Public Assessment Report. Scientific discussion. Pulentia 100/6, 200/6 and 400/12 microgram/ dose inhalation powder, pre-dispensed

Transcription

1 Public Assessment Report Scientific discussion C Pulentia 100/6, 200/6 and 400/12 microgram/ dose inalation powder, pre-dispensed (budesonide/formoterol fumarate diydrate) NL/H/3165/ /DC Date: 23 November 2015 Tis module reflects te scientific discussion for te approval of Pulentia 100/6, 200/6 and 400/12 microgram/dose inalation powder, pre-dispensed. Te procedure was finalised on 2 June For information on canges after tis date please refer to te steps taken after finalisation at te end of tis PAR.

2 List of abbreviations C AUC 0- AUC 0-t BDP CEP CHMP CI Cmax CMD() CMS COPD DD DPI EDQM EMA EPAR ERA EU EWP FDC FPD ICH ICS MAH MEB NNT() OIP OR P.Eur. PIFR PK PL RH RMP RMS SmPC t max TSE t 1/2 Area under te plasma concentration-time curve from time zero to infinity Area under te plasma concentration-time curve from time zero to t ours Beclometasone Dipropionate Certificate of Suitability Committee for Medicinal Products for Human Use Confidence interval Maximum plasma concentration Coordination group for Mutual recognition and Decentralised procedure for uman medicinal products Concerned Member State Cronic Obstructive Pulmonary Disease Delivered Dose Dry Powder Inaler European Directorate for te Quality of Medicines & HealtCare European Medicines Agency European Public Assessment Report Environmental Risk Assessment European Union Efficacy Working Party Fixed Dose Combination Fine Particle Dose International Conference on Harmonization Inaled Corticosteroid Marketing Autorisation Holder Medicines Evaluation Board of te Neterlands Number Needed to Treat to arm Orally Inaled Products Overall Risk European Parmacopoeia Peak Inspiratory Flow Rates Parmacokinetics Package Leaflet Relative Humidity Risk Management Plan Reference Member State Summary of Product information Time for maximum concentration Transmissible Spongiform Encepalopaty Half-life 2/14

3 I. INTRODUCTION Based on te review of te quality, safety and efficacy data, te Member States ave granted a marketing autorisation for Pulentia 100/6, 200/6 and 400/12 microgram/dose inalation powder, predispensed from Elpen Parmaceutical Co. Inc. Pulentia 100/6, 200/6 and 400/12 microgram/dose are indicated in: Astma Te regular treatment of astma were use of a combination (inaled corticosteroid and long acting β2 adrenoceptor agonist) is appropriate: - patients not adequately controlled wit inaled corticosteroids and as needed inaled sort acting β2 adrenoceptor agonists. or - patients already adequately controlled on bot inaled corticosteroids and long-acting β2 adrenoceptor agonists. Additionally, Pulentia 200/6 and 400/12 microgram/dose are indicated in: COPD Symptomatic treatment of patients wit severe COPD (FEV1 < 50% predicted normal) and a istory of repeated exacerbations, wo ave significant symptoms despite regular terapy wit long-acting broncodilators. A compreensive description of te indications and posology is given in te SmPC. Tis decentralised procedure concerns a ybrid application wit reference to te innovator product Symbicort Turbualer (delivered dose strengts: 80/4.5, 160/4.5 and 320/9 µg/inalation, dry powder inaler) wic as been registered in Germany by AstraZeneca GmbH since 2001 (80/4.5 and 160/4.5 µg/inalation) and 2002 (320/9 µg/inalation), respectively. Te Dutc reference product is Symbicort Turbualer 100/6, 200/6 and 400/12 µg/inalation, dry powder (NL License RVG 25886, and 27690), and as been registered by AstraZeneca BV troug procedure SE/H/0230/MR. Te concerned member states (CMS) involved in tis procedure were Germany, Hungary, Iceland, Italy, Portugal and Sweden. Te marketing autorisation as been granted pursuant to Article 10(3) of Directive 2001/83/EC, a ybrid application. II. QUALITY ASPECTS II.1 Introduction Pulentia is a wite, pre-dispensed inalation powder. 100/6 microgram: Eac single dose blister strip contains 100 micrograms of budesonide and 6 micrograms of formoterol fumarate diydrate, wic corresponds to an inaled dose of 97 micrograms budesonide and 5.5 micrograms formoterol fumarate diydrate. 200/6 microgram: eac single dose blister strip contains 200 micrograms of budesonide and 6 micrograms of formoterol fumarate diydrate, wic corresponds to an inaled dose of 194 micrograms budesonide and 5.5 micrograms formoterol fumarate diydrate. 3/14

