Date of Preperation: September 2014 IE/DUOSP/14/0010. Product monograph

Transcription

1 Date of Preperation: September 2014 IE/DUOSP/14/0010 Product monograph

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3 Contents Introduction Part I: Scientific Information 1. Disease background 1.1 Avallable treatments 1.2 GINA guidelines: stepwise treatment for asthma 1.3 GOLD guidelines 1.4 Inhalers: the need for improvement 2. Spiromax mechanism of action 2.1 Introducing Spiromax 2.2 Operation of the Spiromax device 2.3 X-ACT system 2.4 Introducing DuoResp Spiromax 2.5 Patient handling studies 3. Pharmaceutical information on budesonide and formoterol 3.1 Mechanism of action of budesonide and formoterol 3.2 Clinical application of budesonide and formoterol 4. In vitro performance studies 4.1 Dose delivery (over inhaler life) 4.2 Dose delivery: (delivered dose per dose number) 4.3 Particle size distribution 5. Detailed pharmacology 5.1 Requirement for demonstration of therapeutic equivalence 5.2 Pharmacokinetic studies: medium- and high-strength DuoResp Spiromax vs Symbicort Turbohaler (studies 108 and 109) 6. Clinical trials 6.1 Peak inspiratory flow study (Azouz et al.) 6.2 Safety and efficacy of medium-strength DuoResp Spiromax vs Symbicort Turbohaler in asthma (ASSET) 6.3 Ease-of-use study (ELIOT) and Healthcare Professional (HCP) ELIOT (HCP ELIOT) Part II: Healthcare Professional Information 1. Indications and clinical use: DuoResp Spiromax 1.1 Indication 1.2 Contraindications 1.3 General warnings for asthma/copd patients 1.4 Warnings: respiratory risks, systemic effects and skin risks 1.5 Warnings: endocrine risks 1.6 Warnings: infections, interactions and metabolic risks 1.7 Warnings: special patient groups and other risks 1.8 Dosage in special populations 1.9 Adverse reactions

4 Contents 1.10 Summary of adverse events 1.11 Drug interactions 2. Asthma 2.1 Dosage in asthma: DuoResp Spiromax Medium Strength 160/4.5 mcg 2.2 Maintenance dosages in asthma: DuoResp Spiromax Medium Strength 160/4.5 mcg 2.3 Dosage in asthma: DuoResp Spiromax High Strength 320/9 mcg 2.4 Maintenance and reliever dosages in asthma: DuoResp Spiromax Medium Strength 160/4.5 mcg 3. COPD 3.1 Dosages in COPD: DuoResp Spiromax 4. Administration 4.1 IMPORTANT: The DuoResp Spiromax inhaler should not be shaken and should be held with the semi-transparent wine red mouthpiece cover at the bottom 5. Overdose 5.1 Formoterol 6. Storage/stability and special handling instructions 7. Dosage forms, composition and packaging Part III: Consumer Information 1. About this medication 1.1 Warnings and precautions 1.2 Taking DuoResp Spiromax with other medications 1.3 How to use DuoResp Spiromax (part a) 1.4 How to use DuoResp Spiromax 320/9 mcg 1.5 How to use DuoResp Spiromax 160/4.5 mcg 1.6 How to use DuoResp Spiromax (part b) 1.7 Serious side effects 1.8 Other possible side effects 1.9 How to store DuoResp Spiromax 1.10 Further information PART IV: Health economics 1. Asthma and COPD: Economic burden of the disease and unmet needs

5 Introduction This resource is intended to provide comprehensive information on DuoResp Spiromax (Fig. 1). It provides disease background on asthma and chronic obstructive pulmonary disease (COPD), including the need for improvements to existing inhalers. The mechanism of action of the Spiromax inhaler is described, together with details on budesonide and formoterol, the two drugs provided by DuoResp Spiromax. Device operation and clinical data describing the performance of Spiromax are presented, as well as clinical studies on the safety and efficacy of DuoResp Spiromax. Information for healthcare professionals within the resource will relate to the summary of product characteristics, with guidance on indications, warnings, adverse reactions, drug interactions, dose and storage. Corresponding information for patients includes warnings, interactions, guidance on how to use the medication, side effects and storage. A final section of the resource introduces the current economic burden of asthma and COPD, and unmet needs. We hope you find this to be an engaging and valuable tool for learning about DuoResp Spiromax. Glossary Asthma = disease characterised by recurrent attacks of breathlessness and wheezing. It is caused by inflammation of the air passages in the lungs: the lining of these passages swells, causing the airways to become narrow and airflow to be restricted. The condition is usually associated with allergic reaction or other forms of hypersensitivity. Chronic obstructive pulmonary disease (COPD) = progressive lung disease characterised by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible. Symptoms include cough, sputum production, wheezing and shortness of breath. Smoking is the leading cause of COPD. Dry-powder inhaler (DPI) = device for delivering medicine to the lungs in the form of a dry powder; the force from the patient s inhalation results in a measured dose being released. Figure 1. Spiromax dry-powder inhaler (DPI) 5

6 Part I: Scientific Information (Disease Background and DuoResp Spiromax studies) 6

7 1. Disease background 1.1 Available treatments There are many types of drug treatments available for asthma and COPD, which should be prescribed in accordance with current guidelines. Combination therapy consisting of an inhaled corticosteroid (ICS) and a long-acting b 2 -agonist (LABA) is a treatment option for asthma and COPD patients that is bronchodilatory and can provide long-term antiinflammatory activity in the lower airways. 1,2 An overview of the different drug types and how they work is presented in Table 1. Relievers are prescribed by healthcare professionals (HCPs) to provide instant (but temporary) relief from breathlessness caused by involuntary bronchospasms in the airways. 1 3 Patients with milder disease are prescribed such drugs as first treatments. Glossary Asthma = disease characterised by recurrent attacks of breathlessness and wheezing. It is caused by inflammation of the air passages in the lungs: the lining of these passages swells, causing the airways to become narrow and airflow to be restricted. The condition is usually associated with allergic reaction or other forms of hypersensitivity. Bronchodilation (adj. bronchodilatory) = increase in the internal diameter (calibre) of the bronchi (large airways) and/or bronchioles (small airways), allowing increased airflow to and from the lungs. Bronchospasm = contraction of muscle in the walls of the bronchioles (small airways) and/or bronchi (large airways), decreasing the internal diameter (calibre) of the airways. Chronic obstructive pulmonary disease (COPD) = progressive lung disease characterised by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible. Symptoms include cough, sputum production, wheezing and shortness of breath. Smoking is the leading cause of COPD. Table 1. Treatments available for asthma and COPD. 1 3 Controllers (also called maintenance drugs) are prescribed to patients who continue to experience frequent breathlessness despite using relievers. These patients will continue to use as needed reliever medication in addition to their controller medication. Controllers are intended to be taken every day (once- or twice-daily administration), regardless of whether the patient has symptoms at that time. Controllers, by their nature, have longer effects and may control symptoms on a day-to-day basis. Controller monotherapy is usually prescribed as the next step after relievers; they target one particular element of the disease (e.g. anti-inflammatory as with an inhaled corticosteroid [ICS]). Controller combinations usually target more than one aspect of disease. For example, combining an ICS with a long-acting b 2 -agonist (LABA) provides both anti-inflammatory and bronchodilatory control. Controllers prescribed as combination therapies are usually for patients with more severe symptoms (symptomatic despite low-dose ICS, for example, in asthma). Patients may only need one device to administer both treatments (as a fixed-dose combination [FDC]). The combination of budesonide plus formoterol, in addition to providing daily disease control can also be used on an as-needed basis as a reliever. Fixed-dose combination (FDC) = drug containing fixed amounts of two or more ingredients. Inhaled (gluco)corticosteroid (ICS) = corticosteroids are analogues of the hormones secreted by the pituitary gland or hypothalamic-anterior pituitaryadrenocortical (HPA) axis. Corticosteroids include glucocorticoids, which are antiinflammatory agents with a large number of functions. Inhaled corticosteroids are formulated for medicinal use to reduce inflammation in the respiratory tract and lungs. Long-acting β 2 -agonist (LABA) = beta-agonists are bronchodilator medications that relax the muscles around the airways (bronchi and bronchioles), widening the airways to make breathing easier. The effects of long-acting betaagonists last about 12 hours so they are considered as maintenance drugs. 1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). January 2014 update. Available at Accessed 13 May National Heart Lung and Blood Institute (NHLBI). Expert panel report 3: guidelines for the diagnosis and management of asthma. Full report Available at Accessed 16 December Global Initiative for Asthma (GINA) update. Available at Accessed 14 July

8 Glossary Asthma = disease characterised by recurrent attacks of breathlessness and wheezing. It is caused by inflammation of the air passages in the lungs: the lining of these passages swells, causing the airways to become narrow and airflow to be restricted. The condition is usually associated with allergic reaction or other forms of hypersensitivity. 1.2 GINA guidelines: stepwise treatment for asthma The Global Initiative for Asthma (GINA) guidelines 3 recommend a stepwise treatment plan for patients with asthma based on the level of symptom control. Treatment is stepped up for a patient when control is not achieved on the current Global Initiative for Asthma (GINA) = organisation working with healthcare professionals and public health officials around the world to reduce asthma prevalence, morbidity and mortality. Inhaled anticholinergic = bronchodilator medication affecting muscles around the bronchi (large airways). Inhaled (gluco)corticosteroid (ICS) = corticosteroids are analogues of the hormones secreted by the pituitary gland or hypothalamic-anterior pituitaryadrenocortical (HPA) axis. Corticosteroids include glucocorticoids, which are antiinflammatory agents with a large number of functions. Inhaled corticosteroids are formulated for medicinal use to reduce inflammation in the respiratory tract and lungs. Long-acting β 2 -agonist (LABA) = beta-agonists are bronchodilator medications that relax the muscles around the airways (bronchi and bronchioles), widening the airways to make breathing easier. The effects of long-acting betaagonists last about 12 hours so they are considered as maintenance drugs. Short-acting (oral) β 2 -agonist (SABA) = beta-agonists are bronchodilator medications that relax the muscles around the airways (bronchi and bronchioles), widening the airways to make breathing easier. Short-acting beta-agonists work quickly (within 3 to 5 minutes), so they are used as reliever medications; their effect may only last 4 6 hours. Table 2. GINA guidelines for the treatment of asthma. treatment step (Table 2). *Recommended treatment (shaded boxes) based on group mean data. Individual patient needs, preferences, and circumstances (including costs) should be considered; Receptor antagonist or synthesis inhibitor Alternative reliever treatments include inhaled anticholinergics, short-acting oral β 2 -agonists, some long-acting β 2 -agonists, and short-acting theophylline. Regular dosing with short- and long-acting β 2 -agonists is not advised unless accompanied by regular use of an inhaled glucocorticosteroid. ICS = inhaled corticosteroid; IgE = immunoglobulin E Theophylline = bronchodilator drug used in the treatment of asthma and COPD to relax bronchial smooth muscle. 3. Global Initiative for Asthma (GINA) update. Available at Accessed 14 July

9 1.3 GOLD guidelines Treatment options (drug class) for COPD are provided in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines 1, last updated in First choice, second choice and alternative choice recommendations are based on the GOLD group (A D) to which the patient belongs (Table 3 and Fig. 2). Group placement depends on a patient s risk of developing an exacerbation, the current severity of their symptoms and level of airflow limitation. Glossary Chronic obstructive pulmonary disease (COPD) = progressive lung disease characterised by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible. Symptoms include cough, sputum production, wheezing and shortness of breath. Smoking is the leading cause of COPD. Global Initiative for Chronic Obstructive Lung Disease (GOLD) = organisation working with healthcare professionals and public health officials around the world to raise awareness of COPD and improve prevention and treatment of this lung disease. Table 3. GOLD guidelines for the treatment of COPD. *Medications in this column can be used alone or in combination with other options in the first and second choice columns 1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). January 2014 update. Available at Accessed 13 May

