Onbrez Breezhaler

Indacaterol maleate.

150 microgram inhalation powder hard capsules: Each capsule contains 194 microgram indacaterol maleate equivalent to 150 microgram indacaterol.
The delivered dose (the dose that leaves the mouthpiece of the ONBREZ BREEZHALER inhaler) is equivalent to 120 microgram indacaterol.
300 microgram inhalation powder hard capsules: Each capsule contains 389 microgram indacaterol maleate equivalent to 300 microgram indacaterol.
The delivered dose (the dose that leaves the mouthpiece of the ONBREZ BREEZHALER inhaler) is equivalent to 240 microgram indacaterol.
Excipients/Inactive Ingredients: Lactose monohydrate and gelatin.

Pharmacology: Mechanism of Actions (MOA): Indacaterol is an 'ultra' long-acting beta2-adrenergic agonist for once-daily administration. The pharmacological effects of beta2-adrenoceptor agonists, including indacaterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic monophosphate). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown that indacaterol has more than 24-fold greater agonist activity at beta2-receptors compared to beta1-receptors and 20-fold greater agonist activity compared to beta3-receptors. This selectivity profile is similar to formoterol.
When inhaled, indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a nearly full agonist at the human beta2-adrenergic receptor with nanomolar potency. In isolated human bronchus, indacaterol has a rapid onset of action and a long duration of action.
Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the human heart, there are also beta2-adrenergic receptors in the human heart comprising 10% to 50% of the total adrenergic receptors. The precise function of beta2-adrenergic receptors in the heart is not known, but their presence raises the possibility that even highly selective beta2-adrenergic agonists may have cardiac effects.
Pharmacodynamics: Primary Pharmacodynamic Effects: Onbrez Breezhaler provided consistently significant improvement in lung function [as measured by the forced expiratory volume in one second (FEV1)] over 24 hrs in a number of clinical pharmacodynamic and efficacy trials. There was a rapid onset of action within 5 min after inhalation of Onbrez Breezhaler, comparable to the effect of the fast-acting β₂-agonist salbutamol and a peak effect occurring between 2-4 hrs following the dose. There was no evidence for tachyphylaxis to the bronchodilator effect after repeated dosing for up to 52 weeks. The bronchodilator effect did not depend on the time of dosing (morning or evening).
Onbrez Breezhaler reduced both dynamic and resting hyperinflation in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Inspiratory capacity during constant, submaximal exercise increased by 317 mL compared to placebo after administration of 300 mcg once-daily over 14 days. A statistically significant increase in resting inspiratory capacity, exercise endurance and FEV1 were also demonstrated as well as a significant improvement in measures of dyspnoea.
Secondary Pharmacodynamic Effects: The characteristic adverse effects of inhaled β₂-adrenergic agonists occur as a result of activation of systemic β-adrenergic receptors. The most common adverse effects include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in serum potassium and increases in plasma glucose.
Effects on Cardiac Electrophysiology: The effect of Onbrez Breezhaler on the QT-interval was evaluated in a double-blind, placebo- and active (moxifloxacin)-controlled study following multiple doses of indacaterol 150, 300 or 600 mcg once-daily for 2 weeks in 404 healthy volunteers. Fridericia's method for heart rate correction was employed to derive the corrected QT-interval (QTcF). Maximum mean prolongation of QTcF intervals were <5 millisec, and the upper limit of the 90% confidence interval was below 10 ms for all time-matched comparisons versus placebo. This shows that there is no concern for a pro-arrhythmic potential related to QT-interval prolongations at recommended therapeutic doses. There was no evidence of a concentration-delta QTc relationship in the range of doses evaluated.
Electrocardiographic Monitoring in Patients with Chronic Obstructive Pulmonary Disease (COPD): The effect of Onbrez Breezhaler on heart rate and rhythm was assessed using continuous 24-hr electrocardiogram (ECG) recording (Holter monitoring) in a subset of 605 patients with COPD from a 26-week, double-blind, placebo-controlled Phase III study (see text on Clinical Studies as follows). Holter monitoring occurred once at baseline and up to 3 times during the 26-week treatment period (at weeks 2, 12 and 26).
A comparison of the mean heart rate over 24 hrs showed no increase from baseline for both doses evaluated, 150 and 300 mcg once daily. The hourly heart rate analysis was similar for both doses compared to placebo and tiotropium. The pattern of diurnal variation over 24 hrs was maintained and was similar to placebo.
No difference from placebo or tiotropium was seen in the rates of atrial fibrillation, time spent in atrial fibrillation and also the maximum ventricular rate of atrial fibrillation.
No clear patterns in the rates of single ectopic beats, couplets or runs were seen across visits.
Because the summary data on rates of ventricular ectopic beats can be difficult to interpret, specific pro-arrhythmic criteria were analyzed. In this analysis, baseline occurrence of ventricular ectopic beats were compared to change from baseline, setting certain parameters for the change to describe the pro-arrhythmic response. The number of patients with a documented pro-arrhythmic response was very similar across both indacaterol doses compared to placebo and tiotropium.
Overall, there was no clinically relevant difference in the development of arrhythmic events in patients receiving indacaterol treatment over those patients who received placebo or treatment with tiotropium.
Effects on Serum Potassium and Plasma Glucose: Changes in serum potassium and plasma glucose were evaluated in a 26-week, double-blind, placebo-controlled Phase III study (see text on Clinical Studies as follows). At 1 hr post-dose at week 12, mean changes compared to placebo in serum potassium ranging from 0.03-0.05 mmol/L and in mean plasma glucose ranging from 0.25-0.31 mmol/L were observed.
Mechanism of Action: Indacaterol is an 'ultra' long-acting β₂-adrenergic agonist for once-daily administration. The pharmacological effects of β₂-adrenoceptor agonists, including indacaterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown that indacaterol has >24-fold greater agonist activity at β₂-receptors compared to β₁-receptors and 20-fold greater agonist activity compared to β₃-receptors. This selectivity profile is similar to formoterol.
When inhaled, indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a nearly full agonist at the human β₂-adrenergic receptor with nanomolar potency. In isolated human bronchus, indacaterol has a rapid onset of action and a long duration of action.
Although β₂-receptors are the predominant adrenergic receptors in bronchial smooth muscle and β₁-receptors are the predominant receptors in the human heart, there are also β₂-adrenergic receptors in the human heart comprising 10-50% of the total adrenergic receptors. The precise function of β₂-adrenergic receptors in the heart is not known, but their presence raises the possibility that even highly selective β₂-adrenergic agonists may have cardiac effects.
