BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE (JPC)

BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE (JPC) February 2013, Updated September 2013 Review date: September 2016 Bulletin 176 : Choice of Inhaled Corticosteroid / Long Acting Beta 2 Agonist (ICS/LABA) combination therapy for the treatment of asthma in adult patients, updated Sept 2013 JPC Recommendation: To recommend the use of Fostair (beclometasone in combination with formoterol) (+/- a spacer device) for asthma in new patients who fulfil the licensing requirements (including use in a maintenance and reliever treatment regimen ) and NICE TAG 138 criteria. Patients on existing combination inhalers may be switched to Fostair if clinically appropriate, but care must be taken to avoid dose conversion errors as the beclometasone (BDP) in Fostair is present as extra fine particles. 100 micrograms of beclometasone extra-fine is equivalent to 250 micrograms of beclometasone non extra-fine and so dose conversions are required if switching from another CFC free BDP inhaler. Symbicort turbohaler (budesonide in combination with formoterol) is an appropriate second line choice if a dry powder inhaler is the preferred device when an MDI plus a spacer is not suitable for the patients. Salmeterol containing combination products may be prescribed for patients who are intolerant of formoterol. The Committee agreed that a high dose steroid combination product should not be included in the recommendations as use of such products should be considered on an individual patient basis and step down of treatment should be done wherever appropriate. Page 1 of 23

New Medicine Review Choice of Inhaled Corticosteroid / Long Acting Beta 2 Agonist (ICS/LABA) combination therapy for the treatment of asthma Medicine ICS/LABA combination drugs: beclometasone in combination with formoterol ( Fostair ) MDI. The beclometasone/formoterol combination device may be used as part of a maintenance and reliever therapy regimen in addition to regular maintenance treatment. [30] fluticasone propionate in combination with formoterol (Flutiform ) MDI. fluticasone propionate in combination with salmeterol (Seretide ) Evohaler and Accuhaler. budesonide in combination with formoterol (Symbicort ) Turbohaler. The budesonide/formoterol fumarate combination device may be used as part of a flexible dosing regimen, such as adjustable maintenance dosing, and may also be used as a reliever medication[2] Document status Final Updated Bulletin approved by the Bedfordshire and Luton Joint Prescribing Committee, September 2013. Update for Bulletin 137: Fostair (beclometasone dipropionate (BDP) 100mcg and Formoterol fumarate dehydrate 6mcg metered dose inhaler) for asthma approved by the JPC in September 2010 Adapted with permission from the draft review prepared by East Anglia Medicines Information. Date of last revision 18 September 2013 Proposed Sector of prescribing Primary and Secondary Care Introduction Summary Key points Evidence level There are currently 4 ICS / LABA combination inhalers available for asthma or COPD, namely Fostair, Flutiform, Seretide & Symbicort. None of the inhalers contain the same combination of ICS and LABA: Fostair contains beclometasone + formoterol, Flutiform contains fluticasone + formoterol Seretide contains fluticasone + salmeterol and Symbicort contains budesonide + formoterol. Flutiform, Fostair and Seretide Evohaler are delivered via a pressurised MDI. Seretide Accuhaler and Symbicort are delivered via a dry powder breath actuated inhaler. Fostair is only available as low and moderate ICS dose products. Flutiform, Seretide and Symbicort are available as low, moderate and high dose ICS products. Page 2 of 23

All 4 products are licensed for use in asthma. Only Seretide 500 Accuhaler and Symbicort 200/6 and 400/12 Turbohalers are licensed for use in COPD. Symbicort Turbohaler and Fostair MDI are currently licensed for maintenance and reliever therapy in asthma. Fostair is not licensed for use in children. Flutiform can be used by children aged 12 years and over (for the high strength product this is for adults over 18 only). Seretide can be used in children aged 4 years and over. Symbicort can be used in children aged 6 years and over. Fostair needs to be stored in the fridge prior to dispensing, but can be stored at room temperature once dispensed with a reduced shelf life of 5 months. This should not be a problem as patients requiring ICS/LABA combination inhalers should be taking their inhaler every day and one inhaler typically has sufficient doses for one month. National guidelines for asthma and COPD do not highlight/recommend any specific product and suggest prescribing the product with the lowest acquisition cost. Flutiform and Fostair are considered to be non-inferior to Seretide and Symbicort and so have similar efficacy. Seretide and Symbicort are assumed to be clinically equivalent in asthma. Seretide and Symbicort have not been compared in head to head randomised, controlled clinical studies in COPD. The intervention Mechanism of action The aims of pharmacological management of asthma are the control of symptoms, including nocturnal symptoms and exercise induced asthma, prevention of exacerbations and the achievement of best possible pulmonary function, with minimal side effects.[4] In general terms, control of asthma is assessed against these standards: Minimal symptoms during day and night Minimal need for reliever medication No exacerbations No limitation of physical activity Normal lung function (in practical terms FEV1 and/or PEF >80% predicted or best) Page 3 of 23 A stepwise approach as advocated by the Joint British Guidelines on the management of asthma produce by the British Thoracic Society and the Scottish Intercollegiate Network (BTS/SIGN Guidelines) aims to abolish symptoms as soon as possible and to optimise peak flow by starting treatment at the level most likely to achieve this. The aim is to achieve early control and to maintain control by stepping up treatment as necessary and stepping down when control is good. Before initiating a new therapy practitioners should check compliance with existing therapies, inhaler technique and eliminate trigger

