Leaflet BRETARIS GENUAIR 322mcg inhalation powder

Bretaris Genuair 322 micrograms inhalation powder

Each delivered dose (the dose leaving the mouthpiece) contains 375 µg aclidinium bromide equivalentto 322 µg of aclidinium. This corresponds to a metered dose of 400 µg aclidinium bromide equivalentto 343 µg aclidinium.

Each delivered dose contains approximately 12 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 a green dosagebutton.

Bretaris Genuair is indicated as a maintenance bronchodilator treatment to relieve symptoms in adultpatients with chronic obstructive pulmonary disease (COPD) (see section 5.1).

The recommended dose is one inhalation of 322 micrograms aclidinium twice daily.

If a dose is missed the next dose should be taken as soon as possible. However, if it is nearly time forthe next dose, the missed dose should be skipped.

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

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

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

There is no relevant use of Bretaris 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 carefully read the Instructions for Use in the Package Leaflet, which is packed togetherwith each inhaler.

For Instructions for Use, see section 6.6.

Hypersensitivity to aclidinium bromide or to the excipients listed in section 6.1.

Administration of Bretaris Genuair may cause paradoxical bronchospasm. If this occurs, treatmentwith Bretaris Genuair should be stopped and other treatments considered.

Aclidinium bromide is a maintenance bronchodilator and should not be used for the relief of acuteepisodes of bronchospasm, i.e. as a rescue therapy. In the event of a change in COPD intensity whilethe patient is being treated with aclidinium bromide so that the patient considers additional rescuemedication is required, a re-evaluation of the patient and the patients’ treatment regimen should beconducted.

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

Experience in patients with cardiovascular comorbidities in clinical trials is limited (see section 5.1).

These conditions may be affected by the anticholinergic mechanism of action.

Dry mouth, which has been observed with anticholinergic treatment, may in the long term beassociated with dental caries.

Consistent with its anticholinergic activity, aclidinium bromide should be used with caution in patientswith symptomatic prostatic hyperplasia or bladder-neck obstruction or with narrow-angle glaucoma(even though direct contact of the product with the eyes is very unlikely).

This medicinal product contains lactose. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinalproduct.

Co-administration of aclidinium bromide with other anticholinergic-containing medicinal products hasnot been studied and is not recommended.

Although no formal in vivo drug interaction studies have been performed, inhaled aclidinium bromidehas been used concomitantly with other COPD medicinal products including sympathomimeticbronchodilators, methylxanthines, and oral and inhaled steroids without clinical evidence of druginteractions.

In vitro studies have shown that aclidinium bromide or the metabolites of aclidinium bromide at thetherapeutic dose are not expected to cause interactions with active substances that are substrates of P-glycoprotein (P-gp) or active substances metabolised by cytochrome P450 (CYP450) enzymes andesterases (see section 5.2).

There are no data available on the use of aclidinium bromide in pregnant women.

Studies in animals have shown foetotoxicity only at dose levels much higher than the maximumhuman exposure to aclidinium bromide (see section 5.3). Aclidinium bromide should only be usedduring pregnancy if the expected benefits outweigh the potential risks.

It is unknown whether aclidinium bromide/metabolites are excreted in human milk. Animal studieshave shown excretion of small amounts of aclidinium bromide and/or metabolites into milk. A risk tonewborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feedingor to discontinue/abstain from Bretaris Genuair therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Studies in rats have shown slight reductions in fertility only at dose levels much higher than themaximum human exposure to aclidinium bromide (see section 5.3). It is considered unlikely thataclidinium bromide administered at the recommended dose will affect fertility in humans.

Aclidinium bromide may have minor influence on the ability to drive and use machines. Theoccurrence of headache, dizziness or blurred vision following administration of aclidinium bromide(see section 4.8) may influence the ability to drive or to use machinery.

The most frequently reported adverse reactions with Bretaris Genuair were headache (6.6%) andnasopharyngitis (5.5%).

