KAUNAS UNIVERSITY OF MEDICINE FACULTY OF PHARMACY

DEPARTMENT OF BASIC AND CLINICAL PHARMACOLOGY

UTILIZATION AND COSTS OF DRUGS FOR AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE TREATMENT IN LITHUANIA ON 2006-2009 YEAR

MASTER WORK

Supervised by: Edmundas Kaduševi čius, MD., PharmD., PhD., Assoc. professor of clinical pharmacology Performed by: Asta Petraityt ÷, Faculty of Pharmacy, 5/3 gr

Kaunas, 2010 TABLE OF CONTENTS

ABBREVIATIONS...... 3 1. INTRODUCTION...... 4 2. ASTHMA: BASIC FACTS AND PHARMACOLOGICAL MANAGEMENT ...... 7 2.1. Epidemiology ...... 7 2.2. Burden of asthma...... 9 2.3. Classification of asthma...... 10 2.4. Aetiology, pathogenesis and pathophysiology of asthma ...... 11 2.5. Pharmacological management of asthma ...... 14 2.5.1. Reliever ...... 15 2.5.2. Long-term asthma management ...... 17 2.5.3. Treatment steps...... 24 2.5.4. Inappropriate use of inhaled short acting β2-agonists and its association with patient health status ...... 27 3. COPD: BASIC FACTS AND PHARMACOLOGICAL MANAGEMENT ...... 29 3.1. Epidemiology ...... 29 3.2. Burden of COPD ...... 30 3.3. Classification of COPD ...... 32 3.4. Aetiology, pathogenesis and pathophysiology of COPD...... 33 3.5. Pharmacological management of COPD...... 35 4. OBJECTIVE AND AIMS ...... 37 5. MATERIAL AND METHODS...... 38 5.1. The ATC/DDD system...... 38 5.1.1. Anatomical Therapeutic Chemical (ATC) classification system ...... 38 5.1.2. The concept of the defined daily dose (DDD)...... 39 5.1.3. Drug utilization...... 40 5.2. Pharmacoeconomical analysis...... 41 5.2.1. Cost-minimisation analysis ...... 41 5.2.2. Reference price...... 42 5.3. Data sources………………………………………………………………………………….42 6. RESULTS...... 43 6.1. Consumption of drugs of the ATC Code R03...... 43 6.2. Pharmacoeconomical analysis of drugs for obstructive airway diseases ...... 52 6.2.1. Reference price for long-acting β2-agonists ...... 52 6.2.2. Reference price for inhaled corticosteroids...... 54 6.2.3. Reference price for inhaled corticosteroid/long-acting β2-agonist combinations ...... 57 7. DISCUSSION...... 60 8. CONCLUSIONS ...... 66 9. SUMMARY ...... 67 10. SANTRAUKA ...... 68 REFERENCES ...... 69 ANNEXES ...... 77

2 ABBREVIATIONS

AA Arachidonic Acid ATC Anatomical Therapeutic Chemical Classification ATS American Thoracic Society BMD Bone Mineral Density CEA Cost-Effectiveness Analysis CHIF Compulsory Health Insurance Fund COPD Chronic Obstructive Pulmonary Disease CRP C- reactive protein CysLT Cysteinyl DALY Disability-Adjusted Life Year DDD Defined Daily Dose DPI Dry Powder Inhaler ERS European Respiratory Society

FEV 1 Forced Expiratory Volume in one second FVC Forced Vital Capacity GINA Global Initiative for Asthma GOLD Global Initiative for HPA Hypothalamic–Pituitary–Adrenal ICER Incremental Cost-Effectiveness Ratio ICS Inhaled Corticosteroid IgE Immunoglobulin E

LABA Long-Acting β2-Agonist 5-LO 5-Lipoxygenase LTD4 Leukotriene D4 (and similar) LTRA Leukotriene Receptor Antagonist MDI Metered-Dose Inhaler NICE National Institute for Health and Clinical Excellence NO Nitric oxide PEF Peak Expiratory Flow

SABA Short-Acting β2-Agonist SR Slow-release WHO World Health Organization

3 1. INTRODUCTION

Chronic diseases, such as heart disease, stroke, cancer, chronic respiratory diseases and diabetes, are by far the leading cause of mortality in the world, representing 60% of all deaths. This invisible epidemic is an under-appreciated cause of poverty and hinders the economic development of many countries [1]. Respiratory conditions impose an enormous burden on society . Hundreds of millions of people suffer every day from chronic respiratory diseases. According to the latest World Health Organization (WHO) estimates (2007), currently 300 million people have asthma, 210 million people have chronic obstructive pulmonary disease (COPD) while millions have allergic rhinitis and other often under-diagnosed chronic respiratory diseases. Furthermore, asthma is considered to be the most common chronic disease among children [2]. Chronic respiratory diseases are a group of chronic diseases affecting the airways and the other structures of the lungs. Common chronic respiratory diseases include asthma, bronchiectasis, COPD, chronic rhinosinusitis, lung cancer and neoplasms of respiratory and intrathoracic organs, lung fibrosis, chronic pleural diseases, pneumoconiosis, rhinitis and series of other chronic respiratory diseases. Concerning wide amount of the information on chronic respiratory conditions, this study focuses on the following chronic obstructive airway diseases: asthma and COPD. Asthma is an inflammatory disorder of the lungs that affects people of all ages and is a significant source of morbidity and mortality [3, 4]. Asthma is one of the most common chronic diseases in the world. Asthma prevalence increases globally by 50% every decade. If the current trends continue, it is estimated that the number of people with asthma could grow to as many as 400-450 million people worldwide by 2025 – there may be an additional 100 million more asthmatics [5]. COPD is also an increasing public health problem. In 1990 it was ranked as the twelfth leading cause of disability-adjusted life-years (DALYs) lost and, according to projections, it will become the fifth such cause in 2020 [6]. In 2002 COPD was the fifth leading cause of death, 3 million people died of COPD in 2005, which corresponds to 5% of all deaths globally. WHO predicts that it will become the third leading cause of death worldwide by 2030 [7]. The referred statements establish obstructive airway diseases as a serious health problem that affects people in all countries across the globe. With a high global prevalence, asthma and COPD place a considerable burden on patients, society and healthcare systems alike [8].

4 COPD and asthma are costly diseases, generating considerable health-care costs as well as indirect costs. In the European Union, the total direct costs of respiratory diseases are estimated to be about 6% of the total health care budget, with COPD accounting for 56% (€38.6 billion) of this cost of respiratory disease [9]. Asthma is also costly disease – the economic costs associated with asthma are estimated to rank as one of the highest among chronic diseases due to the significant healthcare utilization associated with this condition [10]. Globally, the economic costs associated with asthma exceed those of tuberculosis and HIV/AIDS combined [11]. Developed economies can expect to spend 1 to 2% of their health-care budget on asthma [5]. In Europe, the total cost of asthma currently hovers at approximately €17.7 billion per year. Outpatient costs account for the highest proportion at approximately €3.8 billion, followed by expenses for anti-asthma drugs (€3.6 billion). Inpatient care accounts for a relatively minor cost of just €0.5 billion [12]. In the study of COPD-related illness costs, Sullivan and colleagues had indicated that the largest proportion of total expenditures was for inpatient hospitalization and emergency department care (72.8%). Outpatient clinic and office visits accounted for 15.0% of expenditures, and prescription drug costs were responsible for 12.2% [13]. The overall costs of asthma, including individual direct costs (Annex 1), indirect costs, and intangible quality of life costs, are all related to asthma severity [14]. Patients with severe asthma are responsible for approximately 50% of all direct and indirect costs, even though this patient population represents just 10 to 20% of all asthma sufferers. By contrast, the 70% of asthma patients with mild disease account for only 20 % of total asthma costs [15, 16]. Not surprisingly, there is a striking direct relationship between the severity of COPD and the cost of care and the distribution of costs changes as the disease progresses as well [9]. In Lithuania asthma and COPD are the ones of the diseases, the most part of the compulsory health insurance fund (CHIF) budget is assigned for compensation for medicines. 61.4 million Litas in 2009 was spent for compensation of medicines for the treatment of obstructive airway diseases. Despite the CHIF budget is increasing and the costs for medicines too, the prevalence of the diseases is increasing faster and optimal control of the diseases is not achieved [17, 18].

5 Relevance and novelty of this work

Asthma and COPD are the diseases of considerable importance due to its high consumption of health care resources they generate. According to the statistical statements, prevalence of both asthma and COPD is increasing. Considering to limited government budgets, rising prices and an aging population, it is necessary to dispose the healthcare resources rationally. According to the available literature, studies describing trends in the consumption of drugs for the treatment of obstructive airway diseases in Lithuania or studies on pharmacoeconomics of obstructive airway diseases have not been published yet. Drug consumption studies would let us evaluate the control of the diseases and compare it to other countries. The pharmacoeconomical analysis is important due to its opportunity to make the treatment of obstructive airway diseases more rational and use the limited resources effectively.

6 2. ASTHMA: BASIC FACTS AND PHARMACOLOGICAL MANAGEMENT

Correctly defining asthma is necessary for proper diagnosis and management of the condition. Asthma is defined as a chronic inflammatory disease characterized by airway inflammation, airflow obstruction or bronchoconstriction and bronchial hyper-reactivity [19]. Clinically, asthma is characterised by episodic exacerbations of symptoms such as coughing, wheezing, chest tightness and breathing difficulties in response to various triggers such as tobacco smoke, dust, pollens and exercise. These episodes are typically associated with extensive but variable airflow obstruction that may be reversible either spontaneously or with treatment [20, 21].

2.1. Epidemiology

Global Initiative for Asthma (GINA) defines asthma as one of the most common chronic diseases in the world. It is estimated that around 300 million people in the world currently have asthma. Asthma has become more common in both children and adults around the world in recent decades. Estimates suggest that asthma prevalence increases globally by 50% every decade. The rate of asthma increases as communities adopt western lifestyles and become urbanized. With the projected increase in the proportion of the world's population that is urban from 45 to 59% in 2025, there is likely to be a marked increase in the number of asthmatics worldwide over the next 15 years. It is estimated that there may be an additional 100 million persons with asthma by 2025. The global prevalence of asthma ranges from 1 to 18% of the population in different countries [22]. The highest asthma prevalence between developed countries are found in the United Kingdom (>15%), New Zealand (15.1%), Australia (14.7%), the Republic of Ireland (14.6%), Canada (14.1%) and the United States (10.9%). There have also been sharp increases in South Africa and the countries of the former Eastern Europe, including the Baltic States [11].

United States In the United States (US) asthma affects more than 22 million persons or 7.7% of the population. It is one of the most common chronic diseases of childhood, affecting more than 6 million children [23]. In 2004, asthma exacerbations resulted in 14.7 million outpatient visits, 1.8 million emergency room visits, 497000 hospitalizations and 4055 deaths in the US alone [24].

7 Australia In Australia over 2.2 million Australians have currently diagnosed asthma. The prevalence of asthma in Australia is relatively high, by international standards: 14-16% of children (one in six); 10-12% of adults (one in nine). In 2004, 311 people died from asthma – the latest figures [25]. Europe In Europe around 30 million people have asthma. The United Kingdom has amongst the highest prevalence of asthma in the world, with asthma occurring in 16% of the population. It is estimated that there are 5.2 million people with asthma in the UK [26]. In Scandinavia and Baltic States (Denmark, Estonia, Finland, Iceland, Latvia, Lithuania, Norway, Poland, Sweden) the mean prevalence of clinical asthma is 4.9% of the total population (70.2 million) [22]. According to the Lithuanian Health Information Centre statistics, the morbidity of asthma is increasing in Lithuania. Between 2001 and 2005 the prevalence of asthma has increased almost 50%: from 24209 till 35785. The prevalence rates of the disease were estimated per 1000 inhabitants for two groups – 0-17 years children and adults in 2004-2008. The morbidity of asthma is sharply upper in children (Figure 2) [27]. If the current trends continue, in the future there will be more asthmatics among adults, the costs of asthma will be increasing as well.

30 25,9 25 20,1 23,1 17,6 20

15 8,5 8,9 9,5 10 10

5

0

Prevalence rate per 1000 inhabitants per rate Prevalence 2005 2006 2007 2008

Children (0-17 years) Adults

Figure 2 Prevalence of asthma in Lithuania in 2004-2008

8 2.2. Burden of asthma

Asthma requires significant healthcare utilization. As already mentioned in the introduction, developed economies can expect to spend 1 to 2% of their health-care budget on asthma. In Europe, the total cost of asthma currently hovers at approximately €17.7 billion ($21.65 billion) per year [11] and in the US – $18 billion annually [28]. Despite the availability of effective preventive therapy, costs associated with asthma are increasing. Table 1 provides the costs of asthma in some countries. The studies describing the costs are difficult to compare because of differences in study designs, definitions of costs and different time periods [10].

Table 1 Direct and indirect costs for asthma treatment in different countries Country Total direct costs/person Total indirect costs Total cost (million of (million of dollars)* (million of dollars)* dollars)* United States [29] 7,301 955 8,256 Canada [30] 397 257 654 Switzerland [31] 860 553 1,413 Australia [32] 273 81 354 Denmark [33] 402,668 822,067 1,224 United Kingdom [34] Data not available Data not available 773 *All costs are converted and adjusted into 2008 US dollars. Studies’ duration – 1 year

The costs associated with asthma management can be classified as direct, indirect and intangible [35]. Direct costs include inpatient care, emergency visits, physician visits, nursing services, ambulance use, drugs and devices, blood and diagnostic tests, research, and education. Indirect costs or morbidity costs include school days lost, travelling, waiting time, and lost productivity for the caretaker of asthmatic children. Intangible costs of asthma include grief, fear, pain, unhappiness. These costs apply not only to the patient but also to his/her friends and family and are associated with the quality of life. Medications and hospitalization have been found to be the most important cost driver of direct costs, while work/school absenteeism accounted for the greatest percentage of indirect costs. Series of studies reported medications as forming the largest proportion of the direct costs related to asthma, accounting for 38-89% of the total cost [10]. As the drugs are found to be one of the main contributors to the cost of asthma and the fact that the costs of drugs are increasing worldwide there is a necessity to organize the treatment as more rational as it could be and should be and use the limited resources effectively. Pharmacoeconomical analyses help us to decide on the most cost-effective treatment [28]. Economic analyses have become increasingly important in healthcare in general and with respect to pharmaceuticals in particular. Pharmacoeconomical analyses can take many forms, but generally

9 consider three main characteristics. First of them is the cost-minimization analysis, which is appropriate when alternative therapies have identical outcomes, but differ in costs [36]. The second, a cost-effectiveness analysis (CEA) is a formal method for comparing the benefits and costs of a medical intervention to its next best alternative in order to determine whether it is of sufficient value to adopt or reimburse [37]. The main output from a cost-effectiveness study is the incremental cost- effectiveness ratio (ICER) which compares two alternative interventions’ average costs (C 1 and C 2) and effects (E 1 and E 2) in the form of the following ratio:

The third, cost-consequence analysis is an alternative to cost-effectiveness whereby the analyst presents the disaggregated resource uses, unit costs, and consequences for all of the alternatives. Cost-consequence analysis leaves the weighting of the costs and consequences up to the given decision-maker. Armed with the results of an incremental economic analysis such as a CEA or a cost-consequence analysis, decision makers are better equipped to address an intervention’s value [38]. Examining the cost-effectiveness of different treatments, in addition to their clinical efficacy, allows us to choose the optimal strategy in managing patients (Annex 2). Pharmacoeconomic cost-effectiveness analyses have shown that / is a cost-effective treatment option for moderate persistent asthma management, when compared with fluticasone with or without the addition of leukotriene modifiers. Leukotriene modifiers are less- cost-effective than inhaled corticosteroids or combined inhaled corticosteroids and long-acting β2- agonists for mild or moderate persistent asthma. Anti-IgE antibody has been shown inconsistently, to be cost-effective in patients with moderate to severe allergic asthma. Although the acquisition cost of levalbuterol is higher, one study showed that it may be more cost-effective than albuterol after taking into account reduction in hospitalizations. Cost-effectiveness analyses and clinical efficacy of medications, together with other patient-specific factors, are important information to be considered when selecting treatment regimens for asthma [28].

2.3. Classification of asthma

Previous GINA documents subdivided asthma by severity based on the level of symptoms, airflow limitation and lung function variability into four categories: intermittent, mild persistent, moderate persistent and severe persistent [50]. Its main limitation is its poor value in predicting what treatment will be required and what patients’ response to that treatment might be. For this purpose, a periodic assessment of asthma control is more relevant and useful [51].

10 Asthma control may be defined in a variety of ways. In general, the term control may indicate disease prevention, or even cure. However, in asthma, where neither of these are realistic options at present, it refers to control of the manifestations of disease. Ideally this should apply not only to clinical manifestations, but to laboratory markers of inflammation and pathophysiological features of the disease as well. There is evidence that reducing inflammation with controller therapy achieves clinical control, but because of the cost and/or general unavailability of tests such as endobronchial biopsy and measurement of sputum eosinophils and exhaled nitric oxide, it is recommended that treatment be aimed at controlling the clinical features of disease, including lung function abnormalities [52-56]. Table 3 provides the characteristics of controlled, partly controlled and uncontrolled asthma [50].

Table 3 Levels of asthma control Characteristic Controlled Partly Controlled (Any Uncontrolled (All of the following) measure present in any week) Daytime symptoms None (twice or More than twice/week Three or more features less/week) of partly controlled Limitations of activities None Any asthma present in any Nocturnal None Any week symptoms/awakening Need for reliever/rescue None (twice or More than twice/week treatment less/week) Lung function (PEF or Normal <80% predicted or FEV1)* personal best (if known) Exacerbations None One or more/year§ One in any week† * Lung function is not a reliable test for children 5 years and younger § Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate † By definition, an exacerbation in any week makes that an uncontrolled asthma week

Complete control of asthma is commonly achieved with treatment, the aim of which should be to achieve and maintain control for prolonged periods with due regard to the safety of treatment, potential for adverse effects and the cost of treatment required to achieve this goal [57].

2.4. Aetiology, pathogenesis and pathophysiology of asthma

Factors that influence the risk of asthma can be divided into those that cause the development of asthma and those that trigger asthma symptoms; some do both. The former include host factors (which are primarily genetic) and latter are usually environmental factors [58].

11 Host factors Genetic. Asthma has a heritable component. Multiple genes may be involved in the pathogenesis of asthma. Family studies and case-control association analyses have identified a number of chromosomal regions associated with asthma susceptibility. Obesity. Obesity has also been shown to be a risk factor for asthma. Certain mediators such as leptins may affect airway function and increase the likelihood of asthma development. Sex. Male sex is a risk factor for asthma in children. Prior to the age of 14, the prevalence of asthma is nearly twice as great in boys as in girls. As children get older the difference between the sex’s narrows, and by adulthood the prevalence of asthma is greater in women than in men. The reasons for this difference are not clear. However, lung size is smaller in males than in females at birth, but larger in adulthood [50]. Environmental factors Allergens. Although much childhood and adult asthma is associated with atopy, the classic notion that the majority of exacerbations in atopic patients with asthma are related to allergen exposure with resultant inflammation [59]. Infections. Approximately 80% of exacerbations are associated with respiratory tract viral infections, with rhinoviral infection responsible for about two thirds of cases [60]. Occupational sensitizers. Over 300 substances have been associated with occupational asthma, which is defined as asthma caused by exposure to an agent encountered in the work environment. These substances include highly reactive small molecules such as isocyanates, irritants that may cause an alteration in airway responsiveness, known immunogens such as platinum salts, and complex plant and animal biological products that stimulate the production of IgE. Tobacco smoke, air pollution and diet have also been associated with an increased risk for the onset of asthma, although the association has not been as clearly established as with allergens and respiratory infections [50].

