. The number of moderate or severe acute exacerbations was 0.98 per patient-year (1,265 events) in the product group and 1.19 per patient-year (1,452 events) in the positive control group. The product prolonged the time to the first moderate or severe acute exacerbation with a 22% risk reduction (p<0.001) and prolonged the time to the first severe acute exacerbation with a 19% risk reduction (p=0.046).
The incidence of pneumonia in the product group was 3.2% compared to 4.8% in the positive control group (p=0.017). The time to first pneumonia was prolonged in this product compared to the positive control (p=0.013).
In another controlled study of this product (n=258) versus positive control (n=264), at week 26, the number of acute exacerbations of moderate or severe COPD was 0.15/patient-year and 0.18/patient-year, respectively (18 events versus 22 events) (p=0.512), and the number of acute exacerbations of all (mild, moderate or severe) COPD was 0.72/ patient-year and 0.94/patient-year (86 events versus 113 events), respectively (p=0.098).
Application of emergency medication
Throughout 26 weeks, this product significantly and statistically significant reduced the dosage of emergency medication (salbutamol) by 0.96 sprays per day compared with placebo (p<0.001); 0.54 sprays per day compared with tiotropium bromide (p<0.001) and 0.39 sprays per day compared with positive control (p=0.019). Throughout 64 weeks, there was a reduction of 0.76 sprays per day (p<0.001) compared to tiotropium bromide and throughout 52 weeks, there was a reduction of 0.25 sprays per day (p<0.001) compared to positive control.
Exercise tolerance
This product (administered early in the morning) reduced dynamic hyperinflation and improved exercise duration, with effects that persisted from the first dose. Deep inspiratory volume on the first treatment day was significantly better than in the placebo group (treatment difference least squares mean of 250 ml, p<0.001). 3 weeks of treatment resulted in greater deep inspiratory volume (treatment difference least squares mean of 320 ml, p<0.001) and longer exercise tolerance (treatment difference least squares mean of 59.5 seconds, p= 0.006).
Chinese cohort study
A randomized, double-blind, double-model, parallel-controlled clinical trial including 598 Chinese COPD patients investigated the efficacy and safety of the drug in a Chinese patient population. The 26-week study evaluated the safety and efficacy of the drug compared to a positive control in patients with moderate-to-severe COPD.
At 26 weeks of treatment, statistically and clinically significant improvements in pulmonary function were observed in trough FEV1 (treatment difference least squares mean 0.073 L, p<0.001), trough FVC (treatment difference least squares mean 0.168 L, p<0.001) and FEV1AUC0-4h (treatment difference least squares mean value of 0.122 L, p<0.001). Compared to baseline, patient symptom improvement was clinically significant at 26 weeks, as evidenced by SGRQ (-9.03 vs. -7.28), TDI (3.17 vs. 3.07) and emergency medication use (-1.75 vs. -1.76 sprays/day), and was similar for this product and positive controls. Furthermore, the incidence of acute exacerbations of moderate-to-severe COPD was significantly lower at 26 weeks of treatment compared to positive controls (annual incidence of acute exacerbations of COPD: 0.19 vs. 0.34, p=0.015). The product showed good tolerability and
The safety profile was similar to that of the positive control, however, the incidence of pneumonia was lower in the product group (0.3%) than in the positive control group (2.0%).
In conclusion, the efficacy and safety of the Chinese subgroup were similar to those observed in the total population.
Pharmacology and Toxicology
Pharmacological effects
This product is a compound preparation of indantaterol maleate and gronadione bromide. Indantaterol and grononium are used together in this product, which provide superimposed efficacy by targeting different receptors, achieving smooth muscle relaxation via different routes and by different mechanisms of action.
Indantaterol
Indaterol is a long-acting β2-adrenoceptor agonist. After inhalation of indantaterol its action is localized in the lungs as a bronchodilator. Although β2-agonists are the primary adrenergic receptors in bronchial smooth muscle and β1-agonists are the primary receptors in the heart, β2-adrenergic receptors are also present in the human heart, accounting for 10% to 50% of all adrenergic receptors. Although the exact function of these receptors is not known, their presence suggests the possibility that even highly selective β2-adrenoceptor agonists may have effects on the heart.
