4.1. Therapeutic indications

Trixeo Aerosphere is indicated as a maintenance treatment in adult patients with moderate to severe chronic obstructive pulmonary disease (COPD) who are not adequately treated by a combination of an inhaled corticosteroid and a long‑acting beta2‑agonist or combination of a long-acting beta2‑agonist and a long‑acting muscarinic antagonist (for effects on symptoms control and prevention of exacerbations see section 5.1).

4.2. Posology and method of administration

Posology

The recommended and maximum dose is two inhalations twice daily (two inhalations in the morning and two inhalations in the evening).

If a dose is missed, it should be taken as soon as possible and the next dose should be taken at the usual time. A double dose should not be taken to make up for a forgotten dose.

Special populations

Elderly

No dose adjustments are required in elderly patients (see section 5.2).

Renal impairment

This medicinal product can be used at the recommended dose in patients with mild to moderate renal impairment. It can also be used at the recommended dose in patients with severe renal impairment or end‑stage renal disease requiring dialysis, only if the expected benefit outweighs the potential risk (see sections 4.4 and 5.2).

Hepatic impairment

This medicinal product can be used at the recommended dose in patients with mild to moderate hepatic impairment. It can also be used at the recommended dose in patients with severe hepatic impairment, only if the expected benefit outweighs the potential risk (see sections 4.4 and 5.2).

Paediatric population

There is no relevant use of this medicinal product in children and adolescents (under 18 years of age) for the indication of COPD.

Method of administration

For inhalation use.

Instructions for use

To ensure proper administration of the medicinal product, the patient should be shown how to use the inhaler correctly by a physician or other healthcare professional, who should also regularly check the adequacy of the patient's inhalation technique. The patient should be advised to read the Package Leaflet carefully and follow the instructions for use as given in the leaflet.

Note: It is important to instruct the patients to:

• Not use the inhaler if the drying agent, which is inside the foil pouch, has leaked out of its packet. For best results the inhaler should be at room temperature before use.

• Prime the inhaler by shaking it and actuating into the air four times before first use or two times when the inhaler has not been used for more than seven days, after weekly washing or if it has been dropped.

• Rinse their mouth out with water after inhaling the dose to minimise the risk of oropharyngeal thrush. Do not swallow.

On actuation of Trixeo Aerosphere, a volume of the suspension is expelled from the pressurised container. When the patient inhales through the mouthpiece at the same time as actuating the inhaler, the substance will follow the inspired air into the airways.

Patients who find it difficult to coordinate actuation with inhalation may use Trixeo Aerosphere with a spacer to ensure proper administration of the medicinal product. Trixeo Aerosphere can be used with spacer devices including the Aerochamber Plus Flow-Vu (see section 5.2).

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Not for acute use

This medicinal product is not indicated for the treatment of acute episodes of bronchospasm, i.e. as a rescue therapy.

Paradoxical bronchospasm

Administration of formoterol/glycopyrronium/budesonide may produce paradoxical bronchospasm with an immediate wheezing and shortness of breath after dosing and may be life‑threatening. Treatment with this medicinal product should be discontinued immediately if paradoxical bronchospasm occurs. The patient should be assessed, and alternative therapy instituted if necessary.

Deterioration of disease

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 medical attention must be sought. 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 COPD is potentially life‑threatening and the patient should undergo urgent medical assessment.

Cardiovascular effects

Cardiovascular effects, such as cardiac arrhythmias, e.g. atrial fibrillation and tachycardia, may be seen after the administration of muscarinic receptor antagonists and sympathomimetics, including glycopyrronium and formoterol. This medicinal product should be used with caution in patients with clinically significant uncontrolled and severe cardiovascular disease such as unstable ischemic heart disease, acute myocardial infarction, cardiomyopathy, cardiac arrhythmias, and severe heart failure.

Caution should also be exercised when treating patients with known or suspected prolongation of the QTc interval (QTc > 450 milliseconds for males, or > 470 milliseconds for females), either congenital or induced by medicinal products.

Systemic corticosteroid effects

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur with inhalation treatment than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, cataract and glaucoma. Potential effects on bone density should be considered particularly in patients on high doses for prolonged periods that have co‑existing risk factors for osteoporosis.

