BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE

BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE December 2014 Review Date: December 2017 Bulletin 206 : DuoResp Spiromax 160 / 4.5 and 320 / 9 budesonide & formoterol dry powder inhaler JPC Recommendations DuoResp Spiromax is recommended for use in adults with asthma and COPD as an alternative to first line Symbicort Turbohaler in new and existing patients. Medicine DuoResp Spiromax 160 / 4.5 and 320 / 9 budesonide & formoterol breath-actuated dry powder inhaler. Doses are therapeutically equivalent to Symbicort Turbohaler (budesonide and formoterol) Product Delivered dose (microgram) Metered dose (microgram) Document status Page 1 of 11 DuoResp Spiromax Symbicort Turbohaler DuoResp Spiromax Symbicort Turbohaler Final 160/4.5 200/6 160/4.5 200/6 320/9 400/12 320/9 400/12

Date of last revision November 2014 Proposed Sector of Primary care / secondary care prescribing Introduction Summary Key points Evidence level The intervention Mechanism of action DuoResp Spiromax 160 / 4.5 and 320 / 9 budesonide & formoterol dry powder inhaler is a breath-actuated dry powder inhaler presentation containing the inhaled corticosteroid (ICS), budesonide and the long acting bronchodilator agent (LABA) formoterol. They contain the same active ingredients, and doses have been shown to be therapeutically equivalent to Symbicort (budesonide and formoterol) Turbohaler 200/6 and 400/12. Symbicort Turbohaler is included in the CCG medicine formularies and the Bedfordshire and Luton COPD guidelines. DuoResp Spiromax is less costly than Symbicort Turbohaler and so using this device as a first line option instead of Symbicort Turbohaler would produce financial savings. From October 2013 to September 2014, 895,438 was spent on Symbicort Turbohaler 400/12 and 200/6 strengths within Bedfordshire CCG. If the equivalent doses of DuoResp Spiromax had been used in place of Symbicort Turbohaler, this would have saved 189,220 within Bedfordshire CCG. There is also the potential to disinvest in other more costly ICS/LABA combination dry powder inhalers used in asthma and/or COPD. Inhaled corticosteroid (ICS) and long acting beta2-agonist (LABA) combination inhaler. Licensed indication DuoResp Spiromax 160 / 4.5 and 320 / 9 budesonide & formoterol dry powder inhaler is indicated in adults 18 years of age and older only (1) Asthma DuoResp Spiromax is indicated in the regular treatment of asthma, where use of a combination (inhaled corticosteroid and long-acting β2 adrenoceptor agonist) is appropriate: -in patients not adequately controlled with inhaled corticosteroids and as needed inhaled short-acting β2 adrenoceptor agonists. or -in patients already adequately controlled on both inhaled corticosteroids and long-acting β2 adrenoceptor agonists. COPD Symptomatic treatment of patients with severe COPD (FEV1 < 50% predicted normal) and a history of repeated exacerbations, who have significant symptoms despite regular therapy with long-acting bronchodilators. Page 2 of 11

Formulation/Available Products Usual dosage Treatment alternatives/ place in therapy Breath-actuated dry powder inhaler of inhaled corticosteroid and long-acting beta-agonist. Spiromax is a breath actuated, inspiratory flow-driven inhaler, which means that the active substances are delivered into the airways when the patient inhales through the mouthpiece. DuoResp Spiromax 160 microgram / 4.5 microgram dry powder inhaler. Each delivered dose (the dose that leaves the mouthpiece of the Spiromax) contains 160 of budesonide and 4.5 of formoterol fumarate dihydrate. This is equivalent to a metered dose of 200 budesonide and 6 of formoterol fumarate dihydrate. DuoResp Spiromax 320 microgram / 9 microgram dry powder inhaler. Each delivered dose (the dose that leaves the mouthpiece of the Spiromax) contains 320 of budesonide and 9 of formoterol fumarate dihydrate. This is equivalent to a metered dose of 400 budesonide and 12 of formoterol fumarate dihydrate. A randomised, open-label placebo study was performed in children and adolescents with asthma (aged 6-17 years), adults with asthma (aged 18-45 years), adults with chronic obstructive pulmonary disease (COPD aged >50 years) and healthy volunteers (aged 18-45 years) to evaluate the peak inspiratory flow rate (PIFR) and other related inhalation parameters following inhalation from a Spiromax device (containing placebo) compared with inhalation from an already marketed multi-dose dry powder inhaler device (containing placebo). The impact of enhanced training in dry powder inhaler inhalation technique on inhalation speed and volume was also assessed in these subject groups. The data from the study indicated that regardless of age and underlying disease severity, children, adolescents and adults with asthma as well as patients with COPD were able to able to achieve inspiratory flow rates through the Spiromax device that were similar to those generated through the marketed multi-dose dry powder inhaler device. The mean PIFR achieved by patients with asthma or COPD was over 60L/min, a flow rate at which both devices studied are known to deliver comparable amounts of drug to the lungs. Very few patients had PIFRs below 40L/min; when PIFRs were less than 40L/min there appeared to be no clustering by age or disease severity. 1 or 2 inhalations twice. The BCCG current formulary choice ICS/LABA combination inhalers are (2): Asthma Fostair cfc free inhaler 100microgram/6microgram Page 3 of 11

