Onbrez Breezhaler

Onbrez^® Breezhaler^® 150 microgram inhalation powder, hard capsules

Onbrez^® Breezhaler^® 300 microgram inhalation powder, hard capsules

Onbrez Breezhaler 150 microgram inhalation powder, hard capsules:

Each capsule contains indacaterol maleate equivalent to 150 microgram indacaterol.

The delivered dose leaving the mouthpiece of the inhaler is indacaterol maleate equivalent to 120 microgram indacaterol.

Excipient with known effect:

Each capsule contains 24.8 mg lactose.

Onbrez Breezhaler 300 microgram inhalation powder, hard capsules:

Each capsule contains indacaterol maleate equivalent to 300 microgram indacaterol.

The delivered dose leaving the mouthpiece of the inhaler is indacaterol maleate equivalent to 240 microgram indacaterol.

Excipient with known effect:

Each capsule contains 24.6 mg lactose.

Inhalation powder, hard capsule

Onbrez Breezhaler 150 microgram inhalation powder, hard capsules:

Transparent (uncoloured) capsules containing a white powder, with “IDL 150” printed in black above a black bar and company logo () printed in black below the black bar.

Onbrez Breezhaler 300 microgram inhalation powder, hard capsules:

Transparent (uncoloured) capsules containing a white powder, with "IDL 300" printed in blue above a blue bar and company logo () printed in blue below the blue bar.

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

Posology

The recommended dose is the inhalation of the content of one 150 microgram capsule once a day, using the Onbrez Breezhaler inhaler. The dose should only be increased on medical advice.

The inhalation of the content of one 300 microgram capsule once a day, using the Onbrez Breezhaler inhaler has been shown to provide additional clinical benefit with regard to breathlessness, particularly for patients with severe COPD. The maximum dose is 300 microgram once daily.

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.

Special populations

Elderly population

Maximum plasma concentration and overall systemic exposure increase with age but no dose adjustment is required in elderly patients.

Hepatic impairment

No dose adjustment is required for patients with mild and moderate hepatic impairment. There are no data available for use of Onbrez Breezhaler in patients with severe hepatic impairment.

Renal impairment

No dose adjustment is required for patients with renal impairment.

Paediatric population

There is no relevant use of Onbrez Breezhaler in the paediatric population (under 18 years).

Method of administration

For inhalation use only. Onbrez Breezhaler capsules must not be swallowed.

The capsules must only be removed from the blister immediately before use.

The capsules must be administered only using the Onbrez Breezhaler inhaler. The Onbrez Breezhaler inhaler provided with each new prescription should be used.

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.

Asthma

Onbrez Breezhaler is a long-acting beta₂-adrenergic agonist, which is only indicated for COPD and should not be used in asthma due to the absence of long-term outcome data in asthma.

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 substituted.

Deterioration of disease

Onbrez Breezhaler is not indicated for the treatment of acute episodes of bronchospasm, i.e. as rescue therapy. In the event of deterioration of COPD during treatment with Onbrez Breezhaler, a re-evaluation of the patient and of the COPD treatment regimen should be undertaken. An increase in the daily dose of Onbrez Breezhaler beyond the maximum dose of 300 microgram 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.

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, treatment may need to be discontinued. In addition, beta-adrenergic agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of QT interval and ST segment depression, although the clinical significance of these observations is unknown. Therefore, long-acting beta₂-adrenergic agonists such as Onbrez Breezhaler should be used with caution in patients with known or suspected prolongation of the QT interval or treated with medicinal products affecting the QT interval.

Clinically relevant effects on prolongation of the QT_c-interval have not been observed in clinical studies of Onbrez Breezhaler at recommended therapeutic doses.

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 , 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.

Excipients

The capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sympathomimetic medicinal products

Concomitant administration of other sympathomimetic medicinal products (alone or as part of combination therapy) may potentiate adverse reactions to Onbrez Breezhaler.

Onbrez Breezhaler should not be used in conjunction with other long-acting beta₂-adrenergic agonists or medicinal products containing long-acting beta₂-adrenergic agonists.