Visual disturbances

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes 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 (see section 4.8).

Transfer from oral therapy

Particular care is needed in patients transferring from oral steroids, since they may remain at risk of impaired adrenal function for a considerable time. Patients who have required high dose corticosteroid therapy or prolonged treatment at the highest recommended dose of inhaled corticosteroids, may also be at risk. These patients may exhibit signs and symptoms of adrenal insufficiency when exposed to severe stress. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Pneumonia in patients with COPD

An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid dose but this has not been demonstrated conclusively across all studies.

There is no conclusive clinical evidence for intra‑class differences in the magnitude of the pneumonia risk among inhaled corticosteroid products.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations.

Risk factors for pneumonia in patients with COPD include current smoking, older age, low body mass index (BMI) and severe COPD.

Hypokalaemia

Potentially serious hypokalaemia may result from β2-agonist therapy. This has the potential to produce adverse cardiovascular effects. Particular caution is advised in severe COPD as this effect may be potentiated by hypoxia. Hypokalaemia may also be potentiated by concomitant treatment with other medicinal products which can induce hypokalaemia, such as xanthine derivatives, steroids and diuretics (see section 4.5).

Hyperglycaemia

Inhalation of high doses of β2-adrenergic agonists may produce increases in plasma glucose. Therefore, blood glucose should be monitored during treatment following established guidelines in patients with diabetes.

Co-existing conditions

This medicinal product should be used with caution in patients with thyrotoxicosis.

Anticholinergic activity

Due to its anticholinergic activity, this medicinal product should be used with caution in patients with symptomatic prostatic hyperplasia, urinary retention or with narrow-angle glaucoma. Patients should be informed about the signs and symptoms of acute narrow-angle glaucoma and should be informed to stop using this medicinal product and to contact their doctor immediately should any of these signs or symptoms develop.

Co-administration of this medicinal product with other anticholinergic containing medicinal products is not recommended (see section 4.5).

Renal impairment

As glycopyrronium is predominantly renally excreted, patients with severe renal impairment (creatinine clearance of <30 mL/min), including those with end-stage renal disease requiring dialysis, should only be treated with this medicinal product if the expected benefit outweighs the potential risk (see section 5.2).

Hepatic impairment

In patients with severe hepatic impairment, this medicinal product should be used only if the expected benefit outweighs the potential risk (see section 5.2). These patients should be monitored for potential adverse reactions.

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions

Clinical drug-drug interaction studies have not been conducted with this medicinal product, however, the potential for metabolic interactions is considered to be low based on in-vitro studies (see section 5.2).

Formoterol does not inhibit the CYP450 enzymes at therapeutically relevant concentrations (see section 5.2). Budesonide and glycopyrronium do not inhibit or induce CYP450 enzymes at therapeutically relevant concentrations.

The metabolism of budesonide is primarily mediated by CYP3A4 (see section 5.2). Co-treatment with strong CYP3A inhibitors, e.g. itraconazole, ketoconazole, HIV protease inhibitors and cobicistat-containing products, are expected to increase the risk of systemic side effects, and should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid adverse reactions, in which case patients should be monitored for systemic corticosteroid adverse reactions. This is of limited clinical importance for short-term (1-2 weeks) treatment.

Limited data about this interaction for high-dose inhaled budesonide indicates that marked increases in plasma levels (on average four-fold) may occur if itraconazole, 200 mg once daily, is administered concomitantly with inhaled budesonide (single dose of 1000 micrograms).

Since glycopyrronium is eliminated mainly by the renal route, drug interaction could potentially occur with medicinal products affecting renal excretion mechanisms. In vitro, glycopyrronium is a substrate for the renal transporters OCT2 and MATE1/2K. The effect of cimetidine, a probe inhibitor of OCT2 and MATE1, on inhaled glycopyrronium disposition showed a limited increase in its total systemic exposure (AUC0-t) by 22% and a slight decrease in renal clearance by 23% due to co-administration of cimetidine.