The frequencies assigned to the undesirable effects listed below are based on crude incidence rates ofadverse reactions (i.e. events attributed to Bretaris Genuair) observed with Bretaris Genuair 322 µg(636 patients) in the pooled analysis of one 6-month and two 3-month randomised, placebo-controlledclinical trials or on post-marketing study results.

A placebo-controlled trial in 1791 patients with moderate to very severe COPD treated with Bretaris

Genuair up to 36 months did not identify other adverse reactions.

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 the available data).

System organ class Preferred term Frequency

Infections and infestations Sinusitis Common

Nasopharyngitis Common

Immune system disorders Hypersensitivity Rare

Angioedema Not known

Anaphylactic reaction Not known

Nervous system disorders Headache Common

Dizziness Uncommon

Eye disorders Blurred vision Uncommon

Cardiac disorders Cardiac arrhythmias, Uncommonincluding atrialfibrillation andparoxysmaltachycardia

Tachycardia Uncommon

Palpitations Uncommon

Respiratory, thoracic and Cough Commonmediastinal disorders Dysphonia Uncommon

Gastrointestinal disorders Diarrhoea Common

Nausea Common

Dry mouth Uncommon

Stomatitis Uncommon

Skin and subcutaneous tissue Rash Uncommondisorders Pruritus Uncommon

Renal and urinary disorders Urinary retention 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.

High doses of aclidinium bromide may lead to anticholinergic signs and symptoms.

However, single inhaled doses up to 6,000 µg aclidinium bromide have been administered to healthysubjects without systemic anticholinergic adverse reactions. Additionally, no clinically relevantadverse reactions were observed following 7-day twice daily dosing of up to 800 µg aclidiniumbromide in healthy subjects.

Acute intoxication by inadvertent medicinal product ingestion of aclidinium bromide is unlikely due toits low oral bioavailability and the breath-actuated dosing mechanism of the Genuair inhaler.

Pharmacotherapeutic group: Drugs for obstructive airway diseases, anticholinergics; ATC Code:

R03BB05.

Aclidinium bromide is a competitive, selective muscarinic receptor antagonist (also known as ananticholinergic), with a longer residence time at the M3 receptors than the M2 receptors. M3 receptorsmediate contraction of airway smooth muscle. Inhaled aclidinium bromide acts locally in the lungs toantagonise M3 receptors of airway smooth muscle and induce bronchodilation. Nonclinical in vitro andin vivo studies showed rapid, dose-dependent and long-lasting inhibition by aclidinium ofacetylcholine-induced bronchoconstriction. Aclidinium bromide is quickly broken down in plasma, thelevel of systemic anticholinergic side effects is therefore low.

Clinical efficacy studies showed that Bretaris Genuair provided clinically meaningful improvementsin lung function (as measured by the forced expiratory volume in 1 second [FEV1]) over 12 hoursfollowing morning and evening administration, which were evident within 30 minutes of the first dose(increases from baseline of 124-133 mL). Maximal bronchodilation was achieved within 1-3 hoursafter dosing with mean peak improvements in FEV1 relative to baseline of 227-268 mL at steady-state.

No effects on QT interval (corrected using either the Fridericia or Bazett method or individually-corrected) were observed when aclidinium bromide (200 µg or 800 µg) was administered once dailyfor 3 days to healthy subjects in a thorough QT study.

In addition, no clinically significant effects of Bretaris Genuair on cardiac rhythm were observed on24-hour Holter monitoring after 3 months treatment of 336 patients (of whom 164 received Bretaris

Genuair 322 µg twice daily).

