BEVESPI AEROSPHERE 7.2mcg / 5mcg pressurized inhalation suspension medication leaflet

Bevespi Aerosphere 7.2 micrograms/5 micrograms pressurised inhalation, suspension

Each single actuation (delivered dose, the dose leaving the mouthpiece) contains glycopyrroniumbromide 9 micrograms equivalent to 7.2 micrograms of glycopyrronium, and 5 micrograms offormoterol fumarate dihydrate.

This corresponds to a metered dose (i.e. the dose leaving the valve) of glycopyrronium bromide10.4 micrograms equivalent to 8.3 micrograms of glycopyrronium, and 5.8 microgram of formoterolfumarate dihydrate.

For the full list of excipients, see section 6.1.

Pressurised inhalation, suspension (pressurised inhalation)

White suspension.

Bevespi Aerosphere is indicated as a maintenance bronchodilator treatment to relieve symptoms inadult patients with chronic obstructive pulmonary disease (COPD) (see section 5.1).

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

Patients should be advised not to take more than 2 inhalations twice daily.

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).

Bevespi Aerosphere can be used at the recommended dose in patients with mild to moderate renalimpairment. In patients with severe renal impairment or end-stage renal disease requiring dialysis, itshould be used only if the expected benefit outweighs the potential risk (see sections 4.4 and 5.2).

Bevespi Aerosphere can be used at the recommended dose in patients with mild to moderate hepaticimpairment. There are no relevant data on the use of Bevespi Aerosphere in patients with severehepatic impairment and the medicinal product should be used with caution in these patients (seesections 4.4 and 5.2).

There is no relevant use of Bevespi Aerosphere in children and adolescents (under 18 years of age) forthe indication of COPD.

For inhalation use.

On actuation of Bevespi Aerosphere, a volume of the suspension is expelled from the pressurisedcontainer at high velocity. When the patient inhales through the mouthpiece at the same time asactuating the inhaler, the substance will follow the inspired air into the airways.

Note: Patients should be instructed on the correct inhalation technique. It is important to instruct thepatient to:

* Carefully read the instructions for use in the package leaflet, which is packed together with eachinhaler.

* Not use the inhaler if the drying agent, which is inside the foil pouch, has leaked out of itspacket.

* 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, has been exposed to lowtemperatures, or has been dropped.

To get adequate lung deposition of the active substances, actuation must be co-ordinated withinhalation.

Patients who find it difficult to co-ordinate actuation with inspiration of breath may use Bevespi

Aerosphere with a spacer to ensure proper administration of the product. Compatibility with the

Aerochamber Plus Flow-Vu spacer device has been demonstrated (see section 5.2).

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

Bevespi Aerosphere is not indicated for the treatment of acute episodes of bronchospasm, i.e. as arescue therapy.

Asthma

Bevespi Aerosphere should not be used to treat asthma.

As with other inhalation therapy, administration of this medicinal product may result in paradoxicalbronchospasm, which can be life-threatening. If paradoxical bronchospasm does occur, treatment withthe medicinal product should be stopped and other treatments considered.

Cardiovascular effects, such as cardiac arrhythmias e.g. atrial fibrillation and tachycardia, may be seenafter the administration of muscarinic receptor antagonists and sympathomimetics, includingglycopyrronium or formoterol. Patients with clinically significant uncontrolled cardiovascular diseasewere excluded from clinical studies. Bevespi Aerosphere should be used with caution in patients withsevere cardiovascular disorders, such as ischaemic heart disease, tachyarrhythmias or severe heartfailure.

Caution should also be exercised in patients with thyrotoxicosis or known or suspected prolongation ofthe QTc interval (see section 4.5).

Hypokalaemiaβ2-adrenergic agonists may produce significant hypokalaemia, which may increase the susceptibility tocardiac arrhythmias. The decrease in serum potassium is usually transient, not requiringsupplementation. In patients with severe COPD, hypokalaemia may be potentiated by hypoxia andconcomitant treatment (see section 4.5).