Symbicort 100/6 Turbohaler Symbicort 200/6 Turbohaler COPD Fostair cfc free inhaler 100microgram/6microgram Symbicort 400/12 Turbohaler ICS/LABA combination inhalers are recommended in steps 3 and 4 of the BTS/SIGN asthma guidelines (3). 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 of treatment adherence. If a combination device is chosen then the least costly device that is suitable for the individual is recommended. The Bedfordshire and Luton COPD guidelines recommend an ICS / LABA combination inhaler within the primary care pathway in patients with a FEV1 <50% when a maintenance bronchodilator is required when a short acting bronchodilator (SABA) alone does not control symptoms, and treatment with a LAMA inhaler has been ineffective after 4 weeks (4). Future alternatives Fostair NEXThaler -100 / 6 beclometasone / formoterol dry powder inhaler Page 4 of 11

National guidance BTS/ SIGN asthma guideline- ICS/LABA combination inhalers are recommended in steps 3 and 4 of the guidelines. No specific product is recommended, but it is suggested to prescribe the product with the lowest acquisition cost (3). DuoResp Spiromax is not included in the NICE technology appraisal programme or the topic of a evidence summaries: new medicines. Scottish Medicines Consortium (SMC) will not be reviewing as DuoResp Spiromax fits within criteria no. 13 of the Medicines Outwith SMC remit, The Marketing Authorisation is solely for a new presentation or strength of an existing proprietary medicine, with no associated change to the licensed indication and the new product costs the same or less. This includes new devices for the administration/delivery of established medicines. (6) All Wales Medicines Strategy Group (AWMSG) does not appraise products which represent a new formulation of an established medicine which is costs the same or less than the existing medicine. (7) Local Guidance JPC bulletin 176. Choice of Inhaled Corticosteroid / Long Acting Beta2 Agonist (ICS/LABA) combination therapy for the treatment of asthma in adult patients, updated Sept 2013. (8) 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 of beclometasone extra-fine is equivalent to 250 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 Page 5 of 11

basis and step down of treatment should be done wherever appropriate. The BCCG current formulary choice ICS/LABA combination inhalers are (2): Asthma Fostair cfc free inhaler 100microgram/6microgram Symbicort 100/6 Turbohaler Symbicort 200/6 Turbohaler COPD Fostair cfc free inhaler 100microgram/6microgram Symbicort 400/12 Turbohaler Evidence for use Safety * Bedfordshire and Luton COPD guidelines, Updated 2013.(4) Bedfordshire and Luton COPD guidelines recommend an ICS / LABA combination inhaler within the primary care pathway in patients with a FEV1 <50% when a maintenance bronchodilator is required when a short acting bronchodilator (SABA) alone does not control symptoms, and treatment with a LAMA inhaler has been ineffective after 4 weeks. First choice ICS/LABA combination inhalers are Fostair MDI and Symbicort Turbohaler. Second choice ICS/LABA combination inhaler is Seretide 500 Accuhaler. The European Medicines Agency CHMP assessment report of DuoResp Spiromax concluded that the presence of clinical efficacy studies comparing the test and reference products in adults or adolescents is not required since the clinical efficacy of budesonide and formoterol fumarate dihydrate has been investigated extensively, is well known and has been the subject of many publications. Moreover, this is in line with the CHMP Guideline on orally inhaled products (CHMP/EWP/4151/00 Rev. 1) since equivalence has been demonstrated for the high strength (320/9 microgram per dose) and the middle strength (160/4.5 microgram per dose). The two pivotal pharmacokinetic studies in the high strength (320/9 microgram per dose) and the middle strength (160/4.5 microgram per dose) demonstrated equivalence between budesonide / formoterol Spiromax and Symbicort Turbohaler for all comparisons both with and without a charcoal blockade. (9) Since DuoResp Spiromax contains budesonide and formoterol, the same pattern of adverse reactions as reported for these substances may occur. No increased incidence of adverse reactions has been seen following concurrent administration of the two compounds (1). Refer to the Summary of Product Characteristics for a full list of current potential adverse reactions available at: www.medicines.org.uk. Page 6 of 11

