ENERZAIR BREEZHALER 114 MICROGRAMS / 46 MICROGRAMS / 136 MICROGRAMS INHALATION POWDER HARD CAPSULES - summary of medicine characteristics

Enerzair® Breezhaler® 114 micrograms/46 micrograms/136 micrograms inhalation powder, hard capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 150 mcg of indacaterol (as acetate), 63 mcg of glycopyrronium bromide equivalent to 50 mcg of glycopyrronium and 160 mcg of mometasone furoate.

Each delivered dose (the dose that leaves the mouthpiece of the inhaler) contains 114 mcg of indacaterol (as acetate), 58 mcg of glycopyrronium bromide equivalent to 46 mcg of glycopyrronium and 136 mcg of mometasone furoate.

Excipient(s) with known effect

Each capsule contains 25 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Inhalation powder, hard capsule (inhalation powder).

Capsules with green transparent cap and uncoloured transparent body containing a white powder, with the product code “IGM150–50–160” printed in black above two black bars on the body and with the product logo printed in black and surrounded by a black bar on the cap.

4.1 Therapeutic indications

Enerzair Breezhaler is indicated as a maintenance treatment of asthma in adult patients not adequately controlled with a maintenance combination of a long-acting beta2-agonist and a high dose of an inhaled corticosteroid who experienced one or more asthma exacerbations in the previous year.

4.2 Posology and method of administration

Posology

The recommended dose is one capsule to be inhaled once daily.

The maximum recommended dose is 114 mcg/46 mcg/136 mcg once daily.

Treatment should be administered at the same time of the day each day. It can be administered irrespective of the time of the day. If a dose is missed, it should be taken as soon as possible. Patients should be instructed not to take more than one dose in a day.

Special , populations

Elderly population

No dose adjustment is required in elderly patients (65 years of age or older) (see section 5.2).

Renal impairment

No dose adjustment is required in patients with mild to moderate renal impairment. Caution should be observed in patients with severe renal impairment or end-stage renal disease requiring dialysis (see sections 4.4 and 5.2).

Hepatic impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment. No data are available for the use of the medicinal product in patients with severe hepatic impairment, therefore it should be used in these patients only if the expected benefit outweighs the potential risk (see section 5.2).

Paediatric population

The safety and efficacy of Enerzair Breezhaler in paediatric patients below 18 years of age have not been established. No data are available.

Method of administration

For inhalation use only. The capsules must not be swallowed.

The capsules must be administered only using the inhaler provided (see section 6.6) with each new prescription.

Patients should be instructed on how to administer the medicinal product correctly. Patients who do not experience improvement in breathing should be asked if they are swallowing the medicinal product rather than inhaling it.

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

After inhalation, patients should rinse their mouth with water without swallowing (see sections 4.4 and 6.6).

For instructions on use of the medicinal product before administration, see section 6.6.

Information  for patients using a sensor  for Enerzair Breezhaler

The pack may contain an electronic sensor to be attached to the base of the inhaler.

The sensor and App are not required for administration of the medicinal product to the patient. The sensor and App do not control or interfere with delivery of the medicinal product using the inhaler.

The prescribing physician may discuss with the patient whether the use of the sensor and App is appropriate.

For detailed instructions on how to use the sensor and the App, see the Instructions for Use provided in the sensor pack and the App.

4.3 Contraindi­cations

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Deterioration of disease

This medicinal product should not be used to treat acute asthma symptoms, including acute episodes of bronchospasm, for which a short-acting bronchodilator is required. Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a physician.

Patients should not stop treatment without physician supervision since symptoms may recur after discontinuation.

It is recommended that treatment with this medicinal product should not be stopped abruptly. If patients find the treatment ineffective, they should continue treatment but must seek medical attention. Increasing use of reliever bronchodilators indicates a worsening of the underlying condition and warrants a reassessment of the therapy. Sudden and progressive deterioration in the symptoms of asthma is potentially life-threatening and the patient should undergo urgent medical assessment.

