Trixeo Aerosphere

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

Trixeo Aerosphere 5 micrograms/7.2 micrograms/160 micrograms pressurised inhalation, suspension

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each single actuation (delivered dose, ex-actuator) contains 5 micrograms of formoterol fumarate 
dihydrate, glycopyrronium bromide 9 micrograms, equivalent to 7.2 micrograms of glycopyrronium,
and budesonide 160 micrograms. 

This corresponds to a metered dose of 5.8 micrograms of formoterol fumarate dihydrate, 
glycopyrronium bromide 10.4 micrograms, equivalent to 8.2 micrograms of glycopyrronium, and 
budesonide 182 micrograms.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Pressurised inhalation, suspension.

White suspension.

4. CLINICAL PARTICULARS

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).



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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. Compatibility with the Aerochamber 
Plus Flow-Vu spacer device has been demonstrated (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



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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. 



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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. 



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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



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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 or evidence of safety issues on the use of the propellant norflurane 
(HFA134a) during human pregnancy or lactation. However, studies on the effect of HFA134a 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



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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



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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 national reporting system 
listed in Appendix V.

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination with
anticholinergics including triple combinations with corticosteroids, ATC code: R03AL11

Mechanism of action

Trixeo Aerosphere contains budesonide, a glucocorticosteroid, and two bronchodilators: 
glycopyrronium, a long-acting muscarinic antagonist (anticholinergic) and formoterol, a long-acting 
β2-adrenergic agonist.  

Budesonide is a glucocorticosteroid which when inhaled has a rapid (within hours) and dose 
dependent anti-inflammatory action in the airways.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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Glycopyrronium is a long-acting, muscarinic antagonist, which is often referred to as an 
anticholinergic. The major targets for anticholinergic drugs are muscarinic receptors located in the 
respiratory tract. In the airways, it exhibits pharmacological effects through inhibition of M3 receptor 
at the smooth muscle leading to bronchodilation. Antagonism is competitive and reversible. 
Prevention of methylcholine and acetylcholine-induced bronchoconstrictive effects was dose-
dependent and lasted more than 12 hours. 

Formoterol is a selective β2-adrenergic agonist that when inhaled results in rapid and long-acting 
relaxation of bronchial smooth muscle in patients with reversible airways obstruction. The 
bronchodilating effect is dose dependent, with an onset of effect within 1-3 minutes after inhalation. 
The duration of effect is at least 12 hours after a single dose.

Clinical efficacy

The efficacy and safety of Trixeo Aerosphere was evaluated in patients with moderate to very severe
COPD in two randomised, parallel-group trials, ETHOS and KRONOS. Both studies were 
multicentre, double-blind studies. Patients were symptomatic with a COPD Assessment Test (CAT) 
score ≥10 while receiving two or more daily maintenance therapies for at least 6 weeks prior to 
screening. 

ETHOS was a 52-week trial (N=8,588 randomised; 60% male, mean age of 65) that compared two 
inhalations twice daily of Trixeo Aerosphere, formoterol fumarate dihydrate/glycopyrronium 
(FOR/GLY) MDI 5/7.2 micrograms, and formoterol fumarate dihydrate/budesonide (FOR/BUD) MDI 
5/160 micrograms. Patients had moderate to very severe COPD (post-bronchodilator FEV1 ≥25% to 
<65% predicted) and were required to have a history of one or more moderate or severe COPD 
exacerbations in the year prior to screening. The proportion of patients with moderate, severe and very 
severe COPD was 29%, 61% and 11% respectively. The mean baseline FEV1 across all groups was 
1,021-1,066 mL, and during screening the mean post-bronchodilator percent predicted FEV1 was 43%
and mean CAT score was 19.6. The primary endpoint of the ETHOS trial was the rate of on-treatment 
moderate or severe COPD exacerbations for Trixeo Aerosphere compared with FOR/GLY MDI and 
FOR/BUD MDI.

KRONOS was a 24-week trial (N=1,902 randomised; 71% male, mean age of 65) that compared two 
inhalations twice daily of Trixeo Aerosphere, FOR/GLY MDI 5/7.2 micrograms, FOR/BUD MDI 
5/160 micrograms and open-label active comparator formoterol fumarate dihydrate/budesonide
Turbuhaler (FOR/BUD TBH) 6/200 micrograms. Patients had moderate to very severe COPD (post-
bronchodilator FEV1 ≥25% to <80% predicted). The proportion of patients with moderate, severe and 
very severe COPD was 49%, 43% and 8% respectively. The mean baseline FEV1 across all groups 
was 1,050-1,193 mL, and during screening the mean post-bronchodilator percent predicted FEV1 was 
50%, over 26% of patients reported a history of one or more moderate or severe COPD exacerbation 
in the past year and the mean CAT score was 18.3. There was a 28-week extension, for up to 52 weeks 
of treatment, in a subset of subjects. The primary endpoints of the KRONOS trial were the on-
treatment FEV1 area under the curve from 0-4 hours (FEV1 AUC0-4) over 24 weeks for Trixeo 
Aerosphere compared to FOR/BUD MDI and the on-treatment change from baseline in morning pre-
dose trough FEV1 over 24 weeks for Trixeo Aerosphere compared to FOR/GLY MDI.

At study entry, the most common COPD medications reported in the ETHOS and KRONOS studies 
were ICS+LABA+LAMA (39%, 27% respectively), ICS+LABA (31%, 38% respectively) and 
LAMA+LABA (14%, 20% respectively).

Effect on exacerbations

Moderate or severe exacerbations: 
In the 52-week ETHOS study, Trixeo Aerosphere significantly reduced the annual rate of on-treatment
moderate/severe exacerbations by 24% (95% CI: 17, 31; p<0.0001) compared with FOR/GLY MDI
(rate; 1.08 vs 1.42 events per patient year) and by 13% (95% CI: 5, 21; p=0.0027) compared with 
FOR/BUD MDI (rate; 1.08 vs 1.24 events per patient year). 