factors.[4] In efficacy studies, where there is generally good compliance, there is no difference in efficacy in giving inhaled corticosteroid (ICS) and a long-acting beta2 agonist (LABA) in combination or in separate inhalers. In clinical practice, however it is generally considered that combination inhalers aid compliance and also have the advantage of guaranteeing that the LABA is not taken without the ICS. Combination inhalers are recommended to: guarantee that the LABA is not taken without ICS. improve inhaler adherence. Licensed indication *[1][31] Usual dosage*[2][31] Treatment alternatives See Appendix 1 See Appendix 1 The choice of drug(s) should take into account the person s symptomatic response and preference, and the drug s potential to reduce exacerbations, its side effects and cost. Most patients whatever their age are able to acquire and maintain adequate inhaler technique given adequate instruction. The exception to this is that those with significant cognitive impairment (as a guideline, those with a Hodkinson Abbreviated Mental Test Score of 4 or less) are unable to use any form of inhaler device. In most patients, however, a pragmatic approach guided by individual patient assessment is needed in choosing a device. In most cases bronchodilator therapy is best administered using a hand-held inhaler device (including a spacer device if appropriate). Place in therapy ICS/LABA combination inhalers would be used in steps 3 and 4 of the BTS/SIGN guidelines for the treatment of asthma. NICE has produced a TAG number 138 Inhaled corticosteroids for the treatment of chronic asthma in adults and in children aged 12 years and over [5]. They recommend that : For adults and children aged 12 years and older with chronic asthma in whom treatment with an inhaled corticosteroid (ICS) is considered appropriate, the least costly product that is suitable for an individual, within its marketing authorisation, is recommended. For adults and children aged 12 years and older with chronic asthma in whom treatment with an ICS and long-acting beta-2 agonist (LABA) is considered appropriate, the following apply: The use of a combination device within its marketing authorisation is recommended as an option. The decision to use a combination device or the two agents in separate devices should be made on an individual basis, taking into consideration therapeutic need and the likelihood Page 4 of 23

of treatment adherence. If a combination device is chosen then the least costly device that is suitable for the individual is recommended. Evidence for use Drug comparisons Inhaled Corticosteroids There is a choice of three inhaled corticosteroids which are available in a combination inhaler namely beclometasone, budesonide and fluticasone. Beclomethasone or budesonide are the preferred first line inhaled corticosteroids as they are considered safer than the more potent fluticasone. A meta-analysis looking at the systemic effects of inhaled corticosteroids concluded that All inhaled corticosteroids exhibit dose-related systemic adverse effects, although these are less than with a comparable dose of oral corticosteroids. Meta-analysis shows that fluticasone propionate exhibits greater dose-related systemic bioactivity compared with other available inhaled corticosteroids, particularly at doses above 0.8 mg/d. The long-term systemic burden will be minimized by always trying to achieve the lowest possible maintenance dose that is associated with optimal asthmatic control and quality of life. [29] In asthma, beclometasone dipropionate and budesonide are approximately equivalent in clinical practice, although there may be variations with different delivery devices. There is limited evidence from two open studies of less than ideal design that budesonide via the turbohaler is more clinically effective. However, at present a 1:1 ratio should be assumed when changing between BDP and budesonide. Fluticasone provides equal clinical activity to BDP and budesonide at half the dosage. The evidence that it causes fewer side effects at doses with equal clinical effect is limited. [6] Page 5 of 23 In COPD, the GOLD guidelines state that the dose-response relationships and long term safety of ICSs in COPD are not known. Only moderate to high doses have been used in long-term clinical trials. The efficacy and side effects of ICSs in asthma are dependent on the dose and type of corticosteroid, but whether this is also the case in COPD is unclear. The effects of corticosteroids on pulmonary and systemic inflammation in patients with COPD are controversial and their role in management of stable COPD is limited to specific indications. Regular treatment with ICS improves symptoms, lung function and quality of life and reduces the frequency of exacerbations in COPD patients with an FEV1 <60% predicted. Withdrawal from treatment with ICS may lead to exacerbations in some patients. Regular treatment with ICS does not modify the long term decline of FEV1, nor mortality in patients with COPD. [7]. The NICE Clinical Guideline 101 on COPD states the choice of drug should be based on a person s symptomatic response and preference, the drug s side effects, potential to reduce exacerbations and cost [8}

Long acting beta 2 agonists: There are two LABA drugs available as combination inhalers with an ICS Salmeterol and. Formoterol. Formoterol is the ideal drug choice as: The BNF states that salmeterol should not be used for the relief of an asthma attack as it has a slower onset of action than salbutamol or terbutaline. Formoterol on the other hand is licensed for short term symptom relief and for the prevention of exercise induced bronchospasm; its speed of onset is similar to that of salbutamol. [2] Asthma: The British Guideline on the management of asthma does not name any of the LABAs individually or highlight any differences between them. [4] Therefore if one is required, it is up to the prescriber to decide which one to choose. The BNF However states that salmeterol should not be used for the relief of an asthma attack as it has a slower onset of action than salbutamol or terbutaline. Formoterol on the other hand is licensed for short term symptom relief and for the prevention of exercise induced bronchospasm; its speed of onset is similar to that of salbutamol. [2] In COPD, formoterol and salmeterol significantly improve FEV1 and lung volumes, dyspnoea, and health related quality of life and exacerbation rate but have no effect on mortality and rate of decline of lung function. Salmeterol reduces the rate of hospitalisation. [7] Published head to head, clinical, comparative studies of the combination inhalers in asthma (Flutiform and Fostair not licensed for COPD and there are no published head to head comparisons in COPD for Seretide vs Symbicort ) Flutiform vs Fostair Flutiform vs Seretide Flutiform vs Symbicort Fostair vs Seretide Fostair vs Symbicort Seretide vs Symbicort Asthma X (Refs 11 & 12, Flutiform non-inferior to Seretide) (Ref 13, Flutiform non-inferior to Symbicort) (Ref 14, Fostair has similar efficacy to Seretide) (Ref 16, Fostair has similar efficacy to Symbicort) (ref 17-19, clinical equivalence assumed by NICE) COPD X (Flutiform & Fostair not licensed for COPD) X (Flutiform not licensed for COPD) X (Flutiform not licensed for COPD) X (Fostair not licensed for COPD) X (Fostair not licensed for COPD) Asthma Flutiform The efficacy of fluticasone/formoterol 50/5 micrograms or 125/5 micrograms, two actuations twice daily (Flutiform ) was compared X Page 6 of 23

