DUAKLIR GENUAIR 340mcg / 12mcg inhalation powder medication leaflet

Duaklir Genuair 340 micrograms /12 micrograms inhalation powder

Each delivered dose (the dose leaving the mouthpiece) contains 396 micrograms of aclidiniumbromide (equivalent to 340 micrograms of aclidinium) and 11.8 micrograms of formoterol fumaratedihydrate. This corresponds to a metered dose of 400 micrograms of aclidinium bromide (equivalentto 343 micrograms of aclidinium) and a metered dose of 12 micrograms of formoterol fumaratedihydrate.

Each delivered dose contains approximately 11 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Inhalation powder.

White or almost white powder in a white inhaler with an integral dose indicator and an orange dosagebutton.

Duaklir Genuair is indicated as a maintenance bronchodilator treatment to relieve symptoms in adultpatients with chronic obstructive pulmonary disease (COPD).

The recommended dose is one inhalation 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).

No dose adjustments are required in patients with renal impairment (see section 5.2).

No dose adjustments are required in patients with hepatic impairment (see section 5.2).

There is no relevant use of Duaklir Genuair in children and adolescents (under 18 years of age) for theindication of COPD.

For inhalation use.

Patients should be instructed on how to administer the product correctly as the Genuair inhaler maywork differently from inhalers the patients may have used previously. It is important to instruct thepatients to read the Instructions for Use in the Package Leaflet.

Before first use, the sealed bag should be teared open, and the inhaler removed. The bag and thedesiccant should be thrown away.

For instructions for use, see section 6.6.

Hypersensitivity to the active substances or to the excipient listed in section 6.1.

Asthma

Duaklir Genuair should not be used in asthma; clinical studies of Duaklir Genuair in asthma have notbeen conducted.

In clinical studies, paradoxical bronchospasm was not observed with Duaklir Genuair at itsrecommended dose. However, paradoxical bronchospasm has been observed with other inhalationtherapies. If this occurs, medicinal product should be stopped and other treatment will be considered.

Duaklir Genuair is not indicated for the treatment of acute episodes of bronchospasm.

Cardiovascular effectsβ2-adrenergic agonists may produce increases in pulse rate and blood pressure, electrocardiogram(ECG) changes such as T wave flattening, ST segment depression and prolongation of the QTc-interval in some patients. In case such effects occur, treatment may need to be discontinued. Long-acting β2-adrenergic agonists should be used with caution in patients with history of or knownprolongation of the QTc-interval or treated with medicinal products affecting the QTc interval (seesection 4.5).

Cardiac arrhythmias, including atrial fibrillation and paroxysmal tachycardia were seen after theadministration of Duaklir Genuair (see section 4.8). Therefore, Duaklir Genuair should be used withcaution in patients with cardiac arrhythmias, a history of cardiac arrhythmias or with risk factors forcardiac arrhythmias.

Duaklir Genuair should be used with caution in patients with severe cardiovascular disorders,convulsive disorders, thyrotoxicosis and phaeochromocytoma.

Metabolic effects of hyperglycaemia and hypokalaemia may be observed with high doses ofβ2-adrenergic agonists. In Phase III clinical studies, the frequency of notable increases in bloodglucose with Duaklir Genuair was low (0.1%) and similar to placebo. Hypokalaemia is usuallytransient, not requiring supplementation. In patients with severe COPD, hypokalaemia may bepotentiated by hypoxia and concomitant treatment (see section 4.5). Hypokalaemia increasessusceptibility to cardiac arrhythmias.

Due to its anticholinergic activity, Duaklir Genuair should be used with caution in patients withsymptomatic prostatic hyperplasia, urinary retention or narrow-angle glaucoma (even though directcontact of the product with the eyes is very unlikely). Dry mouth, which has been observed withanticholinergic treatment, may in the long term be associated with dental caries.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

COPD medicinal products

Co-administration of Duaklir Genuair with other anticholinergic and/or long-acting β2-adrenergicagonist containing medicinal products has not been studied and is not recommended.

