Onbrez Breezhaler

Onbrez Breezhaler

indacaterol

Manufacturer:

Novartis

Distributor:

DKSH
Full Prescribing Info
Contents
Indacaterol maleate.
Description
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.
Excipients/Inactive Ingredients: Lactose monohydrate and gelatin.
Action
Pharmacotherapeutic Group: Long-acting beta2-adrenergic agonist.
Pharmacology: Mechanism of Action: 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 hours in a number of clinical pharmacodynamic and efficacy trials. There was a rapid onset of action within 5 minutes after inhalation of Onbrez Breezhaler, comparable to the effect of the fast-acting beta2-agonist salbutamol and a peak effect occurring between 2-4 hours 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).
In a study in 27 patients, Onbrez Breezhaler reduced both dynamic and resting hyperinflation in patients with moderate to severe COPD. Inspiratory capacity during constant, sub-maximal exercise increased by 317 mL compared to placebo after administration of 300 microgram 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 beta2-adrenergic agonists occur as a result of activation of systemic beta-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 microgram, 300 microgram or 600 microgram 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 ms, 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 COPD: The effect of Onbrez Breezhaler on heart rate and rhythm was assessed using continuous 24- hour ECG recording (Holter monitoring) in a subset of 605 patients with COPD from a 26- week, double-blind, placebo-controlled Phase III study (see 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 hours showed no increase from baseline for both doses evaluated, 150 microgram once-daily and 300 microgram once-daily. The hourly heart rate analysis was similar for both doses compared to placebo and tiotropium. The pattern of diurnal variation over 24 hours 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 was 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 CLINICAL STUDIES as follows). At 1 hour post-dose at week 12, mean changes compared to placebo in serum potassium ranging from 0.03 to 0.05mmol/L and in mean plasma glucose ranging from 0.25 to 0.31mmol/L were observed.
Clinical Studies: The Onbrez Breezhaler Phase III clinical development program consisted of 16 key studies and enrolled over 9,000 patients with a clinical diagnosis of moderate to severe COPD, who were 40 years old 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 less than 70%.
In these studies, indacaterol, administered once-daily at doses of 150 microgram and 300 microgram, showed clinically meaningful improvements in lung function (as measured by the forced expiratory volume in one second, FEV1) over 24 hours. At the 12-week primary endpoint (24-hour trough FEV1), the 150 microgram 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 microgram twice a day (p<0.001). The 300 microgram 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 microgram twice a day (p<0.001). Both doses resulted in an increase of 0.04-0.05 L over open-label tiotropium 18- microgram once-daily (150 microgram, p=0.004; 300 microgram, 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 minutes similar to that of salbutamol 200- microgram and statistically significantly faster compared to salmeterol/fluticasone 50/500 microgram, and mean peak improvements in FEV1 relative to baseline of 0.25-0.33 L at steady-state occurring between 2-4 hours following the dose. The 24-hour bronchodilator effect of Onbrez Breezhaler was maintained from the first dose throughout a one-year period with no evidence of loss of efficacy (tachyphylaxis).
In a 26-week, placebo- and active (open label tiotropium)-controlled study in 2,059 patients, the mean improvement relative to baseline in FEV1 at 5 minutes was 0.12 L and 0.13 L for Onbrez Breezhaler 150 microgram and 300 microgram once-daily, respectively, and the mean peak improvement, relative to baseline, after the first 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 end point (Week 12), both Onbrez Breezhaler 150 microgram and 300 microgram 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-hour serial spirometric measurements were performed in a subset of patients throughout daytime hours (12 hours). Serial FEV1 values over 12 hours 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 hours after the first dose and consistently maintained over the 26-week treatment period with no evidence of tolerance. (See Figure 1 and Figure 2.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

