TRIMBOW 88mcg / 5mcg / 9mcg pressurized inhalation solution medication leaflet

Trimbow 87 micrograms/5 micrograms/9 micrograms pressurised inhalation, solution

Each delivered dose (the dose leaving the mouthpiece) contains 87 micrograms of beclometasonedipropionate, 5 micrograms of formoterol fumarate dihydrate and 9 micrograms of glycopyrronium (as11 micrograms glycopyrronium bromide).

Each metered dose (the dose leaving the valve) contains 100 micrograms of beclometasonedipropionate, 6 micrograms of formoterol fumarate dihydrate and 10 micrograms of glycopyrronium(as 12.5 micrograms glycopyrronium bromide).

Trimbow contains 8.856 mg ethanol per actuation.

For the full list of excipients, see section 6.1.

Pressurised inhalation, solution (pressurised inhalation)

Colourless to yellowish liquid solution.

Chronic obstructive pulmonary disease (COPD)

Maintenance treatment in adult patients with moderate to severe COPD who are not adequately treatedby a combination of an inhaled corticosteroid and a long-acting beta2-agonist or a combination of along-acting beta2-agonist and a long-acting muscarinic antagonist (for effects on symptoms controland prevention of exacerbations see section 5.1).

Asthma

Maintenance treatment of asthma, in adults not adequately controlled with a maintenance combinationof a long-acting beta2-agonist and medium dose of inhaled corticosteroid, and who experienced one ormore asthma exacerbations in the previous year.

The recommended dose is two inhalations twice daily.

The maximum dose is two inhalations twice daily.

Patients should be advised to take Trimbow every day even when asymptomatic.

If symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist should be usedfor immediate relief.

Asthma

When choosing the starting dose strength of Trimbow (87/5/9 micrograms or 172/5/9 micrograms), thepatients’ disease severity, their previous asthma therapy including the inhaled corticosteroid (ICS)dose as well as the patients’ current control of asthma symptoms and risk of future exacerbationshould be considered.

Stepping-down treatment

Patients should be regularly reassessed by a doctor, so that their doses ofbeclometasone/formoterol/glycopyrronium remain optimal and are only changed on medical advice.

The doses should be titrated to the lowest doses at which effective control of asthma symptoms ismaintained.

No dose adjustment is required in elderly patients (65 years of age and older).

Trimbow can be used at the recommended dose in patients with mild (glomerular filtration rate [GFR]≥50 to <80 mL/min/1.73 m2) to moderate (GFR ≥30 to <50 mL/min/1.73 m2) renal impairment. Use inpatients with severe (GFR <30 mL/min/1.73 m2) renal impairment or end-stage renal (GFR<15 mL/min/1.73 m2) disease requiring dialysis, especially if associated with significant body weightreduction, should be considered only if the expected benefit outweighs the potential risk (seesections 4.4 and 5.2).

There are no relevant data on the use of Trimbow in patients with severe hepatic impairment(classified as having Child-Pugh class C) and the medicinal product should be used with caution inthese patients (see sections 4.4 and 5.2).

COPD

There is no relevant use of Trimbow in the paediatric population (under 18 years of age) for theindication of COPD.

Asthma

The safety and efficacy of Trimbow in the paediatric population (under 18 years of age) have not yetbeen established. No data are available.

For inhalation use.

To ensure proper administration of the medicinal product, the patient should be shown how to use theinhaler correctly by a physician or other healthcare professional, who should also regularly check theadequacy of the patient’s inhalation technique (see “Instructions for use” below). The patient shouldbe advised to read the Package Leaflet carefully and follow the instructions for use as given in theleaflet.

This medicinal product is provided with a dose counter or dose indicator on the back of the inhaler,which shows how many actuations are left. For the 60 and 120 actuation pressurised containers, eachtime the patient presses the container a puff of the solution is released and the counter counts down byone.

For the 180 actuation pressurised container, each time the patient presses the pressurised container apuff of the solution is released and the indicator rotates by a small amount; the number of puffsremaining is displayed in intervals of 20.

The patient should be advised not to drop the inhaler as this may cause the counter to count down.

Priming the inhaler

Before using the inhaler for the first time, the patient should release one actuation into the air in orderto ensure that the inhaler is working properly (priming). Before priming the 60, 120 or 180 actuationpressurised containers, the counter/indicator should read 61, 121 or 180, respectively. After priming,the counter/indicator should read 60, 120 or 180.

Use of the inhaler

The patient should stand or sit in an upright position when inhaling from the inhaler. The steps belowshould be followed.

IMPORTANT: steps 2 to 5 should not be performed too quickly:1. The patient should remove the protective cap from the mouthpiece and check that themouthpiece is clean and free from dust and dirt or any other foreign objects.2. The patient should breathe out slowly and as deeply as comfortable, in order to empty the lungs.3. The patient should hold the inhaler vertically with its body upwards and place the mouthpiecebetween the teeth without biting. The lips should then be placed around the mouthpiece, withthe tongue flat under it.

4. At the same time, the patient should breathe in slowly and deeply through the mouth until thelungs are full of air (this should take approximately 4 - 5 seconds). Immediately after starting tobreathe in, the patient should firmly press down on the top of the pressurised container torelease one puff.

5. The patient should then hold the breath for as long as comfortably possible, then remove theinhaler from the mouth and breathe out slowly. The patient should not breathe out into theinhaler.

6. The patient should then check the dose counter or dose indicator to ensure it has movedaccordingly.

To inhale the second puff, the patient should keep the inhaler in a vertical position for approximately30 seconds and repeat steps 2 to 6.

If mist appears after the inhalation, either from the inhaler or from the sides of the mouth, theprocedure should be repeated from step 2.

After use, the patient should close the inhaler with the protective mouthpiece cap and check the dosecounter or dose indicator.

After inhaling, the patient should rinse the mouth or gargle with water without swallowing it or brushthe teeth (see also section 4.4).

When to get a new inhaler

The patient should be advised to get a new inhaler when the dose counter or indicator shows thenumber 20. He/she should stop using the inhaler when the counter or indicator shows 0 as any puffsleft in the device may not be enough to release a full actuation.

Additional instructions for specific groups of patients

For patients with weak hands it may be easier to hold the inhaler with both hands. Therefore, the indexfingers should be placed on the top of the pressurised container and both thumbs on the base of theinhaler.