with fixed dose fluticasone/salmeterol 50/25 micrograms or 125/5 micrograms,, two actuations twice daily (Seretide pmdi) in an open label, parallel group,12 week randomised study in 202 adults (189 completed) with mild to moderate to severe persistent asthma. Flutiform was shown to be non-inferior to Seretide in the primary outcome of pre-dose FEV1 at week 12. Non inferiority of Flutiform relative to Seretide was demonstrated as LS mean pre dose FEV1 treatment difference from baseline to the end of Week 12 ( 0.061L; 95% CI: 0.161, 0.040; P=0.007). A secondary outcome showed that Flutiform had a more rapid onset of action than Seretide. [11] A double blind, double dummy, randomised, parallel group, multicentre 12 week study in 279 adults and adolescents (261 completed) with moderate to severe persistent asthma was carried out to demonstrate non inferiority of fluticasone/formoterol (Flutiform ) 125/5 micrograms, two actuations twice daily, (n=140) relative to budesonide/formoterol (Symbicort ) 200/6 micrograms, two actuations twice daily, (n=139). The primary endpoint was difference in FEV1 from baseline to end of week 12. Non inferiority of Flutiform relative to Symbicort was demonstrated as LS mean pre dose FEV1 treatment difference from baseline to the end of Week 12 ( 0.044 L; 95% CI: 0.130, 0.043; P<0.001). Flutiform also had a similar tolerability profile to Symbicort. 29 patients (20.7%) in the Flutiform group and 26 (18.7%) in the Symbicort group reported at least one AE. The majority of AEs were mild or moderate in intensity. [13] Fostair Fostair contains the ICS/LABA preferred treatment options beclometasone and formoterol as discussed earlier In a study comparing beclometasone/formoterol (Fostair ) and budesonide/formoterol (Symbicort ), the dose ratio of beclometasone:budesonide was 1:2, which is different from the traditional equivalence reported in the equivalence table of ICS in several international guidelines. The study enrolled over 200 moderate asthmatic subjects, uncontrolled with ICS at doses lower than 1000 mcg of beclometasone or equivalent, in a double blind, randomised, parallel group 3 month study. The main outcome of the study was morning peak expiratory flow (PEF). In both groups, PEF significantly increased just after few weeks and remained higher than baseline during all the study period, without any significant difference between both groups. The same efficacy was observed in the two groups as regards day-time and nocturnal symptoms, and the rate of asthma exacerbations. [14] In a study comparing beclometasone/formoterol (Fostair ) and fluticasone/salmeterol (Seretide ), the dose ratio of beclometasone:fluticasone was 1:1.25, which is different from the traditional equivalence reported in the equivalence table of ICS in Page 7 of 23

several international guidelines. The characteristics of the study population were identical to the study above, as well as the main outcome (morning PEF). Also this study confirmed the equivalence between beclometasone/formoterol with fluticasone/salmeterol in terms of pulmonary function, asthma symptoms and exacerbations. Furthermore, a significant better improvement in forced vital capacity (FVC) was observed with the new beclometasone/formoterol combination in comparison with fluticasone/salmeterol combination. [15] Seretide and Symbicort Efficacy The NICE TA on use of corticosteroids for asthma in adults and children aged 12 years and over highlighted 3 RCTs which have evaluated the effectiveness of Symbicort (budesonide/formoterol fumarate) (approximately 800 micrograms budesonide, 24 micrograms formoterol fumarate using the Turbohaler device) with Seretide (fluticasone propionate/salmeterol) (approximately 500 micrograms fluticasone propionate, 100 micrograms salmeterol using the Accuhaler device). [17-19] Results of these studies were mixed. Some studies reported statistically significant improvements for some outcomes with Symbicort while others reported statistically significant improvements with Seretide. One RCT reported significant improvements in lung function with the Symbicort inhaler, and two RCTs reported significant improvements in lung function with the Seretide inhaler. Two RCTs reported a significant reduction in the rate of exacerbations with the Symbicort inhaler, and one RCT reported a significant reduction in the rate of exacerbations with the Seretide inhaler. The use of rescue medication was significantly lower with Seretide in one RCT. There were no differences between the Symbicort and the Seretide inhalers in two RCTs which reported on asthma symptoms, health related quality of life, or the rate of adverse events. A third RCT reported a significant reduction in symptom-free days with Seretide. The NICE TA surmised that clinical equivalence of the 2 combination inhalers was assumed. [17-19] Page 8 of 23 Symbicort SMART In selected adult patients at step 3 in the asthma pathway who are poorly controlled or in selected adult patients at step 2 (above BDP 400 micrograms/day and poorly controlled), the use of budesonide/formoterol (Symbicort ) in a single inhaler as rescue medication instead of a short-acting beta 2 agonist, in addition to its regular use as controller therapy has been shown to be an effective treatment regime (SMART). When this management option is introduced the total regular dose of daily ICSs should not be decreased. The regular maintenance dose of ICSs 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. [4] The Drug and Therapeutics Bulletin reviewed the SMART regimen for asthma in November 2011. The article concluded that there is published evidence supporting the use of SMART with regards to the two lower-dose budesonide-formoterol (Symbicort ) Turbohalers, but none for other combination inhalers. In some comparisons the Symbicort SMART regimen appeared to reduce the rate of exacerbations requiring treatment with oral corticosteroids but not those that resulted in hospitalisation. However, SMART was not shown to be more effective than current best practice. In theory, use of the SMART regimen might help by reducing the number of inhalers required. However, patients using this approach would need a clear action plan and close monitoring of the number of inhalations that they are taking. Consequently, its place in practice remains unclear. [7] Fostair (Beclometasone/formoterol) for maintenance and reliever treatment. (See the NICE ESNM22, issued June 2013 for more detailed information http://www.nice.org.uk/mpc/evidencesummariesnewmedicines/ ESNM22.jsp) Page 9 of 23 Fostair was licensed in 2007 for the maintenance therapy of asthma in adults aged 18 years or over; within this licensed indication Fostair is taken as regular maintenance treatment with a separate rapidacting bronchodilator taken as-needed. In December 2012, the licence was extended to include maintenance and reliever therapy in adults, meaning that Fostair is taken as regular maintenance treatment and as needed in response to asthma symptoms. This evidence review is based on a randomised controlled trial that compared the efficacy and safety of beclometasone/formoterol maintenance and reliever treatment with standard maintenance treatment using regular beclometasone/formoterol and as-needed salbutamol. The study included 1714 adults with uncontrolled asthma, the majority of whom were at step 3 or 4 of the British guideline on the management of asthma (SIGN guideline 101). The study found that, compared with beclometasone/formoterol plus as-needed salbutamol, beclometasone/formoterol for both maintenance and reliever treatment statistically significantly increased the time to first severe exacerbation (the primary outcome) by 75 days (134 days versus 209 days respectively; hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.49 to 0.82; p=0.0005). A statistically significant reduction was seen in the yearly rate of severe exacerbations per patient with maintenance and reliever treatment, compared with as-needed salbutamol (14.76 events per 100 patients per year compared with 22.39 respectively; HR 0.66, 95% CI 0.55 to 0.80; p<0.0001).

