ONBREZ BREEZHALER 150mcg inhalation powder capsules medication leaflet

Onbrez Breezhaler 150 microgram inhalation powder, hard capsules

Each capsule contains indacaterol maleate equivalent to 150 microgram indacaterol.

The delivered dose leaving the mouthpiece of the inhaler is indacaterol maleate equivalent to120 microgram indacaterol.

Each capsule contains 24.8 mg lactose.

For the full list of excipients, see section 6.1.

Inhalation powder, hard capsule

Transparent (uncoloured) capsules containing a white powder, with “IDL 150” printed in black abovea black bar and company logo ( ) printed in black below the black bar.

Onbrez Breezhaler is indicated for maintenance bronchodilator treatment of airflow obstruction inadult patients with chronic obstructive pulmonary disease (COPD).

The recommended dose is the inhalation of the content of one 150 microgram capsule once a day,using the Onbrez Breezhaler inhaler. The dose should only be increased on medical advice.

The inhalation of the content of one 300 microgram capsule once a day, using the Onbrez Breezhalerinhaler has been shown to provide additional clinical benefit with regard to breathlessness, particularlyfor patients with severe COPD. The maximum dose is 300 microgram once daily.

Onbrez Breezhaler should be administered at the same time of the day each day.

If a dose is missed the next dose should be taken at the usual time the next day.

Maximum plasma concentration and overall systemic exposure increase with age but no doseadjustment is required in elderly patients.

No dose adjustment is required for patients with mild and moderate hepatic impairment. There are nodata available for use of Onbrez Breezhaler in patients with severe hepatic impairment.

No dose adjustment is required for patients with renal impairment.

There is no relevant use of Onbrez Breezhaler in the paediatric population (under 18 years).

For inhalation use only. Onbrez Breezhaler capsules must not be swallowed.

The capsules must only be removed from the blister immediately before use.

The capsules must be administered only using the Onbrez Breezhaler inhaler (see section 6.6). The

Onbrez Breezhaler inhaler provided with each new prescription should be used.

Patients should be instructed on how to administer the product correctly. Patients who do notexperience improvement in breathing should be asked if they are swallowing the medicine rather thaninhaling it.

For instructions on use of the medicinal product before administration, see section 6.6.

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

Asthma

Onbrez Breezhaler is a long-acting beta2-adrenergic agonist, which is only indicated for COPD andshould not be used in asthma due to the absence of long-term outcome data in asthma.

Long-acting beta2-adrenergic agonists may increase the risk of asthma-related serious adverse events,including asthma-related deaths, when used for the treatment of asthma.

Immediate hypersensitivity reactions have been reported after administration of Onbrez Breezhaler. Ifsigns suggesting allergic reactions (in particular, difficulties in breathing or swallowing, swelling oftongue, lips and face, urticaria, skin rash) occur, Onbrez Breezhaler should be discontinuedimmediately and alternative therapy instituted.

As with other inhalation therapy, administration of Onbrez Breezhaler may result in paradoxicalbronchospasm that may be life-threatening. If paradoxical bronchospasm occurs Onbrez Breezhalershould be discontinued immediately and alternative therapy substituted.

Onbrez Breezhaler is not indicated for the treatment of acute episodes of bronchospasm, i.e. as rescuetherapy. In the event of deterioration of COPD during treatment with Onbrez Breezhaler, a re-evaluation of the patient and of the COPD treatment regimen should be undertaken. An increase in thedaily dose of Onbrez Breezhaler beyond the maximum dose of 300 microgram is not appropriate.

Although no clinically relevant effect on the cardiovascular system is usually seen after theadministration of Onbrez Breezhaler at the recommended doses, as with other beta2-adrenergicagonists, indacaterol should be used with caution in patients with cardiovascular disorders (coronaryartery disease, acute myocardial infarction, cardiac arrhythmias, hypertension), in patients withconvulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to beta2-adrenergic agonists.