Asthma is a complex disease defined by reversible airway narrowing, involving acute and chronic airway inflammation, airway hyper responsiveness and airway tissue remodelling [61]. This definition is based on the pathogenesis and pathophysiology of the condition. It is important to understand the mechanisms of asthma due to improved management of it. Unfortunately, unlike that of many diseases, the pathology of asthma remains not clearly understood [62].

12 Airway inflammation Airway inflammation is a major factor in the pathogenesis and pathophysiology of asthma. Understanding the complex mechanisms of asthma’s inflammatory processes can help to delineate therapeutic implications [63]. As noted in the definition of asthma, airway inflammation involves an interaction of many cell types and multiple mediators with the airways that eventually results in the characteristic pathophysiological features of the disease: bronchial inflammation and airflow limitation that result in recurrent episodes of cough, wheeze, and shortness of breath. The processes by which these interactive events occur and lead to clinical asthma are still under investigation. The phases of asthma Asthma occurs in phases because the inflammatory response is composed of a multitude of mediated interactions, each with its own time frame. The corresponding response in terms of inflammation consists of interactions between an allergen and a mast-cell-bound IgE molecule. This activates the mast cell, which then releases histamine and other mediators of inflammation resulting in smooth muscle contraction, increased vascular permeability, and vasodilation. This early response is rapid, occurring within minutes, and attracts other inflammatory cells that join in the response. Glandular activity is also stimulated by this inflammatory cascade, resulting in the secretion of mucus into the airways. The mucus causes coughing and may result in dyspnea if the obstruction is significant. Wheezing results from the contraction of airway smooth muscle in bronchospasm. The longer-term result of this inflammation is a cellular infiltrate consisting of eosinophils, neutrophils, and basophils, all of which release additional mediators of inflammation. The number of lymphocytes and monocytes within the lung increase within 12 hours. These cells may be particularly important in bringing about the chronic form of inflammatory response in asthma through the release of cytokines and arachidonic acid-derived mediators. This activity takes place in a time frame of from 2 hours to several days and longer following activation of the mast cells by antigen. This is called the late-phase response. Long-term inflammation is also associated with another detrimental response – that of fiber deposition. Fibrosis, together with smooth muscle hypertrophy, thickens the airway walls and causes further obstruction [64]. To sum up, the inflammatory process of asthma involves recruitment and activation of eosinophils and release of cytokines, resulting in changes in airway morphology such as increased smooth muscle mass, subepithelial fibrosis and epithelial cell damage. These pathologic changes, which ultimately are manifested as bronchoconstriction and bronchial hyper responsiveness, must be addressed to manage the disease effectively [65].

13 Bronchoconstriction In asthma, the dominant physiological event leading to clinical symptoms is airway narrowing and a subsequent interference with airflow. In acute exacerbations of asthma, bronchial smooth muscle contraction occurs quickly to narrow the airways in response to exposure to a variety of stimuli including allergens or irritants. The development of airway narrowing is also associated with airway oedema due to increased microvascular leakage in response to inflammatory mediators, and mucus hypersecretion [66]. Airway hyper responsiveness Airway hyper responsiveness – an exaggerated bronchoconstrictor response to a wide variety of stimuli – is a major, but not necessarily unique, feature of asthma. The mechanisms influencing airway hyper responsiveness are multiple and include inflammation, dysfunctional neuroregulation, and structural changes; inflammation appears to be a major factor in determining the degree of airway hyper responsiveness. Treatment directed toward reducing inflammation can reduce airway hyper responsiveness and improve asthma control [19]. Airway remodelling In some persons who have asthma, airflow limitation may be only partially reversible. Permanent structural changes can occur in the airway; these are associated with a progressive loss of lung function that is not prevented by or fully reversible by current therapy. Airway remodelling involves an activation of many of the structural cells, with consequent permanent changes in the airway that increase airflow obstruction and airway responsiveness and render the patient less responsive to therapy [67]. These structural changes can include thickening of the sub-basement membrane, subepithelial fibrosis, airway smooth muscle hypertrophy and hyperplasia, blood vessel proliferation and dilation, and mucous gland hyperplasia and hypersecretion [19].

2.5. Pharmacological management of asthma

According to the GINA, the goals for successful management of asthma are to: • Achieve and maintain control of symptoms; • Maintain normal activity levels, including exercise; • Maintain pulmonary function as close to normal as possible; • Prevent asthma exacerbations; • Avoid adverse effects from asthma medications; • Prevent asthma mortality.

14 International GINA guidelines assign the highest level of evidence to randomized controlled trials. Advances in science have led to an increased understanding of asthma and its mechanisms as well as improved treatment approaches [68]. Both national and international asthma guidelines are now used in virtually every country and have had important benefits in improving the management of asthma. The principles of modern asthma therapy and overall goal of every asthma management programme is to achieve control of the disease [69]. This paper reviews and compares both international GINA and national (British, American and Australian) guidelines and its recommendations to pharmacological treatment of asthma. Lithuanian guidelines of asthma are based on the international GINA recommendations.

2.5.1. Reliever medications

Medications to treat asthma can be classified as relievers and controllers. Relievers are medications used on an as-needed basis that acts quickly to reverse bronchoconstriction and relieve its symptoms such as cough, chest tightness and wheezing. These medications include inhaled short-acting β2-agonists (SABAs), inhaled , short-acting and oral short- acting β2-agonists.

Short-acting β2-agonists All reviewed guidelines recommend that inhaled SABAs are the medications of choice for relief of bronchospasm during acute exacerbations of asthma and for the pre-treatment of exercise- induced bronchoconstriction. Inhaled SABAs work more quickly and/or with fewer side effects than the alternatives. SABAs include (albuterol), , , levalbuterol HFA

(hydrofluoralkane), and . , a long-acting β2-agonist, is approved for symptom relief because of its rapid onset of action, but it should only be used for this purpose on regular controller therapy with inhaled glucocorticosteroids.

β2-agonists achieve their effects by binding to β2-receptors. These receptors belong to a large group of receptors whose effects are brought about by a cascade of events that include activation of a G-protein which, in turn, activates adenylate cyclase to convert adenosine triphosphate to cyclic adenosine monophosphate. In the smooth muscles of the airways, cyclic adenosine monophosphate has the effect of relaxation, thus increasing the diameter of the airway [64].

15 The adverse effects of SABAs include tachycardia, skeletal muscle tremor, hypokalemia, increased lactic acid, headache, hyperglycemia. Inhaled route, in general, causes few systemic adverse effects. Patients with pre-existing cardiovascular disease, especially the elderly, may have adverse cardiovascular reactions with inhaled therapy. Systemic administration as tablets or syrup increases the risk of the side effects [19]. GINA recommends that inhaled SABAs should be used only on an as-needed basis at the lowest dose and frequency required. Good asthma control is associated with little or no need for short-acting β2-agonist. The frequency of SABA use can be clinically useful as a barometer of disease activity, because increasing use of SABA has been associated with increased risk for death or near death in patients who have asthma [19]. Inhaled SABAs, when used regularly, cause subtle but significant worsening of asthma control. Overuse of inhaled β2-agonists is associated with increased risk of death from asthma in a dose–response fashion. β2-agonists enhance airway responses to allergens, including induced airway hyper responsiveness and induced airway inflammation.

Inhaled β2-agonists are effective relievers and preventers of bronchoconstriction and asthma symptoms. SABAs should be used exclusively as needed for relief of symptoms and their requirement should be infrequent: the need for excessive doses of β2-agonists provides a useful marker of asthma (lack of) control [70].

Anticholinergics used in asthma include and . Inhaled ipratropium bromide is a less effective reliever in asthma than SABAs. It has a slower onset of action (30–60 minutes) than other relievers. The bronchodilation is achieved by competitive inhibition of muscarinic cholinergic receptors. Because of the inhibition of these receptors, inhalation of ipratropium or oxitropium can cause a dryness of the mouth and a bitter taste, increased wheezing in some individuals, blurred vision if sprayed in eyes [50]. The clinical implication of anticholinergics in asthma therapy is that these agents may be alternative for patients who do not tolerate SABAs for relief of acute bronchospasm.

Theophylline Short-acting theophylline () may be considered for relief of asthma symptoms. Theophylline is thought to benefit asthma via bronchial smooth muscle relaxation, anti- inflammatory effects and increased diaphragm contractility [25]. Theophylline has the potential for significant adverse effects, although these can generally be avoided by appropriate dosing (7 mg/kg

16 loading dose over 20 min followed by 0.4 mg/kg/hr continuous infusion) and monitoring (serum levels should be maintained between 10-15 g/mL). The adverse effects include nausea, vomiting, headache. At higher serum concentrations: seizures, tachycardia and arrhythmias. Short-acting theophylline should not be administered to patients already on a long-term treatment with sustained-release theophylline unless the serum concentration of theophylline is known to be low and/or can be monitored [50].

Systemic glucocorticosteroids A typical short course of oral glucocorticosteroids for an exacerbation is 40-50 mg prednisolone given daily for 5 to 10 days depending on the severity of the exacerbation [50]. Adverse effects of short-term high-dose systemic therapy are uncommon but include reversible abnormalities in glucose metabolism, increased appetite, fluid retention, weight gain, rounding of the face, mood alteration, hypertension, peptic ulcer and aseptic necrosis of the femur. Consideration should be given to coexisting conditions that could be worsened by systemic corticosteroids, such as herpes virus infections, varicella, tuberculosis, hypertension, peptic ulcer, diabetes mellitus, osteoporosis and Strongyloides [19].

Magnesium sulphate The British guideline on the management of asthma recommends that there is some evidence that, in adults, magnesium sulphate has effects. Giving a single dose of intravenous magnesium sulphate could be considered for patients with: acute severe asthma who have not had a good initial response to inhaled bronchodilator therapy; life threatening or near fatal asthma. Intravenous magnesium sulphate (1.2-2 g intravenous infusion over 20 minutes) should only be used following consultation with senior medical staff. More studies are needed to determine the optimal route, frequency and dose of magnesium sulphate therapy [71].

2.5.2. Long-term asthma management

The medications used for long-term asthma therapy are known as controllers or long-term preventive medications. Controllers are medications taken daily on a long-term basis to keep asthma under clinical control chiefly through their anti-inflammatory effects. They include inhaled and systemic glucocorticosteroids, leukotriene modifiers, long-acting inhaled β2-agonists (LABAs) in combinations with inhaled glucocorticosteroids, sustained-release theophylline, cromones, anti-IgE

17 and other systemic steroid-sparing therapies. Inhaled glucocorticosteroids are the most effective controller medications currently available [50].

Glucocorticosteroids Today, in all national and international guidelines for asthma management, inhaled corticosteroids (ICSs) are the recommended first-line therapy for persistent asthma of all severities and patients of all ages and are the most effective asthma medications currently available [72]. National Institute for Health and Clinical Excellence (NICE) recommends that the introduction of regular preventer therapy with ICSs should be considered when a person has had exacerbations of asthma in the previous 2 years, is using inhaled SABAs three times a week or more, is symptomatic three times a week or more, or is waking at night once a week because of asthma [73]. The corticosteroids available for the treatment of asthma are: beclomethasone dipropionate, , , furoate, , and acetonide. ICSs differ in potency and bioavailability. Budesonide and beclomethasone dipropionate are considered equivalent on a microgram for microgram basis (1:1 dose ratio). Half the dose of fluticasone propionate, mometasone furoate or ciclesonide in micrograms is equivalent to a given dose of budesonide/beclomethasone dipropionate (2:1 dose ratio). Equivalent doses of ICSs are provided in Annex 3 [50, 73]. Mechanism of treatment The mechanism of action of corticosteroids in asthma has not been fully elucidated. However, corticosteroids are known to exert their effects by binding to a glucocorticosteroid receptor located in the cytoplasm of target cells [74]. Acting via the glucocorticosteroid receptor, ICS repress the expression of inflammatory cytokines, their receptors, adhesion molecules and other disease-inducing mediators. These effects of ICS and their ability to promote apoptosis of many cell types including the eosinophil act to reduce the attraction and activation of inflammatory cells in the lungs, thereby attenuating inflammation [ 75 ]. Furthermore, ICS suppress the pro-inflammatory activity of airway epithelial and smooth muscle cells, resident cells with an important pro-inflammatory capacity. Since these cells produce chemokines, cytokines and pro-fibrotic mediators, they are no longer innocent bystanders in the inflammatory process and have become important additional targets for the anti-inflammatory actions of ICS [ 76 ].

18 Starting dose of inhaled steroids The review guidelines recommend start patients at a dose of ICS appropriate to the severity of disease. In adults, a reasonable starting dose will usually be 400 g per day and in children 200 g per day. In children under five years, higher doses may be required if there are problems in obtaining consistent drug delivery. The dose of ICS must be titrate to the lowest dose at which effective control of asthma is maintained [71]. Pharmacokinetics and pharmacodynamics of ICSs Characteristics of ICS that can enhance anti-inflammatory effects include small particle size, prolonged pulmonary residence time, high glucocorticosteroid receptor binding affinity, lipophilicity and lipid conjugation. All of these properties must be balanced to maximize efficacy, safety and tolerability [77]. Clinical effectiveness All types of ICS monotherapy achieve successful control of persistent asthma in a significant proportion of patients [78 ]. According to the NICE, all the ICSs are associated with favourable changes from baseline to endpoint across efficacy outcomes. In pairwise comparisons, there are few statistically significant differences between the ICSs. However, it is concluded that it is reasonable to assume that there are no differences in clinical effectiveness between the different ICSs at both low and high doses [73]. Adverse effects Adverse events associated with ICS use can be categorized into local or systemic events (Table 5). Local adverse effects from ICSs include oropharyngeal candidiasis, dysphonia, occasionally coughing from upper airway irritation, bronchospasm and pharyngitis. For pressurized metered-dose inhalers the prevalence of these effects may be reduced by using certain spacer devices. Mouth washing after inhalation may reduce oral candidiasis. The use of prodrugs that are activated in the lungs but not in the pharynx (e.g., ciclesonide) and new formulations and devices that reduce oropharyngeal deposition may minimize such effects without the need for a spacer or mouth washing [50]. Although the prevalence of systemic side effects of ICS is lower in comparison with systemic corticosteroids, high-dose ICS use has the potential to cause systemic side effects [79]. The most commonly occurring systemic adverse events potentially associated with long-term ICS use are adrenal suppression, growth retardation in infants, children and adolescents, osteoporosis, skin thinning and easy bruising, cataract formation and glaucoma [74].

19 Table 5 Potential local and systemic side effects of inhaled corticosteroids. Local adverse effects Systemic adverse effects Oropharyngeal candidiasis Suppressed HPA-axis function Pharyngitis Adrenal crisis Dysphonia Suppressed growth velocity in children Reflex cough Decreased lower-leg length in children Bronchospasm Reduced bone mineral density Bone fractures Osteoporosis Skin thinning, skin bruising Cataracts Glaucoma

Oral systemic corticosteroids Long-term oral glucocorticosteroid therapy may be required for severely uncontrolled asthma, but its use is limited by the risk of significant adverse effects. Systemic glucocorticosteroids should be used at lowest effective dose. Patients with asthma who are on long-term systemic glucocorticosteroids should receive preventive treatment for osteoporosis. Caution and close medical supervision are recommended when considering the use of systemic glucocorticosteroids in patients with asthma who also have tuberculosis, parasitic infections, osteoporosis, glaucoma, diabetes, severe depression or peptic ulcers. Fatal herpes virus infections have been reported among patients who are exposed to these viruses while taking systemic glucocorticosteroids, even short bursts. Because of the side effects of prolonged use, oral glucocorticosteroids in children with asthma should be restricted to the treatment of acute severe exacerbations [50].

Long-acting β2-agonists ICS therapy is the first line of treatment for asthma of all severities. For patients whose asthma is not sufficiently controlled by a low dose of ICS, an alternative option to increasing the ICS dose is the add-on therapy. According to the reviewed guidelines, the first choice as add-on therapy to inhaled steroids in adults and children (5-12 years) is an inhaled long-acting β2-agonist (LABA), which improves lung function and symptoms and decreases exacerbations. LABA, including formoterol and salmeterol should not be used as monotherapy in asthma as these medications do not appear to influence the airway inflammation in asthma. They are the most effective when combined with ICS and this combination therapy is the preferred treatment when a low dose of inhaled glucocorticosteroids alone fails to achieve control to asthma. Addition of LABA to a daily regimen of ICS improves symptom scores, decreases nocturnal asthma, improves lung function, decreases the use of SABAs, reduces the number of exacerbations and achieves clinical control of asthma in more patients more rapidly and at lower dose of ICS than ICS

20 given alone. Daily use of LABA generally should not exceed 100 g salmeterol or 24 g formoterol.

The most important action of LABAs is stimulating the β2-adrenoreceptors located in airway smooth muscle resulting in smooth muscle relaxation [80].

The two currently available LABAs are highly selective β2-adrenoceptor agonists which produce a bronchodilator effect lasting for at least 12 hours after a single inhalation. Both agents are highly potent. Onset of bronchodilation with formoterol fumarate is within 2–3 minutes whereas the onset of bronchodilation with salmeterol takes approximately 10 minutes and the maximal effect may not be apparent for several hours. Formoterol fumarate is more lipophilic than salmeterol and has a much higher degree of intrinsic agonist activity. Both drugs are relatively well tolerated at recommended doses but their therapeutic window is fairly narrow [74]. Combination medications The greater efficacy of combination treatment has led to the development of fixed combination inhalers that deliver both ICS and LABA simultaneously (fluticasone propionate plus salmeterol, budesonide plus formoterol). Controlled studies have shown that delivering this therapy in a combination inhaler is as effective as giving each drug separately. Fixed combination inhalers are more convenient for patients, may increase compliance and ensure that LABA is always accompanied by a glucocorticosteroid. In addition, combinations inhalers containing formoterol and budesonide may be used for both rescue and maintenance. Both components of budesonide- formoterol given as needed contribute to enhanced protection from severe exacerbations in patients receiving combination therapy for maintenance and provide improvements in asthma control at relatively low doses of treatment [50]. The combination of LABA and ICS should be considered when: • Symptoms or sub-optimal lung function persist on ICS alone. • It is desirable to reduce the current dose of ICS while maintaining optimal asthma control. • Initiating asthma treatment in a patient with moderate to severe asthma in whom rapid symptom improvement is needed. Adverse effects Most adverse effects related to the use of LABAs are a result of systemic absorption (due to stimulation of β2-adrenoceptors in the heart, peripheral vasculature and skeletal muscle) and are dose-related. At standard doses, adverse effects such as tachycardia, increase in the QTc interval, hypokalaemia, hyperglycaemia and tremor are minimal in most individuals. At higher doses (which may be relevant during an acute asthma attack), both salmeterol and formoterol produce dose- related effects on heart rate, diastolic and systolic blood pressure, QTc interval and plasma potassium levels [74].

21 Leukotriene modifiers Currently available leukotriene modifiers include leukotriene receptor antagonists (LTRAs) (, and ) and a 5-lipoxygenase (5-LO) inhibitor , that blocks leukotriene synthesis [81]. Clinical studies have demonstrated that leukotriene modifiers have a small and variable bronchodilation effect, reduce symptoms including cough, improve lung function and reduce airway inflammation and asthma exacerbations. They may be used as an alternative, not preferred, treatment for adult patients with mild persistent asthma. Leukotriene modifiers used as add-on therapy may reduce the dose of ICSs required by patients with moderate to severe asthma and may improve asthma control in patients whose asthma is not controlled with low or high doses of ICS. Several studies have demonstrated that leukotriene modifiers are less effective than inhaled LABAs as add-on therapy [50]. Several types of observations support an important role for LTRAs in asthma control. The early-phase response (most likely caused by acute airway smooth muscle contraction) and the late- phase response (thought to involve oedema and inflammatory cell recruitment and activation) of asthma can be blocked by these agents [65]. Due to the limited efficacy data and the need for liver function monitoring, zileuton is a less desirable alternative than LTRAs, although provides similar efficacy to montelukast [19].