Pharmacokinetics: Absorption: The median time to reach peak serum concentrations of indacaterol was approximately 15 min after single or repeated inhaled doses. Systemic exposure to indacaterol increased with increasing dose (150-600 mcg) in a dose proportional manner. Absolute bioavailability of indacaterol after an inhaled dose was on average 43%. Systemic exposure results from a composite of pulmonary and intestinal absorption.
Indacaterol serum concentrations increased with repeated once-daily administration. Steady state was achieved within 12-14 days. The mean accumulation ratio of indacaterol ie, area under the plasma concentration-time curve (AUC) over the 24-hr dosing interval on Day 14 compared to Day 1, was in the range of 2.9-3.5 for once-daily inhaled doses between 150 mcg and 600 mcg.
Distribution: After IV infusion the volume of distribution (Vz) of indacaterol was 2557 L indicating an extensive distribution. The in vitro human serum and plasma protein binding was 94.1-95.3% and 95.1-96.2%, respectively.
Biotransformation/Metabolism: After oral administration of radiolabelled indacaterol in a human absorption, distribution, metabolism, excretion (ADME) study, unchanged indacaterol was the main component in serum, accounting for about ⅓ of total drug-related AUC over 24 hr. A hydroxylated derivative was the most prominent metabolite in serum. A phenolic O-glucuronide of indacaterol and hydroxylated indacaterol were further prominent metabolites. A diastereomer of the hydroxylated derivative, a N-glucuronide of indacaterol, and C- and N-dealkylated products were further metabolites identified.
In vitro investigations indicated that UGT1A1 is the only UGT isoform that metabolized indacaterol to the phenolic O-glucuronide. The oxidative metabolites were found in incubations with recombinant CYP1A1, CYP2D6 and CYP3A4. CYP3A4 is concluded to be the predominant isoenzyme responsible for hydroxylation of indacaterol. In vitro investigations further indicated that indacaterol is a low affinity substrate for the efflux pump P-glycoprotein (P-gp).
Elimination: In clinical studies which included urine collection, the amount of indacaterol excreted unchanged via urine was generally <2% of the dose. Renal clearance of indacaterol was, on average, between 0.46 L/hr and 1.20 L/hr. When compared with the serum clearance of indacaterol of 23.3 L/hr, it is evident that renal clearance plays a minor role (about 2-5% of systemic clearance) in the elimination of systemically available indacaterol.
In a human ADME study where indacaterol was given orally, the fecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human feces primarily as unchanged parent drug (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose). Mass balance was complete with ≥90% of the dose recovered in the excreta.
Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life ranging from 45.5-126 hrs. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing, ranged from 40-52 hrs which is consistent with the observed time-to-steady state of approximately 12-14 days.
Special Populations: A population analysis of the effect of age, gender and weight on systemic exposure in COPD patients after inhalation indicated that Onbrez Breezhaler can be used safely in all age and weight groups and regardless of gender. It did not suggest any difference between ethnic subgroups in this population. Limited treatment experience is available for the Black population.
The pharmacokinetics of indacaterol was investigated in 2 different UGT1A1 genotypes, the fully functional [(TA)6, (TA)6] genotype and the low activity [(TA)7, (TA)7] genotype (Gilbert's syndrome genotype). The study demonstrated that steady-state AUC and maximum plasma concentration (C_max) of indacaterol were 1.2-fold higher in the [(TA)7, (TA)7] genotype, indicating that systemic exposure to indacaterol is only insignificantly affected by this UGT1A1 genotypic variation.
Patients with mild and moderate hepatic impairment showed no relevant changes in C_max or AUC of indacaterol, nor did protein-binding differ between mild and moderate hepatic-impaired subjects and their healthy controls. Studies in subjects with severe hepatic impairment were not performed.
Due to the very low contribution of the urinary pathway to total body elimination, a study in renally impaired subjects was not performed.
Clinical Studies: The Onbrez Breezhaler Phase III clinical development program consisted of 8 key studies and enrolled 5430 patients with a clinical diagnosis of COPD, who were 40 years or older, had a smoking history of at least 20 pack years, had a post-bronchodilator FEV1 <80% and ≥30% of the predicted normal value and a post-bronchodilator FEV1/FVC ratio of <70%.
In these studies, indacaterol, administered once-daily at doses of 150 mcg and 300 mcg, showed clinically meaningful improvements in lung function (as measured by the FEV1) over 24 hrs. At the 12-week primary endpoint (24-hr trough FEV1), the 150 mcg dose resulted in a 0.13-0.18 L increase compared to placebo (p<0.001) and a 0.06 L increase compared to salmeterol 50 mcg twice daily (p<0.001). The 300 mcg dose resulted in a 0.17-0.18 L increase compared to placebo (p<0.001) and a 0.1 L increase compared to formoterol 12 mcg twice daily (p<0.001). Both doses resulted in an increase of 0.04-0.05 L over open-label tiotropium 18 mcg once daily (150 mcg, p=0.004; 300 mcg, p=0.01).
Indacaterol administered once daily at the same time each day, either in the morning or evening, had a rapid onset of action within 5 min which is similar to that of salbutamol 200 mcg and statistically significantly faster compared to salmeterol/fluticasone 50/500 mcg, and mean peak improvements in FEV1 relative to baseline of 0.25-0.33 L at steady state occurring between 2-4 hrs following the dose. The 24-hr bronchodilator effect of Onbrez Breezhaler was maintained from the 1st dose throughout a 1-year period with no evidence of loss of efficacy (tachyphylaxis).
In a 26-week, placebo- and active (open label tiotropium)-controlled study in 2059 patients, the mean improvement relative to baseline in FEV1 at 5 min was 0.12 and 0.13 L for Onbrez Breezhaler 150 and 300 mcg once daily, respectively, and the mean peak improvement, relative to baseline, after the 1st dose (Day 1) was 0.19 L and 0.24 L, respectively, and improved to 0.23 L and 0.26 L, respectively, when pharmacodynamic steady state was reached (Day 14). At the primary endpoint (Week 12), both Onbrez Breezhaler 150 and 300 mcg once-daily treatment groups showed a significantly higher trough FEV1 value compared to placebo (both 0.18 L, p<0.001) and to tiotropium (0.05 L, p=0.004 and 0.04 L, p=0.01, respectively).
In this study, 12-hr serial spirometric measurements were performed in a subset of patients throughout daytime hours (12 hrs). Serial FEV1 values over 12 hrs at Day 1 and trough FEV1 values at Day 2 are shown in Figure 1, and at Day 182/183 in Figure 2, respectively. Improvement of lung function was maintained for 24 hrs after the 1st dose and consistently maintained over the 26-week treatment period with no evidence of tolerance (see Figures 1 and 2).