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 microgram and 300 microgram 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 microgram 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 end point (Week 12), treatment with Onbrez Breezhaler 150 microgram 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 1,002 patients which evaluated the Onbrez Breezhaler 150 microgram once-daily dose, the mean improvement in FEV1, relative to baseline, at 5 minutes was 0.11 L with a peak improvement of 0.25 L relative to baseline after the first dose (Day 1). At the primary end point (Week 12), treatment with Onbrez Breezhaler 150 microgram 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 1,732 patients which evaluated the Onbrez Breezhaler 300 microgram once-daily dose and a higher dose, the mean improvement in FEV1, relative to baseline, at 5 minutes was 0.14 L with a peak improvement of 0.20 L relative to baseline after the first dose (Day 1). At the primary end point (Week 12), treatment with Onbrez Breezhaler 300 microgram 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-hour spirometry was assessed in 68 patients. Serial spirometry values over 24 hours are displayed in Figure 3. After 14 days of once-daily treatment, improvement of lung function compared to placebo was maintained for 24 hours, and in addition, the trough FEV1 value was statistically significantly higher compared to salmeterol (0.09 L, p=0.011). Similar results from 24-hour 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-hour 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 first assessment (day 29), and this was maintained for the entire 26 weeks in the 150 microgram and 300 microgram once-daily treatments compared to placebo. Onbrez Breezhaler 300 microgram 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 ≥1.0 (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 microgram once-daily and 300 microgram 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 microgram once-daily also significantly improved dyspnea over the entire 26-week treatment period. The proportion of patients who achieved a TDI focal score of ≥1.0 (corresponding to a clinically important difference) was significantly greater in the indacaterol group at all four 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 night time 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 night time 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 beta2-adrenergic agonists with Onbrez Breezhaler 300 microgram 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 microgram once-daily and 300 microgram 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 microgram once-daily.
Patients treated with Onbrez Breezhaler 150 microgram and 300 microgram 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-microgram once-daily and in the 52-week study under treatment with 300 microgram once-daily (p=0.019 and p=0.03, respectively). Pooled analyses showed that patients treated with Onbrez Breezhaler 150 microgram and 300 microgram once-daily had statistically lower risks of COPD exacerbations compared to placebo in both the 6-month 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 microgram and 300 microgram doses once-daily (p=0.005 and p=0.006, respectively) and in the 12-month population under treatment with 300 microgram 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 0.70 (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 microgram and 300 microgram, respectively, and over 12 months the ratio of rates was of 0.78 (95% CI [0.62, 0.98]; p-value 0.034) for treatment with 300 microgram once-daily.
Onbrez Breezhaler also significantly improved health-related quality of life (as measured using the St. George's Respiratory Questionnaire) in long-term trials of 12-, 26- and 52-week treatment duration. Both doses of 150 microgram and 300 microgram 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 and 12 weeks in the 12- week study, and in the 52-week study this was shown for treatment with 300 microgram once-daily at 8, 24, 44 and 52 weeks. In the 26-week study, patients treated with 150-microgram 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 microgram versus placebo after 52 weeks of treatment. In the other 26-week study, treatment with both Onbrez Breezhaler 150 microgram 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 microgram and 300 microgram 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).
Pharmacokinetics: Absorption: Inhalation: 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 microgram to 600 microgram) in a dose proportional manner. Absolute bioavailability of indacaterol after an inhaled dose was on average 43-45%. 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 to 15 days. The mean accumulation ratio of indacaterol, i.e., AUC over the 24-h dosing interval on Day 14 or Day 15 compared to Day 1, was in the range of 2.9 to 3.8 for once-daily inhaled doses between 75 microgram and 600 microgram. Systemic exposure following inhalation results from a composite of oral and pulmonary absorption, with pulmonary absorption accounting for the principal amount.
Oral administration: The oral bioavailability of indacaterol when swallowed from a capsule is approximately 25% when the orogastrointestinal absorption rate of 30-50%. Cmax is reached within 0.5-2 hours.
Distribution: After intravenous infusion the volume of distribution (Vz) of indacaterol was 2,361 L to 2,557 L indicating an extensive distribution. The in vitro human serum and plasma protein binding was 94.1 to 95.3% and 95.1 to 96.2%, respectively.
Biotransformation/Metabolism: After oral administration of radiolabelled indacaterol in a human ADME (absorption, distribution, metabolism, excretion) study, unchanged indacaterol was the main component in serum, accounting for about one third of total drug-related AUC over 24 h. A hydroxylated derivative was the most prominent metabolite in serum. Phenolic O-glucuronides 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-gp.
Elimination: In clinical studies which included urine collection, the amount of indacaterol excreted unchanged via urine was generally lower than 2% of the dose. Renal clearance of indacaterol was, on average, between 0.46 and 1.20 L/h. When compared with the serum clearance of indacaterol of 18.8 to 23.3 L/h, it is evident that renal clearance plays a minor role (about 2 to 6% of systemic clearance) in the elimination of systemically available indacaterol.
In a human ADME study where indacaterol was given orally, the faecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human faeces 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 to 126 hours. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing ranged from 40 to 56 hours which is consistent with the observed time-to-steady state of approximately 12 to 15 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 two 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 Cmax 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 Cmax 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.