Patients who find it difficult to synchronise aerosol actuation with inspiration of breath may use the

AeroChamber Plus spacer device, properly cleaned as described in the relevant leaflet. They should beadvised by their doctor or pharmacist about the proper use and care of their inhaler and spacer andtheir technique checked to ensure optimum delivery of the inhaled active substance to the lungs. Thismay be obtained by the patients using the AeroChamber Plus by one continuous slow and deep breaththrough the spacer, without any delay between actuation and inhalation. Alternatively, patients maysimply breathe in and out (through the mouth) after the actuation, as instructed in the spacer leaflet, toobtain the medicinal product (see sections 4.4 and 5.2).

Cleaning

For the regular cleaning of the inhaler, patients should remove weekly the cap from the mouthpieceand wipe the outside and inside of the mouthpiece with a dry cloth. They should not remove thepressurised container from the actuator and should not use water or other liquids to clean themouthpiece.

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

This medicinal product is not indicated for the treatment of acute episodes of bronchospasm, or to treatan acute disease exacerbation (i.e. as a rescue therapy).

Immediate hypersensitivity reactions have been reported after administration. If signs suggestingallergic reactions occur, in particular, angioedema (including difficulties in breathing or swallowing,swelling of the tongue, lips and face), urticaria or skin rash, treatment should be discontinuedimmediately and alternative therapy instituted.

Paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breathafter dosing. This should be treated immediately with a fast-acting inhaled bronchodilator (reliever).

Treatment should be discontinued immediately, the patient assessed and alternative therapy institutedif necessary.

It is recommended that treatment should not be stopped abruptly. If patients find the treatmentineffective, they should continue treatment but medical attention must be sought. Increasing use ofreliever bronchodilators indicates a worsening of the underlying condition and warrants a reassessmentof the therapy. Sudden or progressive deterioration in symptoms is potentially life-threatening and thepatient should undergo urgent medical assessment.

Due to the presence of a long-acting beta2-agonist and a long-acting muscarinic antagonist, Trimbowshould be used with caution in patients with cardiac arrhythmias, especially third degreeatrioventricular block and tachyarrhythmias (accelerated and/or irregular heartbeat, including atrialfibrillation), idiopathic subvalvular aortic stenosis, hypertrophic obstructive cardiomyopathy, severeheart disease (particularly acute myocardial infarction, ischaemic heart disease, congestive heartfailure), occlusive vascular diseases (particularly arteriosclerosis), arterial hypertension and aneurysm.

Caution should also be exercised when treating patients with known or suspected prolongation of the

QTc interval (QTc > 450 milliseconds for males, or > 470 milliseconds for females), either congenitalor induced by medicinal products. Patients diagnosed with the described cardiovascular conditionswere excluded from clinical studies with Trimbow. Limited data in asthmatic patients withcardiovascular co-morbidities or risk-factors suggest that these patients are also at higher risk ofadverse reactions like local fungal infections or dysphonia (see section 4.8).

If anaesthesia with halogenated anaesthetics is planned, it should be ensured that Trimbow is notadministered for at least 12 hours before the start of anaesthesia as there is a risk of cardiacarrhythmias.

Caution is also required when treating patients with thyrotoxicosis, diabetes mellitus,pheochromocytoma and untreated hypokalaemia.

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

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

Physicians should remain vigilant for the possible development of pneumonia in patients with COPDas the clinical features of such infections overlap with the symptoms of COPD exacerbations.

Risk factors for pneumonia in patients with COPD include current smoking, older age, low body massindex (BMI) and severe COPD.

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed forlong periods. The daily dose of Trimbow corresponds to a medium dose of inhaled corticosteroid;furthermore, these effects are much less likely to occur than with oral corticosteroids. Possiblesystemic effects include: Cushing's syndrome, Cushingoid features, adrenal suppression, growthretardation, decrease in bone mineral density and, more rarely, a range of psychological or behaviouraleffects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression(particularly in children). Therefore, it is important that the patient is reviewed regularly, and the doseof inhaled corticosteroid is reduced to the lowest dose at which effective control of asthma ismaintained (see section 4.2).

Trimbow should be administered with caution in patients with active or quiescent pulmonarytuberculosis and in patients with fungal and viral infections in the airways.

Potentially serious hypokalaemia may result from beta2-agonist therapy. This has the potential toproduce adverse cardiovascular effects. Particular caution is advised in patients with severe disease asthis effect may be potentiated by hypoxia. Hypokalaemia may also be potentiated by concomitanttreatment with other medicinal products which can induce hypokalaemia, such as xanthine derivatives,steroids and diuretics (see section 4.5).

Caution is also recommended when a number of reliever bronchodilators are used. It is recommendedthat serum potassium levels are monitored in such situations.

The inhalation of formoterol may cause a rise in blood glucose levels. Therefore, blood glucose shouldbe monitored during treatment following established guidelines in patients with diabetes.

Anticholinergic effect

Glycopyrronium should be used with caution in patients with narrow-angle glaucoma, prostatichyperplasia or urinary retention. Patients should be informed about the signs and symptoms of acutenarrow-angle glaucoma and should be informed to stop treatment and to contact their doctorimmediately should any of these signs or symptoms develop.

Additionally, due to the anticholinergic effect of glycopyrronium, the long-term co-administrationwith other anticholinergic-containing medicinal products is not recommended (see section 4.5).

Patients with severe renal impairment

In patients with severe renal impairment, including those with end-stage renal disease requiringdialysis, especially if associated with a significant body weight reduction, Trimbow should be usedonly if the expected benefit outweighs the potential risk (see section 5.2). These patients should bemonitored for potential adverse reactions.

Patients with severe hepatic impairment

In patients with severe hepatic impairment, Trimbow should be used only if the expected benefitoutweighs the potential risk (see section 5.2). These patients should be monitored for potential adversereactions.

Prevention of oropharyngeal infections

In order to reduce the risk of oropharyngeal candida infection, patients should be advised to rinse theirmouth or gargle with water without swallowing it or brush their teeth after inhaling the prescribeddose.

Visual disturbance

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

Stepping-down treatment

Patients should be regularly reassessed by a doctor, so that their doses ofbeclometasone/formoterol/glycopyrronium remain optimal and are only changed on medical advice.