Although no formal in vivo drug interaction studies have been performed with Duaklir Genuair, it hasbeen used concomitantly with other COPD medicinal products including short-acting β2-adrenergicbronchodilators, methylxanthines, and oral and inhaled steroids without clinical evidence of druginteractions.

Hypokalaemic treatment

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

β-adrenergic blockersβ-adrenergic blockers may weaken or antagonise the effect of β2-adrenergic agonists. If β-adrenergicblockers are required (including eye drops), cardioselective beta-adrenergic blockers are preferred,although they should also be administered with caution.

Duaklir Genuair should be administered with caution to patients being treated with medicinal productsknown to prolong the QTc interval such as monoamine oxidase inhibitors, tricyclic antidepressants,antihistamines or macrolides because the action of formoterol, a component of Duaklir Genuair, on thecardiovascular system may be potentiated by these medicinal products. Medicinal products that areknown to prolong the QTc interval are associated with an increased risk of ventricular arrhythmias.

Metabolic interactions

In vitro studies have shown that aclidinium or its metabolites at the therapeutic dose are not expectedto cause interactions with P-glycoprotein (P-gp) substrate drugs or drugs metabolised by cytochrome

P450 (CYP450) enzymes and esterases. Formoterol does not inhibit the CYP450 enzymes attherapeutically relevant concentrations (see section 5.2).

There are no data available on the use of Duaklir Genuair in pregnant women.

Studies in animals have shown foetotoxicity only at dose levels much higher than the maximumhuman exposure to aclidinium and adverse effects in reproduction studies with formoterol at very highsystemic exposure levels (see section 5.3).

Duaklir Genuair should only be used during pregnancy if the expected benefits outweigh the potentialrisks.

It is unknown whether aclidinium (and/or its metabolites) or formoterol are excreted in human milk.

As studies in rats have shown excretion of small amounts of aclidinium (and/or its metabolites) andformoterol into milk, the use of Duaklir Genuair by breast-feeding women should only be consideredif the expected benefit to the woman is greater than any possible risk to the infant.

Studies in rats have shown slight reductions in fertility only at dose levels much higher than themaximum human exposure to aclidinium and formoterol (see section 5.3). Nevertheless, it isconsidered unlikely that Duaklir Genuair administered at the recommended dose will affect fertility inhumans.

Duaklir Genuair has no or negligible influence on the ability to drive and use machines. Theoccurrence of blurred vision or dizziness may influence the ability to drive or to use machines.

The presentation of the safety profile is based on the experience with Duaklir Genuair and theindividual components.

The safety experience with Duaklir Genuair comprised exposure in clinical trials at the recommendedtherapeutic dose for up to 12 months, and in post-marketing experience.

Adverse reactions associated with Duaklir Genuair were similar to those of the individual components.

As Duaklir Genuair contains aclidinium and formoterol, the type and severity of adverse reactionsassociated with each of the components may be expected with Duaklir Genuair.

The most frequently reported adverse reactions with Duaklir Genuair were nasopharyngitis (7.9%) andheadache (6.8%).

The Duaklir Genuair clinical development programme was conducted in patients with moderate orsevere COPD. A total of 1222 patients were treated with Duaklir Genuair 340 micrograms/12 micrograms. The frequencies assigned to the adverse reactions are based on crude incidence ratesobserved with Duaklir Genuair 340 micrograms /12 micrograms in the pooled analysis of randomised,placebo-controlled Phase III clinical studies of at least six months duration, or on experience withindividual components or on post-marketing study results.

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).