Hypersensitivity

Immediate hypersensitivity reactions have been observed after administration of this medicinal product. If signs suggesting allergic reactions occur, in particular angioedema (including difficulties in breathing or swallowing, swelling of the tongue, lips and face), urticaria or skin rash, treatment should be discontinued immediately and alternative therapy instituted.

Paradoxical bronchospasm

As with other inhalation therapy, administration of this medicinal product may result in paradoxical bronchospasm, which can be life-threatening. If this occurs, treatment should be discontinued immediately and alternative therapy instituted.

Cardiovascular effects

Like other medicinal products containing beta2-adrenergic agonists, this medicinal product may produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. If such effects occur, treatment may need to be discontinued.

This medicinal product should be used with caution in patients with cardiovascular disorders (coronary artery disease, acute myocardial infarction, cardiac arrhythmias, hypertension), convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to beta2-adrenergic agonists.

Patients with unstable ischaemic heart disease, a history of myocardial infarction in last 12 months, New York Heart Association (NYHA) class III/IV left ventricular failure, arrhythmia, uncontrolled hypertension, cerebrovascular disease, history of long QT syndrome and patients being

treated with medicinal products known to prolong QTc were excluded from studies in the indacaterol/gly­copyrronium/mo­metasone furoate clinical development programme. Thus safety outcomes in these populations are considered unknown.

While beta2-adrenergic agonists have been reported to produce electrocardio­graphic (ECG) changes, such as flattening of the T wave, prolongation of QT interval and ST segment depression, the clinical significance of these findings is unknown.

Long-acting beta2-adrenergic agonists (LABA) or LABA-containing combination products such as Enerzair Breezhaler should therefore be used with caution in patients with known or suspected prolongation of the QT interval or who are being treated with medicinal products affecting the QT interval.

Hypokalaemia with beta agonists

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 asthma, hypokalaemia may be potentiated by hypoxia and concomitant treatment, which may increase the susceptibility to cardiac arrhythmias (see section 4.5).

Clinically relevant hypokalaemia has not been observed in clinical studies of indacaterol/gly­copyrronium/mo­metasone furoate at the recommended therapeutic dose.

Hyperglycaemia

Inhalation of high doses of beta2-adrenergic agonists and corticosteroids may produce increases in plasma glucose. Upon initiation of treatment, plasma glucose should be monitored more closely in diabetic patients.

This medicinal product has not been investigated in patients with Type I diabetes mellitus or uncontrolled Type II diabetes mellitus.

Anticholinergic effect related to glycopyrronium

Like other anticholinergic medicinal products, this medicinal product should be used with caution in patients with narrow-angle glaucoma or urinary retention.

Patients should be advised about signs and symptoms of acute narrow-angle glaucoma and should be instructed to stop treatment and to contact their doctor immediately should any of these signs or symptoms develop.

Patients with severe renal impairment

For patients with severe renal impairment (estimated glomerular filtration rate below 30 ml/min/1.73 m2), including those with end-stage renal disease requiring dialysis, caution should be observed (see sections 4.2 and 5.2).

Prevention of oropharyngeal infections

In order to reduce the risk of oropharyngeal candida infection, patients should be advised to rinse their mouth or gargle with water without swallowing it or brush their teeth after inhaling the prescribed dose.

Systemic effects of corticosteroids

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids and may vary in individual patients and between different corticosteroid preparations.

Possible systemic effects may include Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataracts, glaucoma, and, more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is therefore important that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

Visual disturbance may be reported with systemic and topical (including intranasal, inhaled and intraocular) corticosteroid use. Patients presenting with symptoms such as blurred vision or other visual disturbances should be considered for referral to an ophthalmologist for evaluation of possible causes of visual disturbances, which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

This medicinal product should be administered with caution in patients with pulmonary tuberculosis or in patients with chronic or untreated infections.

Excipients

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

No specific interaction studies were conducted with indacaterol/gly­copyrronium/mo­metasone furoate. Information on the potential for interactions is based on the potential for each of the monotherapy components.