10 Glossary Chronic obstructive pulmonary disease (COPD) = progressive lung disease characterised by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible. Symptoms include cough, sputum production, wheezing and shortness of breath. Smoking is the leading cause of COPD. Global Initiative for Chronic Obstructive Lung Disease (GOLD) = organisation working with healthcare professionals and public health officials around the world to raise awareness of COPD and improve prevention and treatment of this lung disease. Figure 2. Association between symptoms, spirometric classification and future risk of exacerbations. 1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). January 2014 update. Available at Accessed 13 May

11 1.4 Inhalers: the need for improvement In order to achieve the efficacy available from respiratory drugs in asthma or COPD, it is essential that the inhalation device is used correctly to optimise drug delivery, 4,5 thereby avoiding inadequate therapeutic benefit and reducing the risk of adverse events (both of which may, in turn, compromise patient adherence). 6 Effective inhaler technique differs markedly between different inhaler types. 5,7 Pressurised metered-dose inhalers (pmdis) require slow, controlled inhalation in time with actuation of the device. Breath-actuated MDIs (BA-MDIs) do not require coordination with actuation. Dry-powder inhalers (DPIs) do not require coordination but a rapid and forceful inhalation is needed (patients with severe asthma or COPD are not always able to do so). Even patients experienced in using a particular device often have ineffective technique. 8,9 Indeed, the guidelines provided by the National Institute for Health and Clinical Excellence (NICE), GINA, European Respiratory Society (ERS), the Aerosol Management Improvement Team (ADMIT) and GOLD recognise that choosing the correct inhaler is critical for successful management of asthma or COPD. It has been proposed that the ideal inhaler: 5,10 Is easy to use correctly, e.g. few steps to remember (does not require priming) Delivers accurate and consistent dosing irrespective of environmental conditions, inhaler orientation or inhalation technique, and is robust until last regular use Is forgiving of variations in breathing technique Provides positive feedback that dose has been delivered, e.g. dose counter 11 Administers both reliever and maintenance therapy. The patient s satisfaction with an inhaler may not be obvious to the physician and it is liable to receive little attention in clinical practice. However, it has been shown to impact the level of disease control. 12 Prescribing a device that meets an individual s needs helps to ensure good technique and patient adherence, and may reduce the need for healthcare resources in the future. 13 Glossary Breath-actuated metered dose inhaler (BA-MDI) = device for delivering medicine to the lungs; medication is released automatically when the patient inhales. Chronic obstructive pulmonary disease (COPD) = progressive lung disease characterised by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible. Symptoms include cough, sputum production, wheezing and shortness of breath. Smoking is the leading cause of COPD. Dry-powder inhaler (DPI) = device for delivering medicine to the lungs in the form of a dry powder; the force from the patient s inhalation results in a measured dose being released. Global Initiative for Asthma (GINA) = organisation working with healthcare professionals and public health officials around the world to reduce asthma prevalence, morbidity and mortality. Global Initiative for Chronic Obstructive Lung Disease (GOLD) = organisation working with healthcare professionals and public health officials around the world to raise awareness of COPD and improve prevention and treatment of this lung disease. Pressurised metered-dose inhaler (pmdi) = device for delivering medicine to the lungs; when a canister is pushed down, a valve delivers a measured dose. Patient adherence = the degree to which a patient correctly follows medical advice. 4. Crompton GK, Barnes PJ, Broeders M, et al. The need to improve inhalation technique in Europe: a report from the Aerosol Drug Management Improvement Team. Respir Med 2006;100: Smith IJ, Bell J, Bowman N, et al. Inhaler devices: what remains to be done? J Aerosol Med Pulm Drug Deliv 2010;23(Suppl. 2):S McHorney CA. The Adherence Estimator: a brief, proximal screener for patient propensity to adhere to prescription medications for chronic disease. Curr Med Res Opin 2009;25: Price D, Haughney J, Sims E, et al. Effectiveness of inhaler types for real-world asthma management: retrospective observational study using the GPRD. J Asthma Allergy 2011;4: Melani AS, Bonavia M, Cilenti V, et al. Inhaler mishandling remains common in real life and is associated with reduced disease control. Respir Med 2011;105: Small M, Anderson P, Vickers A, et al. Importance of inhaler-device satisfaction in asthma treatment: real-world observations of physician-observed compliance and clinical/patient reported outcomes. Adv Ther 2011;28: Papi A, Haughney J, Virchow JC, et al. Inhaler devices for asthma: a call for action in a neglected field. Eur Respir J 2011;37: Conner JB, Buck PO. Improving asthma management: the case for mandatory inclusion of dose counters on all rescue bronchodilators. J Asthma 2013;50: Al-Jahdali H, Ahmed A, Al-Harbi A, et al. Improper inhaler technique is associated with poor asthma control and frequent emergency department visits. Allergy Asthma Clin Immunol 2013;9: Lenney J, Innes JA, Crompton GK. Inappropriate inhaler use: assessment of use and patient preference of seven inhalation devices. EDICI. Respir Med 2000;94:

12 Glossary Dry-powder inhaler (DPI) = device for delivering medicine to the lungs in the form of a dry powder; the force from the patient s inhalation results in a measured dose being released. Lactose = a sugar found in milk. 2. Spiromax mechanism of action 2.1 Introducing Spiromax Spiromax is a new inspiratory flow-driven DPI containing a single molecule (salbutamol, for example) or a combination of medications (budesonide and formoterol, for example). The Spiromax device (Fig. 3) is easy for patients to use and administration is easy to teach the patient knows their medicine is ready to be inhaled when they hear one loud click on opening the cover. The drug formulations contain lactose so the patient knows by the taste that they have taken the dose. Spiromax has a dose counter linked to 60 or 120 preloaded doses and contains a specific number of preloaded doses. Figure 3. Spiromax dry-powder inhaler (DPI) 12

13 2.2 Operation of the Spiromax device When the mouthpiece cover is opened fully, a cam rotates and the yoke drops (Fig. 4). This indicates that a dose of medication has been metered into the dose cup. The dropping of the yoke allows the metering spring to expand, which compresses the air pump (bellows). The air pulse from the pump forces a precise dose of powder blend to be released into the dose cup below. The movement of the yoke when the mouthpiece cover is fully opened moves the dose cup laterally from the metering position to the inhalation position. The dose is now ready for inhalation. The act of inhalation then activates the Cyclone Separator technology that works by creating a cyclonic flow of air inside the inhaler. When the patient inhales, air enters Spiromax through two tangential inlets above the mouthpiece. The dose is collected by this air as it passes over the dose cup, and carried through the Cyclone Separator where turbulence separates the drug from the lactose carrier. The dose is delivered to the mouthpiece, from where it is inhaled into the lungs. After inhalation, the patient closes the mouthpiece cover. This returns the yoke and dose cup to their original positions and the dose indicator counts down. The inhaler is now ready to deliver another dose. If the mouthpiece is opened and closed when a dose is not needed, the dose indicator will register it as a count and the dose remains available to use when required. Glossary Cyclone Separator = circular chamber designed to facilitate cyclonic air flow. Dry-powder inhaler (DPI) = device for delivering medicine to the lungs in the form of a dry powder; the force from the patient s inhalation results in a measured dose being released. Lactose = a sugar found in milk. Figure 4. Spiromax dry-powder inhaler (DPI) 13

14 Glossary Cyclone Separator = circular chamber designed to facilitate cyclonic air flow. Lactose = a sugar found in milk. 2.3 X-ACT system The Spiromax device provides accurate and consistent dosing through the X-ACT system that contains active metering (Fig. 5) and Cyclone Separator technology (Fig. 6). Active metering (ensures accurate, consistent dose delivery) Spiromax contains a funnel-shaped drug reservoir holding a dry powder blend of the active drug and a lactose carrier (Fig. 5). Spiromax does not rely on gravity for dose metering; it is able to deliver consistent doses even when it is not held vertically. Figure 5. Active metering. Cyclone Separator technology (taking particle size and formulation into account, ensures effective delivery of drug to small airways) The cyclone separator is a circular chamber (Fig. 6). When the patient inhales and air is drawn into the chamber, a cyclone is created. This separates fine drug particles from the larger lactose particles. The drug includes particles fine enough to reach the small airways. Larger lactose particles are deposited mainly in the mouth and throat. Figure 6. Cyclone Separator technology. 14

15 2.4 Introducing DuoResp Spiromax DuoResp Spiromax is the Spiromax device containing the combination of budesonide plus formoterol. DuoResp Spiromax will be available in the following delivered doses: medium strength (160/4.5mcg) and high strength (320/9mcg) (Fig. 7). These delivered doses are equivalent to a metered dose of 200mcg budesonide and 6mcg formoterol for medium strength and 400mcg budesonide and 12mcg formoterol for high strength DuoResp Spiromax. DuoResp Spiromax is designed for the treatment of patients with asthma or COPD. Glossary Asthma = disease characterised by recurrent attacks of breathlessness and wheezing. It is caused by inflammation of the air passages in the lungs: the lining of these passages swells, causing the airways to become narrow and airflow to be restricted. The condition is usually associated with allergic reaction or other forms of hypersensitivity. Chronic obstructive pulmonary disease (COPD) = progressive lung disease characterised by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible. Symptoms include cough, sputum production, wheezing and shortness of breath. Smoking is the leading cause of COPD. Delivered dose/s = is the dose of drug expelled from the inhaler. Also known as the ex-actuator dose or emitted dose. Metered dose/s = the dose of drug held within the device. Also known as the labelled dose. Figure 7. DuoResp Spiromax 15

16 Glossary Pharmaceutical = of or relating to drugs used in medical treatment. Physicochemical = relating to both physical and chemical properties. 2.5 Patient handling studies Inhaler orientation The performance of the Spiromax inhaler was assessed when the inhaler was used at an angle. Orienting DuoResp Spiromax to a 90 or +90 angle (Fig. 8) 14 did not affect performance in delivering a uniform dose of either budesonide or formoterol. Uniformity of delivered dose was maintained when the inhaler was tilted either during actuation or metered-dose discharge, irrespective of strength of inhaler and throughout the device s lifetime. The Spiromax inhaler is forgiving of poor technique and continues to perform well when tilted from the vertical. Although Spiromax will fail to deliver the nominal dose when held upside down, this is unlikely to happen in practice since Spiromax has been designed so that patients will intuitively hold it upright to open the mouthpiece cover. Figure 8. Assessing performance of Spiromax when tilted away from vertical. 14 Stability studies Extensive stability studies have been performed on all Spiromax products in real-world conditions. A study was performed by analysts carrying Spiromax inhalers with them during working day hours, dispensing doses according to specified schemes and cleaning the inhaler mouthpiece weekly with a dry cloth in accordance with the patient leaflet. 15 All strengths of budesonide and formoterol were delivered from Spiromax with consistent particle deposition profiles and dose uniformity in accordance with US Pharmacopeia regulations under simulated real-world conditions. Spiromax products remained physicochemically and pharmaceutically stable for the duration of the stability studies (shelf life: 2 years; after opening foil wrap, 6 months). Significant variations in external temperature ( 20 C to 40 C) or humidity (approx %) do not have a detrimental effect on the performance of BF Spiromax 14. TEVA data on file. 15. Arp J, Goller M, Keegstra H. Uniformity of delivered dose from the first to last dose of the BF SpiromaxR inhaler in the laboratory and under real-world conditions. Abstract number 66 presented at DDL 2013, available online at 16