System organ class Preferred term Frequency

Nasopharyngitis

Infectious and infestations Common

Sinusitis

Tooth abscess

Hypersensitivity Rare

Immune system disorders Angioedema

Not known

Metabolism and nutrition Hypokalaemia Uncommondisorders Hyperglycaemia Uncommon

Insomnia

Common

Psychiatric disorders Anxiety

Agitation Uncommon

Dizziness Common

Tremor

Dysgeusia Uncommon

Eye disorders Blurred vision Uncommon

Cardiac arrhythmias, including atrialfibrillation and paroxysmaltachycardia

Cardiac disorders Tachycardia Uncommon

Electrocardiogram QTc prolonged

Palpitations

Angina pectoris

Cough Common

Respiratory, Thoracic and Dysphonia

Uncommonmediastinal disorders Throat irritation

Bronchospasm, including paradoxical Rare

Nausea Common

Dry mouth

Stomatitis Uncommon

Skin and subcutaneous tissue Rash Uncommondisorders Pruritus

Musculoskeletal and Myalgia

Commonconnective tissue disorders Muscle spasms

Renal and urinary disorders Urinary retention Uncommon

Blood creatine phosphokinase

Common

Investigations increased

Blood pressure increased Uncommon

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.

There is limited evidence on the management of overdose with Duaklir Genuair. High doses of

Duaklir Genuair 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 hypertension.

Duaklir Genuair should be discontinued in case of overdose. Supportive and symptomatic treatment isindicated.

Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination withanticholinergics, ATC code: R03AL05

Duaklir Genuair contains two bronchodilators: aclidinium is a long-acting muscarinic antagonist (alsoknown as an anticholinergic) and formoterol is a long-acting β2-adrenergic agonist. The combinationof these substances with different mechanisms of action results in additive efficacy compared to thatachieved with either component alone. As a consequence of the differential density of muscarinicreceptors and β2-adrenoceptors in the central and peripheral airways of the lung, muscarinicantagonists should be more effective in relaxing central airways and β2-adrenergic agonists should bemore effective in relaxing peripheral airways; relaxation of both central and peripheral airways withcombination treatment may contribute to its beneficial effects on lung function. Further informationregarding these two substances is provided below.

Aclidinium is a competitive, selective muscarinic receptor antagonist, with a longer residence time atthe M3 receptors than the M2 receptors. M3 receptors mediate contraction of airway smooth muscle.

Inhaled aclidinium bromide acts locally in the lungs to antagonise M3 receptors of airway smoothmuscle and induce bronchodilation. Aclidinium has also been shown to provide benefits to patientswith COPD in terms of symptoms reduction, improvement in disease-specific health status, reductionin exacerbation rates and improvements in exercise tolerance. Since aclidinium bromide is quicklybroken down in plasma, the level of systemic anticholinergic undesirable effects is low.

Formoterol is a potent selective β2-adrenoceptor agonist. Bronchodilation is induced by causing directrelaxation of airway smooth muscle as a consequence of the increase in cyclic AMP through activationof adenylate cyclase. In addition to improving pulmonary function, formoterol has been shown toimprove symptoms and quality of life in patients with COPD.

Clinical efficacy studies showed that Duaklir Genuair provides clinically meaningful improvements inlung function (as measured by the forced expiratory volume in 1 second [FEV1]) over 12 hoursfollowing administration.

Duaklir Genuair demonstrated a rapid onset of action within 5 minutes of the first inhalation relative toplacebo (p<0.0001). The onset of action of Duaklir Genuair was comparable to the effect of the fast-acting β2-agonist formoterol 12 micrograms. Maximal bronchodilator effects (peak FEV1) relative tobaseline were evident from day one (304 ml) and were maintained over the 6-month treatment period(326 ml).

No clinically relevant effects of Duaklir Genuair on ECG parameters (including QT-interval)compared with aclidinium, formoterol and placebo were seen in Phase III studies of 6 to 12 monthsduration conducted in approximately 4,000 patients with COPD. No clinically significant effects of

Duaklir Genuair on cardiac rhythm were observed on 24-hour Holter monitoring in a subset of551 patients, of whom 114 received Duaklir Genuair twice daily.