The doses should be titrated to the lowest doses at which effective control of asthma symptoms ismaintained.

Ethanol contents

This medicinal product contains 8.856 mg of ethanol per actuation, which is equivalent to 17.712 mgper dose of two actuations. There is a theoretical potential for interaction in particularly sensitivepatients taking disulfiram or metronidazole.

Since glycopyrronium is eliminated mainly by the renal route, interaction could potentially occur withmedicinal products affecting renal excretion mechanisms (see section 5.2). The effect of organiccation transport inhibition (using cimetidine as a probe inhibitor of OCT2 and MATE1 transporters) inthe kidneys on inhaled glycopyrronium disposition showed a limited increase in its total systemicexposure (AUC0-t) by 16% and a slight decrease in renal clearance by 20% due to co administration ofcimetidine.

Beclometasone is less dependent on CYP3A metabolism than some other corticosteroids, and ingeneral interactions are unlikely; however, the possibility of systemic effects with concomitant use ofstrong CYP3A inhibitors (e.g. ritonavir, cobicistat) cannot be excluded, and therefore caution andappropriate monitoring is advised with the use of such medicinal products.

Related to formoterol

Non-cardioselective beta-blockers (including eye drops) should be avoided in patients taking inhaledformoterol. If they are administered for compelling reasons, the effect of formoterol will be reduced orabolished.

Concomitant use of other beta-adrenergic medicinal products can have potentially additive effects;therefore, caution is required when other beta-adrenergic medicinal products are prescribedconcomitantly with formoterol.

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

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

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

Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate a possiblehypokalaemic effect of beta2-agonists (see section 4.4). Hypokalaemia may increase the dispositiontowards arrhythmias in patients who are treated with digitalis glycosides.

Related to glycopyrronium

The long-term co-administration of Trimbow with other anticholinergic-containing medicinal productshas not been studied and is therefore not recommended (see section 4.4).

There is no experience with or evidence of safety issues on the use of the propellant norflurane(HFA134a) during human pregnancy or lactation. However, studies on the effect of HFA134a on thereproductive function and embryofoetal development in animals revealed no clinically relevantadverse effects.

There are no or limited amount of data from the use of Trimbow in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). Glucocorticoids are known tocause effects in the early gestation phase, while beta2-sympathomimetics like formoterol havetocolytic effects. Therefore, as a precautionary measure, it is preferable to avoid the use of Trimbowduring pregnancy and during labour.

Trimbow should only be used during pregnancy if the expected benefit to the patient outweighs thepotential risk to the foetus. Infants and neonates born to mothers receiving substantial doses should beobserved for adrenal suppression.

There are no relevant clinical data on the use of Trimbow during breast-feeding in humans.

Glucocorticoids are excreted in human milk. It is reasonable to assume that beclometasonedipropionate and its metabolites are also excreted in human milk.

It is unknown whether formoterol or glycopyrronium (including their metabolites) are excreted inhuman milk but they have been detected in the milk of lactating animals. Anticholinergics likeglycopyrronium could suppress lactation.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from

Trimbow therapy taking into account the benefit of breast-feeding for the child and the benefit oftherapy for the woman.

No specific studies have been performed with Trimbow with regard to the safety in human fertility.

Animal studies have shown impairment of fertility (see section 5.3).

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

The most frequently reported adverse reactions in patients with COPD or asthma are respectively:dysphonia (0.3% and 1.5%) and oral candidiasis (0.8% and 0.3%), which are normally associated withinhaled corticosteroids; muscle spasms (0.4% and 0.2%), which can be attributed to the long-actingbeta2-agonist component; and dry mouth (0.4% and 0.5%), which is a typical anticholinergic effect.

In asthmatic patients, adverse reactions tend to cluster during the first 3 months following initiation oftherapy and become less frequent with longer-term use (after 6 months of treatment).

Adverse reactions associated to beclometasone dipropionate/formoterol/glycopyrronium occurredduring clinical studies and post-marketing experience as well as adverse reactions listed for themarketed individual components are provided below, listed by system organ class and frequency.

Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimatedfrom available data).

MedDRA systemorgan class Adverse reaction Frequency

Pneumonia (in COPD patients), pharyngitis, oralcandidiasis, urinary tract infection1, nasopharyngitis1 Common

Infections and Influenza , oral fungal infection, oropharyngealinfestations candidiasis, oesophageal candidiasis, fungal(oro)pharyngitis, sinusitis1, rhinitis1, gastroenteritis1, Uncommonvulvovaginal candidiasis1

Lower respiratory tract infection (fungal) Rare

Blood and lymphatic Granulocytopenia1 Uncommonsystem disorders Thrombocytopenia1 Very rare

Immune system Dermatitis allergic Uncommondisorders Hypersensitivity reactions, including erythema, lips, face,eye and pharyngeal oedema Rare

Endocrine disorders Adrenal suppression1 Very rare

Metabolism and Hypokalaemia, hyperglycaemia Uncommonnutrition disorders Decreased appetite Rare

Restlessness1 Uncommon

Psychomotor hyperactivity1, sleep disorders1, anxiety,

Psychiatric disorders depression1, aggression1, behavioural changes Frequency not(predominantly in children) 1 known

Insomnia Rare

Nervous system Headache Commondisorders Tremor, dizziness, dysgeusia1, hypoaesthesia1 Uncommon

Hypersomnia Rare

Vision, blurred1

Eye disorders (see also section 4.4) Frequency notknown

Glaucoma1, cataract1 Very rare

Ear and labyrinth 1disorders Otosalpingitis Uncommon

Atrial fibrillation, electrocardiogram QT prolonged,tachycardia, tachyarrhythmia1, palpitations Uncommon

Cardiac disorders Angina pectoris (stable1 and unstable), extrasystoles(ventricular1 and supraventricular), nodal rhythm, sinus Rarebradycardia

Vascular disorders Hyperaemia1, flushing1, hypertension Uncommon

Extravasation blood Rare

Dysphonia Common

Respiratory, thoracic Asthmatic crisis1, cough, productive cough1, throatand mediastinal irritation, epistaxis1, pharyngeal erythema Uncommondisorders Bronchospasm paradoxical1, exacerbation of asthma,oropharyngeal pain, pharyngeal inflammation, dry throat Rare