The pharmacological effects of β2-adrenoceptor agonist drugs, including indinaterol, derive at least in part from the activation of intracellular adenylyl cyclase, an enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic- 3′,5′-monophosphate adenosine (cyclic adenosine monophosphate). Elevated levels of cyclic adenosine monophosphate (cAMP) cause relaxation of bronchial smooth muscle. In vitro studies have shown that the long-acting β2-adrenoceptor agonist indantaterol has 24-fold higher agonistic activity at the β2-agonist than at the β1-agonist and 20-fold higher than at the β3-agonist. The clinical significance of these findings is not clear.
Grononium
Grononium is a long-acting acetylcholine receptor antagonist (LAMA) that is four times more selective for human acetylcholinergic M3 receptors than M2 receptors and specifically binds to and inhibits M3-type acetylcholine receptors distributed in bronchial smooth muscle to dilate the airway.
Toxicological studies
Toxicity of repeated administration of compound
A 2-week, 13-week repeat dosing toxicity study in dogs administered by inhalation showed significantly faster heart rates in all dose groups of this product and the single component. The magnitude and duration of the increase in heart rate was consistent with a superimposed effect when compared to single-component administration. Cardiovascular safety pharmacology studies in dogs showed significant ECG interval shortening and reductions in systolic and diastolic blood pressures. Comparable incidence and severity of myocardial damage was seen in dogs given indantaterol single component or this product by inhalation for 13 weeks, with a NOAEL of 386/125 µg/kg/d (indantaterol/gelononium) without cardiac injury, which was 64 and 59 times the AUC of the individual compounds given in humans at 110/50 µg (indantaterol/gelononium), respectively.
Reproductive toxicity
No significant effects on embryo-fetal development were observed in rats given nindaterol/gelononium by inhalation, with a NOAEL of 2120/710 µg/kg/d (nindaterol/gelononium), which were 79 and 126 times higher than the individual compounds at AUC than the human dose of 110/50 µg (nindaterol/gelononium), respectively.
Indantaterol
Repeated dosing toxicity
Mild nasal and laryngeal irritation was observed in rats administered indaterol by inhalation. Cardiovascular effects of β2 agonist properties including: tachycardia, arrhythmias and myocardial damage were seen in dogs given ninhydrin by inhalation. These changes were seen only at exposures significantly above the expected human exposure.
Genotoxicity
The results of the Ames test, the V79 Chinese hamster cell chromosome aberration test and the rat bone marrow micronucleus test for indantaterol were negative.
Reproductive toxicity
Indataterol did not show any significant effect on fertility in rats. No teratogenicity was observed in rats and rabbits at doses up to 1 mg/kg by subcutaneous injection of nindaterol, which was 130 and 260 times higher than the human dose of 75 μg once daily (in mg/m2), respectively.
Carcinogenicity
No significant increase in tumor incidence was seen in carcinogenicity tests in transgenic mice administered orally and in rats administered by inhalation. Increased incidence of benign ovarian smooth muscle tumors and focal hyperplasia of ovarian smooth muscle was seen in female rats administered lifelong at approximately 270 times the human 75 μg once-daily dose (in mg/m2).CB6F1/TgrasH2 hemizygous mice given orally for 26 weeks with indantatrole at approximately 39,000 times the human 75 μg once-daily dose (in mg/m2), showed no evidence of carcinogenicity.
Other β2-adrenoceptor agonists have been shown to increase the incidence of smooth muscle tumors in the reproductive tract of female rats, but the relevance of these findings to humans is unclear.
Grononium
Repeated dosing toxicity
In rats given grononium 0.07, 0.54, and 3.98 mg/kg/d by inhalation for 26 weeks, lens clouding and mild or punctate cataracts were seen, possibly related to localized high ocular exposure due to intranasal inhalation administration. Lens clouding was also seen in long-term studies with other muscarinic antagonists in rats, and may be species-specific. Squamous epithelial metaplasia in the larynx, eosinophilic goblet cells within the respiratory epithelium/olfactory epithelium, and hypertrophy/proliferation of cup cells in the nasal cavity were also seen in rats. Changes in the larynx and nasal cavity were still evident after the recovery period. Slight epithelial changes at the bronchoalveolar junction of the lungs were seen in rats and were considered to be an adaptive response. The dose at which no adverse effects were observed in this test (NOAEL) was 0.07 mg/kg/d, which is equivalent to 30 times the AUC at the recommended daily human clinical dose of 50 μg on an exposure basis.