Like other beta2-adrenergic agonists, indacaterol may produce a clinically significant cardiovasculareffect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. Incase such effects occur, treatment may need to be discontinued. In addition, beta-adrenergic agonistshave been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave,prolongation of QT interval and ST segment depression, although the clinical significance of theseobservations is unknown. Therefore, long-acting beta2-adrenergic agonists (LABA) or LABAcontaining products such as Onbrez Breezhaler should be used with caution in patients with known orsuspected prolongation of the QT interval or treated with medicinal products affecting the QT interval.

Beta2-adrenergic agonists may produce significant hypokalaemia in some patients, which has thepotential to produce adverse cardiovascular effects. The decrease in serum potassium is usuallytransient, not requiring supplementation. In patients with severe COPD, hypokalaemia may bepotentiated by hypoxia and concomitant treatment (see section 4.5), which may increase thesusceptibility to cardiac arrhythmias.

Inhalation of high doses of beta2-adrenergic agonists may produce increases in plasma glucose. Uponinitiation of treatment with Onbrez Breezhaler plasma glucose should be monitored more closely indiabetic patients.

During clinical studies, clinically notable changes in blood glucose were generally more frequent by1-2% on Onbrez Breezhaler at the recommended doses than on placebo. Onbrez Breezhaler has notbeen investigated in patients with not well controlled diabetes mellitus.

The capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, totallactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sympathomimetic medicinal products

Concomitant administration of other sympathomimetic medicinal products (alone or as part ofcombination therapy) may potentiate adverse reactions to Onbrez Breezhaler.

Onbrez Breezhaler should not be used in conjunction with other long-acting beta2-adrenergic agonistsor medicinal products containing long-acting beta2-adrenergic agonists.

Hypokalaemic treatment

Concomitant hypokalaemic treatment with methylxanthine derivatives, steroids, or non-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of beta2-adrenergic agonists,therefore caution is required (see section 4.4).

Beta-adrenergic blockers

Beta-adrenergic blockers and beta2-adrenergic agonists may weaken or antagonise the effect of eachother when administered concurrently. Therefore indacaterol should not be given together with beta-adrenergic blockers (including eye drops) unless there are compelling reasons for their use. Whererequired, cardioselective beta-adrenergic blockers should be preferred, although they should beadministered with caution.

Metabolic and transporter based interactions

Inhibition of the key contributors of indacaterol clearance, CYP3A4 and P-glycoprotein (P-gp) raisesthe systemic exposure of indacaterol by up to two-fold. The magnitude of exposure increases due tointeractions does not raise any safety concerns given the safety experience of treatment with Onbrez

Breezhaler in clinical studies of up to one year at doses up to twice the maximum recommendedtherapeutic dose.

Indacaterol has not been shown to cause interactions with medicinal products administeredconcomitantly. In vitro investigations have indicated that indacaterol has negligible potential to causemetabolic interactions with medicinal products at the systemic exposure levels achieved in clinicalpractice.

There are no data from the use of indacaterol in pregnant women available. Animal studies do notindicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevantexposures (see section 5.3). Like other beta2-adrenergic agonists, indacaterol may inhibit labour due toa relaxant effect on uterine smooth muscle. Onbrez Breezhaler should only be used during pregnancyif the expected benefits outweigh the potential risks.

It is not known whether indacaterol/metabolites are excreted in human milk. Availablepharmacokinetic/toxicological data in animals have shown excretion of indacaterol/metabolites in milk(see section 5.3). A risk to the breast-fed child cannot be excluded. A decision must be made whetherto discontinue breast-feeding or to discontinue/abstain from Onbrez Breezhaler therapy, taking intoaccount the benefit of breast-feeding for the child and the benefit of therapy for the woman.

A decreased pregnancy rate has been observed in rats. Nevertheless, it is considered unlikely thatindacaterol will affect reproductive or fertility performance in humans following inhalation of themaximum recommended dose (see section 5.3).

Onbrez Breezhaler has no or negligible influence on the ability to drive and use machines.

