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

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 reactions are listed by MedDRA system organ class (Table 1). The frequency of the adverse reactions is based on the IRIDIUM study. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse 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

System organ class

Adverse reactions

Frequency category

Infections and infestations

Nasopharyngitis

Very common

Upper respiratory tract infection

Common

Candidiasis*1

Common

Urinary tract infection*2

Common

Immune system disorders

Hypersensitivity*3

Common

Metabolism and nutrition disorders

Hyperglycaemia*4

Uncommon

Nervous system disorders

Headache*5

Common

Eye disorders

Cataract

Uncommon

Cardiac disorders

Tachycardia*6

Common

Respiratory, thoracic and mediastinal disorders

Asthma (exacerbation)

Very common

Oropharyngeal pain*7

Common

Cough

Common

Dysphonia

Common

Gastrointestinal disorders

Gastroenteritis*8

Common

Dry mouth*9

Uncommon

Skin and subcutaneous tissue disorders

Rash*10

Uncommon

Pruritus*11

Uncommon

Musculoskeletal and connective tissue disorders

Musculoskeletal pain*12

Common

Muscle spasms

Common

Renal and urinary disorders

Dysuria

Uncommon

General disorders and administration site conditions

Pyrexia

Common

* Indicates grouping of preferred terms (PTs):

1 Oral candidiasis, oropharyngeal candidiasis.

2 Asymptomatic bacteriuria, bacteriuria, cystitis, urethritis, urinary tract infection, urinary tract infection viral.

3 Drug eruption, drug hypersensitivity, hypersensitivity, rash, rash pruritic, urticaria.

4 Blood glucose increased, hyperglycaemia.

5 Headache, tension headache.

6 Sinus tachycardia, supraventricular tachycardia, tachycardia.

7 Odynophagia, oropharyngeal discomfort, oropharyngeal pain, throat irritation.

8 Chronic gastritis, enteritis, gastritis, gastroenteritis, gastrointestinal inflammation.

9 Dry mouth, dry throat.

10 Drug eruption, rash, rash papular, rash pruritic.

11 Eye pruritus, pruritus, pruritus genital.

12 Back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain.

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.