The NOAEL was 0.020 mg/kg/d, which is 10 times the AUC of the recommended daily human clinical dose of 50 μg based on exposure.
Genotoxicity
The results of Ames test, human lymphocyte chromosome aberration test and rat bone marrow cell micronucleus test were all negative for grononium.
Reproductive toxicity
Continuous subcutaneous administration of grononium 1.5 mg/kg/d to rats resulted in fertility impairment in both males and females, as evidenced by a decrease in the number of engendered and live fetuses. No significant reproductive toxicity was observed at a dose of 0.5 mg/kg/d, which is equivalent to approximately 162 times the AUC of the recommended daily human clinical dose of 50 μg based on exposure.
Grononium was given by inhalation to pregnant rats at doses of 0.09, 0.54 , and 3.05 /kg/d, with a significant reduction in body weight, body weight gain and food intake in animals at a dose of 3.05 mg/kg/d. The maternal NOAEL in this test was 0.54 mg/kg/d. No embryonic lethality, embryotoxicity or teratogenicity was observed at any of the three doses.
In pregnant rabbits, grononium was given by inhalation at 0.40, 1.30, and 3.50 mg/kg/d. At dose levels of ≥1.3 mg/kg/d, a decrease in maternal body weight and food intake was observed, and no embryonic lethality, embryotoxicity, or teratogenicity was observed.
Grononium and its metabolites can be secreted into the milk of rats, and the concentration in milk is about 10 times higher than the maternal blood concentration.
Carcinogenicity
In oral administration to transgenic mice and inhalation administration to rats, grononium was not found to be significantly carcinogenic at doses approximately 53 times and 75 times the AUC above the recommended daily human clinical dose of 50 μg, based on exposure.
Pharmacokinetics
Absorption
Compounding of this product
After inhalation administration, the median time to peak plasma concentrations of indantaterol and griseofulvin were 15 minutes and 5 minutes, respectively.
Based on data from in vitro studies, the amount of nindaterol released into the lungs was similar for this product compared to the single formulation of nindaterol. Steady-state systemic exposure to nindaterol after inhalation administration was similar to or slightly lower than systemic exposure after inhalation administration of nindaterol monoformulations. Steady-state systemic exposure to grononium following inhalation administration is similar to that following inhalation administration of a single formulation of grononium 50 µg.
The estimated absolute bioavailability of indantatrole after inhalation administration averaged 47 to 66%. Absolute bioavailability of grononium was 40%.
Indantatrol.
Steady-state concentrations of indantaterol were achieved within 12 to 15 days of once-daily administration. The mean accumulation ratios of nindaterol ranged from 2.9 to 3.8 (i.e., AUC ratios at 24-hour dosing intervals on study day 14 or 15 versus study day 1) under inhalation administration of 75 µg and 600 µg once-daily.
Grononium.
In patients with COPD, grononium reaches pharmacokinetic steady state within 1 week of continuous dosing. The recommended dose of grononium 50 µg administered once daily resulted in mean steady-state peak and trough plasma concentrations of 166 pg/mL and 8 pg/mL, respectively. steady-state exposure (AUC at 24-hour dosing interval) of grononium was 1.4- to 1.7-fold higher than after the first dose.
Distribution
Indataterol.
After intravenous infusion administration, the volume of distribution (Vz) of indinaterol was 2557 L, indicating wide distribution of the drug. In vitro binding to human serum and plasma proteins ranged from 94.1% to 95.3% and 95.1% to 96.2%, respectively.
Grononium
After intravenous administration, the steady-state volume of distribution of grononium was 83 liters and the end-stage volume of distribution was 376 liters. The apparent end-state volume of distribution after inhalation administration was approximately 20-fold greater, indicating that clearance after inhalation administration was rather slow. The in vitro human plasma protein binding of grononium was 38% to 41% over the concentration range of 1 to 10 ng/mL.