Medicinal products known to prolong the QTc interval

Like other medicinal products containing a beta2-adrenergic agonist, this medicinal product should be administered with caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or medicinal products known to prolong the QT interval, as any effect of these on the QT interval may be potentiated. Medicinal products known to prolong the QT interval may increase the risk of ventricular arrhythmia (see sections 4.4 and 5.1).

Hypokalaemic treatment

Concomitant hypokalaemic treatment with methylxanthine derivatives, steroids, or non-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of beta2-adrenergic agonists (see section 4.4).

Beta-adrenergic blockers

Beta-adrenergic blockers may weaken or antagonise the effect of beta2-adrenergic agonists. Therefore, this medicinal product should not be given together with beta-adrenergic blockers unless there are compelling reasons for their use. Where required, cardioselective beta-adrenergic blockers should be preferred, although they should be administered with caution.

Interaction with CYP3A4 and P-glycoprotein inhibitors

Inhibition of CYP3A4 and P-glycoprotein (P-gp) has no impact on the safety of therapeutic doses of Enerzair Breezhaler.

Inhibition of the key contributors of indacaterol clearance (CYP3A4 and P-gp) or mometasone furoate clearance (CYP3A4) raises the systemic exposure of indacaterol or mometasone furoate up to two-fold.

Due to the very low plasma concentration achieved after inhaled dosing, clinically significant interactions with mometasone furoate are unlikely. However, there may be a potential for increased systemic exposure to mometasone furoate when strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, nelfinavir, ritonavir, cobicistat) are co-administered.

Cimetidine or other inhibitors of organic cation transport

In a clinical study in healthy volunteers, cimetidine, an inhibitor of organic cation transport which is thought to contribute to the renal excretion of glycopyrronium, increased total exposure (AUC) to glycopyrronium by 22% and decreased renal clearance by 23%. Based on the magnitude of these changes, no clinically relevant drug interaction is expected when glycopyrronium is co-administered with cimetidine or other inhibitors of the organic cation transport.

Other long-acting antimuscarinics and long-acting beta2-adrenergic agonists

The co-administration of this medicinal product with other medicinal products containing long-acting muscarinic antagonists or long-acting beta2-adrenergic agonists has not been studied and is not recommended as it may potentiate adverse reactions (see sections 4.8 and 4.9).

4.6 Fertility, pregnancy and lactation

Pregnancy

There are insufficient data from the use of Enerzair Breezhaler or its individual components (indacaterol, glycopyrronium and mometasone furoate) in pregnant women to determine whether there is a risk.

Indacaterol and glycopyrronium were not teratogenic in rats and rabbits following subcutaneous or inhalation administration, respectively (see section 5.3). In animal reproduction studies with pregnant mice, rats and rabbits, mometasone furoate caused increased foetal malformations and decreased foetal survival and growth.

Like other medicinal products containing beta2-adrenergic agonists, indacaterol may inhibit labour due to a relaxant effect on uterine smooth muscle.

This medicinal product should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the foetus.

Breast-feeding

There is no information available on the presence of indacaterol, glycopyrronium or mometasone furoate in human milk, on the effects on a breast-fed infant, or on the effects on milk production. Other inhaled corticosteroids similar to mometasone furoate are transferred into human milk. Indacaterol, glycopyrronium and mometasone furoate have been detected in the milk of lactating rats. Glycopyrronium reached up to 10-fold higher concentrations in the milk of lactating rats than in the blood of the dam after intravenous administration.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Reproduction studies and other data in animals did not indicate a concern regarding fertility in either males or females.

4.7 Effects on ability to drive and use machines

This medicinal product has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

The most common adverse reactions over 52 weeks were asthma (exacerbation) (41.8%), nasopharyngitis (10.9%), upper respiratory tract infection (5.6%) and headache (4.2%).

Tabulated list of adverse reactions

Adverse drug reactions (ADRs) are listed by MedDRA system organ class (Table 1). The frequency of the ADRs is based on the IRIDIUM study. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): 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).

Table 1

Adverse reactions

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.

4.9 Overdose

General supportive measures and symptomatic treatment should be initiated in cases of suspected overdose.