Toxicology: Non-Clinical Safety Data: Non-clinical 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 beta2- agonistic properties of indacaterol. During a chronic toxicity study in dogs, elevated levels of creatinine were detected in the blood, but no evidence of altered renal function was seen in the results of either this or any other study. Other relevant effects noted in repeated-dose toxicity studies were mild irritancy 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 more than 195-fold the maximum recommended daily inhalation dose of 300 microgram in humans (on a mg/m2 basis). The effects, namely an increased incidence of one skeletal variation, were observed in rabbits. Indacaterol was not teratogenic in rats or rabbits following subcutaneous 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 microgram 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 microgram once-daily for humans (on a mg/m2 basis).
Indications/Uses
Onbrez Breezhaler is a long-acting beta2-agonist indicated for maintenance bronchodilator treatment of airflow obstruction in adult patients with chronic obstructive pulmonary disease (COPD).
Dosage/Direction for Use
Adults: The recommended dosage of Onbrez Breezhaler is the once-daily inhalation of the content of one 150 microgram capsule using the Onbrez Breezhaler inhaler. The dosage should only be increased on medical advice.
Once-daily inhalation of the content of one 300 microgram capsule, using the Onbrez Breezhaler inhaler, has been shown to provide additional clinical benefit to some patients, e.g. with regard to breathlessness, particularly for patients with severe COPD. The maximum dose is 300 microgram once-daily.
Dosing in special populations: Elderly patients: No dosage adjustment is required in elderly patients.
Children: COPD is not a disease that is relevant to the paediatric population (under 18 years of age). Onbrez Breezhaler has therefore not been investigated in children.
Hepatic or renal impairment: No dosage adjustment is required in patients with mild or moderate hepatic impairment or with renal impairment. There are no data available for use of Onbrez Breezhaler in patients with severe hepatic impairment (see PHARMACOLOGY under Actions).
Method of administration: Onbrez Breezhaler capsules must be administered only by the oral inhalation route and only using the Onbrez Breezhaler inhaler. Onbrez Breezhaler 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. Instructions on how to use the Onbrez Breezhaler inhaler are provided in INFORMATION FOR PATIENTS under Patient Counselling Information.
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.
Overdosage
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 and QTc interval.
An overdose of indacaterol is likely to lead to exaggerated effects typical of beta2-adrenergic stimulants i.e., tachycardia, tremor, palpitations, headache, nausea, vomiting, drowsiness, ventricular arrhythmias, metabolic acidosis, hypokalaemia and hyperglycaemia.
Supportive and symptomatic treatment is indicated. In serious cases, patients should be hospitalised. Use of cardioselective beta-blockers may be considered, but only under the supervision of a physician and with extreme caution since the use of beta-adrenergic blockers may provoke bronchospasm.
Acute intoxication following inadvertent oral ingestion of Onbrez Breezhaler capsules is unlikely because the bioavailability of indacaterol is low.
Contraindications
Hypersensitivity to the active substances, to lactose or to any other of the other excipients.
Special Precautions
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 initial treatment of acute episodes of bronchospasm, i.e., as a rescue therapy. In case of deterioration of 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 beta2- 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 beta2-adrenergic agonists.
As with other inhaled beta2-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 beta2-adrenergic agonists or medications containing long-acting beta2-adrenergic agonists.
Onbrez Breezhaler contains lactose and should therefore not be used in patients with lactose intolerance.
Cardiovascular effects: Like other beta2-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, the drug may need to be discontinued. In addition, beta-adrenergic agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of QT interval, 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: Beta2-adrenergic agonists may produce significant hypokalaemia 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 beta2-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. Onbrez Breezhaler has not been investigated in patients with not well controlled diabetes mellitus.
Use In Pregnancy & Lactation
Pregnancy: No clinical data are available on pregnant COPD patients treated with Onbrez Breezhaler. Studies in animals have shown reproductive toxicity associated with an increased incidence of one skeletal variation in rabbits (see Pharmacology: Toxicology: NON-CLINICAL 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.
Breast-feeding: 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 beta2-adrenergic drugs, the use of Onbrez Breezhaler by breast-feeding women should only be considered if the expected benefit to the woman is greater than any possible risk to the infant.
Fertility: Reproduction studies or other data in animals did not reveal a problem or potential problem concerning fertility in either males or females.
Adverse Reactions
Summary of safety profile: The safety experience with Onbrez Breezhaler comprises exposure of up to one year at doses two- to four-fold the recommended therapeutic doses.
The most common adverse drug reactions at the recommended doses were nasopharyngitis (16.7%), cough, upper respiratory tract infection, and headache. 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 COPD shows clinically insignificant systemic effects of beta2-adrenergic stimulation. Mean heart rate changes were less than one beat per 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 [i.e., >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 16 key studies and enrolled over 9,000 patients with a clinical diagnosis of moderate to severe COPD. Safety data from 11 of these studies with treatment durations of 12 weeks or longer were pooled from 4,764 patients exposed to indacaterol up to 600 microgram once-daily, of which 2,611 were on treatment with 150 microgram once-daily and 1,157 on treatment with 300 microgram once-daily. Approximately 41% of patients had severe COPD. The mean age of patients was 64 years, with 48% of patients aged 65 years or older, and the majority (80%) was Caucasian.
Tabulated summary of adverse drug reactions from clinical trials: Adverse drug reactions in table as follows are from this pooled COPD safety database, listed according to MedDRA system organ class and sorted in descending order of frequency on indacaterol 150 microgram 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 (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports. (See table.)