Dyspnoea1 Very rare

Gastrointestinal Diarrhoea , dry mouth, dysphagia1, nausea, dyspepsia1,disorders burning sensation of the lips1, dental caries1, (aphthous) Uncommonstomatitis

Skin and subcutaneous Rash1, urticaria, pruritus, hyperhidrosis1 Uncommontissue disorders Angioedema1 Rare

Musculoskeletal and Muscle spasms, myalgia, pain in extremity1,connective tissue musculoskeletal chest pain1 Uncommondisorders Growth retardation1 Very rare

Renal and urinarydisorders Dysuria, urinary retention, nephritis1 Rare

MedDRA systemorgan class Adverse reaction Frequency

General disorders and Fatigue1 Uncommonadministration site Asthenia Rareconditions Oedema peripheral1 Very rare

C-reactive protein increased1, platelet count increased1,free fatty acids increased1, blood insulin increased1, blood Uncommon

Investigations ketone body increased1, cortisol decreased1

Blood pressure increased1, blood pressure decreased1 Rare

Bone density decreased1 Very rare1 Adverse reactions reported in the SmPC of at least one of the individual components, but not observed asadverse reactions in the clinical development of Trimbow

Among the observed adverse reactions the following are typically associated with:

Beclometasone dipropionate

Pneumonia, oral fungal infections, lower respiratory tract infection fungal, dysphonia, throat irritation,hyperglycaemia, psychiatric disorders, cortisol decreased, blurred vision.

Hypokalaemia, hyperglycaemia, tremor, palpitations, muscle spasms, electrocardiogram QTprolonged, blood pressure increased, blood pressure decreased, atrial fibrillation, tachycardia,tachyarrhythmia, angina pectoris (stable and unstable), ventricular extrasystoles, nodal rhythm.

Glaucoma, atrial fibrillation, tachycardia, palpitations, dry mouth, dental caries, dysuria, urinaryretention, urinary tract infection.

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

An overdose of Trimbow may produce signs and symptoms due to the individual component’spharmacological actions, including those seen with overdose of other beta2-agonists oranticholinergics and consistent with the known inhaled corticosteroid class effects (see section 4.4). Ifoverdose occurs, the patient’s symptoms should be treated supportively with appropriate monitoring asnecessary.

Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination withanticholinergics incl. triple combinations with corticosteroids. ATC code: R03AL09.

Mechanism of action and pharmacodynamic effects

Trimbow contains beclometasone dipropionate, formoterol and glycopyrronium (BDP/FF/G) in asolution formulation resulting in an aerosol with extrafine particles with an average mass medianaerodynamic diameter (MMAD) of around 1.1 micrometres and co-deposition of the threecomponents. The aerosol particles of Trimbow are on average much smaller than the particlesdelivered in non-extrafine formulations. For beclometasone dipropionate, this results in a more potenteffect than formulations with a non-extrafine particle size distribution (100 micrograms ofbeclometasone dipropionate extrafine in Trimbow are equivalent to 250 micrograms of beclometasonedipropionate in a non-extrafine formulation).

Beclometasone dipropionate

Beclometasone dipropionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs. Glucocorticoids are widely used for the suppression ofinflammation in chronic inflammatory diseases of the airways. Their action is mediated by the bindingto glucocorticoid receptors in the cytoplasm resulting in the increased transcription of genes coding foranti-inflammatory proteins.

Formoterol is a selective beta2-adrenergic agonist that produces relaxation of bronchial smooth musclein patients with reversible airways obstruction. The bronchodilating effect sets in rapidly, within1-3 minutes after inhalation, and has a duration of 12 hours after a single dose.

Glycopyrronium is a high-affinity, long-acting muscarinic receptor antagonist (anticholinergic) usedfor inhalation as bronchodilator treatment. Glycopyrronium works by blocking the bronchoconstrictoraction of acetylcholine on airway smooth muscle cells, thereby dilating the airways. Glycopyrroniumbromide is a high affinity muscarinic receptor antagonist with a greater than 4-fold selectivity for thehuman M3 receptors over the human M2 receptor as it has been demonstrated.

COPD

The Phase III clinical development programme in COPD was conducted with BDP/FF/G 87/5/9 andincluded two 52-week active-controlled studies. The TRILOGY study compared BDP/FF/G with afixed combination of beclometasone dipropionate and formoterol 100/6 micrograms two inhalationstwice daily (1,368 randomised patients). The TRINITY study compared BDP/FF/G with tiotropium18 micrograms inhalation powder, hard capsule, one inhalation once daily; in addition, effects werecompared with an extemporary triple combination made of a fixed combination of beclometasonedipropionate and formoterol 100/6 micrograms (corresponding to a delivered dose of 84.6/5.0micrograms) two inhalations twice daily plus tiotropium 18 micrograms inhalation powder, hardcapsule, one inhalation once daily (2,691 randomised patients). Both studies were conducted inpatients with a clinical diagnosis of COPD with severe to very severe airflow limitation (FEV1 lessthan 50% predicted), with symptoms assessed as a COPD Assessment Test (CAT) score of 10 orabove, and with at least one COPD exacerbation in the previous year. The two studies includedapproximately 20% of patients who used the AeroChamber Plus spacer.

In addition, two Phase IIIb studies were conducted to support the clinical efficacy and safety of

BDP/FF/G. TRISTAR was a 26-week active-controlled open label study comparing BDP/FF/G withan extemporary combination made of a fixed combination of fluticasone/vilanterol 92/22 microgramsinhalation powder, one inhalation once daily plus tiotropium 18 micrograms inhalation powder, hardcapsule, one inhalation once daily (1,157 randomised patients). TRIBUTE was a 52-week active-controlled study comparing BDP/FF/G with a fixed combination of indacaterol/glycopyrronium 85/43micrograms inhalation powder, hard capsule, one inhalation once daily (1,532 randomised patients).

Both studies were conducted in a similar population of COPD patients as studies TRILOGY and

TRINITY.

