RILTRAVA AEROSPHERE 5mcg / 7.2mcg / 160mcg pressurized inhalation suspension medication leaflet

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

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

This corresponds to a metered dose of 5.3 micrograms of formoterol fumarate dihydrate,glycopyrronium bromide 9.6 micrograms, equivalent to 7.7 micrograms of glycopyrronium, andbudesonide 170 micrograms.

For the full list of excipients, see section 6.1.

Pressurised inhalation, suspension.

White suspension.

Riltrava Aerosphere is indicated as a maintenance treatment in adult patients with moderate to severechronic obstructive pulmonary disease (COPD) who are not adequately treated by a combination of aninhaled corticosteroid and a long-acting beta2-agonist or combination of a long-acting beta2-agonistand a long-acting muscarinic antagonist (for effects on symptoms control and prevention ofexacerbations see section 5.1).

The recommended and maximum dose is two inhalations twice daily (two inhalations in the morningand 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 theusual time. A double dose should not be taken to make up for a forgotten dose.

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

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

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

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

For inhalation use.

To ensure proper administration of the medicinal product, the patient should be shown how to use theinhaler correctly by a physician or other healthcare professional, who should also regularly check theadequacy 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 itspacket. 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 timeswhen the inhaler has not been used for more than seven days, after weekly washing or if it hasbeen dropped.

* Rinse their mouth out with water after inhaling the dose to minimise the risk of oropharyngealthrush. Do not swallow.

On actuation of Riltrava Aerosphere, a volume of the suspension is expelled from the pressurisedcontainer. 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 Riltrava Aerosphere witha spacer to ensure proper administration of the medicinal product. Riltrava Aerosphere can be usedwith spacer devices including the Aerochamber Plus Flow-Vu (see section 5.2).

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

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

Administration of formoterol/glycopyrronium/budesonide may produce paradoxical bronchospasmwith an immediate wheezing and shortness of breath after dosing and may be life-threatening.

Treatment with this medicinal product should be discontinued immediately if paradoxicalbronchospasm occurs. The patient should be assessed, and alternative therapy instituted if necessary.

It is recommended that treatment with this medicinal product should not be stopped abruptly. Ifpatients find the treatment ineffective, they should continue treatment, but medical attention must besought. Increasing use of reliever bronchodilators indicates a worsening of the underlying conditionand 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, such as cardiac arrhythmias, e.g. atrial fibrillation and tachycardia, may beseen after the administration of muscarinic receptor antagonists and sympathomimetics, includingglycopyrronium and formoterol. This medicinal product should be used with caution in patients withclinically significant uncontrolled and severe cardiovascular disease such as unstable ischemic heartdisease, 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 congenitalor induced by medicinal products.

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed forlong periods. These effects are much less likely to occur with inhalation treatment than with oralcorticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenalsuppression, decrease in bone mineral density, cataract and glaucoma. Potential effects on bonedensity should be considered particularly in patients on high doses for prolonged periods that haveco-existing risk factors for osteoporosis.

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presentswith symptoms such as blurred vision or other visual disturbances, the patient should be considered forreferral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucomaor rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after useof systemic and topical corticosteroids (see section 4.8).

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

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

There is no conclusive clinical evidence for intra-class differences in the magnitude of the pneumoniarisk among inhaled corticosteroid products.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPDas 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 massindex (BMI) and severe COPD.

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

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 inpatients with diabetes.

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

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

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

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).

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

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 section5.2).

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

The metabolism of budesonide is primarily mediated by CYP3A4 (see section 5.2). Co-treatment withstrong 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 avoidedunless the benefit outweighs the increased risk of systemic corticosteroid adverse reactions, in whichcase patients should be monitored for systemic corticosteroid adverse reactions. This is of limitedclinical importance for short-term (1-2 weeks) treatment.

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

Since glycopyrronium is eliminated mainly by the renal route, drug interaction could potentially occurwith medicinal products affecting renal excretion mechanisms. In vitro, glycopyrronium is a substratefor the renal transporters OCT2 and MATE1/2K. The effect of cimetidine, a probe inhibitor of OCT2and MATE1, on inhaled glycopyrronium disposition showed a limited increase in its total systemicexposure (AUC0-t) by 22% and a slight decrease in renal clearance by 23% due to co-administration ofcimetidine.

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 itmay potentiate known inhaled muscarinic antagonist or β2-adrenergic agonist adverse reactions (seesection 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 prescribedconcomitantly with formoterol.