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The benefits observed on annualised rate of moderate/severe COPD exacerbations over 24 weeks in 
KRONOS were generally consistent with those observed in ETHOS. Improvements compared with 
FOR/GLY MDI were statistically significant; however improvements compared with FOR/BUD MDI 
and FOR/BUD TBH did not reach statistical significance.

Severe exacerbations (resulting in hospitalisation or death): 
In ETHOS, Trixeo Aerosphere numerically reduced the annual rate of on-treatment severe 
exacerbations by 16% (95% CI: -3, 31; p=0.0944) compared with FOR/GLY MDI (rate; 0.13 vs 0.15 
events per patient year) and significantly reduced the annual rate of on-treatment severe exacerbations 
by 20% (95% CI: 3, 34; p=0.0221) compared with FOR/BUD MDI (rate; 0.13 vs 0.16 events per 
patient year). 

In both studies, benefits on exacerbations were observed in patients with moderate, severe and very 
severe COPD.

Effects on lung function

In ETHOS and KRONOS, Trixeo Aerosphere improved on-treatment lung function (FEV1) compared 
with FOR/GLY MDI and FOR/BUD MDI (see Table 2 for ETHOS and Table 3 for KRONOS). There 
was a sustained effect over the 24-week treatment period in both studies, and over 52 weeks in 
ETHOS. 

Table 2: Lung function analyses – ETHOS (spirometric sub-study)
Trixeo 

Aerosphere
(N=747)

FOR/GLY 

MDI

(N=779)

FOR/BUD 

MDI

(N=755)

Treatment difference
95% CI

Trixeo 
Aerosphere vs. 

FOR/GLY MDI

Trixeo 
Aerosphere vs. 
FOR/BUD MDI

Trough FEV1 (mL) 

over 24 weeks, LS 

mean change from 

baseline (SE)

129 (6.5) 86 (6.6) 53 (6.5) 43 mL
(25, 60)

p<0.0001

76 mL
(58, 94)

p<0.0001#

FEV1 AUC0-4 over 

24 weeks; LS mean 

change from

baseline (SE)

294 (6.3) 245 (6.3) 194 (6.3) 49 mL
(31, 66)

p<0.0001#

99 mL
(82, 117)
p<0.0001

# p-value not adjusted for multiplicity in hierarchical testing plan
LS = least squares, SE = standard error, CI = confidence intervals, N = number in Intent-to-Treat 
population

Table 3: Lung function analyses – KRONOS
Trixeo 
Aero-
sphere
(N=639)

FOR/

GLY 

MDI

(N=625)

FOR/

BUD 

MDI

(N=314)

FOR/

BUD 

TBH

(N=318)

Treatment difference
95% CI

Trixeo 
Aerosphere
vs. FOR/GLY

MDI

Trixeo 
Aerosphere
vs. FOR/BUD

MDI

Trixeo 
Aerosphere
vs. FOR/BUD

TBH

Trough FEV1

(mL) over 24 

weeks, LS mean 

change from 

baseline (SE) 

147 
(6.5)

125 
(6.6)

73 (9.2) 88 (9.1) 22 mL
(4, 39) 

p=0.0139

74 mL
(52, 95) 

p<0.0001

59 mL
(38, 80) 

p<0.0001#

FEV1 AUC0-4

over 24 weeks; 

LS mean change 

305 
(8.4)

288 
(8.5)

201 
(11.7)

214 
(11.5)

16 mL
(-6, 38) 

p=0.1448#

104 mL
(77, 131) 
p<0.0001

91 mL
(64, 117) 
p<0.0001



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from baseline 

(SE)

# p-value not adjusted for multiplicity in hierarchical testing plan
LS = least squares, SE = standard error, CI = confidence intervals, N = number in Intent-to-Treat 
population

Symptom relief

In ETHOS, the baseline average dyspnoea scores ranged from 5.8 – 5.9 across the treatment groups. 
Trixeo Aerosphere significantly improved breathlessness (measured using the Transition Dyspnoea 
Index (TDI) focal score over 24 weeks) compared with FOR/GLY MDI (0.40 units; 95% CI: 0.24, 
0.55; p<0.0001) and compared with FOR/BUD MDI (0.31 units; 95% CI: 0.15, 0.46; p<0.0001). 
Improvements were sustained over 52 weeks. In KRONOS, the baseline average dyspnoea scores 
ranged from 6.3 – 6.5 across the treatment groups. Trixeo Aerosphere significantly improved 
breathlessness over 24 weeks compared with FOR/BUD TBH (0.46 units; 95% CI: 0.16, 0.77; 
p=0.0031). Improvements compared with FOR/GLY MDI, and FOR/BUD MDI did not reach 
statistical significance.

Health-related quality of life 

In ETHOS, Trixeo Aerosphere significantly improved disease-specific health status (as assessed by 
the St. George’s Respiratory Questionnaire [SGRQ] total score) over 24 weeks compared with
FOR/GLY MDI (improvement -1.62; 95% CI: -2.27, -0.97; p<0.0001) and compared with FOR/BUD
MDI (improvement -1.38, 95% CI: -2.02, -0.73; p<0.0001). Improvements were sustained over 52 
weeks. In KRONOS, improvements compared with FOR/GLY MDI, FOR/BUD MDI and FOR/BUD
TBH did not reach statistical significance. 

Use of rescue medication

In ETHOS, Trixeo Aerosphere significantly reduced the on-treatment use of rescue medication over 
24 weeks compared with FOR/GLY MDI (treatment difference -0.51 puffs/day; 95% CI: -0.68, -0.34;
p<0.0001) and FOR/BUD MDI (treatment difference -0.37 puffs/day; 95% CI: -0.54, -0.20;
p<0.0001). Reductions were sustained over 52 weeks. In KRONOS, differences compared with 
FOR/GLY MDI, FOR/BUD MDI and FOR/BUD TBH were not statistically significant. 

Paediatric population 

The European Medicines Agency has waived the obligation to submit the results of studies with 
Trixeo Aerosphere in all subsets of the paediatric population, in COPD (see section 4.2 for 
information on paediatric use).