Inhalation of high doses of β2-adrenergic agonists may produce increases in plasma glucose.

Due to its anticholinergic activity, Bevespi Aerosphere should be used with caution in patients withsymptomatic prostatic hyperplasia, urinary retention or with narrow-angle glaucoma (see section 4.8).

Patients with severe 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 Bevespi Aerosphere if the expected benefit outweighs the potential risk(see section 5.2).

Patients with severe hepatic impairment

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

No interaction studies have been performed with Bevespi Aerosphere; however, the potential formetabolic interactions is considered to be low based on in-vitro studies (see section 5.2).

Since glycopyrronium is eliminated mainly by the renal route, interactions 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 Bevespi Aerosphere with other anticholinergic and/or long-acting β2-adrenergicagonist containing medicinal products has not been studied and is not recommended as it maypotentiate known inhaled muscarinic antagonist or β2-adrenergic agonist adverse reactions (seesections 4.4 and 4.9).

Although no formal in-vivo interaction studies have been performed with Bevespi Aerosphere, studiesindicate no clinical evidence of interactions when used concomitantly with other COPD medicinalproducts including short-acting β2-adrenergic bronchodilators, methylxanthines, and oral and inhaledsteroids.

Drug-induced hypokalaemia

Concomitant treatment with methylxanthine derivatives, steroids, or non-potassium sparing diureticsmay potentiate the possible initial hypokalaemic effect of β2-adrenergic agonists, therefore, caution isadvised in their concomitant use (see section 4.4).

β-adrenergic blockersβ-adrenergic blockers (including eye drops) can weaken or inhibit the effect of β2-adrenergic agonists,such as formoterol. Concurrent use of either non-selective or selective β-adrenergic blockers should beavoided unless there are compelling reasons for their use. If β-adrenergic blockers are required(including eye drops), cardioselective β-adrenergic blockers are preferred, although they should alsobe administered with caution.

Bevespi Aerosphere should be administered with caution to patients being treated with medicinalproducts known to prolong the QTc interval (see section 4.4).

There are no data on the use of Bevespi Aerosphere in pregnant women.

Single-dose studies in humans found that very small amounts of glycopyrronium passed the placentalbarrier. In animal studies, formoterol and glycopyrronium, individually, have caused adverse effects inreproduction studies at very high doses/systemic exposure levels (see section 5.3).

Bevespi Aerosphere should only be used during pregnancy if the expected benefits outweigh thepotential risks.

It is not known whether glycopyrronium or formoterol are excreted in human milk. Evidence oftransfer of glycopyrronium and formoterol into maternal milk in rats has been reported.

Administration of Bevespi Aerosphere to women who are breast-feeding should only be considered ifthe expected benefit to the mother is greater than any possible risk to the infant (see section 5.3).

Studies in rats have shown adverse effects on fertility only at dose levels higher than the maximumhuman exposure to formoterol (see section 5.3). Glycopyrronium did not cause any adverse effects onfertility in rats. It is unlikely that Bevespi Aerosphere administered at the recommended dose willaffect fertility in humans.

Bevespi Aerosphere has no or negligible influence on the ability to drive and use machines. Howeverdizziness and nausea are common side effects which should be taken into account when driving orusing machines.

The safety profile is characterised by anticholinergic and β2-adrenergic class effects related tothe individual components of the combination. The most commonly reported adverse reactions inpatients receiving Bevespi Aerosphere were headache (1.9%), nausea (1.4%), muscle spasms (1.4%),and dizziness (1.3%).

The tabulated list of adverse reactions is based on clinical trials and post-approval experience with

Bevespi Aerosphere as well as experience with the individual components and related products.