Sustained-release theophylline It is available in sustained-release formulations that are suitable for once or twice daily dosing. Data on the relative efficacy of theophylline as a long-term controller is lacking. However, available evidence suggests that sustained-release theophylline has little effect as a first-line controller. It may provide benefit as add-on therapy in patients who do not achieve control on ICSs alone. Additionally in such patients the withdrawal of sustained-release theophylline has been associated with deterioration of control. As add-on therapy, theophylline is less effective than inhaled LABAs. Side effects of theophylline particularly at higher doses (10 mg/kg body weight/day or more) are significant and reduce their usefulness. Side effects can be reduced by careful dose selection and monitoring, and generally decrease or disappear with continued use. Adverse effects include gastrointestinal symptoms, loose stools, cardiac arrhythmias, seizures and even death. Nausea and vomiting are the most common early events. Monitoring is advised when a high dose is started, if the patient develops an adverse effect on the usual dose, when expected therapeutic aims are not achieved, and when conditions known to alter theophylline metabolism exist [50].

22 Cromones Sodium cromoglycate and sodium are alternative, not preferred, medications for the treatment of mild persistent asthma. They can also be used as preventive treatment before exercise or unavoidable exposure to known allergens. The mechanism of cromones appears to involve the blockade of chloride channels and modulate mast cell mediator release and eosinophil recruitment. Adverse effects are infrequent and include headache, nausea, minor throat irritation and cough. Some patients may complain about the distinctive taste of nedocromil [25].

Anti-IgE Anti-IgE therapy () is recommended, within its licensed indication, as an option for the treatment of severe persistent allergic (IgE mediated) asthma as add-on therapy to optimised standard therapy, only in adults and adolescents (12 years and older) who have been identified as having severe unstable disease [82]. In the pathogenesis of allergic disease, IgE plays a central role [63]. IgE is the immunoglobulin that mediates the acute allergic response in mast cells and basophils through cross- linking of high-affinity IgE receptors, and may increase allergen uptake by dendritic cells [83]. Omalizumab, an IgE-specific humanized monoclonal antibody, binds to the IgE molecule, prevents IgE from interacting with high or low affinity IgE receptors and results in rapid decreasing levels of circulating free IgE [84]. The decreased binding of IgE on the surface of mast cells leads to a decrease in the release of mediators in response to allergen exposure [19]. According to the NICE, omalizumab add-on therapy should only be initiated if the patient fulfils the following criteria of severe unstable allergic asthma: • Confirmation of IgE mediated allergy to a perennial allergen by clinical history and allergy skin testing. • Either two or more severe exacerbations of asthma requiring hospital admission within the previous year, or three or more severe exacerbations of asthma within the previous year, at least one of which required admission to hospital, and a further two which required treatment or monitoring in excess of the patient’s usual regimen, in an accident and emergency unit. Omalizumab is administered subcutaneously every 2–4 weeks. The dosage is determined by baseline IgE before the start of treatment (measured in international units per millilitre, IU/ml) and body weight (in kg). Anti-IgE add-on therapy should be discontinued at 16 weeks in patients who have not shown an adequate response to therapy. The most common side effects of omalizumab treatment are bruising, erythema and pain at the site of injection. Rare side effects include increased risk of parasitic infections, anaphylaxis [82].

23 2.5.3. Treatment steps

All current asthma guidelines recommend a stepwise approach to therapy based on asthma control and severity. The GINA guidelines recommend a five-step therapeutic approach (Annex 4).

Intermittent asthma Step 1: As-needed reliever medication Step 1 treatment with an as-needed reliever medication is reserved for untreated patients with occasional daytime symptoms (cough, wheeze, dyspnea occurring twice or less per week, or less frequently if nocturnal) of short duration (lasting only a few hours) comparable with controlled asthma. Between episodes, the patient is asymptomatic with normal lung function and there is no nocturnal awakening. When symptoms are more frequent, and/or worsen periodically, patients require regular controller treatment (see Steps 2 or higher) in addition to as-needed reliever medication.

For the majority of patients of all ages in Step 1, a short-acting inhaled β2-agonist is the recommended reliever treatment. An inhaled anticholinergic, short-acting oral β2-agonist or short- acting theophylline may be considered as alternatives, although they have a slower onset of action and higher risk of side effects. Short course of oral systemic corticosteroids may be needed.

Persistent asthma Step 2: Reliever medication plus a single controller Treatment Steps 2 through 5, combine an as-needed reliever treatment with regular controller treatment. NICE recommends that the introduction of regular preventer therapy should be considered when a person has had exacerbations of asthma in the previous 2 years, is using inhaled SABAs three times a week or more, is symptomatic three times a week or more, or is waking at night once a week because of asthma. At Step 2, a low-dose inhaled glucocorticosteroid is recommended as the initial controller treatment for asthma patients of all ages. Equivalent doses of ICSs, some of which may be given as a single daily dose, are provided in Annex 3. Alternative controller medications include leukotriene modifiers, appropriate particularly for patients who are unable or unwilling to use ICSs or who experience intolerable side effects from ICS treatment and those with concomitant allergic rhinitis. Other options are available but not recommended for routine use as initial or first-line controllers in Step 2. Sustained–release theophylline has only weak anti-inflammatory and controller efficacy and is commonly associated with side effects that range from trivial to

24 intolerable. Cromones (nedocromil sodium and sodium cromoglycate) have comparatively low efficacy, though a favourable safety profile.

Step 3: Reliever medication plus one or two controllers A proportion of patients with asthma may not be adequately controlled at Step 2. At Step 3, the recommended option for adolescents and adults is to combine a low-dose of inhaled glucocorticosteroid with an inhaled long-acting β2-agonist, either in a combination inhaler device or as separate components. Because of the additive effect of this combination, the low-dose of glucocorticosteroid is usually sufficient and need only be increased if control is not achieved within

3 or 4 months with this regimen. The long-acting β2-agonist formoterol, which has a rapid onset of action whether given alone or in combination inhaler with budesonide, has been shown to be as effective as short-acting β2-agonist in acute asthma exacerbation. If a combination inhaler containing formoterol and budesonide is selected, it may be used for both rescue and maintenance. Another option for both adults and children, but the one recommended for children, is to increase to a medium-dose of ICSs. For all patients of all ages on medium or high dose of ICS delivered by a pressurized MDI, use of a spacer device is recommended to improve delivery to the airways, reduce oropharyngeal side effects and reduce systemic absorption. Another option at Step 3 is to combine a low-dose ICS with leukotriene modifiers. Alternatively, the use of sustained-release theophylline given at low-dose may be considered. These options have not been fully studied in children 5 years and younger. In addition, the NICE and the

British guidelines recommend that slow-release β2-agonist tablets may also improve lung function and symptoms, but side effects occur more commonly.

Step 4: Reliever medication plus two or more controllers The selection of treatment at Step 4 depends on prior selections at Steps 2 and 3. However, the order in which additional medications should be added is based, as far as possible, upon evidence of their relative efficacy in clinical trials. Where possible, patients who are not controlled on Step 3 treatments should be referred to a health professional with experience in the management of asthma for investigation of alternative diagnoses and/or causes of difficult-to-treat asthma. The preferred treatment at Step 4 is to combine a medium- or high-dose of ICS with a inhaled LABA. However, in most patients, the increase from a medium- to a high-dose of ICS provides relatively little additional benefit and the high-dose is recommended only on a trial basis for 3 to 6 months when control cannot be achieved with medium-dose ICS combined with LABA and/or third controller (leukotriene modifiers or sustained release theophylline). Prolonged use of

25 high-dose inhaled glucocorticosteroid is also associated with increased potential for adverse effects. At medium- and high-doses, twice-daily dosing is necessary for most but not all inhaled glucocorticosteroids. With budesonide, efficacy may be improved with more frequent dosing (four times daily). Leukotriene modifiers as add-on treatment to medium- to high-dose ICSs have been shown to provide benefit, but usually less than that achieved with the addition of a LABA. The addition of a low-dose sustained-release theophylline to medium- or high-dose ICS and LABA may also provide benefit. In addition, the British guidelines also recommend slow release β2-agonist tablets as the alternative option, though caution needs to be used in patients already on long-acting β2- agonist agonists.

Step 5: Reliever medication plus additional controller options Addition of oral glucocorticosteroids to other controller medications may be effective, but is associated with severe side effects and should only be considered if the patient’s asthma remains severely uncontrolled on Step 4 medications with daily limitation activities and frequent exacerbations. Patients should be counselled about potential side effects and all other alternative treatments must be considered. Addition of anti-IgE treatment to other controller medications has been shown to improve control of allergic asthma when control has not been achieved on combinations of other controllers including high-doses of inhaled or oral glucocorticosteroids.

When asthma control has been achieved, ongoing monitoring is essential to maintain control and to establish the lowest step and dose of treatment necessary, which minimizes the cost and maximizes the safety of treatment.

Asthma management in children 5 years and younger According to the GINA guidelines, all young children with asthma should be prescribed a reliever medication to use as needed for quick relief of symptoms. Parents and caregivers should be aware of how much reliever medication the child is using-regular or increased use indicates that asthma is not well controlled. A short-acting inhaled β2-agonist is the recommended choice of reliever medication for most patients in this age group. If the child’s asthma is not controlled with as-needed use of reliever medication, a low- dose inhaled glucocorticosteroid is the recommended initial controller treatment (Annex 5). If asthma is not controlled within one to three months by doubling the initial dose of inhaled glucocorticosteroids, assess and monitor the child’s inhalation technique, compliance with

26 medication regimen and avoidance of risk factors. If control is maintained for at least 3 months, decrease treatment to the least medication necessary to maintain control. Monitoring is still necessary even after control is achieved, as asthma is a variable disease [85].

2.5.4. Inappropriate use of inhaled short acting β2-agonists and its association with patient health status

There is considerable controversy about the regular use of short-acting β2-agonists for the treatment of asthma. Patients who are on inhaled short-acting bronchodilators are one of the most vulnerable populations. Although case–control studies have suggested that excessive use of these drugs may worsen asthma control and increase the risk of fatal or near-fatal asthma, the controversy remains unresolved because of the confounding that exists among disease control, disease severity and the use of short-acting β2-agonists. Whatever the cause-and-effect relation between the use of short-acting β2-agonists and disease severity, their excessive use, in conjunction with under use of inhaled corticosteroids, may be a marker for poorly controlled asthma and excessive use of health care resources [86].

Use of short-acting β2-agonists is considered as one of the four dimensions of asthma control [87]. Observable indicators of asthma control include the frequency and severity of day-time and night-time symptoms, the extent of activity limitation due to asthma, the level of lung function and the frequency with which short-acting bronchodilator medication is required [88].

Use of short-acting β2-agonists was defined as inappropriate when high doses of short- acting β2-agonists were taken in conjunction with low doses of inhaled corticosteroids. High doses of SABAs were defined as nine or more canisters per year, with each canister giving 200 inhalations of albuterol 100 g or equivalent. Low doses of inhaled corticosteroids were defined as less than beclomethasone 100 g or equivalent per day. In terms of numbers DDD, a high dose of short-acting β2-agonists was defined as equal or more than 225 DDDs per year and a low dose of corticosteroids as less than 45.625 DDDs per year [87]. Appropriate medication use was defined as 4 or fewer canisters of albuterol and at least 400 g/day of beclomethasone [86]. In a cross-sectional study a total of 23 986 patients were identified as having filled a prescription for a short-acting β2-agonists (for inhalation) in 1995. Of these, 3069 (12.8%) filled prescriptions for 9 or more canisters of β2-agonists, and of this group of high-dose β2-agonists users, 763 (24.9%) used no more than 100 g/day of inhaled beclomethasone. Patients with inappropriate use were more likely to be admitted to hospital (adjusted relative risk (RR) 1.68, 95% confidence interval (CI) 1.25–2.26), were admitted to hospital more frequently (adjusted RR 1.81, 95% CI 1.41–2.32) and were more likely to require emergency

27 admission (adjusted RR 1.93, 95% CI 1.35–2.77). It is also found that inappropriately treated asthmatic patients were more likely than appropriately treated patients to receive more prescriptions, more likely to visit more prescribing physicians. Thus, inappropriately treated patients appear to have poorer outcomes, independent of disease severity or control. It is impossible to determine from this analysis whether the high use of health care resources by those with inappropriate use of asthma medication is related specifically to excessive

β2-agonists use. An alternative reason might be that excessive β2-agonists use is a marker of poor asthma management and that under use of inhaled corticosteroids is responsible for the poorer outcomes. It can be concluded, however, that these patients experienced greater asthma related morbidity and generated higher health care costs. Furthermore, because urgent admission is defined as “a need for immediate assessment due to life-threatening conditions”, mortality rate may also be higher in this group.

Despite the inability to say why some patients have high use of β2-agonists, the results do show that patients who receive excessive doses of short-acting β2-agonists with suboptimal doses of inhaled corticosteroid use more health care services. Although it is not surprising that patients with inappropriate use received more prescriptions per prescribing physician, the finding that they received prescriptions from a greater number of unique physicians was unexpected. This may indicate deliberate solicitation of prescriptions from multiple physicians, or it may reflect a lack of continuity of care, which may partially explain the poorer outcomes in this group. The implications of the drug use patterns exemplified by this study are significant. Despite increasing evidence of excessive use of short-acting β2-agonists as either a marker for or a cause of adverse outcomes, such excessive use remains prevalent. Inappropriately managed patients use more health care services, which suggests greater asthma-related morbidity and greater health care costs. It is proposed that the strategy employed in the study may be useful for identifying patients with excessive β2-agonists use who might benefit most from an asthma education program, with the ultimate goal of improving asthma management and reducing utilization of health care services

[86]. To sum up, excessive use of short-acting β2-agonists indicates poor asthma control.

28 3. COPD: BASIC FACTS AND PHARMACOLOGICAL MANAGEMENT

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) classifies COPD as „a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases” [89]. The chronic airflow limitation characteristic of COPD is caused by a mixture of small airway disease (obstructive bronchiolitis) and parenchymal destruction (emphysema), the relative contributors of which vary from person to person. The characteristic symptoms of COPD are chronic and progressive dyspnea, cough and sputum production. Chronic cough and sputum production may precede the development of airway limitation by many years [9].

3.1. Epidemiology

COPD is one of the leading causes of morbidity and mortality worldwide. According to the latest WHO estimates (2007), currently 210 million people have COPD and 3 million people died of COPD in 2005. The WHO estimates that COPD as a single cause of death shares 4th and 5th places with HIV/AIDS (after coronary heart disease, cerebrovascular disease and acute respiratory infection). WHO predicts that COPD will become the third leading cause of death worldwide by 2030 [7].

United States Despite advances in care, the COPD epidemic persists, causing more than 120,000 deaths per year in the United States alone. Population-based surveys show that as many as 24 million people in the United States have airflow limitation consistent with COPD [90]. Australia More than 600,000 Australians are estimated to have COPD and, as the population ages, the burden of COPD is likely to increase.. COPD ranks fourth among the common causes of death in Australian men and sixth in women [91]. Europe The frequency of clinically relevant COPD varies in European countries from 4–10% of the adult population. Approximately 200,000–300,000 people die each year in Europe because of COPD. Among respiratory diseases, COPD is the leading cause of lost work days. In the EU approximately 41,300 lost work days per 100,000 population are due to COPD every year [92].

29 COPD is the fifth leading cause of death in the United Kingdom after ischemic heart disease, stroke, lung cancer, and pneumonia. In England, in 2002/2003, COPD was recorded as the reason for hospital admission in 109,243 cases and accounted for 1,094,922 bed-days, with a median duration of stay of 6 days (2001/2002 data) [93]. According to the Lithuanian Health Information Centre, in Lithuania, the highest prevalence of COPD is between 55-64 years old men. 118640 Lithuanians had COPD in 2003. During 2007 asthma and COPD together were responsible for 2.3 % deaths [27]. COPD is expected to increase globally in the coming decades. The main reasons are the changing age distribution in all countries, with increased life expectancy and an ever-increasing proportion of the population living to > 60 years, and the increased uptake of smoking, especially in developing countries. In the western world, age-specific rates of mortality, as well as morbidity, have started to decrease for males and will presumably stabilise for females in the near future. The time trends in developing countries will depend on tobacco control and control of other particulate exposures [94].

3.2. Burden of COPD

COPD is a costly disease with both direct costs (value of health care resources devoted to diagnosis and medical management) and indirect costs (monetary consequences of disability, missed work, premature mortality, and caregiver or family costs resulting from the illness). In developed countries, exacerbations of COPD account for the greatest burden on the health care system. In the European Union, the total direct costs of respiratory disease are estimated to be about 6% of the total health care budget, with COPD accounting for 56% (€38.6 billion) of this cost of respiratory disease [9]. The major drivers of the direct cost of COPD are hospital care and medication. The cost of COPD management also varies according to the severity of disease and whether patients are managed in hospital or at home. In a study in Spain of 1,510 patients with COPD monitored over 1 year, the hospital costs represented 43% of the mean annual cost per patient, drugs – 40% [93]. Costs per patient vary across countries because these costs depend on how health care is provided and paid (Table 8). Not surprisingly, there is a striking direct relationship between the severity of COPD and the cost of care and the distribution of costs changes as the disease progresses. Data are, however, limited and available only for high income countries [ 95 ].

30 Table 8 Direct and indirect costs associated with COPD in different countries Country Costs Cost per patient per Global costs per year (Year of publication) year (in millions) Spain (1992) Direct and indirect € 959 Direct: € 319 Indirect € 451 USA (2000) Direct Stage I: $ 1681 Stage II: $ 5037 Stage III: $ 10 812 Sweden (2000) Direct and indirect Direct: € 109 Indirect € 541 Italy (2002) Direct Stage I: € 151 Stage II: € 3001 Stage III: € 3912 Spain (2003) Direct Stage I: € 1185 € 427 Stage II: € 1640 Stage III: € 2333 Spain (2004) Direct € 909 € 239 USA (2005) Direct and indirect $ 32 000

Cost-effectiveness of pharmacological treatments There is very little literature documenting the cost-effectiveness of most medical interventions for COPD. Rutten-van Molken and associates investigated the costs and effects of adding inhaled anti-inflammatory therapy to inhaled β2-agonist therapy by analyzing data from a randomized trial of 274 adult participants aged 18 to 60 years. Patients were selected for inclusion if they met the age criteria and had been diagnosed as having moderately severe obstructive airway disease, as defined by pulmonary function criteria. Patients were eligible if they had either asthma or COPD. Each patient was randomized to receive either fixed-dose inhaled terbutaline plus inhaled placebo, inhaled terbutaline plus 800 mg inhaled beclomethasone per day, or inhaled terbutaline plus inhaled ipratropium bromide, 160 mg/d. Patients were followed up for up to 2.5 years or until premature withdrawal. The objective of this study was to determine the relative cost per unit of benefit for the three therapeutic arms. The clinical results indicated that addition of the inhaled corticosteroid to fixed-dose terbutaline led to a significant improvement in pulmonary function (FEV 1 and the provocative dose of a substance causing 20% fall in FEV 1) and symptom-free days, whereas addition of the inhaled ipratropium bromide to fixed-dose terbutaline produced no significant clinical benefits over placebo. The average annual monetary savings associated with the use of inhaled corticosteroids were not offset by the increase in costs from the average annual price of the inhaled product. The incremental cost-effectiveness for inhaled corticosteroid was $201 per 10% improvement in FEV 1 and $5 per symptom-free day gained. The incremental cost-effectiveness of ipratropium bromide was not evaluated because of the lack of clinical benefit relative to placebo.