5.2 Pharmacokinetic properties

Following inhalation of the formoterol, glycopyrronium and budesonide combination, the 
pharmacokinetics of each component was similar to those observed when each active substance was 
administered separately. 

Effect of a spacer
The use of this medicinal product with the Aerochamber Plus Flow-Vu spacer in healthy volunteers 
increased the total systemic exposure (as measured by AUC0-t) to budesonide and glycopyrronium by 
33% and 55%, respectively, while exposure to formoterol was unchanged. In patients with good 
inhalation technique, systemic exposure was not increased with the use of a spacer. 

Absorption

Budesonide



13

Following inhaled administration of this medicinal product in subjects with COPD, budesonide Cmax

occurred within 20 to 40 minutes. Steady state is achieved after approximately 1 day of repeated 
dosing of this medicinal product and the extent of exposure is approximately 1.3 times higher than 
after the first dose.

Glycopyrronium
Following inhaled administration of this medicinal product in subjects with COPD, glycopyrronium 
Cmax occurred at 6 minutes. Steady state is achieved after approximately 3 days of repeated dosing of 
this medicinal product and the extent of exposure is approximately 1.8 times higher than after the first 
dose.

Formoterol
Following inhaled administration of this medicinal product in subjects with COPD, formoterol Cmax 

occurred within 40 to 60 minutes. Steady state is achieved after approximately 2 days of repeated 
dosing with this medicinal product and the extent of exposure is approximately 1.4 times higher than 
after the first dose.

Distribution

Budesonide
The estimated budesonide apparent volume of distribution at steady-state is 1200 L, via population 
pharmacokinetic analysis. Plasma protein binding is approximately 90% for budesonide. 

Glycopyrronium
The estimated glycopyrronium apparent volume of distribution at steady-state is 5500 L, via
population pharmacokinetic analysis. Over the concentration range of 2-500 nmol/L, plasma protein 
binding of glycopyrronium ranged from 43% to 54%.

Formoterol
The estimated formoterol apparent volume of distribution at steady-state is 2400 L, via population 
pharmacokinetic analysis. Over the concentration range of 10-500 nmol/L, plasma protein binding of 
formoterol ranged from 46% to 58%. 

Biotransformation

Budesonide
Budesonide undergoes an extensive degree (approximately 90%) of biotransformation on first passage
through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of 
the major metabolites, 6 β-hydroxy-budesonide and 16-hydroxy-prednisolone, is less than 1% of that 
of budesonide.

Glycopyrronium
Based on literature, and an in-vitro human hepatocyte study, metabolism plays a minor role in the 
overall elimination of glycopyrronium. CYP2D6 was found to be the predominant enzyme involved in 
the metabolism of glycopyrronium. 

Formoterol
The primary metabolism of formoterol is by direct glucuronidation and by O-demethylation followed 
by conjugation to inactive metabolites. Secondary metabolic pathways include deformylation and 
sulfate conjugation. CYP2D6 and CYP2C have been identified as being primarily responsible for 
O-demethylation.

Elimination

Budesonide
Budesonide is eliminated via metabolism mainly catalysed by the enzyme CYP3A4. The metabolites 
of budesonide are excreted in urine as such or in conjugated form. Only negligible amounts of 



14

unchanged budesonide have been detected in the urine. The effective terminal elimination half-life of
budesonide derived via population pharmacokinetic analysis was 5 hours.

Glycopyrronium
After IV administration of a 0.2 mg dose of radiolabelled glycopyrronium, 85% of the dose was 
recovered in urine 48 hours post dose and some of radioactivity was also recovered in bile. The 
effective terminal elimination half-life of glycopyrronium derived via population pharmacokinetic 
analysis was 15 hours.

Formoterol

The excretion of formoterol was studied in six healthy subjects following simultaneous 
administration of radiolabelled formoterol via the oral and IV routes. In that study, 62% of the drug 
related radioactivity was excreted in the urine while 24% was eliminated in the faeces. The effective 
terminal elimination half-life of formoterol derived via population pharmacokinetic analysis was 10 
hours.

Special populations

Age, gender, race/ethnicity and weight

Dose adjustments are not necessary based on the effect of age, gender or weight on the 
pharmacokinetic parameters of budesonide, glycopyrronium and formoterol. There were no 
major differences in total systemic exposure (AUC) for all compounds between healthy 
Japanese, Chinese and Western subjects. Insufficient pharmacokinetic data is available for other 
ethnicities or races.

Hepatic impairment
No pharmacokinetic studies have been performed with this medicinal product in patients with hepatic 
impairment. However, because both budesonide and formoterol are primarily eliminated via hepatic 
metabolism, an increased exposure can be expected in patients with severe liver impairment.
Glycopyrronium is primarily cleared from the systemic circulation by renal excretion and hepatic 
impairment would therefore not be expected to affect systemic exposure.

Renal impairment
Studies evaluating the effect of renal impairment on the pharmacokinetics of budesonide, 
glycopyrronium and formoterol were not conducted.

The effect of renal impairment on the exposure to budesonide, glycopyrronium and formoterol for up 
to 24 weeks was evaluated in a population pharmacokinetic analysis. Estimated glomerular filtration
rate (eGFR) varied from 31-192 mL/min representing a range of moderate to no renal impairment.
Simulation of the systemic exposure (AUC0-12) in subjects with COPD with moderate renal
impairment (eGFR of 45 mL/min) indicates an approximate 68% increase for glycopyrronium compared 
to subjects with COPD with normal renal function (eGFR of >90 mL/min). Renal function was found 
not to affect exposure to budesonide or formoterol. Subjects with COPD with both low body weight 
and moderate-severe impaired renal function may have an approximate doubling of systemic exposure 
to glycopyrronium.

5.3 Preclinical safety data

Non-clinical data reveal no specific hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

No studies have been conducted with the combination of budesonide, glycopyrronium and formoterol 
in respect of genotoxicity, carcinogenic potential and toxicity to reproduction and development.

