New Medicines Committee Briefing March 2013

Transcription

1 New Medicines Committee Briefing March 2013 Fluticasone proprionate/formoterol fumerate inhaler (Flutiform ) for the treatment of patients with asthma. Flutiform is to be reviewed for use within: Summary Primary Care Secondary Care Flutiform is a combination of fluticasone propionate (a corticosteroid) and formoterol fumarate (a long acting beta 2 agonist). Flutiform is indicated for the regular treatment of asthma where the use of a combination product (an inhaled corticosteroid and a long acting beta 2 agonist) is appropriate. NICE states that the use of combination inhaler within its license is appropriate when treatment with an inhaled corticosteroid and long acting beta 2 agonist is considered. The decision to use a combination device or the two agents separately should be made on an individual patient basis and the least costly combination device is recommended. A NICE evidence summary, SMC and MTRAC have all recommended that Flutiform should be considered in patients in whom a long acting beta 2 agonist and corticosteroid combination is appropriate. Evidence from two published studies has demonstrated non-inferiority of Flutiform in efficacy to seretide and non-inferiority to a comparable dose of fluticasone plus formoterol in separate inhalers. Flutiform is a black triangle ( ) drug and is monitored by the MHRA and CHM. 1

2 Formulary application Dr Ashish Patel (General practitioner Stoke) has requested that Flutiform inhaler be considered for inclusion into the Joint Formulary for the treatment of asthma. Dr Patel states that Flutiform will be a useful addition to the formulary as it is cost effective and a viable alternative to Seretide. Dr Patel confirmed that he has experience in the use of Flutiform in Leister Hospital where he works as a Geriatric consultant. He does not intend that all patients on Seretide be switched to Flutiform but he sees it as a good and reliable alternative to Seretide. Background Asthma is a chronic disorder of the airways. It is characterised by airflow obstruction and hyper-responsiveness of the airways to various stimuli including viral respiratory infections, exercise, smoke, cold and allergens such as pollen, mould, animal fur and the house mite. These may lead to symptoms including recurring episodes of wheezing, breathlessness, chest tightness and coughing. Typical asthma symptoms tend to be variable, intermittent and worse at night. 1-3 According to asthma UK, it is estimated that there are 5.4 million people receiving treatment for asthma (4.3 million adults and 1.1million children). 3,6 The BTS/SIGN guidelines recommend a stepwise approach to treatment in both adults and children. Addition of a long-acting beta 2 agonist (LABA), at STEP 3 is appropriate if initial addition of a standard dose of inhaled corticosteroid (ICS) therapy is inadequate to control symptoms. 5 Fluticasone proprionate is a glucocorticoid with potent anti-inflammatory activity within the lungs when inhaled. Formoterol is a long-acting selective beta 2 adrenergic receptor agonist which has a rapid bronchodilating effect, within 1-3 minutes post inhalation and duration of action is at least 12 hours after a single dose. 0 Fluticasone/formoterol (Flutiform ) is a combination inhaler containing Fluticasone (an ICS) and formoterol (a LABA) which was launched in the UK in September It is available in 3 strengths: 50/5 micrograms, 125/5 micrograms and 250/10 micrograms per actuation. 0,5 Flutiform is a black triangle ( ) drug and is currently being monitored by the MHRA and CHM. 0 2

3 Current Formulary Status The North Staffordshire Joint Formulary currently lists the following agents on the formulary: CORTICOSTEROIDS NICE TA10 NICE TA38 NICE TA131 NICE TA138 Beclometasone Beclometasone CFC-free Restriction: See APC Advice APC FF Article Budesonide Restriction: Nebuliser use only Fostair Seretide Symbicort APC Advice: CFC-free Beclometasone: Clenil Modulite & Qvar August 2007 CFC-free beclometasone inhalers should be prescribed by brand not generically. Clenil Modulite requires no dose adjustment from CFC-BDP inhalers. Prescribing of this brand will minimise potential errors associated with changing doses and will reduce patient confusion. Licensed Indications 0 Flutiform inhaler is indicated in the regular treatment of asthma where the use of a combination product an inhaled LABA and ICS is appropriate: For patients not adequately controlled with inhaled corticosteroids and 'as required' inhaled short-acting beta 2 agonist. Or For patients already adequately controlled on both an inhaled corticosteroid and a longacting beta 2 agonist. Flutiform 50 microgram/5 microgram and 125 microgram/5 microgram inhalers are indicated in adults and adolescents aged 12 years and above. Flutiform 250 microgram/10 microgram inhaler is indicated in adults (>18years) only. Dosage and Administration 6 The dose of Flutiform should be titrated to the lowest twice daily dose at which effective control of symptoms is maintained. Flutiform inhaler should not be used in patients with COPD as there is no data available for its use in these patients. Flutiform 50 microgram/5 microgram inhaler Flutiform 125 microgram/5 microgram inhaler Recommended dose for adults and adolescents aged 12 years and above: Two puffs twice daily normally taken in the morning and in the evening 3

