Budesonide + formoterol fumarate dihydrate for the treatment of asthma

Ole D. Wolthers

To cite this article: Ole D. Wolthers (2016): Budesonide + formoterol fumarate dihydrate for the treatment of asthma, Expert Opinion on Pharmacotherapy, DOI: 10.1517/14656566.2016.1165207
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EXPERT OPINION ON PHARMACOTHERAPY, 2016

http://dx.doi.org/10.1517/14656566.2016.1165207

DRUG EVALUATION
Budesonide + formoterol fumarate dihydrate for the treatment of asthma
Ole D. Wolthers
Asthma and Allergy Clinic, Children´s Clinic Randers, Randers, Denmark

ARTICLE HISTORY
Received 24 January 2016
Accepted 9 March 2016 Published online
8 April 2016
KEYWORDS
Asthma; bioavailability; budesonide; formoterol; formoterol fumarate dihydrate; inhaled corticosteroids; inhaled steroids; long-acting β2- agonists; short-acting β2- agonists; pharmacokinetics; systemic activity; hypothalamic-pituitary- adrenal function

1. Introduction
Asthma is a chronic obstructive pulmonary disease that causes significant health problems to patients and a substantial eco- nomic burden on societies.[1] Inhaled corticosteroids are regarded as first-line treatment for patients with persistent asthma irrespective of disease severity.[1] Patients with asthma not sufficiently controlled on an inhaled corticosteroid and a short-acting β-2 agonist (SABA) as needed might have a long-acting β2-agonist (LABA) added.[1] The single-inhaler containing a fixed dose of a glucocorticosteroid and a LABA has been supported by indications that the combination of drugs may improve each other’s actions in the airways.[2] Combining the two drugs in one inhaler, furthermore, may simplify the administration regimen, improve adherence, and ensure that a LABA may not be used as mono-therapy without an anti-inflammatory agent, which appear to be important for the control of pulmonary hyperreactivity.[1,3] Trials in adult asthma patients have suggested that maintenance and relie- ver treatment with a fixed combination of dry powder bude- sonide+formoterol fumarate dihydrate may be clinically advantageous in patients with asthma who are symptomatic despite the use of inhaled corticosteroid mono-therapy.[4,5] Recently, the maintenance and reliever strategy was sup- ported by guideline recommendations.[1] One of the most widely used fixed combinations in asthma management is dry powder budesonide+formoterol fumarate dihydrate,

which is commercially available as Symbicort Turbuhaler® (and generic products), Easyhaler Bufomix®, and DuoRespSpiromax® inhaler. The aim of this paper is to review the role of the fixed dry powder combination of inhaled budesonide+formoterol fumarate dihydrate in asthma treatment.

2. Methods
The following databases were used in the literature search: PubMed, a service of the National Library of Medicine, New York, U.S.A, includes over 25 million citations for biomedical articles from the 1950s to 8 January 2016. The citations are from MEDLINE and additional life science journals and The Cochrane Library. The following search terms were used: inhaled corticosteroids and long acting β-2 agonists, flutica- sone propionate/salmeterol xinofate, fluticasone propionate/ formoterol fumarate, beclomethasone dipropionate/formo- terol fumarate and budesonide/formoterol fumarate, flutica- sone fumarate/vilanterol trifenatate, mometasone furoate/ indacaterol maleate, inhaled glucocorticosteroids, inhaled ster- oids, inhaled corticoids, inhaled glucocorticoids, beclometha- sone dipropionate, budesonide, fluticasone propionate, mometasone furoate, fluticasone fumarate, flunisolide, triam- cinolone acetonide, ciclesonide, salmeterol xinofate, formo- terol fumarate, vilanterol trifenatate, indacaterol maleate, asthma. The literature was also studied by manual searches

© 2016 Informa UK Limited, trading as Taylor & Francis Group

smaller than 5 µm; larger particles are prone to being depos- ited in the mouth and throat, causing a risk of local adverse effects.[7,14] The mass median aerodynamic diameter (MMAD) of dry powder budesonide+formoterol fumarate dihydrate has been found to be in the range of 2–2.5 µm for two of the available combinations, whereas data on the third combina- tion are not available.[15,16] A drug summary is presented in Box 1.

3.3. Chemistry
Like other inhaled corticosteroids budesonide (16,17-(butyli- denebis(oxy))-11,21-dihydroxy-, (11-β,16-α)-pregna-1,4-diene- 3,20-dione) possesses the 17-carbon androstane nucleus derived from cholesterol, Figure 1.[17]
Formoterol fumarate dihydrate (rac-(R,R)-N-[2-hydroxy-5-[1- hydroxy-2-[1-(4-methoxyphenyl) propan-2-ylamino]ethyl] phe- nyl]formamide) is a selective β2-adrenoceptor agonist, Figure 2.[18]

of reference lists for reviews and meta-analyses. For the review of efficacy primarily but not exclusively randomized double- blind trials were included.

3. Body of review
Combination inhalers that deliver an inhaled corticosteroid and a LABAs have been available for approximately two decades.

3.1. Overview of the market
Currently widely available fixed combinations are budesonide/ formoterol fumarate dihydrate, fluticasone propionate/salme- terol xinofate, fluticasone propionate/formoterol fumarate, beclomethasone dipropionate/formoterol fumarate dihydrate, mometasone furoate/indacaterol maleate, and fluticasone fumarate/ vilanterol trifenatate.[6–10] Some of the fixed com- binations may be available as metered dose or as dry powder inhalers or as both formulations. It may vary throughout the world regarding which formulations are available.

3.2. Introduction to the compound
Dry powder budesonide+formoterol fumarate dihydrate is one of the most widely used and most studied fixed combinations for use in asthma management.[11–13]
Emitted particles from an inhaler device may vary from <1 to >10 µm, and to be in the respirable range, i.e. to be deposited throughout the airways, the particles should be

3.4. Pharmacodynamics
The anti-asthmatic effects of budesonide are not known; how- ever, corticosteroids as a drug class downregulate fluid exuda- tion, inflammatory cells, histamine, tryptase, cytokines, chemokines, and other mediators released from inflammatory cells, which suppress inflammatory activity.[7]
Activation of β2-adrenergic receptors by LABAs causes relaxation of bronchial smooth muscle cells and, hence, bronchodilation. The action appears to be by activation of intracellular adenylate cyclase, which results in stimulation of protein kinase, which causes smooth muscle relaxation.[19] Bronchodilation has been detected in adults with asthma from 5–10 minutes after formoterol fumarate dihydrate was inhaled and up to 2 hours after.[18]

Figure 1. Chemical structure of budesonide (16,17-(butylidenebis(oxy))-11,21- dihydroxy-, (11-β,16-α)-pregna-1,4-diene-3,20-dione).

Figure 2. Chemical structure of formoterol fumarate dehydrate (rac-(R,R)-N-[2- hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl) propan-2-ylamino]ethyl] phenyl] formamide).

3.5. Pharmacokinetics and metabolism
Pharmacokinetic key data of budesonide are given in Table 1. Most of the data were derived from in vitro studies and from pharmacokinetic studies in healthy adults.[17]
Virtually all of the budesonide deposited in the lungs will become available in the systemic circulation. Inhaled corticos- teroids penetrate the phospholipid bilayer of cell membranes in the intrapulmonary epithelium to bind with the intracellular glucocorticoid receptor. The rate of uptake depends on a number of factors such as molecular size, charge and config- uration, and lipophilicity of the molecule.[7,20] Receptor bind- ing affinity, pulmonary retention time, and duration of action, thus, depend on lipophilicity. Intracellular reversible fatty acid esterification of inhaled corticosteroids has been suggested as a mechanism by which corticosteroids can be retained longer in the lungs, thus increasing pulmonary retention time and the duration of action.[17] The plasma protein binding of inhaled corticosteroids is being considered important since it is the unbound fraction only that is expected to have pharmacolo- gical activity. The half-life of an inhaled drug is a function of plasma clearance and the volume of distribution of the drug; thus, it is a secondary measure depending on other pharma- cokinetic factors.[19] Inhaled corticosteroids are primarily metabolized by the hepatic cytochrome P450 [CYP) enzyme CYP3A4 and an extensive first-pass hepatic metabolization of budesonide has been documented.[17] The metabolites of budesonide have significantly reduced or no corticosteroid activity.
As budesonide, formoterol fumarate dihydrate is absorbed approximately 100% from the lungs into the systemic circula- tion. The bioavailability after oral and pulmonary deposition is 20–45%.[21] Approximately 64% of the drug in serum is bound to proteins. Half-life in plasma is 8 hours. Formoterol fumarate dihydrate is metabolized primarily by direct conjuga- tion at the phenolic hydroxyl group. A second pathway is by O-demethylation by cytochrome P450 isozymes, followed by conjugation at the 2′-hydroxyl group. About 10% of the inhaled formoterol is excreted unchanged in the urine, while 15–18% is excreted as direct conjugates.[21]
The pharmacokinetic and metabolic characteristics of the fixed combination of budesonide+formoterol fumarate dihy- drate appear to correspond to its individual components and do not appear to vary between specific dry powder devices.
[22] Four studies found equivalent pulmonary deposition rates

Table 1. Pharmacokinetic key data of budesonide.
Pulmonary deposition (% of delivered dose) 27
Bioavailability of oral deposition (%) 11
Bioavailability of pulmonary deposition 27
Bioavailability of oral and pulmonary deposition (%) 39
First-pass hepatic metabolism extensive
Pulmonary retention time (h) <0.5
Esterification yes
Lipophilicity (LogP) 2.32
Mean volume of distribution at SS* (L) 180
Receptor-binding affinity 9.35 times
Dexamethasone
Plasma protein binding (%) 91.4
Half-life in plasma (h) 2.8
*Following intravenous administration.

and systemic exposure characteristics as assessed by area- under-the curve analyses in healthy adult subjects inhaling the fixed combination of budesonide+formoterol fumarate dihydrate from two different inhaler dry powder devices.[22]

3.6. Clinical efficacy
Primary outcome measures in clinical trials of the fixed combination of budesonide+formoterol fumarate dihydrate have been exacerbation rate, hospital admission and emer- gency room visit rate, and frequency of exacerbations requiring treatment with oral corticosteroids. Many second- ary outcome measures have been tested such as diary card morning and evening peak expiratory flow (PEF), clinic spirometry (FEV1), number of rescue medication puffs required per day, symptoms/symptom-free days, nocturnal awakenings, and quality of life. Since the available studies, however, have mostly been power calculated based on the mentioned primary measures in the following focus will be on these measures. Furthermore, the pivotal clinical research into the dry powder combination of budesonide
+formoterol fumarate dihydrate for asthma treatment was performed with one of the fixed combinations.[11] The available data in the literature reflect that and, so, does the present review.

3.6.1. Phase I and II studies
No phase I or II clinical efficacy studies were retrieved by the literature search. Based on the knowledge of comparable pharmacokinetics and pharmacodynamics of the fixed dry powder combination of budesonide+formoterol fumarate dihydrate versus the monoproducts as well as comparable in vitro dose delivery development went directly into phase III studies (Medical Information, Astra-Zeneca Nordic, e-mail com- munication, 4 March 2016).

3.6.2. Phase III studies
Phase III studies are summarized in Table 2. The efficacy of dry powder budesonide+formoterol fumarate compared to mono- therapy with budesonide was evaluated in a randomized, double-blind, parallel-group study of 852 patients with stable asthma.[23] During 12 months twice-daily treatments were budesonide 100 µg+placebo, budesonide 100 µg+formoterol fumarate dihydrate 12 µg, budesonide 400 µg+placebo, or budesonide 400 µg+formoterol fumarate dihydrate 12 µg. The addition of formoterol fumarate dihydrate 12 µg to bude- sonide 100 and 400 µg caused a reduction in severe asthma exacerbations by 26% and 63%, respectively. The findings were taken to suggest that while a fixed combination of budesonide+formoterol fumarate dihydrate was associated with improved asthma control during exacerbations, it would be important to increase the dose of budesonide to suffi- ciently suppress pulmonary inflammation and to avoid mask- ing inflammatory processes.[24–26] The benefit of increasing the dose of budesonide when formoterol fumarate dihydrate is added for treatment of exacerbations was supported by several reports that markers of inflammation were controlled more rapidly when the dose of inhaled budesonide was increased.[27,28] Such observations supported the so-called

Table 2. Summary of phase III efficacy studies of dry powder budesonide+formoterol fumarate dihydrate in bronchial asthma. All studies used a randomized, double-blind, parallel-group design. Where not indicated otherwise, a short-acting β-2 agonist was used for as-needed treatment. The outcomes were statistically significant except where marked by *.

Reference
N
Age(years) Duration of Treatment (months)
Treatment
Primary outcomes
[23] Pauwels RA
852 ≥12 12 bud 100 µg bid
bud+for 100 + 12 µg bid Exacerbation rate reduced
bud 400 µg bid
bud+for 400 + 12 µg bid Exacerbation rate reduced
[29] Rabe KF
697 ≥11 6 bud+for 80/4.5 µg qd+as Exacerbation and hospitalization rates and
bud 160 µg qd use of oral steroids reduced
[30] Scicchitano R
1890 ≥11 12 bud 160 µg bid
bud+for 320 + 9.5 µg od+as Time to first severe exacerbation increased;
exacerbation, hospitalization rates and
use of oral steroids reduced
[31] O´Byrne PM
2760 ≥4 12 bud+for 80 + 4.5 µg bid
bud 320 µg bid
bud+for 80 + 4.5 µg bid+as Exacerbation rate reduced
[32] Rabe KF
3394 ≥12 12 bud+for 160 + 4.5 µg bid nas
bud+for 160 + 4.5 µg bid
bud+for 160 + 4.5 µg bid + for as
bud+for 160 + 4.5 µg bid+as Time to first exacerbation reduced
[33] Kuna P
3335 ≥12 6 bud+for 160 + 4.5 µg bid+as Time to first severe exacerbation increased;
flu+sal 250 + 50 µg bid exacerbation rate and use of oral steroids
bud+for 320 + 9 µg bid reduced
[34] Bousquet J
2309 ≥12 6 bud+for 320 + 9 µg bid+as Time to first severe exacerbation*
flu+sal 500 + 50 µg bid
[35] Patel M
303 ≥16 5.5 bud+for 400 + 12 µg bid+as Exacerbation rate and use of oral steroids reduced
od: once daily; bid.: twice daily; qd: four times daily; as: as needed; nas: no as-needed treatment; bud: budesonide; for: formoterol fumarate dihydrate; flu: fluticasone propionate sal: salmeterol xinafoate.

SMART (Single Inhaler Maintenance and Reliever Therapy) strategy, i.e. the use of budesonide+formoterol fumarate dihy- drate for both maintenance and reliever therapy.[29–34]
In a randomized double-blind trial 2760 adolescent and adult asthma patients received budesonide 80 µg+formoterol
4.5 µg plus a SABAs as reliever therapy, budesonide 320 µg plus a SABA as reliever therapy, or budesonide 80 µg+formo- terol 4.5 µg as maintenance and reliever therapy for
12 months.[31] All treatments were taken twice daily. Treatment with budesonide 80 µg+formoterol 4.5 µg was associated with a statistically significant reduction in the rate of severe exacerbations.
Furthermore, a randomized, double-blind 6-month study compared budesonide+formoterol fumarate dihydrate for maintenance and reliever therapy with conventional treat- ments with inhaled corticosteroids and a SABA for relief in 3335 symptomatic adults.[33] Budesonide+formoterol fuma- rate dihydrate 160 + 4.5 µg twice daily plus additional inhala- tions as needed for maintenance and reliever treatment was found to prolong the time to the first severe exacerbation requiring hospitalization, emergency room treatment, or oral corticosteroids as compared to the two treatment arms of fluticasone propionate+salmeterol xinofoate 125 + 25 µg twice daily and budesonide+formoterol fumarate dihydrate 320 + 9 µg twice daily plus a SABA for reliever therapy. A double-blind, randomized, parallel-group comparison of 6- month treatment with budesonide+formoterol fumarate dihy- drate 320 + 9 µg twice-daily maintenance and reliever and fluticasone propionate+salmeterol xinofoate 500/50 µg twice daily plus a SABA as-needed in 2309 symptomatic asthma patients did not find a difference in the time to the first severe exacerbation.[34] Although statistically significant differences in the number of exacerbations and severe exacerbations

were in favor of budesonide+formoterol fumarate dehydrate, they were marginal and probably not clinically important.[34] However, it was suggested that budesonide+formoterol fuma- rate dihydrate maintenance and reliever treatment may be associated with a reduction in the total intake of corticoster- oids.[33] A randomized, open 24-week parallel two-group trial of 303 patients with asthma was designed to test the hypoth- esis.[35] Treatment in the maintenance plus reliever treatment group was budesonide+formoterol fumarate dihydrate 400 + 12μg twice daily plus 200 + 6 μg for reliever therapy; treatment in the other group was budesonide+formoterol fumarate dihydrate 400 + 12 μg twice daily with one to two doses of the SABA salbutamol 100 μg/actuation as needed for relief of symptoms. The number of severe asthma exacerba- tions was statistically significantly reduced in the maintenance plus reliever group, and the regimen was found to be asso- ciated with a reduction in oral corticosteroid exposure but an increase in inhaled corticosteroid exposure.

3.6.3. Post-marketing surveillance studies
The use of budesonide+formoterol fumarate dihydrate as maintenance and reliever therapy has been evaluated in more than 23 000 adolescent and adult patients as part of four real-world studies, which included open comparisons with fluticasone propionate+salmeterol xinofoate or conven- tional best practice.[36–39] Budesonide+formoterol fumarate dihydrate was found to reduce the rate of exacerbations requiring hospital admissions or emergency room visits and the rate of exacerbations requiring oral corticosteroids as compared with fluticasone propionate+salmeterol xinofoate or conventional best practice.[36,37] Patients treated with budesonide+formoterol fumarate dihydrate maintenance and reliever therapy received lower mean daily dose of

corticosteroid compared with conventional best practice.[37] The use of oral corticosteroids was also lower than with fluti- casone propionate+salmeterol xinofoate or conventional best practice.

3.6.4. Unpublished studies
In addition to searches in online libraries, the authors of a Cochrane analysis contacted manufacturers to confirm data and establish whether unpublished or ongoing studies of bude- sonide+formoterol fumarate dihydrate maintenance and reliever therapy were available for assessment.[40] Searches of clinical trials web sites and a specific clinical trial web site of combination inhaler manufacturers were also performed. In that way the authors were able to identify 13 trials of budesonide+formoterol fumarate dihydrate maintenance and reliever therapy in 13,152 adolescent and adult asthma patients, of which only three were published. Only selected data from four studies were published and no data from six of the studies had been peer review published. All studies were sponsored by the manufacturers. Except for one they were multicenter studies with centers in many countries, and no study provided information on differ- ences between countries or centers. In nine studies patients who were not controlled on monotherapy with inhaled corticoster- oids were randomized to open treatment with maintenance budesonide+formoterol fumarate dihydrate 160 + 4.5 twice daily plus as-needed or to best practice, which included main- tenance inhaled corticosteroids and SABA and LABAs in accord with current guidelines. Mean follow-up in the studies was 6 months. The studies used an open design, and adherence with current best practice was not recorded. Compared with current best practice or higher doses of inhaled corticosteroids, the results showed that maintenance and reliever budesonide
+formoterol fumarate dihydrate reduced the number of exacer- bations requiring treatment with oral corticosteroids; however, the numbers of hospital admissions and emergency room visits were not reduced.

3.7. Safety and tolerability
Inhaled corticosteroids and LABAs become available in the systemic circulation and, thus, systemic adverse effects may occur in patients on the combination of budesonide+formo- terol fumarate dihydrate. Conventionally, systemic activity of inhaled corticosteroids in adults has been assessed by urine cortisol measures of hypothalamic-pituitary-adrenal-function.
[41] Extensive evaluations have not indicated that inhaled budesonide in recommended doses in adults with asthma may cause clinically significant hypothalamic-pituitary-adrenal insufficiency and there are no data to suggest that this may be different with the fixed combination of budesonide-formoterol fumarate dihydrate.[41,42] If sensitive repetitive serum mea- sures of basal adrenal activity are used, however, dose-related suppressive effects with specific application systems may be detected.[41,42] Such evaluations of the fixed combination of budesonide-formoterol fumarate dehydrate appear not to have been reported.
Hypokalemia, hyperglycemia, and tachycardia are possible systemic effects of LABAs.[43] Mortality and asthma-related serious adverse events, overall and cardiac serious adverse

events, and discontinuations due to adverse events were assessed in six double-blind, randomized clinical trials in 14,346 adolescents and adults with asthma during dry powder budesonide+formoterol fumarate dihydrate maintenance and reliever therapy for at least 6 months.[44] The pooled data from the six trials showed that budesonide+formoterol fuma- rate dihydrate was well tolerated and was not found to be associated with an increased risk of death or cardiac-related serious adverse events or discontinuations due to adverse events. A recent analysis with additional data supported the observations.[45] The tolerability profile of the fixed combina- tion of budesonide+formoterol fumarate dihydrate appears to correspond with its individual components, the treatment being generally well tolerated with ≤10% of patients experi- encing treatment-related adverse effects.[44] Oropharyngeal candidiasis, dysphonia, tremor, palpitations, and pneumonia were the most frequent complaints.[44] Tolerability profiles would be expected not to differ between the commercially available dry powder combinations of budesonide+formoterol fumarate dihydrate. There are no tolerability profile head-to- head comparisons with other fixed combinations. Finally, a randomized, double-blind, double-dummy, crossover, pla- cebo-controlled study assessed the acute tolerability of bude- sonide+formoterol fumarate dihydrate in 14 patients with asthma in whom two inhalations of 160/4.5 µg twice daily and 10 additional doses adding up to a total daily dose of 1920 + 54 µg; or formoterol fumarate dihydrate 54 µg/day; or placebo on three separate study days. Statistically significant changes in serum potassium, pulse rate, blood pressure, QT- interval, blood glucose, and plasma lactate occurring with budesonide+formoterol fumarate dihydrate treatment were considered clinically unimportant. The authors concluded that the fixed combination of budesonide+formoterol fuma- rate dihydrate was well tolerated at high doses such as might be used by patients using the combination inhaler for relief of symptoms of asthma.[46]

3.8. Regulatory affairs
The dry powder combinations of budesonide+formoterol fumarate dihydrate are licensed in various strengths for use in the EU; however, not all of them are licensed in the U.S. In the EU the dry powder combinations are licensed for use in patients ≥12 years of age, although in the U.K. it is only
≥18 years of age. Generally they are licensed in patients in whom asthma is not adequately controlled with inhaled corti- costeroids and as-needed inhaled short-acting β2 adrenocep- tor agonists, or in patients already adequately controlled on both inhaled corticosteroids and long-acting β2 adrenoceptor agonists. Some countries, however, may adhere to different regulatory provisions.

4. Discussion
Few studies in children treated with combinations of inhaled corticosteroids and LABAs have been performed and there is no evidence for the use of dry powder budesonide+formo- terol fumarate dihydrate in children ≤12 years of age.[1,31,47– 49] When evaluating the available data on efficacy in

adolescents and adults, it must be appreciated that the pub- lished studies of the budesonide+formoterol fumarate dihy- drate combination have all been sponsored by the manufacturers and a risk of publication bias must be acknowl- edged.[50] Many studies that have found less or no convincing results in favor of the budesonide+formoterol fumarate dihy- drate maintenance and reliever strategy have not been peer review published.[40] Considering that clinical trials sponsored by manufacturers more often than non-pharmaceutical com- pany-sponsored trials have favorable efficacy results and that less-favorable results often remain unpublished in the peer- reviewed literature, it may be argued that non-sponsored evaluations of budesonide+formoterol fumarate dihydrate are needed.[50] Furthermore, it has been argued that many trials comparing budesonide+formoterol fumarate dihydrate with fixed doses of inhaled corticosteroids might have been confounded by the fact that patients became symptomatic when their maintenance treatment was reduced or LABAs were withdrawn during run in, and it has been argued that a more precise typing of asthma severities should be performed in future studies.[51] Also, analyses of secondary outcome measures have often not supported the SMART principle and, finally, it has been argued that clinical trials have applied none or insensitive measures of adherence.[40,51] Having considered that, however, it seems fair to conclude that in patients whose asthma is not controlled on a low dose of inhaled corticosteroids, maintenance and reliever therapy with a single-inhaler fixed combination of budesonide+formo- terol fumarate dihydrate reduces the number of exacerbations requiring treatment with oral corticosteroids. In some patients the strategy may also reduce the total intake of inhaled corti- costeroids. Whether the number of hospitals admissions and emergency room visits due to severe exacerbations may be reduced, however, is more difficult to entangle from the avail- able data. An answer to the question awaits further evidence. The same should be said about suggestions from post hoc pharmaceutical company-sponsored analyses finding that the SMART principle with as-needed use of budesonide+formo- terol fumarate dihydrate in patients needing dose adjustment across GINA guidelines control steps may reduce rates of asthma exacerbations and the need of systemic glucocorti- coids.[52,53]

5. Conclusions
Pharmacokinetics and pharmacodynamics of the fixed combi- nation of budesonide+formoterol fumarate dihydrate appear to correspond to its individual components and would not appear to vary between specific dry powder devices. In patients whose asthma is not controlled on a low dose of inhaled corticosteroids, maintenance and reliever therapy with a single-inhaler fixed combination of budesonide+formo- terol fumarate dihydrate reduces the number of exacerbations requiring treatment with oral corticosteroids. In some patients the strategy may also reduce the total intake of inhaled corti- costeroids and the number of hospital admissions and emer- gency room visits due to severe exacerbations; however, these outcome measures need further evaluation. The tolerability profile of the fixed combination of budesonide+formoterol

fumarate dihydrate appears to correspond with its individual components, the treatment being generally well tolerated.

6. Expert opinion
The fixed combination of budesonide+formoterol fumarate dihydrate is the most well documented of the single-inhaler fixed combinations of inhaled corticosteroids+LABAs on the market today. The launch of the combination inhaler has had a significant impact on current treatment strategies and in accord with this prescription rates by physicians have increased significantly. Without doubt that is partly due to the convenience in single as compared to multiple inhaler use. The concept of maintenance and reliever therapy offers several improvements over conventional treatment with inhaled corticosteroids and SABA, and over inhaled corticos- teroids and reliever LABA regimens. First, adherence rates are probably better with one-inhaler-use than when several inhalers are used. Second, the addition of formoterol fuma- rate dihydrate to budesonide increases the anti-inflamma- tory activity of the corticosteroid, and over time asthma control may be achieved at a lower total dose of budeso- nide. Third, depending on asthma severity the fixed combi- nation of budesonide+formoterol fumarate dihydrate may be more efficacious than high doses of inhaled corticoster- oids. Fourth, compared with current best practice or higher doses of inhaled corticosteroids maintenance and reliever budesonide+formoterol fumarate dihydrate reduces exacer- bations requiring treatment with oral corticosteroids. Although most of the published phase III studies have found reductions in exacerbation rates as measured by hos- pitalization and/or emergency room visits, a number of unpublished trials were not confirmatory and the data might have been influenced by publication bias. Whether asthma control may be obtained at reduced asthma-related health costs may depend on a number of society-related factors, the importance of which may vary considerably
among countries throughout the world.[54]
Several dry powder budesonide+formoterol fumarate dihy- drate inhaler devices are available and they may have different advantages to different patients.[55] There is a paucity of head-to-head comparative clinical efficacy studies of the var- ious devices; however, since new dry powder inhalers have often been designed to show non-inferiority to the Turbuhaler®, one would not expect any clinically relevant differences among the devices. Also, there are few data on children and LABA should not be prescribed to children (<12 years of age).[54]
A disadvantage of the budesonide+formoterol fumarate dihydrate combination is the relatively short half-lives of the drugs, which necessitate twice-daily administration regimens. Recently, a fixed combination of a new corticosteroid and a new LABA, fluticasone furoate+vilanterol trifenatate, with a half-life of approximately 24 hours, has been launched making once-daily treatment possible.[7] It has been suggested that a once-daily administration regimen will make fluticasone furo- ate+vilanterol trifenatate an attractive treatment option.[56] On would expect that in the future once-daily administration of fixed combinations of inhaled corticosteroids and LABA

may threaten current market shares of the combination bude- sonide+formoterol fumarate dihydrate combination, which must be administered in twice-daily regimens.

Declaration of interest
In the past 5 years O D Wolthers has received research funds, advisory board salaries, lecturing salaries, meeting sponsorships from and/or he has been an investigator on clinical trials for Alk-Abello, GlaxoSmithKline, Berlin-Chemie Menarini, Teva UK Ltd and Mundipharma Research Ltd. He has not been and is not employed by any of the companies, and he has no stock ownership or any compensation tied directly to the success of any of the companies. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials dis- cussed in the manuscript apart from those disclosed.

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