In animal reproduction studies, glucocorticosteroids such as budesonide have been shown to induce 
malformations (cleft palate, skeletal malformations). However, these animal experimental results are 



15

not relevant in humans at the recommended doses (see section 4.6). Budesonide demonstrated no 
tumourigenic potential in mice. In rats, an increased incidence of hepatocellular tumours was 
observed, considered to be a class-effect in rats from long-term exposure to corticosteroids.

Animal reproduction studies with formoterol have shown a slightly reduced fertility in male rats at 
high systemic exposure and implantation losses, as well as decreased early postnatal survival and birth 
weight at considerably higher systemic exposures than those reached during clinical use. A slight 
increase in the incidence of uterine leiomyomas has been observed in rats and mice treated with 
formoterol; an effect which is considered to be a class-effect in rodents after long-term exposure to 
high doses of β2-adrenoreceptor agonists.

Animal reproduction studies with glycopyrronium have shown reduced rat and rabbit foetal weights, 
and low body weight gain of rat offspring before weaning at considerably higher systemic exposure 
than those reached during clinical use. No evidence of carcinogenicity was seen in rats and mice.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Norflurane 
1,2-distearoyl-sn-glycero-3-phosphocholine
Calcium chloride

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

To be used within 6 weeks of opening the pouch (56 actuations)
To be used within 3 months of opening the pouch (120 actuations)

6.4 Special precautions for storage

Do not store above 30oC. 
Do not expose to temperatures higher than 50oC. Do not pierce the pressurised container. Store in a 
dry place. 

6.5 Nature and contents of container 

Trixeo Aerosphere is a pressurised metered dose inhaler, comprising an aluminium pressurised 
container with an attached dose indicator, supplied with a white plastic actuator body and mouthpiece 
with a grey dust cap. Each inhaler is individually packaged in a foil laminate pouch containing a 
desiccant sachet and packed in to a carton.

Pack sizes of 1 container of 56 or 120 actuations.
Multipacks of 360 (3 containers of 120) actuations.

Not all pack sizes may be marketed. 

6.6 Special precautions for disposal 

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



16

requirements. The pressurised container should not be broken, punctured or burnt, even when 
apparently empty.

7. MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/20/1498/001 56 actuations
EU/1/20/1498/002 120 actuations
EU/1/20/1498/003 360 actuations (3 packs of 120)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.



17

ANNEX II

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT



18

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release

ASTRAZENECA DUNKERQUE PRODUCTION
224 avenue de la Dordogne
59640 DUNKERQUE
France

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

Medicinal product subject to medical prescription.

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic safety update reports (PSURs)

The requirements for submission of PSURs for this medicinal product are set out in the list of 
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC
and any subsequent updates published on the European medicines web-portal.

The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 
6 months following authorisation.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT  

 Risk management plan (RMP)

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 
activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 
marketing authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.



19

ANNEX III

LABELLING AND PACKAGE LEAFLET



20

A. LABELLING



21

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON – SINGLE INHALER

1. NAME OF THE MEDICINAL PRODUCT

Trixeo Aerosphere 5/7.2/160 micrograms pressurised inhalation, suspension
formoterol fumarate dihydrate/glycopyrronium/budesonide

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each single actuation contains 5 micrograms of formoterol fumarate dihydrate, 9 micrograms 
glycopyrronium bromide equivalent to 7.2 micrograms of glycopyrronium, and 160 micrograms of 
budesonide.

3. LIST OF EXCIPIENTS

Norflurane, 1,2-distearoyl-sn-glycero-3-phosphocholine and calcium chloride.

4. PHARMACEUTICAL FORM AND CONTENTS

Pressurised inhalation, suspension.
56 actuations (1 inhaler)
120 actuations (1 inhaler)

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Shake well before use.
Read the package leaflet before use.
Inhalation use
Open here

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 
OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
To be used within 6 weeks of opening the pouch (56 actuations)
To be used within 3 months of opening the pouch (120 actuations)

9. SPECIAL STORAGE CONDITIONS



22

Do not store above 30oC.
Do not expose to temperatures higher than 50°C. 
Do not pierce the pressurised container.
Store in a dry place.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/20/1498/001 56 actuations
EU/1/20/1498/002 120 actuations

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

trixeo aerosphere

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN 
NN 



23

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON FOR MULTIPACK WITH BLUE BOX

1. NAME OF THE MEDICINAL PRODUCT

Trixeo Aerosphere 5/7.2/160 micrograms pressurised inhalation, suspension
formoterol fumarate dihydrate/glycopyrronium/budesonide

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each single actuation contains 5 micrograms of formoterol fumarate dihydrate, 9 micrograms 
glycopyrronium bromide equivalent to 7.2 micrograms of glycopyrronium, and 160 micrograms of 
budesonide.

3. LIST OF EXCIPIENTS

Norflurane, 1,2-distearoyl-sn-glycero-3-phosphocholine and calcium chloride.

4. PHARMACEUTICAL FORM AND CONTENTS

Pressurised inhalation, suspension.
Multipack: 360 actuations (3 packs of 120)

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Shake well before use.
Read the package leaflet before use.
Inhalation use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 
OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
To be used within 3 months of opening the pouch

9. SPECIAL STORAGE CONDITIONS

Do not store above 30oC.
Do not expose to temperatures higher than 50°C. 



24

Do not pierce the pressurised container.
Store in a dry place.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/20/1498/003 360 actuations (3 packs of 120)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

trixeo aerosphere

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN 
NN 



25

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

INNER CARTON OF MULTIPACK (WITHOUT BLUE BOX)

1. NAME OF THE MEDICINAL PRODUCT

Trixeo Aerosphere 5/7.2/160 micrograms pressurised inhalation, suspension
formoterol fumarate dihydrate/glycopyrronium/budesonide

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each single actuation contains 5 micrograms of formoterol fumarate dihydrate, 9 micrograms 
glycopyrronium bromide equivalent to 7.2 micrograms of glycopyrronium, and 160 micrograms of 
budesonide.