Hypokalaemic treatment

Concomitant hypokalaemic treatment with methylxanthine derivatives, steroids, or non-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of beta₂-adrenergic agonists, therefore caution is required.

Beta-adrenergic blockers

Beta-adrenergic blockers and beta2-adrenergic agonists may weaken or antagonise the effect of each other when administered concurrently. Therefore indacaterol 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 interactions

Inhibition of the key contributors of indacaterol clearance, CYP3A4 and P-glycoprotein (P-gp) raises the systemic exposure of indacaterol by up to two-fold. The magnitude of exposure increases due to interactions does not raise any safety concerns given the safety experience of treatment with Onbrez Breezhaler in clinical studies of up to one year at doses up to twice the maximum recommended therapeutic dose.

Indacaterol has not been shown to cause interactions with medicinal products administered concomitantly. In vitro investigations have indicated that indacaterol has negligible potential to cause metabolic interactions with medicinal products at the systemic exposure levels achieved in clinical practice.

Pregnancy

There are no data from the use of indacaterol in pregnant women available. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant exposures. Like other beta₂-adrenergic agonists, indacaterol may inhibit labour due to a relaxant effect on uterine smooth muscle. Onbrez Breezhaler should only be used during pregnancy if the expected benefits outweigh the potential risks.

Breast-feeding

It is not known whether indacaterol/metabolites are excreted in human milk. Available pharmacokinetic/toxicological data in animals have shown excretion of indacaterol/metabolites in milk. A risk to the breast-fed child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Onbrez Breezhaler therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

A decreased pregnancy rate has been observed in rats. Nevertheless, it is considered unlikely that indacaterol will affect reproductive or fertility performance in humans following inhalation of the maximum recommended dose.

Onbrez Breezhaler has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most common adverse reactions at the recommended doses were nasopharyngitis (14.3%), upper respiratory tract infection (14.2%), cough (8.2%), headache (3.7%) and muscle spasms (3.5%). These were in the vast majority mild or moderate and became less frequent if treatment was continued.

At the recommended doses, the adverse 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 minute, and tachycardia was infrequent and reported at a similar rate as under placebo treatment. Relevant prolongations of QT_cF were not detectable in comparison to placebo. The frequency of notable QT_cF 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 between Onbrez Breezhaler and placebo.

Tabulated summary of adverse reactions

The Onbrez Breezhaler Phase III clinical development programme involved patients with a clinical diagnosis of moderate to severe COPD. 4,764 patients were exposed to indacaterol up to one year at doses up to twice the maximum recommended dose. Of these patients, 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.

Adverse reactions in Table 1 are listed according to MedDRA system organ class in the COPD safety database. Within each system organ class, adverse reactions are ranked by frequency in descending order according to the following convention: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Table 1 Adverse reactions

¹ Reports of hypersensitivity have been received from post-approval marketing experience in association with the use of Onbrez Breezhaler. These were reported voluntarily from a population of uncertain size, and it is therefore not always possible to reliably estimate the frequency or establish a causal relationship to exposure to the medicinal product. Therefore the frequency was calculated from clinical trial experience.

At 600 microgram once-daily, the safety profile of Onbrez Breezhaler was overall similar to that of recommended doses. An additional adverse reaction was tremor (common).

Description of selected adverse reactions

In Phase III clinical studies, healthcare 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 (about 10 seconds in current smokers). It was observed with a higher frequency in female than in male patients and in current smokers than in ex-smokers. This cough experienced post inhalation did not lead to any patient discontinuing from the studies at the recommended doses (cough is a symptom in COPD and only 8.2% 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 QT_c 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.

Pharmacotherapeutic group: Drugs for obstructive airways diseases, selective beta-2-adrenoreceptor agonists, ATC code: R03AC18

Mechanism of action

The pharmacological effects of beta₂-adrenoceptor agonists are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyses 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, a long-acting beta₂-adrenergic agonist, 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.

When inhaled, indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a partial 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 10-50% 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.