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In a 26-week, placebo-controlled safety extension to this study in 414 patients, efficacy was not a primary endpoint, however at the secondary end point (Week 52) of trough FEV1, treatment with both Onbrez Breezhaler 150 mcg and 300 mcg once-daily resulted in a significantly higher trough FEV1 value compared to placebo (0.17 L, p<0.001 and 0.18L, p<0.001, respectively).
Results of a 12-week, placebo-controlled study in 416 patients which evaluated the 150 mcg once-daily dose, were similar to the results for this dose in the 26-week study. The mean peak improvement in FEV1, relative to baseline, was 0.23 L after 1 day of once-daily treatment. At the primary endpoint (Week 12), treatment with Onbrez Breezhaler 150 mcg once-daily resulted in a significantly higher trough FEV1 value compared to placebo (0.13 L, p<0.001).
In a 26-week, placebo- and active (blind salmeterol)-controlled study in 1002 patients which evaluated the Onbrez Breezhaler 150 mcg once-daily dose, the mean improvement in FEV1, relative to baseline, at 5 min was 0.11 L with a peak improvement of 0.25 L relative to baseline after the 1st dose (Day 1). At the primary end point (Week 12), treatment with Onbrez Breezhaler 150 mcg once-daily showed a significantly higher trough FEV1 value compared to both placebo (0.17 L, p<0.001) and to salmeterol (0.06 L, p<0.001).
In a 52-week, placebo- and active (formoterol)-controlled study in 1732 patients which evaluated the Onbrez Breezhaler 300 mcg once-daily dose and a higher dose, the mean improvement in FEV1, relative to baseline, at 5 min was 0.14 L with a peak improvement of 0.20 L relative to baseline after the 1st dose (Day 1). At the primary end point (Week 12), treatment with Onbrez Breezhaler 300 mcg once-daily resulted in a significantly higher trough FEV1 value compared to placebo (0.17 L, p<0.001) and to formoterol (0.1 L, p<0.001). This improvement of lung function was maintained over the 52-week treatment period with no evidence of loss of efficacy over this period. Onbrez Breezhaler was superior to formoterol with regard to trough FEV1 at all visits.
In a 2-week, placebo- and active (open label salmeterol)-controlled crossover study, 24-hr spirometry was assessed in 68 patients. Serial spirometry values over 24 hrs are displayed in Figure 3. After 14 days of once-daily treatment, improvement of lung function compared to placebo was maintained for 24 hrs, and in addition, the trough FEV1 value was statistically significantly higher compared to salmeterol (0.09 L, p=0.011). Similar results from 24-hr serial spirometry were observed after 26 weeks in a subset of patients (n=236) from the 26-week study. Both studies further support the improvement in FEV1 over placebo with Onbrez Breezhaler administered once-daily and that bronchodilation was maintained throughout the 24-hr dosing interval, in comparison to placebo (see Figure 3).