Reduction of COPD exacerbations

Compared with a fixed combination of beclometasone dipropionate and formoterol, BDP/FF/Greduced the rate of moderate/severe exacerbations over 52 weeks by 23% (rate: 0.41 versus 0.53events per patient/year; p = 0.005). Compared with tiotropium, BDP/FF/G reduced the rate ofmoderate/severe exacerbations over 52 weeks by 20% (rate: 0.46 versus 0.57 events per patient/year;p = 0.003). Compared with a fixed combination of indacaterol and glycopyrronium, BDP/FF/Greduced the rate of moderate/severe exacerbations over 52 weeks by 15% (rate: 0.50 versus 0.59events per patient/year; p = 0.043). Compared with tiotropium, BDP/FF/G also reduced the rate ofsevere exacerbations (i.e. excluding moderate exacerbations) by 32% (rate: 0.067 versus 0.098 eventsper patient/year; p = 0.017). No differences were observed when comparing BDP/FF/G with theextemporary triple combination made of beclometasone dipropionate and formoterol fixedcombination plus tiotropium (moderate/severe exacerbation rate: 0.46 versus 0.45 events perpatient/year).

In addition, compared with both a fixed combination of beclometasone dipropionate and formoteroland with tiotropium, BDP/FF/G significantly prolonged the time to first exacerbation (hazard ratio0.80 and 0.84 respectively; p = 0.020 and 0.015 respectively), with no differences between BDP/FF/Gand the extemporary triple combination made of beclometasone dipropionate and formoterol fixedcombination plus tiotropium (hazard ratio 1.06).

Pre-dose FEV1

Compared with a fixed combination of beclometasone dipropionate and formoterol, BDP/FF/Gimproved pre-dose FEV1 by 81 mL after 26 weeks of treatment and by 63 mL after 52 weeks oftreatment. Compared with tiotropium, BDP/FF/G improved pre-dose FEV1 by 51 mL after 26 weeksof treatment and by 61 mL after 52 weeks of treatment. These improvements were statisticallysignificant (p < 0.001). Compared with a fixed combination of indacaterol and glycopyrronium,

BDP/FF/G improved average pre-dose FEV1 over the 52-week treatment period by 22 mL (p=0.018).

Similar improvements, although not statistically significant, were observed at weeks 26 and 52.

No differences were observed when comparing BDP/FF/G and the extemporary triple combinationmade of a fixed combination of beclometasone dipropionate and formoterol plus tiotropium(difference of 3 mL in pre-dose FEV1 after 52 weeks of treatment).

2-hour post-dose FEV1

Compared with a fixed combination of beclometasone dipropionate and formoterol, BDP/FF/Gsignificantly improved 2-hour post dose FEV1 by 117 mL after 26 weeks of treatment and by 103 mLafter 52 weeks of treatment (p < 0.001). This endpoint was only measured in the TRILOGY study.

Inspiratory Capacity (IC)

Compared with tiotropium, BDP/FF/G significantly improved IC by 39 mL (p = 0.025) and 60 mL(p = 0.001) after 26 and 52 weeks of treatment respectively. Similar effects were seen when comparing

BDP/FF/G with the extemporary triple combination. This endpoint was only measured in the

TRINITY study.

Symptomatic outcomes

BDP/FF/G significantly improved dyspnoea (measured as the Transition Dyspnoea Index - TDI -focal score) after 26 weeks of treatment compared with baseline (by 1.71 units; p < 0.001), but theadjusted mean difference versus a fixed combination of beclometasone dipropionate and formoterolwas not statistically significant (0.21 units; p = 0.160). A responder analysis showed that asignificantly greater percentage of patients had a clinically significant improvement (focal scoregreater than or equal to 1) after 26 weeks with BDP/FF/G than with a fixed combination ofbeclometasone dipropionate and formoterol (57.4% versus 51.8%; p = 0.027). TDI was only measuredin the TRILOGY study.

BDP/FF/G was also statistically significantly superior to a fixed combination of beclometasonedipropionate and formoterol, to tiotropium and to a fixed combination of indacaterol andglycopyrronium in terms of improvement in quality of life (measured by the Saint George Respiratory

Questionnaire - SGRQ - total score). No differences were observed when comparing BDP/FF/G andthe extemporary triple combination made of fluticasone and vilanterol fixed combination plustiotropium.

A responder analysis showed that a significantly greater percentage of patients had a clinicallysignificant improvement (reduction versus baseline of greater than or equal to 4) after 26 and 52 weekswith BDP/FF/G than with a fixed combination of beclometasone dipropionate and formoterol and withtiotropium.

Asthma

The Phase III clinical development programme in asthma included two randomized, double-blind,active-controlled studies of 52 weeks duration, one performed with the medium ICS dose strength(BDP/FF/G 87/5/9; TRIMARAN) and another one with the high ICS dose strength (BDP/FF/G172/5/9; TRIGGER).

Both studies were conducted in adult patients with a clinical diagnosis of asthma who wereuncontrolled on dual maintenance treatment using a medium dose (TRIMARAN) or high dose(TRIGGER) ICS/LABA combination (ACQ-7 score ≥1.5). In order to be eligible, patients had to haveexperienced at least one asthma exacerbation requiring treatment with systemic corticosteroids oremergency department visit or in-patient hospitalisation in the previous year.

The TRIMARAN study compared two twice-daily doses of BDP/FF/G 87/5/9 (N=579) with twotwice-daily doses of a fixed combination of beclometasone dipropionate (BDP) and formoterol (FF)100/6 micrograms (delivered dose of 84.6/5.0) (N=576). The TRIGGER study compared two twice-daily doses of BDP/FF/G 172/5/9 (N=573) with two twice-daily doses of a fixed combination of BDPand FF 200/6 micrograms alone (delivered dose 177.7/5.1) (N=576) or on top of two once-daily dosesof tiotropium 2.5 micrograms (N=288) as an open-label extemporary triple combination arm.

The primary objective of the studies was to demonstrate superiority of either BDP/FF/G 87/5/9 or

BDP/FF/G 172/5/9 (two inhalations twice daily) over the respective fixed dual combination product(medium or high dose ICS/LABA) in terms of the co-primary endpoints (change from baseline in pre-dose FEV1 at Week 26 and the rate of moderate and severe exacerbation rate over 52 weeks).

The TRIGGER study was not powered to evaluate the comparative efficacy of BDP/FF/G 172/5/9 vs.

BDP/FF + tiotropium 2.5 micrograms. Descriptive results are included in Table 1.