3. LIST OF EXCIPIENTS

Norflurane, 1,2-distearoyl-sn-glycero-3-phosphocholine and calcium chloride.

4. PHARMACEUTICAL FORM AND CONTENTS

Pressurised inhalation, suspension.
120 actuations (1 inhaler). Component of a multipack, can’t be sold separately.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Shake well before use.
Read the package leaflet before use.
Inhalation use
Open here

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 
OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
To be used within 3 months of opening the pouch

9. SPECIAL STORAGE CONDITIONS

Do not store above 30oC.



26

Do not expose to temperatures higher than 50°C. 
Do not pierce the pressurised container.
Store in a dry place.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/20/1498/003 360 actuations (3 packs of 120)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

trixeo aerosphere

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA



27

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

FOIL POUCH

1. NAME OF THE MEDICINAL PRODUCT

Trixeo Aerosphere 5/7.2/160 micrograms pressurised inhalation, suspension
formoterol fumarate dihydrate/glycopyrronium/budesonide

2. NAME OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca

3. EXPIRY DATE

EXP
To be used within 6 weeks of opening the pouch (56 actuations)
To be used within 3 months of opening the pouch (120 actuations)

4. BATCH NUMBER

Lot

5. OTHER

Inhalation use
Read the package leaflet before use.
Shake well before use.
Do not swallow the desiccant. 



28

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

INHALER LABEL (ACTUATOR)

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Trixeo Aerosphere 5/7.2/160 mcg pressurised inhalation
formoterol fumarate dihydrate/glycopyrronium/budesonide
Inhalation use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

4. BATCH NUMBER

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

56 actuations
120 actuations

6. OTHER

AstraZeneca 

Date pouch opened:



29

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

INHALER LABEL (PRESSURISED CONTAINER)

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Trixeo Aerosphere 5/7.2/160 mcg pressurised inhalation
formoterol fumarate dihydrate/glycopyrronium/budesonide
Inhalation use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

56 actuations
120 actuations

6. OTHER



30

B. PACKAGE LEAFLET



31

Package leaflet: Information for the patient

Trixeo Aerosphere 5 micrograms/7.2 micrograms/160 micrograms, pressurised inhalation, 
suspension

formoterol fumarate dihydrate/glycopyrronium/budesonide

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you.
 Keep this leaflet. You may need to read it again.
 If you have any further questions, ask your doctor or pharmacist.
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.
 If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What Trixeo Aerosphere is and what it is used for 
2. What you need to know before you use Trixeo Aerosphere
3. How to use Trixeo Aerosphere
4. Possible side effects 
5. How to store Trixeo Aerosphere
6. Contents of the pack and other information

Instructions for use

1. What Trixeo Aerosphere is and what it is used for

Trixeo Aerosphere contains three active substances: formoterol fumarate dihydrate, glycopyrronium,
and budesonide. 

 Formoterol fumarate dihydrate and glycopyrronium belong to a group of medicines called 
‘bronchodilators’. They work in different ways to prevent tightening of the muscles around the 
airways, making it easier for air to get in and out of the lungs.

 Budesonide belongs to a group of medicines called ‘corticosteroids’. These work by reducing 
inflammation in your lungs. 

Trixeo Aerosphere is an inhaler that is used for adults with a lung disease called ‘chronic obstructive 
pulmonary disease’ (or ‘COPD’), a long-term disease of the airways in the lungs. 

Trixeo Aerosphere is used to make breathing easier and improve symptoms of COPD such as 
shortness of breath, wheezing and cough. Trixeo Aerosphere can also prevent flare-ups 
(exacerbations) of COPD.

Trixeo Aerosphere delivers the active substances into your lungs as you breathe in. If you use this 
medicine regularly twice a day, it will help to reduce the effects of COPD on your everyday life.

2. What you need to know before you use Trixeo Aerosphere

Do not use Trixeo Aerosphere
 if you are allergic to formoterol fumarate dihydrate, glycopyrronium, budesonide or any of the 

other ingredients of this medicine (listed in section 6).

Warnings and precautions 
Trixeo Aerosphere is used as a long-term maintenance treatment for COPD. Do not use it to treat a 
sudden attack of breathlessness or wheezing.



32

Immediate breathing difficulties 
If you get tightness of the chest, coughing, wheezing or breathlessness immediately after using Trixeo 
Aerosphere, stop using it and tell your doctor straight away (see ‘Serious side effects’ at the top of 
Section 4 for more information).

If your breathlessness, tightness of the chest, wheezing or coughing is getting worse while using 
Trixeo Aerosphere, you should continue to use Trixeo Aerosphere but contact your doctor as soon as 
possible, as you may need additional treatment.

Talk to your doctor before using Trixeo Aerosphere if:
 you have high blood pressure or heart problems
 you have diabetes 
 you have a lung infection
 you have problems with your thyroid gland
 you have low levels of potassium in your blood
 you have prostate problems or any problems passing urine
 you have an eye problem called ‘angle-closure glaucoma’
 you have kidney or liver problems.
Talk to your doctor if you think any of these may apply to you.

Children and adolescents
Trixeo Aerosphere has not been studied in children and adolescents. Do not give this medicine to 
children or adolescents below the age of 18 years.

Other medicines and Trixeo Aerosphere
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This includes medicines obtained without a prescription, and herbal medicines. This is 
because Trixeo Aerosphere can affect the way some medicines work. Also some medicines can affect 
how Trixeo Aerosphere works, or make it more likely that you will have side effects. 