4 Flutiform 250 microgram/10 microgram inhaler Recommended dose for adults only: Two puffs twice daily normally taken in the morning and in the evening Flutiform inhaler in any strength is not recommended for use in children less than 12 years of age Special patient groups: There is no need to adjust the dose in elderly patients. There are no data available for use of Flutiform inhaler in patients with hepatic or renal impairment. These patients should be regularly monitored by a physician to ensure titration to the lowest dose at which effective control of symptoms is maintained. As the fractions of fluticasone and formoterol which reach systemic circulation are primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe hepatic impairment. Flutiform inhaler is delivered by a press-and-breathe pressurised metered dose inhaler (pmdi) which also contains an integrated dose indicator. The actuator is white with a grey integrated dose indicator and a light grey mouthpiece cover. The suspension is contained in an aluminium pressurised canister crimped with a standard metering valve. This canister is inserted into a press-and-breathe actuator fitted with a mouthpiece cover (both made of polypropylene). Each container delivers at least 120 actuations (60 doses). The assembled MDI inhaler is pouched in an aluminium foil laminate and is packed in a cardboard carton. The integrated dose indicator counts down the number of actuations (puffs) remaining. When this is getting near to zero the patient should be advised to contact their prescriber for a replacement inhaler. The inhaler must not be used after the dose indicator reads 0. Use of a spacer device with Flutiform inhaler is recommended in patients who find it difficult to synchronise aerosol actuation with inspiration of breath. The AeroChamber Plus is the only spacer device recommended for use with Flutiform inhaler. Re-titration to the lowest effective dose should always follow the introduction of a spacer device. 1 Guidance National Institute for Health and Clinical Excellence (NICE) Evidence Summary: New medicine. ESNM3: Asthma: fluticasone/formoterol (Flutiform ) combination inhaler. 7 NICE in an evidence summary published in October 2012, stated that Flutiform be considered alongside other treatment options when an ICS plus LABA is appropriate, in accordance with the British guideline on the management of asthma. This was based on the evidence from 2 published studies that indicate that Flutiform is non-inferior to a comparable dose of fluticasone plus formoterol in separate inhalers and non-inferior to a fluticasone/salmeterol (Seretide ) combination inhaler in terms of effect on lung function, as measured by forced expiratory volume in 1 second (FEV 1 ). There were no significant differences in exacerbations of asthma, side effect profile and adverse events. 4