Biotransformation
Indataterol.
In human ADME (absorption, distribution, metabolism, excretion) assays, following oral administration of radiolabeled indaterol, the prototype indaterol was the major component of the serum, accounting for approximately one-third of the total 24-hour drug-related AUC. The hydroxyl derivative was the predominant metabolite in the serum. Indataterol O-glucuronide and hydroxylated indataterol are the secondary major metabolites. Diastereoisomers of hydroxyl derivatives, N-glucuronide indatrol and C- and N-desalkylated products are further metabolites that have been identified.
In vitro studies have shown that only the UGT1A1 isoform of UGT metabolizes indaterol to phenol O-glucuronide. Oxidative metabolite formation was seen in co-incubation experiments with recombinant CYP1A1, CYP2D6, and CYP3A4. CYP3A4 is believed to be the major isoenzyme for hydroxylation of indataterol. In vitro studies further showed that indataterol is a low-affinity substrate for the efflux transport protein P-gp.
Grononium
In vitro metabolism studies have shown that grononium is metabolized by the same pathway in animals as in humans. Different mono- and di-hydroxy metabolites resulting from hydroxylation reactions, and carboxylic acid derivatives (M9) resulting from direct hydrolysis reactions can be detected. In vivo, M9 is generated by the swallowed portion of the dose after oral inhalation administration. Glucuronide and/or sulfate conjugates of grononium can be detected in urine after repeated inhalation administration, representing approximately 3% of the administered dose.
The oxidative metabolic reactions of grononium are catalyzed by a variety of CYP isozymes. Inhibition or induction of grononium metabolism does not cause meaningful changes in systemic exposure of the active ingredient.
In vitro inhibition studies showed that grononium did not inhibit CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5, the efflux transporters MDR1, MRP2 or MXR, and the uptake transporters OCT1 or OCT2. In vitro enzyme induction studies showed no clinically meaningful induction of cytochrome P450 isozymes, UGT1A1, transporter MDR1 and MRP2 by grononium.
Excretion
Indataterol.
In clinical trials with urine collection, urinary excretion of the prototype drug of indantaterol was usually less than 2% of the administered dose. The mean renal clearance of indantaterol ranged between 0.46 and 1.20 L/hour. Renal clearance plays a smaller role in the systemic elimination of nindaterol (approximately 2% to 5% of systemic clearance) compared with nindaterol serum clearance of 18.8 to 23.3 L/hour.
In a human ADME study of oral administration of indantaterol, the fecal route was the major route of excretion more than the urinary route. Indantaterol was excreted into human feces primarily as the prototype parent drug (54% of the administered dose), followed by hydroxylated indantaterol metabolites (23% of the administered dose). Ninety percent or more of the administered dose is recovered from the excretion, achieving a material balance.
Serum concentrations of nindaterol showed a multi-phase decrease with a mean terminal half-life range of 45.5 to 126 hours. The effective half-life range of action obtained from the accumulation rate of nindaterol after repeated dose administration was 40 to 52 hours, which is consistent with the observed time to reach steady state of approximately 12 to 15 days.
Grononium.
After intravenous administration of [3H]-labeled grononium in humans, the mean radioactivity in urine was approximately 85% of the administered dose within 48 hours, with an additional 5% of the administered dose in bile.
Renal clearance of grononium in its prodrug form accounts for approximately 60-70% of total systemic clearance and non-renal clearance accounts for approximately 30-40%. Biliary clearance accounts for a portion of the non-renal clearance, but the non-renal clearance is primarily metabolism related.
The mean renal clearance of grononium after inhalation administration ranged from 17.4 to 24.4 L/h. Part of the renal clearance of grononium is active secretion via the renal tubules. The prodrug in urine accounted for up to 20% of the administered dose.
Plasma concentrations of grononium decreased in a multiphasic manner. The mean terminal clearance half-life after inhalation administration (33-57 h) was significantly longer than for intravenous (6.2 h) and oral administration (2.8 h). Clearance characteristics suggest continued pulmonary absorption and/or transport to the body circulation 24 hours and longer after inhalation administration.
Linearity/nonlinearity
Indataterol.