An overdose will likely produce signs, symptoms or adverse effects associated with the pharmacological actions of the individual components (e.g. tachycardia, tremor, palpitations, headache, nausea, vomiting, drowsiness, ventricular arrhythmias, metabolic acidosis, hypokalaemia, hyperglycaemia, increased intraocular pressure [causing pain, vision disturbances or reddening of the eye], constipation or difficulties in voiding, suppression of hypothalamic pituitary adrenal axis function).

Use of cardioselective beta blockers may be considered for treating beta2-adrenergic effects, but only under the supervision of a physician and with extreme caution, since the use of beta2-adrenergic blockers may provoke bronchospasm. In serious cases, patients should be hospitalised.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination with anticholinergics incl. triple combinations with corticosteroids. ATC code: R03AL12

Mechanism of action

This medicinal product is a combination of indacaterol, a long-acting beta2-adrenergic agonist (LABA), glycopyrronium, a long-acting muscarinic receptor antagonist (LAMA) and mometasone furoate, an inhaled synthetic corticosteroid (IC­S).

Indacaterol

The pharmacological effects of beta2-adrenoceptor agonists, including indacaterol, are at least in part attributable to increased cyclic-3’, 5’-adenosine monophosphate (cyclic AMP) levels, which cause relaxation of bronchial smooth muscle.

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-adrenergic 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.

Glycopyrronium

Glycopyrronium works by blocking the bronchoconstrictor action of acetylcholine on airway smooth muscle cells, thereby dilating the airways. Glycopyrronium bromide is a high-affinity muscarinic receptor antagonist. It demonstrated 4– to 5-fold selectivity for the human M3 and Ml receptors over the human M2 receptor in competition binding studies. It has a rapid onset of action, as evidenced by observed receptor association/dis­sociation kinetic parameters and by the onset of action after inhalation in clinical studies. The long duration of action can be partly attributed to sustained drug concentrations in the lungs, as reflected by the prolonged terminal elimination half-life of glycopyrronium after inhalation via the inhaler in contrast to the half-life after intravenous administration (see section 5.2).

Mometasone furoate

Mometasone furoate is a synthetic corticosteroid with high affinity for glucocorticoid receptors and local anti-inflammatory properties. In vitro, mometasone furoate inhibits the release of leukotrienes from leukocytes of allergic patients. In cell culture, mometasone furoate demonstrated high potency in inhibition of synthesis and release of IL-1, IL-5, IL-6 and TNF-alpha. It is also a potent inhibitor of leukotriene production and of the production of the Th2 cytokines IL-4 and IL-5 from human CD4+ T-cells.

Pharmacodynamic effects

The pharmacodynamic response profile of this medicinal product is characterised by rapid onset of action within 5 minutes after dosing and sustained effect over the whole 24-hour dosing interval.

The pharmacodynamic response profile is further characterised by increased mean peak forced expiratory volume in the first second (FEV1) of 172 ml following indacaterol/gly­copyrronium/mo­metasone furoate 114 mcg/46 mcg/136 mcg once daily compared to salmeterol/flu­ticasone 50 mcg/500 mcg twice daily.

No tachyphylaxis to the lung function benefits of Enerzair Breezhaler was observed over time.

QTc interval

The effect of this medicinal product on the QTc interval has not been evaluated in a thorough QT (TQT) study. For mometasone furoate, no QTc prolonging properties are known.

Clinical efficacy and safety

Comparison of Enerzair Breezhaler to fixed combinations of LABA/ICS

The safety and efficacy of Enerzair Breezhaler in adult patients with persistent asthma was evaluated in the phase III randomised, double-blind study (IRIDIUM). The IRIDIUM study was a 52-week study evaluating Enerzair Breezhaler 114 mcg/46 mcg/68 mcg once daily (N=620) and 114 mcg/46 mcg/136 mcg once daily (N=619) compared to indacaterol/mo­metasone furoate 125 mcg/127.5 mcg once daily (N=617) and 125 mcg/260 mcg once daily (N=618), respectively. A third active control arm included subjects treated with salmeterol/flu­ticasone propionate 50 mcg/500 mcg twice daily (N=618). All subjects were required to have symptomatic asthma (ACQ-7 score >1.5) and were on asthma maintenance therapy using a medium or high dose inhaled synthetic corticosteroid (ICS) and LABA combination therapy for at least 3 months prior to study entry. The mean age was 52.2 years. At screening, 99.9% of patients reported a history of exacerbation in the past year. At study entry, the most common asthma medications reported were medium dose of ICS in combination with a LABA (62.6%) and high dose of ICS in combination with a LABA (36.7%).