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The following health outcome effects were demonstrated in the long-term studies of 12-, 26- and 52-week treatment duration: Onbrez Breezhaler significantly improved dyspnea compared to baseline in the 26-week study [as evaluated using the Transitional Dyspnea Index (TDI)] by the 1st assessment (day 29), and this was maintained for the entire 26 weeks in the 150 mcg and 300 mcg once-daily treatments compared to placebo. Onbrez Breezhaler 300 mcg once-daily was also statistically superior to open label tiotropium at all timepoints (p≤0.01) The proportion of patients who achieved a score of ≥1 (corresponding to a clinically important difference) in TDI focal score was significantly greater in the indacaterol group at all 4 assessment points compared to the placebo group (p≤0.001). At 26 weeks, the proportions were 62.4% and 70.8% with Onbrez Breezhaler 150 mcg once-daily and 300 mcg once-daily, respectively, compared to 57.3% and 46.6% with tiotropium and with placebo, respectively. In the 26-week, placebo- and active (blind salmeterol)-controlled study Onbrez Breezhaler 150 mcg once-daily also significantly improved dyspnea over the entire 26-week treatment period. The proportion of patients who achieved a TDI focal score of ≥1 (corresponding to a clinically important difference) was significantly greater in the indacaterol group at all 4 assessment points (Day 29, Day 57, Day 84, and Day 182) than in the placebo group (p≤0.005).
In this study statistically significant differences between either active treatment and placebo were seen for the change from baseline in mean daily, daytime and nighttime number of puffs of rescue medication at every 4-weekly interval of the 26-week treatment period. Onbrez Breezhaler-treated patients required numerically fewer daily, daytime and nighttime puffs of rescue medication compared with salmeterol-treated patients at certain 4-week intervals, but none of the differences between active treatments were statistically significant.
In the 52-week study there was a statistically significant reduction in the number of puffs of rescue short-acting β₂-adrenergic agonists with Onbrez Breezhaler 300 mcg once-daily compared to formoterol and placebo (1.69, 1.35 and 0.02 fewer puffs, respectively). Similarly, in the 26-week study, reductions in rescue use in the Onbrez Breezhaler 150 and 300 mcg once-daily groups were statistically significant compared to open label tiotropium and placebo (1.45 and 1.56 compared to 0.99 and 0.39 fewer puffs, respectively). In the 12-week study (which had no active comparator), a similar pattern was observed with Onbrez Breezhaler 150 mcg once-daily.
Patients treated with Onbrez Breezhaler 150 and 300 mcg once-daily had numerically lower risks of COPD exacerbation compared to placebo in long-term trials of 12-, 26- and 52-week treatment duration. Time-to-first-COPD exacerbation as compared to placebo was significantly longer in the 26-week study under treatment with 150 mcg once-daily and in the 52-week study under treatment with 300 mcg once-daily (p=0.019 and p=0.03, respectively). Pooled analyses showed that patients treated with Onbrez Breezhaler 150 mcg and 300 mcg once-daily had statistically lower risks of COPD exacerbations compared to placebo in both the 6- and 12-month pooled populations. Time-to-first-COPD exacerbation as compared to placebo was significantly longer in the 6-month population under treatment with 150 and 300 mcg doses once-daily (p=0.005 and p=0.006, respectively) and in the 12-month population under treatment with 300 mcg once-daily (p=0.022). Pooled efficacy analysis over 6 and 12 months of treatment demonstrated that the rate of COPD exacerbations was statistically significantly lower than the placebo rate. Treatment comparisons to placebo over 6 months showed a ratio of rates of 0.7 (95% CI [0.53,0.94]; p-value 0.014) and 0.74 (95% CI [0.57,0.96]; p-value 0.024) for Onbrez Breezhaler 150 and 300 mcg, respectively, and the ratio of rates was of 0.78 (95% CI [0.62,0.98]; p-value 0.034) for treatment with 300 mcg once-daily over 12 months.
Onbrez Breezhaler also significantly improved health-related quality of life [as measured using the St. George's Respiratory Questionnaire (SGRQ) in long-term trials of 12-, 26- and 52-week treatment duration. Both doses of 150 and 300 mcg once-daily demonstrated a significantly lower (improved) mean total score in the SGRQ, as well as each component score, in comparison to placebo: An improvement compared to placebo exceeding the minimal clinically important difference of 4 units was shown at 8 weeks and 12 weeks in the 12-week study, and in the 52-week study, this was shown for treatment with 300 mcg once-daily at 8 weeks, 24 weeks, 44 weeks and 52 weeks. In the 26-week study, patients treated with 150 mcg once-daily showed a significantly lower mean total score in the SGRQ compared to tiotropium (p≤0.05), and at the end of the 26-week placebo-controlled safety extension to this study, the mean change in SGRQ total score was a decrease (improvement) of 3.2 units for Onbrez Breezhaler 150 mcg versus placebo after 52 weeks of treatment. In the other 26-week study, treatment with both Onbrez Breezhaler 150 mcg and salmeterol resulted in a significantly lower (improved) mean SGRQ total scores compared to placebo with mean differences of 6.3 units (p<0.001) and 4.2 units (p<0.001), respectively, that exceeded the minimal clinically important difference of 4 units after 12 weeks and thus, were also clinically relevant. Onbrez Breezhaler also achieved statistical superiority over salmeterol by 2.1 units (p=0.033).
Onbrez Breezhaler 150 and 300 mcg once-daily treatment over 26 weeks significantly improved the percentage of days with no daytime symptoms (p<0.02) and the percentage of days where patients were able to perform their normal daily activities as compared to placebo (p<0.001).
Toxicology: Nonclinical Safety Data: Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. The effects of indacaterol seen in toxicity studies in dogs were mainly on the cardiovascular system and consisted of tachycardia, arrhythmias and myocardial lesions. These effects are known pharmacological effects and could be explained by the β₂-agonistic properties of indacaterol. Other relevant effects noted in repeated-dose toxicity studies were mild irritation of the upper respiratory tract in rats consisting of rhinitis and epithelial changes of the nasal cavity and larynx. All these findings were observed only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to clinical use.
Adverse effects with respect to fertility, pregnancy, embryonal/foetal development, pre- and postnatal development could only be demonstrated at doses >195-fold the maximum recommended daily inhalation dose of 300 mcg in humans (on a mg/m² basis). The effects, namely an increased incidence of 1 skeletal variation, were observed in rabbits. Indacaterol was not teratogenic in rats or rabbits following SC administration. Studies on genotoxicity did not reveal any mutagenic or clastogenic potential. The carcinogenic potential of indacaterol has been evaluated in a 2-year inhalation study in rats and a 26-week oral transgenic mouse study. Lifetime treatment of rats resulted in increased incidences of benign ovarian leiomyoma and focal hyperplasia of ovarian smooth muscle in females at doses approximately 68 times the maximum recommended dose of 300 mcg once-daily for humans (on a mg/m² basis). Increases in leiomyomas of the rat female genital tract have been similarly demonstrated with other β₂-adrenergic agonist drugs. A 26-week oral gavage study in CB6F1/TgrasH2 hemizygous mice with indacaterol did not show any evidence of tumorigenicity at doses approximately 9800 times the maximum recommended dose of 300 mcg once-daily for humans (on a mg/m² basis).