4 400/12 microgram: eac single dose blister strip contains 400 micrograms of budesonide and 12 micrograms of formoterol fumarate diydrate, wic corresponds to an inaled dose of 380 micrograms budesonide and 11 micrograms formoterol fumarate diydrate. Te powder is packed in Alu-alu blisters. 60 blisters are packed in te two-tone colored plastic Elpenaler inalation device. Te only excipient is lactose monoydrate. II.2 Drug Substances Budesonide Te active substance budesonide is an establised active substance described in te European Parmacopoeia (P.Eur.). Te active substance is insoluble in water. It is manufactured as one crystalline form. Te molecule contains 6 ciral centres. Te CEP procedure is used for budesonide. Under te official Certification Procedures of te EDQM of te Council of Europe, manufacturers or suppliers of substances for parmaceutical use can apply for a certificate of suitability concerning te control of te cemical purity and microbiological quality of teir substance according to te corresponding specific monograp, or te evaluation of reduction of Transmissible Spongiform Encepalopaty (TSE) risk, according to te general monograp, or bot. Tis procedure is meant to ensure tat te quality of substances is guaranteed and tat tese substances comply wit te European Parmacopoeia. Manufacturing process A CEP as been submitted; terefore no details on te manufacturing process ave been included. Quality control of drug substance Te drug substance specification of te MAH is in line wit te P.Eur. and CEP. Absence of a test for microbiological purity as been justified. Batc analytical data demonstrating compliance wit te drug substance specification ave been provided for tree production-scale batces. Stability of drug substance Stability data on budesonide ave been provided for tree full-scale batces stored at 25 C/60% RH (60 monts) and 40 C/75% RH (6 monts). All results are witin specification. Te proposed retest period of 60 monts is acceptable. Te substance is stored protected from ligt, altoug te substance was not potosensitive in te potostability study according to ICH Q1B. Formoterol fumarate diydrate Te active substance formoterol fumarate diydrate is an establised active substances described in te P.Eur. It is sligtly soluble in water. No polymorps are known. Te molecule contains two ciral centres. Te CEP procedure is used. Manufacturing process No details on te manufacturing process ave been included, as a CEP is presented. Quality control of drug substance Te drug substance specification of te MAH is in line wit te P.Eur. and CEP. Absence of a test for microbiological purity as been justified. Batc analytical data demonstrating compliance wit te drug substance specification ave been provided for several production-scale batces. Stability of drug substance Stability data on formoterol fumarate diydrate ave been provided for tree full-scale batces stored at 25 C/60% RH (66 monts) and 40 C/75% RH (6 monts). All results are witin specification. In view of tese results, te proposed re-test period of 2 years is acceptable. Te storage condition protect from ligt is justified, altoug te results of te potostability study do not sow degradation upon exposure to ligt. 4/14