5 NICE stated that although the limited published data appear to suggest that the efficacy and safety of Flutiform is similar to other ICS/LABA combination inhalers, choice of inhaler device may be important to individual patients and may need to be taken into account by decision makers. NICE also recommends, where there is need for a combination inhaler, that NICE guidance on Inhaled corticosteroids for the treatment of chronic asthma in adults and in children aged 12 years and over (NICE technology appraisal guidance 138) be adhered to, hence recommending the use of least costly device that is suitable for the individual. Scottish Medicines Consortium (SMC) 8 : SMC accepted Flutiform for use in NHS Scotland in patients for whom fluticasone and formoterol are appropriate choices of ICS and LABA, respectively, and for whom a metered dose inhaler is an appropriate delivery device. They state that it has demonstrated clinical noninferiority to another combination product containing an ICS and LABA and may offer cost savings. Midlands Therapeutics Review and Advisory Committee (MTRAC) MTRAC considered that Flutiform may be a suitable product to commission in primary care. This was based on a 12-week trial which found Flutiform to be of similar efficacy to Seretide They recommend that when making a decision about the use of combination inhaler devices, commissioners may wish to consider the following: The need for regular review of asthma treatment and stepping down treatment to a lower inhaled corticosteroid dose where appropriate. That it may be most appropriate initially to prescribe Flutiform for new patients. When further clinical experience is gained, commissioners may wish to consider switching appropriate patients to Flutiform. At current prices, the Flutiform 125/5 and 250/10 dose formulations are cheaper than the Seretide125 and 250 Evohalers. Efficacy Summary: Flutiform inhaler is as effective as the individual components fluticasone + formoterol in the treatment of asthma. 9 A phase III double-blind randomised, double-dummy four arm parallel-group, multinational study compared the efficacy and safety of Flutiform inhaler with that of the separate inhalers of the individual components administered concurrently and fluticasone alone. It involved 620 adults with severe persistent asthma for at least 6 months who were currently being treated with at least 500 micrograms/day of fluticasone or an equivalent dose of ICS. The 4 study arms were as follows: - Flutiform 250/10 inhaler 2 puffs twice daily (154 patients) - Flutiform 50/5 2 puffs twice daily (155 patients) 5

6 - Fluticasone 250 microgram inhaler plus formoterol 12 microgram inhaler both 2 puffs twice daily (156 patients) - Fluticasone 250 micrograms 2 puffs twice daily (155 patients) The primary objective of this study was to demonstrate non-inferiority of Flutiform 250/10 inhaler over use of separate fluticasone and formoterol inhalers. The primary end point was the mean change in pre-morning dose FEV 1 from baseline to the end of the 8-week treatment period. The co-primary objective was to demonstrate non-inferiority of Flutiform 250/10 over fluticasone and formoterol inhalers as assessed by mean change in FEV 1 from pre-morning dose at baseline to 2 hour post-morning dose at the end of the 8 week treatment period. Secondary outcomes included: mean 12 hour FEV 1 area under curve (AUC) in a subset of 300 patients; discontinuations due to lack of treatment efficacy; Peak expiratory flow rate (PEFR); forced vital capacity (FVC); forced expiratory flow at 25%, 50% and 75% of the volume to be exhaled (FEF25, FEF50, FEF75, FEF25e75); asthma symptom scores; asthma symptom-free days; sleep disturbance scores; awakening-free nights; asthma control days; asthma exacerbations; rescue medication use; rescue medication-free days; patient assessment of study medication; and score on the Asthma Quality of Life Questionnaire (AQLQ). Safety assessments were made at weeks 2, 4, 6 and 8 and included the incidence and type of spontaneously reported adverse events, vital signs, laboratory tests and 12-lead electrocardiograms. Flutiform 250/10 at 2 puffs twice daily was found to be as effective as fluticasone plus formoterol both 2 puffs twice daily, with an increase in mean pre-morning dose FEV 1 of L (n = 133) and L (n = 140), respectively from baseline to week 8 (PPS; least-squares [LS] mean of the treatment difference: L; 95% CI: , 0.180; P < 0.001). Results were similar for the intention to treat (ITT) population with an increase in mean pre-morning dose FEV 1 of L (n = 154) with 2 puffs twice daily of Flutiform 250/10 and L (n = 156) with 2 puffs twice daily of fluticasone plus formoterol, from baseline to week 8 (LS mean of the treatment difference: L; 95% CI:-0.032, 0.190; P < 0.001). Flutiform 250/10 was also non-inferior to fluticasone plus formoterol in terms of change in mean FEV 1 from baseline pre-morning dose to 2 hour post-morning dose at week 8 with a mean increase of L and L, respectively (PPS; LS mean of the treatment difference: L; 95% CI: , 0.135; P < 0.001). Again results were similar for the ITT population with a mean increase of L with Flutiform 250/10 and L with fluticasone plus formoterol (LS mean of the treatment difference: L; 95% CI: 0.069, 0.149; P < 0.001). Flutiform 250/10 demonstrated superiority to fluticasone alone with an increase from baseline in mean pre-morning dose FEV 1 to 2 h post-morning dose at week 8 of L (n = 154) and L (n = 155), respectively (ITT population; LS mean of the treatment difference: L; 95% CI: 0.011, 0.230; P = 0.032). Treatment with Flutiform 250/10 resulted in a larger increase 6