17 3. Pharmaceutical information on budesonide and formoterol 3.1 Mechanism of action of budesonide and formoterol Budesonide and formoterol are both controllers. Budesonide, an inhaled corticosteroid (ICS), acts as an anti-inflammatory. Formoterol, a long-acting β 2 -agonist (LABA), is a fast-acting bronchodilator. ICS/LABA combination therapy targets two key pathophysiological components of asthma and COPD (Fig. 9). The ICS component reduces inflammation and mucus in the airways; it also reduces airway hyper-responsiveness. The LABA component provides bronchodilation of the airways 2,3 and inhibits release of mast cell mediators, plasma exudation, and may also reduce sensory nerve activation. 16 Glossary Airway hyper-responsiveness = state characterised by easily triggered contraction of the bronchioles or small airways; exaggerated bronchoconstrictor response to physical, chemical or pharmacological stimuli. Asthma = disease characterised by recurrent attacks of breathlessness and wheezing. It is caused by inflammation of the air passages in the lungs: the lining of these passages swells, causing the airways to become narrow and airflow to be restricted. The condition is usually associated with allergic reaction or other forms of hypersensitivity. Bronchodilation (adj. bronchodilatory) = increase in the internal diameter (calibre) of the bronchi (large airways) and/or bronchioles (small airways), allowing increased airflow to and from the lungs. Chronic obstructive pulmonary disease (COPD) = progressive lung disease characterised by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible. Symptoms include cough, sputum production, wheezing and shortness of breath. Smoking is the leading cause of COPD. Inhaled (gluco)corticosteroid (ICS) = corticosteroids are analogues of the hormones secreted by the pituitary gland or hypothalamicanterior pituitary-adrenocortical (HPA) axis. Corticosteroids include glucocorticoids, which are anti-inflammatory agents with a large number of functions. Inhaled corticosteroids are formulated for medicinal use to reduce inflammation in the respiratory tract and lungs. Figure 9. Fixed-dose combination (FDC) (ICS/LABA) therapy: mechanism of action. Long-acting β 2 -agonist (LABA) = betaagonists are bronchodilator medications that relax the muscles around the airways (bronchi and bronchioles), widening the airways to make breathing easier. The effects of long-acting beta-agonists last about 12 hours so they are considered as maintenance drugs. Mast cell mediators = mast cells are resident in several tissue types of the body including the mucosa of the lungs. They play a key role in allergic reaction, anaphylaxis and inflammation. Mast cell mediators are molecules released by activated mast cells that stimulate allergic reaction, inflammation and other responses. Histamine is an example of a mast cell mediator. Plasma exudation = filtration of fluid (plasma; the clear fluid portion of blood) from the circulatory system into lesions or areas of inflammation. Sensory nerve activation = activation of a nerve that passes impulses from receptors toward or to the central nervous system. 2. National Heart Lung and Blood Institute (NHLBI). Expert panel report 3: guidelines for the diagnosis and management of asthma. Full report Available at Accessed 16 December Global Initiative for Asthma (GINA) update. Available at Accessed 14 July Barnes PJ. Scientific rationale for inhaled combination therapy with long-acting beta2-agonists and corticosteroids. Eur Respir J 2002;19:

18 Glossary Asthma = disease characterised by recurrent attacks of breathlessness and wheezing. It is caused by inflammation of the air passages in the lungs: the lining of these passages swells, causing the airways to become narrow and airflow to be restricted. The condition is usually associated with allergic reaction or other forms of hypersensitivity. The complementary actions of budesonide and formoterol allow complete targeting of asthma pathophysiology that neither drug class is able to achieve alone (Fig. 10). 16 Interactions between the activities of ICS and LABA in COPD are less well characterised, although the anti-inflammatory effects of ICS/LABA combination therapy appear greater than ICS alone, suggesting synergistic interactions. 17 Chronic obstructive pulmonary disease (COPD) = progressive lung disease characterised by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible. Symptoms include cough, sputum production, wheezing and shortness of breath. Smoking is the leading cause of COPD. Inhaled (gluco)corticosteroid (ICS) = corticosteroids are analogues of the hormones secreted by the pituitary gland or hypothalamic-anterior pituitaryadrenocortical (HPA) axis. Corticosteroids include glucocorticoids, which are antiinflammatory agents with a large number of functions. Inhaled corticosteroids are formulated for medicinal use to reduce inflammation in the respiratory tract and lungs. Long-acting β 2 -agonist (LABA) = beta-agonists are bronchodilator medications that relax the muscles around the airways (bronchi and bronchioles), widening the airways to make breathing easier. The effects of long-acting betaagonists last about 12 hours so they are considered as maintenance drugs. Figure 10. Complementary effects of LABA/ICS on asthma pathophysiology. 16 This presentation has not been reviewed by European Respiratory Society prior to release; therefore the European Respiratory Society may not be responsible for any errors, omissions or inaccuracies, or for any consequences arising there from, in the content. Reproduced with permission of the European Respiratory Society: Eur Respir J January 2002;19: ;doi: / Copyright remains with European Respiratory Society. This figure is copyrighted material and must not be copied, reproduced, transferred, distributed, leased, licensed, placed in a storage retrieval system or publicly performed or used in any way except as specifically permitted in writing by the publishers (European Respiratory Society), as allowed under the terms and conditions of which it was purchased or as strictly permitted by applicable copyright law. Any unauthorised distribution or use of this text may be a direct infringement of the publisher s rights and those responsible may be liable in law accordingly. 16. Barnes PJ. Scientific rationale for inhaled combination therapy with long-acting beta2-agonists and corticosteroids. Eur Respir J 2002;19: Mapel DW, Hurley JS, Dalal AA, et al. The role of combination inhaled corticosteroid/long-acting β-agonist therapy in COPD management. Prim Care Respir J 2010;19:

19 3.2 Clinical application of budesonide and formoterol Fixed-dose ICS/LABA combination therapy is usually administered daily to provide disease control in patients with either asthma or COPD. Alongside this, patients can use a fast-acting reliever medication (short-acting β 2 -agonist; SABA) to treat symptoms as they arise. In patients with asthma, budesonide/formoterol controller therapy can also be taken as needed as reliever treatment. This means that the patient has the benefit of needing one inhaler that provides both preventer and reliever treatment. Patients do not need to carry a separate SABA inhaler. Budesonide/formoterol used as both a reliever and a controller has been shown to be more efficacious than the following treatments in current use: high-dose budesonide monotherapy plus SABA ; budesonide/formoterol controller plus SABA 21,22 ; and fluticasone propionate/salmeterol (FP/SAL) plus SABA 22,23. Figure 11. Budesonide and formoterol fixed-dose combination (FDC). Glossary Asthma = disease characterised by recurrent attacks of breathlessness and wheezing. It is caused by inflammation of the air passages in the lungs: the lining of these passages swells, causing the airways to become narrow and airflow to be restricted. The condition is usually associated with allergic reaction or other forms of hypersensitivity. Chronic obstructive pulmonary disease (COPD) = progressive lung disease characterised by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible. Symptoms include cough, sputum production, wheezing and shortness of breath. Smoking is the leading cause of COPD. Inhaled (gluco)corticosteroid (ICS) = corticosteroids are analogues of the hormones secreted by the pituitary gland or hypothalamic-anterior pituitaryadrenocortical (HPA) axis. Corticosteroids include glucocorticoids, which are antiinflammatory agents with a large number of functions. Inhaled corticosteroids are formulated for medicinal use to reduce inflammation in the respiratory tract and lungs. Long-acting β 2 -agonist (LABA) = beta-agonists are bronchodilator medications that relax the muscles around the airways (bronchi and bronchioles), widening the airways to make breathing easier. The effects of long-acting betaagonists last about 12 hours so they are considered as maintenance drugs. Short-acting (oral) β 2 -agonist (SABA) = Beta-agonists are bronchodilator medications that relax the muscles around the airways (bronchi and bronchioles), widening the airways to make breathing easier. Short-acting beta-agonists work quickly (within 3 to 5 minutes), so they are used as reliever medications; their effect may only last 4 6 hours 18. Scicchitano et al. Efficacy and safety of budesonide/formoterol single inhaler therapy versus a higher dose of budesonide in moderate to severe asthma. Curr Med Res Opin 2004; 20: Rabe et al. Budesonide/formoterol in a single inhaler for maintenance and relief in mild-to-moderate asthma: a randomized, double blind trial. CHEST 2006; 129: O Byrne et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 2005; 171: Rabe et al. Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised, controlled, double-blind study. Lancet 2006; 368: Kuna et al. Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations. Int J Clin Pract 2007; 61: Bousquet et al. Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs high-dose salmeterol/fluticasone. Respir Med 2007; 101: Pulmicort SPC Formoterol SPC Symbicort Turbohaler SPC: Symbicort SMART patient information leaflet: 19

20 4. In vitro performance studies 4.1 Dose delivery (over inhaler life) Assessment of dose delivery from Spiromax inhalers has shown that the dose is delivered accurately and consistently throughout the life of the inhaler (Fig. 12). 15 Although there was a trend for doses at the beginning of inhaler life (BOL) to be slightly lower than middle (MOL)- and end-of-life (EOL) doses, all doses were within limits for appropriate therapeutic doses (between 87% and 117% of the expected dose). There was no apparent dose build-up after reaching the middle of the inhaler s lifetime. Delivered doses increased proportionally with dose increase. Figure 12. Dose delivery throughout the life of DuoResp Spiromax inhalers: (a) budesonide and (b) formoterol Arp J, Goller M, Keegstra H. Uniformity of delivered dose from the first to last dose of the BF SpiromaxR inhaler in the laboratory and under real-world conditions. Abstract number 66 presented at DDL 2013, available online at 20

21 4.2 Dose delivery: (delivered dose per dose number) Assessment of dose consistency with medium-strength formoterol and high-strength budesonide showed consistent dose delivery that remained within the limits specified by the European Pharmacopoeia (Ph. Eur) (Fig. 13). Figure 13a. Formoterol medium-strength dose consistency. 28 Figure 13b. Budesonide high-strength dose consistency TEVA data on file 21

22 4.3 Particle size distribution Assessment of particle size from Spiromax inhalers has shown that particle size distribution is accurate and consistent throughout the inhaler s lifetime (Fig. 14). 28 Aerodynamic particle-size distribution profiles for all strengths of DuoResp Spiromax were consistent for budesonide and formoterol at beginning of life and end of life. There were only minimal differences in the emitted dose between beginning and end of inhaler life. Figure 14. Particle size throughout life of DuoResp Spiromax inhalers: (a) budesonide and (b) formoterol. 28 BOL = beginning of (inhaler) life EOL = end of (inhaler) life MA-IP = mouthpiece adapter-induction port PS = preseparator S1-7 = stage Teva data on file. 22