5 II.3 Medicinal Product Parmaceutical development Te development of te product as been described, te coice of excipients is justified and teir functions explained. Te test product sows a flow-rate dependency regarding fine particle dose (FPD) and delivered dose (DD), altoug tis is smaller tan te reference product. Te flow rate effect on FPD and DD is not te same for all tree strengts. Results of FPD and DD of flow rates of 30 to 90 L/min ave been provided. It as been stated tat te flow-rate at wic a pressure drop of 4 kpa was acieved, was 37 L/min. Te device is terefore caracterized as a device of ig resistance. Te FPD and te DD of te batces used in te PK study ave been determined at te flow rate at wic a pressure drop of 4 kpa is acieved (37-40 L/min). Te reference product and te product at issue differ in te way te dose is metered: in te reference product tis is a device metered dose in wic a multi-dose reservoir of powder is part of te device, wereas te test product is a single-dose pre-metered dose (one dose per blister). Te difference is mecanism is acceptable from a quality point of view. Te mono-compartment Elpenaler consists of a moutpiece and its cover, a surface on wic te blister strip is placed and a storage compartment wic ouses te single dose blister strips (60). Tis mono-compartment Elpenaler intended to administer one metered dose of te dry powder blend consisting of lactose and bot active substances. Te nomenclature of te dose is te metered dose and not te delivered dose. A comparison as been performed per impactor stage, according to te orally inaled products guideline (OIP) CPMP/EWP/4151/00Rev.1 wic sows tat te in vitro caracteristics are not te same for test and reference product. Moreover, in view of te large difference in airflow resistance, an application solely based on in-vitro data is not possible for te proposed products Te bioequivalence study as been performed on te igest strengt of test and reference product. A waiver for te lower strengts is justified from a cemical-parmaceutical perspective. Linearity (doseproportionality) of te FPD of te test product as been sown. Manufacturing process Te manufacturing process consists of mixing pre-sieved lactose, budesonide and formoterol, filling tis into blisters and sealing te blisters. Te manufacturing process as been adequately validated according to relevant European guidelines. Te product is manufactured using conventional manufacturing tecniques, but is considered a non-standard process based on te low amounts of drug substances. Process validation data on te product as been presented for tree full-scale batces of eac strengt and an additional tree batces for te 400/12 and 200/6 microgram strengts. Control of excipients Te excipient lactose complies wit te P.Eur. Tis specification is acceptable. Quality control of drug product Te product specification includes tests for description, identity, assay, uniformity of delivered dose, fine particle dose, water content, related substances and microbiological test. Te release and selflife requirements/limits are te same except for related substances and assay of formoterol. Te specifications are acceptable. Te analytical metods ave been adequately described and validated. Batc analytical data from te proposed production site ave been provided on six batces of 100/6 mcg/blister, tree batces of 200/6 mcg/blister and four batces of 400/12 mcg/blister (one of tese a pilot-scale batc). Te results demonstrate compliance wit te release specification. Stability of drug product Stability data on te product as been provided on tree full-scale batces of eac strengt stored at 25 C/60% RH (24 monts), 30 C/65% RH (12 monts) and 40 C/75% RH (3 monts). Updated stability results (6 monts long-term and intermediate storage conditions) ave been submitted, yet in tese studies FPD at te correct flow (37 L/min) was not tested at all time points. At accelerated conditions a rapid deterioration of formoterol was observed of increase of impurities and decrease of assay and fine particle dose wit several results already out of specification after 3 monts. Te studies at accelerated conditions ave been discontinued and te studies at intermediate conditions will be continued up to 12 monts. In view of te limited data provided, a self-life of 6 monts can be approved for all tree strengts. 5/14

6 Specific measures concerning te prevention of te transmission of animal spongiform encepalopaties Scientific data as been provided on te use of lactose and compliance wit te Note for Guidance on Minimising te Risk of Transmitting Animal Spongiform Encepalopaty Agents via medicinal products as been satisfactorily demonstrated. II.4 Discussion on cemical, parmaceutical and biological aspects Based on te submitted dossier, te member states consider tat Pulentia 100/6, 200/6 and 400/12 microgram/dose as a proven cemical-parmaceutical quality. Sufficient controls ave been laid down for te active substances and finised product. No post-approval commitments were made. III. III.1 NON-CLINICAL ASPECTS Ecotoxicity/environmental risk assessment (ERA) Since Pulentia is intended for substitution of oter products available on te market, tis will not lead to an increased exposure to te environment. An environmental risk assessment is terefore not deemed necessary. III.2 Discussion on te non-clinical aspects Tis product is a ybrid formulation of Symbicort, wic is available on te European market. Reference is made to te preclinical data obtained wit te innovator product. A non-clinical overview on te parmacology, parmacokinetics and toxicology as been provided, wic is based on up-todate and adequate scientific literature. Te overview justifies wy tere is no need to generate additional non-clinical parmacology, parmacokinetics and toxicology data. Terefore, te member states agreed tat no furter non-clinical studies are required. IV. IV.1 CLINICAL ASPECTS Introduction Budesonide and formoterol fumarate diydrate are well-known active substances wit establised efficacy and tolerability. A clinical overview as been provided, wic is based on scientific literature. Te overview justifies wy tere is no need to generate additional clinical data. Terefore, te member states agreed tat no furter clinical studies are required. Te clinical development programme was in line wit te applicable guideline (CHMP Guideline on orally inaled products, CHMP/EWP/4151/00 Rev. 1) assuming tat equivalence troug parmacokinetic studies would be establised. For tis ybrid application one pilot bioequivalence study, and two pivotal 2-stage bioequivalence studies using te 400/12 mcg strengt were submitted. Tese studies are discussed below. IV.2 Parmacokinetics Te combination of budesonide and formoterol is used in te treatment of astma and COPD. Formoterol fumarate is a long-acting selective β2-adrenoceptor agonist. It acts locally in te lungs as a broncodilator. In vitro studies ave sown tat formoterol as 200-fold greater activity at β2-receptors tan β1-receptors. Budesonide is an anti-inflammatory corticosteroid tat exibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide as approximately a 200-fold iger affinity for te glucocorticoid receptor and a 1000-fold iger topical anti-inflammatory potency tan cortisol. 6/14