Tell your doctor or pharmacist if you are taking any of the following:
 medicines called beta-blockers (such as atenolol or propranolol), that may be used for high blood 

pressure or heart problems, or to treat glaucoma (such as timolol) 
 medicines which are used to treat fungal infections – such as ketoconazole or itraconazole 
 medicines which are used to treat HIV infection – such as ritonavir or cobicistat 
 medicines that lower the amount of potassium in your blood, such as:

- corticosteroids that you take by mouth (such as prednisolone),
- diuretics – medicines that increase urine production (such as furosemide or 

hydrochlorothiazide), which can be used for treating high blood pressure,
- some medicines used to treat breathing problems (such as theophylline) – called 

‘methylxanthines’,
 any medicines that work in the same way as Trixeo Aerosphere – such as tiotropium, ipratropium, 

aclidinium, umeclidinium or salmeterol, arformoterol, vilanterol, olodaterol or indacaterol. Do not
use Trixeo Aerosphere if you already use these medicines.

 medicines which are used to treat heart rhythm problems – such as amiodarone
 medicines which can change some electrical activity of the heart (called the ‘QT interval’) – such 

as medicines for:
- depression (such as monoamine oxidase inhibitors or tricyclic antidepressants),
- bacterial infections (such as erythromycin, clarithromycin or telithromycin),
- allergic reactions (anti-histamines).

If any of the above applies to you, or if you are not sure, talk to your doctor or pharmacist before using 
Trixeo Aerosphere.

Pregnancy and breast-feeding



33

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 

Do not use Trixeo Aerosphere if you are pregnant unless your doctor tells you that you can.

Do not use this medicine if you are breast-feeding unless your doctor tells you that you can. 

Driving and using machines
It is unlikely that this medicine will affect your ability to drive or use machines. However, dizziness is 
an uncommon side effect which should be taken into account when driving or using machines. 

3. How to use Trixeo Aerosphere

Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if 
you are not sure.

How much to use
The recommended dose is two puffs twice a day – two puffs in the morning and two puffs in the 
evening.

It is important to use Trixeo Aerosphere every day – even if you have no COPD symptoms at the time. 

Remember: Always rinse your mouth with water after using Trixeo Aerosphere. This is to remove 
any medicine which is left in the mouth. Spit this water out – do not swallow. 

How to use
Trixeo Aerosphere is for inhalation use.
Please read the ‘Instructions for Use’ at the end of this leaflet. If you are not sure how to use Trixeo 
Aerosphere, talk to your doctor or pharmacist. 

Using Trixeo Aerosphere with a spacer
You may find it difficult breathing in and pressing the inhaler at the same time. If this happens, talk to
your doctor or pharmacist. It may help to use a ‘spacer’ with your inhaler.

If you use more Trixeo Aerosphere than you should
If you have used more Trixeo Aerosphere than you should, talk to a doctor or pharmacist straight 
away. You may need medical attention. You may notice that your heart is beating faster than usual, 
you feel shaky, you have problems with your sight, you have a dry mouth or you have a headache or 
feel sick (nausea).

If you forget to use Trixeo Aerosphere
Do not take a double dose to make up for a forgotten dose. Take it as soon as you remember.

However, if it is nearly time for your next dose, skip the missed dose. Do not take more than two puffs 
twice a day on the same day.

If you stop using Trixeo Aerosphere
This medicine is for long-term use. Use this medicine for as long as your doctor tells you to. It will 
only be effective as long as you are using it.

Do not stop unless your doctor tells you to – even if you feel better – as your symptoms may get
worse. If you want to stop treatment, talk to your doctor first.

If you have any further questions on the use of this medicine, talk to your doctor or pharmacist.

4. Possible side effects



34

Like all medicines, this medicine can cause side effects, although not everybody gets them. The 
following side effects may happen with this medicine:

Serious side effects

Uncommon (may affect up to 1 in 100 people)

Immediate breathing difficulties:
 if you get breathing difficulties straight after using Trixeo Aerosphere, such as tightness of the 

chest, coughing, wheezing or feeling breathless, stop using this medicine and tell your doctor 
straight away. 

Allergic reactions:
 swelling of your face, particularly around your mouth (swelling of your tongue or throat may 

make it difficult to swallow)
 rash or hives together with difficulty breathing
 suddenly feeling faint

These symptoms may be signs of an allergic reaction which may become serious. Stop using this 
medicine and call for medical help straight away if you notice the serious side effects above. 

Other side effects
Tell your doctor or pharmacist if you notice any of the following side effects:

Common (may affect up to 1 in 10 people)
 thrush in the mouth (a fungal infection). Rinsing your mouth out with water immediately after 

using Trixeo Aerosphere may help prevent this.
 feeling anxious
 difficulty sleeping
 feeling sick (nausea)
 headache
 coughing or a hoarse voice
 muscle cramps
 awareness of your heart beating (palpitations)
 high blood sugar levels (as shown in tests)
 painful and frequent urination (may be signs of a urinary tract infection)
 pneumonia (infection of the lung).

Tell your doctor if you have any of the following while using Trixeo Aerosphere, they could be 
symptoms of a lung infection:
 fever or chills,
 increased mucus production, change in mucus colour,
 increased cough or increased breathing difficulties.

Uncommon (may affect up to 1 in 100 people)
 shaking, tremor or feeling dizzy
 dry mouth, or mild irritation in the throat 
 bruising of the skin
 feeling restless, nervous or agitated
 depression
 fast heart beat or uneven heart beat
 chest pain or tightening in the chest (angina pectoris)

Very rare (may affect up to 1 in 10,000 people)
 changes in behaviour
 an effect on the adrenal gland



35

Not known (frequency cannot be estimated from the available data):
 blurred vision
 clouding of the lens of your eyes (signs of cataract) 
 increased pressure in the eye (glaucoma)
 swelling of your face, particularly around your mouth (swelling of your tongue or throat may 

make it difficult to swallow)

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine.

5. How to store Trixeo Aerosphere

Keep this medicine out of the sight and reach of children.

Do not use Trixeo Aerosphere after the expiry date which is stated on the carton, pouch and 
pressurised container after ‘EXP’. The expiry date refers to the last day of that month.

After opening the pouch, the inhaler must be used within:
 6 weeks – for an inhaler that contains 56 puffs
 3 months – for an inhaler than contains 120 puffs.