The primary objective of the study was to demonstrate superiority of either Enerzair Breezhaler 114 mcg/46 mcg/68 mcg once daily over indacaterol/mo­metasone furoate 125 mcg/127.5 mcg once daily or Enerzair Breezhaler 114 mcg/46 mcg/136 mcg once daily over indacaterol/mo­metasone furoate 125 mcg/260 mcg once daily in terms of trough FEV1 at week 26.

Enerzair Breezhaler 114 mcg/46 mcg/136 mcg once daily demonstrated statistically significant improvements in trough FEV1 at week 26 compared to indacaterol/mo­metasone furoate at corresponding dose. Clinically meaningful improvements in lung function (change from baseline trough FEV1 at week 26, morning and evening peak expiratory flow) were also observed compared to salmeterol/flu­ticasone propionate 50 mcg/500 mcg twice daily.

Findings at week 52 were consistent with week 26 (see Table 2).

All treatment groups showed clinically relevant improvements from baseline in ACQ-7 at week 26, however no statistically significant differences between groups were observed. The mean change from baseline in ACQ-7 at week 26 (key secondary endpoint) and week 52 was around –1 for all treatment groups. The ACQ-7 responder rates (defined as a change decrease in score of >0.5) at different time points are described in Table 2.

Exacerbations were a secondary endpoint (not part of confirmatory testing strategy). Enerzair Breezhaler 114 mcg/46 mcg/136 mcg once daily demonstrated a reduction in the annual rate of exacerbations compared to salmeterol/flu­ticasone propionate 50 mcg/500 mcg twice daily and indacaterol/mo­metasone furoate 125 mcg/260 mcg once daily (see Table 2).

Results for the most clinically relevant endpoints are described in Table 2.

Table 2 Results of primary and secondary endpoints in IRIDIUM study at weeks 26 and 52

Comparison of Enerzair Breezhaler to the concurrent open-label administration of salmeterol/flu­ticasone + tiotropium

A randomised, partially-blinded, active-treatment-controlled, non-inferiority study (ARGON) comparing Enerzair Breezhaler 114 mcg/46 mcg/136 mcg once daily (N=476) and 114 mcg/46 mcg/68 mcg once daily (N=474) to the concurrent administration of salmeterol/flu­ticasone propionate 50 mcg/500 mcg twice daily + tiotropium 5 mcg once daily (N=475) over 24 weeks of treatment was conducted.

Enerzair Breezhaler demonstrated non-inferiority to salmeterol/flu­ticasone + tiotropium for the primary endpoint (change from baseline for Asthma Quality of Life Questionnaire [AQLQ-S]), in previously symptomatic patients on ICS and LABA therapy with a difference of 0.073 (one-sided lower 97.5% confidence limit [CL]: –0.027).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with indacaterol/gly­copyrronium/mo­metasone furoate in one or more subsets of the paediatric population in asthma (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Following inhalation of Enerzair Breezhaler, the median time to reach peak plasma concentrations of indacaterol, glycopyrronium and mometasone furoate was approximately 15 minutes, 5 minutes and 1 hour, respectively.

Based on the in vitro performance data, the dose of each of the monotherapy components delivered to the lung is expected to be similar for the indacaterol/gly­copyrronium/mo­metasone furoate combination and the monotherapy products. Steady-state plasma exposure to indacaterol, glycopyrronium and mometasone furoate after inhalation of the combination was similar to the systemic exposure after inhalation of indacaterol maleate, glycopyrronium or mometasone furoate as monotherapy products.

Following inhalation of the combination, the absolute bioavailability was estimated to be about 45% for indacaterol, 40% for glycopyrronium and less than 10% for mometasone furoate.