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

Immune system disorders Hypersensitivity reactions including rash and Uncommonpruritus

Metabolism and nutrition Hyperglycaemia1 Uncommondisorders

Psychiatric disorders Anxiety Common

Agitation

Uncommon

Restlessness

Insomnia

Headache1

Nervous system disorders Common

Dizziness

Tremor1

Uncommon

Tachycardia Uncommon

Palpitations

Cardiac disorders Cardiac arrhythmias (atrial fibrillation,supraventricular tachycardia, and extrasystoles)

Gastrointestinal Dry mouth2, Nausea Commondisorders

Musculoskeletal and Muscle spasms1 Commonconnective tissuedisorders

Renal and urinary Urinary tract infection Commondisorders Urinary retention2 Uncommon

General disorders and Chest pain Commonadministration siteconditions1 Adverse reaction relates to formoterol2 Adverse reaction relates to glycopyrronium

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 of Bevespi Aerosphere may lead to exaggerated anticholinergic and/or β2-adrenergicsigns and symptoms, the most frequent of which include blurred vision, dry mouth, nausea, musclespasm, tremor, headache, palpitations and systolic hypertension.

If overdose occurs, the patient should be treated supportively with appropriate monitoring asnecessary.

Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination withanticholinergics, ATC code: R03AL07.

Bevespi Aerosphere contains two bronchodilators: glycopyrronium, a long-acting muscarinicantagonist (also referred to as an anticholinergic), and formoterol, a long-acting β2-adrenergic agonistwith a rapid onset of action.

Glycopyrronium has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways,it exhibits pharmacological effects through inhibition of the M3 receptor at the smooth muscle leadingto bronchodilation. Formoterol causes direct relaxation of airway smooth muscle as a consequence ofthe increase in cyclic AMP through activation of adenylate cyclase. The combination of thesesubstances with different mechanisms of action results in additive efficacy compared to use with eithercomponent alone.

As a consequence of the differential density of muscarinic receptors and β2-adrenoceptors in thecentral and peripheral airways of the lung, muscarinic antagonists are more effective in relaxingcentral airways, and β2-adrenergic agonists are more effective in relaxing peripheral airways;relaxation of both central and peripheral airways with combination treatment may contribute to itsbeneficial effects on lung function.

In three Phase III, 24-week studies (PINNACLE 1, PINNACLE 2 and PINNACLE 4) Bevespi

Aerosphere provided improvements over placebo in lung function (as measured by morning pre-dosetrough forced expiratory volume in 1 second [FEV1]), with a demonstrated onset of action at 5 minutesfollowing administration of the first dose on Day 1 (improvement over placebo by 187 mL, 186 mLand 179 mL in PINNACLE 1, PINNACLE 2 and PINNACLE 4, respectively [p <0.001]). The meanbronchodilator effect derived from serial FEV1 measurements at Day 1 and Week 12 from

PINNACLE 1 are shown in Figure 1. In PINNACLE 2, the results were similar to those observed in

PINNACLE 1.

Figure 1 Mean Change from Baseline in FEV1 over Time on Day 1 and at Week 12

DAY 1

WEEK 12

A placebo- and active-controlled (moxifloxacin) thorough QT study in 69 healthy subjects did notdemonstrate a clinically relevant effect on the QT interval, using a threshold of 10 ms. The largestmean (90% upper confidence bound) differences from placebo in baseline- and individually corrected

QT was 3.1 (4.7) ms for Bevespi Aerosphere (14.4 /10 micrograms) and 7.6 (9.2) ms forglycopyrronium/formoterol with eight times the recommended dose of glycopyrronium and four timesthe recommended dose of formoterol.

The clinical development program for Bevespi Aerosphere included three 24-week, randomised,double-blind, placebo-controlled, parallel-group pivotal Phase III studies in 5,433 patients withmoderate to very severe COPD (PINNACLE 1, PINNACLE 2 and PINNACLE 4).

In studies PINNACLE 1, PINNACLE 2 and PINNACLE 4, Bevespi Aerosphere showedimprovements in trough FEV1 over 24 weeks relative to placebo, glycopyrronium and formoterol(p<0.0001) [see Table 2]. There was no attenuation of the bronchodilator effect over time. Bevespi

Aerosphere also showed improvements in peak FEV1 within 2 hours post-dose over 24 weeks relativeto placebo, glycopyrronium and formoterol (p<0.0001) [see Table 2].