Systemic exposure to nindaterol increases in a dose-proportional manner over the dose range of 150 to 600 µg.
Grononium
In the dose range of 50 to 200 µg, systemic exposure and total urinary excretion of grononium at pharmacokinetic steady state are dose-proportionally increased in COPD patients.
Special Populations
Compounded formulations of this product
Population pharmacokinetic analysis of COPD patients following inhalation of this product showed no significant effects of age, sex, and (lean) body weight on systemic exposure to indantaterol and grononium. Lean body mass (a function of body weight and height) was identified as a covariate. A negative correlation was shown between whole-body exposure and lean body mass (or weight); however, no dose adjustment was recommended given the magnitude of effect or predictive accuracy.
Smoking status and baseline FEV1 did not have a significant effect on systemic exposure to indantaterol and grononium after inhalation administration of this product.
Indantaterol.
A population pharmacokinetic analysis showed no clinically meaningful effect of age (adult to 88 years), sex, weight (32 to 168 kg), or race on the pharmacokinetics of indantaterol.
Grononium.
In patients with COPD, data from population pharmacokinetic analyses suggest that body weight and age are influential factors in the variability of systemic exposure among individual patients. The recommended dose of grononium, 50 µg once daily, was safe in all age groups and weight groups.
Gender, smoking status and baseline FEV1 had no significant effect on systemic exposure.
Patients with hepatic impairment
Compounded formulations of this product
Patients with mild and moderate hepatic impairment may use the recommended dose of the compounded formulation based on the clinical pharmacokinetic profile of the single component. There are no data from studies in subjects with severe hepatic impairment.
Indataterol
There were no relevant changes in Cmax or AUC of indantaterol in patients with mild to moderate hepatic impairment, nor were there differences in protein binding compared to healthy subjects. Studies have not been conducted in subjects with severe hepatic impairment.
Grononium
No clinical studies have been conducted in patients with hepatic impairment. Grononium is cleared from the circulation primarily by renal excretion. Impaired hepatic metabolism does not cause a clinically significant increase in systemic exposure to grononium.
Patients with renal impairment
Compounded formulations of this product
Based on the clinical pharmacokinetic profile of the single component, the recommended dose of the compounded formulation may be used in patients with mild and moderate renal impairment. Data are not available for subjects with severe renal impairment. In patients with severe renal impairment or end-stage renal disease requiring dialysis, this product should be administered only when the expected benefit clearly outweighs the potential risk.
Indataterol
has not been studied in subjects with renal impairment due to the very low contribution of the urinary route to systemic clearance.
Grononium
Renal impairment has an effect on systemic exposure to grononium. Moderate increases in mean total systemic exposure (AUClast) of up to 1.4-fold were observed in subjects with mild and moderate renal impairment and up to 2.2-fold in patients with severe renal impairment and end-stage renal disease. In COPD patients with mild and moderate renal impairment (estimated glomerular filtration rate, eGFR ≥30 mL/min/1.73 m2), the recommended dose of grononium may be administered.
Race
Compounding of this product
The systemic exposure (AUC) of the two active ingredients after inhalation administration of this product did not differ significantly between Chinese, Japanese and Caucasian subjects. Adequate pharmacokinetic data are not available for other races or ethnicities.
Indataterol
No differences were found between racial subgroups. Limited treatment experience in black populations.
Grononium
There were no significant differences in systemic exposure (AUC) between Chinese, Japanese and Caucasian subjects following inhalation administration of grononium. There are no adequate pharmacokinetic data for other races or ethnicities.
[Storage].
Keep sealed, protected from moisture, and stored at no more than 25°C.
The capsule should be kept in a blister and removed only before use. Keep this product out of the reach of children.
Packaging
Aluminum-aluminum blister package, 6 capsules/plate.
Each box contains 6 capsules and 1 Bispheresis® inhaler.
Each box contains 12 capsules and 1 Bisabol® inhaler.
Each box contains 30 capsules and 1 Bisabol® inhaler.
Expiration date】24 months.
Execution Standard
Imported drug registration standard JX20160068.
Imported drug registration number】H20170390, H20170391
【Manufacturer】.