ONBREZ BREEZHALER is indicated for maintenance bronchodilator treatment of airflow obstruction in adult patients with chronic obstructive pulmonary disease (COPD).

Adult: Recommended Dosage: Once-daily inhalation of the content of one 150 mcg cap. The dosage should only be increased on medical advice.
Once-daily inhalation of the content of one 300 mcg cap has been shown to provide additional clinical benefit to some patients eg, with regard to breathlessness, particularly for patients with severe COPD. Maximum Dose: 300 mcg once daily.
Dosing in Special Populations: No dosage adjustment is required for geriatric patients, patients with mild and moderate hepatic impairment, or renally-impaired patients. No data is available for subjects with severe hepatic impairment (see Pharmacology under Actions).
Onbrez Breezhaler should not be used in patients <18 years.
Method of administration: Onbrez Breezhaler cap must be administered only by the oral inhalation route and only using the Onbrez Breezhaler inhaler. Capsules must not be swallowed.
Onbrez Breezhaler should be administered at the same time of the day each day. If a dose is missed, the next dose should be taken at the usual time the next day.
Onbrez Breezhaler capsules must always be stored in the blister, and only removed immediately before use.
Patients should be instructed on how to administer the product correctly. Patients who do not experience improvement in breathing should be asked if they are swallowing the medicine rather than inhaling it.