7 in pre-morning dose FEV 1 compared with treatment with fluticasone alone, but the difference between the two treatment groups was not statistically significant (ITT population; LS mean of the treatment difference: L; 95% CI: , 0.135; P = 0.681). It is vital to note, however that these are not comparable regimens. A similar proportion of patients in the fluticasone plus formoterol group (35.3%) compared with the Flutiform 250/10 group (35.1%) experienced at least 1 mild or moderate exacerbation of asthma (P = 1.0) during the randomised treatment period. On the other hand more patients (3) in the Flutiform 250/10 experienced severe exacerbation of asthma compared to fluticasone plus formoterol group (0) (P = 0.121). Both doses of Flutiform had similar safety and tolerability profiles to fluticasone plus formoterol. In all treatment groups, the most common adverse events reported were nasopharyngitis, headache, pharyngitis, asthma and viral infection. The reported number of adverse events considered to be probably or possibly related to treatment was 3 in the Flutiform 250/10 group, 8 in the Flutiform 50/5 group, 2 in the fluticasone plus formoterol group, and 5 in the fluticasone group. Overall, 6 patients (1.0%) were withdrawn due to adverse events. Discontinuation due to lack of therapeutic effect was the most common reason for withdrawal in all treatment groups. In the ITT population, 6 patients (3.9%) in the fluticasone/ Flutiform 250/10 group, 18 patients (11.6%) in the Flutiform 50/5, 12 patients (7.7%) in the fluticasone plus formoterol group, and 17 patients (11.0%) in the fluticasone alone group discontinued the treatment phase due to lack of efficacy. Similar results were observed with Flutiform 250/10 and fluticasone plus formoterol in several secondary efficacy parameters with no statistical significance demonstrated between groups. The Flutiform 250/10 combination demonstrated superiority to fluticasone monotherapy and Flutiform 50/5 for several secondary efficacy parameters however, these are not comparable regimens. The authors concluded that the Flutiform is as effective as its components administered concurrently from separate inhalers. 9 Flutiform inhaler in comparism to Seretide inhaler in the treatment of asthma 10 Summary: Twice daily inhaled fluticasone/formoterol (Flutiform ) combination therapy is as effective as fluticasone/salmeterol (Seretide ) combination therapy in the treatment of asthma with Flutiform having a more rapid onset of action. An open-label, multicentre, randomised, active-controlled, parallel-group, phase III study conducted at 25 centres across 5 European countries was designed to demonstrate noninferiority of Flutiform to Seretide in controlling mild-to-moderate-severe persistent asthma in 202 adult patients. The primary objective of the study was to demonstrate non-inferiority of 7