Click on icon to see table/diagram/image

At a higher, non-recommended dose, i.e., 600 microgram once-daily, the safety profile of Onbrez Breezhaler was overall similar to that of recommended doses. An additional adverse drug reaction was tremor. Nasopharyngitis, muscle spasm, headache and peripheral oedema 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 17-20% of patients experienced a sporadic cough that occurred usually within 15 seconds following inhalation and typically lasted for 5 seconds. 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 up to 8.2% of patients reported cough as an adverse event). There is no evidence that cough experienced post inhalation is associated with bronchospasm, exacerbations, deterioration of disease or loss of efficacy.
Drug Interactions
Medicinal products known to prolong QTc interval: As with other beta2 agonists, there is a theoretical risk that medicinal products known to prolong the QTc interval may have pharmacodynamic interactions with indacaterol and increase the potential risk of ventricular arrhythmia. Examples of such medicinal products are certain antihistamines (e.g. terfenadine, mizolastine), certain antiarrhythmic agents (e.g. quinidine), phenothiazines, erythromycin and tricyclic antidepressants. Concomitant administration of other sympathomimetic agents may exacerbate adverse cardiovascular effects. Caution is required when giving Onbrez Breezhaler to patients receiving concomitant treatment with MAO inhibitors or tricyclic antidepressants since the action of beta2- stimulants on the cardiovascular system may be potentiated.
Concomitant administration of levodopa, leothyroxine and oxytocin may have a negative impact on cardiac tolerance to beta2-sympathomimetic agents (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).
Hypokalaemia: Concomitant treatment with methylxanthine derivatives, steroids, or non-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of beta2-adrenergic agonists (see PRECAUTIONS).
Beta-adrenergic blockers: Beta-adrenergic blockers may weaken or antagonise the effect of beta2-adrenergic agonists. Therefore Onbrez Breezhaler should not be given together with beta-adrenergic blockers (including eye drops) unless there are compelling reasons for their use. Where required, cardioselective beta-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, CYP3A4 and P-glycoprotein (Pgp), 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 (i.e., ketoconazole, erythromycin, verapamil and ritonavir). Verapamil was used as the prototypic inhibitor of P-gp and resulted in 1.4- to two-fold increase in AUC and 1.5-fold increase in Cmax. 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 Cmax. 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 Cmax, respectively. Concomitant treatment with ritonavir, another dual inhibitor of CYP3A4 and P-gp, resulted in a 1.6- to 1.8-fold increase in AUC whereas Cmax was unaffected. 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 one year at doses two- to four-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.
Caution For Usage
Instructions for Use and Handling: For correct administration/use of the product please refer to DOSAGE & ADMINISTRATION.
Incompatibilities: Not applicable.
Storage
Do not store above 30ºC.
Store in the original packaging in order to protect from moisture.
Shelf-Life: 30 months.
Patient Counseling Information
Information for Patients: This part 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.
Each Onbrez Breezhaler pack contains: one Onbrez Breezhaler inhaler; blisters containing Onbrez Breezhaler capsules to be used in the inhaler.
Do not swallow Onbrez Breezhaler capsules: The Onbrez Breezhaler inhaler enables you to inhale the medicine contained in a Onbrez Breezhaler capsule.
Only use the Onbrez Breezhaler inhaler contained in this pack.
Do not use Onbrez Breezhaler capsules with any other inhaler, and do not use Onbrez Breezhaler inhaler to take any other capsule medicine.
How to use your inhaler: 1. Pull off cap.
2. Open inhaler: Hold the base of the inhaler firmly and tilt the mouthpiece to open the inhaler.
3. Prepare capsule: Immediately before use, with dry hands, remove one capsule from the blister.