Median age of patients enrolled in the two pivotal studies was 54 years. Less than 20% of patientswere aged 65 years or more and approximately 60% of patients were female. During the study, about16% (TRIMARAN) and 23% (TRIGGER) of patients used the AeroChamber Plus spacer.

Reduction of asthma exacerbations

In the TRIMARAN study, BDP/FF/G 87/5/9 significantly reduced the rate of moderate/severeexacerbations compared with the fixed combination of BDP/FF 100/6 micrograms (adjusted rate ratio0.846, 95%CI [0.725; 0.987]).

In the TRIGGER study, BDP/FF/G 172/5/9 also reduced the rate of moderate/severe exacerbationsmore than the fixed combination of BDP/FF 200/6 micrograms but this effect did not achievestatistical significance (adjusted rate ratio 0.880, 95%CI [0.751;1.030], p=0.11). Due to thehierarchical testing, all TRIGGER efficacy endpoints and the pre-specified analysis of severeexacerbations (data pooled across TRIMARAN and TRIGGER studies) resulted in nominal p-valuesonly (Table 1).

Data of TRIMARAN and TRIGGER studies suggest that the time to first moderate/severe exacer-bation (secondary endpoint) was prolonged in the triple combination arm when compared with therespective dual combination arm.

In both studies, BDP/FF/G 87/5/9 and BDP/FF/G 172/5/9 improved the lung function parameters ofpre-dose FEV1 (co-primary endpoint), peak0-3h FEV1, and morning peak expiratory flow (keysecondary endpoints), compared with a fixed combination of beclometasone dipropionate andformoterol 100/6 micrograms and 200/6 micrograms, respectively, after 26 weeks of treatment. Allimprovements were statistically significant (see Table 1).

Table 1 - Results of primary and secondary endpoints

Study TRIMARAN TRIGGER

Comparison of interest BDP/FF/G 87/5/9 BDP/FF/G 172/5/9 BDP/FF/G 172/5/9(N=579) (N=573) (N=573)

N = randomised patients vs vs vs1 1

BDP/FF 84.6/5 BDP/FF1 177.7/5.1 BDP/FF 177.7/5.1 +per treatment arm 2

N=576) (N=576) tiotropium 2.5(N=288)

Primary endpoints

Pre-dose FEV1 after 26 weeks (co-primary endpoint)

Treatment difference +57 mL +73 mL -45 mLp-value p = 0.008 p = 0.003* p = 0.125*

Moderate/severe exacerbations over 52 weeks (co-primary endpoint)

Adjusted rate per 1.83 vs 2.16 1.73 vs 1.96 1.73 vs 1.63patient/year

Rate change -15.4% -12.0% +7.0%p-value p = 0.033 p = 0.110 (n.s.) p = 0.502*

Key secondary and secondary endpoints

Peak0-3h FEV1 after 26 weeks (key secondary endpoint)

Treatment difference +84 mL +105 mL -33 mLp-value p < 0.001 p < 0.001* p = 0.271*

Morning peak expiratory flow (PEF) over 26 weeks (key secondary endpoint)

Treatment difference +8 L/min +8 L/min -0.2 L/minp-value p < 0.001 p = 0.001* p = 0.951*

Rate of severe exacerbations over 52 weeks, pooled analysis (key secondary endpoint)

Adjusted rate perpatient/year 0.24 vs 0.31 n. a.

Rate change -23.0%p-value p = 0.008*

Time to the first moderate/severe exacerbation over 52 weeks (secondary endpoint)

Hazard ratio 0.84 0.80 1.03p-value p = 0.022* p = 0.003* p = 0.777*

Time to the first severe exacerbation over 52 weeks, pooled analysis (secondary endpoint)

Hazard ratio 0.79 n.a.p-value p = 0.011*

Co-primary endpoints (pre-dose FEV1 at Week 26 and the rate of moderate and severe exacerbation rate over52 weeks) and the key secondary endpoints (peak0-3h FEV1 at Week 26, morning PEF over 26 weeks and therate of severe exacerbations [pooled analysis of TRIMARAN and TRIGGER] over 52 weeks) were part ofthe step-down, closed confirmatory testing strategy and thus controlled for multiplicity.

Since the superiority test of one of the co-primary endpoints in the TRIGGER study did not achievestatistical significance, results for TRIGGER efficacy endpoints and the rate of severe exacerbations (pooledanalysis) are nominal p-values and presented for descriptive purposes.

Since the TRIGGER study was not powered to evaluate the comparative efficacy of BDP/FF/G 172/5/9 vs.

BDP/FF 177.7/5.1 plus tiotropium 2.5, it is not clear whether the observed differences are real or a randomresult.

n.a. = not applicablen.s. = not statistically significant1 = fixed combination of beclometasone dipropionate (BDP) plus formoterol fumarate (FF)2 = open-label extemporaneous group

* = nominal p-values

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

Trimbow in all subsets of the paediatric population in COPD.

The safety and efficacy of Trimbow in children and adolescents with asthma under 18 years of agehave not yet been established (see section 4.2 for information on paediatric use).

Trimbow - fixed combination

The systemic exposure to beclometasone dipropionate, formoterol and glycopyrronium has beeninvestigated in a pharmacokinetic study conducted in healthy subjects. The study compared dataobtained after treatment with a single dose of Trimbow (4 inhalations of 100/6/25 micrograms, anon-marketed formulation containing twice the approved strength of glycopyrronium) or a single doseof the extemporary combination of beclometasone dipropionate/formoterol (4 inhalations of100/6 micrograms) plus glycopyrronium (4 inhalations of 25 micrograms). The maximum plasmaconcentration and systemic exposure of beclometasone dipropionate main active metabolite(beclometasone 17-monopropionate) and formoterol were similar after administration of the fixed orextemporary combination. For glycopyrronium, the maximum plasma concentration was similar afteradministration of the fixed or extemporary combination, while the systemic exposure was slightlyhigher after administration of Trimbow than with the extemporary combination. This study alsoinvestigated the potential pharmacokinetic interaction between the active components of Trimbow bycomparing the pharmacokinetic data obtained after a single dose of the extemporary combination orafter a single dose of the single components beclometasone dipropionate/formoterol orglycopyrronium. There was no clear evidence of pharmacokinetic interaction, however theextemporary combination showed formoterol and glycopyrronium levels transiently slightly higherimmediately after dosing compared with the single components. It is noted that single componentglycopyrronium, formulated as pressurised metered dose inhaler, which was used in the PK studies, isnot available on the market.