There were improvements in trough FEV1 irrespective of age, sex, degree of airflow limitation,baseline symptoms, smoking status, or inhaled corticosteroid use.

Symptomatic outcomes

Breathlessness

In PINNACLE 1 and PINNACLE 2, Bevespi Aerosphere provided improvements in breathlessness asdemonstrated by Self-administered Computerised Transitional Dyspnoea Index (SAC TDI) focal scoreover 24 weeks compared to placebo and glycopyrronium (see Table 2). Improvements compared toformoterol were observed in PINNACLE 2 (see Table 2). In PINNACLE 4, Bevespi Aerosphereprovided improvements in breathlessness as demonstrated by TDI focal score over 24 weekscompared to placebo and glycopyrronium (see Table 2).

In PINNACLE 1, PINNACLE 2 and PINNACLE 4, Bevespi Aerosphere provided an improvement indisease-specific health-related quality of life, as indicated by a reduction in the St George’s

Respiratory Questionnaire (SGRQ) total score over 24 weeks compared to placebo andglycopyrronium (see Table 2). There were improvements compared to formoterol in PINNACLE 1and PINNACLE 2.

Table 2 Lung function, symptomatic and health related quality of life outcomes over 24 weeks

Treatment Treatment difference (95% confidence intervals, p-value)comparisonswith Bevespi Trough Peak FEV1 SAC-TDI/SGRQ total Daily rescue

Aersophere FEV1 (ml)a (ml) TDI Focal score Ventolin

Scoreb (inhalations/day)c

PINNACLE 1

Bevespi158 288 0.47 -2.39 -1.08

Aerosphere(N=526) (132, 183) (259, 317) (0.21, 0.72) (-4.07, -0.71) (-1.43, -0.73)vs p<0.0001 p<0.0001# p=0.0003 p=0.0053# p<0.0001#placebo (N=219)

Bevespi60 123 0.27 -1.90 -0.26

Aerosphere(N=526) (39, 80) (100, 146) (0.07, 0.47) (-3.24, 0.57) (-0.53, 0.01)vs p<0.0001 p<0.0001# p=0.0086# p=0.0052# p=0.0619

Glycopyrronium(N=451)

Bevespi64 81 0.16 -0.75 -0.01

Aerosphere(N=526) (44, 84) (59, 104) (-0.03, 0.36) (-2.08, 0.57) (-0.27, 0.26)vs p<0.0001 p<0.0001# p=0.1060 p=0.2640 p=0.9683formoterolfumarate(N=449)

PINNACLE 2

Bevespi129 278 0.33 -1.66 -1.04

Aerosphere(N=510) (103, 155) (249, 308) (0.11, 0.56) (-3.34, 0.02) (-1.37, -0.72)vs p<0.0001 p<0.0001 p=0.0041 p=0.0534 p<0.0001placebo (N=223)

Bevespi55 129 0.21 -1.28 -0.57

Aerosphere(N=510) (34, 76) (106, 153) (0.03, 0.40) (-2.62, 0.06) (-0.83, -0.31)vs p<0.0001 p<0.0001 p=0.0199 p=0.0605 p<0.0001

Glycopyrronium(N=439)

Bevespi57 76 0.28 -1.22 -0.29

Aerosphere(N=510) (36, 78) (52, 99) (0.10, 0.46) (-2.56, 0.13) (-0.55, -0.03)vs p<0.0001 p<0.0001 p=0.0028 p=0.0760 p=0.0274#formoterolfumarate(N=437)

PINNACLE 4

Bevespi155 293 0.80 -3.50 -0.98

Aerosphere(N=551) (129, 180) (265, 321) (0.47, 1.13) (-5.18, -1.82) (-1.47, -0.49)vs p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001placebo (N=235)