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

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

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

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

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

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

Data on the use of inhaled budesonide in more than 2,500 exposed pregnancies indicate no increasedteratogenic risk associated with budesonide. Single-dose studies in humans found that very smallamounts 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 thereproductive function and embryofoetal development in animals revealed no clinically relevantadverse 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 ofglucocorticoids. At very high doses/systemic exposure levels, formoterol caused implantation losses aswell as decreases in birth weight and early postnatal survival, whereas glycopyrronium had nosignificant effects on reproduction (see section 5.3).

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

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 plasmaconcentration. Consequently, no effects due to budesonide are anticipated in breast-fed children whosemothers are receiving therapeutic doses of this medicinal product. It is not known whetherglycopyrronium or formoterol are excreted in human milk. Evidence of transfer of glycopyrroniumand formoterol into maternal milk in rats has been reported.

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

Studies in rats have shown adverse effects on fertility only at dose levels higher than the maximumhuman exposure to formoterol (see section 5.3). Budesonide and glycopyrronium individually, did notcause any adverse effects on fertility in rats. It is unlikely that this medicinal product administered atthe recommended dose will affect fertility in humans.

Riltrava 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 usingmachines.

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

The tabulated list of adverse reactions is based on the experience with this medicinal product inclinical 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 Common

Immune system disorders Hypersensitivity Uncommon

Angioedema Not known

Endocrine disorders Signs or symptoms of systemic Very rareglucocorticosteroid effects, e.g. hypofunctionof the adrenal gland

Metabolism and nutrition Hyperglycaemia Commondisorders

Psychiatric disorders Anxiety Common

Insomnia

Depression Uncommon

Agitation

Restlessness

Nervousness

Abnormal behaviour Very rare

Nervous system disorders Headache Common

Dizziness Uncommon

Tremor

Eye disorders Vision blurred (see section 4.4) Not known

Cataract

Glaucoma

Cardiac disorders Palpitations Common

Angina pectoris Uncommon

Cardiac arrhythmias (atrial fibrillation,supraventricular tachycardia and extrasystoles)

Respiratory, thoracic and Dysphonia Commonmediastinal disorders Cough

Throat irritation Uncommon

Bronchospasm

Gastrointestinal disorders Nausea Common

Dry mouth Uncommon

Skin and subcutaneous Bruising Uncommontissue disorders

Musculoskeletal and Muscle spasms Commonconnective tissue disorders

Renal and urinary Urinary tract infection Commondisorders Urinary retention Uncommon

System Organ Class Preferred term Frequency

General disorders and Chest pain Uncommonadministration siteconditions

KRONOS was a 24-week study in a total of 1,896 patients with moderate to very severe COPD (meanpost-bronchodilator screening FEV1 50% of predicted, standard deviation [SD] 14%), 26% of whomhad experienced a COPD exacerbation in the year prior to study entry. The incidence of confirmedpneumonia events reported up to 24 weeks was 1.9% (12 patients) for Riltrava Aerosphere (n=639),1.6% (10 patients) for formoterol fumarate dihydrate/glycopyrronium (FOR/GLY) MDI 5/7.2micrograms (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 fumaratedihydrate/budesonide Turbuhaler (FOR/BUD) TBH 6/200 micrograms (n=318). In KRONOS, therewere no fatal cases of pneumonia with Riltrava Aerosphere.

ETHOS was a 52-week study in a total of 8,529 patients (in the safety population) with moderate tovery 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 confirmedpneumonia was 4.2% (90 patients) for Riltrava Aerosphere (n=2144), 3.5% (75 patients) forformoterol fumarate dihydrate/glycopyrronium/budesonide (FOR/GLY/BUD) MDI5/7.2/80 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 fatalcases 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 Riltrava Aerosphere).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

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

Riltrava Aerosphere contains budesonide, a glucocorticosteroid, and two bronchodilators:

glycopyrronium, a long-acting muscarinic antagonist (anticholinergic) and formoterol, a long-actingβ2-adrenergic agonist.

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

Glycopyrronium is a long-acting, muscarinic antagonist, which is often referred to as ananticholinergic. The major targets for anticholinergic drugs are muscarinic receptors located in therespiratory tract. In the airways, it exhibits pharmacological effects through inhibition of M3 receptorat 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-actingrelaxation of bronchial smooth muscle in patients with reversible airways obstruction. Thebronchodilating 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.