Indacaterol

Indacaterol 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 3.8 for once-daily inhaled doses between 60 and 480 mcg (delivered dose). 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.

Glycopyrronium

About 90% of systemic exposure following inhalation is due to lung absorption and 10% is due to gastrointestinal absorption. The absolute bioavailability of orally administered glycopyrronium was estimated to be about 5%.

Mometasone  furoate

Mometasone furoate concentrations increased with repeated once-daily administration via the Breezhaler inhaler. Steady state was achieved after 12 days. The mean accumulation ratio of mometasone furoate, i.e. AUC over the 24-h dosing interval on day 14 compared to day 1, was in the range of 1.28 to 1.40 for once-daily inhaled doses between 68 and 136 mcg as part of the indacaterol/gly­copyrronium/mo­metasone furoate combination.

Following oral administration of mometasone furoate, the absolute oral systemic bioavailability of mometasone furoate was estimated to be very low (<2%).

Distribution

Indacaterol

After intravenous infusion the volume of distribution (Vz) of indacaterol was 2361 to 2557 litres, indicating an extensive distribution. The in vitro human serum and plasma protein binding were 94.1 to 95.3% and 95.1 to 96.2%, respectively.

Glycopyrronium

After intravenous dosing, the steady-state volume of distribution (Vss) of glycopyrronium was 83 litres and the volume of distribution in the terminal phase (Vz) was 376 litres. The apparent volume of distribution in the terminal phase following inhalation (Vz/F) was 7,310 litres, which reflects the much slower elimination after inhalation. The in vitro human plasma protein binding of glycopyrronium was 38% to 41% at concentrations of 1 to 10 ng/ml. These concentrations were at least 6-fold higher than the steady-state mean peak levels achieved in plasma for a 44 mcg once-daily dosing regimen.

Mometasone  furoate

After intravenous bolus administration, the Vd is 332 litres. The in vitro protein binding for mometasone furoate is high, 98% to 99% in concentration range of 5 to 500 ng/ml.

Biotransformation

Indacaterol

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, an N-glucuronide of indacaterol, and C- and N-dealkylated products were further metabolites identified.

In vitro investigations indicated that UGT1A1 was 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.

In vitro the UGT1A1 isoform is a major contributor to the metabolic clearance of indacaterol. However, as shown in a clinical study in populations with different UGT1A1 genotypes, systemic exposure to indacaterol is not significantly affected by the UGT1A1-genotype.

Glycopyrronium

In vitro metabolism studies showed consistent metabolic pathways for glycopyrronium bromide between animals and humans. No human-specific metabolites were found. Hydroxylation resulting in a variety of mono- and bis-hydroxylated metabolites and direct hydrolysis resulting in the formation of a carboxylic acid derivative (M9) were seen.

In vitro investigations showed that multiple CYP isoenzymes contribute to the oxidative biotransformation of glycopyrronium. The hydrolysis to M9 is likely to be catalysed by members of the cholinesterase family.

After inhalation, systemic exposure to M9 was on average in the same order of magnitude as the exposure to the parent drug. Since in vitro studies did not show lung metabolism and M9 was of minor importance in the circulation (about 4% of parent drug Cmax and AUC) after intravenous administration, it is assumed that M9 is formed from the swallowed dose fraction of orally inhaled glycopyrronium bromide by pre-systemic hydrolysis and/or via first-pass metabolism. After inhalation as well as after intravenous administration, only minimal amounts of M9 were found in the urine (i.e. <0.5% of dose).

Glucuronide and/or sulfate conjugates of glycopyrronium were found in urine of humans after repeated inhalation, accounting for about 3% of the dose.

In vitro inhibition studies demonstrated that glycopyrronium bromide has no relevant capacity to inhibit CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5, the efflux transporters MDR1, MRP2 or MXR, and the uptake transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2. In vitro enzyme induction studies did not indicate a clinically relevant induction by glycopyrronium bromide for any of the cytochrome P450 isoenzymes tested as well as for UGT1A1 and the transporters MDR1 and MRP2.