Similar numbers of patients in the as-needed beclometasone/formoterol and salbutamol groups experienced serious adverse events (32 [3.7%] and 41 [4.8%] respectively; statistical significance of difference not reported). Adverse drug reactions occurred significantly more often in patients treated with as-needed beclometasone/formoterol compared with as-needed salbutamol (38 [4.4%] compared with 19 [2.2%] respectively; p=0.01). It is not known how the efficacy and safety of beclometasone/formoterol (Fostair) compares directly with the established budesonide/formoterol (Symbicort) maintenance and reliever treatment. More data are available to support the use of budesonide/formoterol for this indication. The British guideline on the management of asthma advises that budesonide/formoterol (Symbicort) regular maintenance and reliever treatment is an option for selected adults at step 3 whose asthma is poorly controlled, or for selected adults at step 2 whose asthma is poorly controlled and who are taking more than 400 micrograms of beclometasone dipropionate or equivalent each day. Careful education of patients about this management strategy is required. Patients taking rescue ICS/LABA once a day or more on a regular basis should have their treatment reviewed. Based on the results of the study, beclometasone/formoterol (Fostair) may also be an option for adults at step 3 whose asthma is poorly controlled. Some people may prefer to follow the traditional steps of the British guideline on the management of asthma. For those at step 3, this involves increasing the dose of ICS in their current maintenance treatment, rather than switching to maintenance and reliever treatment. The choice of treatment (maintenance and reliever therapy or the traditional stepped approach), product (beclometasone/formoterol or budesonide/formoterol) and inhaler device (pressurised metered dose inhaler or dry powder inhaler) may be important to individual patients. Page 10 of 23 COPD Seretide and Symbicort have not been compared in head to head randomised, controlled clinical studies in COPD. A phase II randomised, placebo-controlled, double-blind, doubledummy, crossover study was conducted in 10 centres in Sweden and 9 centres in Hungary to assess the onset of action of two inhalations of Symbicort 200/6, compared with two inhalations of Seretide 250/25, two inhalations of Ventolin (salbutamol) 100mcg, and placebo, all delivered by pressurised MDI, in 90 subjects with COPD. The primary outcome was FEV1 5 minutes after administration of randomised treatment expressed as a percentage of baseline. The aim of the study was to show that Symbicort was superior to Seretide in onset of bronchodilatation at 5 minutes. The results show an increase of 15.33%, 9.83% and 16.64% in FEV1

after 5 minutes for Symbicort, Seretide and Ventolin respectively, with no change for placebo. Symbicort produced greater bronchodilatation compared to Seretide (ratio 105% (95% CI 102.57 107.49); p=0.0001). All of the active treatments were significantly better than placebo (p <0.0001) [23] Safety* Long acting Beta Agonists: The CHM has advised that for the management of asthma long acting beta agonists should: be added only if regular use of standard dose inhaled corticosteroids has failed to control the asthma adequately not be initiated in patients with rapidly deteriorating asthma be introduced at a low dose and the effects be properly monitored before a dose increase is considered not to be used for exercise induced asthma unless inhaled corticosteroids are also used. Be reviewed as clinically appropriate, stepping down therapy should be considered when good long term control is achieved.[2] A Cochrane review assessing serious adverse events from regular treatment with formoterol and an ICS versus regular treatment with salmeterol and an ICS for chronic asthma, identified 7 studies in adults which did not show any significant difference in safety between formoterol and budesonide (Symbicort ) in comparison with salmeterol and fluticasone (Seretide ). Asthma-related serious adverse events were rare, and there were no reported asthmarelated deaths. There was a single, small study comparing formoterol and beclometasone (Fostair ) to salmeterol and fluticasone (Seretide ) in adults, a single study comparing formoterol and mometasone with salmeterol and fluticasone in adults, and a single study comparing formoterol and fluticasone (Flutiform ) with salmeterol and fluticasone (Seretide ) in adults. Overall there is insufficient evidence to decide whether regular formoterol in combination with budesonide (Symbicort ), beclometasone (Fostair ), fluticasone (Flutiform ) or mometasone have equivalent or different safety profiles from salmeterol in combination with fluticasone (Seretide ). [21] A Cochrane systematic review of randomised studies comparing fixed dose fluticasone/salmeterol (Seretide ) and budesonide/formoterol (Symbicort ) in adults or children with a diagnosis of asthma concluded that statistical imprecision in the effect estimates for exacerbations and serious adverse events mean it is not possible to conclude that either therapy is superior. The uncertainty around the effect estimates justify further trials to provide more definitive conclusions; the overall quality of evidence based on GRADE recommendations for the three primary outcomes and withdrawals due to serious adverse events was moderate. The Page 11 of 23