Clinical Efficacy and Safety

The Phase III clinical development programme included approximately 4,000 patients with a clinicaldiagnosis of COPD and comprised two 6-month randomised, placebo- and active-controlled studies(ACLIFORM-COPD and AUGMENT), a 6-month extension of the AUGMENT study and a further12-month randomised controlled study. During these studies, patients were permitted to continue theirstable treatment with inhaled corticosteroids, low doses of oral corticosteroids, oxygen therapy (if lessthan 15h/day) or methylxanthines and to use salbutamol as rescue medication.

Efficacy was assessed by measures of lung function, symptomatic outcomes, disease-specific healthstatus, rescue medication use, and exacerbations. In long-term safety studies, Duaklir Genuair wasassociated with sustained efficacy when administered over a one-year treatment period with noevidence of tachyphylaxis.

Duaklir Genuair 340/12 micrograms twice daily consistently provided clinically meaningfulimprovements in lung function (as assessed by FEV1, forced vital capacity and inspiratory capacity)compared with placebo. In Phase III studies, clinically meaningful bronchodilator effects were seenwithin 5 minutes of the first dose and were maintained over the dosing interval. There was a sustainedeffect over time in the six-months and one-year Phase III studies.

FEV1 at 1 hour post-dose and trough FEV1 (compared to aclidinium 400 micrograms and formoterol12 micrograms, respectively) were defined as co-primary endpoints in both 6-month pivotal Phase IIIstudies to demonstrate the bronchodilator contributions of formoterol and aclidinium in Duaklir

Genuair, respectively.

In study ACLIFORM-COPD, Duaklir Genuair showed improvements in FEV1 at 1 hour post-doserelative to placebo and aclidinium of 299 ml and 125 ml, respectively (both p<0.0001) andimprovements in trough FEV1 relative to placebo and formoterol of 143 ml and 85 ml, respectively(both p<0.0001). In study AUGMENT, Duaklir Genuair showed improvements in FEV1 at 1 hourpost-dose relative to placebo and aclidinium of 284 ml and 108 ml (both p<0.0001), respectively, andimprovements in trough FEV1 relative to placebo and formoterol of 130 ml (p<0.0001) and 45 ml(p=0.01), respectively.

Symptom relief and disease-specific health status benefits

Breathlessness and other symptomatic outcomes:

Duaklir Genuair provided a clinically meaningful improvement in breathlessness (assessed by the

Transition Dyspnoea Index [TDI]) with an improvement in the TDI focal score at 6 months comparedto placebo of 1.29 units in study ACLIFORM-COPD (p<0.0001) and 1.44 units in study AUGMENT(p<0.0001). The percentages of patients with clinically meaningful improvements in TDI focal score(defined as an increase of at least 1 unit) were higher with Duaklir Genuair than with placebo in

ACLIFORM-COPD (64.8% compared to 45.5%; p<0.001) and AUGMENT (58.1% compared to36.6%; p<0.0001).

The pooled analysis of these two studies showed Duaklir Genuair to be associated with statisticallysignificantly greater improvements in TDI focal score compared to aclidinium (0.4 units, p=0.016) orformoterol (0.5 units, p=0.009). In addition, a higher percentage of patients receiving Duaklir Genuairresponded with a clinically meaningful improvement in TDI focal score compared to either aclidiniumor formoterol (61.9% compared to 55.7% and 57.0%, respectively; p=0.056 and p=0.100,respectively).

Duaklir Genuair improved daily symptoms of COPD such as ‘breathlessness’, ‘chest symptoms’,‘cough and sputum’ (assessed by E-RS total score) as well as overall night-time symptoms, overallearly morning symptoms and symptoms limiting early morning activities compared to placebo,aclidinium and formoterol but the improvements were not always statistically significant.

Aclidinium/formoterol did not statistically significantly reduce the average number of night-timeawakenings due to COPD compared with placebo or formoterol.