Mometasone  furoate

The portion of an inhaled mometasone furoate dose that is swallowed and absorbed in the gastrointestinal tract undergoes extensive metabolism to multiple metabolites. There are no major metabolites detectable in plasma. In human liver microsomes, mometasone furoate is metabolised by CYP3A4.

Elimination

Indacaterol

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. Compared with the serum clearance of indacaterol of 18.8 to 23.3 litres/hour, 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 in which 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 to 14 days.

Glycopyrronium

After intravenous administration of [3H]-labelled glycopyrronium bromide to humans, the mean urinary excretion of radioactivity in 48 hours amounted to 85% of the dose. A further 5% of the dose was found in the bile. Thus, mass balance was almost complete.

Renal elimination of parent drug accounts for about 60 to 70% of total clearance of systemically available glycopyrronium whereas non-renal clearance processes account for about 30 to 40%. Biliary clearance contributes to the non-renal clearance, but the majority of non-renal clearance is thought to be due to metabolism.

Mean renal clearance of glycopyrronium was in the range of 17.4 and 24.4 litres/hour. Active tubular secretion contributes to the renal elimination of glycopyrronium. Up to 20% of the dose was found in urine as parent drug.

Glycopyrronium plasma concentrations declined in a multi-phasic manner. The mean terminal elimination half-life was much longer after inhalation (33 to 57 hours) than after intravenous (6.2 hours) and oral (2.8 hours) administration. The elimination pattern suggests a sustained lung absorption and/or transfer of glycopyrronium into the systemic circulation at and beyond 24 h after inhalation.

Mometasone  furoate

After intravenous bolus administration, mometasone furoate has a terminal elimination T% of approximately 4.5 hours. A radiolabelled, orally inhaled dose is excreted mainly in the faeces (74%) and to a lesser extent in the urine (8%).

Interactions

Concomitant administration of orally inhaled indacaterol, glycopyrronium and mometasone furoate under steady-state conditions did not affect the pharmacokinetics of any of the active substances.

Special populations

A population pharmacokinetic analysis in patients with asthma after inhalation of Enerzair Breezhaler indicated no significant effect of age, gender, body weight, smoking status, baseline estimated glomerular filtration rate (eGFR) and FEV1 at baseline on the systemic exposure to indacaterol, glycopyrronium or mometasone furoate.

Patients with renal impairment

The effect of renal impairment on the pharmacokinetics of indacaterol, glycopyrronium and mometasone furoate has not been evaluated in dedicated studies with Enerzair Breezhaler. In a population pharmacokinetic analysis, estimated glomerular filtration rate (eGFR) was not a statistically significant covariate for systemic exposure of indacaterol, glycopyrronium and mometasone furoate following administration of Enerzair Breezhaler in patients with asthma.

Due to the very low contribution of the urinary pathway to the total body elimination of indacaterol and mometasone furoate, the effects of renal impairment on their systemic exposure have not been investigated (see sections 4.2 and 4.4).

Renal impairment has an impact on the systemic exposure to glycopyrronium administered as a monotherapy. A moderate mean increase in total systemic exposure (AUClast) of up to 1.4-fold was seen in subjects with mild and moderate renal impairment and up to 2.2-fold in subjects with severe renal impairment and end-stage renal disease. Based on a population pharmacokinetic analysis of glycopyrronium in asthma patients following Enerzair Breezhaler administration, AUC0–24h increased by 27% or decreased by 19% for patients with an absolute GFR of 58 or 143 ml/min, respectively, compared to a patient with an absolute GFR of 93 ml/min. Based on a population pharmacokinetic analysis of glycopyrronium in chronic obstructive pulmonary disease patients with mild and moderate renal impairment (eGFR >30 ml/min/1.73 m2), glycopyrronium can be used at the recommended dose.

Patients with hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of indacaterol, glycopyrronium and mometasone furoate has not been evaluated in subjects with hepatic impairment following administration of Enerzair Breezhaler. However, studies have been conducted with the monotherapy components indacaterol and mometasone furoate (see section 4.2).

Indacaterol

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.