23 5. Detailed pharmacology 5.1 Requirement for demonstration of therapeutic equivalence Demonstrating therapeutic equivalence [of DuoResp Spiromax to Symbicort Turbohaler] is a requirement of the Points to consider in the Clinical Documentation for orally inhaled products (OIP) by the European Medicines Agency (EMA). Evaluations of therapeutic equivalence required that pharmacokinetic (PK) studies (at label doses) be performed. 5.2 Pharmacokinetic studies: medium- and high-strength DuoResp Spiromax vs Symbicort Turbohaler (studies 108 and 109) Studies 108 and 109 were pharmacokinetic (PK) equivalence studies of medium- and high-strength DuoResp Spiromax and Symbicort Turbohaler. 29,30 They were singlecentre, open-label, randomised, five-period, crossover, single-dose studies in healthy volunteers aged years. In each study, subjects were allocated to one of 10 treatment sequences of five different treatments (Fig. 15). All subjects repeated Treatment B in order to test for intra-subject variability. Glossary Equivalence (adj. equivalent) = condition in which two drugs with identical active ingredients, or two different dosage forms of the same drug, exhibit similar bioavailability and produce the same effect at the site of physiological activity. Pharmacokinetic (PK) = study of the movement of drugs in the body, including the processes of absorption, distribution, localisation in tissues, biotransformation, and excretion. Treatment A: BF Spiromax (without charcoal) Treatment B: BF Turbohaler (without charcoal; repeated to measure intra-subject variability) Treatment C: BF Spiromax (with oral charcoal) Treatment D: BF Turbohaler (with oral charcoal) Figure 15. Design of PK studies 108 and , Weisfeld L, Gopalan G, Shu Y, Baconnet B, Shah TP. Pharmacokinetics (PK) and safety of budesonide plus formoterol (BF) (160/4.5mcg) Spiromax and BF (200/6mcg) turbohaler following two inhalations (+/ charcoal [char] block) in healthy volunteers (HV). Eur Respir J 2013;42(suppl. 57):abstract number Weisfeld L, Gopalan G, Shu Y, Baconnet B, Shah TP. Pharmacokinetics (PK) and safety of budesonide plus formoterol (BF) (320/9mcg) Spiromax and BF (400/12mcg) turbohaler following two inhalations (+/ charcoal [char] block) in healthy volunteers (HV). Eur Respir J 2013;42(suppl. 57):abstract number

24 Glossary AUC 0 t = area under the concentration time curve from time zero to the last measurable concentration at time t. Equivalence (adj. equivalent) = condition in which two drugs with identical active ingredients, or two different dosage forms of the same drug, exhibit similar bioavailability and produce the same effect at the site of physiological activity. Cmax = maximum concentration that a drug achieves after the drug has been administrated. Pharmacokinetic (PK) = study of the movement of drugs in the body, including the processes of absorption, distribution, localisation in tissues, biotransformation, and excretion. Pulmonary = of or relating to the lungs. t max = time to reach maximum concentration (C max ). Budesonide and formoterol were administered concomitantly with oral charcoal ( with charcoal ) to block the gastrointestinal absorption and to assess the pulmonary deposition and absorption of the active substances budesonide and formoterol. Subjects received two inhalations of each treatment such that the total administered doses were 320/9mcg for medium-strength DuoResp Spiromax (160/4.5mcg x 2), 400/12mcg for medium-strength Symbicort Turbohaler, 640/18mcg for high-strength DuoResp Spiromax and 800/24mcg for high-strength Symbicort Turbohaler. Subjects attended a 1-day training period, followed by a 7 (±2)-day washout period, before entering the treatment phase of the study. Study objectives The primary objective of both studies was to assess the PK profile of single doses of DuoResp Spiromax (x2 inhalations) and Symbicort Turbohaler (x2 inhalations), with and without charcoal block. The secondary objectives were to evaluate the safety and tolerability of DuoResp Spiromax and Symbicort Turbohaler and to determine the intra-subject variability of Symbicort Turbohaler (without charcoal block). DuoResp Spiromax and Symbicort Turbohaler (with or without charcoal) were equivalent (90% CIs of the geometric mean ratios within range ) with respect to AUC 0 t and C max of both budesonide and formoterol (Fig. 16). 29 Figure 16a. Equivalence of DuoResp Spiromax to Symbicort Turbohaler (with charcoal) 29 Figure 16b. Equivalence of DuoResp Spiromax to Symbicort Turbohaler (without charcoal) 29 Secondary endpoint results DuoResp Spiromax and Symbicort Turbohaler demonstrated equivalence with respect to t max for budesonide and formoterol. The t max values for budesonide and formoterol did not differ appreciably between DuoResp Spiromax and Symbicort Turbohaler with charcoal. 29 There was no appreciable difference in t max for formoterol between DuoResp Spiromax and Symbicort Turbohaler without charcoal; however, a small difference in t max for budesonide was observed between the treatments without charcoal (median budesonide t max with Symbicort Turbohaler was 2.5 minutes longer than with DuoResp Spiromax) Weisfeld L, Gopalan G, Shu Y, Baconnet B, Shah TP. Pharmacokinetics (PK) and safety of budesonide plus formoterol (BF) (160/4.5mcg) Spiromax and BF (200/6mcg) turbohaler following two inhalations (+/ charcoal [char] block) in healthy volunteers (HV). Eur Respir J 2013;42(suppl. 57):abstract number

25 In study 109, DuoResp Spiromax and Symbicort Turbohaler were shown to be equivalent with respect to AUC 0 t and C max, with or without charcoal. 30 The 90% CIs of the geometric mean ratios for AUC 0 t and C max of budesonide and formoterol with DuoResp Spiromax 320/9mcg and with Symbicort Turbohaler were within the range , with or without charcoal (Fig. 17). 30 Glossary AUC 0 t = area under the concentration time curve from time zero to the last measurable concentration at time t. Equivalence (adj. equivalent) = condition in which two drugs with identical active ingredients, or two different dosage forms of the same drug, exhibit similar bioavailability and produce the same effect at the site of physiological activity. C max = maximum concentration that a drug achieves after the drug has been administrated. Figure 17a. Equivalence of DuoResp Spiromax to Symbicort Turbohaler (with charcoal) 30 Figure 17b. Equivalence of DuoResp Spiromax to Symbicort Turbohaler (without charcoal) 30 Secondary endpoint results DuoResp Spiromax and Symbicort Turbohaler were shown to be equivalent with respect to t max for budesonide and formoterol. The t max values for budesonide and formoterol did not differ appreciably between DuoResp Spiromax and Symbicort Turbohaler either with charcoal or without charcoal. 30 Pharmacokinetic (PK) = study of the movement of drugs in the body, including the processes of absorption, distribution, localisation in tissues, biotransformation, and excretion. t max = time to reach maximum concentration (C max ). 30. Weisfeld L, Gopalan G, Shu Y, Baconnet B, Shah TP. Pharmacokinetics (PK) and safety of budesonide plus formoterol (BF) (320/9mcg) Spiromax and BF (400/12mcg) turbohaler following two inhalations (+/ charcoal [char] block) in healthy volunteers (HV). Eur Respir J 2013;42(suppl. 57):abstract number

26 DuoResp Spiromax is indicated for use in adults aged 18 years and above only Glossary Asthma = disease characterised by recurrent attacks of breathlessness and wheezing. It is caused by inflammation of the air passages in the lungs: the lining of these passages swells, causing the airways to become narrow and airflow to be restricted. The condition is usually associated with allergic reaction or other forms of hypersensitivity. Chronic obstructive pulmonary disease (COPD) = progressive lung disease characterised by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible. Symptoms include cough, sputum production, wheezing and shortness of breath. Smoking is the leading cause of COPD. 6. Clinical trials 6.1 Peak inspiratory flow study (Azouz et al.) Azouz et al. 31 conducted a randomised, crossover study to evaluate PIFR and related inhalation parameters when using a Spiromax placebo device and a Turbohaler placebo device, before and after enhanced training. In total, 50 subjects were recruited to each of the following groups: children and adolescents with asthma, aged 6 17 years; adults with asthma, aged years; adults with COPD, aged >50 years; healthy volunteers, aged years. All subjects in each group used the placebo Spiromax and the placebo Turbohaler, before and after enhanced technique training (Fig. 18). Peak inspiratory flow rate (PIFR) (or peak inspiratory flow, PIF) = the fastest flow rate achieved during the inspiratory cycle. Figure 18. Design of the Azouz study (one treatment group shown) 31 [Figure presented with the kind permission of Professor Henry Chrystyn, UK] 31. Azouz WA, Chetcuti P, Hosker H, Saralaya D, Chrystyn H. Enhanced training on how to use a dry powder inhaler (DPI) improves the inhalation manoeuvre (IM) of patients with asthma (child 6 17yrs and adult >17yrs) or COPD and in healthy adults (HA) when they use a Spiromax (S) and Turbohaler (T) DPI. Eur Respir J. 2013;42(suppl. 57):abstract number

27 DuoResp Spiromax is indicated for use in adults aged 18 years and above only All randomised subjects received standard training on how to use the Spiromax and Turbohaler devices, according to the patient information leaflets. Each subject then made two consecutive inhalation manoeuvres with each device to record PIFR, inhalation volume, time of inhalation, time to reach the PIFR and 90% PIFR, and the acceleration rate. Enhanced training on inhaler technique was then given using an inhalation airflow meter (In-Check Dial ), which was attached to each device to measure the inhalation manoeuvre. Patients were shown their first PIFR and encouraged to inhale faster during a second attempt. The same inhalation parameters were measured after enhanced training as were measured pre-enhanced training. Study objectives The primary objective was to investigate PIFR and related inhalation parameters through placebo Spiromax and placebo Turbohaler devices in patients with asthma or COPD, and in healthy volunteers. The secondary objective was to assess the impact of enhanced training in DPI technique on inhalation speed and volume. Before enhanced training, PIF and maximum change in pressure ( P) were higher with Spiromax versus Turbohaler (Table 4). 32 These differences were statistically significant (p<0.05, all patient groups). There were also trends towards slightly higher inspiratory acceleration with Spiromax. Glossary Acceleration rate = rate at which inhalation flow increases (at the start of inhalation). Asthma = disease characterised by recurrent attacks of breathlessness and wheezing. It is caused by inflammation of the air passages in the lungs: the lining of these passages swells, causing the airways to become narrow and airflow to be restricted. The condition is usually associated with allergic reaction or other forms of hypersensitivity. Chronic obstructive pulmonary disease (COPD) = progressive lung disease characterised by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible. Symptoms include cough, sputum production, wheezing and shortness of breath. Smoking is the leading cause of COPD. Dry-powder inhaler (DPI) = device for delivering medicine to the lungs in the form of a dry powder; the force from the patient s inhalation results in a measured dose being released. Inspiratory acceleration = rate at which inhalation flow increases (at the start of inhalation). Maximum change in pressure ( P) (or maximum pressure change, MPC) = maximum pressure differential during inhalation that an individual is able to achieve. Peak inspiratory flow rate (PIFR) (or peak inspiratory flow, PIF) = the fastest flow rate achieved during the inspiratory cycle. Table 4. Inhalation parameters. 32 [Table presented with the kind permission of Professor Henry Chrystyn, UK] 32. Azouz WA, Chetcuti P, Hosker H, Saralaya D, Chrystyn H. Inhalation characteristics with Spiromax (S) versus Turbuhaler (T) dry powder inhalers (DPI) in healthy adults (HA) and in patients with asthma (A) or COPD. Eur Respir J. 2013;42(suppl. 57):abstract number

28 DuoResp Spiromax is indicated for use in adults aged 18 years and above only Glossary Dry-powder inhaler (DPI) = device for delivering medicine to the lungs in the form of a dry powder; the force from the patient s inhalation results in a measured dose being released. Enhanced technique training using the In-Check Dial improved inhalation outputs with both Spiromax and Turbohaler (Fig. 19). Enhanced training on DPI use may be an important factor in achieving greater drug delivery to the airways. Inspiratory acceleration = rate at which inhalation flow increases (at the start of inhalation). Maximum change in pressure ( P) (or maximum pressure change, MPC) = maximum pressure differential during inhalation that an individual is able to achieve. Figure 19. Improvement after enhanced training in inhalation parameters (a) maximum pressure change (MPC) (b) inspiratory acceleration (ACC). 31 [Figure presented with the kind permission of Professor Henry Chrystyn, UK] 31. Azouz WA, Chetcuti P, Hosker H, Saralaya D, Chrystyn H. Enhanced training on how to use a dry powder inhaler (DPI) improves the inhalation manoeuvre (IM) of patients with asthma (child 6 17yrs and adult >17yrs) or COPD and in healthy adults (HA) when they use a Spiromax (S) and Turbohaler (T) DPI. Eur Respir J. 2013;42(suppl. 57):abstract number