Duaklir Genuair provided a clinically meaningful improvement in disease-specific health status (asassessed by the St. George’s Respiratory Questionnaire [SGRQ]) in study AUGMENT, with animprovement in the SGRQ total score compared to placebo of -4.35 units (p<0.0001). The percentageof patients in AUGMENT who achieved a clinically meaningful improvement from baseline in SGRQtotal score (defined as a decrease of at least 4 units) was higher with Duaklir Genuair than withplacebo (58.2% compared to 38.7%, respectively; p<0.001). In study ACLIFORM-COPD, only asmall decrease in SGRQ total score compared to placebo was observed due to an unexpectedly largeplacebo response (p=0.598) and the percentages of patients who achieved clinically meaningfulimprovements from baseline were 55.3% with Duaklir Genuair and 53.2% with placebo (p=0.669).

In the pooled analysis of these two studies, Duaklir Genuair showed greater improvements in SGRQtotal score compared to formoterol (-1.7 units; p=0.018) or aclidinium (-0.79 units, p=0.273). Inaddition, a higher percentage of patients receiving Duaklir Genuair responded with a clinicallymeaningful improvement in SGRQ total score compared to aclidinium and formoterol (56.6%compared to 53.9% and 52.2%, respectively; p=0.603 and p=0.270, respectively).

COPD exacerbation reductions

Pooled efficacy analysis of the two 6-month Phase III studies demonstrated a statistically significantreduction of 29% in the rate of moderate or severe exacerbations (requiring treatment with antibioticsor corticosteroids or resulting in hospitalisations) with Duaklir Genuair compared to placebo (rates perpatient per year: 0.29 vs. 0.42, respectively; p=0.036).

In addition, Duaklir Genuair statistically significantly delayed the time to first moderate or severeexacerbation compared to placebo (hazard ratio=0.70; p=0.027).

Duaklir Genuair reduced the use of rescue medication over 6 months compared to placebo (by0.9 puffs per day [p<0.0001]), aclidinium (by 0.4 puffs/day [p<0.001]) and formoterol (by0.2 puffs/day [p=0.062]).

Lung volumes, exercise endurance and physical activity

The effect of Duaklir Genuair on lung volumes, exercise endurance and physical activity wasinvestigated in an 8-week parallel, randomised, placebo-controlled clinical study in COPD patientswith hyperinflation (functional residual capacity [FRC] >120%).

After 4 weeks of treatment Duaklir Genuair implied improvement versus placebo in changefrom baseline in morning pre-dose (trough) FRC, the primary endpoint, but the difference was notstatistically significant (-0.125 L; 95% CI=(-0.259, 0.010); p=0.069*).

Duaklir Genuair showed improvements compared to placebo in lung volumes at 2-3h post dose(FRC=-0.366 L [95% CI=-0.515, -0.216; p<0.0001]; residual volume [RV]=-0.465 L [95% CI=-0.648, -0.281; p<0.0001] and inspiratory capacity [IC]= 0.293 L [95% CI=0.208, 0.378; p<0.0001]).

Duaklir Genuair also showed improvements in exercise endurance time compared to placebo after 8weeks of treatment (55 seconds [95% CI=5.6, 104.8; p=0.0292]; baseline value: 456 seconds).

After 4 weeks of treatment, Duaklir Genuair improved the number of steps per day compared toplacebo (731 steps/day; 95% CI=279, 1181; p=0.0016) and reduced the percentage of inactive patients(<6000 steps per day) [40.8% compared to 54.5%; p<0.0001]. Improvements in the PROactive totalscore were observed in patients treated with Duaklir Genuair compared with placebo (p=0.0002).

A behavioural intervention program was added to both treatment groups for an additional 4 weeks.

The number of steps/day in the Duaklir Genuair treatment group was maintained resulting in atreatment effect compared to placebo of 510 steps/day (p=0.1588) and a reduction versus placebo inthe percentage of inactive patients (<6000 steps per day) (41.5% compared to 50.4%; p=0.1134).

*As the primary endpoint did not achieve statistical significance, all p-values for secondary endpointsare tested at a nominal significance level of 0.05, and no formal statistical inference can be drawn.