Glycopyrronium

Clinical studies in patients with hepatic impairment have not been conducted. Glycopyrronium is cleared predominantly from the systemic circulation by renal excretion. Impairment of the hepatic metabolism of glycopyrronium is not thought to result in a clinically relevant increase in systemic exposure.

Mometasone furoate

A study evaluating the administration of a single inhaled dose of 400 mcg mometasone furoate by dry powder inhaler to subjects with mild (n=4), moderate (n=4), and severe (n=4) hepatic impairment resulted in only 1 or 2 subjects in each group having detectable peak plasma concentrations of mometasone furoate (ranging from 50 to 105 pcg/ml). The observed peak plasma concentrations appear to increase with severity of hepatic impairment; however, the numbers of detectable levels (assay lower limit of quantification was 50 pcg/ml) were few.

Other special , populations

There were no major differences in total systemic exposure (AUC) for indacaterol, glycopyrronium or mometasone furoate between Japanese and Caucasian subjects. Insufficient pharmacokinetic data are available for other ethnicities or races. Total systemic exposure (AUC) for glycopyrronium may be up to 1.8-fold higher in asthma patients with low body weight (35 kg) and up to 2.5-fold higher in asthma patients with low body weight (35 kg) and low absolute GFR (45 ml/min).

5.3 Preclinical safety data

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule contents

Lactose monohydrate

Magnesium stearate

Capsule shell

Hypromellose

Printing ink

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

30 months.

6.4 Special precautions for storage

Store in the original package in order to protect from light and moisture. This medicinal product does not require any special temperature storage conditions.

6.5 Nature and contents of container

Inhaler body and cap are made from acrylonitrile butadiene styrene, push buttons are made from methyl metacrylate acrylonitrile butadiene styrene.

Needles and springs are made from stainless steel.

PA/Alu/PVC – Alu perforated unit-dose blister. Each blister contains 10 hard capsules.

Single pack containing 10 × 1, 30 × 1 or 90 × 1 hard capsules, together with

1 inhaler.

Pack containing 30 × 1 hard capsules, together with 1 inhaler and 1 sensor.

Multipacks containing 150 (15 packs of 10 × 1) hard capsules and 15 inhalers.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

The inhaler provided with each new prescription should be used. The inhaler in each pack should be disposed of after all capsules in that pack have been used.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Instructions for handling and use

Please read the full Instructions for Use before using the Enerzair Breezhaler.

Inhale deeply

Check capsule is

empty

Check capsule is empty Open the inhaler to see if any powder is left in the capsule.

Step 1a:

Pull off cap

Step 2a:

Pierce capsule once Hold the inhaler upright. Pierce capsule by firmly pressing both side buttons at the same time.

Step 3a:

Breathe out fully

Do not blow into the inhaler.

If there is powder left in the capsule:

Close the inhaler.

Repeat steps 3a to 3d.

Step 1b:

Open inhaler

You should hear a noise as the capsule is pierced. Only pierce the capsule once.

Powder Empty remaining

Step 2b:

Release side buttons

Step 3b:

Inhale medicine deeply Hold the inhaler as shown in the picture.

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 1c:

Remove capsule

Separate one of the blisters from the blister card.

Peel open the blister and remove the capsule.

Do not push the capsule through the foil.

Do not swallow the

capsule.

Step 3c:

Hold breath

Hold your breath for up to 5 seconds.

Remove empty capsule Put the empty capsule in your household waste. Close the inhaler and replace the cap.

Step 3d:

Rinse mouth

Rinse your mouth with water after each dose and spit it out.

Step 1d:

Insert capsule

Never place a capsule directly into the mouthpiece.

Step 1e:

Close inhaler

Important Information

Enerzair Breezhaler capsules must always be stored in the blister card and only removed immediately before use.

Do not push the capsule through the foil to remove it from the blister.

Do not swallow the capsule.

Do not use the Enerzair Breezhaler capsules with any other inhaler.

Do not use the Enerzair 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.

For detailed instructions on use of the sensor and the App, see the Instructions for Use provided in the sensor pack and the App.