The dose proportionality of systemic and lung exposure to beclometasone dipropionate has beeninvestigated in a pharmacokinetic study conducted in healthy subjects with non-marketed Trimbowformulations, containing twice the approved strength of glycopyrronium (given as metered dose). Thestudy compared data obtained after treatment with a single dose (4 inhalations) of Trimbow200/6/25 micrograms or a single dose (4 inhalations) of Trimbow 100/6/25 micrograms (both are non-marketed formulations containing twice the approved strength of glycopyrronium). Trimbow200/6/25 micrograms treatment resulted in a two times higher systemic and lung exposure tobeclometasone dipropionate and to its main active metabolite (beclometasone 17-monopropionate) incomparison to Trimbow 100/6/25 micrograms, which is consistent with the different strengths of thetwo formulations. The systemic and lung exposure to glycopyrronium and formoterol was similar afterthe two treatments, although a high variability was observed for glycopyrronium bromide Cmax.

A comparison across studies showed that the pharmacokinetics of beclometasone 17-monopropionate,formoterol and glycopyrronium is similar in COPD patients, in patients with asthma and in healthysubjects.

In patients with COPD, the use of Trimbow with the AeroChamber Plus spacer increased the lungdelivery of beclometasone 17-monopropionate, formoterol and glycopyrronium (maximum plasmaconcentration increased by 15%, 58% and 60% respectively). The total systemic exposure (asmeasured by AUC0-t) was slightly reduced for beclometasone 17-monopropionate (by 37%) andformoterol (by 24%), while it was increased for glycopyrronium (by 45%). See also section 4.2.

Effect of renal impairment

Systemic exposure (AUC0-t) to beclometasone dipropionate, to its metabolite beclometasone17-monopropionate and to formoterol was not affected by mild to severe renal impairment. Forglycopyrronium, there was no impact in subjects with mild and moderate renal impairment. However,an increase in total systemic exposure of up to 2.5-fold was observed in subjects with severe renalimpairment (glomerular filtration rate below 30 mL/min/1.73 m2), as a consequence of a significantreduction of the amount excreted in urine (approximately 90% reduction of glycopyrronium renalclearance). Simulations performed with a pharmacokinetic model showed that even when covariateshad extreme values (body weight less than 40 kg and concomitant glomerular filtration rate below27 mL/min/1.73 m²), exposure to Trimbow active substances remains in approximately a 2.5-foldrange compared to the exposure in a typical patient with median covariate values.

Beclometasone dipropionate

Beclometasone dipropionate is a pro-drug with weak glucocorticoid receptor binding affinity that ishydrolysed via esterase enzymes to an active metabolite beclometasone 17-monopropionate which hasa more potent topical anti-inflammatory activity compared with the pro-drug beclometasonedipropionate.

Absorption, distribution and biotransformation

Inhaled beclometasone dipropionate is rapidly absorbed through the lungs; prior to absorption there isextensive conversion to beclometasone 17-monopropionate via esterase enzymes that are found inmost tissues. The systemic availability of the active metabolite arises from lung (36%) and fromgastrointestinal absorption of the swallowed dose. The bioavailability of swallowed beclometasonedipropionate is negligible; however, pre-systemic conversion to beclometasone 17-monopropionateresults in 41% of the dose being absorbed as the active metabolite. There is an approximately linearincrease in systemic exposure with increasing inhaled dose. The absolute bioavailability followinginhalation is approximately 2% and 62% of the nominal dose for unchanged beclometasonedipropionate and beclometasone 17-monopropionate respectively. Following intravenous dosing, thedisposition of beclometasone dipropionate and its active metabolite is characterised by high plasmaclearance (150 and 120 L/h respectively), with a small volume of distribution at steady state forbeclometasone dipropionate (20 L) and larger tissue distribution for its active metabolite (424 L).

Plasma protein binding is moderately high.

Faecal excretion is the major route of beclometasone dipropionate elimination mainly as polarmetabolites. The renal excretion of beclometasone dipropionate and its metabolites is negligible. Theterminal elimination half-lives are 0.5 hours and 2.7 hours for beclometasone dipropionate andbeclometasone 17-monopropionate respectively.

The pharmacokinetics of beclometasone dipropionate in patients with hepatic impairment has not beenstudied, however, as beclometasone dipropionate undergoes a very rapid metabolism via esteraseenzymes present in intestinal fluid, serum, lungs and liver to form the more polar productsbeclometasone 21-monopropionate, beclometasone 17-monopropionate and beclometasone, hepaticimpairment is not expected to modify the pharmacokinetics and safety profile of beclometasonedipropionate.

Following inhalation, formoterol is absorbed from both the lung and the gastrointestinal tract. Thefraction of an inhaled dose that is swallowed after administration with a metered dose inhaler mayrange between 60% and 90%. At least 65% of the fraction that is swallowed is absorbed from thegastrointestinal tract. Peak plasma concentrations of the unchanged active substance occur within 0.5to 1 hours after oral administration. Plasma protein binding of formoterol is 61-64% with 34% boundto albumin. There was no saturation of binding in the concentration range attained with therapeuticdoses. The elimination half-life determined after oral administration is 2-3 hours. Absorption offormoterol is linear following inhalation of 12 to 96 micrograms of formoterol.

Formoterol is widely metabolised and the prominent pathway involves direct conjugation at thephenolic hydroxyl group. Glucuronide acid conjugate is inactive. The second major pathway involves

O-demethylation followed by conjugation at the phenolic 2'-hydroxyl group. Cytochrome P450isoenzymes CYP2D6, CYP2C19 and CYP2C9 are involved in the O-demethylation of formoterol.

Liver appears to be the primary site of metabolism. Formoterol does not inhibit CYP450 enzymes attherapeutically relevant concentrations.