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

Duaklir Genuair in all subsets of the paediatric population in COPD (see section 4.2 for informationon paediatric use).

When aclidinium and formoterol were administered in combination by the inhaled route, thepharmacokinetics of each component showed no relevant differences from those observed when themedicinal products were administered separately.

Following inhalation of a single dose of Duaklir Genuair 340/12 micrograms, aclidinium andformoterol were rapidly absorbed into plasma, reaching peak plasma concentrations within 5 minutesof inhalation in healthy subjects and within 24 minutes of inhalation in patients with COPD. The peakplasma concentrations at steady state of aclidinium and formoterol observed in patients with COPDtreated with Duaklir Genuair twice daily for 5 days were reached within 5 minutes post-inhalation andwere 128 pg/ml and 17 pg/ml, respectively.

Whole lung deposition of inhaled aclidinium via Genuair averaged approximately 30% of the metereddose. The plasma protein binding of aclidinium determined in vitro most likely corresponded to theprotein binding of the metabolites due to the rapid hydrolysis of aclidinium in plasma; plasma proteinbinding was 87% for the carboxylic acid metabolite and 15% for the alcohol metabolite. The mainplasma protein that binds aclidinium is albumin.

The plasma protein binding of formoterol is 61% to 64% (34% primarily to albumin). There is nosaturation of binding sites in the concentration range reached with therapeutic doses.

Aclidinium is rapidly and extensively hydrolysed to its pharmacologically inactive alcohol- andcarboxylic acid-derivatives. Plasma levels of the acid metabolite are approximately 100-fold greaterthan those of the alcohol metabolite and the unchanged active substance following inhalation. Thehydrolysis occurs both chemically (non-enzymatically) and enzymatically by esterases,butyrylcholinesterase being the main human esterase involved in the hydrolysis. The low absolutebioavailability of inhaled aclidinium (<5%) is because aclidinium undergoes extensive systemic andpre-systemic hydrolysis whether deposited in the lung or swallowed. Biotransformation via CYP450enzymes plays a minor role in the total metabolic clearance of aclidinium. In vitro studies have shownthat aclidinium at the therapeutic dose or its metabolites do not inhibit or induce any of the cytochrome

P450 (CYP450) enzymes and do not inhibit esterases (carboxylesterase, acetylcholinesterase andbutyrylcholinesterase). In vitro studies have shown that aclidinium or its metabolites are not substratesor inhibitors of P-glycoprotein.

Formoterol is eliminated primarily by metabolism. The prominent pathway involves directglucuronidation, with O-demethylation followed by glucuronide conjugation being a further metabolicpathway. Cytochrome P450 isoenzymes CYP2D6, CYP2C19, CYP2C9 and CYP2A6 are involved inthe O-demethylation of formoterol. Formoterol does not inhibit CYP450 enzymes at therapeuticallyrelevant concentrations.

Following inhalation of Duaklir Genuair 340/12 micrograms, with plasma sampling up to 24 hourspost-dose, the terminal elimination half-life observed for aclidinium bromide ranged from 11-33 hoursand for formoterol from 12-18 hours.

Mean effective half-lives* observed for both aclidinium and formoterol (based on the accumulationratio) are approximately 10 hours.

*Half-life consistent with product accumulation based on a known dose regimen.

Following intravenous administration of radiolabelled aclidinium 400 micrograms to healthy subjects,approximately 1% of the dose was excreted as unchanged aclidinium bromide in the urine. Up to 65%of the dose was eliminated as metabolites in the urine and up to 33% as metabolites in the faeces.

Following inhalation of aclidinium 200 micrograms and 400 micrograms by healthy subjects orpatients with COPD, the urinary excretion of unchanged aclidinium was very low at about 0.1% of theadministered dose, indicating that renal clearance plays a minor role in the total aclidinium clearancefrom plasma.

The major part of a dose of formoterol is transformed by liver metabolism followed by renalelimination. After inhalation, 6% to 9% of the delivered dose of formoterol is excreted in the urineunchanged or as direct conjugates of formoterol.