29 DuoResp Spiromax is indicated for use in adults aged 18 years and above only Safety and efficacy of medium-strength DuoResp Spiromax vs Symbicort Turbohaler in asthma (ASSET) ASSET (A Spiromax Safety and Efficacy Trial) is a key phase III study of DuoResp Spiromax versus Symbicort Turbohaler. 33 It is a multicentre, international, 12-week efficacy and safety evaluation of DuoResp Spiromax 160/4.5mcg inhalation powder versus Symbicort Turbohaler 200/6mcg in 600 adult and adolescent patients with persistent asthma (Fig. 20). The primary objective is to establish the non-inferiority of DuoResp Spiromax to Symbicort Turbohaler. The primary endpoint is change in weekly average of daily trough morning peak expiratory flow (PEF) over 12 weeks. Glossary Asthma = disease characterised by recurrent attacks of breathlessness and wheezing. It is caused by inflammation of the air passages in the lungs: the lining of these passages swells, causing the airways to become narrow and airflow to be restricted. The condition is usually associated with allergic reaction or other forms of hypersensitivity. Non-inferiority = not inferior to; non-inferiority trials are a type of clinical trial performed to see if a new drug or treatment is not inferior to a current treatment (an active treatment). Peak expiratory flow (PEF) = the greatest rate of airflow that can be achieved during forced expiration. Figure 20. ASSET study design TEVA. Data on file. 29

30 DuoResp Spiromax is indicated for use in adults aged 18 years and above only Ease-of-use study (ELIOT) and Healthcare Professional (HCP) ELIOT (HCP ELIOT) ELIOT (Easy Low Instruction Over Time) is a key phase III study comparing ease of use of Spiromax and Turbohaler devices. The first stage of the study will be a one-visit, non-interventional, observational, randomised, crossover phase to assess the proportion of patients achieving device mastery (no critical errors) and the number of steps required for a patient to achieve device mastery. Patients will be naïve to both devices and mastery will be determined using a seven-step inhaler device training protocol. Stage 2 of the study will be a 12-week, pragmatic, longitudinal, randomised controlled trial to evaluate the maintenance of device mastery with Spiromax versus Turbohaler. The HCP ELIOT study will run in Australia only. 30

31 Part II: Healthcare Professional Information 31

32 Glossary β 2 -adrenoceptor agonist = a class of drugs that cause smooth muscle relaxation by acting on the beta 2 - adrenergic receptor (also known as β 2 adrenergic agonists) FEV 1 = forced expiratory volume in one 1 second 1. Indications and clinical use: DuoResp Spiromax 1,2 1.1 Indication Asthma DuoResp Spiromax is indicated in the regular treatment of asthma, where use of a combination (inhaled corticosteroid and long-acting β 2 -adrenoceptor agonist) is appropriate: In patients not adequately controlled with inhaled corticosteroids and as needed inhaled short-acting β 2 -adrenoceptor agonist OR in patients already adequately controlled on both inhaled corticosteroids and long-acting β 2 -adrenoceptor agonists. COPD DuoResp Spiromax is indicated for symptomatic treatment of patients with severe COPD (forced expiratory volume in one second [FEV 1 ] <50% predicted normal) and a history of repeated exacerbations, who have significant symptoms despite regular therapy with long-acting bronchodilators. 1. DuoResp Spiromax (320 mcg/9 mcg) summary of product characteristics. 2. DuoResp Spiromax (160 mcg/4.5 mcg) summary of product characteristics. 32

33 1.2 Contraindications 1,2 DuoResp Spiromax is contraindicated in patients with hypersensitivity to the active substances or to lactose monohydrate. Glossary Lactose monohydrate (or lactose) = a disaccharide sugar that is found in milk. 1.3 General warnings for asthma/copd patients 1,2 General warnings Treatment with DuoResp Spiromax should not be stopped abruptly. Sudden and progressive deterioration in control of asthma or COPD is potentially life threatening and the patient should undergo urgent medical assessment. Patients should be reminded to take their DuoResp Spiromax maintenance dose as prescribed, even when asymptomatic. Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of DuoResp Spiromax. Regular review of patients as treatment is stepped down is important. The lowest effective dose of DuoResp Spiromax should be used. Patients should not be initiated on DuoResp Spiromax during an exacerbation, or if they have significantly worsening or acutely deteriorating asthma. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation with DuoResp Spiromax, or in the event of asthma-related adverse reactions and exacerbations. For more information visit: 1. DuoResp Spiromax (320 mcg/9 mcg) summary of product characteristics. 2. DuoResp Spiromax (160 mcg/4.5 mcg) summary of product characteristics. 33

34 Glossary Adrenal suppression = suppression of the adrenal gland. Adrenal glands normally produce three classes of hormones: glucocorticoids, mineralocorticoids, and androgens Bone mineral density (or bone density) = the amount of mineral matter per square centimetre of bone, an indirect indicator of osteoporosis and fracture risk Cushing s syndrome = a condition that occurs when the body is exposed to high levels of the hormone cortisol Cushingoid features = obesity, striations, adiposity, hypertension, diabetes, and osteoporosis, usually due to exogenous corticosteroids Paradoxical bronchospasm = a constriction of the airways after treatment with a sympathomimetic bronchodilator Psychomotor hyperactivity = a condition signified by feelings of extreme restlessness accompanied by an increase in motor activity including muscle spasms, tremors and twitching Rhinitis = inflammation of the mucous membrane of the nose, caused by a virus infection (e.g. the common cold) or by an allergic reaction (e.g. hay fever) 1.4 Warnings: respiratory risks, systemic effects and skin risks 1,2 Respiratory risks If the patient experiences paradoxical bronchospasm, DuoResp Spiromax should be discontinued immediately. The patient should be assessed and an alternative therapy instituted, if necessary. Paradoxical bronchospasm responds to a rapid-acting inhaled bronchodilator and they should be treated straight away. Systemic effects Systemic effects may occur, these include: Cushing s syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, cataract and glaucoma and, more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression. In patients on high doses, for prolonged periods, and who have coexisting risk factors for osteoporosis (particularly at doses 400 and 800 mcg [metered dose] in children and adults, respectively) bone density effects should be considered. Joint/muscle pain not skin risks Transfer from oral therapy to DuoResp Spiromax might result in the appearance of allergic or arthritic symptoms such as rhinitis, eczema and muscle and joint pain. Specific treatment should be initiated for these conditions. For more information visit: 1. DuoResp Spiromax (320 mcg/9 mcg) summary of product characteristics. 2. DuoResp Spiromax (160 mcg/4.5 mcg) summary of product characteristics. 34

35 1.5 Warnings: endocrine risks 1,2 Care should be taken when transferring patients to DuoResp Spiromax therapy if adrenal function is impaired from previous systemic steroid therapy. Inhaled budesonide therapy normally minimises the need for oral steroids. However, as patients transferring from oral steroids may remain at risk of impaired adrenal reserve for a considerable time, hypothalamic-pituitary-adrenal (HPA) axis function should be monitored regularly. Prolonged treatment with high doses of inhaled corticosteroids (higher than recommended doses) may result in adrenal suppression; additional systemic corticosteroid cover should be considered. Glossary Adrenal suppression = suppression of the adrenal gland. Adrenal glands normally produce three classes of hormones: glucocorticoids, mineralocorticoids, and androgens Hypothalamic-pituitary-adrenal (HPA) axis function = feedback interactions among the hypothalamus, pituitary gland, and the adrenal gland. The HPA axis is a major part of the neuroendocrine system that controls reactions to stress and regulates many body processes Rapid reduction in the dose of steroids can induce acute adrenal crisis. Symptoms and signs in acute adrenal crisis may include anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, decreased level of consciousness, seizures, hypotension and hypoglycaemia. Treatment with supplementary systematic steroids or inhaled budesonide should not be stopped abruptly. 1. DuoResp Spiromax (320 mcg/9 mcg) summary of product characteristics.. 2. DuoResp Spiromax (160 mcg/4.5 mcg) summary of product characteristic. 35

36 Glossary β 2 -adrenoceptor agonist = a class of drugs that cause smooth muscle relaxation by acting on the beta 2 - adrenergic receptor (also known as β 2 adrenergic agonists) CYP3A4 inhibitors = medicines that inhibit CYP3A4 (an important enzyme involved in the metabolism of xenobiotics in the human body) Hypokalaemia (adj. hypokalaemic) = low concentration of potassium (K + ) in the blood Itraconazole = a medicine indicated for the treatment of the fungal infections Oropharyngeal Candida infection = thrush infection of the mouth and throat Rescue bronchodilators = short-acting bronchodilators that provide quick or rescue relief from acute bronchoconstriction Ritonavir = a medicine indicated in combination with other antiretroviral agents for the treatment of HIV-1 infected patients 1.6 Warnings: infections, interactions and metabolic risks 1,2 Risk of infections To minimise the risk of oropharyngeal Candida infection, the patient should be instructed to rinse their mouth out with water after inhaling the dose. Interaction with other medicinal products Concomitant treatment with itraconazole, ritonavir or other potent CYP3A4 inhibitors should be avoided. If not possible, the time interval between administrations of the interacting medicinal products should be as long as possible. Metabolic risks High doses of β 2 -adrenoceptor agonists may result in hypokalaemia. Concomitant treatment of β 2 -adrenoceptor agonists with drugs that can induce hypokalaemia or potentiate a hypokalaemic effect, e.g. xanthine-derivatives, steroids and diuretics, may add to a possible hypokalaemic risk. Particular caution is recommended in unstable asthma with variable use of rescue bronchodilators. The associated risk may be augmented by hypoxia and in other conditions when the likelihood for hypokalaemia is increased. It is recommended that serum potassium levels are monitored during these circumstances. Additional blood glucose controls should be considered in diabetic patients. 1. DuoResp Spiromax (320 mcg/9 mcg) summary of product characteristics. 2. DuoResp Spiromax (160 mcg/4.5 mcg) summary of product characteristics. 36

37 1.7 Warnings: special patient groups and other risks 1,2 Special patient groups DuoResp Spiromax should be administered with caution in patients with thyrotoxicosis, phaeochromocytoma, diabetes mellitus, untreated hypokalaemia, hypertrophic obstructive cardiomyopathy, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm or other severe cardiovascular disorders, such as ischaemic heart disease, tachyarrhythmias or severe heart failure. Caution should be observed when treating patients with prolongation of the QTc-interval. The need for, and dose of, inhaled corticosteroids should be re-evaluated in patients with active or quiescent pulmonary tuberculosis, fungal and viral infections in the airways. Other risks A general insufficient glucocorticosteroid effect should be suspected if, in rare cases, symptoms such as tiredness, headache, nausea and vomiting should occur. Information about excipients DuoResp Spiromax is not recommended for galactose intolerant patients as this medicinal product contains lactose. Glossary Hypokalaemia (adj. hypokalaemic) = low concentration of potassium (K + ) in the blood Idiopathic subvalvular aortic stenosis = a disease characterized by marked hypertrophy of the left ventricle, in particular involving the interventricular septum and the left ventricular outflow tract Lactose monohydrate (or lactose) = a disaccharide sugar that is found in milk. It is derived from galactose and glucose Phaeochromocytoma = a rare and usually noncancerous (benign) tumor that develops in an adrenal gland QTc-interval = a measure of the time between the start of the Q wave and the end of the T wave in the heart s electrical cycle Tachyarrhythmia = cardiac dysrhythmia; any of a group of conditions in which the electrical activity of the heart is irregular or is faster or slower than normal. The heartbeat may be too fast or too slow, and may be regular or irregular Thyrotoxicosis = a hypermetabolic clinical syndrome resulting from serum elevations in thyroid hormone levels, specifically free thyroxine (T4) and/or triiodothyronine (T3) 1. DuoResp Spiromax (320 mcg/9 mcg) summary of product characteristics. 2. DuoResp Spiromax (160 mcg/4.5 mcg) summary of product characteristics. 37