31 It was performed a retrospective, chart-based cost- minimization analysis of theophylline vs ipratropium bromide for patients with COPD. They found that patients treated with ipratropium had lower costs and a greater number of complication-free months compared with those taking theophylline. A post hoc pharmacoeconomic evaluation of two multicenter, randomized trials comparing salbutamol plus ipratropium with salbutamol alone and ipratropium alone in a total of 1,067 patients with COPD was conducted by Friedman et al. Data on outcomes and the total cost of treatment were compared. The authors concluded that the inclusion of ipratropium in a pharmacologic treatment regimen was associated with a lower rate of exacerbations, lower overall treatment costs, and improved cost-effectiveness. There were, however, no differences in total costs between the ipratropium-alone and salbutamol-plus-ipratropium treatment arms. Because COPD is highly prevalent and can be severely disabling, medical expenditures for treating COPD can represent a substantial economic burden for societies and for public and private health insurers worldwide [96]. Pharmacoeconomical analysis is needed for establishing the values of the treatments and allocating the scarce resources of health care system effectively.

3.3. Classification of COPD

Classification of COPD symptoms, severity, or stages is important as a basis for guidelines for treatment, prognostic indicators regarding various aspects of the disease including progression, exacerbation, hospitalization, and mortality [97]. Stages of COPD that were identified include:

Stage I : Mild COPD – Characterized by mild airflow limitation (FEV 1/FVC < 0.70; FEV 1 ≥ 80% predicted). Symptoms of chronic cough and sputum production may be presented, but not always. At this stage, the individual is usually unaware that his or her lung function is abnormal.

Stage II : Moderate COPD – Characterized by worsening airflow limitation (FEV 1/FVC < 0.70;

50% ≤ FEV 1 < 80% predicted), with shortness of breath typically developing on exertion and cough and sputum production sometimes also present. This is the stage at which patients typically seek medical attention because of chronic respiratory symptoms or an exacerbation of their disease.

Stage III : Severe COPD – Characterized by further worsening of airflow limitation (FEV 1/FVC <

0.70; 30% ≤ FEV 1 < 50% predicted), greater shortness of breath, reduced exercise capacity, fatigue and repeated exacerbations that almost always have an impact on patients’ quality of life.

Stage IV : Very Severe COPD – Characterized by severe airflow limitation (FEV 1/FVC < 0.70;

FEV 1 < 30% predicted or FEV 1 < 50% predicted plus the presence of chronic respiratory failure).

Respiratory failure is defined as an arterial partial pressure of O 2 (PaO 2) less than 60 mm Hg with or

32 without arterial partial pressure of CO 2 (PaCO 2) greater than 50 mm Hg while breathing air at sea level. At this stage, quality of life is very appreciably impaired and exacerbations may be life threatening [9].

3.4. Aetiology, pathogenesis and pathophysiology of COPD

The identification of risk factors is an important step toward developing strategies for prevention and treatment of any disease. The risk factors for COPD are separated into host factors and exposures. Host factors COPD is a polygenic disease and a classic example of gene-environmental interaction.

The genetic risk factor that is best documented is a severe hereditary deficiency of α1-antitrypsin, a major circulating inhibitor of serum proteases. Although α1-antitrypsin deficiency is relevant to only a small part of the world’s population, it illustrates the importance of gene-environment interactions in the pathogenesis of COPD. All patients with airflow limitation and family history of respiratory illnesses, and patients presenting with airflow limitation at relatively early age (4th or 5th decade) should be evaluated for α1-antitrypsin deficiency. Exploratory studies have revealed a number of candidate genes that influence a person’s risk of COPD. However, when several studies of a given trait are available, the results are often inconsistent. Several of these genes are thought to be involved in inflammation and, therefore, are related to potential pathogenic mechanisms of COPD [9, 94]. Airway hyperresponsiveness has also been demonstrated to be a risk factor for COPD. The mechanism for this, however, is not clear. Some asthma patients also develop fixed airflow limitation and thus fulfil the requirements for COPD diagnosis. Worldwide, COPD is more prevalent in males than in females. However, this is a consequence of the marked difference in smoking (and other) exposures between males and females. Recent data from several large studies suggest that females may in fact be more susceptible to the effects of tobacco than males [94]. Exposures Tobacco smoke is by far the most important risk factor for COPD worldwide. It is helpful, conceptually, to think of a person’s exposures in terms of the total burden of inhaled particles. Each type of particle, depending on its size and composition, may contribute a different weight to the risk and the total risk will depend on the integral of the inhaled exposures. For example, tobacco smoke (active and passive tobacco smoke), outdoor and indoor air pollution, and occupational exposures probably act additively to increase a person’s risk of developing COPD.

33 A subject’s socioeconomic background plays an important role that is not only the result of exposure to tobacco and occupational hazards. Whether the effect is due to impaired growth of lungs and airways or an increased rate of infection is not clear [94].

Pathological changes characteristic of COPD are found in the proximal airways, peripheral airways, lung parenchyma and pulmonary vasculature. The pathological changes include chronic inflammation with increased numbers of specific inflammatory cell types in different parts of the lung, and structural changes resulting from repeated injury and repair. In general, the inflammatory and structural changes in the airways increase with disease severity and persist on smoking cessation [9]. Inflammation The inflammation in the respiratory tract of COPD patients appears to be an amplification of the normal inflammatory response of the respiratory tract to chronic irritants such as cigarette smoke. The mechanisms for this amplification are not yet understood but may be genetically determined. Some patients develop COPD without smoking, but the nature of the inflammatory response in these patients is unknown [98]. Lung inflammation is further amplified by oxidative stress and an excess of proteinases in the lung. Together, these mechanisms lead to the characteristic pathological changes in COPD. Oxidative stress Oxidative stress may be an important amplifying mechanism in COPD. Biomakers of oxidative stress are increased in the exhaled breath condensate, sputum and systemic circulation of COPD patients. Oxidative stress is further increased in exacerbations. Oxidants are generated by cigarette smoke and other inhaled particulates and released from activated inflammatory cells such as macrophages and neutrophils. There may also be a reduction in endogenous antioxidants in COPD patients. Oxidative stress has several adverse consequences in the lungs, including activation of inflammatory genes, inactivation of antiproteases, stimulation of mucus secretion and stimulation of increased plasma exudation. Many of these adverse effects are mediated by peroxynitrite, which is formed via an interaction between superoxide anions and nitric oxide. In turn, the nitric oxide is generated by inducible nitric oxide synthase, which is expressed in the peripheral airways and lug parenchyma of COPD patients [99, 100]. Protease-antiprotease imbalance There is compelling evidence for an imbalance in the lungs of COPD patients between proteases that break down connective tissue components and antiproteases that protect against this. Several proteases, derived from inflammatory cells and epithelial cells, are increased in COPD patients. There is increasing evidence that they may interact with each other. Protease-mediated

34 destruction of elastin, a major connective tissue component in lung parenchyma, is an important feature of emphysema and is likely to be irreversible [9].

The different pathogenic mechanisms produce the pathological changes, which, in turn, give rise to the following physiological abnormalities in COPD: mucous hypersecretion, airflow limitation and air trapping, gas exchange abnormalities, pulmonary hypertension, and systemic effects.

3.5. Pharmacological management of COPD

While disease prevention is the ultimate goal, once COPD has been diagnosed, effective management should be aimed at the following goals: • Relieve symptoms; • Prevent disease progression; • Improve exercise tolerance; • Improve health status; • Prevent and treat complications; • Prevent and treat exacerbations; • Reduce mortality.

This paper reviews the guidelines of the management of COPD of Global Initiative for Chronic Obstructive Lung Disease, National Institute for Clinical Excellence and American Thoracic Society-European Respiratory Society. The classes of medications commonly used in treating COPD are shown in Annex 6. The common information of these medications is already described above (2.5. Pharmacological management of asthma). All the reviewed guidelines recommend escalation of drug therapy with increasing severity of disease, starting with short-acting inhaled bronchodilators used on an as-needed basis, proceeding to scheduled administration of long-acting inhaled bronchodilators, and finally advancing to inhaled corticosteroids in patients with severe or very severe disease with frequent exacerbations. All of them recommend combination therapy in patients with more severe disease.

Inhaled bronchodilator therapy Short-acting bronchodilators, as necessary, should be the initial empirical treatment for the relief of breathlessness and exercise limitation. Patients who remain symptomatic should have their

35 inhaled treatment intensified to include long-acting bronchodilators or combined therapy with a short-acting β2-agonist and a short-acting anticholinergic. Long-acting bronchodilators should be used in patients who remain symptomatic despite treatment with short-acting bronchodilators because these drugs appear to have additional benefits over combinations of short-acting drugs. Long-acting bronchodilators should also be used in patients who have two or more exacerbations per year. The choice of drug(s) should take into account the patient’s response to a trial of the drug, the drug’s side effects, patient preference and cost. Methylxanthines Theophylline should only be used after a trial of short-acting bronchodilators and long- acting bronchodilators, or in patients who are unable to use inhaled therapy, as there is a need to monitor plasma levels and interactions. Inhaled corticosteroids In all guidelines, inhaled corticosteroids are recommended, but only for patients whose post- bronchodilator FEV 1 values are ≤ 50% of the predicted value and who have frequent exacerbations; NICE defines the latter as ≥ 2 exacerbations in the last year, GOLD uses ≥ 3 episodes in the last 3 years and the ATS-ERS guideline does not specify an exacerbation frequency. The aim of treatment is to reduce exacerbation rates and slow the decline in health status and not to improve lung function per se. Combination therapy If patients remain symptomatic on monotherapy, their treatment should be intensified by combining therapies from different drug classes. Effective combinations include:

• β2-agonist and anticholinergic;

• β2-agonist and theophylline; • Anticholinergic and theophylline;

• Long-acting β2-agonist and inhaled corticosteroid.

The clinical effectiveness of combined treatments can be assessed by improvements in symptoms, activities of daily living, exercise capacity and lung function. Combination treatment should be discontinued if there is no benefit after 4 weeks [101]. According to GOLD, the pharmacological therapy by the stages of the disease is reviewed in Annex 7.

36 4. OBJECTIVE AND AIMS

Objective:

To evaluate utilization and costs of drugs for the management of asthma and COPD treatment in Lithuania on 2006 − 2009 year and to perform pharmacoeconomical analysis of direct costs of asthma and COPD treatment.

Aims:

1. To evaluate consumption of drugs for asthma and COPD treatment in Lithuania in 2006 – 2009 by the ATC/DDD methodology (by DDD/1000 inhabitants/day). 2. To evaluate direct cost of drugs for asthma and COPD treatment in Lithuania in 2006-2009. 3. To compare utilization data of drugs for asthma and COPD treatment in Lithuania with other European countries. 4. To perform the pharmacoeconomical analysis of drugs for the management of asthma and COPD by cost-minimisation and reference price methodologies.

37 5. MATERIAL AND METHODS

5.1. The ATC/DDD system

A drug classification system represents a common language for describing the drugs marketed in a country or region. This is a prerequisite for national and international comparisons of drug utilization data, which have to be collected and aggregated in a uniform way. Access to standardised and validated information on drug use is essential to monitor drug utilization patterns, identify problems in drug use, initiate educational or other interventions and to monitor outcomes of these interventions. The main purpose of having an international standard is to enable comparison of data between countries [102]. The tool for drug utilization research is the Anatomical Therapeutical Chemical Classification/Defined Daily Doses (ATC/DDD) system, developed by the World Health Organisation. The ATC/DDD system presents and compares the drug consumption statistics at international and other levels. The amount of drug used is measured independent of package size and price of sale; this allows comparisons not only within an institution but also within a region, a country, or even internationally [103]. To sum up, the ATC/DDD system is the methodology used for research purposes to conduct broad scale international drug utilization comparisons [104].

5.1.1. Anatomical Therapeutic Chemical (ATC) classification system

In the Anatomical Therapeutic Chemical (ATC) classification system, the drugs are divided into different groups according to the organ or system on which they act and their chemical, pharmacological and therapeutic properties. Drugs are classified in groups at five different levels. The drugs are divided into fourteen main groups (1st level), with one pharmacological/therapeutic subgroup (2nd level). The 3rd and 4th levels are chemical/pharmacological/therapeutic subgroups and the 5th level is the chemical substance. The 2nd, 3rd and 4th levels are often used to identify pharmacological subgroups when that is considered more appropriate than therapeutic or chemical subgroups. Principles for classification Medicinal products are classified according to the main therapeutic use of the main active ingredient, on the basic principle of only one ATC code for each pharmaceutical formulation (e.g. similar ingredients, strength and pharmaceutical form). A medicinal product may be used for two or more equally important indications, and the main therapeutic use of a drug may differ from one country to another. This will often give several

38 classification alternatives. Such drugs are usually only given one code, the main indication being decided on the basis of the available literature. Problems are discussed in the WHO International Working Group for Drug Statistics Methodology where the final classification is decided. The ATC system is not strictly a therapeutic classification system. At all ATC levels, ATC codes can be assigned according to the pharmacology of the product. Subdivision on the mechanism of action will, however, often be rather broad, since a too detailed classification according to mode of action often will result in having one substance per subgroup which as far as possible is avoided. Some ATC groups are subdivided in both chemical and pharmacological groups. If a new substance fits in both a chemical and pharmacological 4th level, the pharmacological group should normally be chosen. Substances classified in the same ATC 4th level cannot be considered pharmacotherapeutically equivalent since their mode of action, therapeutic effect, drug interactions and adverse drug reaction profile may differ [103].

5.1.2. The concept of the defined daily dose (DDD)

The defined daily dose (DDD) is a unit of measurement used as a tool for presenting drug utilization statistics. The basic definition of this unit is: the DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults . It should be emphasized that the DDD is a unit of measurement and does not necessarily correspond to the recommended or prescribed daily dose (PDD). Doses for individual patients and patient groups will often differ from the DDD as they must be based on individual characteristics (e.g. age and weight) and pharmacokinetic considerations. The DDD is often a compromise based on a review of the available information about doses used in various countries. The DDD may even be a dose that is seldom prescribed, because it is an average of two or more commonly used dose sizes [105]. Drug consumption data presented in DDDs only give a rough estimate of consumption and not an exact picture of actual use. DDDs provide a fixed unit of measurement independent of price and formulation enabling the researcher to assess trends in drug consumption and to perform comparisons between population groups [103]. Combination products The DDDs assigned for combination products are based on the main principle of counting the combination as one daily dose, regardless of the number of active ingredients included in the combination. If a treatment schedule for a patient includes e.g. two single ingredient products, then the consumption will be measured by counting the DDDs of each single ingredient product

39 separately. If, however, a treatment schedule includes a combination product containing two active ingredients, then the calculated consumption measured in DDDs will normally be lower since the DDD for the combination will be counted [103].

5.1.3. Drug utilization

The ATC/DDD system can be used for collection of drug utilization statistics in a variety of settings and from a variety of sources. Examples are: • Sales data such as wholesale data at a national, regional or local level.

• Dispensing data either comprehensive or sampled. In many countries pharmacies are computerised and advantage can be taken of this to collect data on drugs dispensed. Alternatively, sample data can be collected manually. Reimbursement systems, which operate in a number of countries at the national level, provide comprehensive dispensing data down to the individual prescription level, as all prescriptions are submitted and recorded for reimbursement. This is generally called "claims" data. Similar data are often available through health insurance or health maintenance organisations. These databases can sometimes allow collection of demographic information on the patients, and information on dose, duration of treatment and co-prescribing. Less commonly, linkage to hospital and medical databases can provide information on indications, and outcomes such as hospitalisation, use of specific medical services and adverse drug reactions. • Patient encounter based data. This is usually collected by specially designed sampling studies such as those carried out by market research organisations. However, increasing use of information technology at the medical practice level will make such data available more widely in the near future. These methods have the advantage of potentially providing accurate information on Prescribed Daily Doses, patient demographics, duration of therapy, co-prescribing, indications, morbidity and co-morbidity, and sometimes outcomes.

• Patient survey data. Collection of data at the patient level can provide information about actual drug consumption and takes into account compliance in filling prescriptions and taking medications as prescribed. It can also provide qualitative information about perceptions, beliefs and attitudes to the use of medicines.

• Health Facility data. Data on medication use at all the above levels is often available in health care settings such as hospitals and health centres at regional, district or village level.

40 Use of the ATC/DDD system allows standardisation of drug groupings and a stable drug utilization metric to enable comparisons of drug use between countries, regions, and other health care settings, and to examine trends in drug use over time and in different settings. Drug consumption figures should preferably be presented as numbers of DDDs/1000 inhabitants/day or, when in-hospital drug use is considered, as DDDs per 100 bed days [103].

DDDs per 1000 inhabitants per day Sales or prescription data presented in DDDs/1000 inhabitants/day provide a rough estimate of the proportion of the study population treated daily with a particular drug or group of drugs. For example, 10 DDD/1000 inhabitants/day may indicate that 1% of the population on average might receive a certain drug or group of drugs daily. This estimate is only useful for drugs used in the treatment of chronic diseases when there is good agreement between the average prescribed daily dose and the DDD [102]. It may also be important to consider the size of the population used as the denominator. Usually the general utilization is calculated for the total population including all age groups, but some drug groups have very limited use among people below the age of 45 years. To correct for differences in utilization due to differing age structures between countries, simple age adjustments can be made by using the number of inhabitants in the relevant age group as the denominator [105]. In conclusion, the ATC classification system and DDD measuring unit have become the gold standard for international drug utilization research and are recommended by WHO [102].

5.2. Pharmacoeconomical analysis

Pharmacoeconomics has been defined as the description and analysis of the costs of drug therapy to health care systems and society. Pharmacoeconomic research identifies, measures and compares the costs and consequences of pharmaceutical products and services. Within this framework are included the research methods related to cost-minimization, cost-effectiveness, cost- benefit, cost-utility [106].

5.2.1. Cost-minimisation analysis

Cost-minimization analysis is a method of calculating drug costs to project the least costly drug or therapeutic modality. Cost minimization also reflects the cost of preparing and administering a dose. This method of cost evaluation is the one used most often in evaluating the cost of a specific drug. Cost minimization can only be used to compare two products that have been

41 shown to be equivalent in dose and therapeutic effect. Therefore, this method is most useful for comparing generic and therapeutic equivalent drugs. In many cases, there is no reliable equivalence between two products and if therapeutic equivalence cannot be demonstrated, then cost- minimization analysis is inappropriate [107].

5.2.2. Reference price

Reference pricing of medicines is a cost-control mechanism used by health care funders. A reference price is an arbitrary price which the funder/medical aid decides to pay (or reimburse) for a specific medicine or group of medicines. If the actual manufacturer’s price of the medicine is higher than the reference price, the excess is paid by the patient. There are various methods for calculating a reference price which include: • International Reference Pricing • Generic-Equivalence Reference Pricing • Therapeutic-Equivalence Reference Pricing Therapeutic-equivalence reference pricing compares the prices for a range of different medicines in a country which are deemed by the funder to be similar, but are not actually the same medicine. The reference price for the group is determined by an arbitrary statistical calculation [108].

5.3. Data sources

The search for all literature relating to asthma and COPD was performed in MEDLINE database. The data on total sales of drugs for asthma and COPD treatment in Lithuania from 2006 to 2009 were obtained from Softdent, JSC, database. Data were calculated by DDD methodology and expressed in DDDs per 1000 inhabitants per day. Retail and basic prices of drugs for asthma and COPD treatment were obtained from the official Price lists of reimbursed drugs in Lithuania.

42 6. RESULTS

6.1. Consumption of drugs of the ATC Code R03

In this study we evaluated the drugs classified within the R03 therapeutic pharmacological subgroup (drugs for obstructive airway diseases) of the ATC Classification. Drug consumption is expressed as a number of DDDs per 1000 inhabitants per day (DDD/1000 inhabitants/day) between 2006 and 2009. In the studied period the consumption of drugs for obstructive airway diseases increased from 23,70 DDD/1000 inhabitants/day in 2006 to 28,67 DDD/1000 inhabitants/day in 2009 in Lithuania (Figure 3). This represented an increase of 21%. The consumption of drugs of the ATC Code R03 had been increasing yearly. The most significant increase is noticed from 2006 to 2007 – 11,5%. From 2006 to 2009 the rate of increase of consumption of drugs had been declining.