No pharmacokinetics studies have been performed with aclidinium/formoterol in elderly subjects.

Since no dosage adjustments are needed for either aclidinium or formoterol medicinal products inelderly patients, no dosage adjustment is warranted for aclidinium/formoterol in geriatric patients.

Renally and hepatically impaired patients

There are no data regarding the specific use of aclidinium/formoterol in patients with renal or hepaticimpairment. Since no dosage adjustments are needed for either aclidinium or formoterol medicinalproducts in patients with renal or hepatic impairment, no dosage adjustment is warranted foraclidinium/formoterol.

Following repeated inhalations of Duaklir Genuair 340/12 micrograms, the systemic exposure ofaclidinium and formoterol, as measured by AUC, is similar in Japanese and Caucasian patients.

Nonclinical data reveal no special hazard for humans with aclidinium and formoterol based onconventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenicpotential and toxicity to reproduction and development.

Effects of aclidinium in nonclinical studies with respect to reproductive toxicity (foetotoxic effects)and fertility (slight decreases in conception rate, number of corpora lutea, and pre- and post-implantation losses) were observed only at exposures considered sufficiently in excess of themaximum human exposure indication to be of little relevance to clinical use.

Formoterol showed reduced fertility (implantation losses) in rats, as well as decreased early postnatalsurvival and birth weight with high systemic exposure to formoterol. A slight increase in the incidenceof uterine leiomyomas has been observed in rats and mice; an effect which is considered to be a class-effect in rodents after long-term exposure to high doses of β2-adrenoreceptor agonists.

Nonclinical studies investigating the effects of aclidinium/formoterol on cardiovascular parametersshowed increased heart rates and arrhythmias at exposures sufficiently in excess of the maximumhuman exposure indication to be of little relevance to clinical use. These effects are knownexaggerated pharmacological responses observed with β2-agonists.

Lactose monohydrate.

Not applicable.

3 years.

To be used within 60 days of opening the bag.

This medicinal product does not require any special temperature storage conditions.

Keep the Genuair inhaler protected inside the sealed bag until the administration period starts.

The Genuair inhaler is a multicomponent device made of plastic (polycarbonate, acrylonitrile-butadiene-styrene, polyoxymethylene, polyester-butylene-terephthalate, polypropylene, polystyrene)and stainless steel. It is white-coloured with an integral dose indicator and an orange dosage button.

The mouthpiece is covered with a removable orange protective cap. The inhaler is supplied sealed in aprotective aluminium laminate bag containing a silica gel desiccant sachet, placed in a cardboardcarton.

Carton containing 1 inhaler with 30 doses.

Carton containing 1 inhaler with 60 doses.

Carton containing 3 inhalers each with 60 doses.

Not all pack sizes may be marketed.

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

Instructions for Use

Getting Started

Read these Instructions for Use before you start using the medicine.

Become familiar with the parts of your Genuair inhaler.

Control window Dose

Green = inhaler ready to use indicator Orange button

Protective

Cap

Control window

Red = confirms correct inhalation

Mouthpiece

Figure A

a. Before first use, tear open the sealed bag and remove the inhaler. Throw away the bag and thedesiccant.

b. Do not press the orange button until you are ready to take a dose.

c. Pull off the cap by lightly squeezing the arrows marked on each side (Figure B).

Squeeze hereand pull

Figure B

STEP 1: Prepare your dose1.1 Look in the opening of the mouthpiece and make sure nothing is blocking it (Figure C).

1.2 Look at the control window (should be red, Figure C).

RED

Check mouthpieceopening

Figure C1.3 Hold the inhaler horizontally with the mouthpiece facing you and the orange button on top(Figure D).

Figure D1.4 Press the orange button all the way down to load your dose (Figure E).

When you press the button all the way down, the control window changes from red to green.

Make sure the orange button is on top. Do not tilt.

1.5 Release the orange button (Figure F).

Make sure you release the button so the inhaler can work correctly.