38 Glossary β 2 -adrenoceptor agonist = a class of drugs that cause smooth muscle relaxation by acting on the beta 2 - adrenergic receptor (also known as β 2 adrenergic agonists) Cirrhosis = a chronic disease of the liver marked by degeneration of cells, inflammation, and fibrous thickening of tissue. It is typically a result of alcoholism or hepatitis 1.8 Dosage in special populations 1,2 Elderly patients ( 65 years old) There are no special dosing requirements for elderly patients. Patients with renal or hepatic impairment There are no data available for use of DuoResp Spiromax in patients with hepatic or renal impairment. As budesonide and formoterol are primarily eliminated via hepatic metabolism, increased exposure can be expected in patients with severe liver cirrhosis. 1.9 Adverse reactions Summary of safety profile Since DuoResp Spiromax contains both budesonide and formoterol, the same pattern of adverse reactions as reported for these substances may occur. 1,2 No increased incidence of adverse reactions has been seen following concurrent administration of the two compounds. 1,2 The common adverse reactions of β 2 -adrenoceptor agonist therapy, including tremor and palpitations, are pharmacologically predictable. These tend to be mild and usually disappear within a few days of treatment. 1,2 In a 3-year clinical trial with budesonide in COPD, skin bruises and pneumonia occurred at a frequency of 10% and 6%, respectively, compared with 4% and 3% in the placebo group (p<0.001 and p<0.01, respectively) DuoResp Spiromax (320 mcg/9 mcg) summary of product characteristics. 2. DuoResp Spiromax (160 mcg/4.5 mcg) summary of product characteristics. 3. Symbicort Turbohaler SPC: 38

39 1.10 Summary of adverse events 1,2 Adverse reactions, which have been associated with budesonide or formoterol, are given in Table 1 and listed by system organ class and frequency. Frequencies are defined as: very common ( 1/10), common ( 1/100, <1/10), uncommon ( 1/1,000, < 1/100), rare ( 1/10,000, < 1/1,000), very rare (<1/10,000), ), and not known (cannot be estimated from the available data). Glossary Angina pectoris = chest pain caused by ischemia of the heart muscle, generally due to obstruction or spasm of the coronary arteries Angioedema = swelling of the deeper layers of the skin due to accumulation of fluids caused by an allergic reaction Bone mineral density (or bone density) = the amount of mineral matter per square centimetre of bone, an indirect indicator of osteoporosis and fracture risk For more information visit: Table 1: summary of adverse events Cushing s syndrome = a condition that occurs when the body is exposed to high levels of the hormone cortisol Exanthema = a rash, including redness, bumps, and sometimes pustules, covering a large area of the body Extrasystoles = a heartbeat outside of the normal rhythm Hypokalaemia (adj. hypokalaemic) = low concentration of potassium (K + ) in the blood Pruritus = itching Oropharyngeal Candida infection = thrush infection of the mouth and throat Psychomotor hyperactivity = a condition signified by feelings of extreme restlessness accompanied by an increase in motor activity including muscle spasms, tremors and twitching QTc-interval = a measure of the time between the start of the Q wave and the end of the T wave in the heart s electrical cycle Tachycardia = an abnormally rapid heartbeat Urticaria = a skin rash notable for pale red, raised, and itchy bumps. Also referred to as hives 1. DuoResp Spiromax (320 mcg/9 mcg) summary of product characteristics. 2. DuoResp Spiromax (160 mcg/4.5 mcg) summary of product characteristics. 39

40 Glossary Antihistamines = drugs used for the treatment of allergic symptoms Disopyramide = an antiarrhythmic medication used in the treatment of ventricular tachycardia Hypokalaemia (adj. hypokalaemic) = low concentration of potassium (K +) in the blood Monoamine oxidase inhibitors = one of the oldest classes of antidepressants and are typically used when other antidepressants have not been effective Phenothiazine = can be found in various drugs used for a number of different disorders, including allergies and mental health disorders Procainamide = a class Ia antiarrhythmic agent used for the treatment of cardiac arrhythmias QTc-interval = a measure of the time between the start of the Q wave and the end of the T wave in the heart s electrical cycle Quinidine = a class I antiarrhythmic agent (Ia) in the heart 1.11 Drug interactions 1,2 Pharmacodynamic interactions Beta-adrenergic blockers can weaken or inhibit the effect of formoterol. DuoResp Spiromax should not be given with beta-adrenergic blockers (including eye drops). 1,2 Concomitant treatment with quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine), monoamine oxidase inhibitors and tricyclic antidepressants can prolong the QTc-interval. L-Dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards β 2 -sympathomimetics. Concomitant treatment with monoamine oxidase inhibitors including agents with similar properties may precipitate hypertensive reactions. 1 Concomitant use of other beta-adrenergic and anticholinergic medicinal products can have a potentially additive bronchodilating effect. 1,2 Hypokalaemia may increase the disposition towards arrhythmias in patients who are treated with digitalis glycosides. Budesonide and formoterol have not been observed to interact with any other medicinal products used in the treatment of asthma. 1,2 For more information visit: 1. DuoResp Spiromax (320 mcg/9 mcg) summary of product characteristics. 2. DuoResp Spiromax (160 mcg/4.5 mcg) summary of product characteristics. 40

41 DuoResp Spiromax is indicated for use in adults aged 18 years and above only 2. Asthma 2.1 Dosage in asthma: DuoResp Spiromax Medium Strength 160/4.5 mcg 2 DuoResp Spiromax is not intended for the initial management of asthma. Glossary β 2 -adrenoceptor agonist = a class of drugs that cause smooth muscle relaxation by acting on the beta 2 - adrenergic receptor (also known as β 2 adrenergic agonists) Rescue bronchodilators = short-acting bronchodilators that provide quick or rescue relief from acute bronchoconstriction The dosage is individual and should be adjusted to the severity of the disease for both, treatment with combination medicinal products and in maintenance therapy. Appropriate doses of β 2 -adrenoceptor agonist and/or corticosteroids by individual inhalers should be prescribed for patients requiring doses other than those available in the combination inhaler. Patients should be reassessed regularly, the dose of DuoResp Spiromax should be titrated to the lowest dose at which effective control of symptoms is maintained. A test of inhaled corticosteroid alone could be performed when long-term control of symptoms is maintained. For DuoResp Spiromax, there are two treatment approaches: DuoResp Spiromax maintenance therapy: DuoResp Spiromax is taken as regular maintenance treatment with a separate rapid-acting bronchodilator as rescue. DuoResp Spiromax maintenance and reliever therapy: DuoResp Spiromax is taken as regular maintenance treatment and as needed in response to symptoms. For more information visit: 2. DuoResp Spiromax (160 mcg/4.5 mcg) summary of product characteristics 41

42 DuoResp Spiromax is indicated for use in adults aged 18 years and above only Glossary Rescue = called quick-relief or fast-acting asthma medication, work immediately to relieve asthma symptoms when they occur 2.2 Maintenance dosages in asthma: DuoResp Spiromax Medium Strength 160/4.5 mcg 2 Patients should be advised to have their separate rapid-acting bronchodilator available for rescue use at all times. Recommended doses: One or two inhalations twice daily, up to a maximum of four inhalations twice daily. When control of symptoms is achieved with the twice daily regimen, titration to the lowest effective dose could include DuoResp Spiromax given once daily, when in the opinion of the prescriber, a long-acting bronchodilator would be required to maintain control. For more information visit: 2. DuoResp Spiromax (160 mcg/4.5 mcg) summary of product characteristics 42

43 DuoResp Spiromax is indicated for use in adults aged 18 years and above only Dosage in asthma: DuoResp Spiromax High Strength 320/9 mcg 1 DuoResp Spiromax is not intended for the initial management of asthma. Glossary β 2 -adrenoceptor agonist = a class of drugs that cause smooth muscle relaxation by acting on the beta 2 - adrenergic receptor (also known as β 2 adrenergic agonists) The dosage is individual and should be adjusted to the severity of the disease for both, treatment with combination medicinal products and in maintenance therapy. Appropriate doses of β 2 -adrenoceptor agonist and/or corticosteroids by individual inhalers should be prescribed for patients requiring doses other than those available in the combination inhaler. Recommended doses: one inhalation twice daily, up to a maximum of two inhalations twice daily. Patients should be reassessed regularly, the dose of DuoResp Spiromax should be titrated to the lowest dose at which effective control of symptoms is maintained. A test of inhaled corticosteroid alone could be performed when long-term control of symptoms is maintained. With the twice daily regimen, titration to the lowest effective dose could include DuoResp Spiromax given once daily, when in the opinion of the prescriber, a long-acting bronchodilator would be required to maintain control. DuoResp Spiromax 320 mcg/9.0 mcg should be used as maintenance therapy only. A lower strength of DuoResp Spiromax is available for the maintenance and reliever therapy regimen. For more information visit: 1. DuoResp Spiromax (320 mcg/9 mcg) summary of product characteristics. 43

44 DuoResp Spiromax is indicated for use in adults aged 18 years and above only Glossary Rescue = called quick-relief or fast-acting asthma medication, work immediately to relieve asthma symptoms when they occur 2.4 Maintenance and reliever dosages in asthma: DuoResp Spiromax Medium Strength 160/4.5 mcg 2 Patients should be advised to always have DuoResp Spiromax available for rescue use; a daily maintenance dose of DuoResp Spiromax in addition taking DuoResp Spiromax as needed in response to symptoms is recommended. DuoResp Spiromax maintenance and reliever therapy should especially be considered for patients with inadequate asthma control and in frequent need of the reliever, and for those with asthma exacerbations in the past requiring medical intervention. Close monitoring for dose-related adverse reactions is needed in patients who frequently take high numbers of DuoResp Spiromax as-needed inhalations. Recommended doses: Two inhalations per day one inhalation in the morning and evening or as two inhalations in either the morning or evening; one additional inhalation as needed in response to symptoms, no more than six inhalations should be taken on any single occasion. A total daily dose of up to 12 inhalations could be used for a limited period if needed. Patients using more than eight inhalations daily should be strongly recommended to seek medical advice and reassessed; maintenance therapy should be reconsidered. 2. DuoResp Spiromax (160 mcg/4.5 mcg) summary of product characteristics 44

45 DuoResp Spiromax is indicated for use in adults aged 18 years and above only 3. COPD 3.1 Dosages in COPD: DuoResp Spiromax 1,2 Recommended doses: One inhalation twice daily of DuoResp Spiromax High Strength 320/9 mcg Two inhalations twice daily of DuoResp Spiromax Medium Strength 160/4.5 mcg For more information visit: Figure. DuoResp Spiromax : high strength (320/9 mcg) and medium strength (160/4.5 mcg) 1. DuoResp Spiromax (320 mcg/9 mcg) summary of product characteristics. 2. DuoResp Spiromax (160 mcg/4.5 mcg) summary of product characteristics. 45