Bevespi55 141 0.33 -1.62 -0.77

Aerosphere(N=551) (35, 76) (119, 163) (0.07, 0.59) (-2.94, -0.30) (-1.16, -0.38)vs p<0.0001 p<0.0001 p=0.0125 p=0.0165 p<0.0001glycopyrronium(N=474)

Bevespi72 97 0.15 -0.27 -0.41

Aerosphere(N=551) (52, 92) (75, 119) (-0.11, 0.41) (-1.59, 1.05) (-0.80, -0.03)vs p<0.0001 p<0.0001 p=0.2530 p=0.6908 p=0.0345#formoterolfumarate(N=480)

N Number in Intent to Treat populationa Primary endpoint in all studiesb PINNACLE 1 and PINNACLE 2 used SAC-TDI. PINNACLE 4 used TDI. SAC-TDI was a primary endpointin PINNACLE 1 and PINNACLE 2 onlyc From the Rescue Ventolin User Population in PINNACLE 4# A hierarchical statistical testing procedure was used in this study and this comparison was below a comparisonthat did not achieve statistical significance. Therefore, statistical significance on this comparison cannot beinferred.

COPD exacerbations

The individual studies were not specifically designed to evaluate the effect of treatments on COPDexacerbations and patients were withdrawn from the studies if a severe exacerbation or more than 2moderate exacerbations occurred.

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

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

Following inhalation of the glycopyrronium and formoterol combination, the pharmacokinetics ofeach component was similar to those observed when each active substance was administeredseparately. For pharmacokinetic purposes, each component can therefore be considered separately.

The use of Bevespi Aerosphere with the Aerochamber Plus Flow-Vu spacer in COPD patientsincreased the total systemic exposure to glycopyrronium (as measured by AUC0-12) by 16% whileformoterol exposure was unchanged.

Following inhaled administration of Bevespi Aerosphere in subjects with COPD, glycopyrronium Cmaxoccurred at approximately 5 minutes, and formoterol Cmax occurred within 20 to 60 minutes. Steadystate is achieved within 2-3 days of repeated dosing of Bevespi Aerosphere, and the extent of exposureis approximately 2.3 times and 1.5 times higher than after the first dose, for glycopyrronium andformoterol, respectively.

A lung deposition study with Bevespi Aerosphere conducted in healthy volunteers demonstrated thaton average 38% of the nominal dose is deposited into the lung. Both central and peripheral depositionwere observed.

The estimated glycopyrronium Vc/F (volume of the central compartment), and Vp1/F (volume of theperipheral compartment) are 741 L, and 2 990 L, respectively, via population pharmacokineticanalysis. Over the concentration range of 2-500 nmol/L, plasma protein binding of glycopyrroniumranged from 43% to 54%.

The estimated formoterol Vc/F (volume of the central compartment), and Vp1/F (volume of theperipheral compartment) are 1 030 L, and 647 L, respectively, via population pharmacokineticanalysis. Over the concentration range of 10-500 nmol/L, plasma protein binding of formoterol rangedfrom 46% to 58%.

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.

In-vitro studies indicate the glycopyrronium does not inhibit any subtype of cytochrome P450 and thatthere is no induction of CYP1A2, 2B6, or 3A4.

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.

In-vitro studies indicate that formoterol does not inhibit the CYP450 enzymes at therapeuticallyrelevant concentrations.

After intravenous administration of a 0.2 mg dose of radiolabelled glycopyrronium, 85% of the dosewas recovered in urine 48 hours post dose and some of radioactivity was also recovered in bile. Theterminal elimination half-life of glycopyrronium following oral inhalation derived via populationpharmacokinetics analysis was 15 hours.

The excretion of formoterol was studied in six healthy subjects following simultaneous administrationof radiolabelled formoterol via the oral and intravenous routes. In that study, 62% of the radiolabelledformoterol was excreted in the urine while 24% was eliminated in the faeces. The terminal eliminationhalf-life of formoterol following oral inhalation derived via population pharmacokinetics analysis was13 hours.