Costs (Chemist & Druggist October 2014) Tariff status Activity costs Cost effectiveness (if available) Cost comparison for low dose ICS/LABA combination inhaler (200-500 beclometasone) Drug Adult Dosage Beclometason e equivalent dose Fostair NEXThaler 100/6 Fostair MDI 100/6 DuoResp Spiromax DPI 160/4.5 Seretide 50 Evohaler Seretide 100 Accuhaler Flutiform 50/5 MDI Symbicort Turbohaler 200/6 2 puffs twice 2 puffs twice 500 500 400 400 400 400 400 30 day cost Annual Cost per patient 14.66 178 14.66 178 14.99 182 18.00 218 18.00 218 18.00 218 19.00 231 Cost comparison for medium dose ICS/LABA combination inhaler (>500 1000 beclometasone) Drug Adult Dosage Beclometason e equivalent dose 30 day cost Annual Cost per patient Relvar Ellipta 1 puff 1000 27.80 337 92/22 Flutiform 2 puffs twice 1000 29.26 355 125/5 MDI Fostair 2 puffs twice 1000 29.32 356 NEXThaler Fostair MDI 2 puffs twice 1000 29.32 356 DuoResp Spiromax DPI 160/4.5 Seretide 125 Evohaler Seretide 250 Accuhaler Symbicort Turbohaler 200/6 Symbicort Turbohaler 2 puffs twice 2 puffs twice 2 puffs twice 800 1000 1000 800 800 29.97 364 35.00 425 35.00 425 38.00 461 38.00 461 400/12 N.B. Doses are for general comparison and do not imply therapeutic equivalence Potential number of patients in DuoResp Spiromax is less costly than Symbicort Turbohaler and so using this device as an alternative to Symbicort Page 7 of 11

Bedfordshire and Luton Impact per 100,000 population Affordability considerations Decisions from other bodies Comments sought from Turbohaler would produce financial savings. From October 2013 to September 2014, 895,438 was spent on Symbicort Turbohaler 400/12 and 200/6 strengths within Bedfordshire CCG. If the equivalent doses of DuoResp Spiromax had been used in place of Symbicort Turbohaler, this would have saved 189,220 within Bedfordshire CCG. There is also the potential to disinvest in other more costly ICS/LABA combination dry powder inhalers used in asthma and/or COPD. Respiratory Consultants Bedford Hospital and L&D Hospital Respiratory Nurses Bedford Hospital and L&D Hospital BCCG and LCCG GP Respiratory Leads Points for Doses of DuoResp Spiromax are therapeutically equivalent to consideration Symbicort Turbohaler in terms of efficacy and tolerability and the products have been shown to have a similar safety profile. Some patients may find DuoResp Spiromax easier to use than Symbicort Turbohaler. DuoResp Spiromax is less costly than Symbicort Turbohaler. PAC New Drug Template Adapted from East Anglia Medicines Information, NHS Suffolk, NHS Cambridgeshire and NHS Derby templates *Consult Summary of Prescribing Characteristics for full prescribing detail. 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. References / Sources of Review 1) SPC DuoResp Spiromax 160 microgram / 4.5 microgram and 320 microgram / 9 microgram inhalation powder. Teva Pharma B.V. Last updated 22/9/14 and accessed 11/11/14. Available at www.medicines.org.uk. 2) BCCG Primary Care Medicines Formulary last updated September 2014 and available at: http://www.gpref.bedfordshire.nhs.uk/referrals/bccg-primary-care-formulary.aspx 3) British Guidelines on the management of asthma October 2014. SIGN 141. British Thoracic Society / Scottish Intercollegiate Guidelines Network. Available at www.brit-thoracic.org.uk. 4) Bedfordshire and Luton COPD Guidelines Updated 2013. Available at: www.gpref.bedfordshire.nhs.uk 5) SPC DuoResp Spiromax Teva UK Limited. Last updated 22/9/14 and accessed 16/10/14. Available at www.medicines.org.uk 6) Scottish Medicines Consortium (SMC). Guidance to Manufacturers on Medicines outwith SMC Remit. Available at: www.scottishmedicines.org.uk 7) All Wales Medicines Strategy Group (AWMSG). Appraisal exclusion criterion number 6. Available at: www.awmsg.org 8) Bedfordshire and Luton Joint Prescribing Committee, Bulletin 176 Choice of inhaled corticosteroid / long acting beta2 agonist (ICS/LABA) combination therapy for the treatment of asthma in adult patients, updated September 2013. Available at: http://www.gpref.bedfordshire.nhs.uk/media/110485/advguid_bulletin176choiceofics_laba_ UpdatedSept13.pdf 9) The European Medicines Agency. CHP Assessment Report. DuoResp Spiromax. Procedure No. EMEA/H/C/002348. 20 February 2014. Available at: http://www.ema.europa.eu/docs/en_gb/document_library/epar_- _Public_assessment_report/human/002348/WC500167183.pdf N:\Medicines Management\JPC\Approved Bulletins and Papers\from Aug 13 )\Dec 14 Page 8 of 11