Keep the inhaler inside the sealed pouch – only remove the inhaler from the sealed pouch immediately 
before first use. On the day the pouch is opened, write the date on the inhaler label in the space 
provided. 

Do not store above 30oC. Store in a dry place.   

For best results, the inhaler should be at room temperature before you use it.

Do not break, puncture or burn the pressurised container, even when apparently empty. Do not use or 
store near heat or open flames.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Trixeo Aerosphere contains 
The active substances are formoterol fumarate dihydrate, glycopyrronium and budesonide. 

Each single inhalation provides a delivered dose (the dose leaving the mouthpiece) of 5 micrograms of 
formoterol fumarate dihydrate, 9 micrograms glycopyrronium bromide equivalent to 7.2 micrograms 
glycopyrronium and 160 micrograms of budesonide.

The other ingredients are norflurane, 1,2- distearoyl-sn-glycero-3-phosphocholine and calcium 
chloride.

What Trixeo Aerosphere looks like and contents of the pack
Trixeo Aerosphere is a pressurised inhalation, suspension.

Trixeo Aerosphere comes as a pressurised container with a dose indicator, supplied with a white 
plastic actuator body and mouthpiece (see Figure 1 of the Instructions for Use at the end of this

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


36

leaflet). The mouthpiece is covered with a removable grey protective cap. Trixeo Aerosphere is
supplied in a foil pouch that contains a drying packing (desiccant) and packed into a carton.

Each inhaler contains 56 or 120 puffs. Additionally, there are multipacks containing 3 pressurised 
containers with 120 puffs, each.

Marketing Authorisation Holder 

AstraZeneca AB
SE-151 85 Södertälje
Sweden

Manufacturer
AstraZeneca Dunkerque Production
224 Avenue de la Dordogne
Dunkerque
59640
France

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
AstraZeneca S.A./N.V.
Tel: +32 2 370 48 11

Lietuva
UAB AstraZeneca Lietuva
Tel: +370 5 2660550

България
АстраЗенека България ЕООД
Тел.: +359 24455000

Luxembourg/Luxemburg
AstraZeneca S.A./N.V.
Tél/Tel: +32 2 370 48 11

Česká republika
AstraZeneca Czech Republic s.r.o.
Tel: +420 222 807 111

Magyarország
AstraZeneca Kft.
Tel.: +36 1 883 6500

Danmark
AstraZeneca A/S
Tlf: +45 43 66 64 62

Malta
Associated Drug Co. Ltd
Tel: +356 2277 8000

Deutschland
AstraZeneca GmbH
Tel: +49 41 03 7080

Nederland
AstraZeneca BV
Tel: +31 79 363 2222

Eesti
AstraZeneca 
Tel: +372 6549 600

Norge
AstraZeneca AS
Tlf: +47 21 00 64 00

Ελλάδα
AstraZeneca A.E.
Τηλ: +30 210 6871500

Österreich
AstraZeneca Österreich GmbH
Tel: +43 1 711 31 0

España
AstraZeneca Farmacéutica Spain, S.A.
Tel: +34 91 301 91 00

Polska
AstraZeneca Pharma Poland Sp. z o.o.
Tel.: +48 22 245 73 00

France
AstraZeneca

Portugal
AstraZeneca Produtos Farmacêuticos, Lda.



37

Tél: +33 1 41 29 40 00 Tel: +351 21 434 61 00

Hrvatska 
AstraZeneca d.o.o.
Tel: +385 1 4628 000

România
AstraZeneca Pharma SRL
Tel: +40 21 317 60 41

Ireland
AstraZeneca Pharmaceuticals (Ireland) DAC
Tel: +353 1609 7100

Slovenija
AstraZeneca UK Limited
Tel: +386 1 51 35 600

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
AstraZeneca AB, o.z.
Tel: +421 2 5737 7777 

Italia
AstraZeneca S.p.A.
Tel: +39 02 9801 1

Suomi/Finland
AstraZeneca Oy
Puh/Tel: +358 10 23 010

Κύπρος
Αλέκτωρ Φαρµακευτική Λτδ
Τηλ: +357 22490305

Sverige
AstraZeneca AB
Tel: +46 8 553 26 000

Latvija
SIA AstraZeneca Latvija
Tel: +371 67377100

United Kingdom
AstraZeneca UK Ltd
Tel: +44 1582 836 836

This leaflet was last revised in 

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

---------------------------------------------------------------------------------------------------------------------------



38

Instructions for Use
Trixeo Aerosphere 5/7.2/160 micrograms pressurised inhalation, suspension

(formoterol fumarate dihydrate/glycopyrronium/budesonide)
Inhalation use

Read these instructions for use and the package leaflet before you start using Trixeo Aerosphere and 
each time you get a new pack. There may be new information. As well as reading this leaflet, please 
talk to your doctor about your medical condition and treatment.

Important Information:

 For inhalation use only.

 Use Trixeo Aerosphere exactly as your doctor tells you to. 

 If you have any questions about the use of your inhaler, ask your doctor or pharmacist.

 Clean your inhaler once each week. It is very important to keep the plastic actuator clean so that 
medicine does not build-up and block the spray through the mouthpiece. See Steps 1 to 8 under 
“How to clean your Trixeo Aerosphere inhaler”. 

Parts of your Trixeo Aerosphere inhaler (See Figure 1):

 Trixeo Aerosphere comes as a pressurised container with a dose indicator that fits into an actuator. 

- Do not use the Trixeo Aerosphere actuator with any other medicine. 

- Do not use the Trixeo Aerosphere pressurised container with an actuator from any other 
inhaler.

Figure 1

 Trixeo Aerosphere comes with a dose indicator on the top of the pressurised container (see Figure 
1). The dose indicator display window shows you how many puffs of medicine you have left. A 
puff of medicine is released each time you press the centre of the dose indicator. 

Trixeo Aerosphere pressurised canister contains extra puffs to allow for priming. The step-by-step 
instructions for use of the inhaler provided below can be used for either the 14-day (56 puffs) or 30-
day inhaler (120 puffs).