Figure E Figure F

Stop and Check:

1.6 Make sure the control window is now green (Figure G).

Your medicine is ready to be inhaled.

Go to ‘STEP 2: Inhale your medicine’.

GREEN

Figure G

What to do if the control window is still red after pressing the button (Figure H).

Figure H

The dose is not prepared. Go back to ‘STEP 1 Prepare your dose’ and repeat steps 1.1 to 1.6.

STEP 2: Inhale your medicine

Read steps 2.1 to 2.7 fully before use. Do not tilt.

2.1 Hold the inhaler away from your mouth, and breathe out completely. Never breathe out intothe inhaler (Figure I).

Figure I2.2 Hold your head upright, put the mouthpiece between your lips, and close your lipstightly around it (Figure J).

Do not hold the orange button down while inhaling.

Figure J2.3 Take a strong, deep breath through your mouth. Keep breathing in for as long as possible.

A ‘click’ will let you know that you are inhaling correctly. Keep breathing in as long as possibleafter you hear the ‘click’. Some patients may not hear the ‘click’. Use the control window to ensureyou have inhaled correctly.

2.4 Take the inhaler out of your mouth.

2.5 Hold your breath for as long as possible.

2.6 Slowly breathe out away from the inhaler.

Some patients may experience a grainy sensation in their mouth, or a slightly sweet or bitter taste. Donot take an extra dose even if you do not taste or feel anything after inhaling.

Stop and Check:

2.7 Make sure the control window is now red (Figure K). This means you have inhaled yourmedicine correctly.

RED

Figure K

What to do if the control window is still green after inhalation (Figure L).

Figure L

This means you have not inhaled your medicine correctly. Go back to ‘STEP 2 Inhale your medicine’and repeat steps 2.1 to 2.7.

If the control window still does not change to red, you may have forgotten to release the orange buttonbefore inhaling, or you may not have inhaled strongly enough. If this happens, try again. Make sure youhave released the orange button, and you have breathed out completely. Then take a strong, deep breaththrough the mouthpiece.

Please contact your doctor if the control window is still green after repeated attempts.

Push the protective cap back onto the mouthpiece after each use (Figure M), to prevent contaminationof the inhaler with dust and other materials. You should discard your inhaler if you lose the cap.

Figure M

What should you do if you accidently prepare a dose?

Store your inhaler with the protective cap in place until it is time to inhale your medicine, then removethe cap and start at Step 1.6.

How does the dose indicator work?

* The dose indicator shows the total number of doses left in the inhaler (Figure N).

* On first use, every inhaler contains at least 60 doses, or at least 30 doses, depending on thepack size.

* Each time you load a dose by pressing the orange button, the dose indicator moves by a smallamount towards the next number (50, 40, 30, 20, 10, or 0).

When should you get a new inhaler?

You should get a new inhaler:

* If your inhaler appears to be damaged or if you lose the cap, or

* When a red band appears in the dose indicator, this means you are nearing your last dose(Figure N), or

* If your inhaler is empty (Figure O).

Dose indicator moves slowly from60 to 0: 60, 50, 40, 30, 20, 10, 0.

Dose

Red bandindicator

Figure N

How do you know that your inhaler is empty?

When the orange button will not return to its full upper position and is locked in a middle position, youhave reached the last dose (Figure O). Even though the orange button is locked, your last dose maystill be inhaled. After that, the inhaler cannot be used again and you should start using a new inhaler.

Locked

Figure O

How should you clean the inhaler?

NEVER use water to clean the inhaler, as this may damage your medicine.

If you wish to clean your inhaler, just wipe the outside of the mouthpiece with a dry tissue or papertowel.

Covis Pharma Europe B.V.

Gustav Mahlerplein 21082MA Amsterdam

The Netherlands

EU/1/14/964/001

EU/1/14/964/002

EU/1/14/964/003

Date of first authorisation: 19 November 2014

Date of latest renewal: 23 August 2019

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

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