35,00

30,00

25,00 28,12 28,67 26,43 20,00 23,70

15,00

10,00

DDD/1000 inhabitants/day DDD/1000 5,00

0,00 2006 2007 2008 2009

Figure 3 Total consumption of drugs for obstructive airway diseases by DDD/1000 inhabitants/day during 2006-2009 in Lithuania

In comparison to the consumption of drugs for obstructive airway diseases, the expenditures for it (calculated in retail prices) also increased yearly between 2006 and 2008 – from 59,71 million Litas in 2006 to 80,12 million Litas in 2008. However, this tendency was opposite in 2009 when the expenditures decreased to 79,25 million Litas (Figure 4). Meanwhile the consumption from 2008 to 2009 increased fractionally – from 28,12 DDD/1000 inhabitants/day in 2008 to 28,67 DDD/1000 inhabitants/day in 2009. The decrease of expenditures in 2009 may be the result of the marked introduction of generic drugs of leukotriene receptor antagonists to the market.

43 90

80

70 80,12 79,25 60 70,60

50 59,71

40

30

20 Expenditures, millionExpenditures, Litas 10

0 2006 2007 2008 2009

Figure 4 Expenditures for drugs for obstructive airway diseases by million Litas during 2006-2009 in Lithuania

In the pharmacotherapeutical groups of drugs for obstructive airway diseases the most significant increase is found in consumption of inhaled corticosteroids and long-acting β2-agonists – it is important to notice that these are the pharmacotherapeutical groups of combined drugs for asthma and COPD. The consumption of both inhaled corticosteroids and long-acting β2-agonists increased yearly. The increase of consumption of inhaled corticosteroids is represented as 35% (from 6,38 DDD/1000 inhabitants/day in 2006 to 8,60 DDD/1000 inhabitants/day in 2009) and the increase of consumption of long-acting β2-agonists – 32% (from 5,26 DDD/1000 inhabitants/day in 2006 to 6,95 DDD/1000 inhabitants/day in 2009) (Figure 5).

2009 8,60 6,95 6,47 4,17 1,66

Inhaled corticosteroids 2008 8,37 6,90 6,41 3,62 1,95 Long-acting β2-agonists Short-acting β2-agonists Anticholinergics 2007 7,41 6,01 6,28 4,03 2,02

2006 6,38 5,26 6,10 3,38 2,03

0% 20% 40% 60% 80% 100% DDD/1000 inhabitants/day

Figure 5 Consumption of drugs for obstructive airway diseases by DDD/1000 inhabitants/day during 2006-2009

44 The increase of consumption of short-acting β2-agonists is less significant comparing to inhaled corticosteroids and long-acting β2-agonists – it is 6% (from 6,10 DDD/1000 inhabitants/day in 2006 to 6,47 DDD/1000 inhabitants/day in 2009). The consumption of anticholinergics varied during the studied period. Between 2006 and 2007 the use increased by 20% (from 3,38 DDD/1000 inhabitants/day to 4,03 DDD/1000 inhabitants/day). In 2008 it is noticed a 10% decrease of consumption of anticholinergics. In 2009 the use again had a tendency to increase. This increase is represented as 15% (from 3,62 DDD/1000 inhabitants/day in 2008 to 4,17 DDD/1000 inhabitants/day in 2009). The use of xanthines had a tendency to decrease continually throughout the studied period from 2,03 DDD/1000 inhabitants/day in 2006 to 1,66 DDD/1000 inhabitants/day in 2009. Table 11 provides the consumption data expressed by DDD/1000 inhabitants/day by active substances.

Table 11 Consumption of drugs for obstructive airway diseases by DDD/1000 inhabitants/day during 2006-2009

DDD/1000 inhabitants/day Active substance 2006 2007 2008 2009 Fluticasone 3,98 4,62 5,42 5,43 Salbutamol 4,92 5,21 4,87 4,83 Salmeterol 3,59 3,87 4,33 4,20 Ipratropium bromide 2,63 2,98 2,33 2,63 Budesonide 1,75 2,19 2,48 2,78 Formoterol 1,67 2,13 2,57 2,75 Fenoterol 1,18 1,44 1,54 1,64 0,75 1,05 1,29 1,47 Theophylline 1,23 1,28 1,27 1,09 Montelukast 0,55 0,73 0,86 0,81 Aminophylline 0,80 0,74 0,67 0,57 0,65 0,60 0,47 0,42

The most significant yearly increase is noticed in consumption of inhaled corticosteroids fluticasone and budesonide, long-acting β2-agonist formoterol, short-acting β2-agonist fenoterol and anticholinergic agent tiotropium bromide (Figure 6). The use of fluticasone increased from 3,98 DDD/1000 inhabitants/day in 2006 to 5,43 DDD/1000 inhabitants/day in 2009. The most rapid increase of consumption of fluticasone was from 2006 to 2008. Consumption of other inhaled corticosteroid budesonide is also rising – from 1,75 DDD/1000 inhabitants/day in 2006 to 2,78 DDD/1000 inhabitants/day in 2009.

45 The consumption of formoterol is constantly increasing from 1,67 DDD/1000 inhabitants/day in 2006 to 2,75 DDD/1000 inhabitants/day in 2009. Consumption of short-acting

β2-agonist fenoterol also demonstrated a tendency to increase (from 1,18 DDD/1000 inhabitants/day in 2006 to 1,64 DDD/1000 inhabitants/day in 2009).

6

5

4 2006 2007 3 2008

2 2009

DDD/1000 inhabitants/day 1

0 Fluticasone Budesonide Formoterol Fenoterol Tiotropium bromide

Figure 6 Increase of consumption of drugs for obstructive airway diseases by DDD/1000 inhabitants/day during 2006-2009

During the studied period, the use of anticholinergic agent tiotropium bromide almost doubled (from 0,75 DDD/1000 inhabitants/day in 2006 to 1,47 DDD/1000 inhabitants/day in 2009). The tendency of increase of consumption of the active substances in percents is provided in Table 12.

Table 12 Increase of consumption by DDD/1000 inhabitants/day in percent from 2006 to 2009 Active substance DDD/1000 inhabitants/day Increase, % 2006 2009 Fluticasone 3,98 5,43 36 Budesonide 1,75 2,78 59 Formoterol 1,67 2,75 65 Fenoterol 1,18 1,64 39 Tiotropium bromide 0,75 1,47 96

46 The use of salmeterol had also a tendency to increase (by 21%) from 2006 to 2008 (from 3,59 DDD/1000 inhabitants/day to 4,33 DDD/1000 inhabitants/day). However, in 2009 the consumption decreased to 4,20 DDD/1000 inhabitants/day. The changes of consumption of salbutamol, theophylline, ipratropium bromide, montelukast were less considerable: • consumption of salbutamol and theophylline increased from 2006 to 2007 and had a tendency to decrease from 2007 to 2009; • consumption of ipratropium bromide increased in the periods of 2006-2007 and 2008-2009, the decrease is noticed during 2007 and 2008; • consumption of leukotriene receptor antagonist montelukast had a tendency to increase in the period of 2006-2008 and decreased in 2009. In the period of 2006 and 2009 the yearly decrease in the consumption is observed in aminophylline and inhaled corticosteroid beclometasone (Figure 7). The use of aminophylline declined from 0,8 DDD/1000 inhabitants/day in 2006 to 0,57 DDD/1000 inhabitants/day in 2009 – by 29%. The decrease of consumption of beclometasone was similar – 35% (from 0,65 DDD/1000 inhabitants/day in 2006 to 0,42 DDD/1000 inhabitants/day in 2009).

0,9

0,8

0,7

0,6 2006 0,5 2007 0,4 2008 2009 0,3

0,2 DDD/1000 inhabitants/day DDD/1000 0,1

0 Aminophylline Beclometasone

Figure 7 Decrease of consumption of drugs for obstructive airway diseases by DDD/1000 inhabitants/day during 2006-2009

Figure 8 provides the change in the consumption of both inhaled corticosteroids and long- acting β2-agonists – pharmacotherapeutical groups, which consumption increase was the most considerable during 2006-2009. Although the use of beclometasone decreases, rapidly growing consumption of fluticasone and budesonide conditions the increases of the total use of inhaled corticosteroids.

47 Despite the decline in the consumption of salmeterol in 2009, the number of patients treated daily with long-acting β2-agonists (salmeterol and formoterol) in the studied period increased considerably.

6

5

4 2006 2007 3 2008 2 2009

1 DDD/1000 DDD/1000 inhabitants/day

0 Fluticasone Salmeterol Budesonide Formoterol Beclometasone

Figure 8 Consumption of inhaled corticosteroids and long-acting β2-agonists by DDD/1000 inhabitants/day during 2006-2009

In the period from 2006 to 2009 the proportion of consumption of drugs for obstructive airway diseases changed, the most often used active substances in 2009 are provided in Figure 9.

1,47; 6% 1,64; 6% 5,43; 21% Fluticasone 2,75; 11% Salbutamol Salmeterol Ipratropium bromide Budesonide 2,78; 11% 4,83; 19% Formoterol Fenoterol Tiotropium bromide 2,63; 10% 4,2; 16%

Figure 9 The most often used active substances of the ATC Code R03 in 2009 by DDD/1000 inhabitants/day and percents

48 Analyzing the consumption data by the route of administration, the inhaled drugs (the ATC subgroups R03 A and R03 B) occupy 88% - 90% of all the drugs for obstructive airway diseases during the studied period. The consumption of inhalations increases from 20,80 DDD/1000 inhabitants/day in 2006 to 25,80 DDD/1000 inhabitants/day in 2009 as well as the total consumption of drugs of the ATC Code R03 (Figure 10). The major advantage of inhaled drugs is that these drugs are delivered directly to the airways, producing higher local concentrations with significantly less risk of systemic side effects [22]. The consumption of drugs for systemic use (the ATC subgroups R03C and R03D) increased only from 2006 to 2007, later decreasing from 3,18 DDD/1000 inhabitants/day in 2007 to 2,81 DDD/1000 inhabitants/day in 2009.

30,00 25,80 23,25 24,97 25,00 20,80 20,00 Inhalants 15,00 Drugs for systemic use 10,00 2,90 3,18 3,13 2,81 5,00 DDD/1000 inhabitants/day 0,00 2006 2007 2008 2009 Year

Figure 10 Consumption of inhalants and drugs for systemic use by DDD/1000 inhabitants/day during 2006-2009

The other group important to review is combined drugs for obstructive airway diseases. The total use of combinations (salmeterol plus fluticasone, formoterol plus budesonide and fenoterol plus ipratropium bromide) had increased from 11,51 DDD/1000 inhabitants/day in 2006 to 16,51 DDD/1000 inhabitants/day in 2009. It is an increase of 43% (Figure 11).

49 18 16,51 15,70 16 14,13 14 11,51 12

10

8

6

4 DDD/1000 inhabitants/day DDD/1000 2

0 2006 2007 2008 2009

Figure 11 Total consumption of combined drugs for obstructive airway diseases by DDD/1000 inhabitants/day during 2006-2009

A considerable difference of consumption is discovered between the combined and plain forms of the same active substances (Table 13). For example, in 2009 the combined form of fluticasone represented 86% of the total consumption of fluticasone and plain form – 14%; salmeterol – 86% and 14%; ipratropium bromide – 99,6% and 0,4%; budesonide – 79% and 21%; formoterol – 76% and 24%; fenoterol – 80% and 20% accordingly.

Table 13 Consumption of combined and plain forms of drugs for obstructive airway diseases by DDD/1000 inhabitants/day during 2006-2009 DDD/1000 inhabitants/day 2006 2007 2008 2009 Fluticasone Combined 3,28 3,83 4,62 4,67 Fluticasone Plain 0,70 0,79 0,79 0,76 Salmeterol Combined 2,76 3,14 3,66 3,63 Salmeterol Plain 0,83 0,74 0,67 0,57 Ipratropium bromide Combined 1,67 2,56 2,33 2,62 Ipratropium bromide Plain 0,01 0,01 0,003 0,01 Budesonide Combined 1,52 1,81 2,02 2,20 Budesonide Plain 0,23 0,38 0,46 0,57 Formoterol Combined 1,45 1,72 1,91 2,08 Formoterol Plain 0,21 0,41 0,66 0,67 Fenoterol Combined 0,83 1,07 1,16 1,31 Fenoterol Plain 0,35 0,37 0,38 0,33

Increasing consumption of three different combinations (salmeterol plus fluticasone, formoterol plus budesonide and fenoterol plus ipratropium bromide) is provided in Figure 12. The increase of consumption of combination of salmeterol and fluticasone in the period of 2006-2009 is represented accordingly as 37%; formoterol and budesonide – 44%; fenoterol and ipratropium

50 bromide – 58%. In 2009 the combination of salmeterol plus fluticasone represented 29% of the total consumption of drugs for obstructive airway diseases; formoterol plus budesonide – 15%; fenoterol plus ipratropium bromide – 14% accordingly. The total consumption of the combinations had demonstrated a tendency to increase markedly over the 4 years of the study. In 2006 the use of combinations represented 49% of the total consumption of drugs for obstructive airway diseases; in 2007 – 53%; in 2008 – 56% and in 2009 – 58% accordingly. All things considered, the combined drugs for obstructive airway diseases take the most significant part in the market of drugs for obstructive airway diseases. Therefore, the consumption of combined drugs is increasing considerably.

9 8 8,28 8,30 7 6,96 6 2006 6,04 5 2007 4 2008 4,28 3 3,93 3,93 2009 3,53 3,49 3,22 2 2,97

DDD/1000 inhabitants/day 2,49 1 0 Salmeterol plus fluticasone Formoterol plus budesonide Fenoterol plus ipratropium bromide

Figure 12 Consumption of combined drugs for obstructive airway diseases by DDD/1000 inhabitants/day during 2006-2009

51 6.2. Pharmacoeconomical analysis of drugs for obstructive airway diseases

6.2.1. Reference price for long-acting β2-agonists

In 2009 the expenditures on long-acting β2-agonists were 3867368,17 Litas – 4,9% of the total expenditures on drugs for obstructive airway diseases. Formoterol represented the expenditures of 1940267,8 Litas and salmeterol – 1927100,37 Litas in 2009.

Formoterol and salmeterol are equally effective as long-acting β2-agonists. 12 µg dose of formoterol has been demonstrated to be equivalent to a 50 µg dose of salmeterol. Therefore the cost-minimisation analysis may be performed. The price of one DDD of both formoterol and salmeterol together varies from 1,91 Litas to

4,07 Litas. Implementing the lowest price of one DDD of long-acting β2-agonists as the reference price, 975379,87 Litas could be saved per year. The saving at expenditures of formoterol represents 376321,6 Litas and the saving at expenditures of salmeterol - 599058,27 Litas (Table 14). In the study it was also evaluated the saving of expenditures estimating the cost by the basic prices of formoterol and salmeterol. The basic price of one DDD of both formoterol and salmeterol together varies from 1,82 Litas to 2,52 Litas. The calculations present that the Government could save 433841,36 Litas per year if the lowest basic price of one DDD was implemented (Table 15).

Table 14 Expenditures applying the lowest retail price of one DDD as the reference price Active Product, Total DDD Price/DDD Expenditures Reference Expenditures substance administration (Lt) (Lt) Price/DDD using route (Lt) Reference Price (Lt) Formoterol 1, inhal. powder 454560 2,12 964349,04 1,91 868209,6 2, inhal. powder 314490 2,47 777419,28 1,91 600675,9 3, inhal. powder 1800 1,91 3442,8 1,91 3438 4, inhal. powder 47970 4,07 195056,68 1,91 91622,7 Total costs: 1940267,8 1563946,2 Saved by: 376321,6 Salmeterol 1, inhal. aerosol 419670 2,70 1133808,45 1,91 801569,7 2, inhal. powder 275640 2,88 793291,92 1,91 526472,4 Total costs: 1927100,37 1328042,1 Saved by: 599058,27 Total costs (formoterol + salmeterol): 3867368,17 2891988,3 Total saving: 975379,87

52 Table 15 Expenditures applying the lowest basic price of one DDD as the reference price Active Product, Total DDD Basic Expenditures Reference Expenditures substance administration Price/DDD (Lt) Basic using route (Lt) Price/DDD Reference (Lt) Price (Lt) Formoterol 1, inhal. powder 454560 1,82 827905,28 1,82 827299,2 2, inhal. powder 314490 1,82 572791,12 1,82 572371,8 3, inhal. powder 1800 1,82 3278,4 1,82 3276 4, inhal. powder 47970 2,43 116492,48 1,82 87305,4 Total costs: 1520467,28 1490252,4 Saved by: 30214,88 Salmeterol 1, inhal. aerosol 419670 2,32 974753,52 1,82 763799,4 2, inhal. powder 275640 2,52 694337,16 1,82 501664,8 Total costs: 1669090,68 1265464,2 Saved by: 403626,48 Total costs (formoterol + salmeterol): 3189557,96 2755716,6 Total saving: 433841,36

Even the savings implementing the second lowest price of one DDD as the reference price are significant as well. 656560,24 Litas could be saved if the 2,12 Litas price of one DDD would be applied (Table 16). Accordingly the Government would save 62201,36 Litas if the second lowest basic price of one DDD (2,32 Lt) was implemented (Table 17).

Table 16 Expenditures applying the second lowest retail price of one DDD as the reference price Active Product, Total DDD Price/DDD Expenditures Reference Expenditures substance administration (Lt) (Lt) Price/DDD using route (Lt) Reference Price (Lt) Formoterol 1, inhal. powder 454560 2,12 964349,04 2,12 964349,04 2, inhal. powder 314490 2,47 777419,28 2,12 667190,535 3, inhal. powder 1800 1,91 3442,8 1,91 3442,8 4, inhal. powder 47970 4,07 195056,68 2,12 101768,355 Total costs: 1940267,8 1736750,73 Saved by: 203517,07 Salmeterol 1, inhal. aerosol 419670 2,70 1133808,45 2,12 889700,4 2, inhal. powder 275640 2,88 793291,92 2,12 584356,8 Total costs: 1927100,37 1474057,2 Saved by: 453043,17 Total costs (formoterol + salmeterol): 3867368,17 3210807,93 Total saving: 656560,24

53 Table 17 Expenditures applying the second lowest basic price of one DDD as the reference price Active Product, Total DDD Basic Expenditures Reference Expenditures substance administration Price/DDD (Lt) Basic using route (Lt) Price/DDD Reference (Lt) Price (Lt) Formoterol 1, inhal. powder 454560 1,82 827905,28 1,82 827299,2 2, inhal. powder 314490 1,82 572791,12 1,82 572371,8 3, inhal. powder 1800 1,82 3278,4 1,82 3276 4, inhal. powder 47970 2,43 116492,48 2,32 111290,4 Total costs: 1520467,28 1514237,4 Saved by: 6229,88 Salmeterol 1, inhal. aerosol 419670 2,32 974753,52 2,32 973634,4 2, inhal. powder 275640 2,52 694337,16 2,32 639484,8 Total costs: 1669090,68 1613119,2 Saved by: 55971,48 Total costs (formoterol + salmeterol): 3189557,96 3127356,6 Total saving: 62201,36

6.2.2. Reference price for inhaled corticosteroids

The expenditures on inhaled corticosteroids (budesonide and fluticasone) represented 4,4% (3461354,95 Litas) of the total expenditures on drugs for obstructive airway diseases in 2009. The cost of budesonide was 923255,2 Litas and the cost of fluticasone - 2538099,75 Litas. According to the NICE, it is reasonable to assume that there are no differences in clinical effectiveness between different inhaled corticosteroids at both low and high doses. This permits to perform cost-minimisation analysis. The price of one DDD for both budesonide and fluticasone together varies considerably – from 1,30 Litas to 5,57 Litas. Pharmacoeconomical estimations of these significant differences in the prices of one DDD among the inhaled corticosteroids are shown in Table 18. 14971,2 Litas could be saved of the expenditures on budesonide if 1,30 Litas reference price was implemented. 1346636,75 Litas would accordingly be saved of the expenditures on fluticasone. The total saving of both budesonide and fluticasone is estimated as 1361607,95 Litas. The estimations of the expenditures using the lowest basic price and possible savings of the Government are provided in Table 19. 1236132,45 Litas may be saved per year of the costs of both budesonide and fluticasone.