8 Flutiform to Seretide based on mean pre-dose FEV 1. The secondary objectives were to compare the two treatments with regards to: discontinuations due to lack of efficacy; time of onset of action (defined as the first time point post-dose at which the FEV 1 value was >12% increased, compared with pre-dose); PEFRs and other lung function parameters; amount of rescue medication use; asthma symptom scores; sleep disturbance due to asthma; daily oral or parenteral corticosteroids doses asthma exacerbations; patient assessments of study medication; Asthma Quality of Life Questionnaire (AQLQ) scores and the safety outcomes included spontaneously reported adverse events. Patients were randomised 1:1 to one of the two treatment groups with two dose options available within each group. 101 patients were treated with either two puffs of Flutiform 50/5 or Flutiform 125/5 twice daily while the other 101 patients were treated with two puffs of Seretide evohaler 50/25 µg or 125 /25 µg twice daily for a period of 12 weeks. The starting dose depended on the person s asthma history and pre-study medication. Patients who required ICSs at a dose of µg/day fluticasone or equivalent received the low dose of study medication, while patients who required >250µg/day (up to 1000µg/day) received the high dose study medication. Patients receiving the low dose of study medication were permitted to switch to high dose during the treatment period if their asthma was not controlled, at the investigator s discretion. The number of patients allocated to low dose/high dose groups for each arm was not specified. During the treatment phase, patients underwent lung function test at weeks 0 (baseline), 2, 6 and 12. Each of these tests was performed in the 30mins prior to administration of study medication and repeated 5, 10, 30, 60, 90 and 120 mins post-treatment. Patients also recorded their morning and evening peak flow rates daily. Patients were also assessed for asthma exacerbations and safety assessment at weeks 2, 6 and 12. Flutiform was comparable to Seretide for the primary efficacy endpoints. Flutiform inhaler was shown to be non-inferior to the Seretide inhaler. The difference between the treatments (LS mean of the treatment difference: L; 95% CI: , 0.004) was less than the predefined non inferiority margin for change in pre-dose FEV 1 from baseline to week 12. There were no significant differences between Flutiform and Seretide for most secondary outcomes. However, the time to onset of action for those treated with Flutiform was found to be significantly shorter than those given Seretide throughout the 12 weeks of the study (hazard ratio 1.64, 95% CI 1.28 to 2.10, p<0.001). The overall rate of adverse events was 23.8% in both treatment groups (statistical significance not reported); the majority were considered mild/moderate in severity. The most common adverse effects were described as infections and infestations and occurred in 13.9% of the Flutiform group and 12.9% of patients in the Seretide treatment group. Serious adverse events were recorded for 1 patient in each treatment group although these were not judged to be related to treatment. Compliance was over 75% in 99% of patients in the Flutiform group and over 75% in 98% of patients in the Seretide group. 8

9 The authors concluded that Flutiform demonstrates comparable efficacy to Seretide for patients with mild-moderate or severe persistent asthma. Furthermore Flutiform was well tolerated and showed a good safety profile that is similar to Seretide. As Flutiform showed superiority over Seretide in terms of time to onset of action it was suggested this may result in a positive impact on patient s perceived benefits and in turn improve patient preference and adherence. 10 Safety and adverse effects 1 Undesirable effects which have been associated with Flutiform inhaler during clinical development are given in the table below, listed by system organ class. The following frequency categories form the basis for classification of the undesirable effects as: very common ( 1/10), common ( 1/100 and <1/10), uncommon ( 1/1,000 and <1/100), rare ( 1/10,000 < 1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. System Organ Class Adverse Event Frequency Infections and Infestations Metabolism and Nutrition Disorders Psychiatric Disorders Nervous System Disorders Oral candidiasis Acute sinusitis Hyperglycaemia Abnormal dreams Agitation Insomnia Psychomotor hyperactivity, anxiety, depression, aggression, behavioural changes (predominantly in children) Headache Tremor Dizziness Dysgeusia Rare Uncommon Rare Ear and labyrinth disorders Vertigo Rare Not known Uncommon Cardiac Disorders Palpitations Ventricular extrasystoles Angina pectoris Tachycardia Uncommon Rare 9

10 Vascular disorders Hypertension Rare Respiratory, Thoracic and Mediastinal Disorders Gastrointestinal disorders Skin and subcutaneous tissue disorders Exacerbation of asthma Dysphonia Throat irritation Dyspnoea Cough Dry mouth Diarrhoea Dyspepsia Rash Uncommon Rare Uncommon Rare Rare Musculoskeletal and Connective Tissue Disorders General disorders and administration site conditions Muscle spasms Peripheral oedema Asthenia Rare Uncommon Rare As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting inhaled bronchodilator and should be treated straight away. Flutiform inhaler should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary. Since Flutiform inhaler contains both fluticasone propionate and formoterol fumarate, the same pattern of undesirable effects as reported for these substances may occur. The following undesirable effects are associated with fluticasone propionate and formoterol fumarate, but have not been seen during the clinical development of Flutiform inhaler: Fluticasone propionate: Hypersensitivity reactions including, urticaria, pruritus, angiooedema (mainly facial and oropharyngeal), anaphylactic reactions. Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These may include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma, sleep disorders, contusion, skin atrophy and susceptibility to infections. The ability to adapt to stress may be impaired. The systemic effects described, however, are much less likely to occur with inhaled corticosteroids than with oral corticosteroids. Prolonged treatment with high doses of inhaled corticosteroids may result in clinically significant adrenal suppression and acute adrenal crisis. Additional systemic corticosteroid cover may be required during periods of stress (trauma, surgery, infection). Formoterol fumarate: Hypersensitivity reactions (including hypotension, urticaria, angioneurotic oedema, pruritus, exanthema), QTc interval prolongation, hypokalaemia, nausea, myalgia, 10

11 increased blood lactate levels. Treatment with β 2 agonists such as formoterol may result in an increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies. Hypersensitivity reactions have been reported in patients using inhaled sodium cromoglicate as an active ingredient. Whilst Flutiform inhaler contains only a low concentration of sodium cromoglicate as an excipient, it is unknown if hypersensitivity reactions are dose dependent. In the unlikely event of a hypersensitivity reaction to Flutiform inhaler, treatment should be initiated in accordance with standard treatment for any other hypersensitivity reaction, which may include the use of antihistamines and other treatment as required. Flutiform inhaler may need to be discontinued immediately and an alternative asthma therapy may need to be initiated if necessary. Dysphonia and candidiasis may be relieved by gargling or rinsing the mouth with water or brushing the teeth after using the product. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst continuing the treatment with Flutiform inhaler. Drug Interactions 7 No formal drug interaction studies have been performed with Flutiform inhaler. Flutiform inhaler contains sodium cromoglicate at non-pharmacological levels. Patients should not discontinue any cromoglicate containing medication. Fluticasone propionate, an individual component of Flutiform inhaler, is a substrate of CYP 3A4. The effects of short-term co-administration of strong CYP 3A4 inhibitors (e.g. ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nelfinavir, saquinavir, ketoconazole, telithromycin) together with Flutiform inhaler is of minor clinical relevance, but caution needs to be taken in long-term treatment and co-administration with such drugs should be avoided if possible. Particularly co-medication of ritonavir should be avoided unless the benefit outweighs the increased risk of systemic glucocorticoid side-effects. Information about this interaction is lacking for inhaled fluticasone propionate, but a marked increase in fluticasone propionate plasma levels is expected. Cases of Cushing's syndrome and adrenal suppression have been reported. The ECG changes and/or hypokalaemia that may result from the administration of nonpotassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by β agonists, especially when the recommended dose of the β agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the co-administration of a β agonist with non-potassium sparing diuretics. Xanthine derivates and glucocorticosteroids may add to a possible hypokalaemic effect of the β agonists. In addition L-Dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards β 2 sympathomimetics. 11

12 Concomitant treatment with monoamine oxidase inhibitors, including agents with similar properties such as furazolidone and procarbazine, may precipitate hypertensive reactions. There is an elevated risk of arrhythmias in patients receiving concomitant anaesthesia with halogenated hydrocarbons. Concomitant use of other β adrenergic drugs can have a potentially additive effect. Hypokalaemia may increase the risk of arrhythmias in patients who are treated with digitalis glycosides. Formoterol fumarate, as with other β 2 agonists, should be administered with extreme caution to patients being treated with tricyclic antidepressants or monoamine oxidase inhibitors, and during the immediate two week period following their discontinuation, or other drugs known to prolong the QTc interval such as antipsychotics (including phenothiazines), quinidine, disopyramide, procainamide, and antihistamines. Drugs that are known to prolong the QTc interval can increase the risk of ventricular arrhythmias (see section 4.4). If additional adrenergic drugs are to be administered by any route, they should be used with caution, because the pharmacologically predictable sympathetic effects of formoterol may be potentiated. Beta adrenergic receptor antagonists (β blockers) and formoterol fumarate may inhibit the effect of each other when administered concurrently. Beta blockers may also produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with β blockers and this includes β blockers used as eye drops for treatment of glaucoma. However, under certain circumstances, e.g. as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of β blockers in patients with asthma. In this setting, cardioselective β blockers could be considered, although they should be administered with caution. 12