In COPD patients, single doses of 10 times the maximum recommended therapeutic dose were associated with a moderate increase in pulse rate, systolic blood pressure increase and QTc interval.
Symptoms: An overdose of indacaterol is likely to lead to exaggerated effects typical of β₂-adrenergic stimulants ie, tachycardia, tremor, palpitations, headache, nausea, vomiting, drowsiness, ventricular arrhythmias, metabolic acidosis, hypokalaemia and hyperglycaemia.
Treatment: Supportive and symptomatic treatment is indicated. In serious cases, patients should be hospitalised. Use of cardioselective β-blockers may be considered, but only under the supervision of a physician and with extreme caution since the use of β-adrenergic blockers may provoke bronchospasm.

ONBREZ BREEZHALER is contraindicated in patients with hypersensitivity to indacaterol or to any of the excipients.

Asthma: ONBREZ BREEZHALER should not be used in asthma due to the absence of long-term outcome data in asthma with ONBREZ BREEZHALER.
Long-acting beta2-adrenergic agonists may increase the risk of asthma-related serious adverse events, including asthma-related deaths, when used for the treatment of asthma.
Hypersensitivity: Immediate hypersensitivity reactions have been reported after administration of ONBREZ BREEZHALER. If signs suggesting allergic reactions (in particular, difficulties in breathing or swallowing, swelling of tongue, lips and face, urticaria, skin rash) occur, ONBREZ BREEZHALER should be discontinued immediately and alternative therapy instituted.
Paradoxical Bronchospasm: As with other inhalation therapy, administration of Onbrez Breezhaler may result in paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, Onbrez Breezhaler should be discontinued immediately and alternative therapy instituted.
Deterioration of Disease: Onbrez Breezhaler is not indicated for the treatment of acute episodes of bronchospasm ie, as a rescue therapy. In case of deterioration of chronic obstructive pulmonary disease (COPD) whilst on treatment with Onbrez Breezhaler, a re-evaluation of the patient and the COPD treatment regimen should be undertaken. An increase in the daily dose of Onbrez Breezhaler beyond the maximum dose is not appropriate.
Systemic Effects: Although no clinically relevant effect on the cardiovascular system is usually seen after the administration of Onbrez Breezhaler at the recommended doses, as with other β₂-adrenergic agonists, indacaterol should be used with caution in patients with cardiovascular disorders (coronary artery disease, acute myocardial infarction, cardiac arrhythmias, hypertension), in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to β₂-adrenergic agonists.
As with other inhaled β₂-adrenergic drugs, Onbrez Breezhaler should not be used more often or at higher doses than recommended.
Onbrez Breezhaler should not be used in conjunction with other long-acting β₂-adrenergic agonists or medications containing long-acting β₂-adrenergic agonists.
Cardiovascular Effects: Like other β₂-adrenergic agonists, indacaterol may produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. In case such effects occur, Onbrez Breezhaler may need to be discontinued. In addition, β-adrenergic agonists have been reported to produce electrocardiogram changes eg, flattening of the T-wave and ST-segment depression, although the clinical significance of these findings is unknown.
Clinically relevant effects on prolongation of the QTc-interval have not been observed in clinical studies of Onbrez Breezhaler at recommended therapeutic doses (see Pharmacology under Actions).
Hypokalaemia: β₂-adrenergic agonists may produce significant hypokalemia in some patients, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. In patients with severe COPD, hypokalaemia may be potentiated by hypoxia and concomitant treatment (see Interactions) which may increase the susceptibility to cardiac arrhythmias.
Hyperglycaemia: Inhalation of high doses of β₂-adrenergic agonists may produce increases in plasma glucose. Upon initiation of treatment with Onbrez Breezhaler, plasma glucose should be monitored more closely in diabetic patients.
During clinical studies, clinically notable changes in blood glucose were generally more frequent by 1-2% on Onbrez Breezhaler at the recommended doses than on placebo. This product has not been investigated in patients with not well-controlled diabetes mellitus.
Effects on the Ability to Drive or Operate Machinery: Onbrez Breezhaler has no or negligible influence on the ability to drive and use machines.

Pregnancy: No clinical data on exposed pregnancies in COPD patients are available. Studies in animals have shown reproductive toxicity associated with an increased incidence of 1 skeletal variation in rabbits (see Nonclinical Safety Data under Actions). The potential risk for humans is unknown. Because there are no adequate and well-controlled studies in pregnant women, indacaterol should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus.
Labour and delivery: Like other beta2-adrenergic agonists, ONBREZ BREEZHALER may inhibit labor due to a relaxant effect on uterine smooth muscle.
Lactation: It is not known whether indacaterol passes into human breast milk. The substance has been detected in the milk of lactating rats. Because many drugs are excreted in human milk, as with other inhaled β₂-adrenergic drugs, the use of Onbrez Breezhaler by breastfeeding women should only be considered if the expected benefit to the woman is greater than any possible risk to the infant.
Females and males of reproductive potential: Reproduction studies or other data in animals did not reveal a problem or potential problem concerning fertility in either males or females.

Summary of Safety Profile: The safety experience with Onbrez Breezhaler comprises exposure of up to 1 year at doses 2- to 4-fold the recommended therapeutic doses.
The most common adverse drug reactions at the recommended doses were nasopharyngitis, cough, upper respiratory tract infection and muscle spasms. These were in the vast majority mild or moderate and became less frequent when treatment was continued.
At the recommended doses, the adverse drug reaction profile of Onbrez Breezhaler in patients with chronic obstructive pulmonary disease (COPD) shows clinically insignificant systemic effects of β₂-adrenergic stimulation. Mean heart rate changes were <1 beat/min and tachycardia was infrequent and reported at a similar rate as under placebo treatment. Relevant prolongations of QTcF were not detectable in comparison to placebo. The frequency of notable QTcF-intervals [ie, >450 ms (males) and >470 ms (females)] and reports of hypokalaemia were similar to placebo. The mean of the maximum changes in blood glucose were similar on Onbrez Breezhaler and on placebo.
Description of Population: The Onbrez Breezhaler Phase III clinical development program consisted of 8 key studies and enrolled 5430 patients with a clinical diagnosis of moderate to severe COPD. Safety data from 5 of these studies with treatment durations of 12 weeks or longer were pooled from 2484 patients exposed to indacaterol up to 600 mcg once-daily, of which 957 were on treatment with 150 mcg once-daily and 853 on treatment with 300 mcg once-daily. Approximately 41% of patients had severe COPD. The mean age of patients was 63 years, with 47% of patients aged 65 years or older and the majority (86%) was Caucasian.
Tabulated summary of adverse drug reactions from clinical trials: Adverse drug reactions in the table are from this pooled COPD safety database, listed according to MedDRA system organ class and sorted in descending order of frequency on indacaterol 150 mcg once-daily. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category using the following convention (CIOMS III) is also provided for each adverse reaction: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000), including isolated reports. (See table.)


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At a higher dose ie, 600 mcg once-daily, the safety profile of Onbrez Breezhaler was overall similar to that of recommended doses. Additional adverse drug reactions were tremor and anaemia. Nasopharyngitis and muscle spasm occurred more frequently than at the recommended doses.
Selected Adverse Drug Reactions: In Phase III clinical studies, health care providers observed during clinic visits that on average of 17-20% patients experienced a sporadic cough that occurred usually within 15 sec following inhalation and typically lasted for 5 sec. This cough experienced post inhalation was generally well tolerated and did not lead to any patient discontinuing from the studies at the recommended doses (cough is a symptom of COPD and overall only 6.6% of patients reported cough as an adverse event). There is no evidence that cough experienced post inhalation is associated with bronchospasm, exacerbations, deteriorations of disease or loss of efficacy.

Drugs Known to Prolong QTc-Interval: Onbrez Breezhaler, as other β₂-adrenergic agonists, should be administered with caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants or drugs known to prolong the QT-interval, as any effect of these on the QT-interval may be potentiated. Drugs known to prolong the QT-interval may increase the risk of ventricular arrhythmia (see Precautions).
Sympathomimetic Agents: Concomitant administration of other sympathomimetic agents (alone or as part of combination therapy) may potentiate the undesirable effects of Onbrez Breezhaler (see Precautions).
Hypokalemia: Concomitant treatment with methylxanthine derivatives, steroids or non-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of β₂-adrenergic agonists (see Precautions).
Beta-Adrenergic Blockers: β-adrenergic blockers may weaken or antagonise the effect of β₂-adrenergic agonists. Therefore, Onbrez Breezhaler should not be given together with β-adrenergic blockers (including eye drops) unless there are compelling reasons for their use. Where required, cardioselective β-adrenergic blockers should be preferred, although they should be administered with caution.
Metabolic- and Transporter-Based Drug Interaction: Inhibition of the key contributors of indacaterol clearance, cytochrome (CYP) 3A4 and P-gp, has no impact on safety of therapeutic doses of Onbrez Breezhaler. Drug interaction studies were carried out using potent and specific inhibitors of CYP3A4 and P-gp (ie, ketoconazole, erythromycin and verapamil). Verapamil was used as the prototypic inhibitor of P-gp and resulted in 1.4- to 2-fold increase in AUC and 1.5-fold increase in C_max. Co-administration of erythromycin with Onbrez Breezhaler resulted in an increase of 1.4- to 1.6-fold for AUC and 1.2-fold for C_max. Combined inhibition of P-gp and CYP3A4 by the very strong dual inhibitor ketoconazole caused a 2-fold and 1.4-fold increase in AUC and C_max, respectively. Taken together, the data suggest that systemic clearance is influenced by modulation of both P-gp and CYP3A4 activities and that the 2-fold AUC increase caused by the strong dual inhibitor ketoconazole reflects the impact of maximal combined inhibition. The magnitude of exposure increases due to drug interactions does not raise any safety concerns given the safety experience of treatment with Onbrez Breezhaler in clinical trials of up to 1 year at doses 2- to 4-fold the recommended therapeutic doses.
Onbrez Breezhaler has not been shown to cause drug interactions with co-medications. In vitro investigations have indicated that indacaterol has negligible potential to cause metabolic interactions with medications at the systemic exposure levels achieved in clinical practice.