54 Table 18 Expenditures applying the lowest retail price of one DDD as the reference price Active Product, Total Price/DDD Expenditures Reference Expenditures substance administration DDD (Lt) (Lt) Price/DDD using route (Lt) Reference Price (Lt) Budesonide 1, inhal. powder 63720 1,42 90482,4 1,30 82836 2, inhal. powder 91560 1,38 126352,8 1,30 119028 3, inhal. powder 354800 1,30 461240 1,30 461240 4, inhal. powder 188600 1,30 245180 1,30 245180 Total costs: 923255,2 908284,0 Saved by: 14971,2 Fluticasone 1, inhal. aerosol 146600 3,00 439800 1,30 190580 2, inhal. aerosol 215825 2,38 513663,5 1,30 280572,5 3, inhal. aerosol 75860 3,15 238959 1,30 98618 4, inhal. powder 4935 5,57 27487,95 1,30 6415,5 5, inhal. powder 48990 3,97 194490,3 1,30 63687 6, inhal. powder 181600 2,86 519376 1,30 236080 7, inhal. powder 242700 2,49 604323 1,30 315510 Total costs: 2538099,75 1191463,0 Saved by: 1346636,75 Total costs (budesonide + fluticasone): 3461354,95 2099747,0 Total saving: 1361607,95

Table 19 Expenditures applying the lowest basic price of one DDD as the reference price Active Product, Total Basic Expenditures Reference Expenditures substance administration DDD Price/DDD (Lt) Basic using route (Lt) Price/DDD Reference (Lt) Price (Lt) Budesonide 1, inhal. powder 63720 1,15 73278 1,15 73278 2, inhal. powder 91560 1,15 105294 1,15 105294 3, inhal. powder 354800 1,15 408020 1,15 408020 4, inhal. powder 188600 1,15 216890 1,15 216890 Total costs: 803482 803482 Fluticasone 1, inhal. aerosol 146600 2,64 387024 1,15 168590 2, inhal. aerosol 215825 2,27 489922,75 1,15 248198,75 3, inhal. aerosol 75860 2,75 208615 1,15 87239 4, inhal. powder 4935 4,62 22799,7 1,15 5675,25 5, inhal. powder 48990 3,35 164116,5 1,15 56338,5 6, inhal. powder 181600 2,57 466712 1,15 208840 7, inhal. powder 242700 2,27 550929 1,15 279105 Total costs: 2290118,95 1053986,5 Saved by: 1236132,45 Total costs (budesonide + fluticasone): 3093600,95 1857468,5 Total saving: 1236132,45

The practice of the second lowest price of one DDD is also meaningful. The total saving of both the active substances is 1275864,75 Litas per year – 2548,8 Litas for the costs of budesonide and 1273315,95 Litas for the costs of fluticasone (Table 20).

55 Table 20 Expenditures applying the second lowest retail price of one DDD as the reference price Active Product, Total Price/DDD Expenditures Reference Expenditures substance administration DDD (Lt) (Lt) Price/DDD using route (Lt) Reference Price (Lt) Budesonide 1, inhal. powder 63720 1,42 90482,4 1,38 87933,6 2, inhal. powder 91560 1,38 126352,8 1,38 126352,8 3, inhal. powder 354800 1,30 461240 1,30 461240 4, inhal. powder 188600 1,30 245180 1,30 245180 Total costs: 923255,2 920706,4 Saved by: 2548,8 Fluticasone 1, inhal. aerosol 146600 3,00 439800 1,38 202308 2, inhal. aerosol 215825 2,38 513663,5 1,38 297838,5 3, inhal. aerosol 75860 3,15 238959 1,38 104686,8 4, inhal. powder 4935 5,57 27487,95 1,38 6810,3 5, inhal. powder 48990 3,97 194490,3 1,38 67606,2 6, inhal. powder 181600 2,86 519376 1,38 250608 7, inhal. powder 242700 2,49 604323 1,38 334926 Total costs: 2538099,75 1264783,8 Saved by: 1273315,95 Total costs (budesonide + fluticasone): 3461354,95 2185490,2 Total saving: 1275864,75

The total Government saving of expenditures on inhaled corticosteroids implementing the second lowest basic price is estimated as 209641,25 Litas per year (Table 21).

Table 21 Expenditures applying the second lowest basic price of one DDD as the reference price Active Product, Total Basic Expenditures Reference Expenditures substance administration DDD Price/DDD (Lt) Basic using route (Lt) Price/DDD Reference (Lt) Price (Lt) Budesonide 1, inhal. powder 63720 1,15 73278 1,15 73278 2, inhal. powder 91560 1,15 105294 1,15 105294 3, inhal. powder 354800 1,15 408020 1,15 408020 4, inhal. powder 188600 1,15 216890 1,15 216890 Total costs: 803482 803482 Fluticasone 1, inhal. aerosol 146600 2,64 387024 2,27 332782 2, inhal. aerosol 215825 2,27 489922,75 2,27 489922,75 3, inhal. aerosol 75860 2,75 208615 2,27 172202,2 4, inhal. powder 4935 4,62 22799,7 2,27 11202,45 5, inhal. powder 48990 3,35 164116,5 2,27 111207,3 6, inhal. powder 181600 2,57 466712 2,27 412232 7, inhal. powder 242700 2,27 550929 2,27 550929 Total costs: 2290118,95 2080477,7 Saved by: 209641,25 Total costs (budesonide + fluticasone): 3093600,95 2883959,7 Total saving: 209641,25

56 6.2.3. Reference price for inhaled corticosteroid/long-acting β2-agonist combinations

Inhaled corticosteroid/long-acting β2-agonist combinations is the group of drugs for obstructive airway diseases, the increase of consumption is the most considerable during the studied period. The combinations of inhaled corticosteroid and long-acting β2-agonist occupy the major part in the market of drugs for obstructive airway diseases. Two combinations of inhaled corticosteroid and long-acting β2-agonist are available on the market – formoterol/budesonide and salmeterol/fluticasone combinations. The expenditures on them represent 55,75% (44140208,1 Litas) of the total expenditures on drugs for the treatment of asthma and COPD . According to the NICE, it is agreed that there are no consistent differences among the clinical effectiveness of different inhaled corticosteroid/long-acting β2-agonist combinations. The cost-minimisation approach may be used for the pharmacoeconomical analysis of inhaled corticosteroid and long-acting β2-agonist combinations. The price of one DDD for both formoterol/budesonide and salmeterol/fluticasone combinations varies from 3,42 Litas to 6,57 Litas. Implementing the lowest price of one DDD as the reference price, 8121029,4 Litas is saved for the expenditure on formoterol/budesonide combinations and 9857922,9 Litas on salmeterol/fluticasone combinations accordingly. The total saving is estimated as 17978952,3 Litas (Table 22).

Table 22 Expenditures applying the lowest retail price of one DDD as the reference price Active Product, Total Price/DDD Expenditures Reference Expenditures substance administration DDD (Lt) (Lt) Price/DDD using route (Lt) Reference Price (Lt) Formoterol/ 1, inhal. powder 2296590 5,84 13412085,6 3,42 7854337,8 Budesonide 2, inhal. powder 1032060 5,84 6027230,4 3,42 3529645,2 Combination 3, inhal. powder 52140 4,68 244015,2 3,42 178318,8 Total costs: 19683331,2 11562301,8 Saved by: 8121029,4 Salmeterol/ 1, inhal. powder 2072850 6,49 13452796,5 3,42 7089147 Fluticasone 2, inhal. powder 1241070 4,72 5857850,4 3,42 4244459,4 Combination 3, inhal. powder 219180 3,66 802198,8 3,42 749595,6 4, inhal. aerosol 489960 6,57 3219037,2 3,42 1675663,2 5, inhal. aerosol 207960 4,79 996128,4 3,42 711223,2 6, inhal. aerosol 37680 3,42 128865,6 3,42 128865,6 Total costs: 24456876,9 14598954 Saved by: 9857922,9 Total costs ( Formoterol/Budesonide Combination + 44140208,1 26161255,8 Salmeterol/Fluticasone Combination ): Total saving: 17978952,3

57 The estimations of implementing the lowest basic price of one DDD as the reference price and the savings of the Government are provided in Table 23. The total saving is evaluated as 18045426,9 Litas per year.

Table 23 Expenditures applying the lowest basic price of one DDD as the reference price Active Product, Total Basic Expenditures Reference Expenditures substance administration DDD Price/DDD (Lt) Basic using route (Lt) Price/DDD Reference (Lt) Price (Lt) Formoterol/ 1, inhal. powder 2296590 5,65 12975733,5 3,19 7326122,1 Budesonide 2, inhal. powder 1032060 5,42 5593765,2 3,19 3292271,4 Combination 3, inhal. powder 52140 4,44 231501,6 3,19 166326,6 Total costs: 18801000,3 10784720,1 Saved by: 8016280,2 Salmeterol/ 1, inhal. powder 2072850 6,31 13079683,5 3,19 6612391,5 Fluticasone 2, inhal. powder 1241070 4,54 5634457,8 3,19 3959013,3 Combination 3, inhal. powder 219180 3,42 749595,6 3,19 699184,2 4, inhal. aerosol 489960 6,36 3116145,6 3,19 1562972,4 5, inhal. aerosol 207960 4,55 946218 3,19 663392,4 6, inhal. aerosol 37680 3,19 120199,2 3,19 120199,2 Total costs: 23646299,7 13617153 Saved by: 10029146,7 Total costs ( Formoterol/Budesonide Combination + 42447300 24401873,1 Salmeterol/Fluticasone Combination ): Total saving: 18045426,9

The estimations implementing the second lowest price of one DDD as the reference price provide the total yearly saving of expenditure on both formoterol/budesonide and salmeterol/fluticasone combinations as 16152117,9 Litas (Table 24).

Table 24 Expenditures applying the second lowest retail price of one DDD as the reference price Active Product, Total Price/DDD Expenditures, Reference Expenditures substance administration DDD (Lt) (Lt) Price/DDD using route (Lt) Reference Price (Lt) Formoterol/ 1, inhal. powder 2296590 5,84 13412085,6 3,66 8405519,4 Budesonide 2, inhal. powder 1032060 5,84 6027230,4 3,66 3777339,6 Combination 3, inhal. powder 52140 4,68 244015,2 3,66 190832,4 Total costs: 19683331,2 12373691,4 Saved by: 7309639,8 Salmeterol/ 1, inhal. powder 2072850 6,49 13452796,5 3,66 7586631 Fluticasone 2, inhal. powder 1241070 4,72 5857850,4 3,66 4542316,2 Combination 3, inhal. powder 219180 3,66 802198,8 3,66 802198,8 4, inhal. aerosol 489960 6,57 3219037,2 3,66 1793253,6 5, inhal. aerosol 207960 4,79 996128,4 3,66 761133,6 6, inhal. aerosol 37680 3,42 128865,6 3,42 128865,6 Total costs: 24456876,9 15614398,8 Saved by: 8842478,1 Total costs ( Formoterol/Budesonide Combination + 44140208,1 27988090,2 Salmeterol/Fluticasone Combination ): Total saving: 16152117,9

58 Evaluating the costs of basic prices, even the use of the second lowest basic price of one DDD as the reference price, the total saving is represented as 16294710,6 Litas (Table 25).

Table 25 Expenditures applying the second lowest basic price of one DDD as the reference price Active Product, Total Basic Expenditures, Reference Expenditures substance administration DDD Price/DDD (Lt) Basic using route (Lt) Price/DDD Reference (Lt) Price (Lt) Formoterol/ 1, inhal. powder 2296590 5,65 12975733,5 3,42 7854337,8 Budesonide 2, inhal. powder 1032060 5,42 5593765,2 3,42 3529645,2 Combination 3, inhal. powder 52140 4,44 231501,6 3,42 178318,8 Total costs: 18801000,3 11562301,8 Saved by: 7238698,5 Salmeterol/ 1, inhal. powder 2072850 6,31 13079683,5 3,42 7089147 Fluticasone 2, inhal. powder 1241070 4,54 5634457,8 3,42 4244459,4 Combination 3, inhal. powder 219180 3,42 749595,6 3,42 749595,6 4, inhal. aerosol 489960 6,36 3116145,6 3,42 1675663,2 5, inhal. aerosol 207960 4,55 946218 3,42 711223,2 6, inhal. aerosol 37680 3,19 120199,2 3,19 120199,2 Total costs: 23646299,7 14590287,6 Saved by: 9056012,1 Total costs ( Formoterol/Budesonide Combination + 42447300 26152589,4 Salmeterol/Fluticasone Combination ): Total saving: 16294710,6

59 7. DISCUSSION

Asthma and COPD are the diseases of significantly increasing prevalence which has a tendency to grow in the future. According to the Lithuanian Health Information Centre statistics, in Lithuania in 2008 the prevalence of asthma in children (aged 0-17) was 25,9/1000 inhabitants and in adults - 10,0/1000 inhabitants. The morbidity of both asthma and COPD is increasing globally. In the period of 2006-2009 year, the consumption of drugs for the treatment of asthma and COPD had a tendency to increase. The correlation between the increasing prevalence of asthma (there is no official statistics on the prevalence of COPD in Lithuania) and the consumption of drugs for the treatment of asthma and COPD is provided in Figure 13.

30 26,43 28,12 25 23,7

20 Prevalence of asthma in adults (per 1000 inhabitants) 15 Consumption (by DDD/1000 9,5 10 inhabitants/day) 10 8,9

5

0 2006 2007 2008

Figure 13 Correlation between the prevalence of asthma (per 1000 inhabitants) and consumption of drugs for both asthma and COPD (by DDD/1000 inhabitants/day) during 2006-2008

Total consumption of drugs for obstructive airway diseases in different countries varies significantly (Figure 14). In Lithuania (2008) the consumption was about two times lower than in Nordic countries – Norway, Denmark and Finland (2008) and about 1,6 times higher than in Estonia (2007).

60 70

60

61,61 59,7 50 56,47

40

30

20 28,12

DDD/1000 inhabintants/day10 17,43

0 Norway 2008 Denmark 2008 Finland 2008 Lithuania 2008 Estonia 2007

Figure 14 Total consumption of drugs for obstructive airway diseases in different countries by DDD/1000 inhabitants/day

Total consumption of drugs for asthma and COPD treatment increased both in Finland (2005-2008) and Estonia (2005-2007). There was no tendency in increasing the same drugs in Norway and Denmark. In Norway the consumption of asthma and COPD drugs during 2005-2008 was stabilized and in Denmark the consumption varied fractionally, meanwhile in Lithuania the consumption has been increasing yearly (Figure 15).

70

60 59,7 60,6 61,0 61,74 60,3 61,29 61,61

50 61,29 56,47 53,99 54,41 40 51,84

30

20

DDD/1000 10inhabitants/day 17,43 16,11 16,49 0 Norway Denmark Finland Estonia

2005 2006 2007 2008

Figure 15 Consumption of drugs for obstructive airway diseases by DDD/1000 inhabitants/day in different countries during 2005-2008

61 According to the estimations of GINA, the prevalence of asthma and COPD in Scandinavian countries is higher compared with the Baltic States but consumption of drug is lower. This may be because of considerable underdiagnosis and under treatment of the diseases in the Baltic States [22]. Such discrepancy of data needs for father evaluation.

Salbutamol, a short-acting β2-agonist is a marker of poor asthma management and excessive use of health care resources. Case-control studies have suggested that excessive use of short-acting β2-agonists may worsen asthma control and increase the risk of fatal or near-fatal asthma [86]. Consumption of salbutamol in Lithuania represented 17,3% (4,87 DDD/1000 inhabitants/day) of total consumption of drugs for asthma and COPD treatment in 2008, in Denmark – 10,0% (6,0 DDD/1000 inhabitants/day), in Finland – 13,5% (7,65 DDD/1000 inhabitants/day), in Norway – 17,7% (10,95 DDD/1000 inhabitants/day) and in Estonia (in 2007) – 18,0% (3,16 DDD/1000 inhabitants/day) accordingly. These estimations suggest that the most optimal control of asthma and COPD management in the studied countries is achieved in Denmark and Finland and poorer control is found in Lithuania, Norway and Estonia. Consumption of salbutamol decreased from 5,21 DDD/1000 inhabitants/day in 2007 to 4,83 DDD/1000 inhabitants/day in 2009 in Lithuania. The decrease of the use of salbutamol may present that the control of asthma had improved in the last years. It is important to discuss the cost change of drugs for obstructive airway diseases. The costs (calculated in retail prices) of drugs for asthma and CODP increased in the period from 2006 to 2008 from 59,71 million Litas to 80,12 million Litas. Despite the increase of consumption during 2008 and 2009, there was observed the decrease of cost for the drugs in 2009 – it was on the decrease of 79,25 million Litas (Figure 16). The main reason of the decrease of expenditures may be explained by the introduction of generic drugs of leukotriene receptor antagonists to the Lithuanian market. Currently available leukotriene receptor antagonist in the market is montelukast. Monkasta of KRKA (the first enter is found in 2008, however the sales are not meaningful in 2008) and Eonic of Gedeon Richter, having significantly lower prices of one DDD compared to the ethical drug Singulair of Merck Sharp & Dohme, entered to the market of drugs for obstructive airway diseases in 2009. The prices of one DDD vary from 6,14 Litas to 11,20 Litas. In 2009 the consumption of Singulair decreased significantly, permiting the marked increase of consumption of generic alternatives. It is essential to note, that the basic price of one DDD for leukotriene receptor antagonists does not differ. It could be concluded that the significant difference among the prices is overpaid by patients.

62 120,00 80,12 79,25 70,60 100,00 59,71

80,00 Costs (million Litas) 60,00 Consumption (by DDD/1000 inhabitants/day) 40,00 23,70 26,43 28,12 28,67

20,00

0,00 2006 2007 2008 2009

Figure 16 Correlation between costs (by million Litas) and consumption (by DDD/1000 inhabitants/day) of drugs for asthma and COPD treatment during 2006-2009 year

The most considerable increase of consumption is found to be the use of drugs of inhaled corticosteroid/long-acting β2-agonist combinations. The available ones in the market are the combination of salmeterol and fluticasone, and the combination of formoterol and budesonide. In the studied period the increase of consumption of inhaled corticosteroid/long-acting β2-agonist combinations is represented as 43%. The use of combined drugs became more considerable because of the easier management of the diseases for both patients and physicians. Combined inhalers are more convenient for patients, they may increase compliance and ensure that the long-acting β2- agonist is always accompanied by the glucocorticosteroid. In addition, combined inhalers containing formoterol and budesonide may be used for both rescue and maintenance [22]. The most considerable decrease of consumption is the use of aminophylline. The role of aminophylline in the treatment for asthma and COPD has declined in the last years. According to the guidelines, it should not be used as the first line therapy. Aminophylline is associated with more frequent adverse effects and is less effective than salmeterol in improving the lung function, relieving both night and day symptoms and reducing the need of rescue therapy. In addition, aminophylline has a narrow therapeutic index and variable metabolism. The monitoring of plasma concentration is required while the use of aminophylline. The decrease of consumption of beclometasone may be due to the increased use of other inhaled corticosteroids in combinations with long-acting β2-agonists.