7 To support tis ybrid application, te MAH as submitted 3 bioequivalence studies, i.e. - one pilot four-way bioequivalence study of Pulentia mcg/inalation fixed dose combination dry powder inaler (FDC DPI), in ealty volunteers (study FMBD-PBE-01- ELP/09) - one pivotal bioequivalence study of Pulentia mcg/inalation FDC DPI, in patients wit controlled or partly controlled astma (Study FMBD-PKES-INH-02-EPP/11) - one pivotal replicate design single dose bioequivalence study witout carcoal blockade of Pulentia mcg/inalation FDC DPI, in ealty volunteers (Study FMBD-PKES-INH-03- EPP/11). Te reference product used in te studies was Symbicort Turboaler mcg/inalation DPI (Astra Zeneca, Sweden) from te German market. Bioequivalence was assessed bot wit and witout carcoal. Te number and type of studies is in accordance wit te Guideline on te requirements for clinical documentation for orally inaled products (OIP). Te pilot study FMBD-PBE-01-ELP/09 is not discussed in tis report, as its purpose was mainly to aid in te design of te two pivotal bioequivalence studies. Biowaiver Te studies were conducted wit te igest strengt of test and reference product. A biowaiver for additional strengts for tis OIP as been granted, based on te conditions in Guideline on te requirements for clinical documentation for orally inaled products (OIP) including te requirements for demonstration of terapeutic equivalence between two inaled products for use in te treatment of astma and cronic obstructive pulmonary disease (COPD) in adults and for use in te treatment of astma in cildren and adolescents (CPMP/EWP/4151/00 Rev. 1). Bioequivalence studies Parmacokinetic study FMBD-PKES-INH-02-EPP/11 wit carcoal blockade Design Tis was a two stage, two period, two sequences, cross-over, block randomized bioavailability study on controlled and partly controlled astma patients in fasting conditions wit carcoal blockade. One undred subjects (29 males and 71 females, aged years) were enrolled in te first stage as per study protocol. Since bioequivalence was reaced after te first stage, te second stage was not required to be performed and no furter patients were enrolled. Te study medication consisted of one single dose of Pulentia Elpenaler microgram/inalation (budesonide + formoterol test) or one single dose of Symbicort Turboaler mcg/inalation, dry powder for inalation (reference). Subjects were ospitalised until 24 ours post administration. Ten subjects continued te study by visiting te study centre at sceduled time intervals, for te last samples. In eac study period all patients swallowed 5 g of activated carcoal suspended in 50 ml of water 2 minutes before study medication administration, 5 g in 50 ml of water 2 minutes after dosing, and 10 g in 100 ml of water at 60, 120 and 180 minutes after dosing. Plasma samples in tubes containing eparin as anticoagulant for formoterol and budesonide determinations were taken before te administration and at 1 min, 3 min, 5 min, 10 min, 15 min, 30 min, 45 min, 1.0; 1.33; 1.67; 2.0; 2.33; 2.67; 3.0; 4.0; 5.0; 6.0; 8.0; 12.0; 16.0 and 24.0 ours post dose, after eac administration. For formoterol determination only additional samples were drawn at 36.0 and 48.0 ours from dosing. Budesonide was not quantified in tese samples. Te wasout period was 5 to 6 days. Te design of te study is adequate. Considering te t 1/2 of approximately 5 ours for budesonide and of approximately 17 ours for formoterol, te sampling period of 24 ours for budesonide is sufficiently long. For formoterol a sampling period of 48 ours may be sort, as formoterol parmacokinetics is caracterised by a slow, terminal elimination. In tat respect te blood sampling could ave been more opitimised by sampling at a later time point. Te MAH conducted a sensitivity analysis by evaluation of partial AUC values over different time periods. Te results were very consistent wit respect to point estimate and CI. Te MAH adequately discussed tat in tis study te large 7/14