Instructions for use and Handling: For correct administration/use of the product please refer to Dosage & Administration.

Do not store above 30°C. Protect from moisture.

INSTRUCTIONS FOR USE OF ONBREZ BREEZHALER INHALER: This part of the leaflet explains how to use and care for your ONBREZ BREEZHALER inhaler. Please read carefully and follow these instructions.
If you have any questions, ask your doctor or pharmacist.
Please read the full Instructions for Use before using the Onbrez Breezhaler.
1. Insert: Step 1a: Pull off cap.
Step 1b: Open inhaler.
Step 1c: Remove capsule: Remove one capsule from the blister. Do not swallow the capsule.
Step 1d: Insert capsule: Never place a capsule directly into the mouthpiece.
Step 1e: Close inhaler.
2. Pierce and release: Step 2a: Pierce capsule once: Hold the inhaler upright. Pierce capsule by firmly pressing both side buttons at the same time.
You should hear a noise as the capsule is pierced. Only pierce the capsule once.
Step 2b: Release side buttons.
3. Inhale deeply: Step 3a: Breathe out fully: Do not blow into the inhaler.
Step 3b: Inhale medicine deeply: Place the mouthpiece in your mouth and close your lips firmly around it. Do not press the side buttons. Breathe in quickly and as deeply as you can. During inhalation you will hear a whirring noise. You may taste the medicine as you inhale.
Step 3c: Hold breath: Hold your breath for up to 5 seconds.
Check: Check capsule if empty. Open the inhaler to see if any powder is left in the capsule. If there is powder left in the capsule: Close the inhaler. Repeat steps 3a to 3c.
Remove empty capsule. Put the empty capsule in your household waste. Close the inhaler and replace the cap.
Important Information: Onbrez Breezhaler capsules must always be stored in the blister card and only removed immediately before use.
Do not swallow the capsule.
Do not use the Onbrez Breezhaler capsules with any other inhaler.
Do not use the Onbrez Breezhaler inhaler to take any other capsule medicine.
Never place the capsule into your mouth or the mouthpiece of the inhaler.
Do not press the side buttons more than once.
Do not blow into the mouthpiece.
Do not press the side buttons while inhaling through the mouthpiece.
Do not handle capsules with wet hands.
Never wash your inhaler with water.
Your Onbrez Breezhaler Inhaler pack contains: One Onbrez Breezhaler inhaler; One or more blister cards, each containing either 6 or 10 Onbrez Breezhaler capsules to be used in the inhaler.
Cleaning the inhaler: Wipe the mouthpiece inside and outside with a clean, dry, lint-free cloth to remove any powder residue. Keep the inhaler dry. Never wash your inhaler with water.
Disposing of the inhaler after use: Each inhaler should be disposed of after all capsules have been used. Ask your pharmacist how to dispose of medicines and inhalers that are no longer required.
Frequently Asked Questions: Why didn't the inhaler make a noise when I inhaled?: The capsule may be stuck in the capsule chamber. If this happens, carefully loosen the capsule by tapping the base of the inhaler. Inhale the medicine again by repeating steps 3a to 3c.
What should I do if there is powder left inside the capsule?: You have not received enough of your medicine. Close the inhaler and repeat steps 3a to 3c.
I coughed after inhaling - does this matter?: This may happen. As long as the capsule is empty you have received enough of your medicine.
I felt small pieces of the capsule on my tongue - does this matter?: This can happen. It is not harmful. The chances of the capsule breaking into small pieces will be increased if the capsule is pierced more than once.

Antiasthmatic & COPD Preparations

R03AC18 - indacaterol ; Belongs to the class of adrenergic inhalants, selective beta-2-adrenoreceptor agonists. Used in the treatment of obstructive airway diseases.

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