63 The results of pharmacoeconomical estimations in this study demonstrate how unreasonably the resources of health care budget are used. The expenditures of drugs have to be rationalized and the saved budget could be used for the most vulnerable sectors, which require more resources. The cost-minimisation and reference pricing methodologies have been implemented for the pharmacoeconomical analysis of equivalent drugs for obstructive airway diseases. The possible estimated savings are found to be considerable. The meaningful sum of money could be saved every year if the lowest suggested prices of one DDD as the reference prices were used. The savings when the second lowest price is used as the reference price are also important. The saved budget could be used for the improvement of the level of diagnosis of asthma and COPD, identification of the risk factors of the diseases, development of the prevention programmes or organisation of educational projects. The prices of one DDD vary considerably within the groups of equivalent drugs for the treatment of asthma and COPD. Even the prices of one DDD vary considerably within the preparations of the same active substance. One of the most costly groups of drugs for asthma and COPD is salmeterol/fluticasone combinations. All the preparations of this combination contain the same amount of DDDs. The retail prices of one DDD vary from 3,43 Litas to 6,57 Litas within this group. The basic price of one DDD vary from 3,19 Litas to 6,57 Litas. Considering the use of salmeterol/fluticasone combinations is high, the difference between the prices of one DDD is very important. Both the Government and the patient have to overpay these differences. The possible savings for salmeterol/fluticasone combinations implementing the lowest or the second lowest prices of one DDD as the reference prices are provided in Tables 23-26. The saving within the preparations of salmeterol/fluticasone combinations, when the lowest basic price of one DDD is used as reference price, is estimated as 10,03 million Litas. Evaluating the expenditures and the prices of one DDD of both available inhaled corticosteroid/long-acting β2-agonist combinations in the market (salmeterol/fluticasone and formoterol/budesonide), the total saving when the lowest basic price of one DDD is used as the reference price, 18, 04 million Litas would have been saved in 2009. The overpayment and the savings of other groups of alternative drugs are also important.

The prices of one DDD among long-acting β2-agonists or the inhaled corticosteroids vary as well. Considering the use of drugs of these groups separately is lower, the saving of 0,97 million Litas for long-acting β2-agonists (implementing the lowest retail price of one DDD as the reference price) and the saving of 1,36 million Litas for inhaled corticosteroids (implementing the lowest retail price of one DDD as the reference price) are also high.

64 13,45 million Litas (calculated in retail price) was spent for salmeterol/fluticasone (0,05/0,5 mg) combination in 2009. The price of one DDD in Lithuania is calculated as 6,49 Litas, the price of one DDD in United Kingdom is 5,49 Litas [109]. This difference represents a possible saving of 2,07 million Litas in 2009. It can be concluded that there exists a significant difference of prices for the same drugs among the countries. In addition, the use of combined drug of salmeterol/fluticasone (0,05/0,5 mg) is found to be more expensive compared to the salmeterol (0,05 mg) and fluticasone (0,5 mg) when used in the separate inhalers. The total cost of one DDD for both salmeterol and fluticasone together when used separately is 5,37 Litas (2,49 Litas for fluticasone and 2,88 Litas for salmeterol) and the cost of one DDD for combined preparation is estimated as 6,49 Litas. In conclusion, one of the most vulnerable positions of health care system is an ineffective use of its limited budget. Cost-minimisation analysis provides suggestive results. Implementation of the pharmacoeconomical analysis performed in this study, would reduce the overpayment which could be used more effectively in the other sectors of health care system.

65 8. CONCLUSIONS

• Total consumption of drugs for the treatment of asthma and COPD increased by 21% from 23,70 DDD/1000 inhabitants/day in 2006 to 28,67 DDD/1000 inhabitants/day in 2009. The highest increase (by 44%) was in the budesonide/formoterol combination group: from 2,97 DDD/1000 inhabitants/day in 2006 to 4,28 DDD/1000 inhabitants/day. • Total consumption of drugs for the treatment of asthma and COPD (by DDD/1000 inhabitants/day) is about two times higher in Norway, Denmark and Finland and 1,6 times lower in Estonia in comparison with Lithuania. • Direct costs for the asthma and COPD drugs increased by 34% from 59,71 million Litas in 2006 to 80,12 million Litas in 2008. Meanwhile in 2009 direct costs decreased by 1,08% - to 79,25 million Litas due to entering of generic formulations of leukotriene receptor antagonists.

• Pharmacoeconomical analysis (for the year 2009) presents the savings for long-acting β2- agonists from 975379,87 Litas to 656560,24 Litas in retail price and from 433841,36 Litas to 62201,36 Litas in basic price. The same savings for inhaled corticosteroids are estimated from 1361607,95 Litas to 1275864,75 Litas in retail price and from 1236132,45 Litas to 209641,25 Litas in basic price.

• The savings for inhaled corticosteroid/long-acting β2-agonist combinations are estimated from 17978952,3 Litas to 16152117,9 Litas in retail price and from 18045426,9 Litas to 16294710,6 Litas in basic price. • Implementation of reference price for asthma and COPD drugs will help us to use resources of health-care budget more effectively.

66 9. SUMMARY

Objective: To evaluate the utilization and cost of drugs for the treatment of asthma and COPD in Lithuania in 2006-2009.

Methodology: The data on the sales of drugs for asthma and COPD for the year 2006-2009 was obtained from SoftDent, JSC, database. The utilization of the R03 group (drugs for obstructive airway diseases) of the Anatomical Therapeutic Chemical (ATC) classification was analysed. The utilization was expressed as DDD/1000 inhabitants per day. The pharmacoeconomical analysis was performed implementing cost-minimisation and reference pricing methodologies.

Results: The total use of drugs for asthma and COPD increased from 23,70 DDD/1000 inhabitants/day in 2006 to 28,67 DDD/1000 inhabitants/day in 2009. The most significant increase is found in the use of inhaled corticosteroid/long-acting β2-agonist combinations. The costs for drugs for the treatment of asthma and COPD increased from 59,71 million Litas in 2006 to 80,12 million Litas in 2008 and decreased to 79,25 million Litas in 2009. The use of drugs of the ATC group R03 is about 2 times higher in Norway, Denmark and Finland and about 1,6 times lower in Estonia. The pharmacoeconomical analysis shows marked savings if the lowest of the second lowest prices of one DDD were implemented as the reference price. The most considerable saving is found to be for inhaled corticosteroid/long-acting β2-agonist combinations – using the lowest basic price of one DDD as the reference price, total 18,04 million Litas would be saved.

Conclusions: The utilization of drugs for asthma and COPD has a tendency to increase in

Lithuania. The combinations of inhaled corticosteroid/long-acting β2-agonist take a major part in the market of drugs for obstructive airway diseases. Pharmacoeconomical estimations would let us use the resources of health-care budget more effectively.

67 10. SANTRAUKA

Tikslas: Įvertinti vaist ų, vartojam ų astmai ir l ÷tinei obstrukcinei plau čių ligai (LOPL) gydyti suvartojim ą ir išlaidas Lietuvoje 2006-2009 metais.

Metodika: Duomenys apie vaist ų, vartojam ų astmai ir LOPL gydyti pardavimus 2006-2009 metais gauti iš UAB SoftDent duomen ų baz ÷s. Analizuojami vaistai yra klasifikuojami R03 grup÷je (vaistai obstrukcin ÷ms plau čių ligoms) pagal Anatomin ę Terapin ę Chemin ę (ATC) klasifikacij ą. Vaist ų suvartojimas išreikštas DDD skai čiumi, tenkan čiu t ūkstan čiui gyventoj ų per vien ą dien ą. Farmakoekonomin ÷ analiz ÷ atlikta taikant kašt ų mažinimo ir referentin ÷s kainos metodus.

Rezultatai: Bendras vaist ų astmai ir LOPL gydyti suvartojimas Lietuvoje išaugo nuo 23,70 DDD/1000 gyventoj ų per dien ą 2006 metais iki 28,67 DDD/1000 gyventoj ų per dien ą 2009 metais.

Didžiausias suvartojimo augimas nustatytas inhaliuojam ų gliukokortikosteroid ų/ilgo veikimo β2- agonist ų kombinuot ų preparat ų grup ÷je. Išlaidos vaist ų, vartojam ų astmai ir LOPL gydyti augo nuo 59,71 mln. Lit ų 2006 metais iki 80,12 mln. Lit ų 2008 metais ir 2009 metais sumaž ÷jo iki 79,25 mln. Lit ų. Vaist ų, klasifikuojam ų R03 grup ÷je pagal ATC klasifikacij ą, suvartojimas Lietuvoje yra apie 2 kartus mažesnis nei Norvegijoje, Danijoje ir Suomijoje ir apie 1,6 karto didesnis nei Estijoje. Farmakoekonomin ÷ analiz ÷ pateikia ženklius galimo taupymo pavyzdžius, jei mažiausia ar antra mažiausia vieno DDD kaina b ūtų taikoma kaip referentin ÷ kaina. Reikšmingiausi farmakoekonomin ÷s analiz ÷s rezultatai nustatyti inhaliuojam ų gliukokortikosteroid ų/ilgo veikimo

β2-agonist ų kombinuotiems preparatams – taikant mažiausi ą vieno DDD bazin ę kain ą, galima racionaliau panaudoti 18,04 mln. Lit ų.

Išvados: Vaist ų, vartojam ų astmos ir LOPL gydymui suvartojimas Lietuvoje auga. Kombinuoti inhaliuojam ų kortikosteroid ų/ilgo veikimo β2-agonist ų preparatai užima pagrindin ę vaist ų obstrukcin ÷ms plau čių ligoms gydyti rinkos dal į. Farmakoekonomin ÷ analiz ÷ pad ÷tų naudoti sveikatos apsaugos biudžeto išlaidas racionaliau.

68 REFERENCES

1. World Health Organization. Chronic Diseases and Health Promotion. Available from: URL: http://www.who.int/chp/en/. Accessed June 19, 2009. 2. World Health Organization. Chronic respiratory diseases. Available from: URL: http://www.who.int/respiratory/en/index.html. Accessed June 19, 2009. 3. Bousquet J, Knani J, Dhivert H, Richard A, Chicoye A, Ware JE et al. Quality of life in asthma. I. Internal consistency and validity of the SF-36 questionnaire. Am J Respir Crit Care Med 1994; 149(2 Pt 1):371-5. 4. Riccioni G, D'Orazio N, Di Ilio C, Menna V, Guagnano MT, la Vecchia R. Quality of life and clinical symptoms in asthmatic subjects. J Asthma 2004; 41(1):85-9. 5. Masoli M, Fabian D, Holt S, Beasley R. Global Initiative for Asthma (GINA) Program: The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 2004; 59(5):469-78. 6. Murray CJL, Lopez AD. Evidence-based health policy – lessons from the Global Burden of Disease Study. Science 1999;740-743. 7. World Health Organization. Chronic Obstructive Airway Disease. Available from: URL: http://www.who.int/respiratory/copd/en/. Accessed June 19, 2009. 8. M. Decramer, O. Selroos. Asthma and COPD: differences and similarities. Int J Clin Pract, April 2005, 59, 4, 385–398. 9. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the dzagnosis, management and prevention of chronic obstructive pulmonary disease. Updated 2009. Available from: URL: http://www.goldcopd.com/GuidelinesResources.asp?l1=2&l2=0. Accessed March 1, 2010. 10. Bahadori K, Doyle-Waters MM, Marra C, Lynd L, Alasaly K, Swiston J et al. Economic burden of asthma: a systematic review. BMC Pulmonary Medicine 2009; 9:24. Available from: URL: http://www.biomedcentral.com/content/pdf/1471-2466-9-24.pdf. Accessed June 13, 2009. 11. Braman SS. The global burden of asthma. Chest 2006 Jul; 130;4S-12S. Available from: URL: http://www.chestjournal.org/content/130/1_suppl/4S.full.pdf+html. Accessed June 19, 2009. 12. European lung white book. Brussels, Belgium: European Respiratory Society and the European Lung Foundation, 2003. 13. Sean D. Sullivan, Scott D. Ramsey and Todd A. Lee. The Economic Burden of COPD. Chest 2000;117;5S-9S. 14. Godard P, Chanez P, Siraudin L, et al. Costs of asthma are correlated with severity: a 1-yr prospective study. Eur Respir J 2002; 19:61–67.

69 15. Asthma in America: a landmark survey. GlaxoSmithKline, 1998. Available from: URL: http://www.asthmainamerica.com 16. Beasley R. The burden of asthma with specific reference to the United States. J Allergy Clin Immunol 2002; 109(5 Suppl):S482–S489. 17. The State Patients’ Fund at the Ministry of Health of Lithuanian Republic. Available from: URL: http://www.vlk.lt/vlk/sd/?page=item&item_id=127. Accessed July 7, 2009. 18. Information of the expenditures of compulsory health insurance fund budget for compensation of medicines and medical devices in 2009. Available from: URL: http://www.vlk.lt/vlk/pag/?page=kv. Accessed April 1, 2010. 19. National Heart Lung and Blood Institute & National Asthma Education and Prevention Program. (2007). Expert Panel Report 3: Guidelines for the diagnosis and management of asthma (NIH Publication No. 07–4051). Bethesda, MD: National Institutes of Health. Available from: URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed April 17, 2009. 20. Gillissen A. Managing asthma in the real world. Int J Clin Pract. 2004 Jun; 58(6):592-603. Available from: URL: http://www3.interscience.wiley.com/cgi-bin/fulltext/118807946/PDFSTART Accessed June 20, 2009. 21. Dahl R. Systemic side effects of inhaled corticosteroids in patients with asthma. Respir Med. 2006 Aug; 100(8):1307-17. 22. Beasley R. The Global Burden of Asthma Report. Global Initiative for Asthma (GINA). Available from: URL: http://www.ginaasthma.org. Accessed April 17, 2009 23. National Health Interview Survey (NHIS), National Center for Health Statistics, Centers for Disease Control and Prevention. Current asthma prevalence, 2005. 24. CDC National Centre for Health Statistics. Asthma prevalence, health care use and mortality. United States, 2003–2005. Available from: URL: http://www.cdc.gov/nchs/products/pubs/pubd/hestats/ashtma03-05/asthma03-05.htm#fig1. Accessed July 15, 2009. 25. National Asthma Council Australia. Asthma management handbook, 2006. Available from: URL: http://www.nationalasthma.org.au/cms/index.php. Accessed April 17, 2009. 26. National Health Interview Survey (NHIS), National Center for Health Statistics, Centers for Disease Control and Prevention. Current asthma prevalence, 2005. 27. Lithuanian Health Information Centre at the Ministry of Health of Lithuanian Republic; Available from: URL: http://www.lsic.lt. Accessed July 7, 2009. 28. Cheng J, Goldberg Arnold RJ. Pharmacoeconomic review of medical management of persistent asthma. Allergy Asthma Proc 29:109-122, 2008.

70 29. Smith DH, Malone DC, Lawson KA, Okamoto LJ, Battista C, Saunders WB: A national estimate of the economic costs of asthma. Am J Respir Crit Care Med 1997, 156(3 Pt 1):787-93. 30. Krahn MD, Berka C, Langlois P, Detsky AS: Direct and indirect costs of asthma in Canada, 1990. CMAJ 1996, 154(6):821-31. 31. Szucs TD, Anderhub H, Rutishauser M: The economic burden of asthma: direct and indirect costs in Switzerland. Eur Respir J 1999, 13(2):281-6. 32. Mellis CM, Peat JK, Bauman AE, Woolcock AJ: The cost of asthma in New South Wales. Med J Aust 1991, 155(8):522-8. 33. Sorensen L, Weng S, Weng SL, Wulf-Andersen L, Ostergaard D, Bech PG: The cost of asthma in Denmark. Br J Med Econ 1997, 11:103-11. 34. Stevens CA, Turner D, Kuehni CE, Couriel JM, Silverman M: The economic impact of preschool asthma and wheeze. Eur Respir J 2003, 21(6):1000-6. 35. Barnes PJ, Jonsson B, Klim JB. The costs of asthma. Eur Respir J 1996; 9: 636–42. Available from: ULR: http://erj.ersjournals.com/cgi/reprint/9/4/636. Accessed June 19, 2009. 36. Freund DA, Dittus RS. Principles of pharmacoeconomical alysis of drug therapy. Pharmacoeconomics. 1992 Jan; 1(1):20-31. Available from: URL: http://www.ncbi.nlm.nih.gov/pubmed/10147037. Accessed September 4, 2009. 37. Sloan FA. Valuing Health Care: costs, benefits, and effectiveness of pharmaceuticals and other medical technologies. Cambridge: Cambridge University Press, 1996. 38. Campbell JD, Spackman DE, Sullivan SD. Health economics of asthma: assessing the value of asthma interventions. Allergy 2008: 63: 1581–1592. Available from: URL: http://www3.interscience.wiley.com/cgi-bin/fulltext/121515552/PDFSTART. Accessed September 2, 2009. 39. Sheth K, Borker R, Emmett A et al. Cost-effectiveness comparison of salmeterol/fluticasone propionate versus montelukast in the treatment of adults with persistent asthma. Pharmacoeconomics 20:909-918, 2002. 40. Leibman CW, Stanford RH, Emmett A et al. Cost-effectiveness of fluticasone propionate/salmeterol combination versus fluticasone plus montelukast in the treatment of persistent asthma. Am J Respir Crit Care Med 165;B4, 2002. 41. O‘Connor RD, O‘Donnell JC, Pinto LA et al. Two-year retrospective economic evaluation of three dual-controller therapies used in the treatment of asthma. Chest 121:1028-1035, 2002. 42. Price D, Haughney J, Lloyd A et al. An economic evaluation of adjustable and fixed dosing with budesonide/formoterol via a single inhaler in asthma patients. Curr Med Res Opin 20:1671- 1679, 2004.

71 43. Menedez R, Standard RH, Edwards L et al. Cost-efficacy analysis of fluticasone propionate versus zafirlukast in patients with persistent asthma. Pharmacoeconomics 19:865-874, 2001. 44. Bukstein DA, Henk HJ, Luskin AT. A comparision of asthma-related expenditures for patients started on montelukast versus fluticasone propionate as monotherapy. Clin Ther 23:1589-1600, 2001. 45. Stempel DA, Standford RH, Yancey SW et al. One year claims anglysis demonstrantes that fluticasone reduces asthma related hospitalizations, ER visits and total health care costs greater than beclomethasone. Am J Respir Crit Med 161(suppl):A788, 2000. 46. Stempel DA, Standford RH, Thwaites RMA, Price M. Cost-efficacy comparision of inhaled fluticasone propionate and budesonide in the treatment of asthma. Clin Ther 22:1562-1574, 2000. 47. Oba Y, Salzman GA. Cost-effectiveness analysis of omalizumab in adults and adolescents with moderate to severe allergic asthma. J Allergy Clin Immunol 114:265-269, 2004. 48. Truitt T, Witko J, Halpern M. Levalbuterol compared to racemic albuterol: Efficacy and outcomes in patients hospitalized with COPD or asthma. Chest 123:128-135, 2003. 49. Carl JC, Myers TR, Kishner HL, Kercsmar CM. Comparision of racemic albuterol and levalbuterol in treatment of acute asthma. J Peds 143:731-736, 2003. 50. Global Strategy for Asthma Management and Prevention. GINA, 2008. Available from: URL: http://www.ginaasthma.org. Accessed 17 April, 2009. 51. Chen H, Gould MK, Blanc PD, Miller DP, Kamath TV, Lee JH et al. Asthma control, severity and quality of life: quantifying the effect of uncontrolled disease. J Allergy Clin Immunol, 2007 Aug; 120(2):396-402. 52. Pizzichini MM, Popov TA, Efthimiadis A, Hussack P, Evans S, Pizzichini E et al. Spontaneous and induced sputum to measure indices of airway inflammation in asthma. Am J Respir Crit Care Med 1996; 154(4 Pt 1):866-9. 53. Kharitonov S, Alving K, Barnes PJ. Exhaled and nasal nitric oxide measurements: recommendations. The European Respiratory Society Task Force. Eur Respir J 1997; 10(7):1683- 93. 54. Horvath I, Barnes PJ. Exhaled monoxides in asymptomatic atopic subjects. Clin Exp Allergy 1999; 29(9):1276-80. 55. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2000; 360(9347):1715-21. 56. Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 2005; 352(21):2163-73.