46 DuoResp Spiromax is indicated for use in adults aged 18 years and above only Glossary Lactose monohydrate (or lactose) = a disaccharide sugar that is found in milk. It is derived from galactose and glucose 4. Administration 1,2 Method of administration For inhalation use. Spiromax is a breath actuated, inspiratory flow-driven inhaler, the active substances are delivered when the patient inhales through the mouthpiece. Moderate and severe asthmatic patients generate sufficient inspiratory flow rate for Spiromax to deliver the therapeutic dose. DuoResp Spiromax should be used correctly in order to achieve effective treatment. Patients are advised to read the patient information leaflet carefully and follow the instructions for use as detailed in the leaflet. The use of DuoResp Spiromax follows three simple steps (open, breathe and close): Open: Hold the Spiromax with the mouthpiece cover at the bottom and open the mouthpiece cover by folding it down until it is fully opened when one click is heard. Breathe: Place the mouthpiece between the teeth with the lips closed around the mouthpiece, breathe in forcefully and deeply through the mouthpiece. Remove the Spiromax from mouth and hold the breath for 10 seconds or as long as comfortable for the patients. Close: Breathe out gently and close the mouthpiece cover Do not shake the inhaler before use and do not breathe out through the Spiromax and do not block the air vents when preparing the Breathe step. Patients should also be advised to rinse their mouth with water after inhaling. The patient may notice a taste when using DuoResp Spiromax due to the lactose excipient. 1. DuoResp Spiromax (320 mcg/9 mcg) summary of product characteristics. 2. DuoResp Spiromax (160 mcg/4.5 mcg) summary of product characteristics. 46

47 4.1 IMPORTANT: The DuoResp Spiromax inhaler should not be shaken and should be held with the semi-transparent wine red mouthpiece cover at the bottom Cross-section of the Spiromax Device 47

48 Glossary Adrenal suppression = suppression of the adrenal gland. Adrenal glands normally produce three classes of hormones: glucocorticoids, mineralocorticoids, and androgens β 2 -adrenoceptor agonist = a class of drugs that cause smooth muscle relaxation by acting on the beta 2 - adrenergic receptor (also known as β 2 adrenergic agonists) Hypercorticism = a genetic or acquired condition resulting in elevated levels of glucocorticoids, often as a result of tumours in adrenal or pituitary glands; leads to significant weight gain, particularly on the back (causing a buffalo hump ) and face Hypokalaemia (adj. hypokalaemic) = low concentration of potassium (K + ) in the blood QTc-interval = a measure of the time between the start of the Q wave and the end of the T wave in the heart s electrical cycle Tachycardia = abnormally rapid heart rate 5. Overdose 1,2 5.1 Formoterol Overdose effects are typical for β 2 -adrenoceptor agonists and include: tremor, headache, palpitations. In rare cases: tachycardia, hyperglycaemia, hypokalaemia, prolonged QTc-interval, arrhythmia, nausea and vomiting. Acute overdosage with budesonide, even in excessive doses, is not expected to be a clinical problem. When used chronically in excessive doses, systemic glucocorticosteroid effects, such as hypercorticism and adrenal suppression, may appear. If DuoResp Spiromax therapy has to be withdrawn due to overdose of the formoterol component of the medicinal product, provision of appropriate inhaled corticosteroid therapy must be considered. For more information visit: 1. DuoResp Spiromax (320 mcg/9 mcg) summary of product characteristics. 2. DuoResp Spiromax (160 mcg/4.5 mcg) summary of product characteristics. 48

49 6. Storage/stability and special handling instructions 1,2 Shelf life: 2 years. After opening the foil wrap: 6 months. Storage: Do not store above 25 C. Keep the mouthpiece cover closed after removal of the foil wrap. Disposal: There are no special precautions for disposal and other handling. 1. DuoResp Spiromax (320 mcg/9 mcg) summary of product characteristics. 2. DuoResp Spiromax (160 mcg/4.5 mcg) summary of product characteristics. 49

50 Glossary Lactose monohydrate (or lactose) = a disaccharide sugar that is found in milk. It is derived from galactose and glucose 7. Dosage forms, composition and packaging 1,2 7.1 Dosage form Medium dose 2 DuoResp Spiromax 160 mcg/4.5 mcg inhalation powder. Each delivered (inhaled) dose contains 160 mcg of budesonide and 4.5 mcg of formoterol fumarate dihydrate, equivalent to a metered dose of 200 mcg budesonide and 6 mcg of formoterol fumarate dihydrate. Excipient(s) with known effect: Each dose contains approximately 5 milligrams of lactose (as monohydrate). High dose 1 DuoResp Spiromax 320 mcg/9 mcg inhalation powder. Each delivered (inhaled) dose contains: 320 mcg of budesonide and 9 mcg of formoterol fumarate dihydrate, equivalent to a metered dose of 400 mcg budesonide and 12 mcg formoterol fumarate dihydrate. Excipient(s) with known effect: Each dose contains approximately 10 milligrams of lactose (as monohydrate). Nature and contents of container: The inhaler is white with a semi-transparent wine red mouthpiece cover. The inhaler is made acrylonitrile butadiene styrene (ABS), polyethylene terephthalate (PT) and polypropylene (PP). Each pack contains one inhaler of 120 doses and is foil-wrapped. 1. DuoResp Spiromax (320 mcg/9 mcg) summary of product characteristics. 2. DuoResp Spiromax (160 mcg/4.5 mcg) summary of product characteristics. 50

51 Part III: Consumer Information 51

52 Glossary Bronchodilator = a drug that causes widening of the bronchi, which are the major air passages in the lungs Chronic obstructive pulmonary disease (COPD) = progressive lung disease characterised by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible. Symptoms include cough, sputum production, wheezing and shortness of breath. Smoking is the leading cause of COPD. Corticosteroid = a class of drugs that includes steroid hormones, which help to reduce inflammation Inflammation = a localized physical condition in which part of the body becomes reddened and swollen Long-acting β 2 -adrenoceptor agonist (also known as bronchodilators) = = a class of drug that causes smooth muscles in the airways to relax by acting on a specific target called the beta 2 -adrenergic receptor (also known as β 2 adrenergic agonists) Reliever inhaler = provision of quick or rescue relief from acute constriction of the airways 1. About this medication DuoResp Spiromax contains two different active substances: budesonide and formoterol fumarate dihydrate. Budesonide is a corticosteroid medicine that reduces and prevents swelling and inflammation in your lungs. Formoterol fumarate dihydrate is a long-acting β 2 - adrenoceptor agonist or a bronchodilator, which relaxes the muscles in the airways. This helps you to breathe more easily. 1,2 Your doctor has prescribed this medicine to treat asthma or chronic obstructive pulmonary disease (COPD). DuoResp Spiromax is available in two strengths (DuoResp Spiromax 320 mcg/9 mcg and DuoResp Spiromax 160 mcg/4.5 mcg). Your doctor will prescribe you with the most suitable dose for your condition. 1,2 DuoResp Spiromax is indicated to treat asthma or COPD in adults 18 years and above only. 1 Asthma For asthma, your doctor may have prescribed DuoResp Spiromax in two different ways: a) Two asthma inhalers: DuoResp Spiromax and a separate reliever inhaler. 1,2 Use DuoResp Spiromax every day to prevent asthma symptoms from happening. Use your reliever inhaler when you get asthma symptoms. Do not use DuoResp Spiromax 320/9 mcg as a reliever inhaler. 1,2 b) As one asthma inhaler, DuoResp Spiromax 160/ Use DuoResp Spiromax 160/4.5 mcg every day to prevent asthma symptoms from happening also use when you need extra doses for relief of asthma symptoms. 2 Chronic obstructive pulmonary disease (COPD) DuoResp Spiromax can also be used to treat the symptoms of severe COPD in adults. COPD is a long-term disease of the airways in the lungs, which is often caused by cigarette smoking. 1,2 1. DuoResp Spiromax 320 mcg/9 mcg Package Leaflet. 2. DuoResp Spiromax 160 mcg/4.5 mcg Package Leaflet. 52

53 1.1 Warnings and precautions Do not use DuoResp Spiromax if: You are allergic to budesonide, formoterol fumarate dihydrate, or lactose. 1,2 Glossary Thyroid = a gland that secretes hormones vital to metabolism and growth Talk to your doctor, pharmacist or nurse before using DuoResp Spiromax if any of the following apply to you: Are diabetic or have: a lung infection, high blood pressure, or heart problems (including an uneven heart beat, a very fast pulse, narrowing of the arteries or heart failure), thyroid or adrenal glands problems, low levels of potassium in your blood, severe liver problems, or will have a general anaesthetic. 1,2 Pregnancy and breast-feeding If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before using DuoResp Spiromax do not use DuoResp Spiromax unless your doctor tells you to. 1,2 If you get pregnant while using DuoResp Spiromax, do not stop using DuoResp Spiromax but talk to your doctor immediately. 1,2 1. DuoResp Spiromax 320 mcg/9 mcg Package Leaflet. 2. DuoResp Spiromax 160 mcg/4.5 mcg Package Leaflet. 53

54 Glossary Antihistamines = medicines that are used to treat allergic conditions Bronchodilator = a drug that causes widening of the bronchi, which are the major air passages in the lungs Monoamine oxidase inhibitors = one of the oldest classes of antidepressants and are typically used when other antidepressants have not been effective 1.2 Taking DuoResp Spiromax with other medications Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines. In particular, you should tell your doctor if you are taking any of the medicines in the Table 1,2 Phenothiazine = can be found in various drugs used for a number of different disorders, including allergies and mental health disorders Steroid = a class of drugs that can help to reduce inflammation Thyroid = a gland that secretes hormones vital to metabolism and growth Table 1: DuoResp Spiromax and other medications 1. DuoResp Spiromax 320 mcg/9 mcg Package Leaflet. 2. DuoResp Spiromax 160 mcg/4.5 mcg Package Leaflet. 54

55 1.3 How to use DuoResp Spiromax (part a) Use exactly as your doctor or pharmacist has told you. Check with your doctor, pharmacist or nurse if you are not sure. Use DuoResp Spiromax every day, even if you have no asthma or COPD symptoms at the time. If you are using DuoResp Spiromax for asthma, your doctor will want to regularly check your symptoms. If you have been taking steroid tablets for asthma or COPD, your doctor may reduce the number of tablets, once you start to use DuoResp Spiromax and may want you to have blood tests. When reducing oral steroid tablets, you may feel generally unwell even though your chest symptoms may be improving. You might experience a stuffy or runny nose, weakness or joint or muscle pain and rash (eczema). If any of these symptoms bother you, or if symptoms such as headache, tiredness, nausea (feeling sick) or vomiting (being sick) occur, please contact your doctor immediately. 1,2 Other medicines may be needed if you develop allergic or arthritis symptoms. If you are concerned as to whether you should continue to use DuoResp Spiromax ask your doctor (your doctor may add steroid tablets during periods of stress). 1,2 Important information about your asthma or COPD symptoms Continue using DuoResp Spiromax but seek medical advice if you get breathless or wheezy, as you may need additional treatment immediately. 1,2 Glossary Allergic symptoms = may include sneezing, wheezing, sinus pain (pressure or pain high up in the nose, around the eyes and at the front of the skull), runny nose, coughing, nettle rash (hives), swelling, itchy eyes, ears, lips, throat and palate (roof of mouth), shortness of breath sickness, vomiting and diarrhoea Arthritis symptoms = may include joint pain and swelling, fatigue, and weight loss Chronic obstructive pulmonary disease (COPD) = progressive lung disease characterised by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible. Symptoms include cough, sputum production, wheezing and shortness of breath. Smoking is the leading cause of COPD. Eczema = a skin disease that causes areas of the skin to become red, rough, and itchy Steroid = a class of drugs that can help to reduce inflammation Wheezing (adj. wheezy) = a whistling sound that occurs when you breathe. Wheezing is a sign that you may be having difficulty in breathing Contact your doctor immediately if: Your breathing gets worse, you often wake up at night with breathlessness and wheezing, or experience tightness of the chest in the morning lasting longer than usual. 1,2 1. DuoResp Spiromax 320 mcg/9 mcg Package Leaflet. 2. DuoResp Spiromax 160 mcg/4.5 mcg Package Leaflet. 55