Pharmacodynamic effects

Onbrez Breezhaler, administered once a day at doses of 150 and 300 microgram consistently provided clinically significant improvements in lung function (as measured by the forced expiratory volume in one second, FEV₁) over 24 hours across a number of clinical pharmacodynamic and efficacy studies. There was a rapid onset of action within 5 minutes after inhalation, with an increase in FEV₁ relative to baseline of 110-160 ml, comparable to the effect of the fast-acting beta₂-agonist salbutamol 200 microgram and statistically significantly faster compared to salmeterol/fluticasone 50/500 microgram. Mean peak improvements in FEV₁ relative to baseline were 250-330 ml at steady state.

The bronchodilator effect did not depend on the time of dosing, morning or evening.

Onbrez Breezhaler was shown to reduce lung hyperinflation, resulting in increased inspiratory capacity during exercise and at rest, compared to placebo.

Effects on cardiac electrophysiology

A double-blind, placebo- and active (moxifloxacin)-controlled study for 2 weeks in 404 healthy volunteers demonstrated maximum mean (90% confidence intervals) prolongations of the QT_cF interval (in milliseconds) of 2.66 (0.55, 4.77) 2.98 (1.02, 4.93) and 3.34 (0.86, 5.82) following multiple doses of 150 microgram, 300 microgram and 600 microgram, respectively. Therefore, this shows no concern for a pro-arrhythmic potential related to QT-interval prolongations at recommended therapeutic doses or at twice the maximum recommended dose. There was no evidence of a concentration-delta QT_c relationship in the range of doses evaluated.

As demonstrated in 605 patients with COPD in a 26-week, double-blind, placebo-controlled Phase III study, there was no clinically relevant difference in the development of arrhythmic events monitored over 24 hours, at baseline and up to 3 times during the 26-week treatment period, between patients receiving recommended doses of Onbrez Breezhaler treatment and those patients who received placebo or treatment with tiotropium.

Clinical efficacy and safety

The clinical development programme included one 12-week, two six-month (one of which was extended to one year to evaluate safety and tolerability) and one one-year randomised controlled studies in patients with a clinical diagnosis of COPD. These studies included measures of lung function and of health outcomes such as dyspnoea, exacerbations and health-related quality of life.

Lung function

Onbrez Breezhaler, administered once a day at doses of 150 microgram and 300 microgram, showed clinically meaningful improvements in lung function. At the 12-week primary endpoint (24-hour trough FEV₁), the 150 microgram dose resulted in a 130-180 ml increase compared to placebo (p<0.001) and a 60 ml increase compared to salmeterol 50 microgram twice a day (p<0.001). The 300 microgram dose resulted in a 170-180 ml increase compared to placebo (p<0.001) and a 100 ml increase compared to formoterol 12 microgram twice a day (p<0.001). Both doses resulted in an increase of 40-50 ml over open-label tiotropium 18 microgram once a day (150 microgram, p=0.004; 300 microgram, p=0.01). The 24-hour bronchodilator effect of Onbrez Breezhaler was maintained from the first dose throughout a one-year treatment period with no evidence of loss in efficacy (tachyphylaxis).

Symptomatic benefits

Both doses demonstrated statistically significant improvements in symptom relief over placebo for dyspnoea and health status (as evaluated by Transitional Dyspnoea Index [TDI] and St. George's Respiratory Questionnaire [SGRQ], respectively). The magnitude of response was generally greater than seen with active comparators (Table 2). In addition, patients treated with Onbrez Breezhaler required significantly less rescue medication, had more days when no rescue medication was needed compared to placebo and had a significantly improved percentage of days with no daytime symptoms.

Pooled efficacy analysis over 6 months' treatment demonstrated that the rate of COPD exacerbations was statistically significantly lower than the placebo rate. Treatment comparison compared to placebo showed a ratio of rates of 0.68 (95% CI [ 0.47, 0.98]; p-value 0.036) and 0.74 (95% CI [0.56, 0.96]; p-value 0.026) for 150 microgram and 300 microgram, respectively.

Limited treatment experience is available in individuals of African descent.

Table 2 Symptom relief at 6 months treatment duration

Study design with ^a: indacaterol 150 microgram, salmeterol and placebo; ^b: indacaterol 150 and 300 microgram, tiotropium and placebo; ^c: indacaterol 300 microgram, formoterol and placebo

^† MCID = minimal clinically important difference (>1 point change in TDI, >4 point change in SGRQ)

n/e= not evaluated at six months

Paediatric population

Indacaterol is a chiral molecule with R-configuration.