Linear pharmacokinetics were observed for glycopyrronium (dose range: 14.4 to 115.2 mcg) andformoterol (dose range: 2.4 to 19.2 mcg) after oral inhalation.

Based on available data, no adjustment of the dose of Bevespi Aerosphere in geriatric patients isnecessary.

Studies evaluating the effect of renal impairment on the pharmacokinetics of glycopyrronium andformoterol have not been conducted. The effect of renal impairment on the exposure toglycopyrronium and formoterol for up to 12 weeks was evaluated in a population pharmacokineticanalysis. Estimated glomerular filtration rate (eGFR) varied from 30-196 mL/min, representing arange of moderate to no renal impairment. The systemic exposure (AUC0-12) in subjects with COPDwith moderate-severe renal impairment (eGFR of 30-45 mL/min) is approximately 30% higher forglycopyrronium compared to subjects with COPD with normal renal function (eGFR of >90 mL/min).

Subjects with COPD with both low body weight and moderate-severe impaired renal function mayhave an approximate doubling of systemic exposure to glycopyrronium. Renal function was found notto affect exposure to formoterol.

No pharmacokinetic studies have been performed with Bevespi Aerosphere in patients withhepatic impairment. However, because formoterol is 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 andhepatic impairment would therefore not be expected to lead to unsafe systemic exposure.

A population pharmacokinetic analysis of glycopyrronium was performed based on data collected in atotal of 311 subjects with COPD. The pharmacokinetics of glycopyrronium was best described by atwo-compartment disposition model with first-order absorption and linear elimination. The typicalclearance (CL/F) of glycopyrronium was 124 L/h.

A population pharmacokinetic analysis of formoterol was performed based on data collected in a totalof 437 subjects with COPD. The pharmacokinetics of formoterol was best described by a two-compartment disposition model with a first-order rate constant of absorption and linear elimination.

The typical clearance (CL/F) of formoterol was 99 L/h.

Dose adjustments are not necessary based on the effect of age, sex and weight on the pharmacokineticparameters of glycopyrronium and formoterol.

There were no major differences in total systemic exposure (AUC) for both compounds betweenhealthy Japanese and Western subjects. Insufficient pharmacokinetic data are available to compareexposure for other ethnicities or races.

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

The toxicity observed in studies with the combination of glycopyrronium and formoterol in dogs wereassociated with the pharmacological actions of formoterol, including effects mainly on thecardiovascular system, consisting of hyperaemia, tachycardia, arrhythmias and myocardial lesions.

These are known pharmacological manifestations seen after administration of high doses of -adrenoceptor agonists. No significant effects attributable to glycopyrronium were seen.

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. However,these animal experimental results have little relevance to man. A slight increase in the incidence ofuterine leiomyomas has been observed in rats and mice treated with formoterol; an effect which isconsidered to be a class-effect in rodents after long-term exposure to high doses of β2-adrenoreceptoragonists.

Animal reproduction studies with glycopyrronium have shown reduced rat and rabbit fetal weights,and low body weight gain of rat offspring before weaning was observed at considerably highersystemic exposures than those reached during clinical use. No evidence of carcinogenicity was seen in2-year studies in rats and mice.

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

Calcium chloride

Not applicable.

30 months

To be used within 3 months of opening the pouch.

Do not store above 30oC.

Do not expose to temperatures higher than 50°C.

Do not pierce the pressurised container.

The inhaler is a pressurised metered dose inhaler, comprising an aluminium pressurised container withan attached dose indicator, supplied with a white plastic actuator body and mouthpiece with an orangedust cap. Each inhaler is individually packaged in a foil laminate pouch containing a desiccant sachetand packed into a carton.

Pack of 1 inhaler with 120 actuations.

Multipack containing 360 (3 inhalers 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 when apparently empty.

AstraZeneca AB

SE-151 85 Södertälje

Sweden

EU/1/18/1339/001

EU/1/18/1339/002

Date of first authorisation: 18 December 2018

Date of latest renewal: 15 September 2023

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

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