The efficacy and safety of Riltrava Aerosphere was evaluated in patients with moderate to very severe

COPD in two randomised, parallel-group trials, ETHOS and KRONOS. Both studies weremulticentre, 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 toscreening.

ETHOS was a 52-week trial (N=8,588 randomised; 60% male, mean age of 65) that compared twoinhalations twice daily of Riltrava Aerosphere, formoterol fumarate dihydrate/glycopyrronium(FOR/GLY) MDI 5/7.2 micrograms, and formoterol fumarate dihydrate/budesonide (FOR/BUD) MDI5/160 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 COPDexacerbations in the year prior to screening. The proportion of patients with moderate, severe and verysevere COPD was 29%, 61% and 11% respectively. The mean baseline FEV1 across all groups was1,021-1,066 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-treatmentmoderate or severe COPD exacerbations for Riltrava 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 twoinhalations twice daily of Riltrava Aerosphere, FOR/GLY MDI 5/7.2 micrograms, FOR/BUD MDI5/160 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 andvery severe COPD was 49%, 43% and 8% respectively. The mean baseline FEV1 across all groupswas 1,050-1,193 mL, and during screening the mean post-bronchodilator percent predicted FEV1 was50%, over 26% of patients reported a history of one or more moderate or severe COPD exacerbationin the past year and the mean CAT score was 18.3. There was a 28-week extension, for up to 52 weeksof 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 Riltrava

Aerosphere compared to FOR/BUD MDI and the on-treatment change from baseline in morning pre-dose trough FEV1 over 24 weeks for Riltrava Aerosphere compared to FOR/GLY MDI.

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

LAMA+LABA (14%, 20% respectively).

In the 52-week ETHOS study, Riltrava 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).

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 MDIand FOR/BUD TBH did not reach statistical significance.

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

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

In ETHOS and KRONOS, Riltrava 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 over52 weeks in ETHOS.

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

Riltrava FOR/GLY FOR/BUD Treatment difference

Aerosphere MDI MDI 95% CI(N=747) (N=779) (N=755) Riltrava Riltrava

Aerosphere vs. Aerosphere vs.

FOR/GLY MDI FOR/BUD MDI

Trough FEV1 (mL) 129 (6.5) 86 (6.6) 53 (6.5) 43 mL 76 mLover 24 weeks, LS (25, 60) (58, 94)mean change from p<0.0001 p<0.0001#baseline (SE)

FEV1 AUC0-4 over 294 (6.3) 245 (6.3) 194 (6.3) 49 mL 99 mL24 weeks; LS mean (31, 66) (82, 117)change from p<0.0001# p<0.0001baseline (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-Treatpopulation

Table 3: Lung function analyses - KRONOS

Riltrava FOR/ FOR/ FOR/ Treatment difference

Aero- GLY BUD BUD 95% CIsphere MDI MDI TBH Riltrava Riltrava Riltrava(N=639) (N=625) (N=314) (N=318) Aerosphere Aerosphere Aerospherevs. FOR/GLY vs. FOR/BUD vs. FOR/BUD

MDI MDI TBH

Trough FEV1 147 (6.5) 125 73 (9.2) 88 (9.1) 22 mL 74 mL 59 mL(mL) over 24 (6.6) (4, 39) (52, 95) (38, 80)weeks, LS mean p=0.0139 p<0.0001 p<0.0001#change frombaseline (SE)

FEV1 AUC0-4 305 (8.4) 288 201 214 16 mL 104 mL 91 mLover 24 weeks; (8.5) (11.7) (11.5) (-6, 38) (77, 131) (64, 117)

LS mean p=0.1448# p<0.0001 p<0.0001change frombaseline (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-Treatpopulation

In ETHOS, the baseline average dyspnoea scores ranged from 5.8 - 5.9 across the treatment groups.

Riltrava 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 scoresranged from 6.3 - 6.5 across the treatment groups. Riltrava Aerosphere significantly improvedbreathlessness 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 reachstatistical significance.

In ETHOS, Riltrava Aerosphere significantly improved disease-specific health status (as assessed bythe 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 52weeks. In KRONOS, improvements compared with FOR/GLY MDI, FOR/BUD MDI and FOR/BUD

TBH did not reach statistical significance.

In ETHOS, Riltrava Aerosphere significantly reduced the on-treatment use of rescue medication over24 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.