The most common adverse reactions at the recommended doses were nasopharyngitis (14.3%), upperrespiratory tract infection (14.2%), cough (8.2%), headache (3.7%) and muscle spasms (3.5%). Thesewere in the vast majority mild or moderate and became less frequent if treatment was continued.

At the recommended doses, the adverse reaction profile of Onbrez Breezhaler in patients with COPDshows clinically insignificant systemic effects of beta2-adrenergic stimulation. Mean heart ratechanges were less than one beat per minute, and tachycardia was infrequent and reported at a similarrate as under placebo treatment. Relevant prolongations of QTcF were not detectable in comparison toplacebo. The frequency of notable QTcF intervals [i.e. >450 ms (males) and >470 ms (females)] andreports of hypokalaemia were similar to placebo. The mean of the maximum changes in blood glucosewere similar between Onbrez Breezhaler and placebo.

The Onbrez Breezhaler Phase III clinical development programme involved patients with a clinicaldiagnosis of moderate to severe COPD. 4,764 patients were exposed to indacaterol up to one year atdoses up to twice the maximum recommended dose. Of these patients, 2,611 were on treatment with150 microgram once daily and 1,157 on treatment with 300 microgram once daily. Approximately41% of patients had severe COPD. The mean age of patients was 64 years, with 48% of patients aged65 years or older, and the majority (80%) was Caucasian.

Adverse reactions in Table 1 are listed according to MedDRA system organ class in the COPD safetydatabase. Within each system organ class, adverse reactions are ranked by frequency in descendingorder according to 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), not known(cannot be estimated from the available data).

Table 1 Adverse reactions

Adverse reactions Frequency category

Upper respiratory tract infection Common

Nasopharyngitis Common

Sinusitis Common

Hypersensitivity1 Uncommon

Diabetes mellitus and hyperglycaemia Uncommon

Headache Common

Dizziness Common

Paraesthesia Uncommon

Ischaemic heart disease Uncommon

Atrial fibrillation Uncommon

Palpitations Uncommon

Tachycardia Uncommon

Cough Common

Oropharyngeal pain including throat irritation Common

Rhinorrhoea Common

Paradoxical bronchospasm Uncommon

Pruritus/rash Uncommon

Muscle spasm Common

Myalgia Uncommon

Musculoskeletal pain Uncommon

Chest pain Common

Peripheral oedema Common1 Reports of hypersensitivity have been received from post-approval marketing experience inassociation with the use of Onbrez Breezhaler. These were reported voluntarily from a population ofuncertain size, and it is therefore not always possible to reliably estimate the frequency or establish acausal relationship to exposure to the medicinal product. Therefore the frequency was calculated fromclinical trial experience.

At 600 microgram once-daily, the safety profile of Onbrez Breezhaler was overall similar to that ofrecommended doses. An additional adverse reaction was tremor (common).

In Phase III clinical studies, healthcare providers observed during clinic visits that on average 17-20%of patients experienced a sporadic cough that occurred usually within 15 seconds following inhalationand typically lasted for 5 seconds (about 10 seconds in current smokers). It was observed with a higherfrequency in female than in male patients and in current smokers than in ex-smokers. This coughexperienced post inhalation did not lead to any patient discontinuing from the studies at therecommended doses (cough is a symptom in COPD and only 8.2% of patients reported cough as anadverse event). There is no evidence that cough experienced post inhalation is associated withbronchospasm, exacerbations, deteriorations of disease or loss of efficacy.

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.

In COPD patients, single doses of 10 times the maximum recommended therapeutic dose wereassociated with a moderate increase in pulse rate, systolic blood pressure and QTc interval.

An overdose of indacaterol is likely to lead to exaggerated effects typical of beta2-adrenergicstimulants, i.e. tachycardia, tremor, palpitations, headache, nausea, vomiting, drowsiness, ventriculararrhythmias, metabolic acidosis, hypokalaemia and hyperglycaemia.

Supportive and symptomatic treatment is indicated. In serious cases, patients should be hospitalised.