The Bretaris Genuair Phase III clinical development programme included 269 patients treated with

Bretaris Genuair 322 µg twice daily in one 6-month randomised, placebo-controlled study and190 patients treated with Bretaris Genuair 322 µg twice daily in one 3-month randomised, placebo-controlled study. Efficacy was assessed by measures of lung function and symptomatic outcomes suchas breathlessness, disease-specific health status, use of rescue medication and occurrence ofexacerbations. In the long-term safety studies, Bretaris Genuair was associated with bronchodilatoryefficacy when administered over a 1-year treatment period.

Bronchodilation

In the 6-month study, patients receiving Bretaris Genuair 322 µg twice daily experienced a clinicallymeaningful improvement in their lung function (as measured by FEV1). Maximal bronchodilatoryeffects were evident from day one and were maintained over the 6-month treatment period. After6 months treatment, the mean improvement in morning pre-dose (trough) FEV1 compared to placebowas 128 mL (95% CI=85-170; p<0.0001).

Similar observations were made with Bretaris Genuair in the 3 month study.

Disease-Specific Health Status and Symptomatic Benefits

Bretaris Genuair provided clinically meaningful improvements in breathlessness (assessed using the

Transition Dyspnoea Index [TDI]) and disease-specific health status (assessed using the St. George’s

Respiratory Questionnaire [SGRQ]). The Table below shows symptom relief obtained after 6 monthstreatment with Bretaris Genuair.

Variable Treatment Improvement over

Bretaris Genuair Placebo placebo p-value

TDI

Percentage of Patients who cachieved MCIDa 56.9 45.5 1.68-fold increasein likelihood 0.004

Mean Change from baseline 1.9 0.9 1.0 unit <0.001

SGRQ

Percentage of Patients who 57.3 41.0 1.87-foldc increaseachieved MCIDb in likelihood <0.001

Mean Change from baseline -7.4 -2.8 - 4.6 units <0.0001a Minimum clinically important difference (MCID) of at least 1 unit change in TDI.b MCID of at least - 4 units change in SGRQ.c Odds ratio, increase in the likelihood of achieving the MCID compared to placebo.

Patients treated with Bretaris Genuair required less rescue medication than patients treated withplacebo (a reduction of 0.95 puffs per day at 6 months [p=0.005]). Bretaris Genuair also improveddaily symptoms of COPD (dyspnoea, cough and sputum production) and night-time and early morningsymptoms.

Pooled efficacy analysis of the 6-month and 3-month placebo controlled studies demonstrated astatistically significant reduction in the rate of moderate to severe exacerbations (requiring treatmentwith antibiotics or corticosteroids or resulting in hospitalisations) with aclidinium 322 µg twice dailycompared to placebo (rate per patient per year: 0.31 vs 0.44 respectively; p=0.0149).

Long Term Safety and Efficacy Trial up to 3 years

The effect of aclidinium bromide on the occurrence of major adverse cardiovascular events (MACE)was assessed in a randomised, double-blind, placebo-controlled, parallel-group study in 3630 adultpatients between 40 and 91 years of age with moderate to very severe COPD, treated for up to36 months. 58.7% were male and 90.7% were Caucasian, with a mean postbronchodilator FEV1 of47.9% of predicted value and a mean CAT (COPD Assessment Test) of 20.7. All patients had ahistory of cardiovascular or cerebrovascular disease and/or significant cardiovascular risk factors.59.8% of patients had at least one COPD exacerbation within the past 12 months from the screeningvisit. Approximately 48% of enrolled patients had a prior history of at least 1 documented previouscardiovascular event; cerebrovascular disease (13.1%), coronary artery disease (35.4%), peripheralvascular disease or history of claudication (13.6%).

The study had an event-driven design and was terminated once sufficient MACE events for theprimary safety analysis were observed. Patients discontinued treatment if they experienced a MACEevent and entered into the post-treatment follow-up period during the study. 70.7% of patientscompleted the study per investigator assessment. The median time on-treatment in the Bretaris

Genuair and placebo groups was 1.1 and 1 year, respectively. The median time on-study in the

Bretaris Genuair and placebo groups was approximately 1.4 and 1.3 years, respectively.