quality of evidence for mortality was found to be low. Results for lung function outcomes showed that the drugs were sufficiently similar that further research is unlikely to change the effects. No trials were identified in the under-12s and research in this population is a high priority. Evaluation of quality of life is a priority for future research. [22] Inhaled corticosteroids: The common side effects of inhaled corticosteroids include oral candidiasis which can be reduced by using a spacer device and rinsing the mouth with water. [2] High dose inhaled corticosteroids however are related to more severe side effects such as adrenal suppression, growth retardation in children, cataracts and glaucoma, decrease in bone mineral density, a range of psychological and behavioural effects and diabetes onset and progression ( NNH 21 over 5.5 years). [25] In COPD patients in particular there is also a risk of fractures and severe pneumonia. Tariff status Cost (prices from Chemist and Druggist, August 2013) [32] [33] All ICS / LABA drugs are listed in the Drug tariff and are listed as Category C Drugs which means they are paid according to the list price of the brand.[26] These drugs are all within PBR Tariff. Cost/30 Days Low Dose ICS/LABA Fostair Inhaler 100/6 micrograms/puff 1 puff BD 14.66 Seretide Accuhaler 100/50 micrograms/puff, 1 puff BD 18.00 Seretide Evohaler 50/25 micrograms/puff, 2 puffs BD 18.00 Flutiform Inhaler 50/5 micrograms/puff, 2 puffs BD 18.00 Symbicort Turbohaler 200/6 micrograms/puff, 1 puff BD 19.00 Symbicort Turbohaler 100/6 micrograms per puff, 2 puffs BD 33.00 Moderate Dose ICS LABA Flutiform Inhaler 125/5 micrograms/puff, 2 puff BD 29.26 Fostair Inhaler100/6 micrograms/puff, 2 puff BD 29.32 Seretide Accuhaler 250/50 micrograms/puff, 1 puff BD 35.00 Seretide Evohaler 125/25 micrograms/puff, 2 puffs BD 35.00 Symbicort Turbohaler 200/6 38.00 Page 12 of 23

Cost effectiveness (if available) Potential number of patients in Bedfordshire and Luton Impact per 100,000 population Affordability considerations micrograms/puff, 2 puffs BD High dose ICS/LABA Seretide Accuhaler 500/50 micrograms/puff, 1 puff BD 40.92 Flutiform Inhaler 250/10 micrograms/puff, 2 puffs BD 45.56 Seretide Evohaler 250/25 micrograms/puff, 2 puffs BD 59.48 Symbicort Turbohaler 400/12 micrograms/dose 2 puffs bd 76.00 NICE TAG 138 has identified that ICS/LABA combination products are a cost effective treatment option at the appropriate stage of the BTS guidelines in asthma treatment. However the data below shows that a large proportion of patients are on the High dose ICS/LABA combination which if this is for asthma treatment relates to step 4 of the treatment guidelines. BTS state only a small proportion of patients should be at this step of the guidelines which does suggest a large number of patients are being over treated which is neither safe not cost effective. NICE also state that where an ICS/LABA is considered appropriate, the drug with the lowest acquisition cost should be prescribed. Annually (epact Dec 11 to Nov 12) Bedfordshire spend 3.8 million on the ICS/LABA combination products. Not all this spend will be for asthma. As some of these products are also licensed for COPD a significant proportion of this spend will also be for COPD. In addition the ICS /LABA drugs account for 7 out of the top 20 products by cost across Bedfordshire. The majority of this spend is for the Seretide 250 Evohaler (A high dose product which is only licensed for asthma) which accounts for the 1 st and 3 rd highest spend items and almost 1.15 million of the annual spend. Position 1 3 6 11 15 17 20 Total Act BNF Name Cost Fluticasone/Salmeterol_Inh 250/25mcg120D 609,027.06 Seretide 250_Evohaler 250mcg/25mcg(120D) 538,557.80 Fluticasone/Salmeterol_Inh 125/25mcg120D 368,229.60 Seretide 500_Accuhaler 500mcg/50mcg(60D) 294,172.93 Budesonide/Formoterol Inh B/A 200/6(120D 257,345.01 Symbicort _Turbohaler 200mcg/6mcg (120 D) 247,696.82 Seretide 125_Evohaler 125mcg/25mcg(120D) 244,405.89 Page 13 of 23

In addition, Luton Spend 1.52 million annually on the ICS/LABA combination inhalers. The ICS/LABA combination inhalers account for 2 of the top 20 items by cost for Luton both of which are High dose ICS/ LABA combination products. 498,500 of the annual spend) Position BNF Name Total Act Cost 1 Fluticasone/Salmeterol_Inh 250/25mcg120D 299,025.49 4 Seretide 250_Evohaler 250mcg/25mcg(120D) 199,478.50 Ethics Equity Patient choice/ access considerations There are significant savings to be made by choosing cost effective products for asthma as a first line choice and also as a switch option as well as reviewing the use of high dose inhaled corticosteroids in light of the safety concerns and stepping down treatment. PrescQIPP bulletins are available to support this work and are available at http://www.clingov.eoe.nhs.uk/prescqipp/ See attached assessment against Ethical and Commissioning Principles Choice of treatment should be based on the licensed indications, patient s ability to use the inhaler device and also side effects of the drugs chosen. Page 14 of 23

Is the drug on the Luton and Dunstable or Bedford Hospital Formulary The JPC which recommend the use of Fostair for asthma in new patients who fulfil the licensing and NICE TAG 138 criteria (below). Patients on existing combination inhalers may be switched if clinically appropriate, but care must be taken as there is potential for error due to dose inequivalencies as the beclometasone in Fostair is present as extra fine particles and so is not bio or dose equivalent to CFCcontaining BDP. In addition, Fostair has to be stored in a refrigerator prior to dispensing. Once dispensed, a 5 month shelf life is added to the label and the inhaler then does not have to be stored in a refrigerator. The JPC were mindful that this may lead to wastage should prescribers not be aware of this shelf life limitation. Flutiform has not been reviewed by the Bedford Hospital or the L&D DTC at this stage. Symbicort and Seretide have been in use for many years. Decisions from other bodies Page 15 of 23 The MPC (Medicines and Prescribing Centre) which come under the umbrella of NICE has produced a new medicine evidence summary for fluticasone/formoterol (Flutiform ) in September 2012 as the fluticasone/formoterol combination inhaler is not currently being considered for a NICE technology appraisal or other work programme. They have reviewed the evidence and concluded that it is similar in efficacy to the individual component products used as separate inhalers and also to Seretide. They conclude that the use of the product must be considered alongside other treatment option in accordance with the BTS guidelines on the management of asthma. The cost of treatment options will be a factor in local decision making.[9] The SMC accepted beclometasone 100mcg, formoterol 6mcg metered dose inhaler (Fostair ) for use within NHS Scotland in January 2008, for the regular treatment of asthma where use of a combination product (inhaled corticosteroid and LABA) is appropriate: patients not adequately controlled with inhaled corticosteroids and as needed inhaled short acting beta2-agonist; or patients already adequately controlled on both inhaled corticosteroids and LABAs. Fostair should be used in patients for whom beclometasone and formoterol are appropriate choices of corticosteroid and LABA, respectively, and for whom a metered dose inhaler is an appropriate delivery device. Fostair has costs similar to other combination products containing a corticosteroid and LABA to which it was clinically non-inferior. The 100mcg dose of beclometasone in Fostair is not bioequivalent to a 100mcg dose of beclometasone in several other inhaler formulations. The Fostair summary of product characteristics contains information on transferring from these inhalers to Fostair. [27]

The SMC accepted fluticasone propionate and formoterol fumarate metered dose inhaler (Flutiform ) for use in NHS Scotland in October 2012 for the regular treatment of asthma where the use of a combination product [an inhaled corticosteroid (ICS) and LABA] is appropriate: for patients not adequately controlled on ICS and as required inhaled short-acting beta2 agonist or for patients already adequately controlled on both an ICS and a LABA. Flutiform should be used in patients for whom fluticasone and formoterol are appropriate choices of corticosteroid and LABA, respectively, and for whom a metered dose inhaler is an appropriate delivery device. It has demonstrated clinical non-inferiority to another combination product containing a corticosteroid and LABA and may offer cost savings. [28] Comments sought from Points for consideration Bedfordshire Respiratory Consultants Dr S Tariq, Dr T Chapman, Dr E C Thomas, Dr J Ramsey, Dr M Azher, Dr P Pillai. Bedfordshire COPD nurses Farida Parkar, Lorraine Curtin Dr Bhattacharya, Respiratory Consultant, Milton Keynes Hospital (via Secretary Julie Elsasi). Bedfordshire and Luton GPs via Pharmacy Leads. See summary section above PAC New Drug Template Adapted from East Anglia Medicines Information, NHS Suffolk, and NHS Cambridgeshire and NHS Derby templates. *Consult Summary of Product Characteristics for full prescribing details. This guidance is based upon the published information available in English at the time the drug was considered. It remains open to review in the event of significant new evidence emerging. Page 16 of 23

Appendix 1: Comparison of the ICS/LABA combination products Trade name Flutiform Fostair Seretide Symbicort Device Strengths available Pressurised metered dose inhaler (MDI) Fluticasone/formoterol 50 / 5 microgram 125 / 5 microgram 250 / 10 microgram Pressurised MDI Beclometasone/formoterol 100 / 6 microgram Accuhaler (dry powder, breath actuated inhaler) Evohaler (Pressurised MDI) Fluticasone/salmeterol Accuhaler 100 / 50 microgram 250 / 50 microgram 500 / 50 microgram Turbohaler (dry powder, breath actuated inhaler) Budesonide/formoterol 100 / 6 microgram 200 / 6 microgram 400 / 12 microgram Adult asthma prophylaxis / maintenance dose Adult asthma single maintenance and reliever therapy (SMART) 2 puffs BD with all strengths 1-2 puffs BD (maximum 4 puffs daily) Not licensed 1 puff BD for maintenance. Patients should take 1 additional puff PRN in response to symptoms and an additional puff if symptoms persist after a few minutes. Maximum daily dose is 8 puffs/day. Fluticasone/salmeterol Evohaler 50 / 25 microgram 125 / 25 microgram 250 / 25 microgram 100/50: 1 puff BD, reduce to 1 puff OD if controlled 250/50 and 500/50: 1 puff BD 50/25: 2 puffs BD, reduce to 2 puffs OD if controlled 125/25 and 250/25: 2 puffs BD Not licensed 100/6 and 200/6: 1-2 puffs BD (maximum 4 puffs BD, reduce to 1 puff OD if controlled) 400/12: 1 puff BD (maximum 2 puffs BD, reduce to 1 puff OD if controlled) 100/6: 2 puffs daily in 1-2 divided doses, for relief of symptoms use 1 puff PRN up to max 6 puffs, maximum 8 puffs/day (up to 12 puffs daily can be used for a limited time) 200/6: 2 puffs daily in 1-2 divided doses, up to 2 puffs BD; for relief of symptoms use 1 puff PRN up to max 6 puffs, maximum 8 puffs/day (up to 12 puffs daily can be used for a limited time) Page 17 of 23

Child asthma prophylaxis / maintenance dose 2 puffs BD with 50/5 and 125/5 inhalers only in patients aged 12 yrs and over Not licensed 100/50: 1 puff BD, reduce to 1 puff OD if controlled in children aged 4 yrs and over 250/50 and 500/50: 1 puff BD in children over 12 yrs old 50/25: 2 puffs BD, reduce to 2 puffs OD if controlled in children aged 4 yrs and over 125/25 and 250/25: 2 puffs BD in children over 12 yrs old 100/6: 1-2 puffs BD, reduce to 1 puff OD if controlled in children aged 6-17 yrs 200/6 and 400/12: 1-2 puffs BD, reduce to 1 puff OD if controlled in children 12-17 yrs COPD dose Not licensed Not licensed 500/50: 1 puff BD 200/6: 2 puffs BD 400/12: 1 puff BD Price per unit ~30 days supply (see appendix 1 for price per dose) 120 actuations inhaler 50/5: 18 125/5: 29.26 250/10: 45.56 120 actuations inhaler 100/6: 29.32 60 actuations Accuhaler 100/50: 18 250/50: 35 500/50: 40.92 Miscellaneous information Compatible with generic spacers: A2A Spacer, Able Spacer, Optichamber Diamond, Pocket Chamber, Vortex Fridge storage required The 100mcg dose of beclometasone in Fostair is not bioequivalent to a 100mcg dose of beclometasone in other inhalers. Compatible with Aerochamber Plus spacer (and generic spacers) 120 actuations Evohaler 50/25: 18 125/25: 35 250/25: 59.48 Accuhaler preloaded, primed by opening. Easy to use, requires minimal manual dexterity to prime. Red warning seen with last 5 doses. Humidity protected. Evohaler compatible with Volumatic and Aerochamber Plus spacers (and generic spacers) 120 actuations Turbohaler 100/6: 33 200/6: 38 60 actuations Turbohaler 400/12: 38 Turbohaler preloaded, primed by twisting. Easy to use, requires minimal dexterity. Cog wheel dose indicator with last 20 doses marked in red. Separate cap. Humidity protected. Page 18 of 23

References/ Sources of Review 1. Bedfordshire and Luton Joint Prescribing Committee, Bulletin 137 Fostair (beclometasone dipropionate (BDP)100mcg and formoterol fumarate dihydrate 6mcg metered dose inhaler) for asthma 2. British National Formulary No 65. London: British Medical Association and The Royal Pharmaceutical Society of Great Britain; March- September 2013. 3. Smith,K, Suffolk PCT Drug and Therapeutics committee ICS/LABA review, October 2012 4. British Guideline on the management of asthma. Produced jointly by SIGN and the British Thoracic Society (BTS) since 2003, sections of the guideline are updated annually. Guideline 101. May 2008, Revised May 2011, Section 4.3.4 revised Sept 2011, Section 1 revised Jan 2012. http://www.sign.ac.uk/pdf/sign101.pdf 5. NICE TA 138. Corticosteroids for the treatment of chronic asthma in adults and children aged 12 years and over. March 2008. http://guidance.nice.org.uk/ta138 6. MIMS October 2012 7. Anon. Single maintenance and reliever therapy (SMART) for asthma. Drug & Therapeutics Bulletin 2011; 49 (11): 126-9 8. NICE Clinical Guideline 101. Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update). June 2010 http://guidance.nice.org.uk/cg101 9. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Revised 2011 http://www.goldcopd.org/uploads/users/files/gold_report_2011_feb21.pdf 10. Cates CJ, Oleszczuk M, Stovold E, Wieland LS. Safety of regular formoterol or salmeterol in children with asthma: an overview of Cochrane reviews. Cochrane Database of Systematic Reviews 2012, Issue 10. Art. No.: CD010005. DOI: 10.1002/14651858.CD010005.pub2. 11. Bodzenta-Lukaszyk A et al. Fluticasone/formoterol combination therapy is as effective as fluticasone/salmeterol in the treatment of asthma, but has more rapid onset of action: an open label, randomised study. BMC Pulm Med 2011;11:28. Epub 2011 May 23 12. NICE. ESNM3: Asthma: fluticasone/formoterol (Flutiform ) combination inhaler. October 2012 http://www.nice.org.uk/mpc/evidencesummariesnewmedicines/esnm3.jsp 13. Bodzenta Lukaszyk A, Buhl R, Balint B, et al. Fluticasone/formoterol combined in a single aerosol inhaler vs. budesonide/formoterol for the treatment of asthma: a non inferiority trial. Abstract presented at the European Respiratory Society Annual Congress; 2011 Sep 24 28; Amsterdam, Netherlands. 14. Papi A, Paggiaro PL, Nicolini G, Vignola AM, Fabbri LM. Inhaled Combination Asthma Treatment versus Symbicort (ICAT SY) Study Group. Beclomethasone/formoterol versus budesonide/formoterol combination therapy in asthma. Eur Respir J 2007; 29: 682-9. 15. Papi A, Paggiaro P, Nicolini G, Vignola AM, Fabbri LM. ICAT SE study group. Beclomethasone/formoterol vs. fluticasone/salmeterol inhaled combination in moderate to severe asthma. Allergy 2007; 62: 1182-8. 16. NICE TA 138. Corticosteroids for the treatment of chronic asthma in adults and children aged 12 years and over. March 2008. http://guidance.nice.org.uk/ta138 17. Shepherd J, Rogers G et al on behalf of the Peninsula Technology Assessment Group (PenTAG), Peninsula Medical School and Southampton Health Technology Assessments Centre (SHTAC),Wessex Institute for Health Research and Development (WIHRD), University of Southampton. NICE Assessment Report - ICS and LABAs for the treatment of chronic asthma in adults and children aged 12 years and over: Systematic review and economic analysis. December 2006. http://www.nice.org.uk/nicemedia/live/11705/35060/35060.pdf 18. FitzGerald JM, Boulet LP, Follows RMA. The CONCEPT trial: A 1-year, multicenter, randomized, double-blind, double-dummy comparison of a stable dosing regimen of salmeterol/fluticasone propionate with an adjustable maintenance dosing regimen of formoterol/ budesonide in adults with persistent asthma. Clin Ther 2005; 27(4):393-406. 19. Vogelmeier C, D'Urzo A, Pauwels R, Merino JM, Jaspal M, Boutet S et al. Budesonide/formoterol maintenance and reliever therapy: An effective asthma treatment option? Eur Respir J 2005; 26(5):819-828. 20. Aalbers R, Backer V, Kava TTK, Omenaas ER, Sandstrom T, Jorup C et al. Adjustable maintenance dosing with budesonide/formoterol compared with fixed-dose salmeterol/fluticasone in moderate to severe asthma. Current Medical Research & Opinion 2004; 20(2):225-240. 21. Cates CJ, Lasserson TJ. Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD007694. DOI: 10.1002/14651858.CD007694.pub2. Page 19 of 23