Pharmacokinetic data were obtained from a number of clinical studies, from healthy volunteers and COPD patients.

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 microgram to 600 microgram) in a dose proportional manner. Absolute bioavailability of indacaterol after an inhaled dose was on average 43% to 45%. Systemic exposure results from a composite of pulmonary and gastrointestinal absorption; about 75% of systemic exposure was from pulmonary absorption and about 25% from gastrointestinal absorption.

Indacaterol serum concentrations increased with repeated once-daily administration. Steady state was achieved within 12 to 14 days. The mean accumulation ratio of indacaterol, i.e. AUC over the 24-h dosing interval on Day 14 compared to Day 1, was in the range of 2.9 to 3.5 for once-daily inhaled doses between 150 microgram and 600 microgram.

Distribution

After intravenous infusion the volume of distribution of indacaterol during the terminal elimination phase was 2557 litres 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

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 hours. 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 metabolised 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 litres/hour. When compared with the serum clearance of indacaterol of 23.3 litres/hour, it is evident that renal clearance plays a minor role (about 2 to 5% 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 substance (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 52 hours which is consistent with the observed time-to-steady state of approximately 12-14 days.

Special populations

A population pharmacokinetic analysis showed that there is no clinically relevant effect of age (adults up to 88 years), sex, weight (32-168 kg) or race on the pharmacokinetics of indacaterol. It did not suggest any difference between ethnic subgroups in this population.

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.

Effects on the cardiovascular system attributable to the beta₂-agonistic properties of indacaterol included tachycardia, arrhythmias and myocardial lesions in dogs. Mild irritancy of the nasal cavity and larynx were seen in rodents. All these findings occurred at exposures sufficiently in excess of those anticipated in humans.

Although indacaterol did not affect general reproductive performance in a rat fertility study, a decrease in the number of pregnant F₁ offspring was observed in the peri- and post-developmental rat study at an exposure 14-fold higher than in humans treated with Onbrez Breezhaler. Indacaterol was not embryotoxic or teratogenic in rats or rabbits.

Genotoxicity studies did not reveal any mutagenic or clastogenic potential. Carcinogenicity was assessed in a two-year rat study and a six-month transgenic mouse study. Increased incidences of benign ovarian leiomyoma and focal hyperplasia of ovarian smooth muscle in rats were consistent with similar findings reported for other beta₂-adrenergic agonists. No evidence of carcinogenicity was seen in mice. Systemic exposures (AUC) in rats and mice at the no-observed adverse effect levels in these studies were at least 7- and 49-fold higher, respectively, than in humans treated with Onbrez Breezhaler once a day at a dose of 300 microgram.

Capsule content

Lactose monohydrate

Capsule shell

Gelatin

Not applicable.

30 months.

Do not store above 30°C.

Store in the blister in order to protect from moisture and only remove immediately before use.

Onbrez Breezhaler is a single-dose inhalation device. Inhaler body and cap are made from acrylonitrile butadiene styrene, push buttons are made from methyl methacrylate acrylonitrile butadiene styrene. Needles and springs are made from stainless steel.

PA/Alu/PVC - Alu blister containing 10 hard capsules.

Carton containing 10 capsules and one Onbrez Breezhaler inhaler.

Carton containing 30 capsules and one Onbrez Breezhaler inhaler.

Multipack comprising 2 packs (each containing 30 capsules and 1 inhaler).

Multipack comprising 3 packs (each containing 30 capsules and 1 inhaler).

Multipack comprising 30 packs (each containing 10 capsules and 1 inhaler).

Not all pack sizes may be marketed.

Each inhaler should be disposed of after 30 days of use.

Instructions for handling and use

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

Onbrez Breezhaler 150 microgram inhalation powder, hard capsules: EU/1/09/593/001-005

Onbrez Breezhaler 300 microgram inhalation powder, hard capsules: EU/1/09/593/006-010

Date of first authorisation: 30 November 2009

Date of latest renewal: 18 September 2014

23 April 2018