The primary safety endpoint was the time to first occurrence of MACE, defined as any of thefollowing adjudicated events: cardiovascular death, non-fatal myocardial infarction (MI), or non-fatalischemic stroke. The frequency of patients with at least one MACE was 3.85% vs. 4.23% patients inthe aclidinium and placebo groups, respectively. Bretaris Genuair did not increase the MACE risk inpatients with COPD compared to placebo when added to current background therapy (hazard ratio(HR) 0.89; 95% CI: 0.64, 1.23). The upper bound of the confidence interval excluded a pre-definedrisk margin of 1.8.

The rate of moderate or severe COPD exacerbations per patient per year during the first year oftreatment was evaluated as the primary efficacy endpoint in the study. Patients treated with Bretaris

Genuair showed a statistically significant reduction of 22% compared to placebo (rate ratio [RR] 0.78;95% CI 0.68 to 0.89; p<0.001). In addition, Bretaris Genuair showed a statistically significantreduction of 35% in the rate of hospitalisations due to COPD exacerbations while on-treatment duringthe first year compared with placebo (RR 0.65; 95% CI 0.48 to 0.89; p=0.006).

The Bretaris Genuair group showed a statistically significant delay in the time to first moderate orsevere exacerbation while on-treatment compared to the placebo group. Patients in the aclidiniumbromide group had a 18% relative reduction of the risk of an exacerbation (HR 0.82; 95% CI [0.73,0.92], p<0.001).

Exercise tolerance

In a 3-week crossover, randomised, placebo-controlled clinical study Bretaris Genuair was associatedwith a statistically significant improvement in exercise endurance time in comparison to placebo of 58seconds (95% CI=9-108; p=0.021; pre-treatment value: 486 seconds). Bretaris Genuair statisticallysignificantly reduced lung hyperinflation at rest (functional residual capacity [FRC]=0.197 L [95%

CI=0.321, 0.072; p=0.002]; residual volume [RV]=0.238 L [95% CI=0.396, 0.079; p=0.004]) and alsoimproved trough inspiratory capacity (by 0.078 L; 95% CI=0.01, 0.145; p=0.025) and reduceddyspnoea during exercise (Borg scale) (by 0.63 Borg units; 95% CI=1.11, 0.14; p=0.012).

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

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

Aclidinium bromide is rapidly absorbed from the lung, achieving maximum plasma concentrationswithin 5 minutes of inhalation in healthy subjects, and normally within the first 15 minutes in COPDpatients. The fraction of the inhaled dose that reaches the systemic circulation as unchangedaclidinium is very low at less than 5%.

Steady state peak plasma concentrations achieved after dry powder inhalation by COPD patients of400 µg aclidinium bromide were approximately 224 pg/mL. Steady-state plasma levels were attainedwithin seven days of twice daily dosing.

Whole lung deposition of inhaled aclidinium bromide via the Genuair inhaler averaged approximately30% of the metered dose.

The plasma protein binding of aclidinium bromide determined in vitro most likely corresponded to theprotein binding of the metabolites due to the rapid hydrolysis of aclidinium bromide in plasma; plasmaprotein binding was 87% for the carboxylic acid metabolite and 15% for the alcohol metabolite. Themain plasma protein that binds aclidinium bromide is albumin.

Aclidinium bromide is rapidly and extensively hydrolysed to its pharmacologically inactive alcohol-and carboxylic acid-derivatives. The hydrolysis occurs both chemically (non-enzymatically) andenzymatically by esterases, butyrylcholinesterase being the main human esterase involved in thehydrolysis. Plasma levels of the acid metabolite are approximately 100-fold greater than those of thealcohol metabolite and the unchanged active substance following inhalation.

The low absolute bioavailability of inhaled aclidinium bromide (<5%) is because aclidinium bromideundergoes extensive systemic and pre-systemic hydrolysis whether deposited in the lung orswallowed.