13 Cost Analysis Cost of Flutiform compared to Seretide over 30 days treatment (prices including VAT for secondary care) Flutiform Seretide Evohaler Flutiform cost saving Strength Primary care Secondary care Strength Primary care Secondary care Primary care Secondary care High 250/ / Medium 125/ / Low 50/ / Department of Medicines management Keele University Produced a QIPP on inhaled corticosteroids in January This was based on the advanced budgetary notification from Napp Pharmaceuticals, which showed a considerable savings with Flutiform at the two highest strengths compared with related Seretide evohalers. However there will only be a marginal cost saving from switching Fostair to Flutiform 125/5 mcg as the price difference is 6 pence. Below are the expected cost savings as stated in the QIPP. 13

14 Cost for 30 days treatment with combination inhalers equivalent to Flutiform Drug Strength Dose Equivalent BDP daily dose Primary care cost Secondary care cost Flutiform 250/10 2PUFFS BD 2000mcg Seretide Evohaler 250/25 2PUFFS BD 2000mcg Seretide Accuhaler 500/50 1PUFF BD 2000mcg Flutiform 125/5 2 PUFFS BD 1000mcg Seretide Evohaler 125/25 2 PUFFS BD 1000mcg Seretide Accuhaler 250/50 1PUFF BD 1000mcg Fostair 100/6 2 PUFFS BD 1000mcg Flutiform 50/5 2PUFFS BD 400mcg Seretide Evohaler 50/25 2PUFFS BD 400mcg Seretide Accuhaler 100/50 1PUFF BD 400mcg Symbicort 100/6 1PUFF BD 400mcg

15 Flutiform, Fostair, Seretide & Symbicort Usage & Expenditure within the UHNS Acute Trust, Stoke-on-Trent CCG and North Staffs CCG July - December 2012 Drug Strength UHNS (inc VAT) SOT CCG (Ex VAT) North staffs CCG (ex. VAT) Flutiform 250/ Seretide Evohaler 250/25 34, , , Seretide Accuhaler 500/50 24, , , Flutiform 125/ Seretide Evohaler 125/25 6, , , Seretide Accuhaler 250/50 3, , , Fostair 100/ , , Flutiform 50/ Seretide Evohaler 50/ , , Seretide Accuhaler 100/ , , Symbicort 100/ , ,

16 References 1. Clinical topic: Asthma. Clinical Knowledge Summaries NICE. Technology appraisal guidance Inhaled corticosteroids for the treatment of chronic asthma in adults and in children aged 12 years and over, March Accessed via 3. Midlands Therapeutic Review and Advisory Committee MTRAC commissioning support Fluticaseone/formoterol (Flutiform ) For treatment of asthma September Facts for journalists. Asthma UK British Guideline on the Management of Asthma. Scottish Intercollegiate Guidelines Network Summary of Product Characteristics flutiform 50 microgram/5 microgram, 125 microgram/5 microgram and 250 microgram/10 microgram per actuation pressurised inhalation, suspension Napp Pharmaceuticals Limited last updated on the emc: 03/09/2012 Acessed via 7. National Institute for Health and Clinical Excellence (NICE). Evidence summary: new medicine ESNM3 Asthma:fluticasone/formoterol (Flutiform) combination inhaler October Scottish Medicines Consortium Product update fluticasone proprionate and formoterol fumarate metered dose inhaler, 50microgram/5microgram, 125microgram/5 microgram 250microgram/10 microgram (flutiform ) (No:736/11) Issued 7 September Bodzenta-Lukaszyk A, Pulka G, Dymek A et al. (2011) Efficacy and safety of fluticasone and formoterol in a single pressurized metered dose inhaler. Respiratory Medicine 105: Bodzenta-Lukaszyk A, Dymek A, McAulay K et al. Fluticasone/formoterol combination therapy is as effective as fluticasone/salmeterol in the treatment of asthma, but has a more rapid onset of action: an open-label, randomized study. BMC Pulm Med 2011;11: Department of medicines management Keele University Prescriing Information to Support QIPP inhaled corticosteroids January National Health Services England and Wales. Drug Tariff October British National Formulary 64 September Produced by Athenais Djossou Specialist Rotational Pharmacist University Hospital of North Staffordshire Telephone: athenais.djossou@uhns.nhs.uk Produced for use within the NHS. Not to be reproduced for commercial purposes 16