56 DuoResp Spiromax is indicated for use in adults aged 18 years and above only Glossary Bronchodilator = a drug that causes widening of the bronchi, which are the major air passages in the lungs Chronic obstructive pulmonary disease (COPD) = progressive lung disease characterised by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible. Symptoms include cough, sputum production, wheezing and shortness of breath. Smoking is the leading cause of COPD. Reliever inhaler = provision of quick or rescue relief from acute constriction of the airways 1.4 How to use DuoResp Spiromax 320/9 mcg 1 Asthma Use your DuoResp Spiromax every day. This helps to prevent asthma symptoms from happening. Recommended dose: One inhalation (actuation), twice a day. Your doctor may increase this to two inhalations, twice a day. If your symptoms are well controlled, your doctor may ask you to take your medicine once a day. Your doctor (or asthma nurse) will help you to manage your asthma. They will adjust the dose of this medicine to the lowest dose that controls your asthma. However, do not adjust the dose without talking to your doctor (or asthma nurse) first. Use your separate reliever inhaler to treat asthma symptoms when they happen. Always keep your reliever inhaler with you to use when you need it. Do not use DuoResp Spiromax 320/9 mcg to treat asthma symptoms use your separate reliever inhaler. Chronic Obstructive Pulmonary Disease (COPD) Recommended dose: One inhalation twice a day. Your doctor may also prescribe other bronchodilator drugs, for example an anticholinergic (such as tiotropium or ipratropium bromide) for your COPD disease. 1. DuoResp Spiromax 320 mcg/9 mcg Package Leaflet. 56

57 DuoResp Spiromax is indicated for use in adults aged 18 years and above only How to use DuoResp Spiromax 160/4.5 mcg 1 Asthma a) Using DuoResp Spiromax and a separate reliever inhaler. Every day to prevent asthma symptoms from happening. Recommended dose: One or two inhalations (actuations) twice a day (up to four inhalations, twice a day). If symptoms are well controlled, your doctor may ask you to take your medicine once a day. The dose will be adjusted to the lowest dose that controls your asthma do not adjust the dose without talking to your doctor (or nurse) first. Use your separate reliever inhaler to treat asthma symptoms when they happen. Do not use DuoResp Spiromax to treat asthma symptoms use your separate reliever inhaler. Glossary Bronchodilator = a drug that causes widening of the bronchi, which are the major air passages in the lungs Chronic obstructive pulmonary disease (COPD) = progressive lung disease characterised by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible. Symptoms include cough, sputum production, wheezing and shortness of breath. Smoking is the leading cause of COPD. Reliever inhaler = provision of quick or rescue relief from acute constriction of the airways b) Using DuoResp Spiromax when this is prescribed as your only inhaler. Every day to prevent asthma symptoms from happening. Recommended dose: One inhalation in the morning and one inhalation in the evening, or two inhalations in the morning or two inhalations in the evening. Your doctor may increase this to two inhalations twice a day. Also use DuoResp Spiromax as a reliever inhaler to treat asthma symptoms when they happen. Take one inhalation and wait a few minutes. If you do not feel better, take another inhalation, do not take more than six inhalations at a single time. Do not use more than 12 inhalations in total in 24 hours. Chronic Obstructive Pulmonary Disease (COPD) Recommended dose: Two inhalations twice a day. Your doctor may also prescribe other bronchodilator drugs for your COPD disease. For more information visit: 1. DuoResp Spiromax 160 mcg/4.5 mcg Package Leaflet. 57

58 1.6 How to use DuoResp Spiromax 1,2 (part b) Preparing your new DuoResp Spiromax DuoResp Spiromax needs to be prepared for first use as follows: check the dose indicator to see that there are 120 doses (DuoResp Spiromax 160/4.5 mcg) or 60 doses (DuoResp Spiromax 320/9 mcg) in the inhaler. Write the date you opened the foil pouch on the label of the inhaler. Do not shake your Spiromax before use. How to take an inhalation Every time you need to take an inhalation, follow the instructions below. I. Hold your inhaler with the semi-transparent wine red mouthpiece cover at the bottom Open the mouthpiece cover by folding it down and until one loud click is heard. Your medicine is actively metered. Your inhaler is now ready for use II. BREATHE Breathe out gently (as far as is comfortable). Do not breathe out through your inhaler. Place the mouthpiece between your teeth. Close your lips around the mouthpiece. Take care not to block the air vents. 1. DuoResp Spiromax 320 mcg/9 mcg Package Leaflet. 2. DuoResp Spiromax 160 mcg/4.5 mcg Package Leaflet. 58

59 Breathe in through your mouth as deeply and as hard as you can. Hold your breath for 10 seconds or as long as you comfortably can. Remove your inhaler from your mouth. You may notice a taste when you take your inhalation. III. CLOSE Then breathe out gently (do not breathe out through the inhaler). You may notice a taste when you take your dose. Close the mouthpiece cover. If you are to take a second inhalation, repeat these steps. Rinse your mouth with water after every dose, and spit it out. 1. DuoResp Spiromax 320 mcg/9 mcg Package Leaflet. 2. DuoResp Spiromax 160 mcg/4.5 mcg Package Leaflet. 59

60 Do not try to take your inhaler apart 1,2 Do not shake your Spiromax before use 1,2 Do not try to take your inhaler apart, remove or twist the mouthpiece cover, it is fixed to your Spiromax and must not be taken off. Do not use your Spiromax if it has been damaged or if the mouthpiece has come apart from your Spiromax. Do not open and close the mouthpiece cover unless you are taking a dose. Keep your Spiromax dry and clean. If necessary you may wipe the mouthpiece of your Spiromax after use with a dry cloth or tissue. Cross-section of the Spiromax Device 1. DuoResp Spiromax 320 mcg/9 mcg Package Leaflet. 2. DuoResp Spiromax 160 mcg/4.5 mcg Package Leaflet. 60

61 1.7 Serious side effects If any of the side effects in the table happen to you, stop using DuoResp Spiromax and talk to your doctor immediately: 1,2 Glossary Hives = a condition in which an area of your skin becomes red and itchy (raised red, flat-topped, itchy swellings) Wheezing (adj. wheezy) = a whistling sound that occurs when you breathe. Wheezing is a sign that you may be having difficulty in breathing Reliever inhaler = provision of quick or rescue relief from acute constriction of the airways Table 2: Serious side effects that have been reported with budesonide/formoterol 1. DuoResp Spiromax 320 mcg/9 mcg Package Leaflet. 2. DuoResp Spiromax 160 mcg/4.5 mcg Package Leaflet. 61

62 Glossary Palpitations = abnormal heart beats that are too fast or too slow 1.8 Other possible side effects Common (affects less than one in 10 people) Palpitation, trembling, or shaking: usually mild and disappear as you continue to use DuoResp Spiromax. Thrush (a fungal infection) in the mouth. This is less likely if you rinse your mouth out with water after using your medicine. Mild sore throat, coughing and a hoarse voice and headache. 1,2 Uncommon (affects less than one in 100 people) Feeling restless, nervous or agitated, anxious or angry, disturbed sleep, dizziness, nausea (feeling sick), fast heart beat, bruising of the skin, muscle cramps. 1,2 Rare (affect up to 1 in 1,000 people) Low levels of potassium in your blood and uneven heart beat. 1,2 Very rare (affects less than one in 10,000 people) Depression, changes in behaviour (especially in children), chest pain or tightness in the chest (angina pectoris), an increase in the amount of sugar (glucose) in your blood, taste changes, changes in your blood pressure. 1,2 If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed here. 1,2 1. DuoResp Spiromax 320 mcg/9 mcg Package Leaflet. 2. DuoResp Spiromax 160 mcg/4.5 mcg Package Leaflet. 62

63 1.9 How to store DuoResp Spiromax Keep out of the sight and reach of children. Do not store above 25 C. Keep mouthpiece cover closed after removal of the foil wrapping. 1,2 Do not use DuoResp Spiromax after the expiry date, which is stated on the carton or on the label of your inhaler. The expiry date refers to the last day of that month. Use within 6 months of removing from the foil wrapping. Use the label on the inhaler to write down the opening date of the foil pouch. 1,2 Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 1,2 1. DuoResp Spiromax 320 mcg/9 mcg Package Leaflet. 2. DuoResp Spiromax 160 mcg/4.5 mcg Package Leaflet. 63

64 1.10 Further information DuoResp Spiromax contains Each delivered (inhaled) dose contains 160 or 320 mcg of budesonide and 4.5 or 9.0 mcg of formoterol fumarate dehydrate (depending on which dose you have been prescribed). This is equivalent to a metered dose of 200 or 400 mcg of budesonide and 6 or 12 mcg of formoterol fumarate dihydrate. 1,2 The other ingredient is lactose monohydrate. What DuoResp Spiromax looks like and contents of the pack DuoResp Spiromax is an inhaler containing your medicine. Each DuoResp Spiromax inhaler contains 120 doses (DuoResp Spiromax 160/4.5 mcg) or 60 doses (DuoResp Spiromax 320/9 mcg) and has a white body with a semitransparent wine red mouthpiece cover. Figure. DuoResp Spiromax: available as high strength (320/9 mcg) also and medium strength (160/4.5 mcg) 1. DuoResp Spiromax 320 mcg/9 mcg Package Leaflet. 2. DuoResp Spiromax 160 mcg/4.5 mcg Package Leaflet. 64

65 Part IV: Health economics 65

66 Glossary Chronic obstructive pulmonary disease (COPD) = progressive lung disease characterised by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible. Symptoms include cough, sputum production, wheezing and shortness of breath. Smoking is the leading cause of COPD. 1. Asthma and COPD: Economic burden of the disease and unmet needs Asthma and chronic obstructive pulmonary disease (COPD) are the two most common respiratory diseases worldwide including Europe, and impose a considerable healthcare and societal burden on patients and healthcare systems. 1 In the EU, the direct costs (medicines, primary care, inpatient treatment, outpatient treatment) amount to approximately 78% of all respiratory diseases costs. 1,2 Indirect costs (disability, work absence, productivity losses, early retirement, premature mortality, family carers costs) are as high as the direct costs. 1 Ensuring an optimal asthma and COPD treatment strategy is in place is crucial for reducing the cost of disease management. This treatment strategy requires patients and prescribers to select both the appropriate medicine and the appropriate method of delivery. 3 5 The choice of correct inhaler is recognised by authorities as a critical component for successful management of patients with asthma and COPD. 3 5 Misuse of inhalers has a significant negative impact on disease control. 6 It is difficult to train patients on how to use their inhalers correctly and for them to do so consistently; therefore, an unmet need exists for innovative inhalers that address the limitations of currently available devices. 7,8 1. European Respiratory Society. European Lung white book Available from Accessed 9 May Bahadori K, Doyle-Waters M, Marra C, et al. Economic burden of asthma: a systematic review. BMC Pulm Med 2009;9(1): Global Initiative for Chronic Obstructive Lung Disease (GOLD) update. Available at Accessed 9 May National Heart Lung and Blood Institute (NHLBI). Expert panel report 3: guidelines for the diagnosis and management of asthma. Full report Available at Accessed 9 May Global Initiative for Asthma (GINA) update. Available at Accessed 14 July Giraud V, Roche N. Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability. Eur Respir J 2002;19: Patient preference study. Data on file. Teva Pharmaceuticals, Inc Papi A, Haughney J, Virchow JC, et al. Inhaler devices for asthma: a call for action in a neglected field. Eur Respir J 2011;37:

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