Use of cardioselective beta blockers may be considered, but only under the supervision of a physicianand with extreme caution since the use of beta-adrenergic blockers may provoke bronchospasm.

Pharmacotherapeutic group: Drugs for obstructive airways diseases, selective beta-2-adrenoreceptoragonists, ATC code: R03AC18

The pharmacological effects of beta2-adrenoceptor agonists are at least in part attributable tostimulation of intracellular adenyl cyclase, the enzyme that catalyses the conversion of adenosinetriphosphate (ATP) to cyclic-3’, 5’-adenosine monophosphate (cyclic monophosphate). Increasedcyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown thatindacaterol, a long-acting beta2-adrenergic agonist, has more than 24-fold greater agonist activity atbeta2-receptors compared to beta1-receptors and 20-fold greater agonist activity compared to beta3-receptors.

When inhaled, indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a partial agonistat the human beta2-adrenergic receptor with nanomolar potency. In isolated human bronchus,indacaterol has a rapid onset of action and a long duration of action.

Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle andbeta1-receptors are the predominant receptors in the human heart, there are also beta2-adrenergicreceptors in the human heart comprising 10-50% of the total adrenergic receptors. The precisefunction of beta2-adrenergic receptors in the heart is not known, but their presence raises thepossibility that even highly selective beta2-adrenergic agonists may have cardiac effects.

Onbrez Breezhaler, administered once a day at doses of 150 and 300 microgram consistently providedclinically significant improvements in lung function (as measured by the forced expiratory volume inone second, FEV1) over 24 hours across a number of clinical pharmacodynamic and efficacy studies.

There was a rapid onset of action within 5 minutes after inhalation, with an increase in FEV1 relativeto baseline of 110-160 ml, comparable to the effect of the fast-acting beta2-agonist salbutamol200 microgram and statistically significantly faster compared to salmeterol/fluticasone50/500 microgram. Mean peak improvements in FEV1 relative to baseline were 250-330 ml at steadystate.

The bronchodilator effect did not depend on the time of dosing, morning or evening.

Onbrez Breezhaler was shown to reduce lung hyperinflation, resulting in increased inspiratorycapacity during exercise and at rest, compared to placebo.

Effects on cardiac electrophysiology

A double-blind, placebo- and active (moxifloxacin)-controlled study for 2 weeks in 404 healthyvolunteers demonstrated maximum mean (90% confidence intervals) prolongations of the QTcFinterval (in milliseconds) of 2.66 (0.55, 4.77) 2.98 (1.02, 4.93) and 3.34 (0.86, 5.82) followingmultiple doses of 150 microgram, 300 microgram and 600 microgram, respectively. There was noevidence of a concentration-delta QTc relationship in the range of doses evaluated.

As demonstrated in 605 patients with COPD in a 26-week, double-blind, placebo-controlled Phase IIIstudy, there was no clinically relevant difference in the development of arrhythmic events monitoredover 24 hours, at baseline and up to 3 times during the 26-week treatment period, between patientsreceiving recommended doses of Onbrez Breezhaler treatment and those patients who receivedplacebo or treatment with tiotropium.

The clinical development programme included one 12-week, two six-month (one of which wasextended to one year to evaluate safety and tolerability) and one one-year randomised controlledstudies in patients with a clinical diagnosis of COPD. These studies included measures of lungfunction and of health outcomes such as dyspnoea, exacerbations and health-related quality of life.

Onbrez Breezhaler, administered once a day at doses of 150 microgram and 300 microgram, showedclinically meaningful improvements in lung function. At the 12-week primary endpoint (24-hourtrough FEV1), the 150 microgram dose resulted in a 130-180 ml increase compared to placebo(p<0.001) and a 60 ml increase compared to salmeterol 50 microgram twice a day (p<0.001). The300 microgram dose resulted in a 170-180 ml increase compared to placebo (p<0.001) and a 100 mlincrease compared to formoterol 12 microgram twice a day (p<0.001). Both doses resulted in anincrease of 40-50 ml over open-label tiotropium 18 microgram once a day (150 microgram, p=0.004;300 microgram, p=0.01). The 24-hour bronchodilator effect of Onbrez Breezhaler was maintainedfrom the first dose throughout a one-year treatment period with no evidence of loss in efficacy(tachyphylaxis).