Bedfordshire and Luton Joint Prescribing Committee (JPC) Assessment against Ethical and Commissioning Principles Treatment assessed (December 2014): DuoResp Spiromax 160 / 4.5 and 320 / 9 budesonide & formoterol dry powder inhaler JPC Recommendation: DuoResp Spiromax is recommended for use in adults with asthma and COPD as an alternative to first line Symbicort Turbohaler in new and existing patients. 1) Clinical Effectiveness The European Medicines Agency CHMP assessment report of DuoResp Spiromax concluded that the presence of clinical efficacy studies comparing the test and reference products in adults or adolescents is not required since the clinical efficacy of budesonide and formoterol fumarate dihydrate has been investigated extensively, is well known and has been the subject of many publications. Moreover, this is in line with the CHMP Guideline on orally inhaled products (CHMP/EWP/4151/00 Rev. 1) since equivalence has been demonstrated for the high strength (320/9 microgram per dose) and the middle strength (160/4.5 microgram per dose). The two pivotal pharmacokinetic studies in the high strength (320/9 microgram per dose) and the middle strength (160/4.5 microgram per dose) demonstrated equivalence between budesonide / formoterol Spiromax and Symbicort Turbohaler for all comparisons both with and without a charcoal blockade. (9) 2) Cost Effectiveness DuoResp Spiromax is less costly than Symbicort Turbohaler and so using this device as an alternative to Symbicort Turbohaler would produce financial savings. From October 2013 to September 2014, 895,438 was spent on Symbicort Turbohaler 400/12 and 200/6 strengths within Bedfordshire CCG. If the equivalent doses of DuoResp Spiromax had been used in place of Symbicort Turbohaler, this would have saved 189,220 within Bedfordshire CCG. There is also the potential to disinvest in other more costly ICS/LABA combination dry powder inhalers used in asthma and/or COPD. 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) Page 9 of 11

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. COPD prevalence is estimated at 2-4% but the diagnosed prevalence is about 1.5% (1,500 per 100,000) which increases to 10% in men aged over 75. 8 An average GP practice of 6,600 patients is likely to have about 100 patients on its COPD disease register. This equates to approximately 6,100 and 3,000 patients with COPD in Bedfordshire and Luton respectively. 5) Need for healthcare (incorporates patient choice and exceptional need) There are a number of ICS/LABA combination inhalers available to treat asthma and COPD including Symbicort Turbohaler and Fostair 100/6 MDI. 6) Policy drivers ICS/LABA combination inhalers are recommended in steps 3 and 4 of the BTS/SIGN asthma guidelines (3). 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 of treatment adherence. If a combination device is chosen then the least costly device that is suitable for the individual is recommended. The Bedfordshire and Luton COPD guidelines recommend an ICS / LABA combination inhaler within the primary care pathway in patients with a FEV1 <50% when a maintenance bronchodilator is required when a short acting bronchodilator (SABA) alone does not control symptoms, and treatment with a LAMA inhaler has been ineffective after 4 weeks (4). 7) Disinvestment There is the potential to disinvestment in more costly ICS/LABA combination dry powder inhalers. 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 10 of 11