Biotransformation via CYP450 enzymes plays a minor role in the total metabolic clearance ofaclidinium bromide.

In vitro studies have shown that aclidinium bromide at the therapeutic dose or its metabolites do notinhibit or induce any of the cytochrome P450 (CYP450) enzymes and do not inhibit esterases(carboxylesterase, acetylcholinesterase and butyrylcholinesterase). In vitro studies have shown thataclidinium bromide or the metabolites of aclidinium bromide are not substrates or inhibitors of

P-glycoprotein.

The terminal elimination half-life and effective half-life of aclidinium bromide are approximately 14hours and 10 hours, respectively, following inhalation of twice daily 400 µg doses in COPD patients.

Following intravenous administration of 400 µg radiolabelled aclidinium bromide 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 200 µg and 400 µg of aclidinium bromide by healthy subjects or COPDpatients, 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.

Aclidinium bromide demonstrated kinetic linearity and a time-independent pharmacokinetic behaviourin the therapeutic range.

The pharmacokinetic properties of aclidinium bromide in patients with moderate to severe COPDappear to be similar in patients aged 40-59 years and in patients aged ≥70 years. Therefore, no doseadjustment is required for elderly COPD patients.

Hepatically-impaired patients

No studies have been performed on hepatically-impaired patients. As aclidinium bromide ismetabolised mainly by chemical and enzymatic cleavage in the plasma, hepatic dysfunction is veryunlikely to alter its systemic exposure. No dose adjustment is required for hepatically-impaired COPDpatients.

Renally-impaired patients

No significant pharmacokinetic differences were observed between subjects with normal renalfunction and subjects with renal impairment. Therefore, no dose adjustment and no additionalmonitoring are required for renally-impaired COPD patients.

Following repeated inhalations, the systemic exposure of aclidinium bromide has been observed to besimilar in Japanese and Caucasian patients.

Because aclidinium bromide acts locally in the lungs and is quickly broken down in plasma there is nodirect relationship between pharmacokinetics and pharmacodynamics.

Nonclinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity toreproduction and development.

Effects in nonclinical studies with respect to cardiovascular parameters (increased heart rates in dogs),reproductive toxicity (foetotoxic effects), and fertility (slight decreases in conception rate, number ofcorpora lutea, and pre- and post-implantation losses) were observed only at exposures consideredsufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

The low toxicity observed in nonclinical toxicity studies is in part due to rapid metabolism ofaclidinium bromide in plasma and the lack of significant pharmacological activity of the majormetabolites. The safety margins for human systemic exposure with 400 µg twice daily over the noobserved adverse effect levels in these studies ranged from 7- to 73-fold.

Lactose monohydrate.

Not applicable.

3 years.

To be used within 90 days of opening the pouch.

Keep the inhaler inside the pouch until the administration period starts.

The inhaler device is a multicomponent device made of polycarbonate, acrylonitrile-butadiene-styrene,polyoxymethylene, polyester-butylene-terephthalate, polypropylene, polystyrene and stainless steel. Itis white-coloured with an integral dose indicator and a green dosage button. The mouthpiece iscovered with a removable green protective cap. The inhaler is supplied in a plastic laminate pouch,placed in a cardboard carton.

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 Green 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.

b) Do not press the green 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 green button on top(Figure D).

Figure D1.4 Press the green 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 green button is on top. Do not tilt.

1.5 Release the green 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 green 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 green buttonbefore inhaling, or you may not have inhaled strongly enough. If this happens, try again. Make sure youhave released the green 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 or 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 green 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.

Red band

Doseindicator

Figure N

How do you know that your inhaler is empty?

When the green 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 green button is locked, your last dose may stillbe 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/1/12/781/001

EU/1/12/781/002

EU/1/12/781/003

Date of first authorisation: 20 July 2012

Date of last renewal: 20 April 2017

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

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