4. Insert capsule: Place the capsule into the capsule chamber.
Never place a capsule directly into the mouthpiece.
5. Close the inhaler: Close the inhaler fully. You should hear a 'click' as it fully closes.
6. Pierce the capsule: Hold the inhaler upright with the mouthpiece pointing up.
Press both buttons fully one time. You should hear a 'click' as the capsule is being pierced.
Do not press the piercing buttons more than once.
7. Release the buttons fully.
8. Breathe out: Before placing the mouthpiece in your mouth, breathe out fully.
Never blow into the mouthpiece.
9. Inhale the medicine: Before breathing in, place the mouthpiece in your mouth and close your lips firmly around the mouthpiece. Hold the inhaler with the buttons to the left and right (not up and down).
Breathe in rapidly but steadily, as deeply as you can. Do not press the piercing buttons.
10. Note: As you breathe in through the inhaler, the capsule spins around in the chamber and you should hear a whirring noise. You will experience a flavour taste as the medicine goes into your lungs.
If you do not hear a whirring noise, the capsule may be stuck in the capsule cavity. If this occurs, open the inhaler and carefully loosen the capsule by tapping the base of the device. Do not press the piercing buttons to loosen the capsule. Repeat steps 8 and 9 if necessary.
11. Hold breath: Continue to hold your breath for at least 5-10 seconds or as long as comfortably possible while removing the inhaler from your mouth. Then breathe out.
Open the inhaler to see if any powder is left in the capsule. If there is powder left in the capsule, close the inhaler and repeat steps 8 to 11. Most people are able to empty the capsule with one or two inhalations.
Some people occasionally cough soon after inhaling the medicine. If you do, don't worry, as long as the capsule is empty, you have received the full dose.
12. Remove capsule: After you have finished taking your daily dose of Onbrez Breezhaler, open the mouthpiece again, remove the empty capsule by tipping it out, and discard it. Close the inhaler and replace the cap.
Do not store the capsules in the Onbrez Breezhaler inhaler.
13. Mark daily dose tracker: On the inside of the pack there is a daily dose tracker. Put a mark in today's box if it helps to remind you of when your next dose is due.
REMEMBER: Do not swallow Onbrez Breezhaler capsules.
Only use the Onbrez Breezhaler inhaler contained in this pack.
Onbrez Breezhaler capsules must always be stored in the blister, and only removed immediately before use.
Never place a Onbrez Breezhaler capsule directly into the mouthpiece of the Onbrez Breezhaler inhaler.
Do not press the piercing buttons more than once.
Never blow into the mouthpiece of the Onbrez Breezhaler inhaler.
Always release the push buttons before inhalation.
Never wash the Onbrez Breezhaler inhaler with water. Keep it dry. See as follows "How to clean your inhaler".
Never take the Onbrez Breezhaler inhaler apart.
Always use the new Onbrez Breezhaler inhaler that comes with your new Onbrez Breezhaler medication pack.
Do not store the capsules in the Onbrez Breezhaler inhaler.
Always keep the Onbrez Breezhaler inhaler and Onbrez Breezhaler capsules in a dry place.
Additional information: Occasionally, very small pieces of the capsule can get past the screen and enter your mouth. If this happens, you may be able to feel these pieces on your tongue. It is not harmful if these pieces are swallowed or inhaled. The chances of the capsule shattering will be increased if the capsule is pierced more than once (step 6).
How to clean your inhaler: Clean your inhaler once a week. Wipe the mouthpiece inside and outside with a clean, dry lint-free cloth to remove any powder residue. Never wash your inhaler with water. Keep it dry.
ATC Classification
R03AC18 - indacaterol ; Belongs to the class of adrenergic inhalants, selective beta-2-adrenoreceptor agonists. Used in the treatment of obstructive airway diseases.
Presentation/Packing
Inhalation powd cap 150 mcg (black product code "IDL 150" printed above and black company logo printed under black bar on yellowish transparent uncoloured capsule) x 30's.
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