72 57. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA et al. Can guideline- defined asthma control be achieved? The Gaining Optimal Asthma Control study. Am J Respir Crit Care Med 2004; 170(8):836-44. 58. Busse WW, Lemanske RF, Jr. Asthma. N Engl J Med 2001; 344(5):350-62. 59. Sears MR. Epidemiology of asthma exacerbations. J Allergy Clin Immunol. 2008 Oct; 122(4):662-8. Available from: URL: http://www.sciencedirect.com. Accessed June 19, 2009. 60. Sykes A, Johnston SL. Etiology of asthma exacerbations. J Allergy Clin Immunol. 2008 Oct; 122(4):685-8. Available from: URL: http://www.sciencedirect.com. Accessed June 19, 2009. 61. Holgate ST. Pathogenesis of asthma. Clin Exp Allergy 2008; 38(6):872–97. 62. Wenzel S. Pathology of difficult asthma. Paediatr Respir Rev. 2003; 4(4):306-11. Available from: URL: http://www.sciencedirect.com/science. Accessed 19 June, 2009. 63. Hamid Q, Tulic MK, Liu MC, Moqbel R. Inflammatory cells in asthma: mechanisms and implications for therapy. J Allergy Clin Immunol. 2003 Jan; 111(1 Suppl):S5-S12; discussion S12- 7. Available from: URL: http://www.sciencedirect.com/science. Accessed 19 June, 2009. 64. Bone RC. Goals of asthma management. Chest. 1996; 109(4):1056-65. Available from: URL: http://www.chestjournal.org/content/109/4/1056.long. Accessed 19 June, 2009. 65. Bisgaard H. Role of in asthma pathophysiology. Pediatr Pulmonol. 2000 Aug; 30(2):166-76. Available from: URL: http://www3.interscience.wiley.com/cgi- bin/fulltext/72513805/PDFSTART. Accessed 19 June, 2009. 66. Busse WW, Lemanske RF Jr. Asthma. N Engl J Med 2001; 344(5):350–62. 67. Holgate ST, Polosa R. The mechanisms, diagnosis, and management of severe asthma in adults. Lancet 2006; 368(9537):780–93. 68. IPCRG Exchanges. Asthma Guidelines 2008. How useful to primary care professionals around the world are they? Available from: URL: http://www.theipcrg.org. Accessed July 27, 2009. 69. Barnes PJ. Asthma guidelines: recommendations versus reality. Respir Med. 2004 Apr; 98 Suppl A:S1-7. 70. Cockcroft DW. Clinical concerns with inhaled β2-agonists. Adult asthma. Clin Rev Allergy Immunol. 2006 Oct-Dec; 31(2-3):197-208. Available from: URL: http://www.springerlink.com/content/e6n1mk8466r36303/fulltext.pdf. Accessed 19 June, 2009. 71. British Thoracic Society, Scottish Intercollegiate Guidelines Network. British Guideline on the Management of Asthma. A national clinical guideline 2008; updated June 2009. Available from: URL: http://www.brit-thoracic.org.uk. Accessed 7 July, 2009. 72. Baptist AP, Reddy RC. Inhaled corticosteroids for asthma: are they all the same? J Clin Pharm Ther. 2009 Feb; 34(1):1-12. Available from: URL: http://www3.interscience.wiley.com/cgi- bin/fulltext/121541601/PDFSTART. Accessed 20 June, 2009.

73 73. National Institute for Health and Clinical Excellence (NICE). Inhaled corticosteroids for the treatment of chronic asthma in adults and in children aged 12 years and over; 2008. Available from: URL: www.nice.org.uk/TA138. Accessed 17 April, 2009. 74. Main C, Shepherd J, Anderson R, Rogers G, Thompson-Coon J, Liu Z et al. Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting β2-agonists for the treatment of chronic asthma in children under the age of 12 years. Health Technol Assess. 2008 May; 12(20):1-174. Available from: URL: http://www.hta.ac.uk/fullmono/mon1220.pdf. Accessed 20 June, 2009. 75. Barnes PJ. Molecular mechanisms of corticosteroids in allergic diseases. Allergy 2001; 56:928– 936. 76. Postma DS, Kerstjens H, Hacken N. Inhaled corticosteroids and long-acting beta-agonists in adult asthma: a winning combination in all? Naunyn Schmiedebergs Arch Pharmacol. 2008 Aug; 378(2):203-15. Available from: URL: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2493602&blobtype=pdf. Accessed 20 June, 2009. 77. Rossi GA, Cerasoli F, Cazzola M. Safety of inhaled corticosteroids: Room for improvement. Pulm Pharmacol Ther. 2007;20(1):23-35. Available from: URL: http://www.sciencedirect.com/science. Accessed 20 June, 2009. 78. Adams NP, Jones PW. The dose–response characteristics of inhaled corticosteroids when used to treat asthma: an overview of Cochrane systematic reviews. Respiratory Med 2006; 200:1297– 1306 79. Dahl R. Systemic side effects of inhaled corticosteroids in patients with asthma. Respir Med. 2006 Aug; 100(8):1307-17. Available from: URL: http://www.sciencedirect.com/science. Accessed 20 June, 2009. 80. Nelson HS. Long-acting beta-agonists in adult asthma: evidence that these drugs are safe. Prim Care Respir J 2006; 15:271–277. 81. Reddy RC. Severe asthma: approach and management. Postgrad. Med. J. 2008; 84;115-120 Available from: URL: http://pmj.bmj.com/cgi/reprint/84/989/115. Accessed 19 June, 2009. 82. National Institute for Health and Clinical Excellence (NICE). Omalizumab for severe persistent allergic asthma; 2007. Available from: URL: www.nice.org.uk/TA133. Accessed 17 April, 2009. 83. Adcock IM, Gaetano Caramori G, Fan Chung K. New targets for drug development in asthma. Lancet. 2008 Sep; 372(9643):1073-87. Available from: URL: http://www.sciencedirect.com/science. Accessed 19 June, 2009. 84. Long AA. Immunomodulators in the treatment of asthma. Allergy Asthma Proc. 2009 Mar-Apr; 30(2):109-19. Available from: URL: http://docserver.ingentaconnect.com. Accessed 19 June, 2009.

74 85. Pocket Guide for Asthma Management and Prevention in Children 5 Years and Younger. GINA, 2009. Available from: URL: http://www.ginaasthma.org. Accessed 13 August, 2009. 86. Anis AH, Lynd LD, Wang X, Greg King G, Spineli JJ, Fitzgerald M et al. Double trouble: impact of inappropriate use of asthma medication on the use of health care resources. CMAJ 2001; 164(5):625-31. Available from: URL: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=11258208. Accessed September 4, 2009. 87. Hong SH; Sanders BH, West D. Inappropriate use of inhaled short acting β2-agonists and its association with patient health status. Curr Med Res Opin. 2006 Jan; 22(1):33-40. Available from: URL: http://www.informahealthcare.com/doi/abs/10.1185/030079905X74934. Accessed September 4, 2009. 88. King MT, Kenny PM, Marks GB. Measures of asthma control and quality of life: longitudinal data provide practical insights into their relative usefulness in different research contexts. Qual Life Res. 2009 Apr; 18(3):301-12. Available from: URL: http://www.springerlink.com/content/u2w32709j4v16ph6/fulltext.pdf. Accessed September 4, 2009. 89. Mannino DM. COPD. Epidemiology, Prevalence, Morbidity and Mortality, and Disease Heterogeneity. Chest 2002;121;121S-126S. 90. Punturieri A, Croxton TL, Weinmann GG, Kiley JP. Chronic Obstructive Pulmonary Disease. A View from the NHLBI. Am J Respir Crit Care Med. 2008 September 1; 178(5): 441–443. 91. The Australian Lung Foundation and the Thoracic Society of Australia and New Zealand. Australian and New Zealand Gudelines for the management of Chronic Obstructive Pulmonary Disease 2009. 92. European Lung Foundation. COPD: Burden in Europe. Available from: URL: http://www.european-lung-foundation.org/index.php?id=63. Accessed 1 March, 2010. 93. Halpin D, Miravitlles M. Chronic Obstructive Pulmonary Disease The Disease and Its Burden to Society. Proc Am Thorac Soc 2006, Vol 3. pp 619–623. 94. American Thoracic Society, European Respiratiry Society. Standards for the diagnosis and management of patients with COPD 2004. 95.WHO. Global surveillance, prevention and control of chronic respiratory diseases, 2007. 96. Sean D. Sullivan, Scott D. Ramsey and Todd A. Lee. The Economic Burden of COPD. Chest 2000;117;5S-9S. 97. Medifocus Guidebook on Chronic Obstructive Pulmonary Disease. Updated January 27, 2010.

75 98. Birring SS et al. Clinical, radiologic, and induced sputum features of chronic obstructive pulmonary disease in nonsmokers: a descriptive study. Am J Respir Crit Care Med 2002;166(8):1078-83. 99. MacNee W. Oxidative stress and lung inflammation in airways disease. Eur J Pharmacol 2001;429(1-3):195-207. 100. Ito K, Ito M, Elliott WM, Cosio B, Caramori G, Kon OM, et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med 2005;352(19):1967-76. 101. National Institute for Clinical Excellence. COPD. Management of chronic obstructive pulmonary disease in adults in primary and secondary care, 2004.. 102. WHO Collaborating Centre for Drug Statistics Methodology. The ATC/DDD system – International language for drug utilization research. Norway, 2007. Available from: URL: http://www.fhi.no/dav/a0fb3024e7.pdf. Accessed September 14, 2009. 103. WHO Collaborating Centre for Drug Statistics Methodology. Available from: URL: http://www.whocc.no/atcddd/. Accessed September 14, 2009. 104. Wertheimer AI, Santella TM. Problems using the defined daily dose (DDD) as a statistical basis for drug pricing and reimbursement. International Federation of Pharmaceutical Manufacturers and Associations. Switzerland, 2007. Available from: URL: http://www.ifpma.org/documents/NR9737/IFPMA_DDD_2007_EN.pdf. Accessed September 14, 2009. 105. World Health Organisation. Introduction to Drug Utilization Research. Norway, 2003. Available from: URL: http://www.who.int/medicines/areas/quality_safety/safety_efficacy/Drug%20utilization%20researc h.pdf. Accessed September 14, 2009. 106. Bootman JL, Townsend RJ, McGhan WF. Introduction to pharmacoeconomics. In: Bootman JL, Townsend RJ, McGhan WF, eds. Principles of Pharmacoeconomics. 2nd ed. Cincinnati, OH: Harvey Whitney Books Company;1996. 107. World Health Organization. Introduction to Drug Utilization Research. Available from: URL: http://apps.who.int/medicinedocs/en/d/Js4876e/5.2.html. Accessed September 14, 2009. 108. Innovative medicines. Reference Pricing – Background information and IMSA position. Available from: URL: http://www.imsa.org.za/files/Library/IMSA%20Position% 20Statements%2 0and%20Issues(1)/IMSA%20Position%20on%20Reference%20Pricing.pdf. Accessed September 14, 2009. 109. British National Formulary. Available from: URL: http://bnf.org/bnf/bnf/current/76772.htm ?q=seretide&t=search&ss=text&p=1#_76772. Accessed March 1, 2010.

76 ANNEXES

ANNEX 1

3000

2500 2782

2000

1500

1000 1196

500 686 Direct costs (Euros) 263 0 Mild (13,7) Moderate Moderate Severe (14,1) (33,3) severe (38,9) Asthma severity (patients, %)

Figure 1 Severity of asthma and direct costs for asthma in Euros

77 ANNEX 2 Table 2 Cost-effectiveness analysis of different medications used for asthma management Study Number of Regimen Cost-effectiveness patients Combined inhaled 423 Salmeterol plus fluticasone vs. Mean daily cost per patient per symptom long-acting β2-agonist montelukast [39] day: $7.62 for fluticasone plus salmeterol; $14.89 for montelukast. (2001 value) Not Salmeterol plus fluticasone vs. Fluticasone plus salmeterol was dominant available fluticasone plus montelukast strategy compared to fluticasone plus [40] montelukast (less costly $3.64 vs. $4.64 per patient per day) and more effective. (2001 value). Salmeterol plus fluticasone vs. 12-month risk-adjusted total and fluticasone plus montelukast pharmaceutical costs associated with vs. salmeterol plus another patients receiving inhaled salmeterol plus inhaled corticosteroid [41] fluticasone ($975 and $813 for total and pharmacy costs, respectively) were significant lower than those associated with salmeterol plus another inhaled corticosteroid ($1089 and $841) over inhaled corticosteroid plus a leukotriene modifier ($1268 and $996). (Value year not specified). Combined inhaled 1553 Budesonide plus formoterol Main daily cost per patient was £1.13 in long-acting β2-agonist adjustable maintenance dosing adjustable dose patients and £1.31 in fixed plan or budesonide plus dosing patients. (2001 value). formoterol fixed dosing [42] Leukotriene modifiers 451 Fluticasone 88 g twice daily Mean cost-effectiveness ratio per vs. zafirlukast 20 mg twice successfully treated patient was $3.47/day daily [43] for fluticasone vs. $7.81/day for zafirlukast. The mean ICER symptom-free days was $5,51 for fluticasone compared with $14.98 for zafirlukast. (1999 value). 343 Fluticasone vs. montelukast Montelukast had a significant increase in [44] asthma-related pharmacy expenses compared with patients receiving fluticasone ($302 vs. $170 over a 1-year period, p < 0.001). (1997-1999 value). Inhaled 3544 Fluticasone vs. Exact monetary values were not reported; corticosteroids beclomethasone [45] compared to the pre-index period, asthma related costs were reduced in patients using fluticasone but increased in patients using beclomethasone. Meta- Fluticasone vs . budesonide The total daily per person cost of asthma analysis [46] management was higher for patient treated with budesonide than with fluticasone ($3 vs . $2.25, respectively). The daily cost per effectively treated patient was $5.62 with fluticasone and $10.05 with budesonide. (2000 value). Anti-IgE antibody 1071 Omalizumab vs. placebo [47] ICER to achieve an additional successful controlled day was $523. (2003 value). β2-agonist 234 Albuterol 0.5 mg every 4 hr Cost savings with levalbuterol $556 per vs . levalbuterol 1.25 mg every patient. (1999 value). 8 hr [48] 482 Levalbuterol 1.25 mg or Annual savings of $180,000 minus the racemic albuterol 2.5 mg additional drug acquisition costs for administered every 20 min to a levalbuterol ($5 per patient). Significant maximum of 6 doses in 2 hr fewer hospitalizations with levalbuterol than [49] with albuterol (37% vs. 45%, p = 0.02). (Value year not specified).

78 ANNEX 3 Table 4 Estimated equipotent doses of ICSs in adults and children Drug Adults Children Daily dose ( g) † Daily dose ( g) † Low Medium High ‡ Low Medium High ‡ Beclomethasone 200-500 >500-1000 >1000-2000 100-200 >200-400 >400 dipropionate Budesonide* 200-400 >400-800 >800-1600 100-200 >200-400 >400 Budesonide-Neb 500-1000 1000-2000 >2000 250-500 >500-1000 >1000 Inhalation suspension Ciclesonide* 80-160 >160-320 >320-1280 80-160 >160-320 >320 Flunisolide 500-1000 >1000-2000 >2000 500-750 >750-1250 >1250 Fluticasone 100-250 >250-500 >500-1000 100-200 >200-500 >500 Mometasone 200-400 >400-800 >800-1200 100-200 >200-400 >400 furoate* Triamcinolone 400-1000 >1000-2000 >2000 400-800 >800-1200 >1200 acetonide † Comparisons based on efficacy data * Approved for once-daily dosing in mild patients ‡ Patients considered for high daily doses except for short periods should be referred to a specialist for assessment to consider alternative combinations of controllers.

79 ANNEX 4 Table 6 Stepwise approach for managing asthma in children older than 5 years, adolescents and adults Intermittent Persistent asthma: daily medication asthma Step 1 Step 2 Step 3 Step 4 Step 5

Preferred Preferred Preferred Preferred Oral SABAs Low-dose ICS Low-dose ICS plus Medium- or high- glucocorticosteroid LABA dose ICS plus (lowest dose) LABA Anti-IgE treatment

Alternative Alternative Alternative Alternative Inhaled Leukotriene Medium- or high- Medium- or high- anticholinergics; modifiers; dose ICS; dose ICS plus short-acting oral sustained–release low-dose ICS plus either leukotriene β2-agonists; theophylline; either leukotriene modifier or short-acting cromones modifier or sustained-release theophylline sustained-release theophylline theophylline

As-needed reliever therapy Asthma education, environmental control

80 ANNEX 5 Table 7 Asthma management approach based on control for children 5 years and younger

Asthma education, Environmental control, and As needed short-acting β2-agonists Controlled Partly controlled Uncontrolled or only on as needed on as needed partly controlled on short-acting β2-agonists short-acting β2-agonists low-dose inhaled glucocorticosteroid*

Controller options

Continue as needed Preferred Preferred short-acting β2-agonists Low-dose inhaled Double low-dose inhaled glucocorticosteroid glucocorticosteroid

Alternative Alternative Leukotriene modifier Low-dose inhaled glucocorticosteroid plus leukotriene modifier

*Oral glucocorticosteroids should be used only for treatment of acute severe exacerbations of asthma.

81 ANNEX 6 Table 9 Commonly used formulations of drugs used in COPD Drug Inhaler Solution for Oral Vials for Duration (g) Nebulizer injection of action (mg/ml) (mg) (hours) β2-agonists Short-acting Fenoterol 100-200 (MDI) 1 0.05% Syrup 4-6

Levalbuterol 45-90 (MDI) 0.21, 0.42 6-8 Salbutamol 100, 200 (MDI & 5 5 mg Pill, 0.024% 0.1, 0.5 4-6 DPI) Syrup Terbutaline 400, 500 (DPI) 2.5, 5 Pill 0.2, 0.25 4-6 Long-acting Formoterol 4.5-12 (MDI & 0.01* 12+ DPI) Salmeterol 25-50 (MDI & 12+ DPI) Anticholinergics Short-acting Ipratropium bromide 20, 40 (MDI) 0.25-0.5 6-8 Oxitropium bromide 100 (MDI) 1.5 7-9 Long-acting Tiotropium 18 (DPI), 5 (SMI)

Combination short-acting β2-agonists plus anticholinergic in one inhaler Fenoterol/Ipratropium 200/80 (MDI) 1.25/0.5 6-8 Salbutamol/Ipratropium 75/15 (MDI) 0.75/4.5 6-8 Methylxanthines Aminophylline 200-600 mg Pill 240 mg Variable, up to 24 Theophylline (SR) 100-600 mg Pill Variable, up to 24 Inhaled glucocorticosteroids Beclomethasone 50-400 (MDI & 0.2-0.4 DPI) Budesonide 100, 200, 400 0.20, 0.25, (DPI) 0.5 Fluticasone 50-500 (MDI & DPI) Triamcinolone 100 (MDI) 40 40

Combination long-acting β2-agonists plus glucocorticosteroids in one inhaler Formoterol/Budesonide 4.5/160, 9/320 (DPI) Salmeterol/Fluticasone 50/100, 250, 500 (DPI) 25/50, 125, 250 (MDI) Systemic glucocorticosteroids Prednisolone 5-60 mg Pill Methyl-prednisolone 4, 8, 16 mg Pill * Formoterol nebulized solution is based on the unit dose vial containing 20 g in a volume of 2.0 ml

82 ANNEX 7 Table 10 Therapy at each stage of COPD I: Mild II: Moderate III: Severe IV: Very Severe

FEV 1/FVC < 0.70; FEV 1/FVC < 0.70; FEV 1/FVC < 0.70; FEV 1/FVC < 0.70; FEV 1 ≥ 80% predicted 50% ≤ FEV 1 < 80% 30% ≤ FEV 1 < 50% FEV 1 < 30% predicted predicted predicted or FEV 1 < 50% predicted plus chronic respiratory failure

Add short-acting bronchodilator (when needed) Add regular treatment with one or more long-acting bronchodilators (when needed) Add inhaled glucocorticosteroids if repeated exacerbations Add long term oxygen if chronic respiratory

failure; consider surgical treatments

83