Symptomatic benefits

Both doses demonstrated statistically significant improvements in symptom relief over placebo fordyspnoea and health status (as evaluated by Transitional Dyspnoea Index [TDI] and St. George’s

Respiratory Questionnaire [SGRQ], respectively). The magnitude of response was generally greaterthan seen with active comparators (Table 2). In addition, patients treated with Onbrez Breezhalerrequired significantly less rescue medication, had more days when no rescue medication was neededcompared to placebo and had a significantly improved percentage of days with no daytime symptoms.

Pooled efficacy analysis over 6 months’ treatment demonstrated that the rate of COPD exacerbationswas statistically significantly lower than the placebo rate. Treatment comparison compared to placeboshowed a ratio of rates of 0.68 (95% CI [ 0.47, 0.98]; p-value 0.036) and 0.74 (95% CI [0.56, 0.96]; p-value 0.026) for 150 microgram and 300 microgram, respectively.

Limited treatment experience is available in individuals of African descent.

Table 2 Symptom relief at 6 months treatment duration

Treatment Indacaterol Indacaterol Tiotropium Salmeterol Formoterol Placebo

Dose (microgram) 150 300 18 50 12once a day once a day once a day twice a day twice a day

Percentage of57 a 54 a 45 apatients who62 b 71 b 57 b 47 bachieved MCID59 c 54 c 41 c†

TDI

Percentage of53 a 49 a 38 apatients who58 b 53 b 47 b 46 bachieved MCID† 55 c 51 c 40 c

SGRQ

Reduction in1.3 a 1.2 a 0.3 apuffs/day of1.5 b 1.6 b 1.0 b n/e 0.4 brescue medicationuse vs. baseline

Percentage of60 a 55 a 42 adays with no57 b 58 b 46 b n/e 42 brescue medicationuse

Study design with a: indacaterol 150 microgram, salmeterol and placebo; b: indacaterol 150 and300 microgram, tiotropium and placebo; c: indacaterol 300 microgram, formoterol and placebo† MCID = minimal clinically important difference (≥1 point change in TDI, ≥4 point change in SGRQ)n/e= not evaluated at six months

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

Onbrez Breezhaler in all subsets of the paediatric population in chronic obstructive pulmonary disease(COPD) (see section 4.2 for information on paediatric use).

Indacaterol is a chiral molecule with R-configuration.

Pharmacokinetic data were obtained from a number of clinical studies, from healthy volunteers and

COPD patients.

The median time to reach peak serum concentrations of indacaterol was approximately 15 min aftersingle or repeated inhaled doses. Systemic exposure to indacaterol increased with increasing dose(150 microgram to 600 microgram) in a dose proportional manner. Absolute bioavailability ofindacaterol after an inhaled dose was on average 43% to 45%. Systemic exposure results from acomposite of pulmonary and gastrointestinal absorption; about 75% of systemic exposure was frompulmonary absorption and about 25% from gastrointestinal absorption.

Indacaterol serum concentrations increased with repeated once-daily administration. Steady state wasachieved within 12 to 14 days. The mean accumulation ratio of indacaterol, i.e. AUC over the 24-hdosing interval on Day 14 compared to Day 1, was in the range of 2.9 to 3.5 for once-daily inhaleddoses between 150 microgram and 600 microgram.

After intravenous infusion the volume of distribution of indacaterol during the terminal eliminationphase was 2557 litres indicating an extensive distribution. The in vitro human serum and plasmaprotein binding was 94.1-95.3% and 95.1-96.2%, respectively.

After oral administration of radiolabelled indacaterol in a human ADME (absorption, distribution,metabolism, excretion) study, unchanged indacaterol was the main component in serum, accountingfor about one third of total drug-related AUC over 24 hours. A hydroxylated derivative was the mostprominent metabolite in serum. Phenolic O-glucuronides of indacaterol and hydroxylated indacaterolwere further prominent metabolites. A diastereomer of the hydroxylated derivative, a N-glucuronide ofindacaterol, and C- and N-dealkylated products were further metabolites identified.

In vitro investigations indicated that UGT1A1 is the only UGT isoform that metabolised indacaterol tothe phenolic O-glucuronide. The oxidative metabolites were found in incubations with recombinant

CYP1A1, CYP2D6, and CYP3A4. CYP3A4 is concluded to be the predominant isoenzymeresponsible for hydroxylation of indacaterol. In vitro investigations further indicated that indacaterol isa low affinity substrate for the efflux pump P-gp.

In clinical studies which included urine collection, the amount of indacaterol excreted unchanged viaurine was generally lower than 2% of the dose. Renal clearance of indacaterol was, on average,between 0.46 and 1.20 litres/hour. When compared with the serum clearance of indacaterol of23.3 litres/hour, it is evident that renal clearance plays a minor role (about 2 to 5% of systemicclearance) in the elimination of systemically available indacaterol.

In a human ADME study where indacaterol was given orally, the faecal route of excretion wasdominant over the urinary route. Indacaterol was excreted into human faeces primarily as unchangedparent substance (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23%of the dose). Mass balance was complete with ≥90% of the dose recovered in the excreta.

Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-liferanging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation ofindacaterol after repeated dosing ranged from 40 to 52 hours which is consistent with the observedtime-to-steady state of approximately 12-14 days.

A population pharmacokinetic analysis showed that there is no clinically relevant effect of age (adultsup to 88 years), sex, weight (32-168 kg) or race on the pharmacokinetics of indacaterol. It did notsuggest any difference between ethnic subgroups in this population.

Patients with mild and moderate hepatic impairment showed no relevant changes in Cmax or AUC ofindacaterol, nor did protein binding differ between mild and moderate hepatic impaired subjects andtheir healthy controls. Studies in subjects with severe hepatic impairment were not performed.

Due to the very low contribution of the urinary pathway to total body elimination, a study in renallyimpaired subjects was not performed.

Effects on the cardiovascular system attributable to the beta2-agonistic properties of indacaterolincluded tachycardia, arrhythmias and myocardial lesions in dogs. Mild irritancy of the nasal cavityand larynx were seen in rodents. All these findings occurred at exposures sufficiently in excess ofthose anticipated in humans.

Although indacaterol did not affect general reproductive performance in a rat fertility study, a decreasein the number of pregnant F1 offspring was observed in the peri- and post-developmental rat study atan exposure 14-fold higher than in humans treated with Onbrez Breezhaler. Indacaterol was notembryotoxic or teratogenic in rats or rabbits.

Genotoxicity studies did not reveal any mutagenic or clastogenic potential. Carcinogenicity wasassessed in a two-year rat study and a six-month transgenic mouse study. Increased incidences ofbenign ovarian leiomyoma and focal hyperplasia of ovarian smooth muscle in rats were consistentwith similar findings reported for other beta2-adrenergic agonists. No evidence of carcinogenicity wasseen in mice. Systemic exposures (AUC) in rats and mice at the no-observed adverse effect levels inthese studies were at least 7- and 49-fold higher, respectively, than in humans treated with Onbrez

Breezhaler once a day at a dose of 300 microgram.

Lactose monohydrate

Gelatin

Not applicable.

30 months.

Do not store above 30°C.

Store in the blister in order to protect from moisture and only remove immediately before use.

Onbrez Breezhaler is a single-dose inhalation device. Inhaler body and cap are made from acrylonitrilebutadiene styrene, push buttons are made from methyl methacrylate acrylonitrile butadiene styrene.

Needles and springs are made from stainless steel.

PA/Alu/PVC - Alu blister containing 10 hard capsules.

Carton containing 10 capsules and one Onbrez Breezhaler inhaler.

Carton containing 30 capsules and one Onbrez Breezhaler inhaler.

Multipack comprising 2 packs (each containing 30 capsules and 1 inhaler).

Multipack comprising 3 packs (each containing 30 capsules and 1 inhaler).

Multipack comprising 30 packs (each containing 10 capsules and 1 inhaler).

Not all pack sizes may be marketed.

Each inhaler should be disposed of after all capsules have been used.

Instructions for handling and use

Please read the full Instructions for Use before using the Onbrez Breezhaler.

Insert Pierce and release Inhale deeply Check capsule is empty

Chec1 2 3k

Step 1a: Step 2a: Step 3a: Check capsule is empty

Pull off cap Pierce capsule once Breathe out fully Open the inhaler to see if

Hold the inhaler upright. Do not blow into the any powder is left in the

Pierce capsule by firmly inhaler. capsule.

pressing both sidebuttons at the same time.

You should hear a noise If there is powder left inas the capsule is pierced. the capsule:

Only pierce the capsule * Close the inhaler.once. * Repeat steps 3a to 3c.

Step 1b: Step 3b:

Open inhaler Inhale medicine deeply

Powder Empty

Hold the inhaler asremainingshown in the picture.

Place the mouthpiece inyour mouth and closeyour lips firmly around

Step 2b: it.

Release side buttons Do not press the sidebuttons.

Breathe in quickly and asdeeply as you can.

During inhalation youwill hear a whirringnoise.

You may taste themedicine as you inhale.

Step 1c: Remove empty capsule

Remove capsule Put the empty capsule in

Remove one capsule from your household waste.

the blister. Close the inhaler and

Do not swallow the replace the cap.capsule.

Step 3c:

Hold breath

Hold your breath for upto 5 seconds.

Important Information

* Onbrez Breezhalercapsules must always bestored in the blister cardand only removedimmediately before use.

Step 1d:

* Do not swallow the

Insert capsulecapsule.

Never place a capsule

* Do not use the Onbrezdirectly into the

Breezhaler capsules withmouthpiece.any other inhaler.

* Do not use the Onbrez

Breezhaler inhaler totake any other capsulemedicine.

* Never place the capsuleinto your mouth or themouthpiece of the

Step 1e: inhaler.

Close inhaler * Do not press the sidebuttons more than once.

* Do not blow into themouthpiece.

* Do not press the sidebuttons while inhalingthrough the mouthpiece.

* Do not handle capsuleswith wet hands.

* Never wash your inhalerwith water.

Your Onbrez Breezhaler Inhaler pack contains: Frequently Asked Cleaning the inhaler

* One Onbrez Breezhaler inhaler Questions Wipe the mouthpiece

* One or more blister cards, each containing either inside and outside with a6 or 10 Onbrez Breezhaler capsules to be used Why didn’t the inhaler clean, dry, lint-free cloth toin the inhaler make a noise when I remove any powderinhaled? residue. Keep the inhaler

The capsule may be stuck dry. Never wash your

Capsule Mouthpiecechamber in the capsule chamber. If inhaler with water.this happens, carefully

Cap

Screen loosen the capsule bytapping the base of the

Sidebuttons inhaler. Inhale the

Base Blister medicine again byrepeating steps 3a to 3c.

Disposing of the inhaler

Inhaler What should I do if there

Inhaler base Blister Card after useis powder left inside the Each inhaler should becapsule? disposed of after all

You have not received capsules have been used.enough of your medicine. Ask your pharmacist how

Close the inhaler and to dispose of medicinesrepeat steps 3a to 3c. and inhalers that are nolonger required.

I coughed after inhaling- does this matter?

This may happen. As longas the capsule is emptyyou have received enoughof your medicine.

I felt small pieces of thecapsule on my tongue -does this matter?

This can happen. It is notharmful. The chances ofthe capsule breaking intosmall pieces will beincreased if the capsule ispierced more than once.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/09/593/001-005

Date of first authorisation: 30 November 2009

Date of latest renewal: 18 September 2014

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

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