Pharmacodynamic interactions

Other antimuscarinics and sympathomimetics

Co-administration of this medicinal product with other anticholinergic and/or long-acting β2-adrenergic agonist containing medicinal products has not been studied and is not recommended as it may potentiate known inhaled muscarinic antagonist or β2-adrenergic agonist adverse reactions (see section 4.4 and section 4.9).

Concomitant use of other beta-adrenergic medicinal products can have potentially additive effects; therefore, caution is required when other beta-adrenergic medicinal products are prescribed concomitantly with formoterol.

Medicinal product-induced hypokalaemia

Possible initial hypokalaemia may be potentiated by concomitant medicinal products, including xanthine derivatives, steroids and non‑potassium sparing diuretics (see section 4.4). Hypokalaemia may increase the disposition towards arrhythmias in patients who are treated with digitalis glycosides.

β-adrenergic blockers

β-adrenergic blockers (including eye drops) can weaken or inhibit the effect of formoterol. Concurrent use of β-adrenergic blockers should be avoided unless the expected benefit outweighs the potential risk. If β-adrenergic blockers are required, cardio-selective β-adrenergic blockers are preferred.

Other pharmacodynamic interactions

Concomitant treatment with quinidine, disopyramide, procainamide, antihistamines, monoamine oxidase inhibitors, tricyclic antidepressants and phenothiazines can prolong the QT interval and increase the risk of ventricular arrhythmias. In addition, L-dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards beta2-sympathomimetics.

Concomitant treatment with monoamine oxidase inhibitors, including medicinal products with similar properties such as furazolidone and procarbazine, may precipitate hypertensive reactions.

There is an elevated risk of arrhythmias in patients receiving concomitant anaesthesia with halogenated hydrocarbons.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of budesonide, glycopyrronium and formoterol in pregnant women.

Data on the use of inhaled budesonide in more than 2,500 exposed pregnancies indicate no increased teratogenic risk associated with budesonide. Single-dose studies in humans found that very small amounts of glycopyrronium passed the placental barrier.

There is no experience with the use of the propellant HFO-1234ze(E) during human pregnancy or lactation. However, studies on the effect of HFO-1234ze(E) on the reproductive function and embryofoetal development in animals revealed no clinically relevant adverse effects.

No animal reproductive toxicology studies have been conducted with this medicinal product. Budesonide has been shown to induce embryofoetal toxicity in rats and rabbits, a class effect of glucocorticoids. At very high doses/systemic exposure levels, formoterol caused implantation losses as well as decreases in birth weight and early postnatal survival, whereas glycopyrronium had no significant effects on reproduction (see section 5.3).

Administration of this medicinal product to pregnant women should only be considered if the expected benefit to the mother justifies the potential risk to the foetus.

Breast-feeding

A clinical pharmacology study has shown that inhaled budesonide is excreted in breast milk. However, budesonide was not detected in nursing infant blood samples. Based on pharmacokinetic parameters, the plasma concentration in the child is estimated to be less than 0.17% of the mother's plasma concentration. Consequently, no effects due to budesonide are anticipated in breast-fed children whose mothers are receiving therapeutic doses of this medicinal product. It is not known whether glycopyrronium or formoterol are excreted in human milk. Evidence of transfer of glycopyrronium and formoterol into maternal milk in rats has been reported.

Administration of this medicinal product to women who are breast-feeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.

Fertility

Studies in rats have shown adverse effects on fertility only at dose levels higher than the maximum human exposure to formoterol (see section 5.3). Budesonide and glycopyrronium individually, did not cause any adverse effects on fertility in rats. It is unlikely that this medicinal product administered at the recommended dose will affect fertility in humans.

4.7. Effects on ability to drive and use machines

Trixeo Aerosphere has no or negligible influence on the ability to drive and use machines. However, dizziness is an uncommon side effect which should be taken into account when driving or using machines.

4.8. Undesirable effects

Summary of the safety profile

The safety profile is characterised by corticosteroid, anticholinergic and β2-adrenergic class effects related to the individual components of the combination. The most commonly reported adverse reactions in patients receiving this medicinal product were pneumonia (4.6%), headache (2.7%) and urinary tract infection (2.7%).

Tabulated list of adverse reactions

The tabulated list of adverse reactions is based on the experience with this medicinal product in clinical trials and experience with the individual components.

The frequency of adverse reactions is defined using 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) and not known (cannot be estimated from available data).

Table 1: Adverse reactions by frequency and system organ class (SOC)

System Organ Class

Preferred term

Frequency

Infections and infestations

Oral candidiasis

Pneumonia

Common

Immune system disorders

Hypersensitivity

Uncommon

Angioedema

Not known

Endocrine disorders

Signs or symptoms of systemic glucocorticosteroid effects, e.g. hypofunction of the adrenal gland

Very rare

Metabolism and nutrition disorders

Hyperglycaemia

Common

Psychiatric disorders

Anxiety

Insomnia

Common

Depression

Agitation

Restlessness

Nervousness

Uncommon

Abnormal behaviour

Very rare

Nervous system disorders

Headache

Common

Dizziness

Tremor

Uncommon

Eye disorders

Vision blurred (see section 4.4)

Cataract

Glaucoma

Not known

Cardiac disorders

Palpitations

Common

Angina pectoris

Tachycardia

Cardiac arrhythmias (atrial fibrillation, supraventricular tachycardia and extrasystoles)

Uncommon

Respiratory, thoracic and mediastinal disorders

Dysphonia

Cough

Common

Throat irritation

Bronchospasm

Uncommon

Gastrointestinal disorders

Nausea

Common

Dry mouth

Uncommon

Skin and subcutaneous tissue disorders

Bruising

Uncommon

Musculoskeletal and connective tissue disorders

Muscle spasms

Common

Renal and urinary disorders

Urinary tract infection

Common

Urinary retention

Uncommon

General disorders and administration site conditions

Chest pain

Uncommon

Description of selected adverse reactions

Pneumonia

KRONOS was a 24-week study in a total of 1,896 patients with moderate to very severe COPD (mean post-bronchodilator screening FEV1 50% of predicted, standard deviation [SD] 14%), 26% of whom had experienced a COPD exacerbation in the year prior to study entry. The incidence of confirmed pneumonia events reported up to 24 weeks was 1.9% (12 patients) for Trixeo Aerosphere (n=639), 1.6% (10 patients) for formoterol fumarate dihydrate/glycopyrronium (FOR/GLY) MDI 5/7.2 micrograms (n=625), 1.9% (6 patients) for formoterol fumarate dihydrate/budesonide (FOR/BUD) MDI 5/160 micrograms (n=314) and 1.3% (4 patients) for open-labelled formoterol fumarate dihydrate/budesonide Turbuhaler (FOR/BUD) TBH 6/200 micrograms (n=318). In KRONOS, there were no fatal cases of pneumonia with Trixeo Aerosphere.

ETHOS was a 52-week study in a total of 8,529 patients (in the safety population) with moderate to very severe COPD and a history of moderate or severe exacerbations within the prior 12 months (mean post-bronchodilator screening FEV1 43% of predicted, SD 10%). The incidence of confirmed pneumonia was 4.2% (90 patients) for Trixeo Aerosphere (n=2144), 3.5% (75 patients) for formoterol fumarate dihydrate/glycopyrronium/budesonide (FOR/GLY/BUD) MDI 5/7.2/80 micrograms (n=2124), 2.3% (48 subjects) for FOR/GLY MDI 5/7.2 micrograms (n=2125) and 4.5% (96 subjects) FOR/BUD MDI 5/160 micrograms (n=2136). In ETHOS, there were five fatal cases of pneumonia during the treatment phase of the study (two with FOR/GLY/BUD MDI 5/7.2/80, three with FOR/GLY MDI and none with Trixeo Aerosphere).

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 website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

An overdose may lead to exaggerated anticholinergic and/or β2-adrenergic signs and symptoms; the most frequent of which include blurred vision, dry mouth, nausea, muscle spasm, tremor, headache, palpitations and systolic hypertension. When used chronically in excessive doses, systemic glucocorticosteroid effects may appear.

There is no specific treatment for an overdose with this medicinal product. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.