8 extrapolated fraction ad no consequences for te reliability of te outcome of te study. Also te wasout period of 5-6 days is sufficient. Analytical/statistical metods Initially, te statistical analysis did not take into account te multiple testing tat is performed in a 2 stage design study. For suc a design, te analysis of te first stage data sould be treated as an interim analysis and bot analyses (first and second stage) sould be conducted at adjusted significance levels (wit te confidence intervals accordingly using an adjusted coverage probability wic will be iger tan 90%). Te MAH was asked to re-analyse te data using a 94.12% CI (as applied in study FMBD-PKES-INH-03-EPP/11 witout carcoal). Tese data ave been provided (see below). Results Tree subjects were considered drop-outs: one was a drop-out due to consent witdrawal, a second subject was a drop-out because of a positive pregnancy test before study drug administration and a tird subject was a drop-out due to an adverse event (fever) before study drug administration. Parmacokinetic analysis was conducted using data from te 97 volunteers wo completed te study. Table 1. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, t max (median, range)) of budesonide (+ carcoal) Treatment AUC 0-t AUC 0- C max t max N=97 pg./ml pg./ml pg/ml Test 1502 ± ± ± ( ) -- t 1/2 Reference 1725 ± ± ± ( ) -- *Ratio (94.12% CI) 0.88 ( ) ( ) - -- AUC 0- area under te plasma concentration-time curve from time zero to infinity AUC 0-t area under te plasma concentration-time curve from time zero to t ours C max maximum plasma concentration t max time for maximum concentration t 1/2 alf-life CI confidence interval *ln-transformed values Table 2. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, t max (median, range)) of formoterol (+ carcoal) Treatment N=97 AUC 0-t pg./ml AUC 0- pg./ml C max pg/ml t max Test 63.4 ± ± ± ( ) t 1/2 -- Reference 65.2 ± ± ± ( *Ratio (94.12% CI) 0.96 ( ) ( ) AUC 0- area under te plasma concentration-time curve from time zero to infinity AUC 0-t area under te plasma concentration-time curve from time zero to t ours C max maximum plasma concentration t max time for maximum concentration t 1/2 alf-life CI confidence interval *ln-transformed values 8/14

9 C Parmacokinetic study FMBD-PKES-INH-03-EPP/11 witout carcoal blockade Design Tis was a two stage, four period, cross-over, block randomized, replicate design, single dose bioavailability study in ealty volunteers witout carcoal blockade. Forty-eigt ealty volunteers (24 males and 24 females, aged years) were enrolled in te first stage according to study protocol. Bioequivalence was reaced at te first stage according to protocol; terefore te second stage of te study was not required to be performed. Tere were four periods in te first stage: bot test and reference product were given twice according to a replicated design. Te study medication consisted of one single dose of Pulentia Elpenaler microgram/inalation (budesonide + formoterol test) or one single dose of Symbicort Turboaler mcg/inalation, dry powder for inalation (reference). Patients received te study drug witout carcoal blockade. Subjects were ospitalised until 24 post-administration. Ten subjects continued te study by visiting te study centre at sceduled time intervals, for te last samples. Plasma samples in tubes containing eparin as anticoagulant for formoterol and budesonide determinations were taken before te administration and at 1 min, 3 min, 5 min, 10 min, 15 min, 30 min, 45 min, 1.0; 1.33; 1.67; 2.0; 2.33; 2.67; 3.0; 4.0; 5.0; 6.0; 8.0; 12.0; 16.0 and 24.0 ours post dose, after eac administration. For formoterol determination only additional samples at 36.0 and 48.0 ours from dosing were also witdrawn. Budesonide was not quantified in tese samples. Te wasout period was 7 days for stage I. Te replicate design of te study is adequate. Considering te t 1/2 of approximately 5 ours for budesonide and of approximately 17 ours for formoterol, te sampling period of 24 ours for budesonide is sufficiently long. For formoterol a sampling period of 48 ours may be sort. However, it was adequately justified based on a sensitivity analysis. Also te wasout period of 7 days is adequate. Analytical/statistical metods Te analytical metod as been adequately validated and is considered acceptable for analysis of te plasma samples. Te metods used in tis study for te parmacokinetic calculations and statistical evaluation are considered acceptable. Results Forty-six subjects completed te clinical part. One subject was a drop-out and received only once te test formulation, terefore tis subject was excluded from te statistical analysis. A second drop-out received once te reference formulation and once te test formulation - statistics was performed only for period one and period two. Tree subjects ad only 3 study periods included in te statistic evaluation. Tese tree subjects did not perform te administration 100% correctly in te respective study periods and consequently, in agreement wit te study protocol provisions were excluded for tis periods from te parmacokinetic analysis and statistics. A total of forty-seven subjects were included in te statistical analysis. Table 3. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, t max (median, range)) of budesonide (witout carcoal) Treatment N=47 AUC 0-t pg./ml AUC 0- pg./ml C max pg/ml t max Test 2363 ± ± ± ( ) t 1/2 -- Reference 2446 ± ± ± ( ) *Ratio (94.12% CI) 1.02 ( ) ( ) /14

10 AUC 0- area under te plasma concentration-time curve from time zero to infinity AUC 0-t area under te plasma concentration-time curve from time zero to t ours C max maximum plasma concentration t max time for maximum concentration t 1/2 alf-life CI confidence interval *ln-transformed values C Table 4. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, t max (median, range)) of formoterol (witout carcoal) Treatment N=47 AUC 0-t pg./ml AUC 0- pg./ml C max pg/ml t max Test 63.7 ± ± ± ( ) t 1/2 -- Reference 57.4 ± ± ± ( ) *Ratio (94.12% CI) 1.03 ( ) ( ) AUC 0- area under te plasma concentration-time curve from time zero to infinity AUC 0-t area under te plasma concentration-time curve from time zero to t ours C max maximum plasma concentration t max time for maximum concentration t 1/2 alf-life CI confidence interval *ln-transformed values Conclusion on bioequivalence studies Based on te submitted bioequivalence study witout carcoal blockade, Pulentia 400/24 microgram is considered bioequivalent wit Symbicort Turbualer 400/12 microgram. Correct statistical analysis was conduced. Point estimates and 94.12% CI obtained for AUC 0-t and C max were witin te bioequivalence acceptance range of For te study wit carcoal blockade, reanalysis was conducted applying 94.12% CI. Results were witin te acceptance range for AUC 0-t and C max for bot budesonide and formoterol. Terefore, bioequivalence as been demonstrated bot wit and witout carcoal blockade. Te MEB as been assured tat te bioequivalence studies ave been conducted in accordance wit acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and Good Laboratory Practice (GLP, see Directives 2004/9/EC and 2004/10/EC). IV.3 Parmacodynamics, clinical efficacy and safety Te clinical parmacology of budesonide and formoterol fumarate as been investigated extensively in te past, and is well known. No oter clinical studies tan te above described parmacokinetic studies ave been submitted. As outlined in te quality section of tis report, in te in vitro studies at normal flow rates, te Fine Particle Dose is in general comparable between Elpenaler and Symbicort Turbualer, but at te low flow rate of 30 L/min FPD is iger for te Elpenaler tan Symbicort Turbualer. Tese values are for te igest strengt but te same trend is seen (altoug to a lesser extent) in te lower strengts. Te MAH as performed parmacokinetic studies in patients wit mild astma (FMBD-PKES-INH-02- EPP/11) and ealty volunteers (FMBD-PKES-INH-03-EPP/11) as in line wit te OIP guideline. Equivalence as been establised wit tese studies. However, as te Elpenaler is less flow dependent tan te Turbualer, it would be unclear weter te results can be extrapolated to oter populations. In te recent application for DuoResp Spiromax (EPAR, EMEA/H/C/002348), te same issue of devices wit different flow resistance was discussed. In tat dossier te results of a comparative study in different patient populations and ealty volunteers investigating peak inspiratory flow rates (PIFRs) 10/14

11 te Turbualer and te Spiromax inaler sowed tat very few patients ad PIFRs below 40 L/min. Wen PIFRs were less tan 40 L/min tere appeared to be no clustering by age or disease severity. Malmberg (2010) 1 found tat age and gender are more important determinants of inspiratory flow troug DPIs tan te degree of expiratory airway obstruction, wile Weiner (2006) 2 suggests tat women wit severe COPD are more at risk tan oters. Altogeter, te RMS considers tat altoug te deposition of bot budesonide and formoterol would be iger at low flow, tis cannot be translated into a potential safety issue for a specific patient population. Furter data is considered not necessary. Te deposition of te active substances at te upper respiratory tract is iger for te test product compared to Symbicort Turbualer (33%). Te iger deposition of budesonide may cause an increase of te frequency of adverse events like oroparyngeal candidiasis (trus). It as also been suggested tat oroparyngeal candidiasis is peraps a consequence of immunosuppression at te oral mucosal surface. Oter frequently reported adverse events concern oarseness or dysponia. However, a recent Cocrane review failed to sow a relation between a iger delivered ICS dose and side effects. Te overall risk of oroparyngeal candidiasis was increased among ICS users compared wit placebo (OR 2.65, 95% CI ; 5586 participants). Wen focussing on participants randomised to less tan 1000 μg/day beclometasone dipropionate (BDP) equivalent, tis gave a number needed to treat to arm NNT() of 37. In studies assessing more tan 1000 μg/day BDP equivalent, tere was some variation in baseline risk. In participants from te control group of Burge risk was around 7%, and NNT() for participants randomised to steroid was 13 (95% CI 7 to 34), wereas in Calverley 2003a 4 te control group event rate was 1.4%, giving a NNT() of 57 (95% CI 29 to 156). In anoter study, te event rate was 11% amongst tose randomised to ICS giving a NNT() of 13. Tere was also an increased risk of oarseness or dysponia (OR 1.95, 95%CI 1.41 to 2.70, 3267 participants). Tere was minimal eterogeneity, implying a consistent effect across te studies. Te difference in OR (active treatment vs. placebo) does not reveal a clinically relevant difference for less tan 1000 μg/day BDP equivalent (OR 1.81 [1.16, 2.84]) and more tan 1000 μg/day BDP equivalent (OR 2.11, [1.41, 2.70]). In te medium-term studies (longer tan two monts and up to six monts), pooling sowed an increased risk of oroparyngeal candidiasis (OR 5.59, 95% CI 3.58 to 8.74, 2109 participants). Hoarseness and sore troat were more common wit very ig dose BDP (3000 μg/day) over four weeks fluticasone propionate 880 μg/day increased te risk of oarseness. Te application for Pulentia does not concern te paediatric and adolescent population, wile te reference product includes adolescents. A restriction to te adult population is acceptable. Moreover, tere is already a precedent of accepting a product for only adults: Flusaterol (salmeterol xinafoate/fluticasone propionate) inalation powder, pre-dispensed, registered troug procedure SE/H/1190/ /DC. Te presentation of two observational studies was submitted during te procedure (Opinion study and Critical Steps study) following questions from te member states. In te Opinion study out of te 4312 patients wo participated in te study 1152 (26.7%) pointed out advantages and 331 (7.7%) pointed out disadvantages. 106 found te device difficult to use (2.46% of te total of patients recruited and 32% of te subgroup tat reported a disadvantage) and 140 inconvenient to use (3.25% of te total of patients recruited and 42.3% of te subgroup tat reported a disadvantage). In tis study bot te mono-compartment and duo-compartment Elpenaler were investigated. In te second study (Critical Steps) te target was to measure te critical errors tat patients do wen using teir devices. Preliminary results of te study were submitted. Te final report of te study will be submitted once available. 1 L Pekka Malmberg., Paula Rytilä, Pertti Happonen, Tari Haatela. Inspiratory flows troug dry powder inaler in cronic obstructive pulmonary disease: age and gender rater tan severity matters. International Journal of Cronic Obstructive Pulmonary Disease 2010: Paltiel Weiner, Margalit Weiner. Inspiratory Muscle Training May Increase Peak Inspiratory Flow in Cronic Obstructive Pulmonary Disease. Clinical Investigations. Respiration 2006;73: Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients wit moderate to severe cronic obstructive pulmonary disease: te ISOLDE trial. BMJ 2000;320: Calverley PM, Boonsawat W, Cseke Z, Zong N, Peterson S, Olsson H. Maintenance terapy wit budesonide and formoterol in cronic obstructive pulmonary disease. Eur Respir J 2003a;22: /14

12 IV.4 Risk Management Plan Te MAH as submitted a risk management plan, in accordance wit te requirements of Directive 2001/83/EC as amended, describing te parmacovigilance activities and interventions designed to identify, caracterise, prevent or minimise risks relating to Pulentia. Summary table of safety concerns as approved in RMP Important identified risks Risk of cardiovascular undesirable effects Paradoxical broncospasm Hypersensitivity reactions (e.g. exantema, urticaria, pruritus, dermatitis, angioedema and anapylactic reaction) Important potential risks Astma related mortality and morbidity Off-label use in patients under te age of 18 years Off-label use of te ig strengt formulation Off-label use in COPD patients Systemic effects of steroid (including Cusing s syndrome, Cusingoid features, adrenal suppression, growt retardation in cildren and adolescents, cataract, glaucoma and more rarely, a range of psycological or beavioural effects including psycomotor yperactivity, sleep disorders, anxiety, depression or aggression (particularly in cildren) Missing information None Te member states agreed tat routine parmacovigilance activities and routine risk minimisation measures are sufficient for te risks and areas of missing information. IV.5 Discussion on te clinical aspects For tis autorisation, reference is made to te clinical studies and experience wit te innovator product Symbicort Turbualer. No new clinical studies were conducted. Te MAH demonstrated bioequivalence based on in vitro data and parmacokinetic studies, wit and witout carcoal blockade. Risk management is adequately addressed. Tis ybrid medicinal product can be used instead of te reference product. V. USER CONSULTATION Te package leaflet (PL) as been evaluated via a user consultation study in accordance wit te requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. Te test consisted of a pilot test wit 2 participants, followed by two rounds wit 10 participants eac. Te questionnaire contained 17 questions addressing te key safety issues and presentation of information. Four additional, solicited questions were asked to complete te questionnaire wit regards to positive, negative and stylistic feedback about te readability of te PL. Bot rounds of testing sowed tat, for eac question, 100% of participants were able to find te correct information, and all of tem were able to answer te questions correctly. Te user testing results indicate tat te leaflet is well structured and organised, easy to understand and written in a compreensible manner. Te test sows tat te PL is readable and patients/users are able to act upon te information tat it contains. Te package leaflet meets te criteria for readability as set out in te Guideline on te readability of te label and package leaflet of medicinal products for uman use. 12/14

13 VI. C OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Pulentia 100/6, 200/6 and 400/12 microgram/dose inalation powder, pre-dispensed as a proven cemical-parmaceutical quality and is a ybrid form of Symbicort Turbualer. Symbicort is a wellknown medicinal product wit an establised favourable efficacy and safety profile. Bioequivalence between Pulentia Elpenaler and te reference formulation Symbicort Turboaler as been establised, bot wit and witout carcoal blockade. On 30 August 2014 and 30 April 2015, te application was discussed in te Board meetings of te RMS. Concerns were raised regarding te statistical metods applied in te bioequivalence study wit carcoal blockade. Also dose proportionality of Fine Particle Dose (FPC) between strengts was discussed. Te MAH adequately addressed tese matters. An appropriate reanalysis was submitted, using 94.12% confidence intervals, wic demonstrated bioequivalence between test and reference product wit carcoal blockade. Regarding te difference in deposition between Elpenaler and Turbualer, te Board considered tat te iger delivery of te Elpenaler at low inspiratory flow would not present a potential safety issue for a specific patient population. Overall, a positive conclusion was reaced in te Board meeting of 30 April Tere was no discussion in te CMD(). Agreement between member states was reaced during a written procedure. Te member states, on te basis of te data submitted, considered tat terapeutic equivalence as been demonstrated for Pulentia 100/6, 200/6 and 400/12 microgram/dose wit te reference product, and ave terefore granted a marketing autorisation. Te decentralised procedure was finalised wit a positive outcome on 2 June Te following post-approval commitment as been made during te procedure: - Te MAH committed to provide te study report of te usability study ( Opinion - study code: 2014-HAL-EL-45) once te report as been finalised 13/14

14 STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY Scope Procedure number Type of modification Date of start of te procedure Date of end of te procedure Approval/ non approval Assessment report attaced 14/14