Before you use Trixeo Aerosphere for the first time

Dose indicator display 
window

Pointer

Press here

Dose indicator

Pressurised container

Actuator

Mouthpiece

Cap

TOP VIEWSIDE VIEW



39

Before you use Trixeo Aerosphere for the first time, make sure that the pointer on the dose indicator is 
pointing to the right of the “120” inhalation mark in the dose indicator display window (see Figure 1).  

 The pointer points to 120 after 10 puffs are delivered from Trixeo Aerosphere. This means that 
there are 120 puffs of medicine left in the pressurised container (see Figure 2a).

 The pointer points between 100 and 120 after you use 10 more puffs. This means that there are 
110 puffs of medicine left in the pressurised container (see Figure 2b). 

 The pointer points to 100 after you use 10 more puffs. This means that there are 100 puffs of 
medicine left in the pressurised container (see Figure 2c).

 The dose indicator display window will move after every 10 puffs. The number in the dose 
indicator display window will change after every 20 puffs.

Figure 2d

 The colour in the dose indicator display window will change to red, as shown in the shaded area, 
when there are only 20 puffs of medicine left in your inhaler (see Figure 2d).

 The dose indicator for the 14-day inhaler, 56 inhalation pressurised container, moves after every 
10 puffs; with markings for 60, 40, 20 and 0 puffs. The colour in the 14-day inhaler, 56 inhalation 
pressurised container dose indicator display window will change to red when there are only 20 
puffs of medicine left in your inhaler.

 Preparing your Trixeo Aerosphere inhaler for use:
 Your Trixeo Aerosphere inhaler comes in a foil pouch that contains a drying packet (desiccant).

- Take the Trixeo Aerosphere inhaler out of the foil pouch. 
- Throw away the pouch and the drying packet. Do not eat or breathe in the contents of the 

drying packet. 

 Trixeo Aerosphere should be at room temperature before you use it.

Figure 2b
110 puffs

Figure 2a
120 puffs

Figure 2c
100 puffs



40

Figure 3

Priming your Trixeo Aerosphere inhaler:

Before you use Trixeo Aerosphere for the first time, you must prime the inhaler.

 Remove the cap from the mouthpiece (see Figure 3). Check inside the mouthpiece before you use
the inhaler to make sure it is clear. 

 Hold the inhaler upright, away from your face and shake it well (see Figure 4). 

Figure 4

 Press down firmly on the centre of the dose indicator until the pressurised container cannot be 
pressed any further. This will release a puff of medicine from the mouthpiece (see Figure 5). You 
may hear a soft click from the dose indicator as it counts down during use.

Figure 5

 Repeat the priming steps 3 more times (see Figure 4 and Figure 5). Shake the inhaler well 
before each priming puff. 

 After priming 4 times, the dose indicator should be pointing to the right of “120” and your inhaler 
is now ready to use. 

Using your Trixeo Aerosphere inhaler:

Step 1: Remove the cap from the mouthpiece (See Figure 6).

Figure 6



41

Step 2: Shake the inhaler well before each use (see Figure 7).

Figure 7

Step 3: Hold the inhaler with the mouthpiece pointing towards you and breathe out as fully as you 
comfortably can through your mouth (see Figure 8). 

Figure 8

Step 4: Close your lips around the mouthpiece and tilt your head back, keeping your tongue below the 
mouthpiece (see Figure 9).

Figure 9

Step 5: While breathing in deeply and slowly, press down on the centre of the dose indicator as far as 
the pressurised container will go and a puff of medicine has been released (see Figure 10). 
Then stop pressing the dose indicator.



42

Figure 10

Step 6: When you have finished breathing in, remove the mouthpiece from your mouth. Hold your 
breath as long as you comfortably can, up to 10 seconds (see Figure 11). 

Figure 11

Step 7: Breathe out gently (see Figure 12). Repeat steps 2 to 7 to take your second puff of Trixeo 
Aerosphere.

Figure 12

Step 8: Replace the cap over the mouthpiece right away after use (see Figure 13).

Figure 13



43

Step 9: Rinse your mouth with water to remove any medicine which is left in the mouth. Spit this 
water out – do not swallow. 

It is important to store Trixeo Aerosphere in a dry place. 

How to clean your Trixeo Aerosphere inhaler:
Clean the inhaler once each week. It is very important to keep your inhaler clean so that medicine 
does not build-up and block the spray through the mouthpiece (see Figure 14).

Figure 14

Step 1: Take the pressurised container out of the actuator (see Figure 15). Do not clean the 
pressurised container or let it get wet. 

Figure 15

Step 2: Take the cap off the mouthpiece.



44

Step 3: Hold the actuator under the tap and run warm water through it for about 30 seconds. Turn the 
actuator upside down and run warm water through it again for about 30 seconds (see 
Figure 16). 

Figure 16

Step 4: Shake off as much water from the actuator as you can.

Step 5: Look into the actuator and the mouthpiece to make sure any medicine build-up has been 
completely washed away. If there is any build-up, repeat Steps 3 to 5 in this section.

Step 6: Let the actuator air-dry overnight (see Figure 17). Do not put the pressurised container back 
into the actuator if it is still wet.

Figure 17

Step 7: When the actuator is dry, gently press the pressurised container down in the actuator (see 
Figure 18). Do not press down too hard on the pressurised container. This could cause a puff 
of medicine to be released.



45

Figure 18

Step 8: Re-prime your Trixeo Aerosphere inhaler after each cleaning. To re-prime the inhaler, shake 
the inhaler well and press down on the centre of the dose indicator 2 times to release a total of 
2 puffs into the air away from your face. Your inhaler is now ready to use. 

If you do not use your Trixeo Aerosphere for more than 7 days, or your Trixeo Aerosphere is 
dropped, you will need to re-prime it before use.

To re-prime the inhaler, shake the inhaler well and press down on the centre of the dose indicator 
2 times to release a total of 2 puffs into the air away from your face. Your inhaler is now ready to use.


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET