Application to Add a Budesonide/Formoterol Combination Inhaler to the Essential Medicines List

Application to add a budesonide/formoterol combination inhaler to the Essential Medicines List

1. Summary statement of the proposal for inclusion

The successful control of asthma requires controller medicines that reduce airway inflammation, mainly inhaled corticosteroids (= ICS) and reliever medicines or bronchodilators that relax airway smooth muscle. Currently the WHO List of Essential Medicines for asthma contains two ICS, beclometasone and budesonide, and one bronchodilator, salbutamol, each as a separate inhaler. When these medicines are made affordable in low-income countries, a marked reduction of emergency visits and hospitalisations is observed in patients who adhere to therapy. However, asthma control may not be achieved in many patients who stop using the ICS inhaler because it does not provide an immediate relief of symptoms, in contrast to the bronchodilator.

This adherence problem is the reason for the present application to add an ICS/bronchodilator combined formulation to the List of Essential Medicines. Combination inhalers delivering an ICS and a long-acting β2-agonist (LABA) are now standard therapy in high-income countries. In particular, the “single inhaler therapy” has proven highly efficient, where the combined ICS/LABA inhaler is used both for maintenance and for relief therapy. In view of its simplicity and efficacy, the single inhaler therapy appears as an appropriate strategy to cope with adherence problems in resource limited settings. The formulation which has been best validated to this end is the budesonide/formoterol combination inhaler that we propose to add to the List of Essential Medicines. As this medicine is relevant for the treatment of children, it is proposed to add it to the EMLc as well.

2. Name of the WHO technical department supporting the application

Department of Non Communicable Diseases.

3. Name of the organisation(s) consulted and/or supporting the application

Prof. Jean-William Fitting Vice-Chair, Adult & Child Lung Health Section International Union against Tuberculosis and Lung Disease (The Union) Department of Respiratory Medicine Lausanne University Hospital Lausanne, Switzerland [email protected]

Contributors: Karen Bissell, The Union (New Zealand) Nadia Aït-Khaled, The Union (Algeria) Guy Marks, The Union (Australia)

4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine

INN: Budesonide/Formoterol ATC: R03AK07

5. Formulations and strengths proposed for inclusion; including adult and paediatric

Inhalers:

Adults and adolescents ≥ 12 years: budesonide 100 μg + formoterol 6 μg budesonide 200 μg + formoterol 6 μg [1, 2]

Children 6-11 years: budesonide 100 μg + formoterol 6 μg [3, 4]

The medicine is internationally available under the following name:

Trade name: Symbicort Dosage forms: budesonide 100 μg + formoterol 6 μg budesonide 200 μg + formoterol 6 μg budesonide 400 μg + formoterol 12 μg Manufacturer: AstraZeneca

As of 20 April 2014, the European Medicines Agency issued a marketing authorisation for the following generic:

Trade name: DuoResp Spiromax Dosage forms: budesonide 160 μg + formoterol 4.5 μg budesonide 320 μg + formoterol 9 μg Manufacturer: TEVA Pharma B.V.

6. Whether listing is requested as an individual medicine or as a representative of a pharmacological class

The present application requests the inclusion of the budesonide/formoterol combination inhaler as an individual medicine with a square box symbol.

Alternative formulations that may be considered similar:  beclometasone/salbutamol  beclometasone/formoterol

Rationale:

While several ICS/bronchodilator formulations are currently available and additional formulations may be available in the future, only some of these are appropriate for addressing the clinical problem of improving adherence to effective medicines for control of asthma in resource limited settings. This objective is best met by enabling single inhaler therapy, that is, a management strategy in which a single inhaler (combining ICS and bronchodilator) can be used both as regular therapy to control the disease and as rescue therapy to relieve symptoms.

Single inhaler therapy requires that the bronchodilator included in the combination inhaler provide rapid onset bronchodilation and be a full (not partial) β2-agonist. This means that it can be used as a rescue (or reliever)-type medication. Salbutamol and formoterol are both full β2-agonist, rapid-onset bronchodilators with time to onset of bronchodilation of 5 minutes. In contrast, salmeterol is a partial β2-agonist with a longer time to onset of bronchodilation (10 minutes) [5, 6]. For this reason, ICS/salmeterol combination inhalers, which are widely available and used as a combination ICS/bronchodilator inhaler in treatment of patients with persistent asthma and COPD, are not licensed or suitable for single inhaler therapy.

The budesonide/formoterol combination is selected in the present application in view of its extensive validation for the single inhaler therapy. This is the only combination that has been extensively tested, in randomized controlled trials, for its effectiveness in this mode of use. In theory, formoterol used in combination with any inhaled corticosteroid is likely to be equivalent.

It is also possible that salbutamol in combination with any inhaled corticosteroid may be effective as single inhaler therapy, even though salbutamol is a short-acting bronchodilator, in contrast to formoterol, which is a long-active bronchodilator. Salbutamol has the rapid onset of action required for the rescue (reliever) component of single inhaler therapy and is a full β2-agonist. However, salbutamol/ICS combinations have not been extensively tested as single inhaler therapy combinations and, therefore, it is not appropriate to recommend them as first choice at this stage.

The fluticasone furoate/vilanterol combination has been launched recently. Fluticasone furoate is currently the most potent ICS and is designed for once-daily dosing [7]. Vilanterol is a potent β2-agonist with a 24h duration of action. It has a high β2 selectivity and a rapid onset of bronchodilation within 3 minutes [5]. Fluticasone/vilanterol once daily was shown equivalent to fluticasone/salmeterol twice daily in the control of asthma [8]. The fluticasone/vilanterol combination may be suitable for use as single inhaler therapy but this has not yet been validated in randomized controlled trials.

Note: The medicines budesonide, beclometasone and salbutamol are already included as separate inhalers in the current EML.

7. Treatment details (requirements for diagnosis, treatment and monitoring)

GINA Guidelines: Asthma treatment is recommended in a stepwise approach to control symptoms and minimize future risk. Asthma severity is divided in 5 steps according to the level of medication needed to control symptoms. Steps 1 and 2 correspond to mild asthma, step 3 to moderate asthma, and steps 4 and 5 to severe asthma [9].

Dosage regimen: Mild asthma: Controller: low dose ICS (e.g. budesonide 200-400 μg per day) Reliever: as needed short-acting β2-agonist (SABA)

Moderate and severe asthma: Controller: low dose ICS/formoterol (e.g. budesonide 200-400 μg per day) Reliever: as needed low dose ICS/formoterol

British guideline on the management of asthma: Similarly to GINA, a stepwise approach is recommended in 5 steps. With regard to the single inhaler therapy, the guideline states:

“In selected adult patients at step 3 who are poorly controlled or in selected adult patients at step 2 (above beclometasone 400 micrograms/day and poorly controlled), the use of budesonide/formoterol in a single inhaler as rescue medication instead of a short- acting β2-agonist, in addition to its regular use as controller therapy has been shown to be an effective treatment regime. When this management option is introduced the total regular dose of daily ICS should not be decreased. The regular maintenance dose of ICS may be budesonide 200 micrograms twice daily or budesonide 400 micrograms twice daily. Patients taking rescue budesonide/formoterol once a day or more on a regular basis should have their treatment reviewed. Careful education of patients about the specific issues around this management strategy is required” [10].

Note: Current guidelines recommend the single inhaler therapy at steps 2-3 and higher but do not address the question of asthma management in resource-limited settings. Considering the simplicity and efficiency of the single inhaler therapy, its role needs to be explored for all levels of asthma severity in low-income countries [11].

In view of the high prevalence of asthma and of the efficiency of this therapy, listing of budesonide/formoterol combination inhaler is sought in the core list.

8. Information supporting the public health relevance

Globally, asthma affects approximately 334 million people and is the 14th most important disorder in terms of the extent and duration of disability [12]. Although effective therapy exists for treating asthma, it is presently not available for the majority of individuals with asthma living in low-income countries. This is due to a lack of quality and affordable essential medicines, of well-organised health services, and of standardised management of asthma. In particular, inhaled corticosteroids are essential for managing patients with 6 persistent asthma over the long-term. However, ICS are expensive and not affordable for most patients in low-income countries [13].

From 2008 to 2013, the International Union against Tuberculosis and Lung Disease developed the Asthma Drug Facility project to provide affordable and quality-assured asthma medicines in several countries. In Benin, Sudan and China, the medicines used were the ICS beclometasone (controller) and the bronchodilator salbutamol (reliever) in separate inhalers. Asthma control improved markedly in patients who showed good adherence to therapy, with a striking reduction of emergency visits and hospitalisations. However, after one year a majority of patients were lost to follow-up: 52% in Benin, 56% in Sudan and 72% in China. When information could be obtained, half of these patients had stopped using inhaled beclometasone [14-16]. A likely cause of poor adherence lies in the absence of relief of symptoms after taking ICS, in contrast to rapid-onset bronchodilators. Patients may be inclined to believe that bronchodilators are effective because they provide quick relief from symptoms and that ICS are not effective because they observe no immediate effect from them [13, 17].

This particular adherence problem can be solved by using combination inhalers delivering a fixed dose of ICS and of a LABA. Combination inhalers are presently recommended with two aims: to guarantee that the LABA is not taken without ICS, and to improve inhaler adherence [10]. The ICS/LABA combination inhaler is recommended for maintenance therapy and can also be used for rescue reliever therapy provided that it contains a LABA with rapid onset of action, such as formoterol. This is known as the single inhaler therapy where the same inhaler is used both for maintenance and for rescue therapy. The idea is that the anti-inflammatory therapy will be automatically enhanced by taking supplementary doses when asthma gets out of control. Several randomised controlled trials showed that the single inhaler therapy improved the control of asthma and decreased the risk of exacerbation, of emergency visit and of hospitalisation, when compared to ICS/LABA maintenance therapy associated with salbutamol reliever therapy [1, 18-20]. In most studies, the single inhaler therapy was applied using the budesonide/formoterol combination, but the beclometasone/ salbutamol and beclometasone/formoterol combinations were successfully used as well [21-24]. In view of these advantages, the single inhaler therapy has been recommended by several researchers [25-27] and has been endorsed by the GINA guidelines [9].

Considering the adherence problems encountered when using separate controller and reliever inhalers, the use of combination inhalers and the implementation of the single inhaler therapy appear as a logical strategy to improve asthma control in low-income countries [11]. This is all the more appropriate as trained workforce for patient education is lacking in resource limited settings. However, combination inhalers are expensive and are currently not included in the national essential medicine lists of low-income countries [28]. Currently, the WHO List of Essential Medicines for asthma contains two ICS (beclometasone and budesonide) and one bronchodilator (salbutamol), each in a separate inhaler. The objective of this application is to add an ICS/LABA combination inhaler to the WHO List of Essential Medicines in order to promote its availability in low- income countries. The budesonide/formoterol combination is selected in priority in view of its rapid onset of bronchodilation which allows its use according to the single inhaler therapy. 7

9. Review of benefits: summary of comparative effectiveness in a variety of clinical settings

Two Cochrane reviews are relevant for comparative effectiveness of the single inhaler therapy with the budesonide/formoterol combination and are summarised here. Evidence is lacking to assess mortality outcomes. However, exacerbations, and in particular severe exacerbations, are well established as risk factor for death due to asthma and this outcome can be used to draw conclusions about the likely effect on mortality.

 Combination formoterol and budesonide as maintenance and reliever therapy versus current best practice (including inhaled steroid maintenance), for chronic asthma in adults and children (Review) by Cates CJ and Karner C [29].

Objectives: To assess the efficacy and safety of budesonide and formoterol in a single inhaler for maintenance and reliever therapy in asthma compared with maintenance with inhaled corticosteroids (alone or as part of current best practice) and any reliever therapy.

Selection criteria: Parallel, randomised controlled trials of 12 weeks or longer in adults and children with chronic asthma. Studies had to assess the combination of formoterol and budesonide as single inhaler therapy, against a control group that received inhaled steroids and a separate reliever inhaler.

Results: 13 trials involving 13,152 adults, with one trial involving also 224 children.

In eight trials the control group consisted of current best practice and allowed the use of LABA with ICS for maintenance therapy. In four studies the control group consisted of maintenance therapy with higher doses of budesonide, but without LABA. There was no significant advantage for single inhaler therapy in exacerbations needing hospital admission. In contrast, the single inhaler therapy significantly reduced the risk of exacerbations needing a treatment of oral corticosteroids. All studies found a reduction of total ICS dose when using single inhaler therapy. There was no significant difference in fatal or non-fatal serious adverse events (Tables 1-2).

One study included 224 children <12 years of age and compared single inhaler therapy to four times the dose of regular budesonide. There was a significant reduction in exacerbations needing increase in ICS treatment or additional treatment. Less inhaled and oral corticosteroids were used in the single inhaler therapy group and the annual height gain was also greater in the single inhaler therapy group. There was no significant difference found in fatal or non-fatal serious adverse events (Table 3).

 Combination formoterol and budesonide as maintenance and reliever therapy versus combination inhaler maintenance for chronic asthma in adults and children (Review) by Kew KM, Karner C, Mindus SM, Ferrara G [19]

Objectives: To assess the efficacy and safety of budesonide/formoterol in a single inhaler to be used for both maintenance and reliever therapy in asthma in comparison with maintenance treatment provided through combination inhalers with a higher maintenance steroid dose (either fluticasone/salmeterol or budesonide/formoterol), along with additional fast-acting β2-agonists for relief of symptoms.

Selection criteria: Parallel-group, randomised controlled trials of at least 12 weeks’ duration. Studies were included if they compared single inhaler therapy with budesonide/formoterol versus combination inhalers at a higher maintenance dose of steroids than was given in the single inhaler therapy arm (either fluticasone/salmeterol or budesonide/formoterol).

Results: Four trials involving 9130 people with asthma aged 12 years or more.

The number of people who had at least one exacerbation requiring hospitalisation or an emergency room visit was significantly lower in the single inhaler therapy group. The number of people who had an exacerbation requiring a course of oral steroids was also significantly lower in the single inhaler therapy group. Nocturnal awakenings were significantly reduced in the single inhaler therapy group. Serious adverse events were not significantly different in the two groups (Table 4).

10. Review on harms and toxicity: summary of evidence on safety

 Estimate of total patient exposure to date:

It is not possible to estimate the global number of patients exposed to the budesonide/formoterol combined formulation. A recent study reported the safety data of formoterol gathered in 149 AstraZeneca trials comprising 104,463 patients. The risk of asthma-related deaths was not different between the formoterol-randomised patients and the non-LABA-randomised patients, and the nonfatal asthma-related serious adverse events were significantly reduced with formoterol [30].

 Description of the adverse effects/reactions:

Budesonide is already included in the WHO EML and will not be discussed.

Formoterol shares the known side effects of β2-adrenergic receptor agonists [31]:

o Increased heart rate and palpitations o Transient decrease in arterial partial pressure of oxygen (PaO2) in patients with airway obstruction o Increased glycogenolysis and hyperglycaemia o Hypokalaemia o Dose-related tremor

 Summary of available data and comparative safety against comparators:

The following Cochrane Review is relevant to the safety of the budesonide/formoterol combination therapy:

Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events (Review) by Cates CJ, Jaeschke R, Schmidt S, Ferrer M [32].

Objectives: To assess the risk of fatal and non-fatal serious adverse events in people with chronic asthma given regular formoterol with ICS versus the same dose of ICS alone.

Selection criteria: Controlled clinical trials with a parallel design were included if they randomly allocated people of any age and severity of asthma to treatment with regular formoterol and ICS for at least 12 weeks.

Results: Twenty trials involving 10,578 adults and adolescents and seven trials involving 2788 children and adolescents.

In adults and adolescents six deaths occurred in the ICS/formoterol group and one in the ICS alone group. The increased odds of all-cause mortality with formoterol did not reach statistical significance. In the ICS/formoterol group, one death was related to a severe asthma attack with subsequent nosocomial pneumonia and septic shock. The other causes of death were not related to asthma: two suicides, one homicide, one cerebrovascular accident, one uterine leiomyosarcoma and one cardiac arrest. No deaths were reported in the trials on children and adolescents.

In adults and adolescents the proportion of non-fatal serious adverse events was very similar in the ICS/formoterol group and in the ICS alone group. However, the asthma- related non-fatal serious adverse events were significantly reduced with ICS/formoterol in comparison with ICS alone.

In children and adolescents the results were more heterogenous. More non-fatal serious adverse events occurred with formoterol but the difference did not reach statistical significance. The increased odds of asthma-related serious adverse events was imprecise and was not statistically significant (Table 5).

In addition, a postmarketing safety study mandated by the U.S. Food and Drug Administration was recently published. A total of 11,693 patients with persistent asthma with one to four exacerbations in the previous year was randomized to receive either budesonide alone or budesonide/formoterol for 26 weeks. Compared with budesonide alone, treatment with budesonide/formoterol was associated with a lower risk of asthma exacerbations and a similar risk of serious asthma-related events [33].

• Identification of variation in safety that may relate to health systems and patient factors:

The safety of β2-agonists has been questioned since their introduction. Increases in asthma related deaths were first reported in association with SABAs, then with the LABA salmeterol, but were mostly due to poor management and insufficient or absent ICS therapy. The use of a LABA without ICS is strongly discouraged in asthma because of an increased risk of exacerbation [9]. 10

Table 6 summarizes the evidence of benefit of budesonide/formoterol single inhaler therapy in relation to various outcomes and comparators, as presented in tables 1-5.

11. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group

 Range of costs of the proposed medicine:

Cost of treatment for one year (UK, January 2016), according to Regional Drug and Therapeutics Centre, Newcastle (gmmmg.nhs.uk/docs/cost_comparison_charts.pdf):

Low dose:

Symbicort 200/6 2x1/day £ 230.53 (US$ 334.64)

DuoResp Spiromax 160/4.5 2x1/day £ 181.82 (US$ 264.12)

High dose:

Symbicort 200/6 2x2/day £ 461.07 (US$ 669.32)

DuoResp Spiromax 160/4.5 2x2/day £ 363.64 (US$ 527.88)

It is possible that lower cost formulations could be made available in future, in particular in response to EML listing.

 Resource use and comparative cost-effectiveness presented as range of cost per routine outcome:

Two studies assessed the cost-effectiveness of the budesonide/formoterol maintenance therapy versus ICS alone maintenance therapy. A randomised multicentre prospective trial compared maintenance therapy with budesonide/formoterol and with budesonide alone. The SABA terbutaline was used as reliever therapy as needed. Unit cost data were taken from Swedish sources. Patients receiving budesonide/formoterol therapy had more symptom-free days and less exacerbations than patients with budesonide alone, at a slightly higher cost. The incremental cost-effectiveness ration (ICER) was 2.32 Euros (US$ 2.62) per symptom-free day gained [34]. Another randomised multicentre prospective trial compared maintenance therapy with budesonide/formoterol and with fluticasone alone. The SABAs terbutaline or salbutamol were used as reliever therapy as needed. The number of symptom-free days was higher with budesonide/formoterol than with fluticasone alone. Using German costs, the budesonide/formoterol therapy was both more effective and less costly (80 Euros or 90 US$ less per patient over 12 weeks) and was thus dominant [35].

The cost-effectiveness of the single inhaler therapy with the budesonide/formoterol combination was assessed by several studies. Compared with fluticasone/salmeterol therapy plus salbutamol rescue therapy, the single inhaler therapy with 11

budesonide/formoterol was associated with fewer severe exacerbations. This was achieved at a reduced cost (118 Euros or 133 US$ less per year) with German unit costs and at similar cost with Italy, France and UK costs [36]. The budesonide/formoterol single inhaler therapy was also found to be more efficient than higher dose budesonide/formoterol or fluticasone/salmeterol, both with terbutaline rescue therapy. This was achieved at a lower or similar cost, considering UK and Australian costs [37]. The results from five other multicentre trials were reported in Denmark unit costs. The budesonide/formoterol single inhaler therapy was more efficient to reduce exacerbations than either a higher dosage ICS plus SABA reliever therapy, or a similar ICS/LABA therapy plus SABA or LABA reliever therapy, or a higher dosage ICS/LABA therapy plus SABA reliever therapy. In most comparisons, the budesonide/formoterol single inhaler therapy was more effective at a lower total cost, and was thus dominant [38].

12. Summary of regulatory status of the medicine

European Medicines Agency: The budesonide/formoterol combination inhaler is approved:

“It is used for the treatment of asthma in adults for whom a combination product is considered appropriate. It can be used in patients whose disease is not adequately controlled by treatment with other asthma medicines called corticosteroids and ‘short- acting beta-2 agonists’ taken by inhalation, or in patients whose disease is adequately controlled by treatment with corticosteroids and ‘long-acting beta-2 agonists’ taken by inhalation.”

US Food and Drug Administration (FDA): The budesonide/formoterol combination inhaler(Symbicort) is approved:

“SYMBICORT is used for asthma and chronic obstructive pulmonary disease (COPD) as follows: Asthma: SYMBICORT is used to control symptoms of asthma, and prevent symptoms such as wheezing in adults and children ages 12 and older. SYMBICORT contains formoterol (the same medicine found in FORADIL AEROLIZER). LABA medicines such as formoterol increase the risk of death from asthma problems. SYMBICORT is not for adults and children with asthma who: o are well controlled with an asthma-control medicine such as a low to medium dose of an inhaled corticosteroid medicine o have sudden asthma symptoms It is not known if SYMBICORT is safe and effective in children ages 6 to less than 12 years of age with asthma. “

13. Availability of pharmacopoieal standards (British Pharmacopoiea, International Pharmacopoiea, United States Pharmacopoiea, European Pharmacopoiea):

British Pharmacopoiea: Yes International Pharmacopoiea: No United States Pharmacopoiea: Yes European Pharmacopoiea: Yes 12

14. Reference list

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21. Papi, A., et al., Beclometasone-formoterol as maintenance and reliever treatment in patients with asthma: a double-blind, randomised controlled trial. The Lancet Respiratory Medicine, 2013. 1(1): p. 23-31. 22. Papi, A., et al., Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N Engl J Med, 2007. 356(20): p. 2040-52. 23. Martinez, F.D., et al., Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial. Lancet, 2011. 377(9766): p. 650-7. 24. Papi, A., et al., Beclomethasone/formoterol versus budesonide/formoterol combination therapy in asthma. Eur Respir J, 2007. 29(4): p. 682-9. 25. Barnes, P.J., Scientific rationale for using a single inhaler for asthma control. Eur Respir J, 2007. 29(3): p. 587-95. 26. Papi, A., et al., Rescue treatment in asthma. More than as-needed bronchodilation. Chest, 2009. 135(6): p. 1628-33. 27. Beasley, R., et al., Combination corticosteroid/beta-agonist inhaler as reliever therapy: a solution for intermittent and mild asthma? J Allergy Clin Immunol, 2014. 133(1): p. 39-41. 28. Bazargani, Y.T., et al., Essential medicines for COPD and asthma in low and middle-income countries. Thorax, 2014. 69(12): p. 1149-51. 29. Cates, C.J. and C. Karner, Combination formoterol and budesonide as maintenance and reliever therapy versus current best practice (including inhaled steroid maintenance), for chronic asthma in adults and children. Cochrane Database Syst Rev, 2013. 4: p. CD007313. 30. Sears, M.R. and F. Radner, Safety of formoterol in asthma clinical trials: an update. Eur Respir J, 2014. 43(1): p. 103-14. 31. Cazzola, M., et al., beta2-agonist therapy in lung disease. Am J Respir Crit Care Med, 2013. 187(7): p. 690-6. 32. Cates, C.J., et al., Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events. Cochrane Database Syst Rev, 2013. 6: p. CD006924. 33. Peters, S.P., et al., Serious Asthma Events with Budesonide plus Formoterol vs. Budesonide Alone. N Engl J Med, 2016. 375(9): p. 850-60. 34. Jonsson, B., et al., An economic evaluation of combination treatment with budesonide and formoterol in patients with mild-to-moderate persistent asthma. Respir Med, 2004. 98(11): p. 1146-54. 35. Ericsson, K., et al., Cost-effectiveness analysis of budesonide/formoterol compared with fluticasone in moderate-persistent asthma. Respir Med, 2006. 100(4): p. 586-94. 36. Johansson, G., et al., Cost effectiveness of budesonide/formoterol for maintenance and reliever therapy versus salmeterol/fluticasone plus salbutamol in the treatment of asthma. Pharmacoeconomics, 2006. 24(7): p. 695-708. 37. Price, D., A. Wiren, and P. Kuna, Cost-effectiveness of budesonide/formoterol for maintenance and reliever asthma therapy. Allergy, 2007. 62(10): p. 1189-98. 38. Wickstrom, J., et al., Cost-effectiveness of budesonide/formoterol for maintenance and reliever asthma therapy in Denmark--cost-effectiveness analysis based on five randomised controlled trials. Clin Respir J, 2009. 3(3): p. 169-80.

Table 1

Author(s): Jean-William Fitting Date: 2015-01-22 Question: Adults using 160/4.5 mcg BDF single inhaler therapy compared to current best practice for chronic asthma in adults and children [Data only. When citing this record quote "Cochrane Database of Systematic Reviews 2013, Issue 2".] Settings: Bibliography (systematic reviews): Cates CJ, Karner C. Combination formoterol and budesonide as maintenance and reliever therapy versus current best practice (including inhaled steroid maintenance), for chronic asthma in adults and children [Data only. When citing this record quote "Cochrane Database of Systematic Reviews 2013, Issue 2".]. Cochrane Database of Systematic Reviews [Year], Issue [Issue].

Quality assessment № of patients Effect

Adults using 160/4.5 Quality Importance Risk current Relative № of Study Other mcg Absolute of Inconsistency Indirectness Imprecision best (95% studies design considerations BDF (95% CI) bias practice CI) single inhaler therapy

Patients with exacerbations causing hospitalisation

8 21/4433 26/4408 OR 0.81 1 fewer per 1000 (from 3 (0.5%) (0.6%) (0.45 to fewer to 3 more) 1.44)

0.44% 1 fewer per 1000 (from 2 fewer to 2 more)

Patients with exacerbations treated with oral steroids

8 257/4433 304/4408 OR 0.83 11 fewer per 1000 (from 1 (5.8%) (6.9%) (0.7 to fewer to 20 fewer) 0.98)

6.15% 10 fewer per 1000 (from 1 fewer to 18 fewer)

Fatal serious adverse events (fatal)

8 6/4433 3/4408 OR 1.95 1 more per 1000 (from 0 (0.1%) (0.1%) (0.53 to fewer to 4 more) 7.21)

Serious adverse events (non-fatal)

8 105/4431 87/4408 OR 1.2 4 more per 1000 (from 2 (2.4%) (2.0%) (0.9 to fewer to 11 more) 1.6)

1.85% 4 more per 1000 (from 2 fewer to 11 more)

MD – mean difference, RR – relative risk

Table 2

Author(s): Jean-William Fitting Date: 2015-01-22 Question: Adults using BDF single inhaler therapy compared to fixed dose ICS for chronic asthma in adults and children [Data only. When citing this record quote "Cochrane Database of Systematic Reviews 2013, Issue 2".] Settings: Bibliography (systematic reviews): Cates CJ, Karner C. Combination formoterol and budesonide as maintenance and reliever therapy versus current best practice (including inhaled steroid maintenance), for chronic asthma in adults and children [Data only. When citing this record quote "Cochrane Database of Systematic Reviews 2013, Issue 2".]. Cochrane Database of Systematic Reviews [Year], Issue [Issue].

Quality assessment № of patients Effect

Adults using Quality Importance Risk fixed Relative № of Study Other BDF Absolute of Inconsistency Indirectness Imprecision dose (95% studies design considerations single (95% CI) bias ICS CI) inhaler therapy

Patients with exacerbations causing hospitalisation

3 12/2105 22/2104 OR 0.56 5 fewer per 1000 (from 1 (0.6%) (1.0%) (0.28 to more to 8 fewer) 1.09)

1.17% 5 fewer per 1000 (from 1 more to 8 fewer)

Patients with exacerbations treated with oral steroids

4 228/2140 387/2140 OR 0.54 74 fewer per 1000 (from (10.7%) (18.1%) (0.45 to 57 fewer to 90 fewer) 0.64)

14.98% 63 fewer per 1000 (from 48 fewer to 76 fewer)

Fatal serious adverse events

3 1/2105 3/2104 OR 0.37 1 fewer per 1000 (from 1 (0.0%) (0.1%) (0.05 to fewer to 2 more) 2.62)

0.12% 1 fewer per 1000 (from 1 fewer to 2 more)

Serious adverse events (non-fatal)

3 99/2105 102/2104 OR 0.97 1 fewer per 1000 (from 13 (4.7%) (4.8%) (0.73 to fewer to 13 more) 1.29)

5.3% 2 fewer per 1000 (from 14 fewer to 14 more)

Patients with "severe" exacerbation (time to event)

2 -/1301 -/1285 HR 0.59 1 fewer per 1000 (from 0 (0.49 to fewer to 0 fewer) 0.7)

Rescue medication use (puffs per day)

3 0 0 - MD 0.37 lower (0.49 lower to 0.25 lower) 16

Table 3

Author(s): Jean-William Fitting Date: 2015-01-22 Question: Children using 80/4.5 mcg BDF single inhaler therapy compared to higher fixed dose ICS for chronic asthma in adults and children [Data only. When citing this record quote "Cochrane Database of Systematic Reviews 2013, Issue 2".] Settings: Bibliography (systematic reviews): Cates CJ, Karner C. Combination formoterol and budesonide as maintenance and reliever therapy versus current best practice (including inhaled steroid maintenance), for chronic asthma in adults and children [Data only. When citing this record quote "Cochrane Database of Systematic Reviews 2013, Issue 2".]. Cochrane Database of Systematic Reviews [Year], Issue [Issue].

Quality assessment № of patients Effect

Children using 80/4.5 higher Quality Importance Risk № of Study Other mcg fixed Relative Absolute of Inconsistency Indirectness Imprecision studies design considerations BDF dose (95% CI) (95% CI) bias single ICS inhaler therapy

Patients with exacerbations causing hospitalisation

1 0/118 1/106 OR 0.12 8 fewer per 1000 (from 9 (0.0%) (0.9%) (0 to fewer to 46 more) 6.12)

0.94% 8 fewer per 1000 (from 9 fewer to 45 more)

Fatal serious adverse events

1 0/118 0/106 not not estimable (0.0%) (0.0%) estimable

Serious adverse events (non-fatal)

1 2/118 5/106 OR 0.35 30 fewer per 1000 (from (1.7%) (4.7%) (0.07 to 36 more to 44 fewer) 1.83)

4.72% 30 fewer per 1000 (from 36 more to 44 fewer)

Annual height gain (cms)

1 118 106 - MD 1 higher (0.29 higher to 1.71 higher)

Patients with an exacerbation requiring increase in ICS or other treatment

1 9/118 21/106 OR 0.33 123 fewer per 1000 (from (7.6%) (19.8%) (0.15 to 38 fewer to 162 fewer) 0.77)

19.81% 123 fewer per 1000 (from 38 fewer to 162 fewer)

Nocturnal awakenings

1 0 0 - MD 0 higher (0 higher to 0 higher)

MD – mean difference, RR – relative risk 17

Table 4

Author(s): Jean-William Fitting Date: 2015-01-22 Question: SiT compared to higher-dose ICS/LABA + SABA for chronic asthma in adults and children [Data only. When citing this record quote "Cochrane Database of Systematic Reviews 2013, Issue ".] Settings: Bibliography (systematic reviews): Kew KM, Karner C, Mindus SM, Ferrara G. Combination formoterol and budesonide as maintenance and reliever therapy versus combination inhaler maintenance for chronic asthma in adults and children [Data only. When citing this record quote "Cochrane Database of Systematic Reviews 2013, Issue ".]. Cochrane Database of Systematic Reviews [Year], Issue [Issue].

Quality assessment № of patients Effect

higher- Quality Importance Risk Relative № of Study Other dose Absolute of Inconsistency Indirectness Imprecision SiT (95% studies design considerations ICS/LABA (95% CI) bias CI) + SABA

Participants with exacerbations requiring oral steroids

4 342/4202 516/4894 OR 0.75 24 fewer per 1000 (from (8.1%) (10.5%) (0.65 to 12 fewer to 34 fewer) 0.87)

9.37% 22 fewer per 1000 (from 11 fewer to 31 fewer)

Participants with serious adverse events

4 176/4215 213/4915 OR 0.92 3 fewer per 1000 (from 5 (4.2%) (4.3%) (0.74 to more to 11 fewer) 1.13)

3.29% 3 fewer per 1000 (from 4 more to 8 fewer)

Participants with severe exacerbations (hospitalisation or ER visit)

3 118/3321 225/4447 OR 0.72 14 fewer per 1000 (from (3.6%) (5.1%) (0.57 to 5 fewer to 21 fewer) 0.9)

4.83% 13 fewer per 1000 (from 5 fewer to 20 fewer)

Nocturnal awakenings (%)

2 2251 3373 - MD 1.08 lower (2.13 lower to 0.03 lower)

MD – mean difference, RR – relative risk

Table 5

Author(s): Jean-William Fitting Date: 2015-01-22 Question: Formoterol and ICS compared to same dose ICS for chronic asthma: serious adverse events [Data only. When citing this record quote "Cochrane Database of Systematic Reviews 2013, Issue ".] es:question.settings: Bibliography (systematic reviews): Cates CJ, Jaeschke R, Schmidt S, Ferrer M. Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events [Data only. When citing this record quote "Cochrane Database of Systematic Reviews 2013, Issue ".]. Cochrane Database of Systematic Reviews [Year], Issue [Issue].

Quality assessment № of patients Effect

Quality Importance Risk same Relative № of Study Other Formoterol Absolute of Inconsistency Indirectness Imprecision dose (95% studies design considerations and ICS (95% CI) bias ICS CI)

All-cause mortality - Adults and Adolescents

22 6/6163 1/4415 OR 3.56 1 more per 1000 (from (0.1%) (0.0%) (0.79 to 0 fewer to 3 more) 16.03)

All-cause mortality - Children and Adolescents

7 0/1719 see not see comment (0.0%) comment pooled

All-cause non-fatal serious adverse events - Adults and Adolescents

22 142/6163 113/4415 OR 0.98 0 fewer per 1000 (from (2.3%) (2.6%) (0.76 to 6 fewer to 7 more) 1.27)

1.43% 0 fewer per 1000 (from 3 fewer to 4 more)

All-cause non-fatal serious adverse events - Children and Adolescents

7 25/1719 9/1069 OR 1.62 5 more per 1000 (from (1.5%) (0.8%) (0.8 to 2 fewer to 19 more) 3.28)

0.75% 5 more per 1000 (from 1 fewer to 17 more)

Asthma-related non-fatal serious adverse events - Adults and Adolescents

21 17/5981 30/4227 OR 0.49 4 fewer per 1000 (from (0.3%) (0.7%) (0.28 to 1 fewer to 5 fewer) 0.88)

0.39% 2 fewer per 1000 (from 0 fewer to 3 fewer)

Asthma-related non-fatal serious adverse events - Children and Adolescents

7 9/1719 4/1069 OR 1.49 2 more per 1000 (from (0.5%) (0.4%) (0.48 to 2 fewer to 13 more) 4.61)

MD – mean difference, RR – relative risk

Table 6. Conclusiveness of evidence of benefit of budesonide-formoterol single inhaler therapy in relation to various outcomes and comparators (green = significant; yellow = non significant) Comparator Outcomes Current best Fixed dose ICS Fixed higher Fixed higher dose Same dose ICS practice dose ICS ICS/LABA combination Adults Exacerbations OR 0.81 OR 0.56 causing (0.45 to 1.44) (0.28 to 1.09) hospitalisation 1 fewer per 5 fewer per 1000 1000 (from 1 (from 3 fewer more to 8 to 3 more) fewer) Exacerbations OR 0.72 required (0.57 to 0.9) hospitalisation or ER visit 14 fewer per (adults and 1000 (from 5 children) fewer to 21 fewer) Exacerbations OR 0.83 OR 0.54 OR 0.75 treated with oral (0.7 to 0.98) (0.45 to 0.64) (0.65 to 0.87) steroids 11 fewer per 74 fewer per 24 fewer per 1000 (from 1 1000 (from 57 1000 (from 12 fewer to 20 fewer to 90 fewer to 34 fewer) fewer) fewer) Time to severe HR 0.59 exacerbations (0.49 to 0.7) 1 fewer per 1000 (from 0 fewer to 0 fewer) Rescue MD 0.37 lower medications (0.49 lower to 0.25 lower) All cause mortality OR 3.56 (adults and (0.79 to 16.03) adolescents) 1 more per 1000 (from 0 fewer to 3 more) Fatal SAE OR 1.95 OR 0.37 (0.53 to 7.21) (0.05 to 2.62) 1 more per 1 fewer per 1000 (from 0 1000 (from 1 fewer to 4 fewer to 2 more) more) Non-fatal SAE OR 1.2 OR 0.97 OR 0.98 (0.9 to 1.6) (0.73 to 1.29) (0.76 to 1.27) 4 more per 1000 (from 2 1 fewer per 0 fewer per 1000 fewer to 11 1000 (from 13 (from 6 fewer to 7 more) fewer to 13 more) more)

Outcomes Current best Fixed dose ICS Fixed higher Fixed higher dose Same dose ICS practice dose ICS ICS/LABA combination Adults All SAE OR 0.92 (0.74 to 1.13) 3 fewer per 1000 (from 5 more to 11 fewer) Asthma-related OR 0.49 non-fatal SAE (0.28 to 0.88) 4 fewer per 1000 (from 1 fewer to 5 fewer) Nocturnal MD 1.08 lower awakening (adults (2.13 lower to and children) 0.03 lower) Children Exacerbations OR 0.12 causing (0 to 6.12) hospitalisation 8 fewer per 1000 (from 9 fewer to 46 more) Exacerbation OR 0.33 requiring (0.15 to 0.77) treatment 123 fewer per 1000 (from 38 fewer to 162 fewer) Nocturnal Not estimable awakenings All cause mortality Not estimable (children and adolescents) Fatal SAE Not estimable Non-fatal SAE OR 0.35 OR 1.62 (0.07 to 1.83) (0.8 to 3.28) 30 fewer per 5 more per 1000 1000 (from 36 (from 2 fewer to 19 more to 44 more) fewer) Asthma-related OR 1.49 non-fatal SAE (0.48 to 4.61) 2 more per 1000 (from 2 fewer to 13 more) Height gain MD 1 higher (0.29 higher to 1.71 higher)