The European Medicines Agency has waived the obligation to submit the results of studies with

Riltrava Aerosphere in all subsets of the paediatric population, in COPD (see section 4.2 forinformation on paediatric use).

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

The use of this medicinal product with the Aerochamber Plus Flow-Vu spacer in healthy volunteersincreased the total systemic exposure (as measured by AUC0-t) to budesonide and glycopyrronium by33% and 55%, respectively, while exposure to formoterol was unchanged. In patients with goodinhalation technique, systemic exposure was not increased with the use of a spacer.

Following inhaled administration of this medicinal product in subjects with COPD, budesonide Cmaxoccurred within 20 to 40 minutes. Steady state is achieved after approximately 1 day of repeateddosing of this medicinal product and the extent of exposure is approximately 1.3 times higher thanafter the first dose.

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 ofthis medicinal product and the extent of exposure is approximately 1.8 times higher than after the firstdose.

Following inhaled administration of this medicinal product in subjects with COPD, formoterol Cmaxoccurred within 40 to 60 minutes. Steady state is achieved after approximately 2 days of repeateddosing with this medicinal product and the extent of exposure is approximately 1.4 times higher thanafter the first dose.

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

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

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

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

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

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

O-demethylation.

Budesonide is eliminated via metabolism mainly catalysed by the enzyme CYP3A4. The metabolitesof budesonide are excreted in urine as such or in conjugated form. Only negligible amounts ofunchanged budesonide have been detected in the urine. The effective terminal elimination half-life ofbudesonide derived via population pharmacokinetic analysis was 5 hours.

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

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

Dose adjustments are not necessary based on the effect of age, gender or weight on thepharmacokinetic parameters of budesonide, glycopyrronium and formoterol. There were nomajor differences in total systemic exposure (AUC) for all compounds between healthy

Japanese, Chinese and Western subjects. Insufficient pharmacokinetic data is available for otherethnicities or races.

No pharmacokinetic studies have been performed with this medicinal product in patients with hepaticimpairment. However, because both budesonide and formoterol are primarily eliminated via hepaticmetabolism, an increased exposure can be expected in patients with severe liver impairment.

Glycopyrronium is primarily cleared from the systemic circulation by renal excretion and hepaticimpairment would therefore not be expected to affect systemic exposure.

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 upto 24 weeks was evaluated in a population pharmacokinetic analysis. Estimated glomerular filtrationrate (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 renalimpairment (eGFR of 45 mL/min) indicates an approximate 68% increase for glycopyrronium comparedto subjects with COPD with normal renal function (eGFR of >90 mL/min). Renal function was foundnot to affect exposure to budesonide or formoterol. Subjects with COPD with both low body weightand moderate-severe impaired renal function may have an approximate doubling of systemic exposureto glycopyrronium.

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

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

In animal reproduction studies, glucocorticosteroids such as budesonide have been shown to inducemalformations (cleft palate, skeletal malformations). However, these animal experimental results arenot relevant in humans at the recommended doses (see section 4.6). Budesonide demonstrated notumourigenic potential in mice. In rats, an increased incidence of hepatocellular tumours wasobserved, 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 athigh systemic exposure and implantation losses, as well as decreased early postnatal survival and birthweight at considerably higher systemic exposures than those reached during clinical use. A slightincrease in the incidence of uterine leiomyomas has been observed in rats and mice treated withformoterol; an effect which is considered to be a class-effect in rodents after long-term exposure tohigh 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 exposurethan those reached during clinical use. No evidence of carcinogenicity was seen in rats and mice.

Norflurane1,2-distearoyl-sn-glycero-3-phosphocholine

Calcium chloride

Not applicable.

3 years

To be used within 3 months of opening the pouch.

Do not store above 30°C.

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

Riltrava Aerosphere is a pressurised metered dose inhaler, comprising a coated aluminium canister, ayellow plastic actuator and white mouthpiece with an attached grey plastic dust cap, and a doseindicator. Each inhaler is individually packaged in a foil laminate pouch containing a desiccant sachetand packed in to a carton.

Pack sizes of 1 container of 120 actuations.

Multipacks of 360 (3 containers of 120) actuations.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements. The pressurised container should not be broken, punctured or burnt, even whenapparently empty.

AstraZeneca AB

SE-151 85 Södertälje

Sweden

EU/1/21/1604/001 120 actuations

EU/1/21/1604/002 360 actuations (3 packs of 120)

Date of first authorisation: 6 January 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.