Company Name: Novartis Europharm Limited, United Kingdom
Production
Production
Plant: Novartis Pharma Stein AG, Switzerland
Production Address: Schaffhauserstrasse, 4332 Stein, Switzerland
Contact: Novartis Pharma Beijing Co.
Address: No. 31 Yong’an Road, Changping District, Beijing, China
Postal Code: 102200
Telephone number: 8008101555 (dial from landline)
4006213132
Fax number: 010-65057099
Web
Address: www.novartis.com.cn
Instructions for the installation and use of the pharmaceutical powder inhaler.
How to use your inhaler Open the inhaler cap.
Open the inhaler.
Hold the bottom of the inhaler firmly and pull the nozzle part sideways.
The inhaler can then be opened. Prepare the capsule.
Tear the blister plate along the perforations and remove one of the blisters.
Remove the protective foil from the back to expose the capsule.
Do not squeeze the capsule out of the foil. Remove the capsule.
Capsules should always be kept in the blister and removed only before immediate use.
Dry your hands and remove the capsule from the blister.
Do not swallow the capsule.
Inserting the capsule.
Place the capsule into the capsule slot.
Do not place the capsule directly into the mouthpiece. Close the inhaler.
Close the inhaler completely until you hear one “click”. Puncture the capsule.
Hold the inhaler vertically with the mouthpiece up.
Press the buttons on both sides steadily at the same time.
You should hear a “click” when the capsule is pierced. Press only once.
Completely release the buttons on both sides. Exhale.
Exhale deeply before placing the nozzle section in your mouth.
Do not blow into the nozzle. Inhale medication.
Inhale medication into your airway by inhaling deeply.
Hold the inhaler as shown in the diagram. The side buttons should be facing the left and right direction. The side buttons should not be pressed.
Place the inhaler in your mouth and wrap your lips tightly around the inhaler.
Inhale quickly and steadily, as deeply as possible.
Do not press the side buttons. Notes.
As you inhale through the mouthpiece, the capsule will rotate in the groove and you should hear a whirring noise. As the medication enters your lungs, you will feel a sweet aroma.
If you do not hear a whirring noise.
It is possible that the capsule is stuck in the capsule slot. If this happens.
Open the inhaler and gently tap on the bottom of the inhaler to release the capsule. The button on the side must not be pressed.
Repeat steps 9 and 10 again to inhale the medication. Hold your breath.
After you have inhaled the medication.
Hold your breath for at least 5-10 seconds while you remove the inhaler from your mouth, or as long as possible if you are not uncomfortable.
Then exhale and
Open the inhaler and check for any residual powder in the capsule.
If any powder remains in the capsule.
Close the inhaler.
Repeat steps 9 through 12.
Most people can empty the capsule with 1 or 2 inhalations.
Additional Information.
Occasionally, some patients experience a short cough soon after inhaling the medication. If a cough occurs, there is no need to worry. As long as the capsule is empty, you have applied a sufficient amount of medicine. After you have completed your daily inhalation dose with the powder inhaler in this package.
Open the inhaler again and remove the empty capsule. Dispose of the empty capsule in the household garbage.
Close the inhaler and close the cap.
Do not store the capsules in the inhaler. Caution
Do not swallow the capsule.
Use only the powder inhaler contained in this package.
Capsules must be kept in the blister and removed only before use.
Do not place the capsule directly into the mouthpiece.
Press the button only once.
Do not blow air into the inhaler.
Release the button before inhaling the medication.
Do not use water to clean the powder inhaler. Keep dry. See “Product Maintenance” section below
Do not disassemble the medication inhaler.
Use the new powder inhaler provided with each medication purchase. Dispose of each inhaler after 30 days of use.
Do not store capsules in the inhaler
Keep the inhaler and capsules dry.
Additional information
Very small pieces of the capsule may occasionally pass through the screen and enter the mouth. These can be felt by the tongue. Swallowing or inhaling these fragments will not cause harm. Puncturing the capsule more than once will increase the chance of debris (Step 7).
Product Maintenance
The inhaler should not be cleaned with water. If you wish to clean the inhaler, wipe the mouthpiece with a clean, lint-free, dry cloth.
The inhaler should be kept dry.