The cumulative urinary excretion of formoterol after single inhalation from a dry powder inhalerincreased linearly in the 12-96 micrograms dose range. On average, 8% and 25% of the dose wasexcreted as unchanged and total formoterol, respectively. Based on plasma concentrations measuredfollowing inhalation of a single 120 micrograms dose by 12 healthy subjects, the mean terminalelimination half-life was determined to be 10 hours. The (R,R)- and (S,S)-enantiomers representedabout 40% and 60% of unchanged active substance excreted in the urine, respectively. The relativeproportion of the two enantiomers remained constant over the dose range studied and there was noevidence of relative accumulation of one enantiomer over the other after repeated dosing. After oraladministration (40 to 80 micrograms), 6% to 10% of the dose was recovered in urine as unchangedactive substance in healthy subjects; up to 8% of the dose was recovered as the glucuronide. A total67% of an oral dose of formoterol is excreted in urine (mainly as metabolites) and the remainder in thefaeces. The renal clearance of formoterol is 150 mL/min.

The pharmacokinetics of formoterol has not been studied in patients with hepatic impairment;however, as formoterol is primarily eliminated via hepatic metabolism, an increased exposure can beexpected in patients with severe hepatic impairment.

Glycopyrronium has a quaternary ammonium structure which limits its passage across biologicalmembranes and produces slow, variable and incomplete gastrointestinal absorption. Followingglycopyrronium inhalation, the lung bioavailability was 10.5% (with activated charcoal ingestion)while the absolute bioavailability was 12.8% (without activated charcoal ingestion) confirming thelimited gastrointestinal absorption and indicating that more than 80% of glycopyrronium systemicexposure was from lung absorption. After repeated inhalation of twice daily doses ranging from 12.5to 50 micrograms via pressurised metered dose inhaler in COPD patients, glycopyrronium showedlinear pharmacokinetics with little systemic accumulation at steady state (median accumulation ratio2.2-2.5).

The apparent volume of distribution (Vz) of inhaled glycopyrronium was increased compared tointravenous infusion (6,420 L versus 323 L), reflecting the slower elimination after inhalation.

The metabolic pattern of glycopyrronium in vitro (humans, dogs, rats, mice and rabbits livermicrosomes and hepatocytes) was similar among species and the main metabolic reaction was thehydroxylation on the phenyl or ciclopentyl rings. CYP2D6 was found to be the only enzymeresponsible for glycopyrronium metabolism.

The mean elimination half-life of glycopyrronium in healthy volunteers was approximately 6 hoursafter intravenous injection while after inhalation in COPD patients it ranged from 5 to 12 hours atsteady state. After a glycopyrronium single intravenous injection, 40% of the dose was excreted in theurine within 24 hours. In COPD patients receiving repeated twice daily administration of inhaledglycopyrronium, the fraction of the dose excreted in urine ranged from 13.0% to 14.5% at steady state.

Mean renal clearance was similar across the range of doses tested and after single and repeatedinhalation (range 281-396 mL/min).

Safety pharmacology

In an inhalation study in telemetered dogs, the cardiovascular system was a major target system foracute effects of Trimbow (increase in heart rate, decrease in blood pressure, ECG changes at higherdoses), effects probably mainly related to the beta2-adrenergic activity of formoterol and theanti-muscarinic activity of glycopyrronium. There was no evidence for over-additive effects of thetriple combination when compared with the single components.

In repeated dose inhalation studies with Trimbow in rats and dogs of up to 13 weeks duration, themain observed alterations were related to effects on the immune system (probably due to systemiccorticosteroid effects of beclometasone dipropionate and its active metabolite beclometasone-17-monopropionate) and on the cardiovascular system (probably related to the beta2-adrenergicactivity of formoterol and the anti-muscarinic activity of glycopyrronium). The toxicological profile ofthe triple combination reflected that of the single active components without a relevant increase intoxicity and without unexpected findings.

Toxicity to reproduction and development

Beclometasone dipropionate/beclometasone-17-monopropionate was considered responsible forreproductive toxicity effects in rats such as reduction of the conception rate, fertility index, earlyembryonic development parameters (implantation loss), delay in ossification and increased incidenceof visceral variations; while tocolytic and anti-muscarinic effects, attributed to the beta2-adrenergicactivity of formoterol and the anti-muscarinic activity of glycopyrronium, affected pregnant rats in thelate phase of gestation and/or early phase of lactation, leading to loss of pups.

Genotoxicity of Trimbow has not been evaluated, however, the single active components were devoidof genotoxic activity in the conventional test systems.

Carcinogenicity studies have not been performed with Trimbow. However, in a 104-week ratinhalation carcinogenicity study and an oral 26-week carcinogenicity study in transgenic Tg-rasH2mice, glycopyrronium bromide showed no carcinogenic potential and published data concerning long-term studies conducted with beclometasone dipropionate and formoterol fumarate in rats do notindicate a clinically relevant carcinogenic potential.

Ethanol anhydrous

Hydrochloric acid

Norflurane (propellant)

Not applicable.

60 actuation pressurised container21 months.

Chemical and physical in-use stability has been demonstrated for 2 months at 25°C.

After dispensing, the medicinal product may be stored for a maximum of 2 months at a temperature upto 25°C.

120 (from a single or multipack) and 180 actuation pressurised container22 months.

Chemical and physical in-use stability has been demonstrated for 4 months at 25°C.

After dispensing, the medicinal product may be stored for a maximum of 4 months at a temperature upto 25°C.

Do not freeze.

Do not expose to temperatures higher than 50°C.

Do not pierce the pressurised container.

Prior to dispensing

Store in a refrigerator (2°C-8°C).

For in-use storage conditions, see section 6.3.

Pressurised container (coated aluminium), with a metering valve. The pressurised container is insertedin a polypropylene inhaler which incorporates a mouthpiece and a dose counter (60 actuations or120 actuations per pressurised container) or dose indicator (180 actuations per pressurised container)and is provided with a polypropylene mouthpiece cap.

Pack of 1 container with either 60, 120 or 180 actuations.

Multipack containing 240 actuations (2 containers of 120 actuations each).

Multipack containing 360 actuations (3 containers of 120 actuations each).

Not all pack sizes may be marketed.

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

For pharmacists:

Enter the date of dispensing to the patient on the pack.

Chiesi Farmaceutici S.p.A.

Via Palermo 26/A43122 Parma

Italy

EU/1/17/1208/001

EU/1/17/1208/002

EU/1/17/1208/003

EU/1/17/1208/004

EU/1/17/1208/005

Date of first authorisation: 17 July 2017

Date of latest renewal:

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

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