22. Lasserson TJ, Ferrara G, Casali L. Combination fluticasone and salmeterol versus fixed dose combination budesonide and formoterol for chronic asthma in adults and children. Cochrane Database of Systematic Reviews 2011, Issue 12. Art. No.: CD004106. DOI: 10.1002/14651858.CD004106.pub4. 23. Australian Public Assessment Report for Budesonide/eformoterol fumarate dehydrate. Oct 2010 http://www.tga.gov.au/pdf/auspar/auspar-symbicort.pdf 24. NICE website, accessed 24/10/12 http://www.nice.org.uk 25. National Prescribing Centre, Key therapeutic topics- medicines management options for local implementation, April 2012 Version 4.2 26. Drug Tariff August 2013 27. SMC. Beclometasone 100mcg, formoterol 6mcg metered dose inhaler (Fostair ). 373/07, January 2008. http://www.scottishmedicines.org.uk/files/beclometasone%20dipropionate%20%20fostair %20Abbrevi ated%20final%20april%202007%20amended%20february%202008%20for%20website.pdf 28. SMC. fluticasone/formoterol (Flutiform ). 736/11, October 2012. http://www.scottishmedicines.org.uk/files/advice/fluticasone_flutiform.pdf 29. lipworth BJ, Systemic adverse effects of inhaled corticosteroid therapy: A systematic review and metaanalysis. Arch Intern Med. 1999 May 10;159(9):941-55. 30. ESNM22: Asthma: beclometasone/formoterol (Fostair ) for maintenance and reliever treatment, National Institute for Health and Care Excellence, 25 June 2013. 31. Electronic Medicines Compendium (http://www.medicines.org.uk/emc/), accessed 20/8/13 for the Summary of Product Characteristics of Seretide 100,250, 500 Accuhaler; Seretide 50, 125, 250 Evohaler; Fostair 100/6 inhalation solution; Symbicort Turbohaler 400/12 inhalation powder; Symbicort Turbohaler 200/6 inhalation powder; Symbicort Turbohaler 100/6 inhalation powder. 32. Primary Care Switch Protocol Low and Moderate Dose ICS/LABA Combination Inhalers Switch to Fostair 100/6 Inhaler, PrescQipp (East of England) Bulletin 5, issued June 2011, reviewed July 2011 33. Low, Moderate and High dose ICS/LABA Combination Inhalers Switch to Flutiform Inhaler, PrescQipp (East of England) Bulletin 23, issued December 2012. N:\Medicines Management\JPC from Aug 13\Approved Bulletins and Papers\Sept 13\Bulletin 176 Choice of ICS LABA Updated Sept 13.docx Page 20 of 23

Bedfordshire and Luton Joint Prescribing Committee (JPC) Assessment against Ethical and Commissioning Principles Treatment assessed (date): Choice of Inhaled corticosteroid/ Long Acting Beta Agonist (ICS/LABA) combination therapy for the treatment of asthma February 2013, Updated September 2013 JPC Recommendation To recommend the use of Fostair (beclometasone in combination with formoterol) (+/- a spacer device) for asthma in new patients who fulfil the licensing requirements (including use in a maintenance and reliever treatment regimen ) and NICE TAG 138 criteria. Patients on existing combination inhalers may be switched to Fostair if clinically appropriate, but care must be taken to avoid dose conversion errors as the beclometasone (BDP) in Fostair is present as extra fine particles. 100 micrograms of beclometasone extra-fine is equivalent to 250 micrograms of beclometasone non extra-fine and so dose conversions are required if switching from another CFC free BDP inhaler. Symbicort turbohaler (budesonide in combination with formoterol) is an appropriate second line choice if a dry powder inhaler is the preferred device when an MDI plus a spacer is not suitable for the patients. Salmeterol containing combination products may be prescribed for patients who are intolerant of formoterol. The Committee agreed that a high dose steroid combination product should not be included in the recommendations as use of such products should be considered on an individual patient basis and step down of treatment should be done wherever appropriate. 1) Clinical Effectiveness All drugs as individual components have been available for a significant length of time and the clinical effectiveness of the individual components has been demonstrated. Flutiform and Fostair are considered to be non-inferior to Seretide and Symbicort and have similar efficacy. Seretide and Symbicort are assumed to be clinically equivalent in asthma. A 48-week randomised controlled trial in 1714 adults found that beclometasone/formoterol (Fostair) given as maintenance and reliever treatment was more effective than beclometasone/formoterol maintenance treatment plus as-needed salbutamol for reducing exacerbations in adults with uncontrolled asthma. Both treatments were well tolerated but adverse drug reactions occurred more commonly with beclometasone/formoterol maintenance and reliever treatment. Page 21 of 23

2) Cost Effectiveness Seretide 250 Evohaler is the highest prescribed item by cost and accounts for approximately 30% of the total prescribing for the ICS/LABA combination drugs. This suggests not only that patients may be inappropriately over treated on a high dose ICS/LABA combination but also that a product range which is cost effective and offers a high dose treatment option would be required as a treatment option across NHS Bedfordshire and Luton. NICE guidance suggests that for the treatment of asthma, if an ICS/LABA combination drug is required the drug with the lowest acquisition cost should be prescribed. 3) Equity No issues identified. 4) Needs of the community Asthma prevalence (both GP treated and symptoms untreated) is estimated to be 16% in women and 13% in men (Health Survey England, 2001). QoF 2012 prevalence across England showed that prevalence of GP treated asthma was estimated at 5.9% on average. In Bedfordshire the prevalence is slightly higher than national average at 6.4% (27,877 patients approximately) and in Luton it is slightly lower at 5.4% (11,562 patients approximately) (data from NHS information Centre Disease prevalence QoF for 2011-12) Prescribing rates suggest that a large proportion of asthma patients are being over treated on High dose inhaled corticosteroids and there is a need to address this 5) Need for healthcare (incorporates patient choice and exceptional need) There are a number of treatment alternatives available. The costs of the products vary and different strengths of product are the lowest acquisition at different treatment steps of the BTS/SIGN asthma guidelines. To avoid a situation where a patient s inhaler is switched every time they step up and down, treatment options should be chosen that would represent a cost effective choice across the whole range of treatment options. 6) Policy drivers NICE Technology Appraisal Guidance 130 BTS/SIGN Guidelines on the Management of Asthma SMC Product reviews 7) Disinvestment There will be a disinvestment from the use of currently available more expensive ICS/ LABA combination products and also from the currently prescribed higher dose products. The JPC agreed the following sections within the PCT Ethical and Commissioning Framework were not relevant to JPC discussions: Health Outcomes, Access, and Affordability. Page 22 of 23

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